CN1897944A - Benzenesulfonylamino-pyridin-2-yl derivatives and related compounds as inhibitors of 11-beta-hydroxysteroid dehydrogenase type 1 (11-beta-hsd-1) for the treatment of diabetes and obesity - Google Patents

Abstract

The present invention relates to compounds with the formula (I), or a pharmaceutically acceptable satt thereof, formula (I), wherein: R' is selected from the group consisting of (C1--C6)alkyl, -(CR<3>R<4>),(C3-C12)cycloalkyl, -(CR<3>R<4>),(C6-C12)aryl, and -(CR<3>R<4>)t(410)-membered heterocyclyl; b and k are each independently selected from 1 and 2; j is selected from the group consisting of 0, 1, and 2; t, u, p, q, and v are each independently selected from the group consisting of 0, 1, 2, 3, 4, and 5; T is a (6-10)-membered heterocyclyl containing at least one nitrogen atom; R<2> is selected from the group consisting of H, (C1-C6)alkyl, -(CR<3>R)t(C3-C12)cycloalkyl, -(CR<3>R<4>)t(C6-C12)aryt, and -(CR<3>R<4>)t(410)-membered heterocyclyl; each R<3 >and R<4>.is independently selected from H and (C1-C6)alkyl, the carbon atoms of T, R', R<2>,< >R<3> and R<4> may each be optionally, substituted by I to 5 R<5> groups; R<R>is defined in the claims; The compounds of the present invention are 11 ss-hsd-1 inhibitors, and are therefore believed to be useful in the treatment of diabetes, obesity, glaucoma, osteoporosis, cognitive disorders, immune disorders, depression, hypertension, and metabolic diseases.

Description

11-beta-hydroxysteroid dehydrogenase-1 type (inhibitor benzene sulfonamido-pyridine-2-radical derivative and the related compound of 11-β-HSD-1) that is used for the treatment of diabetes and obesity

The application requires the priority of U. S. application 60/531186 that December in 2003 submitted on the 19th and the U. S. application of submitting on March 26th, 2,004 60/556921.

Technical field

The present invention relates to new compound, comprise the pharmaceutical composition of this chemical compound, and this chemical compound is aspect medical and be used for preparation to the human 11-beta-hydroxysteroid dehydrogenase 1 type enzyme (purposes of the medicament of 11-β-HSD-1) work.

Background technology

Since over half a century, people have known glucocorticoid and had middle cardiac status in diabetes.For example, from diabetic animal, hypophysectomize or the adrenal gland has been alleviated the most serious diabetic symptom and reduced (Long.C.D and F.D.W.Leukins (1936) J.Exp.Med.63:465-490 of the concentration of glucose in the blood; Houssay, B.A. (1942) Endocrinology 30:884-892).In addition, determined fully that also glucocorticoid can make glucagon that liver is worked.

Confirmed that fully the effect of 11-β-hsd-1 is the important regulator that generates as influence local glucocorticoid and hepatic glucose (2000) J Endocrinol.165:p.685-692 such as (for example sees) Jamieson.Adopt the sensitivity increase (Walker.B.R. etc. (1995) J.Clin.Endocrinol.Metab.80:3155-3159) of the healthy human body volunteer of non-specific 11-β-hsd-1 inhibitor carbenoxolone treatment to the liver insulin.And, determined the mechanism of expecting by different experiments on mice.These studies show that, reduce in the level of the aborning mRNA of hepatic glucose and the activity of two kinds of key enzymes, i.e. rate-limiting enzyme in gluconeogenesis, PCK (PEPCK) and the glycolytic last common step of G-6-Pase (G6Pase) catalysis gluconeogenesis regulating liver-QI.At last, knocked out 11-β-hsd-1 gene the blood glucose level of mice and hepatic glucose generate and reduced.The data of this model have also confirmed, as what predicted, suppress 11-β-hsd-1 and do not cause hypoglycemia, because fundamental quantity PEPCK and G6Pase regulate glucocorticoid (Kotelevtsev, Y. etc. (1997) Proc.Natl.Acad.Sci.USA 94:14924-14929) independently.

The other factors of abdominal obesity and glucose intolerance, hyperinsulinemia, hypertriglyceridema and so-called metabolic syndrome (for example, hypertension, HDL level reduce and the VLDL level increases) is closely related (Montague ﹠amp; O ' Rahilly, Diabetes 49:883-888,2000).Obesity is the type 2 diabetes mellitus patient's of metabolic syndrome and great majority (＞80%) a important elements, and nethike embrane fat is most important.Show that the enzyme that suppresses in the fatty precursor can reduce the speed that differentiation enters adipose cell.The expansion in this indication nethike embrane fat warehouse has reduced (may reduce),, has reduced centre type obesity (Bujalska, I.J., Kumar, S. and Stewart, P.M. (1997) Lancet 349:1210-1213) that is.

Chemical compound of the present invention is 11 β-hsd-1 inhibitor, therefore thinks that they can be used for treating diabetes, obesity, glaucoma, osteoporosis, cognitive disorder, immunologic derangement, depression, vascular hypertension and metabolic disease.

Summary of the invention

The present invention relates to chemical compound or its pharmaceutically acceptable salt or the solvate of a kind of formula (I):

Wherein:

R ¹Be selected from by (C ₁-C ₆) alkyl ,-(CR ³R ⁴) _t(C ₃-C ₁₂) cycloalkyl ,-(CR ³R ⁴) _t(C ₆-C ₁₂) aryl and-(CR ³R ⁴) _t(4-10) group of first heterocyclic radical composition;

B and k are selected from 1 and 2 independently of one another;

J is selected from the group of forming by 0,1 and 2;

T, u, p, q and v are selected from the group of forming by 0,1,2,3,4 and 5 independently of one another;

T is (6-10) the first heterocyclic radical that contains at least one nitrogen-atoms;

R ²Be selected from by H, (C ₁-C ₆) alkyl ,-(CR ³R ⁴) _t(C ₃-C ₁₂) cycloalkyl ,-(CR ³R ⁴) _t(C ₆-C ₁₂) aryl and-(CR ³R ⁴) _t(4-10) group of first heterocyclic radical composition;

Each R ³And R ⁴Be independently selected from H and (C ₁-C ₆) alkyl;

T, R ¹, R ², R ³And R ⁴In described carbon atom separately randomly by 1-5 R ⁵Base replaces;

Each R ⁵Base be independently selected from by halogen, cyano group, nitro ,-CF ₃,-CHF ₂,-CH ₂F, trifluoromethoxy, azido, hydroxyl, (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl group ,-(C=O)-R ⁶,-(C=O)-O-R ⁶,-O-(C=O)-R ⁷,-O-(C=O)-NR ⁷,-NR ⁸(C=O)-R ⁹,-(C=O)-NR ⁸R ⁹,-NR ⁸R ⁹,-NR ⁸OR ⁹,-S (O) _kNR ⁸R ⁹,-S (O) _j(C ₁-C ₆) alkyl ,-O-SO ₂-R ⁹,-NR ⁸-S (O) _k-R ⁹,-(CR ¹⁰R ¹¹) _v(C ₆-C ₁₂Aryl) ,-(CR ¹⁰R ¹¹) _v(4-10) first heterocyclic radical ,-(CR ¹⁰R ¹¹) _q(C=O) (CR ¹⁰R ¹¹) _v(C ₆-C ₁₂) aryl ,-(CR ¹⁰R ¹¹) _q(C=O) (CR ¹⁰R ¹¹) _v(4-10) first heterocyclic radical ,-(CR ¹⁰R ¹¹) _vO (CR ¹⁰R ¹¹) _q(C ₆-C ₁₂) aryl ,-(CR ¹⁰R ¹¹) _vO (CR ¹⁰R ¹¹) _q(4-10) first heterocyclic radical ,-(CR ¹⁰R ¹¹) _qS (O) _j(CR ¹⁰R ¹¹) _v(C ₆-C ₁₂) aryl and-(CR ¹⁰R ¹¹) _qS (O) _j(CR ¹⁰R ¹¹) _v(4-10) group of first heterocyclic radical composition;

Above R ⁶Any 1 or 2 carbon atom of any (4-10) first heterocyclic radical of base is randomly by the (=O) replacement of oxo base;

Above R ⁵Any (C of base ₁-C ₆) alkyl, any (C ₆-C ₁₂) aryl and arbitrarily any carbon atom in (4-10)-first heterocyclic radical randomly by 1-3 be independently selected from halogen, cyano group, nitro ,-CF ₃,-CFH ₂,-CF ₂H, trifluoromethoxy, azido ,-OR ¹²,-(C=O)-R ¹²,-(C=O)-R ¹³,-O-(C=O)-R ¹³,-NR ¹³(C=O)-R ¹⁴,-(C=O)-NR ¹⁵R ¹⁶,-NR ¹⁷R ¹⁸,-NR ¹⁴OR ¹⁵, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl, (C ₂-C ₆Alkynyl group ,-(CR ¹⁶R ¹⁷) _u(C ₆-C ₁₂) aryl and-(CR ¹⁶R ¹⁷) _u(4-10)-substituent group of first heterocyclic radical replaces;

Each R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶And R ¹⁷Base is independently selected from by H, (C ₁-C ₆) alkyl ,-(C=O) _N(C ₁-C ₆) alkyl ,-(CR ¹⁸R ¹⁹) _p(C ₆-C ₁₂) aryl and-(CR ¹⁸R ¹⁹) _p(4-10) group of first heterocyclic radical composition;

Each described R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶And R ¹⁷Any 1 or 2 carbon atom of (4-10) first heterocyclic radical of base is randomly by the (=O) replacement of oxo base;

Aforementioned R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶And R ¹⁷Any (C of base ₁-C ₆) alkyl, any (C ₆-C ₁₂) aryl and arbitrarily (4-10) first heterocyclic radical any carbon atom randomly by 1-3 be independently selected from by halogen, cyano group, nitro ,-NR ²¹R ²²,-CF ₃,-CHF ₂,-CH ₂F, trifluoromethoxy, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl group, hydroxyl and (C ₁-C ₆) substituent group of the group formed of alkoxyl replaces;

Each R ¹⁸, R ¹⁹, R ²⁰, R ²¹And R ²²Group is independently selected from H and (C ₁-C ₆) alkyl;

And, wherein, comprise be not connected to halogen ,-SO or-SO ₂On the base or on N, O or the S atom-CH ₃(methyl) ,-CH ₂(methylene) or-above-mentioned any substituent group of CH (methine) randomly will be independently selected from by hydroxyl, halogen, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl ,-NH ₂,-NH (C ₁-C ₆) (alkyl) and-N ((C ₁-C ₆) (alkyl)) ₂The substituent group of the group of forming is connected on the described group.

In another embodiment, the present invention relates to a kind of chemical compound according to formula (I), wherein, b is 2.

In another embodiment, the present invention relates to a kind of chemical compound according to formula (I), wherein, T is 6 yuan of heterocyclic radicals that comprise at least one nitrogen-atoms.

In embodiments, the present invention relates to a kind of chemical compound according to formula (I), wherein, described T is (6-10) the first heterocyclic radical that is selected from the group of being made up of following formula:

In another embodiment, the present invention relates to a kind of chemical compound according to formula (I), wherein, T is

In another embodiment, the present invention relates to a kind of chemical compound according to formula (I), wherein, T is

In embodiments, the present invention relates to a kind of chemical compound according to formula (I), wherein, T is

In another embodiment, the present invention relates to a kind of chemical compound according to formula (I), wherein, each R ¹Be selected from the group of forming by phenyl, xenyl, benzo thiophenyl and naphthyl, and randomly by 1-5 R ⁶Base replaces;

Wherein:

Each R ⁶Base be independently selected from by halogen, cyano group ,-CF ₃, hydroxyl, (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl ,-(CR ¹⁰R ¹¹) _p(4-10) first heterocyclic radical ,-(C=O)-R ⁶,-(C=O)-O-R ⁶,-O-(C=O)-R ⁷,-NR ⁸(C=O)-R ⁹,-(C=O)-NR ⁸R ⁹,-NR ⁸R ⁹,-NR ⁸OR ⁹,-(CR ¹⁰R ¹¹)-O-(CR ¹⁰R ¹¹) _p(C ₆-C ₁₂) aryl and-(CR ¹⁰R ¹¹) _p-O-(CR ¹⁰R ¹¹) _p(4-10) group of first heterocyclic radical composition.

The present invention relates to a kind of chemical compound or its pharmaceutically acceptable salt or solvate according to formula (II):

Wherein:

R ¹Be (C ₁-C ₆) alkyl ,-(CR ⁷R ⁸) _t(C ₃-C ₁₀) cycloalkyl ,-(CR ⁷R ⁸) _t(C ₆-C ₁₀) aryl or-(CR ⁷R ⁸) _t(4-10) first heterocyclic radical;

B and k are selected from 1 and 2 independently of one another;

N and j independently are selected from the group of forming by 0,1 and 2 separately;

T, u, p, q and v are selected from the group of forming by 0,1,2,3,4 and 5 independently of one another;

T is (6-10) the first heterocyclic radical that comprises at least one nitrogen-atoms;

W be selected from by

(C ₁-C ₆) alkyl and 5 yuan of groups that heterocyclic radical is formed;

Each R ², R ³And R ⁴Be independently selected from by H, (C ₁-C ₆) alkyl ,-(CR ⁷R ⁸) _t(C ₃-C ₁₀) cycloalkyl ,-(CR ⁷R ⁸) _t(C ₆-C ₁₀) aryl and-(CR ⁷R ⁸) _t(4-10) group of first heterocyclic radical composition;

Each R ²And R ³Randomly form (4-10) first heterocyclic radical with the nitrogen that links to each other with them;

Each R ⁵And R ⁶Be independently selected from by H, (C ₁-C ₆) alkyl ,-(CR ⁷R ⁸) _t(C ₃-C ₁₀) cycloalkyl ,-(CR ⁷R ⁸) _t(C ₆-C ₁₀) aryl and-(CR ⁷R ⁸) _t(4-10) group of first heterocyclic radical composition;

Or R ⁵And R ⁶Randomly form (C with the carbon that links to each other with them ₃-C ₆) cycloalkyl or (3-7) first heterocyclic radical;

Each R ⁷And R ⁸Be independently selected from H and (C ₁-C ₆) alkyl;

T, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸With the carbon atom of described W5 unit heterocyclic radical randomly by 1-5 R ⁹Base replaces;

Each R ⁹Base be independently selected from by halogen, cyano group, nitro ,-CF ₃,-CHF ₂,-CH ₂F, trifluoromethoxy, azido, hydroxyl, (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl group ,-(C=O)-R ¹⁰,-(C=O)-O-R ¹¹,-O-(C=O)-R ¹¹,-NR ¹¹(C=O)-R ¹²,-(C=O)-NR ¹¹R ¹²,-NR ¹¹R ¹²,-NR ¹¹OR ¹²,-S (O) _kNR ¹¹R ¹²,-S (O) _j(C ₁-C ₆) alkyl ,-O-SO ₂-R ¹⁰,-NR ¹¹-S (O) _k-R ¹²,-(CR ¹³R ¹⁴) _v(C ₆-C ₁₀Aryl) ,-(CR ¹³R ¹⁴) _v(4-10) first heterocyclic radical ,-(CR ¹³R ¹⁴) _q(C=O) (CR ¹³R ¹⁴) _v(C ₆-C ₁₀) aryl ,-(CR ¹³R ¹⁴) _q(C=O) (CR ¹³R ¹⁴) _v(4-10) first heterocyclic radical ,-(CR ¹³R ¹⁴) _vO (CR ¹³R ¹⁴) _q(C ₆-C ₁₀) aryl ,-(CR ¹³R ¹⁴) _vO (CR ¹³R ¹⁴) _q(4-10) first heterocyclic radical ,-(CR ¹³R ¹⁴) _qS (O) _j(CR ¹³R ¹⁴) _v(C ₆-C ₁₀) aryl and-(CR ¹³R ¹⁴) _qS (O) _j(CR ¹³R ¹⁴) _v(4-10) first heterocyclic radical;

Above R ⁹Any 1 or 2 carbon atom of any (4-10) first heterocyclic radical of base is randomly by the (=O) replacement of oxo base;

Above R ⁹Any (C of base ₁-C ₆) alkyl, any (C ₆-C ₁₀) aryl and arbitrarily any carbon atom in (4-10)-first heterocyclic radical randomly by 1-3 be independently selected from by halogen, cyano group, nitro ,-CF ₃,-CFH ₂,-CF ₂H, trifluoromethoxy, azido ,-OR ¹⁵,-(C=O)-R ¹⁵,-(C=O)-O-R ¹⁵,-O-(C=O)-R ¹⁵,-NR ¹⁵(C=O)-R ¹⁶,-(C=O)-NR ¹⁵R ¹⁶,-NR ¹⁵R ¹⁶,-NR ¹⁵OR ¹⁶,-NR ¹⁵OR ¹⁶, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl, (C ₂-C ₆Alkynyl group ,-(CR ¹⁷R ¹⁸) _u(C ₆-C ₁₀) aryl and-(CR ¹⁷R ¹⁸) _u(4-10)-substituent group of the group that first heterocyclic radical is formed replaces;

Each R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷And R ¹⁸Base is independently selected from by H, (C ₁-C ₆) alkyl ,-(CR ¹⁹R ²⁰) _p(C ₆-C ₁₀) aryl and-(CR ¹⁹R ²⁰) _p(4-10) group of first heterocyclic radical composition;

Described each R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷And R ¹⁸Any 1 or 2 carbon atom of (4-10) first heterocyclic radical of base is randomly by the (=O) replacement of oxo base;

Aforementioned R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷And R ¹⁸Any (C of base ₁-C ₆) alkyl, any (C ₆-C ₁₀) aryl and arbitrarily (4-10) first heterocyclic radical any carbon atom randomly by 1-3 be independently selected from by halogen, cyano group, nitro ,-NR ²¹R ²²,-CF ₃,-CHF ₂,-CH ₂F, trifluoromethoxy, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl group, hydroxyl and (C ₁-C ₆) substituent group of the group formed of alkoxyl replaces;

Each R ¹⁹, R ²⁰, R ²¹And R ²²Base is independently selected from H and (C ₁-C ₆) alkyl;

And, wherein, comprise be not connected to halogen ,-SO or-SO ₂On the base or on N, O or the S atom-CH ₃(methyl) ,-CH ₂(methylene) or-above-mentioned any substituent group of CH (methine) randomly will be independently selected from by hydroxyl, halogen, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl, amino ,-NH (C ₁-C ₆) (alkyl) and-N (C ₁-C ₆) (alkyl) (C ₁-C ₆) substituent group of (alkyl) group of forming is connected on the described group.

In embodiments, the present invention relates to a kind of chemical compound according to formula (II), wherein, W is

In another embodiment, the present invention relates to a kind of chemical compound according to formula (II), wherein, W is

In another embodiment, the present invention relates to a kind of chemical compound according to formula (II), wherein, W is 5 yuan of heterocyclic radicals.

In another embodiment, the present invention relates to a kind of chemical compound according to formula (II), wherein, described 5 yuan of heterocyclic radicals are selected from the basis set group that becomes of You oxazolyl, thiazolyl, pyrazolyl, triazolyl He oxadiazole.

In another embodiment, the present invention relates to a kind of chemical compound according to formula (II), wherein, b is 2.

In another embodiment, the present invention relates to a kind of chemical compound according to formula (II), wherein, T is 6 yuan of heterocyclic radicals that comprise at least one nitrogen-atoms.

