CN101084219A - Pyrazolo(1,5-alpha)pyrimidinyl derivatives useful as corticotropin-releasing factor (crf) receptor antagonists - Google Patents
Pyrazolo(1,5-alpha)pyrimidinyl derivatives useful as corticotropin-releasing factor (crf) receptor antagonists Download PDFInfo
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Abstract
CRF receptor antagonists are disclosed which may have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in mammals. The CRF receptor antagonists of this invention have the following structure: (I); and pharmaceutically acceptable salts, esters, solvates, stereoisomers and prodrugs thereof, wherein R1, R2a, R2b, Y, Het, n, o, R6, Ar and R7 are as defined herein. Compositions containing a CRF receptor antagonist in combination with a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same.
Description
The cross reference of related application
The application requires to enjoy in the right of priority of the GB 0519957.5 of the U.S. Provisional Application sequence number 60/620,060 of application on October 19th, 2004 and application on September 30th, 2005, at this its full content is incorporated herein by reference.
Invention field
Put it briefly, the present invention relates to the CRF receptor antagonist and by to there being this class antagonist of warm-blooded mammals administration that needs to treat the method for disease.
Background of invention
First kind of corticotropin releasing factor(CRF) (CRF) is isolating by the sheep hypothalamus, and through being accredited as 41-amino acid peptide (people such as Vale, Science 213:1394-1397,1981).After this separated the CRF sequence of people and rat, they are identical after measured, but 7 CRF (Rivier etc., Proc.Natl.Acad.Sci.USA 80:4851,1983 that are different from sheep are arranged in its 41 amino-acid residues; People such as Shibahara, EMBO J.2:775,1983).
Found that CRF can cause internal secretion, nerve and function of immune system generation great shift.It is believed that CRF is the major physiological conditioning agent (people such as Vale who is discharged thyroliberin (" ACTH "), beta-endorphin and other pro-opiomelanocortin (" POMC ") derived peptide by prepituitary gland basic (basal) and irritability, Science 213:1394-1397,1981).In brief, it is believed that CRF is by being distributed widely in brain (people such as DeSouza, Science 224:1449-1451,1984), hypophysis (people such as DeSouza, Methods Enzymol.124:560,1986 in conjunction with a kind of; People such as Wynn, Biochem.Biophys.Res.Comm.110:602-608,1983), suprarenal gland (people such as Udelsman, Nature 319:147-150,1986) and spleen (Webster, E.L., and E.B.DeSouza, Endocrinology 122:609-617,1988) the plasma membrane acceptor in and start its biological effect.CRF acceptor and a kind of GTP-binding proteins matter coupling (Perrin etc., Endocrinology 118:1171-1179,1986), the latter mediates the increase (Bilezikjian that cAMP produces in the CRF-stimulated cells, L.M. and W.W.Vale, Endocrinology 113:657-662,1983).Now from rat (Perrin etc., Endo 133 (6): 3058-3061,1993) and human brain (Chen etc., PNAS 90 (19): 8967-8971,1993; Vita etc., FEBS 335 (1): 1-5,1993) acceptor of having cloned CRF.This acceptor is a kind of 415 amino acid whose protein that have, and wherein comprises seven membrane spaning domains.Identity between rat and the human sequence comparison shows that they have the homology (97%) of height on amino acid levels.
Except in the generation that stimulates ACTH and POMC, having the effect, it is believed that CRF can also coordinate much at stress internal secretion, autonomic response (autonomic) and behavior reaction (behavioralresponses), thereby may relate to the physiopathology of affective disorder.In addition, it is believed that in the contact of CRF between immunity, nervus centralis, internal secretion and cardiovascular systems it is a kind of media (people such as Crofford, J.Clin.Invest.90:2555-2564,1992 of key; People such as Sapolsky, Science 238:522-524,1987; People such as Tilders, Regul.Peptides 5:77-84,1982).In a word, one of seemingly critical central nervous system neurotransmitter of CRF, and integrate body to stress general reaction in played decisive role.
Directly to brain use the caused behavior of CRF, physiology and internal secretion reaction be exposed to stress the environment viewed reacting phase of Mammals down same.For example, cause behavior activation (people such as Sutton to intracerebral ventricle injection CRF, Nature 297:331,1982), continuous activation (people such as Ehlers appears in electroencephalogram, Brain Res.278:332,1983), the sympathoadrenal medullary substance approach (people such as Brown that is upset, Endocrinology 110:928,1982), heart rate and elevation of blood pressure (people such as Fisher, Endocrinology110:2222,1982), oxygen consumption increases people such as (, Life Sciences 30:207,1982) Brown, stomach and intestine are movable to be changed (people such as Williams, Am.J.Physiol.253:G582,1987), food consumption is suppressed (people such as Levine, Neuropharmacology 22:337,1983), sexual behaviour changes (people such as Sirinathsinghji, Nature 305:232,1983), and immunologic function suffer damage (people such as Irwin, Am.J.Physiol.255:R744,1988).Clinical data shows in addition, and in dysthymia disorders, anxiety relative disease and anorexia nervosa, brain may excessive secretion CRF (DeSouza, Ann.Reports in Med.Chem.25:215-223,1990).Therefore, clinical data shows that the CRF receptor antagonist may have been represented the depression and/or the anxiolytic medicament of a class novelty, can be used for treating the neuropsychiatric disorders (neuropsychiatric disorders) that shows as the CRF excessive secretion.
First-generation CRF receptor antagonist is that the peptide class is (referring to people such as for example Rivier, U.S. Patent number 4,605,642; People such as Rivier, Science 224:889,1984).Although these peptide proofs CRF receptor antagonist can weaken the pharmacological reaction to CRF really, peptide class CRF receptor antagonist still has the common disadvantage of peptide therapeutics, promptly comprises deficient in stability and limited Orally active.
Comprise have pyrazolo-the CRF antagonist of the compound of [1,5a]-pyrimidine nuclear is open in following patent and open application: WO9729109, US6313124, WO9803510, WO9938868, WO9808847, JP2000038350, EP1097709 and US6664261.In addition, among the JP10101671 of this nuclear in the application WO9535298 of anodyne, in the application JP10101672 of adenosine potentiator,, open in the application WO2001023387 of neuropeptide Y 1 antagonist, in the application WO2000044754 of accumulation of fat inhibitor and in the application WO2003101993 of hepatitis c viral replication inhibitor at nitric oxide synthase inhibitors.
Because CRF has the The above physiological meaning, therefore exploitation has significant CRF receptor-binding activity and biological activity small molecules that can antagonism CRF acceptor remains desired destination.This class CRF receptor antagonist will can be used for treating internal secretion, spirit and neurological disorder or disease, generally comprise and illness that stress be relevant.
Although realizing having obtained obvious improvement aspect the CRF adjusting by using the CRF receptor antagonist, this area still needs effective small molecules CRF receptor antagonist.Equally also need to contain the pharmaceutical composition of this class CRF receptor antagonist, and relate to its using method, for example be used for the treatment of and illness that stress be relevant.The present invention has finished these needs, and other relevant advantage also is provided.
Summary of the invention
Usually, the present invention relates to the CRF receptor antagonist, more particularly, the present invention relates to have the CRF receptor antagonist of following general formula (I):
And pharmacy acceptable salt, ester, solvate, steric isomer and prodrug,
Wherein:
R
1It is the Heterocyclylalkyl of aralkyl, Heterocyclylalkyl or replacement of alkoxyalkyl, aralkyl, the replacement of haloalkyl, alkoxyalkyl, the replacement of alkyl, haloalkyl, the replacement of hydrogen, alkyl, replacement;
R
2aAnd R
2bBe hydrogen, C independently
1-C
6The C of alkyl, replacement
1-C
6Alkyl, C
1-C
6The C of haloalkyl, replacement
1-C
6The aralkyl of haloalkyl, aralkyl, replacement, C
1-C
6The C of alkoxyalkyl, replacement
1-C
6Alkoxyalkyl, alkyl sulphonyl alkyl, aminoalkyl group, alkyl monosubstituted amino alkyl or dialkyl aminoalkyl;
Or
R
1The nitrogen and the R that are connected with it
2aOr R
2bWith R
2aAnd R
2bThe carbon that is connected forms the 4-7 element heterocycle together;
Or
R
2aAnd R
2bIn the carbon atom that they connected is formed on ring optional containing-O-,-S-or-N (R
3)-3-7 person ring;
R
3Be alkyl, aralkyl, the replacement of alkyl, replacement aralkyl, acyl group ,-C (O) OR
8,-C (O) NR
9R
10Or S (O)
2R
11
Y be independently in all cases direct key or-C (R
4aR
4b)
m-;
M is 1 or 2;
R
4aAnd R
4bBe hydrogen, C independently
1-C
6The C of alkyl, replacement
1-C
6The aralkyl of alkyl, aralkyl, replacement, C
1-C
6The C of alkoxyalkyl, replacement
1-C
6Alkoxyalkyl, alkyl sulphonyl alkyl, aminoalkyl group, alkyl monosubstituted amino alkyl or dialkyl aminoalkyl;
Or
R
4aAnd R
4bIn the carbon atom that they connected is formed on ring optional containing-O-,-S-or-N (R
3)-3-7 person ring;
Het is
R
5Be hydrogen, halogen, C
1-C
6The C of alkyl, replacement
1-C
6Alkyl, C
1-C
6The C of alkoxyl group, replacement
1-C
6Alkoxyl group, amino, alkylamino or dialkyl amido;
R
6Be halogen, C in all cases independently
1-C
6The C of alkyl or replacement
1-C
6Alkyl;
N is the integer that comprises 0 and 3 0-3;
Ar is phenyl or pyridyl;
R
7Be alkyl, the C of halogen, alkyl, replacement in all cases independently
1-C
6The C of alkoxyl group, replacement
1-C
6Alkoxyl group ,-NR
9R
10, alkyl sulphonyl or replacement alkyl sulphonyl;
O is the integer that comprises 0 and 3 0-3; With
R
8, R
9, R
10And R
11In each be hydrogen, C
1-C
6The C of alkyl, replacement
1-C
6The aralkyl of alkyl, aralkyl, replacement, C
1-C
6The C of alkoxyalkyl, replacement
1-C
6Alkoxyalkyl, alkyl sulphonyl alkyl, aminoalkyl group, alkyl monosubstituted amino alkyl or dialkyl aminoalkyl.
These and other aspect of the present invention will become clear after the reference following detailed description.For this reason, various reference described herein, some step of its more detailed description, compound and/or composition, at this with they whole being incorporated herein by reference.
Brief description of drawings
Fig. 1 represents X-ray powder diffraction data, its be by aforesaid [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-polymorphic form of amine 1 obtains.Polymorphic form 1 characterizes by the XRPD figure, and its significant signal is listed in the table 1.
Fig. 2 represents the Raman spectrum of the polymorphic form 1 of [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine.
Fig. 3 represents [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-differential thermogram of the dsc (DSC) of the polymorphic form 1 of [(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine.
Fig. 4 represents the X-ray powder diffraction data that the polymorphic form 2 by aforesaid [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine obtains.Polymorphic form 1 characterizes by the XRPD figure, and its significant signal is listed in the table 1.
Fig. 5 represents the Raman spectrum of the polymorphic form 2 of [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine.
Fig. 6 represents [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-differential thermogram of the dsc (DSC) of the polymorphic form 2 of [(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine.
Detailed description of the invention
Usually, the present invention relates to be used as the compound of cortico-trophin-releasing factor (CRF) (CRF) receptor antagonist. In the first embodiment, CRF receptor antagonist of the present invention has lower array structure (I):
And pharmaceutically acceptable salt, ester, solvate, stereoisomer and prodrug,
Wherein:
R
1It is the Heterocyclylalkyl of aralkyl, Heterocyclylalkyl or replacement of alkoxyalkyl, aralkyl, the replacement of haloalkyl, alkoxyalkyl, the replacement of alkyl, haloalkyl, the replacement of hydrogen, alkyl, replacement;
R
2aAnd R2bHydrogen, C independently1-C
6The C of alkyl, replacement1-C
6Alkyl, C1-C
6The C of haloalkyl, replacement1-C
6The aralkyl of haloalkyl, aralkyl, replacement, C1-C
6The C of alkoxyalkyl, replacement1-C
6Alkoxyalkyl, alkyl sulphonyl alkyl, aminoalkyl, alkyl monosubstituted amino alkyl or dialkyl aminoalkyl;
Or
R
1The nitrogen that is connected with it and R2aOr R2bWith R2aAnd R2bThe carbon that connects forms the 4-7 element heterocycle together;
Or
R
2aAnd R2bThe carbon atom that connects with them be formed on optional containing-O-in the ring ,-S-or-N (R3)-3-7 person ring;
R
3Be alkyl, aralkyl, the replacement of alkyl, replacement aralkyl, acyl group ,-C (O) OR8、
-C(O)NR
9R
10Or S (O)2R
11；
Y be independently in all cases direct key or-C (R4aR
4b)
m-；
M is 1 or 2;
R
4aAnd R4bHydrogen, C independently1-C
6The C of alkyl, replacement1-C
6The aralkyl of alkyl, aralkyl, replacement, C1-C
6The C of alkoxyalkyl, replacement1-C
6Alkoxyalkyl, alkyl sulphonyl alkyl, aminoalkyl, alkyl monosubstituted amino alkyl or dialkyl aminoalkyl;
Or
R
4aAnd R4bThe carbon atom that connects with them be formed on optional containing-O-in the ring ,-S-or-N (R3)-3-7 person ring;
Het is
Or
R
5Hydrogen, halogen, C1-C
6The C of alkyl, replacement1-C
6Alkyl, C1-C
6The C of alkoxyl, replacement1-C
6Alkoxyl, amino, alkyl amino or dialkyl amido;
R
6Halogen, C in all cases independently1-C
6The C of alkyl or replacement1-C
6Alkyl;
N is the integer that comprises 0 and 3 0-3;
Ar is phenyl or pyridine radicals;
R
7Alkyl, the C of halogen, alkyl, replacement in all cases independently1-C
6The C of alkoxyl, replacement1-C
6Alkoxyl ,-NR9R
10, alkyl sulphonyl or replacement alkyl sulphonyl;
O is the integer that comprises 0 and 3 0-3; With
R
8、R
9、R
10And R11In each be hydrogen, C1-C
6The C of alkyl, replacement1-C
6The aralkyl of alkyl, aralkyl, replacement, C1-C
6The C of alkoxyalkyl, replacement1-C
6Alkoxyalkyl, alkyl sulphonyl alkyl, aminoalkyl, alkyl monosubstituted amino alkyl or dialkyl aminoalkyl.
CRF receptor antagonist of the present invention has widely treatment to be used, and can be used for the treatment of various illnesss or disease, comprises stress-associated conditions. These class methods comprise that the mammal to needs gives the CRF receptor antagonist of the present invention of effective dose, preferably with the form of pharmaceutical composition. Therefore, in another embodiment, disclose pharmaceutical composition, it contains one or more CRF receptor antagonist of the present invention and pharmaceutically acceptable carrier and/or diluents.
Have following meanings at this employed above-mentioned term:
" alkyl " is meant straight or branched, acyclic or the ring-type that contains 1-10 carbon atom, unsaturated or saturated aliphatic alkyl, and term " low alkyl group " and " C
1-C
6Alkyl " has the implication same with alkyl, but contains 1-6 carbon atom.Representational straight chain saturated alkyl comprises methyl, ethyl, n-propyl, normal-butyl, n-pentyl, n-hexyl etc.; And saturated branched-chain alkyl comprises sec.-propyl, sec-butyl, isobutyl-, the tertiary butyl, isopentyl etc.Representational saturated cyclic alkyls comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH
2-cyclopropyl ,-CH
2-cyclobutyl, CH
2-cyclopentyl ,-CH
2-cyclohexyl etc.; And the unsaturated cyclic alkyl comprises cyclopentenyl and cyclohexenyl etc.Cyclic alkyl is also referred to as " carbocyclic ring (homocyclic rings) ", comprise two-and many-carbocyclic ring for example naphthane base and adamantyl.Unsaturated alkyl contains at least one two or triple bond (being called " alkenyl " or " alkynyl ") between adjacent carbons.Representational straight chain and branched alkenyl comprise vinyl, propenyl, 1-butylene base, crotyl, isobutenyl, 1-pentenyl, pentenyl, 3-methyl-1-butene base, 2-methyl-2-butene base, 2,3-dimethyl-crotyl etc.; And a representational straight chain and an alkynyl group comprise ethynyl, proyl, ethyl acetylene base, 2-butyne base, 1-pentynyl, valerylene base, 3-methyl isophthalic acid-butynyl etc.
" aryl " is meant for example phenyl or naphthyl of aromatic carbon ring part.
" aralkyl " is meant to have at least one alkyl hydrogen atom by the displaced alkyl of aryl moiety, for example benzyl (promptly-CH
2-phenyl) ,-CH
2-(1-or 2-naphthyl) ,-(CH
2)
2Phenyl ,-(CH
2)
3Phenyl ,-CH (phenyl)
2Deng.
" heteroaryl " is meant 5-to 1 0-person's heteroaromatic, and it has at least one heteroatoms that is selected from nitrogen, oxygen and sulphur, and it contains at least one carbon atom, comprises single-and bicyclic system.Representational heteroaryl includes but is not limited to furyl, benzofuryl, thienyl, benzothienyl, pyrryl, indyl, pseudoindoyl, azaindole base, pyridyl, quinolyl, isoquinolyl, azoles base, different azoles base, benzoxazol base, pyrazolyl, imidazolyl, benzimidazolyl-, thiazolyl, benzothiazolyl, isothiazolyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, cinnolines base, phthalazinyl, quinazolyl and di azoly.
" heteroaralkyl " is meant to have at least one alkyl hydrogen atom by the displaced alkyl of heteroaryl moieties, for example-and CH
2-pyridyl ,-CH
2-pyrimidyl etc.
" heterocycle " (being also referred to as " heterocyclic ring " at this) is meant monocyclic or 7-to the 14-member polycyclic heterocycle of 5-to 7-member, it is saturated, undersaturated or aromatic, and it contains 1-4 heteroatoms that is independently selected from nitrogen, oxygen and sulphur, and wherein said nitrogen and sulfur heteroatom can be chosen wantonly oxidized, and described nitrogen heteroatom can be chosen wantonly by quaternised, also comprise dicyclo, wherein any above-mentioned heterocycle and phenyl ring condense, and three ring (and higher) heterocycles.Heterocycle can connect by any heteroatoms or carbon atom.Heterocycle comprises heteroaryl as defined above.Therefore, except that top listed aromatic series heteroaryl, heterocycle also includes but is not limited to morpholinyl, pyrrolidone-base, pyrrolidyl, piperidyl, piperazinyl, glycolylurea base, Valerolactim base, oxirane base, oxetanyl, tetrahydrofuran base, THP trtrahydropyranyl, tetrahydro pyridyl, tetrahydro-pyrimidine base, tetrahydro-thienyl, tetrahydro thiapyran base, tetrahydro-pyrimidine base, tetrahydro-thienyl, tetrahydro thiapyran base etc.
