CN104684907A - Antidiabetic tricyclic compounds - Google Patents
Antidiabetic tricyclic compounds Download PDFInfo
- Publication number
- CN104684907A CN104684907A CN201380051773.6A CN201380051773A CN104684907A CN 104684907 A CN104684907 A CN 104684907A CN 201380051773 A CN201380051773 A CN 201380051773A CN 104684907 A CN104684907 A CN 104684907A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- unsubstituted
- substituting group
- compound
- halogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 C*C(C)(*C(N=C(C(C1C2C1*)C(C)(C)*)C2(*)C=C)=CC)C(*)(C1)C1(C)C(CCC1)CCCC1C1CCCCCCCC1 Chemical compound C*C(C)(*C(N=C(C(C1C2C1*)C(C)(C)*)C2(*)C=C)=CC)C(*)(C1)C1(C)C(CCC1)CCCC1C1CCCCCCCC1 0.000 description 13
- UTKWMRSNWDXLSD-ALCCZGGFSA-N BCC(C(/C=C\C(C)(C)CCC)F)N Chemical compound BCC(C(/C=C\C(C)(C)CCC)F)N UTKWMRSNWDXLSD-ALCCZGGFSA-N 0.000 description 1
- KRWRTWBHMLJQDQ-UHFFFAOYSA-N C1C2C=NC2C1 Chemical compound C1C2C=NC2C1 KRWRTWBHMLJQDQ-UHFFFAOYSA-N 0.000 description 1
- OBJMDGIZSSENFO-UHFFFAOYSA-N CC(C)(C)CCCc1cc(C)cc(C)c1 Chemical compound CC(C)(C)CCCc1cc(C)cc(C)c1 OBJMDGIZSSENFO-UHFFFAOYSA-N 0.000 description 1
- GIZYIBOGRWJDOI-UHFFFAOYSA-N CC(C)(C1)C(C)(C)OB1c1c(C)ccc(CO)c1 Chemical compound CC(C)(C1)C(C)(C)OB1c1c(C)ccc(CO)c1 GIZYIBOGRWJDOI-UHFFFAOYSA-N 0.000 description 1
- OPNJYTGALDDSSO-UHFFFAOYSA-N CC(C=C1CC=C(C2)CC2O)=C1Br Chemical compound CC(C=C1CC=C(C2)CC2O)=C1Br OPNJYTGALDDSSO-UHFFFAOYSA-N 0.000 description 1
- OJMGVAYIUAKZLF-UHFFFAOYSA-N CC(CC(CCCC(OC)=O)C=C1C)=C1[PoH] Chemical compound CC(CC(CCCC(OC)=O)C=C1C)=C1[PoH] OJMGVAYIUAKZLF-UHFFFAOYSA-N 0.000 description 1
- UAAJXGOFPDQPMF-UHFFFAOYSA-N CC(CCC=C1C)=C1Br Chemical compound CC(CCC=C1C)=C1Br UAAJXGOFPDQPMF-UHFFFAOYSA-N 0.000 description 1
- PQNYRTICMNLEIQ-UHFFFAOYSA-N CC(CCOc(cc1C)cc(C)c1Br)O Chemical compound CC(CCOc(cc1C)cc(C)c1Br)O PQNYRTICMNLEIQ-UHFFFAOYSA-N 0.000 description 1
- FBMUTFMGTHKGMK-UHFFFAOYSA-N COC(C1)=NCC1Br Chemical compound COC(C1)=NCC1Br FBMUTFMGTHKGMK-UHFFFAOYSA-N 0.000 description 1
- JQNYFPONSCQMOV-ZCFIWIBFSA-N C[C@]1(C=CC1)C#N Chemical compound C[C@]1(C=CC1)C#N JQNYFPONSCQMOV-ZCFIWIBFSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N Cc1[n]cccc1 Chemical compound Cc1[n]cccc1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- HKAVYUZQYIMADK-UHFFFAOYSA-N Cc1c(C)c(C)nc([ClH+])c1 Chemical compound Cc1c(C)c(C)nc([ClH+])c1 HKAVYUZQYIMADK-UHFFFAOYSA-N 0.000 description 1
- BUDIVIZAESOLFV-UHFFFAOYSA-N Cc1cc(CCCCO)cc(C)c1O Chemical compound Cc1cc(CCCCO)cc(C)c1O BUDIVIZAESOLFV-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/5765—Six-membered rings condensed with carbocyclic rings or carbocyclic ring systems
Abstract
Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.
Description
Background technology
Diabetes are the diseases derived by multiple paathogenic factor, and it is characterized in that, in the fasted state or during oral glucose tolerance test after administration glucose, plasma glucose levels raises (hyperglycemia).Usually the diabetes of two kinds of generally acknowledged forms are had.In type 1 diabetes or insulin-dependent diabetes (IDDM), patient produces and seldom or not produces Regular Insulin, and Regular Insulin is the hormone for regulating glucose utilization.In diabetes B or non-insulin-dependent diabetes (NlDDM), in body, still produce Regular Insulin.The patient suffering from diabetes B has resistance for Regular Insulin in the effect of main insulin-sensitive tissue (it is muscle, liver and fatty tissue) moderate stimulation glucose and lipid metabolism effect.These patients have the Regular Insulin of normal level usually, and when they compensate the reducing effect of Regular Insulin by the Regular Insulin of secretion increase, they may have hyperinsulinemia (plasma insulin level of rising).It not is the major cause causing insulin resistant that insulin receptor number reduces, and major cause is the binding deficient of post-insulin receptor, is understood not yet completely about this point.This shortage to insulin response causes the deficiency of activation of the absorption of the glucose of Regular Insulin-mediation in muscle, oxidation and storage, also causes the deficiency of the suppression to lipolysis of Regular Insulin-mediation in fatty tissue and the deficiency to the production of glucose in liver and the suppression of secretion.
The persistence occurred with diabetes or uncontrolled hyperglycemia and rising with too early morbidity and lethal relevant.Usually, the change of abnormal glucose homeostasis and obesity, hypertension and lipid, lipoprotein and apolipoprotein metabolism and other metabolic and haemodynamic disorders have and directly and indirectly contact.Diabetes B patient suffers from great vessels and microvascular complication, and the risk comprising atherosclerosis, coronary heart disease, apoplexy, peripheral vascular disease, hypertension, ephrosis, neuropathy and retinopathy significantly increases.Therefore, it is vital for controlling in the Clinical Management and treatment of diabetes to the homeostasis of glucose, lipid metabolism, obesity and hypertensive therapeutics.
The patient suffering from insulin resistant has the symptom that several are referred to as syndrome X or metabolic syndrome usually.According to a kind of definition of widespread use, the feature suffering from the patient of metabolic syndrome is to have three kinds or more kinds of symptom being selected from following five kinds of symptoms: (1) abdominal obesity; (2) hypertriglyceridemia; (3) low hdl cholesterol (HDL); (4) hypertension; (5) fasting glucose raised, if patient is also diabetic subject, so this symptom also can in the scoped features of diabetes B.In these symptoms each all clinical definition in Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel HI, or ATP III), National Institutes of Health, in 2001, N1H Publication No.01-3670.There is the patient of metabolic syndrome, no matter whether they have or be obviously developed into diabetes, all there is the rising developing great vessels and the microvascular complication (such as atherosclerosis and coronary heart disease) occurred together with diabetes B dangerous.
The methods availalbe for the treatment of diabetes B has several, and wherein each method has limitation and the potentially dangerous of himself.Sports and in cutting down one's diet caloric intake usually can improve the situation of diabetes significantly, be generally used for diabetes B and relevant to insulin resistant before suggestion one roentgenism x of diabetic conditions.The food high due to the mode of life and excessive amount food, particularly lipid content that are not easy the custom changed and carbohydrate, the therefore general non-constant of the conformability of this therapy.Pharmacological treatment for diabetes mainly concentrates on three physiopathology regions: (1) liver glucose produces (biguanides, such as phenformin and N1,N1-Dimethylbiguanide), (2) insulin resistant (PPAR agonist, such as rosiglitazone, troglitazone, engliazone, Ba Gelie ketone, MCC-555, netoglitazone, T-131, LY-300512, LY-818 and U-721017E), (3) insulin secretion (sulfonylurea, such as tolbutamide, Glipizide and glimipiride); (4) gut incretin hormones stand-in (GLP-1 derivative and analogue, such as exenatide and liraglitide); (5) inhibitor (DPP-4 inhibitor, such as sitagliptin, alogliptin, vildagliptin, BI 1356, denagliptin and BMS-477118) of gut incretin hormones degraded.
Biguanides is the medicine that a class is widely used in treatment diabetes B.Two kinds of biguanides known most---phenformin and N1,N1-Dimethylbiguanide can make hyperglycemia be corrected to a certain extent.Biguanides plays a role mainly through suppressing liver glucose to be produced, and thinks that they leniently can improve the susceptibility of Regular Insulin.Biguanides may be used for independent therapy or with other antidiabetic medicine (such as Regular Insulin or Insulin secretagogues) conbined usage, and do not have increase hypoglycemic risk.But phenformin and N1,N1-Dimethylbiguanide can bring out lactic acidosis and/diarrhoea of feeling sick.Relative to phenformin, N1,N1-Dimethylbiguanide has lower side effect risk, is therefore extensively opened and be used for the treatment of diabetes B in prescription.
Glitazone drugs (i.e. 5-substituted benzylthiazolidine-2,4-diones) is the compound compared with novel type that a class can improve the symptom of hyperglycemia and other diabetes B.Current commercially available glitazone (rosiglitazone and pioglitazone) is the agonist of peroxisome proliferator-activated acceptor (PPAR) γ hypotype.PPAR-gamma agonist strengthens the insulin sensitivity in muscle, liver and the fatty tissue in several diabetes B animal models significantly, thus causes the plasma glucose levels partly or completely making to raise to recover normal, and hypoglycemia can not occur.It has been generally acknowledged that, the exciting mechanism of PPAR-γ is the reason of the insulin sensitivity of the improvement observed in the human patients for the treatment of with lattice row ketone.Currently developing new PPAR agonist.Multiple newer PPAR compound is the agonist of one or more PPAR α, γ and δ hypotypes.Compound simultaneously as the agonist (PPAR α/γ dual agonists) of PPAR α and PPAR γ hypotype has been produced out and has tested, but is also managed mechanism's approval without any one so far.Current commercially available PPAR gamma agonist leniently plays a role in reduction plasma glucose and hemoglobin A lC.Current commercially available compound does not greatly improve lipid metabolism, and in fact may have negative influence to lipid profile.At present, developing and may same effective as selective PPAR gamma portion agonist (SPPARM ' s), it has less side effect, such as body weight increases and edema.Thus, PPAR compounds represented the important improvement in diabetotherapy.
The pharmacological agent of another kind of widespread use relates to administration Insulin secretagogues, such as sulfonylurea (such as tolbutamide, glipizide and glimepiride).These medicines raise the blood plasma level of Regular Insulin by the stimulating pancreas beta cell more Regular Insulin of secretion.Insulin secretion in pancreas beta cell is by the strict adjustment of glucose and a series of metabolism, nerve and hormone signal.Glucose stimulates Regular Insulin to be formed and secretion by its metabolism to form ATP and other signaling molecule, simultaneously other extracellular signal by the existence of GPCR on cytoplasmic membrane as the synergistic agent of insulin secretion or inhibitor.Sulfonylurea and relevant Insulin secretagogues are by blocking ATP-dependency K in beta cell
+passage plays a role, and this makes cell depolarization and the open Ca depending on voltage
2+passage, stimulates insulin releasing simultaneously.This mechanism is non-dependence on the glucose type mechanism, and thus, no matter ambient glucose levels, insulin secretion can exist.Even if this can make Regular Insulin all be secreted when glucose level is low, thus causes hypoglycemia, in serious situation, this may be fatal.Therefore, Cautious control must be carried out to the administration of Insulin secretagogues.Usually Insulin secretagogues is used as the first-line drug for the treatment of diabetes B.
DPP IV (DPP-4) inhibitor (such as, sitagliptin, vildagliptin, alogliptin, BI 1356, denagliptin and BMS-477118) provide a kind of according to food consumption the new way for increasing insulin secretion.DPP-4 is a kind of cell surface protein, and it has wide tissue distribution, and these tissue distribution are relevant with the biological function of wide region.CD26 is identical for DPP-4 and T-cell activation markers, and it can cracking immunoregulatory, endocrine and neurologic peptide in a large number in vitro.Now clearly set up, incretin GLP-1 (glucagon-like-peptide-1) and GIP (depends on the insulinoptropic peptides of glucose; Also known as Glucose-dependent insulinotropic polypeptide) to stimulate insulin secretion and in vivo by DPP-4 rapid deactivation.These peptidyl hormones are by being arranged in the endocrine cells secrete of intestinal epithelial cell.When the glucose concn in these endocrine cells sensation digestive tube chamber increases, they serve as the triggering device of incretin release.By the circulation in pancreas, incretin is transported to beta cell, and the blood sugar of expection caused by digest food increases, and causes beta cell to secrete more Regular Insulin.To the research of DPP-4 (-/-) defective mouse with use the clinical trial of DPP-4 inhibitor to show: DPP-4 suppresses to add the Css of GLP-1 and GIP, causes glucose tolerance to improve.These peptides can also be worked by the deactivation of DPP-4 in glucose homeostasis.Therefore, DPP-4 inhibitor can be used for treating type ii diabetes and be used for the treatment of and prevent type ii diabetes usual adjoint many illnesss, comprise metabolism syndrome, reactive hypoglycemia and diabetic hyperlipemia.GLP-1 has other effect, and it contributes to reducing blood sugar and promoting glucose homeostasis.GLP-1 suppresses the glucagon secretion in liver.Hyperglycemic-glycogenolytic factor is a kind of hormone, and it stimulates glucose to produce by glycogen storage in liver and increases glucose level.GLP-1 postpones stomach emptying simultaneously, its passing in time and contribute to spreading glucose absorption, and therefore limits hyperglycemia.In addition, zooscopy shows, die by growth promoting effects or by T suppression cell tune, GLP-1 can increase the number of beta cell.Therefore, a kind of like this mode of effect by preventing the degraded of GLP-1 to strengthen it provides the some mechanism reducing the hyperglycemia relevant with type ii diabetes.
Again focus is concentrated on now on the pancreatic island-Ji insulin secretion of the insulin secretion control by depending on glucose.The method can potentially for stable and recovery Instreptozotocin Induced.For this, several lonely G-protein linked receptor (GPCR ' s) obtains qualification recently, and they are preferentially expressed and involve the insulin secretion (GSIS) of glucose stimulation in beta cell.GPR40 is the cell-surface GPCR expressed at the clone camber of the mankind's (and rodent) pancreas islet and excreting insulin.The medium of several naturally occurring longer chain fatty acid (FA ' s) and synthetic compound, comprise several thiazolidinediones PPAR gamma agonist, GPR40 part (people such as Itoh, Y., Nature.422:173 (2003) are confirmed as recently; The people such as Briscoe, C.P., J.Biol.Chem.278:11303 (2003); The people such as Kotarsky, K., Biochem.Biophys.Res.Comm.301:406 (2003)]).Under hyperglycemic conditions, GPR40 agonist can strengthen the release of Regular Insulin from islet cells.By showing that siRNA weakens the result that GSIS that FA-brings out amplifies the GPR40 activity inhibition carried out, propose the specificity of this response.These discoveries show, except being formed in the born of the same parents being considered to the fat-derivative of the FA ' s promoting insulin releasing, in the insulin secretion that FA ' s (with other synthesis GPR40 agonist) can also bring out at mediation FA-, serve as the outer part of born of the same parents in conjunction with GPR40.
GPR40 has several potential advantages as the potential target body for the treatment of diabetes B.The first, because the insulin secretion of GPR40-mediation is dependence on the glucose type, therefore risk of hypoglycemia is very little or do not have risk.The second, limited GPR40 tissue distribution (mainly in pancreas islet) shows that the possibility of relevant side effect active in GPR40 in other tissue is less.3rd, GPR40 agonist active in pancreas islet may have the potentiality recovered or keep islet function.This will be highly favourable, because long-term diabetes treatment can cause the reduction gradually of islet viability usually, makes after long-term treatment, usually needs to treat diabetes B patient with injection of insulin every day.By recovering or keeping islet function, GPR40 agonist can postpone or prevent reduction and the forfeiture of the islet function in diabetes B patient.
As the compound of G-protein-coupled receptor 40 (GPR40) agonist, by improving glucose and lipid metabolism and by reducing body weight, can be used for treating type ii diabetes, obesity, hypertension, hyperlipemia, cancer and metabolism syndrome, and cardiovascular disorder, such as myocardial infarction and apoplexy.Need effectively to have and be suitably used as the pharmacokinetics performance of human body medicine and the GPR40 agonist of drug effect performance.
Benzimidazole compound is at WO 2010/051206; WO 2010/051176; WO 2010/047982; WO 2010/036613; WO 93/07124; WO 95/29897; WO 98/39342; WO 98/39343; WO 00/03997; WO 00/14095; WO 01/53272; WO 01/53291; WO 02/092575; WO 02/40019; WO 03/018061; WO 05/002520; WO 05/018672; WO 06/094209; US 6,312,662; US 6,489,476; US 2005/0148643; DE 3 316 095; JP 6 298 731; EP 0 126 030; EP 0 128 862; EP 0 129 506; With open in EP 0 120 403.
G-protein-coupled receptor 40 (GPR40) agonist is at WO 2007/136572, WO 2007/136573, WO 2009/058237, WO 2006/083612, WO 2006/083781, WO 2010/085522, WO 2010/085525, WO 2010/085528, WO 2010/091176, WO 2004/041266, EP 2004/1630152, WO 2004/022551, WO 2005/051890, WO 2005/051373, EP 2004/1698624, WO 2005/086661, WO 2007/213364, WO 2005/063729, WO 2005/087710, WO 2006/127503, WO 2007/1013689, WO 2006/038738, WO 2007/033002, WO 2007/106469, WO 2007/123225, WO 2008/001931, WO 2008/030618, WO 2008/054674, WO 2008/054675, WO 2008/066097, WO 2008/130514, WO 2009/048527, WO 2009/111056, WO 2010/045258, WO 2010/085522, WO 2010/085525, WO 2010/085528, WO 2010/091176, open in WO 2010/143733 and WO 2012/0004187.
Summary of the invention
Summary of the invention
The present invention relates to the compound of the new replacement of structural formula I:
And pharmacy acceptable salt.The compound of structural formula I and embodiment thereof are the agonists of G-protein-coupled receptor 40 (GPR40), and may be used for treating, prevention and prohibition by the disease of the agonism mediates of G-protein-coupled receptor 40, obstacle and illness, such as type ii diabetes, insulin resistance, hyperglycemia, hyperlipemia, lipid disorder, obesity, hypertension, Metabolic syndrome are sought peace atherosclerosis.
