CN1771231B - Calcium receptor modulating compound and use thereof - Google Patents

Calcium receptor modulating compound and use thereof Download PDF

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CN1771231B
CN1771231B CN03823938.8A CN03823938A CN1771231B CN 1771231 B CN1771231 B CN 1771231B CN 03823938 A CN03823938 A CN 03823938A CN 1771231 B CN1771231 B CN 1771231B
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salt
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CN1771231A (en
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安间常雄
森亮
川瀬雅弘
木村宏之
吉田雅都
艾伯特·C·吉奥科斯
斯科特·A·普拉特
克里斯托弗·P·科雷特
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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Abstract

The invention provides a calcium receptor modulator comprising a compound of the formula (I): wherein ring A is an optionally substituted 5- to 7- membered ring; ring B is an optionally substituted 5- to 7- membered heterocyclic ring; X<1> is CR<1>, CR<1>R<2>, N or NR<13>; X<2> is N or NR<3>; Y is C, CR<4> or N, Z is CR<5>, CR<5>R<6>, N or NR<7>; Ar is an optionally substituted cyclic group; R is H, an optionally substituted hydrocarbon group, etc.; and - is a single bond or a double bond; R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7> and R<13> are independently H, an optionally substituted hydrocarbon group; or a salt thereof or a prodrug thereof. Compounds of the formula (II) and (III): wherein ring A is an optionally substituted 5- to 7- membered ring; Q is C, CR<5> or N; R<8>, R<9>,R<10>, R<11> and R<12> are independently, H, an optionally substituted hydrocarbon group, etc., or a salt thereof are also provided. Also the X<1>, R<3>, R<1>, Y and X<3> in the formula (II) and (III) are defined as above.

Description

Calcium receptor modulating compound and uses thereof
Background of invention
Invention field
The present invention relates to have calcium-irritability acceptor (CaSR is designated hereinafter simply as the Ca acceptor) regulates (excitement or antagonism) active heterogeneous ring compound, contains their pharmaceutical composition and can be used for synthesizing their midbody compound.
Background technology
For example playing an important role in the various cell functions for internal secretion and exocrine cell etc. except that N﹠M kept and regulated to calcium ion (being designated hereinafter simply as Ca).In view of this, blood Ca level is maintained in the narrow scope by strictness.Rat parathyroid hormone 1-34 (PTH) is played the part of core roles in keeping this blood Ca level.Therefore, pth secretion PTH changes in response to blood Ca level observantly, must be regulated in view of the above.In fact, when blood Ca level changed, blood PTH horizontal respone also changed rapidly in this.The outer Ca concentration of parathyroid gland cell competent cell and this information are pointed out by Brown etc. already to the possibility of the mechanism of cell transmission.1993, they successfully cloned and have differentiated Ca-irritability acceptor (CaSR is designated hereinafter simply as the Ca acceptor) (Nature, 366,575-580 (1993)) from bovine parathyroid.
The Ca acceptor is crossed over the intracellular region that 600 amino acid whose large-scale terminal cell outskirts and carboxyl C-end be made up of 200 or following amino acid and is formed by N-is terminal, described large-scale terminal cell outskirt has seven and strides film span structural domain, as other g protein coupled receptors.
It is believed that when extracellular Ca concentration increased, Phospholipid hydrolase (PL)-C was activated, cause that the interior Ca concentration of cell increases and PTH secretes because of inositoltriphosphoric acid (IP 3) increase and suppress.Because when keeping high extracellular Ca concentration value, Ca concentration increases continuously in the cell thereupon, therefore think also to have promoted Ca to flow into from outside.PL-A 2Be activated because of extracellular Ca increases with D, but also exist them to be activated the possibility that is activated via the Ca acceptor simultaneously via protein kinase (PK)-C.The Ca acceptor also via Gi albumen or via arachidonic acid because of PL-A 2Activation and produce and to suppress adenylate cyclase reduces ring AMP (Bone, 20,303-309 (1997)) in the cell.
The Ca receptor mrna is expressed in a lot of tissues, expression amount is very high in following tissue: device (SFO) and hippocampus (Bone under collection tube (IMCD) and the camara in parathyroid gland, parafollicular cells of thyroid gland, kidney ureter medullary substance and the thick ascending branch of cortex (MTAL and CTAL), the marrow, 20,303-309 (1997)).In addition, be expressed in a lot of tissues and be identified, for example hypothalamus, cerebellum and olifactory nerve nuclear, zone, lung, stomach, pancreas, intestines and the skin of kidney ureter except that TAL.Because the Ca acceptor is present in different tissues, so its physiological function still remains to be fully realized.But, expection Ca acceptor is regulated (excitement or antagonism) medicine will provide novel treatment for various disease states, comprise as follows:
1, the medicine of treatment osteopathia
Because the substance metabolism activity gives to have obtained checking by the intermittence of PTH, be to be hopeful to treat osteoporotic medicine so be regarded as to regulate PTH excretory Ca acceptor adjusting medicine.In addition, selectable Ca acceptor adjusting medicine also can effectively be treated osteoporosis by stimulating the thyrocalcitonin secretion with regard to parafollicular cells of thyroid gland.Whether with parathyroid gland in identical Ca acceptor be present in scleroblast, osteoclast and the osteocyte still doubtful.But, wherein there is number of C a-irritability mechanism really, therefore, can expects that the medicine that directly acts on them is the medicine of treatment osteopathia.
2, kidney-functionality medicine
In the kidney to the processing of water and mineral substance not only depend on target organ to hormone for example PTH, vitamins D etc. the effect the result, and in the supposition kidney Ca acceptor in response to the Ca concentration in the extracellular fluid and magnesium ion concentration and bring into play function (Kidney Int, 50,2129-2139 (1996)).And then, think that also the Ca acceptor regulates medicine and can regulate blood volume in the kidney, glomerular filtration amount, renin secretion and vitamins D activation, and the inflow and the outflow of control water and mineral substance.
3, central nervous system and internal secretion-functionality medicine
The Ca acceptor is present in the almost all zones in the central nervous system, is particularly significantly expressed (Brain Res, 744,47-56 (1997)) in the device under hippocampus, cerebellum and arched roof.Although the details of this function is still unclear, but the Ca expression of receptor of birth back in hippocampus meets the collection (Develop Brain Res, 100,13-21 (1997)) of LTP (long tight phenomenon), and therefore, can infer with mnemonic learning has relation.Therefore, the hemato encephalic barrier perviousness is high and have the Ca acceptor of highly selective to regulate medicine to central nervous system can be used for the treatment of Alzheimer.In addition, because the hypercalcemia patient understands dry,, the Ca acceptor also can control them so regulating medicine.The existence existing report (Mol Endocrinol, 10,555-565 (1996)) of Ca acceptor in the pituitary gland cell of mouse secretion ACTH.It is believed that also Ca acceptor adjusting medicine can be used for Sheehan syndrome and subpituitarism or hyperpituitarism.
4, Digestive tract-functionality medicine
It is believed that the Ca acceptor is present in the gastral Auerbach's plexus, the motion of control enteron aisle.In clinical trial, known hypercalcemia patient is with constipation, and known low blood calcium patient is with the excitement of gastrointestinal motor.The existing report of the existence of Ca acceptor in the gastrin secretory cell (G cell) of stomach (J.Clin Invest, 99,2328-2333 (1997)), intestinal absorption, constipation, diarrhoea, defecation and gastric acid secretion can be subjected to acting on the controlled delivery of pharmaceutical agents of Ca acceptor in the digestive tube.And then, have been found that the Ca acceptor is present in the CCL188, its control c-myc expression and propagation (Biochem Biophys Res Commum, 232,80-83 (1997)), this is consistent with this fact of sideration performance negative correlation with the Ca picked-up of the colon and the rectum cancer well, therefore, can expect that it also is prevention and the medicine for the treatment of this class cancer that the Ca acceptor is regulated medicine.
Formerly technology disclosed various heterogeneous ring compounds.For example, WO 01/53266 discloses following formula: compound:
Wherein R, R 1And R 2Be H, hydroxyl etc. independently.This compound has phosphoinositide 3-kinase and suppresses active, can be used for treating coronary artery and blocks etc.Indian J.Chem., Sect.B (1993), 32B (5), 586-9 disclose the synthetic of following formula: compound:
Figure A0382393800192
Wherein R is hydrogen, chlorine, methyl or methoxy.But, openly do not use.United States Patent (USP) 4,746,656 (JP 63-33380A) disclose following formula: compound:
R wherein 1Be aryl or heterocyclic radical, R 2Be aryl etc., R 3And R 4Be H, alkyl etc. independently.This compound is the Ca channel blocker.EP 217142 discloses following formula: compound:
Figure A0382393800202
Wherein R is hydrogen, alkyl etc., R 1Be hydrogen, nitro, cyano group etc., R 2Be phenyl, cycloalkyl etc., R 3Be hydrogen, acyl group etc., R 8Be carboxyl, carbamyl etc.This compound also is the Ca channel blocker.
But, formerly technology does not have discovery to have the heterogeneous ring compound of Ca receptor modulating activities.
Goal of the invention
An object of the present invention is to provide the compound that comprises new compound with Ca receptor modulating activities.
Another object of the present invention provides the pharmaceutical composition that contains The compounds of this invention.
These purposes of the present invention with and other objects and advantages will be that those skilled in the art institute is apparent because of following explanation.
Summary of the invention
The inventor has furtherd investigate the compound with Ca receptor modulating activities.Found that to have the Ca receptor modulating activities, but hyoscine is a new compound by formula as follows (II), (III) and the compound (IIIa) represented wherein by the compound of formula as follows (I) representative.
According to the present invention, provide:
1, formula (II) compound:
Wherein encircling A is the first ring of optional substituted 5-to 7-;
Q is C, CR 5(R wherein 5Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-be-CO-,-CS-,-SO-or-SO 2-, Z 2Be optional substituted alkyl, optional substituted heterocyclic radical, optional substituted hydroxyl or optional substituted amino)) or N;
X 1Be CR 1(R wherein 1Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above)), CR 1R 2(R wherein 1Be as defined above, R 2Be H or optional substituted alkyl), N or NR 13(R wherein 13Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above));
R 3Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above);
Y is C, CR 4(R wherein 4Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above)) or N;
Ar is optional substituted cyclic group;
R 9And R 10Being identical or different, is H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above);
R 11And R 12Being identical or different, is H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1 '-Z 2(wherein-Z 1 '-be-CS-,-SO-or-SO 2-, Z 2Be as defined above);
Or R 9And R 10Or R 11And R 12Can be in conjunction with constituting oxo base, methylene radical or ring; Or R 10And R 11Can be in conjunction with constituting ring;
Be singly-bound or two key;
Its condition is
(1) be that 6-unit ring and Q are C or CR when encircling A 5The time, X 1Be C-Z 1-Z 2, C (Z 1-Z 2) R 2Or N-Z 1-Z 2, R 9And R 10Not H, or R 9And R 10Debond constitutes the oxo base, or R 10And R 11Debond constitutes 5-unit ring,
(2) when ring A be 6-unit ring and Q when being N, X 1Be C-Z 1-Z 2, C (Z 1-Z 2) R 2Or N-Z 1-Z 2, R 9And R 10Debond constitutes the oxo base,
(3) be that 5-unit ring and Q are C or CR when encircling A 5The time, X 1Be C-Z 1-Z 2, C (Z 1-Z 2) R 2Or N-Z 1-Z 2, Z 2Be optional substituted amino and
(4) when ring A be 5-unit ring and Q when being N, R 9And R 10In at least one is CHR 15R 16(R wherein 15And R 16In at least one is identical or different, be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above)), another is not optional substituted phenyl;
Or its salt;
2, formula (III) compound:
Figure A0382393800222
R wherein 1Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted thiol group, optional substituted amino, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-be-CO-,-CS-,-SO-or-SO 2-, Z 2Be optional substituted alkyl, optional substituted heterocyclic radical, optional substituted hydroxyl or optional substituted amino);
R 3Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above);
Y is C, CR 4(R wherein 4Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above)) or N;
R 8Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above);
Ar is optional substituted cyclic group:
R 9And R 10Being identical or different, is H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above); Perhaps R 9And R 10Can be in conjunction with constituting oxo base, methylene radical or ring;
X 3Be a key, Sauerstoffatom, optional oxidized sulphur atom, N, NR 7 '(R wherein 7 'Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted heterocyclic radical or following formula group :-Z 1 '-Z 2(wherein-Z 1 '-be-CS-,-SO-or-SO 2-, Z 2Be as defined above)) or optional substituted divalence C 1-2Alkyl;
Be singly-bound or two key;
Its condition is R 9And R 10In at least one is CHR 15R 16(R wherein 15And R 16Being identical or different, is H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above)), another is the group outside the optional substituted phenyl;
Or its salt;
3, according to above-mentioned 1 or 2 compound, R wherein 1Be (1) optional substituted heterocyclic radical, perhaps (2) following formula group :-Z 1-Z 2(wherein-Z 1-be-CO-,-CS-,-SO-or-SO 2-, Z 2Be optional substituted alkyl, optional substituted heterocyclic radical, optional substituted hydroxyl or optional substituted amino);
4, according to above-mentioned 3 compound, wherein-Z 1-be-CO-Z 2Be optional substituted hydroxyl or optional substituted amino;
5, according to above-mentioned 2 compound, R wherein 3Be H, C 1-6Alkyl or C 7-14Aralkyl;
6, according to above-mentioned 2 compound, R wherein 8Be H, C 1-6Alkyl, C 1-6Alkylthio or C 1-6Alkoxyl group, it can be replaced by hydroxyl;
7, according to above-mentioned 1 or 2 compound, R wherein 9And R 10Being identical or different, is C 1-6Alkyl, perhaps R 9And R 10Be bonded to each other and constitute ring;
8, according to above-mentioned 2 compound, R wherein 1Be following formula group :-Z 1-Z 2(wherein-Z 1-be-CO-,-CS-,-SO-or-SO 2-, Z 2Be optional substituted alkyl, optional substituted heterocyclic radical, optional substituted hydroxyl or optional substituted amino); R 3Be H; Ar is optional substituted aromatics cyclic group; X 3Be CR 11R 12(R wherein 11And R 12Being identical or different, is H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above), perhaps R 11And R 12Can be in conjunction with constituting oxo base, methylene radical or ring); R 9And R 10Being identical or different, is C 1-6Alkyl, perhaps R 9And R 10Can be in conjunction with constituting ring;
9, according to above-mentioned 8 compound, R wherein 1It is optional substituted carbamyl;
10, according to above-mentioned 9 compound, R wherein 1Be following formula group :-CONR 20(CR 21R 22R 23) (R wherein 20Be H or optional substituted alkyl, R 21, R 22And R 23Being identical or different, is optional substituted alkyl or optional substituted heterocyclic radical, perhaps R 20And R 21Can encircle in conjunction with constituting);
11, formula (IIIa) compound:
Figure A0382393800241
R wherein 1aBe (1) optional substituted heterocyclic radical, perhaps (2) following formula group :-Z 1a-Z 2a(wherein-Z 1a-be-CO-,-CS-,-SO-or-SO 2-, Z 2aBe (i) optional substituted heterocyclic radical, (ii)-NR 20a(CR 21aR 22aR 23a) ((a) R wherein 20aBe H or optional substituted alkyl; R 21aBe optional substituted heterocyclic radical, it can condense with optional substituted phenyl ring, perhaps optional substituted phenyl, and it can condense with optional substituted aromatic heterocycle; R 22aAnd R 23aBeing identical or different, is optional substituted alkyl or optional substituted heterocyclic radical, perhaps R 22aAnd R 23aCan be in conjunction with constituting ring, perhaps (b) R 20aBe H or optional substituted alkyl; R 21a, R 22aAnd R 23aBeing identical or different, is optional substituted C 1-8Aliphatic hydrocarbyl, its condition be the summation of carbonatoms be 7 or more than), (iii)-NR 20aR 25a(R wherein 20aBe as defined above, R 25aBe optional substituted C 6-10Aryl-C 2-4Alkyl, C 6-10Aryloxy-C 2-4Alkyl, C 6-10Arylamino-C 2-4Alkyl, C 7-14Aryl alkyl amino-C 2-4Alkyl, heterocycle-C 2-4Alkyl or heterocyclic radical), 5-to the 7-unit cyclic amino that (iv) replaces, perhaps (v)-OR 24a(R wherein 24aBe (a) optional substituted C 7-14Aralkyl, (b) optional substituted C 3-7Alicyclic alkyl, (c) optional substituted C 7-24Aliphatic hydrocarbyl, perhaps (d) optional substituted heterocyclic radical));
R 3Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-be-CO-,-CS-,-SO-or-SO 2-, Z 2Be optional substituted alkyl, optional substituted heterocyclic radical, optional substituted hydroxyl or optional substituted amino);
Y is C, CR 4(R wherein 4Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above)) or N;
R 8Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above);
Ar is optional substituted cyclic group;
R 9And R 10Being identical or different, is H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above), perhaps R 9And R 10Can be in conjunction with constituting oxo base, methylene radical or ring;
X 3Be a key, Sauerstoffatom, optional oxidized sulphur atom, N, NR 7 '(R wherein 7 'Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted heterocyclic radical or following formula group :-Z 1 '-Z 2(wherein-Z 1 '-be-CS-,-SO-or-SO 2-, Z 2Be as defined above)) or optional substituted divalence C 1-2Alkyl;
Figure A0382393800251
Be singly-bound or two key;
Its condition is R 9And R 10In at least one is CHR 15R 16(R wherein 15And R 16Being identical or different, is H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above)), another is not optional substituted phenyl;
Or its salt;
12, according to above-mentioned 11 compound, R wherein 1aBe following formula group :-CONR 20a(CR 21bR 22bR 23b) (R wherein 20aBe as defined above, R 21b, R 22bAnd R 23bIn at least one is optional substituted heterocyclic radical, it can condense with optional substituted phenyl ring, perhaps chooses substituted phenyl wantonly, it can condense with optional substituted aromatic heterocycle);
13, according to above-mentioned 11 compound, wherein:
R 1aBe (1) optional substituted 5-to 7-unit's aromatics or non-aromatic heterocycle, have 1-4 the heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, perhaps (2) following formula group :-CO-Z 2c(Z wherein 2cBe (i) optional substituted 5-to 7-unit's aromatics or non-aromatic heterocycle, have 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, (ii)-NR 20c(CR 21cR 22cR 23c) ((a) R wherein 20cBe H or optional substituted alkyl, be selected from C 1-8Radical of saturated aliphatic alkyl, C 2-8Unsaturated aliphatic alkyl, C 3-7Saturated alicyclic alkyl, C 3-7Unsaturated cycloaliphatic alkyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon base, C 3-7Saturated or undersaturated alicyclic radical-C 1-8Saturated or undersaturated aliphatic hydrocarbyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 1-4Alkyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 2-4Alkenyl, C 6-10Aryl and C 7-14Aralkyl; R 21cBe 1) optional substituted 5-to 7-unit's aromatics or non-aromatic heterocycle, have 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it can condense with optional substituted phenyl ring, perhaps 2) choose substituted C wantonly 6-10Aryl, it can condense with the first aromatic heterocycle of optional substituted 5-to 7-, and described heterocycle has 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom; R 22cAnd R 23cBeing identical or different, is optional substituted alkyl, is selected from C 1-8Radical of saturated aliphatic alkyl, C 2-8Unsaturated aliphatic alkyl, C 3-7Saturated alicyclic alkyl, C 3-7Unsaturated cycloaliphatic alkyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon base, C 3-7Saturated or undersaturated alicyclic radical-C 1-8Saturated or undersaturated aliphatic hydrocarbyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 1-4Alkyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 2-4Alkenyl, C 6-10Aryl and C 7-14Aralkyl perhaps has 1-4 heteroatomic optional substituted 5-to 7-unit's aromatics or non-aromatic heterocycle, perhaps R that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom 22cAnd R 23cCan be in conjunction with constituting C 3-7Carbocyclic ring, perhaps (b) R 20cBe H or optional substituted alkyl, be selected from C 1-8Radical of saturated aliphatic alkyl, C 2-8Unsaturated aliphatic alkyl, C 3-7Saturated alicyclic alkyl, C 3-7Unsaturated cycloaliphatic alkyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon base, C 3-7Saturated or undersaturated alicyclic radical-C 1-8Saturated or undersaturated aliphatic hydrocarbyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 1-4Alkyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 2-4Alkenyl, C 6-10Aryl and C 7-14Aralkyl; R 21c, R 22cAnd R 23cBeing identical or different, is optional substituted C 1-8Aliphatic hydrocarbyl, its condition be the summation of carbonatoms be 7 or more than), (iii)-NR 20cR 25c(R wherein 20cBe as defined above, R 25cBe optional substituted C 6-10Aryl-C 2-4Alkyl, C 6-10Aryloxy-C 2-4Alkyl, C 6-10Arylamino-C 2-4Alkyl, C 7-14Aryl alkyl amino-C 2-4Alkyl, 5-to 7-unit heterocycle (having 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom)-C 2-4Alkyl or 5-to 7-unit heterocyclic radical (having 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom)), 5-to the 7-unit cyclic amino that (iv) replaces, perhaps (v)-OR 24c(R wherein 24cBe (a) optional substituted C 7-14Aralkyl, (b) optional substituted C 3-7Alicyclic alkyl, (c) optional substituted C 7-24Aliphatic hydrocarbyl, perhaps (d) optional substituted 5-to 7-unit's aromatics or non-aromatic heterocycle have 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom));
Wherein said R 1a, Z 2c, R 20c, R 21c, R 22c, R 23c, R 24cAnd R 25cSubstituting group be 1 to 3 be selected from down the group substituting group:
1) C 1-6Alkyl,
2) C 2-6Alkenyl,
3) C 2-6Alkynyl,
4) C 3-7Cycloalkyl,
5) C 6-10Aryl, it can be replaced by 1 to 3 substituting group that is selected from down group: C 1-6Alkyl, amino, N-(C 1-6Alkyl) amino, N, N-two-(C 1-6Alkyl) amino, amidino groups, carbamyl, N-(C 1-6Alkyl) carbamyl, N, N-two-(C 1-6Alkyl) carbamyl, sulfamyl, N-(C 1-6Alkyl) sulfamyl, N, N-two-(C 1-6Alkyl) sulfamyl, carboxyl, C 2-7Alkoxy carbonyl, hydroxyl, C 1-6Alkoxyl group, sulfydryl, C 1-6Alkylthio, sulfo group, cyano group, azido-, halogen, nitro, nitroso-group, phosphono, C 1-6Alkoxy phosphoryl, two-(C 1-6Alkoxyl group) phosphoryl and by phosphono, C 1-6Alkoxy phosphoryl and two-(C 1-6Alkoxyl group) C of phosphoryl replacement 1-6Alkyl (following with the 5th) group is called " C " group),
6) aromatic heterocyclic radical, be selected from (a) aromatics 5-or 6-unit heterocyclic radical, have 1-4 and be selected from nitrogen-atoms, the heteroatoms of Sauerstoffatom and sulphur atom, (b) fused bicyclic heterocyclic radical, be selected from nitrogen-atoms by having 1 to 3, the heteroatomic aromatics 5-of Sauerstoffatom and sulphur atom or 6-unit's heterocyclic radical and phenyl ring or have 1 to 3 and be selected from nitrogen-atoms, the heteroatomic aromatics 5-of Sauerstoffatom and sulphur atom or 6-unit heterocyclic radical condense and form, (c) fused tricyclic heterocycles base, have 1 to 3 by [1] and be selected from nitrogen-atoms, the heteroatomic aromatics 5-of Sauerstoffatom and sulphur atom or 6-unit heterocyclic radical, [2] phenyl ring and [3] have 1 to 3 and are selected from nitrogen-atoms, the heteroatomic aromatics 5-of Sauerstoffatom and sulphur atom or 6-unit's heterocyclic radical or phenyl ring condense and form
7) heterocycle-oxygen base, by each above-mentioned aromatic heterocyclic radical (a) and (b) and (c) with oxygen base be combined into,
8) non-aromatics 4-or 7-unit heterocyclic radical has 1 to 3 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom,
9) C 7-14Aralkyl, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
10) amino,
11) amino of N-list-replacement is selected from N-(C 1-6Alkyl) amino, N-(C 2-6Alkenyl) amino, N-(C 3-7Cycloalkyl) amino and N-(C 6-10Aryl) amino, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
12) be selected from C by two 1-6Alkyl, C 2-6Alkenyl, C 3-7Cycloalkenyl group and C 6-10The amino that the substituting group of aryl replaces, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
13) amidino groups,
14) acyl group is selected from C 2-8Alkyloyl, C 3-8Enoyl-, C 3-7Cycloalkyl-carbonyl, C 3-7Cycloalkenyl group-carbonyl, C 6-10Aryl-carbonyl (it can be replaced by 1 to 3 substituting group that be selected from " C " group) and heterocyclic radical-carbonyl (forming) by having 1 to 3 heteroatomic aromatics that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom or non-aromatics 5-or the first heterocyclic radical of 6-and carbonyl bonding,
15) carbamyl,
16) carbamyl of list-replacement is selected from N-(C 1-6Alkyl) carbamyl, N-(C 2-6Alkenyl) carbamyl, N-(C 3-7Cycloalkyl) carbamyl and N-(C 6-10Aryl) carbamyl, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
17) be selected from C by two 1-6Alkyl, C 2-6Alkenyl, C 3-7Cycloalkyl and C 6-10The carbamyl that the substituting group of aryl replaces, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
18) sulfamyl,
19) sulfamyl of N-list-replacement is selected from N-(C 1-6Alkyl) sulfamyl, N-(C 2-6Alkenyl) sulfamyl, N-(C 3-7Cycloalkyl) sulfamyl and N-(C 6-10Aryl) sulfamyl, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
20) be selected from C by two 1-6Alkyl, C 2-6Alkenyl, C 3-7Cycloalkyl and C 6-10The sulfamyl that the substituting group of aryl replaces, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
21) carboxyl,
22) C 1-6Alkoxyl group-carbonyl,
23) hydroxyl,
24) C 1-6Alkoxyl group,
25) C 2-10Alkene oxygen base,
26) C 3-7Cycloalkyloxy,
27) C 6-10Aryloxy, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
28) C 7-14Aralkoxy, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
29) sulfydryl,
30) C 1-6Alkylthio,
31) C 7-14Aromatic alkylthio, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
