CN101296699B - Pyrazolo[1,5-a]pyrimidine compounds - Google Patents

Pyrazolo[1,5-a]pyrimidine compounds Download PDF

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CN101296699B
CN101296699B CN200680039177.6A CN200680039177A CN101296699B CN 101296699 B CN101296699 B CN 101296699B CN 200680039177 A CN200680039177 A CN 200680039177A CN 101296699 B CN101296699 B CN 101296699B
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chlorphenyl
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pyrimidine
pyrazolo
chemical compound
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CN101296699A (en
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盛谷恭典
白井公博
大井真利子
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Mitsubishi Tanabe Pharma Corp
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Mitsubishi Tanabe Pharma Corp
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Abstract

The present invention relates to a novel pyrazolo[1,5-a]pyrimidine compound of the formula [I]: wherein Ring A is a substituted pyrazole ring fused to the adjacent pyrimidine ring having the following formula (A), (B) or (C), or a pharmaceutically acceptable salt thereof.

Description

Pyrazolo [1,5-a] pyrimidine compound
Technical field
The present invention relates to new pyrazolo [1,5-a] pyrimidine compound or its acceptable salt that has effective maincenter cannabine (cannabine) receptor (CB1) antagonistic activity and thus serve as medicine.
Background technology
People know that taking in Fructus Cannabis can produce reaction on multiple psychosis or the neurological, such as the variation of the mental disorder of temples or spatial impression, glad, memory, analgesia, hallucination etc.The chemical compound Δ 9-tetrahydrocannabinol (Δ 9-THC) that generally is called " cannabine " can cause many above-mentioned reactions.The effect of cannabine is considered to produce by reacting to each other between this chemical compound and the endogenous specificity/high-affinity receptor thereof.Two kinds of hypotype cannabinoid receptors (CB1 and CB2) are identified and clone.The CB1 receptor is distributed in central nervous system (CNS) zone and comprises brain (Nature, Vol.346,1990, pp 561-564), and the CB2 receptor is distributed in immune system and comprises (Nature, Vol.365,1993, pp 61-65) in the spleen.
The material (agonist, antagonist or inverse agonist) that these cannabinoid receptors is had affinity can produce multiple types like the pharmacotoxicological effect of Fructus Cannabis.Particularly, the material that maincenter CB1 receptor is had an affinity can effectively be treated CNS disease for example psychosis, neurological disorder etc.
Known chemical compound lot, comprise for example SR141716 (LifeScience of pyrazole-3-carboxamide chemical compound, Vol.63,1998, PL113-PL117), 4,5-pyrazoline chemical compound is SLV-319 (Journal of Medicinal Chemistry for example, Vol.47 (3), 2004, pp.627-643), dihydro-pyrazolo [3,4-c] the pyridin-7-one chemical compound, 2H-pyrazolo [4,3-d] pyrimidine-7 (6H)-conducts such as ketone (WO2004/094417) have the material of affinity to this type of cannabinoid receptor.Wherein, SR141716 and SLV-319 have been in and have related under its clinical research as the anorexigenic effect (antiadipositas drug) at least.
Summary of the invention
The object of the present invention is to provide new pyrazolo [1,5-a]-pyrimidine compound, it has effective CB1 receptor antagonist activity and thus serves as medicine.
The present invention relates to pyrazolo [1, the 5-a] pyrimidine compound of formula [I]:
Figure S2006800391776D00021
Wherein
R 1And R 2It is identical or different and be the optional aryl that replaces or the optional saturated or unsaturated heterocycle group that replaces,
Q is singly-bound, methylene or formula :-N (R Q)-group,
R QAlkyl,
Ring A has formula (A), (B) or the substituted pyrazolecarboxylic ring that condenses with adjacent pyrimidine ring (C),
R 3And R 4Identical or different and be; (a) hydrogen atom; (b) cyano group; (c) alkyl that is randomly replaced by 1-3 halogen atom; (d) alkoxyl; (moieties of this group randomly is selected from halogen atom by 1-3; hydroxyl; the amino that is randomly replaced by 1 or 2 alkyl; the group of alkoxyl and alkyl sulphonyl replaces); (e) alkylthio group; (f) alkyl sulphinyl; (g) alkyl sulphonyl or; (h) formula :-N; (R '; (the group of R ")
R ' and R " identical or different and (a) hydrogen atom; (b) randomly be selected from the alkyl that following group replaces by 1-3: halogen atom; the amino and the alkoxyl that are randomly replaced by 1 or 2 alkyl; (c) acyl group; (d) alkyl sulphonyl or the amino-sulfonyl that (e) randomly replaced by 1-2 alkyl; or R ' and R " both mutually combine at its end and consist of the saturated or unsaturated nitrogen heterocyclic ring group of choosing replacement wantonly with adjacent nitrogen-atoms, and E is following (i)-(v) one of group:
R 00Alkyl,
Q 1Singly-bound, alkylidene or formula :-N (R 7)-group, R 7Hydrogen atom or alkyl,
Q 2Singly-bound or alkylidene,
R 5And R 6One of be that to be (a) randomly be selected from the alkyl that following group replaces by 1-3 for hydrogen atom or alkyl and another one: halogen atom; cyano group; alkoxyl; the optional cycloalkyl that replaces; the amino that is randomly replaced by 1 or 2 alkyl; alkylthio group; alkyl sulphinyl; alkyl sulphonyl, acyl group, the optional aryl that replaces and the optional saturated or unsaturated heterocycle group that replaces; (b) the optional cycloalkyl that replaces; (c) formula :-N (R) group (R), (d) the optional aryl that replaces or (e) the optional replacement; saturated or unsaturated heterocycle group, or R 5And R 6Both mutually combine and consist of optional replace, saturated or unsaturated nitrogen heterocyclic ring group with adjacent nitrogen atom,
R 8And R 9One of be that to be (a) randomly be selected from the alkyl that following group replaces by 1-3 for hydrogen atom or alkyl and another one: halogen atom; cyano group and aryl; (b) cycloalkyl; (c) the optional aryl that replaces or; (d) acyl group or; (e) the optional saturated or unsaturated heterocycle group that replaces
R 50And R 60One of be hydrogen atom or alkyl and another one is hydrogen atom, alkyl or acyl group, or they both mutually combine and consist of the cyclic group of following formula with adjacent nitrogen atom:
Figure S2006800391776D00031
Its medium ring A 15-to the 7-member aliphatic series nitrogen heterocyclic ring group that is randomly replaced by oxo group,
R 51Alkyl or the optional aryl sulfonyl that replaces,
R 61Alkyl amino or azido, or its acceptable salt.
Preferred forms of the present invention
For chemical compound of the present invention [I], at each R 1And R 2Be in the situation of aryl, the example of described aryl comprises 6-to 10-member monocycle or bicyclic aryl, for example phenyl or naphthyl.Wherein, the preferred embodiment of described aryl is phenyl.
For chemical compound of the present invention [I], at R 1, R 2, R 3Or R 4Saturated or the situation of unsaturated heterocycle group under, the example of described heterocyclic group comprises 5-to 7-member heteromonocyclic group group, wherein contains the hetero atom that 1-3 is selected from sulphur atom, oxygen atom and nitrogen-atoms.More specifically, described heterocyclic group can be saturated or unsaturated 5-to 6-member oxygen heterocycle group, for example furyl, tetrahydrofuran base, pyranose or THP trtrahydropyranyl, saturated or unsaturated 5-to 6-member sulfur heterocyclic ring group, thienyl for example, tetrahydro-thienyl, saturated or unsaturated 5-to the 7-member of thiapyran base or tetrahydro thiapyran base nitrogen heterocyclic ring group, pyrrolidinyl for example, imidazole radicals, pyrazolyl ， oxazolyl isoxazolyl, thiazolyl, isothiazolyl, pyridine radicals, piperidyl, pyrimidine radicals, pyrazinyl, pyridazinyl, morpholinyl, thio-morpholinyl or azepan base.Wherein, R 1Or R 2Preferred embodiment be saturated or unsaturated 5-or 6-person's sulfur-bearing-or nitrogen heterocycle perssad, thienyl for example, pyrrolidinyl, piperidyl or pyridine radicals, and R 3Or R 4Preferred embodiment be unsaturated 5-or 6-person's sulfur-bearing-, oxygen-or nitrogen-heterocyclic group, pyrrolidinyl for example, piperidyl, morpholino base or thiomorpholine are for base.
Above-mentioned R 1, R 2, R 3Or R 4In aryl and/or saturated or unsaturated heterocycle group can be selected from following group by 1-3 and replace: halogen atom; cyano group; the alkyl that is randomly replaced by 1-3 halogen atom; the alkoxyl that is randomly replaced by 1-3 halogen atom; the amino that is randomly replaced by 1-2 alkyl; alkylthio group, alkyl sulphinyl and alkyl sulphonyl.
At R 5, R 6, R 8Or R 9Be in the situation of cycloalkyl, described cycloalkyl can be replaced by 1-2 group that is selected from cyano group and alkyl.
Above-mentioned R 5, R 6, R 8Or R 9In aryl can be 6-to 10-member monocycle or bicyclic aryl, phenyl for example, naphthyl etc., preferred phenyl.Described aryl can be replaced by 1-2 halogen atom.
At R 5, R 6, R 8Or R 9Saturated or the situation of unsaturated heterocycle group under, the example of described heterocyclic group comprises (a) saturated or undersaturated 4-to 7-member heteromonocyclic group group, the hetero atom that 1-4 is selected from oxygen atom, sulphur atom and nitrogen-atoms is contained in this heteromonocyclic group group; (b) by above-mentioned heteromonocyclic group group with 1 or 2 other be selected from C 3-8The cyclic group of cycloalkyl, 5-to 6-member monocyclic aryl and saturated or undersaturated 4-to 7-member heteromonocyclic group group condenses the nitrogenous dicyclo of saturated or undersaturated 8-to 15-member or the tricyclic heterocyclic group that forms, and 1-4 hetero atom that is selected from oxygen atom, sulphur atom and nitrogen-atoms contained in this heteromonocyclic group group; Or (c) the nitrogenous spiroheterocyclic group of saturated or undersaturated 8-to 11-member.
State R 5, R 6, R 8Or R 9In example saturated or the unsaturated heterocycle group be that (A) contains oxygen-or sulfur heterocyclic ring group, be selected from furyl, tetrahydrofuran base, pyranose, THP trtrahydropyranyl, sulfo-cyclobutyl, thienyl, tetrahydro-thienyl, thiapyran base, tetrahydro thiapyran base, benzofuranyl, dihydro benzo furyl, isobenzofuran-base, Chromanyl, different Chromanyl, chromenyl, heterochromatic thiazolinyl, benzothienyl and dihydrobenzo thienyl; Or (B) nitrogen heterocyclic ring group, be selected from azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, pyrrole radicals, 2H-pyrrole radicals, imidazole radicals, pyrazolyl, the pyrazoline base, thiazolidinyl, thiazolyl, isothiazolyl isoxazolyl ， oxazolidinyl, pyridine radicals, dihydropyridine base, tetrahydro pyridyl, piperidyl, pyrazinyl, piperazinyl, pyrimidine radicals, tetrahydro-pyrimidine base, pyridazinyl, morpholinyl, the azepine cyclooctatetraenyl, azepan base, indolizine base, benzimidazolyl, benzotriazole base, indyl, isoindolyl, 3H-indyl, indoline base, the isoindoline base, 1H-indazolyl, pyrrolopyridinyl, pyrrolo-pyrimidine radicals, purine radicals, pteridyl, the 4H-quinolizinyl, quinolyl, dihydroquinoline base, tetrahydric quinoline group, isoquinolyl, dihydro-isoquinoline base, tetrahydro isoquinolyl, phthalazinyl, dihydro phthalazinyl, naphthyridinyl, dihydronaphthridine base, Tetrahydronaphthyridderivates base, quinoxalinyl, quinazolyl, dihydroquinazoline base, the dihydrobenzo thiazinyl, Er hydrogen benzoxazinyl, cinnolines base, xanthyl, carbazyl, B-carboline base, phenanthridinyl, acridinyl, 5H-dihydro-dibenzazepine
Figure S2006800391776D00051
Spiroheterocyclic group with following formula:
Figure S2006800391776D00052
R wherein AAnd R BIdentical or different and hydrogen atom or alkyl, and q and r are integer 1 or 2.
Among them, preferred embodiment saturated or the unsaturated heterocycle group comprises tetrahydrofuran base, pyrrole radicals, pyrrolidinyl, piperidyl, azepan base, THP trtrahydropyranyl, piperazinyl, morpholinyl, thio-morpholinyl, sulfo-cyclobutyl, tetrahydro-thienyl, tetrahydro thiapyran base, thiazolyl, pyridine radicals, pyrimidine radicals, indyl, pyrrolopyridinyl or Tetrahydronaphthyridderivates base.
At R 5And R 6Mutually combine and consist of in the situation of saturated or unsaturated nitrogen heterocyclic ring group, the example of described nitrogen heterocyclic ring group comprises (a) saturated or undersaturated 4-to 7-member nitrogen-containing hetero monocyclic groups, and this heteromonocyclic group group randomly contains two or more nitrogen-atoms and randomly contains 1-2 the hetero atom that is selected from oxygen atom and sulphur atom except described nitrogen-atoms; (b) above-mentioned heteromonocyclic group group with 1 or 2 other be selected from C 3-8The cyclic group of cycloalkyl, 5-to 6-member monocyclic aryl and saturated or undersaturated 4-to 7-member heteromonocyclic group group condenses the nitrogenous dicyclo of saturated or undersaturated 8-to 15-member or the tricyclic heterocyclic group that forms, and 1-4 hetero atom that is selected from oxygen atom, sulphur atom and nitrogen-atoms contained in this heteromonocyclic group group; Or (c) the nitrogenous spiroheterocyclic group of saturated or undersaturated 8-to 11-member.
The example of above-mentioned saturated or unsaturated nitrogen heterocyclic ring group comprises the nitrogen heterocyclic ring group, and it is selected from azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, pyrrole radicals, imidazole radicals, pyrazolyl, pyrazoline base, thiazolidinyl ， oxazolidinyl, dihydropyridine base, tetrahydro pyridyl, piperidyl, piperazinyl, tetrahydro-pyrimidine base, morpholinyl, azepan base, benzimidazolyl, the benzotriazole base, indyl, isoindolyl, the indoline base, isoindoline base, 1H-indazolyl, purine radicals, dihydroquinoline base, tetrahydric quinoline group, dihydro-isoquinolyl, tetrahydro isoquinolyl, dihydro phthalazinyl, the dihydroquinazoline base, dihydrobenzo thiazinyl, Er hydrogen benzoxazinyl, carbazyl, B-carboline base, 5H-dihydro-dibenzazepine Spiroheterocyclic group with following formula :-
Figure S2006800391776D00062
R wherein AAnd R BIdentical or different and hydrogen atom or alkyl, and q and r are integer 1 or 2.
Among them, preferred embodiment saturated or the unsaturated heterocycle group comprises saturated 5-to 7-member's nitrogen-containing hetero monocyclic groups, and morpholino base for example, thiomorpholine be for base, piperidino, Piperazino or azepan base.
In addition, R 5, R 6, R 8Or R 9In saturated or unsaturated heterocycle group (with pass through R 5With R 6In conjunction with the saturated or unsaturated nitrogen heterocyclic ring group that consists of) can be selected from following group replacement by 1-4: halogen atom; hydroxyl; cyano group; oxo group, alkyl is by the alkyl of 1-3 halogen atom replacement; alkoxyalkyl; aminoalkyl, cycloalkyl, aralkyl; alkoxyl; by the alkoxyl that 1-3 halogen atom replaces, acyl group, the amino that is randomly replaced by 1-2 alkyl; acylamino-; alkyl sulphonyl, the amino-sulfonyl that is randomly replaced by 1-2 alkyl, the aryl and saturated or undersaturated 5-to the 6-member nitrogen heterocyclic ring group that are randomly replaced by 1-2 halogen atom.
R 4, R 5, R 6, R 8Or R 9The example of middle acyl group comprises the group that removes hydroxyl from the carboxylic acid with following formula [Ac-I]: R X-COOH[Ac-I], be called formula: R XThe group of-CO-,
R wherein XIt is (a) hydrogen atom; (b) randomly be selected from the alkyl that following group replaces by 1-3: halogen atom; cyano group; alkyl sulphonyl and pyridine radicals; (c) alkoxyl that is randomly replaced by aryl; (d) cycloalkyl, the aryl that (e) is randomly replaced by halogen atom, cyano group, alkyl, tri haloalkyl and alkoxyl, the amino that (f) is randomly replaced by 1-2 alkyl or (g) saturated or unsaturated heterocycle group.The instantiation of described acyl group comprises (a1) formoxyl, (b1) C 1-6Alkyl-carbonyl, acetyl group for example, propiono etc., three halos-C 1-6Alkyl-carbonyl is trifluoroacetyl group etc. for example, cyano group-C 1-6Alkyl-carbonyl is cyano group acetyl group etc. for example, pyridine radicals-C 1-6Alkyl-carbonyl is pyridine radicals acetyl group etc. for example, (c1) C 1-6Alkoxyl-carbonyl is methoxycarbonyl group for example, carbethoxyl group, tert-butyl group carbonyl etc., aryl-C 1-6Alkoxyl-carbonyl, for example benzyloxycarbonyl, (d1) C 3-8Cycloalkyl-carbonyl is cyclopropyl carbonyl for example; cyclopentylcarbonyl etc.; (e1) aryl-carbonyl benzoyl etc. for example; single-or two-halo-aryl-carbonyl chlorobenzene formacyl for example; fluoro benzoyl; difluoro benzoyl etc., cyano group-aryl-carbonyl is the cyano group benzoyl for example, three halos-C 1-6Alkyl-aryl-carbonyl is trifluoromethyl benzoyl etc. for example, C 1-6Alkoxyl-aryl-carbonyl is anisoyl etc. for example, (f) carbamoyl, N-(C 1-6Alkyl) carbamoyl, or (g1) furoyl base, Thenoyl, bromo thiophene formoxyl, cyano thiophene formoxyl, pyridine radicals carbonyl, chloro-pyridine base carbonyl, cyanopyridine-based carbonyl, trifluoromethyl-pyridine radicals carbonyl or pyrazinyl carbonyl.
E in chemical compound of the present invention [I] is that the example of group (ii) comprises the group of following formula in the situation of group of formula (ii):
(a)-C(＝O)-N(R 5)(R 6)，
(b)-C(＝O)-Alk-N(R 5)(R 6)，
(c)-Alk-C (=O)-N (R 5) (R 6), or
(d)-N(R 7)-C(＝O)-N(R 5)(R 6)
Wherein Alk is direct-connected or side chain C 1-6Alkylidene and other symbol definitions are as above.
In chemical compound of the present invention [I], the example of preferred compound comprises the chemical compound of following A-E group.
The A group: chemical compound [I] wherein
R 1And R 2It is identical or different and be that (a) randomly is selected from the phenyl that the group of halogen atom and tri haloalkyl replaces by 1-2,
Q is singly-bound,
Ring A is the substituted pyrazolecarboxylic ring of formula (A),
E is following formula :-C (=O) O-R 00(i) group
R 4That (a) is randomly by 1-2 amino-sulfonyl or its acceptable salt amino or that (b) randomly replaced by 1-2 alkyl that is selected from the group replacement of alkyl and alkyl sulphonyl.
In the chemical compound of A group, preferred embodiment comprises that wherein R is chlorophenyl or three fluoro-C 1-4Alkyl-phenyl, R 2Chlorophenyl, R aC 1-4Alkyl and R 4Be selected from C by 1-2 1-4Alkyl and C 1-4Chemical compound or its acceptable salt of the amino that alkyl sulphonyl replaces.
The B group: chemical compound [I] wherein
R 1And R 2Identical or different and be; (a) randomly be selected from the phenyl that following group replaces by 1-3: halogen atom; cyano group; the alkyl that is randomly replaced by 1-3 halogen atom; the alkoxyl that is randomly replaced by 1-3 halogen atom; the amino that is randomly replaced by 1-2 alkyl and alkyl sulphonyl or; (b) randomly be selected from saturated or undersaturated 5-to the 7-element heterocycle group that following group replaces by 1-3: halogen atom; oxo group; the alkyl that is randomly replaced by 1-3 halogen atom; alkoxyl; alkoxyalkyl and alkoxyl alkoxyl
Ring A is formula (A) or substituted pyrazolecarboxylic ring (B),
A kind of in the group of E following formula (a)-(e):
a)-C(＝O)-N(R 5)(R 6)，
b)-C(＝O)-Alk-N(R 5)(R 6)，
c)-Alk-C(＝O)-N(R 5)(R 6)，
d)-N(R 7)-C(＝O)-N(R 5)(R 6)，
E)-C (=NR 51)-R 61, R 3Hydrogen atom, cyano group or alkoxyl,
R 4It is (a) hydrogen atom; (b) cyano group; (c) randomly be selected from the alkyl that following group replaces by 1-3: halogen atom and hydroxyl (d) randomly are selected from the alkoxyl that following group replaces by 1-3: halogen atom, hydroxyl; the amino that is randomly replaced by 1-2 alkyl; alkoxyl and alkyl sulphonyl, (e) alkylthio group, (f) alkyl sulphinyl; (g) alkyl sulphonyl or (h) formula :-N (R ') (group of R ")
R ' and R " identical or different and (a) hydrogen atom; (b) randomly be selected from the alkyl that following group replaces by 1-3: halogen atom; the amino that is randomly replaced by 1-2 alkyl and alkoxyl; (c) acyl group; (d) alkyl sulphonyl or (e) randomly by the amino-sulfonyl of 1-2 alkyl replacement; or (f) they both mutually combine and consist of randomly by saturated or undersaturated 5-to the 6-member nitrogen-containing hetero monocyclic groups of hydroxyl or alkoxyl, R with adjacent nitrogen atom 5And R 6One of be hydrogen atom or alkyl and another one is
(1) randomly is selected from the alkyl that following group replaces by 1-3: halogen atom, alkoxyl, cycloalkyl, alkylthio group, alkyl sulphonyl, the amino that is randomly replaced by 1 or 2 alkyl, morpholino carbonyl, the phenyl and saturated or undersaturated 5-to the 6-member nitrogen-containing hetero monocyclic groups that are randomly replaced by cyano group, the group that this heteromonocyclic group group randomly is selected from halogen atom, alkyl and tri haloalkyl replaces;
(2) randomly by the cycloalkyl of cyano group or alkyl replacement;
(3) formula :-N (R 8) (R 9) group; Or
(4) phenyl; Or
(5) randomly be selected from saturated or undersaturated 4-to the 10-member monocycle that following group replaces-or bicyclic heterocyclic group by 1-4: halogen atom, cyano group, hydroxyl, oxo group, the alkyl that is randomly replaced by 1-3 halogen atom, cycloalkyl, alkyl-carbonyl, alkoxy carbonyl, alkyl sulphonyl, the amino-sulfonyl that is randomly replaced by 1 or 2 alkyl is randomly by the carbamoyl of 1-2 alkyl, alkoxy carbonyl, the alkoxycarbonyl amino phenyl that is randomly replaced by 1-2 halogen atom and saturated or undersaturated 5-to 6-member heteromonocyclic group group; Or
(6) R 5And R 6Both mutually combine and consist of saturated or undersaturated 4-to the 7-member nitrogen heterocyclic ring group that is randomly replaced by the individual group that is selected from halogen atom and oxo group of 1-2 with adjacent nitrogen atom,
R 8Hydrogen atom or alkyl,
R 9That (a) randomly is selected from the alkyl that following group replaces by 1-3: halogen atom, cyano group and phenyl; (b) randomly be selected from the phenyl that following group replaces: halogen atom, cyano group, alkyl, tri haloalkyl, cycloalkyl, three halogenated alkoxies, alkoxyl, alkylthio group and alkyl sulphonyl; (c) alkoxy carbonyl; Or (d) randomly be selected from halogen atom, saturated or undersaturated 5-to the 6-member heteromonocyclic group group that cyano group, alkyl, the group of alkoxyl and tri haloalkyl replace,
R 7Hydrogen atom,
R 51Alkyl or phenyl sulfonyl and the R that is randomly replaced by 1-2 halogen atom 61Alkyl amino or azido or its acceptable salt.
In the chemical compound of B group, more preferably the example of chemical compound comprises wherein R of chemical compound 1That (a) randomly is selected from the phenyl that following group replaces by 1 or 2: halogen atom, cyano group, dihalo alkyl, tri haloalkyl, alkoxyl, alkoxyalkyl and two (alkyl) is amino or (b) randomly be selected from saturated or undersaturated 5-to the 7-element heterocycle group that following group replaces by 1-2: oxo group, alkyl, tri haloalkyl, alkoxyl, alkoxyalkyl, alkoxyl alkoxyl and two (alkyl) amino
R 2That (a) randomly is selected from halogen atom and the phenyl of cyano group replacement or saturated or undersaturated 5-to the 6-element heterocycle group that (b) is randomly replaced by halogen atom by 1 or 2,
R 3Hydrogen atom,
R 4Hydrogen atom, alkyl, the dihalo alkyl, hydroxyalkyl, tri haloalkyl, alkoxyalkyl, the hydroxy alkoxy base, the alkoxyl alkoxyl, alkyl sulphonyl alkyl or formula :-N (R ') (group of R "),
R ' and R " one of be hydrogen atom or alkyl and another one is acyl group or alkyl sulphonyl,
E is one of following formula (a), (b) and group (e):
(a)-C(＝O)-N(R 5)(R 6)，
(b)-C(＝O)-Alk-N(R 5)(R 6)，
(e)-C(＝NR 51)-R 61，
R 5And R 6One of be hydrogen atom or alkyl; another one is (a) alkyl; (b) cycloalkyl; (c) phenyl, (d) randomly by 1-4 be selected from saturated or undersaturated 4-to the 10-member that following group replaces single-or two-ring-type heterocyclic group: halogen atom, oxo group; cyano group; hydroxyl, alkyl, tri haloalkyl; alkoxyl; alkoxyalkyl, alkyl-carbonyl, two (alkyl) carbamoyl; alkyl sulphonyl; two (alkyl) amino-sulfonyl, phenyl, halogenophenyl and pyridine radicals or (e) formula :-N (R 8) (R 9) group, or (f) they both mutually combine and consist of randomly by 1-2 saturated or undersaturated 5-to 6-member heteromonocyclic group group that is selected from that halogen atom and oxo group replace with adjacent nitrogen atom,
R 8Alkyl,
R 9It is (a) alkyl, (b) phenyl that is randomly replaced by halogen atom, (c) the randomly alkyl that replaces of pyridyl or saturated or undersaturated 4-to the 6-member heteromonocyclic group group that (d) is selected from randomly that following group replaces: halogen atom, alkyl, tri haloalkyl and alkoxyl
R 51Alkyl or halogenophenyl-sulfonyl, and R 61Alkyl amino or azido.
In the chemical compound of B group, the example of further preferred chemical compound comprises wherein R of chemical compound 1That (a) randomly is selected from the chlorine atom, fluorine atom, cyano group, two fluoro-C 1-4Alkyl and three fluoro-C 1-4The phenyl that the group of alkyl replaces or (b) randomly by three fluoro-C 1-4The pyridine radicals that alkyl replaces,
R 2Randomly to be selected from the chlorine atom by 1-2, fluorine atom, the phenyl that the group of bromine atoms and cyano group replaces,
R 3Hydrogen atom,
R 4Hydrogen atom, C 1-4Alkyl, two fluoro-C 1-4Alkyl, three fluoro-C 1-4Alkyl, C 1-4Alkoxy-C 1-4Alkyl or C 1-4Alkyl-carbonyl-amino,
One of following formula (a) and group (b):
(a)-C(＝O)-N(R 5)(R 6)，
(b)-C(＝O)-Alk-N(R 5)(R 6)，
R 5And R 6One of be hydrogen atom and another one is C 1-4Alkyl, pyridine radicals-C 1-4Alkyl, the C5-7 cycloalkyl, chlorophenyl randomly is selected from halogen atom, oxo group and C by 1-2 1-4Alkoxy-C 1-4Saturated or undersaturated 4-to 6-member heteromonocyclic group group or formula that alkyl replaces :-N (R 8) (R 9) group, or they both mutually combine and consist of randomly saturated or undersaturated 5-to the 6-member heteromonocyclic group group that is replaced by 1-2 oxo group with adjacent nitrogen atom,
R 8C 1-4Alkyl and R are C 1-4Alkyl, chlorophenyl, pyridine radicals or C 1-4Alkoxyl-pyridine radicals.
C group: chemical compound [I] or its acceptable salt, wherein R 1And R 2Identical or different and be randomly to be selected from the phenyl that the group of halogen atom and tri haloalkyl replaces by 1-2, Q is singly-bound, and ring A is the substituted pyrazolecarboxylic ring of formula (A), R 3Hydrogen atom, R 4Be hydrogen atom or alkyl, E is the group of formula (iii):
Figure S2006800391776D00111
R 5And R 6One of be hydrogen atom or alkyl and another one is (a) alkyl, (b) cycloalkyl or (c) saturated or undersaturated 5-to 6-member sulfur-bearing-or nitrogenous-heteromonocyclic group group, or (d) they both mutually combine and consist of saturated or unsaturated 5-to the 6-member nitrogen heterocyclic ring group that is randomly replaced by 1-2 oxo group with adjacent nitrogen atom.