The invention still further relates to the pharmaceutical composition comprising compound of the present invention and pharmaceutically acceptable carrier.The invention still further relates to the method being used for the treatment of, controlling or preventing can have the agonism of G-protein-coupled receptor 40 obstacle of response, disease and illness in the experimenter having this to need by giving compound of the present invention and pharmaceutical composition.The invention still further relates to the purposes of compound of the present invention for the preparation of medicine, described medicine is used for the treatment of can have the disease of response, obstacle and illness to the agonism of G-protein-coupled receptor 40.The invention still further relates to the treatment of these diseases, obstacle and illness, by giving compound of the present invention and can be used for treating the drug combination administration of described disease, obstacle and illness with the another kind for the treatment of significant quantity.The invention still further relates to the preparation method of the compounds of this invention.
Detailed description of the invention
The present invention relates to the new compound of structural formula I:
Or its pharmacy acceptable salt; Wherein
X is selected from:
(1) oxygen, and
(2) NH；
T is selected from: CH, N and N-oxide compound;
U is selected from: CH, N and N-oxide compound;
V is selected from: CH, N and N-oxide compound;
Condition is one or two in T, U and V is N or N-oxide compound;
A is selected from:
(1) aryl, and
(2) heteroaryl,
Wherein A is unsubstituted or is selected from R by 1-5
asubstituting group replace;
B is selected from:
(1) aryl,
(2) aryl-O-,
(3) C
3-6cycloalkyl-,
(4) C
3-6cycloalkyl-C
1-10alkyl-,
(5) C
3-6cycloalkyl-C
1-10alkyl-O-,
(6) C
2-5ring mix alkyl-,
(7) heteroaryl,
(8) heteroaryl-O-,
(9) aryl-C
1-10alkyl-, and
(10) heteroaryl-C
1-10alkyl-;
Wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace;
R
1be selected from:
(1) halogen,
(2) -OR
e，
(3) -CN，
(4)-C
1-6alkyl, and
(5)-C
3-6cycloalkyl,
Wherein each-C
1-6alkyl and-C
3-6cycloalkyl is unsubstituted or is selected from R by 1-3
isubstituting group replace;
R
2be selected from:
(1) hydrogen,
(2)-C
1-6alkyl, and
(3)-C
3-6cycloalkyl,
Wherein each-C
1-6alkyl and-C
3-6cycloalkyl is unsubstituted or is replaced by the substituting group that 1-3 is selected from Rj;
R
3be selected from:
(1) hydrogen,
(2) halogen,
(3) -OR
e，
(4)-C
1-6alkyl,
(5)-C
2-6alkenyl,
(6)-C
2-6alkynyl, and
(7)-C
3-6cycloalkyl,
Wherein each C
1-6alkyl, C
2-6alkenyl, C
2-6alkynyl and C
3-6cycloalkyl is unsubstituted or is selected from R by 1-3
lsubstituting group replace;
R
4be selected from:
(1) hydrogen,
(2) halogen,
(3) -OR
e，
(4)-C
1-6alkyl,
(5)-C
2-6alkenyl,
(6)-C
2-6alkynyl, and
(7)-C
3-6cycloalkyl,
Wherein each-C
1-6alkyl ,-C
2-6alkenyl ,-C
2-6alkynyl and-C
3-6cycloalkyl is unsubstituted or is selected from R by 1-3
lsubstituting group replace;
R
5be selected from:
(1) hydrogen,
(2)-C
1-3alkyl, and
(3) halogen;
R
6be selected from:
(1) hydrogen,
(2)-C
1-3alkyl, and
(3) halogen, or
R
5and R
6oxo can be formed together;
R
abe selected from:
(1)-C
1-6alkyl,
(2) halogen,
(3) -OR
e，
(4) -NR
cS(O)mR
e，
(5) -S(O)mR
e，
(6) -S(O)mNR
cR
d，
(7) -NR
cR
d，
(8) -C(O)R
e，
(9) -OC(O)R
e，
(10) -CO
2R
e,
(11) -CN,
(12) -C(O)NR
cR
d,
(13) -NR
cC(O)R
e,
(14) -NR
cC(O)OR
e,
(15) -NR
cC(O)NR
cR
d,
(16) -CF
3,
(17) -OCF
3,
(18) -OCHF
2,
(19)-C
3-6cycloalkyl, and
(20)-C
2-5ring is mixed alkyl;
R
bindependently selected from:
(1)-C
1-10alkyl,
(2)-C
2-10alkenyl,
(3) halogen,
(4) -OH，
(5)-OC
1-10alkyl,
(6)-OC
2-10alkenyl,
(7)-O (CH
2) pOC
1-10alkyl,
(8)-O (CH
2) pC
3-6cycloalkyl,
(9)-O (CH
2) pC
3-6cycloalkyl-C
1-10alkyl-,
(10)-O (CH
2) pC
2-10ring is mixed alkyl,
(11)-O (CH
2) pC
2-5ring is mixed alkyl-C
1-10alkyl-,
(12)-O-aryl,
(13)-O-heteroaryl,
(14)-O-aryl-C
1-10alkyl-,
(15)-O-heteroaryl-C
1-10alkyl-,
(16) -NR
cS(O)
mR
e,
(17) -S(O)
mR
e,
(18) -S(O)
mNR
cR
d,
(19) -NR
cR
d,
(20) -C(O)R
e ,
(21) -OC(O)R
e ,
(22) -CO
2R
e,
(23) -CN,
(24) -C(O)NR
cR
d,
(25) -NR
cC(O)R
e,
(26) -NR
cC(O)OR
e,
(27) -NR
cC(O)NR
cR
d,
(28)-O (CH
2) pO-C
3-6cycloalkyl,
(29)-O (CH
2) pO-C
2-10ring is mixed alkyl,
(30) -CF
3,
(31) -OCF
3,
(32) -OCHF
2,
(33)-(CH
2) p-C
3-6cycloalkyl,
(34)-(CH
2) p-C
2-10ring is mixed alkyl,
(35) aryl,
(36) heteroaryl,
(37) aryl-C
1-10alkyl-, and
(38) heteroaryl-C
1-10alkyl-,
Wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace;
R
cand R
deach independently selected from:
(1) hydrogen,
(2) C
1-10alkyl,
(3) C
2-10alkenyl,
(4) C
3-6cycloalkyl,
(5) C
3-6cycloalkyl-C
1-10alkyl-,
(6) ring is mixed alkyl,
(7) ring is mixed alkyl-C
1-10alkyl-,
(8) aryl,
(9) heteroaryl,
(10) aryl-C
1-10alkyl-, and
(11) heteroaryl-C
1-10alkyl-, or
R
cand R
dformed together with the atom (all atoms) that they connect containing 0-2 extra heteroatomic 4-7 membered cycloheteroalkyl group ring, described heteroatoms is independently selected from oxygen, sulphur and N-R
g, and wherein each R
cand R
dunsubstituted or individual independently selected from R by 1-3
fsubstituting group replace;
Each R
eindependently selected from:
(1) hydrogen,
(2)-C
1-10alkyl,
(3)-C
2-10alkenyl,
(4)-C
3-6cycloalkyl,
(5)-C
3-6cycloalkyl-C
1-10alkyl-,
(6)-C
2-5ring is mixed alkyl,
(7)-C
2-5ring is mixed alkyl-C
1-10alkyl-,
(8) aryl,
(9) heteroaryl,
(10) aryl-C
1-10alkyl-, and
(11) heteroaryl-C
1-10alkyl-,
Wherein each R
ebe unsubstituted or be selected from R by 1-3
hsubstituting group replace;
Each R
fbe selected from:
(1) halogen,
(2) C
1-10alkyl,
(3) -OH，
(4)-O-C
1-4alkyl,
(5)-S (O) m-C
1-4alkyl,
(6) -CN，
(7) -CF
3，
(8)-OCHF
2, and
(9) -OCF
3，
Wherein each C
1-10alkyl be unsubstituted or by 1-3 independently selected from-OH, halogen, cyano group and-S (O)
2cH
3substituting group replace;
Each R
gbe selected from:
(1) hydrogen,
(2)-C (O) R
e, and
(3)-C
1-10alkyl,
Wherein-C
1-10alkyl is unsubstituted or is replaced by 1-5 fluorine;
Each R
hbe selected from:
(1) halogen,
(2) C
1-10alkyl,
(3) -OH，
(4)-O-C
1-4alkyl,
(5)-S (O) m-C
1-4alkyl,
(6) -CN，
(7) -CF
3，
(8)-OCHF
2, and
(9) -OCF
3，
Wherein each C
1-10alkyl be unsubstituted or by 1-3 independently selected from-OH, halogen, cyano group and-S (O)
2cH
3substituting group replace;
R
iindependently selected from:
(1)-C
1-6alkyl,
(2) -OR
e,
(3) -NR
cS(O)
mR
e,
(4) halogen,
(5) -S(O)
mR
e,
(6) -S(O)
mNR
cR
d,
(7) -NR
cR
d,
(8) -C(O)R
e ,
(9) -OC(O)R
e ,
(10) -CO
2R
e,
(11) -CN,
(12) -C(O)NR
cR
d,
(13) -NR
cC(O)R
e,
(14) -NR
cC(O)OR
e,
(15) -NR
cC(O)NR
cR
d,
(16) -CF
3,
(17) -OCF
3,
(18) -OCHF
2,
(19)-C
3-6cycloalkyl, and
(20)-C
2-5ring is mixed alkyl;
R
jindependently selected from:
(1)-C
1-6alkyl,
(2) -OR
e,
(3) -NR
cS(O)
mR
e,
(4) halogen,
(5) -S(O)
mR
e,
(6) -S(O)
mNR
cR
d,
(7) -NR
cR
d,
(8) -C(O)R
e ,
(9) -OC(O)R
e ,
(10) -CO
2R
e,
(11) -CN,
(12) -C(O)NR
cR
d,
(13) -NR
cC(O)R
e,
(14) -NR
cC(O)OR
e,
(15) -NR
cC(O)NR
cR
d,
(16) -CF
3,
(17) -OCF
3,
(18) -OCHF
2,
(19)-C
3-6cycloalkyl, and
(20)-C
2-5ring is mixed alkyl;
Each R
kindependently selected from:
(1) halogen,
(2)-C
1-10alkyl,
(3) -OH，
(4) oxo,
(5) halogen,
(6)-O-C
1-4alkyl,
(7)-SO
2-C
1-6alkyl,
(8)-C
1-6alkyl-SO
2c
1-6alkyl,
(9) -CN,
(10) -CF
3,
(11) -OCHF
2,
(12) -OCF
3,
(13) -NH
2,
(14)-NHSO
2c
1-6alkyl,
(15)-NHCOC
1-6alkyl,
(16) =N(OCH
3),
(17)-P (O) (OH)
2, and
(18)-P (O) (OC
1-6alkyl)
2,
Wherein each C
1-10alkyl be unsubstituted or by 1-3 independently selected from-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6the substituting group of alkyl replaces;
R
lbe selected from:
(1)-C
1-6alkyl,
(2) halogen,
(3) -OR
e,
(4) -NR
cS(O)
mR
e,
(5) -S(O)
mR
e,
(6) -S(O)
mNR
cR
d,
(7) -NR
cR
d,
(8) -C(O)R
e ,
(9) -OC(O)R
e ,
(10) -CO
2R
e,
(11) -CN,
(12) -C(O)NR
cR
d,
(13) -NR
cC(O)R
e,
(14) -NR
cC(O)OR
e,
(15) -NR
cC(O)NR
cR
d,
(16) -CF
3,
(17) -OCF
3,
(18) -OCHF
2,
(19)-C
3-6cycloalkyl, and
(20)-C
2-5ring is mixed alkyl;
Each n is 0,1,2,3 or 4 independently;
Each m is 0,1 or 2 independently; With
Each p independently selected from: 0,1,2,3,4,5,6,7,8,9 or 10.
The present invention has many embodiments, and it is summarized in following.The present invention includes compound as follows, the present invention also comprises each diastereomer of described compound, enantiomer and epimer, and the mixture of its diastereomer and/or its enantiomer, comprises racemic mixture.
In one embodiment of the present invention, X is selected from: oxygen and-NH.In a class of this embodiment, X is oxygen.This embodiment another kind of in, X is NH.
In another embodiment of the invention, T is selected from: CH, N and N-oxide compound.In a class of this embodiment, T is selected from: CH and N.This embodiment another kind of in, T is CH.This embodiment another kind of in, T is N or N-oxide compound.This embodiment another kind of in, T is N.
In another embodiment of the invention, U is selected from: CH, N and N-oxide compound.In a class of this embodiment, U is selected from: CH and N.This embodiment another kind of in, U is CH.This embodiment another kind of in, U is N or N-oxide compound.This embodiment another kind of in, U is N.
In another embodiment of the invention, V is selected from: CH, N and N-oxide compound.In a class of this embodiment, V is selected from: CH and N.This embodiment another kind of in, V is CH.This embodiment another kind of in, V is N or N-oxide compound.This embodiment another kind of in, V is N.
In another embodiment of the invention, T is CH, U is CH, and V is N or N-oxide compound.In a class of this embodiment, T is CH, U is CH, and V is N.
In another embodiment of the invention, T is CH, U is N or N-oxide compound, and V is CH.In a class of this embodiment, T is CH, U is N, and V is CH.
In another embodiment of the invention, T is N or N-oxide compound, and U is CH, and V is CH.In a class of this embodiment, T is N, U is CH, and V is CH.
In another embodiment of the invention, T is CH, U is N or N-oxide compound, and V is N or N-oxide compound.In a class of this embodiment, T is CH, U is N, and V is N.
In another embodiment of the invention, T is N or N-oxide compound, and U is CH, and V is N or N-oxide compound.In a class of this embodiment, T is N, U is CH, and V is N.
In another embodiment of the invention, T is N or N-oxide compound, and U is N or N-oxide compound, and V is CH.In a class of this embodiment, T is N, U is N, and V is CH.
In another embodiment of the invention, A is selected from: aryl and heteroaryl, and wherein A is unsubstituted or is selected from R by 1-5
asubstituting group replace.In a class of this embodiment, A is unsubstituted or is selected from R by 1-4
asubstituting group replace.This embodiment another kind of in, A is unsubstituted or is selected from R by 1-3
asubstituting group replace.This embodiment another kind of in, A is unsubstituted or is selected from R by 1-2
asubstituting group replace.
In another embodiment of the invention, A is selected from: phenyl and pyridine, and wherein A is unsubstituted or is selected from R by 1-5
asubstituting group replace.In a class of this embodiment, A is unsubstituted or is selected from R by 1-4
asubstituting group replace.This embodiment another kind of in, A is unsubstituted or is selected from R by 1-3
asubstituting group replace.This embodiment another kind of in, A is unsubstituted or is selected from R by 1-2
asubstituting group replace.
In another embodiment of the invention, A is aryl, and wherein A is unsubstituted or is selected from R by 1-5
asubstituting group replace.In a class of this embodiment, A is unsubstituted or is selected from R by 1-4
asubstituting group replace.This embodiment another kind of in, A is unsubstituted or is selected from R by 1-3
asubstituting group replace.This embodiment another kind of in, A is unsubstituted or is selected from R by 1-2
asubstituting group replace.
In another embodiment of the invention, A is phenyl, and wherein A is unsubstituted or is selected from R by 1-5
asubstituting group replace.In a class of this embodiment, A is unsubstituted or is selected from R by 1-4
asubstituting group replace.This embodiment another kind of in, A is unsubstituted or is selected from R by 1-3
asubstituting group replace.This embodiment another kind of in, A is unsubstituted or is selected from R by 1-2
asubstituting group replace.
In another embodiment of the invention, A is heteroaryl, and wherein A is unsubstituted or is selected from R by 1-5
asubstituting group replace.In a class of this embodiment, A is unsubstituted or is selected from R by 1-4
asubstituting group replace.This embodiment another kind of in, A is unsubstituted or is selected from R by 1-3
asubstituting group replace.This embodiment another kind of in, A is unsubstituted or is selected from R by 1-2
asubstituting group replace.
In another embodiment of the invention, A is pyridine, and wherein A is unsubstituted or is selected from R by 1-5
asubstituting group replace.In a class of this embodiment, A is unsubstituted or is selected from R by 1-4
asubstituting group replace.This embodiment another kind of in, A is unsubstituted or is selected from R by 1-3
asubstituting group replace.This embodiment another kind of in, A is unsubstituted or is selected from R by 1-2
asubstituting group replace.
In another embodiment of the invention, B is selected from: aryl, aryl-O-, C
3-6cycloalkyl-, C
3-6cycloalkyl-C
1-10alkyl-, C
3-6cycloalkyl-C
1-10alkyl-O-, C
2-5ring mix alkyl-, heteroaryl, heteroaryl-O-, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace.In a class of this embodiment, B is unsubstituted or is selected from R by 1-4
bsubstituting group replace.This embodiment another kind of in, B is unsubstituted or is selected from R by 1-3
bsubstituting group replace.This embodiment another kind of in, B is unsubstituted or is selected from R by 1-2
bsubstituting group replace.
In another embodiment of the invention, B is selected from: aryl and heteroaryl, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace.In a class of this embodiment, B is selected from phenyl, pyridine, pyrimidine, thiazole, benzoglyoxaline, benzothiazole, benzoxazole and benzoisoxazole, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace.In a class of this embodiment, B is unsubstituted or is selected from R by 1-4
bsubstituting group replace.This embodiment another kind of in, B is unsubstituted or is selected from R by 1-3
bsubstituting group replace.This embodiment another kind of in, B is unsubstituted or is selected from R by 1-2
bsubstituting group replace.
In another embodiment of the invention, B is selected from: aryl and heteroaryl, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace.In a class of this embodiment, B is selected from phenyl, pyridine, pyrimidine, thiazole and benzoglyoxaline, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace.In a class of this embodiment, B is unsubstituted or is selected from R by 1-4
bsubstituting group replace.This embodiment another kind of in, B is unsubstituted or is selected from R by 1-3
bsubstituting group replace.This embodiment another kind of in, B is unsubstituted or is selected from R by 1-2
bsubstituting group replace.
In another embodiment of the invention, B is aryl, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace.In a class of this embodiment, B is unsubstituted or is selected from R by 1-4
bsubstituting group replace.This embodiment another kind of in, B is unsubstituted or is selected from R by 1-3
bsubstituting group replace.This embodiment another kind of in, B is unsubstituted or is selected from R by 1-2
bsubstituting group replace.
In another embodiment of the invention, B is phenyl, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace.In a class of this embodiment, B is unsubstituted or is selected from R by 1-4
bsubstituting group replace.This embodiment another kind of in, B is unsubstituted or is selected from R by 1-3
bsubstituting group replace.This embodiment another kind of in, B is unsubstituted or is selected from R by 1-2
bsubstituting group replace.