32) C 6-10Arylthio, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
33) C 1-6Alkyl sulphinyl,
34) C 7-14Aralkyl sulfinyl, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
35) C 6-10Aryl sulfonyl kia, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
36) C 1-6Alkyl sulphonyl,
37) C 7-14The aralkyl alkylsulfonyl, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
38) C 6-10Aryl sulfonyl, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
39) sulfo group,
40) cyano group,
41) azido-,
42) halogen,
43) nitro,
44) nitroso-group,
45) phosphono,
46) C 1-6Alkoxyl group-phosphoryl,
47) two-C 1-6Alkoxyl group-phosphoryl,
48) by phosphono, C 1-6Alkoxy phosphoryl or two-(C 1-6Alkoxyl group) C of phosphoryl replacement 1-6Alkyl,
49) C that is replaced by 1 to 4 halogen atom 1-6Alkyl,
50) C that is replaced by 1 to 4 halogen atom 1-6Alkoxyl group and
51) C 1-6Alkylene dioxo base
(following with the above-mentioned the 1st) is to 51) group be called " B " group);
R 3Be H, C 1-6Alkyl or C 7-14Aralkyl;
Y is CH;
R 8Be H, C 1-6Alkyl, C 1-6Alkylthio or C 1-6Alkoxyl group can be replaced by hydroxyl;
Ar is (1) C 6-10Aryl, (2) 5-to 7-unit's aromatics or non-aromatic heterocycle have 1-4 the heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, perhaps (3) C 3-7Saturated or undersaturated alicyclic alkyl, they can be replaced by 1 to 3 substituting group that is selected from " B " group separately;
R 9And R 10One of be hydrogen atom or C 1-6Alkyl, it can be replaced by 1 to 3 substituting group that is selected from " B " group, and another is (1) alkyl, is selected from C 1-8Radical of saturated aliphatic alkyl, C 2-8Unsaturated aliphatic alkyl, C 3-7Saturated alicyclic alkyl, C 3-7Unsaturated cycloaliphatic alkyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon base, C 3-7Saturated or undersaturated alicyclic radical-C 1-8Saturated or undersaturated aliphatic hydrocarbyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 1-4Alkyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 2-4Alkenyl, C 6-10Aryl and C 7-14Aralkyl, they can be replaced by 1 to 3 substituting group that is selected from " B " group separately, and perhaps (2) 5-to 7-unit's aromatics or non-aromatic heterocycle have 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it can be replaced by 1 to 3 substituting group that is selected from " B " group, perhaps
R 9And R 10Can be in conjunction with constituting C 5-7Carbocyclic ring;
X 3Be CH 2
14, according to above-mentioned 8 compound, R wherein 1Be following formula group :-CONR 20(CR 21R 22R 23) (R wherein 20Be H, R 21, R 22And R 23Being identical or different, is optional substituted alkyl or optional substituted heterocyclic radical); R 3Be H; Ar is optional substituted aromatics cyclic group; X 3Be CH 2Y is CH; R 8Be H or optional substituted alkyl, optional substituted alkoxyl group, optional substituted sulfane base, optional substituted sulfinyl or optional substituted alkylsulfonyl, C 1-6Alkoxyl group-carbonyl; R 9And R 10Being identical or different, is optional substituted alkyl;
15, according to above-mentioned 14 compound, R wherein 21, R 22And R 23In at least one is optional substituted heterocyclic radical or optional substituted phenyl;
16, according to above-mentioned 14 compound, R wherein 20And R 21In conjunction with constituting the first ring of optional substituted 5-to 7-, R 22And R 23Being identical or different, is optional substituted alkyl, optional substituted heterocyclic radical or optional substituted phenyl;
17, according to above-mentioned 14 compound, R wherein 21And R 22Being identical or different, is C 1-8Alkyl, R 23Be the first heterocyclic radical of optional substituted 5-, it can condense with optional substituted phenyl ring, perhaps optional substituted phenyl;
18, according to above-mentioned 16 compound, R wherein 20And R 21In conjunction with constituting 5-or 6-unit ring, it can condense with phenyl ring and/or be replaced by 1 to 3 substituting group that is selected from down group: (1) halogen, and (2) hydrogen, (3) phenoxy group, it can be replaced by 1 to 3 substituting group, and substituting group is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Acyl group, cyano group, amino, list-C 1-6Alkyl-amino, two-C 1-6Alkyl-amino, C 1-6Alkyl-sulfane base, C 1-6Alkyl-sulfinyl, C 1-6Alkyl-alkylsulfonyl, C 1-6Alkoxyl group-carbonyl, carbamyl, N-C 1-6Alkyl-carbamyl and N, N-two-C 1-6Alkyl-carbamyl, (4) C 1-6Alkoxyl group, it can be replaced by 1 to 3 substituting group, and substituting group is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Acyl group, cyano group, amino, list-C 1-6Alkyl-amino, two-C 1-6Alkyl-amino, C 1-6Alkyl-sulfane base, C 1-6Alkyl-sulfinyl, C 1-6Alkyl-alkylsulfonyl, C 1-6Alkoxyl group-carbonyl, carbamyl, N-C 1-6Alkyl-carbamyl, N, N-two-C 1-6Alkyl-carbamyl and the phenyl that can be replaced by 1 to 3 substituting group, substituting group is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Acyl group, cyano group, halo C 1-6Alkyl, amino, list-C 1-6Alkyl-amino, two-C 1-6Alkyl-amino, C 1-6Alkyl-sulfane base, C 1-6Alkyl-sulfinyl, C 1-6Alkyl-alkylsulfonyl, C 1-6Alkoxyl group-carbonyl, carbamyl, N-C 1-6Alkyl-carbamyl and N, N-two-C 1-6Alkyl-carbamyl and (5) C 1-8Alkyl, it can be replaced by 1 to 3 substituting group, and substituting group is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Acyl group, cyano group, amino, list-C 1-6Alkyl-amino, two-C 1-6Alkyl-amino, C 1-6Alkyl-sulfane base, C 1-6Alkyl-sulfinyl, C 1-6Alkyl-alkylsulfonyl, C 1-6Alkoxyl group-carbonyl, carbamyl, N-C 1-6Alkyl-carbamyl, N, N-two-C 1-6Alkyl-carbamyl and the phenyl that can be replaced by 1 to 3 substituting group, substituting group is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Acyl group, cyano group, halo C 1-6Alkyl, amino, list-C 1-6Alkyl-amino, two-C 1-6Alkyl-amino, C 1-6Alkyl-sulfane base, C 1-6Alkyl-sulfinyl, C 1-6Alkyl-alkylsulfonyl, C 1-6Alkoxyl group-carbonyl, carbamyl, N-C 1-6Alkyl-carbamyl and N, N-two-C 1-6Alkyl-carbamyl,
R 22And R 23Being identical or different, is C 1-8Alkyl, it can be replaced by 1 to 3 substituting group, and substituting group is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Acyl group, cyano group, amino, list-C 1-6Alkyl-amino, two-C 1-6Alkyl-amino, C 1-6Alkyl-sulfane base, C 1-6Alkyl-sulfinyl, C 1-6Alkyl-alkylsulfonyl, C 1-6Alkoxyl group-carbonyl, carbamyl, N-C 1-6Alkyl-carbamyl, N, N-two-C 1-6Alkyl-carbamyl and the phenyl that can be replaced by 1 to 3 substituting group, substituting group is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Acyl group, cyano group, halo C 1-6Alkyl, amino, list-C 1-6Alkyl-amino, two-C 1-6Alkyl-amino, C 1-6Alkyl-sulfane base, C 1-6Alkyl-sulfinyl, C 1-6Alkyl-alkylsulfonyl, C 1-6Alkoxyl group-carbonyl, carbamyl, N-C 1-6Alkyl-carbamyl and N, N-two-C 1-6Alkyl-carbamyl;
19, N-(1-ethyl-1-(4-aminomethyl phenyl) propyl group)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also,
N-(1-ethyl-1-(4-aminomethyl phenyl) propyl group)-5-(2-fluorophenyl)-7,7-dimethyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also,
N-(1-ethyl-1-(4-aminomethyl phenyl) propyl group)-2,7,7-trimethylammonium-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also,
N-(1-ethyl-1-(4-ethylphenyl) propyl group)-2,7,7-trimethylammonium-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also,
N-(1-ethyl-1-(4-aminomethyl phenyl) propyl group)-5-(2-fluorophenyl)-2,7,7-trimethylammonium-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also,
N-(1-ethyl-1-(4-ethylphenyl) propyl group)-5-(2-fluorophenyl)-2,7,7-trimethylammonium-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also,
5-(2-chloro-phenyl-)-N-(1-ethyl-1-(4-aminomethyl phenyl) propyl group)-2,7,7-trimethylammonium-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also,
N-(1-(4-dimethylamino phenyl)-1-ethyl propyl)-5-(2-fluorophenyl)-2,7,7-trimethylammonium-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also,
N-(1,1-diethyl butyl)-5-(2-fluorophenyl)-2,7,7-trimethylammonium-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also,
N-(1-ethyl-1-phenyl propyl)-5-(2-fluorophenyl)-2,7,7-trimethylammonium-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also,
3-(5-(1-ethyl-1-(4-aminomethyl phenyl) propyl group)-1,3,4-oxadiazole-2-yl)-2,7,7-trimethylammonium-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine or its salt also,
3-(5-(1-ethyl-1-(4-aminomethyl phenyl) propyl group)-1,3,4-thiadiazoles-2-yl)-2,7,7-trimethylammonium-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine or its salt also,
3-((4-(benzyloxy)-2,2-diethyl-1-pyrrolidyl) carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine or its salt also,
3-((2,2-diethyl-4-methoxyl group-1-pyrrolidyl) carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine or its salt also, or
3-((2,2-diethyl-4-fluoro-1-pyrrolidyl) carbonyl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine or its salt also;
20, according to above-mentioned 19 compound, it is the compound of optically active;
21, according to the prodrug of above-mentioned 1,2 or 13 compound;
22, pharmaceutical composition comprises according to above-mentioned 1,2 or 13 compound or its prodrug;
23, regulate the composition of calcium acceptor, comprise formula (I) compound:
Figure A0382393800331
Wherein encircling A is the first ring of optional substituted 5-to 7-;
Ring B is the first heterocycle of optional substituted 5-to 7-;
X 1Be CR 1(R wherein 1Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-be-CO-,-CS-,-SO-or-SO 2-, Z 2Be optional substituted alkyl, optional substituted heterocyclic radical, optional substituted hydroxyl or optional substituted amino)), CR 1R 2(R wherein 1Be as defined above, R 2Be H or optional substituted alkyl), N or NR 13(R wherein 13Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above));
X 2Be N or NR 3(R wherein 3Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above));
Y is C, CR 4(R wherein 4Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above)) or N;
Z is CR 5(R wherein 5Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above), CR 5R 6(R wherein 5And R 6Being identical or different, is H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above)), N or NR 7(R wherein 7Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above));
Ar is optional substituted cyclic group;
R is H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, optional substituted alkylsulfonyl or optional substituted sulfinyl, and perhaps R and Z can be in conjunction with constituting ring B;
Be singly-bound or two key;
Or its salt or its prodrug;
24, according to above-mentioned 23 composition, it is a Calcilytic;
25, according to above-mentioned 23 composition, it is prevention or the treatment medicine by live body calcium concn or calcium receptor abnormality associated diseases;
26, according to above-mentioned 23 composition, it is the medicine of prevention or treatment osteopathia;
27, according to above-mentioned 23 composition, it is the medicine of prevention or treatment osteoporosis or fracture;
28, regulate the method for calcium acceptor, it comprise to Mammals give significant quantity according to above-mentioned 23 formula (I) compound or its salt or its prodrug;
29, the method for prevention or treatment osteopathia, it comprise to Mammals give significant quantity according to above-mentioned 23 formula (I) compound or its salt or its prodrug;
30, according to above-mentioned 23 formula (I) compound or its salt or the purposes of its prodrug, be used to prepare the calcium receptor modulators; With
31,, be used to prepare the composition of prevention or treatment osteopathia according to above-mentioned 23 formula (I) compound or its salt or the purposes of its prodrug.
The detailed description of preferred implementation
Following formula (I) comprises the condensed heterocyclic compouds that contains the monocyclic heterocycles compound that encircles A and contain ring A and B.
In the following formula, formula (I) and ring A (II) are the first rings of optional substituted 5-to 7-.
The example of " 5-to the 7-unit ring " of " the first ring of optional substituted 5-to 7-" comprises aromatics or non-aromatics 5-to 7-membered hydrocarbon ring or 5-to 7-unit heterocycle, and it can also contain 1 to 3 heteroatoms that is selected from nitrogen, oxygen and sulphur atom as becoming annular atoms except carbon atom.Its specific examples comprises the hydrocarbon ring, for example benzene, cycloheptatriene, pentamethylene, hexanaphthene, suberane, 1-cyclopentenes, 2-cyclopentenes, 3-cyclopentenes, 1-tetrahydrobenzene, 2-tetrahydrobenzene, 3-tetrahydrobenzene, 1-suberene, 2-suberene, 3-suberene, 2,4 cycloheptadiene etc.; Heterocycle, for example pyridine, pyrazine, pyrimidine, imidazoles, furans, thiophene, dihydropyridine, diaza
Figure 10003_0
, the oxygen azepine , tetramethyleneimine, piperidines, pregnancy imines, seven azomethines, tetrahydrofuran (THF), piperazine, high piperazine, tetrahydrochysene oxygen azatropylidene, morpholine, parathiazan, pyrroles, pyrazoles, 1,2,3-triazole, oxazole, oxazolidine, thiazole, thiazolidine, isoxazole, tetrahydroglyoxaline, triazole, thiadiazoles, oxadiazole, Evil thiadiazoles, triazine etc.; Or the like.
The substituent example of " the first cyclic group of optional substituted 5-to 7-" comprises halogen, nitro, cyano group, oxo, optional substituted alkyl, optional substituted heterocyclic radical, optional substituted sulfinyl, optional substituted alkylsulfonyl, chooses substituted hydroxyl, optional substituted thiol group, optional substituted amino, optional substituted acyl group, optional esterified or amidated carboxyl wantonly, chooses substituted phosphoryl etc. wantonly.
The example of halogen comprises fluorine, chlorine, bromine, iodine etc., preferred fluorine and chlorine.
Example as the alkyl in the substituent optional substituted alkyl of 5-to 7-unit cyclic group comprises optional substituted aliphatic hydrocarbyl, optional substituted alicyclic alkyl, optional substituted alicyclic radical-aliphatic hydrocarbyl, optional substituted aromatic hydrocarbyl, optional substituted aromatic-aliphatic alkyl (aralkyl) etc.
The example of described aliphatic hydrocarbyl comprises the radical of saturated aliphatic alkyl (for example alkyl) with 1-8 carbon atom, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl group etc.; With (the alkenyl for example of the unsaturated aliphatic alkyl with 2-8 carbon atom, alkynyl, alkadienyl, alkadiyne base etc.), vinyl for example, allyl group, the 1-propenyl, 2-methyl isophthalic acid-propenyl, the 1-butylene base, crotyl, the 3-butenyl, 3-methyl-2-butene base, the 1-pentenyl, pentenyl, the 3-pentenyl, the 4-pentenyl, 4-methyl-3-pentenyl, the 1-hexenyl, the 2-hexenyl, the 3-hexenyl, the 4-hexenyl, the 5-hexenyl, 2, the 4-hexadienyl, the 1-heptenyl, the 1-octenyl, ethynyl, the 1-proyl, 2-propynyl, the ethyl acetylene base, the 2-butyne base, the 3-butynyl, the 1-pentynyl, the valerylene base, the 3-pentynyl, the 4-pentynyl, 1-hexin base, 2-hexin base, 3-hexin base, 4-hexin base, 5-hexin base, 2,4-hexadiyne base, 1-heptyne base, 1-octyne base etc.
The example of described alicyclic alkyl comprises the saturated alicyclic alkyl (for example cycloalkyl etc.) with 3-7 carbon atom, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc.; Unsaturated cycloaliphatic alkyl (for example cycloalkenyl group, cycloalkadienyl etc.) with 3-7 carbon atom, for example 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadiene base etc.; Fractional saturation and condensed bicyclic hydrocarbon base (preferred C 9-10Fractional saturation and condensed bicyclic hydrocarbon base etc. (comprise wherein the non-aromatics cyclic hydrocarbon group bonded of phenyl ring and 5-or 6-unit those)), for example 1-indenyl, 2-indenyl, 1-dihydro indenyl, 2-dihydro indenyl, 1,2,3,4-tetrahydrochysene-1-naphthyl, 1,2,3,4-tetrahydrochysene-2-naphthyl, 1,2-dihydro-1-naphthyl, 1,2-dihydro-2-naphthyl, 1,4-dihydro-1-naphthyl, 1,4-dihydro-2-naphthyl, 3,4-dihydro-1-naphthyl, 3,4-dihydro-2-naphthyl etc.; Or the like.Described alicyclic alkyl can be crosslinked.
The example of described alicyclic radical-aliphatic hydrocarbyl comprise wherein above-mentioned alicyclic alkyl and above-mentioned aliphatic hydrocarbyl bonded those, for example have those of 4-14 carbon atom, cyclopropyl methyl for example, the cyclopropyl ethyl, cyclobutylmethyl, the cyclobutyl ethyl, cyclopentyl-methyl, 2-cyclopentenyl methyl, 3-cyclopentenyl methyl, the cyclopentyl ethyl, cyclohexyl methyl, 2-cyclohexenyl methyl, 3-cyclohexenyl methyl, the cyclohexyl ethyl, the suberyl methyl, the suberyl ethyl, 2-(3,4-dihydro-2-naphthyl) ethyl, 2-(1,2,3,4-tetrahydrochysene-2-naphthyl) ethyl, (C for example such as 2-(3,4-dihydro-2-naphthyl) vinyl 3-7Cycloalkyl-C 1-4Alkyl, C 3-7Cycloalkenyl group-C 1-4Alkyl, C 3-7Cycloalkyl-C 2-4Alkenyl, C 3-7Cycloalkenyl group-C 2-4Alkenyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 1-4Alkyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 2-4Alkenyl etc.).
The example of described aromatic hydrocarbyl comprises aryl with 6-10 carbon atom (comprise wherein 5-to the 6-non-aromatic hydrocarbon ring of unit and phenyl condensed those), for example phenyl, Alpha-Naphthyl, betanaphthyl, 4-indenyl, 5-indenyl, 4-dihydro indenyl, 5-dihydro indenyl, 5,6,7,8-tetrahydrochysene-1-naphthyl, 5,6,7,8-tetrahydrochysene-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro-4-naphthyl etc.; Or the like.
The example of described aromatic-aliphatic alkyl comprises the aralkyl (C with 7-14 carbon atom 6-10Aryl-C 1-4Alkyl), phenyl-C for example 1-4Alkyl, for example benzyl, styroyl, 1-phenylethyl, 1-phenyl propyl, 2-phenyl propyl, 3-phenyl propyl etc.; Naphthyl-C 1-4Alkyl, for example Alpha-Naphthyl methyl, Alpha-Naphthyl ethyl, betanaphthyl methyl, betanaphthyl ethyl etc.; C 6-10Aryl-C 2-4Alkenyl, for example phenyl-C 2-4Alkenyl, for example styryl, cinnamyl etc.; Or the like.
Example as the heterocyclic radical in the substituent optional substituted heterocyclic radical of 5-to 7-unit ring comprises (i) 5-to 7-unit heterocyclic radical, contain a sulphur atom, a nitrogen-atoms or a Sauerstoffatom, (ii) 5-to 6-unit heterocyclic radical, contain 2-4 nitrogen-atoms, (iii) 5-to 6-unit heterocyclic radical, contain 1-2 nitrogen-atoms and sulphur or Sauerstoffatom etc. and (iv) these heterocyclic radicals can condense with 5-to 6-unit's ring, phenyl ring that contains 2 or following nitrogen-atoms or the 5-unit ring that contains a sulphur atom.In addition, (i) extremely (iv) each heterocyclic radical of institute's illustration can be saturated or undersaturated heterocyclic radical, and undersaturated heterocyclic radical can be aromatics aromatics or non-.
Example as the heterocyclic radical in the substituent optional substituted heterocyclic radical of 5-to 7-unit ring comprises aromatic monocyclic heterocyclic radical, aromatic condensed heterocyclic radical and non-aromatic heterocycle.
Comprise (i) aromatic monocyclic heterocyclic radical (furyl for example as the specific examples of the heterocyclic radical in the substituent optional substituted heterocyclic radical of 5-to 7-unit ring, thienyl, pyrryl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, the furazan base, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, the 1,2,3-triazoles base, 1,2, the 4-triazolyl, tetrazyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl etc.); (ii) aromatic condensed heterocyclic radical (benzofuryl for example, isobenzofuran-base, benzo [b] thienyl, indyl, pseudoindoyl, the 1H-indazolyl, benzimidazolyl-benzoxazolyl, 1,2-benzisothiazole base, 1H-benzotriazole base, quinolyl, isoquinolyl, the cinnolines base, quinazolyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purine radicals, pteridyl, carbazyl, α-carbolinyl, the β-Ka Lin base, the gamma-carbolines base, acridyl phenoxazinyl, phenothiazinyl, phenazinyl, phenoxatinyl, thianthrenyl, phenanthridinyl, the phenanthroline base, the indolizine base, pyrrolo-[1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl etc.); (iii) non-aromatic heterocycle (for example Oxyranyle, azetidinyl, oxetanyl, Thietane base, pyrrolidyl, tetrahydrofuran base, thiacyclopentane base, piperidyl, THP trtrahydropyranyl, morpholinyl, parathiazan base, piperazinyl etc.).
Example as the sulfinyl in the substituent optional substituted sulfinyl of 5-to 7-unit ring comprises wherein-substituent " the optional substituted alkyl " of SO-and 5-to 7-unit ring or " alkyl " or " heterocyclic radical " bonded in " choosing substituted heterocyclic radical wantonly " those.
Preferred examples comprises C 1-8Alkyl sulphinyl, wherein sulfinyl and C 1-8The alkyl combination, described alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl group etc. for example; C 6-10Aryl sulfonyl kia, wherein sulfinyl and C 6-10The aryl combination, described aryl is phenyl, Alpha-Naphthyl, betanaphthyl, 4-indenyl, 5-indenyl, 4-dihydro indenyl, 5-dihydro indenyl, 5,6,7 for example, 8-tetrahydrochysene-1-naphthyl, 5,6,7,8-tetrahydrochysene-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro-4-naphthyl etc.; Group like this, wherein sulfinyl combines with the aromatic monocyclic heterocyclic radical, described heterocyclic radical is furyl, thienyl, pyrryl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2 for example, 3-oxadiazole base, 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, furazan base, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-triazoles base, 1,2,4-triazolyl, tetrazyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl etc.; With such group; wherein sulfinyl combines with aromatic condensed heterocyclic radical; described heterocyclic radical is benzofuryl for example; isobenzofuran-base; benzo [b] thienyl; indyl; pseudoindoyl; the 1H-indazolyl; benzimidazolyl-; benzoxazolyl; 1; 2-benzisothiazole base; 1H-benzotriazole base; quinolyl; isoquinolyl; the cinnolines base; quinazolyl; quinoxalinyl; phthalazinyl; naphthyridinyl; purine radicals; pteridyl; carbazyl; α-carbolinyl; the β-Ka Lin base; the gamma-carbolines base; acridyl phenoxazinyl; phenothiazinyl; phenazinyl; phenoxatinyl; thianthrenyl; phenanthridinyl; the phenanthroline base; the indolizine base; pyrrolo-[1; 2-b] pyridazinyl; pyrazolo [1; 5-a] pyridyl; imidazo [1; 2-a] pyridyl; imidazo [1; 5-a] pyridyl; imidazo [1; 2-b] pyridazinyl; imidazo [1; 2-a] pyridyl; imidazo [1; 5-a] pyridyl; imidazo [1; 2-b] pyridazinyl; imidazo [1; 2-a] pyrimidyl; 1; 2; 4-triazolo [4; 3-a] pyridyl; 1; 2; 4-triazolo [4,3-b] pyridazinyl etc.
Preferred example comprises C 1-8Alkyl sulphinyl, wherein sulfinyl and C 1-8Alkyl combination, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl group etc.
Example as the alkylsulfonyl in the substituent optional substituted alkylsulfonyl of 5-to 7-unit ring comprises wherein-SO 2-with substituent " the optional substituted alkyl " of 5-to 7-unit ring or " alkyl " or " heterocyclic radical " bonded in " optional substituted heterocyclic radical " those.
Preferred examples comprises C 1-8Alkyl sulphonyl, wherein alkylsulfonyl and C 1-8The alkyl combination, described alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl group etc. for example; C 6-10Aryl sulfonyl, wherein alkylsulfonyl and C 6-10The aryl combination, described aryl is phenyl, Alpha-Naphthyl, betanaphthyl, 4-indenyl, 5-indenyl, 4-dihydro indenyl, 5-dihydro indenyl, 5,6,7 for example, 8-tetrahydrochysene-1-naphthyl, 5,6,7,8-tetrahydrochysene-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro-4-naphthyl etc.; Group like this, wherein alkylsulfonyl combines with the aromatic monocyclic heterocyclic radical, described heterocyclic radical is furyl, thienyl, pyrryl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2 for example, 3-oxadiazole base, 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, furazan base, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-triazoles base, 1,2,4-triazolyl, tetrazyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl etc.; With such group; wherein alkylsulfonyl combines with aromatic condensed heterocyclic radical; described heterocyclic radical is benzofuryl for example; isobenzofuran-base; benzo [b] thienyl; indyl; pseudoindoyl; the 1H-indazolyl; benzimidazolyl-; benzoxazolyl; 1; 2-benzisothiazole base; 1H-benzotriazole base; quinolyl; isoquinolyl; the cinnolines base; quinazolyl; quinoxalinyl; phthalazinyl; naphthyridinyl; purine radicals; pteridyl; carbazyl; α-carbolinyl; the β-Ka Lin base; the gamma-carbolines base; acridyl; the Phenazoxine base; phenothiazinyl; phenazinyl; phenoxatinyl; thianthrenyl; phenanthridinyl; the phenanthroline base; the indolizine base; pyrrolo-[1; 2-b] pyridazinyl; pyrazolo [1; 5-a] pyridyl; imidazo [1; 2-a] pyridyl; imidazo [1; 5-a] pyridyl; imidazo [1; 2-b] pyridazinyl; imidazo [1; 2-a] pyridyl; imidazo [1; 5-a] pyridyl; imidazo [1; 2-b] pyridazinyl; imidazo [1; 2-a] pyrimidyl; 1; 2; 4-triazolo [4; 3-a] pyridyl; 1; 2; 4-triazolo [4,3-b] pyridazinyl etc.
Preferred example comprises C 1-8Alkyl sulphonyl, wherein alkylsulfonyl and C 1-8Alkyl combination, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl group etc.
Comprise hydroxyl and have suitable substituent hydroxyl as the first substituent example of choosing substituted hydroxyl wantonly that encircles of 5-to 7-, for example first above-mentioned substituent " choosing substituted alkyl wantonly " or " the choosing substituted heterocyclic radical wantonly " encircled of 5-to 7-.
Preferred examples comprises C 1-8Alkoxyl group, its substituting group is C 1-8Alkyl, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl group etc.; C 6-10Aryloxy, its substituting group is C 6-10Aryl, for example phenyl, Alpha-Naphthyl, betanaphthyl, 4-indenyl, 5-indenyl, 4-dihydro indenyl, 5-dihydro indenyl, 5,6,7,8-tetrahydrochysene-1-naphthyl, 5,6,7,8-tetrahydrochysene-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro-4-naphthyl etc.; By the hydroxyl that the aromatic monocyclic heterocyclic radical replaces, described heterocyclic radical is furyl, thienyl, pyrryl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2 for example, 3-oxadiazole base, 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, furazan base, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl etc.; The hydroxyl that is replaced by aromatic condensed heterocyclic radical, described heterocyclic radical is benzofuryl for example, isobenzofuran-base, benzo [b] thienyl, indyl, pseudoindoyl, the 1H-indazolyl, benzimidazolyl-, benzoxazolyl, 1,2-benzisothiazole base, 1H-benzotriazole base, quinolyl, isoquinolyl, the cinnolines base, quinazolyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purine radicals, pteridyl, carbazyl, α-carbolinyl, the β-Ka Lin base, the gamma-carbolines base, acridyl, the Phenazoxine base, phenothiazinyl, phenazinyl, phenoxatinyl, thianthrenyl, phenanthridinyl, the phenanthroline base, the indolizine base, pyrrolo-[1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl etc.
Preferred example comprises C 6-10Aryloxy (particularly phenoxy group) or the hydroxyl that is replaced by aromatic monocyclic heterocyclic radical (particularly pyridyl) or aromatic condensed heterocyclic radical (particularly quinolyl).