" Heterocyclylalkyl " is meant to have at least one alkyl hydrogen atom by the displaced alkyl of heterocycle, for example-and CH
2-morpholinyl etc.
" haloalkyl " is meant to have at least one alkyl hydrogen atom by the displaced alkyl of halogen, for example CH
2Cl, CHCl
2, CCl
3, CH
2F, CF
3Deng." C
1-C
6Haloalkyl " with " haloalkyl " has identical implication, but contain 1-6 carbon atom.
Be meant that at this employed term " replacement " at least one hydrogen atom on any group described herein (for example, alkyl, alkoxyl group, alkoxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, heterocycle or Heterocyclylalkyl) is substituted basic the replacement.In the situation of oxo substituting group (" (=O) "), two hydrogen atoms are replaced." substituting group " in the context of the invention comprises halogen, hydroxyl, cyano group, nitro, amino, alkylamino, dialkyl amido, alkyl, the alkyl that replaces, alkoxyl group, alkylthio (thioalkyl), haloalkyl, hydroxyalkyl, alkoxyalkyl, halogenated alkoxy, aryl, the aryl that replaces, aralkyl, the aralkyl that replaces, heteroaryl, the heteroaryl that replaces, heteroarylalkyl, the heteroarylalkyl that replaces, heterocycle, the heterocycle that replaces, Heterocyclylalkyl, the Heterocyclylalkyl that replaces,-NR
aR
b,-NR
aC (=O) R
b,-NR
aC (=O) NR
aR
b,-NR
aC (=O) OR
b,-NR
aSO
2R
b,-OR
a,-C (=O) R
a,-C (=O) OR
a,-C (=O) NR
aR
b,-OC (=O) NR
aR
b,-SH ,-SR
a,-S (=O) R
a,-S (=O)
2R
a,-OS (=O)
2R
a,-S (=O)
2OR
a, R wherein
aAnd R
bIt is identical or different and the Heterocyclylalkyl of heterocycle, Heterocyclylalkyl or the replacement of the aralkyl of the aryl of alkyl that be hydrogen, alkyl, haloalkyl, replacement independently, aryl, replacement, aralkyl, replacement, heterocycle, replacement.
" halogen " is meant fluorine, chlorine, bromine or iodine.
" alkoxyl group " be meant the moieties that connects by oxo bridge (that is ,-O-alkyl) for example-the O-methyl ,-O-ethyl etc." C
1-C
6Alkoxyl group " has the implication identical with alkoxyl group, but contains 1-6 carbon atom.
" halogenated alkoxy " is meant to have at least one hydrogen atom by the displaced alkoxyl group of halogen, for example trifluoromethoxy etc.
" alkoxyalkyl " is meant to have the displaced alkyl of at least one hydrogen atom alkoxy, for example methoxymethyl etc." C
1-C
6" identical implication, wherein said alkoxyl group have 1-6 carbon atom to alkoxyalkyl to alkoxyalkyl " have with ".
" alkylthio " be meant the moieties that connects by sulphur bridge (that is ,-S-alkyl) for example-the S-methyl ,-S-ethyl etc.
" alkylamino " and " dialkyl amido " be meant by nitrogen-bridged one or two moieties that connects (that is ,-the NH alkyl or-N (alkyl) (alkyl)) for example methylamino, ethylamino, dimethylamino, diethylin etc.
" hydroxyalkyl " is meant the alkyl that is replaced by at least one hydroxyl.
" single-or two (cycloalkyl) methyl " expression is by the methyl of one or two cycloalkyl substituted, for example cyclopropyl methyl, bicyclic methyl propyl etc.
" alkyl-carbonyl alkyl " expression quilt-C (=O) alkyl of alkyl replacement.
" alkyl carbonyl oxy alkyl " expression quilt-C (=O) the O alkyl or-the OC (=O) alkyl of alkyl replacement.
The alkyl that " alkylthio alkyl " expression is replaced by the S-alkyl.
" single-or two (alkyl) aminoalkyl group " the expression coverlet-or the amino alkyl that replaces of two (alkyl).
" acyl group " expression alkyl-C (=O)-.
The present invention is to illustrate for example in this embodiment of listing, rather than in order to limit the scope of the invention.In one embodiment of the present invention, R
1The Heterocyclylalkyl of aralkyl, Heterocyclylalkyl or replacement that can represent alkoxyalkyl, aralkyl, the replacement of haloalkyl, alkoxyalkyl, the replacement of alkyl, haloalkyl, the replacement of hydrogen, alkyl, replacement.Therefore, representative compounds of the present invention comprises, for example, and R wherein
1Be the following array structure (IIa) of hydrogen, wherein R
1Be the structure (IIb) of methyl, wherein R
1Be the structure (IIc) of methoxymethyl, wherein R
1Be the structure (IId) of benzyl and R wherein
1Be the structure (IIe) of pyridine-2-base-methyl:
In other embodiments of the present invention, R
2aAnd R
2bBe hydrogen, C independently
1-C
6The C of alkyl, replacement
1-C
6Alkyl, C
1-C
6The C of haloalkyl, replacement
1-C
6The aralkyl of haloalkyl, aralkyl, replacement, C
1-C
6The C of alkoxyalkyl, replacement
1-C
6Alkoxyalkyl, alkyl sulphonyl alkyl, aminoalkyl group, alkyl monosubstituted amino alkyl or dialkyl aminoalkyl.Therefore, representative compounds of the present invention comprises wherein R
2aAnd R
2bIt is the following array structure (IIIa) of hydrogen.R wherein
2bOther the representational compound that is hydrogen comprises wherein R
2aBe the structure (IIIb) of alkyl such as methyl, wherein R
2aBe the structure (IIIc) of aralkyl such as benzyl, wherein R
2aBe the structure (IIId) of alkoxyalkyl such as methoxymethyl, wherein R
2aBe the structure (IIIe) of alkyl sulphonyl alkyl such as sulfonyloxy methyl ylmethyl and R wherein
2aIt is the structure (IIIf) of aminoalkyl group such as amino methyl.
In other embodiments of the present invention, R
1The nitrogen and the R that are connected with it
2aOr R
2bWith R
2aAnd R
2bThe carbon that links to each other forms the 4-7 element heterocycle together, 7-piperidines-1-base-pyrazolo [1,5-a] pyrimidine of example shown in 7-tetramethyleneimine-1-base-pyrazolo [1,5-a] pyrimidine of example and the structure (IVb) as shown in structure (IVa).
In other embodiments of the present invention, R
2aAnd R
2bForm 3-7 person ring as the cyclopropyl of example and the ring " A " of example in the structure (Vb) below in the structure (Va) below with the carbon atom that they connected, wherein ring " A " choose wantonly contains-O-,-S-or-N (R
3)-, and R
3Be alkyl, aralkyl, the replacement of alkyl, replacement aralkyl, acyl group ,-C (O) OR
8,-C (O) NR
9R
10Or S (O)
2R
11
In other embodiments of the present invention, Y be independently in all cases direct key or-C (R
4aR
4b)
m-, wherein m is the integer that comprises 1 and 2 1-2, and R
4aAnd R
4bBe hydrogen, C independently
1-C
6The C of alkyl, replacement
1-C
6The aralkyl of alkyl, aralkyl, replacement, C
1-C
6The C of alkoxyalkyl, replacement
1-C
6Alkoxyalkyl, alkyl sulphonyl alkyl, aminoalkyl group, alkyl monosubstituted amino alkyl or dialkyl aminoalkyl.Therefore, representative compounds of the present invention comprises for example following array structure (VIa) when Y is direct key, and as Y is-C (R
4aR
4b)
m-and m be 1 o'clock structure (VIb).
In another embodiment of the invention, R
4aAnd R
4bIn the carbon atom that they connected is formed on ring optional containing-O-,-S-or-N (R
3)-3-7 person ring.Therefore, representative compounds of the present invention comprises and for example works as R
4aAnd R
4bFollowing array structure (VIIa) when forming cyclopropyl rings with the carbon atom that they connected, and work as R
4aAnd R
4bForm ring " B " with the carbon atom that they connected and encircle wherein that " B " is optional to be contained-O-,-S-or-N (R
3)-time structure (VIIb).
In another embodiment of the invention, Het for example is one of diazole of following three kinds of structures (VIIIa)-(VIIIc), wherein R
5Be hydrogen, halogen, C
1-C
6The C of alkyl, replacement
1-C
6Alkyl, C
1-C
6The C of alkoxyl group, replacement
1-C
6Alkoxyl group, amino, alkylamino or dialkyl amido.
(VIIIa) (VIIIb) (VIIIc)
In another embodiment of the invention, R
6Be halogen, C in all cases independently
1-C
6The C of alkyl or replacement
1-C
6Alkyl, and n is the integer that comprises 0 and 3 0-3.Therefore, representative compounds of the present invention comprises and for example descends array structure (IXa-IXh), wherein R
6Occupy the whole possible combination of 2,5 and 6 positions of pyrazolo-[1,5a]-pyrimidine nuclear independently:
In another embodiment of the invention, Ar is phenyl or pyridyl, R
7Be halogen, C in all cases independently
1-C
10The C of alkyl, replacement
1-C
10Alkyl, C
1-C
6The C of alkoxyl group, replacement
1-C
6Alkoxyl group ,-NR
9R
10, alkyl sulphonyl or replacement alkyl sulphonyl, and o is the integer that comprises 0 and 3 0-3.Therefore, representative compounds of the present invention comprises for example following array structure (Xa) when Ar is phenyl, and the structure when Ar is pyridyl (Xb).
Compound of the present invention comprises:
[1-(3-cyclopropyl-[1,2,4] diazole-5-yl)-propyl group]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine (embodiment 11-1);
[1-(3-sec.-propyl-[1,2,4] diazole-5-yl)-propyl group]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine (embodiment 11-2);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-2-phenyl-ethyl]-amine (embodiment 11-3);
[1-(3-sec.-propyl-[1,2,4] diazole-5-yl)-propyl group]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine (embodiment 11-4);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-butyl]-amine (embodiment 11-5);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine (embodiment 11-6);
(3-cyclopropyl-[1,2,4] diazole-5-ylmethyl)-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine (embodiment 11-7);
(3-sec.-propyl-[1,2,4] diazole-5-ylmethyl)-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine (embodiment 11-8);
[2-(3-cyclopropyl-[1,2,4] diazole-5-yl)-(R)-1-methyl-ethyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine (embodiment 11-9);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-methyl-2-(3-methyl-[1,2,4] diazole-5-yl)-ethyl]-amine (embodiment 11-10);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-trifluoromethyl-[1,2,4] diazole-5-yl)-propyl group]-amine (embodiment 11-11);
[1-(3-cyclopropyl-[1,2,4] diazole-5-yl)-cyclopropyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine (embodiment 11-12);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-cyclopropyl]-amine (embodiment 11-13);
[1-(3-ethyl-[1,2,4] diazole-5-yl)-cyclopropyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine (embodiment 11-14);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(3-propyl group-[1,2,4] diazole-5-ylmethyl)-amine (embodiment 11-15);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-trifluoromethyl-[1,2,4] diazole-5-yl)-cyclopropyl]-amine (embodiment 11-16);
[2-(3-ethyl-[1,2,4] diazole-5-yl)-(R)-1-methyl-ethyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine (embodiment 11-17);
[3-(6-dimethylamino-4-methyl-pyridin-3-yl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[the 3-methyl-(R)-1-(3-methyl-[1,2,4] diazole-5-yl)-butyl]-amine (embodiment 11-18);
3-(2,4-dimethoxy-phenyl)-2, the 5-dimethyl-7-[(S)-2-(3-methyl-[1,2,4] diazole-5-yl)-tetramethyleneimine-1-yl]-pyrazolo [1,5-a] pyrimidine (embodiment 11-19);
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine (embodiment 11-20);
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-ethyl]-amine (embodiment 11-21);
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-butyl]-amine (embodiment 11-22);
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[3-methyl isophthalic acid-(3-methyl-[1,2,4] diazole-5-yl)-butyl]-amine (embodiment 11-23);
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-methyl-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine (embodiment 11-24);
Benzyl-[3-(6-dimethylamino-4-methyl-pyridin-3-yl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine (embodiment 11-25);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine (embodiment 11-26);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-methyl-2-(3-methyl-[1,2,4] diazole-5-yl)-ethyl]-amine (embodiment 12-1);
Benzyl-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine (embodiment 12-2);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[2,2,2-three fluoro-1-(3-methyl-[1,2,4] diazole-5-ylmethyl)-ethyl]-amine (embodiment 12-3);
[2-(3-cyclopropyl-[1,2,4] diazole-5-yl)-1-methyl-ethyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine (embodiment 12-4);
[2-(3-sec.-propyl-[1,2,4] diazole-5-yl)-1-methyl-ethyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine (embodiment 12-5);
[2-(3-cyclopropyl-[1,2,4] diazole-5-yl)-(S)-1-methyl-ethyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine (embodiment 12-6);
[2-(3-sec.-propyl-[1,2,4] diazole-5-yl)-(S)-1-methyl-ethyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine (embodiment 12-7);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-methyl-2-(3-methyl-[1,2,4] diazole-5-yl)-ethyl]-amine (embodiment 12-8);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-ylmethyl)-propyl group]-amine (embodiment 12-9);
[1-(3-cyclopropyl-[1,2,4] diazole-5-ylmethyl)-propyl group]-[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine (embodiment 12-10);
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-ylmethyl)-propyl group]-amine (embodiment 12-11);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-butyl]-amine (embodiment 13-1);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[2,2,2-three fluoro-(S)-1-(3-methyl-[1,2,4] diazole-5-ylmethyl)-ethyl]-amine (embodiment 1 3-2);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-methyl-2-(3-trifluoromethyl-[1,2,4] diazole-5-yl)-ethyl]-amine (embodiment 13-3);
[3-(2-chloro-4-methoxyl group-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[2,2,2-three fluoro-(S)-1-(3-methyl-[1,2,4] diazole-5-ylmethyl)-ethyl]-amine (embodiment 13-4);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-methyl-2-(3-trifluoromethyl-[1,2,4] diazole-5-yl)-ethyl]-amine (embodiment 13-5);
[3-(2-chloro-4-methoxyl group-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-methyl-2-(3-trifluoromethyl-[1,2,4] diazole-5-yl)-ethyl]-amine (embodiment 13-6);
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-methyl-2-(3-trifluoromethyl-[1,2,4] diazole-5-yl)-ethyl]-amine (embodiment 1 3-7);
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[2,2,2-three fluoro-(S)-1-(3-methyl-[1,2,4] diazole-5-ylmethyl)-ethyl]-amine (embodiment 13-8);
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[2,2,2-three fluoro-(S)-1-(3-trifluoromethyl-[1,2,4] diazole-5-ylmethyl)-ethyl]-amine (embodiment 13-9);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine (embodiment 14-1);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine (embodiment 14-2);
3-(4-methoxyl group-2-methyl-phenyl)-2, the 5-dimethyl-7-[(S)-2-(3-methyl-[1,2,4] diazole-5-ylmethyl)-tetramethyleneimine-1-yl]-pyrazolo [1,5-a] pyrimidine (embodiment 14-3);
[3-(2-chloro-4-methoxyl group-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine (embodiment 14-4);
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(2-methoxyl group-ethyl)-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine (embodiment 15-1);
(5-{2, the 5-dimethyl-7-[(S)-2-(3-methyl-[1,2,4] diazole-5-yl)-tetramethyleneimine-1-yl]-pyrazolo [1,5-a] pyrimidin-3-yl }-4-methyl-pyridine-2-yl)-dimethyl-amine (embodiment 15-2);
[3-(6-dimethylamino-4-methyl-pyridin-3-yl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(2-methoxyl group-ethyl)-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine (embodiment 15-3);
[3-(4-oxyethyl group-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(2-methoxyl group-ethyl)-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine (embodiment 15-4);
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(2-methoxyl group-ethyl)-[3-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine (embodiment 16-1);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-methyl-2-(5-methyl-[1,2,4] diazole-3-yl)-ethyl]-amine (embodiment 17-1);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(5-methyl-[1,2,4] diazole-3-ylmethyl)-propyl group]-amine (embodiment 17-2);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-(5-methyl-[1,2,4] diazole-3-ylmethyl)-propyl group]-amine (embodiment 17-3);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-methyl-2-(5-methyl-[1,2,4] diazole-3-yl)-ethyl]-amine (embodiment 17-4);
[(R)-2-(5-cyclopropyl-[1,2,4] diazole-3-yl)-1-methyl-ethyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine (embodiment 18-1);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-methyl-2-(5-trifluoromethyl-[1,2,4] diazole-3-yl)-ethyl]-amine (embodiment 18-2);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-2,2,2-three fluoro-1-(5-methyl-[1,2,4] diazole-3-ylmethyl)-ethyl]-amine (embodiment 19-1);
Ethyl-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine (embodiment 20-1);
3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-7-[2-(3-methyl-[1,2,4] diazole-5-ylmethyl)-piperidines-1-yl]-pyrazolo [1,5-a] pyrimidine (embodiment 20-2);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(1-[1,3,4] diazole-2-base-propyl group)-amine (embodiment 21-1);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(5-methyl-[1,3,4] diazole-2-yl)-propyl group]-amine (embodiment 22-1);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-methyl-2-(5-methyl-[1,3,4] diazole-2-yl)-ethyl]-amine (embodiment 23-1);
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-methyl-2-(5-trifluoromethyl-[1,3,4] diazole-2-yl)-ethyl]-amine (embodiment 23-2);
[3-(2-chloro-4-methoxyl group-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine (embodiment 24-1);
[3-(4-chloro-2-methoxyl group-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine (embodiment 24-2);
[3-(3-chloro-4-fluoro-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine (embodiment 24-3);
[3-(4-chloro-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine (embodiment 24-4);
[3-(2-chloro-4-trifluoromethyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine (embodiment 24-5); With
[3-(2-chloro-4-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine (embodiment 24-6).
In another embodiment of the invention, reported [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-polymorphic form of amine (embodiment 14-1).Polymorphic form 1 demonstrates the most significant endotherm(ic)peak and shows as shown in Figure 1 X-ray powder diffraction spectrum in the time of about 108.3 ℃.The X-ray powder diffraction pattern of polymorphic form 1 as shown in Figure 1 presents main peaks (expenditure 2 θ (+/-0.15 degree 2 θ represent): 6.721,11.757,13.323,18.222,21.426 and 21.974 in following one or more positions.More particularly, these characteristic peaks are 11.757 and 21.974, and other is 6.721,13.323,18.222 and 21.426.Polymorphic form 2 presents the most significant endotherm(ic)peak as shown in Figure 6 and shows and has the X-ray powder diffraction spectrum at peak as shown in Figure 4 in the time of about 115.1 ℃.