In another embodiment, the present invention relates to a kind of chemical compound according to formula (II), wherein, described 6 yuan of heterocyclic radicals are selected from the group of being made up of following formula:

In another embodiment, the present invention relates to a kind of chemical compound according to formula (II), wherein, T is

In another embodiment, the present invention relates to a kind of chemical compound according to formula (II), wherein, each R ¹By 1-5 R ⁹The phenyl or naphthyl that base replaces; Wherein, each R ⁹Be independently selected from by halogen, cyano group ,-CF ₃, hydroxyl, (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl ,-(C=O)-R ¹⁰,-(C=O)-O-R ¹¹,-O-(C=O)-R ¹¹,-NR ¹¹(C=O)-R ¹²,-(C=O)-NR ¹¹R ¹²,-NR ¹¹R ¹²With-NR ¹¹OR ¹²The group of forming.

In embodiments, the present invention relates to a kind of chemical compound according to formula (II), wherein, R ²And R ³Be selected from H and (C independently of one another ₁-C ₆) alkyl;

Wherein:

Described (C ₁-C ₆) alkyl is randomly by (C ₂-C ₆) alkenyl or-(CR ⁷R ⁸) _t(C ₃-C ₁₀) cycloalkyl substituted.

In another embodiment, the present invention relates to a kind of chemical compound according to formula (II), wherein, R ²And R ³Randomly form (4-10) first heterocyclic radical with the nitrogen that links to each other with them.

In another embodiment, the present invention relates to a kind of chemical compound according to formula (II), wherein, described (4-10) first heterocyclic radical is selected from the group of being made up of following formula:

In another embodiment, the present invention relates to a kind of chemical compound according to formula (II), wherein, R ²Be (C ₁-C ₆) alkyl.

In another embodiment, the present invention relates to a kind of chemical compound according to formula (II), wherein, n is 0, R ⁵And R ⁶Be H one of at least wherein.

In another embodiment, the present invention relates to a kind of chemical compound that is selected from following formula

Or its pharmaceutically acceptable salt or solvate.

Embodiment of the present invention relate to a kind of pharmaceutical composition, said composition comprise effective dose according to formula (I) or formula (II) chemical compound, or its pharmaceutically acceptable salt or solvate and pharmaceutically acceptable carrier.

In another embodiment, the present invention relates to a kind of method by adjusting 11-β-hsd-1 treatment disease, this method comprises the chemical compound according to formula (I) or formula (II) that mammal is given effective dose, or its pharmaceutically acceptable salt or solvate.

In another embodiment, the present invention relates to that a kind of to treat diabetes, metabolic syndrome, insulin impedance syndrome, obesity, glaucoma, hyperlipemia, hyperglycemia, hyperinsulinemia, osteoporosis, pulmonary tuberculosis, arteriosclerosis, dementia, depression, virosis, inflammation illness or liver be the method for the disease of Target organ, this method comprises chemical compound or its pharmaceutically acceptable salt or the solvate according to formula (I) or formula (II) that mammal is given effective dose.

Definition

Term used herein " comprises " and " comprising " is open, non-circumscribed.

Unless otherwise stated, term used herein " alkyl " comprises the saturated monovalence alkyl with straight chain or branched chain segment (moiety).

Unless otherwise stated, term used herein " alkenyl " comprises the alkyl segment with at least one carbon-to-carbon double bond, and wherein, alkyl and comprises pulsating E of described alkenyl and Z isomer as defined above.

Unless otherwise stated, term used herein " alkynyl group " comprises the alkyl segment with at least one carbon-to-carbon triple bond, and wherein, alkyl as defined above.

Unless otherwise stated, term used herein " alkoxyl " comprises the O-alkyl, and wherein, alkyl as defined above.

Term used herein " amino " comprises-NH ₂The substituent group of basic and any N atom.

Term used herein " halogen " and " halogen " expression chlorine, fluorine, bromine and iodine.

Term used herein " trifluoromethyl " expression-CF ₃Base.

Term used herein " trifluoromethoxy " expression-OCF ₃Base.

Term used herein " cyano group " expression-CN base.

Unless otherwise stated, term used herein " OMs " means methanesulfonate ester.

Unless otherwise stated, term used herein " Me " means methyl.

Unless otherwise stated, term used herein " MeOH " means methanol.

Unless otherwise stated, term used herein " Et " means ethyl.

Unless otherwise stated, term " Et used herein ₂O " mean Anaesthetie Ether.

Unless otherwise stated, term used herein " EtOH " means ethanol.

Unless otherwise stated, term " Et used herein ₃N " mean triethylamine.

Unless otherwise stated, term used herein " EtOAc " means ethyl acetate.

Unless otherwise stated, term " AlMe used herein ₂Cl " mean chlorodimethylalumiu.

Unless otherwise stated, term used herein " Ac " means acetyl group.

Unless otherwise stated, term used herein " TFA " means trifluoroacetic acid.

Unless otherwise stated, term used herein " TEA " means triethanolamine.

Unless otherwise stated, term used herein " HATU " means hexafluorophosphoric acid N, N, N ', N '-tetramethylurea salt.

Unless otherwise stated, term used herein " THF " means oxolane.

Unless otherwise stated, term used herein " TlOH " means thallium hydroxide (I).

Unless otherwise stated, term used herein " TlOEt " means ethoxyquin thallium (I).

Term " PCy used herein ₃" mean tricyclohexyl phosphine.

Unless otherwise stated, term " Pd used herein ₂(dba) ₃" mean three (diphenyl methylene acetone) two palladiums (0).

Unless otherwise stated, term used herein " Pd (OAc) ₂" mean acid chloride (II).

Unless otherwise stated, term used herein " Pd (PPh ₃) ₂Cl ₂" mean dichloro two (triphenylphosphine) palladium (II).

Unless otherwise stated, term used herein " Pd (PPh ₃) ₄" mean tetrakis triphenylphosphine palladium (0).

Term used herein " Pd (dppf) Cl ₂" mean the complex of (1,1 '-two (diphenylphosphine) ferrocene) dichloro palladium (II) and dichloromethane (1: 1).

Unless otherwise stated, term used herein " G6P " means the G-6-P ester.

Unless otherwise stated, term used herein " NIDDM " means non-insulin-dependent diabetes mellitus.

Unless otherwise stated, term used herein " NADPH " means the NADPH ester.

Term " CDCl used herein ₃Or CHLORFORM-D " mean deuterochloroform.

Term " CD used herein ₃OD " mean deuterated methanol.

Term " CD used herein ₃CN " mean deuterium for acetonitrile.

Term used herein " DEAD " means diethyl azodiformate.

Term " TsCH used herein ₂NC " mean tosyl ylmethyl isocyanide.

Term " ClSO used herein ₃H " mean chlorosulfonic acid.

Used herein, term " DMSO-d ₆Or DMSO-D ₆" mean deuterated dimethyl sulfoxide.

Term used herein " DME " means 1, the 2-dimethoxy-ethane.

Term used herein " DMF " means N, dinethylformamide.

Unless otherwise stated, term used herein " DMSO " means dimethyl sulfoxide.

Term used herein " DI " means deionized.

Term used herein " KOAc " means potassium acetate.

Term used herein " pure " expression does not have solvent.

Term used herein " mmol " means mM.

Term used herein " equiv " means equivalent.

Term used herein " mL " means milliliter.

Term used herein " U " unit of meaning.

Term used herein " mm " means millimeter.

Term used herein " g " means gram.

Term used herein " kg " means kilogram.

Term used herein " h " means hour.

Term used herein " min " means minute.

Term used herein " μ L " means microlitre.

Term used herein " μ M " means micro-molar concentration.

Term used herein " μ m " means micron.

Term used herein " M " means molar concentration.

Term used herein " N " means normality.

Term used herein " nm " means nanometer.

Term used herein " nM " means nanomolar concentration.

Term used herein " amu " means atomic mass unit.

Term used herein " ℃ " mean Celsius.

Unless otherwise stated, term used herein " m/z " means the mass ratio.

Term used herein " wt/wt " means w/w.

Term used herein " v/v " means volume/volume.

Term used herein " mL/min " means ml/min.

Term used herein " UV " means ultraviolet.

Term used herein " APCI-MS " means the Atmosphere Pressure Chemical Ionization (APCI) mass spectrum.

Term used herein " HPLC " means high performance liquid chromatography.

Term used herein " LC " means liquid chromatograph.

Term used herein " LCMS " means the liquid chromatography mass coupling.

Term used herein " SFC " means supercritical fluid chromatography.

Term used herein " sat " means saturated.

Term used herein " aq " means aqueous.

Term used herein " ELSD " means evaporative light scattering detector.

Term used herein " MS " means mass spectrum.

Term used herein " HRMS (ESI) " means high resolution mass spectrum (electric mist ionization massspectrum)

Term used herein " Anal " means analysis.

Term used herein " Calcd " means as calculated.

Unless otherwise stated, term used herein " NT " means not test.

Unless otherwise stated, term used herein " NA " means not test.

Unless otherwise stated, term used herein " R.T. " means room temperature.

Unless otherwise stated, term used herein " Mth " means method.

Unless otherwise stated, term " Celite used herein ^{ n}" mean commercially available from being positioned at LosAngeles, the white solid tripolite filling material of the World Minerals of California USA.

Unless otherwise stated, term used herein " Eg. " means embodiment.

For example, for example use-(CR ³R ⁴) _tOr-(CR ¹⁰R ¹¹) _vTerm, for greater than t or each R of v of 1 ³, R ⁴, R ¹⁰And R ¹¹Can change along with the falling generation of each t or v.For example, when t or v are 2, term-(CR ³R ⁴) _tOr-(CR ¹⁰R ¹¹) _vCan equal-CH ₂CH ₂-or-CH (CH ₃) C (CH ₂CH ₃) (CH ₂CH ₂CH ₃)-, or equal any R that drops on ³, R ⁴, R ¹⁰And R ¹¹Similar segment in the scope.

Term " K used herein _i" mean the value that enzyme suppresses constant.

Term " K used herein _i" app means apparent K _j

Term " IC used herein ₅₀" mean at least 50% desired concn when being suppressed by enzyme.

Term " replacement " means specified group or segment has one or more substituent groups.Term " unsubstituted " means specified group and does not have substituent group.Term " randomly by ... replacement " to mean specified group be unsubstituted or replaced by one or more substituent groups.

According to convention, in some structural formulas herein, carbon atom and their bonded hydrogen atom clearly do not mark, for example, The expression methyl,

The expression ethyl,

Representative ring amyl group etc.

Unless otherwise stated, term used herein " cycloalkyl " refers to non-aromatics, saturated or fractional saturation, monocycle or condensed ring, spiral shell or non-thick bicyclo-or tricyctic hydrocarbon herein, and the hydrocarbon of indication comprises 3-10 carbon atom herein, comprises that suitably 5-8 becomes ring carbon atom.Typical cycloalkyl comprises the ring with 3-10 carbon atom, for example cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and adamantyl.The illustrative example of cycloalkyl is as follows, but is not limited thereto:

Unless otherwise stated, term used herein " aryl " comprises the organic group that is derived from the aromatic hydrocarbon of removing a hydrogen, for example phenyl or naphthyl.

Unless otherwise stated, term used herein " (3-7) first heterocycle ", " (6-10) first heterocycle " or " (4-10) first heterocycle " comprise and contain heteroatomic aromatics or the non-aromatic heterocycle that 1-4 is selected from O, S and N respectively, wherein, each heterocyclic radical has 3-7 respectively in its ring system, 6-10 is individual or 4-10 atom, but the ring of described group must not comprise two adjacent O or S atom.Non-aromatic heterocycle is included in their ring system has the only group of 3 atoms, but aromatic heterocyclic radical must have at least 5 atoms in their ring system.Heterocyclic radical comprises the fused benzo ring system.The example of 3 yuan of heterocyclic radicals is azacyclo-propyl group, and the example of 4 yuan of heterocyclic radicals is azelidinyl (being derived from azetidine).The example of 5 yuan of heterocyclic radicals is thiazolyls, and 7 yuan of heterocyclic examples are that azatropylidene base (azepinyl) and 10 yuan of heterocyclic examples are quinolyls.The example of non-aromatic heterocycle is a pyrrolidinyl, tetrahydrofuran base, the dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidino, the morpholino base, thiomorpholine is for basic thioxane base (thioxanyl), piperazinyl, azelidinyl, oxa-cyclobutyl (oxetanyl), Thietane base (thietanyl), single piperidyl (homopiperidinyl), oxepane alkyl (oxepanyl), thia cycloheptane base (thiepanyl), oxygen azatropylidene base (oxazepinyl), diazepine base (diazepinyl), sulfur azatropylidene base (thiazepinyl), 1,2,3, the 6-tetrahydro pyridyl, the 2-pyrrolinyl, the 3-pyrrolinyl, indolinyl, the 2H-pyranose, the 4H-pyranose, dioxacyclohexyl, 1,3-dioxane amyl group, pyrazolinyl, the dithiane base, the dithia cyclopenta, dihydro pyranyl, the dihydro-thiophene base, the dihydrofuran base, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexyl, 3-azabicyclo [4.1.0] heptyl, 3H-indyl and quinolizinyl.The example of aromatic heterocyclic radical is a pyridine radicals, imidazole radicals, pyrimidine radicals, pyrazolyl, triazolyl, pyrazinyl, tetrazole radical, furyl, thienyl isoxazolyl, thiazolyl oxazolyl, isothiazolyl, pyrrole radicals, quinolyl, isoquinolyl, indyl, benzimidazolyl, benzofuranyl, the cinnolines base, indazolyl, indazole piperazine base (indolizinyl), phthalazinyl, pyridazinyl, triazine radical, isoindolyl, pteridyl, purine radicals oxadiazole base, thiadiazolyl group, the furazan base, benzo furazan base, benzothienyl, benzothiazolyl benzoxazolyl, quinazoline, quinoxaline, phthalazinyl (naphthyridinyl) and furo pyridine radicals.Derived from above listed group, aforementioned group can connect or the N-connection by C-each other.For example, the group derived from the pyrroles can be pyrroles-1-base (N-connection) or pyrroles-3-base (C-connection).And, can be imidazoles-1-base (N-connection) or imidazo-3-yl (C-connection) derived from the group of imidazoles.Any ring carbon, sulfur or nitrogen-atoms on each ring of 4-10 unit heterocyclic radical are randomly replaced by one to two oxo base.Wherein the example of the heterocyclic radical that replaced by the oxo base of two ring carbon atoms is 1,1-dioxo-thio-morpholinyl.Other illustrative example of 4-10 unit heterocyclic radical is as follows, but is not limited thereto:

Unless otherwise stated, term " oxo base " refers to=O.

" solvate " means the appointed compound of pharmaceutically acceptable solvate forms, and this solvate keeps this chemical compound of biologic effective dose.The example of solvate comprises the combination of chemical compound of the present invention and water, isopropyl alcohol, ethanol, methanol, DMSO (dimethyl sulfoxide), ethyl acetate, acetic acid or ethanolamine.

Unless otherwise stated, used phrase " pharmaceutically acceptable salt " comprises the acidic-group in formula of may reside in (I) or formula (II) chemical compound or the salt of basic group more than.The formula (I) of alkalescence or the chemical compound of formula (II) can form multiple salt with various mineral acids and organic acid.Those acid that can be used to prepare the pharmaceutically acceptable acid addition salts of the formula (I) of this alkalescence or formula (II) chemical compound are can form the non-toxic acid addition salts (promptly, contain pharmaceutically acceptable anionic salt) those, for example form acetate, benzene sulfonate, benzoate, bicarbonate, disulfate, biatrate, borate, bromide, Ca-EDTA, d-camphorsulfonic acid salt, carbonate, chloride, the little hydrochlorate of carat, citrate, dihydrochloride, edetate (edetate), according to ground sulfonate (edislyate), estolate (estolate), ethane sulfonate (esylate), Ethylsuccinate, fumarate, gluceptate, gluconate, glutamate, Glu, ethylene glycol atoxylate salt (glycollylarsanilate), hexyl resorcin thing (hexylresorcinate), breathe out amine, hydrobromide, hydrochloride, iodide, different thiosulfate, lactate, Lactobionate, month silicate, malate, maleate, mandelate, mesylate, Methylsulfate, mucus hydrochlorate (mucate), naphthalene sulfonate, nitrate, oleate, oxalates, embonate (grace ripple), palmitate, pantothenate, phosphate/diphosphate, Polygalacturonate, Salicylate, stearate, basic acetate, succinate, tannate, tartrate, the teoclate, tosilate, triethiodode and valerate.

Unless otherwise stated, term used herein " liver is the disease of Target organ " means diabetes, hepatitis, hepatocarcinoma, hepatic fibrosis and malaria.

Unless otherwise stated, used herein, term " metabolic syndrome " means psoriasis, diabetes, wound healing, inflammation, neuronal degeneration disease, galactosemia, maple syrup urine disease, phenylketonuria, hypersarcosinemia, thymus pyrimidine uracil urine disease, sulfinuria, isovaleric acidemia, saccharopinuria, 4 hydroxybutyric acid urine disease, G-6-P ester dehydrogenase deficiency disease and pyruvate dehydrogenase deficiency disease.

Unless otherwise stated, term used herein " treatment " means and will reverse, alleviates, suppress the development of applied disorder of this term or disease shape, or prevents one or more symptoms of the applied disorder of this term or disease or this disorder or disease.Unless otherwise stated, term used herein " treatment " also refers to the behavior for the treatment of, and is the same with " treatment " of above direct definition.

Term used herein " adjusting " or " modulation " refer to steroid/thyroid Superfamily the member actuator directly (being bonded on the receptor as part) or indirectly (as the presoma of part or as the inductor that promotes that part is generated by presoma) induce to express under the control and keep the ability of gene expression at hormone, or be suppressed at the ability of keeping gene expression under this control.

Term used herein " obesity " or " obesity " are often referred to body weight and surpass the individuality at least about 20-30% for the average weight of his/her age, sex and height.Technical, for the male, Body Mass Index is greater than 27.8kg/m ²Individuality be defined as " obesity ", for the women, Body Mass Index is greater than 27.3kg/m ²Individuality be defined as " obesity ".It will be readily appreciated by those skilled in the art that method of the present invention is not limited to drop on those in the above standard.In fact, method of the present invention can also advantageously be undertaken by dropping on these traditional standards individuality in addition, for example, is undertaken by being easy to those fat individualities.

More than used term " inflammation disorder " refer to for example rheumatic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, cartilaginous calcification, gout, inflammatory enteritis, ulcerative colitis, CrohnShi disease, fibromyalgia disease and cachectic disorder.

More than used phrase " treatment effective dose " refer to that research worker, veterinary, doctor or other personnel attempt to cause biological or the medicine of medicine reaction or the amount of pharmaceutical agent of tissue, system, animal or human's class.

Phrase used herein " effectively reduces the amount of blood glucose level " and refers to be enough to provide the level of the chemical compound of enough high concentrations to reach desirable effect.This concentration drops in the scope of about 10nM-2 μ M usually, and preferably concentration is in the scope of the about 500nM of about 100nM-.As indicated in above, because it is very big to drop on the activity change of the different chemical compounds in the definition of formula explained above (I) or formula (II), and because there are great changes in individual object of study on the order of severity of disease, therefore the doctor should determine the reaction of object of study to treatment, and correspondingly changes dosage.

Phrase used herein " insulin impedance disease " refers to that the sensitivity of insulin function reduces in whole health or the individual tissue (for example, skeletal muscle tissue, cardiac muscular tissue, fatty tissue or liver organization).Some are suffered from or are not suffered from the individuality of diabetes and have insulin impedance disease.