Can have and substituent " optional substituted alkyl " or " alkyl " or " heterocyclic radical " the identical substituting group in " optional substituted heterocyclic radical " of 5-to 7-unit ring as substituent " alkyl " or " heterocyclic radical " of the hydroxyl of the replacement of top illustration.
The substituent example of choosing substituted thiol group wantonly that encircles as 5-to 7-unit comprises thiol group and the thiol group that is replaced by suitable group, and described substituting group is first substituent " optional substituted alkyl " or " the choosing substituted heterocyclic radical wantonly " encircled of 5-to 7-for example.
Preferred examples comprises C 1-8Alkylthio, its substituting group is C 1-8Alkyl, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl group etc.; C 6-10Arylthio, its substituting group is C 6-10Aryl, for example phenyl, Alpha-Naphthyl, betanaphthyl, 4-indenyl, 5-indenyl, 4-dihydro indenyl, 5-dihydro indenyl, 5,6,7,8-tetrahydrochysene-1-naphthyl, 5,6,7,8-tetrahydrochysene-2-naphthyl, 5,6-dihydro-1-naphthyl, 5,6-dihydro-2-naphthyl, 5,6-dihydro-3-naphthyl, 5,6-dihydro-4-naphthyl etc.; The thiol group that is replaced by the aromatic monocyclic heterocyclic radical, described heterocyclic radical is furyl, thienyl, pyrryl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1 for example, 2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, furazan base, 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl etc.; The thiol group that is replaced by aromatic condensed heterocyclic radical, described heterocyclic radical is benzofuryl for example, isobenzofuran-base, benzo [b] thienyl, indyl, pseudoindoyl, the 1H-indazolyl, benzimidazolyl-, benzoxazolyl, 1,2-benzisothiazole base, 1H-benzotriazole base, quinolyl, isoquinolyl, the cinnolines base, quinazolyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purine radicals, pteridyl, carbazyl, α-carbolinyl, the β-Ka Lin base, the gamma-carbolines base, acridyl, the Phenazoxine base, phenothiazinyl, phenazinyl, phenoxatinyl, thianthrenyl, phenanthridinyl, the phenanthroline base, the indolizine base, pyrrolo-[1,2-b] pyridazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidyl, 1,2,4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl etc.
Can have and substituent " optional substituted alkyl " or " alkyl " or " heterocyclic radical " the identical substituting group in " optional substituted heterocyclic radical " of 5-to 7-unit ring as substituent " alkyl " or " heterocyclic radical " of the thiol group of the replacement of top illustration.
Preferred example comprises C 1-8Alkylthio, it is by C 1-8Alkyl replaces, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl group etc.
Comprise the amino and the N of amino, N-list-replacement, the amino of N-two-replacement as the example of the substituent optional substituted amino of 5-to 7-unit ring.The example of the amino of described replacement comprises having one or two substituent amino: optional substituted alkyl (with the first substituent optional identical group of substituted alkyl that encircles of 5-to 7-, more specifically is C for example 1-8Alkyl, C 3-7Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 3-7Cycloalkenyl group, can have C 1-4The C of alkyl 6-10Aryl etc.), (wherein R ' represents hydrogen atom or optional substituted alkyl or optional substituted heterocyclic radical for optional substituted heterocyclic radical (for example with the first substituent optional identical group of substituted heterocyclic radical that encircles of 5-to 7-) or following formula group :-COR '." optional substituted alkyl " or " alkyl " or " heterocyclic radical " in " optional substituted heterocyclic radical " as for R ', can have substituent " optional substituted alkyl " or " alkyl " or " heterocyclic radical " in " optional substituted heterocyclic radical " with 5-to 7-unit ring identical substituent those), preferred C 1-10Acyl group (C for example 2-7Alkyloyl, benzoyl, nicotinoyl etc.).Its specific examples comprises methylamino-, dimethylamino, ethylamino, diethylin, dipropyl amino, dibutylamino, two allyl amino, hexamethylene amino, phenyl amino, N-methyl-N-phenyl amino, kharophen, propionamido, benzamido, nicotinoyl amino etc.
In addition, two groups in the amino of described replacement can be in conjunction with constituting nitrogenous 5-to 7-unit's ring (for example piperidino-(1-position only), piperadino, morpholino base, parathiazan Dai Ji etc.).
The substituent example of choosing substituted acyl group wantonly as 5-to 7-unit ring comprises (i) formyl radical, perhaps (ii) such group, wherein carbonyl and C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl, C 3-7Cycloalkyl, C 5-7Cycloalkenyl group or aromatic group (for example phenyl, pyridyl etc.) combination (for example ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, isovaleryl, valeryl, caproyl, oenanthyl, capryloyl, tetramethylene carbonyl, pentamethylene carbonyl, hexanaphthene carbonyl, suberane carbonyl, crotonyl, 2-tetrahydrobenzene carbonyl, benzoyl etc.) etc.
Except carboxyl, comprise alkoxy carbonyl, alkenyloxy carbonyl, alkynyloxy group carbonyl, aromatic alkoxy carbonyl, acyloxy carbonyl, aryloxycarbonyl etc. as the first substituent example of choosing esterified carboxyl wantonly that encircles of 5-to 7-.
The example of the alkyl in the described alkoxy carbonyl comprises C 1-6Alkyl (for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl etc.).
Non-limiting examples of alkenyls in the described alkenyloxy carbonyl comprises C 2-6Alkenyl (for example vinyl, allyl group, pseudoallyl, 1-propenyl, 1-butylene base, crotyl, 3-methacrylic etc.).
The example of the alkynyl in the described alkynyloxy group carbonyl comprises C 2-6Alkynyl (for example ethynyl, 2-propynyl etc.).
Aralkyl in the described aromatic alkoxy carbonyl is represented aryl-alkyl (C for example 6-10Aryl-C 1-6Alkyl etc.).Aryl in described aryl-alkyl is represented the aromatic hydrocarbyl of monocycle or fused polycycle, and preferred examples comprises phenyl, naphthyl, anthryl, phenanthryl, acenaphthenyl etc.They can have substituting group, for example C 1-10Alkyl, C 2-10Alkenyl, C 2-10Alkynyl, C 3-8Cycloalkyl, C 3-8Cycloalkenyl group, C 4-8Cycloalkadienyl, aryl (C for example 6-14Aryl etc.), aromatic heterocyclic radical (for example identical aromatic heterocyclic radical etc.), non-aromatic heterocycle (for example identical non-aromatic heterocycle etc.), aralkyl (C for example with the substituting group of above-mentioned substituent alkyl, acyl group, alkylsulfonyl, sulfinyl and the heterocyclic radical of 5-to 7-unit ring with the substituting group of above-mentioned substituent alkyl, acyl group, alkylsulfonyl, sulfinyl and the heterocyclic radical of 5-to 7-unit ring 6-14Aryl-C 1-6Alkyl etc.), amino (amino of for example identical N-list-replacement, the preferred N-list-C of amino, N-list-replacement with the substituting group of first above-mentioned substituent alkyl, acyl group, alkylsulfonyl, sulfinyl and the heterocyclic radical that encircles of 5-to 7- 1-4Alkylamino etc.), N, the amino of N-two-replacement (for example with the identical N of substituting group of above-mentioned substituent alkyl, acyl group, alkylsulfonyl, sulfinyl and the heterocyclic radical of 5-to 7-unit ring, the amino of N-two-replacements, preferred N, N-two-C 1-4Alkylamino etc.), the carbamyl of amidino groups, acyl group (for example identical acyl group etc.), carbamyl, N-list-replacement (N-list-C for example with the substituting group of above-mentioned substituent alkyl, acyl group, alkylsulfonyl, sulfinyl and the heterocyclic radical of 5-to 7-unit ring 1-4Alkyl-carbamyl, for example methyl carbamyl, ethyl carbamyl etc.; The phenylamino formyl radical; Deng), N, the carbamyl of N-two-replacement (N for example, N-two-C 1-4Alkyl-carbamyl, N for example, N-dimethylamino formyl radical, N, N-diethyl amino formyl radical etc.; The piperidino-(1-position only) carbamyl; Morpholino base carbamyl; Deng), the sulfamyl of sulfamyl, N-list-replacement (N-list-C for example 1-4Alkyl-sulfamyl, for example methyl sulfamyl, ethyl sulfamyl etc.; The phenyl sulfamoyl base; Right-the amino toluene alkylsulfonyl; Deng), N, the sulfamyl of N-two-replacement (N for example, the dibasic C of N- 1-4Alkyl-sulfamyl, N for example, N-dimethylamino alkylsulfonyl etc.; N-C 1-4Alkyl-N-phenyl sulfamoyl base, for example N-methyl-N-phenyl sulfamoyl base etc.; The piperidino-(1-position only) sulfamyl; Morpholino base sulfamyl; Deng), carboxyl, C 1-10Alkoxy carbonyl (for example methoxycarbonyl, ethoxy carbonyl, isopropoxy carbonyl, sec-butoxy carbonyl, isobutoxy carbonyl, tert-butoxycarbonyl etc.), hydroxyl, C 1-10Alkoxyl group, C 2-10Alkenyloxy, C 3-7Cycloalkyloxy, aralkoxy (C for example 6-14Aryl-C 1-6Alkoxyl group etc.), aryloxy (C for example 6-14Aryloxy etc.), sulfydryl, C 1-10Alkylthio, aromatic alkylthio (C for example 6-14Aryl-C 1-6Alkylthio etc.), arylthio (C for example 6-14Arylthio etc.), sulfo group, cyano group, azido-, nitro, nitroso-group, halogen atom etc.As for the alkyl in described aryl-alkyl, C 1-6Alkyl (for example methyl, ethyl, propyl group, butyl etc.) is preferred.Described aralkyl, be that the example of aryl-alkyl comprises benzyl, styroyl, 3-phenyl propyl, (1-naphthyl) methyl, (2-naphthyl) methyl etc.Wherein, benzyl, styroyl etc. are preferred.
Acyl group as in the described acyloxy carbonyl for example has formyl radical, C 2-4Alkyloyl, C 3-4Alkenoyl, C 3-4Alkynes acyl group etc.
As the aryl in the described aryloxycarbonyl, phenyl, naphthyl etc. are for example arranged.
Comprise the carboxyl of the substituent optional substituted aminoacyl amination of the above-mentioned substituent alkyl, acyl group, alkylsulfonyl and the heterocyclic radical that are used as 5-to 7-unit ring as the example of the substituent amidation carboxyl of substituent alkyl, acyl group, alkylsulfonyl, sulfinyl and the heterocyclic radical of 5-to 7-unit ring, they can be substituted separately.
The example of the substituent optional substituted phosphoryl of 5-to 7-unit ring comprises phosphoryl; (C 1-6Alkoxyl group) phosphoryl, for example oxyethyl group phosphoryl; Two-(C 1-6Alkoxyl group) phosphoryl, for example diethoxy phosphoryl etc.; By the rudimentary (C of optional esterified phosphono replacement 1-6) alkyl, for example phosphono-C 1-6Alkyl; C 1-6Alkoxyl group-phosphoryl-C 1-6Alkyl; Two-(C 1-6Alkoxyl group) phosphoryl-C 1-6Alkyl, for example diethoxy phosphoryl methyl etc.; Or the like.
Substituent " optional substituted alkyl ", " the optional substituted heterocyclic radical " of 5-to 7-unit ring, " alkyl ", " heterocyclic radical ", " sulfinyl " or " alkylsulfonyl " in " optional substituted sulfinyl " or " optional substituted alkylsulfonyl " can further be replaced by 1 to 3 substituting group.
In above-mentioned substituting group, when hydroxyl is positioned at rudimentary (C 1-6) during the alkoxyl group ortho position, they can constitute C 1-6Alkylene dioxo base, for example methylene-dioxy, ethylenedioxy etc.
Above-mentioned C 6-10Aryl, as the substituent C of aromatic heterocyclic radical 6-10Aryl, as the substituent C of the amino of N-list-replacement 6-10Aryl, as N, the substituent C of the amino of N-two-replacement 6-10Aryl, as the substituent C of the carbamyl of N-list-replacement 6-10Aryl, as N, the substituent C of the carbamyl of N-two-replacement 6-10Aryl, as the substituent C of the sulfamyl of N-list-replacement 6-10Aryl, as N, the substituent C of the sulfamyl of N-two-replacement 6-10Aryl, as C 6-10The substituent C of aryloxy 6-10Aryl, C 7-14The C of aralkoxy 6-10Aryl, C 7-14The C of aromatic alkylthio 6-10Aryl, C 6-10The C of arylthio 6-10Aryl, C 7-14The C of aralkyl sulfinyl 6-10Aryl, C 6-10The C of aryl sulfonyl kia 6-10Aryl, C 7-14The C of aralkyl alkylsulfonyl 6-10Aryl and C 6-10The C of aryl sulfonyl 6-10Aryl can further be replaced by 1 to 3 substituting group.Described substituent example comprises rudimentary (C 1-6) alkyl, amino, N-(C 1-6Alkyl) amino, N, N-two-(C 1-6Alkyl) amino, amidino groups, carbamyl, N-(C 1-6Alkyl) carbamyl, N, N-two-(C 1-6Alkyl) carbamyl, sulfamyl, N-(C 1-6Alkyl) sulfamyl, N, N-two-(C 1-6Alkyl) sulfamyl, carboxyl, rudimentary (C 2-7) alkoxy carbonyl, hydroxyl, rudimentary (C 1-6) alkoxyl group, sulfydryl, rudimentary (C 1-6) alkylthio, sulfo group, cyano group, azido-, halogen atom, nitro, nitroso-group, optional substituted phosphono (for example phosphono, C 1-6Alkoxy phosphoryl, two-(C 1-6Alkoxyl group) phosphoryl etc.), choose rudimentary (the C of esterified phosphono replacement 1-6) alkyl (phosphono-C for example 1-6Alkyl, C 1-6Alkoxyl group-phosphoryl-C 1-6Alkyl, two-(C 1-6Alkoxyl group) phosphoryl-C 1-6Alkyl, for example diethoxy phosphoryl methyl etc.) etc.
In above-mentioned substituting group, when hydroxyl is positioned at rudimentary (C 1-6) during the alkoxyl group ortho position, they can constitute C 1-6Alkylene dioxo base, for example methylene-dioxy, ethylenedioxy etc.
The substituting group quantity of 5-to 7-unit ring is 1 to 3, and preferred 1 to 2, substituting group can be identical or different, is present in any possible position of this ring.
The Q of formula (II) is C, CR 5Or N.
R 5Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-be-CO-,-CS-,-SO-or-SO 2-, Z 2Be optional substituted alkyl, optional substituted heterocyclic radical, optional substituted hydroxyl or optional substituted amino).
R 5Or Z 2The example of optional substituted alkyl, optional substituted hydroxyl, optional substituted amino and optional substituted heterocyclic radical comprise those identical groups of the above-mentioned substituting group institute illustration that encircles with 5-to 7-unit about ring A.
R 5Halogen and the example of optional substituted thiol group those identical groups of comprising the above-mentioned substituting group institute illustration that encircles with 5-to 7-unit about ring A.
Formula (I) and (II) in X 1Be CR 1, CR 1R 2, N or NR 13
R 1Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above).
R 1The example of optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, halogen and optional substituted heterocyclic radical comprise those identical groups of the substituting group institute illustration that encircles with 5-to 7-unit about ring A.
R 2Be H or optional substituted alkyl, R 2The example of optional substituted alkyl comprise and those identical groups about the substituting group institute illustration of 5-to the 7-unit ring of ring A.
R 13Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above).
R 13The example of optional substituted alkyl, optional substituted hydroxyl, optional substituted amino and optional substituted heterocyclic radical comprise those identical groups of the substituting group institute illustration that encircles with 5-to 7-unit about ring A.
The R of formula (III) 1Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted thiol group, optional substituted amino, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-be-CO-,-CS-,-SO-or-SO 2-, Z 2Be optional substituted alkyl, optional substituted heterocyclic radical, optional substituted hydroxyl or optional substituted amino).
R at formula (III) 1In, following formula group :-Z 1-Z 2Preferred embodiment be following formula group :-CONR 20(CR 21R 22R 23), R wherein 20Be H or optional substituted alkyl, R 21, R 22And R 23Being identical or different, is optional substituted alkyl or optional substituted heterocyclic radical, perhaps R 20And R 21Can be in conjunction with constituting ring.
R 1, R 20, R 21, R 22And R 23Optional substituted alkyl, R 1, R 21, R 22And R 23Optional substituted heterocyclic radical and R 1The example of optional substituted hydroxyl, optional substituted amino, optional substituted thiol group and halogen comprise and those identical groups about the first substituting group institute illustration that encircles of 5-to 7-of formula (I) and ring A (II).
Preferably, R 21, R 22And R 23In at least one is optional substituted heterocyclic radical, it can condense with optional substituted phenyl ring, perhaps chooses substituted phenyl wantonly, it can condense with optional substituted aromatic heterocycle.
R 21, R 22And R 23" optional substituted heterocyclic radical; it can condense with optional substituted phenyl ring " " annelated heterocycles base " and " optional substituted phenyl, it can with optional substituted aromatic heterocycle " the example of " fused phenyl " comprise those identical groups with the substituent aromatic condensed heterocyclic radical institute illustration that encircles about 5-to 7-unit as ring A.
These substituent examples comprise and those identical groups about the substituting group institute illustration of the 5-to 7-of formula (I) and ring A (II) unit ring.
With R 20And R 21In conjunction with the first ring of the preferably optional substituted 5-to 7-of the ring that is constituted, more preferably optional substituted 5-or 6-unit ring, and can condense with optional substituted phenyl ring.This class ring comprises and those identical rings about " 5-to 7-unit ring " institute's illustration of " optional substituted 5-to 7-unit ring " among formula (I) and the ring A (II).
These rings can have 1 to 3 substituting group, are selected from the group of being made up of following groups: (1) halogen, and (2) hydrogen, (3) phenoxy group, it can be replaced by 1 to 3 substituting group, and described substituting group is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Acyl group (for example formyl radical, C 2-6Alkyloyl etc.), cyano group, amino, list-C 1-6Alkyl-amino, two-C 1-6Alkyl-amino, C 1-6Alkyl-sulfane base, C 1-6Alkyl-sulfinyl, C 1-6Alkyl-alkylsulfonyl, C 1-6Alkoxyl group-carbonyl, carbamyl, N-C 1-6Alkyl-carbamyl and N, N-two-C 1-6Alkyl-carbamyl, (4) C 1-6Alkoxyl group, it can be replaced by 1 to 3 substituting group, and described substituting group is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Acyl group, cyano group, amino, list-C 1-6Alkyl-amino, two-C 1-6Alkyl-amino, C 1-6Alkyl-sulfane base, C 1-6Alkyl-sulfinyl, C 1-6Alkyl-alkylsulfonyl, C 1-6Alkoxyl group-carbonyl, carbamyl, N-C 1-6Alkyl-carbamyl, N, N-two-C 1-6Alkyl-carbamyl and phenyl, it can be replaced by 1 to 3 substituting group, and described substituting group is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Acyl group, cyano group, halo C 1-6Alkyl (for example trifluoromethyl etc.), amino, list-C 1-6Alkyl-amino, two-C 1-6Alkyl-amino, C 1-6Alkyl-sulfane base, C 1-6Alkyl-sulfinyl, C 1-6Alkyl-alkylsulfonyl, C 1-6Alkoxyl group-carbonyl, carbamyl, N-C 1-6Alkyl-carbamyl and N, N-two-C 1-6Alkyl-carbamyl and (5) C 1-8Alkyl (C for example 1-8Alkyl, C 3-7Cycloalkyl, C 2-8Alkenyl, C 2-8Alkynyl, C 3-7Cycloalkenyl groups etc.), it can be replaced by 1 to 3 substituting group, and described substituting group is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Acyl group, cyano group, amino, list-C 1-6Alkyl-amino, two-C 1-6Alkyl-amino, C 1-6Alkyl-sulfane base, C 1-6Alkyl-sulfinyl, C 1-6Alkyl-alkylsulfonyl, C 1-6Alkoxyl group-carbonyl, carbamyl, N-C 1-6Alkyl-carbamyl, N, N-two-C 1-6Alkyl-carbamyl and phenyl, described phenyl can be replaced by 1 to 3 substituting group, and described substituting group is selected from halogen, hydroxyl, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Acyl group, cyano group, halo C 1-6Alkyl (for example trifluoromethyl etc.), amino, list-C 1-6Alkyl-amino, two-C 1-6Alkyl-amino, C 1-6Alkyl-sulfane base, C 1-6Alkyl-sulfinyl, C 1-6Alkyl-alkylsulfonyl, C 1-6Alkoxyl group-carbonyl, carbamyl, N-C 1-6Alkyl-carbamyl and N, N-two-C 1-6Alkyl-carbamyl.
These substituent specific exampless comprise and those identical groups about the substituting group institute illustration of the 5-to 7-of formula (I) and ring A (II) unit ring.
The R of formula (IIIa) 1aBe (1) optional substituted heterocyclic radical, perhaps (2) following formula group :-Z 1a-Z 2a(wherein-Z 1a-be-CO-,-CS-,-SO-or-SO 2-, Z 2aBe (i) optional substituted heterocyclic radical, (ii)-NR 20a(CR 21aR 22aR 23a) ((a) R wherein 20aBe H or optional substituted alkyl; R 21aBe optional substituted heterocyclic radical, it can condense with optional substituted phenyl ring, perhaps optional substituted C 6-10Aryl, it can condense with optional substituted aromatic heterocycle; R 22aAnd R 23aBeing identical or different, is optional substituted alkyl or optional substituted heterocyclic radical, perhaps R 22aAnd R 23aCan be in conjunction with constituting ring, perhaps (b) R 20aBe H or optional substituted alkyl; R 21a, R 22aAnd R 23aBeing identical or different, is optional substituted C 1-8Aliphatic hydrocarbyl, its condition be the summation of carbonatoms be 7 or more than), (iii)-NR 20aR 25a(R wherein 20aBe as defined above, R 25aBe optional substituted C 6-10Aryl-C 2-4Alkyl, C 6-10Aryloxy-C 2-4Alkyl, C 6-10Arylamino-C 2-4Alkyl, C 7-14Aryl alkyl amino-C 2-4Alkyl, heterocycle-C 2-4Alkyl or heterocyclic radical), 5-to the 7-unit cyclic amino that (iv) replaces, perhaps (v)-OR 24a(R wherein 24aBe (a) optional substituted C 7-14Aralkyl, (b) optional substituted C 3-7Alicyclic alkyl, (c) optional substituted C 7-24Aliphatic hydrocarbyl, perhaps (d) optional substituted heterocyclic radical)).
R 20a, R 22aAnd R 23aOptional substituted alkyl and R 1a, Z 2a, R 21a, R 22aAnd R 23aThe example of optional substituted heterocyclic radical comprise and those identical groups about the substituting group institute illustration of 5-to the 7-unit ring of formula (I) and ring A (II).
R 21a, R 22aAnd R 23aThe example of " fused phenyl " of " annelated heterocycles base " and " optional substituted phenyl, it can condense with optional substituted aromatic heterocycle " of " optional substituted heterocyclic radical; it can condense with optional substituted phenyl ring " comprise those identical groups with the substituent aromatic condensed heterocyclic radical institute illustration that encircles about 5-to 7-unit as ring A.
With R 20aAnd R 21aIn conjunction with the example of the ring that is constituted and substituting group thereof comprise with about with R 20And R 21Those identical rings and substituting group in conjunction with ring that is constituted and substituting group institute illustration thereof.
R 20a" optional substituted C 1-8Aliphatic hydrocarbyl " example comprise with about those identical groups as the substituent aliphatic hydrocarbyl institute illustration of 5-to the 7-unit ring of ring A.
R 24a" optional substituted C 7-14Aralkyl ", " optional substituted C 3-7Alicyclic alkyl " comprise those identical groups of the substituting group institute illustration that encircles with 5-to 7-unit respectively with the example of " optional substituted heterocyclic radical " about ring A.
R 24aIn " optional substituted C 7-24Aliphatic hydrocarbyl " " C 7-24Aliphatic hydrocarbyl " example for example comprise C 7-24Alkyl, C 7-24Alkenyl, C 7-24Alkynyl, C 7-24Alkadienyl, C 7-24Alkadiyne base, for example heptyl, octyl group, 1-heptenyl, 1-octenyl, 1-heptyne base, 1-octyne base etc.
R 24aIn " optional substituted C 7-24Aliphatic hydrocarbyl " substituent example comprise with about those identical substituting groups as the substituting group institute illustration of the substituent alkyl of 5-to the 7-unit ring of ring A.