In the chemical compound of group C, the example of preferred chemical compound comprises wherein R of chemical compound 1Tri haloalkyl-phenyl, R 2Halogenophenyl,
R 4Alkyl,
R 5And R 6One of be hydrogen atom or alkyl, another one is (a) alkyl, (b) cycloalkyl, (c) randomly by saturated or undersaturated 5-to the 6-member sulfur-bearing of 1-2 oxo group-or nitrogenous-heteromonocyclic group group, or (d) they both mutually combine and consist of randomly saturated or undersaturated 5-to the 6-member heteromonocyclic group group that is replaced by 1-2 oxo group with adjacent nitrogen atom.
D group: chemical compound [I] or its acceptable salt, wherein R 1And R 2Identical or different and be randomly to be selected from the phenyl that the group of halogen atom and tri haloalkyl replaces by 1-2, Q is singly-bound, and ring A is the substituted pyrazolecarboxylic ring of formula (A), R 3Hydrogen atom, R 4Be hydrogen atom or alkyl, E is the group of formula (iv):
Figure S2006800391776D00112
R 50And R 60They be hydrogen atom or alkyl and another one is alkyl or acyl group, or they both mutually combine and consist of randomly by saturated or undersaturated 5-to the 6-member nitrogen heterocyclic ring group of 1-2 oxo group with adjacent nitrogen atom.
The E group: chemical compound [I] is R wherein 1And R 2Identical or different and be randomly to be selected from the phenyl that the group of halogen atom and tri haloalkyl replaces by 1-2, Q is singly-bound, ring A be formula (C) obtain pyrazole ring, R 3Hydrogen atom, R 4That (group of R "), R ' and R are " identical or different and be hydrogen atom or alkyl, or they both mutually combine and consist of saturated or undersaturated 5-to 6-member nitrogen heterocyclic ring group with adjacent nitrogen atom for formula-N (R ').
In chemical compound of the present invention [I], the example of particularly preferred chemical compound comprises that chemical compound is selected from:
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-piperidino carbamoyl) pyrazolo [1,5-a]-pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[(N '-methyl-N '-phenyl diazanyl)-and carbonyl] pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-cyclohexyl carboxyamide base) pyrazolo [1,5-a]-pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[(N ', N '-dimethyl diazanyl) carbonyl]-pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-pyrrolidine carbamoyl) pyrazolo [1,5-a]-pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-cyclopenta carbamoyl) pyrazolo [1,5-a]-pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(4-THP trtrahydropyranyl) carbamoyl]-pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(1,1-dioxo-Tetramethylene sulfide-3-yl)-carbamoyl] pyrazolo [1,5-a] pyrimidine;
(R)-and 6-(2-chlorphenyl)-7-(4-difluoromethyl phenyl)-3-[N-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-) carbamoyl] pyrazolo [1,5-a] pyrimidine;
(R)-and 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-2-methyl-3-[N-(1,1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;
(S)-and 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-2-methyl-3-[N-(1,1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-[-(2-pyridine radicals) ethyl] carbamoyl]-pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-cyclopenta carbamoyl)-2-methoxyl group-pyrazolo [1,5-a] pyrimidine;
(R)-and 6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-methyl-3-[N-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-) carbamoyl] pyrazolo [1,5-a] pyrimidine;
(S)-and 6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-methyl-3-[N-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-) carbamoyl] pyrazolo [1,5-a] pyrimidine;
6-(2-bromophenyl)-7-(4-chlorphenyl)-3-(N-cyclopenta carbamoyl) pyrazolo [1,5-a]-pyrimidine;
(R, S)-6-(2-bromophenyl)-7-(4-chlorphenyl)-3-[N-(1,1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;
(S)-and 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[N-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-) carbamoyl] pyrazolo [1,5-a] pyrimidine;
(R)-and 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[N-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-) carbamoyl] pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-[N-(3-chlorphenyl)-N-methylamino]-carbamoyl] pyrazolo [1,5-a] pyrimidine;
6-(2-cyano-phenyl)-7-(4-chlorphenyl)-3-[N-[N-methyl-N-(2-pyridine radicals) amino]-carbamoyl] pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-isobutylamino formoxyl) pyrazolo [1,5-a]-pyrimidine;
6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[N-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-) carbamoyl] pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-(N-cyclopenta carbamoyl)-pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[N-[N-methyl-N-(2-pyridine radicals)-amino] carbamoyl] pyrazolo [1,5-a] pyrimidine;
(R)-and 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(1,1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-cyano-phenyl)-3-(N-cyclopenta carbamoyl) pyrazolo [1,5-a]-pyrimidine;
(R, S)-6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-methyl-3-[N-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-) carbamoyl j pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-fluorophenyl)-3-(N-cyclopenta carbamoyl) pyrazolo [1,5-a]-pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-[N-methyl-N-(2-pyridine radicals) amino]-carbamoyl] pyrazolo [1,5-a] pyrimidine;
(S)-and 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(1,1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-ethylamino formoxyl) pyrazolo [1,5-a]-pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-cyclopropylamino formoxyl)-pyrazolo [1,5-a] pyrimidine;
(S)-and 6-(2-chlorphenyl)-7-(4-chloro-2-fluorophenyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl] pyrazolo [1,5-a] pyrimidine;
(S)-and 6-(2-chlorphenyl)-7-(4-difluoromethyl phenyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl] pyrazolo [1,5-a] pyrimidine;
(R)-6-(2-cyano-phenyl)-7-(4-trifluoromethyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl]-2-methylpyrazole [1,5-a] pyrimidine also;
(S)-6-(2-cyano-phenyl)-7-(4-trifluoromethyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl]-2-methylpyrazole [1,5-a] pyrimidine also;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[[N '-methyl-N '-(2-methoxypyridine-5-yl)-diazanyl] carbonyl] pyrazolo [1,5-a] pyrimidine;
6-(2-cyano-phenyl)-7-(4-chlorphenyl)-3-[N-(1-pyrrolidinyl) carbamoyl]-pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(2-5-flumethiazine-5-yl)-3-(N-cyclopenta carbamoyl)-pyrazolo [1,5-a] pyrimidine;
(R)-6-(2-cyano-phenyl)-7-(4-chlorphenyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl]-2-methylpyrazole [1,5-a] pyrimidine also;
6-(2-cyano-phenyl)-7-(4-chlorphenyl)-3-[[N '-methyl-N '-(2-pyridine radicals) diazanyl]-carbonyl]-2-methylpyrazole [1,5-a] pyrimidine also;
(R)-6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl]-2-trifluoromethyl pyrazol [1,5-a] pyrimidine also;
6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[(N ' N '-dimethyl diazanyl)-carbonyl]-2-acetyl-amino pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[[N '-methyl-N '-(2-pyridine radicals) diazanyl]-carbonyl]-2-acetyl-amino pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[[N '-methyl-N '-(2-pyridine radicals) diazanyl]-carbonyl]-2-(trifluoromethyl) pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(1-pyrrolidinyl) carbamoyl]-2-difluoromethyl pyrazole [1,5-a] pyrimidine also;
(R)-6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl]-2-difluoromethyl pyrazole [1,5-a] pyrimidine also;
(S)-6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl]-2-difluoromethyl pyrazole [1,5-a] pyrimidine also;
6-(2-cyano-phenyl)-7-(4-chlorphenyl)-3-(N-piperidino carbamoyl)-2-difluoromethyl pyrazole is [1,5-a] pyrimidine also;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(1,1-dioxo sulfo-Tetramethylene .-3-yl)-carbamoyl] pyrazolo [1,5-a] pyrimidine;
7-(4-chlorphenyl)-6-(2-cyano group-4-fluorophenyl)-3-[N-(1-pyrrolidinyl) carbamoyl]-pyrazolo [1,5-a] pyrimidine;
7-(4-chlorphenyl)-6-(2-cyano-phenyl)-3-(N-piperidino carbamoyl)-2-methyl-pyrazolo [1,5-a] pyrimidine;
7-(4-chlorphenyl)-6-(2-cyano-phenyl)-3-[N-(1-pyrrolidinyl) carbamoyl]-2-methyl-pyrazolo [1,5-a] pyrimidine;
(S)-and 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(2-methoxy-1-pyrrolidinyl)-carbamoyl] pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(4-fluorine piperidino) carbamoyl]-pyrazolo [1,5-a] pyrimidine;
(R)-7-(4-chloro-2-fluorophenyl)-6-(2-cyano-phenyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl]-2-methylpyrazole [1,5-a] pyrimidine also;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[[N '-methyl-N '-(2-ethoxy pyridine-5-yl)-diazanyl] carbonyl] pyrazolo [1,5-a] pyrimidine;
(R)-6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl]-2-methoxy pyrazolo [1,5-a] pyrimidine;
(S)-6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl]-2-methoxy pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[[N '-methyl-N '-(2-pyridine radicals) diazanyl]-carbonyl]-2-methoxy pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(1-pyrrolidinyl) carbamoyl]-2-methoxy pyrazolo [1,5-a] pyrimidine;
7-(4-chloro-2-fluorophenyl)-6-(2-cyano-phenyl)-3-[N-(1-pyrrolidinyl) carbamoyl]-2-methylpyrazole [1,5-a] pyrimidine also;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[-(1,1-dioxo thiomorpholine generation) acetyl group]-2-methylpyrazole [1,5-a] pyrimidine also;
6-(2-cyano-phenyl)-7-(4-chlorphenyl)-3-[N-(4-fluorine piperidino) carbamoyl]-2-methylpyrazole [1,5-a] pyrimidine also; With
6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[N-(Tetramethylene sulfide-3-yl)-carbamoyl] pyrazolo [1,5-a] pyrimidine
Or its acceptable salt.
When chemical compound of the present invention [I] has asymmetric carbon atom in its molecule, can there be (diastereomer in it with the form of its stereoisomer because of its asymmetric carbon atom, optical isomer), and the present invention also comprise a kind of and composition thereof of stereoisomer.
Chemical compound of the present invention [I] demonstrates effective antagonistic activity of CB1 receptor and can be as the medicine of disease that prevents and/or treats CB1 receptor-mediation, and for example psychosis comprises schizophrenia, anxiety disorder, stress, depression, epilepsy, neurodegenerative disease, spinocerebellar disease, cognitive disorder, craniocerebral trauma, panic attack, peripheral neurophaty, glaucoma, migraine, parkinson, Alzheimer, Huntingtons chorea, Raynaud's syndrome, tremble mandatory Value and Behaviors disease, amnesia, alzheimer disease, disease of thymus gland, Tourette's syndrome, tardive dyskinesia, bipolarity obstacle, cancer, the drug-induced dyskinesia, dystonia, septic shock, hemorrhagic shock, hypotension, insomnia, immunological diseases comprise inflammation, multiple sclerosis, vomiting, diarrhoea, asthma, the appetite for example bulimia nerovsa of lacking of proper care, anorexia etc., fat, noninsulindependent diabetes (NIDDM), dysmnesia, urinary disorders, cardiovascular disease, infertility infects the disease that demyelination is relevant, the neuritis, viral encephalitis, cerebrovascular events, hepatitis interstitialis chronica or gastroenteropathy comprise intestinal trafficability characteristic obstacle.
In addition, chemical compound of the present invention [I] can be as ending long-term treatment, alcohol dependence or drug dependence (for example, opium, barbital, Fructus Cannabis, ***e, amfetamine (amphethamine), phencyclidine, hallucinogen, benzodiazepine
Figure DEST_PATH_G40094481150138000D000061
Chemical compound etc.) medicine.
In addition, chemical compound of the present invention [I] can be as the medicine of the analgesic activities that improves analgesics or anaesthetic etc.; Or as the medicine (giving up smoking or Nicotine Dependence) of giving up smoking.
And chemical compound of the present invention [I] can be used for the treatment of the disease relevant with metabolic disease, comprises obesity, diabetes, impaired glucose-tolerant, hyperinsulinemia, hyperlipemia, hypercholesterolemia, hypertriglyceridemia, the lipid metabolism disease, atherosclerosis, hypertension, cardiovascular disease, coronary heart disease, depression, anxiety, drug dependence, and substance addiction.
In addition, chemical compound of the present invention [I] is applicable as medicine because of its hypotoxicity.
Chemical compound of the present invention [I] can use with the form of free form or its acceptable salt clinically.The pharmaceutically acceptable salt of chemical compound [I] comprises the salt with mineral acid, hydrochlorate for example, sulfate, phosphate or hydrobromate, or with organic acid salt acetate for example, fumarate, oxalates, citrate, mesylate, benzene sulfonate, tosilate or maleate.In addition, when chemical compound of the present invention [I] had carboxyl and similar group in its molecule, the example of pharmaceutically acceptable salt comprised that the salt that becomes with alkali is alkali metal (for example, sodium salt, potassium salt) or alkaline-earth metal (for example, calcium salt) for example.
Chemical compound [I] or its acceptable salt comprise molecule inner salt or its addition salts, and its solvate or hydrate.
Chemical compound of the present invention [I] or its acceptable salt can oral administration or parenterai administrations, and can be formulated as the conventional medicine preparation, for example tablet, granule, capsule, powder, injection or inhalant.
The dosage of chemical compound of the present invention [I] or its acceptable salt can change according to route of administration, patient's age, body weight and disease.For example, when with the ejection preparation administration, normally in about 0.0001-1.0mg/kg/ days scope, preferably in about 0.001-0.1mg/kg/ days scope.When with oral preparation drug administration, normally in about 0.001-100mg/kg/ days scope, preferably in 0.01-10mg/kg/ days scope.
Chemical compound of the present invention [I] also can as the treatment above-mentioned disease/disease adjuvant, append or replacement therapy.Described adjuvant, append or replacement therapy refers to chemical compound of the present invention is administered to simultaneously or sequentially the patient of the therapeutic agent of accepting, accepting or preparing to accept the above-mentioned disease of one or more other treatments, for example, one or more known antidepressants, antipsychotic drug or anxiolytic medicine.
Chemical compound of the present invention [I] can prepare by following method but be not limited to this.
(1) in chemical compound of the present invention, its medium ring of chemical compound [I] A is that substituted pyrazolecarboxylic ring and the E of formula (A) is the group of following formula (ii):
Figure S2006800391776D00171
Can be according to for example following method A-D preparation.
(method A)
Q wherein 2Be chemical compound [I] or its salt of singly-bound, namely have following formula [I-A]:
Symbol wherein has above-mentioned definition, chemical compound that can through type [II-A]:
Figure S2006800391776D00182
R wherein aBe hydrogen atom, alkyl or benzyl and another symbol definition as above react to make with the ammoniate of following formula [III]:
HN(R 5)(R 6) [III]
Wherein symbol definition as above.
Work as R aWhen being hydrogen atom, above-mentioned reaction can be in solvent in the presence of condensing agent, and activator and alkali exists or non-existent condition under carry out.The example of described solvent comprises the solvent of any not disturbance reponse, dichloromethane for example, chloroform, dimethyl formamide, dimethyl acetylamide, oxolane ， diox, toluene, benzene, 1,2-dichloroethanes, 1-methyl pyrrolidone, 1,2-dimethoxy-ethane etc.Condensing agent can be dicyclohexylcarbodiimide (DCC); 1-ethyl-3-(3-dimethylamino-propyl group) carbodiimide hydrochloride (WSC HCl); diphenyl phosphoryl azide (DPPA); the two imidazoles (CDI) of carbonyl; diethyl cyano group phosphate (DEPC); DIC (DIPCI); benzotriazole-1-base oxygen base tripyrrole Wan Phosphonium hexafluorophosphate (PyBOP); the two triazoles of carbonyl; N-carbodicyclo hexylimide-N '-propoxyl group methylated polystyrene (PS-carbodiimide); N-ethoxy carbonyl-2-ethyoxyl-1; 2-dihydroquinoline (EEDQ); 2-(7-azepine benzo triazol-1-yl)-1; 1; 3; 3-tetramethyl uronium hexafluorophosphate (HATU); 2-(1H-benzotriazole-1-base-1; 1; 3; 3-tetramethyl uronium hexafluorophosphate (HBTU); bromine tripyrrole Wan Phosphonium hexafluorophosphate (PyBroP); 2-(1H-benzotriazole-1-yl)-1; 1; 3; 3-tetramethyl uronium tetrafluoroborate (TBTU); chloro-1; 1; 3,3-tetramethyl-uronium hexa chloro-antimonate (ACTU) etc., the example of activator comprises I-hydroxybenzotriazole (HOBt); 1-N-Hydroxysuccinimide (HOSu); dimethyl aminopyridine (DMAP), 1-hydroxyl-7-azepine benzotriazole (HOAt), hydroxyl phthalyl imines (HOPht); pentafluranol (Pfp-OH), I-hydroxybenzotriazole-6-sulfonamido methylated polystyrene (PS-HOBt) etc.Described alkali comprises, for example, and pyridine, triethylamine, diisopropyl ethyl amine, 4-methyl morpholine, 1,8-diazabicyclo [5,4,0]-7-hendecene (DBU) etc.
At said method, the consumption of chemical compound [II-A] can be that per 1 mole chemical compound [III] uses the 0.33-1.5 mole, preferred 0.5-1.2 mole.The consumption of condensing agent can be that per 1 mole chemical compound [II-A] or [III] uses the 1.0-3.0 mole, preferred 1.0-1.2 mole condensing agent.The consumption of described alkali can be that per 1 mole chemical compound [II-A] or [III] uses the 1.0-3.0 mole, preferred 1.0-1.2 mol alkali.The consumption of activator can be that per 1 mole chemical compound [II-A] or [III] uses the 0.01-2.0 mole, preferred 0.1-1.0 mole activator.This reaction can be at 0-150 ℃, carries out under preferred 20-80 ℃.
R in chemical compound [II-A] aWhen being hydrogen atom, chemical compound [I-A] can be by (for example being converted into corresponding reactive derivatives with chemical compound [II-A], etheride, mixed acid anhydride) and with this type of reactive derivatives and chemical compound [III] in the presence of the alkali, exist or do not exist under the solvent reaction to make.
R in chemical compound [II-A] aWhen being alkyl or benzyl, method A of the present invention also can by with ester compounds by conventional methods reactions such as Hydrolyze method, acid hydrolyzation and hydrochloric acid, formic acid, trifluoroacetic acid or hydrogenolysis be converted into the carboxylic acid compound of corresponding following formula [II-Aa]:
Figure S2006800391776D00191
Wherein said symbol definition as above and makes carboxylic acid compound [II-Aa] and chemical compound [III] react in the same manner as described above to make subsequently.
And its medium ring A is the chemical compound [I] of the group of following formula (C):
Figure S2006800391776D00192
Wherein this symbol definition can be the by-product in the reaction of chemical compound [II-Aa] and chemical compound [III] as above.
(method B)
Q wherein 2Chemical compound [I] or its salt of alkylidene, the namely chemical compound of following formula [I-B]:
Q wherein 21Be alkylidene and another symbol definition as above, can pass through the chemical compound of following formula [II-B]:
Figure DEST_PATH_G40094481150138000D000072
Wherein X be halogen atom and another symbol definition as above, make with chemical compound [III] reaction.
The reaction of chemical compound [II-B] and chemical compound [III] can be in solvent, carry out under the condition that has or do not exist alkali.The example of described solvent comprises the solvent of any not disturbance reponse, dichloromethane for example, chloroform, dimethyl formamide, dimethyl acetylamide, dimethyl sulfoxide, oxolane ， diox, toluene, benzene, 1,2-dichloroethanes, 1-methyl-ketopyrrolidine, 1,2-dimethoxy-ethane etc.Described alkali comprises, for example, and sodium hydride, potassium carbonate, pyridine, triethylamine, diisopropyl ethyl amine, 4-methyl morpholine, 1,8-diazabicyclo [5,4,0]-7-endecatylene (DBU) etc.
In said method, the consumption of chemical compound [III] can be that per 1 mole chemical compound [II-B] uses the 1.0-20 mole, preferred 1.0-3.0 mole.Described alkali can be that per 1 mole chemical compound [III] or [II-B] uses the 0-20 mole, preferred 1.0-3.0 mole.This reaction can be at-20 to 100 ℃, carry out under preferred 0-50 ℃.
(method C)
In chemical compound of the present invention [I], chemical compound is Q wherein 1Formula :-N (R 7)-group and Q 2Singly-bound, the chemical compound of following formula [I-C] namely:
Figure S2006800391776D00211
Wherein this symbol definition as above can be passed through the chemical compound of following formula [II-C]:
Figure S2006800391776D00212
Wherein this symbol definition is as above reacted in the presence of the chemical compound of formula [a] with chemical compound [III] and to be made:
W 1-CO-W 2 [a]
W wherein 1And W 2Identical or different and be to remove group.
In chemical compound [a], W 1And W 2Example comprise imidazole radicals, halogen atom, phenoxy group etc.The instantiation of this compounds comprises 1,1 '-the two imidazoles of carbonyl, phosgene, triphosgene etc. the example of described solvent comprises the solvent of any not disturbance reponse, for example acetonitrile, dichloroethanes, chloroform, 1,2-dichloroethanes, oxolane diox, benzene, toluene, dimethyl formamide etc.The consumption of chemical compound [III] can be per 1 mole chemical compound [II-C] use the 1.0-5.0 mole, preferred 1.0-1.2 mole.The consumption of chemical compound [a] can be that per 1 mole chemical compound [II-C] or [III] uses the 0.33-5.0 mole, preferred 1.0-2.0 mole.This reaction can be at-20 to 100 ℃, carry out under preferred 0 to 50 ℃.
And chemical compound [I-C] also can obtain by chemical compound [II-C] and the reaction of chemical compound [a] chemical compound of formula [IV]:
Figure S2006800391776D00221
Wherein this symbol definition as above, and its product or reactive derivatives and chemical compound [III] reaction, or chemical compound [III] and chemical compound [a] reaction obtain the chemical compound of formula [V]:
Wherein said symbol definition as above, and its product or reactive derivatives and chemical compound [II-C] reaction.
The example of the reactive derivatives of chemical compound [IV] or [V] comprises those wherein W 2Be converted into the group of following formula:
Figure S2006800391776D00223
Can pass through wherein W with this reactive derivatives 2Chemical compound [IV] or [V] be that imidazole radicals and iodomethane reaction obtain.
Chemical compound [II-C] or chemical compound [III] can carry out in solvent with the reaction of chemical compound [a].The example of described solvent comprises the solvent of any not disturbance reponse, acetonitrile for example, dichloroethanes, 1,2-dichloroethanes, benzene, toluene, oxolane ， diox, 1,2-dimethoxy-ethane, dimethyl formamide etc.Chemical compound [a] consumption can be that per 1 mole chemical compound [II-C] or chemical compound [III] uses the 1.0-3.0 mole, preferred 1.0-2.0 mole.
Reaction of the present invention can be at 0-150 ℃, carries out under preferred 20-80 ℃.
The reactive derivatives of chemical compound [IV] or [V] can pass through, for example, with chemical compound [IV] or [V] with alkyl halide for example iodomethane in solvent, process and prepare.Reaction of the present invention can at 0-150 ℃, preferably be carried out under 20-80 ℃.
The reaction of the reaction of chemical compound [IV] (or its reactive derivatives) and chemical compound [III] or chemical compound [V] (or its reactive derivatives) and chemical compound [II-C] can be in solvent, carry out in the presence of alkali.The example of described solvent comprises the solvent of any not disturbance reponse, dichloromethane for example, chloroform, dimethyl formamide, dimethyl acetylamide, dimethyl sulfoxide, oxolane ， diox, toluene, benzene, 1,2-dichloroethanes, 1-methyl pyrrolidone, 1,2-dimethoxy-ethane etc.The example of described alkali comprises pyridine, triethylamine, diisopropyl ethyl amine, 4-methyl morpholine, 1,8-diazabicyclo [5,4,0] endecatylene etc.The consumption of described reactive derivatives can be that per 1 mole chemical compound [III] or [II-C] uses the 0.33-3.0 mole, preferred 0.5-1.2 mole.Reaction of the present invention can be at-30-100 ℃, carries out under preferred at 0-50 ℃.
(method D)
The chemical compound of following formula [II-D]:
Figure S2006800391776D00231
Wherein said symbol definition as above can be passed through the chemical compound of following formula [II-D]:
Figure S2006800391776D00232
Wherein said symbol definition is as above reacted in the presence of alkali in appropriate solvent with divinylsulfone and to be made.The example of described solvent comprises the solvent of any not disturbance reponse, ethanol for example, isopropyl alcohol ， diox, toluene, DMF, dimethyl sulfoxide etc.The example of described alkali comprises triethylamine, diisopropyl ethyl amine, N-methylmorpholine, dimethyl aminopyridine etc.The consumption of divinylsulfone can be that per 1 mole chemical compound [II-D] uses the 1.0-3.0 mole, preferred 1.2-1.5 mole.This reaction can at 60-200 ℃, preferably be carried out under 80-150 ℃.
(2) in chemical compound of the present invention, its medium ring A is the substituted pyrazolecarboxylic ring of formula (B) and the chemical compound [I] of the group that E is following formula (ii):
Figure S2006800391776D00241
Can be according to for example,
A) chemical compound [II-A 01]:
Figure S2006800391776D00242
Wherein said symbol definition as above, processing as the described mode of said method A, or
B) chemical compound [II-B 01]:
Figure S2006800391776D00243
Wherein said symbol definition as above, processing as the mode of said method B, or
C) chemical compound [II-C 01]:
Wherein said symbol definition as above, processing as the mode of said method C, or
D) chemical compound [II-D 01]:
Figure DEST_PATH_G40094481150138000D000081
Wherein said symbol definition as above, to process as the mode of said method D.
In addition, R in the group of its Chinese style (iv) 50And R 60The chemical compound [I] that is alkyl can pass through, for example, and R wherein 7Chemical compound [II-C] or the chemical compound [II-C of hydrogen atom 01] (chemical compound [II-Ca] or chemical compound [II-Ca 01]) with the aldehyde compound of formula [a-1]:
R y-CHO [a-1]
R wherein yBe hydrogen atom or alkyl, in the presence of Reducing agent, exist or do not exist under the alkali reaction to make (method E).The example of described Reducing agent comprises sodium triacetoxy borohydride, sodium borohydride, sodium cyanoborohydride etc.The example of described alkali comprises triethylamine, diisopropyl ethyl amine, N-methylmorpholine, dimethyl aminopyridine etc.The consumption of chemical compound [a-1] can be that per 1 mole chemical compound [II-Ca] uses the 1.0-3.0 mole, preferred 1.2-1.5 mole.The consumption of described alkali can be that per 1 mole chemical compound [II-Ca] uses the 1.2-5.0 mole, preferred 1.5-2.0 mole.This reaction can be at-50-100 ℃, preferably carries out under-10-40 ℃.
In addition, R in the group of its Chinese style (iv) 50And R 60The chemical compound [I] that is alkyl is the cyclic group of following formula:
Its medium ring A 1Be randomly by the 5-to 7-of oxo group member aliphatic series nitrogen-containing hetero monocyclic groups, can pass through that for example the below legal system is standby,
A) R wherein 7Chemical compound [II-C] or the chemical compound [II-C of hydrogen atom 01] (chemical compound [II-Ca] or chemical compound [II-Ca 01]) with the chemical compound of following formula:
X 01-Alk 1-X 02
X wherein 01And X 02Halogen atom and Alk 1C 4-6Alkylidene, in solvent such as acetonitrile etc., in the presence of alkali such as potassium carbonate and have or do not exist the lower reaction such as additive such as sodium iodide, or
B) chemical compound [II-Ca] or chemical compound [II-Ca 01] react with divinylsulfone.Chemical compound [II-Ca] or chemical compound [II-Ca 01] with the reaction of divinylsulfone can be to carry out as the described mode of said method D.
(3) in chemical compound of the present invention [I], its medium ring A is that formula (A) or substituted pyrazolecarboxylic ring (B) and E are that the preparation of chemical compound of the group of formula (v) can be passed through, such as chemical compound [II-Aa] or chemical compound [II-Da] and alkylamine such as methyl amine etc. in solvent such as methanol etc., in the presence of condensing agent such as water-soluble carbodiimide etc. and activator such as I-hydroxybenzotriazole etc., react, and products therefrom Lawesson agent treated subsequently, and further make the sulfone azide (sulfoneazide) of product and following formula:
Ar-SO 2-N 3
Wherein Ar is the optional aryl that replaces, and reacts in solvent such as pyridine etc.Simultaneously, the substituent group example among the Ar comprises halogen atom.
Target compound of the present invention [I] can also pass through, for example with the R of described chemical compound [I] 1, R 2Deng in substituent group in molecule, transform into other required substituent groups.Conversion method can be selected according to the substituent kind of target in the molecule, and can be for example according to method (a)-(h) carry out.
Method (a): having cyano group can be by as the respective compound [I] of substituent group (or halogen-containing-or contain alkyl sulphonyl-group) and cyanide chemical compound (for example having halogen atom or alkyl sulphonyl as the chemical compound [I] of the substituent group group of cyano group (or contain); zinc cyanide; copper cyanider; trimethyl silyl cyanogen, potassium cyanide etc.) under the condition that has or do not exist catalyst, alkali and additive, react and prepare.The example of described alkali comprises triethylamine, N-methyl piperidine, diisopropyl ethyl amine etc.The example of this catalyst comprises palladium catalyst, palladium for example, three (dibenzalacetones), two palladiums, anti--dichloro two (tricyclohexyl phosphine)-palladium, four-(triphenylphosphine) palladiums etc. or Raney nickel be dibromo two (triphenylphosphine) nickel etc. for example.The example of additive comprises for example triphenylphosphine of phosphine compound, 1,1 '-two (diphenylphosphine)-ferrocene, raceme 2,2 '-two (diphenylphosphine)-1,1 '-dinaphthalene, 2-(di-t-butyl-phosphine) biphenyl, 2-(dicyclohexylphosphontetrafluoroborate) biphenyl, 2-dicyclohexylphosphontetrafluoroborate-2 '-(N, N-dimethylamino) biphenyl or three-tert-butyl group phosphine etc.