In another embodiment of the invention, B is heteroaryl, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace.In a class of this embodiment, B is unsubstituted or is selected from R by 1-4
bsubstituting group replace.This embodiment another kind of in, B is unsubstituted or is selected from R by 1-3
bsubstituting group replace.This embodiment another kind of in, B is unsubstituted or is selected from R by 1-2
bsubstituting group replace.
In another embodiment of the invention, B is selected from: pyridine, pyrimidine, thiazole, benzoglyoxaline, benzothiazole, benzoxazole and benzoisoxazole, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace.In another embodiment of the invention, B is selected from: pyridine, pyrimidine, thiazole and benzoglyoxaline, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace.In a class of this embodiment, B is unsubstituted or is selected from R by 1-4
bsubstituting group replace.This embodiment another kind of in, B is unsubstituted or is selected from R by 1-3
bsubstituting group replace.This embodiment another kind of in, B is unsubstituted or is selected from R by 1-2
bsubstituting group replace.
In another embodiment of the invention, B is pyridine or benzoglyoxaline, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace.In a class of this embodiment, B is unsubstituted or is selected from R by 1-4
bsubstituting group replace.This embodiment another kind of in, B is unsubstituted or is selected from R by 1-3
bsubstituting group replace.This embodiment another kind of in, B is unsubstituted or is selected from R by 1-2
bsubstituting group replace.
In another embodiment of the invention, R
1be selected from: halogen ,-OR
e,-CN ,-C
1-6alkyl and C
3-6cycloalkyl, wherein each C
1-6alkyl and C
3-6cycloalkyl is unsubstituted or is selected from R by 1-3
isubstituting group replace.In a class of embodiment, R
1be selected from: halogen ,-OR
e,-CN and-C
1-6alkyl, wherein each C
1-6alkyl is unsubstituted or is selected from R by 1-3
isubstituting group replace.This embodiment another kind of in, R
1be selected from: halogen ,-CN and-C
1-6alkyl, wherein each C
1-6alkyl is unsubstituted or is selected from R by 1-3
isubstituting group replace.This embodiment another kind of in, R
1-C
1-6alkyl, wherein each C
1-6alkyl is unsubstituted or is selected from R by 1-3
isubstituting group replace.
In another embodiment of the invention, R
2be selected from: hydrogen ,-C
1-6alkyl and C
3-6cycloalkyl, wherein each C
1-6alkyl and C
3-6cycloalkyl is unsubstituted or is selected from R by 1-3
jsubstituting group replace.In a class of this embodiment, R
2be selected from: hydrogen and-C
1-6alkyl, wherein each C
1-6alkyl is unsubstituted or is selected from R by 1-3
jsubstituting group replace.This embodiment another kind of in, R
2-C
1-6alkyl, wherein each C
1-6alkyl is unsubstituted or is selected from R by 1-3
jsubstituting group replace.This embodiment another kind of in, R
2hydrogen.
In another embodiment of the invention, R
3be selected from: hydrogen, halogen ,-OR
e,-C
1-6alkyl ,-C
2-6alkenyl ,-C
2-6alkynyl and-C
3-6cycloalkyl, wherein each-C
1-6alkyl ,-C
2-6alkenyl ,-C
2-6alkynyl and-C
3-6cycloalkyl is unsubstituted or is selected from R by 1-3
lsubstituting group replace.In a class of this embodiment, R
3be selected from: hydrogen, halogen ,-OR
e,-C
1-6alkyl ,-C
2-6alkenyl and-C
2-6alkynyl, wherein each-C
1-6alkyl ,-C
2-6alkenyl and-C
2-6alkynyl is unsubstituted or is selected from R by 1-3
lsubstituting group replace.This embodiment another kind of in, R
3be selected from: hydrogen, halogen and-C
1-6alkyl, wherein each C
1-6alkyl is unsubstituted or is selected from R by 1-3
lsubstituting group replace.In another embodiment of the invention, R
3be selected from: hydrogen, halogen and-C
1-6alkyl, wherein each C
1-6alkyl is unsubstituted or is selected from R by 1-3
lsubstituting group replace.In this type of a subclass, R
3be selected from: hydrogen, F and-CH
3.In another embodiment of the invention, R
3hydrogen.
In another embodiment of the invention, R
4be selected from: hydrogen, halogen ,-OR
e,-C
1-6alkyl ,-C
2-6alkenyl ,-C
2-6alkynyl and-C
3-6cycloalkyl, wherein each-C
1-6alkyl ,-C
2-6alkenyl ,-C
2-6alkynyl and-C
3-6cycloalkyl is unsubstituted or is selected from R by 1-3
lsubstituting group replace.In a class of this embodiment, R
4be selected from: hydrogen, halogen ,-OR
e,-C
1-6alkyl ,-C
2-6alkenyl and-C
2-6alkynyl, wherein each-C
1-6alkyl ,-C
2-6alkenyl and-C
2-6alkynyl is unsubstituted or is selected from R by 1-3
lsubstituting group replace.This embodiment another kind of in, R
4be selected from: hydrogen, halogen and-C
1-6alkyl, wherein each C
1-6alkyl is unsubstituted or is selected from R by 1-3
lsubstituting group replace.In another embodiment of the invention, R
4be selected from: hydrogen, halogen and-C
1-6alkyl, wherein each C
1-6alkyl is unsubstituted or is selected from R by 1-3
lsubstituting group replace.In this type of a subclass, R
4be selected from: hydrogen, F and-CH
3.In another embodiment of the invention, R
4hydrogen.
In another embodiment of the invention, R
5be selected from: hydrogen ,-C
1-3alkyl and halogen.In a class of this embodiment, R
5be selected from: hydrogen ,-C
1-3alkyl and halogen.This embodiment another kind of in, R
5be selected from: hydrogen and-C
1-3alkyl.This embodiment another kind of in, R
5-C
1-3alkyl.This embodiment another kind of in, R
5hydrogen.
In another embodiment of the invention, R
6be selected from: hydrogen ,-C
1-3alkyl and halogen, or R
5and R
6oxo can be formed together.In a class of this embodiment, R
6be selected from: hydrogen ,-C
1-3alkyl and halogen.This embodiment another kind of in, R
6be selected from: hydrogen and-C
1-3alkyl.This embodiment another kind of in, R
6-C
1-3alkyl.This embodiment another kind of in, R
6hydrogen.
In another embodiment of the invention, R
abe selected from :-C
1-6alkyl, halogen ,-OR
e,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-CF
3,-OCF
3,-OCHF
2,-C
3-6cycloalkyl and-C
2-5ring is mixed alkyl, and condition is when A is phenyl, so R
abe not selected from :-C
1-6alkyl and halogen.In a class of this embodiment, R
abe selected from :-C
1-6alkyl, halogen ,-OR
e,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-oC (O) R
e ,-cO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-CF
3,-OCF
3,-OCHF
2,-C
3-6cycloalkyl and-C
2-5ring is mixed alkyl, and condition is when A is phenyl, so R
abe not selected from :-CH
3and F.
In another embodiment of the invention, R
abe selected from :-C
1-6alkyl, halogen ,-OR
e,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-CF
3,-OCF
3,-OCHF
2,-C
3-6cycloalkyl and-C
2-5ring is mixed alkyl, and condition is when A to be phenyl and B be phenyl or imidazopyridine, so R
abe not selected from :-C
1-6alkyl and halogen.In a class of this embodiment, R
abe selected from :-C
1-6alkyl, halogen ,-OR
e,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-CF
3,-OCF
3,-OCHF
2,-C
3-6cycloalkyl and-C
2-5ring is mixed alkyl, and condition is when A to be phenyl and B be phenyl or imidazopyridine, so R
abe not selected from :-CH
3and F.
In another embodiment of the invention, R
abe selected from :-C
1-6alkyl, halogen ,-OR
e,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-CF
3,-OCF
3,-OCHF
2,-C
3-6cycloalkyl and-C
2-5ring is mixed alkyl.In a class of this embodiment, R
abe selected from :-C
1-6alkyl, halogen ,-OR
e,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-oC (O) R
e ,-cO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-CF
3,-OCF
3with-OCHF
2.This embodiment another kind of in, R
abe selected from :-C
1-6alkyl, halogen ,-OR
e,-S (O)
mr
e,-NR
cr
d,-CN ,-CF
3,-OCF
3with-OCHF
2.This embodiment another kind of in, R
abe selected from :-C
1-6alkyl, halogen ,-CN ,-CF
3,-OCF
3with-OCHF
2.This embodiment another kind of in, R
abe selected from :-C
1-6alkyl, halogen and-CF
3.In this type of a subclass, R
abe selected from :-CH
3, F and-CF
3.This embodiment another kind of in, R
abe selected from :-C
1-6alkyl and halogen.In this type of a subclass, R
abe selected from :-CH
3and F.This embodiment another kind of in, R
a-C
1-6alkyl.In this type of a subclass, R
a-CH
3.This embodiment another kind of in, R
ait is halogen.In this type of a subclass, R
af.
In another embodiment of the invention, R
abe selected from: halogen ,-OR
e,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-CF
3,-OCF
3,-OCHF
2,-C
3-6cycloalkyl and-C
2-5ring is mixed alkyl.In a class of this embodiment, R
abe selected from: halogen ,-OR
e,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-CF
3,-OCF
3with-OCHF
2.This embodiment another kind of in, R
abe selected from: halogen ,-OR
e,-S (O)
mr
e,-NR
cr
d,-CN ,-CF
3,-OCF
3with-OCHF
2.This embodiment another kind of in, R
abe selected from: halogen ,-CN ,-CF
3,-OCF
3with-OCHF
2.This embodiment another kind of in, R
abe selected from: halogen and-CF
3.In this type of a subclass, R
abe selected from: F and-CF
3.In this type of a subclass, R
a-CF
3.This embodiment another kind of in, R
af.
In another embodiment of the invention, R
abe selected from :-OR
e,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-CF
3,-OCF
3,-OCHF
2,-C
3-6cycloalkyl and-C
2-5ring is mixed alkyl.In a class of this embodiment, R
abe selected from :-OR
e,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-CF
3,-OCF
3with-OCHF
2.This embodiment another kind of in, R
abe selected from :-OR
e,-S (O)
mr
e,-NR
cr
d,-CN ,-CF
3,-OCF
3with-OCHF
2.This embodiment another kind of in, R
abe selected from :-CN ,-CF
3,-OCF
3with-OCHF
2.This embodiment another kind of in, R
a-CF
3.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl, halogen ,-OH ,-OC
1-10alkyl ,-OC
2-10alkenyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
3-6cycloalkyl-C
1-10alkyl-,-O (CH
2) pC
2-10ring is mixed alkyl ,-O (CH
2) pC
2-5ring is mixed alkyl-C
1-10alkyl-,-O-aryl ,-O-heteroaryl ,-O-aryl-C
1-10alkyl-,-O-heteroaryl-C
1-10alkyl-,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-O (CH
2) pO-C
3-6cycloalkyl ,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace, condition be when B be phenyl or imidazopyridine time, so R
bbe not selected from: halogen ,-OC
1-10alkyl ,-O (CH
2) pO-C
2-10ring is mixed alkyl and-CF
3.In a class of this embodiment, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl, halogen ,-OH ,-OC
1-10alkyl ,-OC
2-10alkenyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
3-6cycloalkyl-C
1-10alkyl-,-O (CH
2) pC
2-10ring is mixed alkyl ,-O (CH
2) pC
2-5ring is mixed alkyl-C
1-10alkyl-,-O-aryl ,-O-heteroaryl ,-O-aryl-C
1-10alkyl-,-O-heteroaryl-C
1-10alkyl-,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-O (CH
2) pO-C
3-6cycloalkyl ,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace, condition be when B be phenyl or imidazopyridine time, so R
bbe not selected from: F, Cl ,-OCH
3,-OCH
2-trimethylene oxide and-CF
3.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl, halogen ,-OH ,-OC
1-10alkyl ,-OC
2-10alkenyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
3-6cycloalkyl-C
1-10alkyl-,-O (CH
2) pC
2-10ring is mixed alkyl ,-O (CH
2) pC
2-5ring is mixed alkyl-C
1-10alkyl-,-O-aryl ,-O-heteroaryl ,-O-aryl-C
1-10alkyl-,-O-heteroaryl-C
1-10alkyl-,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-O (CH
2) pO-C
3-6cycloalkyl ,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace, condition be when B be phenyl or imidazopyridine time, so R
bbe not selected from halogen and-OC
1-10alkyl.In a class of this embodiment, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl, halogen ,-OH ,-OC
1-10alkyl ,-OC
2-10alkenyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
3-6cycloalkyl-C
1-10alkyl-,-O (CH
2) pC
2-10ring is mixed alkyl ,-O (CH
2) pC
2-5ring is mixed alkyl-C
1-10alkyl-,-O-aryl ,-O-heteroaryl ,-O-aryl-C
1-10alkyl-,-O-heteroaryl-C
1-10alkyl-,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-O (CH
2) pO-C
3-6cycloalkyl ,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace, condition be when B be phenyl or imidazopyridine time, so R
bbe not selected from F, Cl and-OCH
3.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl, halogen ,-OH ,-OC
1-10alkyl ,-OC
2-10alkenyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
3-6cycloalkyl-C
1-10alkyl-,-O (CH
2) pC
2-10ring is mixed alkyl ,-O (CH
2) pC
2-5ring is mixed alkyl-C
1-10alkyl-,-O-aryl ,-O-heteroaryl ,-O-aryl-C
1-10alkyl-,-O-heteroaryl-C
1-10alkyl-,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-O (CH
2) pO-C
3-6cycloalkyl ,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace, condition be when B be phenyl or imidazopyridine time, so R
bbe not selected from :-OC
1-10alkyl.In a class of this embodiment, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl, halogen ,-OH ,-OC
1-10alkyl ,-OC
2-10alkenyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
3-6cycloalkyl-C
1-10alkyl-,-O (CH
2) pC
2-10ring is mixed alkyl ,-O (CH
2) pC
2-5ring is mixed alkyl-C
1-10alkyl-,-O-aryl ,-O-heteroaryl ,-O-aryl-C
1-10alkyl-,-O-heteroaryl-C
1-10alkyl-,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-O (CH
2) pO-C
3-6cycloalkyl ,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace, condition be when B be phenyl or imidazopyridine time, so R
bbe not selected from :-OCH
3.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl, halogen ,-OH ,-OC
1-10alkyl ,-OC
2-10alkenyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
3-6cycloalkyl-C
1-10alkyl-,-O (CH
2) pC
2-10ring is mixed alkyl ,-O (CH
2) pC
2-5ring is mixed alkyl-C
1-10alkyl-,-O-aryl ,-O-heteroaryl ,-O-aryl-C
1-10alkyl-,-O-heteroaryl-C
1-10alkyl-,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-O (CH
2) pO-C
3-6cycloalkyl ,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl, heteroaryl, aryl-C
1-10alkyl-, and heteroaryl-C
1-10alkyl-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment of the present invention, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl, halogen ,-OH ,-OC
1-10alkyl ,-OC
2-10alkenyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
3-6cycloalkyl-C
1-10alkyl-,-O (CH
2) pC
2-10ring is mixed alkyl ,-O (CH
2) pC
2-5ring is mixed alkyl-C
1-10alkyl-,-O-aryl ,-O-heteroaryl ,-O-aryl-C
1-10alkyl-,-O-heteroaryl-C
1-10alkyl-,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.This embodiment another kind of in, R
bindependently selected from :-C
1-10alkyl, halogen ,-OH ,-OC
1-10alkyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
2-10ring is mixed alkyl ,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
2-10ring is mixed alkyl and-S (O)
2c
1-10alkyl, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace, or its pharmacy acceptable salt.This embodiment another kind of in, R
bindependently selected from :-C
1-10alkyl, halogen ,-OH ,-OC
1-10alkyl ,-O (CH
2) pC
2-10ring is mixed alkyl ,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-CF
3,-(CH
2) p-C
2-10ring is mixed alkyl, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace, or its pharmacy acceptable salt.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl, halogen ,-OH ,-OC
1-10alkyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
2-10ring is mixed alkyl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
2-10ring is mixed alkyl ,-O-C
1-6alkyl-O-Isosorbide (isosorbide) and-O-C
1-6the different mannitol of alkyl-O-(isomannide), wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment, R
bindependently selected from :-C
1-10alkyl, halogen ,-OH ,-OC
1-10alkyl ,-O (CH
2) pC
2-10ring is mixed alkyl ,-CF
3,-(CH
2) p-C
2-10ring is mixed alkyl ,-O-C
1-6alkyl-O-Isosorbide and-O-C
1-6the different mannitol of alkyl-O-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-CH
3,-CH
2cH
3,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH ,-(CH
2)
4sO
2cH
3, F, Cl, I ,-OH ,-OC
1-10alkyl ,-OCH
3,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-OCH
2cF
2cF
3,-O (CH
2)
3c (CH
3)
2cN ,-O (CH
2)
3c (=N-OCH
3) CH
3,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2cyclopropane ,-O (CH
2)
3cyclopropane ,-O-CH
2tetramethylene ,-O (CH
2)
2tetramethylene ,-O-hexanaphthene ,-O-tetramethylene ,-OCH
2-trimethylene oxide ,-OCH
2-tetrahydropyrans ,-O (CH
2)
3azetidine ,-O-tetrahydric thiapyran ,-O (CH
2)
3tetramethyleneimine ,-CF
3,-OCF
3,-OCHF
2,-CH
2-trimethylene oxide ,-piperazine, azetidine, tetramethyleneimine, morpholine and spiral shell (indenes-Isosorbide-5-Nitrae-piperidines) ,-O-C
1-6alkyl-O-Isosorbide and-O-C
1-6the different mannitol of alkyl-O-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment, R
bindependently selected from :-CH
3,-CH
2cH
3,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH ,-(CH
2)
4sO
2cH
3, F, Cl, I ,-OH ,-OC
1-10alkyl ,-OCH
3,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN ,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2cyclopropane ,-O (CH
2)
3cyclopropane ,-O (CH
2)
2tetramethylene ,-O-hexanaphthene ,-OCH
2-trimethylene oxide ,-OCH
2-tetrahydropyrans ,-O (CH
2)
3azetidine ,-O-tetrahydric thiapyran ,-O (CH
2)
3tetramethyleneimine ,-CF
3,-OCF
3,-OCHF
2, tetramethyleneimine ,-O-C
1-6alkyl-O-Isosorbide and-O-C
1-6the different mannitol of alkyl-O-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.This embodiment another kind of in, R
bindependently selected from :-CH
3,-(CH
2)
4sO
2cH
3, F, I ,-OH ,-OC
1-10alkyl ,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN ,-OCH
2-trimethylene oxide ,-OCH
2-tetrahydropyrans ,-CF
3and tetramethyleneimine, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl, halogen ,-OH ,-OC
1-10alkyl ,-OC
2-10alkenyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
3-6cycloalkyl-C
1-10alkyl-,-O (CH
2) pC
2-10ring is mixed alkyl ,-O (CH
2) pC
2-5ring is mixed alkyl-C
1-10alkyl-,-O-aryl ,-O-heteroaryl ,-O-aryl-C
1-10alkyl-,-O-heteroaryl-C
1-10alkyl-;-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl, halogen ,-OH ,-OC
1-10alkyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
2-10ring is mixed alkyl ,-O-aryl ,-O-heteroaryl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl and heteroaryl, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl, halogen ,-OH ,-OC
1-10alkyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
2-10ring is mixed alkyl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl, halogen ,-OH ,-OC
1-10alkyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
2-10ring is mixed alkyl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
2-10ring is mixed alkyl, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment, R
bindependently selected from :-C
1-10alkyl, halogen ,-OH ,-OC
1-10alkyl ,-O (CH
2) pC
2-10ring is mixed alkyl ,-CF
3,-(CH
2) p-C
2-10ring is mixed alkyl,
Wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-CH
3,-CH
2cH
3,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH ,-(CH
2)
4sO
2cH
3, F, Cl, I ,-OH ,-OC
1-10alkyl ,-OCH
3,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-OCH
2cF
2cF
3,-O (CH
2)
3c (CH
3)
2cN ,-O (CH
2)