Phrase used herein " insulin impedance syndrome " refers to that one group of reveal any symptoms, this symptom comprise insulin impedance disease, hyperinsulinemia, NIDDM, Arterial Hypertention, center (internal organs) obesity and dyslipoproteinemia.

Some chemical compound of formula (I) or formula (II) can have asymmetric center, so there is different enantiomeric forms in they.All optical isomers and the stereoisomer of formula (I) or formula (II) chemical compound and its mixture are considered within the scope of the invention.About the chemical compound of formula (I) or formula (II), the present invention includes the purposes of racemic modification, one or more enantiomeric forms, one or more diastereomeric form or its mixture.Also can there be tautomeride in formula (I) or formula (II) chemical compound.The present invention relates to the purposes of these tautomerides and its mixture.

Some functional group that is included in the chemical compound of the present invention can substitute with bioisostere, in other words, this bioisostere is to have and similar space of parent or electronics needs, but shows group different or improvement physicochemical properties or other character.Suitable example is well known by persons skilled in the art, and includes, but are not limited at Chem.Rev such as Patini, 1996,96, and those described in 3147-3176 and the list of references cited herein.

The present invention also comprises isotope-labeled chemical compound, cited those are identical in these chemical compounds and formula (I) or the formula (II), except one or more atoms by atomic mass or mass number with usually the different atom of the atomic mass of the atom that occurring in nature is found or mass number replaces.Can insert the isotope that isotopic example in the chemical compound of the present invention comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine respectively, for example, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl.Comprising other the isotopic chemical compound of the present invention of above isotope and/or other atom and the pharmaceutically acceptable salt or the solvate of described chemical compound falls within the scope of the invention.Some isotope-labeled chemical compound of the present invention (for example, as ³H and ¹⁴The radiosiotope of C inserts those chemical compounds wherein) can be used in the medicine and/or the test of culture medium tissue distribution in.Preferred especially tritium (promptly ³H) and carbon-14 ( ¹⁴C) isotope is because their preparation and detections easily.And, with heavier for example deuterium ( ²H) isotope replaces can provide some treatment advantage, and this replacement causes higher metabolic stability, for example, is increased in the intravital half-life or reduces the dosage demand, and therefore, this method is preferred in some cases.The chemical compound of isotope-labeled formula of the present invention (I) or formula (II) can prepare by following process usually: implement disclosed process among following scheme and/or the embodiment, and replace nonisotopically labelled reagent with the isotope-labeled reagent that is easy to get.

By following detailed description, others of the present invention, advantage and feature are apparent.

Detailed description of the present invention and embodiment

Following reaction scheme has illustrated the preparation method of chemical compound of the present invention.Unless otherwise stated, in the reaction scheme and following in question R ¹-R ²², T and W as above define.

Scheme 1

Referring to above scheme 1, the chemical compound of formula Ia can prepare by following process: with chemical compound (wherein, the group CO of formula Ic ₂R ²³Be methyl ester (CO for example ₂-CH ₃) or ethyl ester (CO ₂-CH ₂CH ₃) ester group) with aluminum amide (Me ₂Al-NR ²R ³) or (MeAl (Cl)-NR ²R ³) advantageously in appropriate solvent (for example, dichloromethane or toluene), react down in room temperature to the temperature between the boiling point of solvent (usually from about 20 ℃-Yue 100 ℃).The chemical compound of formula Ia can also prepare by following process: utilize standard amides coupling chemical reaction, with chemical compound (wherein, the group CO of formula Ic ₂R ²³Be carboxylic acid (CO ₂H)) with formula HNR ²R ³Amine reaction.The chemical compound of formula Ic can prepare by following process: with chemical compound (wherein, the group CO of formula IIa ₂R ²³Be methyl ester (CO for example ₂-CH ₃) or ethyl ester (CO ₂-CH ₂CH ₃) ester group) and R ¹-sulfonic acid halide or R ¹The reaction of-sulfenyl halogen.Interchangeable, the chemical compound of formula Ia can prepare by following process: with chemical compound and the R of formula Id ¹-sulfonic acid halide or R ¹The reaction of-sulfenyl halogen.The chemical compound of formula Id can prepare by following process: with formula IIa chemical compound (wherein, group CO ₂R ²³Be methyl ester (CO for example ₂-CH ₃) or ethyl ester (CO ₂-CH ₂CH ₃) ester group) with aluminum amide (Me ₂Al-NR ²R ³) or (MeAl (Cl)-NR ²R ³) in appropriate solvent (for example, dichloromethane or toluene), in room temperature (about 20 ℃-Yue 100 ℃ usually) reaction to the temperature of solvent boiling point.The chemical compound of formula Ib can be by obtaining suitable acyl ammonia Ia dehydration ring formation.

Scheme 2

Scheme 3

About above scheme 2, the chemical compound of formula A can pass through B and R ¹-sulfonic acid halide, R ¹-sulfenyl halogen or R ¹-sulfinic acid ester reacts in the presence of the alkali of for example amine and prepares.Suitable alkali comprises pyridine, triethylamine and diisopropyl ethyl amine.Suitable solvent comprises pyridine, dichloromethane or THF.Above-mentioned reaction can at room temperature be carried out, or heating appropriate time (for example 2-16 hour), and this depends on employed dicyandiamide solution.After reaction was finished basically, vacuum was removed lixiviating, and utilized traditional purification technique to come purification the residue of gained.

About scheme 3, represented another synthetic method of chemical compound, wherein, R ¹It is the non-condensed ring system of an above aryl or heterocyclic radical.The palladium catalyzed coupling reaction that the chemical compound of formula A3 can pass through A2 (wherein, X is halogen or trifluoromethyl sulfonyl) and reagent Y-N (wherein, Y is aryl or heterocyclic radical, and N is boric acid, borate, stannane or zincate) prepares.The suitable palladium source of this reaction comprises Pd (PPh ₃) ₄, Pd ₂(dba) ₃, Pd (PPh ₃) ₂Cl ₂Or Pd (OAc) ₂Also can add for example part of diphenylphosphino ethane, diphenylphosphino ferrocene or triphenylphosphine.The suitable solvent of palladium catalyzed coupling reaction comprises dimethyl formamide, oxolane or toluene.More than reaction can not adopted microwave heating or is adopted the about 15min-of microwave heating to carry out in about 16 hours under about 15 ℃ one 150 ℃ temperature.For adopting the boric acid coupling, can add for example Na ₂CO ₃, Cs ₂CO ₃, TlOH, TlOEt alkalinity additive.

Arbitrarily with following formula Ia, Ib, Ic, Id, IIa, A, B, A ₂And A ₃Chemical compound can change into other similar compound by standard chemical operation.Unless otherwise stated, all raw materials, reagent and solvent are that commerce can get and are well known by persons skilled in the art.These chemical operation are well known by persons skilled in the art, comprise that (a) passes through at T.W.Greene and P.G.M.Wuts " ProtectiveGroups in Organic Synthesis ", second edition, John Wiley and Sons, New York, the method for general introduction is removed protecting group in 1991; (b) substitute leaving group (halogenide, methanesulfonates, tosylate) with primary amine or secondary amine, mercaptan or alcohol and form secondary amine or tertiary amine, thioether or ether respectively; (c) obtain corresponding urea, acyl ammonia, carbamate or sulfonamide with isocyanates, carboxylic acid halides (or other active carboxylic acid derivative), alkyl chloro-formate or sulfonic acid halide processing primary amine or secondary amine; (d) utilize aldehyde reduction amination primary amine or secondary amine.

Chemical compound of the present invention can have asymmetric carbon atom.Mixture of diastereomers can be isolated their diastereomers separately by method known to those skilled in the art (for example, by chromatography or fractional distillation crystallization) based on their physicochemical differences.Enantiomer can separate by the following method: diastereomeric mixture by with suitable Photoactive compounds (for example, ethanol) reaction changes into mixture of diastereomers, diastereomer is separated, and each diastereomer is changed into corresponding pure enantiomer (for example, hydrolysis).All these comprise that the isomer of mixture of diastereomers and pure enantiomer is considered to a part of the present invention.

The formula (I) or formula (II) chemical compound of alkalescence can form various salt with various mineral acids and organic acid.Although these salt must be pharmaceutically acceptable being used for the animal dispenser, but usually wish in practice, at the beginning formula (I) or formula (II) chemical compound are separated from reactant mixture with the form of unacceptable salt pharmaceutically, pharmaceutically unacceptable salt changes into free alkali compound by handling with alkaline reagent then, subsequently, free alkali compound is changed into pharmaceutically acceptable acid-addition salts.The acid-addition salts of alkali cpd of the present invention is easily by following process preparation: with alkali cpd selected mineral acid or organic acid processing in the aqueous solvent medium or in appropriate organic solvent (for example, methanol or ethanol) of equimolar amounts basically.After the careful evaporating solvent, promptly obtain desirable solid salt.Desirable hydrochlorate also can be by in the organic solvent solution that suitable mineral acid or organic acid is added to free alkali compound and be precipitated out from this solution.

Those tart formulas (I) or formula (II) chemical compound can form basic salt with various pharmaceutically acceptable cationes.The example of these salt comprises alkali metal salt or alkali salt, particularly sodium salt and potassium salt.These salt all prepare by routine techniques.Those chemical bases that can be used for preparing the pharmaceutically acceptable basic salt of the present invention are to form those of nontoxic basic salt with the acid compound of formula (I) or formula (II).These nontoxic basic salts comprise and are derived from for example pharmaceutically acceptable cationic those salt of sodium, potassium, calcium and magnesium etc.These salt prepare easily by the following method: corresponding acid compound is handled with containing the pharmaceutically acceptable cationic aqueous solution that is hopeful, then with the gained solution evaporation with drying, vapourisation under reduced pressure preferably.Replacedly, they also can prepare by the following method: admixed together with acid compound than low alkalinity solution and desirable alkali metal alcoholates, then, gained solution is evaporated with drying in previous identical mode.In another case, the reagent that preferably adopts stoichiometric number with guarantee to react completely and the productive rate of desirable end product the highest.

Chemical compound of the present invention can be the regulator of 11-β-hsd-1.Chemical compound of the present invention can be regulated the process by 11-β-hsd-1 mediation (mediated), this process refers to the bioprocess by receptor or receptor combination mediation (11-β described herein-hsd-1 inhibitor is reacted), physiological process, endocrine process and other body processes are (for example, diabetes, hyperlipemia, fat, carbohydrate tolerance reduces, hypertension, fatty liver, diabetic complication (for example, retinopathy, nephropathy, neuropathy, cataract and coronary heart disease etc.), arteriosclerosis, gestational diabetes, polycystic ovarian syndrome, cardiovascular disease (for example, ischemic heart desease etc.), the cell injury that is caused by arteriosclerosis or ischemic heart desease (for example, by in wind-induced brain injury etc.), gout, inflammation illness (for example, osteoarthritis, pain, heating, rheumatic arthritis, infective enteritis, acne, sunburn, psoriasis, eczema, anaphylactia, asthma, Gl ulcer, cachexia, autoimmune disease, pancreatitis etc.), cancer, osteoporosis and cataract).The adjusting of these processes can be external or finish in vivo.Adjusting can implemented in the object of study on a large scale in the body, for example, and the mankind, rodent, sheep, pig, cattle etc.

Can be used in the various indications according to chemical compound of the present invention, these indications relate to regulates 11-β-hsd-1 enzyme.Therefore, can be used for prevention dull-witted (seeing WO97/07789) according to chemical compound of the present invention, osteoporosis (is seen Canalis E 1996, " Mechanisms ofGlucocorticoid Action in Bone:Implications to Glucocorticoid-InducedOsteoporosis ", Journal of Clinical Endocrinology and Metabolism, 81,3441-3447), and can also be used in the immune system disorder and (see Franchimont etc., " Inhibition of Th1 Immune Response by Glucocorticoids:DexamethasoneSelectively Inhibits IL-12-induced Stat 4 Phosphorylation in T Lymphocytes ", The Journal of Immunology 2000, Feb 15, vol 164 (4), pages 1768-74) and above listed indication in.

In isolated murine pancreas beta cell, suppress insulin secretion (Davani, B. etc., (2000) J.Biol.Chem.Nov.10,2000,275 (45): 34841-4) that 11-β-hsd-1 has improved to be stimulated through glucose.The previously known glucocorticoid can reduce the release (Billaudel, B. and B.C.J.Sutter (1979) Horm.Metab.Res.11:555-560) of pancreas insulin in the body.Therefore, can predict and suppress 11-β-hsd-1 except effective, treating diabetes is also produced other beneficial effect liver and fat.

Recently data show that the level of glucocorticoid target recipient and 11-β-hsd-1 enzyme determines glaucomatous susceptibility (Stokes, J. etc., (2000) Invest.Ophthalmol.41:1629-1638).And, recently, studies show that the method that suppresses 11-β-hsd-1 and can be used as a kind of new reduction intraocular pressure (Walker E.A. etc., 12-15 day in June, 1999 is in the Endocrine of San Diego society meeting, poster P3-698).Experiment shows that normal object of study picked-up carbenoxolone (non-specific 11-β-hsd-1 inhibitor) has reduced by 20% intraocular pressure.In eyes, the expression of 11-β-hsd-1 is defined in the basal cell of the nonpigmented epithelium position of water (produce) of corneal epithelium and cornea, is defined in the ciliary muscle and is defined in the sphincter and dilator of iris.On the contrary, isoazyne 1 1-beta-hydroxysteroid dehydrogenase-2 type far away is expressed at non-pigmented eyelashes epithelium and corneal epithelium camber.Locate not find enzyme at trabecular reticulum (place of ejection).Thereby hint 11-β-hsd-1 has played effect in water generates, and does not work in drainage, but whether this is by hindering the activity of glucocorticoid or mineralcorticoid receptor, or by these two activity obtain still unknown at present.

Bile acid suppresses 11-beta-hydroxysteroid dehydrogenase-2 type.As ratio (Quattropani C by the studying uropoiesis metabolite, Vogt B, Odermatt A, Dick B, Frey B M, Frey F is Clin Invest.Nov 108 (9) J.2001.J: 1299-305. " Reduced Activity of 11-beta-hydroxysteroid dehydrogenase in Patients with Cholestasis ") indicated, this process causes the variation in the whole balance to help hydrocortisone (cortisol) but not corticosterone (cortisone).Can predict by the activity of 11-β-hsd-1 in the selective depressant reduction liver and can reverse this imbalance, and make for example hypertensive symptom, wait the operative treatment of excision bile duct occlusion simultaneously to oppositely moving.

Chemical compound of the present invention can also be used for the treatment of with glucose and utilizes impaired other relevant metabolism disorder, and the disease relevant with the insulin impedance, the most of late complication that comprises NIDDM, for example, diabetic angiopathy, arteriosclerosis, diabetic nephropathy, diabetic neuropathy and diabetes vision complication are (for example, retinopathy, cataract forms and glaucoma), other disease relevant with NIDDM with other (comprises the insulin impedance disease that the lipidemia glucocorticoid brings out, lipidemia, polycystic ovary syndrome, fat, hyperglycemia, hyperlipemia, hypercholesterolemia, hypertriglyceridema, hyperinsulinemia and hypertension).In any medical dictionary, can obtain the definition of these diseases, for example, Stedman ' s Medical Dictionary (the tenth edition).

Test

11 β-hsd-1 test is carried out in 100mM triethanolamine buffer, the pH of this buffer is 8.0, comprises 200mM NaCl, 0.02% dodecyl β-D-maltoside (n-dodecyl β-D-maltoside), 5% glycerol, 5mM beta-mercaptoethanol.Be used for determining K _IappThe type reaction of value is carried out in Corning  u-bottom 96 orifice plates under R.T., this reaction is described below: with 11-β-hsd-1 enzyme (5nM, ultimate density) in the test buffer, cultivating at least 30 minutes in advance under the existence of inhibitor and NADPH (500 μ M, ultimate density).When finishing pre-cultivation, by adding regenerating system (2mM G-6-P ester, 1U/ml G-6-P ester dehydrogenase and 6mM MgCl ₂, the concentration of all reports is in the ultimate density of test in the buffer) and 3H-corticosterone (200nM, ultimate density) begin this reaction.After 60 minutes, 60 μ L test mixtures are transferred in the 2 96 orifice plate, and mixed with stopped reaction with isopyknic dimethyl sulfoxine.15 μ L aliquots of reaction mixture are contained in the C-18 post (from the Polaris C18-A of Varian in the future, 50 * 4.6mm, 5 μ, 180 dusts) in, this post is connected to the automatic high flow capacity chromatograph of liquid that has β-RAM 3 type Radio-HPLC detectors (from IN/US, can derive from Tampa by commercial sources, Florida USA) and (is developed by Cohesive Technologies, can be by commercial sources from Franklin, Massachusetts USA obtains).The methanol by adopting 43: 57 (v/v) and the non-gradient mixture of water under the flow velocity of 1.0mL/min, separate the peak of culture medium and product.

Primary response speed is measured by the following method: at 60min reaction is stopped, and measure the zone that product forms lacking and exist under the situation of various inhibitor concentration.Utilize Morrison JF (Morrison JF.Biochim Biophys Acta.1969; 185:269-86) Kai Fa the equation that closes inhibitor (tight-binding inhibitor) that is used to be right after is determined K _IappValue.

Radiolabeled [1,2-3H]-corticosterone can be by commercial sources from St.Louis, and the American Radiolabelled Chemical Inc of MissouriUSA obtains.NADPH, G-6-P ester and G-6-P ester dehydrogenase are available from Sigma ^

The K that is used for the chemical compound of the present invention of 11-β-hsd-1 enzyme _IappValue is generally the about 10 μ M of about 10nM-.All tested chemical compounds of the present invention SPA test wherein at least it-in have K less than 1 μ M _Iapp, preferably have K less than 100nM _IappSome preferred group of chemical compound has different selectivitys to various 11-β-hsd.A group of preferred compound is better than selectivity to 11-β-hsd-2 to the selectivity of 11-β-hsd-1.Another preferred group of chemical compound is better than selectivity (Morrison JF.Biochim Biophys Acta.1969:185:269-86) to 11-β-hsd-1 to the selectivity of 11-β-hsd-2.

Inhibiting percentage rate determines that in 100mM triethanolamine buffer the pH of this buffer is 8.0, comprises 200mM NaCl, 0.02% dodecyl β-D-maltoside and 5mM β-ME.Type reaction is carried out in Corning  u-bottom 96 orifice plates under R.T., this reaction is described below: with 11-β-hsd-1 enzyme (5nM, ultimate density) under the existence of inhibitor and NADPH (500 μ M, ultimate density), in the test buffer, the pre-cultivation at least 30 minutes.When finishing pre-cultivation, by adding regenerating system (2mM G-6-P ester, 1U/ml G-6-P ester dehydrogenase and 6mM MgCl ₂, the concentration of all reports is in the ultimate density of test in the buffer) and 3H-corticosterone (200nM, ultimate density) begin this reaction.After 60 minutes, 60 μ L test mixtures are transferred in the 2 96 orifice plate, and mixed with stopped reaction with isopyknic dimethyl sulfoxine.15 μ L aliquots of reaction mixture are contained in the C-18 post (from the Polaris C18-A of Varian in the future, 50 * 4.6mm, 5 μ, 180 dusts) in, this post is connected to the automatic high flow capacity chromatograph of liquid that has β-RAM 3 type Radio-HPLC detectors (from IN/US, can be by commercial sources from Tampa, FloridaUSA obtains) and (is developed by Cohesive Technologies, can be by commercial sources from Franklin, Massachusetts USA obtains).The methanol by adopting 43: 57 (v/v) and the non-gradient mixture of water under the flow velocity of 1.0mL/min, separate the peak of culture medium and product.