Method (b): have alkyl amino or cycloalkyl amino as substituent group (or contain alkyl amino-or cycloalkyl amino-group) chemical compound [I] can be by having halogen atom respective compound [I] with single-or two-alkylamine or Cycloalkyl amine in appropriate solvent, in the presence of catalyst, additive and alkali, react and make.The example of catalyst can be palladium compound or the copper compound that uses in the method (a).The example of additive can be the phosphine compound that uses in the method (a).The example of described alkali comprises potassium acetate, potassium carbonate, cesium carbonate, potassium tert-butoxide etc.
Method (c): have alkoxyl and can pass through as the acquisition of the chemical compound [I] of the substituent group group of alkoxyl (or contain); for example; (i) having hydroxyl reacts in solvent with alkyl halide as the respective compound [I] of substituent group (or hydroxyl-group); or (ii) have hydroxyl as the respective compound [I] of substituent group (or hydroxyl-group) and alkanol in solvent at alkali (for example; potassium carbonate; cesium carbonate; sodium hydride etc.) or under the existence of activator (for example, diethylazodicarboxylate etc.) and three replace phosphines in the presence of reaction or the respective compound [I] that (iii) has an alkyl sulphonyl (or containing alkyl sulphonyl-group) react in appropriate solvent with alkali alcoholate.
Method (d): have alkyl sulphinyl or alkyl sulphonyl as substituent group (or contain alkyl sulphinyl-or contain alkyl sulphonyl-group) chemical compound [I] can by have alkylthio group as the respective compound [I] of substituent group (or containing alkylthio group-group) and oxidant for example 3-chlorine benzylhydroperoxide in appropriate solvent, react and make.
Method (e): have acylamino-for example alkyl-carbonyl-amino as the chemical compound [I] of substituent group (or containing acylamino--group) can be by having amino (or containing amino-group) the carboxylic acid compound of respective compound [I] and following formula react to make:
R X-COOH [Ac-I]
R wherein XAlkyl or optional aryl or its reactive derivatives (for example, corresponding anhydride or corresponding etheride) that replaces that replaces.This reaction can be in solvent alkali such as triethylamine etc. or condensing agent for example water-soluble carbodiimide in the presence of and exist or do not exist activator for example to carry out under the condition of I-hydroxybenzotriazole.In addition, described acyl group can be according to the kind of acyl group, and for example acid treatment or catalytic hydrogenation remove by conventional method.
Method (f): have carbamoyl and can in appropriate solvent, react with ammonia as the respective compound [I] of substituent group (or containing alkoxy carbonyl-group) and make by having alkoxy carbonyl as the chemical compound [I] of substituent group (or containing carbamoyl-group).
Method (g): have alkyl-carbamoyl amino and can react in appropriate solvent with alkyl isocyanate and make by having amino respective compound [I] as substituent group (or containing amino-group) as the chemical compound [I] of substituent group (or containing alkyl-carbamoyl amino-group).
Method (h): the chemical compound [I] with following formula:
Figure S2006800391776D00281
Its medium ring A 1That the nitrogenous aliphatic heterocyclic group of 5-to 7-member can be by having the chemical compound of amino respective compound [I] with formula:
X 01-Alk-X 02
Wherein said symbol definition as above, solvent for example in the acetonitrile alkali for example potassium carbonate in the presence of and exist or do not exist additive for example to react under the condition of sodium iodide to make.The example of described nitrogenous aliphatic heterocyclic group comprises 1-pyrrolidinyl, piperidino etc.
If necessary, the chemical compound of the present invention [I] of said method acquisition can be converted into its acceptable salt by conventional methods.
I) for example, Q wherein 1The chemical compound [II-A] that is singly-bound or alkylidene can be to prepare in the described mode of following reaction scheme A1-A4.
(reaction scheme A1)
(reaction scheme A2)
Figure S2006800391776D00291
(reaction scheme A3)
Figure S2006800391776D00292
(reaction scheme A4)
Figure DEST_PATH_G40094481150138000D000111
In above-mentioned reaction scheme A1-A4, R AaHydrogen atom or alkyl, R cAlkyl, W 3And W 4Reactive residue, R 01Alkyl, R 11And R 21The optional aryl that replaces, the optional heteroaryl that replaces or the optional nitrogenous aliphatic heterocyclic group that replaces, R 12And R 22The optional aryl that replaces or the optional heteroaryl that replaces, R 13And R 23The optional nitrogenous aliphatic heterocyclic group that replaces, R 14The optional aryl that replaces or the optional heteroaryl that replaces, R 02And R 03Identical or different and be both formation alkylidenes that mutually combine of hydrogen atom or alkyl or they, t-Bu is the tert-butyl group, W 01And W 02Be halogen atom and another symbol definition as above.
R 11, R 12, R 21Or R 22In the aryl example comprise 6-to 10-member single-or bicyclic aryl, for example phenyl or naphthyl.Wherein, preferred phenyl.
R 11, R 12, R 21Or R 22In the example of heteroaryl comprise have 1-3 heteroatomic 5-to 10-member who is selected from oxygen atom, sulphur atom and nitrogen-atoms single-or bicyclic heteroaryl.Wherein, preferred furyl, thienyl or pyridine radicals.
R 11, R 12, R 21Or R 22In the example of nitrogenous aliphatic heterocyclic group comprise further have 1 or 2 heteroatomic 5-to 10-member who is selected from oxygen atom, sulphur atom and nitrogen-atoms single-or dicyclo aliphatic series heterocyclic group.Wherein, preferred furyl, 1-pyrrolidinyl, piperidino, morpholino base or thiomorpholine are for base.
R 11, R 12, R 21Or R 22In each aryl, heteroaryl or nitrogenous aliphatic heterocyclic group can by 1-3 be selected from halogen atom, cyano group, the alkyl that is randomly replaced by 1-3 halogen atom, randomly by the alkoxyl of 1-3 halogen atom replacement and alkyl sulphonyl replacement.
Pass through R 02And R 03Alkylidene in conjunction with formation can be direct-connected or side chain C 2-6Alkylidene, for example ethylidene, propylidene or 1,1,2,2-tetramethyl ethylidene.The substituent group example of alkylidene comprises alkyl, for example methyl.
Each reaction described in the above-mentioned route A1-A4 can for example be carried out according to the mode that exemplifies below.
Steps A 1-1:
Chemical compound [VI] can carry out under heating in appropriate solvent with the reaction of chemical compound [VII].The example of described solvent comprises the solvent of any not disturbance reponse, dimethyl formamide for example, dimethyl acetylamide ， diox, 1,2-dichloroethanes, toluene, dimethylbenzene etc.The consumption of chemical compound [VII] can be that per 1 mole chemical compound [VI] uses the 1.0-10 mole, preferred 1.0-3.0 mole.This reaction can be at 50-200 ℃, carries out under preferred 80-150 ℃.
Steps A 1-2:
The reaction of chemical compound [VIII] and chemical compound [i] can or not exist under the alkali in appropriate solvent, in existence to be carried out.The example of described alkali comprises piperidines, morpholine, N methyl piperazine, diethylamide etc.The example of described solvent comprises the solvent of any not disturbance reponse, acetic acid for example, methanol, ethanol, isopropyl alcohol, ethylene glycol etc.The consumption of chemical compound [i] can be that per 1 mole chemical compound [VIII] uses the 0.5-2.0 mole, preferred 0.8-1.2 mole.The consumption of described alkali can be that per 1 mole chemical compound [VIII] uses the 0.01-2.0 mole, preferred 0.1-1.0 mole.This reaction can be at 50-150 ℃, carries out under preferred 70-100 ℃.
In addition, this reaction can be in solvent, under the condition that has or do not exist acid, carry out.The example of acid comprises hydrobromic acid, hydrochloric acid, acetic acid etc.The example of described solvent comprises the solvent of any not disturbance reponse, acetic acid for example, methanol, ethanol, isopropyl alcohol, ethylene glycol etc.The consumption of chemical compound [i] can be that per 1 mole chemical compound [VIII] uses the 0.5-2.0 mole, preferred 0.8-1.2 mole.The consumption of described acid can be that per 1 mole chemical compound [VIII] uses the 0.1-3.0 mole, preferred 0.3-1.0 mole.This reaction can be at 0-150 ℃, carries out under preferred 60-100 ℃.
Steps A 2-1:
The chemical compound of chemical compound [VI-a] and chemical compound [VII] can be to carry out as the described mode of steps A 1-1.
Steps A 2-2:
Chemical compound [VIII-a] can be to carry out as the described mode of steps A 1-2 with the reaction of chemical compound [i].In addition, when this reaction was carried out in the presence of acetic acid, chemical compound [X-a] can need not to carry out following steps A 2-3 and just can obtain.
Steps A 2-3:
The intramolecular cyclization reaction of chemical compound [IX-a] can be in solvent, carry out in the presence of alkali.The example of described solvent comprises the solvent of any not disturbance reponse, ethanol for example, acetonitrile, chloroform, oxolane ， diox, toluene, DMF etc.The example of described alkali comprises sodium carbonate, cesium carbonate, triethylamine, diisopropyl ethyl amine, dimethyl aminopyridine etc.The consumption of described alkali can use the 0.1-10.0 mole with per 1 mole chemical compound [IX-a], preferred 1.2-3.0 mole.This reaction can be at 30-150 ℃, carries out under preferred 60-100 ℃.
Steps A 2-4:
Chemical compound [X-a] to the conversion of chemical compound [XII-a] can be in solvent, in the presence of the halide reagent and exist or do not exist under the condition of alkali and carry out.The example of described solvent comprises the solvent of any not disturbance reponse, acetonitrile for example, chloroform, oxolane ， diox, toluene, DMF etc.Halide reagent comprises phosphorus oxychloride, thionyl chloride, phosphorus pentachloride, oxalyl chloride etc.The example of alkali comprises DMA, diisopropyl ethyl amine, N-methylmorpholine etc.The consumption of halide reagent can be that per 1 mole chemical compound [X-a] uses the 1.1-5.0 mole, preferred 1.2-1.5 mole.The consumption of described alkali can be that per 1 mole chemical compound [X-a] uses the 1.2-10.0 mole, preferred 1.5-2.0 mole.This reaction can be at 50-200 ℃, carries out under preferred 80-150 ℃.
Steps A 2-5:
(1) reaction of chemical compound [XII-a] and borinic acid ester compounds [XIII-a] can be in solvent, in the presence of catalyst and alkali, carry out.The example of borinic acid ester compounds [XIII-a] comprises wherein R of chemical compound 02And R 03Hydrogen atom or alkyl, methyl for example, ethyl, isopropyl etc., or R 02And R 03Both formation alkylidenes that mutually combine, ethylidene for example, propylidene, 1,1,2,2-tetramethyl ethylidene etc.Wherein, preferred embodiment comprises wherein R of chemical compound [XIII-a] 02And R 03Hydrogen atom or formula: [R 12-BO] 3Respective rings boroxane chemical compound.The example of described solvent comprises the solvent of any not disturbance reponse, diox for example, toluene, dimethoxy-ethane, ethanol, DMF, oxolane, water etc.The example of catalyst comprises for example tetrakis triphenylphosphine palladium (0) of palladium catalyst, palladium (II), two (dibenzylidene-acetone) palladium (0), two (triphenylphosphine) palladium (II) dichloride, two (three-o-tolyl-phosphine) palladium (II) dichloride, two (tricyclohexyl phosphine) palladium (II) dichloride or [1,1 '-two (diphenylphosphine) ferrocene] palladium (II) dichloride, Raney nickel for example 1,3-two (diphenylphosphine) propane nickel (II) dichloride or two (triphenylphosphine) nickel (II) dichloride etc.The example of described alkali comprises potassium phosphate, sodium carbonate, cesium carbonate, sodium carbonate, potassium fluoride, triethylamine, lithium chloride etc.The consumption of chemical compound [XIII-a] can be that per 1 mole chemical compound [XII-a] uses the 1.0-5.0 mole, preferred 1.1-2.0 mole.The consumption of described catalyst can be that per 1 mole chemical compound [XII-a] uses the 0.001-0.5 mole, preferred 0.01-0.05 mole.The consumption of described alkali can be that per 1 mole chemical compound [XII-a] uses the 1.0-10.0 mole, preferred 2.0-5.0 mole.This reaction can be at 20-150 ℃, carries out under preferred 60-120 ℃.
(2) reaction of chemical compound [XII-a] and nitrogen-containing heterocycle compound [XIII-b] can be in solvent, in the presence of alkali, carry out.The example of described solvent comprises the solvent of any not disturbance reponse, DMF for example, toluene ， diox, oxolane etc.The example of described alkali comprises potassium carbonate, sodium carbonate, cesium carbonate, sodium carbonate, potassium fluoride, triethylamine, diisopropyl ethyl amine, dimethyl aminopyridine etc.The consumption of chemical compound [XIII-b] can be that per 1 mole chemical compound [XII-a] uses the 0.8-5.0 mole, preferred 1.0-1.5 mole.The consumption of described alkali can be that per 1 mole chemical compound [XII-a] uses the 1.0-10.0 mole, preferred 2.0-5.0 mole.This reaction can be at 80-200 ℃, carries out under preferred 120-180 ℃.
Steps A 2-6:
The reaction of chemical compound [XII-a] and chemical compound [XIII-c] can be in solvent, carry out in the presence of alkali.The example of described solvent comprises the solvent of any not disturbance reponse, DMF for example, dimethyl sulfoxide, dimethoxy-ethane, oxolane etc.The example of described alkali comprises sodium hydride, hydrofining, Sodium ethylate, potassium tert-butoxide etc. the consumption of chemical compound [XIII-c] can be that per 1 mole chemical compound [XII-a] uses the 0.5-5.0 mole, preferred 1.0-3.0 mole.The consumption of described alkali can be that per 1 mole chemical compound [XII-a] uses the 0.5-10.0 mole, preferred 1.2-6.0 mole.This reaction can be at 40-200 ℃, carries out under preferred 60-120 ℃.
Steps A 2-7:
The reaction of chemical compound [XII-a] and chemical compound [XIII-d] can be carried out in the presence of catalyst and zinc in solvent.The example of described solvent comprises the solvent of any not disturbance reponse, dimethoxy-ethane for example, oxolane, DMF etc.The example of described catalyst comprises for example two (triphenylphosphine) palladium (II) dichloride of palladium catalyst, tetrakis triphenylphosphine palladium (0), palladium (II), two (dibenzylidene-acetone) palladium (0), two (three-o-tolylphosphine) palladium (II) dichloride, two (tricyclohexyl phosphine) palladium (II) dichloride or [1,1 '-two (diphenylphosphine)-ferrocene] palladium (II) dichloride etc.The consumption of chemical compound [XIII-d] can be that per 1 mole chemical compound [XII-a] uses the 0.5-5.0 mole, preferred 1.0-3.0 mole.The consumption of catalyst can be that per 1 mole chemical compound [XII-a] uses the 0.001-1.0 mole, preferred 0.01-0.3 mole.The consumption of zinc can be that per 1 mole chemical compound [XII-a] uses the 1.0-5.0 mole, preferred 1.5-3.0 mole.This reaction can be at 40-200 ℃, carries out under preferred 60-120 ℃.
Steps A 3-1:
Chemical compound [VI-b] can be in solvent or without any carrying out under the condition of solvent with the reaction of chemical compound [VII-b].The example of described solvent comprises the solvent of any not disturbance reponse, dimethyl formamide for example, toluene ， diox, oxolane, dimethoxy-ethane etc.The consumption of chemical compound [VII-b] can be that per 1 mole chemical compound [VI-b] uses the 0.5-5.0 mole, preferred 0.9-1.5 mole.This reaction can be at 0-150 ℃, carries out under preferred 50-80 ℃.
Steps A 3-2:
The halogenation of chemical compound [VIII-b] can be carried out in the presence of halide reagent and under the condition that has or do not exist alkali in solvent.The example of described solvent comprises the solvent of any not disturbance reponse, dichloromethane for example, carbon tetrachloride, chloroform, acetic acid, oxolane etc.The example of halide reagent comprises bromine, N-bromine butanimide, N-chloro-succinimide etc.The example of described alkali comprises triethylamine, diisopropyl ethyl amine, potassium carbonate, sodium carbonate etc. the consumption of described halide reagent can be that per 1 mole chemical compound [VIII-b] uses the 0.5-10.0 mole, preferred 1.0-3.0 mole.This reaction can be at-40 to 100 ℃, carry out under preferred-5 to 20 ℃.
Steps A 3-3:
Chemical compound [IX-b] can be to carry out with the described identical mode of steps A 1-2 with the reaction of chemical compound [i].
Steps A 3-4:
The reaction of chemical compound [X-b] and borinic acid ester compounds [XIII-c] or nitrogen-containing heterocycle compound [XIII-d] can be respectively carried out in the mode identical with steps A 2-5 (1) or (2).
Steps A 4-1:
Chemical compound [II-A11] can carry out in a usual manner to the conversion reaction of corresponding response derivative (chemical compound [IX]).The example of described response derivative comprises corresponding etheride (chemical compound [IX], wherein W 3Halogen atom) or corresponding mixed acid anhydride (chemical compound [IX], wherein W 3Alkoxyl carbonyl oxygen base etc.).The preparation of corresponding etheride can be passed through, and for example, chemical compound [II-A11] and halide reagent are (for example, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride etc.) solvent or solvent-free lower, under the dimethyl formamide condition that has or do not exist catalytic amount, carry out.The example of described solvent comprises the solvent of any not disturbance reponse, dichloromethane for example, chloroform, oxolane, benzene, toluene etc.This reaction can be at-20 to 150 ℃, carry out under preferred 0 to 120 ℃.In addition, the preparation of corresponding mixed acid anhydride can be passed through, and for example, chemical compound [II-A11] and alkyl formate ester (for example, Ethyl formate etc.) are in solvent, react under the existence of alkali (for example, triethylamine, diisopropyl ethyl amine etc.).The example of described solvent comprises the solvent of any not disturbance reponse, dichloromethane for example, chloroform, oxolane, benzene, toluene etc.This reaction can be at-60 to 100 ℃, carry out under preferred-40 to 80 ℃.
Steps A 4-2:
Chemical compound [IX] to the conversion reaction of chemical compound [X] can be in solvent, under the existence of Azimethylene. chemical compound (for example, Azimethylene., trimethyl silyl Azimethylene. etc.), carry out.The example of described solvent comprises the solvent of any not disturbance reponse, Anaesthetie Ether ， diox for example, benzene, toluene etc.The consumption of this Azimethylene. chemical compound can be that per 1 mole chemical compound [IX] uses the 1.0-10 mole, preferred 1.0-3.0 mole.This reaction can be at-50 to 80 ℃, carry out under preferred-10 to 50 ℃.
Steps A 4-3:
Chemical compound [X] to the conversion reaction of chemical compound [II-A12] can be in solvent, under heating, carry out existing or do not exist under the silver salt condition.The example of described solvent comprises the solvent of any not disturbance reponse, water for example, alkanol (for example, methanol, ethanol) etc.The example of described silver salt comprises silver oxide, silver benzoate etc.The consumption of silver salt can be that per 1 mole chemical compound [X] uses the 1.0-20 mole, preferred 1.0-5.0 mole.This reaction can be at 50-200 ℃, carries out under preferred 80-150 ℃.
Steps A 4-4:
The reaction that obtains chemical compound [XI] by reducing compound [II-A11] is to carry out under the existence of Reducing agent (for example, lithium aluminium hydride etc.) in solvent.The example of described solvent comprises the solvent of any not disturbance reponse, Anaesthetie Ether for example, oxolane etc.The consumption of this Reducing agent can be that per 1 mole chemical compound [II-A11] uses the 0.25-20 mole, preferred 2.0-5.0 mole.This reaction can be at-50 to 100 ℃, carry out under preferred-10 to 40 ℃.
Simultaneously, chemical compound [XI] also can be by reducing wherein R aThe chemical compound [II-A1] that is alkyl is made.This reaction can be carried out in the presence of Reducing agent such as sodium borohydride etc. in solvent.The example of described solvent comprises the solvent of any not disturbance reponse, such as mixture of oxolane and methanol etc.The consumption of described Reducing agent can be that per 1 mole chemical compound [II-A1] uses the 1.0-20 mole, preferred 2.0-5.0 mole.Described reaction can be at 30-100 ℃, carries out under preferred 50-80 ℃.
Steps A 4-5:
Chemical compound [XI] can carry out in a usual manner to the conversion reaction of corresponding response derivative (chemical compound [XII]).For example, W wherein 4The preparation that is the chemical compound [XII] of halogen atom or alkylsulfonyloxy can be passed through chemical compound [XI] respectively with for example thionyl chloride or for example mesyl chloride processing of alkyl sulphonyl halogenide of thionylhalides.
Steps A 4-6:
Chemical compound [XII] can carry out in the presence of alkali in solvent with the reaction of chemical compound [d] or its salt.The example of the salt of chemical compound [d] comprises slaine, for example potassium salt.The example of described solvent comprises the solvent of any not disturbance reponse, Anaesthetie Ether for example, oxolane, benzene, dimethyl formamide, dimethyl acetylamide, methanol, ethanol etc. the example of described alkali comprises sodium hydride, hydrofining, Feldalat NM, Sodium ethylate, diisopropyl amination lithium, hexamethyl-disilazane lithium etc.The consumption of chemical compound [d] or its salt can be that per 1 mole chemical compound [XII] uses the 1.0-10.0 mole, preferred 1.5-3.0 mole.The consumption of the consumption of described alkali can be that per 1 mole chemical compound [XII] uses the 1.0-10.0 mole, preferred 1.5-3.0 mole.This reaction can be at-20 to 200 ℃, carry out under preferred 20-100 ℃.
Q wherein 1Be have 3 or the chemical compound [II-A] of the alkylidene of more carbon atoms can pass through, for example, the target compound that above-mentioned steps A4-3 (or steps A 4-6) is obtained is converted into corresponding carboxylic acid compound through the defat reaction and obtains, how to need, and make subsequently this carboxylic acid compound carry out steps A 4-1, the course of reaction of A4-2 and A4-3 (or steps A 4-4, A4-5 and A4-6), where necessary between in repeat.
In addition, Q wherein 1Formula :-N (R 7)-the acquisition of chemical compound [II-A] of group can pass through, for example, make chemical compound [II-Ae] or chemical compound [II-Af] (reference, below reactions steps C1-4 described) through conventional defat reaction.
Reaction .ii) can prepare chemical compound [II-B], for example, take following manner (reaction scheme B1) by using chemical compound [II-Aa] or corresponding amide compound (for example, corresponding dimethylformamide, corresponding N-alkyl-N-alkoxyl amide compound etc.).
(reaction scheme B1)
Figure DEST_PATH_G40094481150138000D000121
In above-mentioned route B 1, R cAlkyl, Y be halogen atom and another symbol definition as above.
Each reaction described in the route B 1 can be carried out according to the mode that for example exemplifies below.
Step B1-1:
The reaction of chemical compound [II-Aa] or corresponding acyl compound and chemical compound [b1] or chemical compound [b2] can be carried out in solvent.The example of described solvent comprises the solvent of any not disturbance reponse, Anaesthetie Ether for example, oxolane diox, dimethoxy-ethane, benzene, toluene etc. the consumption of chemical compound [b1] or chemical compound [b2] can be that per 1 mole chemical compound [II-Aa] or corresponding amide compound uses the 1.0-3.0 mole, preferred 1.0-2.2 mole.This reaction can be at-78 to 50 ℃, carry out under preferred-40 to 30 ℃.
Step B1-2:
The halogenation of chemical compound [XIV] can be carried out in solvent.The example of halide reagent comprises bromine, N-bromine butanimide, two (N,N-dimethylacetamide) dibromo hydrobromate etc.The example of described solvent comprises the solvent of any not disturbance reponse, Anaesthetie Ether for example, dichloroethanes, 1,2-dichloroethanes, chloroform, carbon tetrachloride etc.The consumption of halide reagent can be that per 1 mole chemical compound [XIV] uses the 1.0-3.0 mole, preferred 1.0-2.0 mole.This reaction can be at-10 to 50 ℃, carry out under preferred 0-30 ℃.
Iii) preparation of chemical compound [II-C] can, for example, by using wherein Q 1Be the chemical compound [II-Aa] (chemical compound [IIa]) of singly-bound and carry out in the described mode of following reaction scheme C1.
(reaction scheme C1)
Figure S2006800391776D00381
At above-mentioned reaction scheme, R 71Alkyl, and tBu be the tert-butyl group and another symbol definition as above.
Each reaction described in the route C1 can for example be carried out according to the mode that exemplifies below.
Step C1-1:
The reaction of chemical compound [IIa] and Azide reagent can be in solvent, carry out under the condition that has or do not exist alkali.The example of described solvent comprises the solvent of any not disturbance reponse, acetone for example, benzene, toluene, oxolane, Anaesthetie Ether etc.The example of Azide reagent comprises diphenylphosphine acyl azide compound, Hydrazoic acid,sodium salt etc.The example of described alkali comprises pyridine, triethylamine, diisopropyl ethyl amine, 4-methyl morpholine, 1,8-diazabicyclo-5,4,0] endecatylene (DBU) etc.The consumption of Azide reagent can be that per 1 mole chemical compound [IIa] uses the 1.1-5.0 mole, preferred 1.2-1.5 mole.The consumption of the consumption of described alkali can be that per 1 mole chemical compound [IIa] uses the 1.2-10.0 mole, preferred 1.5-3.0 mole.This reaction can be at-30 to 50 ℃, carry out under preferred-10 to 10 ℃.
Step C1-2:
The preparation feedback reaction for preparing chemical compound [XVI-a] by the Crutius rearrangement reaction can be carried out under heating in solvent.The example of described solvent comprises the solvent of any not disturbance reponse, benzene for example, toluene ， diox, chloroform etc.This reaction can be at 40-200 ℃, carries out under preferred 60-120 ℃.In addition, chemical compound [XVI-b] can react to make by carry out this in the tert-butyl alcohol.
Step C1-3:
Chemical compound [XVI-a] or [XVI-b] can carry out in solvent or under solvent-free with the reaction of acid.The example of described solvent comprises water, ethyl acetate, oxolane ， diox, dichloromethane, chloroform, toluene etc.The example of acid comprises for example sulphuric acid of strong acid, hydrochloric acid, nitric acid, trifluoroacetic acid, hydrobromic acid etc.This sour consumption can be that per 1 mole chemical compound [XVI-a] or [XVI-b] uses the 1.0-50.0 mole, preferred 5.0-10.0 mole.This reaction can be at-20 to 200 ℃, carry out under preferred 20 to 120 ℃.
Step C1-4:
The alkylated reaction of chemical compound [II-Ca] can in solvent, carry out by, for example, 1) at alkali (for example, sodium hydride, potassium carbonate, pyridine, triethylamine, diisopropyl ethyl amine, the 4-methyl morpholine, 1,8-diazabicyclo-[5,4,0] endecatylene etc.) and under the existence of the alkyl halide of formula [XVIII]:
R 72-X 4 [XVIII]
R wherein 72Alkyl and X 4It is halogen atom; Or 2) under the existence of Reducing agent (for example, lithium aluminium hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride etc.), acid (for example, acetic acid, formic acid etc.) and aldehyde compound [XIX]:
R 73-CHO [XIX]
R wherein 73It is alkyl; Or 3) under the existence of the chain triacontanol compound of activator (for example, diethylazodicarboxylate etc.), three-replacement phosphine (for example, triphenylphosphine, tributylphosphine etc.) and formula [XX]:
R 74-OH [XX]
R wherein 74It is alkyl.The example of described solvent comprises dichloromethane, chloroform, dimethyl formamide, dimethyl acetylamide, dimethyl sulfoxide, oxolane ， diox, toluene, benzene, 1,2-dichloroethanes, 1-methyl pyrrolidone, 1,2-dimethoxy-ethane etc.This reaction can be at-20 to 100 ℃, carry out under preferred 0 to 40 ℃.
Simultaneously, if necessary, before its alkylated reaction, suitable protecting group (for example, alkoxy carbonyl is tert-butoxycarbonyl for example, aryl-alkoxy carbonyl such as benzyloxycarbonyl etc.) can be incorporated on the 3-amino in the chemical compound [II-Ca].Described protecting group can be introduced or remove by conventional methods, and this depends on the type of this protecting group.
Chemical compound [II-Cb] can also obtain by carry out above-mentioned Crutius rearrangement reaction in the alkanol of formula [e]:
R e-OH [e]
R wherein eThe chemical compound that the tert-butyl group or benzyl obtain following formula [II-Ae]:
And make chemical compound [II-Ae] and abovementioned alkyl halogenated compound [XVIII] or chain triacontanol compound [XX] reaction obtain chemical compound [II-Af]:
Figure S2006800391776D00402
Wherein said symbol definition as above and is removed the acyl group that the group of formula represents: R subsequently 6OCO-.Removing of this acyl group can be by following (1) product [II-Af] that carries out with acid hydrochloric acid for example, trifluoroacetic acid, the processing such as hydrobromic acid; Or (2) are in about 150 ℃ of lower heating; Or (3) make described product carry out catalytic hydrogenation.Iv) preparation of chemical compound [II-D] can be passed through the hydrazine compound of chemical compound [II-Aa] and following formula [c]:
H 2N-NHZ [c]
Wherein Z is that acyl group or its salt react according to the mode identical with said method A, and removes acyl group (Z) from product in a usual manner subsequently.
