CN1878758A - Crf antagonists and heterobicyclic compounds - Google Patents

Crf antagonists and heterobicyclic compounds Download PDF

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CN1878758A
CN1878758A CN 200480032942 CN200480032942A CN1878758A CN 1878758 A CN1878758 A CN 1878758A CN 200480032942 CN200480032942 CN 200480032942 CN 200480032942 A CN200480032942 A CN 200480032942A CN 1878758 A CN1878758 A CN 1878758A
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substituted
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pyrimidine
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中井久郎
斋藤哲二
小柜彻夫
源智秋
吉田真幸
岸昭宏
胜又清至
片山英夫
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Ono Pharmaceutical Co Ltd
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Abstract

CRF antagonists containing as the active ingredient compounds represented by the general formula (I): (I) wherein A is an optionally substituted 5- or 6-membered monocycle; B is a 5- to 7-membered monocyclic unsaturated heterocycle which may additionally contain one or two heteroatoms and which may be additionally substituted; W<1> and W<2> are each carbon or nitrogen; Z is NR<3>, oxygen, optionally oxidized sulfur, or CR<4>R<5>; R<1> is optionally substituted, alkyl, alkenyl, or alkynyl, optionally protected amino, optionally protected hydroxyl, optionally protected SH, S(O)nR<6>, COR<7>, or an optionally substituted cyclic group; and R<2> is an unsaturated cyclic group which may be substituted.

Description

CRF antagonist and bicyclic heterocyclic compounds
Technical field
The present invention relates to a kind of Corticotropin releasing factor antagonists, a kind of bicyclic heterocyclic compounds of novelty (bi-heterocyclic ring compound), its salt, its N-oxide compound, its solvate or its prodrug, and contain their medicines as active ingredient.More particularly, the present invention relates to contain the Corticotropin releasing factor antagonists (I) of formula (I) compound as activeconstituents:
Wherein all symbols are as hereinafter definition;
And the new bicyclic heterocyclic compounds of formula (I-A):
Figure A20048003294200112
Wherein all symbols are as hereinafter definition;
Its salt, its N-oxide compound, its solvate or its prodrug, and contain their medicines as activeconstituents.
Background technology
Corticotropin releasing factor(CRF) (CRF) is a kind of peptide that contains 41 amino-acid residues, and it was separated from sheep hypothalamus (ovine hypothalamic) in 1981.CRF is considered to discharge from hypothalamus, and is controlling thyroliberin (ACTH) from pituitary body secretion [Science, 218,377-379 (1982)].
ACTH discharges by stimulating CRF, and the ACTH stimulation secretes hydrocortisone from adrenal cortex, and relevant with the general action (systemic action) of reproduction, growth, gastrointestinal function, inflammation, immunity system, neural system etc.Therefore, CRF is believed the effect that has as the conditioning agent of these functions.Given this, the relation between CRF and central nervous system disease or the neuropsychiatric disorders has caused extensive attention.
On the other hand, depressive patient and anxiety disorder patient are more and more, and the depressive patient quantity with minor ailment is also increasing recently simultaneously.In addition, the gerontal patient accounts for major part in depressive patient.Under such situation,, more and more wish to obtain psychosis and the neurotherapy method that conveniently to use in order to show effect as early as possible and to the consideration of side effect.
At present, in order to treat psychosis and neuropathy, for example use tricyclic antidepressants, tetracyclic antidepressant, oxidase inhibitor, serotonin and noradrenaline reuptake inhibitor (serotonin andnoradrenaline reuptake inhibitors, SNRI), selectivity serotonin reuptake inhibithors (SSRI) etc. is as thymoleptic.Yet its result of treatment is unsatisfactory; Need just can demonstrate curative effect for a long time; Occur that side effect is for example sleepy, dry and constipation and sensation difficulty etc. when urinating.As anxiolytic, use for example benzodiazepine derivatives anxiolytic, thieno-diaza  class anxiolytic, non-benzodiazepine derivatives anxiolytic etc.Yet its result of treatment is equally also undesirable; Occur that side effect for example intellection function reduction and concentrated force and attention reduce, sleepy, dizzy (stagger), dizziness, headache, forgetful etc.
Expection can be used compounds for treating depression and the anxiety disorder with CRF antagonistic activity.Formula (A) compound has for example been described in WO 02/53565 brochure:
Figure A20048003294200121
X wherein AAnd Y ABe carbon or nitrogen independently of one another, but the two is not nitrogen simultaneously; W ABe carbon or nitrogen; U AAnd Z ABe CR independently of one another 2A, NR 13A, nitrogen, oxygen, sulphur, C=O or C=S;
Figure A20048003294200122
Be singly-bound or two key;
Be C4-6 carbocyclic ring or the 4-6 that contains at least one nitrogen, oxygen and sulphur unit heterocycle, described ring is not substituted or is selected from C1-4 alkyl, C1-4 alkoxyl group, halogen atom and CF by 1-3 3In substituting group replace;
R 1ABe that (i) is not substituted or by 1-5 R 14AThe C1-8 alkyl that replaces (ii) is not substituted or by 1-5 R 14AThe C2-8 alkenyl that replaces (iii) is not substituted or by 1-5 R 14AThe C2-8 alkynyl that replaces, (iv) NR 4AR 5A, (v) OR 6A, (vi) SH, (vii) S (O) nR 7A, (viii) COR 6A, (ix) COOR 6A, (x) CONR 4AR 5A, (xi) NR 8ACOR 6aA, (xii) NR 8ACOOR 6A, (xiii) NR 8ACONR 4AR 5A, (xiv) unsubstituted or by 1-5 R 15AC3-15 monocycle carbocyclic ring that replaces or two ring carbocyclic rings, (xv) unsubstituted or by 1-5 R 15AThe 3-15 unit's monocyclic heterocycles or the bicyclic heterocycles that contain 1-4 nitrogen, a 1-2 oxygen and/or 1-2 sulphur that replace;
R 3ABe that (i) is by 1-5 R 16AC5-10 monocycle carbocyclic ring that replaces or two ring carbocyclic rings or (ii) by 1-5 R 16AThe 5-10 unit's monocyclic heterocycles or the bicyclic heterocycles that contain 1-4 nitrogen, a 1-2 oxygen and/or 1-2 sulphur that replace.
On the other hand, for bicyclic heterocyclic compounds, formula (B) compound as anodyne has for example been described in WO 97/11946 brochure:
Figure A20048003294200131
R wherein 11BThe phenyl, N-low alkyl group pyrryl or the pyrazinyl that are hydrogen, low alkyl group, pyridyl, furyl, thienyl, can be replaced by low alkyl group or thiophenyl; R 12BBe hydrogen, halogen atom, phenyl can be selected from the phenyl that the substituting group in halogen atom, thiophenyl and trifluoromethyl and the nitro replaces, perhaps by the phenyl of lower alkoxy and thiophenyl replacement; R 13BThe low alkyl group, ethylenedioxy (ethylenedixoy), lower alkanoyloxy, lower alkoxy, lower alkylthio, carboxyl, halogen or thienyl, low-grade alkenyl, cycloalkyl, phenyl, furyl or the thienyl that are hydrogen, can be replaced by oxo (oxo), they can be by 1-3 low alkyl group, halogen and lower alkoxy replacement; R 14BBe hydrogen, carboxyl, lower alkoxycarbonyl, nitro, halogen atom or the low alkyl group that is replaced by lower alkoxycarbonyl or an alkali metal salt residue of carboxylic acid; Perhaps R 13BAnd R 14BCan form low-grade alkylidene together; R 15BThe phenyl, pyridyl, quinolyl or the isoquinolyl that are hydrogen, alkali metal atom, low alkyl group, can be replaced by 1-3 low alkyl group and lower alkoxy, they can be replaced by low alkyl group or halogen; A BBe key or low-grade alkylidene.
In WO 01/32632 brochure, formula (C) compound as the mGluR1 antagonist has been described:
Figure A20048003294200132
X wherein 1CBe O or NH; L CIt is key or optional by O, S, SO, SO 2Or the C1-6 alkylidene group of NH partition and optional by fluorine, hydroxyl, C1-4 alkoxyl group or oxo replacement on the carbon of this alkylidene group; R 1CBe unsubstituted or substituted carbocyclic ring or heterocycle; R 2CBe hydrogen, halogen atom, carboxyl, cyano group, SCH 2CH or X 2C-R 5C, X wherein 2CBe key, O, S, SO, SO 2Or NH, R 5CBe C1-8 alkyl, C3-10 cycloalkyl, halo (C1-6) alkyl, hydroxyl (C1-6) alkyl, dihydroxyl (C1-6) alkyl, phenyl or phenyl (C1-4) alkyl, wherein phenyl is not substituted or is replaced by 1 or 2 substituting group that independently is selected from halogen atom, C1-4 alkyl and the C1-4 alkoxyl group etc.; R 3CAnd R 4CBe independently of one another the C1-4 alkyl or and coupled carbon atom form together and be not substituted or substituted carbocyclic ring or heterocycle.
Summary of the invention
The object of the invention is to provide a kind of medicament that can conveniently handle, and simultaneously this medicament has the strong effect that prevents and/or treats in the preventing and/or treating of psychosis and neuropathy (psychiatric and neurologic disorder), peripheral organ's disease etc.
In order to address the above problem, the inventor is by concentrating on studies, and found that following bicyclic heterocycles can realize above-mentioned purpose.
The present invention relates to following aspect:
1. CRF antagonist, described CRF antagonist contain compound shown in the formula (I), its salt, its N-oxide compound, its solvate or its prodrug as activeconstituents:
Figure A20048003294200141
Wherein encircle A and represent 5-or 6-unit monocycle, it can be selected from following substituting group by 1-3 and replace: halogen atom, CF 3, OCF 3, hydroxyl, sulfydryl, carboxyl, (C1-6 alkoxyl group) carbonyl, carbamyl, nitro, cyano group, oxo, and can be selected from halogen atom, CF by 1-3 separately 3The C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl group or the C1-6 alkylthio that replace with substituting group in the hydroxyl;
Ring B represents 5-to 7-unit monocycle unsaturated heterocycle, and it can contain except that nitrogen-atoms, W 1And W 2Outside 1 or 2 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and/or the sulphur atom that can be oxidized, and described 5-to 7-unit monocycle unsaturated heterocycle can further be substituted;
W 1And W 2Represent carbon atom or nitrogen-atoms independently of one another;
Z represents-NR 3-, R wherein 3The expression hydrogen atom separately can substituted C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl ,-CO-(can substituted C1-6 alkyl) ,-SO 2-(can substituted C1-6 alkyl), Sauerstoffatom, sulphur atom that can be oxidized, perhaps-CR 4R 5-, R wherein 4And R 5Represent independently of one another hydrogen atom or separately can substituted C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, perhaps R 4And R 5Can represent (i) oxo together, (ii) C2-5 alkylene base (alkylene), one of them carbon atom can be replaced by 1 Sauerstoffatom, nitrogen-atoms or sulphur atom that can be oxidized, wherein said C2-5 alkylene base can be replaced by one or more substituting groups, perhaps (iii) can substituted C1-6 alkylidene (alkylidene);
R 1Expression:
(i) separately can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl,
(ii) can protected amino,
But (iii) protected hydroxyl,
(iv) can protected sulfydryl,
(v)-S (O) nR 6, wherein n represents 1 or 2, and R 6Expression (a) separately can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl or (b) can substituted cyclic group,
(vi)-COR 7, R wherein 7Expression (a) hydrogen atom (b) separately can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, but (c) protected hydroxyl, (d) can protected amino, perhaps (e) can substituted cyclic group, perhaps
(vii) can substituted cyclic group;
R 2Expression can substituted unsaturated cyclic group, wherein said substituting group can with R 3Forming together can substituted C2-5 alkylene base.
2. the compound shown in the formula (I-A), its salt, its N-oxide compound, its solvate or its prodrug:
Figure A20048003294200151
Wherein
Figure A20048003294200152
Expression is selected from following ring:
(1) cyclic group 1:
With
Figure A20048003294200155
And
(2) cyclic group 2:
Figure A20048003294200161
Figure A20048003294200162
With
Figure A20048003294200163
Wherein encircle A and can be selected from following substituting group replacement: halogen atom, CF by 1-3 3, OCF 3, hydroxyl, sulfydryl, carboxyl, (C1-6 alkoxyl group) carbonyl, carbamyl, nitro, cyano group, oxo, and can be selected from halogen atom, CF by 1-3 separately 3The C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl group or the C1-6 alkylthio that replace with substituting group in the hydroxyl, and ring B can further be substituted;
R 1Expression:
(i) separately can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl,
(ii) can protected amino,
But (iii) protected hydroxyl,
(iv) can protected sulfydryl,
(v)-S (O) nR 6, wherein n represents 1 or 2, and R 6Expression (a) separately can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, or (b) can substitutedly encircle,
(vi)-COR 7, R wherein 7Expression (a) hydrogen atom (b) separately can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, but (c) protected hydroxyl, (d) can protected amino, or (e) can substituted cyclic group, perhaps
(vii) can substituted cyclic group;
R 1aExpression:
(i) can be substituted C1-15 alkyl or the C2-15 alkenyl that base group (substituent group) 1 replaces,
(ii) NR 8R 9, R wherein 8Represent (a) hydrogen atom or (b) can be substituted base separately to organize 1 C1-15 alkyl or the C2-15 alkenyl that replaces, and R 9Expression (a) hydrogen atom (b) can be substituted C1-15 alkyl or the C2-15 alkenyl that base group 1 replaces, (c)-and COR 10, R wherein 10Represent (aa) hydrogen atom or (bb) can be substituted base separately to organize 1 C1-15 alkyl or the C2-15 alkenyl that replaces, (d)-COOR 10, R wherein 10Has above-mentioned identical meanings, perhaps (e)-CON (R 8) 2, R wherein 8Have above-mentioned identical meanings independently of one another,
(iii) OR 10, R wherein 10Have above-mentioned identical meanings,
(iv) SR 10, R wherein 10Have above-mentioned identical meanings,
(v) S (O) nR 11, wherein n represents 1 or 2, and R 11Expression can be substituted C1-15 alkyl or the C2-15 alkenyl that base group 1 replaces separately, perhaps
(vi) COR 12, R wherein 12Expression (a) hydrogen atom (b) can be substituted C1-15 alkyl or the C2-15 alkenyl that base group 1 replaces separately, (c)-and OR 10, R wherein 10Has above-mentioned identical meanings, perhaps (d)-NR 8R 9, R wherein 8And R 9Has above-mentioned identical meanings;
Described substituting group group 1 expression (1) halogen atom, (2) CF 3, (3) OCF 3(4) cyano group, (5) nitro, (6) hydroxyl; (7) C1-6 alkoxyl group; (8) carboxyl, (9) (C1-6 alkoxyl group) carbonyl, (10) C1-5 acyl group; (11) wherein nitrogen-atoms can be by the carbamyl of 1 or 2 C1-6 alkyl protection; (12) C1-6 alkylthio, (13) C1-6 alkyl sulphonyl, perhaps (14) NR 13R 14, R wherein 13Expression (a) hydrogen atom, (b) C1-6 alkyl, or (c) C2-6 alkenyl, and R 14Expression (a) hydrogen atom, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d)-COR 15, R wherein 15Expression (aa) hydrogen atom, (bb) C1-6 alkyl or (cc) C2-6 alkenyl, (e)-COOR 15, R wherein 15Has above-mentioned identical meanings, perhaps (f)-CON (R 16) 2, each R wherein 16Represent hydrogen atom or C1-6 alkyl independently;
Z aExpression-NR 3-, R wherein 3The expression hydrogen atom separately can substituted C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl ,-CO-(can substituted C1-6 alkyl) ,-SO 2-(can substituted C1-6 alkyl), Sauerstoffatom, sulphur atom that can be oxidized, perhaps-CR 4R 5-, R wherein 4And R 5Represent hydrogen atom independently of one another, or separately can substituted C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, perhaps R 4And R 5Can represent (i) oxo together, (ii) C2-5 alkylene base, one of them carbon atom can be replaced by 1 Sauerstoffatom, nitrogen-atoms or sulphur atom that can be oxidized, and wherein said C2-5 alkylene base can be replaced by one or more substituting groups, perhaps (iii) can substituted C1-6 alkylidene;
R 2aExpression (1) can encircle unsaturated carbocyclics by substituted C5-12 monocycle or two, (2) can substituted pyridine, (3) can substituted bicyclic heterocycles, wherein benzene and 5-or 6-unit monocyclic heterocycles condenses, (4) can substituted bicyclic heterocycles, wherein pyridine ring and C5-6 monocycle are carbocyclic fused, and perhaps (5) can substituted bicyclic heterocycles, and wherein pyridine ring and 5-or 6-unit monocyclic heterocycles condenses.
3. according to above-mentioned 2 compound, its salt, its N-oxide compound, its solvate or its prodrug, ring wherein
Figure A20048003294200181
Be
Figure A20048003294200182
Or
Figure A20048003294200184
Wherein each symbol has and implication identical described in the claim 2.
4. according to above-mentioned 2 compound, its salt, its N-oxide compound, its solvate or its prodrug, wherein R 1Be can protected amino, or R 1aBe NR 8R 9, R wherein 8And R 9Have and identical implication described in above-mentioned 2.
5. according to above-mentioned 2 compound, its salt, its N-oxide compound, its solvate or its prodrug, wherein Z aBe-NR 3-, R wherein 3Have and identical implication described in above-mentioned 2.
6. according to above-mentioned 2 compound, its salt, its N-oxide compound, its solvate or its prodrug, wherein Z aBe-CR 4bR 5b-, R wherein 4bAnd R 5bRepresent the C2-5 alkylene base together, one of them carbon atom can be replaced by 1 Sauerstoffatom, nitrogen-atoms or sulphur atom that can be oxidized, and wherein said C2-5 alkylene base can be replaced by one or more substituting groups.
7. according to above-mentioned 2 compound, its salt, its N-oxide compound, its solvate or its prodrug, it is suc as formula shown in (I-A-3):
Wherein
Figure A20048003294200191
Be
Figure A20048003294200192
R 1-AExpression can by 1 or 2 can be substituted the amino of C1-15 alkyl protection;
G A1Represent hydrogen atom independently of one another, halogen atom, CF 3, OCF 3, hydroxyl, sulfydryl, carboxyl, (C1-6 alkoxyl group) carbonyl, carbamyl, nitro, cyano group perhaps can be selected from halogen atom, CF by 1 or 2 separately 3The C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl group or the C1-6 alkylthio that replace with substituting group in the hydroxyl;
G 2The expression hydrogen atom can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, but protected hydroxyl, cyclopropane base, tetramethylene base, pentamethylene base, cyclohexyl, phenyl, halogen atom, CF 3, perhaps cyano group; And all the other symbols have with above-mentioned 2 in identical implication.
8. according to above-mentioned 2 compound, its salt, its N-oxide compound, its solvate or its prodrug, it is suc as formula shown in (I-A-4):
Figure A20048003294200193
Wherein Be
Or
Figure A20048003294200196
R 1a-AExpression NR 8AR 9A, R wherein 8AAnd R 9AOne of expression can be substituted the C1-15 alkyl that base group 1 replaces, another expression hydrogen atom maybe can be substituted the C1-15 alkyl that base group 1 replaces, wherein said substituting group group 1 have with above-mentioned 2 in identical implication;
G A2Represent hydrogen atom independently of one another, halogen atom, CF 3, OCF 3, hydroxyl, sulfydryl, carboxyl, (C1-6 alkoxyl group) carbonyl, carbamyl, nitro, oxygen base (oxy), oxo (oxo) perhaps can be selected from halogen atom, CF by 1 or 2 separately 3The C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl group or the C1-6 alkylthio that replace with substituting group in the hydroxyl; And all the other symbols have and above-mentioned 2 or 7 described identical implications.
9. according to above-mentioned 2 compound, its salt, its N-oxide compound, its solvate or its prodrug, it is:
(1) N 5-(2-chloro-4-methoxyphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines,
(2) N 5-(2-chloro-4-methoxyphenyl)-N 7-(1-ethyl propyl)-6-methylpyrazole is [1,5-a] pyrimidine-5 also, the 7-diamines,
(3) N 5-(2-chloro-4-methoxyphenyl)-6-ethyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines,
(4) N 2-(2-chloro-4-methoxyphenyl)-N 2-ethyl-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines,
(5) N 5-(2-chloro-4-methoxyphenyl)-6-methoxyl group-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines,
(6) N 2-allyl group-N 2-(2-chloro-4-methoxyphenyl)-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines,
(7) 6-methyl-N 5-[2-methyl-4-(trifluoromethoxy) phenyl]-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines,
(8) N 7-butyl-N 5-(2-chloro-4-methoxyphenyl)-N 7-ethyl-6-methylpyrazole is [1,5-a] pyrimidine-5 also, the 7-diamines,
(9) N 5-(2-ethyl-4-aminomethyl phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines,
(10) 6-methoxyl group-N 5-(4-methyl-2-ethenylphenyl)-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines or
(11) N 5-(2-ethyl-4-aminomethyl phenyl)-6-methoxyl group-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines.
10. pharmaceutical composition, described pharmaceutical composition contains compound shown in good grounds above-mentioned 2 the formula (I-A), its salt, its N-oxide compound, its solvate or its prodrug as activeconstituents.
11. the pharmaceutical composition according to above-mentioned 10, described pharmaceutical composition are the CRF antagonists.
12. the pharmaceutical composition according to above-mentioned 10, described pharmaceutical composition are the medicines that is used to prevent and/or treat by the disease of CRF mediation.
13. the pharmaceutical composition according to above-mentioned 12, wherein said disease by the CRF mediation is psychosis and neuropathy or digestion disease.
14. the pharmaceutical composition according to above-mentioned 13, wherein said psychosis and neuropathy or digestion disease are mood disorders, anxiety disorder (anxiety disorder), with disease (stress-relateddisorders) that stress be relevant, eating disorder disease (eating disorders), by to spirituality material or symptom that its dependency is caused, OMD (organic mental disorder), schizophrenic disturbance, scatterbrained hyperactivity disorder (attention-deficit hyperactivity disorder) or irritable bowel syndrome (irritable bowel syndrome).
15. the pharmaceutical composition according to above-mentioned 14, wherein said psychosis and neuropathy or digestion disease are that depression, mood disorder, eating disorder disease, medicine are habit-forming, pharmacological dependence or irritable bowel syndrome.
16. a medicine, described medicine contain compound shown in good grounds above-mentioned 2 the formula (I-A), its salt, its N-oxide compound, its solvate or its prodrug and at least a combination (combination) that is selected from following medicament: tricyclic antidepressants, tetracyclic antidepressant, oxidase inhibitor, serotonin and noradrenaline reuptake inhibitor, selectivity serotonin reuptake inhibithors, serotonin reuptake inhibithors (serotonin reuptake inhibitor), incitantia, anxiolytic, antipsychotic (antipsychotic agent), plastosome benzodiazepine receptors ligand (mitochondrialbenzodiazepine receptor ligand), the NK1 antagonist, gi tract promotor (gastrointestinalpromotility agent), the 5-HT3 antagonist, the 5-HT4 agonist, anticholinergic drug, diarrhea, short rushing down and the conditioning agent of restraining oneself (autonomic modulating agent).
17. the method for an antagonism CRF, described method comprise to compound shown in the formula of administration significant quantity (I), its salt, its N-oxide compound, its solvate or its prodrug:
Wherein all symbols have and identical implication described in above-mentioned 1.
18. a method that prevents and/or treats by the disease of CRF mediation, described method comprises to compound shown in the formula of administration significant quantity (I-A), its salt, its N-oxide compound, its solvate or its prodrug:
Figure A20048003294200221
Wherein all symbols have and identical implication described in above-mentioned 2.
19. compound shown in the formula (I), its salt, its N-oxide compound, its solvate or its prodrug purposes in preparation CRF antagonist:
Wherein all symbols have and identical implication described in above-mentioned 1.
20. compound shown in the formula (I), its salt, its N-oxide compound, its solvate or its prodrug are used for purposes by the medicine of the disease of CRF mediation in manufacturing:
Figure A20048003294200223
Wherein all symbols have and identical implication described in above-mentioned 2.
In the present invention, ring For example comprise
Or
Figure A20048003294200227
In the present invention, described 5-or 6-unit monocycle comprises 5-or 6-unit's monocycle carbocyclic ring or monocyclic heterocycles.
Described 5-or 6-unit monocycle carbocyclic ring comprise for example pentamethylene, hexanaphthene, cyclopentenes, tetrahydrobenzene, cyclopentadiene, cyclohexadiene and phenyl ring.
Described 5-or 6-unit monocyclic heterocycles comprises and contains 1-4 heteroatomic 5-or 6-unit monocyclic heterocycles that is selected from nitrogen-atoms, Sauerstoffatom and/or the sulphur atom that can be oxidized.Example comprises pyrroline, tetramethyleneimine, tetrahydroglyoxaline, imidazolidine (imidazolidine), triazoline, triazolidine, the tetrazolium quinoline, tetrazolium alkane, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidines, the dihydro pyrazine, the tetrahydrochysene pyrazine, piperazine, dihydro-pyrimidin, tetrahydropyrimidine, perhydro pyrimidine (perhydropyrimidine), dihydrogen dazin, tetrahydro pyridazine, perhydro pyridazine (perhydropyridazine), dihydrofuran, tetrahydrofuran (THF), dihydropyrane, tetrahydropyrans, dihydro-thiophene, tetramethylene sulfide, the dihydro thiapyran, tetrahydric thiapyran, dihydro  azoles, tetrahydrochysene  azoles ( azoles alkane), the different  azoles of dihydro, the different  azoles of tetrahydrochysene (different  azoles alkane), thiazoline, thiazolidine (thiazolidine), dihydro isothiazole, tetrahydrochysene isothiazole (isothiazolidine), dihydro furazan (dihydrofurazan), tetrahydrochysene furazan (tetrahydrofurazan), dihydro  diazole, tetrahydrochysene  diazole ( diazole alkane), dihydro  piperazine, tetrahydrochysene  piperazine, dihydro  diazine, tetrahydrochysene  diazine, thiodiazoline, thiodiazolidine (thiadiazolidine), the dihydro thiazine, the tetrahydrochysene thiazine, the dihydro thiadiazine, the tetrahydrochysene thiadiazine, morpholine, parathiazan (thiomorpholine), oxathiane, the pyrroles, imidazoles, triazole, tetrazolium, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, furans, thiophene, the  azoles, different  azoles, thiazole, isothiazole, furazan, thiadiazoles, pyrans, thiapyran, the  piperazine, the  diazine, thiazine and thiadiazine ring.
In the present invention, (it can contain except that nitrogen-atoms, W the first monocycle unsaturated heterocycle of described 5-to 7- 1And W 2Outside 1 or 2 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and/or the sulphur atom that can be oxidized, and described heterocycle can further be substituted) comprising can be by the first monocycle unsaturated heterocycle of the 5-to 7-that 1 or 2 substituting group that is selected from the substituting group group 2 replaces, it contains a nitrogen-atoms usually, and can contain except that nitrogen-atoms, W 1And W 2Outside 1 or 2 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and/or the sulphur atom that can be oxidized.Example comprises pyrroles, imidazoles, triazole, pyridine, pyrimidine, pyridazine, triazine, azepine  (azepine), diaza  (diazepine),  piperazine,  diazine, oxygen azepine  (oxazepine), oxygen diaza  (oxadiazepine), thiazine, thiadiazine, sulphur azepine  (thiazepine) and sulphur diaza  (thiadiazepine) ring.
In this respect, in ring A and ring B, institute's nitrogen atom add up to 5 or still less, and among ring A and the ring B contained Sauerstoffatom and sulphur atom that can be oxidized add up to 2 or still less.
In the present invention, substituting group group 2 comprises:
(i) can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl,
(ii) can protected amino,
But (iii) protected hydroxyl,
(iv) can protected sulfydryl,
(v)-S (O) nR 6, wherein n and R 6Have above-mentioned identical meanings,
(vi)-COR 7, R wherein 7Have above-mentioned identical meanings,
(vii) can substituted cyclic group, and
(viii) halogen atom, CF 3, OCF 3, nitro or cyano group.
In the present invention, can comprise S, SO and SO by oxidized sulphur atom 2
In the present invention, can substituted C1-15 alkyl comprising can substituted straight or branched C1-15 alkyl, and the example comprises separately can substituted methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and pentadecyl.
In the present invention, can substituted C2-15 alkenyl comprise can the substituted 1-3 of having two keys straight or branched C2-15 alkenyl, the example comprises can substituted vinyl, propenyl, butenyl, pentenyl, hexenyl, hexadienyl, heptenyl, heptadiene base, octenyl, octadienyl, nonene base, nonadiene base, decene base, decadiene base, undecenyl, dodecenyl succinic, tridecylene base, tetradecene base and 15 carbene bases.