3c (=N-OCH
3) CH
3,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2cyclopropane ,-O (CH
2)
3cyclopropane ,-O-CH
2tetramethylene ,-O (CH
2)
2tetramethylene ,-O-hexanaphthene ,-O-tetramethylene ,-OCH
2-trimethylene oxide ,-OCH
2-tetrahydropyrans ,-O (CH
2)
3azetidine ,-O-tetrahydric thiapyran ,-O (CH
2)
3tetramethyleneimine ,-CF
3,-OCF
3,-OCHF
2,-CH
2-trimethylene oxide ,-piperazine, azetidine, tetramethyleneimine, morpholine and spiral shell (indenes-Isosorbide-5-Nitrae-piperidines), wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment, R
bindependently selected from :-CH
3,-CH
2cH
3,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH ,-(CH
2)
4sO
2cH
3, F, Cl, I ,-OH ,-OC
1-10alkyl ,-OCH
3,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN ,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2cyclopropane ,-O (CH
2)
3cyclopropane ,-O (CH
2)
2tetramethylene ,-O-hexanaphthene ,-OCH
2-trimethylene oxide ,-OCH
2-tetrahydropyrans ,-O (CH
2)
3azetidine ,-O-tetrahydric thiapyran ,-O (CH
2)
3tetramethyleneimine ,-CF
3,-OCF
3,-OCHF
2and tetramethyleneimine, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.This embodiment another kind of in, R
bindependently selected from :-CH
3,-(CH
2)
4sO
2cH
3, F, I ,-OH ,-OC
1-10alkyl ,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN ,-OCH
2-trimethylene oxide ,-OCH
2-tetrahydropyrans ,-CF
3and tetramethyleneimine, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-CH
3,-CH
2cH
3,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH ,-(CH
2)
4sO
2cH
3, F, Cl, I ,-OH ,-OCH
3,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-OCH
2cF
2cF
3,-O (CH
2)
3c (CH
3)
2cN ,-O (CH
2)
3c (=N-OCH
3) CH
3,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2-hydroxyl cyclopropane ,-O (CH
2)
3cyano group cyclopropane ,-O-CH
2difluoro tetramethylene ,-O (CH
2)
2difluoro tetramethylene ,-O-hydroxycyclohexan ,-O-cyano group, methyl-tetramethylene ,-OCH
2-methy oxetane ,-OCH
2-fluorine tetrahydropyrans ,-O (CH
2)
3difluoro azetidine ,-O-two oxo bridge tetrahydric thiapyran ,-O (CH
2)
3-oxo-pyrrolidine ,-CF
3,-OCF
3,-OCHF
2, spiral shell (indenes-1; 4-piperidines), (methyl sulphonyl)-piperazine, (methyl sulphonyl) methyl azetidine, (methyl sulphonyl) crassitude and (methylsulfonamido) tetramethyleneimine), wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment, R
bindependently selected from :-CH
3,-CH
2cH
3,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH ,-(CH
2)
4sO
2cH
3, F, Cl, I ,-OH ,-OCH
3,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN ,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2-hydroxyl cyclopropane ,-O (CH
2)
3cyano group cyclopropane ,-O (CH
2)
2difluoro tetramethylene ,-O-hydroxycyclohexan ,-O-cyano group, methyl-tetramethylene ,-OCH
2-methy oxetane ,-OCH
2-fluorine tetrahydropyrans ,-O (CH
2)
3difluoro azetidine ,-O-two oxo bridge tetrahydric thiapyran ,-O (CH
2)
3-oxo-pyrrolidine ,-CF
3,-OCF
3,-OCHF
2(methyl sulphonyl) crassitude, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.This embodiment another kind of in, R
bindependently selected from :-CH
3,-(CH
2)
4sO
2cH
3, F, I ,-OH ,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN ,-OCH
2-methy oxetane ,-OCH
2-fluorine tetrahydropyrans ,-CF
3(methyl sulphonyl) crassitude, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl ,-OH ,-OC
2-10alkyl ,-OC
2-10alkenyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
3-6cycloalkyl-C
1-10alkyl-,-O (CH
2) pC
2-10ring is mixed alkyl ,-O (CH
2) pC
2-5ring is mixed alkyl-C
1-10alkyl-,-O-aryl ,-O-heteroaryl ,-O-aryl-C
1-10alkyl-,-O-heteroaryl-C
1-10alkyl-,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-O (CH
2) pO-C
3-6cycloalkyl ,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment of the present invention, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl ,-OH ,-OC
2-10alkyl ,-OC
2-10alkenyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
3-6cycloalkyl-C
1-10alkyl-,-O (CH
2) pC
2-10ring is mixed alkyl ,-O (CH
2) pC
2-5ring is mixed alkyl-C
1-10alkyl-,-O-aryl ,-O-heteroaryl ,-O-aryl-C
1-10alkyl-,-O-heteroaryl-C
1-10alkyl-,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.This embodiment another kind of in, R
bindependently selected from :-C
1-10alkyl ,-OH ,-OC
2-10alkyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
2-10ring is mixed alkyl ,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
2-10ring is mixed alkyl and-S (O)
2c
1-10alkyl, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace, or its pharmacy acceptable salt.This embodiment another kind of in, R
bindependently selected from :-C
1-10alkyl, halogen ,-OH ,-OC
1-10alkyl ,-O (CH
2) pC
2-10ring is mixed alkyl ,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-CF
3,-(CH
2) p-C
2-10ring is mixed alkyl, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace, or its pharmacy acceptable salt.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl ,-OH ,-OC
2-10alkyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
2-10ring is mixed alkyl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
2-10ring is mixed alkyl ,-O-C
1-6alkyl-O-Isosorbide and-O-C
1-6the different mannitol of alkyl-O-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment, R
bindependently selected from :-C
1-10alkyl ,-OH ,-OC
2-10alkyl ,-O (CH
2) pC
2-10ring is mixed alkyl ,-CF
3,-(CH
2) p-C
2-10ring is mixed alkyl ,-O-C
1-6alkyl-O-Isosorbide and-O-C
1-6the different mannitol of alkyl-O-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-CH
3,-CH
2cH
3,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH ,-(CH
2)
4sO
2cH
3,-OH ,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-OCH
2cF
2cF
3,-O (CH
2)
3c (CH
3)
2cN ,-O (CH
2)
3c (=N-OCH
3) CH
3,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2cyclopropane ,-O (CH
2)
3cyclopropane ,-O-CH
2tetramethylene ,-O (CH
2)
2tetramethylene ,-O-hexanaphthene ,-O-tetramethylene ,-OCH
2-trimethylene oxide ,-OCH
2-tetrahydropyrans ,-O (CH
2)
3azetidine ,-O-tetrahydric thiapyran ,-O (CH
2)
3tetramethyleneimine ,-CF
3,-OCF
3,-OCHF
2,-CH
2-trimethylene oxide ,-piperazine, azetidine, tetramethyleneimine, morpholine and spiral shell (indenes-Isosorbide-5-Nitrae-piperidines) ,-O-C
1-6alkyl-O-Isosorbide and-O-C
1-6the different mannitol of alkyl-O-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment, R
bindependently selected from :-CH
3,-CH
2cH
3,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH ,-(CH
2)
4sO
2cH
3,-OH ,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN ,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2cyclopropane ,-O (CH
2)
3cyclopropane ,-O (CH
2)
2tetramethylene ,-O-hexanaphthene ,-OCH
2-trimethylene oxide ,-OCH
2-tetrahydropyrans ,-O (CH
2)
3azetidine ,-O-tetrahydric thiapyran ,-O (CH
2)
3tetramethyleneimine ,-CF
3,-OCF
3,-OCHF
2, tetramethyleneimine ,-O-C
1-6alkyl-O-Isosorbide and-O-C
1-6the different mannitol of alkyl-O-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.This embodiment another kind of in, R
bindependently selected from :-CH
3,-(CH
2)
4sO
2cH
3,-OH ,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN ,-OCH
2-trimethylene oxide ,-OCH
2-tetrahydropyrans ,-CF
3and tetramethyleneimine, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl ,-OH ,-OC
2-10alkyl ,-OC
2-10alkenyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
3-6cycloalkyl-C
1-10alkyl-,-O (CH
2) pC
2-10ring is mixed alkyl ,-O (CH
2) pC
2-5ring is mixed alkyl-C
1-10alkyl-,-O-aryl ,-O-heteroaryl ,-O-aryl-C
1-10alkyl-,-O-heteroaryl-C
1-10alkyl-;-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl ,-OH ,-OC
2-10alkyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
2-10ring is mixed alkyl ,-O-aryl ,-O-heteroaryl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl and heteroaryl, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl ,-OH ,-OC
2-10alkyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
2-10ring is mixed alkyl ,-CF
3,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl ,-OH ,-OC
2-10alkyl ,-O (CH2) pOC1-10 alkyl ,-O (CH2) pC
3-6cycloalkyl ,-O (CH2) pC
2-10ring is mixed alkyl ,-CF3 ,-OCF3 ,-OCHF
2,-(CH
2) p-C
2-10ring is mixed alkyl, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment, R
bindependently selected from :-C
1-10alkyl ,-OH ,-OC
2-10alkyl ,-O (CH
2) pC
2-10ring is mixed alkyl ,-CF
3,-(CH
2) p-C
2-10ring is mixed alkyl, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-CH
3,-CH
2cH
3,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH ,-(CH
2)
4sO
2cH
3,-OH ,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-OCH
2cF
2cF
3,-O (CH
2)
3c (CH
3)
2cN ,-O (CH
2)
3c (=N-OCH
3) CH
3,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2cyclopropane ,-O (CH
2)
3cyclopropane ,-O-CH
2tetramethylene ,-O (CH
2)
2tetramethylene ,-O-hexanaphthene ,-O-tetramethylene ,-OCH
2-trimethylene oxide ,-OCH
2-tetrahydropyrans ,-O (CH
2)
3azetidine ,-O-tetrahydric thiapyran ,-O (CH
2)
3tetramethyleneimine ,-CF
3,-OCF
3,-OCHF
2,-CH
2-trimethylene oxide ,-piperazine, azetidine, tetramethyleneimine, morpholine and spiral shell (indenes-Isosorbide-5-Nitrae-piperidines), wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment, R
bindependently selected from :-CH
3,-CH
2cH
3,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH ,-(CH
2)
4sO
2cH
3,-OH ,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN ,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2cyclopropane ,-O (CH
2)
3cyclopropane ,-O (CH
2)
2tetramethylene ,-O-hexanaphthene ,-OCH
2-trimethylene oxide ,-OCH
2-tetrahydropyrans ,-O (CH
2)
3azetidine ,-O-tetrahydric thiapyran ,-O (CH
2)
3tetramethyleneimine ,-CF
3,-OCF
3,-OCHF
2and tetramethyleneimine, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.This embodiment another kind of in, R
bindependently selected from :-CH
3,-(CH
2)
4sO
2cH
3,-OH ,-OC
2-10alkyl ,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN ,-OCH
2-trimethylene oxide ,-OCH
2-tetrahydropyrans ,-CF
3and tetramethyleneimine, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-CH
3,-CH
2cH
3,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH,
-(cH
2)
4sO
2cH
3,-OH ,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-OCH
2cF
2cF
3,-O (CH
2)
3c (CH
3)
2cN ,-O (CH
2)
3c (=N-OCH
3) CH
3,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2-hydroxyl cyclopropane ,-O (CH
2)
3cyano group cyclopropane ,-O-CH
2difluoro tetramethylene ,-O (CH
2)
2difluoro tetramethylene ,-O-hydroxycyclohexan ,-O-cyano group, methyl-tetramethylene ,-OCH
2-methy oxetane ,-OCH
2-fluorine tetrahydropyrans ,-O (CH
2)
3difluoro azetidine ,-O-two oxo bridge tetrahydric thiapyran ,-O (CH
2)
3-oxo-pyrrolidine ,-CF
3,-OCF
3,-OCHF
2, spiral shell (indenes-1; 4-piperidines), (methyl sulphonyl)-piperazine, (methyl sulphonyl) methyl azetidine, (methyl sulphonyl) methyi-pyrrofidinium; (methylsulfonamido)-tetramethyleneimine, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment, R
bindependently selected from :-CH
3,-CH
2cH
3,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH ,-(CH
2)
4sO
2cH
3,-OH ,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN ,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2-hydroxyl cyclopropane ,-O (CH
2)
3cyano group cyclopropane ,-O (CH
2)
2difluoro tetramethylene ,-O-hydroxycyclohexan ,-O-cyano group, methyl-tetramethylene ,-OCH
2-methy oxetane ,-OCH
2-fluorine tetrahydropyrans ,-O (CH
2)
3two fluoro-azetidines ,-O-two oxo bridge tetrahydric thiapyran ,-O (CH
2)
3-oxo-pyrrolidine ,-CF
3,-OCF
3,-OCHF
2(methyl sulphonyl) crassitude, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.This embodiment another kind of in, R
bindependently selected from :-CH
3,-(CH
2)
4sO
2cH
3,-OH ,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN ,-OCH
2-methy oxetane ,-OCH
2-fluorine tetrahydropyrans ,-CF
3(methyl sulphonyl) methyi-pyrrofidinium, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl, OH ,-OC
2-10alkyl ,-OC
2-10alkenyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
3-6cycloalkyl-C
1-10alkyl-,-O-aryl ,-O-heteroaryl ,-O-aryl-C
1-10alkyl-,-O-heteroaryl-C
1-10alkyl-,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-O (CH
2) pO-C
3-6cycloalkyl ,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment of the present invention, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl, OH ,-OC
2-10alkyl ,-OC
2-10alkenyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
3-6cycloalkyl-C
1-10alkyl-,-O-aryl ,-O-heteroaryl ,-O-aryl-C
1-10alkyl-,-O-heteroaryl-C
1-10alkyl-,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.This embodiment another kind of in, R
bindependently selected from :-C
1-10alkyl, OH ,-OC
2-10alkyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-OCF
3,-OCHF
2,-(CH
2) p-C
2-10ring is mixed alkyl and-S (O)
2c
1-10alkyl, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace, or its pharmacy acceptable salt.This embodiment another kind of in, R
bindependently selected from :-C
1-10alkyl ,-OC
2-10alkyl ,-O (CH
2) pO-C
2-10ring is mixed alkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace, or its pharmacy acceptable salt.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl, OH ,-OC
2-10alkyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-OCF
3,-OCHF
2,-(CH
2) p-C
2-10ring is mixed alkyl ,-O-C
1-6alkyl-O-Isosorbide and-O-C
1-6the different mannitol of alkyl-O-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment, R
bindependently selected from :-C
1-10alkyl, OH ,-OC
2-10alkyl ,-O-C
1-6alkyl-O-Isosorbide and-O-C
1-6the different mannitol of alkyl-O-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-CH
3,-CH
2cH
3, OH ,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH ,-(CH
2)
4sO
2cH
3,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-OCH
2cF
2cF
3,-O (CH
2)
3c (CH
3)
2cN ,-O (CH
2)
3c (=N-OCH
3) CH
3,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2cyclopropane ,-O (CH
2)
3cyclopropane ,-O-CH
2tetramethylene ,-O (CH
2)
2tetramethylene ,-O-hexanaphthene ,-O-tetramethylene ,-OCF
3,-OCHF
2,-CH
2-trimethylene oxide ,-piperazine, azetidine, tetramethyleneimine, morpholine and spiral shell (indenes-Isosorbide-5-Nitrae-piperidines) ,-O-C
1-6alkyl-O-Isosorbide and-O-C
1-6the different mannitol of alkyl-O-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment, R
bindependently selected from :-CH
3,-CH
2cH
3, OH ,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH ,-(CH
2)
4sO
2cH
3,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN ,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2cyclopropane ,-O (CH
2)
3cyclopropane ,-O (CH
2)
2tetramethylene ,-O-hexanaphthene ,-OCF
3,-OCHF
2, tetramethyleneimine ,-O-C
1-6alkyl-O-Isosorbide and-O-C
1-6the different mannitol of alkyl-O-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.This embodiment another kind of in, R
bindependently selected from :-CH
3,-(CH
2)
4sO
2cH
3,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN, and tetramethyleneimine, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl ,-OC
2-10alkyl ,-OC
2-10alkenyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O (CH
2) pC
3-6cycloalkyl-C
1-10alkyl ,-O-aryl ,-O-heteroaryl ,-O-aryl-C
1-10alkyl-,-O-heteroaryl-C
1-10alkyl-;-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl ,-OC
2-10alkyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-O-aryl ,-O-heteroaryl ,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, aryl and heteroaryl, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl ,-C
2-10alkenyl ,-OC
2-10alkyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-OCF
3,-OCHF
2,-(CH
2) p-C
3-6cycloalkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-C
1-10alkyl ,-OC
2-10alkyl ,-O (CH
2) pOC
1-10alkyl ,-O (CH
2) pC
3-6cycloalkyl ,-OCF
3,-OCHF
2,-(CH
2) p-C
2-10ring is mixed alkyl, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment, R
bindependently selected from :-C
1-10alkyl ,-OC
2-10alkyl ,-(CH
2) p-C
2-10ring is mixed alkyl, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-CH
3,-CH
2cH
3,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH ,-(CH
2)
4sO
2cH
3,-OC
2-10alkyl ,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-OCH
2cF
2cF
3,-O (CH
2)
3c (CH
3)
2cN ,-O (CH
2)
3c (=N-OCH
3) CH
3,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2cyclopropane ,-O (CH
2)
3cyclopropane ,-O-CH
2tetramethylene ,-O (CH
2)
2tetramethylene ,-O-hexanaphthene ,-O-tetramethylene ,-OCF
3,-OCHF
2,-CH
2-trimethylene oxide ,-piperazine, azetidine, tetramethyleneimine, morpholine and spiral shell (indenes-Isosorbide-5-Nitrae-piperidines), wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment, R
bindependently selected from :-CH
3,-CH
2cH
3,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH ,-(CH
2)
4sO
2cH
3,-OC
2-10alkyl ,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN ,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2cyclopropane ,-O (CH
2)
3cyclopropane ,-O (CH
2)
2tetramethylene ,-O-hexanaphthene ,-OCF
3,-OCHF
2and tetramethyleneimine, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.This embodiment another kind of in, R
bindependently selected from :-CH
3,-(CH
2)
4sO
2cH
3,-OC
2-10alkyl ,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN and tetramethyleneimine, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
bindependently selected from :-CH
3,-CH
2cH
3,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH ,-(CH
2)
4sO
2cH
3,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-OCH
2cF
2cF
3,-O (CH
2)
3c (CH
3)
2cN ,-O (CH
2)
3c (=N-OCH
3) CH
3,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2-hydroxyl cyclopropane ,-O (CH
2)
3cyano group cyclopropane ,-O-CH
2difluoro tetramethylene ,-O (CH
2)
2difluoro tetramethylene ,-O-hydroxycyclohexan ,-O-cyano group, methyl-tetramethylene ,-OCF
3,-OCHF
2spiral shell (indenes-1; 4-piperidines), (methyl sulphonyl)-piperazine, (methyl sulphonyl) methyl azetidine, (methyl sulphonyl) crassitude and (methylsulfonamido) tetramethyleneimine), wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In a class of this embodiment, R
bindependently selected from :-CH
3,-CH
2cH
3,-(CH
2)
2c (CH
3)
2oH ,-(CH
2)
3c (CH
3)
2oH ,-(CH
2)
4sO
2cH
3,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-OCH
2cH (OH) CH
3,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2cH (OH) CH
2oH ,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN ,-O-(CH
2)
2-o-CH
2c (CH
3)
2oH ,-O (CH
2)
2-hydroxyl cyclopropane ,-O (CH
2)
3cyano group-cyclopropane ,-O (CH
2)
2difluoro tetramethylene ,-O-hydroxycyclohexan ,-O-cyano group, methyl-tetramethylene ,-OCF
3,-OCHF
2(methyl sulphonyl)-crassitude, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.This embodiment another kind of in, R
bindependently selected from :-CH
3,-(CH
2)
4sO
2cH
3,-OCH
2c (CH
3)
2oH ,-O (CH
2)
2c (CH
3)
2oH ,-O (CH
2)
3c (CH
3)
2oH ,-O (CH
2)
2cH (OH) CH
3,-O (CH
2)
3sO
2cH
3,-OCH
2c (CH
2oH)
2cH
3,-O (CH
2)
3c (CH
3)
2cN and (methyl sulphonyl) crassitude, wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.