Midbody compound [II-A 01], [II-B 01] or [II-C 01] preparation can pass through, for example, on 2 of pyrazolo [1,5-a] pyrimidine part, have required substituent corresponding initial compounds and process with the same way as that reaction scheme A1, B1 or C1 exemplify.In addition, chemical compound [II-D 01] preparation can pass through, for example, the chemical compound of following formula [II-Da]:
Figure S2006800391776D00411
Wherein said symbol definition as above.React in the mode identical with said method A with hydrazine compound [c], and remove acyl group (Z) by conventional method subsequently.
In above-mentioned intermediate, each chemical compound [I], chemical compound [VI], chemical compound [VI-a], chemical compound [VI-b], chemical compound [VII], chemical compound [XIII-a], chemical compound [XHI-b], chemical compound [XIII-c] and chemical compound [XIII-d] are the chemical compounds that known chemical compound or the conventional method of utilizing synthetic chemistry obtain from known compound.
In present specification and claims full text, " halogen atom " refers to fluorine, chlorine, iodine or bromine atoms." alkyl " refers to the alkyl with 1-6 carbon atom, preferred 1-4 carbon atom of direct-connected or side chain." cycloalkyl " refers to have 3-8 carbon atom, the cycloalkyl of preferred 5-7 carbon atom." alkylidene " refers to have 1-6 carbon atom, the straight or branched alkylidene of preferred 1-4 carbon atom.
Embodiment
Chemical compound of the present invention is described in more detail by the following example, but is not limited to this.
Embodiment 1
To 3-carboxyl-6-(2-chlorphenyl)-7-(4-chlorphenyl)-pyrazolo [1,5-a] pyrimidine (200mg, the chemical compound that obtains in the reference example 1) adds thionyl chloride (114 μ L) in the suspension in toluene (1.5mL), and mixture was at room temperature stirred 2 hours.Be dissolved in dichloromethane (1.5mL) with the reactant mixture vacuum concentration and with the gained crude product.Add triethylamine (217 μ L) and 1-amino piperidine (56 μ L) and mixture was at room temperature stirred 10 minutes to this solution.With reactant mixture vacuum concentration and gained crude product by column chromatography on silica gel purification (solvent: chloroform/methanol=100/0-19/5 and hexane/ethyl acetate=67/3-2/3) obtain 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-piperidino carbamoyl)-pyrazolo [1,5-a] pyrimidine (162mg; Yield: 67%), it is powder.
MS(APCI)m/z；466/468[M+H] +
Embodiment 2
Add oxalyl chloride (136 μ L) in the suspension of chemical compound 1 (200mg) in toluene (2mL) that obtains in the reference example, and with this mixture 60 ℃ of lower stirrings 1 hour.Be dissolved in dichloromethane (2mL) with the reactant mixture vacuum concentration and with the gained crude product.Add triethylamine (217 μ L) and 1-methyl isophthalic acid-phenyl hydrazine (61 μ L) in the solution and mixture was at room temperature stirred 2 hours.Add entry and dichloromethane and organic layer to this reactant mixture and wash with saturated brine, with dried over mgso and filtration.With filtrate vacuum concentration and gained crude product by column chromatography purification (solvent: hexane/ethyl acetate=4/1-7/3) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[(N '-methyl-N '-phenyl diazanyl) carbonyl on silica gel] pyrazolo [1,5-a] pyrimidine (204mg; Yield: 80%), it is powder.
MS(APCI)m/z；488/490[M+H] +
Embodiment 3
Add I-hydroxybenzotriazole monohydrate (0.23mL in the chemical compound 1 (57.6mg) that obtains in the reference example and the solution of 1-amino-pyrrolidine HCl (24.5mg) in chloroform (1.0mL contains amylene), the 0.5M chloroformic solution that contains amylene), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (0.23mL, 0.5M DMF solution) and triethylamine (63 μ L) and this mixture at room temperature stir and spend the night.Add saturated aqueous sodium carbonate (2mL) to this reactant mixture, water (2mL) and chloroform (5mL) are also with this mixture vigorous stirring 15 minutes.After separating organic layer, water layer extracts with chloroform (3mL).The organic layer that merges is used saturated aqueous sodium carbonate (3mL) and saturated brine (3mL) washing and vacuum concentration successively.The gained crude product is by liquid chromatography-mass spectrum chromatograph purification (LCMS) (post; XTerra MS C 18, solvent; 10mM ammonium carbonate/methanol=40/60-10/90).The fraction of eluting is concentrated and residue is dissolved in the tert-butyl alcohol and lyophilization obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-pyrrolidine carbamoyl) pyrazolo [1,5-a] pyrimidine (47.2mg; Yield: 70%), it is powder.
MS(APCI)m/z；452[M+H] +
Embodiment 4-27
Corresponding initiation material has gone out to obtain chemical compound as shown in table 1 below in the described identical mode of one of embodiment 1-3.
Table 1 (No.1)
Figure S2006800391776D00431
Table 1 (No.2)
Figure S2006800391776D00441
Table 1 (No.3)
Figure S2006800391776D00451
Table 1 (No.4)
Embodiment 28
To 3-carboxyl-6-(2-chlorphenyl)-7-(4-chlorphenyl)-pyrazolo [1,5-a] pyrimidine (chemical compound that obtains in the reference example 1 (4), 165mg) in chloroform, add the chemical compound that obtains in the reference example 13 (2) in the solution of (1.0mL contains amylene), water-soluble carbodiimide HCl (123mg), I-hydroxybenzotriazole monohydrate (97mg), and triethylamine (178 μ L) and this mixture at room temperature stir and spend the night.Add saturated aqueous sodium carbonate (2mL) and this mixture is stirred and use chloroform extraction to this reactant mixture.With the extract vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=90/10-70/30) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(4-tetrahydro thiapyran base) carbamoyl] pyrazolo [1,5-a] pyrimidine (50mg; Yield: 24 %), it is buff powder.
MS(APCI)m/z；483/485[M+H] +
Embodiment 29
Add methanesulfonic acid (20 μ L) and 3-chlorine benzylhydroperoxide (57mg) in the solution of embodiment 28 products therefroms in dichloromethane (1.0mL) and mixture was at room temperature stirred 1 hour.Add saturated aqueous sodium carbonate and stir this mixture to this reactant mixture.Extraction organic layer and with the extract vacuum concentration.The gained crude product is by column chromatography purification (solvent on silica gel; Chloroform/ethyl acetate=100/0-70/30) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-[-(1,1-dioxo) tetrahydro thiapyran base] carbamoyl] pyrazolo [1,5-a] pyrimidine (37.3mg; Yield: 73%), it is buff powder.
MS(APCI)m/z；515/517[M+H] +
Embodiment 30
Add 36% formalin (118 μ L) in the solution of chemical compound (50mL) in methanol (1mL) that obtains in the reference example 9 (2), sodium triacetoxy borohydride (75mg) and triethylamine (39 μ L) and mixture at room temperature stirred 3 hours.With this reactant mixture with chloroform dilution and to wherein adding aqueous sodium carbonate.This mixture is with chloroform extraction and with the extract vacuum concentration.The gained crude product is by column chromatography purification (solvent on silica gel; Chloroform/ethyl acetate=100/0-70/30), be dissolved in the tert-butyl alcohol and lyophilization and obtain 3-dimethylamino-6-(2-chlorphenyl)-7-(4-chlorphenyl) pyrazolo [1,5-a] pyrimidine (13.5mg; Yield: 26%), it is red powder.
MS(APCI)m/z；383/385[M+H] +
Embodiment 31
(1) with corresponding raw material (200mg) to obtain 6-(2-bromophenyl)-7-(4-chlorphenyl)-3-[[N '-methyl-N '-(2-pyridine radicals) diazanyl with embodiment 3 described identical modes] carbonyl] pyrazolo [1,5-a] pyrimidine (249mg), it is yellow powder.
MS(APCI)m/z；533/535[M+H] +
(2) add zinc cyanide (20mg) and four-(triphenylphosphine) palladium (0) in the solution of product (80mg) in dimethyl formamide (1mL) of above-mentioned steps (1) gained (17mg) and with this mixture blanket of nitrogen and 110 ℃ of lower stirrings 19 hours.Make reactant mixture be cooled to room temperature and to wherein adding entry and ethyl acetate and stirring this mixture.Extraction organic layer and with the extract vacuum concentration.The gained crude product is by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=50/50-25/75), be dissolved in the tert-butyl alcohol and lyophilization and obtain 7-(4-chlorphenyl)-6-(2-cyano-phenyl)-3-[N '-methyl-N '-(2-pyridine radicals) diazanyl] carbonyl-pyrazolo [1,5-a] pyrimidine (42mg; Yield: 58%), it is colorless solid.
MS(APCI)m/z；480/482[M+H] +
Embodiment 32
Add cyclopenta amine (260mg) in the solution of chemical compound (1.0g) in chloroform (20mL) that obtains in the reference example 6, water-soluble carbodiimide HCl salt (620mg) and I-hydroxybenzotriazole (540mg) and this mixture at room temperature stirred spend the night.Add saturated aqueous sodium carbonate and chloroform and stir this mixture to this reactant mixture.Extraction organic layer and with the extract vacuum concentration.The gained crude product is by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=82/18-67/33) obtains also [1,5-a] pyrimidine (940mg of 6-(2-chlorphenyl)-7-(4-chloro-phenyl)-3-(N-cyclopenta carbamoyl)-2-methylthiazol; Yield: 81%), it is yellow solid.
MS(APCI)m/z；497/499[M+H] +
Embodiment 33
Under ice-cold condition, add 3-chlorine benzylhydroperoxide (1.09g) in the solution of chemical compound (940mg) in dichloromethane (40mL) that obtains to embodiment 32 and mixture was at room temperature stirred 3 hours.Add sodium thiosulfate solution and this mixture is stirred and use chloroform extraction to this reactant mixture.With the extract vacuum concentration and with the gained crude product by column chromatography purification (Chromatorex NH silica gel/Fuji Silicia Chem., solvent on NH-silica gel; Hexane/ethyl acetate=50/50-0/100) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-cyclopenta carbamoyl)-2-methyl sulphonyl-pyrazolo [1,5-a] pyrimidine (1.0g; Yield: 100%), it is colorless solid.
MS(APCI)m/z；529/531[M+H] +
Embodiment 34
Add Feldalat NM (102mg) in the solution of chemical compound (100mg) in oxolane/methanol (3mL/3mL) that obtains to embodiment 33 and this mixture is spent the night 50 ℃ of lower stirrings.After being cooled to room temperature, adding entry and ethyl acetate and stir this mixture to this reactant mixture.Organic layer also filters with dried over mgso.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=80/20-60/40) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-cyclopenta carbamoyl)-2-methoxyl group pyrazolo [1,5-a] pyrimidine (57.2mg; Yield: 63%), it is buff powder.
MS(APCI)m/z；481/483[M+H] +
Embodiment 35
Add Cyanogran. (167mg) in the solution of chemical compound (300mg) in dimethyl formamide (7mL) that obtains to embodiment 33 and this mixture is spent the night 50 ℃ of lower stirrings.After being cooled to room temperature, adding ethyl acetate and sodium carbonate liquor and stir this mixture to this reactant mixture.After separating organic layer, the water layer ethyl acetate extraction.The organic layer that merges also filters with dried over mgso.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=90/10-70/30) obtains respectively 6-(2-chlorphenyl)-7-(4-chlorphenyl)-5-cyano group-2-methyl sulphonyl-3-(N-cyclopenta arbamoyl) pyrazolo [1,5-a] pyrimidine (chemical compound (a), 138mg; Yield: 44%) and 6-(2-chlorphenyl)-7-(4-chlorphenyl)-2,5-dicyano-3-(N-cyclopenta carbamoyl)-pyrazolo [1,5-a] pyrimidine (chemical compound (b), 18.3mg; Yield: 6%), it is light yellow solid.
Chemical compound (a): MS (APCI) m/z; 554/556[M+H] +
Chemical compound (b): MS (APCI) m/z; 501/503[M+H] +
Embodiment 36
The chemical compound (a) that obtains to embodiment 35 (50mg) adds Feldalat NM (49mg) and this mixture in the solution in methanol/oxolane (3mL/3mL) and at room temperature stirs and spend the night.Add ethyl acetate with saturated brine and separate organic layer to this reactant mixture.Organic layer also filters with dried over mgso.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=80/20-30/70) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-cyclopenta carbamoyl)-5-methoxyl group-2-methyl sulphonyl pyrazolo [1,5-a] pyrimidine (50.5mg; Yield: 100%), it is colorless solid.
MS(APCI)m/z；559/561[M+H] +
Embodiment 37
Add Feldalat NM (23mg) in the solution of chemical compound (24mg) in methanol/oxolane (2mL/1mL) that obtains in the embodiment 36 and in microwave reactor with mixture 100 ℃ of lower stirrings 2 hours.After being cooled to room temperature, adding chloroform with water and separate organic layer to this reactant mixture, vacuum concentration and with the gained crude product by column chromatography purification (ChromatorexNH-silica gel/Fuji Silicia Chem., solvent on NH-silica gel; Hexane/ethyl acetate=65/35-30/70) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-cyclopenta carbamoyl)-2,5-dimethoxy pyra zolo[1,5-a] pyrimidine (17.8mg; Yield: 81%), it is colorless solid.
MS(APCI)m/z；511/513[M+H] +
Embodiment 38
Add Cyanogran. (42.1mg) in the solution of chemical compound (300mg) in dimethyl formamide (10mL) that obtains in the embodiment 33 and in microwave reactor with mixture 100 ℃ of lower stirrings 1.5 hours.After being cooled to room temperature, adding ethyl acetate and aqueous sodium carbonate and stir this mixture to this reactant mixture.Organic layer washes with water and vacuum concentration.The gained crude product is by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=80/20-65/35) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-cyano group-3-(N-cyclopenta carbamoyl) pyrazolo [1,5-a] pyrimidine (17.8mg; Yield: 81%), it is light yellow solid.
MS(APCI)m/z；476/478[M+H] +
Embodiment 39
Add divinylsulfone (42 μ L) and triethylamine (72 μ L) in the solution of chemical compound (138mg) in ethanol (7mL) that obtains in the reference example 10 (2) and with this mixture heated backflow 6 hours.After being cooled to room temperature, with this reactant mixture vacuum concentration.Add entry and dichloromethane and stir this mixture to this residue, the extraction organic layer.Extract salt water washing is with dried over sodium sulfate and filtration.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Chloroform/methanol=100/0-95/5) and purification (Chromatorex NH-silica gel/Fuji Silicia Chem., solvent on NH-silica gel subsequently; Hexane/ethyl acetate=50/50-20/80), be dissolved in the tert-butyl alcohol and lyophilization and obtain 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-[-(1, the 1-dioxo) thiomorpholine] carbamoyl]-pyrazolo [1,5-a] pyrimidine (57mg; Yield: 31%), it is buff powder.
MS(APCI)m/z；516/518[M+H] +
Embodiment 40
Add acetic acid (7mL) in the solution of chemical compound (1.1g) in oxolane/water (2.8mL/4.2mL) that obtains in the reference example 11 and in microwave reactor with mixture 100 ℃ of lower stirrings 1 hour.After being cooled to room temperature, add the A2N sodium hydrate aqueous solution and with this mixture chloroform extraction to this reactant mixture.Extract also filters with dried over mgso.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=80/20-60/40) obtains 2-amino-6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-cyclopenta carbamoyl) pyrazolo [1,5-a] pyrimidine (529mg; Yield: 75%), it is yellow solid.
MS(APCI)m/z；466/468[M+H] +
Embodiment 42
With the chemical compound (60mg) that obtains among the embodiment 40, the mixture of pyridine (600 μ L) and acetic anhydride (200 μ L) is 100 ℃ of lower stirrings 3 days.After being cooled to room temperature, adding 1NHCl aqueous solution and ethyl acetate and stir this mixture to this reactant mixture.Extract also filters with dried over mgso.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (Chromatorex NH-silica gel/Fuji Silicia Chem., solvent on NH-silica gel; Hexane/ethyl acetate=90/10-50/50) obtains 2-acetyl-amino-6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-cyclopenta carbamoyl) pyrazolo [1,5-a] pyrimidine (38.2mg; Yield: 58%), it is light yellow solid.
MS(APCI)m/z；508/510[M+H] +
Embodiment 43
Add 1 in the solution of chemical compound (60mg) in water/acetonitrile (0.3mL/2.4mL) that obtains in the embodiment 40,4-dichloroetane (81.6mg), potassium carbonate (88.8mg) and sodium iodide (6.8mg) also stir mixture 3 hours under 150 ℃ in microwave reactor.After being cooled to room temperature, adding ethyl acetate and water and stir this mixture to this reactant mixture.Extraction organic layer and with dried over mgso and filter.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=90/10-70/30) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-cyclopenta carbamoyl)-2-(1-pyrrolidinyl)-pyrazolo [1,5-a] pyrimidine (25mg; Yield: 37%), it is yellow solid.
MS(APCI)m/z；520/522[M+H] +
Embodiment 44
Add water-soluble carbodiimide HCl (58mg) in the solution of chemical compound (77mg) in dichloromethane (1mL) that obtains in the reference example 1 (4), I-hydroxybenzotriazole (46mg) and triethylamine (84 μ L) and this mixture at room temperature stirred spend the night.Add aqueous sodium carbonate and dichloromethane and stir this mixture to this reactant mixture.Separate organic layer and vacuum concentration and obtain 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(4-cyano group-tetrahydric thiapyran-4-group) carbamoyl] pyrazolo [1,5-a] pyrimidine (50.8mg; Yield: 50%), it is buff powder.MS(APCI)m/z；508/510[M+H] +
Embodiment 45-202
Corresponding raw material is to process and to obtain showing the chemical compound shown in the 2-4 with embodiment 1, one of 2 and 3 described identical modes.
Table 2 (No.1)
Figure S2006800391776D00521
Table 2 (No.2)
Table 2 (No.3)
Figure S2006800391776D00541
Table 2 (No.4)
Figure S2006800391776D00551
Table 2 (No.5)
Figure S2006800391776D00561
Table 2 (No.6)
Figure S2006800391776D00571
Table 2 (No.7)
Table 2 (No.8)
Figure S2006800391776D00591
Table 2 (No.9)
Table 2 (No.10)
Figure S2006800391776D00611
Table 2 (No.11)
Table 2 (No.12)
Figure S2006800391776D00631
Table 2 (No.13)
Figure S2006800391776D00641
Table 2 (No.14)
Figure S2006800391776D00651
Table 2 (No.15)
Figure S2006800391776D00661
Table 2 (No.16)
Figure S2006800391776D00671
Table 3 (No.1)
Figure S2006800391776D00681
Table 3 (No.2)
Figure S2006800391776D00691
Table 4
Figure S2006800391776D00701
Embodiment 203
Corresponding raw material obtains 6-(2-chloropyridine-3-yl)-7-(4-chlorphenyl)-3-(N-cyclopenta-carbamoyl) pyrazolo [1 to process with embodiment 3 described same way as; 5-a] pyrimidine (39mg; yield: 67%), it is buff powder.
MS(APCI)m/z：452/454[M+H] +
Embodiment 204
The chemical compound that obtains among the embodiment 181 (36mg) with the described same way as of embodiment 33 process obtain 6-(2-chlorphenyl)-7-(4-chlorphenyl)-; 2-methyl sulphonyl-3-[N-(1; 1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl] pyrazolo [1; 5-a]-pyrimidine (33.1mg; yield: 86%), it is colorless solid.
MS(APCI)m/z：579/581[M+H] +
Embodiment 205
The chemical compound that obtains among the embodiment 204 obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-methoxyl group-3-[N-(1 to process with embodiment 34 described same way as; 1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl] pyrazolo [1; 5-a] pyrimidine (72mg; yield: 79%), it is powder.
MS(APCI)m/z：531/533[M+H] +
Embodiment 206
The chemical compound that obtains among the embodiment 144 (80mg) obtains 6-(2-chlorphenyl)-7-(4-three fluoro-methoxyphenyls)-3-[N-(1 to process with embodiment 29 described same way as; 1-dioxo-tetrahydric thiapyran-4-group) carbamoyl] pyrazolo [1; 5-a]-pyrimidine (61.1mg; yield: 72%), it is buff powder.
MS(APCI)m/z：565/567[M+H] +
Embodiment 207
(1) chemical compound (300mg) that obtains among the embodiment 204 is to process greatly 5-cyano group-6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-methyl sulphonyl-3-[N-(1 with embodiment 35 described same way as; 1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl]-pyrazolo [1; 5-a] pyrimidine (60mg; yield: 19%), it is light yellow solid.
MS(APCI)m/z：604/606[M+H] +
(2) chemical compound (60mg) that obtains of above-mentioned steps (1) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-5-methoxyl group-2-methyl sulphonyl-3-[N-(1 to process with embodiment 36 described same way as; 1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl] pyrazolo [1; 5-a] pyrimidine (29mg; yield: 49%), it is buff powder.
MS(APCI)m/z：609/611[M+H] +
Embodiment 208-209
The chemical compound that obtains in the reference example 18 or 19 obtains the chemical compound shown in the following table 5 to process with embodiment 39 described same way as.
Table 5
Figure S2006800391776D00721
Embodiment 210-212
The chemical compound that obtains among the embodiment 152,194 or 156 obtains chemical compound as shown in table 6 below to process with embodiment 29 described same way as.
Table 6
Figure S2006800391776D00722
Embodiment 213-214
Corresponding initiation material is to process with embodiment 28 described identical modes and to obtain the chemical compound shown in the following table 7 with afterproduct to process with embodiment 29 described same way as.
Table 7
Figure DEST_PATH_G40094481150138000D000131
Embodiment 215
The chemical compound that obtains among the embodiment 40 obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-morpholino-3-(N-cyclopenta carbamoyl) pyrazolo [1 with the 2-chloroethyl ether to process with embodiment 43 described identical modes; 5-a] pyrimidine (23mg; yield: 33%), it is powder.MS(APCI)m/z：536/538[M+H] +
Embodiment 216-223
Corresponding initiation material is to process with embodiment 11 described identical modes and to obtain the chemical compound shown in the following table 8 with afterproduct to process with embodiment 40 described same way as.
Table 8
Figure S2006800391776D00741
Embodiment 224-231
Corresponding initiation material obtains the chemical compound shown in the following table 9 to process with embodiment 42 described identical modes.
Table 9
Embodiment 232-237
Corresponding initiation material obtains the chemical compound shown in the following table 10 to process with embodiment 43 described identical modes.
Table 10
Figure S2006800391776D00761
Embodiment 238
To pyrrolidine (15.5 μ L) and pyridine (20 μ L) in the solution in chloroform (2mL) drip under the ice-cold condition chemical compound (60mg) that reference example 54 obtains in chloroform (1mL) solution and mixture at room temperature stirred 2.5 hours.Further adding pyrrolidine (15.5 μ L) to this reactant mixture also stirs this mixture 2.5 hours.Add entry and with this mixture chloroform extraction to this reactant mixture.Organic layer vacuum concentration and gained crude product by column chromatography on silica gel purification (solvent: hexane/ethyl acetate=82/18-67/33) obtains also [1,5-a] pyrimidine (43.8mg of 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-2-methyl-3-(1-pyrrolidinyl) sulfonyl pyrazole; Yield: 68%), it is colorless solid.
MS(APCI)m/z；521/523[M+H] +
Embodiment 239
Add divinylsulfone (20 μ L) in the solution of chemical compound (60mg) in ethanol (0.5mL) that obtains in the reference example 53 and in microwave reactor with this mixture 120 ℃ of lower stirred 1 hour and 130 ℃ of lower stirrings 4 hours.After being cooled to room temperature, add entry to this reactant mixture, this mixture ethyl acetate extraction.Organic layer vacuum concentration and gained crude product by column chromatography on silica gel purification (solvent: hexane/ethyl acetate=70/30-55/45) obtains 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-(1,1-dioxo thiomorpholine generation) pyrazolo [1,5-a] pyrimidine (40mg; Yield: 51%), it is red solid.
MS(APCI)m/z；507/509[M+H] +
Embodiment 240
Add in the solution of chemical compound (128mg) in chloroform (2mL) that obtains in the reference example 55 bromine (21 μ L) in chloroform (1.3mL) solution and mixture at room temperature stirred 2 hours.With the reactant mixture vacuum concentration, add dimethyl formamide (2mL) and methylphenylamine (181 μ L) and mixture was at room temperature stirred 2 hours to residue.Add entry and saturated aqueous sodium carbonate to this reactant mixture, this mixture ethyl acetate extraction.With organic layer vacuum concentration and gained crude product by column chromatography on silica gel purification (solvent: hexane/ethyl acetate=88/12-75/25) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[-(N-methyl-N-phenyl amino) acetyl group]-pyrazolo [1,5-a] pyrimidine (115mg; Yield: 70%), it is yellow solid.
MS(APCI)m/z；487/489[M+H] +
Embodiment 241
Adding m-chloro-benzylhydroperoxide (146mg) and this mixture in the solution of chemical compound (125mg) in dichloroethanes (2mL) that obtains in the embodiment 434 at room temperature stirs and spends the night.Add saturated aqueous sodium carbonate and this mixture ethyl acetate extraction to this reactant mixture.Organic layer washs with saturated brine, with dried over mgso and filtration.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (Chromatorex NH-silica gel, solvent: hexane/ethyl acetate=50/50) on NH-silica gel.The fraction of concentrated eluting and precipitation obtain 6-(2-chlorphenyl)-7-(1,1-dioxo thiomorpholine generation)-2-methyl-3-[[N '-methyl-N '-(2-pyridine radicals) diazanyl with the hexane washing] carbonyl] pyrazolo [1,5-a] pyrimidine (70mg; Yield: 53%), it is solid.
MS(APCI)m/z；526/528[M+H] +
Embodiment 242
(1) corresponding initiation material obtains also [1,5-a] pyrimidine (1.51g of 6-(2-bromophenyl)-7-(4-chloro-2-fluorophenyl)-3-carboxyl-2-methylpyrazole to process with reference example 2 described identical modes; Yield: 20%), it is buff powder.
MS(APCI)m/z；460/462[M+H] +
(2) add 1-methyl isophthalic acid-(2-pyridine radicals) hydrazine (37mg) in the solution of chemical compound (100mg) in dichloromethane (3mL) that obtains to above-mentioned steps (1), water-soluble carbodiimide hydrochlorate (58mg) and I-hydroxybenzotriazole hydrate (46mg) and this mixture at room temperature stir and spend the night.Add saturated aqueous sodium carbonate and this mixture is stirred and use chloroform extraction to this reactant mixture.With the extract vacuum concentration and with the gained crude product by column chromatography purification (ChromatorexNH-silica gel on NH-silica gel, solvent: hexane/ethyl acetate=80/20-55/45) obtains 6-(2-bromophenyl)-7-(4-chloro-2-fluorophenyl)-2-methyl-3-[[N '-methyl-N '-(2-pyridine radicals) diazanyl] carbonyl] pyrazolo [1,5-a] pyrimidine (119.5mg; Yield: 96%), it is light yellow solid.
MS(APCI)m/z；565/567[M+H] +
(3) add zinc cyanide (15.5mg) in the solution of chemical compound (119mg) in dimethyl formamide (2mL) that obtains to above-mentioned steps (2), three (dibenzylidene-acetone), two palladiums (4.2mg) and 1,1 '-two (diphenylphosphine) ferrocene (5.1mg) also stir this mixture 20 minutes under 180 ℃ in microwave reactor.Add saturated aqueous sodium carbonate and this mixture is stirred and use chloroform extraction to this reactant mixture.Extract washes with water and vacuum concentration.The gained crude product is by column chromatography purification (Chromatorex NH-silica gel on NH-silica gel, solvent: hexane/ethyl acetate=70/30-55/45) obtains 6-(2-cyano-phenyl)-7-(4-chloro-2-fluorophenyl)-2-methyl-3-[[N '-methyl-N '-(2-pyridine radicals)-diazanyl] carbonyl] pyrazolo [1,5-a] pyrimidine (22.1mg; Yield: 21%), it is yellow solid.
MS(APCI)m/z；512/514[M+H] +
Embodiment 243
(1) chemical compound (2.08g) that obtains in the reference example 33 is at N, add 2M methyl amine-methanol solution (5mL) in the solution in the dinethylformamide (20mL), water-soluble carbodiimide (1.92g) and I-hydroxybenzotriazole (1.53g) and triethylamine (1.01g) and this mixture at room temperature stir and spend the night.Add entry and this mixture ethyl acetate extraction to this reactant mixture.Organic layer also filters with dried over mgso.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (Chromatorex NH-silica gel on NH-silica gel, solvent: chloroform/methanol=100/0-95/5) obtains 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-(N-methylamino formoxyl) pyrazolo [1,5-a] pyrimidine (1.83g; Yield: 85%), it is yellow powder.