In another embodiment, [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine is to exist with the composition (composition) of one or more other crystal, solvate, amorphous substance or other form or the form of mixture with polymorphic form 1.More particularly, described composition can comprise trace to up to 100% polymorphic form 1, or between any amount, for example, based on [3-(4-methoxyl group-2-methyl-phenyl)-2 in the composition, 5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-total amount of amine, described composition can comprise the polymorphic form 1 less than 0.1%, 0.5%, 1%, 2%, 5%, 10%, 20%, 30%, 40% or 50% weight.Perhaps, based on [3-(4-methoxyl group-2-methyl-phenyl)-2 in the composition, 5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-total amount of amine, described composition can comprise the polymorphic form 1 of at least 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, 99.5% or 99.9% weight.
In another embodiment, [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine is to exist with the composition of one or more other crystal, solvate, amorphous substance or other form or the form of mixture with polymorphic form 2.More particularly, described composition can comprise trace to up to 100% polymorphic form 2, or between any amount, for example, based on [3-(4-methoxyl group-2-methyl-phenyl)-2 in the composition, 5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-total amount of amine, described composition can comprise the polymorphic form 2 less than 0.1%, 0.5%, 1%, 2%, 5%, 10%, 20%, 30%, 40% or 50% weight.Perhaps, based on [3-(4-methoxyl group-2-methyl-phenyl)-2 in the composition, 5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-total amount of amine, described composition can comprise the polymorphic form 2 of at least 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, 99%, 99.5% or 99.9% weight.
Usually, compound of the present invention can use with the form of free alkali.Perhaps, compound of the present invention can use with the form of acid salt.The acid salt of free alkali aminocompound of the present invention can prepare by means commonly known in the art, and can be made by organic and mineral acid.Appropriate organic comprises toxilic acid, fumaric acid, phenylformic acid, xitix, succsinic acid, methylsulfonic acid, acetate, oxalic acid, propionic acid, tartrate, Whitfield's ointment, citric acid, gluconic acid, lactic acid, amygdalic acid, styracin, aspartic acid, stearic acid, palmitinic acid, oxyacetic acid, L-glutamic acid and Phenylsulfonic acid.Suitable mineral acid comprises hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid and nitric acid.Therefore, " pharmacy acceptable salt " of nomenclature structure (I) comprises any and all acceptable salt forms.
Usually, the compound of structure (I) can be prepared according to the known organic synthesis technology of those skilled in the art and by the exemplary process described in the embodiment.For example, the synthetic of structure (I) can carry out according to following reaction scheme 1-reaction scheme 6 usually, and wherein these schemes are to be used to illustrate rather than to be used to limit the present invention.
Reaction scheme 1
7-chloro-pyrazolo-[1,5a]-pyrimidine a and amino acid ester react under anhydrous condition, obtain amino acid ester b.The amidoxim of compound b and NaH and replacement reacts under anhydrous condition, obtains 5-base-[1,2,4] diazole compounds c.
Reaction scheme 2
7-chloro-pyrazolo-[1,5a]-pyrimidine a and amino acid ester react under anhydrous condition, obtain amino acid ester b.Compound b is taken off in the presence of LiOH-esterification, obtains amino acid b '.Compound b ' react in the presence of DIC and HOBT with amidoxim obtains compound b ", ring-closure reaction is carried out in its insulation at high temperature in pyridine, obtains 5-base-[1,2,4] diazole compounds c.
Reaction scheme 3
7-chloro-pyrazolo-[1,5a]-pyrimidine a and amino acid reaction obtain amino acid b '.Compound b ' react in the presence of DIC and HOBT with amidoxim obtains compound b ", ring-closure reaction is carried out in its insulation at high temperature in pyridine, obtains 5-base-[1,2,4] diazole compounds c.
Reaction scheme 4
The amine reaction of 7-chloro-pyrazolo-[1,5a]-pyrimidine a and replacement obtains compound d, and itself and bromo-ester react, and obtain amino acid ester b.Compound b and amidoxim react in the presence of NaH, obtain 5-base-[1,2,4] diazole compounds c.
Reaction scheme 5
7-chloro-pyrazolo-[1,5a]-pyrimidine a and amino alcohol (aminol) and triethylamine (TEA) react in acetonitrile, obtain amino alcohol e, and can there be the carapax et plastruw testudinis sulfonylation in it at TEA by Tosyl chloride, obtains compound f.(functionality) is incorporated among the compound f with cyano functional group, obtains compound g, its can with azanol reaction, obtain compound h.Compound h carries out ring-closure reaction in the presence of DMA-DMA, obtain 3-base-[1,2,4] diazole compounds i.
Reaction scheme 6
7-chloro-pyrazolo-[1,5a]-pyrimdinyl-amino acid esters b and hydrazine reaction obtains compound j, then with the ethyl formate reaction, obtains compound k, carries out ring-closure reaction with TsCl and DBU, obtains 5-base-[1,3,4] diazole compounds 1.
Reaction scheme 7
3-bromo-7-amino-pyrazolo-[1,5a]-pyrimdinyl-amino acid esters m reacts under the Suzuki reaction conditions with aryl boric acid, obtains 3-aryl-7-amino-pyrazolo-[1,5a]-pyrimdinyl-amino acid esters b, and the amidoxim reaction of itself and NaH and replacement obtains compound c.
Compound can be measured by various test methods as the effectiveness of CRF receptor antagonist.The specificity that CRF antagonist of the present invention can suppress CRF and its acceptor in conjunction with and antagonism (associated) activity relevant with CRF.The compound of structure (I) can be estimated activity as the CRF antagonist by one or more generally acknowledged tests for this purpose, include but is not limited to (J.Neuroscience 7:88 such as DeSouza, 1987) and (Synapse 1:572,1987) disclosed test such as Battaglia.As mentioned above, CRF antagonist of the present invention comprises the compound that shows the CRF receptor affinity.The CRF receptor affinity can be by measuring in conjunction with research, described in conjunction with research be used to measure compound suppress radiolabeled CRF (for example, [
125I] tyrosine-CFR) and its acceptor (for example, the acceptor that makes by the rat cerebral cortex film) bonded ability.The described radioligand of DeSouza etc. (ibid, 1987) provides a kind of test method of measuring compound to the CRF receptor affinity in conjunction with test.This activity is typically by IC
50Calculate IC
50Be meant the required compound concentration of radiolabeled part by displacement 50% in the described acceptor, and " the K to obtain by following Equation for Calculating
i" value the form record:
Wherein L=radioligand and K
D=radioligand is to the avidity (Cheng and Prusoff, Biochem.Pharmacol.22:3099,1973) of acceptor.
Except suppressing the CRF receptors bind, the CRF receptor antagonist activity of compound can also be determined by the compound antagonism active ability relevant with CRF.For example, known CRF can stimulate various Biochemical processes, comprises adenylate cyclase activity.Therefore, the ability (for example by measurement cAMP level) of the compound adenylate cyclase activity that can stimulate because of their antagonism CRF-is be evaluated as the CRF antagonist.The adenylate cyclase activity assay method that the described CRF-of people such as Battaglia (ibid, 1987) stimulates provides the assay method that is used to measure the active ability of compound antagonism CRF.Therefore, the CRF receptor antagonist activity can be measured by such measuring method, (for example (ibid by DeSouza wherein to generally comprise initial combination mensuration, 1987) disclosed in conjunction with measuring), then carry out cAMP screening scheme (for example by the disclosed scheme of Battaglia (ibid, 1987)).
About CRF receptors bind avidity, CRF receptor antagonist of the present invention can have the K less than 10 μ M
iIn one embodiment of the invention, the CRF receptor antagonist has the K less than 1 μ M
i, and in another embodiment, K
iLess than 0.25 μ M (i.e. 250 nM).As being described in more detail below, K
iValue can be measured by the method described in the embodiment 25.The CRF receptor antagonist of the present invention that has less than the Ki of 0.10 μ M (being 100nM) comprises embodiment 11-1,11-2,11-3,11-4,11-5,11-6,11-9,11-10,11-11,11-13,11-17,11-18,11-20,11-23,11-26,12-1,12-2,12-3,12-4,12-5,12-9,12-10,12-11,13-1,13-2,13-3,13-4,13-5,13-6,13-7,13-8,13-9,14-1,14-2,14-3,14-4,15-1,17-1,17-2,17-3,18-1,18-2,19-1,20-1,20-2,21-1,22-1,23-2,24-1,24-2,24-4 and 24-6.
CRF receptor antagonist of the present invention confirms to have activity in the CRF receptor site, and can be used as treatment various disease conditions or treatment of diseases agent, and described illness or disease comprise internal secretion, spirit and neurological disorder or disease.More particularly, CRF receptor antagonist of the present invention can be used for treating physiology disease or the illness that is caused by the CRF excessive secretion.It is believed that because CRF is a kind of critical neurotransmitter, its activation and coordinate at stress internal secretion, behavior reaction and reaction (automatic response) automatically, so CRF receptor antagonist of the present invention can be used for treating neuropsychopathy.Can comprise affective disorder (affective disorders), for example dysthymia disorders by the neuropsychopathy of CRF receptor antagonist treatment of the present invention; The illness relevant, for example generalized-anxiety disorder, panic disorder (panic disorder), obsessive compulsive disorder (obsessive-compulsive disorder), unusual (abnormal aggression), the Cardiovascular abnormality (for example unstable angina and reactive high blood pressure (reactive hypertension)) of attacking with anxiety; And eating disorder, for example anorexia nervosa, Bulimia nerovsa and irritable bowel syndrome.The CRF antagonist also can be used for the treatment of stress-immunosuppression and the apoplexy relevant of bringing out with various disease states.Other purposes of CRF antagonist of the present invention comprises that (Cushing ' sdisease), infantile spasms, epilepsy and other see baby and adult's epileptic seizures and various substance abuse and de-addiction (comprising alcoholism) for treatment inflammation (for example rheumatoid arthritis, uveitis, asthma, inflammatory bowel and G.I. wriggling (G.I.motility)), pain, Cushing's disease.
In the context of the invention, the following term of description illness used herein is according to theDiagnostic and Statistical Manual of Mental Disorders, 4th Edition, publish (DSM-IV) and/or the IntemationalClassification of Diseases by theAmerican Psychiatric Association, 10th Edition (ICD-10) classifies.It is a part of the present invention that the hypotype of the various illnesss that this paper is mentioned all is considered as.Numeral in the bracket of listed hereinafter disease back refers to the classification code in DSM-IV.
In the context of the invention, term " mental disorder " comprising:
Schizophrenia, it comprises the hypotype of paranoid schizophrenia (Paranoid Type) (295.30), disorganized schizophrenia (Disorganised Type) (295.10), catatonic schizophrenia (CatatonicType) (295.20), undifferentiated schizophrenia (Undifferentiated Type) (295.90) and residual schizophrenia (Residual Type) (295.60); Schizophreniform disorder (295.40); Schizoaffective disorder (295.70) comprises the hypotype of bipolar disorder (Bipolar Type) and depressibility mental disorder (Depressive Type); Vain hope (class paranoia) property (spirit) obstacle (297.1) comprises lagnosis's type (Erotomanic Type), exaggerative type (Grandiose Type), envy type (Jealous Type), persecution type (Persecutory Type), body type (Somatic Type), mixed type (Mixed Type) and does not indicate the hypotype of type; Brief psychotic disorder (298.8); Shared psychotic disorder (297.3); Because the mental disorder (Psychotic Disorder Due to a General Medical Condition) that the general medicine situation causes comprises the hypotype that has the vain hope and have illusion; The mental disorder that material causes comprises having vain hope (293.81) and have the hypotype of illusion (293.82); And the mental disorder (298.9) of NOS.
The The compounds of this invention that comprises its salt and pharmaceutically acceptable solvate also can be used for treating following illness:
Depressed (disease) and mood disorder comprise major depressive episode, manic episode, mixed type outbreak (MixedEpisode) and hypomania; Dysthymia disorders comprises the dysthymia disorders (311) of serious depressibility obstacle, dysthymic disorder (300.4), NOS; Bipolar disorder comprises the bipolar disorder (296.80) of I type bipolar disorder, II type bipolar disorder (with the major depressive episode of sending out again of hypomania) (296.89), circulation emotionality (spirit) obstacle (301.13) and NOS; Other mood disorder comprises because the mood disorder (293.83) that the general medicine situation causes, it comprises the hypotype that has depressed feature, has main depressed sample outbreak (Major Depressive-like Episode), has manic feature and have composite character), the mood disorder (296.90) of mood disorder that material causes (comprise and have depressed feature, have manic feature and have the hypotype of composite character) and NOS;
Anxiety disorder comprises social anxiety disorder, panic attack, agoraphobia, panic disorder, the agoraphobia (300.22) that does not have the panic disorder history, specific phobia (300.29) comprises animal-type, the physical environment type, blood-injection-damage type (Blood-Injection-Injury Type), the hypotype of situation type (Situational Type) and other type), social phobia (300.23), obsessive compulsive disorder (300.3), posttraumatic stress disorder (309.81), acute stress disorder (308.3), generalized-anxiety disorder (300.02), since the anxiety disorder (293.84) that the general medicine situation causes, anxiety disorder that material causes and the anxiety disorder of NOS (300.00);
The relevant obstacle (Substance-related disorders) of material comprises that psychoactive substance use disorders (Substance Use Disorders) is as substance depilatory, material addiction (Substance Craving) and substance abuse; The persistence perceptual disturbance (flashback) that obstacle that material causes such as material poisoning, material de-addiction (Substance Withdrawal), delirium that material causes, persistence dementia that material causes, persistence amnestic disorder that material causes, mental disorder that material causes, mood disorder that material causes, anxiety disorder that material causes, sexual dysfunction that material causes, somnopathy that material causes and halluoinogen cause; Obstacle relevant such as alcohol dependence (303.90) with alcohol, alcohol abuse (305.00), alcoholism (303.00), abstinence from alcohol (Alcohol Withdrawal) (291.81), alcoholic delirium, alcohol withdrawal delirium, the persistence dementia that alcohol causes (Alcohol Induced PersistingDementia), the persistence amnestic disorder that alcohol causes, psychotic disorders due to the alcohol, the mood disorder that alcohol causes, the anxiety disorder that alcohol causes, the sexual dysfunction that alcohol causes, the illness (291.9) relevant of somnopathy that alcohol causes and NOS with alcohol; Obstacle relevant with Amphetamine (or amphetamine-type material) such as Amphetamine (Amphetamine) rely on (304.40), amphetamine abuse (305.70), amphetamine intoxication (292.89), amphetamine withdrawal (292.0), amphetamine intoxication delirium, the mental disorder that Amphetamine causes, the mood disorder that Amphetamine causes, the anxiety disorder that Amphetamine causes, the sexual dysfunction that Amphetamine causes, the obstacle (292.9) relevant of somnopathy that Amphetamine causes and NOS with Amphetamine; The relevant obstacle (292.9) with caffeine of the anxiety disorder that obstacle relevant with caffeine such as caffeinism (305.90), caffeine cause, the somnopathy that caffeine causes and NOS; The obstacle relevant with hemp such as cannabis rely on the relevant obstacle (292.9) with hemp of (304.30), cannabis abuse (305.20), cannabism (292.89), cannabis intoxication delirium, mental disorder that hemp causes, anxiety disorder that hemp causes and NOS; The obstacle relevant with Cocaine such as Cocaine rely on the relevant obstacle (292.9) with Cocaine of (304.20), cocaine abuse (305.60), cocaine poisoning (292.89), cocaine withdrawal (292.0), cocaine intoxication delirium, mental disorder that Cocaine causes, mood disorder that Cocaine causes, anxiety disorder that Cocaine causes, sexual dysfunction that Cocaine causes, somnopathy that Cocaine causes and NOS; The relevant obstacle (292.9) with halluoinogen of the mental disorder that persistence perceptual disturbance (flashback) (292.89), hallucinogen intoxication delirium, the halluoinogen that obstacle relevant with halluoinogen such as hallucinogen dependence (304.50), hallucinogen abuse (305.30), hallucinogen intoxication (292.89), halluoinogen cause causes, the mood disorder that halluoinogen causes, anxiety disorder that halluoinogen causes and NOS; The relevant obstacle (292.9) with inhalation of obstacle relevant such as inhalant dependence (304.60), inhalant abuse (305.90), inhalant intoxication (292.89), inhalant intoxication delirium, persistence dementia that inhalation causes, mental disorder that inhalation causes, mood disorder that inhalation causes, anxiety disorder that inhalation causes and NOS with inhalation; The relevant obstacle (292.9) with Nicotine of obstacle relevant such as nicotine dependence (305.1), nicotine withdrawal (Nicotine Withdrawal) (292.0) and NOS with Nicotine; Obstacle relevant such as opioid dependence (Opioid Dependence) (304.00) with opioid (Opioid), opioid abuse (Opioid Abuse) (305.50), opium poisping (Opioid Intoxication) (292.89), opioid withdrawal (Opioid Withdrawal) (292.0), opioid intoxication delirium, the mental disorder that opium causes, the mood disorder that opium causes, the sexual dysfunction that opium causes, the obstacle (292.9) relevant of somnopathy that opium causes and NOS with opium; The relevant obstacle (292.9) with phencyclidine of obstacle relevant such as phencyclidine dependence (304.60), phencyclidine abuse (305.90), phencyclidine intoxication (292.89), phencyclidine intoxication delirium, mental disorder that phencyclidine causes, mood disorder that phencyclidine causes, anxiety disorder that phencyclidine causes and NOS with phencyclidine (or Phencyclidines material); With tranquilizer-, soporific-or anxiolytic-relevant obstacle such as tranquilizer, soporific or anxiolytic rely on (304.10), tranquilizer, soporific or anxiolytic abuse (305.40), tranquilizer, soporific or anxiolytic intoxication (292.89), tranquilizer, soporific or anxiolytic de-addiction (292.0), tranquilizer, soporific or anxiolytic intoxication delirium, tranquilizer, soporific or anxiolytic de-addiction delirium (Withdrawal Delirium), tranquilizer-, soporific-or anxiolytic-persistence dementia, tranquilizer-, soporific-or anxiolytic-persistence amnestic disorder, tranquilizer-, soporific-or the mental disorder that causes of anxiolytic, tranquilizer-, soporific-or the mood disorder that causes of anxiolytic, tranquilizer-, soporific-or the anxiety disorder that causes of anxiolytic, tranquilizer-, soporific-or the sexual dysfunction that causes of anxiolytic, tranquilizer-, soporific-or the somnopathy that causes of anxiolytic and NOS with tranquilizer-, soporific-or anxiolytic-relevant obstacle (292.9); The obstacle relevant with many materials (Polysubstance-Related Disorder) is as many substance depilatories (304.80); With other (or unknown) relevant obstacle such as anabolic steroid, nitrate inhalation (Nitrate Inhalants) and Nitrous Oxide of material;
Somnopathy, it comprise primary somnopathy such as dyssomnias such as primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), with the somnopathy (307.47) of breathing relevant somnopathy (780.59), circadian rhythm sleep disorder (307.45) and NOS; The parasomnia (307.47) of primary somnopathy such as parasomnias such as nightmare disorder (307.47), night terror (307.46), somnambulism (307.46) and NOS; The somnopathy that relates to other mental disorder is as insomnia (307.42) that relates to other mental disorder and the hypersomnia (307.44) that relates to other mental disorder; Because the somnopathy that the general medicine situation causes; With the somnopathy that material causes, comprise the hypotype of insomnia type, hypersomnia type, parasomnia type and mixed type;
Eating disorder such as anorexia nervosa (307.1) comprise the hypotype of restricted type (Restricting Type) and carousing-feed type (Binge-Eating)/purgation type (Purging Type); Bulimia nervosa (307.51) comprises the hypotype of purgation type and non-purgation type (Nonpurging Type); Obesity; Mandatory eating disorder; Eating disorder (307.50) with NOS.