In another embodiment of the invention, R
b-OC
1-10alkyl, wherein R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In another embodiment of the invention, R
b-OC
2-10alkyl, wherein R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In another embodiment of the invention, R
b-OC
3-10alkyl, wherein R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace.In another embodiment of the invention, R
b-O (CH
2)
3sO
2cH
3.
In another embodiment of the invention, R
cand R
deach independently selected from hydrogen ,-C
1-10alkyl ,-C
2-10alkenyl ,-C
3-6cycloalkyl ,-C
3-6cycloalkyl-C
1-10alkyl-,-C
2-5ring is mixed alkyl ,-C
2-5ring is mixed alkyl-C
1-10alkyl-, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, or R
cand R
dformed together with the atom (all atoms) that they connect containing 0-2 extra heteroatomic 4-7 membered cycloheteroalkyl group ring, described heteroatoms is independently selected from oxygen, sulphur and N-R
g, and wherein each R
cand R
dunsubstituted or individual independently selected from R by 1-3
fsubstituting group replace.In a class of this embodiment, R
cand R
deach independently selected from hydrogen ,-C
1-10alkyl ,-C
2-10alkenyl ,-C
3-6cycloalkyl ,-C
2-5ring is mixed alkyl, aryl and heteroaryl, or R
cand R
dformed together with the atom (all atoms) that they connect containing 0-2 extra heteroatomic 4-7 membered cycloheteroalkyl group ring, described heteroatoms is independently selected from oxygen, sulphur and N-R
g, and wherein each R
cand R
dunsubstituted or individual independently selected from R by 1-3
fsubstituting group replace.This embodiment another kind of in, R
cand R
deach independently selected from hydrogen ,-C
1-10alkyl and-C
2-10alkenyl, or R
cand R
dformed together with the atom (all atoms) that they connect containing 0-2 extra heteroatomic 4-7 membered cycloheteroalkyl group ring, described heteroatoms is independently selected from oxygen, sulphur and N-R
g, and wherein each R
cand R
dunsubstituted or individual independently selected from R by 1-3
fsubstituting group replace.
In another embodiment of the invention, R
cand R
deach independently selected from hydrogen ,-C
1-10alkyl ,-C
2-10alkenyl ,-C
3-6cycloalkyl ,-C
3-6cycloalkyl-C
1-10alkyl-,-C
2-5ring is mixed alkyl ,-C
2-5ring is mixed alkyl-C
1-10alkyl-, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
cand R
dunsubstituted or individual independently selected from R by 1-3
fsubstituting group replace.In a class of this embodiment, R
cand R
deach independently selected from hydrogen ,-C
1-10alkyl ,-C
2-10alkenyl ,-C
3-6cycloalkyl ,-C
2-5ring is mixed alkyl, aryl and heteroaryl, wherein each R
cand R
dunsubstituted or individual independently selected from R by 1-3
fsubstituting group replace.This embodiment another kind of in, R
cand R
deach independently selected from hydrogen ,-C
1-10alkyl and-C
2-10alkenyl, wherein each R
cand R
dunsubstituted or individual independently selected from R by 1-3
fsubstituting group replace.
In another embodiment of the invention, R
cindependently selected from: hydrogen ,-C
1-10alkyl ,-C
2-10alkenyl ,-C
3-6cycloalkyl ,-C
3-6cycloalkyl-C
1-10alkyl-,-C
2-5ring is mixed alkyl ,-C
2-5ring is mixed alkyl-C
1-10alkyl-, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
cunsubstituted or individual independently selected from R by 1-3
fsubstituting group replace.In a class of this embodiment, R
cindependently selected from: hydrogen ,-C
1-10alkyl ,-C
2-10alkenyl ,-C
3-6cycloalkyl ,-C
2-5ring is mixed alkyl, aryl and heteroaryl, wherein each R
cunsubstituted or individual independently selected from R by 1-3
fsubstituting group replace.This embodiment another kind of in, R
cindependently selected from: hydrogen ,-C
1-10alkyl and-C
2-10alkenyl, wherein each R
cunsubstituted or individual independently selected from R by 1-3
fsubstituting group replace.
In another embodiment of the invention, R
dindependently selected from: hydrogen ,-C
1-10alkyl ,-C
2-10alkenyl ,-C
3-6cycloalkyl ,-C
3-6cycloalkyl-C
1-10alkyl-,-C
2-5ring is mixed alkyl ,-C
2-5ring is mixed alkyl-C
1-10alkyl-, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
dunsubstituted or individual independently selected from R by 1-3
fsubstituting group replace.In a class of this embodiment, R
dindependently selected from: hydrogen ,-C
1-10alkyl ,-C
2-10alkenyl ,-C
3-6cycloalkyl ,-C
2-5ring is mixed alkyl, aryl and heteroaryl, wherein each R
dunsubstituted or individual independently selected from R by 1-3
fsubstituting group replace.This embodiment another kind of in, R
dindependently selected from: hydrogen ,-C
1-10alkyl and-C
2-10alkenyl, wherein each R
dunsubstituted or individual independently selected from R by 1-3
fsubstituting group replace.
In another embodiment of the invention, each R
eindependently selected from: hydrogen ,-C
1-10alkyl ,-C
2-10alkenyl ,-C
3-6cycloalkyl ,-C
3-6cycloalkyl-C
1-10alkyl-, mix alkyl, ring of-ring mix alkyl-C
1-10alkyl-, aryl, heteroaryl, aryl-C
1-10alkyl-and heteroaryl-C
1-10alkyl-, wherein each R
ebe unsubstituted or be selected from R by 1-3
hsubstituting group replace.In a class of this embodiment, each R
eindependently selected from: hydrogen ,-C
1-10alkyl ,-C
2-10alkenyl ,-C
3-6cycloalkyl ,-ring are mixed alkyl, aryl, heteroaryl, wherein each R
ebe unsubstituted or be selected from R by 1-3
hsubstituting group replace.This embodiment another kind of in, each R
eindependently selected from: hydrogen ,-C
1-10alkyl and-C
2-10alkenyl, wherein each R
ebe unsubstituted or be selected from R by 1-3
hsubstituting group replace.This embodiment another kind of in, each R
eindependently selected from: hydrogen and-C
1-10alkyl, wherein each R
ebe unsubstituted or be selected from R by 1-3
hsubstituting group replace.This embodiment another kind of in, each R
e-C
1-10alkyl, wherein each R
ebe unsubstituted or be selected from R by 1-3
hsubstituting group replace.This embodiment another kind of in, each R
e-C
1-10alkyl.This embodiment another kind of in, each R
ehydrogen.
In another embodiment of the invention, each R
fbe selected from: halogen ,-C
1-10alkyl ,-OH ,-O-C
1-4alkyl ,-S (O)
m-C
1-4alkyl ,-CN ,-CF
3,-OCHF
2with-OCF
3, wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH, halogen, cyano group and-S (O)
2cH
3.In a class of this embodiment, each R
fbe selected from: halogen ,-C
1-10alkyl ,-OH ,-O-C
1-4alkyl ,-CN ,-CF
3,-OCHF
2with-OCF
3, wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH, halogen, cyano group and-S (O)
2cH
3.This embodiment another kind of in, each R
fbe selected from: halogen ,-C
1-10alkyl ,-OH ,-CN ,-CF
3,-OCHF
2with-OCF
3, wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH, halogen, cyano group and-S (O)
2cH
3.This embodiment another kind of in, each R
fbe selected from: halogen and-C
1-10alkyl, wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH, halogen, cyano group and-S (O)
2cH
3.
In another embodiment of the invention, each R
gbe selected from: hydrogen ,-C (O) R
ewith-C
1-10alkyl, wherein-C
1-10alkyl is unsubstituted or is replaced by 1-5 fluorine.
In another embodiment of the invention, each R
hbe selected from: halogen ,-C
1-10alkyl ,-OH ,-O-C
1-4alkyl ,-S (O)
m-C
1-4alkyl ,-CN ,-CF
3,-OCHF
2with-OCF
3, wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from following substituting group by 1-3 :-OH, halogen, cyano group and-S (O)
2cH
3.In a class of this embodiment, each R
hbe selected from: halogen ,-C
1-10alkyl ,-OH ,-O-C
1-4alkyl ,-CN ,-CF
3,-OCHF
2with-OCF
3, wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH, halogen, cyano group and-S (O)
2cH
3.This embodiment another kind of in, each R
hbe selected from: halogen ,-C
1-10alkyl ,-OH ,-CN ,-CF
3,-OCHF
2with-OCF
3, wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH, halogen, cyano group and-S (O)
2cH
3.This embodiment another kind of in, each R
hbe selected from: halogen and-C
1-10alkyl, wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH, halogen, cyano group and-S (O)
2cH
3.
In another embodiment of the invention, R
iindependently selected from :-C
1-6alkyl ,-OR
e,-NR
cs (O)
mr
e, halogen ,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-CF
3,-OCF
3,-OCHF
2,-C
3-6cycloalkyl and-C
2-5ring is mixed alkyl.
In a class of this embodiment, R
ibe selected from :-C
1-6alkyl, halogen ,-OR
e,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-CF
3,-OCF
3with-OCHF
2.This embodiment another kind of in, R
ibe selected from :-C
1-6alkyl, halogen ,-CN ,-CF
3,-OCF
3with-OCHF
2.This embodiment another kind of in, R
i-CF
3.
In another embodiment of the invention, R
jindependently selected from :-C
1-6alkyl ,-OR
e,-NR
cs (O)
mr
e, halogen ,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-CF
3,-OCF
3,-OCHF
2,-C
3-6cycloalkyl and-C
2-5ring is mixed alkyl.
In a class of this embodiment, R
jbe selected from :-C
1-6alkyl, halogen ,-OR
e,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-CF
3,-OCF
3with-OCHF
2.This embodiment another kind of in, R
jbe selected from :-C
1-6alkyl, halogen ,-CN ,-CF
3,-OCF
3with-OCHF
2.This embodiment another kind of in, R
j-CF
3.
In another embodiment of the invention, each R
kindependently selected from: halogen ,-C
1-10alkyl ,-OH, oxo, halogen ,-O-C
1-4alkyl ,-SO
2-C
1-6alkyl ,-C
1-6alkyl-SO
2c
1-6alkyl ,-CN ,-CF
3,-OCHF
2,-OCF
3,-NH
2,-NHSO
2c
1-6alkyl ,-NHCOC
1-6alkyl ,=N (OCH
3) ,-P (O) (OH)
2with-P (O) (OC
1-6alkyl)
2, wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl.In a class of this embodiment, each R
kindependently selected from :-C
1-10alkyl ,-O-C
1-4alkyl ,-OH, halogen ,-SO
2-C
1-6alkyl ,-C
1-6alkyl-SO
2c
1-6alkyl ,-CN ,-NHSO
2c
1-6alkyl and=N (OCH
3) and-P (O) (OC
1-6alkyl)
2, wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl; Or its pharmacy acceptable salt.In this type of a subclass, each R
kindependently selected from :-CH
3,-CH
2oH ,-OH, F ,-SO
2cH
3,-CH
2sO
2cH
3, CN and-P (O) (OCH
3)
2, wherein each-CH
3be unsubstituted or replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl.In this type of another subclass, each R
kindependently selected from :-CH
3,-CH
2oH ,-OH, F ,-SO
2cH
3,-CH
2sO
2cH
3, CN and-P (O) (OCH
3)
2, wherein each-CH
3be unsubstituted or replaced by 1-3-OH.In this type of another subclass, each R
kindependently selected from :-CH
3,-CH
2oH ,-OH, F ,-SO
2cH
3,-CH
2sO
2cH
3with-P (O) (OCH
3)
2.
In another embodiment of the invention, each R
kindependently selected from: halogen ,-C
1-10alkyl ,-OH, oxo, halogen ,-O-C
1-4alkyl ,-SO
2-C
1-6alkyl ,-C
1-6alkyl-SO
2c
1-6alkyl ,-CN ,-CF
3,-OCHF
2,-OCF
3,-NH
2,-NHSO
2c
1-6alkyl ,-NHCOC
1-6alkyl and=N (OCH
3), wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl.In a class of this embodiment, each R
kindependently selected from :-C
1-10alkyl ,-OH, halogen ,-SO
2-C
1-6alkyl ,-C
1-6alkyl-SO
2c
1-6alkyl ,-CN ,-NH
2,-NHSO
2c
1-6alkyl ,-NHCOC
1-6alkyl and=N (OCH
3), wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl.This embodiment another kind of in, each R
kindependently selected from :-C
1-10alkyl ,-OH, halogen ,-SO
2-C
1-6alkyl ,-C
1-6alkyl-SO
2c
1-6alkyl ,-CN ,-NHSO
2c
1-6alkyl and=N (OCH
3), wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl.This embodiment another kind of in, each R
kindependently selected from :-C
1-10alkyl ,-OH, halogen ,-SO
2-C
1-6alkyl ,-C
1-6alkyl-SO
2c
1-6alkyl and-CN, wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl.In this type of a subclass, each R
kindependently selected from :-CH
3,-CH
2oH ,-OH, F ,-SO
2cH
3,-CH
2sO
2cH
3and CN, wherein each-CH
3be unsubstituted or replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl.In this type of another subclass, each R
kindependently selected from :-CH
3,-CH
2oH ,-OH, F ,-SO
2cH
3,-CH
2sO
2cH
3and CN, wherein each-CH
3be unsubstituted or replaced by 1-3-OH.In this type of another subclass, each R
kindependently selected from :-CH
3,-CH
2oH ,-OH, F ,-SO
2cH
3,-CH
2sO
2cH
3.
In another embodiment of the invention, each R
kindependently selected from :-C
1-10alkyl ,-O-C
1-4alkyl ,-OH, halogen ,-SO
2-C
1-6alkyl ,-C
1-6alkyl-SO
2c
1-6alkyl ,-CN ,-NHSO
2c
1-6alkyl and=N (OCH
3), wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl, or its pharmacy acceptable salt.In a class of this embodiment, each R
kindependently selected from :-CH
3, OCH
3,-CH
2oH ,-OH, F ,-SO
2cH
3,-CH
2sO
2cH
3and CN, wherein each-CH
3be unsubstituted or replaced by 1-3-OH.
In another embodiment of the invention, each R
kindependently selected from: halogen ,-C
1-10alkyl ,-OH, oxo, halogen ,-O-C
1-4alkyl ,-SO
2-C
1-6alkyl ,-C
1-6alkyl-SO
2c
1-6alkyl ,-CN ,-CF
3,-OCHF
2,-OCF
3,-NH
2,-NHSO
2c
1-6alkyl ,-NHCOC
1-6alkyl ,=N (OCH
3) ,-P (O) (OH)
2with-P (O) (OC
1-6alkyl)
2, wherein each C
1-6alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl.In a class of this embodiment, each R
kindependently selected from :-C
1-10alkyl ,-O-C
1-4alkyl ,-OH, halogen ,-SO
2-C
1-6alkyl ,-C
1-6alkyl-SO
2c
1-6alkyl ,-CN ,-NHSO
2c
1-6alkyl and=N (OCH
3) and-P (O) (OC
1-6alkyl)
2, wherein each C
1-6alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl.