In the present invention, can substituted C2-15 alkynyl comprising can the substituted 1-3 of having triple-linked straight or branched C2-15 alkynyl, and the example comprises separately can substituted ethynyl, proyl, butynyl, pentynyl, hexin base, hexadiyne base, heptyne base, heptadiyne base, octyne base, hot diynyl, n-heptylacetylene base, decynyl, hendecyne base, dodecyne base, 13 carbyne bases, 14 carbyne bases and 15 carbyne bases.
In the present invention, " can be substituted C1-15 alkyl or C2-15 alkenyl that base group 1 replaces " but in substituting group group 1 can on 1-4 the position of substitution of described C1-15 alkyl or C2-15 alkenyl, replace.
Substituting group group 1 comprises (1) halogen atom, (2) CF 3, (3) OCF 3(4) cyano group, (5) nitro, (6) hydroxyl; (7) C1-6 alkoxyl group; (8) carboxyl, (9) (C1-6 alkoxyl group) carbonyl, (10) C1-5 acyl group; (11) wherein nitrogen-atoms can be by the carbamyl of 1 or 2 C1-6 alkyl replacement; (12) C1-6 alkylthio, (13) C1-6 alkyl sulphonyl, and (14) NR 13R 14, R wherein 13Be (a) hydrogen atom, (b) C1-6 alkyl or (c) C2-6 alkenyl, and R 14Expression (a) hydrogen atom, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d)-COR 1, R wherein 15Expression (aa) hydrogen atom, (bb) C1-6 alkyl or (cc) C2-6 alkenyl, (e)-COOR 15, R wherein 15Has above-mentioned identical meanings, perhaps (f)-CON (R 16) 2, R wherein 16Represent hydrogen atom or C1-6 alkyl independently of one another.
In the present invention, described can substituted C1-6 alkyl comprising can substituted straight or branched C1-6 alkyl, and the example comprises separately can substituted methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group and hexyl.
In the present invention, the described straight or branched C2-6 alkenyl that can substitutedly have two keys that can substituted C2-6 alkenyl comprise, the example comprise separately can substituted vinyl, propenyl, butenyl, pentenyl and hexenyl.
In the present invention, describedly can comprise substitutedly having a triple-linked straight or branched C2-6 alkynyl by substituted C2-6 alkynyl, the example comprises can substituted ethynyl, proyl, butynyl, pentynyl and hexin base.
In the present invention, described C2-5 alkylene base or describedly can comprise methylene radical (methylene), 1 by substituted C2-5 alkylene base, 2-ethylidene (ethylene), 1,3-propylidene (trimethylene), 1,4-butylidene (tetramethylene), pentamethylene (pentamethylene) and isomer thereof.
In the present invention, describedly can comprise methyne (methylidene), 1 by substituted C1-6 alkylidene, 1-ethylidene (ethylidene), 1,1-propylidene (propylidene), 1,1-pentylidene (pentylidene), 1,1-hexylidene (hexylidene) and isomer thereof.
In the present invention, described " can substituted C1-6 alkyl ", described " can substituted C2-6 alkenyl ", described " can substituted C2-6 alkynyl ", described " can substituted C2-5 alkylene base ", described " can substituted C1-6 alkylidene ", described " can substituted C1-15 alkyl ", described " can substituted C2-15 alkenyl ", described " can substituted C2-15 alkynyl " and described " can substituted C1-15 alkoxyl group " comprises " replacing or unsubstituted C1-6 alkyl ", " replace or unsubstituted C2-6 alkenyl ", " replace or unsubstituted C2-6 alkynyl ", " replace or unsubstituted C2-5 alkylene base ", " replace or unsubstituted C1-6 alkylidene ", " replace or unsubstituted C1-15 alkyl ", " replace or unsubstituted C2-15 alkenyl ", " replace or unsubstituted C2-15 alkynyl " and " replacing or unsubstituted C1-15 alkoxyl group ", and described " substituting group " comprises following substituting group group 3.
Substituting group group 3 comprises (1) halogen atom, (2) CF 3, (3) OCF 3(4) cyano group; (5) nitro; (6) can or have the hydroxyl of the protecting group protection of function of leaving away (leaving ability) by C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cyclic group; (7) C1-7 acyl group; (8) can be by the carbonyl of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or cyclic group protection; (9) can be by the carbamyl of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or cyclic group protection; (10) can be by the thiol group of C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or cyclic group protection, (11) NR 17R 18, R wherein 17Expression (a) hydrogen atom, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl or (e) cyclic group; And R 18Expression (a) hydrogen atom, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d) C2-6 alkynyl, (e)-COR 20, R wherein 20Expression (aa) hydrogen atom, (bb) C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl or (cc) cyclic group, (f)-COOR 20, R wherein 20Has above-mentioned identical meanings, perhaps (g)-CON (R 17) 2, R wherein 17Has above-mentioned identical meanings independently of one another, (12)-S (O) nR 19, wherein n has above-mentioned identical meanings, and R 19Expression (a) hydrogen atom, (b) C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl or (c) cyclic group, (13)-COR 20, R wherein 20Have above-mentioned identical meanings, and (14) can substituted cyclic group.But these substituting groups can replace on 1-4 the position of substitution.In addition, described C1-6 alkyl, C2-6 alkenyl and the C2-6 alkynyl in the substituting group group 3 can be replaced by one or more substituting groups that are selected from the substituting group group 5, and described cyclic group can be replaced by one or more substituting groups that are selected from the substituting group group 4.
In the present invention, described halogen atom comprises fluorine, chlorine, bromine and iodine.
In the present invention, the C1-6 alkyl comprises for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group and hexyl.
In the present invention, the C2-6 alkenyl comprises for example vinyl, propenyl, butenyl, pentenyl, hexenyl and hexadienyl.
In the present invention, the C2-6 alkynyl comprises for example ethynyl, proyl, butynyl, pentynyl, hexin base and hexadiyne base.
In the present invention, describedly can be comprised the C1-6 alkoxyl group by the hydroxyl that the C1-6 alkyl is protected.
In the present invention, described C1-6 alkoxyl group comprises for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, the second month in a season-butoxy, uncle-butoxy, pentyloxy and hexyloxy.
In the present invention, described C1-15 alkoxyl group comprises for example straight or branched C1-15 alkoxyl group, and the example comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, the second month in a season-butoxy, uncle-butoxy, pentyloxy, hexyloxy, heptan oxygen base, octyloxy, ninth of the ten Heavenly Stems oxygen base, last of the ten Heavenly stems oxygen base, hendecane oxygen base, 12 carbon alkoxyl groups, n-tridecane oxygen base, n-tetradecane oxygen base and pentadecane oxygen base.
In the present invention, described C1-6 alkylthio comprises for example methylthio group, ethylmercapto group, rosickyite base, iprotiazem base, positive butylthio, isobutyl sulfenyl, secondary butylthio, uncle's butylthio, penta sulfenyl and own sulfenyl.
In the present invention, described C1-5 acyl group comprises for example formyl radical, ethanoyl, propionyl, butyryl radicals, 2-methylpropionyl and valeryl (pivaloyl).
In the present invention, described C1-7 acyl group comprises for example formyl radical, ethanoyl, propionyl, valeryl and benzoyl.
In the present invention, described (C1-6 alkoxyl group) carbonyl comprises for example methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, butoxy carbonyl, isobutyl boc, secondary butoxy carbonyl, tertbutyloxycarbonyl, penta oxygen carbonyl and own oxygen carbonyl.
In the present invention, wherein nitrogen-atoms can be comprised N-(C1-6 alkyl) carbamyl and N, N-two (C1-6 alkyl) carbamyl by the carbamyl of 1 or 2 C1-6 alkyl protection.
In the present invention, describedly can protected amino comprise unsubstituted amino and by the amino of 1 or 2 following protecting group protection.Described amino protecting group comprises that (a) can substituted C1-15 alkyl, (b) can substituted C2-15 alkenyl, (c) can substituted C2-15 alkynyl, and (d) can substituted cyclic group, (e)-COR 21, R wherein 21Expression (aa) hydrogen atom, (bb) separately can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl or (cc) can substituted cyclic group, (f)-and COOR 21, R wherein 21Have above-mentioned identical meanings, and (g)-CON (R 22) 2, R wherein 22Independently of one another expression (aa) hydrogen atom or (bb) separately can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl.
In the present invention; but protected hydroxyl for example comprises that (a) can substituted C1-15 alkyl separately; (b) can substituted C2-15 alkenyl; (c) can substituted C2-15 alkynyl; (d) can substituted cyclic group, and (e) hydroxyl or can be had the hydroxyl of the protecting group protection of the function of leaving away.In this article; described protecting group with the function of leaving away for example comprises trityl, methoxyl methyl (MOM), 1-ethoxyethyl (EE), methoxy (ethoxy) ylmethyl (MEM), 2-THP trtrahydropyranyl (THP), trimethyl silyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), ethanoyl (Ac), valeryl, benzoyl, benzyl (Bn), to methoxy-benzyl, allyloxycarbonyl (Alloc) and 2; 2,2-trichloro-ethoxycarbonyl (Troc).In addition, by can be substituted the hydroxyl of C1-15 alkyl protection comprise can substituted C1-15 alkoxyl group.
In the present invention; described can protected sulfydryl comprise can by (a) can substituted C1-15 alkyl, (b) can substituted C2-15 alkenyl, (c) can substituted C2-15 alkynyl or sulfydryl that (d) can substituted cyclic group protection, and not protected sulfydryl.
In the present invention, described cyclic group comprises carbon ring group and heterocyclic group.Described carbocyclic ring comprises C3-12 monocycle or two ring carbon ring groups, and the example comprises cyclopropane, tetramethylene, pentamethylene, hexanaphthene, suberane, cyclopentenes, tetrahydrobenzene, suberene, cyclopentadiene, cyclohexadiene, cycloheptadiene, benzene, pentalene (pentalene), perhydro pentalene (perhydropentalene), Azulene, perhydro Azulene, indenes, perhydro indenes, indane, naphthalene, dialin, tetraline, Perhydronaphthalene, heptalene (heptalene), perhydro heptalene (perhydroheptalene) and dicyclo [3.1.1] heptane cyclic group.
Heterocyclic group comprises that containing 1-4 is selected from nitrogen-atoms, heteroatomic C3-12 monocycle or bicyclic heterocycles group in Sauerstoffatom and/or the sulphur atom that can be oxidized, the example comprises oxyethane, thiirane, ethylenimine (aziridine), propylene oxide, epithio propane (thietane), azetidine, pyrroline, tetramethyleneimine, tetrahydroglyoxaline, imidazolidine, triazoline, triazolidine, the tetrazolium quinoline, tetrazolium alkane, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidines, the dihydro pyrazine, the tetrahydrochysene pyrazine, piperazine, dihydro-pyrimidin, tetrahydropyrimidine, the perhydro pyrimidine, dihydrogen dazin, tetrahydro pyridazine, the perhydro pyridazine, dihydro azepine , tetrahydrochysene azepine , perhydro azepine , dihydro diaza , tetrahydrochysene diaza , perhydro diaza , dihydrofuran, tetrahydrofuran (THF), dihydropyrane, tetrahydropyrans, dihydro oxa- (dihydrooxepine), tetrahydrochysene oxa-, perhydro oxa-, dihydro-thiophene, tetramethylene sulfide, the dihydro thiapyran, tetrahydric thiapyran, dihydro thia  (dihydrothiepine), tetrahydrochysene thia , perhydro thia , dihydro  azoles, tetrahydrochysene  azoles ( azoles alkane), the different  azoles of dihydro, the different  azoles of tetrahydrochysene (different  azoles alkane), thiazoline, thiazolidine (thiazolidine), dihydro isothiazole, tetrahydrochysene isothiazole (isothiazolidine), the dihydro furazan, the tetrahydrochysene furazan, dihydro  diazole, tetrahydrochysene  diazole ( diazole alkane), dihydro  piperazine, tetrahydrochysene  piperazine, dihydro  diazine, tetrahydrochysene  diazine, two hydrogen-oxygen azepine  (dihydrooxazepine), tetrahydrochysene oxygen azepine , perhydro oxygen azepine , two hydrogen-oxygen diaza , tetrahydrochysene oxygen diaza , perhydro oxygen diaza , thiodiazoline, thiodiazolidine (thiadiazolidine), the dihydro thiazine, the tetrahydrochysene thiazine, the dihydro thiadiazine, the tetrahydrochysene thiadiazine, dihydro sulphur azepine  (dihydrothiazepine), tetrahydrochysene sulphur azepine , perhydro sulphur azepine , dihydro sulphur diaza , tetrahydrochysene sulphur diaza , perhydro sulphur diaza , morpholine, parathiazan, oxathiane (oxathiane), indoline, xylylenimine, Dihydrobenzofuranes, the perhydro cumarone, dihydroisobenzofuran (dihydroisobenzofuran), the perhydro isobenzofuran, the dihydrobenzo thiophene, the perhydro thionaphthene, the different thionaphthene of dihydro (dihydroisobenzothiophene), the different thionaphthene of perhydro, dihydro-indazol, the perhydro indazole, dihydroquinoline, tetrahydroquinoline, the perhydro quinoline, dihydro-isoquinoline, tetrahydroisoquinoline, perhydro isoquinoline 99.9, the dihydro phthalazines, the tetrahydrochysene phthalazines, the perhydro phthalazines, the dihydro naphthyridines, Tetrahydronaphthyridderivates, the perhydro naphthyridines, dihydro-quinoxaline, tetrahydroquinoxaline, the perhydro quinoxaline, dihydroquinazoline, tetrahydro quinazoline, the perhydro quinazoline, the dihydro cinnoline, the tetrahydrochysene cinnoline, the perhydro cinnoline, benzo oxathiane (benzoxathiane), dihydrobenzo  piperazine, the dihydrobenzo thiazine, pyrazine and morpholine, dihydrobenzo  azoles, the perhydro benzoxazol, dihydro-benzothiazole, the perhydro benzothiazole, the dihydrobenzo imidazoles, the perhydro benzoglyoxaline, dihydrobenzo azepine , tetrahydro benzo azepine , dihydrobenzo diaza , tetrahydro benzo diaza , dihydrobenzo dioxane heptene (benzodioxepane), dihydrobenzo oxygen azepine , tetrahydro benzo oxygen azepine , the pyrroles, imidazoles, triazole, tetrazolium, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, azepine , diaza , furans, pyrans, oxa-, thiophene, thiapyran, thia  (thiepine), the  azoles, different  azoles, thiazole, isothiazole, furazan, the  diazole, the  piperazine, the  diazine, oxygen azepine  (oxazepine), oxygen diaza  (oxadiazepine), thiadiazoles, thiazine, thiadiazine, sulphur azepine  (thiazepine), sulphur diaza  (thiadiazepine), indoles, isoindole, indolizine, cumarone, isobenzofuran (isobenzofuran), thionaphthene, different thionaphthene (isobenzothiephene), dithia naphthalene (dithianaphthalene), indazole, quinoline, isoquinoline 99.9, quinolizine, purine, phthalazines, pteridine, naphthyridines, quinoxaline, quinazoline, cinnoline, benzoxazol, benzothiazole, benzoglyoxaline, chromene (chromene), benzo oxa-, benzo oxygen azepine , benzo oxygen diaza , benzo thia , benzothiazepine, benzimidazole thiophanate diaza , benzazepine, benzodiazepine, the benzo furazan, diazosulfide and benzotriazole cyclic group.
In the present invention, can be substituted carbocyclic ring and the heterocycles that base group 4 replaces separately described can substituted cyclic group comprising.Described carbocyclic ring and described heterocycle comprise above-mentioned group.
Substituting group group 4 comprises (1) C1-6 alkyl; (2) C2-6 alkenyl; (3) C2-6 alkynyl; (4) can be by the C1-6 alkyl; the C2-6 alkenyl; the C2-6 alkynyl; cyclic group or have the hydroxyl of the protecting group protection of the function of leaving away; (5) can be by the C1-6 alkyl; the C2-6 alkenyl; the sulfydryl of C2-6 alkynyl or cyclic group protection; (6) can be selected from the C1-6 alkyl by 1 or 2; the C2-6 alkenyl; the amino of the radical protection in C2-6 alkynyl and the cyclic group; (7) can be selected from the C1-6 alkyl by 1 or 2; the C2-6 alkenyl; the carbamyl of the radical protection in C2-6 alkynyl and the cyclic group; (8) can be selected from the C1-6 alkyl by 1 or 2; the C2-6 alkenyl; the sulfamyl of the radical protection in C2-6 alkynyl and the cyclic group; (9) can be by the C1-6 alkyl; the C2-6 alkenyl; the carboxyl of C2-6 alkynyl or cyclic group protection; (10) nitro; (11) cyano group; (12) amidino groups; (13) halogen atom, (14) CF 3, (15) OCF 3, (16) C1-7 acyl group, (17) oxo, and (18) sulfo-(thio).But these substituting groups can replace on 1-5 the position of substitution.In addition, in substituting group group 4, described C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl can be replaced by one or more groups that are selected from the substituting group group 5, and described cyclic group can be replaced by one or more groups that are selected from the substituting group group 6.
Substituting group group 5 comprises (1) C1-6 alkoxyl group; (2) C1-6 alkylthio; (3) halogen atom, (4) can or have the hydroxyl of the protecting group protection of the function of leaving away, (5) CF by C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cyclic group, cyclic group-C1-6 alkyl 3, (6) OCF 3(7) nitro; (8) cyano group; (9) carboxyl, (10) (C1-6 alkoxyl group) carbonyl, (11) carbobenzoxy-(Cbz); (12) sulfydryl; (13) amino, (14) C1-6 alkylamino, (15) two (C1-6 alkyl) amino; (16) carbamyl; (17) N-(C1-6 alkyl) carbamyl, (18) N, N-two (C1-6 alkyl) carbamyl; (19) sulfamyl; (20) N-(C1-6 alkyl) sulfamyl, (21) N-two (C1-6 alkyl) sulfamyl, (22) C1-7 acyl group and (23) can be substituted the cyclic group that base group 6 replaces.
Substituting group group 6 comprises (1) C1-6 alkyl, (2) C2-6 alkenyl, (3) C2-6 alkynyl, (4) C1-6 alkoxyl group, (5) C1-6 alkylthio, (6) halogen atom, (7) CF 3, (8) OCF 3(9) nitro; (10) cyano group; (11) can be by the C1-6 alkyl; the C2-6 alkenyl; the C2-6 alkynyl; cyclic group; cyclic group-C1-6 alkyl or have the hydroxyl of the protecting group protection of the function of leaving away; (12) carboxyl, (13) (C1-6 alkoxyl group) carbonyl, (14) carbobenzoxy-(Cbz); (15) sulfydryl; (16) amino, (17) C1-6 alkylamino, (18) two (C1-6 alkyl) amino; (19) carbamyl; (20) N-(C1-6 alkyl) carbamyl, (21) N, N-two (C1-6 alkyl) carbamyl; (22) sulfamyl; (23) N-(C1-6 alkyl) sulfamyl, (24) N-two (C1-6 alkyl) sulfamyl, (25) C1-7 acyl group; (26) oxo, and (27) sulfo-.
In the present invention, cyclic group-C1-6 alkyl comprises carbon ring group-C1-6 alkyl and heterocyclic group-C1-6 alkyl, for example respectively by the C1-6 alkyl of a carbon ring group replacement with by the C1-6 alkyl of a heterocyclic group replacement.Described carbon ring group, heterocyclic group and C1-6 alkyl have above-mentioned identical meanings.
In the present invention, can comprise unsaturated carbon cyclic group and unsaturated heterocycle group by substituted unsaturated cyclic group, they can be replaced by 1-5 substituting group that is selected from the substituting group group 7.
Described unsaturated carbon cyclic group comprises C5-12 monocycle or two ring unsaturated carbon cyclic groups, and the example comprises benzene, pentalene, indenes, indane, naphthalene, dialin, tetraline and Azulene cyclic group.In this respect, for the situation of indenes, indane, dialin and tetraline cyclic group, the phenyl ring in these cyclic groups combines with group Z.
Described unsaturated heterocycle group comprises that containing 1-4 is selected from heteroatomic 5-to 12-unit's monocycle or two ring unsaturated heterocycle groups in nitrogen-atoms, Sauerstoffatom and/or the sulphur atom that can be oxidized.Example comprises the pyrroles, imidazoles, triazole, tetrazolium, pyrazoles, pyridine, pyrazine, pyrimidine, pyridazine, azepine , furans, pyrans, oxa-, thiophene, thiapyran, thia , the  azoles, different  azoles, thiazole, isothiazole, furazan, the  diazole, the  piperazine, the  diazine, thiadiazoles, thiazine, thiadiazine, indoles, isoindole, cumarone, isobenzofuran, thionaphthene, different thionaphthene, the dithia naphthalene, indazole, quinoline, isoquinoline 99.9, phthalazines, quinoxaline, quinazoline, cinnoline, naphthyridines, benzoxazol, benzothiazole, benzoglyoxaline, chromene, the benzo furazan, diazosulfide, the benzotriazole cyclic group.In this respect, for the situation of indoles, isoindole, cumarone, isobenzofuran, thionaphthene, different thionaphthene, dithia naphthalene, indazole, phthalazines, quinoxaline, quinazoline, cinnoline, benzoxazol, benzothiazole, benzoglyoxaline, chromene, benzo furazan, diazosulfide and benzotriazole cyclic group, the phenyl ring in these cyclic groups combines with group Z.
Described substituting group group 7 comprises that (1) can substituted C1-15 alkyl; (2) can substituted C2-15 alkenyl; (3) can substituted C2-15 alkynyl; (4) but protected hydroxyl, (5) can protected sulfydryl, (6) can protected amino; (7) can protected carbamyl; (8) can protected sulfamyl, (9) can protected carboxyl, and (10) can protected sulfo group (SO 3H), (11) can protected sulfino (sulfino) (SO 2H), (12) nitro, (13) cyano group, (14) amidino groups, (15) imido grpup, (16) halogen atom, (17) can substituted cyclic group, (18) C1-7 acyl group, (19) oxo, (20) sulfo-and (21) can protected sulfo group (SOH).But these substituting groups can replace on 1-5 the position of substitution.
In the present invention, " protecting group " among described " can protected carbamyl ", " can protected sulfamyl ", " can protected carboxyl ", " can protected sulfo group ", " can protected sulfino " and " can protected sulfo group " comprise (a) can substituted C1-15 alkyl, (b) can substituted C2-15 alkenyl, (c) can substituted C2-15 alkynyl and (d) can substituted cyclic group.
In the present invention, described can substituted C5-12 monocycle or two ring unsaturated carbocyclics comprise the C5-12 monocycle or the two ring unsaturated carbocyclics that can be replaced by 1-5 substituting group that is selected from the above-mentioned substituting group group 7, the example comprises benzene, pentalene, indenes, indane, naphthalene, dialin, tetraline and Azulene ring.In this respect, for the situation of indenes, indane, dialin and tetrahydro-naphthalene nucleus, phenyl ring and Z in these rings aIn conjunction with.
In the present invention, described substituting group in can substituted pyridine comprises 1-4 substituting group that is selected from the above-mentioned substituting group group 7.
In the present invention, described can be substituted and wherein benzene and 5-or 6-unit monocyclic heterocycles condensed bicyclic heterocycles comprise can be replaced by 1-5 substituting group that is selected from the above-mentioned substituting group group 7 and wherein benzene and 5-or the first monocyclic heterocycles condensed of 6-bicyclic heterocycles, the example comprises indoles, isoindole, indoline, xylylenimine, cumarone, isobenzofuran, Dihydrobenzofuranes, dihydroisobenzofuran, thionaphthene, different thionaphthene, the dihydrobenzo thiophene, the different thionaphthene of dihydro, chroman and heterochromatic full ring (isochroman), wherein phenyl ring and the group Z in these rings aIn conjunction with.
In the present invention, described can be substituted and wherein the carbocyclic fused bicyclic heterocycles of pyridine ring and C5-6 monocycle comprise can be replaced by 1-5 substituting group that is selected from the above-mentioned substituting group group 7 and wherein pyridine ring and the carbocyclic fused bicyclic heterocycles of C5-6 monocycle, the example comprises quinoline, isoquinoline 99.9, tetrahydroquinoline and tetrahydroisoquinoline ring.In the situation of tetrahydroquinoline and tetrahydroisoquinoline ring, pyridine ring and group Z aIn conjunction with.
In the present invention, described can be substituted and wherein pyridine ring and 5-or 6-unit monocyclic heterocycles condensed bicyclic heterocycles comprise can be replaced by 1-5 substituting group that is selected from the above-mentioned substituting group group 7 and wherein pyridine ring and 5-or the first monocyclic heterocycles condensed of 6-bicyclic heterocycles, the example comprises naphthyridines.
In the present invention, describedly can contain 1 or 2 heteroatomic C3-6 cycloalkyl that is selected from Sauerstoffatom, sulphur atom and the nitrogen-atoms and comprise cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxyethane, propylene oxide, tetrahydrofuran (THF), tetrahydropyrans, thiirane, epithio propane (thietane), tetramethylene sulfide, tetrahydric thiapyran, ethylenimine, azetidine, tetramethyleneimine, piperidines, morpholine and parathiazan.
In the present invention, the preferred ring as ring A is pentamethylene, hexanaphthene, cyclopentenes, tetrahydrobenzene, cyclopentadiene, cyclohexadiene, benzene, pyrroline, tetramethyleneimine, pyrroles, tetrahydroglyoxaline, imidazolidine, imidazoles, pyrazoles, triazoline, triazolidine, triazole, tetrazolium quinoline, tetrazolium alkane, tetrazolium, dihydrofuran, tetrahydrofuran (THF), furans, dihydro-thiophene, tetramethylene sulfide, thiophene, dihydro furazan, tetrahydrochysene furazan, furazan, dihydro  diazole, tetrahydrochysene  diazole ( diazole alkane), thiodiazoline, thiodiazolidine (thiadiazolidine) and thiadiazoles.Be preferably pentamethylene, cyclopentenes, pyrroles, imidazoles, pyrazoles, triazole, tetrahydrofuran (THF), furans, furazan and thiadiazoles especially.
In the present invention, ring A is preferred unsubstituted or be selected from following substituting group by 1 or 2 and replace: halogen atom, CF 3, OCF 3, hydroxyl, sulfydryl, carboxyl, (C1-6 alkoxyl group) carbonyl, carbamyl, nitro, cyano group, oxo, and can be selected from halogen atom, CF by 1 or 2 separately 3The C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl group or the C1-6 alkylthio that replace with substituting group in the hydroxyl.The more preferably unsubstituted ring of ring A A, perhaps by 1 or 2 ring A that is selected from the substituting group replacement in the following substituting group, described substituting group comprises halogen atom, CF 3, hydroxyl, carboxyl, (C1-6 alkoxyl group) carbonyl, cyano group, the oxygen base, and can be selected from halogen atom, CF by 1 or 2 separately 3The C1-6 alkyl or the C1-6 alkoxyl group that replace with substituting group in the hydroxyl.
In the present invention, the preferred ring as ring B is pyrroles, imidazoles, pyridine, pyrimidine, pyridazine, triazine, azepine , diaza ,  piperazine, oxygen azepine , thiazine and sulphur azepine .Particularly preferably be pyridine, pyrimidine, pyridazine and triazine.
In the present invention, ring B is preferably except that R 1With-Z-R 2Outer other substituent ring of nothing, perhaps ring for further being replaced by 1 or 2 substituting group that is selected from the above-mentioned substituting group group 2.Ring B does not more preferably have other substituent ring B; perhaps be the ring B that is further replaced by 1 or 2 following substituting group that is selected from the above-mentioned substituting group group 2; described substituting group comprises: can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, but protected hydroxyl, cyclopropane; tetramethylene; pentamethylene, hexanaphthene, phenyl; halogen atom, CF 3And cyano group.Ring B most preferably is does not have other substituent ring B or for further being selected from the ring B that following substituting group replaces by 1, described substituting group comprise can substituted C1-6 alkyl or the C2-6 alkenyl, can be by hydroxyl, cyclopropane, tetramethylene, halogen atom, CF that can substituted C1-6 alkyl protection 3And cyano group.In this respect, the substituting group on C1-6 alkyl, C2-6 alkenyl or the C2-6 alkynyl is preferably a substituting group that is selected among C1-6 alkoxyl group, halogen atom, hydroxyl, CN and the COOH.
In the present invention, Z or Z aBe preferably wherein R 3Have above-mentioned identical meanings-NR 3-; Sauerstoffatom, sulphur atom that can be oxidized ,-CR 4aR 5a-, R wherein 4aAnd R 5aExpression (i) oxo, the (ii) C2-5 alkylene base that replaced by Sauerstoffatom, nitrogen-atoms or sulphur atom that can be oxidized of one of them carbon atom together, described C2-5 alkylene base is replaced by one or more substituting groups or (iii) can substituted C1-6 alkylidene.Z or Z aBe preferably wherein R 3Have above-mentioned identical meanings-NR 3-, or-CR 4bR 5b-, R wherein 4bAnd R 5bRepresent the C2-5 alkylene base that one of them carbon atom is replaced by Sauerstoffatom, nitrogen-atoms or sulphur atom that can be oxidized together, described C2-5 alkylene base is replaced by one or more substituting groups, most preferably is-NR 3-, R wherein 3Has above-mentioned identical meanings.Wherein, especially be preferably-NR 3a-, R wherein 3aIt is the C2-6 alkenyl of C1-6 alkyl, C2-6 alkenyl or the replacement of hydrogen atom, C1-6 alkyl, replacement.