In the formula (IIIa), R 1aPreferably (1) optional substituted 5-to 7-unit's aromatics or non-aromatic heterocycle have 1-4 the heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, perhaps (2) following formula group :-CO-Z 2c(Z wherein 2cBe (i) optional substituted 5-to 7-unit's aromatics or non-aromatic heterocycle, have 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, (ii)-NR 20c(CR 21cR 22cR 23c) ((a) R wherein 20cBe H or optional substituted alkyl, be selected from C 1-8Radical of saturated aliphatic alkyl, C 2-8Unsaturated aliphatic alkyl, C 3-7Saturated alicyclic alkyl, C 3-7Unsaturated cycloaliphatic alkyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon base, C 3-7Saturated or undersaturated alicyclic radical-C 1-8Saturated or undersaturated aliphatic hydrocarbyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 1-4Alkyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 2-4Alkenyl, C 6-10Aryl and C 7-14Aralkyl; R 21cBe 1) optional substituted 5-to 7-unit's aromatics or non-aromatic heterocycle, have 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it can condense with optional substituted phenyl ring, perhaps 2) choose substituted C wantonly 6-10Aryl (for example phenyl), it can condense with the first aromatic heterocycle of optional substituted 5-to 7-, and described heterocycle has 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom; R 22cAnd R 23cBeing identical or different, is optional substituted alkyl, is selected from C 1-8Radical of saturated aliphatic alkyl, C 2-8Unsaturated aliphatic alkyl, C 3-7Saturated alicyclic alkyl, C 3-7Unsaturated cycloaliphatic alkyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon base, C 3-7Saturated or undersaturated alicyclic radical-C 1-8Saturated or undersaturated aliphatic hydrocarbyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 1-4Alkyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 2-4Alkenyl, C 6-10Aryl and C 7-14Aralkyl, perhaps optional substituted 5-to 7-unit's aromatics or non-aromatic heterocycle have 1-4 the heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, perhaps R 22cAnd R 23cCan be in conjunction with constituting C 3-7Carbocyclic ring, perhaps (b) R 20cBe H or optional substituted alkyl, be selected from C 1-8Radical of saturated aliphatic alkyl, C 2-8Unsaturated aliphatic alkyl, C 3-7Saturated alicyclic alkyl, C 3-7Unsaturated cycloaliphatic alkyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon base, C 3-7Saturated or undersaturated alicyclic radical-C 1-8Saturated or undersaturated aliphatic hydrocarbyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 1-4Alkyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 2-4Alkenyl, C 6-10Aryl and C 7-14Aralkyl; R 21c, R 22cAnd R 23cBeing identical or different, is optional substituted C 1-8Aliphatic hydrocarbyl, its condition be the summation of carbonatoms be 7 or more than), (iii)-NR 20cR 25c(R wherein 20cBe as defined above, R 25cBe optional substituted C 6-10Aryl-C 2-4Alkyl, C 6-10Aryloxy-C 2-4Alkyl, C 6-10Arylamino-C 2-4Alkyl, C 7-14Aryl alkyl amino-C 2-4Alkyl, 5-to 7-unit heterocycle (having 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom)-C 2-4Alkyl or 5-to 7-unit heterocyclic radical (having 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom)), 5-to the 7-unit cyclic amino (for example piperidino-(1-position only), piperadino, morpholino base, parathiazan Dai Ji etc.) that (iv) replaces, perhaps (v)-OR 24c(R wherein 24cBe (a) optional substituted C 7-14Aralkyl, (b) optional substituted C 3-7Alicyclic alkyl, (c) optional substituted C 7-24Aliphatic hydrocarbyl, perhaps (d) optional substituted 5-to 7-unit's aromatics or non-aromatic heterocycle have 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom));
Wherein said R 1a, Z 2c, R 20c, R 21c, R 22c, R 23c, R 24cAnd R 25cSubstituting group be 1 to 3 be selected from down the group substituting group:
1) C 1-6Alkyl,
2) C 2-6Alkenyl,
3) C 2-6Alkynyl,
4) C 3-7Cycloalkyl,
5) C 6-10Aryl, it can be replaced by 1 to 3 substituting group that is selected from down group: C 1-6Alkyl, amino, N-(C 1-6Alkyl) amino, N, N-two-(C 1-6Alkyl) amino, amidino groups, carbamyl, N-(C 1-6Alkyl) carbamyl, N, N-two-(C 1-6Alkyl) carbamyl, sulfamyl, N-(C 1-6Alkyl) sulfamyl, N, N-two-(C 1-6Alkyl) sulfamyl, carboxyl, C 2-7Alkoxy carbonyl, hydroxyl, C 1-6Alkoxyl group, sulfydryl, C 1-6Alkylthio, sulfo group, cyano group, azido-, halogen, nitro, nitroso-group, phosphono, C 1-6Alkoxy phosphoryl, two-(C 1-6Alkoxyl group) phosphoryl and by phosphono, C 1-6Alkoxy phosphoryl and two-(C 1-6Alkoxyl group) C of phosphoryl replacement 1-6Alkyl (following with the 5th) group is called " C " group),
6) aromatic heterocyclic radical, be selected from (a) aromatics 5-or 6-unit heterocyclic radical, have 1-4 and be selected from nitrogen-atoms, the heteroatoms of Sauerstoffatom and sulphur atom, (b) fused bicyclic heterocyclic radical, (have 1 to 3 and be selected from nitrogen-atoms by aromatics 5-or 6-unit heterocyclic radical, the heteroatoms of Sauerstoffatom and sulphur atom) (has 1 to 3 and be selected from nitrogen-atoms with phenyl ring or aromatics 5-or 6-unit heterocyclic radical, the heteroatoms of Sauerstoffatom and sulphur atom) condenses and form, (c) fused tricyclic heterocycles base, (have 1 to 3 and be selected from nitrogen-atoms by [1] aromatics 5-or 6-unit heterocyclic radical, the heteroatoms of Sauerstoffatom and sulphur atom), [2] phenyl ring and [3] aromatics 5-or 6-unit heterocyclic radical (has 1 to 3 and is selected from nitrogen-atoms, the heteroatoms of Sauerstoffatom and sulphur atom) or phenyl ring condense and form
7) heterocyclic oxy group, by each above-mentioned aromatic heterocyclic radical (a) and (b) and (c) with oxygen base be combined into,
8) non-aromatics 4-or 7-unit heterocyclic radical has 1 to 3 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom,
9) C 7-14Aralkyl, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
10) amino,
11) amino of N-list-replacement is selected from N-(C 1-6Alkyl) amino, N-(C 2-6Alkenyl) amino, N-(C 3-7Cycloalkyl) amino and N-(C 6-10Aryl) amino, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
12) be selected from C by two 1-6Alkyl, C 2-6Alkenyl, C 3-7Cycloalkenyl group and C 6-10The amino that the substituting group of aryl replaces, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
13) amidino groups,
14) acyl group is selected from C 2-8Alkyloyl, C 3-8Enoyl-, C 3-7Cycloalkyl-carbonyl, C 3-7Cycloalkenyl group-carbonyl, C 6-10Aryl-carbonyl (it can be replaced by 1 to 3 substituting group that be selected from " C " group) and heterocyclic radical-carbonyl (forming) by aromatics or non-aromatics 5-or 6-unit's heterocyclic radical (having 1 to 3 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom) and carbonyl bonding,
15) carbamyl,
16) carbamyl of list-replacement is selected from N-(C 1-6Alkyl) carbamyl, N-(C 2-6Alkenyl) carbamyl, N-(C 3-7Cycloalkyl) carbamyl and N-(C 6-10Aryl) carbamyl, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
17) be selected from C by two 1-6Alkyl, C 2-6Alkenyl, C 3-7Cycloalkyl and C 6-10The carbamyl that the substituting group of aryl replaces, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
18) sulfamyl,
19) sulfamyl of N-list-replacement is selected from N-(C 1-6Alkyl) sulfamyl, N-(C 2-6Alkenyl) sulfamyl, N-(C 3-7Cycloalkyl) sulfamyl and N-(C 6-10Aryl) sulfamyl, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
20) be selected from C by two 1-6Alkyl, C 2-6Alkenyl, C 3-7Cycloalkyl and C 6-10The sulfamyl that the substituting group of aryl replaces, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
21) carboxyl,
22) C 1-6Alkoxyl group-carbonyl,
23) hydroxyl,
24) C 1-6Alkoxyl group,
25) C 2-10Alkene oxygen base,
26) C 3-7Cycloalkyloxy,
27) C 6-10Aryloxy, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
28) C 7-14Aralkoxy, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
29) sulfydryl,
30) C 1-6Alkylthio,
31) C 7-14Aromatic alkylthio, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
32) C 6-10Arylthio, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
33) C 1-6Alkyl sulphinyl,
34) C 7-14Aralkyl sulfinyl, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
35) C 6-10Aryl sulfonyl kia, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
36) C 1-6Alkyl sulphonyl,
37) C 7-14The aralkyl alkylsulfonyl, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
38) C 6-10Aryl sulfonyl, it can be replaced by 1 to 3 substituting group that is selected from " C " group,
39) sulfo group,
40) cyano group,
41) azido-,
42) halogen,
43) nitro,
44) nitroso-group,
45) phosphono,
46) C 1-6Alkoxyl group-phosphoryl,
47) two-C 1-6Alkoxyl group-phosphoryl,
48) by phosphono, C 1-6Alkoxy phosphoryl or two-(C 1-6Alkoxyl group) C of phosphoryl replacement 1-6Alkyl,
49) C that is replaced by 1 to 4 halogen atom 1-6Alkyl,
50) C that is replaced by 1 to 4 halogen atom 1-6Alkoxyl group and
51) C 1-6Alkylene dioxo base
(following with the above-mentioned the 1st) is to 51) group be called " B " group).
These substituent specific exampless comprise those identical groups of the substituting group institute illustration that encircles with 5-to the 7-unit of ring A.
R as formula (IIIa) 1a, more preferably by the group of following formula representative :-CONR 20c(CR 21cR 22cR 23c) (R wherein 20c, R 21c, R 22cAnd R 23cBe as defined above).
And then more preferably, R 1aBe (1) 5-to 7-unit aromatic heterocyclic radical, have 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom (for example 1,3,4-oxadiazole base, 1,3,4-thiadiazolyl group etc., it is by C 1-4Alkyl-C 7-14Aralkyl (for example 1-ethyl-1-(4-aminomethyl phenyl) propyl group etc.) replaces, and perhaps (2) are by the group of following formula representative :-CO-Z 2c '(Z wherein 2c 'Be (i)-NR 20c '(CR 21c 'R 22c 'R 23c ') ((a) R wherein 20c 'Be H or C 1-6Alkyl; R 21c 'Be C 6-10Aryl or 5-to 7-unit aromatic heterocyclic radical have 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, and they can be replaced by 1 to 3 substituting group that is selected from down group separately: halogen, C 1-6Alkyl, C 2-6Alkenyl, halo C 1-6Alkyl, hydroxyl C 1-6Alkyl, C 1-6Alkoxyl group, carboxyl, C 1-6Alkoxyl group-carbonyl, C 1-6Alkyl-carbonyl oxygen base, C 1-6Alkyl-carbonyl oxygen base-C 1-6Alkyl, carboxyl-C 1-6Alkoxyl group, C 1-6Alkoxyl group-carbonyl-C 1-6Alkyl, C 1-6Alkoxyl group-carbonyl-C 1-6Alkoxyl group, C 1-6Alkoxyl group-carbonyl-C 1-6Alkoxy-C 1-6Alkyl, carbonyl, C 1-6Alkyl-carbonyl, amino, list-or two-C 1-6(described phenyl can be replaced by 1 to 3 substituting group, and described substituting group is selected from halogen, C for alkylamino, phenyl 1-6Alkyl and halo C 1-6Alkyl) and 5-to 7-unit aromatic heterocyclic radical, have 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom; R 22c 'And R 23c 'Being identical or different, is C 1-6Alkyl, C 5-7(described phenyl can be replaced by 1 to 3 substituting group, and described substituting group is selected from C for cycloalkyl, phenyl 1-6Alkyl, halo C 1-6Alkyl and C 1-6Alkoxyl group), C 1-6Alkoxyl group-carbonyl-C 1-6Alkyl or C 1-6Alkyl-carbonyl-C 2-6Alkenyl, perhaps R 22c 'And R 23c 'Can be bonded to each other and constitute C 3-7Carbocyclic ring; Perhaps (b) R 20c 'And R 21c 'Being bonded to each other constitutes 5-to 7-unit ring, and described ring can be by C 1-6Alkoxyl group or C 7-14Aralkyl replaces, R 22c 'And R 23c 'Be C 1-6Alkyl), (ii)-NR 20c 'R 25c '(R wherein 20c 'Be H or C 1-6Alkyl; R 25c 'Be C 6-10Aryl-C 2-4Alkyl, C 6-10Aryloxy-C 2-4Alkyl, C 6-10Arylamino-C 2-4Alkyl, C 7-14Aryl alkyl amino-C 2-4Alkyl, the heterocycle-C of 5-to 7-unit 2-4Alkyl or 5-to 7-unit heterocyclic radical, they can be replaced by 1 or 2 substituting group that is selected from down group separately: halogen, C 1-6Alkyl, C 6-10Aryl, C 1-6Alkoxyl group, amino, list-or two-C 1-6Alkylamino, 5-to 7-unit cyclic amino, hydroxyl, oxo, C 1-6Alkoxyl group-carbonyl and cyano group), perhaps (iii) 5-to 7-unit cyclic amino, it is by 1 to 3 substituting group replacement that is selected from down group: halogen, C 1-6Alkyl, C 2-6Alkenyl, C 1-6Alkoxy-C 1-6Alkyl, C 5-7Cycloalkyl, C 6-10(described aryl can have 1 or 2 substituting group to aryl, is selected from halogen, C 1-6Alkyl, halo C 1-6Alkyl and C 1-6Alkoxyl group), C 7-14(described aralkyl can have 1 or 2 substituting group to aralkyl, is selected from halogen, C 1-6Alkyl, halo C 1-6Alkyl and C 1-6Alkoxyl group), hydroxyl, hydroxyl-C 1-6Alkyl, C 6-10(described aryloxy can have 1 or 2 substituting group to aryloxy, is selected from halogen, C 1-6Alkyl, halo C 1-6Alkyl and C 1-6Alkoxyl group), C 7-14Aralkoxy, C 6-10Aryl-carbonyl, carboxyl, C 1-6Alkoxyl group-carbonyl, carbamyl, C 6-10Aryl-carbamyl, amino, C 6-10Aryl-carbonyl amino, C 1-6Alkyl-carbonyl amino, C 1-6Alkoxyl group-carbonyl amino, C 6-10Arylthio, C 6-10Aryl sulfonyl, cyano group, oxo and 5-to 7-unit heterocyclic radical).
Formula (II), (III) and R (IIIa) 3Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above).
R 3The example of optional substituted alkyl, optional substituted hydroxyl, optional substituted amino and optional substituted heterocyclic radical comprise those identical groups of the substituting group institute illustration that encircles with 5-to 7-unit about ring A.
R 3Preferably H, C 1-6Alkyl or C 7-14Aralkyl, more preferably, R 3Be H.
Formula (I), (II), (III) and (IIIa) in Y be C, CR 4Or N.
R 4Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above).
R 4The example of optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted heterocyclic radical and halogen comprise those identical groups of the substituting group institute illustration that encircles with 5-to 7-unit about ring A.
Y is CH preferably.
Formula (III) and R (IIIa) 8Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above).
R 8The example of optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, halogen atom and optional substituted heterocyclic radical comprise those identical groups of the substituting group institute illustration that encircles with 5-to 7-unit about ring A.
R 8Preferably H, C 1-6Alkyl, C 1-6Alkylthio or C 1-6Alkoxyl group can be replaced by hydroxyl, more preferably, and R 8Be H or C 1-6Alkyl.
Formula (I), (II), (III) and (IIIa) in Ar be optional substituted cyclic group.
The example of the optional substituted cyclic group of Ar comprises optional substituted aromatics or non-aromatics hydrocarbon cyclic base or optional substituted aromatics or non-aromatic heterocycle etc.
The aromatic hydrocarbon cyclic group of Ar and the example of heterocyclic radical comprise and those identical aromatic hydrocarbyls and heterocyclic radical about the above-mentioned substituting group institute illustration of 5-to the 7-unit ring of ring A.
The example of non-aromatics hydrocarbon cyclic base comprises the saturated alicyclic alkyl (for example cycloalkyl etc.) with 3-7 carbon atom, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc.; Unsaturated cycloaliphatic alkyl (for example cycloalkenyl group, cycloalkadienyl etc.) with 3-7 carbon atom, for example 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2,4-cycloheptadiene base etc.; Fractional saturation and condensed bicyclic hydrocarbon base (preferred C 9-10Fractional saturation and condensed bicyclic hydrocarbon base etc. (comprise wherein the non-aromatics cyclic hydrocarbon group bonded of phenyl ring and 5-or 6-unit those)), for example 1-indenyl, 2-indenyl, 1-dihydro indenyl, 2-dihydro indenyl, 1,2,3,4-tetrahydrochysene-1-naphthyl, 1,2,3,4-tetrahydrochysene-2-naphthyl, 1,2-dihydro-1-naphthyl, 1,2-dihydro-2-naphthyl, 1,4-dihydro-1-naphthyl, 1,4-dihydro-2-naphthyl, 3,4-dihydro-1-naphthyl, 3,4-dihydro-2-naphthyl etc.; Or the like.
The substituent example of the optional substituted aromatics cyclic group of Ar and optional substituted heterocyclic radical comprises those identical groups of the above-mentioned substituting group institute illustration that encircles with 5-to 7-unit about ring A.
Ar is (1) C preferably 6-10Aryl, (2) 5-to 7-unit's aromatics or non-aromatic heterocycle have 1-4 the heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, perhaps (3) C 3-7Saturated or undersaturated alicyclic alkyl, they can be replaced by 1 to 3 substituting group that is selected from " B " group separately.
More preferably, Ar is C 6-10Aryl, it can be replaced by 1 to 3 substituting group that is selected from " B " group; 5-to 7-unit aromatic heterocyclic radical has 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, and it can be replaced by 1 to 3 substituting group that is selected from " B " group; Perhaps C 3-7Saturated or undersaturated alicyclic alkyl.
And then more preferably, Ar is (1) C 6-10Aryl (for example phenyl, naphthyl etc.), it can be replaced by 1 or 2 substituting group that is selected from down group: halogen atom, C 1-6Alkyl, C 1-6Alkoxyl group, hydroxyl, C 7-14Aralkoxy and list-or two-C 1-4Alkylamino, (2) 5-to 7-unit aromatic heterocyclic radical has 1-4 heteroatoms (for example pyridyl, furyl, thiazolyl, thienyl etc.) that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, and it can be by C 1-4Alkyl replaces, perhaps (3) C 5-7Cycloalkyl (for example cyclohexyl etc.), most preferably, Ar is optional by halogenated phenyl.
Formula (II), (III) and R (IIIa) 9And R 10Being identical or different, is H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above), perhaps R 9And R 10Can be in conjunction with constituting oxo base, methylene radical or ring.
R 9And R 10The example of optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, halogen atom and optional substituted heterocyclic radical comprise those identical groups of the above-mentioned substituting group institute illustration that encircles with 5-to 7-unit about ring A.
R 9And R 10One of preferably hydrogen atom or C 1-6Alkyl, it can be replaced by 1 to 3 substituting group that is selected from " B " group, and another is (1) alkyl, is selected from C 1-8Radical of saturated aliphatic alkyl, C 2-8Unsaturated aliphatic alkyl, C 3-7Saturated alicyclic alkyl, C 3-7Unsaturated cycloaliphatic alkyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon base, C 3-7Saturated or undersaturated alicyclic radical-C 1-8Saturated or undersaturated aliphatic hydrocarbyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 1-4Alkyl, C 9-10Fractional saturation and condensed bicyclic hydrocarbon-C 2-4Alkenyl, C 6-10Aryl and C 7-14Aralkyl, they can be replaced by 1 to 3 substituting group that is selected from " B " group separately, and perhaps (2) 5-to 7-unit's aromatics or non-aromatic heterocycle have 1-4 heteroatoms that is selected from nitrogen-atoms, Sauerstoffatom and sulphur atom, it can be replaced by 1 to 3 substituting group that is selected from " B " group, perhaps R 9And R 10Can be in conjunction with constituting C 5-7Carbocyclic ring.
More preferably, R 9And R 10One of be hydrogen atom or C 1-6Alkyl, another is optional by halogenated C 1-6Alkyl, C 6-10Aryl, C 7-10Aralkyl or 5-to 7-unit aromatic heterocyclic radical, perhaps R 9And R 10Be the C that constitutes by combining 5-7Carbocyclic ring.
The R of formula (II) 11And R 12Example be identical or different, be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1 '-Z 2(wherein-Z 1 '-be-CS-,-SO-or-SO 2-, Z 2Be as defined above).
R 11And R 12The example of optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, halogen atom and optional substituted heterocyclic radical comprise those identical groups of the above-mentioned substituting group institute illustration that encircles with 5-to 7-unit about ring A.
R 9And R 10Perhaps R 11And R 12Can be in conjunction with constituting oxo base, methylene radical or ring, for example C 3-6Saturated or undersaturated carbocyclic ring (for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl etc.); Perhaps R 10And R 11Can be in conjunction with constituting ring, for example C 3-6Saturated or undersaturated carbocyclic ring (for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl etc.).
Figure A0382393800581
Be singly-bound or two key.
Z in the formula (I) is CR 5, CR 5R 6, N or NR 7, CR 5Be as defined above.
R 6Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above).
R 6The example of optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group and optional substituted heterocyclic radical comprise those identical groups of the above-mentioned substituting group institute illustration that encircles with 5-to 7-unit about ring A.
R 7Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above).
R 7The example of optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, halogen atom and optional substituted heterocyclic radical comprise those identical groups of the above-mentioned substituting group institute illustration that encircles with 5-to 7-unit about ring A.
R 5, R 6And R 7Can be identical or different.
R 5Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, optional substituted alkylsulfonyl or optional substituted sulfinyl.
R 5The example of optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, optional substituted alkylsulfonyl and optional substituted sulfinyl comprise those identical groups of the above-mentioned substituting group institute illustration that encircles with 5-to 7-unit about ring A.
R and Z can be in conjunction with constituting ring B.
Ring B in the formula (I) is the first heterocycle of optional substituted 5-to 7-, and the example comprises and encircle about 5-to the 7-unit of ring A those identical groups of institute's illustration.
The X of formula (I) 2Be N or NR 3, R 3Be as defined above.
Formula (III) and X (IIIa) 3Be a key, Sauerstoffatom, optional oxidized sulphur atom, N, NR 7 'Or optional substituted divalence C 1-2Alkyl.
R 7 'Be H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted heterocyclic radical or following formula group :-Z 1 '-Z 2(wherein-Z 1 '-be-CS-,-SO-or-SO 2-, Z 2Be as defined above).
R 7 'The example of optional substituted alkyl, optional substituted hydroxyl, optional substituted amino and optional substituted heterocyclic radical comprise those identical groups of the substituting group institute illustration that encircles with 5-to 7-unit about ring A.
Optional substituted divalence C 1-2The example of alkyl comprises-CH 2-,-(CH 2) 2-,-CH=CH-etc., it can be replaced by one or two substituting group, and described substituting group is selected from about those of the substituting group institute illustration of 5-to the 7-unit ring of ring A.
In the formula (IIIa), X 3CH preferably 2
Preferred formula (I) compound not only comprises formula (IIIa) compound, and comprises other compounds, in the described compound-and Z 1-be-CO-Z 2Be optional substituted hydroxyl (for example hydroxyl, C 1-6Alkoxyl groups etc.) or amino, its is replaced (3-dihydro-1H-indenes-5-base is amino for phenyl amino, 3 for example, 5-Dimethoxyphenyl amino, 3-xenyl amino, 2, quinoline-6-base amino etc.) by optional substituted phenyl or optional substituted fused phenyl.
In the formula (II),
(1) be that 6-unit ring and Q are C or CR when encircling A 5The time, X 1Be C-Z 1-Z 2, C (Z 1-Z 2) R 2Or N-Z 1-Z 2, R 9And R 10Not H, or R 9And R 10Debond constitutes the oxo base, or R 10And R 11Debond constitutes 5-unit ring,
(2) when ring A be 6-unit ring and Q when being N, X 1Be C-Z 1-Z 2, C (Z 1-Z 2) R 2Or N-Z 1-Z 2, R 9And R 10Debond constitutes the oxo base,
(3) be that 5-unit ring and Q are C or CR when encircling A 5The time, X 1Be C-Z 1-Z 2, C (Z 1-Z 2) R 2Or N-Z 1-Z 2, Z 2Be optional substituted amino and
(4) when ring A be 5-unit ring and Q when being N, R 9And R 10In at least one is CHR 15R 16(R wherein 15And R 16Being identical or different, is H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above)).
The example of optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, halogen atom and optional substituted heterocyclic radical comprises those identical groups of the above-mentioned substituting group institute illustration that encircles with 5-to 7-unit about ring A.
Formula (II) and (III) in, preferably, R 1Be following formula group :-Z 1-Z 2-Z 1-be-CO-Z 2Be optional substituted hydroxyl or optional substituted amino; Ar is optional substituted aromatics cyclic group; R 9And R 10All being identical or different, is C 1-6Alkyl, perhaps R 9And R 10In conjunction with constituting ring, for example aforesaid saturated or undersaturated C 3-6Ring.
In the formula (III), preferably, R 3Be H.More preferably, in formula (III), R 1Be following formula group-Z 1-Z 2(wherein-Z 1-be-CO-,-CS-,-SO-or-SO 2-, Z 2Be optional substituted alkyl, optional substituted heterocyclic radical, optional substituted hydroxyl or optional substituted amino); R 3Be H; Ar is optional substituted aromatics cyclic group; X 3Be CR 11R 12(R wherein 11And R 12Being identical or different, is H, optional substituted alkyl, optional substituted hydroxyl, optional substituted amino, optional substituted thiol group, cyano group, halogen atom, optional substituted heterocyclic radical or following formula group :-Z 1-Z 2(wherein-Z 1-and Z 2Be as defined above), perhaps R 11And R 12Can be in conjunction with constituting oxo base, methylene radical or ring, for example aforesaid saturated or undersaturated C 3-6Ring); R 9And R 10Being identical or different, is C 1-6Alkyl, perhaps R 9And R 10Can be in conjunction with constituting ring, for example aforesaid saturated or undersaturated C 3-6Ring.
As for formula (I), (II), (III) or (IIIa) salt of compound (below be sometimes referred to as compound (I), (II), (III) or (IIIa)), pharmacy acceptable salt is preferred.The example comprises inorganic base salts, organic alkali salt, inorganic acid salt, organic acid salt, alkalescence or acidic amino acid salt etc.The preferred embodiment of inorganic base salts comprises an alkali metal salt, for example sodium salt, sylvite etc.; Alkaline earth salt, for example calcium salt, magnesium salts etc.; Aluminium salt; Ammonium salt; Or the like.The preferred embodiment of organic alkali salt comprises Trimethylamine 99, triethylamine, pyridine, picoline, thanomin, diethanolamine, trolamine, dicyclohexyl amine, N, the salt of N '-dibenzyl-ethylenediamin etc.The preferred embodiment of inorganic acid salt comprises the salt of hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid etc.The preferred embodiment of organic acid salt comprises the salt of formic acid, acetate, trifluoroacetic acid, fumaric acid, oxalic acid, tartrate, toxilic acid, citric acid, succsinic acid, oxysuccinic acid, methylsulfonic acid, Phenylsulfonic acid, right-toluenesulphonic acids etc.The preferred embodiment of alkaline amino acid salt comprises the salt of arginine, Methionin, 2,5-diaminovaleric acid etc.The preferred embodiment of acidic amino acid salt comprises the salt of aspartic acid, L-glutamic acid etc.
Compound (I), (II), (III) or (IIIa) can be the form of its prodrug.Compound (I), (II), (III) or prodrug (IIIa) are represented such compound, under the physiological condition in live body, be converted into compound (I), (II), (III) or (IIIa) by reaction with enzyme, hydrochloric acid in gastric juice etc., (i) such compound just, be converted into compound (I), (II), (III) or (IIIa) by the oxidation of enzyme, reduction, hydrolysis etc., (ii) such compound is converted into compound (I), (II), (III) or (IIIa) by the hydrolysis of hydrochloric acid in gastric juice etc.The example of compound used therefor (I), (II), (III) or prodrug (IIIa) comprises such compound or its salt, wherein compound (I), (II), (III) or (IIIa) in hydroxyl by acidylate, alkylation, phosphorylated or be converted into borate (compound or its salt so for example, wherein compound (I), (II), (III) or (IIIa) in hydroxyl be converted into acetoxyl group, palm acyloxy, propionyloxy, new pentane acyloxy, amber acyloxy, fumaryl oxygen base, alanyl oxygen base, dimethylamino methyl carbonyl oxygen base etc.); Compound or its salt like this, compound (I) wherein, (II), (III) or the carboxyl (IIIa) is esterified or amidation (such compound or its salt for example, compound (I) wherein, (II), (III) or the carboxyl (IIIa) be subjected to the ethyl esterification, the phenyl esterification, carboxylic oxygen methyl-esterified, the dimethylamino methyl esterification, the oxy acid methyl neopentyl esterification, the esterification of oxyethyl group carbonyl oxygen base ethyl, phthalidyl (phthalidyl) esterification, (5-methyl-2-oxo-1,3-dioxolane-4-yl) methyl-esterified, the cyclohexyloxy carbonyl esterification or be converted into methyl nitrosourea etc.) etc.These prodrugs can be improved one's methods according to known method itself or its and be prepared.
And then, compound (I), (II), (III) or prodrug (IIIa) can be such compound or its salts, under physiological condition, be converted into compound (I), (II), (III) or (IIIa), as " Developmentof Drugs ", Volume 7, Molecular Design, Hirokawa Shoten, 1990; Pages163-198 is described.
Compound (I), (II), (III) or (IIIa) can be (for example with isotropic substance 2H, 3H, 14C, 35S, 125I etc.) mark such as.
When gained compound or its salt of the present invention has two keys and has Z or during the steric configuration of E, every kind of steric isomer and composition thereof all comprises in the present invention in its molecule.
When having asymmetric carbon to have steric configuration in the molecule owing to gained compound or its salt of the present invention, every kind of configuration and composition thereof all comprises in the present invention.