Suppress percent based on following Equation for Calculating: (100-(having the peak area of the peak area of the 3H-hydrocortisone of inhibitor/not) * 100) with inhibitor 3H-hydrocortisone.Some group of chemical compound has different selectivitys to various 11-β-hsd enzyme.A group of chemical compound is better than selectivity to 11-β-hsd-2 enzyme to the selectivity of 11-β-hsd-1 enzyme.Yet another preferred group of chemical compound is better than selectivity to 11-β-hsd-1 to the selectivity of 11-β-hsd-2

Radiolabeled [1,2-3H]-corticosterone can be by commercial sources from St.Louis, the American Radiolabelled Chemical Inc. of MissouriUSA obtains, and NADPH, G-6-P ester and G-6-P ester dehydrogenase are available from Sigma ^

Pharmaceutical composition/prescription, dosage and mode

The method that preparation has the various pharmaceutical compositions of particular active compounds amount is known, or apparent to those skilled in the art.In addition, those of ordinary skills are familiar with prescription and medicine-feeding technology.At the The of for example Goodman and Gilman Pharmaceutical Basis ofTherapeutics, current version, Pergamon Press and Remington ' s PharmaceuticalSciences, current version, Mack Publishing, Co., Easton has discussed these problems among the PA.Adopt these technology herein in the suitable embodiment of described method and composition.The example that below provides only is for explanatory purpose, and does not mean that and be used to limit the present invention.

In suitable part, oral and injectable drug prescription, can provide the chemical compound of formula (I) or formula (II) to be used for the treatment of disease through 11-β-hsd-1 mediation.Chemical compound of the present invention can tablet or capsule, oiliness or to contain the form of aqueous suspension agent, lozenge, tablet, powder, granule, emulsion, syrup or elixir oral.Orally administered composition can comprise that one or more kind reagent are used for seasoning, increase sweet, painted and anticorrosion medicine to prepare exquisiteness and easily to enter the mouth.Tablet can comprise that pharmaceutically acceptable excipient is with the auxiliary agent as this tablet of preparation.Usually in the art, these tablets can adopt pharmaceutically acceptable enteric solubility coating (for example, monostearate glycerine ester and distearyl acid glycerine ester) to apply so that delay the disintegrate in gastrointestinal tract and absorb so that the continuous action of long period to be provided.

Formula of oral can be the hard gel capsule, and wherein, active component mixes with inert solid diluent, for example calcium carbonate, calcium phosphate or Kaolin.They can also be soft gel capsules, and wherein, active component mixes with water or oily medium, for example, and Oleum Arachidis hypogaeae semen, liquid paraffin or olive oil.

Containing aqueous suspension agent comprises usually and is suitable for preparing the blended active component of the excipient that contains aqueous suspension agent.These excipient can be suspending agent (for example, sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth and arabic gum), can be to disperse or wetting agent, these dispersions or wetting agent can be naturally occurring phospholipid (for example, lecithin), the condensation product of oxirane and long-chain fatty acid (for example, polyoxyethylene stearic acid ester), the condensation product of oxirane and long chain aliphatic (for example, 17 carbon ethyleneoxy hexadecanol), the condensation product of oxirane and the partial ester that derives from fatty acid and hexitol (for example, single oleic acid polyoxyethylene sorbitan ester) or fatty acid hexitol anhydride (for example, single oleic acid polyoxyethylene sorbitan esters).

Pharmaceutical composition can be sterile aqueous or oily injection suspensions.This suspension can be according to known method, and suitable dispersant of having mentioned more than the utilization or wetting agent and suspending agent are prepared.Aseptic parenteral solution also can be can accept the dispersion liquid prepared in diluent or the solvent at nontoxic vein, for example, and the solution in 1,3 butylene glycol.In can accepting excipient and solvent, operable is water, Ringer solution and isobaric sodium chloride solution.Purpose can be used any non-irritating expressed oi hereto, comprises synthetic monoglyceride or two glyceride.In addition, find that for example oleic fatty acid can be used in the preparation injection.

The chemical compound of formula (I) or formula (II) can also be used for rectally with the form of suppository.These compositionss can prepare by medicine is mixed with suitable non-stimulated excipient, and above-mentioned excipient is solid down at about 25 ℃, is liquid under rectal temperature, and therefore, this excipient melts in rectum with the release medicine.This material comprises cupu oil and other glyceride.

Use for the part, for example use Emulsion, ointment, gel solution or the suspension that comprises The compounds of this invention.

The chemical compound of formula (I) or formula (II) can also be with the form administration of liposome induction system, for example small unilamellar vesicle, big unilamellar liposome and multilamellar liposome.Liposome can be formed by the phospholipid of various for example cholesterol, stearamide or lecithin.

The dosage level of chemical compound of the present invention is that about 0.5mg/kg body weight is to about 100mg/kg body weight.Preferred dosage is that about 30mg/kg body weight is to about 100mg/kg body weight.Yet, be to be understood that, any specific patient's concrete dosage level depends on a large amount of factors, comprise the order of severity of the activity of the specific compound that gives, patient's age, body weight, general health, sex, diet, administration time, route of administration, drainage number of times, drug combination and the specified disease for the treatment of.In order to improve the curative effect of this chemical compound, they can be taken together with other Orally active antidiabetic compound (for example, sulfonylureas), for example tolbutamide (tolbutamide) etc.

Embodiment

The method of chemical compound of the present invention and these chemical compounds of preparation is further set forth and enumerated to embodiment that below provides and preparation method.Be to be understood that scope of the present invention is not limited to the scope of following examples and preparation method.In following examples, unless otherwise stated, the molecule with single chiral centre exists as racemic mixture.Unless otherwise stated, have the racemic mixture existence of those molecules of two or more chiral centres as diastereomer.Single enantiomer/diastereomer can obtain by method known to those skilled in the art.

The structure of chemical compound confirms that by elementary analysis or NMR wherein, the feature proton peak in the title compound is present in suitable position.Provide ¹H nmr chemical displacement (δ _H) arrange downwards by the interior per 1,000,000/portion (ppm) that is marked with.

The present invention now describes following examples.These embodiment should not think and limit the scope of the invention, and as just the mode of explanation.

Method A

Embodiment 1:[6-(3-chloro-2-methyl-benzene sulfonamido)-pyridine-2-yl] ethyl acetate

Under 24 ℃, (3.4g, 15mmol 1.5equiv) are added to (6-amino-pyridine-2-yl)-ethyl acetate (1.8g, 10mmol, (Goto, J. in pyridine 1equiv) (75mL) solution in batches with 3-chloro-2-Methyl benzenesulfonyl chlorine; Sakane, K.; Nakai, Y.; Teraji, T.; Kamiya, TJ.Antibiot.1984,37,532).After 16 hours, (＜1mm Hg) removes with the pyridine vacuum, and the gained residue is dissolved in (200mL) in the ethyl acetate.With organic solution water successively (3 * 100mL) and saturated sodium-chloride water solution (100mL) washing.With Organic substance anhydrous sodium sulfate drying, the filtration and concentrated of collecting.Obtain product (2.76g, 75%) by efficient flash chromatography (flashchromatography) (0 → 5% in dichloromethane methanol) purification.

Method B

Embodiment 8:3-chloro-2-methane-N-[6-(2-morpholine-4-base-2-oxo-ethyl)-pyridine-2-yl]-benzsulfamide

Chlorodimethylalumiu (5.0equiv is in the 1.0M hexane for 1.36mL, 1.36mmol) is added drop-wise to morpholine, and (0.119mL, 1.36mmol is in the ice-cold solution of dichloromethane 5.0equiv) (3mL).(0.100g, 0.271mmol before dichloromethane 1equiv) (2mL) solution, are heated to 24 ℃ and kept 1 hour with gained solution adding [6-(3-chloro-2-methyl-benzene sulfonamido)-pyridine-2-yl]-ethyl acetate.After 1 hour, 20% sodium tartrate aqueous solutions of potassium (5mL) slowly is added in the reactant mixture, and with other 1 hour of gained suspension vigorous stirring.(2 * 25mL) extract with dichloromethane with the gained mixture.With Organic substance anhydrous sodium sulfate drying, the filtration and concentrated of collecting.Obtain light yellow solid (0.107g, 96%) by efficient flash chromatography (0 → 10% in dichloromethane methanol) purification.

Method C

Embodiment 19:2-[6-(5-chloro-3-methyl-benzo [b] thiophene-2-sulfoamido)-pyridine-2-yl]-N, N-diethyl-acetamide

Preparation (2-(6-amino-pyridine-2-yl)-N, N-diethyl-acetamide

Chlorodimethylalumiu (5.0equiv is in the 1.0M hexane solution for 4.3mL, 4.3mmol) is added to diethylamine, and (445 μ L, 4.30mmol is in the ice-cold solution of dichloromethane 5.0equiv) (4mL).Behind 10min, solution is heated to 24 ℃ and keep 1h.Under 24 ℃, add (6-amino-pyridine-2-yl)-ethyl acetate (155mg, 0.860mmol, dichloromethane 1equiv) (4mL) solution (Goto, J.; Sakane, K.; Nakai, Y.; Teraji, T.; Kamiya, T.J.Antibiot.1984,37,532).Behind 21.5h, (20%wt/wt 10mL) and hexane (20mL), and spends the night gained mixture vigorous stirring to add the sodium tartrate aqueous solutions of potassium successively.Add saturated sodium-chloride water solution (30mL), and (3 * 30mL) extract with ethyl acetate with the gained mixture.With Organic substance anhydrous sodium sulfate drying, the filtration and concentrated of collecting.Obtain product (120mg, 67%) by efficient flash chromatography (0 → 4.5% methanol in dichloromethane+0.1% ammonium hydroxide) purification. ¹H?NMR(400MHz，CDCl ₃)，δ：7.37(m，1H)，6.66(d，J＝7.6Hz，1H)，6.35(d，J＝8.1Hz，1H)，4.34(br?s，2H)，3.69(s，2H)，3.30-3.44(m，4H)，1.06-1.16(m，6H)。

2-[6-(5-chloro-3-methyl-benzo [b] thiophene-2-sulfoamido)-pyridine-2-yl]-N, N-diethyl-acetamide

Under 24 ℃, (163mg, 0.580mmol 1.1equiv) are added to 2-(6-amino-pyridine-2-yl)-N, and (100mg, 0.483mmol is in pyridine 1equiv) (4mL) solution for N-diethyl-acetamide with 5-chloro-3-methyl benzo [B] thiophene-2-sulfonic acid chloride.Behind 18h, reactant mixture is diluted with ethyl acetate (30mL).Gained solution with water (60mL) is washed.With organic facies anhydrous sodium sulfate drying, filtration and concentrated.Obtain title compound (93mg, 43%) by efficient flash chromatography (0 → 5% in dichloromethane methanol) purification.

Method D

Embodiment 26[6-(3-chloro-2-methyl-benzenesulfonyl)-pyridine-2-yl]-acetic acid

Under 24 ℃, (0.843g, 15.0mmol 6.00equiv) are added to [6-(3-chloro-2-methyl-benzene sulfonamido)-pyridine-2-yl]-ethyl acetate, and (0.922g, 2.50mmol is 1equiv) in 20: 1 ethanol/water (21mL) solution with potassium hydroxide.Behind 1h, reactant mixture vacuum (～25mm Hg) is concentrated, and with in the gained residue water-soluble (50mL).By add 10% aqueous hydrochloric acid solution with acidified aqueous solution up to pH=2.Then, heterogeneous solution is filtered, and with solid water successively (50mL) and Anaesthetie Ether (2 * 50mL) flushings.Solid vacuum (＜1mm Hg, 50 ℃) drying is obtained dark brown solid product (0.810g, 71%).

Method E

Embodiment 27:N-diamantane (obsolete)-1-base-2-[6-(3-chloro-2-methyl-benzene sulfonamido)-pyridine-2-yl]-acetamide

With O-(7-azepine benzo triazol-1-yl-N, N, N ', N '-tetramethylurea hexafluorophosphoric acid ester (0.11g, 0.29mmol, 0.98equiv) be added to [6-(3-chloro-2-methyl-benzene sulfonamido)-pyridine-2-yl]-acetic acid (0.100g, 0.293mmol in batches, 1equiv), 1-amantadine (0.200g, 1.32mmol, 4.51equiv) and N, N-diisopropyl ethyl amine (0.462mL, 2.65mmol, 9.04equiv) in the ice-cold solution of dimethyl formamide (5mL).Solution is heated to 24 ℃ and stir and to spend the night.(～1mm Hg) removes with the dimethyl formamide vacuum, and the gained residue is dissolved in the dichloromethane in (20mL).Organic substance is used deionized water (2 * 20mL) and saturated sodium-chloride water solution (20mL) washing successively.With Organic substance anhydrous sodium sulfate drying, the filtration and concentrated of collecting.The amide (82mg, 65%) that obtains wishing by efficient flash chromatography (0 → 2% in dichloromethane methanol) purification.

The link coupled another kind of universal method of amide

The reactant A reactant B

1?equiv 1?equiv

With stirring rod, amine (reactant B, 400 μ L, 80 μ mol, 1.00equiv in the 0.2M dry DMF), [6-(3-chloro-2-methyl-benzene sulfonamido)-pyridine-2-yl]-acetic acid (reactant A 200 μ L, 80 μ mol are in the 1.00equiv 0.2M dry DMF), TEA (160 μ L, 80 μ mol, 1.00equiv in the 0.5M dry DMF), HATU (160 μ L, 80 μ mol are in the 1.00equiv 0.5M dry DMF) is placed in 10 * 75mm test tube.Test tube is sealed with cellophane, and reactant mixture is at room temperature stirred 16h.With solvent evaporation, and residue is dissolved in obtains 0.05M solution among the DMSO that contains 0.01%BHT.Injection of solution is gone into purification in the automatic HPLC system.To comprise the product solvent evaporation of fraction, and residue will be dissolved among the DMSO, analyzes the row filter of going forward side by side.

Gneral analysis and purge process

Utilize method 1 to analyze crude product mixture by HPLC.Before purification, all samples passes through Whatman ^GF/F Unifilter (#7700-7210) (can derive from Clifton by commercial sources, the Whatman of New Jersey USA ^) filter.Utilize method 3 to carry out the sample purification by reversed-phase HPLC.Fraction is collected in the preweighted test tube of 23mL, and the centrifugal drying that is evaporated to.Desciccate is weighed and be dissolved among the DMSO.Then, utilize method 5 assay products, and product is screened.

Analyze LCMS method 1 (prepurification)

Post: Peeke Scientific ^HI-Q C-18,50 * 4.6mm can be by commercial sources from Redwood City, the Peeke Scientific of CA ^Obtain 5tm, eluent A: the water that has 0.05%TFA, eluent B: have the acetonitrile of 0.05%TFA, gradient: the linear gradient 3.0min of 0-100%B keeps 100%B 0.5min then, the linear gradient 0.25min of 100-0%B keeps 100%A 0.75min then; Flow velocity: 2.25mL/min, column temperature: 25 ℃, injection volume: the thick solution of 15 μ l, 286 μ M in methanol/DMSO/ water 90/5/5, UV detect: 260 and 210nm, mass spectrum: APCI, forward scan, mass scanning scope 111.6-1000amu.

Preparation LC method 3 (Gilson)

Post: Peeke Scientific ^HI-Q C18,50mm * 20mm, 5um, eluent A: have the water of 0.05%TFA, eluent B: have the acetonitrile of 0.05%TFA, preform injection balance: 0.50min, injection back keeps: 0.16min, gradient: from 0-100%B 2.55 minutes, then from 100%-0%0.09min; Flow velocity: 50.0mL/min, column temperature: room temperature, injection volume: the crude product mixture among the filtered DMSO of 1200 μ L, detect: the UV of 210nm or 260nm.

Analyze LCMS method 5 (back purification Post-purification)

Post: Peeke Scientific ^HI-Q C-18,50 * 4.6mm, 5 μ m, eluent A: have the water of 0.05%TFA, eluent B: have the acetonitrile of 0.05%TFA, gradient: the linear gradient 1.75min of 0-100%B keeps 100%B 0.35min, then 100-50%B 0.5min then; Flow velocity: 3.00mL/min, column temperature: 25 ℃, injection volume: the solution of 15 μ l, 300 μ M in methanol/DMSO 99/1, UV detects: 260rm, mass spectrum: APCI, forward scan, mass scanning scope 100-1000amu, ELSD: gain=9,40 ℃ of temperature, nitrogen pressure 3.5bar.

Method F

Embodiment 33:4 '-cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine

(32.00g, 115mmol) (13.70g, pyridine solution 127mmol) at room temperature stirs 18h with 2-amino-6-picoline with 4 '-cyano group-xenyl-4-sulfonic acid chloride.Solvent is removed, and residue is poured in the water (500mL).With ethyl acetate (4 * 200mL) extraction products.The organic extract that merges is also concentrated with the salt water washing.Obtain title compound (28.80g, 72%) by fast silica gel chromatogram at (40% in hexane ethyl acetate → ethyl acetate) purification on the silica gel.

Preparation 4 '-cyanobiphenyl base-4-sodium sulfonate

(Himmelsbach, F., Austel, V., Pieper, H., Eisert, W., Mueller, T., Weisenberger, J., Linz, G., Krueger, G. european patent application 1992, and EP 483667 A2 improve one's methods) under-14 ℃, with chlorosulfonic acid (116.5mL, 1.744mmol) (156.2g in the solution of dichloromethane 0.872mol) (3L), remains below reaction temperature-10 ℃ simultaneously to be added to 4-xenyl nitrile.Mixture at 1 hour internal heating to 10 ℃, and is kept 6h down at 8-10 ℃.Add triethylamine, keep temperature to be lower than 12 ℃ simultaneously.Mixture is stirred 15min up to all black/brown in color solid dissolvings and formation precipitation.Add entry (300mL), serosity is stirred 10min and concentrated.Add sodium hydroxide solution (2L, 15%), and concentrate up to distilling out at least one halfbody reactant mixture long-pending.The adding concentrated hydrochloric acid (～300mL) reach 7 up to pH, and final volume is adjusted to 2.2L by adding water.Add sodium chloride saturated solution (2.2L), and the gained mixture is stirred 10min.With solid filtering and in vacuum drying oven (80 ℃) drying obtain 251.0g white to yellow solid product.Product comprises a large amount of sodium chloride.

Preparation 4 '-cyanobiphenyl base-4-sulfonic acid chloride

(Himmelsbach, F., Austel, V., Pieper, H., Eisert, W., Mueller, T., Weisenberger, J., Linz, G., Krueger, G. european patent application 1992, and EP 483667 A2 improve one's methods) with the mixture backflow 16h of 4 '-cyanobiphenyl base-4-sodium sulfonate (251g) and phosphorus oxychloride.Reactant mixture is poured in a large amount of ice/water, and with the serosity of gained with dichloromethane (1 * 1.8L) extraction.With organic extract salt water washing, use dried over mgso, and be concentrated into about 200mL.Add hexane (200mL).Serosity is stirred 30min, filter, with dichloromethane/heptane wash of 1: 1, and drying obtained the 82.1g product.Mother solution concentrated and be further purified and obtain other 16.2g white solid by flash chromatography (40 → 70% dichloromethane/hexane) on silica gel. ¹HNMR(300MHz，CDCl ₃)：8.13-8.19(m，2H)，7.80-7.86(m，4H)，7.72-7.77(m，2H)。 ¹³C?NMR(75MHz，CDCl ₃)：146.2，144.2，143.0，133.2，128.7，128.4，128.0，118.5，113.1。

Form the another kind of universal method of sulfonamide

With sulfonic acid chloride (104 μ mol, 1.3equiv, the 0.26M anhydrous pyridine solution of 400 μ L) and 2-amino-6-picoline (80 μ mol, 1.0equiv, the 0.2M anhydrous pyridine solution of 400 μ L) be placed in the test tube (75 * 10mm is at 110 ℃ of following dry heat 16h) that has stirring rod.With test tube Parafilm ^Cover, and reactant mixture was at room temperature stirred 24 hours.Evaporating solvent is dissolved in residue among the EtOAc (1mL).After dissolving forms thin suspension fully or, add NaHCO ₃(0.5mL saturated aqueous solution).To respectively be separated with the stirring of reactant mixture whirlpool and by centrifugal.Organic layer is transferred in the new test tube (95 * 10mm), and with water with EtOAc (2 * 0.8mL) extractions.Organic facies is merged,, and residue is dissolved in DMSO (1.340mL) solvent evaporates.