In the present invention, when by R 2And R 2aThe ring of expression is to contain two ring unsaturated carbocyclics of benzene or pyridine ring or two rings during unsaturated heterocycles, described benzene or pyridine ring and group Z or Z aIn conjunction with.
In the present invention, the preferred compound shown in the formula (I) is the compound that exemplifies in the following table.
Table 1
Figure A20048003294200341
Figure A20048003294200342
Table 2
Figure A20048003294200351
In the present invention, preferred compound is formula (I-A) compound.
In the present invention, the preferred compound shown in the formula (I-A) is compound and the back that exemplifies in the following table
The embodiment compound.
Table 3
Figure A20048003294200361
Figure A20048003294200362
Table 4
Figure A20048003294200371
Figure A20048003294200372
In table 1-4, ring A is preferably unsubstituted or is selected from following substituting group by 1 or 2 and replaces: halogen atom, CF 3, OCF 3, hydroxyl, sulfydryl, carboxyl, (C1-6 alkoxyl group) carbonyl, carbamyl, nitro, cyano group, oxo and can be selected from halogen atom, CF by 1 or 2 separately 3The C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl group or the C1-6 alkylthio that replace with substituting group in the hydroxyl.Encircle A more preferably unsubstituted ring A or be selected from halogen atom, CF by 1 or 2 3, hydroxyl, carboxyl, (C1-6 alkoxyl group) carbonyl, cyano group, oxo and can be selected from halogen atom, CF by 1 or 2 separately 3The ring A that C1-6 alkyl that replaces with substituting group in the hydroxyl or the substituting group in the C1-6 alkoxyl group replace.
In table 1-4, but each ring shown in the ring B can be replaced by 1 or 2 substituting group that is selected from the above-mentioned substituting group group 2 on one or more the position of substitution.In substituting group group 2, being preferably separately can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, but protected hydroxyl, cyclopropane, tetramethylene, pentamethylene, hexanaphthene, phenyl, halogen atom, CF 3And cyano group.Ring B more preferably unsubstituted ring B, perhaps being selected from separately by one can substituted C1-6 alkyl or C2-6 alkenyl, can be by the hydroxyl of can substituted C1-6 alkyl protecting, cyclopropane, tetramethylene, halogen atom, CF 3And cyano group.
R 1Being preferably (i) separately can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, (ii) can protected amino, but (iii) protected hydroxyl, (iv) can protected sulfydryl, perhaps (v) can substituted cyclic group.Work as R 1Be can substituted cyclic group and described cyclic group be when containing the heterocycle of nitrogen-atoms, described nitrogen-atoms preferably links to each other with ring B.
In the present invention, R 1More preferably can protected amino.Described can protected amino be preferably can by 1 or 2 can substituted C1-15 alkyl protection amino; more preferably by one can be substituted the amino that replaces of C1-15 branched-chain or straight-chain alkyl, perhaps by two amino that can substituted C1-15 branched-chain or straight-chain alkyl replace.Describedly can be preferably unsubstituted C1-15 branched-chain or straight-chain alkyl by substituted C1-15 branched-chain or straight-chain alkyl, perhaps be selected from halogen atom, CF by 1 or 2 3, cyano group, hydroxyl, C1-6 alkoxyl group and can contain the C1-15 branched-chain or straight-chain alkyl that 1 or 2 substituting group in the heteroatomic C3-6 cycloalkyl that is selected from Sauerstoffatom, sulphur atom and the nitrogen-atoms replaces.
R 1aBeing preferably (i) separately can be by C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, the (ii) NR of above-mentioned substituting group group 1 replacement 8R 9, R wherein 8And R 9Has above-mentioned identical meanings, (iii) OR 10, R wherein 10Has above-mentioned identical meanings.R 1aNR more preferably 8R 9, R wherein 8And R 9The C1-15 alkyl, C2-15 alkenyl or the C2-15 alkynyl that are preferably (a) hydrogen atom separately or (b) can be replaced by above-mentioned substituting group group 1 separately.
NR 8R 9Be preferably NR 8AR 9A, R wherein 8AAnd R 9AOne of for can being substituted the C1-15 alkyl that base group 1 replaces, another be a hydrogen atom or can be by the C1-15 alkyl of above-mentioned substituting group group 1 replacement.More particularly, at NR 8AR 9AIn, be preferably (1) following combination: R wherein 8ABe hydrogen atom, and R 9ABe combination and (2) following combination of the C1-15 branched-chain or straight-chain alkyl that can be replaced by above-mentioned substituting group group 1: R wherein 8AAnd R 9AEach naturally can be by the C1-15 branched-chain or straight-chain alkyl of above-mentioned substituting group group 1 replacement.Describedly can be preferably unsubstituted C1-15 branched-chain or straight-chain alkyl, perhaps be selected from halogen atom, CF by 1 or 2 by the C1-15 branched-chain or straight-chain alkyl that above-mentioned substituting group group 1 replaces 3, the C1-15 branched-chain or straight-chain alkyl that replaces of the substituting group in cyano group, hydroxyl and the C1-6 alkoxyl group.
R 2Be preferably and encircle unsaturated carbocyclics or can encircle unsaturated heterocycles by substituted monocycle or two by substituted monocycle or two.R 2R more preferably 2aShown ring, promptly (1) can substituted monocycle or two ring unsaturated carbocyclics, (2) can substituted pyridine, (3) can substituted bicyclic heterocycles, wherein benzene and 5-or 6-unit monocyclic heterocycles condenses, (4) can substituted bicyclic heterocycles, wherein pyridine ring and C5-6 monocycle carbocyclic fused or (5) can substituted bicyclic heterocycles, wherein pyridine ring and 5-or 6-unit monocyclic heterocycles condenses.R 2aBeing preferably can substituted benzene, indenes, indane, naphthalene, tetraline, indoles, isoindole, cumarone, isobenzofuran, thionaphthene, different thionaphthene, pyridine or naphthyridines ring, more preferably can substituted benzene, naphthalene, tetraline or pyridine ring.In this respect, for indenes, indane and tetrahydro-naphthalene nucleus, phenyl ring and Z or Z in these rings aIn conjunction with.
In addition, at R 2And R 2aShown in nuclear substituted " substituting group " be preferably the substituting group shown in the above-mentioned substituting group group 7.These substituting groups are preferably (1) can substituted C1-15 alkyl, (2) can substituted C1-15 alkenyl, (3) but protected hydroxyl, (4) can protected sulfydryl, (5) can protected amino, (6) can protected carbamyl, (7) can protected carboxyl, (8) can protected sulfo group, (9) can protected sulfino, (10) cyano group, (11) halogen atom, (12) can substituted cyclic groups or (13) can protected sulfo group.Described substituting group is (1) C1-6 alkyl more preferably; (2) C2-6 alkenyl; (3) unsubstituted hydroxyl or by can substituted C1-6 alkyl or have a hydroxyl (wherein especially being preferably C1-6 alkoxyl group and trifluoromethoxy) of the protecting group protection of the function of leaving away, (4) carboxyl or can substituted cyclic group by the carboxyl of C1-6 alkyl or benzyl protection, (6) halogen atom or (7).These substituting groups can be at R 2And R 2aBut shown in replace on 1-5 the position of substitution on the ring, especially be preferably 1,2 or 3 substituting group.Especially, work as R 2And R 2aDuring for 6-unit monocycle, especially preferred benzene or the pyridine ring that on (1) 2-position, (2) 3-position, (3) 4-position, (4) 2-and 4-position or (5) 2-, 4-and 6-position, replaces.
R 3Be preferably hydrogen atom, can substituted C1-6 alkyl (for example separately can substituted methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group or hexyl), perhaps can substituted C2-6 alkenyl (for example separately can substituted vinyl, propenyl, butenyl, pentenyl or hexenyl).
In formula (I-A-1) and (I-A-2) in the compound,
Figure A20048003294200391
Or More preferably
Figure A20048003294200402
Or
Figure A20048003294200403
It is unsubstituted wherein encircling A, perhaps is selected from following substituting group by 1 or 2 and replaces: halogen atom, CF 3, hydroxyl, carboxyl, (C1-6 alkoxyl group) carbonyl, cyano group, oxo and can be selected from halogen atom, CF separately 3C1-6 alkyl or C1-6 alkoxyl group with 1 or 2 replacement in the hydroxyl;
Ring B is not substituted, and perhaps being selected from can substituted C1-15 alkyl, the C2-15 alkenyl, but protected hydroxyl, cyclopropane, tetramethylene, halogen atom, CF 3But on one or more the position of substitution, replace with the substituting group in the cyano group.
In addition, formula (I-A) compound compound shown in the formula (I-A-3) more preferably:
Figure A20048003294200404
Wherein
Figure A20048003294200405
Expression
R 1AExpression can by 1 or 2 can be substituted the amino of C1-15 alkyl protection; G A1Represent hydrogen atom, halogen atom, CF independently of one another 3, OCF 3, hydroxyl, sulfydryl, carboxyl, (C1-6 alkoxyl group) carbonyl, carbamyl, nitro, cyano group or can be selected from halogen atom, CF by 1 or 2 separately 3The C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl group or the C1-6 alkylthio that replace with substituting group in the hydroxyl; G 2The expression hydrogen atom can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, but protected hydroxyl, cyclopropane, tetramethylene, pentamethylene, hexanaphthene, phenyl, halogen atom, CF 3Perhaps cyano group, all the other symbols have above-mentioned identical meanings, perhaps
Compound shown in the formula (I-A-4):
Figure A20048003294200411
Wherein Expression
Or
Figure A20048003294200414
R wherein 1aAExpression NR 8AR 9A, R wherein 8AAnd R 9AOne of the expression C1-15 alkyl that can be replaced by above-mentioned substituting group group 1, another be a hydrogen atom or can be by the C1-15 alkyl of above-mentioned substituting group group 1 replacement; G A2Represent hydrogen atom independently of one another, halogen atom, CF 3, OCF 3, hydroxyl, sulfydryl, carboxyl, (C1-6 alkoxyl group) carbonyl, carbamyl, nitro, cyano group, oxo perhaps can be selected from halogen atom, CF by 1 or 2 separately 3With C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl group or C1-6 alkylthio that substituting group in the hydroxyl replaces, all the other symbols have above-mentioned identical implication.
In the present invention, concrete compound is the following compound of describing among the embodiment.Preferred compound is
(1) N 5-(2-chloro-4-methoxyphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines,
(2) N 5-(2-chloro-4-methoxyphenyl)-N 7-(1-ethyl propyl)-6-methylpyrazole is [1,5-a] pyrimidine-5 also, the 7-diamines,
(3) N 5-(2-chloro-4-methoxyphenyl)-6-ethyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines,
(4) N 2-(2-chloro-4-methoxyphenyl)-N 2-ethyl-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines,
(5) N 5-(2-chloro-4-methoxyphenyl)-6-methoxyl group-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines,
(6) N 2-allyl group-N 2-(2-chloro-4-methoxyphenyl)-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines,
(7) 6-methyl-N 5-[2-methyl-4-(trifluoromethoxy) phenyl]-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines,
(8) N 7-butyl-N 5-(2-chloro-4-methoxyphenyl)-N 7-ethyl-6-methylpyrazole is [1,5-a] pyrimidine-5 also, the 7-diamines,
(9) N 5-(2-ethyl-4-aminomethyl phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines,
(10) 6-methoxyl group-N 5-(4-methyl-2-ethenylphenyl)-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines or
(11) N 5-(2-ethyl-4-aminomethyl phenyl)-6-methoxyl group-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines.
Except as otherwise noted, the present invention includes all isomer.For example, alkyl, alkenyl, alkynyl, alkoxyl group, alkylthio, alkylene base, alkenylene and alkylidene comprise straight chain and branched chain isomer.The present invention includes based on two keys, ring, isomer (the E of fused rings, Z, cis, trans), because of isomer (the R-configuration that exists one or more asymmetric carbons to cause, the S-configuration, α-configuration, beta configuration, enantiomer, diastereomer), optically-active compound (D with opticity, L, d, the l-configuration), polar compound (high polar compound by the chromatographic separation acquisition, low polar compound), equilibrium compound (equilibriumcompound), rotational isomer, the mixture that exists with any ratio, racemic mixture.
Except as otherwise noted, in the present invention, as it will be apparent to those skilled in the art,
Symbol Show that key is positioned at the another side of paper (α-configuration),
Symbol Show that key is positioned at the front of paper (beta configuration),
Symbol
Figure A20048003294200423
Show that key is α-configuration or beta configuration, and
Symbol
Figure A20048003294200424
Show that key is the mixture of α-configuration and beta configuration.
The compound of formula of the present invention (I) can be converted into non-toxic salt or corresponding pharmacologically acceptable salt by currently known methods.The present invention includes non-toxic salt or pharmacologically acceptable salt.Because pharmacologically acceptable salt is nontoxic, therefore be preferably water-soluble salt.
Suitable salt is for example salt of potassium, sodium, lithium of basic metal; Alkaline-earth metal is the salt of calcium, magnesium for example; Ammonium salt is tetramethyl ammonium, 4-butyl ammonium for example; Organic amine is the salt of triethylamine, methylamine, dimethylamine, cyclopentamine, benzylamine, phenylethylamine, piperidines, monoethanolamine, diethanolamine, trihydroxymethylaminomethane, Methionin, arginine, N-methyl D-glycosamine for example, and acid salt is inorganic acid salt example hydrochloric acid salt, hydrobromate, hydriodate, vitriol, phosphoric acid salt, nitrate for example; Organic acid salt is acetate, trifluoroacetate, lactic acid salt, tartrate, oxalate, fumarate, maleate, benzoate, Citrate trianion, mesylate, esilate, benzene sulfonate, tosylate, isethionate, glucuronate, gluconate for example.
The N-oxide compound is meant the oxidized compound of nitrogen in formula (I) and formula (I-A) compound.The compounds of this invention can be converted into the N-oxide compound by any known method.
In addition, in the present invention, also comprise the solvate of the N-oxide compound of the solvate of the non-toxic salt of the solvate of formula (I) compound, above-mentioned formula (I) or its corresponding pharmacologically acceptable salt and above-mentioned formula (I) compound.These solvates are preferably nontoxic and water miscible.The The suitable solvent thing comprises for example solvate of water, alcoholic solvent (ethanol etc.) etc.
The prodrug of formula (I) or formula (I-A) compound is meant in vivo by being converted into the compound of formula (I) or formula (I-A) compound with reactions such as enzyme, hydrochloric acid in gastric juice.The prodrug example of formula (I) or formula (I-A) compound comprises that amino in its Chinese style (I) or formula (I-A) compound is by acyl group, alkyl, (for example the amino in its Chinese style (I) or formula (I-A) compound is by petrosilane base (eicosanyl) for the compound that phosphoric acid etc. replace, alanyl (alanyl), penta aminocarboxyl, (5-methyl-2-oxo-1, the 3-Dioxol-4-yl) methoxycarbonyl ((5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonyl), tetrahydrofuran base, pyrrolidinomethyl (pyrrolidylmethyl), oxy acid methyl neopentyl, acetyl-o-methyl, the compound that the tertiary butyl etc. replace); The compound that hydroxyl in its Chinese style (I) or formula (I-A) compound is replaced by acyl group, alkyl, phosphoric acid, boric acid etc. (for example the hydroxyl in its Chinese style (I) or formula (I-A) compound replaced compound) by ethanoyl, palmitoyl, propionyl, valeryl, succinyl, fumaroyl, alanyl, dimethylamino methyl carbonyl etc.; The compound that carboxyl in its Chinese style (I) or formula (I-A) compound is modified by ester, acid amides etc. (for example the carboxyl in its Chinese style (I) or formula (I-A) compound is by the compound of modifications such as ethyl ester, isopropyl esters, phenylester, carboxymethyl ester, dimethylamino methyl ester, oxy acid methyl neopentyl ester, ethoxycarbonyl-oxygen base ethyl ester, phthalidyl ester (phthalidyl ester), (5-methyl-2-oxo-1,3-Dioxol-4-yl) methyl ester, cyclohexyloxy carbonyl ethyl ester, methyl nitrosourea) etc.The compound that carboxyl in preferred its Chinese style (I) or formula (I-A) compound is modified by methylol.These compounds can be according to the method preparation of itself.In addition, the prodrug of formula (I) or formula (I-A) compound can be hydrate or non-hydrate.
The preparation method of The compounds of this invention
The compounds of this invention can be by for example following method preparation.
Compound shown in the formula (I) can be by obtaining compound prepared in reaction shown in compound shown in the formula (II) and the formula (III); Compound shown in its Chinese style (I):
Figure A20048003294200441
Wherein all symbols have above-mentioned identical meanings;
Compound shown in the formula (II):
Figure A20048003294200442
Wherein Y represents leavings group (for example halogen atom, methylsulfonyl (mesyl), tosyl group (tosyl), mesyloxy (mesyloxy), tosyloxy (tosyloxy), trifluoro-methanesulfonyl oxy, methylthio group);
Compound shown in the formula (III):
H-Z-R 2 (III)
Wherein all symbols have above-mentioned identical meanings.
Above-mentioned reaction is known, and can by for example organic solvent (as N-Methyl pyrrolidone, dimethyl formamide, Virahol) or do not having under the situation of solvent in 50 ℃ to 250 ℃ down heating carry out.Heating is finished by water-bath, oil bath, sand-bath or microwave.
In addition, The compounds of this invention can also be by obtaining formula (I-1) compound with compound shown in compound shown in the formula (II) and the formula (III-1) reaction, then carries out the N-alkylated reaction again and prepare.
Compound shown in the formula (III-1):
H 2N-R 2 (III-1)
R wherein 2Has above-mentioned identical meanings;
Formula (I-1) compound:
Wherein all symbols have above-mentioned identical meanings.
The reaction of compound shown in compound shown in the formula (II) and the formula (III-1) is according to carrying out with the mode together of compound reacting phase shown in compound shown in the above-mentioned formula (II) and the formula (III).
Described N-alkylated reaction is known, can be by for example using corresponding alkyl halide (for example methyl-iodide) under 0-40 ℃, under the organic solvent of alkali (for example sodium hydride) (for example dimethylformamide, N,N-DIMETHYLACETAMIDE, 1,3-dimethyl-2-imidazolidone, tetrahydrofuran (THF)) exists, finish.
In addition, the ring in the compound shown in the formula (I)
Figure A20048003294200451
Be that also the compound of [3,4-d] pyrimidine ([1,2,5] thiadiazol[3,4-d] pyrimidine) can be by obtaining compound shown in its Chinese style (IV) with compound shown in the formula (IV) and thionyl chloride or thionyl aniline prepared in reaction for [1,2,5] thiazole:
Figure A20048003294200452
Wherein all symbols have above-mentioned identical meanings.
Above-mentioned reaction is known, can for example 50-120 ℃ organic solvent or do not have to carry out under the situation of solvent.
In addition, compound shown in the formula (I) can be by obtaining compound shown in the formula (XI) with compound prepared in reaction shown in compound shown in the formula (XI) and the formula (VI):
Wherein all symbols have above-mentioned identical meanings;
Compound shown in the formula (VI):
H-R 1 (VI)
R wherein 1Has above-mentioned identical meanings.
Above-mentioned reaction is known, can be for example room temperature to reflux temperature, in the presence of the organic solvent (for example tetrahydrofuran (THF), Virahol) of tertiary amine (for example triethylamine, diisopropyl ethyl amine) or room temperature to reflux temperature, do not have to carry out under the situation of solvent.
In addition, wherein Z be-formula (I) of CO-shown in compound can be by compound prepared in reaction shown in compound shown in the formula (XII) and the formula (XIII) be obtained compound shown in its Chinese style (XII):
Figure A20048003294200461
Wherein E represents the C1-4 alkyl, and all the other symbols have above-mentioned identical meanings;
Compound shown in the formula (XIII):
M-R 2 (XIII)
Wherein M is magnesium-Y a, Y wherein aExpression halogen atom or lithium; R 2Has above-mentioned identical meanings.
Above-mentioned reaction is known, can for example-40 ℃ carry out to 0 ℃ organic solvent (for example tetrahydrofuran (THF), diethyl ether).In addition, compound shown in the formula (XIII) can be by for example obtaining compound shown in the formula (XIV) and green reagent (for example methylmagnesium-bromide, bromination isopropyl-magnesium, phenyl-magnesium-bromide, butyllithium, phenyl lithium etc.) or alkyl lithium reagents (for example butyllithium, s-butyl lithium, tert-butyl lithium etc.) prepared in reaction; Compound shown in its Chinese style (XIV):
Y a-R 2 (XIV)
Wherein all symbols have above-mentioned identical meanings.
Compound shown in the formula (II) can be by for example preparation of the method shown in the following reaction scheme figure A, and wherein all symbols have above-mentioned identical meanings:
Option A
Figure A20048003294200462
Formula (IV) compound can be by for example preparation of the method shown in the following reaction scheme figure B, and wherein all symbols have above-mentioned identical meanings:
Option b
Formula V and (X) shown in compound itself be known, perhaps can prepare by currently known methods, for example 2,4-two chloro-6,7-dihydro-5H-cyclopentano [d] pyrimidine is described in J.Amer.Chem.Soc., 81, among the 3118-3111 (1959).
In addition, 4-chloro-2-(methylthio group) pyrazolo [1,5-a] [1,3,5] triazine can prepare by for example method shown in the following reaction scheme figure C:
Scheme C
In addition, 2-ethylmercapto group thieno-[3,2-d] pyrimidin-4-one can be by being described in the method preparation among the JP-A-3-17083, and 2-ethylmercapto group thieno-[2,3-d] pyrimidin-4-one can be by being described in United States Patent (USP) 4,146, the method preparation in 716.
In addition, 2,4-two chloro-5,7-dihydrofuran also [3,4-d] pyrimidine, 5,7-dichloro pyrazolo [1,5-a] pyrimidine, 5,7-two chloro-6-methylpyrazoles also [1,5-a] pyrimidine, 5, the 7-dichloro-imidazole is [1,2-a] pyrimidine and 5 also, 7-two chloro-6-Methylimidazoles also [1,2-a] pyrimidine can be respectively by being described in the method preparation among the embodiment of back.
Compound shown in the formula (XI) can be by obtaining compound prepared in reaction shown in compound shown in the formula V and the formula (III).In addition, it can also be by being described in the method preparation among the embodiment of back.
Compound shown in the formula (XII) can be by for example being described in the method preparation among the following proposal figure D, and wherein all symbols have above-mentioned identical meanings:
Scheme D
Figure A20048003294200481
In addition, other raw material among the present invention and each reagent itself are known, perhaps can prepare by currently known methods.
In each reaction in specification sheets of the present invention, reaction product can be by purification process purifying commonly used, the high performance liquid chromatography of for example air distillation or underpressure distillation, use silica gel or Magnesium Silicate q-agent, tlc, column chromatography, washing method, recrystallization method etc.Purifying can carry out after per step reaction or the reaction of a few step.
And starting raw material among the present invention and reagent itself are known, perhaps can prepare by currently known methods.
In each reaction in specification sheets of the present invention, reaction product can be by purification process purifying commonly used, high performance liquid chromatography, tlc or the column chromatography of for example normal atmosphere or underpressure distillation, use silica gel or Magnesium Silicate q-agent; Perhaps by washing or recrystallization.Purifying can carry out after per step reaction or series reaction.
Toxicity
The toxicity of formula of the present invention (I) and formula (I-A) compound is extremely low, confirms that therefore these compounds are safe as medicine.
Medicinal application
For CRF receptor-binding activity and antagonistic activity are provided, formula of the present invention (I) and formula (I-A) compound can be used for preventing and/or treating the disease by the CRF mediation, for example psychosis and neuropathy, digestion disease, tuberculosis, endocrinopathy, metabolic disease, cardiovascular disorder, dermatosis, Genito-urinary disease, ophthalmic diseases or musculoskeletal disease.
Specifically, can enumerate for psychosis and neuropathy, mood disorder for example, the depression of bringing out as depression, sporadic depression (single episode depression), recurrent depression (recurrent depression), postpartum depression, child abuse, bipolar disorder, premenstrual dysphoric disorder, contiguous involutional dysphoria disease, climacterium dysphoria disease; Anxiety disorder, as general anxiety disease, panic disorder, strong obsessive-compulsive disorder, phobic disorder is as acrophobia, claustrophobia, agoraphobia, social phobia; Adjustment disorder, as emotional injury, conduct disorder or performance simultaneously be in a bad mood that damage and the adjustment disorder of conduct disorder, uncomfortable (physical complaint), society are isolated, occupation blunt (occupational stagnant), scholastic attainment stagnation (stagnant academicachievement); With disease that stress be relevant, as the pain of the fever of the headache of the immunosuppression of posttraumatic stress disorder (PTSD), stress induction, stress induction, stress-induced, stress-induced, postoperative stress, the gastrointestinal tract disease of stress-induced, irritable bowel syndrome; The eating disorder disease is as anorexia nervosa, carousing eating disorder (binge eating disorder), nervous vomiting; By to spirituality material or symptom that its dependency is caused, as alcohol Withrawal symptom (alcoholic withdrawal symptom), alcohol dependence, habit-forming, the pharmacological dependence of medicine; OMD is as senile dementia, the multi infarct dementia of alzheimer's type; Schizophrenic disturbance; Scatterbrained hyperactivity disorder; Neurodegenerative disease is as Alzheimer's, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis; Pain; The convulsibility disease is as convulsions, muscle spasm; Paroxysmal disease (isodic diseases) is as epilepsy, outbreak, migraine; The disease of perhaps sleeping such as non-organic disease, the fibromyalgia sleep disease of sleeping.Can enumerate for digestion disease, for example slide ulcer; Inflammatory bowel disease such as ulcerative colitis, Crohn disease; Irritable bowel syndrome; Gastrointestinal tract disease; Diarrhoea; Constipation.Can enumerate for tuberculosis, for example asthma, bronchitis, chronic obstructive pulmonary disease, rhinallergosis.Can enumerate for endocrinopathy, for example dysthyroid, Cushing syndrome or antidiuretic hormone supersecretion syndromes.Can enumerate for metabolic disease, for example obesity or hypoglycemia.Can enumerate for cardiovascular disorder, for example hypertension, ischemic heart disease or cerebrovascular disease.Can enumerate for dermatosis, for example atopic dermatitis, contact dermatitis or psoriatic.Can enumerate for example urine disorder, frequent micturition or the urinary incontinence for the Genito-urinary disease.Can enumerate for ophthalmic diseases, for example uveitis.Can enumerate for musculoskeletal disease, for example chronic rheumatoid arthritis, osteoarthritis or osteoporosis.
Replenish and/or strengthen the effect that prevents and/or treats of The compounds of this invention in order to reach following purpose (1); (2) improve the kinetics of The compounds of this invention and/or the dosage that absorption reduces The compounds of this invention simultaneously; And/or (3) eliminate the side effect of The compounds of this invention, can use the associating medicament (combination drug) that obtains by association type (I) or formula (I-A) compound and other medicines.
The combination that contains formula (I) or formula (I-A) compound or its salt, its solvate or its prodrug and other medicines can be to be incorporated in these compositions the dosage form administration in the same preparation, also can be with independent dosage form administration.In the situation of various medicines with independent dosage form administration, they can be simultaneously or in the different time administration.For the latter, formula (I) or formula (I-A) compound or its salt, its solvate or its prodrug can administrations before other medicines.Perhaps, other medicines also can administration before formula (I) or formula (I-A) compound or its salt, its solvate or its prodrug.The method of these medicines of administration is identical or different.
Do not have concrete restriction for using above-mentioned combined preparation can demonstrate the various diseases that prevents and/or treats effect, they can be to treat and/or prevent effect behind those use formulas (I) or formula (I-A) compound or its salt, its solvate or its prodrug or the other medicines can access the disease of replenishing and/or strengthening.
Part by weight for formula (I) or formula (I-A) compound or its salt, its solvate or its prodrug and other medicines does not have concrete restriction.
Described other medicines are not limited to low molecular compound, can be macromolecule protein, polypeptide and polynucleotide (DNA, RNA, gene), antigen (antisense), bait (decoy), antibody or vaccine etc.The dosage of other medicines can suitably be regulated according to its clinical application.
Part by weight for formula (I) or formula (I-A) compound or its salt, its solvate or its prodrug and other medicines does not have concrete restriction, its can according to age for example, body weight, route of administration, treatment time length, the disease for the treatment of, symptom or take all factors into consideration above-mentioned several situation and suitably select.For example, described other medicines can use according to the 0.01-100% of formula (I) compound or its salt, its solvate or its prodrug weight.Described other medicines can be selected from following medicine similar and the inhomogeneity group according to arbitrary proportion and one or more and form the combination administration.