Autism (299.00); Attention deficit/hyperkinetic syndrome comprises attention deficit/hyperkinetic syndrome mating type (Hyperactivity Disorder Combined Type) (314.01), the inattentiveness type that attention deficit/hyperkinetic syndrome is dominant (Hyperactivity Disorder Predominantly Inattentive Type) (314.00), the various hypotypes of the attention deficit/hyperkinetic syndrome (314.9) of attention deficit/hyperkinetic syndrome hyperactivity hyperkinesia impulsive style (Hyperactivity Disorder Hyperactive-ImpulseType) (314.01) and NOS; Supermotility sexual dysfunction (Hyperkinetic Disorder); Disruptive behaviour obstacle (disruptive behaviourdisorder) is outbreak type (321.81), adolescency outbreak type (312.82) and do not indicate outbreak type (312.89), the various Asia property of the disruptive behaviour obstacle of oppositional defiant disorder (313.81) and NOS Childhood of comprising as conduct disorder; And tic disorder such as tourette (family name) mental disorder (307.23).
Personality disorder, comprise paranoid personality disorder (Paranoid Personality Disorder) (301.0), personality disorder (301.20), schizotypal personality disorder (301,22), antisocial personality disorder (301.7), borderline personality disorder (301,83), the hypotype of the personality disorder (301.9) of histrionic personality disorder (301.50), narcissistic personality disorder (301,81), avoidant personality disorder (301.82), dependent personality disorder (301.6), compulsive personality disorder (301.4) and NOS;
Improve cognitively, comprise that treatment is at other disease such as schizophrenia, bipolar disorder, depression (disease), other psychiatric disorders and the psychotic symptoms relevant with the cognitive impairment cognitive impairment in the Alzheimer's for example; And
Sexual dysfunction, it comprises dysaphrodisia such as hypothyroid dysaphrodisia (302.71) and sexual aversion disorder (302.79); Sexual arousal dysfunction such as female sexual arousal disorder (302.72) and male erectile disorder (302.72); Orgasm disorder (orgasmic disorders) is as female orgasmic disorder (302.73), male orgasmic disorder (302.74) and premature ejaculation (302.75); Sexual pain disorder such as dyspareunia (302.76) and vulvismus (306.5 1); The sexual dysfunction of NOS (302.70); The parasexuality (302.9) of sexual perversion such as exhibitionism (302.4), fetishism (302.81), frotteurism (302.89), PEDoPhIlIa (302.2), masochism (302.83), sexual sadism (302.84), eonism (302.3), Voyeurism (302.82) and NOS; Gender identity disorder such as children's gender identity disorder (302.6) and teenager or adult's gender identity disorder (302.85); And the sexual dysfunction (302.9) of NOS;
All of mentioned obstacle are multi-form herein all is considered as a part of the present invention with hypotype.
" treatment " comprises prevention, and wherein this is suitable for relevant illness.
In another embodiment of the invention, the pharmaceutical composition that contains one or more CRF receptor antagonists is disclosed.In order to carry out administration, compound of the present invention can be mixed with pharmaceutical composition.Pharmaceutical composition of the present invention contains pharmaceutically the CRF receptor antagonist of the present invention of significant quantity (being the compound of structure (I)) and pharmaceutically acceptable carrier or thinner.Therefore, the CRF receptor antagonist is present in the composition with the amount that is enough to effectively to treat particular disorder.In one embodiment of the present invention, pharmaceutical composition of the present invention can comprise every dosage 0.1mg to 250mg CRF receptor antagonist, and this depends on the approach of administration.In another embodiment, described dosage can be in the scope of 1mg to 60mg.In other embodiments, described dosage for example can be 5mg, 10mg, 15mg or 20mg.Those skilled in the art can determine suitable concentration and dosage easily.
Pharmaceutically acceptable carrier and/or thinner are that those skilled in the art are familiar with.With regard to the composition that is mixed with liquor agent form, pharmaceutically acceptable carrier and/or thinner comprise salt solution and sterilized water, and can randomly contain antioxidant, buffer reagent, fungistat (bacteriostats) and other typical additives.Also composition can be mixed with pill, capsule, granule or tablet form, wherein except containing the CRF receptor antagonist, also contain thinner, dispersion agent and tensio-active agent, tackiness agent and lubricant.Those skilled in the art can further prepare the CRF receptor antagonist, for example Remington ' s PharmaceuticalSciences by rights according to the convention of generally acknowledging, the Gennaro work, Mack Publishing Co., Easton, disclosed method among the PA 1990.
In addition, prodrug also is included in the scope of the invention.Prodrug is meant the carrier of any covalent bonding, with this class prodrug when the patient uses, they disengage structure (I) compound in vivo.Prodrug is generally prepared by modifying functional group in such a way, causes by conventional processing or in vivo can cracking remove this modification to obtain parent compound.
Therefore about steric isomer, structure (I) compound can have chiral centre, can racemoid, racemic mixture and discrete enantiomer or diastereomer exist.All these class isomeric form, comprise that its mixture all is included in the scope of the invention.In addition, the structure of some crystallized forms (I) compound can exist with the form as polymorphic form, and they are included in the scope of the invention.In addition, some structures (I) compound can also form solvate with water or other organic solvent.This kind solvent compound is included in the scope of the invention equally.
In another embodiment, the invention provides the method for treatment various disease conditions or disease, comprise internal secretion, spirit and neurological disorder or disease.These class methods comprise to Mammals (for example people) according to the consumption administration compound of the present invention that is enough to treat this illness or disease.These class methods comprise that the pharmaceutical composition of the CRF receptor antagonist of the present invention of significant quantity carries out the whole body administration with containing pharmaceutically.Whole body administration used herein comprises oral and the administered parenterally method.With regard to oral administration, the pharmaceutical composition of suitable CRF receptor antagonist comprises pulvis, granule, pill, tablet and capsule, and liquid, syrup, suspensoid and emulsion.These compositions can also comprise seasonings, sanitas, suspending agent, thickening material and emulsifying agent and other pharmaceutically acceptable additive.With regard to administered parenterally, compound of the present invention can be become moisture injection solution, wherein except containing the CRF receptor antagonist, can also contain buffer reagent, antioxidant, fungistat (bacteriostats) and other and be usually used in additive in this class solution.
In another embodiment, by using radioactivity or on-radiation medicament, the present invention can realize the diagnostic visual (diagnostic visualization) of specific site in the body.Use compound of the present invention physiological, functional or biological evaluation to be provided or to provide disease or pathology detection and evaluation method as the patient.Radiopharmaceuticals preparation be used to scintigraphy (scintigraphy), positron emission tomography (positron emission tomography) (PET), computed tomography (CT) and single photon emission computerized tomography (SPECT).In order to realize this class application, the radio isotope that mixes such as iodine (I) element comprises
123I (PET),
125I (SPECT) and
131I, the radio isotope of technetium (Tc) element comprises
99Tc (PET), the radio isotope of phosphorus (P) element comprises
31P and
32P, the radio isotope of chromium (Cr) element comprises
51Cr, the radio isotope of carbon (C) element comprises
11C, the radio isotope of fluorine (F) element comprises
18F, the radio isotope of thallium (T1) element comprises
201Emission of positron such as T1 and ionizing rays.The on-radiation medicine be used to nuclear magnetic resonance (MRI), zyglo and ultrasonic in.In order to realize this class application, the isotropic substance that mixes such as gadolinium (Gd) element comprises
153Gd, iron (Fe), barium (Ba), manganese (Mn) and thallium (T1).This class entity also can be used for whether existing in definite mixture the molecule in specific target position and the mark mixture.
Property explanation and non-limiting purpose provides the following example presented for purpose of illustration.
Embodiment
CRF receptor antagonist of the present invention can be by disclosed method preparation among the embodiment.Embodiment 25 has provided a kind of method of measuring receptors bind avidity, and embodiment 26 discloses the analytical procedure of the adenylate cyclase activity of the CRF-stimulation of screening The compounds of this invention.
Abbreviation:
AcCN, MeCN: acetonitrile
AcCN: acetonitrile
DBU: DAB
DCM: methylene dichloride
DEAD: diethylazodicarboxylate
DIC:N, N '-DIC
DIU:N, N '-di-isopropyl urea
DMA-DMA:N, the N-dimethylacetamide dimethylacetal
DME:1, the 2-glycol dimethyl ether
DMF: dimethyl formamide
DMF-DMA:N, the dinethylformamide dimethylacetal
EAA: ethyl 3-oxobutanoate
The HOBT:1-hydroxybenzotriazole
LC/MS: liquid chromatography-mass spectrography
MDA: mda is two-dimethylacetal
MsCl: methylsulfonyl chloride
NaBH (OAc)
3: sodium triacetoxy borohydride
Pd-C: palladium (10%)/carbon
TEA: triethylamine
TFA: trifluoroacetic acid
THF: tetrahydrofuran (THF)
TosMIC: isocyanic acid p-toluenesulfonyl methyl ester
TsCl: Tosyl chloride
TsOH: tosic acid
Preparation HPLC-MS
Gilson HPLC-MS is equipped with Gilson 215 automatic samplers/fraction (fraction) collector, UV detector and ThermoFinnigan AQA Single QUAD mass detector (electron spray(ES));
HPLC post: BHK ODS-O/B, 5 μ, 30 * 75mm
HPLC gradient: 35mL/min, the aqueous solution to 100% acetonitrile of 10% acetonitrile keep 100% acetonitrile 3min in 7min.
Analytical procedure 1--high performance liquid chromatography (HPLC-MS)
Platform:HP 1100 series: be equipped with automatic sampler, UV detector (220nM and 254nM), MS detector (electron spray(ES));
Post: Phenomenex SynergiMAX-RP, 4 microns, 2 * 50mm;
Moving phase: A=water, 0.025%TFA; The B=acetonitrile, 0.025%TFA;
Flow velocity: 1.0mL/min;
Gradient: 5%B/95%A-95%B/5%A keeps 2.5min then in 13min;
Analytical procedure 2--supercritical fluid chromatography (SFC)
Platform:Berger FCM1200 SFC pump, Agilent diode-array detector, AgilentModel 220 Microplate automatic samplers, Agilent Model 1946 MSD (APCI interface);
Post: Berger Pyridine 60A, 4 microns, 3 * 150mm;
Solvent: SFC level CO
2, Optima-level methyl alcohol contains 1.5% water and 0.025% ethyl sulfonic acid;
Flow velocity: 4.0mL/min, 120 crust back pressures;
Gradient: 5-55% methyl alcohol/CO
2In 2.4min.
Analytical procedure 3--analyzes HPLC-MS (LC-MS)
Platform:HP 1100 series: be equipped with automatic sampler, UV detector (220nM and 254nM) and MS detector (APCI);
Post: Waters XTerra 3 * 250mm;
Solvent orange 2 A: the water that contains 0.025%TFA
Solvent B: the acetonitrile that contains 0.025%TFA
Flow velocity: 1.0mL/min;
Gradient: 5%B 1.55min, 10-90%B (amounts to 47.55min) in 46min then
Analytical procedure 4--analyzes HPLC-MS (LC-MS),
Platform:HP/agilent 1100 series: be equipped with automatic sampler, UV detector (220nM and 254nM) and MS detector (APCI);
Post: Phenomonex Synergymax RP 2.0 * 50mm;
Flow velocity: 1.0mL/min;
The aqueous solution of solvent orange 2 A: 0.05%TFA
The acetonitrile solution of solvent B:0.05%TFA
Gradient: 5%B 0.25min, 5%B-90%B is from 0.25 to 2.25min then, then 90%B from 2.25 to 3.25min.
Embodiment 1
Synthesizing of reagent [5-(7-chloro-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-3-yl)-4-methyl-pyridine-2-yl]-dimethyl-amine
Step 1A:
Under 0 ℃ in 2 hours, to 2-amino-4-picoline (33g), NaBH
3(37% aqueous solution 240mL) drips acetate (60ml) in the mixture in acetonitrile (1 L) and water (200mL) for CN (57g), formaldehyde.Gained solution at room temperature stirred 7 days, concentrated in a vacuum then.Resistates alkalizes to pH 10 with solid NaOH, then with hexane (3 * 700mL) extractions.The extraction liquid that merges is used Na with the 1NNaOH aqueous solution and salt water washing
2SO
4Drying is then evaporated in a vacuum, obtains the 2-dimethylamino-4-picoline (compound 1a, 36g, 88%) of colorless oil.
1H NMR(CDCl
3)：2.26(s，3H)，3.07(s，6H)，6.33(s，1H)，6.40(d，1H)，8.02(d，1H)；MS(CI)m/e137(MH
+).
Step 1B:
Under 0 ℃, in 0.5 hour, to compound 1a (32g), Na
2CO
3(30g) in the mixture in DCM (50mL) and water (400mL) solution of dripping bromine (13mL) in DCM (50mL) to handle.The light brown suspension of gained stirred 0.5 hour down at 0 ℃.Gains extract with hexane (2x600mL), and the salt water washing of the extraction liquid of merging is at Na
2SO
4Middle dry, then evaporation in a vacuum.Thick gains are purified with 1: 5 ethyl acetate/hexane wash-out with silica gel chromatography, obtain the 5-bromo-2-dimethylamino-4-picoline (compound 1b, 78% yield) of brown solid.
1H NMR(CDCl
3)：2.30(s，3H)，3.04(s，6H)，6.38(s，1H)，8.14(s，1H)；MS(CI)m/e 216(MH
+).
Step 1C:
The solution of compound 1b (48.5g) in THF (100mL) that in the suspension of magnesium (11.3g) in THF (20mL), adds 1/4th step 1B.Under the situation of heating a little, by adding 5 glycol dibromide initiation reactions.After beginning reaction, add 10mL THF.The rest part of the solution of dropping compound 1b is to keep gentle backflow.After adding was finished, mixture at room temperature stirred 0.5 hour, then injected DMF (1.5eq.) under 0 ℃ lentamente.The gained mixture at room temperature stirs and spends the night and use saturated NH
4The cancellation of the Cl aqueous solution.(2 * 500mL) extractions, the salt water washing of the extraction liquid of merging is through MgSO with ether for gains
4Drying is filtered and is concentrated in a vacuum.Gains are purified with 1: 5 ethyl acetate/hexane wash-out with silica gel chromatography, obtain the 2-dimethylamino-4-methyl-5-formylpyridine (compound 1c, 77% yield) of brown solid.Use the ether/hexane crystallization, obtain analytic sample.
1H NMR(CDCl
3)：2.57(s，3H)，3.11(s，6H)，6.28(s，1H)，8.43(s，1H)，9.87(s，1H)；MS(CI)m/e 165(MH
+).
Step 1D:
Under-50 ℃, in the suspension of tBuOK (12.5g) in DME (70mL), drip the solution of TosMIC (15.6g) in DME (70mL).Brown solution is stirred 10min down at-50 ℃, then drip the solution of compound 1c (11g) in DME (70mL).The gained mixture stirred 0.5 hour down at-50 ℃, then with methyl alcohol (70mL) cancellation.This mixture heating up was refluxed 1 hour, and steaming desolventizes and distributes between ethyl acetate-water.Organic layer salt water washing is through MgSO
4Drying is then filtered with ethyl acetate by silica filler (pad).After handling like this, obtain 2-dimethylamino-4-methyl-5-(cyano methyl) pyridine (compound 1d, 9.5g, 80%) of yellow solid.
1H NMR(CDCl
3)：2.31(s，3H)，3.08(s，6H)，3.54(s，2H)，6.36(s，1H)，7.99(s，1H)；MS(CI)m/e176(MH
+)
Step 1E:
(40g adds the ethyl acetate of about 5mL 0.23mol) and in the suspension of NaH (2.5eq.) in THF (100mL) to compound 1d.Mixture at room temperature stirs, till beginning thermopositive reaction and violent releasing hydrogen gas.Then, drip ethyl acetate (50mL) to keep gentle backflow.Mixture at room temperature stirred 2 hours, then with its water (100mL) cancellation.Separate organic phase, water washs several times with ether.Then, water acetate acidifying, (5 * 800mL) extract gains with ethyl acetate.The extraction liquid that merges is with salt solution (50mL) washing, then through MgSO
4Dry.Concentrate in a vacuum, obtain keto-acid 1-cyano group-1-(6-dimethylamino-4-picoline-3-yl) acetone and the 3-hydroxyl-but-2-ene nitrile enol form (compound 1e) (40g, 80% yield) of brown solid.
1H NMR (CDCl
3): 1: 1 mixture of enol and keto-acid, 2.24 (s, 1.5x3H), 2.32 (s, 0.5x3H), 2.88 (s, 0.5x6H), 3.09 (s, 0.5x6H), 4.50 (brs, 0.5x1H), 4.62 (s, 0.5x1H), 6.13 (s, 0.5x1H), 6.35 (s, 0.5x1H), 7.60 (s, 0.5x1H), 8.05 (s, 0.5x1H); MS (CI) m/e 218 (MH
+).
Step 1F:
Mixture heating up in ethanol (150mL) and water (20mL) refluxed 1 hour with compound 1e (30g) and hydrazine hydrobromate (62g).Remove ethanol in a vacuum, resistates water (50mL) dilution.Water solid Na
2CO
3Alkalization, the gains ethyl acetate extraction.Extraction liquid is through MgSO
4Drying is filtered and is concentrated in a vacuum, obtains brown buttery 3-amino-4-(6-dimethylamino-4-picoline-3-yl)-5-methylpyrazole (compound 1f, 30g, 93% yield), and it uses ether-hexane crystallization.