Below, will set forth the preparation of The compounds of this invention.
The process of preparation The compounds of this invention (II), compound (III) and compound (IIIa) is with shown in the following flow process 1 to 13.
Can prepare such compound (II) according to flow process 1 to 3, wherein Q is N, and Y is C or CR 4
Can prepare such compound (II) according to flow process 4, wherein Q is C, and Y is C or CR 4
Can prepare such compound (II) according to flow process 5, wherein Q is N, and Y is N.
Can prepare such compound (III) and compound (IIIa) by flow process 6, wherein Y is C or CR 4
Can prepare such compound (III) and compound (IIIa) by flow process 7, wherein Y is N.
Can prepare such compound (II) by flow process 13, wherein Q is C, and Y is N.
Flow process 1
Figure A0382393800621
Wherein A-1 is identical with A, and other symbols are as defined above.
In the steps A, compound (II-1) is to prepare like this, utilizes acid or alkali to carry out the cyclization of compound (IV-1) and compound (X).The example that is used in the acid in this reaction comprises: mineral acid, for example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid; Organic acid, for example acetate, trifluoroacetic acid, methylsulfonic acid, Phenylsulfonic acid and right-toluenesulphonic acids; And Lewis acid, for example zinc chloride (II), tin chloride (IV), aluminum chloride etc.
The example of alkali comprises an alkali metal salt, for example potassium hydroxide, sodium hydroxide, sodium bicarbonate and salt of wormwood; Amine, for example pyridine, triethylamine, N, accelerine and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene; Metal hydride, for example potassium hydride KH and sodium hydride; And alkali metal alcoholate, for example sodium methylate, sodium ethylate and potassium tert.-butoxide.
The consumption of these acid or alkali is preferably about 0.1 to about 5 molar equivalents, for compound (IV-1).
There is not the example of the solvent of disadvantageous effect to comprise aromatic hydrocarbon to reaction, for example benzene, toluene and dimethylbenzene; Ether, for example tetrahydrofuran (THF), glycol dimethyl ether, diox and diethyl ether; Acid amides, N for example, dinethylformamide; Alcohol, for example ethanol, propyl alcohol, the trimethyl carbinol and methyl cellosolve; And sulfoxide, for example dimethyl sulfoxide (DMSO).These solvents can mix use by suitable proportion.
Temperature of reaction is generally-50 ℃ to about 200 ℃ approximately, preferred-10 ℃ to about 150 ℃ approximately.
Reaction times is generally about 0.5 to about 60 hours.
Gained compound (II-1) can be separated and purifying with purification process by known separation, for example concentrates, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolving and chromatogram.
Here compound used therefor (IV-1) for example can be according to Bilestein, vol.25, and p.2033 described method is prepared.In addition, compound (X) for example can be according to Organometallics, and p.954 vol.11 is prepared.
Among the step B, compound (II-2) is to prepare like this, makes compound (II-1) carry out reduction reaction.
In this reaction, use palladium carbon, palladium hydroxide etc. to carry out the catalytic hydrogenation method, perhaps use reductive agent to reduce.As reductive agent, use sodium borohydride, lithium aluminum hydride and lithium borohydride.In this reaction, if necessary, can use any solvent, need only their not inhibited reactions.Especially, alcohol (C for example 1-3Alcohol, for example methyl alcohol, ethanol, propyl alcohol etc.) or ether (for example diethyl ether, diisopropyl ether, glycol dimethyl ether, tetrahydrofuran (THF), diox etc.) be preferred.
Reaction times is generally about 0.5 to about 20 hours.
Gained compound (II-2) can be separated and purifying with purification process by known separation, for example concentrates, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolving and chromatogram.
Flow process 2
Figure A0382393800631
Wherein A-1 is identical with A, and other symbols are as defined above.
Among the step C, compound (V) is to prepare like this, makes compound (IV-1) and compound (XI) carry out cyclization.This reaction is according to ordinary method, in the presence of acid, in the solvent that reaction is not had disadvantageous effect or do not have solvent to carry out.
The example of acid comprises mineral acid, for example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid; Organic acid, for example acetate, trifluoroacetic acid, methylsulfonic acid, Phenylsulfonic acid and right-toluenesulphonic acids; Lewis acid, for example zinc chloride (II), tin chloride (IV), aluminum chloride etc.
The amount of these acid is preferably about 0.1 to about 5 molar equivalents, for compound (IV-1).
There is not the example of the solvent of disadvantageous effect to comprise aromatic hydrocarbon to reaction, for example benzene, toluene and dimethylbenzene; Ether, for example tetrahydrofuran (THF), diox and diethyl ether; Halohydrocarbon, for example chloroform and methylene dichloride; Acid amides, N for example, dinethylformamide; And sulfoxide, for example dimethyl sulfoxide (DMSO).These solvents can mix use by suitable proportion.
Temperature of reaction is generally-50 ℃ to 150 ℃ approximately, preferred-10 ℃ to about 120 ℃ approximately.
Reaction times is generally about 0.5 to about 20 hours.
Gained compound (V) can be separated and purifying with purification process by known separation, for example concentrates, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolving and chromatogram.
Among the step B, compound (II-3) can be prepared according to the step B in the flow process 1.
Flow process 3
Figure A0382393800641
Wherein Y ' is C or CR 4, L and L ' they are leavings groups, and the reactivity of L is bigger than L ', and other symbols are as defined above.
Among the step D, compound (VI-1) prepares from compound (IV-1).Present method is according to ordinary method, carries out in the presence of alkali, in the solvent that reaction is not had disadvantageous effect.The specific examples of leavings group L and L ' comprises halogen atom; Sulfonyloxy, for example right-tosyloxy, mesyloxy and trifluoro-methanesulfonyl oxy; And acyloxy, for example acetoxyl group and benzoyloxy.
The example of alkali comprises an alkali metal salt, for example potassium hydroxide, sodium hydroxide, sodium bicarbonate and salt of wormwood; Amine, for example pyridine, triethylamine, N, accelerine and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene; Metal hydride, for example potassium hydride KH and sodium hydride; And alkali metal alcoholate, for example sodium methylate, sodium ethylate and potassium tert.-butoxide.
The consumption of these alkali is preferably about 1 to about 5 molar equivalents, for compound (IV).
There is not the example of the solvent of disadvantageous effect to comprise aromatic hydrocarbon to reaction, for example benzene, toluene and dimethylbenzene; Ether, for example tetrahydrofuran (THF), diox and diethyl ether; Acid amides, N for example, dinethylformamide; And sulfoxide, for example dimethyl sulfoxide (DMSO).These solvents can mix use by suitable proportion.
Temperature of reaction is generally-50 ℃ to 150 ℃ approximately, preferred-10 ℃ to about 120 ℃ approximately.
Reaction times is generally about 0.5 to about 20 hours.
Gained compound (VI-1) can be separated and purifying with purification process by known separation, for example concentrates, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolving and chromatogram.
In the step e, compound (II-4) is to prepare like this, makes compound (VI-1) carry out intramolecular cyclization reaction.Present method is according to ordinary method, what carry out in the presence of acid or the alkali, in the solvent that reaction is not had disadvantageous effect.The specific examples of leavings group L ' comprises halogen atom, right-tosyloxy, mesyloxy and trifluoro-methanesulfonyl oxy.
The example of acid comprises mineral acid, for example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid; Organic acid, for example acetate, trifluoroacetic acid, methylsulfonic acid, Phenylsulfonic acid and right-toluenesulphonic acids; And Lewis acid, for example zinc chloride (II), tin chloride (IV), aluminum chloride etc.The example of alkali comprises an alkali metal salt, for example salt of wormwood; Amine, for example pyridine, triethylamine, N, accelerine and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene; Metal hydride, for example potassium hydride KH and sodium hydride; And alkali metal alcoholate, for example sodium methylate, sodium ethylate and potassium tert.-butoxide.
The consumption of these acid or alkali is preferably about 1 to about 5 molar equivalents, for compound (IV-1).
There is not the example of the solvent of disadvantageous effect to comprise aromatic hydrocarbon to reaction, for example benzene, toluene and dimethylbenzene; Ether, for example tetrahydrofuran (THF), diox and diethyl ether; Halohydrocarbon, for example chloroform and methylene dichloride; Acid amides, N for example, dinethylformamide; And sulfoxide, for example dimethyl sulfoxide (DMSO).These solvents can mix use by suitable proportion.
Temperature of reaction is generally-50 ℃ to 150 ℃ approximately, preferred-10 ℃ to about 120 ℃ approximately.
Reaction times is generally about 0.5 to about 20 hours.
Gained compound (II-4) can be separated and purifying with purification process by known separation, for example concentrates, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolving and chromatogram.
Flow process 4
Figure A0382393800661
Wherein A-2 is identical with A, and other symbols are as defined above.
In the step F, compound (VI-2) is from compound (IV-2) and compound (XII) preparation.Present method is according to ordinary method, carries out in the presence of alkali, in the solvent that reaction is not had disadvantageous effect.
The example of alkali comprises an alkali metal salt, for example salt of wormwood, yellow soda ash and cesium carbonate; Amine, for example pyridine, triethylamine, N, accelerine and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene; Metal hydride, for example potassium hydride KH and sodium hydride; And alkali metal alcoholate, for example sodium methylate, sodium ethylate and potassium tert.-butoxide.
The consumption of these alkali is preferably about 1 to about 5 molar equivalents, for compound (IV-2).
There is not the example of the solvent of disadvantageous effect to comprise aromatic hydrocarbon to reaction, for example benzene, toluene and dimethylbenzene; Ether, for example tetrahydrofuran (THF), diox and diethyl ether; Halohydrocarbon, for example chloroform and methylene dichloride; Acid amides, N for example, dinethylformamide; And sulfoxide, for example dimethyl sulfoxide (DMSO).These solvents can mix use by suitable proportion.
Temperature of reaction is generally-50 ℃ to 200 ℃ approximately, preferred-10 ℃ to about 150 ℃ approximately.
Reaction times is generally about 0.5 to about 20 hours.
Gained compound (VI-2) can be separated and purifying with purification process by known separation, for example concentrates, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolving and chromatogram.
Among the step G, compound (II-5) is to prepare like this, makes compound (VI-2) carry out reduction reaction.
In this reaction, use palladium carbon, palladium hydroxide or Raney nickel to carry out the catalytic hydrogenation method, perhaps use reductive agent to reduce.As reductive agent, use sodium borohydride, lithium aluminum hydride and lithium borohydride.In this reaction, if necessary, can use any solvent, need only their not inhibited reactions.Especially, alcohol (C for example 1-3Alcohol, for example methyl alcohol, ethanol, propyl alcohol etc.) or ether (for example diethyl ether, diisopropyl ether, glycol dimethyl ether, tetrahydrofuran (THF), diox etc.) be preferred.
Reaction times is generally about 0.5 to about 20 hours.
Gained compound (II-5) can be separated and purifying with purification process by known separation, for example concentrates, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolving and chromatogram.
Flow process 5
Figure A0382393800671
Ar wherein 1Be optional substituted non-aromatic hydrocarbon ring or optional substituted non-aromatic heterocyclic, Ar 2Be optional substituted aromatic hydrocarbon ring or optional substituted aromatic heterocycle, A-3 is identical with A, and other symbols are as defined above.
Among the step H, make the amino of compound (IV-3) be converted into diazonium salt, again with inner salt prepared in reaction compound (VIII-1).Diazotization in present method is according to ordinary method, carries out in the presence of acid, in the solvent that reaction is not had disadvantageous effect.As acid, for example use acetate and hydrochloric acid.As diazotization agent, use Sodium Nitrite, alkyl nitrite or sulfation nitrosyl.
As solvent, make water, diox, tetrahydrofuran (THF) etc.
Temperature of reaction is generally-50 ℃ to about 150 ℃ approximately, preferred-10 ℃ to about 100 ℃ approximately.
Reaction times is generally about 0.5 to about 20 hours.
Make the diazonium salt and the interior reactant salt that generates from compound (XIII-1) of gained compound (IV-3), preparation compound (VIII-1).This step is in the presence of alkali, carries out in the solvent that reaction is not had disadvantageous effect.The example of alkali comprises an alkali metal salt, for example salt of wormwood; Amine, for example pyridine, triethylamine, N, accelerine and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene; Metal hydride, for example potassium hydride KH and sodium hydride; And alkali metal alcoholate, for example sodium methylate, sodium ethylate and potassium tert.-butoxide.
The consumption of these alkali is preferably about 1 to about 3 molar equivalents, for compound (XIII-1).
There is not the example of the solvent of disadvantageous effect to comprise aromatic hydrocarbon to reaction, for example benzene, toluene and dimethylbenzene; Ether, for example tetrahydrofuran (THF), diox and diethyl ether; Halohydrocarbon, for example chloroform and methylene dichloride; Acid amides, N for example, dinethylformamide; And sulfoxide, for example dimethyl sulfoxide (DMSO).These solvents can mix use by suitable proportion.
Because gained compound (VIII-1) because of the kind of this compound but unsettled, need not to separate and purifying promptly is used for next step.
Among the step I, make compound (VIII-1) carry out reduction reaction, preparation compound (IX-1).In this reaction, use platinum oxide, Raney nickel, palladium carbon or palladium hydroxide to carry out the catalytic hydrogenation method, perhaps use reductive agent to reduce.
As reductive agent, use sodium borohydride, lithium aluminum hydride and lithium borohydride.In this reaction, if necessary, can use any solvent, need only their not inhibited reactions.Especially, alcohol (C for example 1-3Alcohol, for example methyl alcohol, ethanol, propyl alcohol etc.) or ether (for example diethyl ether, diisopropyl ether, glycol dimethyl ether, tetrahydrofuran (THF), diox etc.) be preferred.
Reaction times is generally about 0.5 to about 20 hours.
Gained compound (IX-1) can be separated and purifying with purification process by known separation, for example concentrates, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolving and chromatogram.
Among the step J, compound (II-7) is to prepare like this, carries out the reductive amination reaction between compound (IX-1) and ketone (XV).Present method is in the presence of reductive agent, carries out in the solvent that reaction is not had disadvantageous effect.The example of reductive agent comprises sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride and lithium borohydride.Although used alcoholic solvent (for example ethanol and methyl alcohol), methylene dichloride, chloroform and tetracol phenixin as solvent, but can use any solvent, need only their not inhibited reactions.
Gained compound (II-7) can be separated and purifying with purification process by known separation, for example concentrates, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolving and chromatogram.
In the step K, make bismuthiol act on compound (IX-1), preparation compound (II-8).Present method is in the presence of metal catalyst, carries out in the solvent that reaction is not had disadvantageous effect.As metal catalyst, for example use copper catalyst, for example venus crystals (II) and PIVALIC ACID CRUDE (25) copper (II).
Although use methylene dichloride, chloroform and tetracol phenixin as solvent, but can use any solvent, need only their not inhibited reactions.
Temperature of reaction is generally-80 ℃ to 150 ℃ approximately, preferred-80 ℃ to about 100 ℃ approximately.
Reaction times is generally about 0.5 to about 20 hours.
Gained compound (II-8) can be separated and purifying with purification process by known separation, for example concentrates, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolving and chromatogram.
Flow process 6
X wherein 4With X 3Identical, other symbols are as defined above.
Step D and step e can be carried out according to the step D and the step e of flow process 3 respectively, preparation compound (III-1).
Flow process 7
Figure A0382393800692
Ar wherein 3Be optional substituted hydrocarbon ring, optional substituted non-aromatic heterocyclic, aromatic hydrocarbon ring or aromatic heterocycle, X 5With X 3Identical, other each symbols have above-mentioned identical meanings.
Step H, step I, step J and step K can be carried out according to step H, step I, step J and the step K of flow process 5 respectively, preparation compound (III-2).
In the compound (II), work as X 1Be C-COOR 16The time, it can be by following conversion:
Flow process 8
Figure A0382393800693
Wherein A-4 represents the implication identical with A, R 16The optional substituted carbon atom of expression, other symbols are as defined above.
Among the step L, compound (II-10) is to prepare like this, carries out the reaction of cracking carboxyl-blocking group.
This reaction can adopt all routines to be used for the method for the reaction of cracking carboxyl-blocking group, for example hydrolysis, reduction and use the Lewis acid cancellation.Preferably hydrolysis is to carry out in the presence of alkali or acid.The example of the alkali that is fit to comprises mineral alkali, alkali metal hydroxide (for example sodium hydroxide and potassium hydroxide) for example, alkaline earth metal hydroxides (for example magnesium hydroxide and potassium hydroxide), alkaline carbonate (for example yellow soda ash and salt of wormwood), alkaline earth metal carbonate (for example magnesiumcarbonate and lime carbonate), alkali metal hydrocarbonate (for example sodium bicarbonate and saleratus), alkali metal acetate (for example sodium acetate and potassium acetate), alkali earth metal phosphate (for example trimagnesium phosphate and calcium phosphate) and alkali metal hydrogen phosphate (for example Sodium phosphate dibasic and dipotassium hydrogen phosphate), and organic bases, trialkylamine (for example Trimethylamine 99 and triethylamine) for example, picoline, the N-crassitude, N-methylmorpholine, 1,5-diazabicylo [4.3.2] ninth of the ten Heavenly Stems-5-alkene, 1,4-diazabicylo [2.2.2] ninth of the ten Heavenly Stems-5-alkene and 1,8-diazabicylo [4.3.0]-7-undecylene.Under many circumstances, basic hydrolysis is carried out in water or hydrophilic organic solvent or mixed solvent.The example of the acid that is fit to comprises formic acid, Hydrogen bromide and sulfuric acid.
This hydrolysis reaction normally carries out in organic solvent, water or its mixed solvent.Temperature of reaction is not particularly limited, but suitably selects according to the kind and the elimination method of carboxyl-blocking group.Be performed such with the Lewis acid cancellation, make the reaction of compound (II-9) or its salt and Lewis acid, for example boron trihalides (for example boron trichloride and boron trifluoride), titanium tetrahalide (for example titanium tetrachloride and titanium tetrabromide) and aluminum halide (for example aluminum chloride and aluminum bromide), perhaps organic acid (for example three aluminium acetate and trifluoroacetic acids).This elimination reaction is preferably carried out in the presence of cation removal agent (for example phenylmethylether and phenol), normally in solvent, carry out, for example nitro-paraffin (for example Nitromethane 99Min. and nitroethane), alkylidene group halogen (for example methylene dichloride and ethylene dichloride), diethyl ether, dithiocarbonic anhydride and reaction is not had the solvent of disadvantageous effect.These solvents can use their mixture.
Preferably, the reduction cancellation is used for the cancellation blocking group, for example haloalkyl (for example 2-iodine ethyl and 2,2,2-three chloroethyls) ester and aralkyl (for example benzyl) ester.The example that is used in the method for reducing in this elimination reaction comprises conventional catalytic reduction, carries out in the presence of the combination of metal (for example zinc and zinc amalgam) or chromium cpd salt (for example chromium chloride and chromium acetate) and organic or inorganic acid (for example acetate, propionic acid and hydrochloric acid) or common metal catalyzer (for example palladium carbon and Raney nickel).Temperature of reaction is not particularly limited, but reaction is carried out under cooling, room temperature or heating.
Gained compound (II-10) can be separated and purifying with purification process by known separation, for example concentrates, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolving and chromatogram.
Flow process 9
Figure A0382393800711
R wherein 17And R 18Be optional substituted alkyl, allyl group or hydroxyl, perhaps R 17And R 18Can be bonded to each other and constitute ring, Y " identical with Y, other symbols are as defined above.
In present method, compound (II-12) is to prepare like this, makes compound (II-11) or its carboxyl-reactive derivative or salt and above-claimed cpd (XVI) or its amino-reactive derivative or reactant salt.Compound (XVI) the amino-reactive derivative that is fit to comprises the schiff's base type imino-, by compound (XVI) and for example reaction such as aldehyde, ketone generation of carbonyl compound; The silyl derivative is generated by compound (XVI) and silyl compound reaction, for example two (trimethylsilyl) ethanamides, list (trimethylsilyl) ethanamide, two (trimethylsilyl) urea etc.; The derivative that is generated by compound (XVI) and phosphorus trichloride or phosgene reaction.
The specific examples of compound (II-11) the carboxyl-reactive derivative that is fit to comprises carboxylic acid halides, acid anhydrides, activating terephthalamide amine, Acibenzolar etc.The example of the reactive derivatives that is fit to comprises: acyl chlorides; Acid azide; With the mixed acid anhydride of acid, for example phosphoric acid of Qu Daiing, for example dialkyl group phosphoric acid, phosphenylic acid, diphenylphosphoric acid, dibenzyl phosphoric acid, halophosphoric acid etc., dialkyl group phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid, methylsulfonic acid etc. for example, aliphatic carboxylic acid, for example acetate, propionic acid, butyric acid, isopropylformic acid, PIVALIC ACID CRUDE (25), valeric acid, isovaleric acid, trichoroacetic acid(TCA) etc., perhaps aromatic carboxylic acid, for example phenylformic acid etc.; Symmetric anhydride; With imidazoles activatory acid amides; Imidazoles, dimethyl pyrazole, triazole or tetrazolium that 4-replaces; Acibenzolar; cyano methyl ester for example; methoxymethyl ester; the dimethylimino methyl ester; vinyl ester; propargyl ester; right-the nitrophenyl ester; the trichlorophenyl ester; the five chlorophenyl ester; the methylsulfonyl phenylester; phenylazo phenyl ester; the phenyl thioester; right-the nitrophenyl ester; right-the tolyl thioester; the carboxymethyl thioester; the pyranyl ester; pyridyl ester; the piperidyl ester; 8-quinolyl thioester etc.; the perhaps ester of N-oxy-compound; N for example, the N-dimethyl hydroxylamine; 1-hydroxyl-2-(1H)-pyridone; N-hydroxy-succinamide; N-hydroxyl phthalimide; 1-hydroxyl-1H-benzotriazole etc.These reactive derivatives can be selected arbitrarily according to the kind of compound used therefor (II-11).The example of compound (II-12) reactive derivatives that is fit to comprises an alkali metal salt, for example sodium salt, sylvite etc.; Alkaline earth salt, for example calcium salt, magnesium salts etc.; And alkali salt, for example organic alkali salt, for example ammonium salt, front three amine salt, triethylamine salt, pyridinium salt, picoline salt, dicyclohexyl amine salt, N, N-dibenzyl ethylenediamine salt etc.Although reaction is normally carried out in conventional solvent, for example water, alcohol (for example methyl alcohol, ethanol etc.), acetone, diox, acetonitrile, chloroform, methylene dichloride, ethylene dichloride, tetrahydrofuran (THF), ethyl acetate, N, dinethylformamide and pyridine, but reaction can carried out in other organic solvents arbitrarily, as long as they do not have disadvantageous effect to reaction.These conventional solvents can use the mixture with water.
When the free acid that in this reaction, uses compound (II-11) or its salt form, preferably reaction is in the presence of for example so-called Vilsmeier reagent of condensing agent commonly used etc., by N, N '-dicyclohexylcarbodiimide, N-cyclohexyl-N '-morpholino ethyl carbodiimide, N-cyclohexyl-N '-(4-diethylin cyclohexyl) carbodiimide, N, N '-diethyl carbodiimide, N, N '-DIC, N-ethyl-N '-(3-dimethylamino-propyl) carbodiimide, N, N '-carbonyl two (glyoxal ethyline), pentamethylene ketene-N-cyclohexyl imines, diphenylethlene ketone-N-cyclohexyl imines, oxyethyl group acetylene, 1-alkoxyl group-1-vinylchlorid, trialkyl phosphite, the polyphosphoric acid ethyl ester, the polyphosphoric acid isopropyl ester, phosphoryl chloride, phenylbenzene azide phosphinylidyne, thionyl chloride, oxalyl chloride, halo formic acid lower alkyl esters (Vinyl chloroformate for example, isopropyl chlorocarbonate etc.), triphenyl phosphine, 2-ethyl-7-hydroxy benzo isoxazolium salt, 2-ethyl-5-(-sulfo group phenyl) isoxazole hydroxide inner salt, the N-hydroxybenzotriazole, 1-(right-the chlorobenzene sulfonyloxy)-6-chloro-1H-benzotriazole, N, N '-dimethyl formamide and thionyl chloride, phosgene, trichloro-methyl chloroformate, the reaction of phosphoryl chloride etc. is prepared.Select as an alternative, reaction can be carried out in the presence of mineral alkali or organic bases, for example alkali metal hydrocarbonate, three (rudimentary) alkylamine, pyridine, N-(rudimentary) alkyl morpholine, N, N-two (rudimentary) alkylbenzylamine etc.Temperature of reaction is not particularly limited, but reaction is carried out under cooling or heating.
The consumption of compound (XVI) is 1 to 10 molar equivalent, and preferred 1 to 3 equivalent is for compound (II-11).
Temperature of reaction is generally-30 ℃ to 100 ℃.
Reaction times is generally 0.5 to 20 hour.
In addition, when using mixed acid anhydride, make compound (II-11) and chlorine carbonic ether (for example methyl-chlorocarbonate, chlorine ethyl-carbonate, chlorine isobutyl carbonate butyl ester etc.) at alkali (for example triethylamine, N-methylmorpholine, N, accelerine, sodium bicarbonate, yellow soda ash, salt of wormwood etc.) down reaction of existence, further react again with compound (XVI).
The consumption of compound (XVI) is 1 to 10 molar equivalent, and preferred 1 to 3 equivalent is for compound (II-11).
Temperature of reaction is generally-30 ℃ to 100 ℃.
Reaction times is generally 0.5 to 20 hour.
Gained compound (II-12) can be separated and purifying with purification process by known separation, for example concentrates, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolving and chromatogram.
X in compound (III) 1Be C-COOR 16The time, conversion can followingly be carried out:
Flow process 10
Wherein each symbol is as defined above.
Step L and step M can carry out according to the step M in step L in the flow process 8 and the flow process 9 respectively, preparation compound (III-4) and compound (III-5).
Flow process 11
R wherein 19Be optional substituted alkyl, allyl group, hydroxyl, amino or sulfane base, other symbols are as defined above.
In present method, compound (II-13) is to prepare like this, reacts between compound (V) and nucleophilic reagent.
The example of the nucleophilic reagent that uses comprises metal phenates, metal alkoxide, Grignard reagent, alkylmetal reagent, metal arylide reagent and thiolate.
The consumption of nucleophilic reagent is preferably about 1 to about 5 molar equivalents, for compound (V).
There is not the example of the solvent of disadvantageous effect to comprise ether to reaction, for example diethyl ether, tetrahydrofuran (THF) He diox; Aromatic hydrocarbon, for example benzene, toluene and dimethylbenzene; Acid amides, N for example, dinethylformamide and 1-methyl-2-pyrrolidone; And sulfoxide, for example dimethyl sulfoxide (DMSO).These solvents can mix use by suitable proportion.
Temperature of reaction is generally-50 ℃ to 150 ℃ approximately, preferred-10 ℃ to about 100 ℃ approximately.
Reaction times is generally about 0.5 to about 20 hours.
Gained compound (II-13) can be separated and purifying with purification process by known separation, for example concentrates, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolving and chromatogram.
Flow process 12
Figure A0382393800741
Wherein each symbol is as defined above.
Step N can carry out according to the step N in the flow process 11, preparation compound (III-4).
Flow process 13
Figure A0382393800742
Wherein A-6 is identical with A, and other symbols are as defined above.