MS(APCI)m/z；431/433[M+H] +
(2) add Lawesson reagent (809mg) in the solution of chemical compound (832mg) in toluene (10mL) that obtains to above-mentioned steps (1) and with this mixture 110 ℃ of lower stirrings 2 hours.After the cooling, add NH-silica gel (2.0g) and filter this mixture to this reactant mixture.Residue is with the ethyl acetate washing and merge organic layer and vacuum concentration.The gained crude product by column chromatography on silica gel purification (solvent: hexane/ethyl acetate=80/20-60/40) obtains 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[N-(methyl) thiocarbamoyl] pyrazolo [1,5-a] pyrimidine (730mg; Yield: 82%), it is yellow powder.
MS(APCI)m/z；447/449[M+H] +
(3) add in the solution of 4-chlorobenzene sulfonyl chloride (5.28g) in oxolane (25mL) Hydrazoic acid,sodium salt (1.79g) in water (12.5mL) solution and this mixture at room temperature stirred spends the night.Add entry and this mixture ethyl acetate extraction to this reactant mixture.Organic layer also filters with dried over mgso.The filtrate vacuum concentration is obtained 4-chlorobenzene sulfuryl azide, and (4.27g, yield: 78%), it is colourless liquid.
(4) with the solution of chemical compound (326mg) in pyridine (5mL) that obtains in the chemical compound (223mg) that obtains in the above-mentioned steps (2) and the above-mentioned steps (3) 110 ℃ of lower stirrings 2 days.After the cooling, add entry and with this mixture chloroform extraction to this reactant mixture.With organic layer vacuum concentration and gained crude product by column chromatography on silica gel purification (solvent: hexane/ethyl acetate=30/70-50/50) obtains compound a (24mg; Yield: 8%) and compound b (0.8mg, yield: 0.4%), shown in following table table 11.
Table 11
Figure S2006800391776D00791
Embodiment 244
The chemical compound that obtains among the embodiment 332 obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N '-methyl-N '-(6-cyanopyridine-3-yl) diazanyl to process with embodiment 31 (2) described same way as] carbonyl] pyrazolo [1,5-a] pyrimidine.
MS(APCI)m/z；514/516[M+H] +
Embodiment 245
Add diisopropyl ethyl amine (52 μ L) and morpholine (26 μ L) in the solution of the chemical compound that obtains in the embodiment 292 (6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[[N '-methyl-N '-(6-fluorine pyridine-2-yl) diazanyl] carbonyl] pyrazolo [1,5-a] pyrimidine) in N-methyl piperidine (1mL) and covering in the container this mixture is spent the night and 120 ℃ of lower stirrings 4 hours 90 ℃ of lower stirrings.After being cooled to room temperature, to this reactant mixture add morpholine (60 μ L) and in covering container with this mixture 120 ℃ lower stir spend the night and in microwave reactor 100 ℃ of lower stirrings 15 minutes.After being cooled to room temperature, this reactant mixture vacuum concentration and gained crude product are by column chromatography purification (solvent: hexane/ethyl acetate=70/30-40/60) and the fraction of concentrated eluting on silica gel.Residue is by gel permeation chromatography (mobile phase: the chloroform) fraction of purification and concentrated eluting.The gained residue is dissolved in the tert-butyl alcohol and the solution lyophilization is obtained 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[[N '-methyl-N '-(6-morpholino pyridine-2-yl) diazanyl] carbonyl] pyrazolo [1,5-a] pyrimidine (12.9mg; Yield: 23%), it is buff powder.
MS(APCI)m/z；574/576[M+H] +
Embodiment 246
(1) corresponding initiation material obtains 6-(2-bromophenyl)-7-(4-chloro-2-fluoro-phenyl)-3-carboxyl pyrazolo [1,5-a] pyrimidine (2.09g to process with embodiment 2 described identical modes; Yield: 22%), it is buff powder.
MS(APCI)m/z；446/448[M+H] +
(2) chemical compound that obtains in the above-mentioned steps (1) obtains 6-(2-bromophenyl)-7-(4-chloro-2-fluorophenyl)-3-[[N '-methyl-N '-(2-pyridine radicals) diazanyl with corresponding initiation material to process with embodiment 3 described identical modes] carbonyl] pyrazolo [1,5-a] pyrimidine (148mg, yield: 89%), it is light yellow solid.
MS(APCI)m/z；551/553[M+H] +
(3) chemical compound (119mg) that obtains in the above-mentioned steps (2) obtains 6-(2-cyano-phenyl)-7-(4-chloro-2-fluorophenyl)-3-[[N '-methyl-N '-(2-pyridine radicals) diazanyl to process with embodiment 242 (3) described same way as] carbonyl] pyrazolo [1,5-a] pyrimidine (compound a: 51.6mg, yield: 40%), it is yellow solid and 6-(2-cyano-phenyl)-7-(4-cyano group-2-fluorophenyl)-3-[[N '-methyl-N '-(2-pyridine radicals) diazanyl] carbonyl] pyrazolo [1,5-a] pyrimidine (compound b: 34.1mg, yield: 27%), it is yellow solid.
Compound a: MS (APCI) m/z; 498/500[M+H] +
Compound b: MS (APCI) m/z; 489[M+H] +
Embodiment 247
(1) corresponding initiation material (3-carboxyl-6-(2-chlorphenyl)-7-(4-chlorphenyl) pyrazolo [1,5-a] pyrimidine; 576mg) obtain 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-[1-(tert-butoxycarbonyl) pyrrolidin-3-yl to process with embodiment 3 described same way as] carbamoyl] pyrazolo [1; 5-a] pyrimidine (656mg; yield: 79%), it is yellow solid.
MS(APCI)m/z；552/554[M+H] +
(2) solution of chemical compound (650mg) in 4N-HCl-diox (5mL) that obtains in the above-mentioned steps (1) is at room temperature stirred spend the night.With saturated aqueous sodium carbonate under ice-cold with this reactant mixture neutralization (pH 7-8).This mixture dichloromethane extraction, organic layer is with dried over mgso and vacuum concentration.The gained crude product is by column chromatography purification (Chromatorex NH-silica gel on NH-silica gel, solvent: chloroform/methanol=100/0-95/5) and vacuum drying obtain 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(pyrrolidin-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (515.8mg; Yield: 97%), it is light yellow solid.
MS(APCI)m/z；452/454[M+H] +
(3) add triethylamine (28 μ L) in the solution of chemical compound (46mg) in dichloroethanes (1mL contains amylene) that obtains in the above-mentioned steps (2) and under blanket of nitrogen to wherein dripping chloroacetic chloride (9 μ L), mixture was at room temperature stirred 2 hours.Add saturated aqueous sodium carbonate and this mixture dichloromethane extraction to this reactant mixture.With extract vacuum concentration and gained crude product by column chromatography purification (solvent: chloroform/methanol=100/0-95/5) and with the fraction vacuum concentration of eluting on silica gel.The gained residue is dissolved in the tert-butyl alcohol and lyophilization obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(1-acetyl-pyrrolidine-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine (50.7mg; Yield: 100%), it is buff powder.
MS(APCI)m/z；494/496[M+H] +
Embodiment 248-250
Corresponding initiation material obtains the chemical compound shown in the following table 12 to process with embodiment 247 described identical modes.
Table 12
Figure S2006800391776D00821
Embodiment 251-278
Corresponding initiation material obtains the chemical compound shown in the following table 13 to process with embodiment 31 or 242 described identical modes.
Table 13 (No.1)
Figure S2006800391776D00831
Table 13 (No.2)
Figure S2006800391776D00841
Table 13 (No.3)
Figure S2006800391776D00851
Table 13 (No.4)
Figure S2006800391776D00861
Embodiment 279-423
Corresponding initiation material obtains the chemical compound shown in the following table 14 to process with embodiment 3 described identical modes.
Table 14 (No.1)
Figure S2006800391776D00871
Table 14 (No.2)
Figure S2006800391776D00881
Table 14 (No.3)
Figure S2006800391776D00891
Table 14 (No.4)
Table 14 (No.5)
Figure S2006800391776D00911
Table 14 (No.6)
Figure S2006800391776D00921
Table 14 (No.7)
Figure S2006800391776D00931
Table 14 (No.8)
Table 14 (No.9)
Table 14 (No.10)
Figure S2006800391776D00961
Table 14 (No.11)
Figure S2006800391776D00971
Table 14 (No.12)
Figure S2006800391776D00981
Table 14 (No.13)
Figure S2006800391776D00991
Table 14 (No.14)
Table 14 (No.15)
Figure S2006800391776D01011
Table 14 (No.16)
Figure S2006800391776D01021
Table 14 (No.17)
Table 14 (No.18)
Figure S2006800391776D01041
Table 14 (No.19)
Figure S2006800391776D01051
Table 14 (No.20)
Figure S2006800391776D01061
Table 14 (No.21)
Figure S2006800391776D01071
Table 14 (No.22)
Figure S2006800391776D01081
Table 14 (No.23)
Figure S2006800391776D01091
Embodiment 424-427
Corresponding initiation material obtains the chemical compound shown in the following table 15 to process with embodiment 3 or 242 described identical modes.
Table 15
Figure S2006800391776D01101
Embodiment 428-430
Corresponding initiation material obtains the chemical compound shown in the following table 16 to process with embodiment 28 described identical modes.
Table 16
Figure S2006800391776D01102
Embodiment 431-439
Corresponding initiation material obtains the chemical compound shown in the following table 17 to process with embodiment 1 described identical mode.
Table 17
Embodiment 440
(1) under ice-cold condition, progressively adds methane sulfonyl chloride (1.0g) in the chemical compound (1.0g) that obtains in the embodiment 484 (2) and the solution of triethylamine (1.81mL) in oxolane (20mL) and mixture was at room temperature stirred 40 minutes.This reactant mixture with ethyl acetate dilution and under ice-cold condition to wherein adding entry.After the stirring, the water layer ethyl acetate extraction.Organic layer also filters with dried over mgso.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (Chromatorex NH-silica gel on NH-silica gel; solvent: hexane/ethyl acetate=80/20-60/40) obtains 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-ethoxy carbonyl-2-[N; N-two (methyl sulphonyl) amino]-pyrazolo [1; 5-a] pyrimidine (1.01g; yield: 75%), it is light yellow solid.
MS(APCI)m/z；617/619[M+H] +
(2) add 4-butyl ammonium fluoride trihydrate (1.03g) in the solution of chemical compound (1.01g) in oxolane (20mL) that obtains in the above-mentioned steps (1) and mixture was at room temperature stirred 15 minutes.Add entry and this mixture is stirred and use chloroform extraction to this reactant mixture.Extract is with dried over mgso and filtration, with the filtrate vacuum concentration.The gained crude product by column chromatography on silica gel purification (solvent: hexane/ethyl acetate=70/30-50/50) obtains 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-ethoxy carbonyl-2-(methyl sulphonyl-amino) pyrazolo [1; 5-a] pyrimidine (0.71g; yield: 81%), it is buff powder.
MS(APCI)m/z；539/541[M+H] +
(3) chemical compound (0.69g) and the solution of Sodium ethylate (0.87g) in ethanol (20mL) that obtains in the above-mentioned steps (2) was stirred 10 minutes under 80 ℃.Spend the night to this reactant mixture dropping iodomethane (1.59mL) and with this mixture stirring.With the reactant mixture vacuum concentration, add entry to residue.This mixture also filters with dried over mgso with ethyl acetate extraction and organic layer.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (Chromatorex NH-silica gel on NH-silica gel; solvent: hexane/ethyl acetate=75/25-60/40) obtains 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-ethoxy carbonyl-2-[N-methyl-N-(methyl sulphonyl) amino] pyrazolo [1; 5-a] pyrimidine (0.70g; yield: 99%), it is powder.
MS(APCI)m/z；553/555[M+H] +
Embodiment 441-452
Corresponding initiation material obtains the chemical compound shown in the following table 18 to process with embodiment 1 (3) and embodiment 3 described identical modes.
Table 18 (No.1)
Figure S2006800391776D01131
Table 18 (No.2)
Embodiment 453-454
Corresponding initiation material obtains the chemical compound shown in the following table 19 to process with embodiment 3 described identical modes.
Table 19
Figure S2006800391776D01151
Embodiment 455-460
Corresponding initiation material obtains the chemical compound shown in the following table 20 to process with embodiment 238 described identical modes.
Table 20
Figure S2006800391776D01152
Embodiment 461
Add two iodo pentanes (34.5 μ L) and sodium carbonate (24.5mg) in the solution of chemical compound (60mg) in oxolane (1mL)-dimethyl acetylamide (0.2mL) that obtains in the reference example 53 and with mixture 70 ℃ of lower stirrings 17 hours.Add entry and this mixture ethyl acetate extraction to this reactant mixture.With extract vacuum concentration and gained crude product by column chromatography on silica gel purification (solvent: hexane/ethyl acetate=85/15-60/40) obtains 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-(piperidin-1-yl) pyrazolo [1,5-a] pyrimidine (17mg, yield: 24%), it is red powder.
MS(APCI)m/z；457/459[M+H] +
Embodiment 462-465
Corresponding initiation material obtains the chemical compound shown in the following table 21 to process with embodiment 240 described identical modes.
Table 21
Embodiment 466
(1) chemical compound that obtains in the reference example 33 obtains 6-(2-chlorphenyl)-7-(4-trifluoromethyl-phenyl)-3-[N-(1-2-hydroxy-4-methylthio-2-butyl) carbamoyl to process with embodiment 1 described same way as] pyrazolo [1; 5-a] pyrimidine (357mg; yield: 56%), it is yellow powder.
MS(APCI)m/z；535/537[M+H] +
(2) add thionyl chloride (170 μ L) in the solution of chemical compound (349mg) in dichloromethane (2mL) that obtains in the above-mentioned steps (1) and mixture was at room temperature stirred 23 hours.Adding chloroform (2mL) to this reactant mixture also stirs this mixture 5 hours under 60 ℃.After being cooled to room temperature; this reactant mixture vacuum concentration and gained crude product are by column chromatography purification (solvent: hexane/ethyl acetate=85/15-60/40) obtains 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[(Tetramethylene sulfide-3-yl) carbamoyl on silica gel] pyrazolo [1; 5-a] pyrimidine (106mg; yield: 32%), it is buff powder.
MS(APCI)m/z；503/505[M+H] +
(3) add in the solution of chemical compound (96mg) in dichloromethane (3mL) that under ice-cold condition, obtains in the above-mentioned steps (2) m-chloro-benzylhydroperoxide (75%, 44mg) and with this mixture under uniform temp, stirred 15 minutes.Add sodium sulfite and aqueous sodium carbonate and with this mixture chloroform extraction to this reactant mixture.With extract vacuum concentration and gained crude product by column chromatography purification (solvent: chloroform/methanol=100/0-92/8) obtains 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[(1-oxo-Tetramethylene sulfide-3-yl) carbamoyl on silica gel] pyrazolo [1; 5-a] pyrimidine (81mg; yield: 82%), it is colourless powder.
MS(APCI)m/z；519/520[M+H] +
Embodiment 467
The chemical compound that obtains in the reference example 47 obtains (R)-6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[(1 to process with embodiment 3 described same way as; 1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl]-2-(2-methoxy ethoxy) pyrazolo [1; 5-a] pyrimidine (77mg; yield: 67%), it is powder.
MS(APCI)m/z；575/577[M+H] +
Embodiment 468
Corresponding initiation material obtains (R)-6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[(1 to process with embodiment 3 described identical modes; 1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl]-2-(2-hydroxyl-oxethyl) pyrazolo [1; 5-a] pyrimidine (91mg; yield: 84%), it is powder.
MS(APCI)m/z；561/563[M+H] +
Embodiment 469
(1) chemical compound that obtains in the reference example 59 obtains (R)-6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[(1 to process with embodiment 3 described same way as; 1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl]-2-methylthiomethyl pyrazolo [1; 5-a] pyrimidine (183.6mg; yield: 91%), it is buff powder.
MS(APCI)m/z；561/563[M+H] +
(2) chemical compound (183mg) that obtains in the above-mentioned steps (1) obtains (R)-6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[(1 to process with embodiment 29 described same way as; 1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl]-2-(sulfonyloxy methyl ylmethyl) pyrazolo [1; 5-a] pyrimidine (91.6mg; yield: 47%), it is powder.
MS(APCI)m/z；593/595[M+H] +
Embodiment 470
The chemical compound that obtains in the reference example 9 (50mg) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[[-(2-pyridine radicals) acetyl group with 3-pyridine radicals acetate salt hydrochlorate (31.8mg) to process with embodiment 3 described identical modes] amino] pyrazolo [1; 5-a] pyrimidine (52.6mg; yield: 79%), it is yellow powder.
MS(APCI)m/z；474/476[M+H] +
Embodiment 471
(1) chemical compound (7.3g) that obtains in the reference example 5 obtains also [1,5-a] pyrimidine (1.43g) of 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-ethoxy carbonyl-2-amino-pyrazol to process with embodiment 484 described same way as.
MS(APCI)m/z；427/429[M+H] +
(2) chemical compound (2.64g) that obtains in the above-mentioned steps (1) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-ethoxy carbonyl-2-(methyl sulphonyl is amino) pyrazolo [1,5-a] pyrimidine (2.20g) to process with the described same way as in embodiment 440 (1)-(2).
MS(APCI)m/z；505/507[M+H] +
(3) chemical compound (70mg) that obtains in the above-mentioned steps (2) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-carboxyl-2-(methyl sulphonyl is amino) pyrazolo [1 to process with reference example 1 (3) described same way as; 5-a] pyrimidine, it is crude product.
MS(APCI)m/z；477/479[M+H] +
(4) chemical compound that obtains in the above-mentioned steps (3) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[[N '-methyl-N '-(2-pyridine radicals) diazanyl to process with embodiment 3 described same way as] carbonyl]-2-(methyl sulphonyl is amino) pyrazolo [1; 5-a] pyrimidine (27mg; yield: 32%), it is powder.
MS(APCI)m/z；596/598[M+H] +
Embodiment 472
Corresponding initiation material obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-isobutylamino formoxyl)-2-(methyl sulphonyl is amino) pyrazolo [1 to process with embodiment 471 described identical modes; 5-a] pyrimidine (52mg; yield: 79%), it is powder.
MS(APCI)m/z；546/548[M+H] +
Embodiment 473
Add Carbimide. phenylester (30.5 μ L) and triethylamine (49 μ L) in the solution of chemical compound (50mg) in oxolane (1.5mL) that obtains in the reference example 9 (2) and this mixture is spent the night 60 ℃ of lower stirrings.Add entry and this mixture ethyl acetate extraction to this reactant mixture.With extract vacuum concentration and gained crude product by column chromatography on silica gel purification (solvent: hexane/ethyl acetate=75/25-65/35) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N '-phenyl urea groups) pyrazolo [1,5-a] pyrimidine (37.8mg, yield: 57%), it is powder.
MS(APCI)m/z；474/476[M+H] +
Embodiment 474
Corresponding initiation material obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N '-cyclopenta urea groups) pyrazolo [1 to process with embodiment 473 described identical modes, 5-a] pyrimidine (48.3mg, yield: 74%), it is powder.
MS(APCI)m/z；466/468[M+H] +
Embodiment 475-478
Corresponding initiation material obtains the chemical compound shown in the following table 22 to process with embodiment 3 described identical modes.
Table 22
Figure S2006800391776D01201
Embodiment 479
Corresponding initiation material obtains 6-(2-cyano-phenyl)-7-(4-trifluoromethyl)-3-[N-(1 to process with embodiment 31 described identical modes; 1-dioxo thiomorpholine generation) carbamoyl] pyrazolo [1; 5-a] pyrimidine, it is powder.
MS(APCI)m/z；541[M+H] +
Embodiment 480
(1) chemical compound (440mg) that obtains among the embodiment 471 (1) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-carboxyl-2-amino-pyrazol also [1 to process with the described same way as of reference example 1 (3), 5-a] pyrimidine, it is crude product.
MS(APCI)m/z；399/401[M+H] +
(2) chemical compound that obtains in the above-mentioned steps (1) obtains (R)-6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(1 to process with embodiment 3 described same way as; 1-dioxo Tetramethylene sulfide-3-yl) carbamoyl]-2-amino-pyrazol also [1; 5-a] pyrimidine (254mg; yield: 48%), it is powder.
MS(APCI)m/z；516/518[M+H] +
(3) chemical compound (250mg) that obtains in the above-mentioned steps (2) obtains (R)-6-(2-chlorphenyl)-7-(4-chloro-phenyl)-3-[N-(1 to process with embodiment 43 described same way as; 1-dioxo Tetramethylene sulfide-3-yl) carbamoyl]-2-(pyrrolidin-1-yl)-pyrazolo [1; 5-a] pyrimidine (106mg; yield: 38%), it is powder.
MS(APCI)m/z；570/572[M+H] +
(4) chemical compound (95mg) that obtains in the above-mentioned steps (3) obtains the chemical compound shown in the following table 23 to process with embodiment 33 described same way as.
Table 23
Figure S2006800391776D01211
Embodiment 481
The chemical compound that obtains in the reference example 46 (3.0g) is processed according to reference example 1 (2) described identical mode with 3-(N5N-dimethylamino)-1-(4-chlorphenyl)-2-(2-chlorphenyl)-2-propylene-1-ketone (6.18g) and is obtained 6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-ethoxy carbonyl pyrazolo [1,5-a] pyrimidine (3.57g, yield: 45%), it is colourless powder.
MS(APCI)m/z；412/414[M+H] +
Embodiment 482
(1) chemical compound (2.5g) that obtains among the embodiment 481 obtains 2-carboxyl-6-(2-chlorphenyl)-7-(4-chlorphenyl) pyrazolo [1 to process with reference example 1 (3) described same way as, 5-a] pyrimidine (1.65g), it is crude product.
MS(APCI)m/z；384/386[M+H] +
(2) chemical compound (80mg) that obtains in the above-mentioned steps (1) and 1-methyl isophthalic acid-(2-pyridine radicals) hydrazine (26mg) is processed with embodiment 3 described same way as and is obtained 6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-[[N '-methyl-N '-(2-pyridine radicals) diazanyl] carbonyl] pyrazolo [1,5-a] pyrimidine (85mg), it is colourless powder.
MS(APCI)m/z；489/491[M+H] +
Embodiment 483
The chemical compound that obtains in the reference example 18 (5-amino-4-ethoxy carbonyl-3-methyl mercapto-1H-pyrazoles, 10.1g) and 3-(N, the N-dimethylamino)-1-(4-trifluoromethyl-phenyl)-2-(2-chlorphenyl)-2-propylene-1-ketone (17.7g) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-ethoxy carbonyl-2-methyl mercapto pyrazolo [1 to process with the described same way as of reference example 5 (1), 5-a] pyrimidine (11.4g, yield: 45%), it is colourless powder.
MS(APCI)m/z；492/494[M+H] +
Embodiment 484
(1) chemical compound (11g) that obtains among the embodiment 483 obtains 2-azido-6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-ethoxy carbonyl pyrazolo [1 to process with reference example 5 (2) described same way as, 5-a] pyrimidine (10.6g, yield: 91%), it is crude product (colourless powder).This product (10.6g) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-ethoxy carbonyl-2-(the inferior phosphoranyl of triphenyl is amino) pyrazolo [1 to process with reference example 11 described same way as, 5-a]-pyrimidine (11.4g), it is colourless powder.
(2) chemical compound (11.1g) that obtains in the above-mentioned steps (1) and acetic acid (70mL) obtain 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-ethoxy carbonyl-2-amino-pyrazol also [1 according to processing with embodiment 40 described identical modes, 5-a] pyrimidine (5.2g, yield: 73%), it is colorless solid.
MS(APCI)m/z；461/463[M+H] +
Embodiment 485
The chemical compound that obtains among the embodiment 484 (2.1g) and 1,4-dichloroetane (2.9g) obtains 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-ethoxy carbonyl-2-(pyrrolidin-1-yl) pyrazolo [1 to process with embodiment 43 described identical modes, 5-a]-pyrimidine (0.61g, yield: 26%), it is yellow oil.
MS(APCI)m/z；515/517[M+H] +
Embodiment 486
The chemical compound that obtains among the embodiment 485 (0.61g) obtains 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-carboxyl-2-(pyrrolidin-1-yl) pyrazolo [1 to process with reference example 8 described same way as, 5-a] pyrimidine (0.45g), it is crude product.This product (70mg) and 1-amino pyrrolidine hydrochloride (17.6mg) are processed in the mode identical with embodiment 3 and are obtained respectively 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[N-(pyrrolidin-1-yl) carbamoyl]-2-(pyrrolidin-1-yl) pyrazolo [1,5-a] pyrimidine (14.8mg; Compound a) and 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-2-(pyrrolidin-1-yl) pyrazolo [1,5-a]-pyrimidine (32.6mg; Compound b), it is yellow powder.
Compound a: MS (APCI) m/z; 555/557[M+H] +
Compound b: MS (APCI) m/z; 443/445[M+H] +
Embodiment 487
(1) drip in the solution of chemical compound (300mg) in dimethyl formamide (5mL) that under blanket of nitrogen, obtains in the reference example 4B sodium hydride (60%, 137mg) and stir this mixture.Progressively add 4-chloro-methylphenylamine (125 μ L) and this mixture is descended stirring 30 minutes at 80 ℃ to this mixture.After being cooled to room temperature, adding entry and ethyl acetate and water layer to this reactant mixture and neutralize with 2N HCl.Organic layer washes with water, with dried over mgso and filtration.With filtrate vacuum concentration and gained crude product by column chromatography on silica gel purification (solvent: chloroform/methanol=98/2-85/15) obtains 6-(2-chlorphenyl)-7-[N-methyl-N-(4-chlorphenyl) amino]-3-carboxyl-2-methyl-pyrazolo [1,5-a] pyrimidine (54.2mg, yield: 15%), it is colourless powder.
MS(APCI)m/z；427/429[M+H] +
(2) state the chemical compound (1) that obtains in the step and (27mg) obtain 6-(2-chlorphenyl)-7-[N-methyl-N-(4-chlorphenyl) amino to process 3 with the described same way as of embodiment]-3-[N '-methyl-N '-(pyrimidine-2-base) diazanyl]-2-methylpyrazole o-[1,5-a] pyrimidine (18.5mg, yield: 55%), it is colourless powder.
MS(APCI)m/z；532/533[M+H] +
Embodiment 488-489
Corresponding initiation material obtains the chemical compound shown in the following table 24 to process with embodiment 487 described identical modes.
Table 24
Figure S2006800391776D01241
Embodiment 490-500
Corresponding initiation material obtains the chemical compound shown in the following table 25 to process with embodiment 487 described identical modes.
Table 25 (No.1)
Figure S2006800391776D01251
Table 25 (No.2)
Figure S2006800391776D01261
Reference example 1
(1) adds the iodine of magnesium (6.04g) and catalytic amount and stir this mixture to Anaesthetie Ether (250mL), to wherein dripping gradually 2-chlorobenzyl chloride (20.0g).When the temperature of this mixture begins to rise, begin to calculate and stir after 1 hour, to wherein adding the solution of 4-chlorobenzonitrile (18.8g) in oxolane/Anaesthetie Ether (20mL/50mL) and this mixture being stirred 3 hours.Add 2N HCl (150mL) and mixture was at room temperature stirred 2 hours to this reactant mixture down ice-cold.This reactant mixture ethyl acetate extraction, organic layer is with 1N HCl, water and saturated brine washing, with dried over mgso and filtration.With filtrate vacuum concentration and gained crude product by column chromatography on silica gel purification (solvent: hexane/ethyl acetate=40/1-20/1) obtains 2-(chlorobenzyl) (4-chlorphenyl) ketone (24.40g; Yield: 74%), it is powder.
MS(APCI)m/z；265/267[M+H] +
(2) chemical compound (6.4g) that obtains in the above-mentioned steps (1) and the solution of DMF dimethyl-acetal (6.4mL) in DMF (24mL) are 150 ℃ of lower stirrings 4 hours.After reactant mixture is cooled to room temperature, to wherein adding entry and this mixture mixture extraction with ethyl acetate and hexane (x3).Organic layer washs with saturated brine, with dried over mgso and filtration.The filtrate vacuum concentration is obtained 3-(N, N-dimethylamino)-1-(4-chlorphenyl)-2-(2-chlorphenyl)-2-propylene-1-ketone, and it is oil.In the solution of chemical compound in acetic acid (8mL), add 3-amino-4-ethoxy carbonyl-1H-pyrazoles (3.75g) and piperidines (0.48mL), this mixture was heated 16 hours under 80 ℃.After this reactant mixture is cooled to room temperature, wash with saturated brine to wherein adding entry and ethyl acetate and organic layer, with dried over mgso and filtration.With filtrate vacuum concentration and gained crude product by column chromatography on silica gel purification (solvent: hexane/ethyl acetate=17/3-67/33) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-ethoxy carbonyl pyrazolo [1,5-a] pyrimidine (5.02g, yield: 50%), it is powder.
MS(APCI)m/z；412/414[M+H] +
(3) add 2N sodium hydroxide (6mL) in the solution of chemical compound (2.5g) in ethanol (30mL) that obtains in the above-mentioned steps (2) and mixture was at room temperature stirred 5 hours.Add 2N HCl (6mL) and stir this mixture and vacuum concentration to this reactant mixture.Residue washs with saturated brine with ethyl acetate extraction and organic layer, with dried over mgso and filtration.The filtrate vacuum concentration is obtained 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-carboxyl pyrazolo [1,5-a] pyrimidine, and (2.1g, yield: 90%), it is powder.