Other medicines in the combination of described formula (I) or formula (I-A) compound or its salt, its solvate or its prodrug have following medicine.If compound has the mechanism of action of the said medicine of being similar to, so not only comprise the compound that has been found that at present, also comprise the compound that will find from now on.
Be used for replenishing and/or enhanced (I) or formula (I-A) compound comprise antidepressive for the other medicines example that prevents and/or treats effect of mood disorder, for example tricyclic antidepressants, tetracyclic antidepressant, monoamine oxidase (MAO) inhibitor, serotonin and noradrenaline reuptake inhibitor (SNRI), selectivity serotonin reuptake inhibithors (SSRI), serotonin reuptake inhibithors; Incitantia, anxiolytic, antipsychotic, plastosome benzodiazepine acceptor (MBR) part, NK1 antagonist etc.
Be used for replenishing and/or enhanced (I) or formula (I-A) compound comprise anxiolytic for the other medicines example that prevents and/or treats effect of anxiety disorder, for example benzodiazepine anxiolytic, thieno-diaza  anxiolytic, non--the benzodiazepine anxiolytic, MBR part etc.
Be used for replenishing and/or enhanced (I) or formula (I-A) compound comprise gi tract promotor, 5-HT for the other medicines example that prevents and/or treats effect of irritable bowel syndrome 3Antagonist, 5-HT 4Agonist, anticholinergic drug, diarrhea, short purgatives, self-discipline conditioning agent, antidepressive, anxiolytic etc.
Can enumerate for antidepressive, tricyclic antidepressants for example, example hydrochloric acid amitriptyline (amitriptylinehydrochloride), imipramine hydrochloride (imipramine hydrochloride), clomipramine hydrochloride (clomipramine hydrochloride), Depresym (dosulepin hydrochloride), hydrochloric acid desipramine (nortriptyline hydrochloride), Leo 640 (lofepraminehydrochloride), trimipramine maleate (trimipramine maleate), amoxapine (amoxapine); Tetracyclic antidepressant, example hydrochloric acid maprotiline (maprotiline hydrochloride), Mianserin Hydrochloride (mianserin hydrochloride), toxilic acid setiptilinie (setiptiline maleate); The MAO inhibitor, example hydrochloric acid Safrazine (safrazine hydrochloride); SNRI, example hydrochloric acid Midalcipran (milnacipranhydrochloride), VENLAFAXINE HCL (venlafaxine hydrochloride); SSRI is as fluvoxamine maleate (fluvoxamine maleate), paroxetine hydrochloride (paroxetine hydrochloride), fluoxetine Hydrochloride (fluoxetine hydrochloride), hydrochloric acid citalopram (italopram hydrochloride); The serotonin reuptake inhibithors, example hydrochloric acid trazodone (trazodone hydrochloride).
Can enumerate for anxiolytic, benzodiazepine anxiolytic for example is as alprazolam (alprazolam), oxazepam (oxazepam), oxazolam (oxazolam), chlorine  azoles logical sequence (cloxazolam), dipotassium chlorine nitrogen  (clorazepate dipotassium), chlorine nitrogen  (chlordiazepoxide), diazepam (diazepam), tofisopam (tofisopam), triazolam (triazolam), prazepam (prazepam), fludiazepam (fludiazepam), flutazolam (flutazolam), flutoprazepam (flutoprazepam), Bromazepam (bromazepam), mexazolam (mexazolam), medazepam (medazepam), chlorine fluorine  ethyl ester (ethyl loflazepate), lorazepam (lorazepam); Thieno-diaza  anxiolytic is as etizolam (etizolam), clotiazepam (clotiazepam); Non--the benzodiazepine anxiolytic, as citric acid Tandospirone (tandospirone citrate) and hydrazine hydrochloride (hydroxylzine hydrochloride).
Can enumerate for incitantia, for example methylphenidate hydrochloride (methylphenidate hydrochloride) and pemoline (pemoline).
Can enumerate for antipsychotic, for example Sulpiride (sulpiride), trazodone hydrochloride, serotonin-dopamine antagonist such as risperidone (risperidone), hydrochloric acid Perospirone hydrate (perospironehydrochloride hydrate), fumaric acid sulphur quinoline flat (quetiapine fumarate) and olanzapine (olanzapine).
Can enumerate for gi tract promotor, for example Trimebutine Maleate (trimebutine maleate) and polycarbophil calcium (polycarbophil calcium).
For 5-HT 3Antagonist can be enumerated, for example Lotronex (alosetron).
For 5-HT 4Agonist can be enumerated, for example Tegaserod (tegaserod), cisapride (cisapride) and citric acid mosapride (mosapride citrate).
The part by weight of formula (I) or formula (I-A) compound and other medicines there is no concrete restriction.
Can use any combination of two or more other medicines.
In addition, the other medicines that prevent and/or treat effect that are used for additional and/or enhanced (I) or formula (I-A) compound not only comprise present known drug, also comprise according to the medicine that will find after the above-mentioned mechanism.
To achieve these goals, the combination of described formula (I) or formula (I-A) compound, its non-toxic salt or formula (I) compound and other medicines usually can whole body administration or topical, normally by oral or parenterai administration.
Institute's application dosage depends on age for example, body weight, symptom, required result of treatment, route of administration and treatment time length.For the adult, everyone dosage is generally: 1mg to 1000mg, and oral administration reaches for several times every day; 0.1mg to 100mg, parenterai administration reaches for several times every day; Perhaps by 1-24 every day hour successive administration of vein.
As mentioned above, used dosage depends on the different state of an illness.Therefore, existence may be used the situation of the dosage that is below or above above-mentioned specified range.
In order to use formula of the present invention (I) compound, the external preparation of usefulness solid preparation and interior usefulness oral liquid and injection formulations, parenterai administration, suppository, eye drops, nasal drop, inhalation etc. in can using.
In comprise tablet, pill, capsule, powder, granule etc. with oral solid formulation.Capsule comprises hard capsule and soft capsule.Tablet comprises sublingual tablet, buccal tablet (oral patch) and Orally disintegrating tablet.
Prepare by the common dosage forms method with solid preparation in above-mentioned, use undressed active substance, perhaps one or more active substances and vehicle (lactose, N.F,USP MANNITOL, glucose, Microcrystalline Cellulose, starch etc.), tackiness agent (hydroxypropylcellulose, Polyvinylpyrolidone (PVP), neusilin (magnesiummetasilicate aluminate) etc.), disintegrating agent (calcium celluloseglycolate (calcium celluloseglycolate) etc.), lubricant (Magnesium Stearate etc.), stablizer, solubilizing agent (L-glutamic acid, aspartic acid etc.) mixture.If necessary, it can be used Drug coating (sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate etc.) dressing.Can dressing two-layer or more multi-layered.In addition, by absorbable material for example the capsule made of gelatin also fall in the above-mentioned scope.
In comprise pharmaceutically acceptable solution (pharmaceutically acceptableaqueous solution), suspensoid, emulsion, syrup, elixir etc. with oral liquid.By with the dissolving of one or more active substances, suspending or being emulsifiable in the thinner commonly used (purified water, ethanol or its mixture etc.) prepares the aforesaid liquid preparation.This class I liquid I formulation can also further contain some additive for example wetting Agent for Printing Inks, suspension agent, emulsifying agent, sweeting agent, seasonings, spices, sanitas, buffer reagent etc.
The external preparation of parenterai administration comprises ointment (ointment), gelifying agent, creme (cream), hot compress agent (fomentation), paster (parch), liniment (liniment), propellant (atomized agent), inhalation, spray, eye drops and nasal drop etc.Above-mentioned preparation contains one or more active substances, can prepare by well-known method or formulation method commonly used.
Except thinner commonly used, propellant, inhalation and spray can also contain stablizer for example sodium bisulfite, the buffer reagent for example isotonic agent such as sodium-chlor, Trisodium Citrate or the citric acid that are used to provide isotonicity.The inhalation of parenterai administration comprises aerosol, sucks powder or inhalant liquid body preparation.Can or be suspended in water or other the suitable matrix this class inhalant liquid body preparation dissolving during use.Inhalation can be according to the method preparation of knowing.For example, if necessary, the inhalant liquid body preparation can prepare by selecting suitable preservatives (benzalkonium chloride, p-Hydroxybenzoate (paraben) etc.), tinting material, buffer reagent (sodium phosphate, sodium-acetate etc.), isotonic agent (sodium-chlor, concentrated glycerin etc.), thickening material (carboxy vinyl polymer etc.), absorption enhancer etc.
If necessary, sucking powder (powder for inhalation) can prepare by selecting suitable lubricant (stearic acid and salt thereof etc.), tackiness agent (starch, dextrin etc.), vehicle (lactose, Mierocrystalline cellulose etc.), tinting material, sanitas (benzalkonium chloride, p-Hydroxybenzoate etc.), absorption enhancer etc.
When using the inhalant liquid body preparation, use sprinker (spray bottle (atomizer), atomizer (nebulizer)) usually.When using suction powder, be used for the inhalation device of powder usually.
The method for preparing spray for example is described in detail in the U.S. Patent number 2,868,691 and U.S. Patent number 3,095,355.
The injection of parenterai administration comprises solution, suspensoid, emulsion and the solid injection that dissolved or suspended before using.Above-mentioned injection is by dissolving one or more active substances, suspend or be emulsifiable in the water and use.Solvent comprises for example injects distilled water, physiological saline, vegetables oil, alcohols for example propylene glycol, polyoxyethylene glycol and ethanol and composition thereof.Injection can also further contain stablizer, solubility promoter (L-glutamic acid, aspartic acid, polysorbate80 (registered trademark) etc.), outstanding mixture, emulsifying agent, soothing agent, buffer reagent, sanitas etc.This class injection can or use aseptic operation to prepare by step sterilization in the end.Perhaps can also prepare for example freeze-drying prods of sterile solid product, then before use in Injectable sterile distilled water or other solvent with its sterilization or dissolving.
Other composition of parenterai administration comprises suppository that contains one or more active substances and the vaginal suppository (pessaries) that is used for vagina administration, and they can prepare according to the conventional formulation method.
The invention effect
Compound of the present invention has CRF receptor-binding activity and intensive antagonistic activity.
Embodiment
Below with reference to following embodiment the present invention is described in more detail, certainly this and do not mean that the present invention is subjected to the restriction of these embodiment.
Relate to the solvent that provides in the bracket of chromatographic separation and TLC and be meant employed various eluting solvent or developping agent, its ratio is represented with volume ratio.
Relate to the solvent that provides in the bracket of NMR and be meant all kinds of SOLVENTS that uses in the measurement.
The compound title of using in the specification sheets of the present invention is according to ACD/Name TM(version 6.00, Advanced Chemistry Development Inc.) name.
Embodiment 1
5, the 7-dihydrofuran also [3,4-d] pyrimidine-2,4 (1H, 3H)-diketone:
In 4-oxo-tetrahydrofuran-3-carboxylate methyl ester (18.30g), add urea (11.44g), methyl alcohol (100mL) and concentrated hydrochloric acid (5mL).Mixture heating up refluxed 2 hours.Resulting suspension stirred in ice bath 15 minutes.Behind the precipitation filtration under diminished pressure, wash with water (20mL * 2 time).In resulting precipitation, add 2mol/L aqueous sodium hydroxide solution (100mL) and water (30mL).Mixture heating up refluxed 1 hour.Drip concentrated hydrochloric acid in the reaction soln in ice bath.Behind the precipitation filtration under diminished pressure, precipitation water and washing with acetone, drying under reduced pressure obtains title compound (15.7g), and it has following physical parameter:
TLC:Rf0.32 (methyl alcohol: ethyl acetate=10: 1);
1H-NMR(300MHz，DMSO-d 6)：δ11.23，11.44-11.10，11.00，4.70。
Embodiment 2
2,4-two chloro-5,7-dihydrofuran are [3,4-d] pyrimidine also:
Under argon gas atmosphere, phenyl phosphonyl chloride (16.1mL) is added in the compound (15.7g) of embodiment 1 preparation.Mixture stirred 6 hours down at 135 ℃, stirred 30 minutes down at 165 ℃ again.After the reaction mixture cooling, it is splashed into to frozen water (100mL).In mixture solution, add ethyl acetate (100mL).Filtration under diminished pressure is removed insoluble substance, washs with ethyl acetate then.After filtrate and washings merged, the mixture jolting also separated.Organic layer washs with saturated sodium bicarbonate and saturated sodium-chloride successively, anhydrous sodium sulfate drying, and concentrating under reduced pressure final vacuum drying obtains title compound (3.66g), and it has following physical parameter:
TLC:Rf0.60 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ5.17，5.09。
Embodiment 3
2-chloro-4-N, N-two-n-propyl amino-5,7-dihydrofuran be [3,4-d] pyrimidine also:
Under argon gas atmosphere, tetrahydrofuran (THF) (4mL) is added in the compound (757mg) of embodiment 2 preparations, mixture stirs in ice bath.In mixture, drip triethylamine (1.4mL) and di-n-propyl amine (1.3mL).Mixture at room temperature stirred 4 hours.In 10% aqueous citric acid solution that the reaction mixture impouring was cooled off, mixture ethyl acetate extraction subsequently.Extraction liquid is successively with saturated aqueous solution of sodium bicarbonate, saturated sodium-chloride water solution washing, anhydrous sodium sulfate drying and concentrating under reduced pressure.Resulting resistates by the silica gel column chromatography purifying (hexane: ethyl acetate=9: 1) obtain title compound (784mg), it has following physical parameter:
TLC:Rf0.71 (normal hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ5.19，4.86，3.32，1.62，0.94。
Embodiment 4
N 2-(2-chloro-4-methoxyphenyl)-N 4, N 4-dipropyl-5,7-dihydrofuran be [3,4-d] pyrimidine-2 also, the 4-diamines:
The compound (300mg) and the 2-chloro-4-anisidine (554mg) of embodiment 3 preparations were reacted 60 minutes by microwave (90 watts, 120 ℃).Reaction mixture is cooled to room temperature, in the mixing solutions of impouring ethyl acetate then/saturated aqueous solution of sodium bicarbonate, and the mixture ethyl acetate extraction.Extraction liquid water and saturated aqueous sodium chloride washing, dried over mgso and concentrating under reduced pressure.Resulting resistates by the silica gel column chromatography purifying (toluene: ethyl acetate=20: 1 → hexane: ethyl acetate=8: 1 → 6: 1) obtain title compound (385mg) into buff powder, it has following physical parameter:
TLC:Rf0.29 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ?0.93，1.59，3.30，3.79，4.82，5.18，6.81，6.94，7.03，8.28。
Embodiment 4 (1)-4 (21)
Use respective compound, prepare following compound according to the step identical with series reaction among the embodiment 4.
Embodiment 4 (1)
N 2-(2-chloro-4-methoxyphenyl)-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
TLC:Rf0.18 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ0.92，1.63，2.00，2.74，2.97，3.43，3.78，6.79，6.93，6.98，8.34。
Embodiment 4 (2)
N 2-(2-chloro-4-methoxyphenyl)-N 4-(1-ethyl propyl)-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
TLC:Rf0.23 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ0.94，1.58，2.08，2.59，2.80，3.78，4.02，6.81，6.93，7.07，8.46。
Embodiment 4 (3)
N 2-(5,7-dimethyl-2,1,3-benzothiazole-4-yl)-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
TLC:Rf0.21 (hexane: ethyl acetate=1: 2);
1H-NMR(300MHz，CDCl 3)：δ0.64，1.31，1.99，2.41，2.68，2.73，2.91，3.14，6.68，7.28。
Embodiment 4 (4)
N 2-(5,7-methyl-2,1,3-benzothiazole-4-yl)-N 4-(1-ethyl propyl)-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
TLC:Rf0.18 (hexane: ethyl acetate=1: 2);
1H-NMR(300MHz，CDCl 3)：δ0.75，1.37，2.06，2.40，2.55?2.68，2.76，3.68，3.92，6.87，7.28。
Embodiment 4 (5)
N 2-(2-chloro-4-methoxyphenyl)-N 4-(1-ethyl propyl)-5,7-dihydrofuran be [3,4-d] pyrimidine-2 also, the 4-diamines:
TLC:Rf0.15 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.94，1.58，3.79，4.03，4.85，4.98，6.82，6.94，7.10，8.33。
Embodiment 4 (6)
N 2-(5,7-dimethyl-2,1,3-benzothiazole-4-yl)-N 4, N 4-dipropyl-5,7-dihydrofuran be [3,4-d] pyrimidine-2 also, the 4-diamines:
TLC:Rf0.30 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ0.69，1.37，2.41，2.69，3.05，4.79，5.14，6.75，7.29。
Embodiment 4 (7)
N 2-(5,7-dimethyl-2,1,3-benzothiazole-4-yl)-N 4-(1-ethyl propyl)-5,7-dihydrofuran be [3,4-d] pyrimidine-2 also, the 4-diamines:
TLC:Rf0.28 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ0.80，1.40，2.40，2.69，3.60，4.00，4.80，4.94，6.97，7.29。
Embodiment 4 (8)
N 5-(2-chloro-4-methoxyphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.48 (hexane: ethyl acetate=8: 1);
1H-NMR(300MHz，CDCl 3)：δ0.86，1.48，2.35，3.35，3.81，6.23，6.91，6.98，7.86，8.62。
Embodiment 4 (9)
N 5-(2-chloro-4-methoxyphenyl)-N 7-(1-ethyl propyl)-6-methylpyrazole is [1,5-a] pyrimidine-5 also, the 7-diamines:
TLC:Rf0.38 (hexane: ethyl acetate=8: 1);
1H-NMR(300MHz，CDCl 3)：δ0.98，1.66，2.30，3.72，3.80，5.78，6.16，6.74，6.90，6.97，7.81，8.50。
Embodiment 4 (10)
N 5-(2-chloro-4-methoxyphenyl)-6-methyl-N 7, N 7-dipropyl [1,2,4] triazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.14 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ0.85，1.49，2.33，3.37，3.80，6.89，6.97，7.11，8.12，8.78。
Embodiment 4 (11)
N 5-(2-chloro-4-methoxyphenyl)-N 7-(1-ethyl propyl) pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.24 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ0.97，1.66，3.29，3.82，5.29，5.98，6.13，6.51，6.87，6.99，7.83，7.93。
Embodiment 4 (12)
N 5-(2-chloro-4-methoxyphenyl)-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.30 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ0.90，1.64，3.58，3.81，5.36，6.13，6.48，6.86，6.99，7.84，7.94。
Embodiment 4 (13)
N 5-(2-chloro-4-methoxyphenyl)-N 7-(1-ethyl propyl)-6-methyl [1,2,4] triazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.21 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ0.97，1.65，2.29，3.79，3.85，5.33，6.87，6.95，8.07，8.67。
Embodiment 4 (14)
N 5-(2-chloro-4-methoxyphenyl)-N 7, N 7-dipropyl [1,2,4] triazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.16 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ0.92，1.69，3.64，3.82，5.33，6.66，6.86，7.00，7.94，8.07。
Embodiment 4 (15)
N 5-(2-chloro-4-methoxyphenyl)-N 7-(1-ethyl propyl) [1,2,4] triazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.14 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ0.97，1.67，3.29，3.82，5.35，5.71，6.73，6.87，7.00，7.97，8.10。
Embodiment 4 (16)
N 7-(2-chloro-4-methoxyphenyl)-N 5-(1-ethyl propyl) imidazo [1,2-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.15 (ethyl acetate: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ0.97，1.70，3.27，3.81，4.42，5.33，6.72，6.84，6.97，7.13，7.43，8.17。
Embodiment 4 (17)
N 7-(2-chloro-4-methoxyphenyl)-N 5, N 5-dipropyl imidazo [1,2-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.50 (ethyl acetate: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ0.91，1.64，3.18，3.81，5.65，6.73，6.86，6.97，7.21，7.42，8.32。
Embodiment 4 (18)
N 7-(2-chloro-4-methoxyphenyl)-N 5-(1-ethyl propyl)-6-Methylimidazole is [1,2-a] pyrimidine-5 also, the 7-diamines:
TLC:Rf0.32 (ethyl acetate: methyl alcohol=9: 1);
1H-NMR(300MHz，CDCl 3)：δ0.98，1.58，2.23，3.51，3.65，3.78，6.86，6.92，6.94，7.26，7.40，8.87。
Embodiment 4 (19)
N 7-(2-chloro-4-methoxyphenyl)-6-methyl-N 5, N 5-dipropyl imidazo [1,2-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.42 (methylene dichloride: methyl alcohol=9: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.52，2.29，3.18，3.81，6.90，6.96，7.03，7.27，7.40，8.95。
Embodiment 4 (20)
N 2-(2,4 dichloro benzene base)-3-methyl-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [b] pyridine-2, the 4-diamines:
TLC:Rf0.57 (hexane: ethyl acetate=9: 1);
1H-NMR(300MHz，CDCl 3)：δ8.35，7.34，7.17，6.70，3.00，2.92-2.83，2.20，2.06，1.43，0.84。
Embodiment 4 (21)
N 2-(2,4 dichloro benzene base)-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
TLC:Rf0.15 (benzene: ethyl acetate=9: 1);
1H-NMR(300MHz，CDCl 3)：δ8.56，7.34，7.23，7.17，3.46，2.98，2.76，2.01，1.72-1.57，0.94。
Embodiment 5
N 2-(2-chloro-4-methoxyphenyl)-N 2-methyl-N 4, N 4-dipropyl-5,7-dihydrofuran be [3,4-d] pyrimidine-2 also, the 4-diamines:
Under argon gas atmosphere, in ice bath to the N of the compound (225mg) of embodiment 4 preparation, add successively in dinethylformamide (6mL) solution sodium hydride (60% oil dispersion, 36mg) and methyl-iodide (0.075mL).Mixture at room temperature stirred 1 hour.Add ammonium chloride saturated aqueous solution in reaction mixture, mixture extracts with hexane/ethyl acetate (1/1) then.Organic layer is water and saturated aqueous sodium chloride washing successively, dried over mgso and concentrating under reduced pressure.Resulting resistates by the silica gel column chromatography purifying (hexane: ethyl acetate=8: 1 → 4: 1) obtain title compound (224mg) into buff powder, it has following physical parameter:
TLC:Rf0.30 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ0.74，1.42，3.04，3.37，3.81，4.80，5.13，6.82，6.99，7.18。
Embodiment 5 (1)-5 (9)
Use the compound of embodiment 4 (1), 4 (3), 4 (7), 4 (8), 4 (10), 4 (12), 4 (14), 4 (17) or 4 (21) preparations, prepare following compound according to the step identical with series reaction among the embodiment 5.
Embodiment 5 (1)
N 2-(2-chloro-4-methoxyphenyl)-N 2-methyl-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
TLC:Rf0.20 (toluene: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.70，1.40，1.95，2.75，2.90，3.14，3.37，3.80，6.80，6.98，7.18。
Embodiment 5 (2)
N 2-(5,7-dimethyl-2,1,3-benzothiazole-4-yl)-N 2-methyl-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
TLC:Rf0.49 (hexane: ethyl acetate=1: 2);
1H-NMR(300MHz，DMSO-d 6)：δ0.56，1.21，1.89，2.25，2.58，2.64，2.87，3.07，3.40，7.41。
Embodiment 5 (3)
N 2-(5,7-dimethyl-2,1,3-benzothiazole-4-yl)-N 2-methyl-N 4, N 4-dipropyl-5,7-dihydrofuran be [3,4-d] pyrimidine-2 also, the 4-diamines:
TLC:Rf0.48 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，DMSO-d 6)：δ0.58，1.24，2.27，2.65，2.96，3.42，4.60，5.03，7.42。
Embodiment 5 (4)
N 5-(2-chloro-4-methoxyphenyl)-N 5, 6-dimethyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.40 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ0.78，1.40，1.55，3.31，3.81，6.32，6.71，6.82，7.03，7.90。
Embodiment 5 (5)
N 5-(2-chloro-4-methoxyphenyl)-N 5, 6-dimethyl-N 7, N 7-dipropyl [1,2,4] triazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.30 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ0.77，1.41，1.51，3.30，3.37，3.81，6.73，6.86，7.02，8.16。
Embodiment 5 (6)
N 5-(2-chloro-4-methoxyphenyl)-N 5-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.30 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ0.77，1.53，3.41，3.85，4.78，6.15，6.89，7.06，7.23，7.81。
Embodiment 5 (7)
N 5-(2-chloro-4-methoxyphenyl)-N 5-methyl-N 7, N 7-dipropyl [1,2,4] triazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.28 (toluene: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ0.78，1.55，3.45，3.85，4.75，6.90，7.07，7.23，8.04。
Embodiment 5 (8)
N 7-(2-chloro-4-methoxyphenyl)-N 7-methyl-N 5, N 5-dipropyl imidazo [1,2-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.36 (ethyl acetate: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ0.80，1.48，2.97，3.45，3.86，5.09，6.89，7.06，7.12，7.21，7.37。
Embodiment 5 (9)
N 2-(2,4 dichloro benzene base)-N 2-methyl-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
TLC:Rf0.26 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ7.44，7.26-7.19，3.38，3.14，2.90，2.75，1.96，1.41，0.72。
Embodiment 6
N 2-(2-chloro-4-methoxyphenyl)-N 4-(1-ethyl propyl)-N 2-methyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
With 2-chloro-4-methoxyl group-methylphenylamine (150mg) and 2-chloro-4-(1-ethyl propyl amino)-6, the mixture of 7-dihydro-5H-cyclopentano [d] pyrimidine (322mg) heated 9 hours down at 120 ℃, heated 6 hours down at 160 ℃ then.Reaction mixture is cooled to room temperature, crude product by the silica gel column chromatography purifying (toluene: ethyl acetate=1: 1 → 1: 3) obtain title compound (147mg) into dun oily matter, it has following physical parameter:
TLC:Rf0.21 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ0.76，1.37，2.04，2.52，2.77，3.37，3.56，3.81，6.81，6.98，7.18。
Embodiment 6 (1)
N 5-(2-chloro-4-methoxyphenyl)-N 7-(1-ethyl propyl)-N 5-methyl [1,2,4] triazolo [1,5-a] pyrimidine-5, the 7-diamines:
Use corresponding compounds, prepare following compound according to the step identical with series reaction among the embodiment 6.
TLC:Rf0.23 (toluene: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ0.85，1.51，3.00，3.46，3.87，4.78，5.50，6.91，7.09，7.24，8.07。
Embodiment 7
2-(methylthio group)-N, N-dipropyl pyrazolo [1,5-a] [1,3,5] triazine-4-amine:
Under 0 ℃, in tetrahydrofuran (THF) (5.0mL) solution of 4-chloro-2-(methylthio group) pyrazolo [1,5-a] [1,3,5] triazines (1.0g), add triethylamine (1.0mL) and di-n-propylamine (1.0mL).Mixture at room temperature stirs and spends the night.Reaction soln filters by diatomite (celite), concentrating under reduced pressure.Resistates by the silica gel column chromatography purifying (hexane: ethyl acetate=10: 1) obtain title compound (1.1g) into white powder, it has following physical parameter:
TLC:Rf0.85 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.95，1.75，2.52，3.94，6.13，7.83。
Embodiment 8
2-(methylsulfonyl)-N, N-dipropyl pyrazolo [1,5-a] [1,3,5] triazine-4-amine:
Add metachloroperbenzoic acid (1.1g) in methylene dichloride (11mL) solution of the compound (660mg) that embodiment 7 prepares, mixture at room temperature stirred 4 hours.In reaction mixture, add sodium sulfite aqueous solution.The mixture dichloromethane extraction.Organic layer washs with 2N aqueous sodium hydroxide solution and saturated aqueous sodium chloride, and anhydrous magnesium sulfate drying and concentrating under reduced pressure obtain the title compound (590mg) into white powder, and it has following physical parameter:
TLC:Rf0.62 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ0.98，1.80，3.27，3.74，4.30，6.54，8.02。
Embodiment 9
N 2-(2-chloro-4-methoxyphenyl)-N 4, N 4-dipropyl pyrazolo [1,5-a] [1,3,5] triazine-2, the 4-diamines:
Figure A20048003294200651
Use the compound (250mg) and the 2-chloro-4-anisidine (280mg) of embodiment 8 preparations, prepare title compound (70mg) into white powder according to the step identical with series reaction among the embodiment 6, it has following physical parameter:
TLC:Rf0.68 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.94，1.74，3.78，3.89，5.96，6.83，6.90，6.94，7.77，8.22。
Embodiment 10
N 2-(2-chloro-4-methoxyphenyl)-N 2-methyl-N 4, N 4-dipropyl pyrazolo [1,5-a] [1,3,5] triazine-2, the 4-diamines:
Use the compound (42mg) of embodiment 9 preparations, prepare title compound (41mg) into the whitening compound according to the step identical with series reaction among the embodiment 5.