1HNMR(CDCl
3)：2.07(s，3H)，2.14(s，3H)，3.10(s，6H)，4.10(brs，3H)，6.45(s，1H)，7.92(s，1H)；MS(CI)m/e 232(MH
+)
Step 1G:
Vlil in two alkane (100mL) is 20 hours with compound 1f (29.5g) and methyl aceto acetate (2.5eq.).Cooling suspension, and add ether (200mL).Solid is collected in vacuum filtration, obtains 2 of brown solid, and 5-dimethyl-3-(6-dimethylamino-4-picoline-3-yl)-7-hydroxypyrazoles is [1,5-a] pyrimidine (compound 1g, 23.5g, 62% yield) also.Filtrate concentrates in a vacuum, in resistates water-soluble (50mL).(3 * 300mL) extractions are to remove starting material and impurity with ether with this water.Then, (5 * 300mL) extractions obtain other 6g (total recovery 78%) compound 1g to product with DCM.
1H NMR(CDCl
3)：2.10(s，3H)，2.20(s，3H)，2.33(s，3H)，2.91(s，6H)，5.64(s，1H)，6.24(s，1H)，7.65(s，1H).MS(CI)m/e 298(MH
+)
Step 1H:
With compound 1g (11g) and POCl
3(2eq.) the suspension reflux in acetonitrile (50mL) is 8 hours.With icing the cancellation reaction and using Na
2CO
3Alkalization.(2 * 200mL) extract product with ethyl acetate.Extraction liquid is through MgSO
4Drying is filtered and is concentrated in a vacuum by silica filler (pad), obtains [5-(the 7-chloro-2 of light yellow solid, 5-dimethyl-pyrazolo [1,5-a] pyrimidin-3-yl)-4-methyl-pyridine-2-yl]-dimethyl-amine (compound 1h, 11.5g, 99% yield).
1H NMR(CDCl
3)：2.13(s，3H)，2.43(s，3H)，2.53(s，3H)，3.11(s，6H)，6.49(s，1H)，6.78(s，1H)，8.01(s，1H)；MS(CI)m/e316(MH
+)
Embodiment 2
Synthesizing of reagent (2,4-dimethoxy-phenyl)-acetonitrile
Step 2:
Under-30 ℃ (dry ice/acetone batch), in the suspension of t-BuOK (47.3g) in DME (150mL), drip the solution of TosMIC (58.8g) in DME (150mL), keep the temperature of mixture to be lower than-30 ℃.It is cooled to-60 ℃ with solution stirring and in 10 minutes, drips 2 then, the solution of 4-dimethoxy benzaldehyde (50gl) in DME (150mL) keeps the temperature of reaction mixture to be lower than-50 ℃.Reaction mixture stirred 1 hour down at-50 to-60 ℃, added methyl alcohol (200mL) then.This mixture heating up was refluxed 2 hours.Steaming desolventizes, and resistates distributes between ethyl acetate and water under the situation that adds acetate (40mL).The water layer ethyl acetate extraction of a part in addition, the ethyl acetate layer of He Binging salt water washing then through dried over mgso, is filtered, and is then concentrated.Resistates is purified with silica gel column chromatography, with 1: 1 hexane/ethyl acetate wash-out, obtains 2 (48.8g).
Embodiment 3
Synthesizing of reagent 2-chloro-4-methoxyl group-phenyl aldehyde and (2-chloro-4-methoxyl group-phenyl)-acetonitrile
Step 3A:
2-chloro-4-hydroxy benzaldehyde (9.56g) and K
2CO
3(25.3g) at room temperature stir 30min with DMF (30mL).Add methyl iodide (4.0mL), the reactor sealing was then at room temperature stirred mixture 16 hours.Add 2: 1 hexane/ethyl acetate of 300mL, then mixture is washed with water three times, use the salt water washing then once.Organic layer filters through dried over sodium sulfate, then is evaporated to the volume of about 50mL.Filter the precipitation that forms, use hexane wash, obtain the compound 3a (6.0g) of brown solid.
Step 3B:
According to the method for step 2, use t-BuOK and TosMIC in DME, make cyanide compound 3b.
Embodiment 4
Reagent 7-chloro-3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidine synthetic
Step 4A:
At room temperature, in nitrogen, sodium hydride (60% suspension in oil of 12.0g) is joined in the 4-methoxyl group-solution of 2-aminomethyl phenyl acetonitrile (30g) in anhydrous THF (300mL).The ethyl acetate that adds about 2mL is followed the internal temperature that mixture is heated to gradually 66 ℃.After about 10 minutes, vigorous reaction taking place, stop heating, dripped extra ethyl acetate (75mL) simultaneously and reflux with maintenance in about 20 minutes.Observe violent releasing hydrogen gas.Adding ethyl acetate when finishing, begin the reaction mixture cooling, then mixture is stirred and in 3 hours with its cooling.Add 150mL water, then add the 300mL ether.Water layer washs with extra two parts of ether.Discard ether extraction liquid.Water layer is with 20mL concentrated hydrochloric acid acidifying (pH～5), and mixture is with three parts of ethyl acetate extractions then.The acetic acid ethyl acetate extract that merges filters and evaporation through dried over sodium sulfate, obtains the thick ketone nitrile 4a (39g) of slight amber oily, and it is not having just to be used for next step under the situation of further purifying.
Optional step 4A:
At room temperature, (60% suspension in oil of 35.44g, (148.8g is 0.92mol) in the solution in anhydrous THF (2 L) 1.48mol) to join 4-methoxyl group-2-aminomethyl phenyl acetonitrile with sodium hydride.Add EtOAc (30mL), then mixture is heated to gradually 70.1 ℃ internal temperature.Begin reaction,, stop heating immediately by thoroughly removing heating jacket.Drip EtOAc (374 mL amount to 4.14mol) to keep backflow.Observe violent releasing hydrogen gas, after adding whole EtOAc, will react and stir 2 hours.Add entry (750mL), then under vigorous stirring, add hexane (750mL), separate water layer and be acidified to pH～2 with dense HCl.Water layer extracts with EtOAc (3x400mL), the extraction liquid drying (MgSO of merging
4) and concentrate in a vacuum, obtain the 4a (183.8g, 0.90mol, 98%, 99% purity) of amber oily.
Step 4B:
The mixture of thick 4a (37.8g) and hydrazine monohydrobromide (23.1g) is suspended in dehydrated alcohol (225mL) and the water (25mL).Mixture was refluxed about 3 hours.With the reaction mixture cooling, steaming desolventizes then.Add ethyl acetate, mixture is by adding saturated NaHCO
3The aqueous solution (200mL) neutralizes, and then mixture is extracted with ethyl acetate (4x100mL).The organic layer that merges, filters through dried over mgso with salt solution (100mL) washing, and evaporation obtains light orange buttery crude compound 4b (45g), is not having just to be used for next step under the situation of further purifying.
Optional step 4B:
With compound 4a (183.8g 0.9mol) is dissolved in EtOH (1.09L) and the water (109mL), then add the hydrazine hydrobromate (112.39g, 0.99mol).At this moment mixture backflow (bathing temperature for 90 ℃) 2.5 hours shows to react with the LC/MS monitoring and finishes.With the reaction mixture cooling, concentrate in a vacuum, remove EtOH, then at NaHCO
3Distribute between (950mL, saturated aqueous solution) and the EtOAc (400mL).Separate water layer, and (3 * 400mL) extractions once more, the organic layer of merging washs with salt solution (400mL), dry (MgSO with EtOAc
4) and concentrate in a vacuum, obtaining the thick amino-pyrazol 4b (168.8,80% purity) of amber oily, it is not having just use under the situation of further purifying.
Step 4C:
Methyl aceto acetate (EAA) (28.4mL) is joined 4b, and (40.2g is 0.18mol) in the solution in anhydrous two alkane (180mL).Mixture refluxed about 20 hours down at 115 ℃, separated out the pyrazolopyrimidine 4c of white solid during this period from solution.With reaction mixture cooling, leach precipitation and wash with cold diethyl ether.Then, precipitation is dry in a vacuum, obtains the compound 4c of 22.5g (0.079mol, 42.7%) pale solid.
Optional step 4C:
Methyl aceto acetate (EAA) (200mL) is joined thick 4b, and (180g is 0.62mol) in the solution in dehydrated alcohol (500mL) and glacial acetic acid (500mL).Mixture heating up was refluxed 2 hours, from solution, separate out the pyrazolopyrimidine 4c of white solid during this period.With reaction mixture cooling, leach precipitation and wash with cold diethyl ether.Then, precipitation is dry in a vacuum, obtains the compound 4c of 131g (0.46mol, 75%) pale solid.
Step 4D:
At room temperature, phosphoryl chloride (12mL) is joined in the suspension of 4c (12.1g) in anhydrous acetonitrile (60mL).Mixture was heated 30 hours down at 80 ℃, and at this moment, reaction mixture is a kind of clarifying, dark red solution.Reaction mixture is poured into 300mL ice/waterborne, with reaction flask with the rinsing of 100mL ethyl acetate.Then, neutralize with the mixture stirring and with saturated aqueous sodium carbonate.When in and the time, red mixture becomes yellow.Separating layer, (4 * 100mL) extract water layer with ethyl acetate.The organic layer that merges, filters through dried over mgso with salt solution (100mL) washing, concentrates, and obtains a kind of clarifying brown oil.Crude product carries out silica gel chromatography to be separated, and uses 2: 1 hexane/ethyl acetate, obtains the compound 4d (12.1g, 94%) of clarified yellow oil shape, and it solidifies when leaving standstill.
Optional step 4D:
At room temperature, to pyrazolopyrimidine 4c (235.1g, 0.83mol) add in the suspension in anhydrous acetonitrile (1.2L) phosphoryl chloride (232mL, 2.49mol).With mixture heating up to 80 ℃ and stirred 20 hours, then with its cooling and be concentrated into about 1/4 volume in a vacuum.Add trash ice and water carefully under stirring, so that cumulative volume reaches 1L.Use ice bath and always be lower than 5 ℃ to guarantee temperature by in mixture, adding more trash ice, use NaOH (2M, the aqueous solution) with pH regulator to about 6-7.The cold suspension of gained extracts the organic layer drying (MgSO of merging with EtOAc (3x500mL)
4), concentrate in a vacuum, obtain the chloropyrimide 4d (258.3g, 93% purity) of red wax shape crystalline solid, it is directly used in next step.
Also prepared following compound by this method:
4e 2,5-dimethyl-3-(2, the 4-Dimethoxyphenyl)-7-chlorine pyrazolo [1,5-a]-pyrimidine (since 2);
4f 2,5-dimethyl-3-(2-chloro-4-p-methoxy-phenyl)-7-chlorine pyrazolo [1,5-a]-pyrimidine (from 3b); With
4g 2,5-dimethyl-3-(4-ethoxyl phenenyl)-7-chlorine pyrazolo [1,5-a]-pyrimidine (from 4-ethoxyl phenenyl acetonitrile).
Embodiment 5
Synthesizing of reagent 2-(3-bromo-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl amino)-methyl-butyrate
Step 5A:
The solution of 3-amino-5-methylpyrazole (20.0g), methyl aceto acetate (32.0g), acetate (6mL) and two alkane (150mL) was refluxed 16 hours.Separate out white solid, it is filtered collect.Filter cake washs with ether, obtains the 5a (29.0g, 86%) of white solid.
Step 5B:
1, add triethylamine (8.50mL) and phosphoryl chloride (7.4mL) in the suspension in the 4-two alkane (30mL) to 5a (5.0g).To be reflected in the nitrogen and heat 2 hours down at 100 ℃.Reaction mixture is cooled off in ice bath, and water and sodium bicarbonate aqueous solution are handled (final pH 8) successively then.Add methylene dichloride, mixture is washed with water three times.The organic layer that merges filters through dried over mgso, concentrates, and obtains dun oil.Thick gains are purified with silica gel chromatography, and the hexane solution that uses 30% ethyl acetate obtains the 5b (3.8g, 70%) of white solid as elutriant.LC/MS：182.0(MH
+)
Step 5C:
Under-10 ℃, bromine (0.51mL) is joined in the solution of 5b (1.5g) in 1: 1 methanol (40mL).Behind the 10min, mixture is filtered, collect the precipitation that forms.The cold MeOH/H of filter cake
2O (1: 1) washs, and is dry in a vacuum then till filtrate becomes clarification, obtains the 5c (3.0g) of pale solid, and it is not having use immediately under the situation of further purifying.
Step 5D:
In compound 5c (above preparation), add (RS) 2-aminobutyric acid methyl ester hydrochloride (1.3g), then add the molecular sieve of acetonitrile (40mL) and 4 dusts.Reaction mixture was heated 5 hours down at 110 ℃.Ethyl acetate and sodium bicarbonate aqueous solution are joined in the refrigerative reaction mixture organic layer salt water washing three times then.Organic layer filters through dried over mgso, and evaporation obtains a kind of thick yellow solid.Purify by silica gel chromatography, use 30% ethyl acetate/hexane, obtain the 5d (800mg, 28%) of pale solid as elutriant.
Embodiment 6
Synthesizing of reagent N-hydroxyl-ethanamidine
Step 6:
At room temperature, sodium hydroxide (50% aqueous solution of 39g) is joined in the suspension of oxammonium hydrochloride (34g) in methyl alcohol (100mL).Add acetonitrile (20g), then mixture was heated 15 hours down at 60 ℃.Mixture cooling and steaming are desolventized, then 300mL ethanol is joined in the resistates.Leach solid and use the rinsing of 200mL ethanol, then filtrate is evaporated to the volume of 75mL.The gained precipitation is collected in filtration, uses the ethanol rinsing, and is dry in a vacuum then, obtains the acetyl amidoxime 6a (19.5g) of white solid.
Also prepared following compound by this method:
6b: the propionyl amidoxime and
6c: butyryl amidoxime.
Embodiment 7
Reagent 2,2,2-three fluoro-N-hydroxyl-ethanamidines synthetic
Step 7:
At room temperature, sodium methoxide solution (the 25%w/w solution of 35.9mL in methyl alcohol) is joined in the suspension of oxammonium hydrochloride (10.9g) in methyl alcohol (200mL).Mixture stirs 10min, filters then, then with the solid methanol rinse.With filtrate cooling and in ice bath, stir, in 30min, in this solution, blast trifluoro acetonitrile gas (16.7g) then.Reaction mixture is warmed to room temperature, is evaporated to the volume of 100mL then, then solids removed by filtration.The filtrate evaporation obtains a kind of waxy stone shape solid (18g).This solid part is further purified with bulb-to-bulb vacuum distilling, obtain the compound 7 of brown waxy solid.
Embodiment 8
Reagent (S)-4,4,4-three fluoro-3 Methylbutanoic acid ethyl esters synthetic
Step 8A:
(R)-Alpha-Methyl benzylamine (16.0g) is joined 4,4, in the solution of 4-trifluoroacetic acid ethyl ester (24.4g) in toluene (75mL).Add tosic acid hydrate (630mg), then mixture heating up is refluxed, remove by dean stark trap and anhydrate.After 2 hours,, add ethyl acetate (100mL), then solution is washed with sodium bicarbonate aqueous solution, then use the salt water washing the mixture cooling.Organic layer filters through dried over sodium sulfate, and evaporation obtains a kind of yellow oil.This oil is carried out vacuum distilling (at 102-110 ℃, about 5mm Hg collects down), obtain the compound 8a of 17.5g colorless oil.
Step 8B:
DBU (18.1mL) is joined among the 8a (17.44g), then the brown mixture was heated 12 hours down at 70 ℃.The refrigerative mixture is joined in the silica filler,, obtain the compound 8b (14.5g) of yellow oily with 4: 1 hexane/ethyl acetate wash-outs.
Step 8C:
(7.0mL 2N) joins in the solution of compound 8b (800mg) in ether (10mL) with hydrochloric acid.With mixture at room temperature vigorous stirring 15 hours, separating layer then.Water layer is evaporated to dried with ether washing three times then.Resistates and toluene coevaporation twice, dry in a vacuum then, obtain gelationus compound 8c (410mg).
Embodiment 9
Synthesizing of reagent 3-amino-methyl valerate
Step 9A:
Benzylamine (2.51mL) is joined instead-solution of 2-amylene-4 acid methyl ester (2.62g) in methyl alcohol (10mL) in.With the reactor sealing, solution was heated 3 hours down at 85 ℃.Steaming desolventizes, and resistates carries out silica gel chromatography to be separated, and with 3: 1 hexane/ethyl acetate wash-outs, obtains the 9a (2.9g) of yellow oily.
Step 9B:
The mixture of 9a (2.3g), 20% palladium hydroxide/carbon (530mg) and ethanol (10mL) was at room temperature stirred 17 hours in hydrogen (1atm, balloon).In reaction mixture, blast nitrogen, filter then and evaporate.Resistates is dissolved among the DCM, through dried over sodium sulfate, filters and evaporation, obtain the compound 9b (1.7g) of colorless oil, its corresponding ethyl ester by about 20% pollutes.
Embodiment 10
Synthesizing of reagent (S)-valine methyl ester hydrochloride
Step 10:
Acetyl Chloride 98Min. (3.0mL) is joined in the methyl alcohol in ice bath (60mL) under stirring.(S)-norvaline (3.0g) is joined in the methanol solution, then mixture heating up was refluxed 19 hours.To doing, resistates and toluene coevaporation are three times then with the refrigerative solution evaporation, and be dry in a vacuum then, obtains the compound 10 (4.3g) of white solid.
Embodiment 11
Synthesizing of [1-(3-cyclopropyl-[1,2,4] diazole-5-yl)-propyl group]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine
Step 11A:
(RS)-methyl-2-aminobutyric acid ester hydrochloride (0.81g) is joined in the solution of compound 4d (0.800g) in anhydrous acetonitrile (4mL).Add triethylamine (0.74mL), then mixture is heated 35min down at 150 ℃ in sealed tube in microwave reactor.Steaming desolventizes, and then thick resistates is purified with silica gel chromatography, uses 2: 1 hexane/ethyl acetate as elutriant, obtains the slightly compound 11a (0.585g, 58%) of yellow solid.
Step 11B:
Sodium hydride (60% suspension of 7mg in mineral oil) is joined in the suspension of N-hydroxyl cyclopropane carbonamidine (20mg) in anhydrous THF (1mL).Mixture is at room temperature stirred 45min, add the solution of 11a (50mg) in anhydrous THF (0.5mL) then, then mixture was heated 1 hour down at 75 ℃.With mixture cooling and concentrated, resistates is purified with silica gel chromatography then, uses 2: 1 hexane/ethyl acetate as elutriant, obtains the compound 11-1 (20mg) of yellow oily.
According to pyrazolo-[1,5a]-pyrimidine, amino acid ester and oxime reagent, make the compound in the following table:
Table 1.
Embodiment 12
Synthesizing of [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-methyl-2-(3-methyl-[1,2,4] diazole-5-yl)-ethyl]-amine
Step 12A:
Will (R, S)-ethyl 3-aminobutyric acid ester (150mg) joins in the solution of 4d (150mg) in anhydrous acetonitrile (0.75mL).Mixture is heated 35min down at 150 ℃ in microwave reactor in sealed tube.Steaming desolventizes, and then thick resistates is purified with silica gel chromatography, uses 2: 1 hexane/ethyl acetate as elutriant, obtains the compound 12a (170mg, 76%) of yellow oily.