Gneral analysis and purge process

Utilize method 2 to analyze crude product mixture by SFC.Before purification, all samples passes through Whatman ^GF/F Unifilter (#7700-7210) filters.Utilize method 4 to carry out the sample purification by SFC.Fraction is collected in the preweighted test tube of 23mL, and the centrifugal drying that is evaporated to.Desciccate is weighed and be dissolved among the DMSO.Then, utilize method 5 assay products, and product is screened.

Analyze SFC method 2 (prepurifications)

Post: Zymor Pegasus, 150 * 4.6mm i.d., 5 μ m, gradient: the CO of 5% methanol modification ₂Change to 50% Jia Chun @18%/min and keep 0.1min, flow velocity: 5.6mL/min, column temperature: 50 ℃, equipressure: 140bar, UV detects: 260nm.

Preparation SFC method 4

Post: Zymor Pegasus, 150 * 21.2mm i.d., 5 μ m, semi-preparative column, Lot2174, column temperature: 35 ℃, gradient: the CO of 5% methanol modification ₂Kept 0.1 minute, and change to 60% Jia Chun @10%/min and keep 1.0min again, flow velocity: 53mL/min, equipressure: 140bar, UV detects: 260nm.

Analyze LCMS method 5 (back purification (Post-purification))

Post: Peeke Scientific ^HI-Q C-18,50 * 4.6mm, 5 μ m, eluent A: have the water of 0.05%TFA, eluent B: have the acetonitrile of 0.05%TFA, gradient: the linear gradient 1.75min of 0-100%B keeps 100%B 0.35min, then 100-50%B 0.5min then; Flow velocity: 3.00mL/min, column temperature: 25 ℃, injection volume: methanol/DMSO 99/1 solution of 15 μ l, 300 μ M, UV detects: 260nm, mass spectrum: APCI, forward scan, mass scanning scope 100-1000amu, ELSD: gain=9,40 ℃ of temperature, nitrogen pressure 3.5bar.

Method G

Embodiment 110:4 '-cyano group-xenyl-4-sulfonic acid methyl-(6-methyl-pyridine-2-yl)-amine

Under R.T., (1.56mL 1.56mmol) is added to N, and (0.15g is in THF 1.24mmol) (5mL) solution for 6-lutidines-2-amine with NaHMDS.Behind 15min, with 4 '-(0.28g 1.03mmol) is added in the reactant mixture and stirred 1 hour cyanobiphenyl base-4-sulfonic acid chloride.Reactant mixture is diluted with ethyl acetate (30mL), and (2 * 30mL) wash with saturated sodium bicarbonate aqueous solution.With organic layer anhydrous sodium sulfate drying, the filtration and concentrated of collecting.The gained residue is obtained water white oil with radial chromatography (2mm silicon plate, 2: 1 hexane/ethyl acetate) purification.By being dissolved in the 5mL Anaesthetie Ether, and the HCl that drips in the 1N Anaesthetie Ether changes into HCl salt with product.Solid ground with other ether and under fine vacuum drying obtain product (0.11g, 29.5%).

Method H

Embodiment 111:4 '-cyano group-xenyl-4-sulfonic acid (6-isopropyl-pyridine-2-yl)-amine

Preparation N-(6-bromo-pyridine-2-yl)-2,2-dimethyl-propionic acid amide.

With 2,2-dimethyl propylene acyl chlorides (5.23mL, 42.48mmol) and diisopropyl ethyl amine (13.6mL 82.9mmol) is added to 6-bromopyridine-2-amine (7.0g, 60mL CH 40.5mmol) successively ₂Cl ₂In the ice-cold solution.With solution stirring 1h, and dilute with the 50mL Anaesthetie Ether.(2 * 50mL) wash with saturated sodium bicarbonate aqueous solution with mixture.With organic layer Na ₂SO ₄Dry, filtration and concentrated.Residue is dissolved in ethyl acetate (10mL) and the heptane (20mL), and makes it keep 3h.Product is filtered, obtain white solid title compound (9.56g, 93%) with 1: 1 heptane/ethyl acetate rinse and vacuum drying. ¹H?NMR(400MHz，CD ₃CN)，δ：8.22(d，J＝8.4Hz，1H)，7.99(bs，1H)，7.55(t，J＝8.1Hz，1H)，7.22(d，J＝7.3Hz，1h)，1.31(s，9H)；LCMS(ESI)：m/z：258.0。

Preparation N-(6-isopropyl-pyridine-2-yl)-2,2-dimethyl-propionic acid amide.

Under-78 ℃, (7.40g 38.8mmmol) is added to N-(6-bromopyridine-2-yl)-2, and (5.0g is in THF 19.4mmol) (100mL) solution for 2-dimethyl propylene amide with Cu (I).After 0.5 hour, under-78 ℃, drip isopropylmagnesium chloride (48.5mL is among the 1M THF), and described solution is heated to 25 ℃ and kept 2 hours.This reaction stops with saturated ammonia chloride water solution (50mL), and dilutes with ethyl acetate (100mL).Solids removed by filtration.With solution use successively saturated ammonia chloride water solution (2 * 50mL) and saturated sodium bicarbonate aqueous solution (2 * 50mL) washing.With organic layer Na ₂SO ₄Dry, filtration and concentrated.Obtain amber oily title compound (2.60g, 60.4%) by flash column chromatography (2: 1 hexane/ethyl acetate) purification. ¹H?NMR(400MHz，CD ₃CN)，δ：8.04(d，J＝7.8Hz，1H)，7.97(bs，1H)，7.63(t，J＝7.8Hz，1H)，6.90(d，J＝7.5Hz，1H)，2.95-2.88(m，1H)，1.34(s，9H)1.28(d，J＝7.1Hz，6H)；LCMS(ESI)：m/z：221.2。

Preparation 6-isopropyl-pyridine-2-base amine

(9N 10mL) is added to N-(6-isopropyl pyridine-2-yl)-2, and (2.0g is in dioxane 9.08mmol) (5mL) solution for 2-dimethyl propylene amide with HCl.Mixture was stirred 18 hours down at 80 ℃.After being cooled to 25 ℃, with NaOH with the pH regulator of reactant mixture to pH 9.Solution is diluted with ethyl acetate (120mL), and (2 * 30mL) wash with saturated sodium bicarbonate aqueous solution.Then, organic layer and toluene (10mL) azeotropic are obtained 6-isopropyl pyridine-2-base amine water white oil (0.68g, 55%). ¹H?NMR(400MHz，CD ₃CN)，δ：7.36(t，J＝7.8Hz，1H)，6.64(d，J＝8.7，1H)，6.32(d，J＝8.1Hz，1H)，1.25(d，J＝4.5Hz，9H)；LCMS(ESI)：m/z：137.2。

4 '-cyano group-xenyl-4-sulfonic acid (6-isopropyl-pyridine-2-yl)-amine

According to described 4 '-process of the preparation method of cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replace to 6-isopropyl-pyridine-2-base-amine, and do a little unessential changes.

Method 1

Embodiment 112:4 '-cyano group-xenyl-4-sulfonic acid (6-cyclopropyl-pyridine-2-yl)-amine

Preparation N-(6-cyclopropyl-pyridine-2-yl)-2,2-dimethyl-propionic acid amide.

With K ₃PO ₄(2.8g, 60.3mmo1) and water (1mL) be added to N-(6-bromopyridine-2-yl)-2,2-dimethyl propylene amide (4.20g, 16.3mmol), cyclopropylboronic acid (1.82g, 21.8mmol), Pd (OAc) ₂(0.18g, 0.82mmol) and PCy ₃(0.38g is in toluene 1.62mmol) (20mL) solution.Mixture is stirred 12h down at 95 ℃, be cooled to 25 ℃ then.With reactant mixture Et ₂O (30mL) dilutes, and washs with saturated sodium bicarbonate aqueous solution.With organic layer Na ₂SO ₄Drying, filtration and the concentrated water white oil that obtains.With residue flash column chromatography (5: 1 hexane/Et ₂O) purification obtains water white oil title compound (2.25g, 63.3%). ¹H?NMR(400MHz，CDCl ₃)，δ：7.98(d，J＝8.3，1H)，7.88(bs，1H)，7.53(t，J＝7.8Hz，1H)6.85(d，J＝7.5Hz，1H)，1.98-1.91(m，1H)，1.32(s，9H)，0.94(d，J＝6.6Hz，4H)：LCMS(ESI)：219.2。

Preparation 6-cyclopropyl-pyridine-2-base amine

Process according to the preparation method of described 6-isopropyl-pyridine-2-base-amine is prepared, but replaces to N-(6-cyclopropyl-pyridine-2-yl)-2,2-dimethyl-propionic acid amide., and do a little unessential changes. ¹H?NMR(400MHz，CDCl ₃)，δ：7.70(t，J＝7.8，1H)，6.85((t，J＝7.4，1H)，6.65(d，J＝7.5Hz，1H)，4.79(bs，2H)；LCMS(ESI)：m/z：135.2。

4 '-cyano group-xenyl-4-sulfonic acid (6-cyclopropyl-pyridine-2-yl)-amine

According to described 4 '-process of the preparation method of cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replace to 6-cyclopropyl-pyridine-2-base-amine, and do a little unessential changes.

Method J

Embodiment 113:4 '-cyano group-xenyl-4-sulfonic acid (6-amino-4-methyl-pyridine-2-yl)-amine

(287uL 1.65mmol), follows 4-(dimethylamino) pyridine (5mg with diisopropyl ethyl amine, 0.04mmol) adding 4-picoline-2,6-diamidogen (J.Org.Chem.2001,61,6513) (102mg is in THF 0.825mmol) (6mL) solution.CH with 4 '-cyanobiphenyl base-4-sulfonic acid chloride ₂Cl ₂(3mL) solution is added in the gained solution.Non-homogeneous mixture at room temperature stirred spend the night.To early morning, all solids dissolves, with solution for vacuum concentration.The gained residue is dissolved in MeOH/CH ₂Cl ₂In, and can be by commercial sources from DOW Companyof Midland, the DOWEX that Michigan USA obtains ^50WX2-400 ion exchange resin (2wt equiv) is added in this solution, and mixture was at room temperature stirred 1 hour.With the mixture filtration and with resin MeOH and CH ₂Cl ₂Washing.Then,, resin is separated by with the washing of 3.5N methanol ammonia, and with the mother solution vacuum concentration.MeOH is added in the residue, and solid filtering is obtained title compound (50mg, 25%).

Method K

Embodiment 114:3-chloro-N-[6-(2-hydroxyl-ethyl)-pyridine-2-yl]-2-methyl-benzsulfamide

With borine-tetrahydrofuran complex (0.924mL, 0.924mmol, 3.0equiv, 1.0M tetrahydrofuran solution) and be added to [6-(3-chloro-2-methyl-benzene sulfonamido)-pyridine-2-yl]-acetic acid (105mg, 0.308mmol, in the ice-cold solution of oxolane 1equiv).Behind 1h, reactant mixture is heated to 24 ℃ and keep 17.5h.Add aqueous hydrochloric acid solution (3mL, 5wt%), and with the solution vigorous stirring of gained.Behind 30min, add saturated sodium bicarbonate aqueous solution (8mL), and (3 * 15mL) extract with dichloromethane.With organic extract anhydrous sodium sulfate drying, the filtration and concentrated of collecting.Obtain product (45.5mg, 45%) with efficient flash chromatography (0 → 5% in dichloromethane methanol) purification.

Method L

Embodiment 115:5-chloro-3-methyl-benzo [b] thiophene-2-sulfonic acid [6-(2-hydroxyl-ethyl)-pyridine-2-yl]-amine

With lithium aluminium hydride reduction (0.015g, 0.310mmol, 1.3equiv) be added to [6-(5-chloro-3-methyl-benzo [b] thiophene-2-sulfoamido)-pyridine-2-yl]-ethyl acetate (0.100g, 0.235mmol is in the ice-cold solution of oxolane 1equiv) (4mL) in batches.Behind 5min, reactant mixture is heated to 24 ℃ and keep 16h.Reactant mixture is cooled to 0 ℃, and excessive lithium aluminium hydride reduction stops with saturated aqueous ammonium chloride (10mL).Gained solution is heated to 24 ℃ and stir other 30min.Reactant mixture is passed through Celite ^Stopper filter, with gained filtrate with dichloromethane (60mL) extraction.With organic extract anhydrous sodium sulfate drying, filtration and concentrated.Obtain product (0.0421g, 47%) with efficient flash chromatography (0 → 1% in dichloromethane methanol) purification.

Method M

Embodiment 118:2-(4-cyano group-phenyl)-4-methyl-thiazole-5-sulfonic acid (6-methyl-pyridine-2-yl)-amine

Preparation N-[4-methyl-5-(6-methyl-pyridine-2-base sulfamoyl)-thiazol-2-yl]-acetyl ammonia

According to described 4 '-process of the preparation method of cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replace to 2-acetylaminohydroxyphenylarsonic acid 4-methyl-5-thiazole sulfonic acid chloride, and do a little unessential changes. ¹H NMR (400MHz, CDCl ₃) δ: 7.56 (dd, J=8.7,7.2Hz, 1H), 7.10 (d, J=8.6Hz, 1H), 6.58 (d, J=7.3Hz, 1H), 2.53 (s, 3H), 2.47 (s, 3H), 2.24 (s, 3H); C ₁₂H ₁₅N ₄O ₃S ₂MS (ESI) m/z:327.0.

Preparation 2-amino-4-methyl-thiazole-5-sulfonic acid (6-methyl-pyridine-2-yl)-amine

With N-[4-methyl-5-(6-methyl-pyridine-2-base sulfamoyl)-thiazol-2-yl]-acetyl ammonia (2.15g, 6.58mmol, 1equiv) and aqueous hydrochloric acid solution (1.6mL, the backflow of ethanol 12M) (30mL) solution is spent the night.When being cooled to 24 ℃, with the reactant mixture vacuum (～25mmHg) concentrate.In gained solid water-soluble (10mL).Solution is neutralized up to pH=7 with saturated sodium bicarbonate aqueous solution.Collect the gained solid by filtering.The solid lyophilizing is obtained white solid (1.67g, 89%). ¹H NMR (400MHz, DMSO-d ₆) δ: 7.64 (t, J=8.0Hz, 1H), 7.44 (s, 2H), 6.93 (m, 1H), 6.70 (m, 1H), 2.32 (s, and 3H) 2.27 (s, 3H); C ₁₀H ₁₃N ₄O ₂S ₂MS (ESI) m/z:285.1.

Preparation 2-bromo-4-methyl-thiazole-5-sulfonic acid (6-methyl-pyridine-2-yl)-amine

At 65 ℃, with tert-butyl group nitrile (0.128mL, 1.08mmol, 1.5equiv) be added to 2-amino-4-methyl-thiazole-5-sulfonic acid (6-methyl-pyridine-2-yl)-amine (0.200g, 0.703mmol, 1equiv) and copper bromide (III) (0.098g, 0.68mmol is in acetonitrile 0.62equiv) (6mL) suspension.Reactant mixture becomes redness from green, and observes the gas generation.When stopping the gas generation after 10 minutes, reactant mixture is cooled to 24 ℃ also with ethyl acetate (60mL) dilution.(2 * 30mL) wash with saturated sodium-chloride water solution with the gained mixture.With organic facies anhydrous sodium sulfate drying, the filtration and concentrated of collecting.Obtain product (0.156g, 64%) by efficient flash chromatography (0 → 2% in dichloromethane methanol) purification. ¹H NMR (400MHz, CDCl ₃) δ: 7.61 (dd, J=8.8,7.1Hz, 1H), 7.00 (d, J=8.8Hz, 1H), 6.58 (d, J=7.3Hz, 1H), 2.65 (s, 3H), 2.49 (s, 3H); C ₁₀H ₁₁BrN ₃O ₂S ₂MS (ESI) m/z:349.9.

2-(4-cyano group-phenyl)-4-methyl-thiazole-5-sulfonic acid (6-methyl-pyridine-2-yl)-amine

With 2-bromo-4-methyl-thiazole-5-sulfonic acid (6-methyl-pyridine-2-yl)-amine (0.080g, 0.23mmol, 1equiv), 4-cyano-phenyl boric acid (0.034g, 0.23mmol, 1.0equiv) and cesium carbonate (0.225g, 0.690mmo1,3.00equiv) the solution nitrogen wash 15min in 2: 1 dimethoxy-ethane/water (1.5mL).Then, add dichloro [1,1 '-two (diphenylphosphine) ferrocene] Palladous chloride. (II) (0.008g, 0.009mmol, 0.04equiv), and with gained mixture other 15 minutes with nitrogen wash.With reactant mixture at 1h internal heating to 80 ℃.After being cooled to 24 ℃, gained solution is diluted with ethyl acetate (40mL), and (2 * 30mL) wash with saturated sodium-chloride water solution.With organic facies anhydrous sodium sulfate drying, the filtration and concentrated of collecting.Obtain title compound (62mg, 73%) by efficient flash chromatography (0 → 1% in dichloromethane methanol) purification.

Method N

Preparation 4-bromo-N-(6-methyl-pyridine-2-yl)-benzsulfamide

According to described 4 '-process of the preparation method of cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replace to the 4-bromobenzene sulfonyl chloride, and do a little unessential changes.1HNMR(400MHz，CDCl ₃)，δppm?7.61-7.68(m，2H)7.40-7.46(m，2H)7.36(dd，J＝8.6，7.3Hz，1H)6.77-6.83(d，J＝8.8Hz，1H)6.42(d，J＝7.1Hz，1H)2.28(s，3H)。

Preparation 4-bromo-2-methyl-N-(6-methyl-pyridine-2-yl)-benzsulfamide

According to described 4 '-process of the preparation method of cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, (can be but replace to 4-bromo-2-methylbenzene-1-sulfonic acid chloride by commercial sources from ASDI, Inc.of Newark, Delaware USA obtains), and do a little unessential changes.APCI ⁺342[M+H] ⁺100％。

Preparation 4-bromo-3-methyl-N-(6-methyl-pyridine-2-yl)-benzsulfamide

According to described 4 '-process of the preparation method of cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replace to 4-bromo-3-methylbenzene-1-sulfonic acid chloride (can derive from Lancaster), and do a little unessential changes.APCI ⁺342[M+H] ⁺100％。

The universal method of microwave-assisted Suzuki-Miyaura cross-coupling

This scheme discloses the process by the synthetic biaryl of Suzuki-miyama cross-coupling of 4-bromobenzene sulfonamide (reactant A) and aryl boric acid (reactant B).