MS(APCI)m/z；384/386 M+H] +
Reference example 2
(1) adds 4-chlorobenzyl bromine (4.1g) to dimethoxy-ethane (100mL); 4-chlorobenzene formacyl chlorine (2.56mL), dichloride two (triphenylphosphine) palladium (702mg) and zinc powder (2.6g) also stir this mixture 2 hours under blanket of nitrogen.This reactant mixture is filtered, with the filtrate vacuum concentration and use ethyl acetate extraction.Organic layer washs with saturated brine, with dried over mgso and filtration.With filtrate vacuum concentration and gained crude product by column chromatography on silica gel purification (solvent: hexane/ethyl acetate=49/1-9/1) obtain (4-chlorobenzyl) (4-chlorphenyl) ketone (4.85g, yield: 91＞%), it is powder.MS(GC-EI)m/z；264[M] +
(2) chemical compound that obtains in the above-mentioned steps (1) obtains 3-carboxyl-6-(4-chlorphenyl)-7-(4-chlorphenyl) pyrazolo [1 to process with reference example 1 (2) and (3) described same way as, 5-a] pyrimidine (165mg, yield: 20%), it is powder.
MS(APCI)m/z；384/386M+H] +
Reference example 3
Corresponding initiation material obtains 3-carboxyl-6-phenyl-7-(4-chlorphenyl)-pyrazolo [1,5-a] pyrimidine (2.06g, yield: 22%), it is powder to process with embodiment 1 described identical mode.
MS(APCI)m/z；350/352M+H] +
Reference example 4
(1) in the solution of 2-chlorophenylacetic acid methyl ester (10g) in dimethyl formamide (150mL), adds DMF dimethyl-acetal (14.4mL) and descend stirring to spend the night at 85 ℃ in this mixture.After being cooled to room temperature, adding ethyl acetate and water and stir this mixture to this reactant mixture.The extraction organic layer is with dried over sodium sulfate and filtration.With the filtrate vacuum concentration, residue dilutes with acetic acid (18mL).To wherein adding 3-amino-4-ethoxy carbonyl-1H-pyrazoles (8.4g) and piperidines (1.1mL), this mixture is 80 ℃ of lower stirrings 3.5 hours.After being cooled to room temperature, adding ethyl acetate and water and stir this mixture and filtration to this reactant mixture.It is amino that dry gained solid material obtains 5-[-(2-chlorphenyl)-2-methoxycarbonyl vinyl]-(11.8g, yield: 62%), it is powder to 4-methoxycarbonyl-1H-pyrazoles.
MS(APCI)m/z；350/352[M+H] +
(2) add sodium carbonate 3.24g in the solution of chemical compound (10.7g) in ethanol (250mL) that obtains in the above-mentioned steps (1) and this mixture heated was refluxed 4 days.After being cooled to room temperature, this reactant mixture filters, with the filtrate vacuum concentration.Add entry and stir this mixture and filtration (this filtration step repeat 5 this) to this residue.Dry gained solid material obtains 6-(2-chlorphenyl)-3-ethoxy carbonyl-7-oxo-4, and (8.5g, yield: 87%), it is powder to 7-dihydro-pyrazolo [1,5-a] pyrimidine.
MS(APCI)m/z；318/320M+H] +
(3) add DMA (319 μ L) and phosphorus oxychloride (270 μ L) in the solution of chemical compound (300mg) in acetonitrile (2mL) that obtains in the above-mentioned steps (2) and with this mixture heated backflow 1 day.After being cooled to room temperature, this reactant mixture impouring is contained the water of ice and uses dichloromethane extraction.Extract is with dried over mgso and filtration, with the filtrate vacuum concentration.The gained crude product is by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=(108mg, yield: 34%), it is powder 80/20-60/40) to obtain 7-chloro-6-(2-chlorphenyl)-3-ethoxy carbonyl pyrazolo [1,5-a]-pyrimidine.
MS(APCI)m/z；336/338M+H] +
(4) with the chemical compound (100mg) that obtains in the above-mentioned steps (3), [1,1,-two (diphenylphosphino) ferrocene] palladium (II) dichloride-dichloromethane complex (7.3mg), potassium phosphate (189mg) and the solution of 4-fluorophenyl boric acid (846mg) in Isosorbide-5-Nitrae-dioxs (3mL) are 80 ℃ of lower stirrings 5 hours of blanket of nitrogen.After being cooled to room temperature, adding dichloromethane and saline and stir this mixture to this reactant mixture.Extraction organic layer and extract also filter with dried over mgso.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=(106mg, yield: 90%), it is powder 80/20-65/35) to obtain 6-(2-chlorphenyl)-3-ethoxy carbonyl-7-(4-fluorophenyl) pyrazolo [1,5-a] pyrimidine.
MS(APCI)m/z；396/398M+H] +
Reference example 4B
The solution of 2-chlorophenylacetic acid methyl ester (25g) in dimethyl formamide (400mL) is added DMF dimethyl-acetal (36mL) and stir these mixture overnight under 90 ℃.After being cooled to room temperature, adding ethyl acetate and water and stir this mixture and extraction to this reactant mixture.Organic layer also filters with dried over mgso.With the filtrate vacuum concentration, residue dilutes with acetic acid (60mL).To wherein adding 3-amino-4-ethoxy carbonyl-2-methyl isophthalic acid H-pyrazoles (19.7g) and under 120 ℃, stirring these mixture overnight.After being cooled to room temperature, obtain 6-(2-chlorphenyl)-3-ethoxy carbonyl-2-methyl-7-oxo-4 by filtering collecting precipitation and washing, (26.0g, the yields in two steps: 62%), it is powder to 7-dihydro-pyrazolo [1,5-a] pyrimidine.
MS(APCI)m/z；332/334[M+H] +
Reference example 5
(1) with 5-amino-4-ethoxy carbonyl-3-methyl mercapto-1H-pyrazoles (chemical compound that obtains in the reference example 18,6.8g), 3-(N, N-dimethylamino)-1-(4-chlorphenyl)-2-(2-chlorphenyl)-2-propylene-1-ketone (10.9g) and the solution of piperidines (578mg) in acetic acid (13mL) spend the night 80 ℃ of lower stirrings.After being cooled to room temperature, add entry and ethyl acetate to this reactant mixture.Organic layer salt water washing is with dried over mgso and filtration.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=(5.88g, yield: 38%), it is yellow solid 85/15-70/30) to obtain 6-(2-chlorphenyl)-7-(4-fluorophenyl)-3-ethoxy carbonyl-2-methyl mercapto pyrazolo [1,5-a] pyrimidine.
(2) add in the solution of chemical compound (5.86g) in dichloromethane (200mL) that obtains in the above-mentioned steps (1) under the ice-cold condition 3-chlorine benzylhydroperoxide (70%, 9.46g) and under uniform temp, stirred this mixture 10 minutes and at room temperature stirred 3 hours.Add sodium thiosulfate solution to this reactant mixture.This mixture at room temperature stirs and to wherein adding ethyl acetate and water.Organic layer also filters with dried over mgso.With the filtrate vacuum concentration and with the gained crystal with ice-cold washing with alcohol and drying; obtain 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-ethoxy carbonyl-2-methyl sulphonyl pyrazolo [1; 5-a] (5.52g, yield: 88%), it is light yellow solid to pyrimidine.
(3) add Sodium ethylate (1.66g) in the solution of chemical compound (1.0g) in ethanol/oxolane (26mL/30mL) that obtains in the above-mentioned steps (2) and this mixture heated is refluxed.After being cooled to room temperature, add entry and sodium acetate to this reactant mixture.Organic layer salt water washing is with dried over mgso and filtration.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=(86mg, yield: 9.2%), it is light yellow solid 80/20-40/60) to obtain 6-(2-chlorphenyl)-7-(4-fluorophenyl)-2-ethyoxyl-3-ethoxy carbonyl pyrazolo [1,5-a] pyrimidine.
MS(APCI)m/z；456/458M+H] +
(4) chemical compound (455mg) that obtains in the above-mentioned steps (3) obtains 3-carboxyl-6-(2-chlorphenyl)-7-(4-fluorophenyl)-2-ethyoxyl pyrazolo [1 to process with reference example 1 (3) described same way as, 5-a] pyrimidine (490mg), it is light yellow solid.
MS(APCI)m/z；428/430M+H] +
Reference example 6
(1) with 1-(4-chlorphenyl) ethane ketone (13.1g) and C-tert-butoxy-N, N, N ', the mixture of N '-tetramethyl methylene diamine (16.3g) spends the night 60 ℃ of lower stirrings.After being cooled to room temperature, this reactant mixture vacuum concentration obtains 1-(4-chlorphenyl)-3-(N, N-dimethylamino)-2-propylene-1-ketone, and (18.4g, yield: 100%), it is yellow solid.
MS(APCI)m/z；210/212M+H] +
(2) solution of the chemical compound (18.4g) that obtains in the above-mentioned steps (1) under ice-cold condition in dichloromethane (105mL) drips bromine (13.6g) and stirred this mixture 30 minutes under uniform temp in inherent about 10 minute.In 5 minutes, drip the solution of triethylamine (11.8mL) in Anaesthetie Ether (130mL) to this reactant mixture, this mixture was stirred 2 hours.After rising to room temperature, this reactant mixture is filtered, add dichloromethane (20mL) and Di Iso Propyl Ether (50mL) to residue.Stir after 1 hour, (20.2g, yield: 82%), it is light yellow solid to obtain 2-bromo-1-(4-chlorphenyl)-3-(N, N-dimethylamino)-2-propylene-1-ketone by filtration collection gained crystal and vacuum drying.
MS(APCI)m/z；288/290M+H] +
(3) add 25% hydrogen bromine/acetic acid solution (13mL) in the chemical compound (20.2g) that obtains in the above-mentioned steps (2) and the 3-amino-solution of 4-ethoxy carbonyl pyrazoles (10.9g) in ethanol (65mL) and this mixture heated was refluxed 1 hour.After being cooled to room temperature, this reactant mixture vacuum concentration and residue is dissolved in chloroform (200mL).This solution is with saturated aqueous sodium carbonate and salt water washing, with dried over mgso and filtration.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Ethyl acetate/chloroform=0/100-10/90) also obtains 6-bromo-7-(4-fluorophenyl)-3-ethoxy carbonyl pyrazolo [1,5-a]-pyrimidine by the Di Iso Propyl Ether crystallization (13.8g, yield: 52%), it is colorless solid.
MS(APCI)m/z；380/382M+H] +
(4) chemical compound (1.0g) that under blanket of nitrogen, obtains in the above-mentioned steps (3), 2-(trifluoromethyl) phenylboric acid (549mg), [1,1 '-two (diphenylphosphino) ferrocene] palladium (II) dichloride-dichloromethane complex (77mg) and the solution of potassium phosphate (1.55g) in Isosorbide-5-Nitrae-dioxs (51mL) spends the night and 90 ℃ of lower stirrings 8 hours 80 ℃ of lower stirrings.After being cooled to room temperature, this reactant mixture dilutes with ethyl acetate and filters.With the filtrate vacuum concentration, residue dilutes with oxolane (34mL).To wherein adding 1N lithium hydroxide aqueous solution (16mL) and this mixture being spent the night 55 ℃ of lower stirrings.After being cooled to room temperature, add chloroform to this reactant mixture, water is with 1N HCl aqueous solution and separate organic layer.Organic layer salt water washing is with dried over sodium sulfate and filtration.With the filtrate vacuum concentration and the products therefrom recrystallization is obtained 3-carboxyl-7-(4-chlorphenyl)-6-(2-trifluoromethyl) pyrazolo [1,5-a] pyrimidine (370mg, yield: 34%), it is light yellow solid.
MS(APCI)m/z；418/420M+H] +
Reference example 7
Add pyrrolidine (50 μ L) and potassium carbonate (138mg) in the solution of chemical compound (168mg) in dimethyl formamide (5mL) that obtains in the reference example 4 (3) and in microwave reactor in 160 ℃ of lower these mixture of stirring 5 minutes.After being cooled to room temperature, adding entry and stir this mixture and use dichloromethane extraction to this reactant mixture.With the extract vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=(116mg, yield: 63%), it is powder 80/20-65/35) to obtain 6-(2-chlorphenyl)-3-ethoxy carbonyl-7-(1-pyrrolidinyl) pyrazolo [1,5-a] pyrimidine.
[0838] MS(APCI)m/z；371/373M+H] +
Reference example 7B
(1) corresponding initiation material obtains also [1,5-a] pyrimidine of 6-(2-chlorphenyl)-7-chloro-3-ethoxy carbonyl-2-methylpyrazole to process with embodiment 4B and 4 (3) described identical modes.
(2) add thiomorpholine (103 μ L) and potassium carbonate (237mg) in the solution of chemical compound (300mg) in dimethyl formamide (3mL) that obtains in the above-mentioned steps (1) and in 80 ℃ of lower these mixture of stirring 40 minutes.After being cooled to room temperature, adding entry and stir this mixture and use ethyl acetate extraction to this reactant mixture.Extract also filters with dried over mgso.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=5/2) (324mg, yield: 91%), it is powder to obtain 6-(2-chlorphenyl)-7-thiomorpholine generation-3-ethoxy carbonyl-2-methyl-pyrazolo [1,5-a] pyrimidine.
MS(APCI)m/z；417/419M+H] +
Reference example 8
Add 2N sodium hydrate aqueous solution (50.2mL) in the solution of chemical compound (11.5g) in ethanol/oxolane (58mL/58mL) that obtains in the reference example 5 (1) and with this mixture 60 ℃ of lower stirrings 8 hours.After being cooled to room temperature, this reactant mixture vacuum concentration.Add chloroform to this residue, saline and 2N HCl aqueous solution also stir this mixture (pH 2-3).Organic layer also filters with dried over mgso.The crystallization of filtrate vacuum concentration and precipitation is obtained 3-carboxyl-6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-methyl mercapto pyrazolo [1,5-a] pyrimidine with the Anaesthetie Ether washing, and (11.1g, yield: 100%), it is light yellow solid.
MS(APCI)m/z；430/432M+H] +
Reference example 9
(1) chemical compound (2.0g) that obtains in the reference example 1 (4) adds diphenyl phosphoryl azide (1.15mL) and triethylamine (725 μ L) and this mixture and descends stirring to spend the night at 80 ℃ in the solution of tert-butyl group alcohol (15mL).After being cooled to room temperature, adding entry and ethyl acetate and stir this mixture to this reactant mixture.Organic layer salt water washing is with dried over mgso and filtration.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=(1.0g, yield: 42%), it is powder 80/20-55/45) to obtain 3-tert-butoxycarbonyl amino-6-(2-chlorphenyl)-7-(4-chlorphenyl) pyrazolo [1,5-a] pyrimidine.
MS(APCI)m/z；455/457M+H] +
(2) add 4N HCl-1 in the solution of chemical compound (1.0g) in Isosorbide-5-Nitrae-diox (8mL) that obtains in the above-mentioned steps (1), 4-diox (16mL) and mixture at room temperature stirred 1.5 hours.At room temperature stirred 3.5 hours to this reactant mixture adding methanol (2mL) and with mixture.Reactant mixture vacuum concentration and residue are obtained 3-amino-6-(2-chlorphenyl)-7-(4-chlorphenyl) pyrazoles o-[1,5-a by the Di Iso Propyl Ether crystallization] (809mg, yield: 94%), it is the light orange powder to the pyrimidine hydrochlorate.
MS(APCI)m/z；355/357M+H] +
Reference example 10
(1) chemical compound (300mg) that obtains in the reference example 1 (4) adds N-tert-butoxycarbonyl hydrazine (135mL) at dichloromethane (4.0mg), water-soluble carbodiimide HCl (224mg), I-hydroxybenzotriazole (179mg) and triethylamine (326mg) and this mixture at room temperature stir and spend the night.Add aqueous sodium carbonate and dichloromethane and stir this mixture to this reactant mixture.Organic layer salt water washing is with dried over mgso and filtration.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (Chromatorex NH-silica gel/Fuji Silicia Chem., solvent on NH-silica gel; Hexane/ethyl acetate=70/30-40/60) obtains 3-(N '-tert-butoxycarbonyl diazanyl), and (379mg, yield: 97%), it is powder to carbonyl-6-(2-chlorphenyl)-7-(4-chlorphenyl) pyrazolo [1,5-a] pyrimidine.
MS(APCI)m/z；498/500M+H] +
(2) add 4N HCl-1 in the solution of chemical compound (345mg) in Isosorbide-5-Nitrae-diox (5mL) that obtains in the above-mentioned steps (1), 4-diox (500 μ L) also spends the night this mixture 40 ℃ of lower stirrings.Stirred 8 hours under 40 ℃ to this reactant mixture adding 2N HCl and this mixture.Add aqueous sodium carbonate and dichloromethane and stir this mixture to this reactant mixture.Extraction organic layer and dry extract also filter.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=(142mg, yield: 52%), it is yellow jelly 80/20-0/100) to obtain 3-diazanyl carbonyl-6-(2-chlorphenyl)-7-(4-chlorphenyl) pyrazolo [1,5-a] pyrimidine.
MS(APCI)m/z；398/400M+H] +
Reference example 11
(1) adds Hydrazoic acid,sodium salt (1.11g) in the solution of chemical compound (1.5g) in dimethyl formamide (20mL) that obtains in the embodiment 33 and this mixture is spent the night 110 ℃ of lower stirrings.After being cooled to room temperature, adding saturated brine and stir this mixture and use ethyl acetate extraction to this reactant mixture.Organic layer wash with water with vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=80/20-30/70) obtains 2-azido-6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-cyclopenta carbamoyl) pyrazolo [1,5-a] pyrimidine (1.15g, yellow viscosity).Add triphenylphosphine (896mg) and this mixture in the solution of product (870mg) in oxolane (16mL) 40 ℃ of lower stirrings 1 hour.After being cooled to room temperature, this reactant mixture vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Chloroform/methanol=(942mg, yield: 58%), it is yellow solid 100/0-97/3) to obtain inferior phosphoranyl amino-pyrazolo [1, the 5-a] pyrimidine of 6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-triphenyl
MS(APCI)m/z；726/728M+H] +
Reference example 12
(1) with 7-chloro-6-(2-chlorphenyl)-3-ethoxy carbonyl pyrazolo [1; 5-a] pyrimidine (1g) obtains 6-(2-chlorphenyl)-3-ethoxy carbonyl-7-(4-formoxyl phenyl) pyrazolo [1 to process with the described same way as of reference example 4 (5); 5-a] pyrimidine (910mg), it is buff powder.
MS(APCI)m/z；428/430M+H] +
(2) add two-(2-methoxy ethyl) amino sulfur trifluorides (trade name: Deoxo-Fluor, Scott Inc.) (184 μ L) in the solution of chemical compound (406mg) in dichloromethane (1mL) that obtains in the above-mentioned steps (1) and mixture was at room temperature stirred 4 hours.Organic layer is with the salt water washing and use dichloromethane extraction.Extract also filters with dried over sodium sulfate.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=(25mg, yield: 37%), it is light yellow solid 70/30-60/40) to obtain 6-(2-chlorphenyl)-7-(4-difluoromethyl phenyl)-3-ethoxy carbonyl pyrazolo [1,5-a]-pyrimidine.
MS(APCI)m/z；428/430M+H] +
(3) chemical compound that obtains in the above-mentioned steps (2) (278mg) obtains 3-carboxyl-6-(2-chlorphenyl)-7-(4-difluoromethyl phenyl) pyrazolo [1 to process 1 (3) with the described same way as of reference example, 5-a] pyrimidine (223mg, yield: 86%), it is light yellow solid.
MS(APCI)m/z；400/402M+H] +
Reference example 13
(1) adds sodium acetate (3.28g) and azanol HCl (1.81g) and this mixture was stirred 2 hours in the tetrahydrochysene-4H-thiapyran-solution of 4-ketone (2.32g) in ethanol (100mL) under the room temperature under uniform temp.Add ethyl acetate and aqueous sodium carbonate with the reactant mixture vacuum concentration and to residue.After the stirring, this mixture is with ethyl acetate extraction and organic layer salt water washing, with dried over sodium sulfate and filtration.The filtrate vacuum concentration is obtained 4-oxyimino-tetrahydrochysene-4H-thiapyran, and (2.53g, yield: 96%), it is colorless solid.
MS(APCI)m/z；132M+H] +
(2) in blanket of nitrogen and the ice-cold lower solution of chemical compound (500mg) in Anaesthetie Ether (10mL) that obtains in the above-mentioned steps (1), add lithium aluminium hydride (289mg) and this mixture was stirred 30 minutes under uniform temp and at room temperature stirred 1 hour.Stirred 2 hours under 40 ℃ to this reactant mixture adding lithium aluminium hydride (72mg) and this mixture.Add entry (1mL) and 2N sodium hydrate aqueous solution (1mL) and stir this mixture and filtration to this reactant mixture under the room temperature.The filtrate vacuum concentration is obtained 4-amino-tetrahydrochysene-4H-thiapyran, and (150mg, yield: 34%), it is yellow fluid.
MS(APCI)m/z，118M+H] +
Reference example 14A
(1) under the blanket of nitrogen with (R)-methioninol (4.95g), the mixture of benzonitrile (8.3mL) and zinc bromide (250mg) is 120 ℃ of lower stirrings 90 hours.After being cooled to room temperature, this reactant mixture filters, and filtrate water and salt water washing are with dried over mgso and again filtration.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=5/1-3/1) obtain (R)-4-(2-methylmercaptoethyl)-2-phenyl-4, (3.94g, yield: 48.6%), it is water white oil to the 5-dihydro-oxazole.
MS(APCI)m/z；222M+H] +
(2) concentrated hydrochloric acid (7.7mL) in the solution of chemical compound (3.94g) in acetic acid (65mL) that obtains in the above-mentioned steps (1), this mixture flows through night next time in heating.After being cooled to room temperature, this reactant mixture vacuum concentration.Add sodium hydrate aqueous solution (50mL) and chloroform (100mL) and stir this mixture to this residue.Add magnesium sulfate and silica gel and stir this mixture and filtration to organic layer.With the filtrate vacuum concentration and the gained crude product is obtained (R)-N-(Tetramethylene sulfide-3-yl) Benzoylamide with isopropyl ether washing and drying (2.80g, yield: 76%), it is colorless solid.
MS(APCI)m/z；208M+H] +
(3) in the ice-cold lower solution of chemical compound (3.59g) in dichloromethane (70mL) that obtains in the above-mentioned steps (2), progressively add 3-chlorine benzylhydroperoxide (75%, 10g), this mixture at room temperature stirred spends the night.Add entry (35mL) to this reactant mixture, sodium sulfite (3.5g) and saturated aqueous sodium carbonate (100mL) also stir this mixture 30 minutes, use chloroform extraction.Extract also filters with dried over sodium sulfate with saturated aqueous sodium carbonate washing and organic layer.With the filtrate vacuum concentration, the gained solid material obtains (R)-N-(1,1-dioxo-Tetramethylene sulfide-3-yl) Benzoylamide with the ethyl acetate washing, and (3.5g, yield: 85%), it is colorless solid.
MS(APCI)m/z；240M+H] +
(4) add 6N HCl (52mL) in the solution of chemical compound (3.51g) in ethanol (13mL) that obtains in the above-mentioned steps (3) and this mixture heated was refluxed 1 day.After being cooled to room temperature, water layer washs and vacuum concentration with ethyl acetate.The solid material of precipitation washs with ethanol/Anaesthetie Ether, obtain (R)-N-(1 by filtering to collect and further wash with Anaesthetie Ether, 1-dioxo-Tetramethylene sulfide-3-yl) (2.52g, yield: 100%), it is colorless solid to amine hydrochlorate.
MS(APCI)m/z；136M+H] +
Reference example 14B
(S)-and Methioninol (4.83g) is to obtain (S)-N-(1,1-dioxo-Tetramethylene sulfide-3-yl) amine hydrochlorate (3.86g) with the described same way as processing of reference example 14A, and it is colorless solid.
MS(APCI)m/z；136M+H] +
Reference example 15
(1) adds 2N sodium hydroxide (7.6mL) and mixture at room temperature stirred 1 hour in the solution of 4,4-difluoro piperidine hydrochlorate (2.0g) in water.Add Chile saltpeter (1.75g) and at ice-cold lower adding acetic acid (1.27mL) to this reactant mixture under the room temperature, and mixture was at room temperature stirred 2 hours.To this reactant mixture adding aqueous sodium carbonate and with this mixture chloroform extraction.Extract dried over mgso and filtration, and filtrate vacuum concentration.The gained crude product is by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=4/1) (1.89g, yield: 99%), it is light yellow solid to obtain 4,4-, two fluoro-1-nitroso-piperidines.
MS(APCI)m/z；151M+H] +
(2) (1.89g) drip lithium aluminium hydride (837mg) in the solution in oxolane and this mixture heated was refluxed 1 hour at the ice-cold lower chemical compound (1) that obtains in the above-mentioned steps.Add entry and this mixture heated was refluxed 30 minutes to this reactant mixture down ice-cold.After being cooled to room temperature, this reactant mixture filters and the filtrate vacuum concentration.Add aqueous sodium carbonate and chloroform and stir this mixture to this residue.Organic layer obtains 1-amino-4 with dried over sodium sulfate and filtration and filtrate vacuum concentration, and (500mg, yield: 29%), it is light yellow oil to 4-difluoro piperidines.
MS(APCI)m/z；137M+H] +
Reference example 16
(1) ice-cold lower add in the solution of 3-fluorine methoxyphenyl methyl amine (278mg) in water (400 μ L) acetic acid (125 μ L) and Chile saltpeter (201mg) in water (600 μ L) solution and stir this mixture.At room temperature stir and spend the night to wherein adding methanol (500 μ L) and oxolane (500 μ L) and this mixture.Add saturated aqueous sodium carbonate and stir this mixture and use ethyl acetate extraction to this reactant mixture.With the extract vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=(282mg, yield: 88%), it is light yellow oil 100/0-87/13) to obtain N-(3-Trifluoromethoxyphen-l) methyl nitroso-amines.
MS(APCI)m/z；192M+H] +
(2) ice-cold lower add in the solution of lithium aluminium hydride (82.7mg) in oxolane (5mL) chemical compound (282mg) that obtains in the above-mentioned steps (1) in oxolane (2.5mL) solution and mixture stirred 1 hour under room temperature and blanket of nitrogen.Add entry (90 μ L) to this reactant mixture, 15% sodium hydrate aqueous solution (90 μ L) and water (180 μ L) also stir this mixture and filtration.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=(187mg, yield: 71%), it is orange viscosity 85/15-65/35) to obtain N-methyl-N-(3-Trifluoromethoxyphen-l) hydrazine.
MS(APCI)m/z；207M+H] +
Reference example 17
Add potassium cyanide (1.4g) and ammonium chloride (1.15g) in the tetrahydrochysene-4H-thiapyran-solution of 4-ketone (500mg) in water/ethanol (10mL/10mL) and mixture was at room temperature stirred 4 days.Add Anaesthetie Ether and 1N sodium hydrate aqueous solution and stir this mixture to this reactant mixture.Separate organic layer and water layer Anaesthetie Ether and ethyl acetate extraction.The organic layer that merges is dry and filtration with calcium chloride.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=70/30-30/70) obtain 4-amino-4-cyano group-tetrahydrochysene-4H-thiapyran (315mg), it is colorless solid.
Reference example 18
With 2-cyano group-3,3-dimethyl sulphur-based ethyl acrylate (40g), hydrazine hydrochloride (12.6g) and the solution of sodium acetate (22.6g) in ethanol are 90 ℃ of lower stirrings 2 hours.After being cooled to room temperature, this reactant mixture vacuum concentration.Add entry with ethyl acetate and separate organic layer to this residue, with dried over mgso and filtration.Add ethyl acetate and hexane with the filtrate vacuum concentration and to residue.Solid material by filtering collecting precipitation and drying obtain 5-amino-4-ethoxy carbonyl-3-methyl mercapto-1H-pyrazoles, and (17.4g, yield: 47%), it is colorless solid.
Reference example 19-20
3-carboxyl-6-(2-chlorphenyl)-7-(4-Trifluoromethoxyphen-l) pyrazolo [1,5-a]-pyrimidine or 3-carboxyl-6-(2-chlorphenyl)-7-(4-trifluoromethyl) pyrazolo-[1,5-a] pyrimidine obtain following compounds to process with reference example 10 described same way as
(Ref.Ex.19) 3-diazanyl carbonyl-6-(2-chlorphenyl)-7-(4-trifluoromethoxy-phenyl) pyrazolo [1,5-a] pyrimidine; MS (APCI) m/z; 448/450M+H] +
(Ref Ex.20) 3-diazanyl carbonyl-6-(2-chlorphenyl)-7-(4-trifluoromethyl-phenyl) pyrazolo [1,5-a] pyrimidine; MS (APCI) m/z; 432/434M+H] +
Reference example 21-40
Corresponding initiation material obtains the chemical compound that following table B1 shows according to above-mentioned reference example 1,4 and 6 described same way as.
Table B1 (No.1)
Figure S2006800391776D01391
Table B1 (No.2)
Figure S2006800391776D01401
Table B1 (No.3)
Figure S2006800391776D01411
Table B1 (No.4)
Figure S2006800391776D01412
Reference example 41-45
Corresponding initiation material obtains the chemical compound shown in the following table B2 to process with embodiment 7 described identical modes.