Step 12B:
At room temperature, sodium hydride (60% suspension of 21mg in mineral oil) is joined in the suspension of acetyl amidoxime (60mg) in anhydrous THF (2mL).Mixture is at room temperature stirred 45min, add the solution of 12a (160mg) in anhydrous THF (1.6mL) then, then, mixture was heated 1.5 hours down at 80 ℃ the reactor sealing.With mixture cooling and concentrated, resistates is purified with silica gel chromatography then, uses 1: 1 hexane/ethyl acetate as elutriant, obtains the 12-1 (72mg) of dark yellow oily.
According to pyrazolo-[1,5a]-pyrimidine, amino acid ester and oxime reagent, make the compound in the following table:
Table 2.
*Whole HPLC operational analysis methods 1.
Embodiment 13
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-butyl]-amine synthetic
Step 13A:
The mixture of compound 10 (416mg) and 4d (500mg), triethylamine (0.35mL) and acetonitrile (4mL) is heated 35min in microwave reactor under 150 ℃.Mixture distributes between ethyl acetate and sodium bicarbonate aqueous solution, and organic layer filters through dried over sodium sulfate then, then concentrates.Resistates carries out silica gel chromatography to be separated, and with 4: 1 hexane/ethyl acetate wash-outs, obtains the 13a (340mg) of yellow oily.
Step 13B:
Lithium hydroxide monohydrate (44mg) is joined in the mixture of compound 13a (320mg), THF (2mL) and water (1mL).With mixture vigorous stirring 30min at room temperature, add hexane (5mL) then.Separating layer, water layer 2N hcl acidifying (0.6mL, final pH value 3-4).The gained precipitation is collected in filtration, washes with water, and is dry in a vacuum then with the toluene coevaporation, obtains the compound 13b (215mg) of white solid.
Step 13C:
The mixture of 13b (160mg), HOBT (79mg), acetyl amidoxime (47mg), DCM (2mL) and DMF (0.25mL) is cooled to-15 ℃.Add DIC (0.085mL), then mixture was warmed to room temperature in 2 hours.Steaming desolventizes, and adds ethyl acetate (50mL) then, with mixture once with the saturated sodium bicarbonate aqueous solution washing, and then once with the washing of 10% potassium dihydrogen phosphate aqueous solution.Ethyl acetate layer filters through dried over sodium sulfate, concentrates, and obtains compound 13c.
Step 13D:
Pyridine (1.5mL) is joined among the compound 13c that makes in the step in front, then with mixture in sealed tube 100 ℃ of heating 2.5 hours down.Steaming desolventizes.Resistates is dissolved in the ether, removes by filter DIU then, with the ether rinse of several portions.The filtrate evaporation, resistates carries out the silica gel chromatography separation then, with 3: 1 hexane/ethyl acetate wash-outs, obtains the compound 13-1 of yellow oily.Free alkali 13-1 (115mg) is dissolved in the ether (2mL), at room temperature is added in the 2M HCl (0.205mL) in the ether then, the result generates a kind of white precipitate.Decant supernatant liquor, all the other solids ether washed twice.Dry in a vacuum under 35 ℃, obtain the 13-1 hydrochloride (121mg) of white solid.
According to pyrazolo-[1,5a]-pyrimidine, amino acid ester and oxime reagent, make the compound in the following table:
Table 3.
Embodiment 14
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine synthetic
Step 14A:
With sodium bicarbonate (28.7g) and (S)-suspension of 2-aminobutyric acid (21.7g) in water (250mL) joins in the solution of 4d (39.7g) in two alkane (250mL).Mixture stirred and reflux (102 ℃ of baths) 14 hours.Mixture is cooled to room temperature, in 10min, add then dense HCl (16mL) to final pH be 4.5.Generate a large amount of white precipitates.Mixture is concentrated into the weight of about 250g, then resistates is carried out coevaporation with several parts of ethyl acetate, generate a kind of aqueous slurries thick, pasty state.Filtering mixt, filter cake water (total 350mL) washing.Then, filter cake is dry in a vacuum under 35 ℃, obtain the compound 14a (45.2g) of white solid.
Optional step 14A.
With NaHCO
3(97.45g, 1.16mol) and (S)-(74.25g 0.72mol) is suspended in the water (900mL) the 2-aminobutyric acid.Add the solution of chloropyrimide 4d (134.4g) in two alkane (900mL) in this suspension, the gained mixture heating up refluxes and stirred 2.5 hours.Mixture is cooled to room temperature, it is acidified to pH 4, generate a large amount of white precipitates by dripping dense HCl (about 88mL).Mixture is concentrated in a vacuum, and the gained solid forms slurry in water (1L), stirs then and filters, and washes with water.From mother liquor, can observe more product precipitation, and the two batches of products of can reentrying.The solid that merges is dry in a vacuum, obtains the required carboxylic acid 14a (159.3g, 0.4mol,＞93% purity) of beige solid.In a kind of optional aftertreatment, after dense HCl acidifying, reaction mixture is filtered immediately, then the solid that obtains is dissolved in the methylene dichloride.Separate all the other water of removing in the solid, then that dichloromethane layer is dry and concentrated, obtain 14a.
Step 14B:
Be suspended in compound 14a (10g) in the toluene (50mL) and be evaporated to dried.Add anhydrous DCM (100mL), then add HOBT (4.8g) and acetyl amidoxime (2.7g).Add dry DMF (11mL), then reaction mixture is stirred and in nitrogen atmosphere, in ethylene glycol/the dry ice bath, be cooled to-15.5 ℃ internal temperature.Then, add DIC (5.3mL) by syringe.Reaction mixture is stirred and warm 2 hours, and the internal temperature of this moment is+16.5 ℃.Steaming desolventizes, and adds ethyl acetate (150mL) then, with mixture with the washing of 10% potassium dihydrogen phosphate aqueous solution once, uses the saturated sodium bicarbonate aqueous solution washed twice, with the washing of 10% potassium dihydrogen phosphate aqueous solution once, uses the salt water washing at last once more.Ethyl acetate layer filters through dried over sodium sulfate, concentrates, and obtains crude compound 14b.
Optional step 14B:
(411.91g 0.95mol) is suspended in CH with compound 4a
2CH
2(3.8L) and among the DMF (300mL), in nitrogen atmosphere to wherein add acetyl amidoxime (acetamidoxime) (95.12g, 1.28mol) and HOBt (167.56g, 1.24mol).Mixture is cooled to-30 ℃ internal temperature, (194.15mL is 1.24mol) so that make temperature keep below-20 ℃ to drip DIC.To be reflected under this temperature and stir 1 hour, in ensuing 3 hours, be warmed to 10 ℃ subsequently.Mixture is concentrated in a vacuum and is dissolved among the EtOAc (5L) again.This EtOAc solution NaHCO
3(3 * 1.5 L, saturated aqueous solution), KH
2PO
4(1500mL, 1M), salt solution (2 * 1.5 L) washing, dry (MgSO
4) and concentrate in a vacuum, obtain yellow foamed 14b.
Step 14C:
Pyridine (50mL) is joined among the compound 14b from step 14B, then with mixture in nitrogen 100 ℃ of heating 4 hours down.With gained solution cooling, steaming desolventizes, resistates and twice of ethyl acetate coevaporation and with the heptane coevaporation once.Resistates is dissolved in the 50mL ether, removes by filter DIU then, with the ether rinse of several portions.The filtrate evaporation, resistates carries out the silica gel chromatography separation then, with 2: 1 hexane/ethyl acetate wash-outs, obtains the compound 14-1 that yellow slightly foamed part is purified.With this foam and heptane coevaporation twice, add 5: 1 heptane/ethyl acetate (60mL) then, the gained slurry was at room temperature stirred 24 hours.This solid filtering is also used the hexane rinsing, obtain the 14-1 free alkali (7.3g) of white solid.Filtrate is concentrated and collects is second batch of 14-1 free alkali (0.7g) of white solid equally.
Described free alkali 14-1 (6.0g) is dissolved in the 80mL acetone and in ethylene glycol/the dry ice bath is cooled to-12 ℃ (inside).Disposable adding hydrogenchloride (diethyl ether solutions of 8.9mL 2.0 M).This clear yellow solution is stirred 1min, and steaming desolventizes then.With resistates and two batches of acetone coevaporations, dry in a vacuum then, make a kind of amber foam.This foam is pulverized, in a vacuum at room temperature dry 24 hours then, obtained the hydrochloride 14-1 (6.7g) of amorphous brown powder form.
Optional step 14C:
To be dissolved in the pyridine (1.8L) from the compound 4b of optional step 14B, be warmed to 100 ℃, and stir and concentrated in a vacuum then in 2 hours, obtain a kind of brown toughening oil.Purify by flash chromatography, use EtOAc: hexane (1: 9,2: 8,3: 7,4: 6) wash-out, obtain a kind of beige solid.This solid is become slurry and becomes fine powder by agitation grinding in heptane (4 L), obtain the 14-1 (248.5g, 98.3% purity) of white crystalline solid.
According to pyrazolo-[1,5a]-pyrimidine, amino acid ester and oxime reagent, make the compound in the following table:
Table 4.
Embodiment 14A
The sign of the polymorphic form 1 of [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine
Make the free alkali 14-1 of 248.5g as shown in optional step 14C, it for example can characterize by X-ray powder diffraction spectrography, Raman spectroscopy and/or dsc (DSC).The free alkali of 14-1 shows the XPRD pattern of Fig. 1 and is confirmed as [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-polymorphic form 1 of [(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine.
The XRPD angle and the d spacing of the polymorphic form 1 of table 1 expression [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine.
The X-ray powder diffraction spectral line of table 1 polymorphic form 1
| Degree 2-θ | D value |
| 6.721 | 13.1397 |
| 8.361 | 10.5663 |
| 10.698 | 8.26247 |
| 11.757 | 7.52055 |
| 13.323 | 6.64016 |
| 15.112 | 5.85779 |
| 15.492 | 5.71491 |
| 15.959 | 5.54892 |
| 18.222 | 4.86461 |
| 18.965 | 4.67554 |
| 20.291 | 4.37294 |
| 21.428 | 4.14338 |
| 21.974 | 4.04163 |
| 22.664 | 3.92018 |
| 24.002 | 3.70457 |
| 25.082 | 3.54736 |
| 26.268 | 3.38993 |
| 26.941 | 3.30677 |
| 30.544 | 2.92437 |
| 31.289 | 2.85642 |
The X-ray powder diffraction pattern of polymorphic form 1 as shown in Figure 1 reveals main peaks (expenditure 2 θ (+/-0.15 degree 2 θ represent): 6.721,11.757,13.323,18.222,21.426 and 21.974 in following one or more location tables.More particularly, these characteristic peaks are 11.757 and 21.974, and other is 6.721,13.323,18.222 and 21.426.
Description of drawings:
Fig. 1 represents X-ray powder diffraction data, its be by aforesaid [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-polymorphic form of amine 1 obtains.Polymorphic form 1 characterizes by the XRPD figure, and its significant signal is listed in the table 1.
Fig. 2 represents the Raman spectrum of the polymorphic form 1 of [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine.
Fig. 3 represents [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-differential thermogram of the dsc (DSC) of the polymorphic form 1 of [(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine.
Can know that spectrum and diffraction data will change a little according to various factors such as temperature, concentration and employed instrument.Those skilled in the art will recognize that the XRPD peak position is subjected to the influence of height of specimen difference.Therefore, change with+/-0.15 degree 2-θ in this peak position that marks.
As shown in Figure 3, polymorphic form 1 shows the most significant endotherm(ic)peak at about 108.3 ℃.Should be understood that the endotherm(ic)peak that so records depends on that many factors comprise the humidity and the purity of employed machine, rate of heating, calibration standard, the sample that uses.Therefore, term " the about 108.3 ℃ " meaning is to comprise that these instruments change.
The X-ray powder diffraction
X-ray powder diffraction (XRPD) analysis is carried out on Bruker D5005, uses the Sol-X detector.Condition determination is: radiation: Cu K α, generator voltage: 40kV, dynamo current: 50mA, initial angle: 2.0 ° of 2 θ, end angle: 45.0 ° of 2 θ, step-length: 0.02 ° of 2 θ, per time in step: 0.5 second.Sample prepares on zero background sample holder.
Raman spectroscopy
Instrument model: Kaiser RXNl Kaiser Optical System Micro Raman.Sample on the aluminium sample disc, laser 1=785nm.
Dsc (DSC)
Instrument model: PE DSC 7, not ermetic sample disc, run@_10K/min to 150 ℃, sample 1.5-5mg.
Embodiment 14B
The polymorphic form 2 of [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine synthetic and characterizing
Be prepared as follows [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-polymorphic form 2 of [(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine:
With [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine polymorphic form 1 (0.74g) becomes slurry in 50% isopropanol water solution (4ml).Temperature circulated 24 hours between 0 ℃ and 40 ℃, then mixture was stirred 3 days at ambient temperature, then temperature was circulated 24 hours between 0 ℃ and 40 ℃.Leach residual solid, dry at ambient temperature, obtain 0.70g[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine polymorphic form 2.
The extensive following polymorphic form 2 that repeats preparation [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine.
Except that in step 14C, not having the chromatogram purification, to prepare free alkali 14-1 with the similar approach described in the foregoing description 14.The formation of mesylate and release continuously obtain highly purified required compound, do not need chromatogram to purify.
Free alkali 14-1 (2.48kg, 6.10mol, chemical purity 90%) was stirred 30 to 45 minutes with n-butyl acetate (12.5 L), add then methylsulfonic acid (1.2eq, 7.32Mol, 703g)., after 2-3 hour mixture is filtered 25-30 ℃ of stirring.Described solid forms slurry, with n-butyl acetate (5L) washing, then with heptane (7.5 L) washing.Then, 50 ± 5 ℃ dry in a vacuum 4-6 hour, obtain mesylate (2.48kg, chemical purity 97.37%).
This mesylate stirred 15 to 30 minutes with DM water (12.5 L).Add the pH value of ammonia soln to 9.0-10.Suspension extracts with ethyl acetate (3 * 7.5 L).Then, the extraction liquid of merging washs with DM water (5L) and 20% salt brine solution (5L).Organic solution concentrates being lower than 50 ± 5 ℃ in a vacuum, removes the 85-90% solvent, resistates is cooled to 30 ± 5 ℃ then.Add heptane (15L), mixture was stirred 2-3 hour at 25-30 ℃, be lower than 50 ± 5 ℃ of solvents that steam 60-70% in a vacuum then.Mixture is cooled to 30 ± 5 ℃, stirred 1-2 hour, filter then.Solid forms slurry, wash with heptane (5 L), then be lower than under 50 ± 5 ℃ dry in a vacuum, obtain [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-polymorphic form 1 (1.70kg, chemical purity 99.34%) of amine.
With [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-the polymorphic form 1 (1.37kg of amine, 3.37Mol, HPLC 99.34% purity) and the mixture heating up of ethyl acetate (2.05 L) to 40-45 ℃ (observing a kind of clear solution).Then, solution is cooled to 30 ± 5 ℃, adds heptane (6.85 L), then be heated to 60 ± 2.5 ℃.Under 60 ± 2.5 ℃, add [the 3-(4-methoxyl group-2-methyl-phenyl)-2 that makes as mentioned above, 5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-seed crystal material of the polymorphic form 2 of amine, mixture is cooled to 40 ± 2.5 ℃ then, when adding other seed crystal material (0.5%w/w), heat back 50 ± 2.5 ℃ then.The gained slurry is cooled to 30 ± 5 ℃ and stirred 12 hours at 30 ± 5 ℃.Add heptane (2.74 L), with mixture extra 12 hours of 30 ± 5 ℃ of following restir.Filter slurry, solid-state slurry washs with heptane (2.74 L).With this solid under 50 ± 5 ℃ dry in a vacuum 8 hours, obtain [the 3-(4-methoxyl group-2-methyl-phenyl)-2 of 0.97kg, 5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-polymorphic form 2 (HPLC purity 99.58%) of amine.
The HPLC method
Post: (150 * 4.6mm), 3.5 microns of Zorbax SB-C18
Moving phase-A:0.05%TFA (aqueous solution)
Moving phase-B:0.025%TFA (acetonitrile solution)
Column temperature: 40 ℃
Flow velocity: 1.0mL/min
Detect wavelength: 225nm
Inject volume: 5 μ L
Working time: 30mins
Concentration: 0.3mg/ml
Gradient program: linear gradient
| Time (min) | Moving phase-A (%) | Moving phase-B (%) |
| 0 25 29 30 | 75 5 5 75 | 25 95 95 25 |
Back working time: 5min
Retention time: polymorphic form 2 about 9min
Thinner: moving phase-A: moving phase-B (1: 1)
The polymorphic form 2 of [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine shows XPRD figure (Fig. 4).
The XRPD angle and the d spacing of the polymorphic form 2 of table 2 expression [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine.
Table 2: the X-ray powder diffraction spectral line of polymorphic form 1
| Degree 2-θ | D value |
| 10.415 | 8.48651 |
| 12.125 | 7.29347 |
| 12.36 | 7.15526 |
| 13.177 | 6.7136 |
| 13.527 | 6.5406 |
| 15.121 | 5.85426 |
| 16.045 | 5.51918 |
| 16.331 | 5.42339 |
| 19.457 | 4.55852 |
| 20.133 | 4.40682 |
| 20.2941 | 4.2386 |
| 21.28 | 4.1718 |
| 22.239 | 3.99412 |
| 22.823 | 3.89318 |
| 23.51 | 3.78098 |
| 24.714 | 3.59933 |
| 25.488 | 3.49186 |
| 26.261 | 3.39074 |
| 27.858 | 3.19988 |
| 29.537 | 3.02169 |
Description of drawings:
Fig. 4 represents by described [3-(4-methoxyl group-2-methyl-phenyl)-2 before, 5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-X-ray powder diffraction data that the polymorphic form 2 of [(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine obtains.Polymorphic form 2 characterizes by the XRPD figure, and its significant signal is listed in the table 1.
Fig. 5 represents the Raman spectrum of the polymorphic form 2 of [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine.
Fig. 6 represents [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-differential thermogram of the dsc (DSC) of the polymorphic form 2 of [(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine.
Can know that spectrum and diffraction data will change a little according to various factors such as temperature, concentration and employed instrument.Those skilled in the art will recognize that the XRPD peak position is subjected to the influence of height of specimen difference.Therefore, change with+/-0.15 degree 2-θ in this peak position that marks.