Preferred condition:

In glove box, following each thing is added in the Personal Chemistry Microwave reaction tube of 2.0mL:

(1) triangle stirring rod,

(2) 4-bromobenzene sulfonamide (80 μ mol, 1.0equiv, 0.25M is in dry DMF for reactant A, 320 μ L),

(3) suitable aromatics boric acid (80 μ mol, 1.0equiv, 0.25M is in dry DMF for reactant B, 320 μ L),

(4) catalyst P d (PPh ₃) ₄(320 μ L, 4 μ mol, 0.05equiv, 0.0125M is in anhydrous THF) and

(5) K ₂CO ₃(100 μ L, 200 μ mol, 2.5equiv, 2M is in degassing deionized water).

(6) microwave tube is sealed with diaphragm cap.

Outside glove box, with reactant mixture at Personal Chemistry MicrowaveSynthesizer (SmithCreator ^TM) in 130 ℃ of following heating 15min (the energy control model is arranged at the high sample shelves that absorb).Remove diaphragm cap, and reactant mixture transferred to remove any solid residue in 13 * 100mm test tube simultaneously.The microwave test tube is washed and DMF is added in the test tube of gained with DMF (1mL).

Then, evaporating solvent (SpeedVac, vacuum, the medium heating, 16h), add EtOAc (1mL) and water (1.0mL), and mixture whirlpool stirring is at room temperature dissolved (note: some palladiums in the reactant mixture form a small amount of insoluble atrament) up to residue.Test tube is centrifugal up to phase-splitting (some black palladium materials are positioned on organic layer/water layer interface).Organic layer is transferred in the new test tube (13 * 100mm).With EtOAc (2 * 1mL) aqueous layer extracted, and extract is added in the test tube that has organic layer.With the organic facies that merges water (1mL) successively, saline (1mL) washing.Evaporating solvent, and residue is dissolved among the DMSO.Carry out purification by anti-phase preparation HPLC.

Gneral analysis and purge process

Utilize method 1 to analyze crude product mixture by HPLC.Before purification, all samples passes through Whatman ^GF/F Unifilter (#7700-7210) filters.Utilize method 3 to carry out the sample purification by reversed-phase HPLC.Fraction is collected in the preweighted test tube of 23mL, and the centrifugal drying that is evaporated to.Desciccate is weighed and be dissolved among the DMSO.Then, utilize method 5 assay products, and product is screened.

Analyze LCMS method 1 (prepurification)

Post: Peeke Scientific ^HI-Q C-18,50 * 4.6mm, eluent A: the water that has 0.05%TFA, eluent B: have the acetonitrile of 0.05%TFA, gradient: the linear gradient 3.0min of 0-100%B keeps 100%B 0.5min then, the linear gradient 0.25min of 100-0%B keeps 100%A 0.75min then; Flow velocity: 2.25mL/min, column temperature: 25 ℃, injection volume: the thick solution of 15 μ l, 286 μ M methanol/DMSO/ water 90/5/5, UV detect: 260 and 210nm, mass spectrum: APCI, forward scan, mass scanning scope 111.6-1000amu.

Preparation LC method 3 (Gilson)

Post: Peeke Scientific ^HI-Q C18,50mm * 20mm, 5 μ m, the aqueous solution of eluent A:0.05%TFA, the acetonitrile solution of eluent B:0.05%TFA, preform injection balance: 0.50min, injection back keeps: 0.16min, gradient: from 0-100%B 2.55 minutes, then from 100%-0%0.09min; Flow velocity: 50.0mL/min, column temperature: room temperature, injection volume: the crude product mixture among the filtered DMSO of 1200 μ L, detect: the UV of 210nm or 260nm.

Analyze LCMS method 5 (back purification Post-purification)

Post: Peeke Scientific ^HI-Q C-18,50 * 4.6mm, 5 μ m, eluent A: have the water of 0.05%TFA, eluent B: have the acetonitrile of 0.05%TFA, gradient: the linear gradient of 0-100%B is 1.75min, keep 100%B 0.35min then, then 100-50%B 0.5min; Flow velocity: 3.00mL/min, column temperature: 25 ℃, injection volume: methanol/DMSO 99/1 solution of the 300 μ M of 15 μ l, UV detects: 260nm, mass spectrum: APCI, forward scan, mass scanning scope 100-1000amu, ELSD: gain=9,40 ℃ of temperature, nitrogen pressure 3.5bar.

Method O

Embodiment 249:4 '-chloro-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine

With Na ₂CO ₃Aqueous solution (2.0M, 0.625mL, 1.25mmol), then with Pd (PPh ₃) ₄(28mg, (160mg, 0.489mmol) (76.5mg is in DMF 0.489mmol) (2mL) mixture with the 4-chlorophenylboronic acid 0.0245mmol) to add 4-bromo-N-(6-methyl-pyridine-2-yl)-benzsulfamide.The gained mixture is heated 15min down at 130 ℃ in microwave oven.With mixture cooling and between ethyl acetate and water, distribute.With organic layer dried over sodium sulfate, filtration and concentrated.With residue by silica gel chromatography (50%EtoAc/ hexane) purification to obtain yellow solid title compound (130mg, 74%).

Method P

Embodiment 259:N-(6-methyl-pyridine-2-yl)-4-pyridine-2-base-benzsulfamide

With 4-bromo-N-(6-methyl-pyridine-2-yl)-benzsulfamide (117mg, 0.358mmol), 2-pyridine radicals tributyl tin (197mg, 0.536mol) and Pd (PPh ₃) ₂Cl ₂(13mg, DMF 0.018mmol) (2mL) mixture heats 1h in microwave oven.Vacuum is removed DMF.Residue is obtained white solid title compound (42mg, 0.129mmol, 36%) by anti-phase preparation HPLC purification.

Method Q

Embodiment 262:4 '-(6-methyl-pyridine-2-base sulfamoyl)-xenyl-4-carboxylic acid amine

4N NaOH (0.2mL) is added to 4 '-cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine (144mg, 30%H 0.286mmol) ₂O ₂(1mL) and in EtOH (1mL) solution.This mixture becomes clarification.Behind 12h, this mixture is at EtOAc and H ₂Distribute between the O.With organic layer salt water washing, with dried over sodium sulfate and concentrated.Residue is gone up chromatographic isolation at silica gel (60%EtOAc/ hexane) obtain the white solid title compound.

Method R

Embodiment 263:4 '-(2-amino-ethyoxyl)-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine

With DEAD (72 μ L, 0.454mmol) be added to 4-hydroxyl-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine (129mg, 0.378mmol), N-hydroxyethyl phthalic amide (80mg, 0.416mmol), (119mg is in THF 0.454mmol) (3mL) yellow solution for triphenylphosphine.After stirring is spent the night, mixture is concentrated.Residue is gone up chromatographic isolation at silica gel (40-70%EtOAc/ hexane) obtain ether intermediate (152mg, 79%).(74 μ L, (152mg is in MeOH 0.3mmol) (3ml) solution 1.5mmol) to be added to above ether intermediate with hydrazine.Mixture is at room temperature stirred 2h, and the concentrated residue that obtains.This residue is obtained white solid end product (60mg, 52%) by preparation HPLC purification.

Method S

Embodiment 264:N-(6-methyl-pyridine-2-yl)-4-oxazole-5-base-benzsulfamide

Preparation 4-formyl-N-(6-methyl-pyridine-2-yl)-benzsulfamide

According to described 4 '-process of the preparation method of cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replaces to 4-formyl benzene sulfonyl chloride.

N-(6-methyl-pyridine-2-yl)-4-oxazole-5-base-benzsulfamide

With the sulfonamide of step 1 (449mg, 1.63mmol), TsCH ₂NC (349mg, 1.79mmol) and K ₂CO ₃(450mg, MeOH 3.25mmol) (5mL) solution backflow 12h.Mixture is cooled to R.T. and between EtOAc and water, distributes.With organic layer with dried over sodium sulfate and concentrate and to obtain residue.This residue is obtained white solid title compound (301mg, productive rate 58%) by flash chromatography (60%EtOAc/ hexane) purification. ¹H?NMR(400MHz，CDCl ₃)，δ：8.21(s，1H)，7.90(d，J＝8.3Hz，1H)，7.62(d，J＝8.3Hz，1H)7.56(s，1H)7.54(m，1H)7.04(m，1H)，6.56(m，1H)，2.30)s，3H)。Analytical calculation C ₁₅H ₁₃N ₃O ₃S:C, 57.13; H, 4.16; N, 13.33; Test result: C, 57.31; H, 4.22; N, 12.92.

Method T

Embodiment 265:4 '-cyano group-xenyl-4-sulfonic acid (2-dimethylamino-ethyl)-(6-methyl-pyridine-2-yl)-amine

Under 24 ℃, with 2-(dimethylamino) ethyl chloride hydrochloride (70mg, 0.49mmol, 1.8equiv) be added to 4 '-cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine (93.1mg, 0.266mmol, 1equiv), (184mg, 1.33mmol is in dimethyl formamide 5.00equiv) (2.5mL) solution for potassium carbonate.Solution heterogeneous is heated to 50 ℃ and kept 22 hours.When being cooled to 24 ℃, reactant mixture vacuum (＜1mm Hg) is concentrated.The gained residue is diluted with saturated sodium-chloride water solution (5mL), saturated sodium bicarbonate aqueous solution (5mL) and ethyl acetate (5mL).Separate organic facies, and (2 * 5mL) extract with ethyl acetate with obtained aqueous solution.With organic facies anhydrous sodium sulfate drying, the filtration and concentrated of collecting.Obtain alkylate by efficient flash chromatography (0 → 5% ethanol/methylene+0.1% ammonium hydroxide) purification, this product is handled being converted into hydrochloride salt (96.6mg, 76%) by the methanol hydrogen chloride solution.

Method U

Embodiment 266:4 '-cyano group-xenyl-4-sulfonic acid (2-hydroxyl-ethyl)-(6-methyl-pyridine-2-yl)-amine

Preparation 4 '-cyano group-xenyl-4-sulfonic acid [2-(tert-butyl-dimethyl-siloxy)-ethyl]-(6-methyl-pyridine-2-yl)-amine

Under 24 ℃, with (2-bromine oxethyl)-tert-butyl group dimethylsilane (91 μ L, 0.42mmol, 1.5equiv) be added to 4 '-cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine (99.1mg, 0.284mmol, 1equiv) and potassium carbonate (202mg, 1.46mmol is in the solution of dimethyl formamide 5.2equiv) (2.5mL).Reactant mixture is kept down 4.7h at 24 ℃, then be heated to 70 ℃ and keep 15.7h.With reactant mixture be cooled to 24 ℃ and vacuum (＜1mmHg) concentrate.The gained residue is diluted with ethyl acetate (5mL), saturated sodium-chloride water solution (3mL) and saturated sodium bicarbonate aqueous solution (3mL).Separate organic facies, and (2 * 5mL) extract with ethyl acetate with obtained aqueous solution.With organic extract liquid anhydrous sodium sulfate drying, the filtration and concentrated of collecting.Obtain product (85.3mg, 59%) by efficient flash chromatography (12 → 50% in hexane ethyl acetate) purification. ¹H?NMR(400MHz，CDCl ₃)，δ：7.57-7.83(m，9H)，7.40(d，J＝8.1Hz，1H)，6.99(d，J＝7.6Hz，1H)，4.00(t，J＝6.2Hz，2H)，3.78(t，J＝6.2Hz，2H)，2.41(s，3H)，0.78(s，9H)，-0.03(s，6H)。

4 '-cyano group-xenyl-4-sulfonic acid (2-hydroxyl-ethyl)-(6-methyl-pyridine-2-yl)-amine

With tetrabutylammonium (371mL, 0.371mmol, 2.0equiv, 1.0M in the oxolane) be added drop-wise to 4 '-cyano group-xenyl-4-sulfonic acid [2-(tert-butyl-dimethyl-siloxanes)-ethyl]-(6-methyl-pyridine-2-yl)-amine (85.3mg, 0.186mmol, in the ice-cold solution of oxolane 1equiv) (3mL).Behind 50min, saturated sodium-chloride water solution is added in the reactant mixture, and (3 * 5mL) extract with ethyl acetate with gained solution.With organic extract anhydrous sodium sulfate drying, the filtration and concentrated of collecting.Obtain product by efficient flash chromatography (ethyl acetate → ethyl acetate in 13% hexane) purification, this product is handled being converted into hydrochloride salt (58mg, 76%) by the methanol hydrogen chloride solution.

Method V

Embodiment 267:6-(4-cyano group-phenyl)-pyridine-3-sulphonic acid (6-methyl-pyridine-2-yl)-amine

Preparation 6-chloro-pyridine-3-sulphonic acid (6-methyl-pyridine-2-yl)-amine

According to described 4 '-process of the preparation method of cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replaces to 6-chloro-3-pyridine radicals sulfonic acid chloride (Naegeli, C.; Kundig, W.; Brandenburger, H.Helv.Chem.Acta.1939,21, (1746)), and do a little unessential changes.APCI ⁺284[M+H] ⁺100％。

6-(4-cyano group-phenyl)-pyridine-3-sulphonic acid (6-methyl-pyridine-2-yl)-amine

With 6-chloro-pyridine-3-sulphonic acid (6-methyl-pyridine-2-yl)-amine (188mg, 0.573mmol), 4-cyano group boric acid (88mg, 0.602mmol), Pd (PPh ₃) ₄(33mg, 0.03mmol), moisture Na ₂CO ₃(0.72mL, DMF 1.43mmol) (3mL) solution heats 30min under microwave.Black mixture is distributed between EtOAc and water.Then, with organic layer salt water washing, Na ₂SO ₄Dry also concentrating obtains oil, and this oil chromatographic isolation on silica gel obtains the title compound (86.3mg, 43%) of yellow solid shape.

Method W

Embodiment 269:N-(6-picoline-2-yl)-6-piperidines-1-yl pyridines-3-sulfonamide

With 6-chloro-pyridine-3-sulphonic acid (6-methyl-pyridine-2-yl)-amine (233mg, 0.823mmol) and the mixture of the dioxane (5mL) of piperidines (4.17mmol) 100 ℃ of following heating 30min in PersonalChemistry Microwave baking oven.With mixture cooling and between EtOAc and water, distribute.With organic layer dried over sodium sulfate, filtration and concentrated.Obtain the title compound (177mg, 65%) of brown solid shape by flash column chromatography (50-70%EtOAc/ hexane) purification.

Method X

Embodiment 270:4 '-cyano group-3 '-methoxyl group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine

Preparation N-(6-methyl-pyridine-2-yl)-4-(4,4,5,5-tetramethyl-[1,3,2] two oxa-bora rings, penta-2-yl)-benzsulfamide

With 4-bromo-N-(6-methyl-pyridine-2-yl)-benzsulfamide (13.7g, 41.9mmol), pinacol two boron (bis (pinacolato) diboron) (10.7g, 41.9mmol), KOAc (14g, 143mmol) and Pd (dppf) Cl ₂(1.7g, 2.1mmol) mixture in DMSO (100mL) heated 2 hours down at 100 ℃.Mixture is cooled to room temperature, between EtOAc and water, distributes, and pass through Celite ^Filter.Organic layer is dry and concentrated.Obtain solid borate (15.5g, 98%) by flash column chromatography (50%EtOAc/ hexane) purification.

4 '-cyano group-3 '-methoxyl group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine

Process according to the preparation method of described 4 ' chlorodiphenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replace to N-(6-methyl-pyridine-2-yl)-4-(4,4,5,5-tetramethyl-[1,3,2] two oxa-bora rings, penta-2-yl)-benzsulfamide and 4-bromo-2-methoxybenzene cyanogen, and do a little unessential changes.

Method Y

Embodiment 276:4 '-cyano group-3-methoxyl group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine

Preparation 4-bromo-2-methoxyl group-N-(6-methyl-pyridine-2-yl)-benzsulfamide

Under 0 ℃, with ClSO ₃(3.3mL 48mmol) is added to 1-bromo-3-methoxybenzene (3.1g, CH 16.6mmol) to H ₂Cl ₂In the solution.With mixture heated to R.T. and stir 2h.Mixture is poured in the frozen water, and used CH ₂Cl ₂(3 * 30mL) extractions.With organic layer Na ₂SO ₄Dry, filter and concentrate and obtain sulfonic acid chloride mixture oil, this mixture does not need purification and is used for next step reaction.

Above sulfonic acid chloride is dissolved in the pyridine (50mL), and adding 2-methyl-6-aminopyridine (1.7g, 16mmol).Mixture stirred under R.T. spend the night.Mixture is distributed between EtOAc and water.With the dry and concentrated sulfonamide mixture (with LCMS 3 to 1) that obtains of organic layer.Residue is obtained the isomer (0.87g, two steps 15%) of desirable white solid by the flash column chromatography purification.

4 '-cyano group-3-methoxyl group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine

According to described 4 '-process of the preparation method of chlorodiphenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replace to 4-bromo-2-methoxyl group-N-(6-methyl-pyridine-2-yl)-benzsulfamide and 4-cyano-phenyl boric acid, and do a little unessential changes.

Method Z

Embodiment 277:4 '-cyano group-3-methyl-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine

Will [2-[(D-κ N) methyl] phenyl-κ C] (tricyclohexyl phosphine) (trifluoroacetic acid-κ O-(SP-4-3)-palladium (Bedford, R.B.; Cazin, C.S.J.; Coles, S.J.; Gelbrich, T.; Horton, P.N.; Hursthouse, M.B.; Light, M.E.Organometallics 2003,22,987) (2mg, 0.5mol%) be added to 4-bromo-2-methyl-N-(6-methyl-pyridine-2-yl)-benzsulfamide (200mg, 0.6mmol), 4-cyano-phenyl boric acid (102mg, 0.7mmol) and cesium carbonate (585mg is 1.8mmol) in the mixture of 1-4-dioxane (6mL).Mixture heated was refluxed 4 hours.After during this period of time, with the reactant mixture cool to room temperature, by a Celite ^Filter and vacuum concentration.Residue is passed through flash column chromatography (SiO ₂2g, dichloromethane, methanol 0%﹠amp; 1%) purification obtains desirable white solid product (19mg, 0.05mmol, productive rate 9%).

Method AA

Embodiment 282:4 '-cyano group-3 '-methyl-xenyl-4-sulfonic acid (6-amino-pyridine-2-yl)-amine

Preparation 2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2] two oxa-bora rings, penta-2-yl)-benzonitrile

According to described N-(6-methyl-pyridine-2-yl)-4-(4,4,5,5-tetramethyl-[1,3,2] two oxa-bora rings, penta-2-yl)-process of the preparation method of benzsulfamide is prepared, but replace to 4-bromo-2-methylbenzene cyanogen, and do a little unessential changes. ¹H?NMR(400MHz，CDCl ₃)，δppm7.63(s，1H)7.56(d，J＝7.6Hz，1H)7.45(d，J＝7.6Hz，1H)2.42(s，3H)1.24(s，12H)。

4 '-cyano group-3 '-methyl-xenyl-4-sulfonic acid (6-amino-pyridine-2-yl)-amine

According to described 4 '-process of the preparation method of chlorodiphenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replace to 2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2] two oxa-bora rings, penta-2-yl)-benzene cyanogen and N-(6-amino-pyridine-2-yl)-benzsulfamide, and do a little unessential changes.

Method AB

Embodiment 283:4 '-cyano group-3-fluoro-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine

Preparation 4-bromo-2-fluoro-N-(6-methyl-pyridine-2-yl)-benzsulfamide

According to described 4 '-process of the preparation method of cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replace to 4-bromo-2-fluorobenzene sulfonic acid chloride, and do a little unessential changes.Crude product is used in next step.