Table B2
Figure S2006800391776D01421
Reference example 46
(1) in 5 minutes, drips thionyl chloride (9.7mL) and this mixture refluxed 4 hours in the 5-nitropyrazole-solution of 5-carboxylic acid (19.9g) in ethanol (200mL).After being cooled to room temperature, this reactant mixture water (25mL) and ethanol (50mL) dilution, this mixture neutralizes with sodium carbonate (54g).This mixture is filtered and the residue washing with alcohol.Merging filtrate and cleaning mixture and vacuum concentration.Residue and ethanol azeotropic distillation and residue is dissolved in ethyl acetate are with dried over mgso and filter.With the filtrate vacuum concentration, add isopropyl ether to residue.By filtering collecting precipitation, (20g, yield: 85%), it is colorless solid to obtain ethyl 5-nitropyrazole-3-carboxylic salt with ethyl acetate/Di Iso Propyl Ether (1/2) washing.
MS(APCI)：18[omicron][M+H] +
(2) add under 10% carbon calamity palladium (4.1g) and the calamity blanket of nitrogen in the solution of chemical compound (22.5g) in acetic acid (130mL) and oxolane (130mL) that obtains in the above-mentioned steps (1) and stirred this mixture 4 hours.This reactant mixture is filtered and the filtrate vacuum concentration.Add hexane and stir this mixture and decant is removed hexane to this residue.Add ether/Di Iso Propyl Ether (1/1) and obtain 5-amino-pyrazol-3-carboxylic acid, ethyl ester (17.2g, yield: 91%), it is colorless solid by filtering collecting precipitation to this residue.
MS(APCI)：156[M+H] +
Reference example 47
(1) to 2-[(cyano group) (ethoxy carbonyl) vinyl]-1, add in the solution of 3-diox (2.0g) in ethanol (20mL) that 80 ℃ of hydrazonium salt hydrochlorate (748mg) and sodium acetate (1.34g) and calamities are lower to stir these mixture (outside warm) 1 hour.After being cooled to room temperature, this reactant mixture is through diatomite filtration and filtrate vacuum concentration.The gained crude product is by column chromatography purification (solvent on silica gel; Chloroform/methanol=(2.01g, yield: 86%), it is the lightpink solid 100/0-85/15) to obtain 3-amino-4-ethoxy carbonyl-5-(2-hydroxyl) ethyoxyl pyrazoles.
MS(APCI)m/z；216M+H] +
(2) add ethanol (20mL) in the chemical compound (2.65g) that obtains in the above-mentioned steps (1) and the solution of 3-(N, N-dimethylamino)-1-(4-chlorphenyl)-2-(2-chlorphenyl)-2-propylene-1-ketone (cf. reference example 1 (2)) and contain the ethanol (5mL) of 21% Sodium ethylate and mixture was at room temperature stirred 15 minutes.Add ethyl acetate and water to this reactant mixture, this mixture is with 2N HCl acidify and use ethyl acetate extraction.Organic layer washs with saturated brine, with dried over mgso and filtration.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=72/28-30/70) and with the Anaesthetie Ether development obtain 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-ethoxy carbonyl-2-(2-hydroxyl-oxethyl) pyrazolo [1,5-a] pyrimidine (2.25g, yield: 39%), it is colorless solid.
MS(APCI)m/z；472/474M+H] +
(3) add silver oxide (I) in the solution of chemical compound (100mg) in acetonitrile (10mL) that obtains in the above-mentioned steps (2) (320mg) and iodomethane (350 μ L) and mixture at room temperature stirred 3 days.This reactant mixture is through diatomite filtration and with the filtrate vacuum concentration.The gained crude product is by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=80/20-50/50) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-ethoxy carbonyl-2-(2-methoxy ethoxy) pyrazolo [1,5-a] pyrimidine (98.6mg, yield: 96%), it is colourless powder.
MS(APCI)m/z；486/488M+H] +
(4) chemical compound (98mg) that obtains in the above-mentioned steps (3) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-carboxyl-2-(2-hydroxyl-oxethyl) pyrazolo [1 to process with reference example 1 (3) described same way as, 5-a] pyrimidine (92mg, yield: 99%), it is colourless powder.
MS(APCI)m/z；458/460M+H] +
Reference example 48
(1) adds sodium sulfate (9.46g) and with the lower stirring of 110-140 ℃ of this mixture calamity (outer temperature) 30 minutes in the solution of 1,3-, two bromo-2,2-dimethoxypropanes (26.45g) in dimethyl sulfoxide (200mL).This reactant mixture with Anaesthetie Ether in ice-cold lower dilution and to wherein adding saturated aqueous sodium carbonate and water.This mixture extracts with Anaesthetie Ether (x2).Organic layer washs with saturated brine, with dried over mgso and filtration.With the filtrate vacuum concentration and with the gained crude product by column chromatography purification (solvent on silica gel; Hexane/Anaesthetie Ether=(10.55g, yield: 78%), it is light yellow liquid 100/0-15/1) to obtain 3,3-dimethoxy sulfo-Tetramethylene..
MS(APCI)m/z；103[M+H-MeOH] +
(2) add ion exchange resin (Amberlyt 15E, 3.5g) in the solution of chemical compound (9.0g) in acetone (70mL) that obtains in the above-mentioned steps (1) and mixture was at room temperature stirred 21 hours.This reactant mixture is through diatomite filtration and residue washing with acetone.Merging filtrate and cleaning mixture and vacuum concentration.(1.58g, yield: 27%), it is clear crystal by filtering collecting precipitation and obtaining 3-oxo sulfo-Tetramethylene. with cold hexane washing.
(3) add oxammonium hydrochloride. (236mg) and sodium carbonate (360mg) in the solution of chemical compound (100mg) in ethanol (3mL) that obtains in the above-mentioned steps (2) and with this mixture heated backflow 17 hours.After being cooled to room temperature, add aqueous sodium carbonate and water to this reactant mixture.This mixture chloroform extraction.With the organic layer vacuum concentration, the gained crude product is by column chromatography purification (solvent on silica gel; Hexane/Anaesthetie Ether=(93mg, yield: 80%), it is colorless solid 90/10-50/50) to obtain 3-oxyimino sulfo-Tetramethylene..
(4) under ice-cold and blanket of nitrogen, in the solution of lithium aluminium hydride (58mg) in oxolane (2mL), drip the solution of chemical compound (93mg) in oxolane (1.5mL) that obtains in the above-mentioned steps (3).This mixture at room temperature stirred 1 hour.Add successively entry (60 μ L) to this reactant mixture down ice-cold, stir this mixture under 15% sodium hydroxide solution (60 μ L) and water (120 μ L) and the room temperature and through diatomite filtration.The filtrate vacuum concentration is obtained the amino Tetramethylene. that flows of 3-, and it is crude product.
Reference example 49
(1) drips cyan-acetic ester (4.7mL) and mixture at room temperature stirred 1 hour in the solution of Sodium ethylate (14.32g) in ethanol (20mL).Add difluoroacetic acid (4.85mL) and mixture at room temperature stirred 4 hours and subsequently 60 ℃ of (outer temperature) lower stirrings 17 hours to this reactant mixture.With the reactant mixture vacuum concentration, also this mixture was stirred 1 hour under 45 ℃ to residue adding toluene (10mL) and phosphorus chloride (3.2g).Adding phosphorus chloride (1.9g) to this reactant mixture also stirs this mixture 2 hours under 55 ℃.This reactant mixture is with ice-cooled and through diatomite filtration, with the filtrate vacuum concentration.Add ethanol (20mL) to this residue, hydrazine monohydrate (0.8mL) and triethylamine (3.0mL) also stir this mixture 2 hours under 60 ℃.After being cooled to room temperature, add saturated aqueous sodium carbonate and water to this reactant mixture.This mixture also filters with dried over mgso with chloroform extraction (x 4) and organic layer.With filtrate vacuum concentration and gained crude product by column chromatography purification (solvent on silica gel; Chloroform/methanol=100/0-94/6) and obtain 3-amino-4-ethyoxyl glycosyl-5-difluoromethyl pyrazole with the chloroform washing (1.26g, yield: 41%), it is colorless solid.
MS(APCI)m/z；206[M+H] +
(2) chemical compound (400mg) that obtains in the above-mentioned steps (1) obtains 3-carboxyl-6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-difluoromethyl pyrazole also [1 to process with the described same way as in reference example 1 (2)-(3), 5-a] pyrimidine (405mg, yield: 48%), it is powder.
MS(APCI)m/z；434/436[M+H] +
Reference example 50
(1) adds trifluoroacetic anhydride (37.2g) and this mixture is at room temperature stirred in the solution of malonic methyl ester nitrile (14.6g) in dichloromethane (260mL).Drip triethylamine (51.7mL) to this mixture under 0 ℃, this mixture is at room temperature stirred spend the night.Add entry and this mixture dichloromethane extraction to this reactant mixture.Organic layer also filters with dried over mgso.The filtrate vacuum concentration is obtained 2-cyano group-2-(2-trifluoroacetyl group) methyl acetate (chemical compound 2a) and 2-cyano group-4,4,4-three fluoro-3-trifluoromethoxy carbonyls-2-butylene acid methyl ester (chemical compound 2b), it is mixture (55.3g).
Chemical compound 2a:MS (APCI) m/z; 196[M+H] +
Chemical compound 2b:MS (APCI) m/z; 292[M+H] +
(2) drip oxalyl chloride (31.6mL) and several pyridine and with this mixture heated backflow 4 hours in the mixture in dichloromethane (200mL) to chemical compound 2a and 2b (27.6g).With this reactant mixture progressively in the impouring water and with this mixture dichloromethane extraction.Organic layer also filters with dried over mgso.The filtrate vacuum concentration is obtained 2-cyano group-3-chloro-4,4,4-three fluoro-2-butylene acid methyl ester, it is crude product.
The chemical compound that obtains in the above-mentioned steps (2) under (3) 0 ℃ add entry (20mL) and to wherein drip the hydrazine monohydrate (80%, 6.74g).Adding triethylamine (2mL) to this mixture under the room temperature also stirs this mixture 1 hour.Add entry and this mixture ethyl acetate extraction to this reactant mixture.Organic layer also filters with dried over mgso.Add chloroform and obtain 3-amino-4-ethoxy carbonyl-5-trifluoromethyl pyrazol (3.96g) by filtering collecting precipitation with the filtrate vacuum concentration and to residue, it is orange solids.
MS(APCI)m/z；210[M+H] +
(4) chemical compound (2.37g) that obtains in the above-mentioned steps (3) obtains 3-carboxyl-6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-trifluoromethyl pyrazol also [1 to process with the described same way as in reference example 1 (2)-(3), 5-a] pyrimidine (1.81g), it is crude product (powder).
MS(APCI)m/z；452/454[M+H] +
Reference example 51
(1) to 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-ethoxy carbonyl-2-methylpyrazole also [1,5-a] pyrimidine (1.50g: the ethyl ester compound that obtains in the corresponding reference example 39) adding N-bromine butanimide (1.88g) and 2,2 in the solution in carbon tetrachloride (20mL) '-azodiisobutyronitrile (30mg).This mixture was stirred 26 hours in that 85 ℃ (outside temperature) are lower.After being cooled to room temperature, this reactant mixture nitrile diatomite filtration and filtrate vacuum concentration.The gained crude product is by column chromatography purification (solvent on silica gel; Hexane/Anaesthetie Ether=(827mg, yield: 47%), it is light yellow solid 85/15-67/33) to obtain 2-bromomethyl-6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-ethoxy carbonyl pyrazolo [1,5-a] pyrimidine.
MS(APCI)m/z；504/506[M+H] +
(2) add 28% Feldalat NM-methanol solution (3mL) in the solution of chemical compound (825mg) in methanol/oxolane (7mL/4mL) that obtains in the above-mentioned steps (1) and mixture was at room temperature stirred 1 hour.This reactant mixture is with the ethyl acetate dilution and to wherein adding entry.This mixture washs with saturated brine with ethyl acetate extraction and organic layer, with dried over mgso and filtration.With filtrate vacuum concentration and gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=(404mg, yield: 56%), it is light yellow solid 75/25-60/40) to obtain 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-methoxycarbonyl-2-methoxy pyrazolo [1,5-a] pyrimidine.
MS(APCI)m/z；442/444[M+H] +
(3) chemical compound (404mg) that obtains in the above-mentioned steps (2) obtains 3-carboxyl-6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-methoxy pyrazolo [1 to process with reference example 1 (3) described same way as, 5-a] pyrimidine (367mg, yield: 94%), it is colorless solid.
MS(APCI)m/z；428/430[M+H] +
Reference example 52
(1) under blanket of nitrogen, adds sodium hydride (60% to dimethyl formamide (75mL), 6.77g) and in 15 minutes to wherein dripping the solution of cyan-acetic ester (9.57g) in dimethyl formamide (15mL), mixture was at room temperature stirred 10 minutes.20 minutes introversive these mixture drip the solution of Carbon bisulfide (5.09mL) in dimethyl formamide (12mL) that is cooled to 40 ℃ (interior temperature＜10 ℃).This mixture at room temperature stir spend the night ice under 0 ℃ to this reactant mixture drip the solution of benzyl bromide a-bromotoluene (20.1mL) in dimethyl formamide (23mL) (interior temperature＜25 ℃) and with this mixture 70 ℃ of lower stirrings 7 hours, at room temperature stir subsequently and spend the night.With this reactant mixture impouring frozen water and stir this mixture.By filtering collecting precipitation, obtain 2-cyano group-3 by the hot ethanol recrystallization and with cold washing with alcohol, (25.63g, yield: 82%), it is colorless solid to the 3-dibenzyl sulfide for ethyl acrylate.
MS(APCI)m/z；370[M+H] +
Add in the solution of chemical compound (15.0g) in oxolane/ethanol (16mL/41mL) that obtains in the above-mentioned steps (1) in (2) 5 minutes hydrazine monohydrate (2.04g) in ethanol (18mL) solution and this mixture at room temperature stirred spends the night.With reactant mixture vacuum concentration and residue by Di Iso Propyl Ether/hexane crystallization.Obtain 3-amino-4-ethoxy carbonyl-5-benzylthio-pyrazoles (9.45g, yield 84%) by the crystal that filters collecting precipitation, it is colorless solid.
MS(APCI)m/z；278[M+H] +
(3) chemical compound (8.15g) that obtains in the above-mentioned steps (2) obtains 2-benzylthio-6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-ethoxy carbonyl pyrazolo [1 to process with reference example 5 (1) described same way as, 5-a] pyrimidine (8.24g, yield: 51%), it is light yellow solid.
MS(APCI)m/z；534/536[M+H] +
Reference example 53
(1) chemical compound (3.0g) that obtains in the reference example 33 obtains 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-(tert-butoxycarbonyl is amino) pyrazolo [1 to process with reference example 9 (1) described same way as, 5-a] pyrimidine (1.06g, yield: 30%), it is orange powder.
MS(APCI)m/z；489/491[M+H] +
(2) solution of the chemical compound (1.06g) that obtains in the above-mentioned steps (1) in diox (5mL) adds 4N HCl-diox (10mL) and mixture was at room temperature stirred 7 hours.With the reactant mixture vacuum concentration, add saturated aqueous sodium carbonate to residue. this mixture chloroform extraction, with the organic layer vacuum concentration.The gained crude product is by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=(850mg, yield: 80%), it is light yellow solid 70/30-40/60) to obtain 3-amino-6-(2-chlorphenyl)-7-(4-trifluoromethyl) pyrazolo [1,5-a] pyrimidine.
MS(APCI)m/z；389/391[M+H] +
Reference example 54
(1) corresponding initiation material obtains (2-chlorobenzyl) (4-trifluoromethyl) ketone to process with embodiment 1 (1) described identical mode.
(2) chemical compound (3.0g) that obtains in the above-mentioned steps (1) and 3-amino-5-methylpyrazole (977mg) obtain 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-2-methyl-pyrazolo [1 to process with reference example 1 (2) described same way as, 5-a] pyrimidine (2.63g, yield: 67%), it is brown oil.
MS(APCI)m/z；388/390[M+H] +
(3) progressively drip chloro sulfonic acid (1.35mL) in the solution of chemical compound (2.27g) in chloroform (50mL) that obtains in the above-mentioned steps (2) and with this mixture 70 ℃ of lower stirrings 3.5 hours.Refluxed 2 hours with the reactant mixture vacuum concentration and to residue adding thionyl chloride (20mL) and with this mixture heated.With the reactant mixture vacuum concentration and to residue adding ice-water and with this mixture chloroform extraction.Organic layer also filters with dried over sodium sulfate.With filtrate vacuum concentration and gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=85/15-60/40) obtain 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-chlorosulfonyl-2-methylpyrazole also [, 5-a] (2.71g, yield: 95%), it is light yellow solid to pyrimidine.
MS(APCI)m/z；486/488[M+H] +
Reference example 55
(1) adds magnesium chloride (309mg) and triethylamine (580 μ L) and mixture at room temperature stirred 2 hours (solution A) in the solution of malonic ester potassium (465mg) in acetonitrile (3.5mL).Adding the two imidazoles (232mg) of carbonyl and oxolane (2mL) in the solution of chemical compound (500mg) in acetonitrile (3mL) that obtains in the reference example 1 under the room temperature also stirs this mixture 2 hours under uniform temp.Add the solution A of above-mentioned acquisition also with this mixture stirring 4 hours to this reactant mixture under the room temperature.Add 2N HCl and this mixture ethyl acetate extraction to this reactant mixture.Organic layer water and saturated brine washing are with dried over mgso and filtration.With filtrate vacuum concentration and gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=90/10-75/25) obtains 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(2-ethoxy carbonyl acetyl group) pyrazolo [1,5-a] pyrimidine (488mg, yield: 83%).
MS(APCI)m/z；454/456[M+H] +
(2) add 2N sodium hydrate aqueous solution (1.05mL) in the solution of chemical compound (475mg) in ethanol/oxolane (2.5mL/2.5mL) that obtains in the above-mentioned steps (1) and with this mixture 60 ℃ of lower stirrings 1 hour.Add 2N sodium hydrate aqueous solution (1.05mL) and ethanol (2.5mL) to this reactant mixture, and this mixture was stirred 18 hours under uniform temp.After being cooled to room temperature, adding 2N HCl (2.1mL) aqueous solution to this reactant mixture and dilute with ethyl acetate with this mixture.Add entry and this mixture ethyl acetate extraction to this solution.With the organic layer vacuum concentration, the gained crude product is by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=(233mg, yield: 58%), it is light yellow solid 80/20-70/30) to obtain 3-acetyl group-6-(2-chlorphenyl)-7-(4-chlorphenyl) pyrazolo [1,5-a] pyrimidine.
MS(APCI)m/z；382/384[M+H] +
Reference example 56
(1) corresponding initiation material obtains (2-chlorobenzyl) (5-chlorothiophene-2-yl) ketone (5.06g, yield: 61%) to process with embodiment 2 (1) described identical modes.
(2) chemical compound (2.92g) that obtains in the above-mentioned steps (1) obtains 3-(N to process with reference example 1 (2) described same way as, the N-dimethylamino)-and 2-(2-chlorphenyl)-1-(5-chlorothiophene-2-yl)-2-propylene-1-ketone, it is crude product.
(3) adding 3-amino-4-ethoxy carbonyl-5-methylpyrazole (1.3g) and piperidines (153 μ L) and this mixture in the solution of chemical compound in acetic acid (2mL) that obtains in the above-mentioned steps (2) spends the night 80 ℃ of lower stirrings.Also this mixture was stirred 7 hours under uniform temp to this reactant mixture adding acetic acid (3mL) and toluene (30mL).After being cooled to room temperature, ice-cold lower to this reactant mixture adding saturated aqueous sodium carbonate.This mixture ethyl acetate extraction, organic layer be water and saturated brine washing successively, with dried over mgso and filtration.With the filtrate vacuum concentration with by filtering collecting precipitation, wash with Anaesthetie Ether.Filtrate is by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=80/20-60/40) and the fraction of concentrated eluting.Precipitation obtains 6-(2-chlorphenyl)-7-(5-chlorothiophene-2-yl)-3-ethoxy carbonyl-2-methylpyrazole also [1 with ethyl acetate/hexane (1/10) washing and with above-mentioned precipitation merging, 5-a] pyrimidine (1.52g, the yield in two steps is: 45%), it is yellow solid.
MS(APCI)m/z；432/434[M+H] +
(4) chemical compound (1.51g) that obtains in the above-mentioned steps (3) obtains 3-carboxyl-6-(2-chlorphenyl)-7-(5-chlorothiophene-2-yl)-2-methylpyrazole also [1 to process with the described same way as of reference example 1 (3), 5-a] pyrimidine (1.18g, yield: 84%), it is yellow solid.
MS(APCI)m/z；404/406[M+H] +
Reference example 57
(1) corresponding initiation material obtains 6-(2-chlorphenyl)-7-chloro-3-ethoxy carbonyl pyrazolo [1,5-a] pyrimidine to process 4 (1)-(4) with the described identical mode of embodiment.
(2) add palladium (2.2mg) in the solution of chemical compound (672mg) in oxolane (6mL) that under blanket of nitrogen, obtains in the above-mentioned steps (1), 2-dicyclohexyl-phosphine-2 ', 6 '-dimethoxy-biphenyl (4.1mg), potassium phosphate trihydrate (1.27g) and water (120 μ L) and mixture at room temperature stirred 2 hours are subsequently 100 ℃ of lower stirrings 24 hours.After being cooled to room temperature, add entry and this mixture ethyl acetate extraction to this reactant mixture.Organic layer is successively with 1N sodium hydrate aqueous solution, water and saturated brine washing, with dried over mgso and filtration.With filtrate vacuum concentration and gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=80/20-50/50).The fraction of concentrated eluting and precipitation obtain 6-(2-chlorphenyl)-7-(4-dimethylamino-phenyl)-3-ethoxy carbonyl pyrazolo [1,5-a] pyrimidine with Anaesthetie Ether/hexane, and (288mg, yield: 34%), it is yellow powder.
MS(APCI)m/z；421/423[M+H] +
Reference example 58
The chemical compound that obtains among the embodiment 440 (0.67g) obtains 3-carboxyl-6-(2-chlorphenyl)-7-(4-trifluoromethyl)-2-[N-methyl-N-(methyl sulphonyl) amino to process with reference example 1 (3) described same way as] pyrazolo [1; 5-a]-pyrimidine (0.64g), it is crude product (powder).
MS(APCI)m/z；525/527[M+H] +
Reference example 59
(1) chemical compound (200mg) that obtains in the reference example 51 (1) at room temperature stirred 1 hour at dimethyl sulfoxide (2mL) adding sulfo-Feldalat NM (15mg) and with mixture.Add entry and this mixture ethyl acetate extraction to this reactant mixture.With extract vacuum concentration and gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=(170mg, yield: 91%), it is light yellow solid 87/13-60/40) to obtain 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-ethoxy carbonyl-2-methyl mercapto pyrazolo [1,5-a] pyrimidine.
MS(APCI)m/z；472/474[M+H] +
(2) chemical compound (170mg) that obtains in the above-mentioned steps (1) obtains 3-carboxyl-6-(2-chlorphenyl)-7-(4-trifluoromethyl)-2-methylthiomethyl pyrazolo [1 to process with reference example 1 (3) described same way as, 5-a]-pyrimidine, it is buff powder.
MS(APCI)m/z；444/446[M+H] +
Reference example 60
(1) adds metachloroperbenzoic acid (12.17g) and mixture at room temperature stirred 3 days in the 1-benzyloxycarbonyl-solution of 3-pyrroles (5.0g) in dichloromethane (125mL).Adding saturated aqueous sodium thiosulfate (100mL) to this reactant mixture also stirs this mixture 30 minutes.This reactant mixture is used 2N sodium hydrate aqueous solution (100mL * 2) and saturated brine washing successively with chloroform (x2) extraction and organic layer, obtain 6-oxa--3-azabicyclo [3 with dried over mgso and vacuum concentration, 1,0] own-3-benzyl carboxylate (5.58g, yield: 100%), it is oil.
MS(APCI)m/z；220[M+H] +
(2) with the chemical compound (26.5g) that obtains in the above-mentioned steps (1), (1R, 2R)-(-)-[1,2-cyclohexane extraction diamino-N, N '-two (3,5-di-t-butyl salicylidene)] mixture of Chlorizate chromium (1.57g) and trimethyl silyl azide (17.7mL) at room temperature stirred 2 days.Add chloroform to this reactant mixture, this mixture is water and saturated brine washing successively, uses dried over mgso.With the organic layer vacuum concentration, residue is by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=10/1-2/1 → chloroform/methanol=20/1-9/1) obtain respectively (3S, 4S)-4-azido-1-benzyloxycarbonyl-3-trimethylsiloxy pyrrolidine (compound a: 20.6g, 55%) and (3S yield:, 4S)-4-azido-1-benzyloxycarbonyl-3-hydroxyl pyrrolidine (compound b: 8.16g, yield: 28%), it is oil.
Compound a: MS (APCI) m/z; 335[M+H] +
Compound b: MS (APCI) m/z; 263[M+H] +
(3) adding triphenylphosphine (26.67g) and this mixture in the solution in oxolane (740mL) to compound a (20.6g) and compound b (8.16g) at room temperature stirs and spends the night.Add methanol (380mL) and 0.5N sodium hydrate aqueous solution (380mL) and this mixture at room temperature stirred with the reactant mixture vacuum concentration and to residue and spend the night.Add 6N HCl (pH 3) aqueous solution with the reactant mixture vacuum concentration and to residue.This mixture washs with chloroform and water layer 5N sodium hydrate aqueous solution alkalization (pH 9).This mixture obtains (3S, 4S)-4-amino-1-benzyloxycarbonyl-3-hydroxyl pyrrolidine with chloroform extraction (x3) and organic layer with dried over mgso and vacuum concentration, and (19.6g, yield: 90%), it is oil.
MS(APCI)m/z；237[M+H] +
(4) drip in the solution of chemical compound (14.61g) in chloroform (135mL) that obtains in the above-mentioned steps (3) under the ice-cold condition di-t-butyl di-tert-butyl dicarboxylate (16.18g) in chloroform (20mL) solution and mixture at room temperature stirred 2 hours.Add saturated aqueous sodium carbonate (100mL) and stir this mixture to this reactant mixture.This mixture is with chloroform extraction and organic layer dried over mgso.To wherein adding NH-silica gel (2g) and stirring this mixture and filtration.With the filtrate vacuum concentration and the gained crude product is obtained (3S, 4S)-1-benzyloxycarbonyl-3-hydroxyl-4-(tert-butoxy-carbonyl) pyrrolidine with hexane/ethyl acetate development (18.59g, yield: 94%), it is crystal.
MS(APCI)m/z；337[M+H] +
(5) adding 10% carbon in the solution of chemical compound (18.56g) in methanol (200mL) that obtains in the above-mentioned steps (4) carries palladium (1.16g) and this mixture was stirred 3 hours under room temperature and blanket of nitrogen.This reactant mixture is through diatomite filtration and filtrate vacuum concentration.Residue is with methanol/the Di Iso Propyl Ether development obtains (3S, 4S)-3-hydroxyl-4-(tert-butoxycarbonyl) pyrrolidine, and (10.8g, yield: 97%), it is crystal.
MS(APCI)m/z；203[M+H] +
Reference example 61-83
Corresponding initiation material is to process and to obtain the chemical compound shown in the following table B3 with embodiment 1,4 or 6 described identical modes.
Table B3 (No.1)
Table B3 (No.2)
Figure S2006800391776D01541
Table B3 (No.3)
Figure S2006800391776D01551
Reference example 84-87
Corresponding initiation material obtains the chemical compound shown in the following table B4 to process with embodiment 40 or 50 described identical modes.
Table B4
Figure S2006800391776D01561
Reference example 88
Corresponding initiation material with embodiment 51 described identical modes process obtain 3-carboxyl-6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-ethoxyl methyl pyrazolo [1,5-a] pyrimidine (602mg, yield: 95%), it is colorless solid..
MS(APCI)m/z；442/444[M+H] +
Reference example 89
(1) adding acetic acid (200 μ L) and this mixture under the ice-cold condition in the solution of 4-methoxyl group piperidines (202mg) in water (4mL) at room temperature stirs and spends the night.Add saturated aqueous sodium carbonate and stir this mixture and use chloroform extraction to this reactant mixture.With extract vacuum concentration and gained crude product by column chromatography purification (solvent on silica gel; Ethyl acetate) (260mg, yield: 100%), it is light yellow oil to obtain 4-methoxyl group-1-nitroso-piperidine.
MS(APCI)m/z；145[M+H] +
(2) add zinc powder (654mg) in the solution of chemical compound (280mg) in methanol (3mL) that obtains in the above-mentioned steps (1).Under the ice-cold condition to wherein dripping acetic acid (3mL) and mixture at room temperature being stirred 2 hours.This reactant mixture is filtered and the filtrate vacuum concentration.Add saturated aqueous sodium carbonate and chloroform to this residue, and stir this mixture and use chloroform extraction.The extract vacuum concentration is obtained 1-amino-4-methoxyl piperidines, and (119mg, yield: 57%), it is light yellow oil.
MS(APCI)m/z；131[M+H] +
Reference example 90
With the mixture of 2,5-dibromo pyridine (500mg) and methyl hydrazine (1mL) 100 ℃ of heating.After being cooled to room temperature, this reactant mixture washs with the ethyl acetate dilution and with saturated brine.Organic layer is with dried over sodium sulfate and vacuum concentration.The gained crude product is by column chromatography purification (solvent on silica gel; Chloroform) and the fraction of concentrated eluting.Residue is dissolved in the tert-butyl alcohol and lyophilization obtains 5-bromo-2-(N-methyl diazanyl) pyridine (460mg), it is oil.