In another embodiment of the invention, each R
kindependently selected from: halogen ,-C
1-10alkyl ,-OH, oxo, halogen ,-O-C
1-4alkyl ,-SO
2-C
1-6alkyl ,-C
1-6alkyl-SO
2c
1-6alkyl ,-CN ,-CF
3,-OCHF
2,-OCF
3,-NH
2,-NHSO
2c
1-6alkyl ,-NHCOC
1-6alkyl and=N (OCH
3), wherein each C
1-6alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl.In a class of this embodiment, each R
kindependently selected from :-C
1-10alkyl ,-OH, halogen ,-SO
2-C
1-6alkyl ,-C
1-6alkyl-SO
2c
1-6alkyl ,-CN ,-NH
2,-NHSO
2c
1-6alkyl ,-NHCOC
1-6alkyl and=N (OCH
3), wherein each C
1-6alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl.This embodiment another kind of in, each R
kindependently selected from :-C
1-10alkyl ,-OH, halogen ,-SO
2-C
1-6alkyl ,-C
1-6alkyl-SO
2c
1-6alkyl ,-CN ,-NHSO
2c
1-6alkyl and=N (OCH
3), wherein each C
1-6alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl.This embodiment another kind of in, each R
kindependently selected from :-C
1-10alkyl ,-OH, halogen ,-SO
2-C
1-6alkyl ,-C
1-6alkyl-SO
2c
1-6alkyl and-CN, wherein each C
1-6alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl.
In another embodiment of the invention, each R
kindependently selected from :-SO
2-C
1-6alkyl and-C
1-6alkyl-SO
2c
1-6alkyl, wherein each C
1-6alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl.In a class of this embodiment, each R
kindependently selected from :-SO
2cH
3with-CH
2sO
2cH
3, wherein each-CH
3be unsubstituted or replaced by 1-3-OH.This embodiment another kind of in, each R
kindependently selected from :-SO
2cH
3with-CH
2sO
2cH
3.
In another embodiment of the invention, R
lbe selected from :-C
1-6alkyl, halogen ,-OR
e,-NR
cs (O)
mr
e,-S (O)
mr
e,-S (O)
mnR
cr
d,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-C (O) NR
cr
d,-NR
cc (O) R
e,-NR
cc (O) OR
e,-NR
cc (O) NR
cr
d,-CF
3,-OCF
3,-OCHF
2,-C
3-6cycloalkyl and-C
2-5ring is mixed alkyl.In a class of this embodiment, R
lbe selected from :-C
1-6alkyl, halogen ,-OR
e,-NR
cr
d,-C (O) R
e ,-OC (O) R
e ,-CO
2r
e,-CN ,-CF
3,-OCF
3with-OCHF
2.This embodiment another kind of in, R
lbe selected from :-C
1-6alkyl, halogen ,-CN ,-CF
3,-OCF
3with-OCHF
2.This embodiment another kind of in, R
l-CF
3.
In another embodiment of the invention, n is 0,1,2,3 or 4.In a class of this embodiment, n is 0,1,2 or 3.This embodiment another kind of in, n is 0,1 or 2.In a class of this embodiment, n is 0 or 1.In a class of this embodiment, n is 1,2,3 or 4.This embodiment another kind of in, n is 1,2 or 3.This embodiment another kind of in, n is 1 or 2.This embodiment another kind of in, n is 0.This embodiment another kind of in, n is 1.This embodiment another kind of in, n is 2.This embodiment another kind of in, n is 3.This embodiment another kind of in, n is 4.
In another embodiment of the invention, m is 0,1 or 2.In a class of this embodiment, m is 0 or 1.This embodiment another kind of in, m is 1 or 2.This embodiment another kind of in, m is 0.This embodiment another kind of in, m is 1.This embodiment another kind of in, m is 2.
In another embodiment of the invention, p is 0,1,2,3,4,5,6,7,8,9 or 10.In another embodiment of the invention, p is 0,1,2,3,4,5,6,7 or 8.In another embodiment of the invention, p is 0,1,2,3,4,5 or 6.In another embodiment of the invention, p is 0,1,2,3 or 4.In a class of this embodiment, p is 0,1,2 or 3.In a class of this embodiment, p is 0,1 or 2.In another embodiment of the invention, p is 1,2,3,4,5,6,7,8,9 or 10.In another embodiment of the invention, p is 1,2,3,4,5,6,7 or 8.In another embodiment of the invention, p is 1,2,3,4,5 or 6.In another embodiment of the invention, p is 1,2,3 or 4.In a class of this embodiment, p is 1,2 or 3.In a class of this embodiment, p is 1 or 2.This embodiment another kind of in, p is 0 or 1.This embodiment another kind of in, p is 0 or 2.This embodiment another kind of in, p is 0.This embodiment another kind of in, p is 1.This embodiment another kind of in, p is 2.This embodiment another kind of in, p is 3.This embodiment another kind of in, p is 4.This embodiment another kind of in, p is 5.This embodiment another kind of in, p is 6.This embodiment another kind of in, p is 7.This embodiment another kind of in, p is 8.This embodiment another kind of in, p is 9.This embodiment another kind of in, p is 10.
In another embodiment of the invention, the present invention relates to the compound of structural formula Ia:
Or its pharmacy acceptable salt.
In another embodiment of the invention, the present invention relates to the compound of structural formula Ib:
Or its pharmacy acceptable salt.
In another embodiment of the invention, the present invention relates to the compound of structural formula Ic:
Or its pharmacy acceptable salt.
In another embodiment of the invention, the present invention relates to the compound of structural formula Id:
Or its pharmacy acceptable salt.
In another embodiment of the invention, the present invention relates to the compound of structural formula Ie:
Or its pharmacy acceptable salt.
In another embodiment of the invention, the present invention relates to the compound of structural formula If:
Or its pharmacy acceptable salt.
The compound of structural formula I, comprises the compound of structural formula Ia, Ib, Ic, Id, Ie, And if Ig, and its pharmacy acceptable salt, hydrate and solvate.
Another embodiment of the present invention relates to the compound of structural formula I, wherein:
N is 1;
X is oxygen;
T is CH;
U is N;
V is CH;
A is selected from: aryl and heteroaryl, and wherein A is unsubstituted or is selected from R by 1-5
asubstituting group replace;
B is selected from: aryl and heteroaryl, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace,
R
1, R
2, R
5and R
6hydrogen; And
R
3and R
4be selected from: hydrogen, halogen and-C
1-6alkyl, wherein each C
1-6alkyl is unsubstituted or is selected from R by 1-3
lsubstituting group replace;
Or its pharmacy acceptable salt.
Another embodiment of the present invention relates to the compound of structural formula I, wherein:
N is 1;
X is oxygen;
T is CH;
U is N;
V is CH;
A is selected from: phenyl and pyridine, and wherein A is unsubstituted or is selected from R by 1-5
asubstituting group replace;
B is selected from phenyl, pyridine, pyrimidine, thiazole, benzoglyoxaline, benzothiazole, benzoxazole and benzoisoxazole, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace;
R
1, R
2, R
3, R
4, R
5and R
6hydrogen;
R
abe selected from :-C
1-6alkyl, halogen and-CF
3;
R
bindependently selected from:
(1)-C
1-10alkyl,
(2) halogen,
(3) -OH，
(4)-OC
1-10alkyl,
(5)-O (CH
2) pOC
1-10alkyl,
(6)-O (CH
2) pC
3-6cycloalkyl,
(7)-O (CH
2) pC
2-10ring is mixed alkyl,
(8)-O (CH
2) pO-C
3-6cycloalkyl,
(9)-O (CH
2) pO-C
2-10ring is mixed alkyl,
(10) -CF
3,
(11) -OCF
3,
(12) -OCHF
2,
(13)-(CH
2) p-C
2-10ring is mixed alkyl, and
(14)-S (O)
2c
1-10alkyl,
Wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace; With
Each R
kindependently selected from:
(1)-C
1-10alkyl,
(2)-O-C
1-4alkyl,
(3) -OH,
(4) halogen,
(5)-SO
2-C
1-6alkyl,
(6)-C
1-6alkyl-SO
2c
1-6alkyl,
(7) -CN,
(8)-NHSO
2c
1-6alkyl,
(9)=N (OCH
3), and
(10)-P (O) (OC
1-6alkyl)
2,
Wherein each C
1-10alkyl be unsubstituted or by 1-3 independently selected from-OH ,-OC
1-6alkyl, halogen, cyano group He – S (O)
2c
1-6the substituting group of alkyl replaces;
Or its pharmacy acceptable salt.
Another embodiment of the present invention relates to the compound of structural formula I, wherein:
N is 1;
X is oxygen;
T is CH;
U is N;
V is CH;
A is phenyl, and wherein phenyl is unsubstituted or is selected from R by 1-5
asubstituting group replace;
B is selected from: phenyl and pyridine, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace;
R
1, R
2, R
3, R
4, R
5and R
6hydrogen;
R
abe selected from :-C
1-6alkyl, halogen and-CF
3;
R
bindependently selected from:
(1)-C
1-10alkyl,
(2) halogen,
(3) -OH,
(4)-OC
1-10alkyl,
(5)-O (CH
2) pC
2-10ring is mixed alkyl,
(6)-CF
3, and
(7)-(CH
2) p-C
2-10ring is mixed alkyl,
Wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace; With
Each R
kindependently selected from:
(1)-C
1-10alkyl,
(2) -OH,
(3) halogen,
(4)-SO
2-C
1-6alkyl,
(5)-C
1-6alkyl-SO
2c
1-6alkyl, and
(6) -CN,
Wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl;
Or its pharmacy acceptable salt.
The illustrative of the compounds of this invention but nonrestrictive embodiment, described compound is used as the agonist of G-protein-coupled receptor 40 (GPR40), is following compounds:
And pharmacy acceptable salt.
In one embodiment of the present invention, the compound of formula I has absolute stereochemical two solid (stereogenic) carbon center, as pointed in the compound of structural formula Ig:
And pharmacy acceptable salt.
Although above-mentioned specific stereochemistry is preferred, other steric isomer, it is also useful for comprising diastereomer, enantiomer, epimer and these mixture in the disease for the treatment of GPR40 mediation.
The synthetic method preparing described compound is disclosed in hereafter shown embodiment.If do not provide the detail of synthesis in embodiment, so this compound can easily by the those of ordinary skill in the field of medical chemistry or synthetic organic chemistry by utilizing composite signal given in this article to prepare.If do not limit stereochemical center, so mixture of this representation steric isomer of the heart hereinto.For such compound, each steric isomer described, comprising enantiomer, diastereomer and these mixture is also compound of the present invention.
definition:
" Ac " is ethanoyl, and it is CH
3c (=O)-.
" alkyl " refer to can for straight chain or side chain or saturated carbon chains of its combination, unless separately had definition to carbochain.Other has the group of prefix " alkane " (alk), such as alkoxyl group and alkyloyl, also can be straight chain or side chain, or its combination, unless separately had definition to carbochain.The example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl and the tertiary butyl, amyl group, hexyl, heptyl, octyl group, nonyl etc.
" alkenyl " refers to the carbochain containing at least one carbon-to-carbon double bond, and its can be straight chain or side chain or its combination, unless otherwise defined.The example of alkenyl comprises vinyl, allyl group, pseudoallyl, pentenyl, hexenyl, heptenyl, 1-propenyl, crotyl, 2-methyl-2-butenyl etc.
" alkynyl " refers to the carbochain containing at least one carbon-to-carbon triple bond, and its can be straight chain or side chain or its combination, unless otherwise defined.The example of alkynyl comprises ethynyl, propargyl, 3-methyl-1-pentene alkynyl, 2-heptyne base etc.
" cycloalkyl " refer to have specify monocycle that carbonatoms object is saturated, dicyclo or the ring of carbocyclic ring of bridge joint.This term can also be used for the ring describing the carbocyclic ring being fused to aryl.The example of cycloalkyl comprises cyclopropyl, cyclopentyl, cyclohexyl, suberyl etc.In one embodiment of the present invention, cycloalkyl is selected from: cyclopropane, tetramethylene and hexanaphthene.
" cycloalkenyl group " refers to the monocycle of the non-aromatic containing at least one double bond or bicyclic carbocyclic ring.The example of cycloalkenyl group comprises cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctene base (cyclooxtenyl) etc.
" ring mix alkyl " refers to ring or the member ring systems of the carbocyclic ring of the monocycle of the undersaturated non-aromatic of saturated or part, dicyclo or bridge joint, and it contains at least one and is selected from N, NH, S and (comprises SO and SO
2) and the ring hetero atom of O.Described ring alkyl ring of mixing can be substituted on ring carbon atom and/or on theheterocyclic nitrogen atom (all atom).The mix example of alkyl of ring comprises tetrahydrofuran (THF), tetramethyleneimine, tetramethylene sulfide, azetidine, piperazine, piperidines, morpholine, trimethylene oxide and tetrahydropyrans, hexose, pentose, Isosorbide and different mannitol, two anhydromannitol, Isosorbide-5-Nitrae: 3, the two anhydromannitol, 1 of 6-, the two dehydration of 4:3,6-[D] N.F,USP MANNITOL, hexahydro furyl also [3,2-b] furans and 2,3,3a, 5,6,6a-hexahydro furyl is [3,2-b] furans also.In one embodiment of the present invention, ring alkyl of mixing is selected from: hexose, pentose, Isosorbide and different mannitol.In another embodiment of the invention, ring alkyl of mixing is selected from: Isosorbide and different mannitol.In another embodiment of the invention, ring alkyl of mixing is selected from: trimethylene oxide, tetrahydropyrans, azetidine, tetrahydric thiapyran and tetramethyleneimine.In another embodiment of the invention, ring alkyl of mixing is selected from: trimethylene oxide ,-piperazine, azetidine, tetramethyleneimine, morpholine and spiral shell (indenes-1,4-piperidines), in another embodiment of the invention, ring alkyl of mixing is trimethylene oxide.
" ring mix thiazolinyl " refers to ring or the member ring systems of the carbocyclic ring of non-aromatic monocyclic, dicyclo or bridge joint, its heteroatoms containing at least one double bond and be selected from N, NH, S and O containing at least one.
" aryl " refers to aromatic ring or the member ring systems of monocycle, dicyclo or three ring carbocyclic rings containing 5-14 carbon atom, and wherein at least one ring is aromatic.The example of aryl comprises phenyl and naphthyl.In one embodiment of the present invention, aryl is phenyl.
" heteroaryl " refers to ring or the member ring systems of monocycle, dicyclo or three rings, and it contains 5-14 carbon atom and is selected from N, NH, S (comprises SO and SO containing at least one
2) and the ring hetero atom of O, be wherein aromatic containing at least one in heteroatomic ring.The example of heteroaryl comprises pyrryl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl group, thiazolyl, imidazolyl, triazolyl, tetrazyl, furyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoisoxazole base, benzoxazolyl, benzothiazolyl, benzimidazolyl-, benzofuryl, benzothienyl (comprising S-oxide compound and dioxide), furo (2,3-b) pyridyl, quinolyl, indyl, isoquinolyl, quinazolyl, dibenzofuran group, etc.In one embodiment of the present invention, heteroaryl is selected from: pyridine, pyrimidine, thiazole, benzoglyoxaline, benzothiazole, benzoxazole and benzoisoxazole.In another embodiment of the invention, heteroaryl is pyridine.In another embodiment of the invention, heteroaryl is imidazopyridine.
" halogen " comprises fluorine, chlorine, bromine and iodine.
" Me " represents methyl.
As any variable (such as R
1, R
a, etc.) at any composition or when occurring in formula I once, its when its definition when occurring at every turn and another time occur defines and have nothing to do each other.In addition, the combination of substituting group and/or variable allows, as long as these combinations produce stable compound.Wavy line across key in substituting group variable represents tie point.
Running through in the standard name that openly full text uses of this specification sheets, first the terminal part of indication side chain is described, and be then neighbouring functional group, it is towards tie point.Such as, C
1-5alkyl-carbonyl-amino C
1-6alkyl substituent is equivalent to:
。
When selecting compound of the present invention, it will be recognized by those of ordinary skills, various substituting group, i.e. R
1, R
2deng, the known principle connected according to chemical structure with stability is selected.
Term " replacement " should be considered to pass through named substituting group and comprise multiple substitution value.When multiple substituting group part is disclosed or is required protection, the compound of described replacement can independently by one or more disclosed or substituting group part replacement single or multiple required for protection.Term is substituted independently and refers to that (two or more) substituting group can be identical or different.
The phrase " pharmaceutically acceptable " used in this article refers to and utilizes perfect medical judgment and follow all applicable government regulations, for carrying out the mankind of administration or animal safety and applicable those compounds, material, composition, salt and/or formulation.
Term " % enantiomer is excessive " (abbreviation " ee ") refers to that the main enantiomer of % deducts the secondary enantiomer of %.Therefore, 70% enantiomer is excessive is equivalent to a kind of enantiomer of generation 85% and the another kind of enantiomer of 15%.Term " enantiomer is excessive " is the same with the meaning of term " optical purity ".
The compound of formula I can contain one or more asymmetric center, therefore can occur with racemic modification and racemic mixture, single enantiomer, the mixture of diastereomer and the form of each diastereomer.This invention is intended to all these isomeric form comprising described formula I.
As known in the art by carrying out suitable improvement to method disclosed herein, independence synthesis or their chromatographic separation of optical isomer and diastereomer can be realized.By the X-radiocrystallography of crystallized product or crystallization of intermediate (if necessary, derivative with the reagent of the asymmetric center containing known absolute configuration), their absolute stereochemical can be determined.
If necessary, the racemic mixture of described compound can be separated, to be separated each enantiomorph.Can be separated by means commonly known in the art, the racemic mixture of such as compound and the coupling compounds of enantiomer-pure to form non-enantiomer mixture, then by standard method as fractionation crystallization or chromatography are separated each diastereomer.The acid of enantiomer-pure or the coupled reaction of alkali is used usually to generate salt.Then, pass through the cracking of added chiral residue, described non-enantiomer derivative is converted into pure enantiomorph.The racemic mixture of described compound directly can also be separated by using the chromatography of chiral stationary phase, and the method is known in the art.
Alternatively, use optically pure starting material or the reagent of configuration known, by means commonly known in the art, any enantiomorph of compound can be obtained by stereoselective syntheses.
Compounds more described herein contain olefinic double bond, and except as otherwise noted, this invention is intended to comprise E and Z two kinds of geometrical isomers.
Tautomer is defined as such compound, wherein proton another atom rapidly from an atomic migration of described compound to this compound.Compounds more described herein can exist as the tautomer with different hydrogen tie points.Such example can be the ketone and the Enol forms thereof that are called as keto-enol tautomerism body.Each tautomer and composition thereof is all included in the compound of formula I.
In the compound of general formula I, described all atoms can demonstrate their natural isotopic abundance, or one or more described atom can enrichment artificially in the concrete isotropic substance with same atoms number, but its atomic mass or total mass number are different from the atomic mass or total mass number that mainly find at occurring in nature.This invention is intended to all suitable isotopic variations comprising Compounds of structural formula I.Such as, the different isotope form of hydrogen (H) comprise protium (
1h), deuterium (
2h) and tritium (
3h).Protium is the main hydrogen isotope that nature finds.The enrichment of deuterium can provide some treatment advantage, and such as increasing Half-life in vivo or reducing dosage needs, or can as the compound of useful standard, for characterising biological sample.Tritium is radioactive, and therefore, it can be used as radiolabeled compound, as tracer in metabolism research or dynamics research.By the known routine techniques of those skilled in the art, or by being similar to those the method described in scheme herein and embodiment, use reagent and/or the intermediate of suitable isotopic enrichment, when not needing undo experimentation, the compound of the isotopic enrichment in structural formula I can be prepared.