4 '-cyano group-3-fluoro-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine

According to described 4 '-process of the preparation method of chlorodiphenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replace to 4-bromo-2-fluoro-N-(6-methyl-pyridine-2-yl)-benzsulfamide and 4-cyano-phenyl boric acid, and do a little unessential changes.

Method AC

Embodiment 284:4 '-cyano group-2-fluoro-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine

Preparation 4-bromo-3-fluoro-N-(6-methyl-pyridine-2-yl)-benzsulfamide

According to described 4 '-process of the preparation method of cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replace to 4-bromo-3-(trifluoromethyl) benzene sulfonyl chloride, and do a little unessential changes.Crude product is used in next step.

4 '-cyano group-2-fluoro-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine

According to described 4 '-process of the preparation method of chlorodiphenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replace to 4-bromo-3-fluoro-N-(6-methyl-pyridine-2-yl)-benzsulfamide and 4-cyano-phenyl boric acid, and do a little unessential changes.

Method AD

Embodiment 285:4 '-cyano group-2-trifluoromethyl-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine

Preparation 4-bromo-N-(6-methyl-pyridine-2-yl)-3-trifluoromethyl-benzsulfamide

According to described 4 '-process of the preparation method of cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replace to 4-bromo-3-(trifluoromethyl) benzene sulfonyl chloride, and do a little unessential changes.Crude product is used in next step.

4 '-cyano group-2-trifluoromethyl-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine

According to described 4 '-process of the preparation method of chlorodiphenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replace to 4-bromo-N-(6-methyl-pyridine-2-yl)-3-trifluoromethyl-benzsulfamide and 4-cyano-phenyl boric acid, and do a little unessential changes.

Method AE

Embodiment 286:4 '-cyano-3-hydroxy-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine

Under 0 ℃, with BBr ₃(0.2mL, 1.0M CH ₂Cl ₂In) be added to 4 '-cyano group-3-methoxyl group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine (28mg, CH 0.073mmol) ₂Cl ₂(2mL) in the solution.With mixture heated to 23 ℃ and stir 1h.Then, mixture is used saturated NaHCO ₃Stop and extract with EtOAc.With the organic layer dried over sodium sulfate, and concentrate and to obtain residue, this residue is obtained white solid title compound (17mg, productive rate 65%) by the flash column chromatography purification.

Method AF

Embodiment 287:4-pyridine-2-base-N-quinoline-2-base-benzsulfamide

Preparation 4-bromo-N-quinoline-2-base benzsulfamide

According to described 4 '-process of the preparation method of cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replace to 6-bromophenyl sulfonic acid chloride and 2-quinolin-2-ylamine, and do a little unessential changes.1H?NMR(400MHz，DMSO-d6)，δppm?7.37(t，J＝7.58Hz，1H)7.44-7.51(m，1H)7.56(d，J＝8.34Hz，1H)7.64-7.70(m，1H)7.70-7.74(m，2H)7.81(d，J＝8.59Hz，3H)8.23(d，J＝9.60Hz，1H)；APCI?MS：m/z?365.0(M+2)。

4-pyridine-2-base-N-quinoline-2-base-benzsulfamide

2-bromopyridine (22mg), tetrakis triphenylphosphine palladium (16mg), hexa methyl ditin (50mg) are added to 1 of 4-bromo-N-quinoline-2-base benzsulfamide (50mg), in the solution of 4-dioxane (2.0mL).With the gained mixture in microwave at 130 ℃ down behind the heating 30min, this mixture is filtered and under reduced pressure concentrates.With 1,4-dioxane (2.0mL), 2-bromopyridine (30mg), tetrakis triphenylphosphine palladium (20mg), hexa methyl ditin (50mg) are added in the gained residue.With the gained mixture in microwave at 130 ℃ down behind the heating 90min, this mixture is filtered and under reduced pressure concentrates.Residue is utilized anti-phase Kromasil ^C18 (0.05%TFA is in water and in acetonitrile) purification obtains title product (5.4mg).

Method AG

Embodiment 290:6-(4-cyano group-phenyl)-pyridine-3-sulphonic acid quinoline-2-base amine

Preparation 6-chloro-N-quinoline-2-yl pyridines-3-sulfonamide

According to described 4 '-process of the preparation method of cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replaces to 2-quinolin-2-ylamine and 2-chloro-pyridine-5-sulfonic acid chloride (Naegeli, C.; Kundig, W.; Brandenburger, H.Helv.Chem.Acta.1939,21,1746), and do a little unessential changes.

6-(4-cyano group-phenyl)-pyridine-3-sulphonic acid quinoline-2-base amine

With DME (1.5mL), N,N-dimethylacetamide (2.0mL), H ₂O (0.5mL), Cs ₂CO ₃(451mg 1.39mmol) is added to and contains 6-chloro-N-quinoline-2-yl pyridines-3-sulfonamide (148mg, 0.46mmol) (136mg is in reaction bulb 0.92mmol) with 4-cyano-phenyl boric acid.Reactant mixture is carried out degasification by alternative vacuum and nitrogen.After adding [1,1-two (diphenylphosphine)-ferrocene] dichloro palladium (II)-dichloromethane complex (16mg), with reactant mixture degasification once more.With reactant mixture 80 ℃ of down heating after 19 hours, reactant mixture filtered and with EtOAc (30mL), saturated NaHCO ₃(5mL) dilution.The gained mixture at room temperature stirred 5 minutes, filtered and use saturated NaHCO then ₃(5mL) dilution.Layering.(2 * 15mL) extract with EtOAc with water layer.With the organic extract K that merges ₂CO ₃Drying, filtration and the concentrated solid that obtains.Using CH ₂C1 ₂After grinding the gained solid, obtain desirable product (59.7mg).The efficient flash chromatography of mother solution utilization (0 → 30% dichloromethane is in acetone) purification is obtained extra desirable product (33.3mg).

Method AH

Embodiment 293:6-(4-cyano group-phenyl)-pyridine-3-sulphonic acid (6-cyclopropyl-pyridine-2-yl)-amine

Preparation 6-chloro-pyridine-3-sulphonic acid (6-cyclopropyl-pyridine-2-yl)-amine

According to described 4 '-process of the preparation method of cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replaces to 6-cyclopropyl-pyridine-2-base amine and 6-chloro-3-pyridine radicals sulfonic acid chloride (Naegeli, C.; Kundig, W.; Brandenburger, H.Helv.Chem.Acta.1939,21,1746), and do a little unessential changes. ¹H?NMR(400MHz，CDCl ₃)，δ：8.91(d，J＝2.5Hz，1H)，8.18(dd，J＝8.4，2.5Hz，1H)，7.53(t，J＝7.5Hz，1H)，7.43(d，J＝8.3Hz，(d，J＝8.6Hz，1H)，6.55(d，J＝7.3Hz，1H)，6.27(d，J＝8.1Hz，1H)，1.98-1.92(m，1H)，1.14-1.09(m，2H)0.93-0.89(m，2H)；LCMS(ESI)：310.1.

6-(4-cyano group-phenyl)-pyridine-3-sulphonic acid (6-cyclopropyl-pyridine-2-yl)-amine

According to described 4 '-process of the preparation method of chlorodiphenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replace to 6-chloro-pyridine-3-sulphonic acid (6-cyclopropyl-pyridine-2-yl)-amine and 4-cyano-phenyl boric acid, and do a little unessential changes.

Method AI

Embodiment 295:5-cyano group-3-methyl-benzo [b] thiophene-2-sulfonic acid (6-methyl-pyridine-2-yl)-amine

Preparation 5-bromo-3-methyl-benzo [b] thiophene-2-sulfonic acid (6-methyl-pyridine-2-yl)-amine

According to described 4 '-process of the preparation method of cyano group-xenyl-4-sulfonic acid (6-methyl-pyridine-2-yl)-amine is prepared, but replace to 5-bromo-3-methyl-benzo [b] thiophene-2-sulfonic acid chloride, and do a little unessential changes. ¹H NMR (400MHz, CDCl ₃), δ: 7.88 (d, J=1.8Hz, 1H), 7.62 (d, J=8.6Hz, 1H), 7.47-7.58 (m, 2H), 7.11 (d, J=9.1Hz, 1H), 6.54 (d, J=7.3Hz, 1H), 2.68 (s, 3H), 2.51 (s, 3H); C ₁₅H ₁₄BrN ₂O ₂S ₂MS (ESI) m/z:398.0.

5-cyano group-3-methyl-benzo [b] thiophene-2-sulfonic acid (6-methyl-pyridine-2-yl)-amine

Under 24 ℃, ((126mg, 0.317mmol is in dimethyl formamide 1equiv) (2.5mL) solution 1.5equiv) to be added to 5-bromo-3-methyl-benzo [b] thiophene-2-sulfonic acid (6-methyl-pyridine-2-yl)-amine for 43mg, 0.476mmol with copper cyanider (I).With solution by microwave heating to 250 ℃ and kept 10 minutes.Add deionized water (5mL), hexane (2.5mL) and Anaesthetie Ether (2.5mL), and the dark brown solid by filtration of gained is collected.By preparation reversed-phase HPLC (Kromasil ^C18,10 μ m, 250 * 50.8mm, mobile phase: water/acetonitrile/0.05% trifluoroacetic acid) the purification solid obtains title compound (30mg, 27.5%).

Method AJ

Embodiment 296: pyrrolidine-2-carboxylic acid [6-(3-chloro-2-methyl-benzene sulfonamido)-pyridine-2-yl]-amine

With (6-amino-pyridine-2-yl)-3-chloro-2-methyl-benzsulfamide (140mg, 0.47mmol), pyrrolidine-1,2-dicarboxylic acids uncle 1--butyl ester (106mg, 0.50mmol), HATU (215mg, 0.57mmol) and Et ₃The mixture of N (0.2mL) in DMF (3mL) stirs 12h down at 23 ℃.Mixture is distributed between EtOAc and water.With the dry and concentrated crude amide oil that obtains of organic layer, this crude amide oil directly is used in next reaction.Amide is dissolved in CH ₂Cl ₂(2mL), and add HCl (4ml; 4N is in dioxane).Mixture is stirred 12h down at 23 ℃.Mixture is concentrated, and residue is obtained white solid title compound (99mg, 53%) by the reversed-phase HPLC purification.

Method AK

Embodiment 297:3-pyridin-4-yl-pyrrole is alkane-1-sulfonic acid (6-methyl-pyridine-2-yl)-amine slightly

Preparation N-(6-picoline-2-yl)-2-oxo-1,3-oxazolidine-3-sulfonamide

(0.27mL 4.1mmol) is dissolved in 40mL CH with chloro sulfonyl isocyanate ₂Cl ₂In, and be cooled to 0 ℃.(0.27mL 4.1mmol) and with reactant mixture stirs 1.5h down at 0 ℃ slowly to add 2-chloroethyl alcohol.With 6-methyl-2-aminopyridine (444mg, 4.1mmol) and Et3N (1.3ml, CH 12.4mmol) ₂Cl ₂(50mL) solution makes reaction temperature be no more than 5 ℃ slow the adding.Reaction solution slowly is heated to room temperature, and stirs and spend the night.After acidify, crude product is passed through to adopt CH ₂Cl ₂Grind purification with hexane. ¹H?NMR(400MHz，CDCl ₃)δ：12.34(s，1H)7.62(dd，J＝8.8，7.3Hz，1H)6.77(d，J＝8.8Hz，1H)6.57(d，J＝7.1Hz，1H)4.39(t，J＝8.0Hz，2H)4.15(t，J＝7.8Hz，2H)2.50(s，3H)。

3-pyridin-4-yl-pyrrolidine-1-sulfonic acid (6-methyl-pyridine-2-yl)-amine

With N-(6-picoline-2-yl)-2-oxo-1,3-oxazolidine-3-sulfonamide (0.23g, 0.894mmol), 4-pyrrolidine-3-yl pyridines (0.40g, 2.23mmol) and acetonitrile (1mL) the soln using microwave heating of diisopropyl ethyl amine (1mL) be heated to 130 ℃ and kept 0.5 hour.Reactant mixture is cooled to 25 ℃, and dilutes with ethyl acetate (50mL).With the mixture of gained with saturated aqueous ammonium chloride (2 * 30mL) and saturated sodium bicarbonate aqueous solution (2 * 30mL) wash.With the concentrated water white oil that obtains of organic layer.Residue is utilized radial chromatography (2mm silicon plate; 1: 1: 0.1 dichloromethane/ethyl acetate/methanol) purification.Grinding also with other Anaesthetie Ether product, vacuum drying obtains title compound (0.19g, 65.4%).Also can be without microwave, spend the night and also can form sulfonamide but reactant mixture is heated to 82 ℃ (in acetonitriles) or is heated to 110 ℃ (in dimethyl formamides).

Method AL

Embodiment 317:4-(4-cyano group-phenyl)-piperidines-1-sulfonic acid (6-amino-pyridine-2-yl)-amine

Preparation (6-{[(2-oxo-1,3-oxazolidine-3-yl) sulfonyl] amino } pyridine-2-yl) t-butyl carbamate

According to described N-(6-picoline-2-yl)-2-oxo-1, the process of the preparation method of 3-oxazolidine-3-sulfonamide is prepared, but replaces to (6-amino-2-yl) t-butyl carbamate, and does a little unessential changes. ¹H?NMR(400MHz，CD ₂Cl ₂)，δ：1.50(s，9H)4.05-4.11(m，2H)4.24-4.30(m，2H)6.64(d，J＝7.83Hz，1H)7.32(d，J＝8.08Hz，1H)7.50(t，J＝8.08Hz，1H)。

4-(4-cyano group-phenyl)-piperidines-1-sulfonic acid (6-amino-pyridine-2-yl)-amine

With (6-{[(2-oxo-1; 3-oxazolidine-3-yl) sulfonyl] amino } pyridine-2-yl) t-butyl carbamate (150mg; 0.420mmol), diisopropyl ethyl amine (219 μ L; 1.26mmol) and 4-(4-cyano-phenyl) piperidines (82mg, solution 0.44mmol) under microwave at 110 ℃ of following heating 30min.Reactant mixture is concentrated, and with the purification by flash chromatography of crude product by employing hexane/ethyl acetate (0-25%) eluting.TFA (1mL) is added to the CH of gained material ₂Cl ₂(1mL) in the cooling solution (0-5 ℃).After 2 hours, reactant mixture is concentrated, and with residue at EtOAc (50mL) and saturated NaHC0 ₃Distribute (10mL).Organic layer separated and with saline (10mL) washing, drying (MgSO ₄), filter and vacuum concentration.Crude product is passed through to adopt CH ₂Cl ₂The purification by flash chromatography of/MeOH (0-5%) eluting obtains title compound (30mg, 20%).

Following table 1 has further described structural formula, title, physics and biological experimental data and method.

Table 1

Below described various embodiments of the present invention, but those skilled in the art recognize that further small change falls within the scope of the invention.Range of the present invention and scope should not be limited to the embodiment of above-mentioned example, only should limit according to following claim and their equivalent.

Claims

(according to the modification of the 19th of treaty)

[international office receives that on May 13rd, 2005 former claim 1-15 is replaced by new claim 1-19]

1. the chemical compound of formula (I)

Or its pharmaceutically acceptable salt or solvate,

Wherein:

R ¹Be (C ₁-C ₆) alkyl ,-(CR ⁷R ⁸) _t(C ₃-C ₁₀) cycloalkyl ,-(CR ⁷R ⁸) _t(C ₆-C ₁₀) aryl or-(CR ⁷R ⁸) _t(4-10) first heterocyclic radical;

B and k independently are 1 or 2 separately;

N and i independently are 0,1 or 2 separately;

T, u, p, q and v independently are 0,1,2,3,4 or 5 separately;

T is (6-10) the first heterocyclic radical that comprises at least one nitrogen-atoms;

W be selected from by (C ₁-C ₆) alkyl and 5 yuan of groups that heterocyclic radical is formed;

R ², R ³And R ⁴Independently be H, (C ₁-C ₆) alkyl ,-(CR ⁷R ⁸) _t(C ₃-C ₁₀) cycloalkyl ,-(CR ⁷R ⁸) _t(C ₆-C ₁₀) aryl or-(CR ⁷R ⁸) _t(4-10) first heterocyclic radical;

R ²And R ³Randomly form (4-10) first heterocyclic radical with the nitrogen that links to each other with them;

R ⁵And R ⁶Independently be H, (C ₁-C ₆) alkyl ,-(CR ⁷R ⁸) _t(C ₃-C ₁₀) cycloalkyl ,-(CR ⁷R ⁸) _t(C ₆-C ₁₀) aryl or-(CR ⁷R ⁸) _t(4-10) group of first heterocyclic radical composition;

Or R ⁵And R ⁶Randomly form (C with the carbon that links to each other with them ₃-C ₆) cycloalkyl or (3-7) first heterocyclic radical;

R ⁷And R ⁸Independently be H or (C ₁-C ₆) alkyl;

T, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸With the carbon atom of 5 yuan of heterocyclic radicals of described W randomly by 1-5 R ⁹Base replaces;

Each R ⁹Base be independently selected from by halogen, cyano group, nitro ,-CF ₃,-CHF ₂,-CH ₂F, trifluoromethoxy, azido, hydroxyl, (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl group ,-(C=O)-R ¹⁰,-(C=O)-O-R ¹¹,-O-(C=O)-R ¹¹,-NR ¹¹(C=O)-R ¹²,-(C=O)-NR ¹¹R ¹²,-NR ¹¹R ¹²,-NR ¹¹OR ¹²,-S (O) _kNR ¹¹R ¹²,-S (O) _i(C ₁-C ₆) alkyl ,-O-SO ₂-R ¹⁰,-NR ¹¹-S (O) _k-R ¹²,-(CR ¹³R ¹⁴) _v(C ₆-C ₁₀Aryl) ,-(CR ¹³R ¹⁴) _v(4-10) first heterocyclic radical ,-(CR ¹³R ¹⁴) _q(C=O) (CR ¹³R ¹⁴) _v(C ₆-C ₁₀) aryl ,-(CR ¹³R ¹⁴) _q(C=O) (CR ¹³R ¹⁴) _v(4-10) first heterocyclic radical ,-(CR ¹³R ¹⁴) _vO (CR ¹³R ¹⁴) _q(C ₆-C ₁₀) aryl ,-(CR ¹³R ¹⁴) _vO (CR ¹³R ¹⁴) _q(4-10) first heterocyclic radical ,-(CR ¹³R ¹⁴) _qS (O) _j(CR ¹³R ¹⁴) _v(C ₆-C ₁₀) aryl and-(CR ¹³R ¹⁴) _qS (O) _j(CR ¹³R ¹⁴) _v(4-10) group of first heterocyclic radical composition;

Above R ⁹Any 1 or 2 carbon atom of any (4-10) first heterocyclic radical of base is randomly by the (=O) replacement of oxo base;

Above R ⁹Any (C of base ₁-C ₆) alkyl, any (C ₆-C ₁₀) aryl and arbitrarily any carbon atom in (4-10)-first heterocyclic radical randomly by 1-3 independently be selected from halogen, cyano group, nitro ,-CF ₃,-CFH ₂,-CF ₂H, trifluoromethoxy, azido ,-OR ¹⁵,-(C=O)-R ¹⁵,-(C=O)-O-R ¹⁵,-O-(C=O)-R ¹⁵,-NR ¹⁵(C=0)-R ¹⁶,-(C=O)-NR ¹⁵R ¹⁶,-NR ¹⁵R ¹⁶,-NR ¹⁵OR ¹⁶, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl group ,-(CR ¹⁷R ¹⁸) _u(C ₆-C ₁₀) aryl or-(CR ¹⁷R ¹⁸) _u(4-10)-substituent group of first heterocyclic radical replaces;

Each R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷And R ¹⁸Base independently is H, (C ₁-C ₆) alkyl ,-(CR ¹⁹R ²⁰) _p(C ₆-C ₁₀) aryl and-(CR ¹⁹R ²⁰) _p(4-10) first heterocyclic radical;

Described each R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷And R ¹⁸Any 1 or 2 carbon atom of (4-10) first heterocyclic radical of base is randomly by the (=O) replacement of oxo base;

Aforementioned R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷And R ¹⁸(the C of base ₁-C ₆) alkyl, (C ₆-C ₁₀) aryl and (4-10) first heterocyclic radical any carbon atom randomly by 1-3 be independently selected from halogen, cyano group, nitro ,-NR ²¹R ²²,-CF ₃,-CHF ₂,-CH ₂F, trifluoromethoxy, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl group, hydroxyl and (C ₁-C ₆) substituent group of alkoxyl replaces;

Each R ¹⁹, R ²⁰, R ²¹And R ²²Base is independently selected from H or (C ₁-C ₆) alkyl;

And, wherein, comprise be not connected to halogen ,-SO or-SO ₂On the base or on N, O or the S atom-CH ₃(methyl) ,-CH ₂(methylene) or-above-mentioned any substituent group of CH (methine) randomly will be independently selected from hydroxyl, halogen, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl, amino ,-NH (C ₁-C ₆) (alkyl) and-N (C ₁-C ₆) (alkyl) (C ₁-C ₆) substituent group of (alkyl) is connected on the described group.