TLC:Rf0.67 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.75，1.53，3.57，5.96，6.81，6.98，7.17，7.71。
Embodiment 11
2,6-two chloro-5-nitro-N, N-dipropyl pyrimidine-4-amine:
Under 0 ℃,, drip di-n-propyl amine (1.03mL) and triethylamine (1.04mL) in tetrahydrofuran (THF) (20mL) solution of 6-three chloro-5-nitro-pyrimidines (1.7g) to 2,4.Mixture stirred 2 hours.Reaction mixture dilutes with ethyl acetate.Solution with water after the dilution and saturated aqueous sodium chloride washing, anhydrous magnesium sulfate drying and concentrating under reduced pressure obtain title compound, and it has following physical parameter:
TLC:Rf0.50 (hexane: ethyl acetate=20: 1);
1H-NMR(300MHz，CDCl 3)：δ3.36，1.61，0.91。
Embodiment 12
2-chloro-5-nitro-N, N-dipropyl pyrimidine-4, the 6-diamines:
Add ethanol (7mL) solution of ammoniacal liquor in ethanol (15mL) solution of the compound (2.26g) that embodiment 11 prepares, mixture at room temperature stirred 2 hours then.Reaction mixture dilutes with ethyl acetate.Solution with water after the dilution and saturated aqueous sodium chloride washing, anhydrous sodium sulfate drying and concentrating under reduced pressure.Resistates by the silica gel column chromatography purifying (hexane: ethyl acetate=8: 1) obtain title compound (534mg) into yellow crystal, it has following physical parameter:
TLC:Rf0.24 (hexane: ethyl acetate=9: 1);
1H-NMR(300MHz，CDCl 3)：δ3.37，1.62，0.90。
Embodiment 13
N 2-(2-chloro-4-methoxyphenyl)-N 4, N 4-dipropyl-N 2-methyl-5-nitro pyrimidine-2,4, the 6-triamine:
Use the compound (534 mg) and N-(2-chloro-4-the methoxyphenyl)-N-methylamine (1.3g) of embodiment 12 preparations, prepare title compound (691mg) into light yellow oil according to the step identical with series reaction among the embodiment 6.
TLC:Rf0.33 (hexane: ethyl acetate=4: 1).
Embodiment 14
N 2-(2-chloro-4-methoxyphenyl)-N 4, N 4-dipropyl-N 2-methylpyrimidine-2,4,5, the 6-tetramine:
Under 50 ℃, in ethanol (12mL) solution of the compound (440mg) that embodiment 13 prepares, add entry (10mL), add V-Brite B (1.5g) again.Mixture stirred 30 minutes.After the reaction mixture cooling, dilute with ethyl acetate.Solution with water after the dilution and saturated aqueous sodium chloride washing, dried over mgso and concentrating under reduced pressure obtain the title compound (443mg) into brown solid, and it has following physical parameter:
TLC:Rf0.33 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ7.16，6.99，6.84，6.01，3.81，3.40，3.23，1.47，0.75。
Embodiment 15
N 5-(2-chloro-4-methoxyphenyl)-N 5-methyl-N 7, N 7-dipropyl [1,2,5] thiazole is [3,4-d] pyrimidine-5 also, the 7-diamines:
Thionyl chloride (5.0mL) is added in the compound (437mg) of embodiment 14 preparations, mixture refluxed 2.5 hours.After the reaction mixture cooling, in the impouring frozen water.Solution is used ethyl acetate extraction by adding the saturated aqueous solution of sodium bicarbonate alkalization.Organic layer washs anhydrous magnesium sulfate drying and concentrating under reduced pressure with saturated aqueous solution of sodium bicarbonate and saturated aqueous sodium chloride.Resistates by the silica gel column chromatography purifying (hexane: ethyl acetate=5: 1) obtain title compound (344mg) into light yellow solid, it has following physical parameter:
TLC:Rf0.45 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，DMSO-d 6)：δ0.77，1.55，3.74，6.96，7.10，7.30。
Embodiment 16
N 2-mesityl-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2,4-diamines (N 2-mesityl-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopenta[d] pyrimidine-2,4-diamine):
According to embodiment 3 (use by the compound for preparing in the series reaction of utilizing respective compound in embodiment 1 → embodiment 2) → embodiment 4 (use corresponding compounds) in the identical step of series reaction, prepare title compound, it has following physical parameter:
TLC:Rf0.34 (ethyl acetate: methyl alcohol=100: 1);
1H-NMR(300MHz，CDCl 3)：δ0.68，1.39，1.98，2.19，2.26，2.71，2.91，3.16，5.85，6.87。
Embodiment 17
2-[(2-chloro-4-methoxyphenyl) amino]-4-(dipropyl amino)-6,7-dihydro-5H-cyclopentano [b] pyridine-3-nitrile:
According to embodiment 3 (use by the compound for preparing in the series reaction of utilizing respective compound in embodiment 1 → embodiment 2) → embodiment 4 in the identical step of series reaction, prepare title compound, it has following physical parameter:
TLC:Rf0.68 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ0.89，1.64，1.78，2.00，2.66，3.51，3.77，6.25，6.73，6.92，6.99。
Embodiment 18
N 2-(2-chloro-4-methoxyphenyl)-3-methyl-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [b] pyridine-2, the 4-diamines:
According to embodiment 3 (use by the compound for preparing in the series reaction of utilizing respective compound in embodiment 1 → embodiment 2) → embodiment 4 in the identical step of series reaction, prepare title compound, it has following physical parameter:
TLC:Rf0.61 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ8.28，6.94，6.82，6.48，3.77，2.93-3.04，2.80-2.92，2.20，1.97-2.12，1.34-1.52，0.84。
Embodiment 19
The 6-methylpyrazole is [1,5-a] pyrimidine-5 also, the 7-glycol:
Under argon gas atmosphere, sodium (6.92g) is added in the ethanol (250mL) bit by bit, stir this ethanolic soln and stir up to sodium dissolving fully at room temperature.In above-mentioned solution, drip ethanol (20mL) solution and the methyl-malonic ester (52mL) of 3-amino-pyrazol (25.0g) successively.Mixture refluxes down at 90 ℃.Reaction mixture is cooled to room temperature, mixes vacuum filtration.Add cold 5N hydrochloric acid (70mL) dissolving in the solid.Precipitation is collected by filtering, and vacuum-drying obtains title compound (36.7g).
Embodiment 20
5,7-two chloro-6-methylpyrazoles are [1,5-a] pyrimidine also:
Under argon gas atmosphere, successively with phosphoryl chloride (102g) and N, N-Diethyl Aniline (8.4g) drops in the compound of embodiment 19 preparations.Mixture refluxed 4 hours down at 150 ℃.In addition, with N, N-Diethyl Aniline (8.4g) drops in the said mixture, and mixture refluxes under uniform temp.Reaction mixture is cooled to concentrating under reduced pressure after the room temperature.Resistates is dissolved in the frozen water.In solution, add sodium bicarbonate aqueous solution.In the mixture and after pass through diatomite filtration.Filtrate is used twice of ethyl acetate extraction.Organic layer is water and normal saline solution washing successively, and dried over mgso is filtered the back concentrating under reduced pressure.Resulting resistates obtains title compound (22.2g) by silica gel column chromatography purifying (hexane: ethyl acetate=12: 1,10: 1,8: 1,6: 1), and it has following physical parameter:
TLC:Rf0.46 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ2.56，6.70，8.16。
Embodiment 21
N 5-(4-methoxyl group-2-aminomethyl phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
Use 5,7-two chloro-6-methyl-pyrazolo [1,5-a] pyrimidines prepare title compound according to the step identical with series reaction in embodiment 3 → respective embodiments 4, and it has following physical parameter:
TLC:Rf0.29 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.49，2.28，2.29，3.34，3.81，6.04，6.14，6.81，7.70，7.81。
Embodiment 21 (1)-21 (89)
Use corresponding compounds, prepare following compound according to the step identical with series reaction among embodiment 19 → embodiment 20 → embodiment 3 → embodiment 4.
Embodiment 21 (1)
N 5-(2-chloro-4-methoxyphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.18 (hexane: ethyl acetate=10: 1);
1H-NMR(300MHz，CDCl 3)：δ0.86，1.42，1.50，2.34，3.34，4.03，6.23，6.90，6.98，7.86，8.61。
Embodiment 21 (2)
N 5-mesityl-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.52 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.88，1.51，2.20，2.31，2.32，3.34，5.76，6.07，6.95，7.77。
Embodiment 21 (3)
N 5-(2, the 4-3,5-dimethylphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.50 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.40-1.58，2.28，2.30，2.32，3.35，6.10-6.20，7.01-7.12，7.77-7.88。
Embodiment 21 (4)
N 5-(2-fluoro-4-aminomethyl phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.64 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.86，1.32-1.64，2.32，2.33-2.36，3.36，6.25，6.63，6.83-7.09，7.87，8.52。
Embodiment 21 (5)
N 5-(2-fluoro-4-aminomethyl phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.68 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.23-1.77，2.33，2.36，3.36，6.26，7.08，7.14，7.22，7.88，8.67。
Embodiment 21 (6)
3-chloro-4-{[7-(dipropyl amino)-6-methylpyrazole is [1,5-a] pyrimidine-5-yl also] amino } benzonitrile:
TLC:Rf0.53 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.86，1.30-1.70，2.38，3.09-3.64，6.36，7.47，7.62，7.69，7.94，9.15。
Embodiment 21 (7)
N 5-(2, the 4-Dimethoxyphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.43 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.86，1.35-1.63，2.31，3.18-3.50，3.83，3.91，6.21，6.48-6.65，7.06，7.84，8.64。
Embodiment 21 (8)
N 5-(4-fluoro-2-aminomethyl phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.39 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ7.89，7.83，6.96，6.16，6.09，3.35，2.30，1.48，0.87。
Embodiment 21 (9)
4-{[7-(dipropyl amino)-6-methylpyrazole is [1,5-a] pyrimidine-5-yl also] amino }-3-methyl benzonitrile:
TLC:Rf0.68 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ8.70，7.92，7.58，7.49，6.53，6.32，3.39，2.38，2.35，1.49，0.87。
Embodiment 21 (10)
N 5-(4-chloro-2-aminomethyl phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.46 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ8.09，7.85，7.12-7.32，6.20，6.18，3.26-3.45，2.31，1.40-1.60，0.87。
Embodiment 21 (11)
N 5-(4-chloro-2-fluorophenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.62 (toluene: ethyl acetate=9: 1);
1H-NMR(300MHz，CDCl 3)：δ8.73，7.89，7.09-7.23，6.68，6.27，3.25-3.45，2.32，1.38-1.57，0.86。
Embodiment 21 (12)
N 5-[2-fluoro-4-(trifluoromethyl) phenyl]-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.66 (toluene: ethyl acetate=9: 1);
1H-NMR(300MHz，CDCl 3)：δ8.98，7.92，7.47，7.38，6.90，6.32，3.21-3.55，2.35，1.38-1.60，0.86。
Embodiment 21 (13)
N 5-(2,4 difluorobenzene base)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.54 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ8.58-8.71，7.88，6.83-7.02，6.56，6.25，3.36，2.32，1.39-1.60，0.86。
Embodiment 21 (14)
N 5-[2-chloro-4-(trifluoromethyl) phenyl]-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.64 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ9.08，7.93，7.67，7.59，7.37，6.33，3.26-3.50，2.39，1.39-1.59，0.87。
Embodiment 21 (15)
4-{[7-(dipropyl amino)-6-methylpyrazole is [1,5-a] pyrimidine-5-yl also] amino }-3-ethyl benzonitrile:
TLC:Rf0.29 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ8.66，7.91，7.57，7.50，6.62，6.30，3.27-3.49，2.71，2.34，1.42-1.61，1.36，0.87。
Embodiment 21 (16)
N 5-(2-chloro-4-fluorophenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.59 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ8.81，7.89，7.17，7.04-7.13，7.02，6.26，3.37，2.36，1.41-1.58，0.87。
Embodiment 21 (17)
N 5-(2,4 dichloro benzene base)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.65 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ8.86，7.90，7.41，7.31，7.14，6.29，3.37，2.36，1.38-1.61，0.86。
Embodiment 21 (18)
N 5-(4-chloro-2,5-Dimethoxyphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.48 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ8.81，7.88，7.31，6.91，6.23，3.97，3.91，3.35，2.32，1.38-1.55，0.86。
Embodiment 21 (19)
N 5-[4-fluoro-2-(trifluoromethyl) phenyl]-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.51 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ8.52，7.88，7.19-7.44，6.79，6.22，3.22-3.48，2.29，1.39-1.62，0.87。
Embodiment 21 (20)
N 5-[4-chloro-2-(trifluoromethyl) phenyl]-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.56 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ8.64，7.89，7.59，7.54，6.91，6.25，3.29-3.43，2.29，1.33-1.60，0.87。
Embodiment 21 (21)
N 5-(2-chloro-4,6-3,5-dimethylphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.40 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ7.80，7.13，7.02，6.10，6.07，3.30-3.41，2.35，2.32，2.24，1.38-1.63，0.88。
Embodiment 21 (22)
6-methyl-N 5-[2-methyl-4-(trifluoromethoxy) phenyl]-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.45 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ8.19，7.86，7.05-7.18，6.15-6.27，3.25-3.46，2.34，2.32，1.40-1.59，0.87。
Embodiment 21 (23)
6-methyl-N 7, N 7-dipropyl-N 5-(2) pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.45 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ7.82，7.61，7.00，6.17，6.09，3.35，2.28，2.26，2.24，2.23，1.41-1.57，0.87。
Embodiment 21 (24)
N 5-(5-chloro-2,4-Dimethoxyphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.37 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ8.85，7.86，7.05，6.58，6.28，3.96，3.91，3.34，2.30，1.37-1.55，0.86。
Embodiment 21 (25)
N 5-(4,5-dimethoxy-2-aminomethyl phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.26 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ7.83，7.53，6.74，6.15，6.08，3.89，3.88，3.35，2.30，2.25，1.42-1.56，0.87。
Embodiment 21 (26)
N 5-(6-methoxyl group-2,3-dihydro-1H-indenes-5-yl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.51 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ8.58，7.85，6.81，6.25，3.91，3.21-3.47，2.95，2.89，2.32，2.01-2.15，1.39-1.55，0.86。
Embodiment 21 (27)
N 5-(2,6-dimethyl-3-pyridyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf 0.26 (hexane: ethyl acetate=1: 3);
1H-NMR(300MHz，CDCl 3)：δ8.34，7.86，7.07，6.19，6.16，3.25-3.47，2.55，2.53，2.33，1.40-1.58，0.87。
Embodiment 21 (28)
N 5-(2, the 6-3,5-dimethylphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.40 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ7.78，7.13，6.06，5.81，3.21-3.46，2.33，2.24，1.41-1.62，0.89。
Embodiment 21 (29)
N 5-(4-chloro-2-methoxyl group-5-aminomethyl phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.42 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ8.68，7.87，7.19，6.88，6.28，3.92，3.35，2.39，2.31，1.34-1.59，0.86。
Embodiment 21 (30)
3-chloro-4-{[7-(dipropyl amino)-6-methylpyrazole is [1,5-a] pyrimidine-5-yl also] amino } methyl benzoate:
TLC:Rf0.37 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ9.04，8.10，8.02，7.93，7.47，6.35，3.92，3.29-3.46，2.39，1.40-1.61，0.86。
Embodiment 21 (31)
6-methyl-N 5-(4-methyl-2-ethenylphenyl)-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.41 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ7.88，7.83，7.28，7.14，6.87，6.30，6.17，5.70，5.38，3.35，2.36，2.28，1.39-1.61，0.87。
Embodiment 21 (32)
N 5-[4-chloro-2-(trifluoromethoxy) phenyl]-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.73 (toluene: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ8.87，7.89，7.26-7.36，6.89，6.28，3.27-3.45，2.31，1.40-1.56，0.86。
Embodiment 21 (33)
N 5-(2-ethyl-4-methoxyphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.42 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ7.80，7.67，6.71-6.89，6.12，6.06，3.82，3.19-3.47，2.63，2.28，1.39-1.58，1.25，0.87。
Embodiment 21 (34)
6-methyl-N 7, N 7-dipropyl-N 5-(2,4,6-trimethylammonium-3-pyridyl) pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.51 (ethyl acetate: methyl alcohol=9: 1);
1H-NMR(300MHz，CDCl 3)：δ7.78，6.94，6.05，5.75，3.18-3.50，2.51，2.44，2.33，2.20，1.37-1.63，0.88。
Embodiment 21 (35)
6-methoxyl group-N 7-(2-methoxyethyl)-N 7-propyl group-N 5-(2) pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.36 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ7.89，7.81，6.99，6.94，6.16，3.99，3.86，3.56-3.63，3.52，3.25，2.25-2.30，2.22，1.54-1.67，0.87。
Embodiment 21 (36)
3-chloro-4-{[7-(dipropyl amino)-6-methylpyrazole is [1,5-a] pyrimidine-5-yl also] amino }-N-methyl-benzamide:
TLC:Rf0.57 (methylene dichloride: methyl alcohol=9: 1);
1H-NMR(300MHz，CDCl 3)：δ8.99，7.89-7.93，7.65，7.38，6.32，6.07，3.30-3.45，2.99-3.05，2.38，1.41-1.56，0.86。
Embodiment 21 (37)
N 5-(3,5-two chloro-2-pyridyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.48 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ0.86，1.41-1.63，2.19，3.29-3.59，6.36，7.08，7.68，7.93，8.16。
Embodiment 21 (38)
N 5-[2-chloro-4-(trifluoromethoxy) phenyl]-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.61 (toluene: ethyl acetate=9: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.38-1.59，2.37，3.22-3.50，6.28，7.14，7.17-7.27，7.31，7.89，8.93。
Embodiment 21 (39)
N 5-[4-sec.-propyl-2-(methylthio group) phenyl]-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5,7-diamines (N 5-[4-isopropyl-2-(methylsulfanyl) phenyl]-6-methyl-N 7, N 7-dipropylpyrazolo[1,5-a] pyrimidine-5,7-diamine):
TLC:Rf0.58 (toluene: ethyl acetate=9: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.26，1.40-1.57，2.37，2.41，2.79-2.96，3.35，6.23，7.23，7.37，7.85，7.89，8.63。
Embodiment 21 (40)
N 5-(2-ethyl-4-aminomethyl phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.40 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.26，1.39-1.58，2.29，2.34，2.64，3.35，6.16，6.19，7.01-7.12，7.75-7.86。
Embodiment 21 (41)
N 5-(4-chloro-2-ethylphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.38 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.29，1.41-1.57，2.30，2.65，3.36，6.19，6.24，7.18-7.28，7.85，8.06。
Embodiment 21 (42)
N 5-mesityl-6-methoxyl group-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.49 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ0.90，1.53-1.71，2.23，2.30，3.51-3.66，3.84，6.04，6.42，6.95，7.77。
Embodiment 21 (43)
N 5-mesityl-N 7, N 7-two (2-methoxyethyl)-6-methylpyrazoles are [1,5-a] pyrimidine-5 also, the 7-diamines:
TLC:Rf0.36 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ7.76，6.95，6.07，5.79，3.56-3.68，3.45，3.28，2.35，2.31，2.19。
Embodiment 21 (44)
N 5-(4,6-dimethyl-3-pyridyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.26 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ?0.87，1.41-1.58，2.26，2.32，2.53，3.28-3.43，6.05，6.13，7.05，7.83，8.80。
Embodiment 21 (45)
N 5-(4-chloro-2-methoxyphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.56 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.85，1.37-1.56，2.32，3.34，3.94，6.26，6.88，7.01，7.24，7.86，8.78。
Embodiment 21 (46)
6-methoxyl group-N 7, N 7-dipropyl-N 5-(2) pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.40 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.89，1.51-1.69，2.22，2.27，2.28，3.52-3.64，3.82，6.16，6.90，6.98，7.82，7.87。
Embodiment 21 (47)
6-methoxyl group-N 5-(4-methyl-2-ethenylphenyl)-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.49 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.88，1.52-1.68，2.35，3.52-3.63，3.81，5.39，5.70，6.16，6.89，7.12，7.15，7.23-7.30，7.83，8.10。
Embodiment 21 (48)
N 5-[2-chloro-4-(methylsulfonyl) phenyl]-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.61 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.41-1.57，2.40，3.08，3.31-3.51，6.36，7.49，7.89，7.95，7.99，9.18。
Embodiment 21 (49)
N 5-(2-ethyl-4,5-Dimethoxyphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.49 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ0.88，1.25，1.42-1.57，2.29，2.62，3.35，3.88，3.90，6.13，6.14，6.76，7.49，7.82。
Embodiment 21 (50)
N 5-(2-ethyl-4-aminomethyl phenyl)-6-methoxyl group-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.34 (hexane: ethyl acetate=8: 1);
1H-NMR(300MHz，CDCl 3)：δ8.07，7.82，7.00-7.11，6.14，3.82，3.53-3.63，2.66，2.33，1.53-1.68，1.27，0.88。
Embodiment 21 (51)
N 5-(4-chloro-2-ethylphenyl)-6-methoxyl group-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.40 (hexane: ethyl acetate=8: 1);
1H-NMR(300MHz，CDCl 3)：δ8.34，7.85，7.16-7.29，7.12，6.18，3.82，3.53-3.65，2.67，1.52-1.69，1.30，0.88。
Embodiment 21 (52)
N 5-(2,4-dimethyl-6-ethenylphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.27 (hexane: acetone=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.89，1.43-1.60，2.18，2.31，2.35，3.25-3.44，5.22，5.67，5.81，6.07，6.81，7.05，7.27，7.78。
Embodiment 21 (53)
N 5-(2-ethyl-4,6-3,5-dimethylphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.30 (hexane: acetone=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.89，1.17，1.43-1.59，2.19，2.32，2.33，2.57，3.34，5.77，6.06，6.97，7.77。
Embodiment 21 (54)
N 5-(2-pseudoallyl-4-aminomethyl phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.58 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.86，1.37-1.56，2.09，2.22，2.33，3.33，5.10，5.37-5.46，6.22，6.97，7.02，7.13，7.84，8.47。
Embodiment 21 (55)
N 5-(2-sec.-propyl-4-aminomethyl phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.50 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.88，1.27，1.42-1.58，2.29，2.36，3.01-3.18，3.35，6.13，6.15，7.05，7.13，7.61，7.81。
Embodiment 21 (56)
N 5-(2-ethyl-4-methoxyphenyl)-6-methoxyl group-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.31 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ7.89-7.96，7.81，6.87，6.79-6.84，6.11，3.83，3.82，3.54-3.62，2.66，1.53-1.69，1.27，0.89。
Embodiment 21 (57)
6-methyl-N 5-[4-(methylthio group)-2-(trifluoromethyl) phenyl]-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.51 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.41-1.59，2.29，2.52，3.29-3.44，6.23，6.87，7.46-7.55，7.88，8.53。
Embodiment 21 (58)
N 5-[4-sec.-propyl-2-(methylsulfinyl) phenyl]-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.45 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ0.86，1.25，1.26，1.42-1.58，2.32，2.83-2.96，2.93，3.23-3.49，6.23，7.16，7.40，7.88，8.64，9.72。
Embodiment 21 (59)
N 5-[4-sec.-propyl-2-(methylsulfonyl) phenyl]-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.62 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.28，1.42-1.59，2.32，2.90-3.03，3.07，3.31-3.44，6.25，7.53，7.77，7.90，8.61，8.78。
Embodiment 21 (60)
N 5-(2-chloro-4,5-3,5-dimethylphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.72 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.86，1.39-1.57，2.22，2.30，2.34，3.36，6.27，6.98，7.15，7.87，8.50。
Embodiment 21 (61)
N 5-(5-chloro-2,3-3,5-dimethylphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.62 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.42-1.56，2.17，2.30，2.31，3.30-3.42，6.19，6.21，6.98，7.84，7.85。
Embodiment 21 (62)
N 5-[2-(dimethylamino)-4-aminomethyl phenyl]-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.68 (toluene: ethyl acetate=9: 1);
1H-NMR(300MHz，CDCl 3)：δ0.86，1.38-1.56，2.32，2.70，3.34，6.23，6.96-7.02，7.85，8.16，8.65。
Embodiment 21 (63)
6-methoxyl group-N 7-(2-methoxyethyl)-N 5-(4-methyl-2-ethenylphenyl)-N 7-propyl group pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.38 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ8.12，7.82，7.24-7.29，7.12-7.19，6.89，6.16，5.70，5.40，3.99，3.85，3.55-3.64，3.48-3.55，3.25，2.35，1.54-1.65，0.87。
Embodiment 21 (64)
N 5-(2-ethyl-4-aminomethyl phenyl)-6-methoxyl group-N 7-(2-methoxyethyl)-N 7-propyl group pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf 0.35 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ8.09，7.81，7.02-7.13，6.15，3.98，3.86，3.55-3.64，3.52，3.25，2.67，2.33，1.52-1.66，1.28，0.87。
Embodiment 21 (65)
N 5-(4-chloro-2-ethylphenyl)-6-methoxyl group-N 7-(2-methoxyethyl)-N 7-propyl group pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.39 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ8.36，7.84，7.21-7.27，7.20，7.17，6.19，4.01，3.87，3.56-3.65，3.52，3.24，2.68，1.52-1.67，1.31，0.87。
Embodiment 21 (66)
6-methyl-N 7, N 7-dipropyl-N 5-(2,3,5-trimethylammonium-4-pyridyl) pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.34 (methylene dichloride: methyl alcohol=9: 1);
1H-NMR(300MHz，CDCl 3)：δ0.89，1.43-1.64，2.15，2.18，2.34，2.54，3.28-3.45，5.85，6.12，7.82，8.24。
Embodiment 21 (67)
N 5-(2-cyclopropyl-4-aminomethyl phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.61 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.66-0.78，0.87，0.94-1.07，1.39-1.57，1.74-1.92，2.31，2.35，3.35，6.23，7.00，7.10，7.17，7.85，8.42。
Embodiment 21 (68)
N 5-[4-sec.-propyl-2-(methylthio group (methylsulfanyl)) phenyl]-6-methoxyl group-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.60 (hexane: ethyl acetate=8: 1);
1H-NMR(300MHz，CDCl 3)：δ8.69，8.45，7.86，7.38，7.23，6.21，3.85，3.54-3.66，2.81-2.96，2.42，1.52-1.68，1.26，0.88。
Embodiment 21 (69)
N 5-(4-cyclopropyl-2-aminomethyl phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.61 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.64-0.72，0.87，0.90-0.97，1.40-1.57，1.80-1.93，2.28，2.29，3.35，6.14，6.16，6.92-6.99，7.80-7.89。
Embodiment 21 (70)
N 5-(2-ethyl-4-methoxyphenyl)-N 7-(2-methoxyethyl)-6-methyl-N 7-propyl group pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.25 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ7.80，7.69，6.77-6.85，6.13，6.10，3.83，3.56-3.68，3.42，3.31-3.39，3.28，2.64，2.30，1.43-1.58，1.25，0.88。
Embodiment 21 (71)
N 5-(2-ethyl-4-aminomethyl phenyl)-N 7-(2-methoxyethyl)-6-methyl-N 7-propyl group pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.33 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ7.77-7.85，7.03-7.11，6.22，6.16，3.56-3.67，3.42，3.33-3.39，3.27，2.64，2.34，2.31，1.43-1.58，1.26，0.87。
Embodiment 21 (72)
N 5-(4-chloro-2-ethylphenyl)-N 7-(2-methoxyethyl)-6-methyl-N 7-propyl group pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.38 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ8.02-8.11，7.84，7.18-7.28，6.27，6.20，3.58-3.69，3.42，3.32-3.38，3.26，2.65，2.32，1.42-1.58，1.29，0.87。
Embodiment 21 (73)
N 5-(2-methyl-4-ethylphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.52 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.24，1.42-1.57，2.30，2.62，3.35，6.16，6.17，7.03-7.14，7.83，7.89。
Embodiment 21 (74)
N 5-(2-methyl-4-ethenylphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.52 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.41-1.56，2.31，2.34，3.36，5.18，5.69，6.21，6.28，6.69，7.28，7.33，7.85，8.14。
Embodiment 21 (75)
N 5-(3,5-dimethyl-2-pyridyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.61 (hexane: ethyl acetate=1: 5);
1H-NMR(300MHz，CDCl 3)：δ0.86，1.42-1.57，2.24，2.25，2.30，3.27-3.46，6.16，6.57，7.39，7.84，8.04。
Embodiment 21 (76)
6-methyl-N 5-[4-methyl-2-(methylthio group) phenyl]-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.63 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.40-1.57，2.33，2.37，2.40，3.35，6.24，7.17，7.33，7.86，7.88，8.62。
Embodiment 21 (77)
6-methyl-N 5-[2-methyl-4-(methylthio group) phenyl]-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.57 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.41-1.56，2.30，2.49，3.28-3.43，6.16-6.22，7.14-7.24，7.84，8.03。
Embodiment 21 (78)
6-methyl-N 5-[2-methyl-4-(methylsulfinyl) phenyl]-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.53 (methyl alcohol: ethyl acetate=1: 9);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.40-1.57，2.34，2.42，2.74，3.27-3.47，6.26，6.43，7.49，7.58，7.89，8.54。
Embodiment 21 (79)
6-methyl-N 5-[2-methyl-4-(methylsulfonyl) phenyl]-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.33 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.41-1.58，2.35，2.42，3.05，3.27-3.53，6.31，6.54，7.77，7.83，7.91，8.70。
Embodiment 21 (80)
N 5-(4-sec.-propyl-2-aminomethyl phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.63 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.25，1.41-1.56，2.29，2.31，2.79-2.96，3.35，6.13-6.20，7.08，7.12，7.83，7.92。
Embodiment 21 (81)
N 7-(methoxyethyl)-6-methyl-N 5-(4-methyl-2-ethenylphenyl)-N 7-propyl group pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.38 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.41-1.58，2.29，2.36，3.27，3.32-3.39，3.42，3.57-3.68，5.38，5.70，6.18，6.33，6.86，7.15，7.28，7.82，7.88。
Embodiment 21 (82)
N 5-[4-sec.-propyl-2-(methylthio group) phenyl]-N 7-(2-methoxyethyl)-6-methyl-N 7-propyl group pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.56 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.26，1.43-1.58，2.39，2.41，2.83-2.95，3.26，3.33-3.39，3.42，3.57-3.69，6.25，7.20-7.28，7.39，7.86，7.93，8.65。
Embodiment 21 (83)
N 5-(2-ethyl-4,5-Dimethoxyphenyl)-N 7-(2-methoxyethyl)-6-methyl-N 7-propyl group pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.43 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ0.88，1.25，1.44-1.60，2.31，2.61，3.28，3.32-3.40，3.43，3.57-3.68，3.88，3.90，6.14，6.15，6.76，7.50，7.82。
Embodiment 21 (84)
N 5-(4-ethyl-6-methyl-3-pyridyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.31 (hexane: ethyl acetate=1: 2);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.26，1.41-1.59，2.31，2.55，2.62，3.25-3.51，6.05，6.13，7.08，7.83，8.81。
Embodiment 21 (85)
N 5-(4-sec.-propyl-2-ethenylphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.50 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.27，1.40-1.59，2.26，2.82-3.01，3.35，5.40，5.72，6.19，6.41，6.89，7.21，7.30，7.84，7.94。
Embodiment 21 (86)
N 5-(4-ethyl-2-isopropyl phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.49 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.26，1.28，1.42-1.57，2.27，2.67，2.81-2.99，3.35，6.17，6.30，7.07-7.16，7.83，7.88。
Embodiment 21 (87)
N 5-(4-chloro-2-(methylthio group) phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.73 (toluene: ethyl acetate=9: 1);
1H-NMR(300?MHz，CDCl 3)：δ8.75，7.88，7.86，7.47，7.31，6.27，3.36，2.44，2.37，1.49，0.87。
Embodiment 21 (88)
N 5-(2-methyl-4-(2-dimethylamino ethoxy) phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.28 (ethyl acetate: methyl alcohol: triethylamine=9: 1: 0.3);
1H-NMR(300MHz，CDCl 3)：δ7.81，7.69，6.86-6.78，6.13，6.05，4.08，3.34，2.75，2.36，2.29，2.27，1.49，0.87。
Embodiment 21 (89)
N 5-(2-methyl-4-(3-dimethylamino propoxy) phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.25 (ethyl acetate: methyl alcohol: triethylamine=9: 1: 0.3);
1H-NMR(300MHz，CDCl 3)：δ7.81，7.66，6.84-6.75，6.13，6.04，4.02，3.34，2.48，2.29，2.28，2.27，1.97，1.49，0.87。
Embodiment 22 (1)-embodiment 22 (7)
The respective compound that use makes by the step identical with series reaction among embodiment 19 → embodiment 20 prepares following compound according to the step identical with series reaction among embodiment 3 → embodiment 4.