In addition, some crystallized forms of the compounds of this invention can exist with the form of polymorphic form, and therefore these polymorphic forms are also included within the present invention.In addition, compounds more of the present invention can form solvate with water or common organic solvents.These solvates comprise within the scope of the invention.
Usually, compound of the present invention is preferably with the form administration of the preparation of enantiomer-pure.By any one in many ordinary methods, racemic mixture can be become their each enantiomer.These comprise chiral chromatography, use chiral auxiliary(reagent) derivatize, then by chromatogram or Crystallization Separation, and carry out fractional crystallization to diastereoisomeric salt.
salt:
Be appreciated that, just as used in this, quoting of compound of the present invention is also intended to comprise pharmacy acceptable salt and also has pharmaceutically unacceptable salt, when these pharmaceutically unacceptable salt when using as precursor for discharging free cpds or their pharmacy acceptable salt or using in other synthetic operation time.
Compound of the present invention can administration as a pharmaceutically acceptable salt form.Term " pharmacy acceptable salt " refers to by the obtained salt of pharmaceutically acceptable nontoxic alkali or acid (comprising inorganic or organic bases and inorganic or organic acid).The salt being included in the basic cpd in term " pharmacy acceptable salt " refers to the non-toxic salt of the compounds of this invention, and it is prepared by free alkali and suitable organic or inorganic acid-respons usually.The exemplary salt of basic cpd of the present invention includes, but are not limited to, following: acetate, benzene sulfonate, benzoate, supercarbonate, hydrosulfate, bitartrate, borate, bromide, d-camphorsulfonic acid salt, carbonate, muriate, clavulanate, Citrate trianion, dihydrochloride, edetate, ethanedisulphonate, estolate, esilate, fumarate, gluceptate, gluconate, glutaminate, bismuth glycolyl arsanilate salt, hexylresorcinate, breathe out amine, hydrobromate, hydrochloride, Hydroxynaphthoate, iodide, different thiosulphate, lactic acid salt, Lactobionate, lauroleate, malate, maleate, mandelate, mesylate, MB, methyl nitrate, Methylsulfate, mucate, naphthalenesulfonate, nitrate, N-METHYL-ALPHA-L-GLUCOSAMINE ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphoric acid salt/diphosphate, polygalacturonate, salicylate, stearate, vitriol, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide compound and valerate.In addition, if compound of the present invention carries an acidic moiety, so its suitable pharmacy acceptable salt includes, but are not limited to, and the salt being derived from mineral alkali comprises the salt of aluminium, ammonium, calcium, copper, iron, ferrous iron, lithium, magnesium, manganic salt, bivalent manganese, potassium, sodium, zinc etc.Particularly preferably be ammonium, calcium, magnesium, potassium and sodium salt.The salt being derived from pharmaceutically acceptable organic nontoxic alkali comprises primary, the salt of the second month in a season and tertiary amine, cyclammonium and alkali ion-exchange resin, such as arginine, trimethyl-glycine, caffeine, choline, N, N-dibenzyl-ethylenediamin, diethylamine, 2-diethylaminoethanol, DMAE, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine, breathe out amine, Isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, purines, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, tromethane etc.
In addition; when carboxylic acid (-COOH) or alcohol radical are present in the compounds of this invention; the pharmaceutically acceptable ester of carboxylic acid derivative can be used; such as methyl, ethyl or oxy acid methyl neopentyl ester; or the acyl derivative of alcohol, such as O-ethanoyl, O-valeryl, O-benzoyl and O-aminoacyl.Included by it is those esters being used as slowly-releasing or prodrug formulation for modifying solubleness or hydrolysis properties known in the art and carboxyl groups.
The solvate of the compounds of this invention, and particularly hydrate, comprise in the present invention equally.
purposes
The compounds of this invention is effective agonist of GPR40 acceptor.The compounds of this invention and pharmacy acceptable salt thereof can treat the disease regulated by GPR40 part (it is agonist normally) effectively.These diseases many are summarized as follows.
By the compounds of this invention for the treatment of significant quantity or its pharmacy acceptable salt being administered to the patient needing to carry out treating, one or more these diseases can be treated.And the compounds of this invention may be used for manufacturing the medicine that may be used for treating one or more these diseases:
(1) non insulin dependent diabetes (diabetes B);
(2) hyperglycemia;
(3) insulin resistance;
(4) metabolic syndrome;
(5) obesity;
(6) hypercholesterolemia;
(7) hypertriglyceridemia (level being rich in the lipoprotein of tri-glyceride of rising);
(8) that mix or diabetic dyslipidemia;
(9) low HDL cholesterol;
(10) high LDL-C;
(11) high lipoprotein B mass formed by blood stasis; With
(12) atherosclerosis.
The preferable use of the compounds of this invention can be by the described compound administration for the treatment of significant quantity is used for the treatment of one or more following diseases to needing the patient for the treatment of.The compounds of this invention may be used for manufacturing the medicine being used for the treatment of one or more these diseases:
(1) type ii diabetes, and hyperglycemia relevant with type ii diabetes specifically;
(2) metabolic syndrome;
(3) obesity; With
(4) hypercholesterolemia.
The compounds of this invention can reduce glucose in the glucose tolerance that diabetic patient neutralization has weakening and/or the non-diabetic patient being in pre-diabetic illness and lipid effectively.The compounds of this invention can alleviate the hyperinsulinemia be usually present in diabetic or pre-diabetic patient, by regulating the fluctuation of the serum level of glucose be usually present in these patients.Described compound can also effectively be treated or reduce insulin resistance.Described compound can effectively be treated or prevent gestational diabetes.
Described compound can also effectively be treated or prevent lipid disorder.Described compound effectively can be treated or be prevented the obstacle relevant with diabetes.Described compound effectively can also be treated or be prevented the obstacle relevant with obesity.
Compound of the present invention can also be used for improving or recovering Instreptozotocin Induced, and they may be used for treatment type i diabetes or delay or prevent type ii diabetes needs of patients insulin treatment like this.
The present invention also comprises the pharmacy acceptable salt of described compound, and comprises the pharmaceutical composition of described compound and pharmaceutically acceptable carrier.Described compound can be used for treating insulin resistance, type ii diabetes, hyperglycemia and the hyperlipemia relevant with type ii diabetes and insulin resistance.Described compound also can be used for treatment of obesity.
Compound of the present invention or its pharmacy acceptable salt may be used for preparing a kind of medicine, and described medicine is used for the treatment of the type ii diabetes in people or other mammalian subject.
Treat a method for type ii diabetes, it comprises compound of the present invention or its pharmacy acceptable salt of the bacterium giving needs treatment, or comprises the pharmaceutical composition of described compound.Other medical usage of the compounds of this invention is set forth in this article.
Compound of the present invention, at least one wherein in T, U and V is N or N-oxide compound, compd A-1 such as in Table A, A-2, A-3 and A-4, CH with wherein T, the compound of U to be CH and V be CH, compd B-1 such as in Table A, B-2, B-3 are compared with B-4, measure in (+/-100% human serum) at GPR40 inositol monophosphate circulation (IP1), have the benefit of the inherent drug effect (2-20 doubly) of unexpected raising.Due to the drug effect that they increase in this measures, compound of the present invention is desirably under lower blood plasma exposes to the open air and shows glucose minimizing effect, and therefore may need lower dosage.
Compound of the present invention, such as, compd A-1 in Table A and A-3, with the compound of wherein T is CH, U to be CH and V be CH, such as, compd B-1 in Table A is compared with B-3, at minimizing and ionic channel, Kv11.1 connection aspect (5-10-doubly) also has unexpected benefit.This ionic channel, is also referred to as hERG passage, and the heart arrythymias (QTc intermittent extension) sometimes with fatal is relevant.It reduce the combination of ionic channel and ionic channel Kv11.1 under target, increase with the GPR40 activity on target and connect, due in the molecule in conjunction with single nitrogen-atoms, compound of the present invention is caused to have the unexpected benefit improving 20-100 times in selectivity.
In addition, compound of the present invention, at least one wherein in T, U and V is N or N-oxide compound, compd A-1 such as in Table A, A-2, A-3 and A-4, with the compound of wherein T is CH, U to be CH and V be CH, such as, compd B-1 in Table A, B-2, B-3 are compared with B-4, at water-bearing media, such as, in phosphate buffered saline (PBS) (PBS) solution, pH 7 times, and/or the medium relevant with biology, such as FaSSIF (fasting state simulated intestinal fluid), pH 7 times, has the benefit of unexpected larger solubleness (2-5 is doubly).Solubleness larger in water-bearing media and/or FaSSIF makes it possible to cause using conventional preparation and compound method.Larger solubleness can also be improved and exposes to the open air, and it can cause lower dosage.
Table A
Nd=do not measure/not test.
Term used herein " diabetes " comprises insulin-dependent diabetes (i.e. IDDM, also known as type i diabetes) and non-insulin-dependent diabetes mellitus (NIDDM) (i.e. NIDDM, also known as type ii diabetes).Type i diabetes or insulin-dependent diabetes are the results definitely lacking Regular Insulin, and Regular Insulin is the hormone regulating glucose utilization.Type ii diabetes or do not rely on the diabetes (i.e. non-insulin-dependent diabetes mellitus (NIDDM)) of Regular Insulin, usually occurring under the condition that normally or even insulin level raises, and seemingly tissue can not suitably to the result that Regular Insulin is replied.Overwhelming majority type ii diabetes patient is also fat.Composition of the present invention can be used for treatment I type and type ii diabetes.Term " diabetes relevant to obesity " refers to caused by obesity or results from the diabetes of obesity.
The feature of diabetes is: fasting blood glucose level is more than or equal to 126 mg/dl.Diabetic subjects has the fasting blood glucose level being more than or equal to 126 mg/dl.Pre-diabetes experimenter (pre diabetic subject) is the people suffering from pre-diabetes (prediabetes).The feature of pre-diabetes is fasting plasma glucose (FPG) level weakened, and it is more than or equal to 110 mg/dl and is less than 126 mg/dl; Or the glucose tolerance weakened; Or insulin resistance.Pre-diabetes experimenter suffers from impaired fasting glucose (IFG) (fasting plasma glucose (FPG) level is more than or equal to 110 mg/dl and is less than 126 mg/dl) or impaired glucose tolerance (2 hours plasma glucose levels
>140 mg/dl and < 200 mg/dl) or the experimenter of insulin resistance, cause the danger forming diabetes to increase.
The treatment of diabetes refers to and gives compound of the present invention or composition to treat diabetic subject.A kind of result for the treatment of can be reduce the glucose levels suffered from the patient of high glucose levels.Another result for the treatment of can be reduce the insulin level suffered from the patient of high insulin levels.Another result for the treatment of can be reduce the plasma triglyceride suffered from the patient of high plasma triglyceride.Another result for the treatment of reduces the LDL-C suffered from the patient of high LDL-C level.Another result for the treatment of can be improve the HDL cholesterol had in the patient of low HDL cholesterol levels.Another result for the treatment of improves insulin sensitivity.Another result for the treatment of can be improve the glucose tolerance had in the patient of glucose intolerance.Another result for the treatment of can be reduce the insulin resistant in the patient suffering from insulin resistant raising or insulin level rising.The prevention of diabetes, the prevention of especially relevant with obesity diabetes, refers to and gives compound of the present invention or composition, to prevent the morbidity of diabetes in the patient needing it.The patient of prevent diabetes is needed to be overweight or fat pre-diabetes (prediabetic) patient.
Should be appreciated that, term " diabetes relevant illness " refers to illness that is relevant to diabetes, that produce caused by it or by it.The example of diabetes related disorders comprises: retina injury, ephrosis and nerve injury.
Term used herein " atherosclerosis " comprising: the vascular disease of the doctor institute awareness and understanding put into practice in related drugs field and illness.Atherosclerotic cardiovascular disease, coronary heart disease (being also called coronary artery disease or ischemic heart disease), cerebrovascular disease and peripheral vascular disease are all atherosclerotic clinical manifestations, and therefore by term " atherosclerosis " and " atheromatosis " are contained.Can give by the antihypertensive agents coupling medicine that constitute jointly of the anti-obesity agents for the treatment of significant quantity with treatment significant quantity, thus prevention or reduce may exist coronary heart disease situation, cerebrovascular situation or the appearance of intermittent claudication or the danger of recurrence.Coronary heart disease situation is intended to comprise CHD death, myocardial infarction (that is, having a heart attack) and revascularization process coronarius.Cerebrovascular situation is intended to comprise ischemia or hemorrhagic stroke (also known as cerebrovascular accident) and transient ischemic attack (TIA).Intermittent claudication is the clinical manifestation of peripheral vascular disease.Term used herein " atheromatosis situation " is intended to comprise coronary heart disease situation, cerebrovascular situation and intermittent claudication.The people of one or more non-lethal atheromatosis situation of experience was those people that there is this situation recurrence possibility in the past.Should be appreciated that, term " atherosclerosis relevant disease " refers to disease that is relevant to atherosclerosis, that produce caused by it or by it.
Term used herein " hypertension " comprising: wherein also do not understand the cause of disease or wherein hypertension be idiopathic because more than one cause of disease causes or essential hypertension, such as, heart and blood vessel all change; The wherein secondary hypertension of the known cause of disease.The reason of secondary hypertension is including, but not limited to obesity; Ephrosis; Hormonal conditions; Use some drugs, such as, oral contraceptive, corticosteroid steroid, S-Neoral, etc.Term " hypertension " comprising: wherein systolic pressure and diastolic pressure level raise the hypertension of (>=140 mmHg/ >=90 mmHg), wherein only have systolic pressure to be increased to and be more than or equal to 140 mm Hg, and diastolic pressure is lower than the isolated systolic hypertension of 90 mm Hg.Normal arterial pressure can be defined as: systolic pressure is lower than 120 mmHg, and diastolic pressure is lower than 80 mmHg.Hyperpietic suffers from hypertensive patient.Prehypertensive (pre-hypertensive) patient is the patient of blood pressure between 120 mmHg/80 mmHg and 139 mmHg/89 mmHg.A result for the treatment of reduces the blood pressure of hyperpietic.Hypertensive treatment refers to hypertension in order to treat hyperpietic and gives compound of the present invention and composition.The treatment of the illness relevant to hypertension refer to and give compound of the present invention or composition in order to treat with hypertension associated conditions.The prevention of hypertension or hypertension associated conditions refers to and gives prehypertensive (pre-hypertensive) patient composition of the present invention, thus the morbidity of preventing hypertension or hypertension associated conditions.Hypertension associated conditions is herein relevant with hypertension, caused by hypertension or result from hypertension.The example of hypertension associated conditions is including, but not limited to heart trouble (heart disease), in heart failure, heart attack (heart attack), renal failure and apoplexy.
Hyperlipemia and lipid disorders are the illnesss of lipid metabolism, comprise with one or more lipid (i.e. cholesterol and triglyceride level) and/or lipophorin (namely, aPoA, B, C and E) and/or lipoprotein is (namely, the macromolecular complex formed by lipid and lipophorin, they make lipid circulate in blood, such as LDL, VLDL and IDL) abnormal concentrations be the various illnesss of feature.The lipid of hyperlipidemia and unusual high levels, LDL and VLDL cholesterol and/or triglyceride level are relevant.The treatment of hyperlipemia refers to and gives patients with dyslipidemia composition of the present invention.The prevention of hyperlipemia refers to and gives hyperlipemia (pre-dyslipidemic) patient in early stage composition of the present invention.Hyperlipemia patient in early stage refers to have higher than normal lipid level but also do not reach the patient of hyperlipemia.
Term " hyperlipemia relevant illness " and " illness that lipid disorders is relevant " are interpreted as referring to illness that is relevant to hyperlipemia or lipid disorders, that produce caused by it or by it.The example of the illness that the hyperlipemia illness of being correlated with is relevant with lipid disorders is including, but not limited to hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, high-density lipoprotein (HDL) (HDL) level is low, plasma low density lipoprotein (LDL) level is high, atherosclerosis and its sequela, coronary artery or carotid disease, heart attack and apoplexy.
Term used herein " obesity " is the illness that wherein there is excess body fat.The working definition of obesity based on weight index (BMI), its be with body weight divided by height rice number square the (kg/m of form calculus
2)." obesity " refers to that the weight index (BMI) of the patient of other aspect health is more than or equal to 30 kg/m
2illness, or there is the coexist BMI of patient of symptom of at least one be more than or equal to 27 kg/m
2illness." obesity patient " is that weight index (BMI) is more than or equal to 30 kg/m
2the patient of other aspect health, or BMI is more than or equal to 27 kg/m
2, there is at least one to coexist the patient of symptom.Overweight patient is the patient be among risk therefor." to be in the patient among risk therefor " be BMI is 25 kg/m
2extremely lower than 30 kg/m
2the patient of other aspect health, or BMI is 25 kg/m
2extremely lower than 27 kg/m
2, there is at least one to coexist the patient of symptom.
In Aisa people, in the people of comparatively under-weight index (BMI), there is the danger relevant with obesity increased.In Asian countries, comprise Japan, " obesity " refers to following illness: the BMI that the patient with that at least one obesity causes or relevant to the obesity symptom that coexists (this symptom needs to lose weight or can improve by losing weight) has is more than or equal to 25 kg/m
2.In Asian countries, comprise Japan, " obese patient " refers to following patient: have that at least one obesity is brought out or relevant to the obesity symptom that coexists (this symptom needs to lose weight or can improve by losing weight) and the BMI that has is more than or equal to 25 kg/m
2.In Asian-Pacific area, " being in the patient among risk therefor " is that BMI is greater than 23 kg/m
2to being less than 25 kg/m
2patient.
Term used herein " obesity " refers to the definition comprising all above-mentioned obesity.
What that obesity is brought out or obesity was relevant coexist symptom is including, but not limited to diabetes, II type non insulin dependent diabetes, the diabetes relevant to obesity, impaired glucose tolerance, impaired fasting glucose (IFG), insulin resistance syndrome, hyperlipemia, hypertension, the hypertension relevant to obesity, hyperuricemia, gout, coronary artery disease, myocardial infarction, stenocardia, sleep apnea syndrome, pickwickian syndrome, fatty liver; Cerebral infarction, cerebral thrombosis, transient ischemic attack (TIA), orthopedic illness, joint deformity, pain in the back, menopathy and infertile.Especially, the symptom that coexists comprises: vascular hypertension, hyperlipidemia, hyperlipemia, glucose intolerance, cardiovascular disorder, the illness that sleep apnea and other obesity are correlated with.