2. chemical compound as claimed in claim 1, wherein, W is

3. chemical compound as claimed in claim 1, wherein, W is

4. chemical compound as claimed in claim 1, wherein, W is 5 yuan of heterocyclic radicals.

5. chemical compound as claimed in claim 4, wherein, described 5 yuan of heterocyclic radicals are selected from the basis set group that becomes of You oxazolyl, thiazolyl, pyrazolyl, triazolyl He oxadiazole.

6. chemical compound as claimed in claim 1, wherein, b is 2.

7. chemical compound as claimed in claim 1, wherein, T is 6 yuan of heterocyclic radicals that comprise at least one nitrogen-atoms.

8. chemical compound as claimed in claim 7, wherein, described 6 yuan of heterocycles squeeze and are selected from the group that following formula is formed:

9. chemical compound as claimed in claim 1, wherein, T is

10. chemical compound as claimed in claim 1, wherein, R ¹By 1-5 R ⁹The phenyl or naphthyl that base replaces; And wherein, each R ⁹Base be independently selected from by halogen, cyano group ,-CF ₃, hydroxyl, (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl ,-(C=O)-R ¹⁰,-(C=O)-O-R ¹¹,-O-(C=O)-R ¹¹,-NR ¹¹(C=O)-R ¹²,-(C=O)-NR ¹¹R ¹²,-NR ¹¹R ¹²With-NR ¹¹OR ¹²The group of forming.

11. chemical compound as claimed in claim 2, wherein, R ²And R ³Independently be H, (C separately ₁-C ₆) alkyl, wherein, described (C ₁-C ₆) alkyl is randomly by (C ₂-C ₅) alkenyl or-(CR ⁷R ⁸) _t(C ₃-C ₁₀) cycloalkyl substituted.

12. chemical compound as claimed in claim 2, wherein, R ²And R ³Form (4-10) first heterocyclic radical with the nitrogen that links to each other with them.

13. chemical compound as claimed in claim 12, wherein, described (4-10) first heterocyclic radical is selected from the group of being made up of following formula:

14. chemical compound as claimed in claim 3, wherein, R ²Be (C ₁-C ₆) alkyl.

15. chemical compound as claimed in claim 1, wherein, n is 0, R ⁵And R ⁶Be H one of at least wherein.

16. be selected from chemical compound by the following various group of forming:

Or its pharmaceutically acceptable salt or solvate.

17. a pharmaceutical composition, described compositions comprise chemical compound or its pharmaceutically acceptable salt or the solvate according to claim 1 of effective dose, and pharmaceutically acceptable carrier.

18. a treatment is regulated the method for the disease of mediation by 11-β-hsd-1, this method comprises the chemical compound according to formula claim 1 that mammal is given effective dose, or its pharmaceutically acceptable salt or solvate.

19. treatment diabetes, metabolic syndrome, insulin impedance syndrome, obesity, glaucoma, hyperlipemia, hyperglycemia, hyperinsulinemia, osteoporosis, pulmonary tuberculosis, arteriosclerosis, dementia, depression, virosis, inflammation illness or liver are the methods of the disease of Target organ, described method comprises chemical compound or its pharmaceutically acceptable salt or the solvate according to claim 1 that mammal is given effective dose.

Claims (15)

1. the chemical compound of a formula (I):

Or its pharmaceutically acceptable salt or solvate,

Wherein:

R ¹Be selected from by (C ₁-C ₆) alkyl ,-(CR ³R ⁴) _t(C ₃-C ₁₂) cycloalkyl ,-(CR ³R ⁴) _t(C ₆-C ₁₂) aryl and-(CR ³R ⁴) _t(4-10) group of first heterocyclic radical composition;

B and k are selected from 1 and 2 independently of one another;

J is selected from the group of forming by 0,1 and 2;

T, u, p, q and v are selected from the group of forming by 0,1,2,3,4 and 5 independently of one another;

T is (6-10) the first heterocyclic radical that contains at least one nitrogen-atoms;

R ²Be selected from by H, (C ₁-C ₆) alkyl ,-(CR ³R ⁴) _t(C ₃-C ₁₂) cycloalkyl ,-(CR ³R ⁴) _t(C ₆-C ₁₂) aryl and-(CR ³R ⁴) _t(4-10) group of first heterocyclic radical composition;

Each R ³And R ⁴Be independently selected from H and (C ₁-C ₆) alkyl;

T, R ¹, R ², R ³And R ⁴In carbon atom separately randomly by 1-5 R ⁵Base replaces;

Each R ⁵Base be independently selected from by halogen, cyano group, nitro ,-CF ₃,-CHF ₂,-CH ₂F, trifluoromethoxy, azido, hydroxyl, (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl group ,-(C=O)-R ⁶,-(C=O)-O-R ⁶,-O-(C=O)-R ⁷,-O-(C=O)-NR ⁷,-NR ⁸(C=O)-R ⁹,-(C=O)-NR ⁸R ⁹,-NR ⁸R ⁹,-NR ⁸OR ⁹,-S (O) _kNR ⁸R ⁹,-S (O) _j(C ₁-C ₆) alkyl ,-O-SO ₂-R ⁹,-NR ⁸-S (O) _k-R ⁹,-(CR ¹⁰R ¹¹) _v(C ₆-C ₁₂Aryl) ,-(CR ¹⁰R ¹¹) _v(4-10) first heterocyclic radical ,-(CR ¹⁰R ¹¹) _q(C=O) (CR ¹⁰R ¹¹) _v(C ₆-C ₁₂) aryl ,-(CR ¹⁰R ¹¹) _q(C=O) (CR ¹⁰R ¹¹) _v(4-10) first heterocyclic radical ,-(CR ¹⁰R ¹¹) _vO (CR ¹⁰R ¹¹) _q(C ₆-C ₁₂) aryl ,-(CR ¹⁰R ¹¹) _vO (CR ¹⁰R ¹¹) _q(4-10) first heterocyclic radical ,-(CR ¹⁰R ¹¹) _qS (O) _j(CR ¹⁰R ¹¹) _v(C ₆-C ₁₂) aryl and-(CR ¹⁰R ¹¹) _qS (O) _j(CR ¹⁰R ¹¹) _v(4-10) group of first heterocyclic radical composition;

Above R ⁶Any 1 or 2 carbon atom of any (4-10) first heterocyclic radical of base is randomly by the (=O) replacement of oxo base;

Above R ⁵Any (C of base ₁-C ₆) alkyl, any (C ₆-C ₁₂) aryl and arbitrarily any carbon atom in (4-10)-first heterocyclic radical randomly by 1-3 be independently selected from halogen, cyano group, nitro ,-CF ₃,-CFH ₂,-CF ₂H, trifluoromethoxy, azido ,-OR ¹²,-(C=O)-R ¹²,-(C=O)-R ¹³,-O-(C=O)-R ¹³,-NR ¹³(C=O)-R ¹⁴,-(C=O)-NR ¹⁵R ¹⁶,-NR ¹⁷R ¹⁸,-NR ¹⁴OR ¹⁵, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl group ,-(CR ¹⁶R ¹⁷) _u(C ₆-C ₁₂) aryl and-(CR ¹⁶R ¹⁷) _u(4-10)-substituent group of first heterocyclic radical replaces;

Each R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶And R ¹⁷Base is independently selected from by H, (C ₁-C ₆) alkyl ,-(C=O) N (C ₁-C ₆) alkyl ,-(CR ¹⁸R ¹⁹) _p(C ₆-C ₁₂) aryl and-(CR ¹⁸R ¹⁹) _p(4-10) group of first heterocyclic radical composition;

Each described R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶And R ¹⁷Any 1 or 2 carbon atom of (4-10) first heterocyclic radical of base is randomly by the (=O) replacement of oxo base;

Aforementioned R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶And R ¹⁷Any (C of base ₁-C ₆) alkyl, any (C ₆-C ₁₂) aryl and arbitrarily (4-10) first heterocyclic radical any carbon atom randomly by 1-3 be independently selected from by halogen, cyano group, nitro ,-NR ²¹R ²²,-CF ₃,-CHF ₂,-CH ₂F, trifluoromethoxy, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl group, hydroxyl and (C ₁-C ₆) substituent group of the group formed of alkoxyl replaces;

Each R ¹⁸, R ¹⁹, R ²⁰, R ²¹And R ²²Group is independently selected from H and (C ₁-C ₆) alkyl;

And, wherein, comprise be not connected to halogen ,-SO or-SO ₂On the group or be not connected on N, O or the S atom-CH ₃(methyl) ,-CH ₂(methylene) or-above-mentioned any substituent group of CH (methine) randomly will be independently selected from by hydroxyl, halogen, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl ,-NH ₂,-NH (C ₁-C ₆) (alkyl) and-N ((C ₁-C ₆) (alkyl)) ₂The substituent group of the group of forming is connected on the described group.

2. chemical compound as claimed in claim 1, wherein, b is 2.

3. chemical compound as claimed in claim 1, wherein, T is 6 yuan of heterocyclic radicals that contain at least one nitrogen-atoms.

4. chemical compound as claimed in claim 1, wherein, each R ¹Be selected from the group of forming by phenyl, xenyl, benzo thiophenyl and naphthyl, and randomly by 1-5 R ⁶Base replaces;

Wherein:

Each R ⁶Base be independently selected from by halogen, cyano group ,-CF ₃, hydroxyl, (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl ,-(CR ¹⁰R ¹¹) _p(4-10) first heterocyclic radical ,-(C=O)-R ⁶,-(C=O)-O-R ⁶,-O-(C=O)-R ⁷,-NR ⁸(C=O)-R ⁹,-(C=O)-NR ⁸R ⁹,-NR ⁸R ⁹,-NR ⁸OR ⁹,-(CR ¹⁰R ¹¹)-O-(CR ¹⁰R ¹¹) _p(C ₆-C ₁₂) aryl and-(CR ¹⁰R ¹¹) _p-O-(CR ¹⁰R ¹¹) _p(4-10) group of first heterocyclic radical composition.

5. the chemical compound of formula (II)

Or its pharmaceutically acceptable salt or solvate,

Wherein:

R ¹Be (C ₁-C ₆) alkyl ,-(CR ⁷R ⁸) _t(C ₃-C ₁₀) cycloalkyl ,-(CR ⁷R ⁸) _t(C ₆-C ₁₀) aryl or-(CR ⁷R ⁸) _t(4-10) first heterocyclic radical;

B and k are selected from 1 and 2 independently of one another;

N and j independently are selected from the group of forming by 0,1 and 2 separately;

T, u, p, q and v are selected from the group of forming by 0,1,2,3,4 and 5 independently of one another;

T is (6-10) the first heterocyclic radical that comprises at least one nitrogen-atoms;

W be selected from by

(C ₁-C ₆) alkyl and 5 yuan of groups that heterocyclic radical is formed;

Each R ², R ³And R ⁴Be independently selected from by H, (C ₁-C ₆) alkyl ,-(CR ⁷R ⁸) _t(C ₃-C ₁₀) cycloalkyl ,-(CR ⁷R ⁸) _t(C ₆-C ₁₀) aryl and-(CR ⁷R ⁸) _t(4-10) group of first heterocyclic radical composition;

Each R ²And R ³Randomly form (4-10) first heterocyclic radical with the nitrogen that links to each other with them;

Each R ⁵And R ⁶Be independently selected from by H, (C ₁-C ₆) alkyl ,-(CR ⁷R ⁸) _t(C ₃-C ₁₀) cycloalkyl ,-(CR ⁷R ⁸) _t(C ₆-C ₁₀) aryl and-(CR ⁷R ⁸) _t(4-10) group of first heterocyclic radical composition;

Or R ⁵And R ⁶Randomly form (C with the carbon that links to each other with them ₃-C ₆) cycloalkyl or (3-7) first heterocyclic radical;

Each R ⁷And R ⁸Be independently selected from H and (C ₁-C ₆) alkyl;

T, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, R ⁷, R ⁸With the carbon atom of described W5 unit heterocyclic radical randomly by 1-5 R ⁹Base replaces;

Each R ⁹Base be independently selected from by halogen, cyano group, nitro ,-CF ₃,-CHF ₂,-CH ₂F, trifluoromethoxy, azido, hydroxyl, (C ₁-C ₆) alkoxyl, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl group ,-(C=O)-R ¹⁰,-(C=O)-O-R ¹¹,-O-(C=O)-R ¹¹,-NR ¹¹(C=O)-R ¹²,-(C=O)-NR ¹¹R ¹²,-NR ¹¹R ¹²,-NR ¹¹OR ¹²,-S (O) _kNR ¹¹R ¹²,-S (O) _j(C ₁-C ₆) alkyl ,-O-SO ₂-R ¹⁰,-NR ¹¹-S (O) _k-R ¹²,-(CR ¹³R ¹⁴) _v(C ₆-C ₁₀Aryl) ,-(CR ¹³R ¹⁴) _v(4-10) first heterocyclic radical ,-(CR ¹³R ¹⁴) _q(C=O) (CR ¹³R ¹⁴) _v(C ₆-C ₁₀) aryl ,-(CR ¹³R ¹⁴) _q(C=O) (CR ₁₃R ₁₄) _v(4-10) first heterocyclic radical ,-(CR ¹³R ¹⁴) _vO (CR ¹³R ¹⁴) _q(C ₆-C ₁₀) aryl ,-(CR ¹³R ¹⁴) _vO (CR ₁₃R ₁₄) _q(4-10) first heterocyclic radical ,-(CR ¹³R ¹⁴) _qS (O) _j(CR ¹³R ¹⁴) _v(C ₆-C ₁₀) aryl and-(CR ¹³R ¹⁴) _qS (O) _j(CR ¹³R ¹⁴) _v(4-10) first heterocyclic radical;

Above R ⁹Any 1 or 2 carbon atom of any (4-10) first heterocyclic radical of base is randomly by the (=O) replacement of oxo base;

Above R ⁹Any (C of base ₁-C ₆) alkyl, any (C ₆-C ₁₀) aryl and arbitrarily any carbon atom in (4-10)-first heterocyclic radical randomly by 1-3 be independently selected from by halogen, cyano group, nitro ,-CF ₃,-CFH ₂,-CF ₂H, trifluoromethoxy, azido ,-OR ¹⁵,-(C=O)-R ¹⁵,-(C=O)-O-R ¹⁵,-O-(C=O)-R ¹⁵,-NR ¹⁵(C=O)-R ¹⁶,-(C=O)-NR ¹⁵R ¹⁶,-NR ¹⁵R ¹⁶,-NR ¹⁵OR ¹⁶, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl group ,-(CR ¹⁷R ¹⁸) _u(C ₆-C ₁₀) aryl and-(CR ¹⁷R ¹⁸) _u(4-10)-substituent group of the group that first heterocyclic radical is formed replaces;

Each R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷And R ¹⁸Base is independently selected from by H, (C ₁-C ₆) alkyl ,-(CR ¹⁹R ²⁰) _p(C ₆-C ₁₀) aryl and-(CR ¹⁹R ²⁰) _p(4-10) group of first heterocyclic radical composition;

Described each R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷And R ¹⁸Any 1 or 2 carbon atom of (4-10) first heterocyclic radical of base is randomly by the (=O) replacement of oxo base;

Aforementioned R ¹⁰, R ¹¹, R ¹², R ¹³, R ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷And R ¹⁸Any (C of base ₁-C ₆) alkyl, any (C ₆-C ₁₀) aryl and arbitrarily (4-10) first heterocyclic radical any carbon atom randomly by 1-3 be independently selected from by halogen, cyano group, nitro ,-NR ²¹R ²²,-CF ₃,-CHF ₂,-CH ₂F, trifluoromethoxy, (C ₁-C ₆) alkyl, (C ₂-C ₆) alkenyl, (C ₂-C ₆) alkynyl group, hydroxyl and (C ₁-C ₆) substituent group of the group formed of alkoxyl replaces;

Each R ¹⁹, R ²⁰, R ²¹And R ²²Base is independently selected from H and (C ₁-C ₆) alkyl;

And, wherein, comprise be not connected to halogen ,-SO or-SO ₂On the base or be not connected on N, O or the S atom-CH ₃(methyl) ,-CH ₂(methylene) or-above-mentioned any substituent group of CH (methine) randomly will be independently selected from by hydroxyl, halogen, (C ₁-C ₆) alkyl, (C ₁-C ₆) alkoxyl, amino ,-NH (C ₁-C ₆) (alkyl) and-N ((C ₁-C ₆) (alkyl)) ₂The substituent group of the group of forming is connected on the described group.

6. chemical compound as claimed in claim 5, wherein, W is

7. chemical compound as claimed in claim 5, wherein, W is

8. chemical compound as claimed in claim 5, wherein, W is 5 yuan of heterocyclic radicals.

9. chemical compound as claimed in claim 8, wherein, described 5 yuan of heterocyclic radicals are selected from the basis set group that becomes of You oxazolyl, thiazolyl, pyrazolyl, triazolyl He oxadiazole.

10. chemical compound as claimed in claim 5, wherein, b is 2.

11. chemical compound as claimed in claim 5, wherein, T is 6 yuan of heterocyclic radicals that comprise at least one nitrogen-atoms.

12. chemical compound as claimed in claim 6, wherein, each R ²And R ³Randomly form (4-10) first heterocyclic radical with the nitrogen that links to each other with them.

13. be selected from the chemical compound of the group of forming by following formula:

Or its pharmaceutically acceptable salt or solvate.

14. a pharmaceutical composition, described compositions comprise chemical compound or its pharmaceutically acceptable salt or the solvate according to claim 1 or claim 5 of effective dose, and pharmaceutically acceptable carrier.

15. treatment diabetes, metabolic syndrome, insulin impedance syndrome, obesity, glaucoma, hyperlipemia, hyperglycemia, hyperinsulinemia, osteoporosis, pulmonary tuberculosis, arteriosclerosis, dementia, depression, virosis, inflammation illness or liver are the methods of the disease of Target organ, described method comprises chemical compound or its pharmaceutically acceptable salt or the solvate according to claim 1 or claim 5 that mammal is given effective dose.