Embodiment 22 (1)
N 5-(2-chloro-4-methoxyphenyl)-6-ethyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
Use 5,7-two chloro-6-ethyl pyrazolo [1,5-a] pyrimidines prepare title compound according to the step identical with series reaction among embodiment 3 → embodiment 4, and it has following physical parameter:
TLC:Rf0.34 (hexane: ethyl acetate=9: 1);
1H-NMR(300MHz，CDCl 3)：δ8.64，7.86，7.04，6.98，6.92，6.22，3.81，3.24-3.39，2.92，1.41-1.58，1.35，0.88。
Embodiment 22 (2)
N 5-(2-chloro-4-methoxyphenyl)-N 7, N 7, 6-tripropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.32 (hexane: ethyl acetate=10: 1);
1H-NMR(300MHz，CDCl 3)：δ0.88，1.13，1.50，1.72，2.82，3.29，3.81，6.22，6.91，6.98，7.05，7.86，8.68。
Embodiment 22 (3)
N 5-(2-chloro-4-methoxyphenyl)-6-sec.-propyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.64 (hexane: ethyl acetate=10: 1);
1H-NMR(300MHz，CDCl 3)：δ0.88，1.50，3.20，3.38，3.81，4.24，6.20，6.91，6.98，7.09，7.85，8.63。
Embodiment 22 (4)
N 5-(2-chloro-4-methoxyphenyl)-6-methoxyl group-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.5 (hexane: ethyl acetate=10: 1);
1H-NMR(300MHz，CDCl 3)：δ0.88，1.60，3.60，3.81，3.85，6.20，6.91，6.98，7.67，7.86，8.70。
Embodiment 22 (5)
6-butyl-N 5-(2-chloro-4-methoxyphenyl)-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.3 (hexane: ethyl acetate=10: 1);
1H-NMR(300MHz，CDCl 3)：δ0.88，1.03，1.58，2.84，3.30，3.81，6.22，6.92，6.98，7.05，7.86，8.67。
Embodiment 22 (6)
N 5-(2-chloro-4-methoxyphenyl)-6-phenyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.24 (hexane: ethyl acetate=9: 1);
1H-NMR(300MHz，CDCl 3)：δ0.75，1.41，3.08，3.76，6.24，6.74，6.86，7.45，7.57，7.91，8.61。
Embodiment 22 (7)
N 5-(2-chloro-4-methoxyphenyl)-6-cyclopentyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.28 (hexane: ethyl acetate=9: 1);
1H-NMR(300MHz，CDCl 3)：δ0.88，1.46，1.81，1.98，3.31，3.81，4.22，6.18，6.69，6.90，6.97，7.85，8.37。
Embodiment 23 (1)-embodiment 23 (38)
Use corresponding amine, prepare following compound according to the step identical with series reaction among embodiment 3 → embodiment 4.
Embodiment 23 (1)
N 5-(2-chloro-4-methoxyphenyl)-N 7-(2-methoxyethyl)-6-methyl-N 7-propyl group pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.13 (hexane: ethyl acetate=6: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.40-1.58，2.36，3.26，3.29-3.50，3.52-3.72，3.81，6.23，6.87-6.97，6.98，7.86，8.63。
Embodiment 23 (2)
N 5-(2-chloro-4-methoxyphenyl)-N 7, N 7-two (2-methoxyethyl)-6-methylpyrazoles are [1,5-a] pyrimidine-5 also, the 7-diamines:
TLC:Rf0.32 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ2.38，3.26，3.38-3.48，3.53-3.72，3.81，6.24，6.87-6.96，6.99，7.85，8.63。
Embodiment 23 (3)
N 5-(2-chloro-4-methoxyphenyl)-N 7-(cyclopropyl methyl)-6-methyl-N 7-(4-methyl-benzyl) pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.36 (hexane: ethyl acetate=8: 1);
1H-NMR(300MHz，CDCl 3)：δ-0.13--0.02，0.25-0.41，0.78-0.95，2.31，2.34，3.08-3.35，3.81，4.57，6.25，6.86-6.95，6.98，7.07，7.19，7.90，8.64。
Embodiment 23 (4)
N 5-(2-chloro-4-methoxyphenyl)-N 7-(cyclopropyl methyl)-N 7-(2-methoxyethyl)-6-methylpyrazole is [1,5-a] pyrimidine-5 also, the 7-diamines:
TLC:Rf0.38 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ0.09-0.10，0.29-0.46，0.81-0.98，2.41，3.21-3.36，3.37-3.49，3.55-3.76，3.81，6.24，6.92，6.96，6.99，7.85，8.66。
Embodiment 23 (5)
N 5-(2-chloro-4-methoxyphenyl)-N 7-ethyl-N 7-(2-methoxyethyl)-6-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.32 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ8.64，7.85，6.99，6.88-6.96，6.23，3.81，3.56-3.70，3.35-3.55，3.27，2.37，1.06。
Embodiment 23 (6)
N 5-(2-chloro-4-methoxyphenyl)-N 7-(cyclopropyl methyl)-6-methyl-N 7-propyl group pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.30 (hexane: ethyl acetate=8: 1);
1H-NMR(300MHz，CDCl 3)：δ-0.11-0.09，0.28-0.44，0.78-0.97，1.39-1.56，2.41，3.15-3.50，3.81，6.23，6.87-6.97，6.99，7.85，8.66。
Embodiment 23 (7)
N 5-(2-chloro-4-methoxyphenyl)-N 7-[2-methoxyl group-1-(methoxyl methyl) ethyl]-6-methylpyrazole is [1,5-a] pyrimidine-5 also, the 7-diamines:
TLC:Rf0.30 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ8.50，7.82，6.97，6.89，6.75，6.16，6.08，4.13-4.26，3.80，3.53-3.66，3.39，2.30。
Embodiment 23 (8)
2-[{5-[(2-chloro-4-methoxyphenyl) amino]-6-methylpyrazole [1,5-a] pyrimidin-7-yl also } (propyl group) amino] ethanol:
TLC:Rf0.30 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.33-1.54，2.32，3.30-3.53，3.53-3.76，3.82，4.98-5.15，6.26，6.87-6.97，6.99，7.86，8.58。
Embodiment 23 (9)
N 7-butyl-N 5-(2-chloro-4-methoxyphenyl)-6-methyl-N 7-propyl group pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.35 (hexane: ethyl acetate=9: 1);
1H-NMR(300MHz，CDCl 3)：δ0.81-0.91，1.20-1.37，1.37-1.56，2.34，3.28-3.46，3.81，6.23，6.87-6.95，6.98，7.86，8.64。
Embodiment 23 (10)
N 5-(2-chloro-4-methoxyphenyl)-N 7-(2-methoxyl group-1-methylethyl)-6-methylpyrazole is [1,5-a] pyrimidine-5 also, the 7-diamines:
TLC:Rf0.15 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ1.34，2.30，3.38，3.48，3.80，4.07-4.25，5.88，6.16，6.75，6.90，6.97，7.81，8.50。
Embodiment 23 (11)
N 5-(2-chloro-4-methoxyphenyl)-N 7, N 7-diethyl-6-methylpyrazole is [1,5-a] pyrimidine-5 also, the 7-diamines:
TLC:Rf0.28 (hexane: ethyl acetate=12: 1);
1H-NMR(300MHz，CDCl 3)：δ8.64，7.85，6.99，6.87-6.96，6.23，3.81，3.46，2.36，1.05。
Embodiment 23 (12)
N 5-(2-chloro-4-methoxyphenyl)-N 7-ethyl-6-methyl-N 7-propyl group pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.32 (hexane: acetone=9: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.05，1.39-1.56，2.35，3.29-3.40，3.40-3.52，3.81，6.23，6.87-6.96，6.98，7.86，8.63。
Embodiment 23 (13)
N 5-(2-chloro-4-methoxyphenyl)-N 7-[(1R)-1-(methoxyl methyl) propyl group]-6-methylpyrazole is [1,5-a] pyrimidine-5 also, the 7-diamines:
TLC:Rf0.20 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ1.00，1.52-1.89，2.30，3.35，3.43-3.57，3.80，3.86-4.03，5.87，6.16，6.76，6.89，6.97，7.81，8.50。
Embodiment 23 (14)
N 7-(sec-butyl)-N 5-(2-chloro-4-methoxyphenyl)-6-methylpyrazole is [1,5-a] pyrimidine-5 also, the 7-diamines:
TLC:Rf0.18 (hexane: ethyl acetate=9: 1);
1H-NMR(300MHz，CDCl 3)：δ8.50，7.80，6.97，6.89，6.75，6.16，5.76，3.82-3.94，3.80，2.30，1.53-1.79，1.30，0.99。
Embodiment 23 (15)
N 5-(2-chloro-4-methoxyphenyl)-6-methoxyl group-N 7-(2-methoxyethyl)-N 7-propyl group pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.45 (toluene: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ8.70，7.85，7.71，6.98，6.91，6.20，4.00，3.89，3.81，3.57-3.66，3.51，3.24，1.51-1.68，0.87。
Embodiment 23 (16)
N 5-(2-chloro-4-methoxyphenyl)-N 7-[1-(methoxyl methyl) butyl]-6-methylpyrazole is [1,5-a] pyrimidine-5 also, the 7-diamines:
TLC:Rf0.26 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ0.93，1.32-1.83，2.30，3.34，3.42-3.55，3.80，3.96-4.10，5.85，6.16，6.76，6.90，6.97，7.81，8.51。
Embodiment 23 (17)
N 5-(2-chloro-4-methoxyphenyl)-N 7-(3-methoxycarbonyl propyl)-6-methyl-N 7-propyl group pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.23 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ0.86，1.38-1.55，1.64-1.80，2.34，3.23，3.28-3.43，3.42-3.55，3.81，6.21，6.83-6.95，6.97，7.84，8.60。
Embodiment 23 (18)
N 7-butyl-N 5-(2-chloro-4-methoxyphenyl)-N 7-ethyl-6-methylpyrazole is [1,5-a] pyrimidine-5 also, the 7-diamines:
TLC:Rf0.34 (hexane: ethyl acetate=8: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.05，1.20-1.52，2.35，3.28-3.53，3.81，6.23，6.86-6.96，6.98，7.85，8.63。
Embodiment 23 (19)
N-(2-chloro-4-methoxyphenyl)-7-[(2S, 4R)-4-methoxyl group-2-(methoxyl methyl)-1-pyrrolidyl]-6-methylpyrazole [1,5-a] pyrimidine-5-amine also:
TLC:Rf0.40 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ8.59，7.85，6.98，6.91，6.86，6.22，4.74-4.86，4.10-4.20，4.00-4.10，3.81，3.38-3.45，3.36，3.17-3.31，3.15，2.30-2.40，2.29，2.03-2.13。
Embodiment 23 (20)
N 5-(2-chloro-4-methoxyphenyl)-6-methyl-N 7-propyl group-N 7-(2-pyridylmethyl) pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.30 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ0.85，1.47-1.65，2.27，3.31-3.54，3.81，4.74，6.25，6.84，6.91，6.97，7.09-7.20，7.34-7.45，7.54-7.65，7.91，8.50-8.56，8.59。
Embodiment 23 (21)
7-(1-azepan base)-N-(2-chloro-4-methoxyphenyl)-6-methylpyrazole also [1,5-a] pyrimidine-5-amine (7-(1-azepanyl)-N-(2-chloro-4-methoxyphenyl)-6-methylpyrazolo[1,5-a] pyrimidine-5-amine):
TLC:Rf0.57 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ8.58，7.86，6.98，6.91，6.88，6.23，3.81，3.39-3.46，2.37，1.74-1.88。
Embodiment 23 (22)
N-(2-chloro-4-methoxyphenyl)-6-methyl-7-(1,4-oxaza heptane-4-yl) pyrazolo [1,5-a] pyrimidine-5-amine (N-(2-chloro-4-methoxyphenyl)-6-methyl-7-(1,4-oxazepan-4-yl) pyrazolo[1,5-a] pyrimidine-5-amine):
TLC:Rf0.49 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ8.56，7.85，6.98，6.91，6.87，6.24，3.97-4.03，3.91-3.96，3.81，3.55-3.62，2.38，2.03-2.12。
Embodiment 23 (23)
N-(2-chloro-4-methoxyphenyl)-6-methyl-7-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) pyrazolo [1,5-a] pyrimidine-5-amine (N-(2-chloro-4-methoxyphenyl)-6-methyl-7-(4-methyl-1,4-diazepan-1-yl) pyrazolo[1,5-a] pyrimidine-5-amine):
TLC:Rf0.31 (chloroform: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ8.56，7.85，6.98，6.90，6.86，6.23，3.81，3.49-3.62，2.80-2.86，2.75-2.80，2.46，2.37，2.02-2.11。
Embodiment 23 (24)
N 5-(2-chloro-4-methoxyphenyl)-6-methyl-N 7-propyl group-N 7-(1,3-thiazoles-4-ylmethyl) pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.49 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ8.74，8.59，7.90，7.20，6.97，6.90，6.85，6.24，4.79，3.80，3.37-3.50，2.24，1.47-1.62，0.87。
Embodiment 23 (25)
[{ 5-[(2-chloro-4-methoxyphenyl) amino]-6-methylpyrazole is [1,5-a] pyrimidin-7-yl also } (ethyl) amino] methyl acetate:
TLC:Rf0.30 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ1.14，2.20，3.58，3.79，4.03，4.08，6.34，6.81，6.96，7.82，7.86，10.62。
Embodiment 23 (26)
N 5-(2-chloro-4-methoxyphenyl)-N 7-(cyclopropyl methyl)-6-methoxyl group-N 7-propyl group pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.56 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ8.71，7.85，7.70，6.98，6.91，6.20，3.91，3.81，3.62-3.68，3.61，1.53-1.67，0.98-1.15，0.88，0.40-0.49，0.07-0.17。
Embodiment 23 (27)
N-(2-chloro-4-methoxyphenyl)-7-[(2S)-2-(methoxyl methyl)-1-pyrrolidyl]-6-methylpyrazole [1,5-a] pyrimidine-5-amine also:
TLC:Rf0.40 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ8.61，7.83，6.98，6.91，6.88，6.23，4.67-4.76，3.81，3.58-3.67，3.35-3.44，3.24，3.18，2.32，2.26-2.37，2.01-2.13，1.83-1.96。
Embodiment 23 (28)
N-(2-chloro-4-methoxyphenyl)-7-[(2R)-2-(methoxyl methyl)-1-pyrrolidyl]-6-methylpyrazole [1,5-a] pyrimidine-5-amine also:
TLC:Rf0.40 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ8.61，7.83，6.98，6.84-6.94，6.23，4.66-4.77，3.81，3.57-3.67，3.34-3.45，3.20-3.27，3.18，2.32，2.26-2.41，2.01-2.14，1.83-1.95。
Embodiment 23 (29)
N-(2-chloro-4-methoxyphenyl)-7-[(2R, 6S)-2,6-dimethyl-4-morpholinyl]-6-methylpyrazole [1,5-a] pyrimidine-5-amine also:
TLC:Rf0.44 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ8.55，7.84，6.98，6.91，6.84，6.21，3.89-4.02，3.81，3.31-3.46，3.10-3.26，2.32，1.24。
Embodiment 23 (30)
N-(2-chloro-4-methoxyphenyl)-6-methyl-7-(4-methyl isophthalic acid-piperazinyl) pyrazolo [1,5-a] pyrimidine-5-amine:
TLC:Rf0.24 (chloroform: methyl alcohol=19: 1);
1H-NMR(300MHz，CDCl 3)：δ2.31，2.39，2.52-2.74，3.43-3.69，3.80，6.20，6.81，6.90，6.97，7.83，8.54。
Embodiment 23 (31)
7-(4-ethanoyl-1-piperazinyl)-N-(2-chloro-4-methoxyphenyl)-6-methylpyrazole is [1,5-a] pyrimidine-5-amine also:
TLC:Rf0.21 (hexane: ethyl acetate=1: 3);
1H-NMR(300MHz，CDCl 3)：δ2.17，2.35，3.32-3.99，3.81，6.22，6.86，6.91，6.99，7.83，8.54。
Embodiment 23 (32)
N-(2-chloro-4-methoxyphenyl)-7-[(2S, 4R)-2-(methoxyl methyl)-4-methyl isophthalic acid-pyrrolidyl]-6-methylpyrazole [1,5-a] pyrimidine-5-amine also:
TLC:Rf0.18 (hexane: ethyl acetate=8: 1);
1H-NMR(300MHz，CDCl 3)：δ1.14，1.89-2.11，2.31，2.42-2.63，2.97-3.10，3.18，3.22，3.69，3.81，4.67-4.87，6.23，6.87，6.91，6.98，7.85，8.60。
Embodiment 23 (33)
N-(2-chloro-4-methoxyphenyl)-7-[(2S, 4R)-4-oxyethyl group-2-(ethoxymethyl)-1-pyrrolidyl]-6-methylpyrazole [1,5-a] pyrimidine-5-amine also:
TLC:Rf0.20 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.94，1.21，1.99-2.14，2.26-2.41，2.29，3.16-3.34，3.34-3.43，3.43-3.62，3.81，4.03-4.14，4.20-4.32，4.66-4.81，6.22，6.84，6.91，6.98，7.84，8.57。
Embodiment 23 (34)
N-(2-chloro-4-methoxyphenyl)-7-[(2S, 4S)-2-(methoxyl methyl)-4-fluoro-1-pyrrolidyl]-6-methylpyrazole [1,5-a] pyrimidine-5-amine also:
TLC:Rf0.26 (hexane: ethyl acetate=12: 1);
1H-NMR(300MHz，CDCl 3)：δ2.09-2.30，2.40，2.57-2.88，3.23，3.33-3.48，3.49-3.68，3.71-3.94，3.81，4.43-4.60，5.25-5.53，6.25，6.92，6.95，6.99，7.80，8.62。
Embodiment 23 (35)
N-(2-chloro-4-methoxyphenyl)-7-[(2S, 4S)-2-(methoxyl methyl)-4-methyl isophthalic acid-pyrrolidyl]-6-methylpyrazole [1,5-a] pyrimidine-5-amine also:
TLC:Rf0.20 (toluene: ethyl acetate=19: 1);
1H-NMR(300MHz，CDCl 3)：δ1.15，1.44-1.59，2.27-2.42，2.31，2.46-2.67，3.15，3.17-3.25，3.25-3.47，3.81，4.93-5.06，6.22，6.86，6.91，6.98，7.84，8.59。
Embodiment 23 (36)
N-(2-chloro-4-methoxyphenyl)-7-[(2S, 4R)-4-ethyl-2-(methoxyl methyl)-1-pyrrolidyl]-6-methylpyrazole [1,5-a] pyrimidine-5-amine also:
TLC:Rf 0.25 (toluene: ethyl acetate=19: 1);
1H-NMR(300MHz，CDCl 3)：δ0.96，1.44-1.65，1.95-2.09，2.23-2.43，2.31，3.03-3.14，3.19，3.20-3.29，3.63-3.76，3.81，4.64-4.77，6.23，6.87，6.91，6.98，7.84，8.60。
Embodiment 23 (37)
N-(2-chloro-4-methoxyphenyl)-7-[(2R, 4S)-2-(methoxyl methyl)-4-methyl isophthalic acid-pyrrolidyl]-6-methylpyrazole [1,5-a] pyrimidine-5-amine also:
TLC:Rf0.19 (toluene: ethyl acetate=19: 1);
1H-NMR(300MHz，CDCl 3)：δ1.14，1.93-2.08，2.30，2.41-2.63，2.98-3.08，3.18，3.23，3.64-3.75，3.81，4.71-4.87，6.23，6.84-6.96，6.98，7.85，8.51-8.66。
Embodiment 23 (38)
N-(2-chloro-4-methoxyphenyl)-7-[(2S)-2-(methoxyl methyl)-4-phenyl-2,5-dihydro-1H-pyrroles-1-yl]-6-methylpyrazole [1,5-a] pyrimidine-5-amine also:
TLC:Rf0.19 (hexane: ethyl acetate=6: 1);
1H-NMR(300?MHz，CDCl 3)：δ2.42，3.24，3.43，3.82，4.57-4.70，4.74-4.89，5.46-5.63，6.28，6.33-6.39，6.93，6.98，7.00，7.22-7.49，7.86，8.58-8.70。
Embodiment 24 (1)-embodiment 24 (4)
The respective compound that use prepares by the step identical with series reaction among embodiment 19 → embodiment 20 prepares following compound according to the step identical with series reaction among embodiment 3 → embodiment 4.
Embodiment 24 (1)
N 5-(2-chloro-4-methoxyphenyl)-2,6-dimethyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
Use 2,6-dimethyl-5,7-dichloro pyrazolo [1,5-a] pyrimidine prepares title compound according to the step identical with series reaction among embodiment 3 → embodiment 4, and it has following physical parameter:
TLC:Rf0.78 (hexane: ethyl acetate=6: 1);
1H-NMR(300MHz，CDCl 3)：δ0.85，1.45，2.30，2.40，3.33，3.79，5.99，6.83，6.89，6.96，8.60。
Embodiment 24 (2)
N 5-(2-chloro-4-methoxyphenyl)-N 7-(1-ethyl propyl)-2,6-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
Use 2,6-dimethyl-5,7-dichloro pyrazolo [1,5-a] pyrimidine prepares title compound according to the step identical with series reaction among embodiment 3 → embodiment 4, and it has following physical parameter:
TLC:Rf0.42 (hexane: ethyl acetate=6: 1);
1H-NMR(300MHz，CDCl 3)：δ0.96，1.65，2.25，2.38，3.68，3.78，5.72，5.92，6.67，6.87，6.95，8.45。
Embodiment 24 (3)
N 5-(2-chloro-4-methoxyphenyl)-2-ethyl-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
Use 2-ethyl-5,7-two chloro-6-methylpyrazoles are [1,5-a] pyrimidine also, prepares title compound according to the step identical with series reaction among embodiment 3 → embodiment 4, and it has following physical parameter:
TLC:Rf0.64 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.86，1.31，1.46，2.32，2.77，3.34，3.80，6.03，6.84，6.90，6.97，8.62。
Embodiment 24 (4)
5-[(2-chloro-4-methoxyphenyl) amino]-7-(dipropyl amino)-6-methylpyrazole [1,5-a] pyrimidine-3-nitrile also:
Use 3-cyano group-5,7-two chloro-6-methylpyrazoles are [1,5-a] pyrimidine also, prepares title compound according to the step identical with series reaction among embodiment 3 → embodiment 4, and it has following physical parameter:
TLC:Rf0.48 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.86，1.41-1.55，2.34，3.27-3.43，3.83，6.91-7.04，7.18，8.05，8.77。
Embodiment 25:
N 2-(2-chloro-4-methoxyphenyl)-N 2-ethyl-N 4, N 4-dipropyl-5,7-dihydrofuran be [3,4-d] pyrimidine-2 also, the 4-diamines:
Use the respective compound and the corresponding halogenide of preparation among the embodiment 4, prepare title compound according to the step identical with series reaction among the embodiment 5, it has following physical parameter:
TLC:Rf0.42 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ0.72，1.18，1.43，3.01，3.68，3.81，4.10，4.77，5.12，6.82，7.00，7.14。
Embodiment 26:
N 2-ethyl-N 2-mesityl-N 4, N 4-dipropyl-5,7-dihydrofuran be [3,4-d] pyrimidine-2 also, the 4-diamines:
Use the respective compound and the corresponding aniline of preparation among the embodiment 3, prepare title compound according to the step identical with series reaction among embodiment 4 → embodiment 5, it has following physical parameter:
TLC:Rf0.16 (hexane: ethyl acetate=8: 1);
1H-NMR(300MHz，DMSO-d 6)：δ0.70，1.13，1.39，2.01，2.23，3.09，3.74，4.57，5.03，6.87。
Embodiment 27:
2-[(2-chloro-4-methoxyphenyl) (methyl) amino]-4-(dipropyl amino) furo [3,4-d] pyrimidines-7 (5H)-ketone:
Use 2,4-dichloro furo [3,4-d] pyrimidines-7 (5H)-ketone prepare title compound according to the step identical with series reaction among embodiment 3 → embodiment 4 → embodiment 5, and it has following physical parameter:
TLC:Rf0.27 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ0.34-1.09，1.14-1.61，2.84-3.20，3.47，3.81，5.19-5.38，6.83，7.00，7.17。
Embodiment 28 (1)-embodiment 28 (11)
Use the compounds and the corresponding halogenide of preparation among the embodiment 4 (1), prepare following compound according to the step identical with series reaction among the embodiment 5.