As shown in Figure 6, polymorphic form 2 shows the most significant endotherm(ic)peak at about 115.1 ℃.Should be understood that the endotherm(ic)peak that so records depends on that many factors comprise the humidity and the purity of employed machine, rate of heating, calibration standard, the sample that uses.Therefore, term " the about 115.1 ℃ " meaning is to comprise that these instruments change.
The X-ray powder diffraction
X-ray powder diffraction (XRPD) analysis is carried out on Bruker D5005, uses the Sol-X detector.Condition determination is: radiation: Cu K α, generator voltage: 40kV, dynamo current: 50mA, initial angle: 2.0 ° of 2 θ, end angle: 45.0 ° of 2 θ, step-length: 0.04 ° of 2 θ, per time in step: 1 second.Sample prepares on zero background sample holder.
Raman spectroscopy
Instrument model: Kaiser RXN1 Kaiser Optical System Micro Raman.Sample on the aluminium sample disc, laser 1=785nm.
Dsc (DSC)
Instrument model: Q 1000 TA, not ermetic sample disc, run@_10K/min to 150 ℃, N2 flow velocity=50mL/min, sample 1.5-5mg.
Embodiment 15
Synthesizing of [3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(2-methoxyl group-ethyl)-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine
Step 15A:
In the solution of 2-methoxyethyl amine (2.9mL) in THF (40mL), add triethylamine (9.3mL), then add methyl bromoacetate (2.8mL).Mixture was at room temperature stirred 16 hours, and steaming desolventizes then.Resistates is dissolved in the ethyl acetate (100mL), and water (2x50mL), salt solution (50mL) washing also concentrate organic layer through dried over mgso then.Resistates is purified with silica gel chromatography, uses 95: 5 methylene chloride as elutriant, obtains the 15a (1.8g, 37% yield) of colourless liquid.1HNMR(CDCl3，300MHz)：2.78(t，2H，J＝3Hz)，3.33(s，3H)，3.43(s，2H)，3.48(t，2H，J＝3Hz)，3.70(s，3H).
Step 15B:
DBU (0.22mL) and compound 15a (220mg) are joined in the solution of compound 4e (400mg) in acetonitrile (4mL).With solution 80 ℃ of heated and stirred 16 hours.Cooled mixture is concentrated, add ethyl acetate (20mL) then.With the mixture water (2 * 10mL), salt solution (10mL) washing, then with the gained organic layer through dried over mgso, filter also and concentrate.Resistates is purified with silica gel column chromatography, and the methylene chloride of using 95: 5 obtains buttery compound 15b as elutriant.Quality (Mass): 428.8 (MH
+); HPLC: analytical procedure 2, retention time 1.46min.
Step 15C:
The suspension of acetyl amidoxime (60mg) in anhydrous THF (5mL) is at room temperature stirred, add NaH (60% the dispersion in oil of 32mg).Mixture is at room temperature stirred 45min, add the solution of compound 15b (173mg) then at anhydrous THF (among the 5mL).Mixture was refluxed 2 hours.Cooled mixture concentrates, and is dissolved in the ethyl acetate (10mL) then water (2x10mL) and salt solution (10mL) washing then.The gained organic layer through dried over mgso, is filtered evaporation.Resistates is purified with preparation property LC/MS, obtain compound 15-1.Quality: 452.8 (MH
+); HPLC: analytical procedure 2, retention time 1.406min.
According to pyrazolo-[1,5a]-pyrimidine, amino acid ester and oxime reagent, make the compound in the following table:
Table 5.
Embodiment 16
Synthesizing of [3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(2-methoxyl group-ethyl)-[3-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine
Step 16A:
In the compound 4e (200mg) in acetonitrile (5mL), add 2-methoxyethyl amine (2mL).With solution 80 ℃ of heated and stirred 16 hours.Mixture is concentrated in a vacuum.Resistates is dissolved in the ethyl acetate (5mL) gained solution with water (2 * 5mL) and salt solution (5mL) washing.Through dried over mgso, filter, concentrate, obtain yellow oil, compound 16a, it is not having to be used for the following step under the situation of purifying.
Step 16B:
Sodium hydride (60% dispersion of 76mg in oil) is joined in the solution of 16a in DMF (5mL) that makes in step 16A.After at room temperature 5 minutes, add 4-bromo-butyric acid methyl esters (0.21mL).Mixture was heated 48 hours in sealed tube under 60 ℃.Cooled mixture is concentrated, is dissolved in then in the ethyl acetate (25mL), then water (2 * 10mL) and salt solution wash successively.Organic layer through dried over mgso, is filtered, concentrate.This thick resistates 16b is not having just use under the situation of further purifying.
Step 16C:
The crude compound 16b that makes among the step 16B is in the above carried out the method for step 15C.Crude product mixture is diluted with methyl alcohol, directly purifies by preparation property LC/MS then, obtains compound 16-1.Quality: 480.8 (MH
+); HPLC: analytical procedure 2, retention time 1.353min.
Embodiment 17
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-methyl-2-(5-methyl-[1,2,4] diazole-3-yl)-ethyl]-amine synthetic
Step 17A:
With the mixture of compound 4d (1.0g), (R)-2-amino-1-propyl alcohol (0.5g), triethylamine (0.91mL) and acetonitrile (5mL) 90 ℃ of following stirring heating 4 hours.Reaction mixture distributes between saturated sodium bicarbonate aqueous solution and ethyl acetate.Water layer another part ethyl acetate extraction, the organic layer of He Binging concentrates through dried over sodium sulfate then, obtains the compound 17a of yellow oily, and it is not having just use under the situation of further purifying.
Step 17B:
The drips of solution of methylsulfonyl chloride (0.68g) in DCM (1.0mL) is added in the mixture of crude compound 17a under stirring (above preparation), triethylamine (0.91mL) and DCM.Produce a kind of clarifying brown solution, then mixture is at room temperature stirred 30min.Add saturated sodium bicarbonate aqueous solution, then (2 * 25mL) extract with ethyl acetate with mixture.The organic layer that merges with the solution of potassium carbonate washing once then through dried over sodium sulfate, filters, and concentrates, and obtains the compound 17b of white foam shape.This material is not further purified and is just used.
Step 17C:
Pulverous sodium cyanide (0.33g) and salt of wormwood (0.92g) are joined in the solution of compound 17b (top preparation) in DMF (10mL).Mixture was heated 4 hours down at 100 ℃ in sealed tube, generate a kind of viscous gel.Add saturated sodium bicarbonate aqueous solution (25mL), then mixture is extracted with ethyl acetate (2x25mL).The organic layer that merges through dried over sodium sulfate, is filtered, concentrate.Resistates is purified with silica gel chromatography, and the hexane solution that uses 30% ethyl acetate obtains the compound 17c of yellow oily (0.72g, 62% yield) slightly as elutriant.
Step 17D:
The solution of compound 17c (200mg) in ethanol (4mL) is handled with oxammonium hydrochloride (50mg) and potassium hydroxide (40mg).Mixture under 100 ℃ in sealed tube heated and stirred 4 hours.Filter cooled mixture, twice of the cold washing with alcohol of 5mL of filter cake.The filtrate that merges concentrates, and obtains the compound 17d of white solid, and it just uses under the situation that does not have further purification.
Step 17E:
Compound 17d (top preparation) is dissolved in the N,N-dimethylacetamide dimethylacetal (4mL).Mixture was heated 2 hours down at 100 ℃.Mixture concentrates, and resistates is purified with silica gel chromatography, with the hexane solution wash-out of 30% ethyl acetate.According to
Step 14CMethod, product is converted into HCl salt: 72mg (28% yield).
According to pyrazolo-[1,5a]-pyrimidine, amino acid ester and oxime reagent, make the compound in the following table:
Table 6.
*All HPLC operational analysis methods 1.
Embodiment 18
[(R)-2-(5-cyclopropyl-[1,2,4] diazole-3-yl)-1-methyl-ethyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine synthetic
Step 18A:
Crude compound 17d (100mg) is dissolved in the 2mL pyridine also with cyclopropane carbonyl chloride (0.024mL) processing.Mixture was heated 2 hours down at 80 ℃ in sealed tube, and steaming desolventizes then, and resistates is purified with preparation property LC/MS.
According to pyrazolo-[1,5a]-pyrimidine and carbonyl chloride reagent, make the compound in the following table:
Table 7.
*All HPLC operational analysis methods 1.
Embodiment 19
Synthesizing of [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-2,2,2-three fluoro-1-(5-methyl-[1,2,4] diazole-3-ylmethyl)-ethyl]-amine
Step 19A:
Mixture in acetonitrile (3.5mL) heats 30min down at 150 ℃ in microwave reactor in sealed tube with 4d (565mg) and 8c (400mg).Add sodium bicarbonate aqueous solution, mixture extracts once with 3: 1 hexane/ethyl acetate, then with ethyl acetate extraction once.The organic layer that merges through dried over sodium sulfate, is filtered, concentrate.Resistates is purified with silica gel chromatography, uses 3: 1 hexane/ethyl acetate as elutriant, obtains the 19a of yellow oily (410mg, 53%) a little.
Step 19B:
The mixture of 19a (1.1g), lithium hydroxide (300mg), THF (10mL) and water (2mL) heated 2 hours down at 90 ℃.Cooled reaction mixture is handled with 4M hydrochloric acid (5mL) and water (25mL), then with twice of ethyl acetate extraction of gained mixture.The organic layer that merges filters through dried over sodium sulfate, evaporates, and obtains the thick 19b (1.1g) of yellow oily, and it just uses under the situation that does not have further purification.
Step 19C:
The thick solution of 19b (1.1g) in THF (10mL) at room temperature uses oxalyl chloride (0.34g) to handle, and then handles with two DMF.Observe and acutely emit gas, then mixture was at room temperature stirred 1 hour.Reaction mixture is concentrated, add ammoniacal liquor (the two alkane solution of 2.0 M of 20mL) then, then gained suspension was at room temperature stirred 16 hours.Add sodium bicarbonate aqueous solution, then twice of ethyl acetate extraction of mixture.Merge organic layer, through dried over sodium sulfate, filter, concentrate, obtain light green buttery 19c (700mg), it just uses under the situation that does not have further purification.
Step 19D:
Solution in two alkane (10mL) at room temperature uses trifluoroacetic anhydride (TFAA) (1.5g) to handle with 19c (700mg) and TEA (750mg).Reaction mixture at room temperature stirred 2 hours, add sodium bicarbonate aqueous solution then and with mixture with twice of dichloromethane extraction.The organic layer that merges through dried over sodium sulfate, is filtered, concentrate.Resistates is purified with silica gel chromatography, and the hexane solution that uses 30% ethyl acetate obtains the 19d (400mg) of yellow oily as elutriant.
Step 19E:
In the solution of 19d (400mg) in ethanol (10mL), add oxammonium hydrochloride (85mg) and potassium hydroxide (70mg).Mixture was heated 4 hours down at 100 ℃.Reaction mixture is cooled to room temperature then filters the filter cake washing with alcohol.The filtrate that merges is concentrated, then resistates is dissolved among the DMA-DMA (10mL) and and heated 2 hours down at 90 ℃.Reaction mixture is concentrated, and resistates is purified with silica gel chromatography, with 3: 1 hexane/ethyl acetate wash-outs, obtains the 19e free alkali (70mg) of yellow oily.Described free alkali is dissolved in the acetone (5mL) also with hydrogenchloride (the 2.0 M diethyl ether solutions of 2mL) processing.Mixture concentrates in a vacuum, obtains the 19-1 HCl salt (75mg) of yellow solid.Quality: 461.0 (MH
+); HPLC: analytical procedure 1, retention time 5.28min.
Synthesizing of ethyl-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine
Step 20A:
Thionyl chloride (0.71mL) is joined Ethylglycocoll (0.50g) carefully to be dissolved in the cold soln in the anhydrous methanol (8mL).Mixture was heated 14 hours in sealed tube under 60 ℃.Mixture is concentrated, use toluene (2x) and acetonitrile (3x) to carry out coevaporation then.Dry in a vacuum, obtain white gluey solid amino ester hydrochloride 20a, it is not having just direct use the under the situation of further purifying.
Step 20B:
Compound 20a and 4d then carry out silica gel chromatography and purify by the method condensation of step 11A, obtain the compound 20b (164mg) of yellow oily.
Step 20C:
Compound 20b (164mg) carries out the method for step 11B, carries out silica gel chromatography and purifies, and uses hexane/ethyl acetate as elutriant, obtains the compound 20-1 (105mg) of yellow oily a little.
According to pyrazolo-[1,5a]-pyrimidine, amino acid ester and oxime reagent, make the compound in the following table:
Table 8.
*All HPLC operational analysis methods 1.
Embodiment 21
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(1-[1,3,4] diazole-2-base-propyl group)-amine synthetic
Step 21A:
At room temperature, hydrazine hydrate (0.50mL) is joined in the suspension of compound 11a (230mg) in ethanol (1.5mL).With reactor sealing and 75 ℃ of following heated and stirred 17 hours.With this clear solution cooling and concentrated, obtain buttery hydrazide compound 21a (230mg).
Step 21B:
To be dissolved in from the thick 21a (70mg) of preceding step in the ethyl formate (2mL) and and heating 72 hours down at 65 ℃.Cooled solution is concentrated, obtain the thick dihydrazide compound 21b of buttery (70mg).
Step 21C:
Will from the mixture of compound 21b (29mg), Tosyl chloride (27mg), DBU (0.053mL) and the THF (0.5mL) of preceding step in microwave reactor at 150 ℃ of heating 10min down.Add sodium bicarbonate aqueous solution, then the mixture ethyl acetate extraction.The organic extract liquid that merges through dried over sodium sulfate, is filtered evaporation.Resistates is purified with the preparation of lamina silica gel chromatography, with 1: 2 hexane/ethyl acetate wash-out, obtains buttery compound 21-1 (12mg).Quality: 393.0 (MH
+); HPLC: analytical procedure 4, retention time 2.40min.
Embodiment 22
Synthesizing of [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(5-methyl-[1,3,4] diazole-2-yl)-propyl group]-amine
Step 22A:
Compound 11a carries out the lithium hydroxide hydrolysis according to the method for step 13C, obtains the compound 22a of white waxy solid.
Step 22B:
Compound 22a (100mg) and N-acethydrazide carry out the method for step 14B.Thick acetic acid ethyl acetate extract filters through dried over mgso, concentrates, and obtains the compound 22b (110mg, 96%) of white solid.
Step 22C:
Compound 22b (50mg) is heated 15min down at 150 ℃ in microwave reactor, carry out the method for step 21C.Gains are purified with the preparation of lamina silica gel chromatography, with 48: 48: 4 hexane/ethyl acetate/methanol-eluted fractions, obtain solid compound 22-1 (8mg, 71%).Quality: 407.0 (MH
+); HPLC: analytical procedure 1, retention time 4.543min.
Embodiment 23
Synthesizing of [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-methyl-2-(5-methyl-[1,3,4] diazole-2-yl)-ethyl]-amine
Step 23A:
According to the method for step 11A, (RS)-ethyl 3-aminobutyric acid ester (435mg) is joined among the compound 4d (500mg), carry out silica gel chromatography and purify, use 2: 1 hexane/ethyl acetate as elutriant, obtain compound 23a (540mg).
Step 23B:
Compound 23a (400mg) carries out the method for step 21A, obtains compound 23b (367mg).
Step 23C:
At room temperature, compound 23b (180mg) and triethylamine (0.100mL) solution in DCM (4mL) is handled with diacetyl oxide (0.53mL).After 17 hours, add extra triethylamine (0.100mL) and diacetyl oxide (0.53mL).Steaming desolventizes, and adds sodium bicarbonate aqueous solution then, and then mixture extracts with DCM (4x10mL).With the organic extract liquid salt water washing that merges,, filter evaporation through dried over sodium sulfate.Resistates carries out silica gel chromatography to be separated, and with the DCM eluant solution of 5% methyl alcohol, obtains compound 23c (165mg).
Step 23D:
With 1,3,4,6,7,8-six hydrogen-1-methyl-2H-Mi Dingbing [1,2-A] pyrimidine replaces DBU, compound 23c (50 mg) is carried out the method for step 21C.Purify (hexane/acetone was as elutriant in 1: 1) with the preparation of lamina silica gel chromatography, obtain compound 23-1 (12mg).
According to pyrazolo-[1,5a]-pyrimidine, amino acid ester and oxime reagent, make the compound in the following table:
Table 9.
*All HPLC operational analysis methods 1.
Embodiment 24
Synthesizing of [3-(2-chloro-4-methoxyl group-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine
Step 24A:
In compound 5d (100mgl), add 2-chloro-4-anisole ylboronic acid (70mg), then add the solution of salt of wormwood (80mg) and two alkane/water (0.9mL/0.2mL).Reaction mixture nitrogen bubble 5min adds four (triphenylphosphines) then and closes palladium (0) (80mg), then with the reactor sealing and 85 ℃ of heating 16 hours.Steaming desolventizes, and resistates is directly purified with the preparation of lamina silica gel chromatography, and the hexane solution that uses 30% ethyl acetate obtains solid compound 24a (31mg, 26%) as elutriant.LC/MS：403.0(MH
+)
Step 24B:
Compound 24a (31mg) and acetyl amidoxime carry out the method for S 1Bb, and being prepared property thin layer silica gel chromatography (1: 1 hexane/ethyl acetate elutriant) is purified, and obtains compound 24-1 (5.17mg).
According to pyrazolo-[1,5a]-pyrimidine, amino acid ester and oxime reagent, make the compound in the following table:
Table 10.
*All HPLC operational analysis methods 1.
Embodiment 25
The CRF receptor-binding activity
According to usually as people such as Grigoriadis (Mol.Pharmacol vol 50, pp 679-686,1996) and people (Mol.Pharmacol vol 63 such as Hoare, pp 751-765,2003) the standard radioligand of Miao Shuing is in conjunction with mensuration, and it is active to the combination of CRF acceptor to estimate The compounds of this invention.Utilize radiolabeled CRF part, it is active to the combination of any CRF receptor subtype that this mensuration can be used for estimating The compounds of this invention.
Briefly, this relates in conjunction with mensuration displace radiolabeled CRF part from the CRF acceptor.More particularly, this is in 96 hole assay plate in conjunction with mensuration, uses 1-10 μ g to have the cytolemma of the cell of human CRF acceptor to finish from stable transfection.Each hole is accepted about 0.05ml and is measured damping fluid (for example Dulbecco ' s phosphate buffered saline (PBS), 10mM magnesium chloride, 2mM EGTA), wherein contain compound of interest or with reference to part (for example sauvagine, Urocortin (urocortin) I or CRF), 0.05mL [
125I] (ultimate density is for～150pM or be approximately according to Scatchard and analyze the K that records for tyrosine-sauvagine
D) and 0.1mL contain the cytolemma suspension of CRF acceptor.With mixture 22 ℃ down cultivate 2 hours after, on glass fibre filter, make and combinedly separate with the free radioligand by quick filtration.After washing three times, with the strainer drying, use scintillometer to radioactivity (from
125The Auger of I (Auger) electronics) counts.All the radioligand binding data can use nonlinear least square method curve fitting procedure Prism (GraphPad Software Inc) or XLfit (ID Business Solutions Ltd) to analyze.