MS(APCI)m/z；202/204[M+H] +
Reference example 91-93
Corresponding initiation material is to process the chemical compound that obtains following table B5 with embodiment 90 described identical modes.
Table B5
Figure S2006800391776D01571
Reference example 94
(1) add 4-hydroxy piperidine (361mg) and triethylamine (830 μ L) in the solution of chemical compound (1.0g) in oxolane (10mL) that obtains in the reference example 4 (2) and with this mixture 60 ℃ of lower stirrings 2 hours.After being cooled to room temperature, add entry and this mixture ethyl acetate extraction to this reactant mixture.The extract with saturated brine washing is with dried over sodium sulfate and filtration.With the filtrate vacuum concentration and the gained crude product is obtained 6-(2-chlorphenyl)-7-(4-hydroxyl-piperidino)-3-ethoxy carbonyl pyrazolo [1,5-a] pyrimidine with Di Iso Propyl Ether development (646mg, yield: 54%), it is colorless solid.
MS(APCI)m/z；401/403[M+H] +
(2) add sodium hydride (48mg) in the ice-cold lower solution of chemical compound (200mg) in dimethyl formamide (3mL) that obtains in the above-mentioned steps (1) and mixture was at room temperature stirred 15 minutes.At room temperature stirred 1 hour to this reactant mixture adding iodoethane (120 μ L) and with mixture.This reactant mixture is with the ethyl acetate dilution and to wherein adding dilution HCl aqueous solution.This mixture is with ethyl acetate extraction with the extract vacuum concentration.The gained crude product is by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=(65mg, yield: 30%), it is colourless viscosity 82/18-60/40) to obtain 6-(2-chlorphenyl)-7-(4-ethyoxyl-piperidino)-3-ethoxy carbonyl pyrazolo [1,5-a]-pyrimidine.
MS(APCI)m/z；429/431[M+H] +
(3) chemical compound (65mg) that obtains in the above-mentioned steps (2) obtains 3-carboxyl-6-(2-chlorphenyl)-7-(4-ethyoxyl-piperidino) pyrazolo [1 to process with reference example 1 (3) described same way as, 5-a] pyrimidine, it is colourless powder.
MS(APCI)m/z；401/403[M+H] +
Reference example 95
(1) corresponding initiation material obtains also [1,5-a] pyrimidine of 6-chloro-7-(4-chlorobenzyl)-3-ethoxy carbonyl-2-methylpyrazole to process with embodiment 4 (3) described identical modes.
(2) add p-chlorobenzyl bromine (370mg) in the solution of chemical compound (525mg) in dimethoxy-ethane (5mL) that obtains in the above-mentioned steps (1), two (triphenyl-phosphine) palladium chloride (53mg) and zinc powder (235mg) and with the backflow 2 hours under the lower and blanket of nitrogen in heating of this mixture.This reactant mixture is filtered and the filtrate vacuum concentration.Add entry and this mixture ethyl acetate extraction to this residue.Organic layer washs with saturated brine, with dried over mgso and filtration.With filtrate vacuum concentration and gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=4/1) obtain 7-(4-chlorobenzyl)-6-(2-chlorphenyl)-3-ethoxy carbonyl-2-methylpyrazole also [1,5-a]-pyrimidine (113mg, yield: 17%), it is buff powder.
MS(APCI)m/z；440/442[M+H] +
Reference example 96
(1) add potassium acetate (116mg) in the solution of chemical compound (200mg) in dimethyl formamide (2mL) that obtains in the reference example 51 (1) and with this mixture 60 ℃ of lower stirrings 1 hour.After being cooled to room temperature, to this reactant mixture with ethyl acetate dilution and to wherein adding entry.Separate organic layer and vacuum concentration.The gained crude product is by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=(109.4mg, yield: 57%), it is colourless powder 80/20-55/45) to obtain 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-ethoxy carbonyl-2-acetoxy-methyl pyrazolo [1,5-a] pyrimidine.
MS(APCI)m/z；484/486[M+H] +
(2) add 21% Sodium ethylate/ethanol (0.2mL) in the solution of chemical compound (109mg) in ethanol/oxolane (3mL/3mL) that obtains in the above-mentioned steps (1) and with this mixture 60 ℃ of lower stirrings 30 minutes.After being cooled to room temperature, to this reactant mixture with ethyl acetate dilution and to wherein adding entry.This mixture ethyl acetate extraction is with the organic layer vacuum concentration.The gained crude product is by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=80/20-50/50) obtain 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-ethoxy carbonyl-2-hydroxymethylpyrazolcompound also [1,5-a] pyrimidine (75mg, yield: 75%), it is colorless solid.
MS(APCI)m/z；442/444[M+H] +
(3) add imidazoles (23mg) and tert-butyldimethylsilyl chloride (31mg) in the solution of chemical compound (75mg) in dimethyl formamide (2mL) that obtains in the above-mentioned steps (2) and mixture was at room temperature stirred 22 hours.Also this mixture was stirred 6 hours to this reactant mixture adding imidazoles (10mg) and tert-butyldimethylsilyl chloride (15mg).Add entry and this mixture ethyl acetate extraction to this reactant mixture.With extract vacuum concentration and gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=85/15-60/40) obtain 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-ethoxy carbonyl-2-(t-butyldimethylsilyloxy ylmethyl) pyrazolo [, 5-a] pyrimidine (66.8, mg, yield: 71%), it is colorless solid.
MS(APCI)m/z；556/558[M+H] +
(4) chemical compound (66.8mg) that obtains in the above-mentioned steps (3) obtains 3-carboxyl-6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-hydroxymethylpyrazolcompound also [1 to process with the described same way as of reference example 1 (3), 5-a] pyrimidine, it is colourless powder.
MS(APCI)m/z；414/416[M+H] +
Reference example 97
(1) add in the solution of 4-hydroxyl-1-piperidine carboxylic acid benzyl ester (1.0g) in toluene/2N sodium hydrate aqueous solution (10mL/10mL) tetrabutyl ammonium bromide (550mg) and methoxy ethyl bromine (1.2mL) and with this mixture 60 ℃ of lower stirrings 2.5 hours, subsequently 80 ℃ of lower stirrings 17 hours.Add sodium hydroxide (0.95g) and methoxy ethyl bromine (1.2mL) and this mixture 80 ℃ of lower stirrings 24 hours to this reactant mixture.After being cooled to room temperature, add entry and this mixture ethyl acetate extraction to this reactant mixture.Organic layer washs with saturated brine, with dried over mgso and filtration.With filtrate vacuum concentration and gained crude product by column chromatography purification (solvent on silica gel; Hexane/ethyl acetate=(266mg, yield: 21%), it is light yellow liquid 75/25-40/60) to obtain 4-(2-methoxy ethoxy)-1-piperidine carboxylic acid benzyl ester.
MS(APCI)m/z；294[M+H] +
(2) adding 10% carbon in the solution of chemical compound (266mg) in ethanol (5mL) that obtains in the above-mentioned steps (1) carries palladium (30mg) and under blanket of nitrogen this mixture is at room temperature stirred.This reactant mixture filtered and the filtrate vacuum concentration obtains 4-(2-methoxy ethoxy) piperidines (138mg, yield: 96%), it is colourless liquid.
MS(APCI)m/z；160[M+H] +
Reference example 98-99
Corresponding initiation material with process with embodiment 484 described identical modes and subsequently products therefrom process according to reference example 1 (3) and obtain the chemical compound shown in the following table B6.
Table B6
Figure S2006800391776D01601
Reference example 100-102
Corresponding initiation material obtains the chemical compound shown in the following table B7 to process with the described identical mode of embodiment 7B.
Table B7
Figure S2006800391776D01611
Test 1
(1) preparation of people CB1 receptor (film fraction):
Material)
People CB1-express cell system: hCB1/CHO#C3 (Euroscreen)
Culture medium: F-12 (GIBCO# 11765-062), 10% hyclone, antibiotic (400 μ g, Geneticin (GIBCO# 11811-031)
Buffer A: 50mM tris-HCl (pH 7.5) contains ethylenediaminetetraacetic acid (2.5mM), MgCl 2(5mM) and sucrose (200mM)
Method)
The expression of receptor cell of in above-mentioned culture medium, cultivating with phosphate buffer (x2) washing and ice-cold or 4 ℃ under to wherein add buffer A (2mL) (following method is also carried out) under uniform temp.Utilize cell curette collecting cell, process 20 seconds (adding pulse: 2 seconds, close pulse: 1 second) and centrifugal (500xg, 15min) with little sharp type ultrasonic device.Separate supernatant and centrifugal (43000xg, 60min).Gained precipitation group is suspended in the buffer A and uses pottery type homogenizer homogenize.Add isopyknic 80% glycerol and be stored under-80 ℃ to equal compound.
(2) method of CB1 receptor binding assays:
Material)
Buffer B: 50mM tris-HCl (pH 7.5) contains ethylenediaminetetraacetic acid (2.5mM), MgCl 2(5mM) and bovine serum albumin (2mg/mL, FAF, SIGMA-A7030)
Buffer C:50mM tris-HCl (pH 7.5) contains ethylenediaminetetraacetic acid (2.5mM), MgCl 2(5mM) and bovine serum albumin (2mg/mL, SIGMA-A7906)
Coating solution: 0.3% second diimine polymer
Radioligand: [ 3H]-CP55940 (30nM/7992dpm/ μ L), prepare by 8.3 μ M solution with buffer B dilution radioligand,
Method)
(96-hole, each hole to this test panel, Costar Code#3371) fills buffer B (140 μ L), solution (the 20 μ Ls of each test compound in dimethyl sulfoxide, final concentration: 0.1%), radioligand (20 μ L) and film specimen (20 μ L, 0.5 μ g/20 μ L) are also cultivated 90 minutes to promote this association reaction with this mixture under 30 ℃.This reactant mixture is gathered in the crops in each hole of flat board, this flat board is with above-mentioned coating solution pre-soaking (Packard Unifilter GF/B, #6005177).Described dull and stereotyped with buffer C (200 μ L * 10) washing and 50 ℃ lower dry 1 hour, Microscinti 40 (40 μ L) is joined in each hole.In conjunction with radioactive label come quantitative analysis (Top Count NXT, Packard) by scinticounting.The IC of each test compound antagonism radioligand and CB1 receptors bind 50Value is to utilize Graphpad Prism3.02 to calculate on the basis of quantification radioactive label activity.
3) result:
The IC of each chemical compound 50Shown in following table C1.Simultaneously, symbol (++ and +++) is defined as follows:
++：10nM＜IC 50＜100nM
+++：10nM＞IC 50
Table C1
Test compound IC 50(nM)
The chemical compound of embodiment 10 ++
The chemical compound of embodiment 131 ++
The chemical compound of embodiment 185 ++
The chemical compound of embodiment 224 ++
The chemical compound of embodiment 238 ++
The chemical compound of embodiment 287 ++
The chemical compound of embodiment 289 ++
The chemical compound of embodiment 309 +++
The chemical compound of embodiment 324 ++
The chemical compound of embodiment 410 ++
The chemical compound of embodiment 252 ++
The chemical compound of embodiment 253 +++
The chemical compound of embodiment 427 ++
The chemical compound of embodiment 452 +++
The chemical compound of embodiment 462 ++
Industrial applicibility
The disease that chemical compound of the present invention [I] effectively treats and/or prevents different CB1 receptors-mediation for example psychosis comprises schizophrenia.Chemical compound of the present invention [I] is also effectively given up long-time treatment, alcohol dependence or drug dependence.In addition, chemical compound of the present invention [I] is effectively as the medicament that improves analgesic activities or the medicament of smoking cessation.

Claims (11)

1. pyrazolo [1,5-a] pyrimidine compound or its pharmaceutically acceptable salt of formula [I]:
Figure FSB00000871223800011
Wherein
R 1And R 2Identical or different and be optional to be selected from the phenyl that following group replaces by 1-2: halogen atom, cyano group, optional by the C of 1-3 halogen atom replacement 1-6Alkyl,
Q is singly-bound,
Ring A is the substituted pyrazolecarboxylic ring that condenses with adjacent pyrimidine ring with formula (A),
Figure FSB00000871223800012
R 3It is hydrogen atom;
R 4(a) hydrogen atom, the C that (b) is randomly replaced by 1-3 halogen atom 1-6Alkyl, or (c) formula-N (R ') (group of R "),
R ' and R " identical or different and be (a) hydrogen atom, (b) C 1-6Alkyl, (c) acetyl group, or (d) C 1-6Alkyl sulphonyl,
E is following groups (ii):
Figure FSB00000871223800013
Q 1Singly-bound,
Q 2Singly-bound,
R 5And R 6One of be hydrogen atom and another one is (a) C 1-6Alkyl, (b) unsubstituted C 3-8Cycloalkyl, (c) formula :-N (R 8) (R 9) group, or (e) saturated or unsaturated heterocycle group, be selected from (i) saturated or undersaturated 4-to 7-member heteromonocyclic group group, 1-4 hetero atom that is selected from oxygen atom, sulphur atom and nitrogen-atoms contained in described heteromonocyclic group group, (ii) condense the nitrogenous bicyclic heterocyclic group of saturated or undersaturated 8-to 15-member that forms by aforementioned 4-to 7-member heteromonocyclic group group and 5-to 6-member monocyclic aryl, described heterocyclic radical (i) and (ii) optional by 1-4 group replacement that is selected from halogen atom and oxo group; Or
R 5And R 6Both mutually combine and consist of (a) saturated 4-to 7-member nitrogen-containing hetero monocyclic groups with adjacent nitrogen atom, this heteromonocyclic group group chooses wantonly to contain plural nitrogen-atoms and also choose wantonly except described nitrogen-atoms and contains 1-2 hetero atom that is selected from oxygen atom and sulphur atom, and described heterocyclic radical (a) is optional to be replaced by 1-3 oxo group
R 8And R 9One of be C 1-6Alkyl and another one is (a) C 1-6Alkyl, (b) the optional phenyl that is replaced by halogen, or (c) saturated or undersaturated 4-to 7-member heteromonocyclic group group, 1-4 hetero atom that is selected from oxygen atom, sulphur atom and nitrogen-atoms contained in described heteromonocyclic group group.
2. chemical compound claimed in claim 1 or its pharmaceutically acceptable salt, wherein
R 1And R 2Identical or different and be randomly to be selected from the phenyl that following group replaces by 1-2: halogen atom, cyano group, and randomly by the C of 1-3 halogen atom replacement 1-6Alkyl,
E is following formula (a) group:
a)-C(＝O)-N(R 5)(R 6)，
R 4(a) hydrogen atom, the C that (b) is randomly replaced by 1-3 halogen atom 1-6Alkyl, or (c) formula-N (R ') (group of R "),
R ' and R " identical or different and be (a) hydrogen atom, (b) C 1-6Alkyl, (c) acetyl group, or (d) C 1-6Alkyl sulphonyl,
R 5And R 6One of be hydrogen atom and another one is
(1) C 1-6Alkyl;
(2) C 3-8Cycloalkyl;
(3) formula-N (R 8) (R 9) group;
(4) randomly by 1-4 saturated or undersaturated 4-to 10-member heteromonocyclic group group or two heterocyclic radical that is selected from the group replacement of halogen atom and oxo group; Or
(5) R 5And R 6Both mutually combine and consist of saturated or undersaturated 5-to the 7-member nitrogen-containing hetero monocyclic groups that is randomly replaced by 1-2 oxo group with adjacent nitrogen atom,
R 8C 1-6Alkyl,
R 9It is the phenyl that (a) randomly replaced by halogen atom; Or (b) saturated or undersaturated 5-to 6-member heteromonocyclic group group.
3. chemical compound claimed in claim 2 or its pharmaceutically acceptable salt, wherein
R 1Randomly to be selected from the phenyl that following group replaces by 1 or 2: halogen atom, cyano group, and three halo C 1-6Alkyl,
R 2Randomly to be selected from the phenyl that halogen atom and cyano group replace by 1 or 2,
R 3Hydrogen atom,
R 4Hydrogen atom, alkyl, three halo C 1-6Alkyl, or formula-N (R ') (group of R "), R ' and R " one of be hydrogen atom or C 1-6Alkyl and another one is acetyl group or C 1-6Alkyl sulphonyl,
E is following formula (a) group:
(a)-C(＝O)-N(R 5)(R 6)，
R 5And R 6One of be hydrogen atom, another one is (a) C 1-6Alkyl, (b) C 3-8Cycloalkyl, saturated or undersaturated 4-to the 10-member list that (c) is randomly replaced by the individual group that is selected from halogen atom and oxo group of 1-4-or two-ring heterocyclic group, (d) formula :-N (R 8) (R 9) group, or (e) they both mutually combine and consist of randomly saturated or unsaturated 5-to the 6-member heteromonocyclic group group that is replaced by 1-2 oxo group with adjacent nitrogen atom,
R 8C 1-6Alkyl,
R 9The phenyl that (a) randomly replaced by halogen atom, or (b) saturated or undersaturated 5-to 6-member heteromonocyclic group group.
4. chemical compound claimed in claim 2 or its pharmaceutically acceptable salt, wherein R 1Randomly be selected from the phenyl that following group replaces: chlorine atom, fluorine atom, cyano group, two fluoro-C 1-4Alkyl and three fluoro-C 1-4Alkyl,
R 2Randomly to be selected from the phenyl that following group replaces by 1-2: the chlorine atom, fluorine atom, bromine atoms and cyano group,
R 3Hydrogen atom,
R 4Hydrogen atom, C 1-4Alkyl, two fluoro-C 1-4Alkyl, three fluoro-C 1-4Alkyl, or C 1-4Alkyl-carbonyl-amino,
E is following formula (a) group:
(a)-C(＝O)-N(R 5)(R 6)，
R 5And R 6One of be hydrogen atom and another one is C 1-4Alkyl, C 5-7Cycloalkyl is randomly by 1-2 saturated or undersaturated 4-to 6-member heteromonocyclic group group or formula-N (R that is selected from halogen atom and oxo group replacement 8) (R 9) group, or they both mutually combine and consist of randomly saturated or unsaturated 5-to the 6-member heteromonocyclic group group that is replaced by 1-2 oxo group with adjacent nitrogen atom,
R 8C 1-4Alkyl, and
R 9Chlorophenyl or pyridine radicals.
5. be selected from following chemical compound:
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-piperidino carbamoyl) pyrazolo [1,5-a]-pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[(N '-methyl-N '-phenyl diazanyl)-and carbonyl] pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-cyclohexyl carboxyamide base) pyrazolo [1,5-a]-pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[(N ', N '-dimethyl diazanyl) carbonyl]-pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-pyrrolidin-1-yl carbamoyl) pyrazolo [1,5-a]-pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-cyclopenta carbamoyl) pyrazolo [1,5-a]-pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(4-THP trtrahydropyranyl) carbamoyl]-pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(1,1-dioxo-Tetramethylene sulfide-3-yl)-carbamoyl] pyrazolo [1,5-a] pyrimidine;
(R)-and 6-(2-chlorphenyl)-7-(4-difluoromethyl phenyl)-3-[N-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-) carbamoyl] pyrazolo [1,5-a] pyrimidine;
(R)-and 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-2-methyl-3-[N-(1,1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;
(S)-and 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-2-methyl-3-[N-(1,1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;
(R)-and 6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-methyl-3-[N-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-) carbamoyl] pyrazolo [1,5-a] pyrimidine;
(S)-and 6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-methyl-3-[N-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-) carbamoyl] pyrazolo [1,5-a] pyrimidine;
6-(2-bromophenyl)-7-(4-chlorphenyl)-3-(N-cyclopenta carbamoyl) pyrazolo [1,5-a]-pyrimidine;
(R, S)-6-(2-bromophenyl)-7-(4-chlorphenyl)-3-[N-(1,1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;
(S)-and 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[N-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-) carbamoyl] pyrazolo [1,5-a] pyrimidine;
(R)-and 6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[N-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-) carbamoyl] pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-[N-(3-chlorphenyl)-N-methylamino]-carbamoyl] pyrazolo [1,5-a] pyrimidine;
6-(2-cyano-phenyl)-7-(4-chlorphenyl)-3-[N-[N-methyl-N-(2-pyridine radicals) amino]-carbamoyl] pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-isobutylamino formoxyl) pyrazolo [1,5-a]-pyrimidine;
6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[N-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-) carbamoyl] pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-(N-cyclopenta carbamoyl)-pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[N-[N-methyl-N-(2-pyridine radicals)-amino] carbamoyl] pyrazolo [1,5-a] pyrimidine;
(R)-and 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(1,1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-cyano-phenyl)-3-(N-cyclopenta carbamoyl) pyrazolo [1,5-a]-pyrimidine;
(R, S)-6-(2-chlorphenyl)-7-(4-chlorphenyl)-2-methyl-3-[N-(1,1-dioxo-tetrahydrochysene-thiene-3-yl-] carbamoyl] pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-fluorophenyl)-3-(N-cyclopenta carbamoyl) pyrazolo [1,5-a]-pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-[N-methyl-N-(2-pyridine radicals) amino]-carbamoyl] pyrazolo [1,5-a] pyrimidine;
(S)-and 6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(1,1-dioxo-Tetramethylene sulfide-3-yl) carbamoyl] pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-ethylamino formoxyl) pyrazolo [1,5-a]-pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-(N-cyclopropylamino formoxyl)-pyrazolo [1,5-a] pyrimidine;
(S)-and 6-(2-chlorphenyl)-7-(4-chloro-2-fluorophenyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl] pyrazolo [1,5-a] pyrimidine;
(S)-and 6-(2-chlorphenyl)-7-(4-difluoromethyl phenyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl] pyrazolo [1,5-a] pyrimidine;
(R)-6-(2-cyano-phenyl)-7-(4-trifluoromethyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl]-2-methylpyrazole [1,5-a] pyrimidine also;
(S)-6-(2-cyano-phenyl)-7-(4-trifluoromethyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl]-2-methylpyrazole [1,5-a] pyrimidine also;
6-(2-cyano-phenyl)-7-(4-chlorphenyl)-3-[N-(1-pyrrolidinyl) carbamoyl]-pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(2-5-flumethiazine-5-yl)-3-(N-cyclopenta carbamoyl)-pyrazolo [1,5-a] pyrimidine;
(R)-6-(2-cyano-phenyl)-7-(4-chlorphenyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl]-2-methylpyrazole [1,5-a] pyrimidine also;
6-(2-cyano-phenyl)-7-(4-chlorphenyl)-3-[[N '-methyl-N '-(2-pyridine radicals) diazanyl]-carbonyl]-2-methylpyrazole [1,5-a] pyrimidine also;
(R)-6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl]-2-trifluoromethyl pyrazol [1,5-a] pyrimidine also;
6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[(N ', N '-dimethyl diazanyl)-carbonyl]-2-acetyl-amino pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[[N '-methyl-N '-(2-pyridine radicals) diazanyl]-carbonyl]-2-acetyl-amino pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[[N '-methyl-N '-(2-pyridine radicals) diazanyl]-carbonyl]-2-(trifluoromethyl) pyrazolo [1,5-a] pyrimidine;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(1-pyrrolidinyl) carbamoyl]-2-difluoromethyl pyrazole [1,5-a] pyrimidine also;
(R)-6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl]-2-difluoromethyl pyrazole [1,5-a] pyrimidine also;
(S)-6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl]-2-difluoromethyl pyrazole [1,5-a] pyrimidine also;
6-(2-cyano-phenyl)-7-(4-chlorphenyl)-3-(N-piperidino carbamoyl)-2-difluoromethyl pyrazole is [1,5-a] pyrimidine also;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[N-(1,1-dioxo Thietane-3-yl)-carbamoyl] pyrazolo [1,5-a] pyrimidine;
7-(4-chlorphenyl)-6-(2-cyano group-4-fluorophenyl)-3-[N-(1-pyrrolidinyl) carbamoyl]-pyrazolo [1,5-a] pyrimidine;
7-(4-chlorphenyl)-6-(2-cyano-phenyl)-3-(N-piperidino carbamoyl)-2-methyl-pyrazolo [1,5-a] pyrimidine;
7-(4-chlorphenyl)-6-(2-cyano-phenyl)-3-[N-(1-pyrrolidinyl) carbamoyl]-2-methyl-pyrazolo [1,5-a] pyrimidine;
(R)-7-(4-chloro-2-fluorophenyl)-6-(2-cyano-phenyl)-3-[N-(1,1-dioxo tetrahydrochysene-thiene-3-yl-) carbamoyl]-2-methylpyrazole [1,5-a] pyrimidine also;
7-(4-chloro-2-fluorophenyl)-6-(2-cyano-phenyl)-3-[N-(1-pyrrolidinyl) carbamoyl]-2-methylpyrazole [1,5-a] pyrimidine also;
6-(2-chlorphenyl)-7-(4-chlorphenyl)-3-[2-(1,1-dioxo thiomorpholine generation) acetyl group]-2-methylpyrazole [1,5-a] pyrimidine also;
6-(2-chlorphenyl)-7-(4-trifluoromethyl)-3-[N-(Tetramethylene sulfide-3-yl)-carbamoyl] pyrazolo [1,5-a] pyrimidine,
Or its pharmaceutically acceptable salt.
6. one kind contains pyrazolo [1, the 5-a] pyrimidine compound of the formula [I] as active component or the pharmaceutical composition as the CB1 receptor antagonist of its pharmaceutically acceptable salt:
Figure FSB00000871223800071
Wherein
R 1And R 2Identical or different and be optional to be selected from halogen atom, cyano group, optional by the C of 1-3 halogen atom replacement by 1-2 1-6The phenyl that the group of alkyl replaces,
Q is singly-bound,
Ring A is the substituted pyrazolecarboxylic ring that condenses with the adjacent pyrimidine ring with formula (A) structure:
Figure FSB00000871223800081
R 3It is hydrogen atom;
R 4(a) hydrogen atom, the C that (b) is randomly replaced by 1-3 halogen atom 1-6Alkyl, or (c) formula-N (R ') (group of R "),
R ' and R are " identical or different and be (a) hydrogen atom, (b) unsubstituted C 1-6Alkyl, (c) acetyl group, or (d) C 1-6Alkyl sulphonyl,
E is following groups (ii):
Figure FSB00000871223800082
Q 1Singly-bound,
Q 2Singly-bound,
R 5And R 6One of be hydrogen atom and another one is
(a) C 1-6Alkyl,
(b) unsubstituted C 3-8Cycloalkyl,
(c) formula-N (R 8) (R 9) group, or
(d) saturated or unsaturated heterocycle group, be selected from (i) saturated or undersaturated 4-to 7-member heteromonocyclic group group, 1-4 hetero atom that is selected from oxygen atom, sulphur atom and nitrogen-atoms contained in described heteromonocyclic group group, (ii) condense the nitrogenous bicyclic heterocyclic group of saturated or undersaturated 8-to 15-member that forms by aforementioned 4-to 7-member heteromonocyclic group group and 5-to 6-member monocyclic aryl, described heterocyclic group (i) and (ii) optional by 1-4 group replacement that is selected from halogen atom and oxo base; Or
R 5And R 6Both mutually combine and consist of (a) saturated 4-to 7-member nitrogen-containing hetero monocyclic groups with adjacent nitrogen atom, this heteromonocyclic group group chooses wantonly to contain two or more nitrogen-atoms and also choose wantonly except described nitrogen-atoms and contains 1-2 hetero atom that is selected from oxygen atom and sulphur atom, replaced by 1-3 oxo group with described heterocyclic group (a) is optional
R 8And R 9One of be C 1-6Alkyl and another one is (a) C 1-6Alkyl, (b) the optional phenyl that is replaced by halogen atom, or (c) saturated or undersaturated 4-to 7-member heteromonocyclic group group, 1-4 hetero atom that is selected from oxygen atom, sulphur atom and nitrogen-atoms contained in described heteromonocyclic group group.
7. the pharmaceutical composition of claim 6, described compositions is the medicament that prevents and/or treats the disease of CB1 receptor-mediation.
8. the pharmaceutical composition of claim 7, wherein the disease of CB1 receptor-mediation is psychosis, comprises that psychosis comprises schizophrenia, anxiety disorder, stress, depression, epilepsy, neurodegenerative disease, spinocerebellar disease, cognitive disorder, craniocerebral trauma, the panic attack, peripheral neurophaty, glaucoma, migraine, parkinson, Alzheimer, Huntingtons chorea, Raynaud's syndrome trembles, mandatory Value and Behaviors disease, amnesia, alzheimer disease, disease of thymus gland, Tourette's syndrome, tardive dyskinesia, bipolarity obstacle, cancer, the drug-induced dyskinesia, dystonia, septic shock, hemorrhagic shock, hypotension, the insomnia, immunological diseases comprise inflammation, multiple sclerosis, vomiting, diarrhoea, asthma, the appetite imbalance comprises bulimia nerovsa and anorexia, fat, noninsulindependent diabetes (NIDDM), dysmnesia, urinary disorders, cardiovascular disease, infertility infects the disease that demyelination is relevant, the neuritis, viral encephalitis, cerebrovascular events, hepatitis interstitialis chronica or gastroenteropathy comprise intestinal trafficability characteristic obstacle.
9. the pharmaceutical composition of claim 6, described compositions is to give up the medicament of long-term treatment, alcohol dependence or drug dependence.
10. the pharmaceutical composition of claim 6, described compositions are the medicaments that improves the analgesic activities of analgesia or anaesthetic.
11. the pharmaceutical composition of claim 6, described compositions are the medicaments of smoking cessation (give up and smoke or nicotine dependence).
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