Embodiment 28 (1)
N 2-(2-chloro-4-methoxyphenyl)-N 2-ethyl-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
TLC:Rf0.18 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ0.72，1.17，1.42，1.93，2.70，2.89，3.17，3.80，4.10，6.81，6.99，7.14。
Embodiment 28 (2)
N 2-(2-chloro-4-methoxyphenyl)-N 2, N 4, N 4-tripropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
TLC:Rf0.25 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ0.73，0.90，1.44，1.60，1.93，2.69，2.89，3.17，3.58，3.80，4.01，6.80，6.98，7.15。
Embodiment 28 (3)
N 2-(2-chloro-4-methoxyphenyl)-N 2-sec.-propyl-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
TLC:Rf0.65 (hexane: tetrahydrofuran (THF)=2: 1);
1H-NMR(300MHz，CDCl 3)：δ0.70，1.06，1.34，1.94，2.72，2.89，3.12，3.81，5.11，6.80，7.00，7.10。
Embodiment 28 (4)
N 2-allyl group-N 2-(2-chloro-4-methoxyphenyl)-N 4, N 4Propyl group-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
TLC:Rf0.24 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ0.72，1.43，1.94，2.70，2.89，3.17，3.79，4.16，4.82，5.05，6.02，6.78，6.98，7.13。
Embodiment 28 (5)
N 2-(2-chloro-4-methoxyphenyl)-N 2-(2-methyl-2-propenyl)-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
TLC:Rf0.32 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ0.72，1.42，1.79，1.94，2.69，2.89，3.18，3.79，3.98，4.76，4.80，4.94，6.77，6.97，7.17。
Embodiment 28 (6)
N 2-(2-chloro-4-methoxyphenyl)-N 2-isobutyl--N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
TLC:Rf0.23 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ0.71，0.94，1.43，1.90，2.66，2.89，3.15，3.41，3.80，4.02，6.80，6.98，7.18。
Embodiment 28 (7)
N-(2-chloro-4-methoxyphenyl)-N-[4-(dipropyl amino)-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2-base] ethanamide:
TLC:Rf0.48 (ethyl acetate);
1H-NMR(300MHz，CDCl 3)：δ0.77，1.38，2.01，2.46，2.81，2.96，3.21，3.80，6.81，7.00，7.19。
Embodiment 28 (8)
N-(2-chloro-4-methoxyphenyl)-N-[4-(dipropyl amino)-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2-base] Toluidrin:
TLC:Rf0.35 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ0.73，1.39，1.99，2.78，2.93，3.16，3.71，3.81，6.85，6.98，7.36。
Embodiment 28 (9)
N 2-(2-chloro-4-methoxyphenyl)-N 2-(cyclopropyl methyl)-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
TLC:Rf0.18 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ0.02-0.19，0.29-0.47，0.57-0.84，0.99-1.19，1.30-1.54，1.85-2.04，2.60-2.78，2.83-2.96，2.99-3.30，3.30-3.51，3.80，3.96-4.14，6.80，6.97，7.23。
Embodiment 28 (10)
N 2-(2-chloro-4-methoxyphenyl)-N 2-(2-methoxyethyl)-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
TLC:Rf0.41 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ7.21，6.97，6.80，4.23-4.39，3.80，3.51-3.78，3.31，3.05-3.26，2.85-2.93，2.65-2.75，1.87-2.01，1.33-1.50，0.66-0.79。
Embodiment 28 (11)
N 2-ethyl-N 2-mesityl-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines:
According to (using 2 with embodiment 3,4-dimethyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine) → and the identical step of series reaction among embodiment 4 (using corresponding aniline) → embodiment 5 (using corresponding halogenide) prepares title compound, and it has following physical parameter:
TLC:Rf0.52 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，DMSO-d 6)：δ0.70，1.11，1.39，1.89，2.00，2.23，2.53，2.87，3.18，3.72，6.86。
Embodiment 29 (1)-embodiment 29 (10)
Use the compound and the corresponding halogenide of embodiment 4 (12) preparations, prepare following compound according to the step identical with series reaction among the embodiment 5.
Embodiment 29 (1)
N 5-(2-chloro-4-methoxyphenyl)-N 5-ethyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.20 (hexane: ethyl acetate=8: 1);
1H-NMR(300MHz，CDCl 3)：δ0.76，1.20，1.51，3.39，3.78，3.85，4.19，4.72，6.12，6.90，7.08，7.20，7.81。
Embodiment 29 (2)
N 5-(2-chloro-4-methoxyphenyl)-N 5-(2-methyl-2-propenyl)-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.25 (hexane: ethyl acetate=8: 1);
1H-NMR(300MHz，CDCl 3)：δ0.77，1.55，1.82，3.42，3.84，3.99，4.80，5.07，6.10，6.86，7.06，7.22，7.80。
Embodiment 29 (3)
N 5-allyl group-N 5-(2-chloro-4-methoxyphenyl)-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.21 (hexane: ethyl acetate=8: 1);
1H-NMR(300MHz，DMSO-d 6)：δ0.69，1.46，3.43，3.80，4.16，4.73，5.09，5.92，6.00，7.02，7.22，7.34，7.81。
Embodiment 29 (4)
N 5-(2-chloro-4-methoxyphenyl)-N 5-(cyclopropyl methyl)-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.50 (hexane: ethyl acetate=6: 1);
1H-NMR(300MHz，CDCl 3)：δ0.06-0.20，0.34-0.46，0.76，1.00-1.18，1.42-1.60，3.33-3.56，3.85，4.03-4.23，4.73，6.11，6.89，7.06，7.29，7.80。
Embodiment 29 (5)
N 5-(2-chloro-4-methoxyphenyl)-N 5-[2-(dimethylamino) ethyl]-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5,7-diamines tri hydrochloride:
TLC:Rf0.42 (chloroform: methyl alcohol=9: 1);
1H-NMR(300MHz，CDCl 3)：δ0.80，1.53-1.72，2.96，3.05，3.42-3.76，3.86，3.88-3.95，4.39-4.40，4.53-4.66，4.80-4.93，6.90，7.06，7.10，7.55，7.87。
Embodiment 29 (6)
N 5-(2-chloro-4-methoxyphenyl)-N 5-[3-(dimethylamino) propyl group]-N 7, N 7-propyl group pyrazolo [1,5-a] pyrimidine-5,7-diamines mesylate:
TLC:Rf0.38 (chloroform: methyl alcohol=9: 1);
1H-NMR(300MHz，CDCl 3)：δ0.78，1.47-1.66，2.16-2.40，2.80，2.93，3.21-3.35，3.37-3.63，3.73-3.93，4.11-4.31，4.51，6.24-6.60，7.00，7.09，7.39，7.83。
Embodiment 29 (7)
N 5-(2-chloro-4-methoxyphenyl)-N 5, N 7, N 7-tripropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.56 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ7.80，7.20，7.07，6.89，6.11，4.66-4.75，3.95-4.23，3.85，3.51-3.72，3.34-3.45，1.42-1.70，0.94，0.76。
Embodiment 29 (8)
N 5-(2-chloro-4-methoxyphenyl)-N 5-(2-methoxyethyl)-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.57 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ7.81，7.31，7.05，6.89，6.11，4.73，4.35-4.55，3.84，3.55-3.81，3.40，3.32，1.43-1.59，0.76。
Embodiment 29 (9)
Ethyl { (2-chloro-4-methoxyphenyl) [7-(dipropyl amino) pyrazolo [1,5-a] pyrimidine-5-yl] amino } acetate:
TLC:Rf0.61 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ7.80，7.62，7.06，6.88，6.08，5.11-5.33，4.83，4.15-4.28，3.75-3.98，3.38-3.48，1.46-1.60，1.28，0.77。
Embodiment 29 (10)
N 5-(2-chloro-4-methoxyphenyl)-N 5-(methoxyl methyl)-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.57 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，DMSO-d 6)：δ7.80，7.38，7.18，7.04，6.00，5.19，4.92，3.84，3.48-3.57，3.37，1.44-1.60，0.76。
Embodiment 30
6-methyl-5-(5-methyl-2,3-dihydro-1H-indoles-1-yl)-N, N-dipropyl pyrazolo [1,5-a] pyrimidine-7-amine:
To use 5,7-two chloro-6-methylpyrazoles also [1,5-a] pyrimidine, the compound dissolution for preparing according to the step identical with series reaction among the embodiment 3 in N, in the N-methylimidazole alkane ketone (2.5mL).Under argon gas atmosphere, in room temperature, in the mixture of above-mentioned solution and indoline (149mg), add three (diphenylmethylene acetone) two palladiums (34mg), N, N-two-2,4,6-trimethylphenyl imidazolium salts hydrochlorate (25mg) and six dimethyl, two silicon sodiumazide (sodium hexadimethyldisilazide) are (275mg).In argon gas atmosphere, under 100 ℃, stirred the mixture 1 hour.After the reaction mixture cooling, in mixture, add saturated aqueous ammonium chloride (2.0mL) with termination reaction.In mixture, add entry (3.0mL), hexane (4.0mL) and ethyl acetate (1.0mL), then it was stirred 10 minutes.After separating organic layer, water layer extracts with the mixture (4: 1) of hexane and ethyl acetate.The organic layer that merges is with anhydrous magnesium sulfate drying and concentrating under reduced pressure.In resistates, add tetrahydrofuran (THF) (2.0mL) and pyridine (0.3mL).Tetrahydrofuran (THF) (1.3mL) solution that in mixture, adds Tetra hydro Phthalic anhydride then.Mixture at room temperature stirred 30 minutes.The Tutofusin tris resin (trisamine resin) of reaction mixture by being supported by polystyrene, after tetrahydrofuran (THF) washing three times, solution decompression concentrates.Resistates by the column chromatography purifying (hexane: acetone=5: 1) obtain title compound (136mg), it has following physical parameter:
TLC:Rf0.48 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ7.93，7.04，6.90，6.48，6.31，4.11，3.38-3.59，3.08，2.29，2.14，1.47-1.66，0.88。
Embodiment 31
5-(5-methyl-2,3-dihydro-1H-indoles-1-yl)-N, N-dipropyl pyrazolo [1,5-a] pyrimidine-7-amine:
Use is by utilizing 5,7-dichloro pyrazolo [1,5-a] pyrimidine, the compound for preparing according to the step identical with series reaction among the embodiment 3, prepare title compound according to the step identical with series reaction among the embodiment 30, it has following physical parameter:
TLC:Rf0.61 (toluene: ethyl acetate=9: 1);
1H-NMR(300MHz，CDCl 3)：δ7.98，7.87，6.92-7.07，6.19，5.66，4.13，3.59-3.74，3.15，2.31，1.61-1.79，0.93。
Embodiment 31 (1)
5-(5-chloro-1H-indoles-1-yl)-N, N-dipropyl pyrazolo [1,5-a] pyrimidine-7-amine:
Use corresponding compounds, prepare title compound according to the step identical with series reaction among the embodiment 31, it has following physical parameter:
TLC:Rf0.64 (toluene: ethyl acetate=9: 1);
1H-NMR(300MHz，CDCl 3)：δ8.23，7.98，7.69，7.60，7.25，6.63，6.43，6.02，3.65-3.94，1.67-1.90，0.98。
Embodiment 32
Imidazo [1,2-a] pyrimidine-5, the 7-glycol:
Under argon gas atmosphere, sodium (1.39g) is added in the ethanol (36mL) bit by bit, stir ethanolic soln then and dissolve fully up to sodium.In above-mentioned solution, drip the solution of 2-aminooimidazole 1/2 hydrochloride (4.00g) and diethyl malonate (4.6mL) successively.Mixture refluxed 6 hours down at 90 ℃.After reaction mixture is cooled to room temperature, concentrating under reduced pressure.In resistates, add entry (50mL).Solution stirs in ice bath by adding 5N hydrochloric acid (10mL) acidifying (pH=1) simultaneously.By the vacuum filtration collecting precipitation, vacuum-drying obtains title compound, and it has following physical parameter:
1H-NMR(300MHz，CDCl 3)：δ4.97，7.33，7.41，10.39-12.49。
Embodiment 33
5, the 7-dichloro-imidazole is [1,2-a] pyrimidine also:
Under argon gas atmosphere, phosphoryl chloride (12.4g) is dropped in the compound (680mg) of embodiment 32 preparations.Mixture stirred 4 hours down at 100 ℃.After the reaction mixture cooling, concentrating under reduced pressure.Resulting resistates slowly is dissolved in the frozen water.Solution by add sodium bicarbonate nitrated after, use ethyl acetate extraction.Organic layer water and the washing of standard physiological saline, dried over mgso is filtered and concentrating under reduced pressure obtains title compound (680mg), and it has following physical parameter:
TLC:Rf0.63 (ethyl acetate);
1H-NMR(300MHz，CDCl 3)：δ7.05，7.71，7.86。
Embodiment 34
N 7-(2-chloro-4-methoxyphenyl)-N 7-ethyl-N 5, N 5-dipropyl imidazo [1,2-a] pyrimidine-5, the 7-diamines:
Use is by the compound that utilizes corresponding halogenide, prepares in embodiment 33 → embodiment 4 → embodiment 5, prepares title compound according to the step identical with series reaction among the embodiment 3, and it has following physical parameter:
TLC:Rf0.23 (ethyl acetate: methyl alcohol=9: 1);
1H-NMR(300MHz，CDCl 3)：δ0.80，1.22，1.36-1.59，2.84-3.06，3.75-3.86，3.86，4.14-4.39，5.02，6.90，7.08，7.12，7.19，7.37。
Embodiment 34 (1)-embodiment 34 (13)
According to embodiment 3 (using the compound or the corresponding compounds of embodiment 33 preparations) → embodiment 4 in the identical step of series reaction, perhaps prepare following compound according to the step identical with series reaction among embodiment 3 (using the compound or the corresponding compounds of embodiment 33 preparations) → embodiment 4 → embodiment 5 (using corresponding halogenide).
Embodiment 34 (1)
N 7-allyl group-N 7-(2-chloro-4-methoxyphenyl)-N 5, N 5-dipropyl imidazo [1,2-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.45 (chloroform: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ7.37，7.17，7.13，7.06，6.87，5.98-6.14，4.91-5.15，4.19，3.85，2.94-3.02，1.40-1.55，0.80。
Embodiment 34 (2)
N 7-(2-chloro-4-methoxyphenyl)-N 5, N 5, N 7-tripropyl imidazo [1,2-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.44 (chloroform: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ7.37，7.20，7.12，7.07，6.90，5.02，4.08-4.23，3.86，3.61-3.74，2.92-3.02，1.62-1.75，1.40-1.56，0.93，0.80。
Embodiment 34 (3)
N 7-(2-chloro-4-methoxyphenyl)-N 7-(2-methoxyethyl)-N 5, N 5-dipropyl imidazo [1,2-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.36 (chloroform: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ7.38，7.32，7.12，7.04，6.90，5.05，4.44-4.57，3.70-3.93，3.59-3.69，3.31，2.92-3.03，1.40-1.56，0.80。
Embodiment 34 (4)
N 7-(2-chloro-4-methoxyphenyl)-6-methoxyl group-N 5-(2-methoxyethyl)-N 5-propyl imidazole is [1,2-a] pyrimidine-5 also, the 7-diamines:
TLC:Rf0.49 (chloroform: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ9.01，7.79，7.40，7.35，6.97，6.90，3.89，3.81，3.48-3.60，3.32-3.42，3.29，1.51-1.66，0.89。
Embodiment 34 (5)
6-methoxyl group-N 5, N 5-dipropyl-N 7-(2) imidazo [1,2-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.52 (chloroform: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ8.28，7.38，7.21，7.04，6.95，3.82，3.22-3.33，2.28，2.21，1.54-1.70，0.90。
Embodiment 34 (6)
N 7-(2-chloro-4-methoxyphenyl)-6-methoxyl group-N 5, N 5-dipropyl imidazo [1,2-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.50 (chloroform: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ9.00，7.78，7.40，7.24，6.97，6.90，3.86，3.81，3.23-3.33，1.54-1.69，0.90。
Embodiment 34 (7)
N 7-(2,4 dichloro benzene base)-6-methoxyl group-N 5, N 5-dipropyl imidazo [1,2-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.5 (ethyl acetate: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ9.19，8.00，7.45，7.39，7.30，7.27，3.86，3.24-3.39，1.52-1.71，0.90。
Embodiment 34 (8)
N 7-(4-chloro-2-aminomethyl phenyl)-6-methoxyl group-N 5, N 5-dipropyl imidazo [1,2-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.51 (chloroform: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ8.70，7.40，7.21-7.26，7.15-7.18，3.84，3.25-3.33，2.33，1.55-1.69，0.90。
Embodiment 34 (9)
4-{[5-(dipropyl amino)-6-methoxyl group imidazo [1,2-a] pyrimidin-7-yl] amino }-3-ethyl benzonitrile:
TLC:Rf0.71 (chloroform: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ9.16，7.55-7.62，7.45-7.49，7.28，3.85，3.28-3.36，2.72，1.56-1.70，1.36，0.91。
Embodiment 34 (10)
6-methoxyl group-N 7-(4-methoxyl group-2-aminomethyl phenyl)-N 5, N 5-dipropyl imidazo [1,2-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.42 (chloroform: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ8.28，7.36，7.20，6.95，6.74-6.85，3.83，3.80，3.22-3.33，2.32，1.54-1.70，0.90。
Embodiment 34 (11)
N 7-(2-ethyl-4-aminomethyl phenyl)-6-methoxyl group-N 5, N 5-dipropyl imidazo [1,2-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.32 (chloroform: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ8.45，7.37，7.21，7.17，7.08，7.02，3.83，3.21-3.34，2.67，2.33，1.53-1.70，1.29，0.90。
Embodiment 34 (12)
N 7-(4-chloro-2-ethylphenyl)-6-methoxyl group-N 5, N 5-dipropyl imidazo [1,2-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.41 (chloroform: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ8.68，7.40，7.20-7.26，7.17，3.84，3.25-3.33，2.67，1.54-1.70，1.31，0.90。
Embodiment 34 (13)
6-methoxyl group-N 7-(4-methyl-2-ethenylphenyl)-N 5, N 5-dipropyl imidazo [1,2-a] pyrimidine-5, the 7-diamines:
TLC:Rf0.33 (chloroform: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ8.50，7.38，7.29，7.21，7.18-7.21，7.15，6.88，5.69，5.43，3.81，3.23-3.33，2.34，1.54-1.69，0.90。
Embodiment 35
N 7-mesityl-6-methyl-N 5, N 5-dipropyl imidazo [1,2-a] pyrimidine-5, the 7-diamines:
The compound that use prepares according to the step identical with series reaction among embodiment 32 → embodiment 33, and corresponding aniline, prepare title compound according to the step identical with series reaction among the embodiment 4, it has following physical parameter:
TLC:Rf0.21 (methylene dichloride: methyl alcohol=9: 1);
1H-NMR(300MHz，CDCl 3)：δ0.89，1.54，2.19，2.24，2.29，3.17，5.84，6.90，7.19，7.28。
Embodiment 36
N-(2-chloro-4-methoxyphenyl)-N-methylguanidine:
2-chloro-4-methoxyphenyl monomethylaniline (2.0g) and cyanamide (cyanamide) (490mg) are suspended in the water (12mL).At room temperature add concentrated hydrochloric acid (0.97mL) in suspension, mixture was 90 ℃ of following heated and stirred 9 hours subsequently.After the reaction mixture cooling, solids removed by filtration.Concentrated filtrate.In resistates, add ethyl acetate and methyl alcohol.Collect resulting solid by filtering, vacuum-drying obtains title compound (1.4g), and it has following physical parameter:
TLC:Rf0.03 (chloroform: methyl alcohol=10: 1);
1H-NMR(300MHz，CDCl 3)：δ7.46，7.24，7.04，3.81，3.17。
Embodiment 37
N-(2-chloro-4-methoxyphenyl)-N-methyl-6-(methylthio group)-1,3,5-triazines-2, the 4-diamines
Under 40 ℃, to the compound (400mg) of embodiment 36 preparation and nitrilimine (iminonitrile) (233mg) in the suspension in water (1.6mL), adding potassium hydroxide aqueous solution (KOH 180mg, H 2O 1.6mL).Mixture stirred 2 hours.After reaction mixture is cooled to room temperature, collect the solid that is generated, vacuum-drying by filtering.Solid is dissolved in the hexane/ethyl acetate (1/1), by the column chromatography purifying (hexane: ethyl acetate=1: 1) obtain title compound (360mg), it has following physical parameter:
TLC:Rf0.47 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ7.27，7.08，6.94，6.50，3.81，3.28，2.09-2.41。
Embodiment 38
N-(2-chloro-4-methoxyphenyl)-N-methyl-4-(methylthio group) imidazo [1,2-a] [1,3,5] triazine-2-amine:
At room temperature, water (0.07mL) and Hydrogen bromide (0.07mL) are added in the bromoacetaldehyde dimethylacetal (291mg), mixture heating up refluxed 30 minutes.After the reaction mixture cooling, in mixture, add dimethoxy ethane (1.0mL).Then it is neutralized with sodium bicarbonate.Solution washs and filters with dimethoxy ethane.At room temperature, the compound (360mg) that in filtrate, adds embodiment 37 preparations.Mixture heating up refluxed 3.5 hours.After the reaction mixture cooling, concentrating under reduced pressure.Resulting resistates by the column chromatography purifying (hexane: ethyl acetate=50: 50, hexane: ethyl acetate=0: 100, methylene dichloride: methyl alcohol=20: 1) obtain title compound (50mg), it has following physical parameter:
TLC:Rf0.21 (hexane: ethyl acetate=1: 2);
1H-NMR(300MHz，CDCl 3)：δ7.35，7.20，7.09，7.01，6.85，3.84，3.48，2.22。
Embodiment 39
N 2-(2-chloro-4-methoxyphenyl)-N 2-methyl-N 4, N 4-dipropyl imidazo [1,2-a] [1,3,5] triazine-2, the 4-diamines:
3-aminopentane (1.0mL) is added in the compound (49mg) of embodiment 38 preparations.Mixture heating up refluxed 10 hours.After the reaction mixture cooling, concentrating under reduced pressure.Resulting resistates is by the column chromatography purifying, and 100% eluent ethyl acetate obtains title compound (22mg), and it has following physical parameter:
TLC:Rf0.25 (ethyl acetate);
1H-NMR(300MHz，CDCl 3)：δ0.74，1.53，3.21，3.42，3.80，6.81，6.97，7.07，7.15，7.24。
Embodiment 40
N 2-(2-chloro-4-methoxyphenyl)-N 4-(1-ethyl propyl)-N 2-thiotolene is [3,2-d] pyrimidine-2 also, the 4-diamines:
According to (using 2-ethylmercapto group thieno-[3 with embodiment 4,2-d] pyrimidin-4-one (2-ethylthiothieno[3,2-d] pyrimidin-4-one) (being described among the JP 3-17083)) → the identical step of series reaction among embodiment 5 → embodiment 3 (using corresponding amine), prepare title compound, it has following physical parameter:
TLC:Rf0.18 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ0.80，1.45，3.44，3.67，3.83，4.26，6.84，7.01，7.22，7.51。
Embodiment 40 (1)
N 2-(2-chloro-4-methoxyphenyl)-N 2-methyl-N 4, N 4-dipropyl thieno-[3,2-d] pyrimidine-2, the 4-diamines:
TLC:Rf0.36 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CDCl 3)：δ0.77，1.50，3.30，3.44，3.81，6.83，7.00，7.22，7.54。
Embodiment 41
N 2-(2-chloro-4-methoxyphenyl)-N 4-(1-ethyl propyl)-N 2-thiotolene is [2,3-d] pyrimidine-2 also, the 4-diamines:
According to (using 2-ethylmercapto group thieno-[2 with embodiment 4,3-d] pyrimidin-4-one (be described in US4,146,716 in)) → the identical step of series reaction among embodiment 5 → embodiment 3 (using corresponding amine), prepare title compound, it has following physical parameter:
TLC:Rf0.24 (hexane: ethyl acetate=6: 1);
1H-NMR(300MHz，CDCl 3)：δ0.78，1.43，3.43，3.63，3.83，4.54，6.83，6.91，7.00，7.21。
Embodiment 42
4-(dipropyl amino)-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2-carboxylic acid, ethyl ester:
Under argon gas atmosphere, under room temperature to by using 2,4-two chloro-6,7-dihydro-5H-cyclopentano [d] pyrimidine, the compound for preparing according to the step identical with series reaction among the embodiment 3 adds palladium (8.8mg), diphenylphosphine ferrocene (diphenylphosphinoferrocene) (22g) and salt of wormwood (89mg) in the solution of dehydrated alcohol (1.4mL) and dimethyl formamide (0.7mL).After the carbon dioxide displacement, mixture heating up refluxed 1 hour.After the reaction mixture cooling, add ammonium chloride saturated aqueous solution with termination reaction.The mixture ethyl acetate extraction.Organic layer water and saturated aqueous sodium chloride washing, anhydrous magnesium sulfate drying and concentrating under reduced pressure.Resistates by the column chromatography purifying (hexane: ethyl acetate=1: 1) obtain title compound (80mg), it has following physical parameter:
TLC:Rf0.26 (hexane: ethyl acetate=1: 1);
1H-NMR(300MHz，CDCl 3)：δ4.34-4.57，3.36-3.69，3.06，2.94，1.93-2.22，1.51-1.78，1.35-1.52，0.74-1.08。
Embodiment 43
(2-chloro-4-methoxyphenyl) [4-(dipropyl amino)-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2-base] ketone:
At room temperature, in 3-chloro-4-bromine phenylmethylether (3-chloro-4-bromoaniso1) tetrahydrofuran (THF) (2.3mL) solution (1.0mg), drip bromination isopropyl-magnesium (2.3mL, 2.0M tetrahydrofuran solution).Mixture stirred 2 hours.Under-30 ℃, solution is added in tetrahydrofuran (THF) (3.0mL) solution of compound (190mg) of embodiment 42 preparation.Mixture stirred 30 minutes down at-10 ℃.In reaction mixture, add ammonium chloride saturated aqueous solution with termination reaction.The mixture ethyl acetate extraction.Organic layer washs with saturated aqueous sodium chloride, anhydrous magnesium sulfate drying and concentrating under reduced pressure.Resulting resistates by the column chromatography purifying (hexane: acetone=2: 1) obtain title compound (84.2mg), it has following physical parameter:
TLC:Rf0.27 (hexane: acetone=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.76，1.42-1.58，1.95-2.18，2.96，3.06，3.22-3.40，3.84，6.85，6.90，7.55。
Embodiment 44
1-(2-chloro-4-methoxyphenyl) cyclopropane nitrile:
Under 0 ℃, in dimethyl formamide (16.0mL) suspension of sodium hydride (1.0g), drip dimethyl formamide (10.0mL) solution of 2-chloro-4-methoxy-phenyl-acetonitrile (2.0g).Mixture at room temperature stirred 1 hour.Under 0 ℃, (1.1mL) drops in the mixture with glycol dibromide.Mixture at room temperature stirred 20 minutes.After reaction mixture is cooled to 0 ℃, in mixture, add entry with termination reaction.Mixture extracts three times with the mixture (4: 1) of hexane and ethyl acetate.Organic layer water that merges and saturated aqueous sodium chloride washing, anhydrous magnesium sulfate drying and concentrating under reduced pressure.Resulting resistates by the column chromatography purifying (hexane: ethyl acetate=8: 1, hexane: ethyl acetate=4: 1) obtain title compound, it has following physical parameter:
TLC:Rf0.35 (hexane: ethyl acetate=4: 1);
1H-NMR(300MHz，CHCl 3-D)：δ7.25，6.97，6.78，3.80，1.60-1.80，1.17-1.40。
Embodiment 45
1-(2-chloro-4-methoxyphenyl) encircles propionyl imines carboxylic acid amide (1-(2-chloro-4-methoxyphenyl) cyclopropanimidocarboxylic acid amide):
In ice bath, in dry toluene (4.0mL) suspension of ammonium chloride (433mL), add trimethyl aluminium (3.9mL, 2.0M toluene solution).Mixture at room temperature stirred 2 hours.Toluene (3.8mL) solution that in mixture, adds the compound (800mg) of embodiment 44 preparations.Mixture stirred 2 days down at 80 ℃.After the reaction mixture cooling,, stirred then 10 minutes the suspension of its slow impouring silica gel (3.0g) in chloroform (10mL).Reaction mixture is by diatomite filtration, and filtrate decompression concentrates.In resistates, add 2N hydrochloric acid (5.0mL), use the diethyl ether decantation.Water layer adds sodium-chlor then by adding 5N aqueous sodium hydroxide solution (3.0mL) neutralization.Solution extracts three times with tetrahydrofuran (THF).Organic layer anhydrous magnesium sulfate drying, concentrating under reduced pressure obtain title compound (740mg), and it has following physical parameter:
TLC:Rf0.17 (methylene dichloride: methyl alcohol=9: 1);
1H-NMR(300MHz，CHCl 3-D)：δ7.38，7.04，6.90，3.76，1.39-1.74，0.91-1.24。
Embodiment 46
2-[1-(2-chloro-4-methoxyphenyl) cyclopropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-4-alcohol:
At room temperature, sodium hydroxide (163mg) is dissolved in the ethanol (3.7mL), in this solution, adds the compound (640mg) and the 2-oxygen basic ring pentane carboxylic acid, ethyl ester (0.78mL) of embodiment 45 preparations.Mixture heating up refluxed 5 hours.After the reaction mixture cooling, add entry in mixture, mixture is by adding the neutralization of 1N hydrochloric acid then.The mixture ethyl acetate extraction.Organic layer washs with saturated aqueous sodium chloride, anhydrous magnesium sulfate drying and concentrating under reduced pressure.Add hexane in resulting resistates, resulting solid by filtration is collected and is dry, obtains title compound (630mg), and it has following physical parameter:
TLC:Rf0.43 (hexane: ethyl acetate=1: 2);
1H-NMR(300MHz，CHCl 3-D)：δ7.34，7.02，6.87，3.85，2.64-2.96，1.98-2.17，1.81-1.96，1.30-1.43。
Embodiment 47
4-chloro-2-[1-(2-chloro-4-methoxyphenyl) cyclopropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine:
In the compound (600mg) of embodiment 46 preparations, add phosphoryl chloride (2.0mL).Mixture heating up refluxed 20 minutes.After the reaction mixture cooling, in the impouring ice bath.The mixture ethyl acetate extraction.Organic layer washs with saturated aqueous solution of sodium bicarbonate and saturated aqueous sodium chloride, and anhydrous magnesium sulfate drying and concentrating under reduced pressure obtain title compound (660mg), and it has following physical parameter:
TLC:Rf0.57 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CHCl 3-D)：δ7.30，6.95，6.80，3.81，2.77-3.01，1.98-2.19，1.74-1.88，1.27-1.43。
Embodiment 48
2-[1-(2-chloro-4-methoxyphenyl) cyclopropyl]-N, N-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-4-amine:
With 3-aminopentane (1.0mL) vlil of the compound (300mg) of embodiment 47 preparation 24 hours.After the reaction mixture cooling, in its impouring water.The mixture ethyl acetate extraction.Organic layer washs with saturated aqueous sodium chloride, anhydrous magnesium sulfate drying and concentrating under reduced pressure.Resulting resistates by the column chromatography purifying (hexane: ethyl acetate=5: 1) obtain title compound (152mg), it has following physical parameter:
TLC:Rf0.35 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CHCl 3-D)：δ0.71，1.21，1.39，1.74，1.94，2.74，2.92，3.15，3.78，6.75，6.91，7.27。
Embodiment 49
4-(2-chloro-4-methoxyphenyl)-2-methyl-3-ketobutyric acid methyl esters:
Under argon gas atmosphere, with tetrahydrofuran (THF) (16mL) the solution backflow of zinc powder (1.81g).In this mixture, drip 2-bromide methyl butyrate (4), add 2-chloro-4-methoxy-phenyl-acetonitrile (1.0g), drip 2-bromo propionic acid A ester (2.46mL) then.Mixture refluxed 10 minutes.After the reaction mixture cooling, dilute with tetrahydrofuran (THF).Add 50% wet chemical in the solution after dilution, mixture stirred 30 minutes.Reaction mixture washs with tetrahydrofuran (THF) after filtering.In filtrate, add 2N hydrochloric acid (6mL).Mixture stirs after 30 minutes and concentrates.Resistates by the silica gel column chromatography purifying (hexane: ethyl acetate=92: 8 → 71: 29) obtain title compound (1.22g), it has following physical parameter:
TLC:Rf0.55 (hexane: ethyl acetate=2: 1).