Embodiment 26
The adenylate cyclase activity that CRF-stimulates
Also can estimate The compounds of this invention by various function tests.For example can screen compound of the present invention according to the adenylate cyclase activity that CRF-stimulates.The mensuration that is used for the adenylate cyclase activity of definite CRF-stimulation can be carried out according to the method for describing as people such as Battaglia usually (Synapse 1:572,1987), and the suitable modification of do makes said determination be applicable to full cellular preparations.
More particularly, the standard test mixture can contain following component in the final volume of 0.1ml: the 2mM L-glutaminate in the DMEM damping fluid, 20mM HEPES and 1mM IMBX.In stimulation study, in order to set up the pharmacology rank order distribution (profile) of special receptor hypotype, the full cell bed board (plated) that transfection is had the CRF acceptor was cultivated 30 minutes with the relevant and incoherent peptide of the CRF of different concns down at 37 ℃ in 96 orifice plates then.After the cultivation, use the standard reagent box be available commercially for example from the cAMP-Screen of Applied Biosystems
TM, measure the cAMP in the sample.For compound is carried out functional evaluation, cell and the CRF or the related peptides that cause the single concentration that 50% stimulation cAMP produces were cultivated under 37 ℃ 30 minutes with the competitive compound of different concns, and measure cAMP according to the method described above.
Although it should be understood that property illustrative purposes presented for purpose of illustration, various specific embodiments of the present invention are described, still can under situation without departing from the spirit and scope of the present invention, carry out various improvement.Therefore, the present invention is except the restriction that is subjected to back claims, and is unrestricted.
Claims (25)
1. the compound of following structure representative:
Or its pharmacy acceptable salt, ester, solvate, steric isomer or prodrug,
R
1It is the Heterocyclylalkyl of aralkyl, Heterocyclylalkyl or replacement of alkoxyalkyl, aralkyl, the replacement of haloalkyl, alkoxyalkyl, the replacement of alkyl, haloalkyl, the replacement of hydrogen, alkyl, replacement;
R
2aAnd R
2bBe hydrogen, C independently
1-C
6The C of alkyl, replacement
1-C
6Alkyl, C
1-C
6The C of haloalkyl, replacement
1-C
6The aralkyl of haloalkyl, aralkyl, replacement, C
1-C
6The C of alkoxyalkyl, replacement
1-C
6Alkoxyalkyl, alkyl sulphonyl alkyl, aminoalkyl group, alkyl monosubstituted amino alkyl or dialkyl aminoalkyl;
Or
R
1The nitrogen and the R that are connected with it
2aOr R
2bWith R
2aAnd R
2bThe carbon that is connected forms the 4-7 element heterocycle together;
Or
R
2aAnd R
2bIn the carbon atom that they connected is formed on ring optional containing-O-,-S-or-N (R
3)-3-7 person ring;
R
3Be alkyl, aralkyl, the replacement of alkyl, replacement aralkyl, acyl group ,-C (O) OR
8,-C (O) NR
9R
10Or S (O)
2R
11
Y be independently in all cases direct key or-C (R
4aR
4b)
m-;
M is 1 or 2;
R
4aAnd R
4bBe hydrogen, C independently
1-C
6The C of alkyl, replacement
1-C
6The aralkyl of alkyl, aralkyl, replacement, C
1-C
6The C of alkoxyalkyl, replacement
1-C
6Alkoxyalkyl, alkyl sulphonyl alkyl, aminoalkyl group, alkyl monosubstituted amino alkyl or dialkyl aminoalkyl;
Or
R
4aAnd R
4bIn the carbon atom that they connected is formed on ring optional containing-O-,-S-or-N (R
3)-3-7 person ring;
Het is
R
5Be hydrogen, halogen, C
1-C
6The C of alkyl, replacement
1-C
6Alkyl, C
1-C
6The C of alkoxyl group, replacement
1-C
6Alkoxyl group, amino, alkylamino or dialkyl amido;
R
6Be halogen, C in all cases independently
1-C
6The C of alkyl or replacement
1-C
6Alkyl;
N is the integer that comprises 0 and 3 0-3;
Ar is phenyl or pyridyl;
R
7Be alkyl, the C of halogen, alkyl, replacement in all cases independently
1-C
6The C of alkoxyl group, replacement
1-C
6Alkoxyl group ,-NR
9R
10, alkyl sulphonyl or replacement alkyl sulphonyl;
O is the integer that comprises 0 and 3 0-3; With
R
8, R
9, R
10And R
11In each be hydrogen, C
1-C
6The C of alkyl, replacement
1-C
6The aralkyl of alkyl, aralkyl, replacement, C
1-C
6The C of alkoxyalkyl, replacement
1-C
6Alkoxyalkyl, alkyl sulphonyl alkyl, aminoalkyl group, alkyl monosubstituted amino alkyl or dialkyl aminoalkyl.
2. according to the compound of claim 1, wherein:
R
1Be hydrogen, C
1-C
6The C of alkyl, replacement
1-C
6Alkyl, C
1-C
6The C of haloalkyl, replacement
1-C
6Haloalkyl or C
1-C
6Alkoxyalkyl;
R
2aAnd R
2bBe hydrogen, C independently
1-C
6The C of alkyl, replacement
1-C
6Alkyl, C
1-C
6The C of haloalkyl or replacement
1-C
6Haloalkyl;
Or
R
1The nitrogen and the R that are connected with it
2aOr R
2bWith R
2aAnd R
2bThe carbon that is connected forms the 4-7 element heterocycle together;
Or
R
2aAnd R
2bForm 3-7 person's carbocyclic ring with the carbon atom that they connected;
R
5Be hydrogen, halogen, C
1-C
6The C of alkyl, replacement
1-C
6Alkyl, C
1-C
6The C of haloalkyl or replacement
1-C
6Haloalkyl;
R
6Be C in all cases independently
1-C
6The C of alkyl or replacement
1-C
6Alkyl;
N is 0,1 or 2;
R
7Be halogen, C in all cases independently
1-C
6The C of alkyl, replacement
1-C
6Alkyl, C
1-C
6The C of alkoxyl group, replacement
1-C
6Alkoxyl group or-NR
9R
10With
O is 1 or 2.
3. according to the compound of claim 2, wherein:
R
1Be hydrogen, C
1-C
6Alkyl, C
1-C
6Haloalkyl or C
1-C
6Alkoxyalkyl;
R
2aAnd R
2bBe hydrogen, C independently
1-C
6The C of alkyl, replacement
1-C
6Alkyl or C
1-C
6Haloalkyl;
Or
R
1The nitrogen and the R that are connected with it
2aOr R
2bWith R
2aAnd R
2bThe carbon that is connected forms the 4-7 element heterocycle together;
Or
R
2aAnd R
2bForm 3-7 person's carbocyclic ring with the carbon atom that they connected;
Y be direct key or-C (R
4aR
4b)-, be R wherein
4aAnd R
4bEach is a hydrogen;
R
5Be C
1-C
6Alkyl or C
1-C
6Haloalkyl;
R
6Be C in all cases independently
1-C
6Alkyl;
N is 1 or 2;
R
7Be halogen, C in all cases independently
1-C
6Alkyl, C
1-C
6Alkoxyl group or-NR
9R
10With
O is 1 or 2.
4. according to the compound of claim 3, wherein:
R
1Be hydrogen;
R
2aAnd R
2bBe hydrogen or C independently
1-C
6Alkyl;
Or
R
1The nitrogen and the R that are connected with it
2aOr R
2bWith R
2aAnd R
2bThe carbon that is connected forms the 4-7 element heterocycle together;
Or
R
2aAnd R
2bForm 3-7 person's carbocyclic ring with the carbon atom that they connected;
R
5Be C
1-C
6Alkyl or C
1-C
6Haloalkyl;
R
6Be C in all cases independently
1-C
6Alkyl;
N is 1;
Ar is a phenyl;
R
7Be C in all cases
1-C
6Alkyl, C
1-C
6Alkoxyl group or-NR
9R
10With
O is 2.
5. according to the compound of claim 4, wherein:
R
1Be hydrogen;
R
2aAnd R
2bBe hydrogen or C independently
1-C
6Alkyl;
R
5Be C
1-C
6Alkyl or C
1-C
6Haloalkyl;
R
6Be C in all cases independently
1-C
3Alkyl;
Het is
R
7Be C in all cases
1-C
6Alkyl or C
1-C
6Alkoxyl group.
6. according to the compound of claim 5, wherein:
R
2aAnd R
2bOne of be C
1-C
6Alkyl and another one are hydrogen;
R
5Be C
1-C
6Alkyl; With
A R
7Be C
1-C
6Alkyl, and another one is C
1-C
6Alkoxyl group.
7. according to the compound of claim 1, wherein said compound is selected from:
[1-(3-cyclopropyl-[1,2,4] diazole-5-yl)-propyl group]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine;
[1-(3-sec.-propyl-[1,2,4] diazole-5-yl)-propyl group]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-2-phenyl-ethyl]-amine;
[1-(3-sec.-propyl-[1,2,4] diazole-5-yl)-propyl group]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-butyl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine;
(3-cyclopropyl-[1,2,4] diazole-5-ylmethyl)-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine;
(3-sec.-propyl-[1,2,4] diazole-5-ylmethyl)-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine;
[2-(3-cyclopropyl-[1,2,4] diazole-5-yl)-(R)-1-methyl-ethyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-methyl-2-(3-methyl-[1,2,4] diazole-5-yl)-ethyl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-trifluoromethyl-[1,2,4] diazole-5-yl)-propyl group]-amine;
[1-(3-cyclopropyl-[1,2,4] diazole-5-yl)-cyclopropyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-cyclopropyl]-amine;
[1-(3-ethyl-[1,2,4] diazole-5-yl)-cyclopropyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(3-propyl group-[1,2,4] diazole-5-ylmethyl)-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-trifluoromethyl-[1,2,4] diazole-5-yl)-cyclopropyl]-amine;
[2-(3-ethyl-[1,2,4] diazole-5-yl)-(R)-1-methyl-ethyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine;
[3-(6-dimethylamino-4-methyl-pyridin-3-yl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[the 3-methyl-(R)-1-(3-methyl-[1,2,4] diazole-5-yl)-butyl]-amine;
3-(2,4-dimethoxy-phenyl)-2, the 5-dimethyl-7-[(S)-2-(3-methyl-[1,2,4] diazole-5-yl)-tetramethyleneimine-1-yl]-pyrazolo [1,5-a] pyrimidine;
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine;
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-ethyl]-amine;
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-butyl]-amine;
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[3-methyl isophthalic acid-(3-methyl-[1,2,4] diazole-5-yl)-butyl]-amine;
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-methyl-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine;
Benzyl-[3-(6-dimethylamino-4-methyl-pyridin-3-yl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-methyl-2-(3-methyl-[1,2,4] diazole-5-yl)-ethyl]-amine;
Benzyl-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[2,2,2-three fluoro-1-(3-methyl-[1,2,4] diazole-5-ylmethyl)-ethyl]-amine;
[2-(3-cyclopropyl-[1,2,4] diazole-5-yl)-1-methyl-ethyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine;
[2-(3-sec.-propyl-[1,2,4] diazole-5-yl)-1-methyl-ethyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine;
[2-(3-cyclopropyl-[1,2,4] diazole-5-yl)-(S)-1-methyl-ethyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine;
[2-(3-sec.-propyl-[1,2,4] diazole-5-yl)-(S)-1-methyl-ethyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-methyl-2-(3-methyl-[1,2,4] diazole-5-yl)-ethyl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-ylmethyl)-propyl group]-amine;
[1-(3-cyclopropyl-[1,2,4] diazole-5-ylmethyl)-propyl group]-[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine;
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-ylmethyl)-propyl group]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-butyl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[2,2,2-three fluoro-(S)-1-(3-methyl-[1,2,4] diazole-5-ylmethyl)-ethyl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-methyl-2-(3-trifluoromethyl-[1,2,4] diazole-5-yl)-ethyl]-amine;
[3-(2-chloro-4-methoxyl group-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[2,2,2-three fluoro-(S)-1-(3-methyl-[1,2,4] diazole-5-ylmethyl)-ethyl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-methyl-2-(3-trifluoromethyl-[1,2,4] diazole-5-yl)-ethyl]-amine;
[3-(2-chloro-4-methoxyl group-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-methyl-2-(3-trifluoromethyl-[1,2,4] diazole-5-yl)-ethyl]-amine;
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-methyl-2-(3-trifluoromethyl-[1,2,4] diazole-5-yl)-ethyl]-amine;
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[2,2,2-three fluoro-(S)-1-(3-methyl-[1,2,4] diazole-5-ylmethyl)-ethyl]-amine;
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[2,2,2-three fluoro-(S)-1-(3-trifluoromethyl-[1,2,4] diazole-5-ylmethyl)-ethyl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine;
3-(4-methoxyl group-2-methyl-phenyl)-2, the 5-dimethyl-7-[(S)-2-(3-methyl-[1,2,4] diazole-5-ylmethyl)-tetramethyleneimine-1-yl]-pyrazolo [1,5-a] pyrimidine;
[3-(2-chloro-4-methoxyl group-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine;
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(2-methoxyl group-ethyl)-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine;
(5-{2, the 5-dimethyl-7-[(S)-2-(3-methyl-[1,2,4] diazole-5-yl)-tetramethyleneimine-1-yl]-pyrazolo [1,5-a] pyrimidin-3-yl }-4-methyl-pyridine-2-yl)-dimethyl-amine;
[3-(6-dimethylamino-4-methyl-pyridin-3-yl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(2-methoxyl group-ethyl)-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine;
[3-(4-oxyethyl group-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(2-methoxyl group-ethyl)-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine;
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(2-methoxyl group-ethyl)-[3-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-methyl-2-(5-methyl-[1,2,4] diazole-3-yl)-ethyl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(5-methyl-[1,2,4] diazole-3-ylmethyl)-propyl group]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-(5-methyl-[1,2,4] diazole-3-ylmethyl)-propyl group]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-methyl-2-(5-methyl-[1,2,4] diazole-3-yl)-ethyl]-amine;
[(R)-2-(5-cyclopropyl-[1,2,4] diazole-3-yl)-1-methyl-ethyl]-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-methyl-2-(5-trifluoromethyl-[1,2,4] diazole-3-yl)-ethyl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-2,2,2-three fluoro-1-(5-methyl-[1,2,4] diazole-3-ylmethyl)-ethyl]-amine;
Ethyl-[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(3-methyl-[1,2,4] diazole-5-ylmethyl)-amine;
3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-7-[2-(3-methyl-[1,2,4] diazole-5-ylmethyl)-piperidines-1-yl]-pyrazolo [1,5-a] pyrimidine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-(1-[1,3,4] diazole-2-base-propyl group)-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(5-methyl-[1,3,4] diazole-2-yl)-propyl group]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-methyl-2-(5-methyl-[1,3,4] diazole-2-yl)-ethyl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-methyl-2-(5-trifluoromethyl-[1,3,4] diazole-2-yl)-ethyl]-amine;
[3-(2-chloro-4-methoxyl group-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine;
[3-(4-chloro-2-methoxyl group-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine;
[3-(3-chloro-4-fluoro-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine;
[3-(4-chloro-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine;
[3-(2-chloro-4-trifluoromethyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine; With
[3-(2-chloro-4-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine.
8. according to the compound of claim 7, wherein said compound is selected from:
[3-(2,4-dimethoxy-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[2,2,2-three fluoro-(S)-1-(3-methyl-[1,2,4] diazole-5-ylmethyl)-ethyl]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine;
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine;
[3-(2-chloro-4-methoxyl group-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine; With
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-methyl-2-(5-trifluoromethyl-[1,2,4] diazole-3-yl)-ethyl]-amine.
9. compound according to Claim 8, wherein said compound is selected from:
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine; With
[3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine.
10. according to the compound of claim 9, wherein said compound is [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine.
11. according to the compound of claim 9, wherein said compound is [3-(4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-[(R)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine.
(12.[3-4-methoxyl group-2-methyl-phenyl)-2,5-dimethyl-pyrazolo [1,5-a] pyrimidin-7-yl]-polymorphic form 1 of [(S)-1-(3-methyl-[1,2,4] diazole-5-yl)-propyl group]-amine.
13. according to the polymorphic form 1 of claim 12, wherein said polymorphic form demonstrates the most significant heat absorption at about 108.3 ℃.
14. according to the polymorphic form 1 of claim 12, wherein said polymorphic form demonstrates the X-ray powder diffraction pattern that has at 6.721,11.757 and 21.974 places with the peak of spending 2 θ (+/-0.15 degree 2 θ) expression.
15. comprise pharmaceutically acceptable carrier or thinner and the pharmaceutical composition of the compound of the claim 1 of significant quantity pharmaceutically.
16. comprise pharmaceutically acceptable carrier or thinner and the pharmaceutical composition of the compound of the claim 8 of significant quantity pharmaceutically.
17. comprise pharmaceutically acceptable carrier or thinner and the pharmaceutical composition of the compound of the claim 10 of significant quantity pharmaceutically.
18. treat individual method for one kind, described individuality suffers from the illness with CRF antagonist for treating sensitivity, comprise giving described individuality a kind of pharmaceutical composition that described pharmaceutical composition comprises the pharmaceutically acceptable carrier and the compound of the claim 1 of significant quantity pharmaceutically.
19. treat individual method for one kind, described individuality suffers from the illness with CRF antagonist for treating sensitivity, comprise giving described individuality a kind of pharmaceutical composition that described pharmaceutical composition comprises the pharmaceutically acceptable carrier and the compound of the claim 8 of significant quantity pharmaceutically.
20. treat individual method for one kind, described individuality suffers from the illness with CRF antagonist for treating sensitivity, comprise giving described individuality a kind of pharmaceutical composition that described pharmaceutical composition comprises the pharmaceutically acceptable carrier and the compound of the claim 10 of significant quantity pharmaceutically.
21. according to the method for claim 17, wherein said illness is a neuropsychiatric disorders.
22. according to the method for claim 18, wherein said neuropsychiatric disorders is selected from anxiety, dysthymia disorders and irritable bowel syndrome.
23. according to the method for claim 19, wherein said neuropsychiatric disorders is an anxiety.
24. according to the method for claim 19, wherein said neuropsychiatric disorders is a dysthymia disorders.
25. according to the method for claim 19, wherein said neuropsychiatric disorders is an irritable bowel syndrome.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US62006004P | 2004-10-19 | 2004-10-19 | |
| US60/620,060 | 2004-10-19 | ||
| GB0519957.5 | 2005-09-30 |
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| ZA (1) | ZA200702467B (en) |
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