Among the step H, the amino of compound (IV-5) is converted into diazonium salt, again with inner salt prepared in reaction compound (VIII-3).Diazotization in this method is according to ordinary method, carries out in the presence of acid, in the solvent that reaction is not had disadvantageous effect.As acid, for example use acetate and hydrochloric acid.As diazotization agent, use Sodium Nitrite, alkyl nitrite or sulfation nitrosyl.
As solvent, make water, diox, tetrahydrofuran (THF) etc.
Temperature of reaction is generally-50 ℃ to about 150 ℃ approximately, preferred-10 ℃ to about 100 ℃ approximately.
Reaction times is generally about 0.5 to about 20 hours.
Make the diazonium salt and the interior reactant salt that generates from compound (XVII) of gained compound (IV-5), preparation compound (VIII-3).This step is in the presence of alkali, carries out in the solvent that reaction is not had disadvantageous effect.The example of alkali comprises an alkali metal salt, for example salt of wormwood; Amine, for example pyridine, triethylamine, N, accelerine and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene; Metal hydride, for example potassium hydride KH and sodium hydride; And alkali metal alcoholate, for example sodium methylate, sodium ethylate and potassium tert.-butoxide.
The consumption of these alkali is preferably about 1 to about 3 molar equivalents, for compound (XVII).
There is not the example of the solvent of disadvantageous effect to comprise aromatic hydrocarbon to reaction, for example benzene, toluene and dimethylbenzene; Ether, for example tetrahydrofuran (THF), diox and diethyl ether; Halohydrocarbon, for example chloroform and methylene dichloride; Acid amides, N for example, dinethylformamide; And sulfoxide, for example dimethyl sulfoxide (DMSO).These solvents can mix use by suitable proportion.
Because gained compound (VIII-3) because of the kind of this compound but unsettled, need not to separate and purifying can be used for next step.
Step I, step J and step K can be carried out according to the step I in the flow process 5, step J and step K respectively, preparation compound (II-14) and compound (II-15).
R in compound (II) 3When being hydrogen atom, following conversion is possible.
Flow process 14
Figure A0382393800751
Wherein each symbol is the same.
Among the step O, compound (II-4) is subjected to alkylation, acidylate, carbamylation, oxidation of coal or thiocarbamoylization, preparation compound (II-16).
Reaction is carried out according to ordinary method.In alkylation, react respectively with alkylogen; In acidylate, with carboxylic acid halides or anhydride reaction; In carbamylation,, react with amine then with isocyanic ester or carbonylic imidazole reaction; In oxidation of coal, with oxygen base carbonyl halogen or oxygen carbonic anhydride (oxycarboic acidanhydride) reaction; In thiocarbamoylization,, prepare this compound with the reaction of isothiocyanic acid ester.This reaction generally is in the presence of alkali, carries out in the solvent that reaction is not had disadvantageous effect.The example of alkali comprises an alkali metal salt, for example potassium hydroxide, sodium hydroxide, sodium bicarbonate and salt of wormwood; Amine, for example pyridine, triethylamine, N, accelerine and 1,8-diazabicylo [5.4.0] 11 carbon-7-alkene; Metal hydride, for example potassium hydride KH and sodium hydride; And alkali metal alcoholate, for example sodium methylate, sodium ethylate and potassium tert.-butoxide.
The consumption of these alkali is preferably about 1 to about 5 molar equivalents, for compound (II-4).
There is not the example of the solvent of disadvantageous effect to comprise aromatic hydrocarbon to reaction, for example benzene, toluene and dimethylbenzene; Ether, for example tetrahydrofuran (THF), diox and diethyl ether; Halohydrocarbon, for example chloroform and methylene dichloride; Acid amides, N for example, dinethylformamide; And sulfoxide, for example dimethyl sulfoxide (DMSO).These solvents can mix use by suitable proportion.
Temperature of reaction is generally-50 ℃ to 150 ℃ approximately, preferred-10 ℃ to about 120 ℃ approximately.
Reaction times is generally about 0.5 to about 20 hours.
Gained compound (II-6) can be separated and purifying with purification process by known separation, for example concentrates, concentrating under reduced pressure, solvent extraction, crystallization, recrystallization, transfer dissolving and chromatogram.
R in compound (III) 3When being hydrogen atom, following conversion is possible.
Flow process 15
Wherein each symbol is the same.
Step O, step J and step K can be carried out according to the step O in the flow process 14 respectively, preparation compound (III).
All uses in the present invention or the compound that obtains all comprise corresponding salt, even concrete regulation is arranged; They can be by itself known method or its exchange each other of improving one's methods.
When being the asymmetric minute period of the day from 11 p.m. to 1 a.m by the resulting compound or its salt of the present invention, they can be separated into d-type isomer and 1-type isomer according to conventional encompasses processes for optical resolution.
Can be used as its reaction mixture by the resulting compound or its salt of the present invention and be used for next step, need not abundant purifying.
Compound of the present invention (I), (II), (III) or the Ca receptor modulating activities that (IIIa) has excellence, strengthen the secretion of PTH, therefore can be used as medicine, kidney-functionality medicine, central nervous system and the internal secretion-functionality medicine for the treatment of osteopathia, Digestive tract-functionality medicine etc.And then toxicity is lower.Therefore, compound (I), (II), (III) or (IIIa) can be by safely to Mammals administration (for example people, rat, mouse, dog, rabbit, cat, ox, horse, pig etc.).
Thereby, contain The compounds of this invention (I), (II), (III) or pharmaceutical composition (IIIa) the expection disease that can be used for treating and wherein need preventing the Ca receptor modulating activities, for example the Ca acceptor is regulated medicine: primary or Secondary cases hyperparathyroidism, hypoparathyroidism, hyperthyroidism, thyroprivia, Graves' disease, Hashimoto is poisoned, osteitis deformans, the hypercalcemia relevant with malignant tumour, hypercalcemia, low blood calcium, through osteoporosis without offspring, senile osteoporosis, secondary osteoporosis, the osteomalacia, renal osteodystrophy, fracture, osteoarthritis, rheumatoid arthritis, osteosarcoma, myelomatosis, hypertension, diabetes, myocardial infarction, the HachingtonShi disease, Parkinson's disease, Alzheimer, dull-witted, cerebral apoplexy, cerebral tumor, Spinal injury, diabetic kidney disease, renal insufficiency, stomach ulcer, duodenal ulcer, Basedow's disease, parathyroidoma, thyroid tumor, arteriosclerosis etc.; Ca receptor agonism medicine: hyperthyroidism, low blood calcium, through osteoporosis without offspring, senile osteoporosis, secondary osteoporosis, osteomalacia, renal osteodystrophy, fracture, osteoarthritis, rheumatoid arthritis, osteosarcoma, myelomatosis, central nervous system disease etc., particularly osteoporosis.
Compound (I), (II), (III) or dosage (IIIa) can be selected by variety of way according to the route of administration and the patient's that treats symptom.Adult (body weight 50kg) can select usually like this with compound (I), (II), (III) or dosage (IIIa), under case of oral administration, at about 0.1mg to the scope of about 500mg, preferred about 1mg is to about 100mg, under the situation of administered parenterally, to the scope of about 100mg, further preferred about 0.1mg is to about 10mg at about 0.01mg.This dosage can divide give for 1-3 time every day.
Can be with compound of the present invention (I), (II), (III) or (IIIa) prepare with pharmaceutically acceptable carrier, can oral or administered parenterally, solid preparation is tablet, capsule, granule, pulvis etc. for example, and liquid preparation is syrup, injection etc. for example.And, can make Percutaneously administrable preparation, for example patch, paste, ointment (comprising creme), plaster, band agent, lotion, liquid and solution, suspension, emulsion, sprays etc.
As for pharmaceutically acceptable carrier, use multiple organic or inorganic carrier substance, they are conventionally used as preparation material, be combined into swelling agent, lubricant, tackiness agent and disintegrating agent in the solid preparation and carrier, solubilizing agent, suspension agent, isotonic agent, buffer reagent and the pain killer in the liquid preparation.If necessary, can use formulation excipients, for example sanitas, antioxidant, stablizer, tinting material, sweeting agent etc.
The preferred embodiment of swelling agent (bulky agent) comprises lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid etc.The preferred embodiment of lubricant comprises Magnesium Stearate, potassium stearate, talcum, colloid silica etc.The preferred embodiment of tackiness agent comprises crystalline cellulose, Alpha-starch, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, Vltra tears, polyvinylpyrrolidone etc.The preferred embodiment of disintegrating agent comprises starch, carboxymethyl cellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium starch glycolate, the low hydroxypropylcellulose that replaces etc.The preferred embodiment of carrier comprises water for injection, ethanol, propylene glycol, polyoxyethylene glycol, sesame oil, corn wet goods.
If necessary, for the purpose of taste masking, enteric coated or prolongation effect, oral preparations can be by known method dressing itself.The example of this Drug coating comprises Vltra tears, ethyl cellulose, Walocel MT 20.000PV, hydroxypropylcellulose, polyoxyethylene glycol, tween 80, Pluronic F68 (polyoxyethylene (160) polyoxypropylene (30) glycol), rhodia phthalate, Vltra tears phthalate, acetate Walocel MT 20.000PV phthalate, Eudragit (made by Rohm Company, first is for vinylformic acid-acrylic copolymer) etc.
The preferred embodiment of solubilizing agent comprises polyoxyethylene glycol, propylene glycol, phenylformic acid benzyl ester, ethanol, Trisaminomethane, cholesterol, trolamine, yellow soda ash, Trisodium Citrate etc.The preferred embodiment of suspension agent comprises tensio-active agent, for example stearyl trolamine, Sodium Lauryl Sulphate BP/USP, laurylamino-propionic acid, Yelkin TTS, benzalkonium chloride, benzethonium chloride, Zerol etc.; Hydrophilic macromolecule material, for example polyvinyl alcohol, polyvinylpyrrolidone, Xylo-Mucine, methylcellulose gum, Walocel MT 20.000PV, Natvosol, hydroxypropylcellulose etc.; Or the like.The preferred embodiment of isotonic agent comprises sodium-chlor, glycerine, D-mannitol etc.The preferred embodiment of buffer reagent comprises the buffered soln of phosphoric acid salt, acetate, carbonate, Citrate trianion etc.The preferred embodiment of pain killer comprises benzylalcohol etc.The preferred embodiment of sanitas comprises p-Hydroxybenzoate, butylene-chlorohydrin, benzylalcohol, phenylethyl alcohol, dehydroacetic acid (DHA), Sorbic Acid etc.The preferred embodiment of antioxidant comprises sulphite, xitix etc.
The following example, preparation and experiment are described preparation and used mode of the present invention and process, and be only unrestricted for setting forth.Dissociable is can have other embodiments in the defined spirit and scope of the invention by claims.
Abbreviation used herein is following defined.
The DCM=methylene dichloride
The DCE=ethylene dichloride
The DMAP=Dimethylamino pyridine
The DMF=dimethyl formamide
WSC=1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
The single isotopic mass of M+H=adds a proton
The Me=methyl
The Et=ethyl
The Ph=phenyl
H=hour
Min=minute
The HPLC=high performance liquid chromatography
The HOBt=hydroxybenzotriazole
The LC/MS=liquid chromatography/mass spectrometry
The MS=mass spectrum
The Rt=retention time
The TEA=triethylamine
The TFA=trifluoroacetic acid
The IPE=diisopropyl ether
The TLC=thin-layer chromatography
The THF=tetrahydrofuran (THF)
TMSCN=trimethylsilyl prussiate
HATU=O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate
The DIPEA=diisopropylethylamine
Embodiment 1
5-phenyl-7-(trifluoromethyl)-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester also
Figure A0382393800791
Steps A: with 4,4,4-three fluoro-1-phenyl-1, (6.97g, 32.24mmol) (5.0g, 32.22mmol) mixture in AcOH (100ml) refluxed 4 hours 3-dimethyl diketone 1 with 3-amino-pyrazol-4-carboxylic acid, ethyl ester 2.Mixture is cooled to room temperature, concentrates, filter and collect sedimentary crystal, obtain 8.63g (79%) title compound, be yellow crystals.
1H?NMR(CDCl 3，200MHz)：1.47(3H，t，J＝7.0Hz)，4.47(2H，q，J＝7.0Hz)，7.54-7.61(3H，m)，7.80(1H，s)，8.23-8.28(2H，m)，8.68(1H，s).
Step B: at room temperature, to 3 (3.51g, MeOH solution adding NaBH 10.3mmol) 4(1.4g, 3.7mmol).Whole mixtures are stirred 5h under uniform temp,, concentrate in a vacuum, extract with AcOEt with saturated citric acid solution quencher.Extraction liquid is used aq.NaHCO continuously 3, water and salt water washing, through MgSO 4Drying concentrates then, obtains 1.73g (49%) compound 4, is colourless oil.
1H?HMR(CDCl 3，200MHz)：1.32(3H，t，J＝6.8Hz)，2.28-2.46(1H，m)，2.50-2.61(1H，m)，4.25(2H，q，J＝6.8Hz)，4.58(1H，dd，J＝11.4，3.4Hz)，4.85(1H，ddd，J＝3.4，3.0，2.6Hz)，6.15(1H，s)7.34-7.48(5H，m)，7.74(1H，s).
According to preparing embodiment 2-14 compound, as shown in table 1 to embodiment 1 described similar mode.
Table 1
Figure A0382393800801
Figure A0382393800811
Figure A0382393800821
Embodiment 15
7,7-dimethyl-5-(2-pyridyl)-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester also
Figure A0382393800832
Steps A: under-78 ℃, to the compound 1 that is stirring (7.0g, THF 44.3mmol) (100ml) solution add n-BuLi (the 1.6M hexane solution, 28ml, 44.8mmol).After mixture stirred 30 minutes, to wherein add compound 2 (6.34g, 44.3mmol).The gained mixture is stirred 2h down at-78--50 ℃,, extract with AcOEt with saturated citric acid solution quencher.With continuous water of extraction liquid and salt water washing, through MgSO 4Drying concentrates then in a vacuum.Resistates is handled through silica gel chromatography, as eluent, obtains 3.16g (44% yield) compound 3 with AcOEt/ hexane (1: 9), is colourless liquid.
Step B: under frozen water cooling, to the methyl cellosolve solution (60ml) of compound 3 and compound 4 add TFA (4.47g, 39.2mmol).With the mixture 12h that refluxes, with the AcOEt dilution, with the saturated NaHCO of mixture 3Solution, water and salt water washing are through MgSO 4Drying concentrates then in a vacuum.Resistates is handled through silica gel chromatography, as eluent, obtains 2.03g (36% yield) compound 5 with AcOEt/ hexane (1: 4), is colourless prism.
Step C: with 5 (1.98g, 6.96mmol) with 10%Pd-C (1.0g) at EtOH (100ml) prescribed mixt at H 2Atmosphere (gasbag pressure) stirs 2h down.After leaching insolubles, resistates is concentrated in a vacuum, obtain resistates.Crystallization from hexane/IPE obtains title compound 6 (1.00g, 48%), is colorless solid.
1H?NMR(CDCl3，200MHz)：1.34(3H，t，J＝7.0Hz)，4.26(2H，q，J＝7.0Hz)，4.80(1H，dd，J＝11.4，2.6Hz)，6.39(1H，s)，7.24-7.31(1H，m)，7.51(1H，d，J＝7.6Hz)，7.76(1H，td，J＝7.6，1.8Hz)，8.60-8.63(1H，m).
According to preparing embodiment 16-20,439-447 and 924-938 compound, as shown in table 2 to embodiment 15 described similar modes.
Table 2
Figure A0382393800841
Figure A0382393800871
Figure A0382393800881
Embodiment 21
5-phenyl-7-(trifluoromethyl)-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-carboxylic acid also
Figure A0382393800882
With 1,1.5N KOH solution (14ml) stirs 12h with the mixture of EtOH (20ml) down at 60 ℃, with saturated citric acid solution acidifying, filter and collect institute's precipitated solid, water and IPE washing, obtain 1.59g (76% yield) title compound, be colourless prism.
mp?184.8-185.0℃， 1H?NMR(CDCl3，300MHz)：2.31-2.44(1H，m)，2.50-2.59(1H，m)，4.59(1H，dd，J＝11.4，3.0Hz)，4.79(1H，m)，6.10(1H，s)，7.20-7.26(5H，m)，7.78(1H，s).
According to preparing embodiment 22-39,448-458 and 939-953 compound, as shown in table 3 to embodiment 21 described similar modes.
Table 3
Figure A0382393800901
Figure A0382393800921
Figure A0382393800941
Figure A0382393800951
Embodiment 40
N-encircles octyl group-5-phenyl-7-(trifluoromethyl)-4,5,6, and the 7-tetrahydro-pyrazole is [1,5-a] pyrimidine-3-methane amide also
With cyclooctylamine (24mg, 0.19mmol) join compound 1 (0.05g, 0.16mmol), WSC (37mg, 0.19mmol), (29mg, 0.19mmol) (23mg is in DMF 0.19mmol) (1.5ml) suspension with DMAP for HOBt.Reaction mixture is at room temperature stirred 14h, with DCM (0.5ml) and saturated NaHCO 3Solution (0.5ml) dilution separates with the PHASE-SEP filtration syringe then.Organic layer is concentrated, load onto preparation HPLC (Gilson 215 systems).Merge the purest part, obtain 64.6mg (96% yield) title compound, be white solid.Anti-phase LC/MS:CAPCELLPAKCC18UG120, S-3 μ m, 2.0 * 50mm, UV detects 220,8min. gradient 10-100% solvent B/A (solvent orange 2 A: CH 3CN and 0.1%TFA, solvent B:H 2O and 0.1%TFA), 0.5ml/min.Rt=1.90min, (96% is pure) .MS (M+H:421).
Embodiment 41
N-(1-ethyl-1-(4-(trifluoromethyl) phenyl) propyl group)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide also
Figure A0382393800962
At room temperature, to 3 (0.5g, 1.84mmol) with HATU (0.84g, DMF 2.21mmol) (3ml) solution add DIPEA (0.67ml, 3.68mmol).Behind the 30min, to wherein add compound 2 (0.59g, 2.21mmol).The gained mixture is stirred 18h down at 80 ℃, concentrate in a vacuum, resistates is handled through silica gel chromatography, as eluent, obtains 0.28g (31% yield) compound 4 with AcOEt/ hexane (1/1), is colourless prism.mp?193-194℃
According to preparing embodiment 42-434,459-867 and 954-1008 compound, as shown in table 4 to embodiment 40 or 41 described similar modes.
Table 4
Figure A0382393800971
Figure A0382393800981
Figure A0382393800991
Figure A0382393801001
Figure A0382393801011
Figure A0382393801021
Figure A0382393801031
Figure A0382393801061
Figure A0382393801071
Figure A0382393801081
Figure A0382393801101
Figure A0382393801131
Figure A0382393801161
Figure A0382393801171
Figure A0382393801181
Figure A0382393801191
Figure A0382393801221
Figure A0382393801241
Figure A0382393801261
Figure A0382393801281
Figure A0382393801291
Figure A0382393801301
Figure A0382393801321
Figure A0382393801331
Figure A0382393801351
Figure A0382393801361
Figure A0382393801381
Figure A0382393801411
Figure A0382393801421
Figure A0382393801431
Figure A0382393801441
Figure A0382393801451
Figure A0382393801491
Figure A0382393801511
Figure A0382393801521
Figure A0382393801541
Figure A0382393801551
Figure A0382393801621
Figure A0382393801651
Figure A0382393801661
Figure A0382393801671
Figure A0382393801681
Figure A0382393801701
Figure A0382393801711
Figure A0382393801721
Figure A0382393801731
Figure A0382393801751
Figure A0382393801771
Figure A0382393801791
Figure A0382393801801
Figure A0382393801811
Figure A0382393801821
Figure A0382393801831
Figure A0382393801841
Figure A0382393801851
Figure A0382393801861
Figure A0382393801871
Figure A0382393801911
Figure A0382393801931
Figure A0382393801981
Figure A0382393801991
Figure A0382393802031
Figure A0382393802041
Figure A0382393802051
Figure A0382393802061
Figure A0382393802091
Figure A0382393802101
Figure A0382393802111
Figure A0382393802121
Figure A0382393802131
Figure A0382393802161
Figure A0382393802171
Figure A0382393802181
Figure A0382393802191
Figure A0382393802211
Figure A0382393802221
Figure A0382393802251
Figure A0382393802261
Figure A0382393802271
Figure A0382393802281
Figure A0382393802291
Figure A0382393802301
Figure A0382393802341
Figure A0382393802351
Figure A0382393802401
Figure A0382393802431
Figure A0382393802441
Figure A0382393802461
Figure A0382393802481
Figure A0382393802501
Figure A0382393802511
Embodiment 1009
7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester also
Embodiment 16 gained racemic compounds (80g) are prepared type high performance liquid chromatography (HPLC) to be handled, obtain optically pure material (38g, 99.8%ee (shorter retention time) and 39g, 99.4%ee (longer retention time)) (pillar: CHIRALCEL OD 50mm φ * 500mm (making) by DaicelKagaku Kogyo Kabushiki Kaisha, temperature: 30 ℃, mobile phase: hexane/ethanol=95/5, flow velocity: 60ml/ minute, detect wavelength: 254nm, a shot: 800mg).
According to preparing embodiment 1010-1017 compound, shown in table 8-11 to embodiment 1009 described similar modes.
Table 8
Figure A0382393802521
The mensuration of optical purity is the (pillar: CHIRALCEL OD4.6mm φ * 250mm (being made by Daicel Kagaku Kogyo Kabushiki Kaisha) that utilizes chiral column HPLC to carry out, temperature: about 30 ℃, mobile phase: hexane/ethanol=96/4, flow velocity: 0.5ml/ minute, detect wavelength: 254nm).
Table 9
Figure A0382393802522
The mensuration of optical purity is the (pillar: CHIRALCEL OD4.6mm φ * 250mm (being made by Daicel Kagaku Kogyo Kabushiki Kaisha) that utilizes chiral column HPLC to carry out, temperature: about 30 ℃, mobile phase: hexane/IPA=95/5, flow velocity: 0.5ml/ minute, detect wavelength: 254nm).
Table 10
The mensuration of optical purity is the (pillar: CHIRALCEL OD4.6mm φ * 250mm (being made by Daicel Kagaku Kogyo Kabushiki Kaisha) that utilizes chiral column HPLC to carry out, temperature: about 30 ℃, mobile phase: hexane/ethanol=995/5, flow velocity: 0.5ml/ minute, detect wavelength: 220nm).
Table 11
The mensuration of optical purity is the (pillar: CHIRALCEL OD4.6mm φ * 250mm (being made by Daicel Kagaku Kogyo Kabushiki Kaisha) that utilizes chiral column HPLC to carry out, temperature: about 30 ℃, mobile phase: hexane/ethanol=95/5, flow velocity: 0.5ml/ minute, detect wavelength: 258nm).
Embodiment 1018
(-)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydro-pyrazole are [1,5-a] pyrimidine-3-carboxylic acid also
With embodiment 1009 gained 1 (0.73g), KOH (0.41g), H 2O (20ml) stirs 12h with the mixture of EtOH (20ml) down at 90 ℃, with 1N HCl acidifying, extracts with AcOEt.With extraction liquid salt water washing, through MgSO 4Drying concentrates in a vacuum, obtains 0.55g (83% yield) title compound, is colourless prism
([α] D 20 ℃=-85.33, at CHCl 3 li, C=0.46) .mp 205-206 ℃, 1H NMR (CDCl3,300MHz): 1.59 (3H, s), 1.66 (3H, s), 2.05-2.15 (2H, m), 4.64 (1H, dd, J=9.6,5.4Hz), 6.04 (1H, s), 7.30-7.41 (5H, m), 7.73 (1H, s).
According to preparing embodiment 1019-1027 compound, as shown in table 12 to embodiment 1018 described similar modes.
Table 12
Embodiment 1028
(S)-and N-(1-(4-chloro-phenyl-)-1-ethyl propyl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-carboxamide hydrochloride also
Steps A: at room temperature, to 1 (0.4g, 1.47mmol) with HATU (0.67g, DMF 1.77mmol) (5ml) solution add DIPEA (0.57g, 4.41mmol).Behind the 1h, to wherein add compound 2 (0.41g, 1.77mmol).The gained mixture is stirred 12h down at 80 ℃, concentrate in a vacuum.Resistates is diluted with AcOEt, use saturated NaHCO 3The aqueous solution and salt water washing are through MgSO 4Drying concentrates in a vacuum.Resistates is handled through silica gel chromatography, with AcOEt/ hexane (1/1) wash-out, obtains 0.41g (62% yield) compound 4, is colourless prism.mp?105-106℃.[α] D 20℃＝-17.68，CHCl 3，C＝0.30。
Step B: at room temperature, to the compound 3 that is stirring (90mg, Et 0.2mmol) 2O (3ml) solution adding 4M HCl-AcOEt (0.1ml, 0.4mmol).Filter collecting precipitation, obtain 60mg (62% yield) compound 4, be prism.mp?130-132℃.[α] D 20℃＝24.3，CHCl 3，C＝0.48.
According to preparing embodiment 1029-1122 compound, as shown in table 13 to embodiment 1028 described similar modes.
Table 13
Figure A0382393802571
Figure A0382393802591
Figure A0382393802601
Figure A0382393802611
Figure A0382393802621
Figure A0382393802631
Figure A0382393802641
Figure A0382393802691
Figure A0382393802711
Figure A0382393802721
Embodiment 435
N-(1-adamantyl)-7-ethyl-5-phenyl-7-(trifluoromethyl)-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide also
Figure A0382393802732
Steps A: at room temperature, to the compound 1 that is stirring (2.00g, DCM 6.00mmol) (50ml) solution add triethyl aluminum (the 2.0M hexane solution, 18ml, 36mmol).After mixture stirred 2h, the water quencher extracted with AcOEt.With continuous water of extraction liquid and salt water washing, through MgSO 4Drying concentrates then in a vacuum, obtains compound 2 (2.20g, 100% yield), is yellow slurry.MS(ESI，m/z)366(M+H) +。
Step B: with compound 2 (2.20g, 6.00mmol), LiOH (0.51g, 12.15mmol), EtOH (50ml) and H 2The mixture of O (30ml) stirs 12h down at 70 ℃, concentrates in a vacuum, with the aqueous citric acid solution dilution, extracts with AcOEt.With the continuous water of extraction liquid, saturated NaHCO 3Solution and salt water washing are through MgSO 4Drying concentrates then, obtains compound 3 (2.00g, 100%), is clear crystal.MS(ESI，m/z)352(M+H) +。
Step C: with the 1-adamantanamines (0.72g, 4.76mmol) join compound 3 (1.60g, 4.74mmol), WSC (0.91g, 4.74mmol), (0.64g, 4.74mmol) (0.58g is in DMF 4.75mmol) (20ml) suspension with DMAP for HOBt.Reaction mixture is stirred 13h down at 70 ℃, concentrate in a vacuum then.Resistates is handled through silica gel chromatography, as eluent, obtains compound 4 (0.71g, 32%) with AcOEt/ hexane (1/6), is clear crystal.MS(ESI，m/z)472(M+H) +。
Step D: at room temperature, to 4 (0.58g, EtOH solution adding NaBH 1.23mmol) 4(0.2g, 5.29mmol).Whole mixtures are stirred 3h down at 60 ℃, concentrate in a vacuum, dilute with water extracts with AcOEt.Extraction liquid is used aq.NaHCO continuously 3, water and salt water washing, through MgSO 4Drying concentrates then, obtains 0.43g (74%) compound 5, is clear crystal.MS(ESI，m/z)474(M+H) +。
According to preparing embodiment 436 compounds, as shown in table 5 to embodiment 435 described similar modes.