Embodiment 50
5-(2-chloro-4-methoxybenzyl)-6-methylpyrazole is [1,5-a] pyrimidin-7-ol also:
Acetate (4.0mL) solution of the compound (886mg) of 3-amino-pyrazol (272mg) and embodiment 49 was refluxed 2 hours.After the reaction mixture cooling, dilute with ethyl acetate.Product is collected by filtering, and obtains title compound (421mg), and it has following physical parameter:
TLC:Rf0.52 (chloroform: methyl alcohol=10: 1).
Embodiment 51
7-chloro-5-(2-chloro-4-methoxybenzyl)-6-methylpyrazole is [1,5-a] pyrimidine also:
Under argon gas atmosphere, in toluene (5.0mL) solution of the compound (511mg) that embodiment 50 prepares, add Diethyl Aniline (270 μ L) and phosphoryl chloride (776mg).Mixture refluxed 2.5 hours.After the reaction mixture cooling, the impouring frozen water adds saturated aqueous solution of sodium bicarbonate in this solution.The solution ethyl acetate extraction.Solution with water after the extraction and saturated aqueous sodium chloride washing, anhydrous magnesium sulfate drying also concentrates.Resistates by the silica gel column chromatography purifying (hexane: ethyl acetate=92: 8 → 71: 29) obtain title compound (528mg), it has following physical parameter:
TLC:Rf0.54 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CHCl 3-D)：δ8.12，6.98，6.94，6.72，6.68，4.28，3.79，2.35。
Embodiment 52
5-(2-chloro-4-methoxybenzyl)-6-methyl-N-(1-ethyl propyl) pyrazolo [1,5-a] pyrimidine-7-amine:
Use the compound (150mg) and the 3-aminopentane (220 μ L) of embodiment 51 preparations, prepare title compound (175mg) according to the step identical with series reaction among the embodiment 3, it has following physical parameter:
TLC:Rf0.57 (hexane: ethyl acetate=2: 1);
1H-NMR(300MHz，CDCl 3)：δ7.95，6.96，6.89，6.67，6.44，6.02，4.20，3.82-3.95，3.77，2.16，1.49-1.72，0.93。
Embodiment 52 (1)-embodiment 52 (4)
Use corresponding compounds, prepare following compound according to the step identical with series reaction among embodiment 49 → embodiment 50 → embodiment 51 → embodiment 52.
Embodiment 52 (1)
5-[1-(2-chloro-4-methoxyphenyl) cyclopropyl]-N, N-dipropyl pyrazolo [1,5-a] pyrimidine-7-amine:
TLC:Rf0.59 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ0.78，1.25-1.33，1.46-1.65，1.85-1.94，3.42-3.58，3.83，5.39，6.33，6.85，6.99，7.38，7.91。
Embodiment 52 (2)
5-(2-chloro-4-methoxybenzyl)-6-methyl-N, N-dipropyl pyrazolo [1,5-a] pyrimidine-7-amine:
TLC:Rf0.64 (hexane: ethyl acetate=3: 1);
1H-NMR(300MHz，CDCl 3)：δ8.01，6.97，6.91，6.69，6.54，4.22，3.78，3.32-3.42，2.17，1.37-1.54，0.75-0.87。
Embodiment 52 (3)
5-2,4,6-trimethylphenyl methyl-6-methyl-N, N-dipropyl pyrazolo [1,5-a] pyrimidine-7-amine:
TLC:Rf0.64 (hexane: ethyl acetate=5: 1);
1H-NMR(300MHz，CDCl 3)：δ0.84，1.40-1.55，2.18，2.30，2.36，3.32-3.42，4.09，6.40，6.89，7.92。
Embodiment 52 (4)
5-(2, the 4-dichloro benzyl)-6-methyl-N, N-dipropyl pyrazolo [1,5-a] pyrimidine-7-amine:
TLC:Rf0.63 (hexane: ethyl acetate=4: 1);
1H-NMR(300?MHz，CDCl 3)：δ0.82，1.38-1.55，2.18，3.29-3.48，4.24，6.53，6.97，7.13，7.43，8.01。
Embodiment 53:
5-(4-chloro-2-methylphenoxy)-6-methyl-N, N-dipropyl pyrazolo [1,5-a] pyrimidine-7-amine:
To 5-chloro-6-methyl-N, in dimethyl formamide (3.0mL) solution of N-dipropyl pyrazolo [1,5-a] pyrimidine-7-amine (150mg), add 4-chloro-neighbour-cresols (96mg) and cesium carbonate (276mg).Mixture stirred 5 hours down at 80 ℃.Reaction mixture dilutes with ethyl acetate.Solution with water after the dilution and saturated aqueous sodium chloride washing, anhydrous magnesium sulfate drying also concentrates.Resistates by the silica gel column chromatography purifying (hexane: ethyl acetate=100: 0 → 95: 5) obtain title compound (190mg), it has following physical parameter:
TLC:Rf0.60 (hexane: ethyl acetate=7: 1);
1H-NMR(300MHz，CDCl 3)：δ7.87，7.24-7.28，7.18-7.24，7.07，6.21，3.40-3.48，2.33，2.16，1.46-1.61，0.88。
Embodiment 53 (1)-embodiment 53 (2)
Use corresponding compounds, prepare following compound according to the step identical with series reaction among the embodiment 53.
Embodiment 53 (1)
5-(4-ethyl-2-methoxy phenoxy)-6-methyl-N, N-dipropyl pyrazolo [1,5-a] pyrimidine-7-amine:
Use corresponding compounds, prepare title compound according to the step identical with series reaction among the embodiment 53, it has following physical parameter:
TLC:Rf0.36 (hexane: ethyl acetate=7: 1);
1H-NMR(300MHz，CDCl 3)：δ0.87，1.28，1.45-1.60，2.35，2.69，3.37-3.47，3.75，6.20，6.80-6.87，7.07，7.85。
Embodiment 53 (2)
5-[(3-chloro-1,1 '-biphenyl-4-yl) the oxygen base]-6-methyl-N, N-dipropyl pyrazolo [1,5-a] pyrimidine-7-amine:
TLC:Rf0.40 (hexane: ethyl acetate=10: 1);
1H-NMR(300MHz，CDCl 3)：δ0.88，1.48-1.62，2.39，3.42-3.50，6.24，7.32-7.41，7.41-7.50，7.50-7.64，7.70，7.88。
Pharmacologically active
Formula of the present invention (I) compound has the CRF receptor antagonist activity, has for example confirmed this effect of The compounds of this invention by following test.
Test 1
In conjunction with measuring:
＜preparation cytolemma 〉
(expressed clone: the CHO-K1 cell) be cultured to reach and converge back (reached confluence), cell is gathered with scraper plate with the clone of expressing human CRF acceptor 1.The cell PBS washed twice of gathering, be suspended in then ice-cooled in conjunction with the mensuration damping fluid (Tris-HCl (50mM, pH 7.0), EDTA (and 2mM, pH8.0), MgCl 2(10mM)).The Downs type homogenizer homogenize of cell after the suspension, then with 10,000g carries out centrifugally operated to it, collection membrane part (membrane fraction).The cytolemma part of gathering suspends in conjunction with measuring damping fluid with a small amount of once more, further is diluted to 1mg/mL with described damping fluid then.Resulting membrane portions is used in conjunction with measuring.
＜in conjunction with measuring 〉
To measure the 50 μ L[that buffer preparation becomes 0.5nM with combination 125I] h/r CRF is added in the 1.5mL test tube of siliconizing.The compound, DMSO (being used for total combination uses) or the h/r CRF solution (100 μ M are used for non-specific binding and use) that respectively 1 μ L are diluted to suitable multiple add test tube.The sample of 50 each membrane portions product of μ L is added in the test tube, with initiation reaction ([ 125I] ultimate density of h/r CRF: 0.25nM), mixture was at room temperature cultivated 2 hours then.Behind the reaction terminating, with 20,000g carries out centrifugally operated to test tube, the collection membrane part.Abandoning supernatant, granule washs with the cold PBS (-) that contains 0.01%TritonX-100.Use γ-counter to measure the radioactivity value of each test tube respectively.
Each associated value deducts the non-specific binding value and obtains the specificity combination.
The result shows that compound of the present invention shows intensive avidity (IC to the CRF acceptor 50:＜1 μ M).
Test 2
Receptor antagonist activity (cAMP (ring AMP) is measured):
Use 10% N of fetal blood cleer and peaceful 37 ℃ contain microbiotic and antimycotic 1%F-12 nutritional blend, 5% carbonic acid gas, 95% air, the clone of culture expression people CRF1 acceptor.In the day before yesterday of measurement ring AMP, with cell inoculation in the 96-orifice plate, every hole 1 * 10 4Cell.Measuring the same day, cell adds F-12 nutritional blend/1mM 3-isobutyl--1-methyl xanthin (mensuration substratum) (178 μ L) with F-12 nutritional blend washed twice in each hole.Cultivation is after 10 minutes down at 37 ℃ with them, and the solution (2 μ L) of the various concentration of adding test compounds perhaps adds DMSO (2 μ L) in CRF group and blank the group.Cultivation is after 15 minutes down at 37 ℃, and adding 10nM contains the mensuration substratum (20 μ L) of people/rat CRF in test compounds group and CRF group.In the blank group, add the mensuration substratum (20 μ L) that contains 0.00001% acetate.Continuation is cultivated them 15 minutes down at 37 ℃.Remove supernatant liquor, use ice-cooled termination reaction.In addition, all reactions are undertaken by 3 holes.Intracellular ring AMP integral dose is measured by Biotrak enzyme immunizing dose system (Amersham Biosciences).The mean value that deducts blank group three holes from the mean value in three holes obtains encircling the integral dose of AMP.The logarithm concentration of using compound is as independent variable(s), and ring AMP integral dose is calculated IC as dependent variable by non-linear regression 50Value.
The result shows that compound (1) shows intensive antagonistic activity (IC to the CRF acceptor 50:＜1 μ M).
Formulation example 1
Mix following component according to ordinary method, compressing tablet obtains 10,000 pieces of tablets that contain the 10mg activeconstituents then.
N 2-(2-chloro-4-methoxyphenyl)-N 4, N 4-dipropyl-5,7-dihydrofuran and 100g
[3,4-d] pyrimidine-2, the 4-diamines
Calcium carboxymethylcellulose (disintegrating agent) 20g
Magnesium Stearate (lubricant) 10g
Microcrystalline Cellulose 870g
Formulation example 2
Mix following component according to ordinary method., filter by cleaning apparatus solution sterilization with ordinary method, 5ml is partly placed ampoule, obtain 10,000 ampoules by the autoclave sterilization, wherein each ampoule contains the 20mg activeconstituents.
N 2-(2-chloro-4-methoxyphenyl)-N 4, N 4-dipropyl-5,7-dihydrofuran and 200g
[3,4-d] pyrimidine-2, the 4-diamines
N.F,USP MANNITOL 20g
Distilled water 50L
Industrial applicibility
For in conjunction with the CRF acceptor and demonstrate the CRF receptor antagonist activity, The compounds of this invention can be used in advance The disease anti-and/or treatment is mediated by CRF, for example neuropsychopathy, digestion property disease.

Claims (20)

1. CRF antagonist, described CRF antagonist contain compound shown in the formula (I), its salt, its N-oxide compound, its solvate or its prodrug as activeconstituents:
Figure A2004800329420002C1
Wherein encircle A and represent 5-or 6-unit monocycle, it can be selected from following substituting group by 1-3 and replace: halogen atom, CF 3, OCF 3, hydroxyl, sulfydryl, carboxyl, (C1-6 alkoxyl group) carbonyl, carbamyl, nitro, cyano group, oxo, and can be selected from halogen atom, CF by 1-3 separately 3The C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl group or the C1-6 alkylthio that replace with substituting group in the hydroxyl;
Ring B represents 5-to 7-unit monocycle unsaturated heterocycle, and it can contain except that nitrogen-atoms, W 1And W 2Outside 1 or 2 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and/or the sulphur atom that can be oxidized, and described 5-to 7-unit monocycle unsaturated heterocycle can further be substituted;
W 1And W 2Represent carbon atom or nitrogen-atoms independently of one another;
Z represents-NR 3-, R wherein 3The expression hydrogen atom separately can substituted C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl ,-CO-(can substituted C1-6 alkyl) ,-SO 2-(can substituted C1-6 alkyl), Sauerstoffatom, sulphur atom that can be oxidized, perhaps-CR 4R 5-, R wherein 4And R 5Represent independently of one another hydrogen atom or separately can substituted C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, perhaps R 4And R 5Can represent (i) oxo together, (ii) C2-5 alkylene base, one of them carbon atom can be replaced by 1 Sauerstoffatom, nitrogen-atoms or sulphur atom that can be oxidized, and wherein said C2-5 alkylene base can be replaced by one or more substituting groups, perhaps (iii) can substituted C1-6 alkylidene;
R 1Expression:
(i) separately can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl,
(ii) can protected amino,
But (iii) protected hydroxyl,
(iv) can protected sulfydryl,
(v)-S (O) nR 6, wherein n represents 1 or 2, and R 6Expression (a) separately can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl or (b) can substituted cyclic group,
(vi)-COR 7, R wherein 7Expression (a) hydrogen atom (b) separately can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, but (c) protected hydroxyl, (d) can protected amino, perhaps (e) can substituted cyclic group, perhaps
(vii) can substituted cyclic group;
R 2Expression can substituted unsaturated cyclic group, wherein said substituting group can with R 3Forming together can substituted C2-5 alkylene base.
2. the compound shown in the formula (I-A), its salt, its N-oxide compound, its solvate or its prodrug:
Wherein Expression is selected from following ring:
(1) cyclic group 1:
(2) cyclic group 2:
Figure A2004800329420004C1
Wherein encircle A and can be selected from following substituting group replacement: halogen atom, CF by 1-3 3, OCF 3, hydroxyl, sulfydryl, carboxyl, (C1-6 alkoxyl group) carbonyl, carbamyl, nitro, cyano group, oxo, and can be selected from halogen atom, CF by 1-3 separately 3The C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl group or the C1-6 alkylthio that replace with substituting group in the hydroxyl, and ring B can further be substituted;
R 1Expression:
(i) separately can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl,
(ii) can protected amino,
But (iii) protected hydroxyl,
(iv) can protected sulfydryl,
(v)-S (O) nR 6, wherein n represents 1 or 2, and R 6Expression (a) separately can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, or (b) can substitutedly encircle,
(vi)-COR 7, R wherein 7Expression (a) hydrogen atom (b) separately can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, but (c) protected hydroxyl, (d) can protected amino, or (e) can substituted cyclic group, perhaps
(vii) can substituted cyclic group;
R 1aExpression:
(i) can be substituted C1-15 alkyl or the C2-15 alkenyl that base group 1 replaces,
(ii) NR 8R 9, R wherein 8Represent (a) hydrogen atom or (b) can be substituted base separately to organize 1 C1-15 alkyl or the C2-15 alkenyl that replaces, and R 9Expression (a) hydrogen atom (b) can be substituted C1-15 alkyl or the C2-15 alkenyl that base group 1 replaces, (c)-and COR 10, R wherein 10Represent (aa) hydrogen atom or (bb) can be substituted base separately to organize 1 C1-15 alkyl or the C2-15 alkenyl that replaces, (d)-COOR 10, R wherein 10Has above-mentioned identical meanings, perhaps (e)-CON (R 8) 2, R wherein 8Have above-mentioned identical meanings independently of one another,
(iii) OR 10, R wherein 10Have above-mentioned identical meanings,
(iv) SR 10, R wherein 10Have above-mentioned identical meanings,
(v) S (O) nR 11, wherein n represents 1 or 2, and R 11Expression can be substituted C1-15 alkyl or the C2-15 alkenyl that base group 1 replaces separately, perhaps
(vi) COR 12, R wherein 12Expression (a) hydrogen atom (b) can be substituted C1-15 alkyl or the C2-15 alkenyl that base group 1 replaces separately, (c)-and OR 10, R wherein 10Has above-mentioned identical meanings, perhaps (d)-NR 8R 9, R wherein 8And R 9Has above-mentioned identical meanings;
Described substituting group group 1 expression (1) halogen atom, (2) CF 3, (3) OCF 3(4) cyano group, (5) nitro, (6) hydroxyl; (7) C1-6 alkoxyl group; (8) carboxyl, (9) (C1-6 alkoxyl group) carbonyl, (10) C1-5 acyl group; (11) wherein nitrogen-atoms can be by the carbamyl of 1 or 2 C1-6 alkyl protection; (12) C1-6 alkylthio, (13) C1-6 alkyl sulphonyl, perhaps (14) NR 13R 14, R wherein 13Expression (a) hydrogen atom, (b) C1-6 alkyl, or (c) C2-6 alkenyl, and R 14Expression (a) hydrogen atom, (b) C1-6 alkyl, (c) C2-6 alkenyl, (d)-COR 15, R wherein 15Expression (aa) hydrogen atom, (bb) C1-6 alkyl or (cc) C2-6 alkenyl, (e)-COOR 15, R wherein 15Has above-mentioned identical meanings, perhaps (f)-CON (R 16) 2, each R wherein 16Represent hydrogen atom or C1-6 alkyl independently;
Z aExpression-NR 3-, R wherein 3The expression hydrogen atom separately can substituted C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl ,-CO-(can substituted C1-6 alkyl) ,-SO 2-(can substituted C1-6 alkyl), Sauerstoffatom, sulphur atom that can be oxidized, perhaps-CR 4R 5-, R wherein 4And R 5Represent hydrogen atom independently of one another, or separately can substituted C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl, perhaps R 4And R 5Can represent (i) oxo together, (ii) C2-5 alkylene base, one of them carbon atom can be replaced by 1 Sauerstoffatom, nitrogen-atoms or sulphur atom that can be oxidized, and wherein said C2-5 alkylene base can be replaced by one or more substituting groups, perhaps (iii) can substituted C1-6 alkylidene;
R 2aExpression (1) can encircle unsaturated carbocyclics by substituted C5-12 monocycle or two, (2) can substituted pyridine, (3) can substituted bicyclic heterocycles, wherein benzene and 5-or 6-unit monocyclic heterocycles condenses, (4) can substituted bicyclic heterocycles, wherein pyridine ring and C5-6 monocycle are carbocyclic fused, and perhaps (5) can substituted bicyclic heterocycles, and wherein pyridine ring and 5-or 6-unit monocyclic heterocycles condenses.
3. according to compound, its salt, its N-oxide compound, its solvate or its prodrug of claim 2,
Wherein encircle Be
Figure A2004800329420006C2
Wherein each symbol has and implication identical described in the claim 2.
4. according to compound, its salt, its N-oxide compound, its solvate or its prodrug, the wherein R of claim 2 1Be can protected amino, or R 1aBe NR 8R 9, R wherein 8And R 9Have and implication identical described in the claim 2.
5. according to compound, its salt, its N-oxide compound, its solvate or its prodrug, the wherein Z of claim 2 aBe-NR 3-, R wherein 3Have and implication identical described in the claim 2.
6. according to compound, its salt, its N-oxide compound, its solvate or its prodrug, the wherein Z of claim 2 aBe-CR 4bR 5b-, R wherein 4bAnd R 5bRepresent the C2-5 alkylene base together, one of them carbon atom can be replaced by 1 Sauerstoffatom, nitrogen-atoms or sulphur atom that can be oxidized, and wherein said C2-5 alkylene base can be replaced by one or more substituting groups.
7. according to compound, its salt, its N-oxide compound, its solvate or its prodrug of claim 2, it is suc as formula shown in (I-A-3):
Wherein
Figure A2004800329420006C4
Be
Figure A2004800329420007C1
R 1-AExpression can by 1 or 2 can be substituted the amino of C1-15 alkyl protection;
G A1Represent hydrogen atom independently of one another, halogen atom, CF 3, OCF 3, hydroxyl, sulfydryl, carboxyl, (C1-6 alkoxyl group) carbonyl, carbamyl, nitro, cyano group perhaps can be selected from halogen atom, CF by 1 or 2 separately 3The C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl group or the C1-6 alkylthio that replace with substituting group in the hydroxyl;
G 2The expression hydrogen atom can substituted C1-15 alkyl, C2-15 alkenyl or C2-15 alkynyl, but protected hydroxyl, cyclopropane, tetramethylene, pentamethylene, hexanaphthene, phenyl, halogen atom, CF 3, perhaps cyano group; And all the other symbols have with claim 2 in identical implication.
8. according to compound, its salt, its N-oxide compound, its solvate or its prodrug of claim 2, it is suc as formula shown in (I-A-4):
Wherein Be
R 1a-AExpression NR 8AR 9A, R wherein 8AAnd R 9AOne of expression can be substituted the C1-15 alkyl that base group 1 replaces, another expression hydrogen atom maybe can be substituted the C1-15 alkyl that base group 1 replaces, wherein said substituting group group 1 have with claim 2 in identical implication;
G A2Represent hydrogen atom independently of one another, halogen atom, CF 3, OCF 3, hydroxyl, sulfydryl, carboxyl, (C1-6 alkoxyl group) carbonyl, carbamyl, nitro, the oxygen base, oxo perhaps can be selected from halogen atom, CF by 1 or 2 separately 3The C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxyl group or the C1-6 alkylthio that replace with substituting group in the hydroxyl; And all the other symbols have and claim 2 or 7 described identical implications.
9. according to the compound of claim 2, described compound is:
(1) N 5-(2-chloro-4-methoxyphenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines,
(2) N 5-(2-chloro-4-methoxyphenyl)-N 7-(1-ethyl propyl)-6-methylpyrazole is [1,5-a] pyrimidine-5 also, the 7-diamines,
(3) N 5-(2-chloro-4-methoxyphenyl)-6-ethyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines,
(4) N 2-(2-chloro-4-methoxyphenyl)-N 2-ethyl-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines,
(5) N 5-(2-chloro-4-methoxyphenyl)-6-methoxyl group-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines,
(6) N 2-allyl group-N 2-(2-chloro-4-methoxyphenyl)-N 4, N 4-dipropyl-6,7-dihydro-5H-cyclopentano [d] pyrimidine-2, the 4-diamines,
(7) 6-methyl-N 5-[2-methyl-4-(trifluoromethoxy) phenyl]-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines,
(8) N 7-butyl-N 5-(2-chloro-4-methoxyphenyl)-N 7-ethyl-6-methylpyrazole is [1,5-a] pyrimidine-5 also, the 7-diamines,
(9) N 5-(2-ethyl-4-aminomethyl phenyl)-6-methyl-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines,
(10) 6-methoxyl group-N 5-(4-methyl-2-ethenylphenyl)-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines or
(11) N 5-(2-ethyl-4-aminomethyl phenyl)-6-methoxyl group-N 7, N 7-dipropyl pyrazolo [1,5-a] pyrimidine-5, the 7-diamines.
10. pharmaceutical composition, described pharmaceutical composition contain compound, its salt, its N-oxide compound, its solvate or its prodrug shown in the formula (I-A) of with good grounds claim 2 as activeconstituents.
11. according to the pharmaceutical composition of claim 10, described pharmaceutical composition is the CRF antagonist.
12. according to the pharmaceutical composition of claim 10, described pharmaceutical composition is the medicine that is used to prevent and/or treat by the disease of CRF mediation.
13. according to the pharmaceutical composition of claim 12, wherein said disease by the CRF mediation is psychosis and neuropathy or digestion disease.
14. according to the pharmaceutical composition of claim 13, wherein said psychosis and neuropathy or digestion disease be mood disorder, anxiety disorder, the disease with stress be relevant, eating disorder disease, by to spirituality material or the symptom that its dependency is caused, OMD, schizophrenic disturbance, scatterbrained hyperactivity disorder or irritable bowel syndrome.
15. according to the pharmaceutical composition of claim 14, wherein said psychosis and neuropathy or digestion disease are that depression, mood disorder, eating disorder disease, medicine are habit-forming, pharmacological dependence or irritable bowel syndrome.
16. a medicine, described medicine contain compound, its salt, its N-oxide compound, its solvate or its prodrug and at least a combination that is selected from following medicament shown in the formula (I-A) of with good grounds claim 2: tricyclic antidepressants, tetracyclic antidepressant, oxidase inhibitor, serotonin and noradrenaline reuptake inhibitor, selectivity serotonin reuptake inhibithors, serotonin reuptake inhibithors, incitantia, anxiolytic, antipsychotic, plastosome benzodiazepine receptors ligand, NK1 antagonist, gi tract promotor, 5-HT 3Antagonist, 5-HT 4Agonist, anticholinergic drug, diarrhea, short rushing down and the conditioning agent of restraining oneself.
17. the method for an antagonism CRF, described method comprise to compound shown in the formula of administration significant quantity (I), its salt, its N-oxide compound, its solvate or its prodrug:
Wherein all symbols have and implication identical described in the claim 1.
18. a method that prevents and/or treats by the disease of CRF mediation, described method comprises to compound shown in the formula of administration significant quantity (I-A), its salt, its N-oxide compound, its solvate or its prodrug:
Figure A2004800329420009C2
Wherein all symbols have and implication identical described in the claim 2.
19. compound shown in the formula (I), its salt, its N-oxide compound, its solvate or its prodrug purposes in preparation CRF antagonist:
Figure A2004800329420010C1
Wherein all symbols have and implication identical described in the claim 1.
20. compound shown in the formula (I), its salt, its N-oxide compound, its solvate or its prodrug are used for purposes by the medicine of the disease of CRF mediation in manufacturing:
Wherein all symbols have and implication identical described in the claim 2.
CN 200480032942 2003-09-09 2004-09-08 Crf antagonists and heterobicyclic compounds Pending CN1878758A (en)

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Cited By (2)

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CN106188063A (en) * 2015-05-08 2016-12-07 中国科学院上海药物研究所 As Lp-PLA2dicyclo compounds, its preparation method and the medical usage of inhibitor
CN111518103A (en) * 2020-05-29 2020-08-11 赣南师范大学 Pyrazolo 1,3,5-triazine compound and preparation method thereof

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106188063A (en) * 2015-05-08 2016-12-07 中国科学院上海药物研究所 As Lp-PLA2dicyclo compounds, its preparation method and the medical usage of inhibitor
CN107709325A (en) * 2015-05-08 2018-02-16 中国科学院上海药物研究所 Double cyclics, its preparation method and medical usage as Lp PLA2 inhibitor
CN107709325B (en) * 2015-05-08 2019-04-12 中国科学院上海药物研究所 Double cyclics, preparation method and medical usage as Lp-PLA2 inhibitor
CN111518103A (en) * 2020-05-29 2020-08-11 赣南师范大学 Pyrazolo 1,3,5-triazine compound and preparation method thereof
CN111518103B (en) * 2020-05-29 2021-04-30 赣南师范大学 Pyrazolo 1,3,5-triazine compound and preparation method thereof

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