Table 5
Embodiment 437
2-cyclohexyl-4-methyl-N-(1-methyl isophthalic acid-phenylethyl)-1,2,3,4-tetrahydro-pyrazole be [5,1-c] [1,2,4] triazine-8-methane amide also
Steps A: in the 250ml round-bottomed flask of being furnished with magnetic agitator arm and 2 addition funnels, add 1.0g (6.44mmol), 3.5ml concentrated hydrochloric acid and 7.0ml water.Solution is cooled to 0 ℃, drips the 2ml aqueous solution of 0.50g (7.25mmol) Sodium Nitrite.After adding fully, reactant is stirred 30min down at 0 ℃,, keep temperature of reaction simultaneously and be lower than 10 ℃ succeeded by adding 65ml methylene dichloride and 35ml saturated sodium bicarbonate solution.Drip the 30ml dichloromethane solution of 2.05g (6.44mmol) 1-triphen phosphino--2-acetone then.After adding fully, reactant is stirred 5min,, wash with water with the dilution of 50ml methylene dichloride.Separate organic phase, under reduced pressure remove and desolvate, obtain 3.50g (100%) crude compound 2, need not to be further purified and to use.MS calculated value: 206; Measured value 207 (M+H).
Step B: under nitrogen atmosphere, add 1.20g (3.72mmol) sodium borohydride to the 30ml of above-mentioned crude product ethanol and 30ml THF solution.Reactant is at room temperature stirred 30min.Reactant is diluted with ethyl acetate, wash with water.Organic phase is through MgSO 4Dry.Filter, remove and desolvate, resistates with 70%AcOEt/ hexane wash-out, obtains 0.79g (58.9%) compound 3 via the Biotage chromatogram purification, is faint yellow solid.MS calculated value: 208; Measured value 209 (M+H).
Step C: the 15ml ethanol and the 10ml aqueous solution of 0.54g (2.59mmol) compound 3 and 0.18g LiOH (7.52mmol) are heated to 70 ℃.1.5h after, the HPLC of reaction mixture shows does not have the raw material residue.Under reduced pressure remove ethanol,, use ethyl acetate extraction resistates 1N hcl acidifying.Organic phase is through dried over mgso.Filter, remove and desolvate, obtain 0.48g (92.2%) compound 4.MS calculated value: 180; Measured value 181 (M+H).
Step D: under nitrogen atmosphere, to the 150ml DMF solution adding 6.50g (17.10mmol) of 2.80g (15.54mmol) compound 4 HATU, 2.31g (17.10mmol) cumyl amine and 2.98ml (17.10mmol) diisopropylethylamine.Reactant is heated to 50 ℃ spends the night,, wash with water with the ethyl acetate dilution.Organic phase is through dried over mgso.Filter, remove and desolvate, resistates with 60%AcOEt/ hexane wash-out, obtains 3.09g (66.9%) compound 5 via the Biotage chromatogram purification.MS calculated value: 297; Measured value 298 (M+H).
Step e: in the Parr flask, add 1.11g (3.90mmol) compound 5 and 75ml EtOH.Flask is purified with nitrogen, add the 0.30g platinum oxide.With the flask emptying, be forced into 20psig hydrogen (3x), be forced into 50psig hydrogen then, vibration 1h.After definite reaction is finished according to HPLC, make reactant pass through the GF/F filter paper filtering, under reduced pressure concentrated filtrate obtains 1.1g (100%) compound 6.MS calculated value: 299; Measured value 300 (M+H).
Step F: under nitrogen atmosphere, to the 40ml DCE solution adding 0.30ml (2.89mmol) of 0.43g (1.44mmol) compound 6 pimelinketone, succeeded by 0.90g (4.25mmol) sodium triacetoxy borohydride.Reactant at room temperature stirred spend the night.Reactant is diluted with methylene dichloride, wash with saturated sodium bicarbonate solution.Organic phase is through MgSO 4Dry.Filter, remove and desolvate, resistates with 75%AcOEt/ hexane wash-out, obtains 0.35g (63.7%) compound 7 via the Biotage chromatogram purification.MS calculated value: 381; Measured value 382 (M+H).
Embodiment 438
4-methyl-N-(1-methyl isophthalic acid-phenylethyl)-2-phenyl-1,2,3,4-tetrahydro-pyrazole be [5,1-c] [1,2,4] triazine-8-methane amide also
Under nitrogen atmosphere and-78 ℃, add 0.36g (0.64mmol) triphenyl bismuth diacetin to the 25ml DCM solution of 0.20g (0.71mmol) compound 1, succeeded by 0.02g (0.075mmol) two PIVALIC ACID CRUDE (25) copper (II).Make reactant go through 1.5h and be warmed to 0 ℃.Reactant is diluted with methylene dichloride, wash with saturated sodium bicarbonate.Organic phase is through dried over mgso.Filter, remove and desolvate, resistates with 70%AcOEt/ hexane wash-out, obtains 0.025g (9.4%) compound 2 via the Biotage chromatogram purification.MS calculated value: 375; Measured value 376 (M+H).
Embodiment 1123
1-(7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidin-3-yl also)-2-methyl-2-(4-aminomethyl phenyl)-1-acetone
Steps A
4-benzyl-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydro-pyrazole also [1,5-a] pyrimidine-3-carboxylic acid (2): in the 100ml round-bottomed flask of being furnished with the magnetic agitator arm, add 1.80g (6.01mmol) 7,7-dimethyl-5-phenyl-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyrimidine-3-carboxylic acid ethyl ester, 30ml DMF and 0.786ml (6.61mmol) bromotoluene also, succeeded by dividing some parts to add 0.265g (6.6mmol) sodium hydride (60% mineral oil dispersion).Behind the 2h, will react the water quencher, product extracts with AcOEt.Merge organic layer, use the salt water washing,, filter, concentrate, obtain thick N-benzyl ester, be golden oil through dried over sodium sulfate.Thick ester is dissolved in 15ml ethanol, adds 2.5ml 6N potassium hydroxide.Solution is heated to 70 ℃ then and reaches 18h, analyze can detect according to HPLC this moment does not have raw material.Crude product mixture is concentrated in a vacuum dilute with water.Institute's solution with 6N HCl acidifying, is filtered and collects gained lacteous precipitation.The isolating thick acid of institute is dissolved in AcOEt,, filters, be concentrated into the lacteous powder through dried over sodium sulfate.Gained acid is with some parts of hexane wash, dry in a vacuum, obtain 1.95g (90%) title compound, be pale powder. 1H NMR (DMSO-d 6) δ 1.10 (s, 3H), 1.40 (s, 3H), 1.98-2.16 (m, 2H), 3.71 (d, J=15.4Hz, 1H), 4.36 (dd, J=4.5,11.5Hz, 1H), 5.81 (d, J=15.6Hz), 6.97 (dd, J=1.4,7.2Hz, 2H), and 7.26-7.45 (m, 7H), 7.67 (s, 1H), 11.81 (s, 1H) .MS calculated values: 361; Measured value: 344 (M-OH).
Step B
4-benzyl-7,7-dimethyl-5-phenyl-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyrimidine-3-carboxylic acid methoxyl group-methyl-acid amides (3) also: the 5ml nmp solution to 0.72g (1.99mmol) 2 adds 0.91g (2.39mmol) O-7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate (HATU) and 0.416ml (2.39mmol) diisopropylethylamine.After stirring 30min, add 0.233g (2.39mmol) O, the N-dimethyl hydroxylamine hydrochloride is heated to 50 ℃ with reactant.Behind the 1h, reaction mixture is poured in the water, extracted with AcOEt.Merge organic layer, use the salt water washing,, filter, concentrate in a vacuum, obtain thick oil through dried over sodium sulfate.This oil is through purification by flash chromatography, with 60 to 50% hexane/AcOEt gradient elution, obtains 0.65g (81%) title compound, is shallow golden solid. 1H NMR (CDCl 3) δ 1.37 (s, 3H), 1.56 (s, 3H), 2.06-2.16 (m, 2H), 3.25 (s, 3H), 3.49 (s, 3H), 3.90 (d, J=16.0Hz, 1H), 4.45 (dd, J=5.1,11.3Hz, 1H), 5.06 (d, J=16.2Hz, 1H), 6.98 (dd, J=1.8,6.1Hz, 2H), and 7.20-7.24 (m, 3H), 7.30-7.34 (m, 1H), and 7.37-7.41 (m, 4H), 7.74 (s, 1H) .MS calculated values: 404; Measured value: 405 (M+H).
Step C
1-(4-benzyl-7,7-dimethyl-5-phenyl-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyrimidin-3-yl also)-2-(4-aminomethyl phenyl) ethyl ketone (4): go through the THF solution that 10min adds 6.4ml (3.2mmol) 0.5M 4-methyl-benzyl magnesium chloride via syringe to the 20ml THF of 0.65g (1.61mmol) 3 solution.After at room temperature stirring 1h, add about 2ml saturated aqueous ammonium chloride to reactant and carry out quencher.Then reactant is diluted with AcOEt, through dried over sodium sulfate.By short silica gel plug filtering solution, concentrate in a vacuum, obtain crude product, be oil.This oil with 75% hexane/AcOEt wash-out, obtains 0.64g (89%) title compound through purification by flash chromatography, is white foam.MS calculated value: 449; Measured value 450 (M+H).
Step D
1-(4-benzyl-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydro-pyrazole also [1,5-a] pyrimidin-3-yl)-2-(4-aminomethyl phenyl)-1-acetone (5): add 0.177ml (2.85mmol) methyl iodide to the 10ml THF of 0.64g (1.42mmol) 4 solution, succeeded by 0.11g (2.8mmol) sodium hydride (60% mineral oil dispersion).After at room temperature stirring 2h, add about 2ml saturated aqueous ammonium chloride to reactant and carry out quencher.Then reactant is diluted with AcOEt, through dried over sodium sulfate.By short silica gel plug filtering solution, concentrate in a vacuum, obtain crude product.Through purification by flash chromatography, with 90% hexane/ethyl acetate wash-out, obtain 0.42g (64%) title compound, be the lacteous powder.MS calculated value: 463; Measured value 464 (M+H).
Step e
1-(4-benzyl-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydro-pyrazole also [1,5-a] pyrimidin-3-yl)-2-methyl-2-(4-aminomethyl phenyl)-1-acetone (6): under-78 ℃, add the hexane solution of 0.314ml (0.785mmol) 2.5M n-Butyl Lithium to the 5ml THF solution of 0.110ml (0.785mmol) Diisopropylamine.After stirring 30min, add the 1ml THF solution of 0.28g (0.604mmol) 5.Reactant is at room temperature stirred 1h, add the 1ml THF solution of 0.049ml (0.79mmol) methyl iodide then.Behind the 1h, add about 0.5ml saturated aqueous ammonium chloride to reactant and carry out quencher, with the AcOEt dilution, through dried over sodium sulfate.By short silica gel plug filtering solution, concentrate in a vacuum, obtain crude product.Through purification by flash chromatography, with 90% hexane/AcOEt wash-out, obtain 0.067g (23%) title compound, be pale solid.MS calculated value: 477; Measured value 478 (M+H).
Step F
1-(7,7-dimethyl-5-phenyl-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyrimidin-3-yl also)-2-methyl-2-(4-aminomethyl phenyl)-1-acetone (7): to 1: 1 THF of the 4ml of 0.060g (0.126mmol) 6: ethanolic soln adds 0.080g 10% palladium on carbon.Reaction vessel is covered rubber septum, fill with hydrogen via air bag.Behind the 1h, remove by filter catalyzer, concentrated filtrate is to the lacteous solid.Through purification by flash chromatography, with 90% hexane/ethyl acetate wash-out, obtain 0.041g (84%) title compound, be white solid.
1H NMR (CDCl 3) δ 1.49 (s, 3H), 1.54 (s, 9H), 2.04-2.11 (m, 2H), 2.32 (s, 3H), 4.63 (dd, J=4.1,10.7Hz, 1H), 6.66 (s, 1H), 7.12-7.26 (m, 5H), 7.31-7.44 (m, 5H) .MS calculated value: 387; Measured value: 388 (M+H).
According to preparing embodiment 1124-1131 compound, as shown in table 14 to embodiment 1123 described similar modes.
Table 14
Figure A0382393802801
Figure A0382393802811
Embodiment 1132
7,7-dimethyl-3-((1-methyl isophthalic acid-(4-aminomethyl phenyl) ethyl) alkylsulfonyl)-5-phenyl-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyrimidine also
Figure A0382393802812
Steps A
Right-tolyl methylsulfonyl acetonitrile (2): under 0 ℃, to 4.1g (30mmol) right-the 10ml ethanolic soln of tolyl thiomethyl alcohol adds 4.1ml (30mmol) triethylamine and 4.4g (30mmol) sodium iodide.After reactant at room temperature stirred about 30min, reactant is cooled to 0 ℃, drips the 10ml ethanolic soln of 1.9ml (30mmol) chloromethyl cyanide.Make reactant reach ambient temperature overnight, subsequent filtration concentrates.Concentrated solution is distributed between water and ether, separate.The ether layer is used 2N yellow soda ash and salt water washing continuously, be concentrated into oil then, solidify.Then thick solid is dissolved in the 90ml glacial acetic acid,, is heated to 100 ℃ with 12.1ml (107mmol) 30% hydrogen peroxide treatment.Behind the 3h reactant is cooled to room temperature, this moment, the adularescent solid precipitation came out.Filter collecting precipitation, dry in a vacuum with the glacial acetic acid washing, obtain 6.4g (69%) title compound, be white solid. 1H?NMR(CDCl 3)δ2.39(s，3H)，3.70(s，2H)，4.48(s，2H)，7.32(dd，J＝7.3，40.2Hz，4H).
Step B
3-oxyethyl group-2-is right-tolyl methylsulfonyl vinyl cyanide (3): add 9.9ml (105mmol) diacetyl oxide to the 17.5ml of 4.4g (21mmol) 2 (105mmol) triethyl orthoformate solution.Gained solution is heated to backflow reaches 18h, be concentrated into solid then.Recrystallization from the AcOEt-hexane obtains 5.0g (90%) title compound, is white solid.
1H?NMR(CDCl 3)δ1.29(t，J＝7.0Hz，3H)，2.36(s，3H)，4.19(q，J＝7.0Hz，2H)，4.35(s，2H)，7..23(dd，J＝8.0，19.9Hz)7.37(s，1H).
Step C
7,7-dimethyl-3-((4-methyl-benzyl) alkylsulfonyl)-5-phenyl-4,7-dihydro-pyrazolo [1,5-a] pyrimidine (4): the 25ml ethanol slurries of 1.9g (7.2mmol) 3 are handled with 0.38ml (7.9mmol) hydrazine hydrate, and being heated to refluxes reaches 3h.Concentration response thing in a vacuum, obtain thick 4-right-tolyl methylsulfonyl-2H-pyrazole-3-yl amine, be the tawny solid.Thick pyrazoles, 1.3g (7.9mmol) 3-methyl isophthalic acid-phenyl-but-2-ene-1-ketone and 2.8ml (36mmol) trifluoroacetic acid are dissolved in the 25ml 2-methyl cellosolve, and being heated to refluxes reaches 3 days.Then reactant is cooled to room temperature, concentrates in a vacuum, be dissolved in AcOEt.This solution is used saturated sodium bicarbonate, water and salt water washing continuously, then through dried over sodium sulfate.Solution is filtered, concentrate in a vacuum, the gained crude product is through purification by flash chromatography, with 75 to 33% hexane/AcOEt gradient elution, obtains 1.25g (44%) title compound, is powder.
1H NMR (CDCl 3) δ 1.67 (s, 6H), 2.13 (s, 3H), 4.26 (s, 2H), 4.81 (d, J=2.0Hz, 1H), 6.39 (s, 1H), 7.05 (dd, J=8.0,18.5Hz, 4H), 7.20 (dd, J=3.7,7.4Hz, 2H), 7.36-7.39 (m, 3H), 7.52 (s, 1H) .MS calculated values: 393; Measured value: 394 (M+H).
Step D
7,7-dimethyl-3-((4-methyl-benzyl) alkylsulfonyl)-5-phenyl-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyrimidine (5) also: to 1: 1 THF of the 8ml of 0.500g (1.27mmol) 4: ethanolic soln adds 0.50g 10% palladium on carbon.Reaction vessel is covered rubber septum, fill with hydrogen via air bag.After at room temperature 2 days, remove by filter catalyzer, concentrated filtrate is to solid.Through purification by flash chromatography, with 75 to 33% hexane/AcOEt gradient elution, obtain 0.385g (77%) title compound, be white solid.
1H NMR (CDCl 3) δ 1.49 (s, 3H), 1.59 (s, 3H), 1.83-1.97 (m, 2H), 2.37 (s, 3H), 4.09-4.24 (m, 3H), 5.03 (s, 1H), 7.06-7.13 (m, 6H), 7.30-7.39 (m, 3H), 7.45 (s, 1H) .MS calculated values: 395; Measured value: 396 (M+H)
Step e
4-benzyl-7; 7-dimethyl-3-((4-methyl-benzyl) alkylsulfonyl)-5-phenyl-4; 5; 6; 7-tetrahydro-pyrazole also [1; 5-a] pyrimidine (6): under 0 ℃, add 0.128ml (1.07mmol) bromotoluene to the 10ml THF of 0.34g (0.86mmol) 5 solution, succeeded by 0.034g (0.86mmol) sodium hydride (60% mineral oil dispersion).Make reactant be warmed to room temperature behind the 30min, stir other 30min, water quencher then.Reactant after the quencher with the dilution of five body constituents ponding, is extracted with AcOEt.Merge organic layer, use the salt water washing,, filter, concentrate in a vacuum through dried over sodium sulfate.Crude product with 70% hexane/AcOEt wash-out, obtains 0.39g (93%) title compound through purification by flash chromatography, is white solid. 1HNMR(CDCl 3)δ1.27(s，3H)，1.52(s，3H)，1.93-2.05(m，2H)，2.27(s，3H)，3.83(d，J＝15.8Hz，1H)，4.18-4.30(m，3H)，5.51(d，J＝15.8Hz，1H)，6.98-7.00(m，2H)，7.09(dd，J＝8.2，12.1Hz，4H)，7.17(d，J＝6.8Hz，2H)，7.26-7.30(m，3H)，7.32-7.40(m，3H)，7.47(s，1H).
Step F
4-benzyl-7; 7-dimethyl-3-((1-(4-aminomethyl phenyl) ethyl) alkylsulfonyl)-5-phenyl-4; 5; 6; 7-tetrahydro-pyrazole also [1; 5-a] pyrimidine (7): the 4ml THF solution of 0.23g (0.47mmol) 6 is cooled to 0 ℃, handles, reach room temperature and reach 20min with 0.24ml (0.59mmol) n-Butyl Lithium (2.5M hexane solution).After reactant is cooled to 0 ℃, add the 2mlTHF solution of 0.103ml (1.66mmol) methyl iodide.Make reactant be warmed to room temperature and reach 30min, this moment with reactant with several saturated ammonium chloride quenchers.Reactant through dried over sodium sulfate, is filtered, concentrate in a vacuum.Resistates with 80% hexane/AcOEt wash-out, obtains 0.14g (60%) title compound through purification by flash chromatography, is white solid.MS calculated value: 499; Measured value 500 (M+H).
Step G
4-benzyl-7,7-dimethyl-3-((1-methyl isophthalic acid-(4-aminomethyl phenyl) ethyl) alkylsulfonyl)-5-phenyl-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyrimidine (8) also: utilize 7 synthetic described method, preparation title compound, separation yield 51%.MS calculated value: 513; Measured value 514 (M+H).
Step H
7,7-dimethyl-3-((1-methyl isophthalic acid-(4-aminomethyl phenyl) ethyl) alkylsulfonyl)-5-phenyl-4,5,6, the 7-tetrahydro-pyrazole is [1,5-a] pyrimidine (9) also: to 1: 1 THF of the 6ml of 0.075g (0.146mmol) 8: ethanolic soln adds the 0.10g palladium on carbon.Reaction vessel is covered rubber septum, fill with hydrogen via air bag.At room temperature behind the 2h, remove by filter catalyzer, concentrated filtrate obtains 0.056g (91%) title compound, is white solid.MS calculated value: 423; Measured value 424 (M+H).
According to preparing embodiment 1133-1134 compound, as shown in Table 15 to embodiment 1132 described similar modes.
Table 15
Figure A0382393802851
Embodiment 1135
3-(3-benzyl-pyrrole alkane-1-alkylsulfonyl)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine also
Figure A0382393802852
Steps A
(3-benzyl-pyrrole alkane-1-alkylsulfonyl) acetonitrile (2): the 10ml diethyl ether solution that adds 0.61g (4.4mmol) 2-cyano group ethyl sulfonyl chloride to the 20ml diethyl ether solution that is cooled to-45 ℃ 1.34g (8.31mmol) 3-benzyl-pyrrole alkane.Make reactant be warmed to room temperature, stir 24h, on flask walls, have oil to generate during this period.Pour out ethereal solution from oil, filter by short silica gel plug.Concentrate gained filtrate in a vacuum, obtain solid,,, obtain 1.25g (44%) title compound, be wax with 75% hexane/AcOEt wash-out through purification by flash chromatography.
1H?NMR(CDCl 3)δ1.73-1.83(m，1H)，2.08-2.15(m，1H)，2.57-2.67(m，1H)，2.71-2.79(m，2H)，3.21(dd，J＝8.2，9.7，Hz，1H)，3.49-3.55(m，1H)，3.63(dd，J＝7.0，9.4Hz，1H)，3.69-3.74(m，1H)，3.95(s，2H)，7.16(d，J＝7.4Hz，2H)，7.21-7.33(m，3H).
Step B
2-(3-benzyl-pyrrole alkane-1-alkylsulfonyl)-3-ethoxy propylene nitrile (3): add 0.25ml (2.6mmol) diacetyl oxide to the 0.43ml of 0.14g (0.53mmol) 2 (2.6mmol) triethyl orthoformate solution.Gained solution is heated to backflow reaches 4h, be concentrated into oil then.The thick oil of gained with 75% hexane/AcOEt wash-out, obtains 0.079g (46%) title compound through purification by flash chromatography, is xanchromatic oil.
1H?NMR(CDCl 3)δ1.42(t，J＝7.2Hz，3H)，1.67-1.77(m，1H)，2.01-2.09(m，1H)，2.53-2.62(m，1H)，2.71(d，J＝7.4Hz，2H)，3.05(dd，J＝8.4，9.8Hz，1H)，3.35-3.41(m，1H)，3.48(dd，J＝7.0，9.5Hz，1H)，3.53-3.59(m，1H)，4.31(q，J＝7.2Hz，2H)，7.15-7.17(m，2H)，7.19-7.23(m，1H)，7.26-7.31(m，2H)，7.76(s，1H).
Step C
3-(3-benzyl-pyrrole alkane-1-alkylsulfonyl)-7,7-dimethyl-5-phenyl-4,5; 6; the 7-tetrahydro-pyrazole is [1,5-a] pyrimidine (4) also: the 2ml ethanolic soln of 0.079g (0.247mmol) 3 is handled with 0.013ml (0.27mmol) hydrazine hydrate, and being heated to refluxes reaches 5h.The concentration response thing obtains thick 4-(3-benzyl-pyrrole alkane-1-alkylsulfonyl)-2H-pyrazole-3-yl amine in a vacuum.The pyrazoles that gained is thick is dissolved in the 2ml 2-methyl cellosolve that contains 0.044g (0.27mmol) 3-methyl isophthalic acid-phenyl-but-2-ene-1-ketone, adds 0.038ml (0.49mmol) trifluoroacetic acid.Mixture was refluxed 3 days, concentrate then, through purification by flash chromatography; with 60% hexane/AcOEt wash-out, obtain 3-(3-benzyl-pyrrole alkane-1-alkylsulfonyl)-7,7-dimethyl-5-phenyl-4; 7-dihydro-pyrazolo [1,5-a] pyrimidine analyze to find only to be 90% pure according to HPLC.Then this product is dissolved in 1: 1 THF of 1ml: ethanol adds 0.010g 10% palladium on carbon.Reaction vessel is covered rubber septum, fill with hydrogen via air bag.At room temperature behind the 90min, remove by filter catalyzer, concentrated filtrate is to oil.Through purification by flash chromatography, with 75% hexane/AcOEt wash-out, obtain 0.024g (20%) title compound from 3, be light yellow oil.
1H NMR (CDCl 3) δ 1.55-1.66 (m, 7H), 1.94-2.03 (m, 1H), 2.08-2.16 (m, 2H), and 2.37-2.50 (m, 1H), 2.58-2.70 (m, 2H), 2.90-2.97 (m, 1H), 3.18-3.27 (m, 1H), 3.31-3.42 (m, 2H), 4.53-4.60 (m, 1H), 5.71 (s, 1H), 7.11-7.14 (m, 2H), 7.19-7.23 (m, 1H), 7.26-7.40 (m, 7H), 7.53 (s, 1H) .MS calculated values: 450; Measured value: 451 (M+H).
Embodiment 1136
4,4-dimethyl-8-[5-(1-methyl isophthalic acid-phenylethyl)-[1,3,4] oxadiazole-2-yl]-2-phenyl-1,2,3, the 4-Pyrrolidine is [1,2-a] pyrimidine also
Steps A
2-amino-1H-pyrroles-3-carboxylic acid ethyl ester (1): (3.357g 25.8mmol) is dissolved in AcOEt (20ml) with the amidino groups ethyl acetate.At room temperature add rapidly monochloroacetaldehyde (50% aqueous solution, 1.8ml, 28.7mmol).With solution stirring 2 minutes, until there being precipitation to generate.Solution is heated to 65 ℃ then and reaches 0.5h.With the reaction mixture cooling, handle then, use the AcOEt wash-out through flash chromatography.Concentrate the part that contains product, obtain required product, be green solid.Obtain 0.68g, yield 31%.
1H NMR (400MHz, CDCl 3) δ 1.32 (t, J=7.2Hz, 3H), 4.24 (q, J=7.0Hz, 2H), 5.08 (brs, 2H), 6.10-6.13 (m, 1H), 6.25 (t, J=3.12,1Hz), 8.60 (brs, 1H); MS calculated value: 154; Measured value 155 (M+H).
Step B
4,4-dimethyl-2-phenyl-1,2,3,4-Pyrrolidine be [1,2-a] pyrimidine-8-carboxylic acid ethyl ester (2) also: (0.68g 4.41mmol) is dissolved in DMF (5ml) with compound 1.(60% mineral oil dispersion, 0.19g 4.7mmol), have gas to emit rapidly at room temperature to add NaH.Reactant is stirred 0.5h, to wherein add 3-methyl isophthalic acid-phenyl-but-2-ene-1-ketone (0.50g, 3.15mmol).Reactant is stirred 0.5h, to wherein adding EtOH (5ml) and NaBH 4(1.19g).Solution is heated to 60 ℃ reaches 0.5h, be cooled to room temperature then.With the solution with water quencher, use Et 2O extracts (3 times), dry (Na 2SO 4), concentrate.Handle (10%AcOEt) through flash chromatography, obtain required product, be tawny solid (0.60g, 63% yield).MS calculated value: 298; Measured value 299 (M+H).
Step C
4,4-dimethyl-2-phenyl-1,2,3,4-Pyrrolidine be [1,2-a] pyrimidine-8-carboxylic acid hydrazides (3) also: compound 2 (0.210g) with anhydrous hydrazine (5ml) dilution, is heated to 100 ℃ and reaches 3 days.Then with reactant cooling, dilute with water.Solution is extracted (3 times) with AcOEt, dry (Na 2SO 4), concentrate.Resistates is handled (10%MeOH/AcOEt) through flash chromatography, obtains required product (0.12g, 60% yield).
1H NMR (400MHz, CDCl 3) δ 1.54 (s, 6H), 1.99-2.13 (m, 2H), 3.89 (brs, 2H), 4.64 (dd, J=3.5,11.7Hz, 1H), 6.02 (d, J=3.9Hz), 6.22 (d, J=3.9Hz, 1H), 6.55 (brs, 1H), 6.74 (brs, 1H), 7.31-7.46 (m, 5H) .MS calculated value: 284; Measured value 285 (M+H).
Step D
4,4-dimethyl-2-phenyl-1,2,3,4-Pyrrolidine be [1,2-a] pyrimidine-8-carboxylic acid N-(2-methyl-2-phenyl propionyl) hydrazides (4) also: (0.085g 0.30mmol) is dissolved in THF (2ml) with compound 3.Add HBTU (0.136g, 0.36mmol), α, the alpha-alpha-dimethyl phenylacetic acid (0.059g, 0.36mmol) and DIEA (0.10ml, 0.60mmol).Reactant is stirred 2h, concentrate.Handle (50%AcOEt/ hexane) through flash chromatography, obtain required product.Obtain 0.123g (96% yield).
1H NMR (400MHz, CDCl 3) δ 1.49 (s, 3H), 1.50 (s, 3H), 1.60 (s, 3H), 1.61 (s, 3H), 1.95-2.10 (m, 2H), 4.56 (dd, J=3.1,11.3Hz, 1H), 6.13 (d, J=3.5Hz, 1H), 6.17 (d, 3.5Hz, 1H), 6.65 (brs, 1H), 7.22-7.43 (m, 10H), 7.81 (brs, 1H), 7.92 (brs, 1H) .MS calculated values: 430; Measured value 431 (M+H).
Step e
4,4-dimethyl-8-[5-(1-methyl isophthalic acid-phenylethyl)-[1,3,4] oxadiazole-2-yl]-2-phenyl-1,2,3, the 4-Pyrrolidine is [1,2-a] pyrimidine (5) also: (0.060g 0.14mmol) is diluted in POCl with compound 4 3(3ml).Solution is heated to 75 ℃ reaches 3h.With solution cooling, water quencher carefully.Solution is diluted with AcOEt, and mixture is used saturated NaHCO carefully 3Neutralization.Separate organic layer, water layer is with AcOEt part extracting twice.Merge organic layer, dry (Na 2SO 4), concentrate, handle through flash chromatography, obtain required product, be white solid.Obtain 0.016g (28% yield).
1H NMR (400MHz, CDCl 3) δ 1.55 (s, 6H), 1.80 (s, 6H), 2.02-2.16 (m, 2H), 4.68 (dd, J=3.2,11.6Hz, 1H), 6.23 (d, J=3.2Hz, 1H), 6.30 (d, J=3.2Hz, 1H), 7.20-7.46 (m, 10H) .MS calculated value.; 412; Measured value 413 (M+H).
Embodiment 1137
3-methyl-2-phenyl-2,3-dihydro-1H-imidazo [1,2-b] pyrazoles-7-carboxylic acid [1-ethyl-1-(4-trifluoromethyl) propyl group] acid amides
Steps A
5-amino-1-(1-methyl-2-oxo-2-phenylethyl)-1H-pyrazoles-4-carboxylic acid ethyl ester (1): (7.35g 47.3mmol) is dissolved in 160ml DMF with 5-amino-1H-pyrazoles-4-carboxylic acid ethyl ester.Add Na 2CO 3(5.02g, 47.3mmol), succeeded by 2-bromophenyl ethyl ketone (7.2ml, 47.3mmol).Reactant was at room temperature stirred 2 days.Solution is diluted the saturated NaHCO of organic layer with AcOEt 3, the salt water washing, dry (MgSO 4), concentrate.Handle (20-45%AcOEt/ hexane) through flash chromatography, obtain required product (1.58g, 12% yield).
1H?NMR(400MHz，CDCl 3)δ1.3(t，J＝7.0Hz，3H)，1.7(d，J＝7.4Hz，3H)，4.2(q，J＝7.0Hz，2H)，5.4(bs，2H)，5.9(q，J＝7.0Hz，1H)，7.41-7.59(m，3H)，7.60(s，1H)，8.0(d，J＝8.0Hz，2H).
Step B
5-amino-1-(2-hydroxyl-1-methyl-2-phenylethyl)-1H-pyrazoles-4-carboxylic acid ethyl ester (2): (0.7g 2.43mmol) is dissolved in 34ml EtOH with compound 1.Disposable adding NaBH 4(0.18g, 4.87mmol).Reactant is at room temperature stirred 0.5h.With the saturated NH of solution 4CH is used in the Cl quencher 2Cl 2Extraction (3 times).With organic layer salt water washing, dry (MgSO 4), concentrate and obtain fine hair shape white solid 2 (0.69g, 98% yield).MS calculated value: 289; Measured value 290 (M+H).
Step C
3-methyl-2-phenyl-2,3-dihydro-1H-imidazo [1,2-b] pyrazoles-7-carboxylic acid ethyl ester (3): (0.80g 2.8mmol) is dissolved in CH with compound 2 2Cl 2Drip SOCl 2(0.61ml, 8.3mmol).After 90 minutes, concentrated solution obtains yellow solid.Pumping high-vacuum is dissolved in CHCl with solid after reaching 5 minutes 3Drip Et 3(2.7ml 19.5mmol), stirs reaction mixture 1 hour N.With the quencher of reactant water, dilute with AcOEt.With the saturated NH of solution 4Cl, saturated NaHCO 3, the salt water washing, dry then (MgSO 4).Handle (20%AcOEt/ hexane) through flash chromatography, obtain cis (0.10g, 14%) and trans (0.62g, 82%) isomer 3.Trans-isomer(ide)
1H NMR (400MHz, CDCl 3) δ 1.23 (t, J=7.0Hz, 3H), 1.80 (d, J=6.6Hz, 3H), 4.10-4.20 (m, 2H), 4.25-4.35 (m, 1H), 4.38 (brs, 1H), 5.10 (d, J=9.8Hz, 1H), 7.17-7.25 (m, 5H), 7.59 (s, 1H). cis-isomeride 1HNMR (400MHz, CDCl 3) δ 1.28 (d, J=7.0Hz, 3H), 7.38 (t, J=7.4Hz, 3H), 4.25-4.35 (m, 2H), 7.43-7.52 (m, 1H), 5.17 (brs, 1H), 5.23 (d, J=9.8Hz, 1H), 7.37-7.45 (m, 5H).
Step D and E
3-methyl-2-phenyl-2,3-dihydro-1H-imidazo [1,2-b] pyrazoles-7-carboxylic acid [1-ethyl-1-(4-trifluoromethyl) propyl group] acid amides (5): (0.085g 0.3mmol) is dissolved in EtOH (3ml) with compound 3.Adding KOH (the 6M aqueous solution, 0.9ml, 1.78mmol).Reactant is stirred 3h down at 60 ℃.With the solution cooling, with AcOEt (10ml) and water (10ml) dilution, thermal agitation.Separate water layer, be acidified to pH=3.Then this acidic layer is extracted (3 times) with AcOEt.Merge the AcOEt layer, use the salt water washing, dry (Na 2SO 4), concentrate.Then resistates is dissolved in NMP (1ml), add 1-ethyl-1-(4-trifluoromethyl) propyl group amine (0.087g, 0.37mmol), HATU (0.14g, 0.37mmol) and DIEA (0.14ml, 0.78mmol).Reactant is heated to 80 ℃ reaches 2 days.With the solution cooling, wash dry (MgSO then with water 4), concentrate.Handle (20%AcOEt/ hexane) through flash chromatography, obtain 0.017g (12% yield) acid amides 5.
1H NMR (400MHz, CDCl 3) δ 0.79-0.83 (m, 6H), 1.26 (d, J=7.0Hz, 3H), 1.99-2.05 (m, 2H), 2.23-2.31 (m, 2H), 4.44-4.48 (m, 1H), 5.19 (brs, 1H), 5.24 (d, J=10Hz, 1H), 5.66 (brs, 1H), 7.37-7.63 (m, 9H) .MS calculated value: 456; Measured value: 457 (M+H).
Embodiment 1138
8-methyl-5-phenyl-5,6,7,8-tetrahydrochysene-4H-pyrazolo [1,5, a] [1,3] diaza
Figure 10003_2
-3-carboxylic acid (1-methyl isophthalic acid-phenylethyl) acid amides
Figure A0382393802911
Steps A
5-amino-1-[4-the tertiary butyl-dimethyl-siloxy-]-1-methyl-4-phenyl butyl]-1H-pyrazoles-4-carboxylic acid ethyl ester (1): (1.60g 10.3mmol) is dissolved in 10ml DMF with 5-amino-1H-pyrazoles-4-carboxylic acid ethyl ester.Solution is cooled to 0 ℃, and disposable adding NaH (60% mineral oil dispersion, 0.82g, 20.6mmol).At H 2Emit stop after, make reactant be warmed to room temperature.Reactant is stirred 0.5h, continue to exist until light orange.Reactant is cooled to 0 ℃ once more, adds methylsulfonic acid 4-(tertiary butyl-dimethyl-siloxy-)-1-methyl-4-phenyl butyl ester (3.49g, 6ml DMF solution 9.38mmol) then.Make reactant be warmed to room temperature, stirred 2.5 days.With the solution with water quencher, dilute with AcOEt.Separate organic layer, water layer AcOEt extracting twice.Merge organic layer, dry (MgSO 4), concentrate, through purification by flash chromatography (15%AcOEt/ hexane), obtain the required product of 0.530g (13% yield), be oil.
1H NMR (400MHz, CDCl 3) δ 0.16 (s, 3H), 0.17 (s, 3H), 1.04 (d, J=10Hz, 9H), 1.48-1.52 (m, 3H), 1.55 (d, J=6.4Hz, 3H), (1.60 d, J=6.8Hz, other diastereomer of 3H-), 1.62-1.75 (m, 2H), and 1.97-2.07 (m, 2H), 2.10-2.20 (m, other diastereomer of 2H-), and 4.02-4.07 (m, 1H), 4.21-4.29 (m, other diastereomer of 1H-), and 4.40-4.43 (m, 2H), 4.79-4.86 (m, 1H), 5.04 (brs, 1H), (5.25 brs, other diastereomer of 1H-), 7.36-7.47 (m, 5H), 7.79 (s, 1H); MS calculated value: 431; Measured value 432 (M+H).
Step B and C
8-methyl-5-phenyl-5,6,7,8-tetrahydrochysene-4H-pyrazolo [1,5, a] [1,3] diaza
Figure 10003_3
-3-carboxylic acid ethyl ester (3): (2.0g 4.6mmol) is dissolved in 9ml THF with compound 1.At room temperature add TBAF (1M THF solution, 13.9ml, 13.9mmol).Reactant is stirred 0.5h.Reactant is diluted with ether, with salt solution and water washing.With ether layer drying (MgSO 4), concentrate, obtain thick pure product 2.MS calculated value: 317; Measured value 318 (M+H).
Alcohol 2 is dissolved in CH 2Cl 2(80ml).Add SOCl 2(1.7ml, 23.4mmol).Behind the 1h,, be dissolved in 80ml DMF again with solution concentration.Add CsCO 3(12.6g, 39mmol).Behind the 3h, add additional C sCO 3(12.6g, 39mmol).Reaction was carried out 1.5 days.With the quencher of reactant water, dilute with AcOEt.After separating organic layer, water layer AcOEt washed twice.Merge organic layer, dry (MgSO 4), concentrate, handle through flash chromatography, obtain the mixture of 0.35g (26% yield) cis and trans-isomer(ide), they are segregative.Trans-isomer(ide)- 1H NMR (400MHz, CDCl 3) δ 1.24 (t, J=7.0Hz, 3H), 1.40 (d, J=7.0Hz, 3H), 1.93-2.34 (m, 4H), 4.05 (d, 1H), 4.09-4.23 (m, 2H), 4.79-4.85 (m, 1H), 6.40 (bs, 1H), 7.27-7.44 (m, 5H), 7.64 (s, 1H) .MS calculated values: 299; Measured value 300 (M+H). cis isomerism stops- 1H NMR (400MHz, CDCl 3) δ 1.24 (t, J=7.0Hz, 3H), 1.68 (d, J=7.0Hz, 3H), 1.70-1.80 (m, 1H), 2.00-2.23 (m, 3H), 4.17-4.30 (m, 4H), 6.43 (brs, 1H), 7.22-7.40 (m, 5H), 7.63 (s, 1H) .MS calculated values: 299; Measured value 300 (M+H).
Step D
8-methyl-5-phenyl-5,6,7,8-tetrahydrochysene-4H-pyrazolo [1,5, a] [1,3] diaza
Figure 10003_4
-3-carboxylic acid (1-methyl isophthalic acid-phenylethyl) acid amides (4): (0.074g is 0.25mmol) with EtOH (0.8ml) dilution with compound 3.(the 6M aqueous solution 0.23ml), stirs 3.5h with reactant down at 60 ℃ to add KOH.With the solution cooling, with AcOEt and water dilution.Behind the thermal agitation, remove water layer, be acidified to pH=3.Then water layer is extracted (3 times) with AcOEt.Merge organic layer, dry (MgSO 4), concentrate, obtain the required carboxylic acid of 0.070g.MS calculated value: 271; Measured value 272 (M+H).
(0.070g 0.26mmol) is dissolved in NMP (2ml) with this sour resistates.Add HATU (0.12g, 0.31mmol) and cumyl amine (0.042g, 0.31mmol), succeeded by DIEA (0.090ml, 0.52mmol).Reactant is stirred 2h down at 90 ℃.Solution is cooled to room temperature, dilute with water.Solution is extracted (3 times) with AcOEt, dry (MgSO 4), concentrate.Handle (30%AcOEt/ hexane) through flash chromatography, obtain required product.Obtain 0.065g (65% yield).
1H NMR (400MHz, CDCl 3) δ 1.65 (d, J=6.6Hz, 3H), 1.71 (s, 3H), 1.75 (s, 3H), 2.00-2.21 (m, 4H), 4.21-4.29 (m, 2H), 5.80 (brs, 1H), 7.02 (brs, 1H), 7.18-7.47 (m, 10H), 7.49 (s, 1H); MS calculated value: 388; Measured value 389 (M+H).
Embodiment 1142
(1R, 4S)-1,3, in 3-trimethylammonium two ring [2.2.1] heptan-2-base 5-(2-fluorophenyl)-2,7,7-trimethylammonium-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-carboxylicesters also
At room temperature, (0.4g, 1.32mmol) toluene (4ml) solution with DMF (1) adds SOCl to 1 2(0.31g, 2.64mmol).60 ℃ down stir 1h after, concentrated solvent in a vacuum.With the resistates dilution with toluene, to wherein add borneol (0.3g, 1.98mmol) and Et 3N (0.3g, 2.90mmol).After stirring 1h under 60 ℃, with reaction mixture 1N HCl and salt water washing, through MgSO 4Drying concentrates in a vacuum.Handle through flash chromatography, obtain required product, be oil.At room temperature to the gained oil that is stirring (90mg, AcOEt 0.2mmol) (2ml) solution add 4M HCl-AcOEt (0.5ml, 2.0mmol).Filter collecting precipitation, obtain 2, be HCl salt.MS calculated value: 440; Measured value 441 (M+H).
According to preparing embodiment 1139-1141 compound, shown in table 16 to embodiment 1142 described similar modes.
Table 16
Figure A0382393802942
Figure A0382393802951
According to preparing embodiment 868-923 and 1143-1146 compound, as shown in table 6 to the described similar mode of following reference 1-6.
1)Poulan?R?F.，Tartar?A?L.，Deprez?B?p.，Tetrahedron?Lett.2001，42，1495.
2)Rigo?B.，Cauliesz?P.，Fasseur?D.，Couturier?D.，SyntheticCommunications?1986，16，1665.
3)Carlsen?H?J.，Jorgensen?K?B.，J.Heterocyclic?Chem.，1994，31，805.
4)Kiryanov?A?A.，Sampson?P.，Seed?J.，J.Or.Chem.，2001，66，7925.
5)Kelly?T?R.，Lang?F?R.，Tetrahedron?Lett.，1995，36，5319.
6)Walia?J?S.，Walia?A?S.，Lankin?D?C.，Petterson?R?C.，Singh?J.，J.Heterocyclic?Chem.，1985，22，1117.
Table 6
Figure A0382393802952
Figure A0382393802971
Figure A0382393802991
Figure A0382393803001
Figure A0382393803031
Experiment 1
Clone's strategy of the cDNA of coding people CaR
Clone's strategy of the cDNA of coding people CaR is as follows.For the cDNA of amplification coding people CaR N-terminal portions, make up synthetic DNA primer Ca1-U:5 '-AGAGTCGACGCCACCATGGCATTTTATAGCTGCTGCTGG-3 ' and Ca1-L:5 '-AAATGAGCTCTCGGTTGGTGGCCTTGAC-3 '.In this case, add the SalI site at 5 of the cDNA that is increased ' end.For the cDNA of amplification coding people CaR C-terminal portions, make up synthetic DNA primer Ca2-U:5 '-AAACGAGCTCTCCTACCTCCTCCTCTTC-3 ' and Ca2-L:5 '-TCTGCGGCCGCTCCCTAGCCCAGTCTTCTCCTTCC-3 '.In this case, add the NotI site at 3 of the cDNA that is increased ' end.Utilize Hot Start method to carry out PCR.Add 1pg people kidney cDNA (TOYOBO), 0.3mM dNTPs and the 2.5 LA Taq of unit archaeal dna polymerases (Takara shuzo Co.) to upper strata phase reaction solution, water and enzyme buffer liquid are mended to 30 μ l.Adding to lower floor's phase reaction solution respectively is synthetic primer and the 0.5mM dNTPs of 12.5 μ M, and water and enzyme buffer liquid are mended to 20 μ l.Upper strata phase reaction solution is joined lower floor go up mutually, cover with AmpliWaxPCR Gem100 (Takara Shuzo Co.).Utilize Thermal Cycler (Perkin-ElmerCo.) that sample is carried out pcr amplification.The cDNA that is increased obtains the affirmation of agarose gel electrophoresis.
Experiment 2
CaR-expresses the preparation of Chinese hamster ovary celI
Utilize agarose gel electrophoresis separating experiment 1 gained PCR product.Excision PCR product, purifying from gel, subclone is to pT7Blue-T carrier (Takara Shuzo Co.).With the pT7Blue-T carrier of SalI and SacI processing process subclone, therefrom discharge the cDNA fragment of coding people CaR N-terminal portions.With the pT7Blue-T carrier of SacI and NotI processing process subclone, therefrom discharge the cDNA fragment of coding people CaR C-terminal portions.Utilize DNA binding test kit (Takara Shuzo Co.), insert these fragments between SalI in the pMSR α neo carrier that is digested and the NotI site.Thereby, make up pMSR α neo-CaR for animal cell expression.
10 μ g pMSR α neo-CaR are joined contain 8 * 10 6In the solution of CHO-K1 cell, (960mF) (BioRad Laboratories) carries out transfection for 0.4cm cuvette, 0.25kV to utilize Gene Pulser.Cell was cultivated one day in the HamF12 that contains 10% foetal calf serum.After going down to posterity, cell is cultivated in the HamF12 that contains 10% foetal calf serum and 500 μ g/ml genetisine.Cell is pressed 1 * 10 3Cells/well is seeded on the 96 hole flat boards, selects the transfection body in selected substratum, promptly expresses the Chinese hamster ovary celI of CaR.
Experiment 3
Utilize calcium activity assay method to select to express the Chinese hamster ovary celI system of CaR
Calcium activity assay method is as follows.To express the Chinese hamster ovary celI of CaR by 2 * 10 4Cells/well is seeded in the white flat board of 96 holes, succeeded by cultivating 48 hours.Cell with after the phosphate buffered saline (PBS) washing, is added 100 μ l buffered soln (120mM NaCl, the 22mM NaHCO that contain 5 μ M FuraPE3AM (Texas FluorescenceLaboratories) to aperture 3, 6mM KCl, 0.2mM CaCl 2, 1mM MgCl 2, 5mM glucose, 5mM HEPES (pH 7.4)), kept 1 hour down at 37 ℃.With cell phosphate buffered saline (PBS) washed twice.Add 180 μ l reaction buffered soln (130mM NaCl, 5.4mM KCl, 0.2mM CaCl to aperture 2, 0.9mMMgCl 2, 10mM glucose, 20mM HEPES (pH 7.4)) after, add 20 μ l 60mM CaCl 2, utilize fluorescence imaging plate reader (FDSS 2000, Hamamatsu photonics) to measure intracellular calcium concentration.Select a kind of clone body that increases progressively intracellular calcium concentration, be used for the experiment of back.
Experiment 4
GTP γ S binding assay
Being prepared as follows of membrane portions is described.The Chinese hamster ovary celI of expressing human CaR is pressed 1.8 * 10 5Cell/bottle is seeded in the F500 flask, succeeded by cultivating 2 days.Utilization contains the 10ml phosphate buffered saline (PBS) collecting cell of 0.02%EDTA.Cell centrifugation (2000rpm, 10min) after, the cell pellet is suspended in 12ml homogenate buffered soln (10mM NaHCO again 3, 1mM EDTA, 1x proteinase inhibitor cocktail (pH 7.4)) in, Polytron utilized TMHomogenize (20000rpm, 1min).It is centrifugal that (2000rpm 1min) removes cell debris, utilizes super centrifugal (Beckman 70Ti type rotor, 30000rpm, 1 hour) to collect the cytolemma part of expressing CaR then.
GTP γ S is following measurement in conjunction with activity.20 μ g are expressed cytolemma and the test compound of CaR and cultivate 10min.At room temperature measure 1 hour, the reaction soln mixture contains 20mMHEPES (pH 7.4), 100mM NaCl, 1mM MgCl 2, 167 μ g/ml DTT, 5 μ M guanosines 5 '-bisphosphate, 0.4nM[ 35S]-guanosine 5 '-(γ-sulphur) triphosphoric acid ([ 35S]-GTP γ S) and 6mM CaCl 2Making mixture pass through the GF/C filter filters.After 300 μ l phosphate buffered saline (PBS)s washing four times, utilize the Top-count scintillometer measure with the filter bonded [ 35S]-GTP γ S amount.
Test compound to [ 35S]-GTP γ S bonded influence represents with per-cent.This from equation [100 * (t '-b)]/(t-b) calculate, wherein t ', t and b be [ 35S]-GTP γ S associated value (dpm), t ' is in the presence of 6mM calcium and test compound, t is only in the presence of 6mM calcium, b for do not have 6mM calcium and test compound in the presence of.
Antagonist with the dose-dependently mode reduce in the membrane prepare thing [ 35S]-GTP γ S combination.Agonist with the dose-dependently mode increase in the membrane prepare thing [ 35S]-GTP γ S combination.
The result is as shown in table 7.
Table 7
Embodiment No. [ 35S]-GTP γ S combination (%)
318 * 34(1μM)
335 * 0(1μM)
310 * 0(1μM)
312 * 10(1μM)
436 * 12(1μM)
423 * 0(1μM)
111 ** 256(10μM)
*: antagonist
*: agonist
Industrial applicibility
Compound of the present invention (I), (II), (III) or the Ca receptor modulating activities that (IIIa) has excellence, strengthen the secretion of PTH, therefore can be used as medicine, kidney-functionality medicine, central nervous system and endocrine-functionality medicine, the digestive system-functionality medicine for the treatment of bone disease etc.

Claims (20)

  1. (1.N-1-ethyl-1-(4-aminomethyl phenyl) propyl group)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also,
    N-(1-ethyl-1-(4-aminomethyl phenyl) propyl group)-5-(2-fluorophenyl)-7,7-dimethyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also,
    N-(1-ethyl-1-(4-aminomethyl phenyl) propyl group)-2,7,7-trimethylammonium-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also,
    N-(1-ethyl-1-(4-ethylphenyl) propyl group)-2,7,7-trimethylammonium-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also,
    N-(1-ethyl-1-(4-aminomethyl phenyl) propyl group)-5-(2-fluorophenyl)-2,7,7-trimethylammonium-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also,
    N-(1-ethyl-1-(4-ethylphenyl) propyl group)-5-(2-fluorophenyl)-2,7,7-trimethylammonium-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also,
    5-(2-chloro-phenyl-)-N-(1-ethyl-1-(4-aminomethyl phenyl) propyl group)-2,7,7-trimethylammonium-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also,
    N-(1-(4-(dimethylamino) phenyl)-1-ethyl propyl)-5-(2-fluorophenyl)-2,7,7-trimethylammonium-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also, or
    N-(1-ethyl-1-phenyl propyl)-5-(2-fluorophenyl)-2,7,7-trimethylammonium-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also.
  2. (2.N-1-ethyl-1-(4-aminomethyl phenyl) propyl group)-7,7-dimethyl-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also.
  3. (3.N-1-ethyl-1-(4-aminomethyl phenyl) propyl group)-5-(2-fluorophenyl)-7,7-dimethyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also.
  4. (4.N-1-ethyl-1-(4-aminomethyl phenyl) propyl group)-2,7,7-trimethylammonium-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also.
  5. (5.N-1-ethyl-1-(4-ethylphenyl) propyl group)-2,7,7-trimethylammonium-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also.
  6. (6.N-1-ethyl-1-(4-aminomethyl phenyl) propyl group)-5-(2-fluorophenyl)-2,7,7-trimethylammonium-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also.
  7. (7.N-1-ethyl-1-(4-ethylphenyl) propyl group)-5-(2-fluorophenyl)-2,7,7-trimethylammonium-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also.
  8. (8.5-2-chloro-phenyl-)-N-(1-ethyl-1-(4-aminomethyl phenyl) propyl group)-2,7,7-trimethylammonium-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also.
  9. (9.N-1-(4-(dimethylamino) phenyl)-1-ethyl propyl)-5-(2-fluorophenyl)-2,7,7-trimethylammonium-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also.
  10. 10.N-(1-ethyl-1-phenyl propyl)-5-(2-fluorophenyl)-2,7,7-trimethylammonium-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also.
  11. 11. according to the compound or its salt of one of claim 3 and 5-9, it is the compound of optically active.
  12. 12. (5R)-and N-(1-ethyl-1-(4-ethylphenyl) propyl group)-2,7,7-trimethylammonium-5-phenyl-4,5,6,7-tetrahydro-pyrazole be [1,5-a] pyrimidine-3-methane amide or its salt also.
  13. 13. pharmaceutical composition comprises the compound or its salt according to one of claim 1-12.
  14. 14. regulate the composition of calcium acceptor, comprise compound or its salt according to one of claim 1-12.
  15. 15. according to the composition of claim 14, it is a Calcilytic.
  16. 16. according to the composition of claim 14, it is that prevention or treatment are by the medicine of live body calcium concn or calcium receptor abnormality associated diseases.
  17. 17. according to the composition of claim 14, it is the medicine of prevention or treatment osteopathia.
  18. 18. according to the composition of claim 14, it is the medicine of prevention or treatment osteoporosis or fracture.
  19. 19. the purposes according to the compound or its salt of one of claim 1-12 is used to prepare the calcium receptor modulators.
  20. 20., be used to prepare the composition of prevention or treatment osteopathia according to the purposes of the compound or its salt of one of claim 1-12.
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