The treatment of obesity and obesity related condition refers to and gives compound of the present invention, to reduce or to keep the body weight of obese patient.Relative to the body weight the patient just before giving the compounds of this invention, a result for the treatment of can reduce the body weight of obese patient.Another result for the treatment of can prevent previously owing to going on a diet, taking exercise or pharmacological agent and lose the weight recovery of body weight.Another result for the treatment of can reduce appearance and/or the severity of obesity-related disorder.This treatment can suitably cause the food of patient or the minimizing of energy intake in the patient needing it, comprises and reduces food intake total amount, or the absorption of the concrete integral part cut down one's diet, such as, reduce the absorption of carbohydrate or fat; And/or suppression dietetic alimentation; And/or suppress the reduction of metabolic rate; With reduction weight.Treatment also can cause the change of metabolic rate, such as, increase metabolic rate, instead of reduces metabolic rate, or except suppressing the reduction of metabolic rate; And/or make usually to result from the metabolic resistance lost weight to minimize.
The prevention of obesity and obesity related condition refers to and gives compound of the present invention, to reduce or to remain in the body weight of the patient among risk therefor.Relative to the body weight the patient just before giving the compounds of this invention, a result of prevention can reduce the body weight of the patient be among risk therefor.Another result of prevention can prevent previously owing to going on a diet, taking exercise or pharmacotherapy and lose the weight recovery of body weight.If treated before the obesity morbidity being in patient among risk therefor, another result of prevention can prevent obesity from occurring.If treated before the obesity morbidity being in patient among risk therefor, then another result of preventing can reduce appearance and/or the severity of obesity related condition.In addition, if in fat patient begin treatment, then this treatment can prevent the appearance of obesity related condition, progress or severity, obesity related condition is such as, but be not limited to arteriosclerosis, type ii diabetes, polycystic ovarian disease, cardiovascular disorder, osteoarthritis, tetter, vascular hypertension, insulin resistance, hypercholesterolemia, hypertriglyceridemia and gallbladdergallstonecholetithiasis.
Obesity related condition is herein relevant with obesity, caused by obesity or result from obesity.The example of the illness that obesity is correlated with comprises: excessive eating and exessive appetite, vascular hypertension, diabetes, plasma insulin concentrations raises and insulin resistance, hyperlipemia, hyperlipidemia, uterine endometrium, breast, prostate gland and colorectal carcinoma, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallbladdergallstonecholetithiasis, heart trouble, abnormal heart cyclical movement and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, apoplexy, polycystic ovarian disease, craniopharyngioma, Prader-Willi syndrome, Frohlich's syndrome, the patient that GH lacks, normal variant Short stature, Turner's syndrome, and display Metabolic activity reduces or other pathological disorders of rest energy consumption reduction (per-cent as total fat-free mass), such as, suffer from the children of acute lymphoblastic leukemia.The further example of obesity related condition is: metabolism syndrome, also known as syndrome X, insulin resistance syndrome, property and reproductive dysfunction, such as infertile, hypogonadism in males and female hirsutism, gastrointestinal motility disorders, such as, stomach-esophageal reflux that obesity is relevant, dyspnoea, such as obesity-hypoventilation syndrome (pickwickian syndrome), cardiovascular disorder, inflammation, such as, the Systemic inflammation of vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia, back pain, gallbladder disease, gout and kidney.Compound of the present invention also can be used for the danger of the secondary consequences reducing obesity, such as, reduce the danger of left ventricular hypertrophy.
Term " metabolism syndrome ", also known as syndrome X, be defined in following: The Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III), National Institutes of Health, 2001, NIH Publication No. 01-3670. E.S. Ford et al., JAMA, vol. 287 (3), Jan. 16, 2002, pp 356-359.In brief, if people has the following illness of three kinds or more kind, then this people can be defined as and have metabolism syndrome: abdominal obesity, hypertriglyceridemia, HDL cholesterol reduces, hypertension and high fasting blood glucose.For these standard definition in ATP-III.The treatment of metabolism syndrome refers to and gives Metabolic Syndrome Patients composition of the present invention.The prevention of metabolism syndrome refers to patient's composition of the present invention of two kinds of symptoms with definition metabolism syndrome.The patient of two kinds of symptoms with definition metabolism syndrome be formed definition metabolism syndrome two kinds of symptoms but also do not form the patient of the three kinds or more kind symptom of definition metabolism syndrome.
Should be appreciated that, term " administration " and/or " giving " compound show the prodrug needing the individuality for the treatment of or Mammals to provide compound of the present invention or the compounds of this invention.
The compound giving structural formula I in order to put into practice this methods for the treatment of is that the compound of the structural formula I of Mammals significant quantity by needing this treatment or prevention carries out.For the demand of the preventive administration according to the inventive method by using well-known Hazard Factor to determine.The significant quantity of single compound is determined in final analysis by the doctor of responsible case or animal doctor, but depend on following factors, such as, the definite disease treated, the severity of the disease that patient suffers from and Other diseases or illness, the other medicines that patient may need simultaneously and the route of administration selected by treatment, and the other factors in doctor's judgement.
The purposes of the compounds of this invention in these diseases or illness can prove with the animal disease model reported in document.
administration and dosage range
In order to Mammals, particularly the mankind provide the compounds of this invention of effective dose, can use any suitable route of administration.Such as, can use oral, rectum, locally, parenteral, eye, lung, nose etc. route of administration.Formulation comprises tablet, tablet, dispersion agent, suspensoid, solution, capsule, ointment, paste and aerosol etc.Preferred oral administration compound of the present invention.
Need in the illness of the agonism of GPR40 receptor active in treatment or prevention, suitable dosage level will be generally about 0.01-500 mg every kg weight in patients every day, and it can with single dose or multiple dose administration.Preferably, described dosage level will be about 0.1-about 250 mg/kg every day; Be more preferably about 0.5-about 100 mg/kg every day.Suitable dosage level can be about 0.01-250mg/kg every day, about 0.05-100 mg/kg every day, or about 0.1-50 mg/kg every day.Within the scope of this, described dosage can be 0.05-0.5,0.5-5 or 5-50 mg/kg every day.For oral administration, described composition preferably provides with the form of tablet, described tablet contains the activeconstituents of 1.0 to 1000 mg, activeconstituents particularly containing 1.0,5.0,10.0,15.0,20.0,25.0,50.0,75.0,100.0,150.0,200.0,250.0,300.0,400.0,500.0,600.0,750.0,800.0,900.0 and 1000.0 mg, it adjusts dosage according to the symptom of treated patient.Described compound can with every day 1-4 time, the preferably Dosage Regimens Dosage of once a day or twice.
When treat or prevent diabetes and/or hyperglycemia or hypertriglyceridemia or other need the disease of compound of the present invention time, when the compounds of this invention carries out administration with every per daily dose of about 0.1 milligram ~ about 100 mg/kg the weight of animals, preferably with single daily dose or with dosage 2 ~ 6 administrations every day separated, or during with sustained release forms administration, usually can obtain gratifying result.For most of Mammals, total every per daily dose is about 1.0 milligrams ~ about 1000 milligrams, preferably about 1 mg to about 50 mg.For the situation of 70kg grownup, described total every per daily dose will be generally about 7 milligrams ~ about 350 milligrams.Can regulate this dosage regimen, to provide best therapeutics response.
In addition, need in the illness of the agonism of GPR40 receptor active in treatment or prevention, suitable dosage level will be typically the every kg weight in patients of about 0.01-500 mg weekly, and it can with single dose or multiple dose administration.Preferably, described dosage level will for about 0.1-about 250 mg/kg weekly; Be more preferably about 0.5-about 100 mg/kg weekly.Suitable dosage level can be about 0.01-250mg/kg weekly, weekly, or about 0.1-50 mg/kg is weekly for about 0.05-100 mg/kg.Within the scope of this, described dosage can be 0.05-0.5,0.5-5 or 5-50 mg/kg weekly.For oral administration, described composition preferably provides with the form of tablet, described tablet contains the activeconstituents of 1.0 to 1000 mg, activeconstituents particularly containing 1.0,5.0,10.0,15.0,20.0,25.0,50.0,75.0,100.0,150.0,200.0,250.0,300.0,400.0,500.0,600.0,750.0,800.0,900.0 and 1000.0 mg, it adjusts dosage according to the symptom of treated patient.Described compound can also with 1-4 time weekly, preferably weekly the or Dosage Regimens Dosage of twice.
When treat prevent diabetes and/or hyperglycemia or hypertriglyceridemia or compound of the present invention treatable Other diseases time, when compound of the present invention is with the dosed administration weekly of the every kg animal weight of about 0.1 mg-about 100 mg, preferably with single every weekly dose or with the dosage separated 2-6 administration weekly, or during with sustained release forms administration, usually can obtain gratifying result.For most of Mammals, total every weekly dose is about 1.0 mg-about 1000 mg, is preferably about 1 mg-about 50 mg.When the grownup of 70 kg body weight, total every weekly dose will be typically about 7 mg-about 350 mg.This dosage can be regulated to provide best treatment response.
But, be appreciated that, can change for the concrete dosage level of any particular patient and administration frequency, and will depend on that various factors comprises the activity of used particular compound, time length of the metabolic stability of this compound and effect, age of host, body weight, general health situation, sex, diet, mode of administration and the severity of administration time, drainage rate, drug combination and concrete illness and the treatment of host's experience.
Compound of the present invention may be used in pharmaceutical composition, and described pharmaceutical composition comprises (a) described compound (or all compounds) or its pharmacy acceptable salt, and (b) pharmaceutically acceptable carrier.Compound of the present invention may be used in pharmaceutical composition, and described pharmaceutical composition comprises one or more other active pharmaceutical ingredients.Compound of the present invention can also be used in pharmaceutical composition, and wherein in described pharmaceutical composition, compound of the present invention or its pharmacy acceptable salt are unique activeconstituentss.
Term " composition " in pharmaceutical composition is intended to comprise such product, it comprises activeconstituents (all) and forms the inert component (all) of carrier and any product, it is directly or indirectly by the associating of two or more compositions any, complexing or gathering, or by the decomposition of one or more compositions, or obtained by the reaction of other type of one or more compositions or interaction.Therefore, pharmaceutical composition of the present invention comprises any composition obtained by being mixed with pharmaceutically acceptable carrier by compound of the present invention.
Compound of the present invention can with other medicines conbined usage, described other medicines also may be used for treatment or improve compound of the present invention to its useful disease or illness.These other medicines can by the route of administration that is generally used for it and consumption simultaneously or administration together with compound of the present invention successively.Suffer from type ii diabetes, insulin resistance, obesity, metabolism syndrome and the patient with the complication of these diseases in treatment, usually give more than a kind of medicine.Usually, compound of the present invention can give such patient, and this patient has given one or more other medicines in order to these illnesss.Described compound will usually give such patient, and it has been treated with one or more antidiabetic compounds, such as N1,N1-Dimethylbiguanide, sulfonylurea and/or PPAR gamma agonist, when the glucose level of this patient does not respond fully for treatment.
When compound of the present invention and one or more other medicines use simultaneously, preferably with the pharmaceutical composition containing these other drugs and compound of the present invention of the form of unit dosage.But described combination therapy also comprises wherein by compound of the present invention and the therapy of one or more other medicines in different staggered time table administrations.Also consider when with one or more other active ingredient combination medications, the compound of the present invention than dosage lower during respective medication separately and other activeconstituents can be used.Therefore, in addition to the present compounds, pharmaceutical composition of the present invention comprises also containing those of one or more other activeconstituentss.
Can with each general formula compound described herein join together administration respectively or in same medicinal compositions the example of other activeconstituents of administration include, but are not limited to:
(1) other dipeptidyl peptidase-IV (DPP-4) inhibitor (such as, sitagliptin (sitagliptin), alogliptin, BI 1356 (linagliptin), vildagliptin (vildagliptin), BMS-477118 (saxagliptin), teneligliptin (teneligliptin), omarigliptin);
(2) insulin sensitizer, comprise (i) PPAR gamma agonist, such as glitazone (such as U-721017E, AMG 131, MBX2044, mitoglitazone, lobeglitazone, IDR-105, rosiglitazone and balaglitazone), and other PPAR part, comprise (1) PPAR α/γ dual agonists (such as, ZYH2, ZYH1, GFT505, chiglitazar, muraglitazar, aleglitazar, sodelglitazar and naveglitazar); (2) such as fenofibric acid derivative is (such as PPAR alfa agonists, gemfibrozil, clofibrate, Win-35833, fenofibrate, bezafibrate), (3) selective PPARγ modulator is (SPPAR γ M ' s), (such as, such as those disclosed in WO02/060388, WO02/08188, WO2004/019869, WO2004/020409, WO2004/020408 and WO2004/066963); (4) PPAR gamma portion agonist; (ii) biguanides, such as N1,N1-Dimethylbiguanide and pharmacy acceptable salt thereof, especially, Walaphage, and sustained release preparation, such as Glumetza, Fortamet and GlucophageXR; (iii) Protein Tyrosine Phosphatases-1B (PTP-1B) inhibitor (such as, ISIS-113715 and TTP814);
(3) Regular Insulin or insulin analog (such as, insulin detemir, paddy relies Regular Insulin, moral paddy Regular Insulin, Lantus, Insulin lispro, SBS1000 and Regular Insulin and insulin analog oral and suck preparation);
(4) leptin and leptin derivative and agonist;
(5) dextrin and dextrin analogue (such as, tripro-amylin);
(6) sulfonylurea and non-sulfonylurea insulin are urged to secrete agent (such as, tolbutamide, Glyburide, Glipizide, glimepiride, mitiglinide, meglitinides, nateglinide and repaglinide);
(7) alpha-glucosidase inhibitor (such as, acarbose, voglibose and miglitol);
(8) glucagon receptor antagonist (such as, NOXG15, LY2409021);
(9) gut incretin hormones stand-in, such as GLP-1, GLP-1 analogue, derivative, and stand-in; With GLP-1 receptor stimulant (such as, dulaglutide, semaglutide, albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide, GSK2374697, ADX72231, RG7685, NN9924, ZYOG1, CJC-1131, and BIM-51077, comprise in its nose, through skin and weekly preparation), and oxyntomodulin and oxyntomodulin sum analogous to general Dedekind sum;
(10) LDL-C reduces medicament, such as (i) HMG-CoA reductase inhibitor (such as, Simvastatin, lovastatin, Pravastatin, crivastatin, Fluvastatin, Zarator, pitavastatin and superstatin), (ii) bile acid chelating agent (such as, colestilan, colestimide, colesevalam hydrochloride, colestipol, QUESTRAN, with the dialkylaminoalkyl derivative of cross linked dextran), (iii) cholesterol absorption inhibitor, (such as, ezetimibe), (iv) acyl-CoA: chole-sterol acyltransferase inhibitor, (such as, avasimibe),
(11) HDL-enhanced drug, (such as, niacin and nicotinic acid receptor agonists, and delayed release form; MK-524A, it is the combination of niacin delayed release and DP-1 antagonist MK-524);
(12) antiobesity compounds;
(13) medicament for inflammation is intended to, such as Asprin, NSAID (non-steroidal anti-inflammatory drug) or NSAIDs, glucocorticoids and selective cyclooxygenase-2 or cox 2 inhibitor;
(14) antihypertensive agents, such as ACE inhibitor (such as, lisinopril, enalapril, Ramipril, captopril, quinapril and tandolapril), A-II receptor-blocking agent (such as, losartan, Candesartan, irbesartan, Olmesartan medoxomil, valsartan, telmisartan and eprosartan), renin inhibitor is (such as, aliskiren), beta-blocker, and calcium channel blocker;
(15) glucokinase activating agents (GKAs) (such as, AZD6370);
The inhibitor of (16) 11 beta-hydroxysteroid dehydrogenase 1 types, (such as, such as at U.S. Patent number 6,730, disclosed in 690 those, and LY-2523199);
(17) CETP inhibitor (such as, anacetrapib, evacetrapib and torcetrapib);
(18) inhibitor of fructose 1,6-diphosphatase, (such as, such as at U.S. Patent number 6,054,587; 6,110,903; 6,284,748; 6,399,782 and 6,489, disclosed in 476 those);
(19) acetylCoA carboxylase-1 or 2 inhibitor (ACC1 or ACC2);
(20) protein kinase (AMPK) activator of AMP-activation, such as MB1055, ETC 1002;
(21) other agonist of G-protein-coupled receptor: (i) GPR-109, (ii) GPR-119 (such as, MBX2982, APD597, GSK1292263, HM47000 and PSN821), and (iii) GPR-40 (such as, TAK875, MR 1704, TUG 469, TUG499, ASP 4178);
(22) SSTR3 antagonist (such as, such as those disclosed in WO 2009/001836);
(23) Neuromedin U receptor agonists (such as, such as disclosed in WO 2009/042053 those, include, but not limited to neuromedin S (NMS));
(24) SCD inhibitor;
(25) GPR-105 antagonist (such as, such as those disclosed in WO 2009/000087);
(26) SGLT inhibitor (such as, ASP1941, SGLT-3, empagliflozin, dapagliflozin, Ka Gelie is clean, BI-10773, PF-04971729, remogloflozin, TS-071, Tuo Gelie are clean, ipragliflozin, and LX-4211);
(27) inhibitor of acyl-CoA: Diacrylglycerol acyl transferase 1 and 2 (DGAT-1 and DGAT-2);
(28) inhibitor of Fatty acid synthetase;
(29) inhibitor of acyl-CoA: monoacylglyceroyl transferring enzyme 1 and 2 (MGAT-1 and MGAT-2);
(30) agonist (being also called GPBAR1, BG37, GPCR19, GPR131 and M-BAR) of TGR5 acceptor;
(31) ileal bile acid carrier inhibitor;
(32) PACAP, PACAP stand-in and PACAP acceptor 3 agonist;
(33) PPAR agonist;
(34) Protein Tyrosine Phosphatases-1B (PTP-1B) inhibitor;
(35) IL-1b antibody, (such as, XOMA052 and canakinumab);
(36) bromocriptine mesylate and quick-release formulation thereof;
(37) GPR 120 agonist (such as KDT501.
Can with compound drug combination of the present invention and respectively administration or in same medicinal compositions other suitable activeconstituents/medicament of administration include, but are not limited to:
(a) anti-diabetic medicament, such as (1) PPAR gamma agonist, such as glitazone (such as ciglitazone, darglitazone, englitazone, isaglitazone (MCC-555), pioglitazone (ACTOS), rosiglitazone (AVANDIA), troglitazone, RIVOGLITAZONE, BRL49653, CLX-0921, 5-BTZD, GW-0207, LG-100641, R483 and LY-300512, etc., and be disclosed in the compound in WO97/10813,97/27857,97/28115,97/28137,97/27847,03/000685 and 03/027112, with SPPARMS (optionally PPAR gamma modulators), such as T131 (Amgen), FK614 (Fujisawa), netoglitazone and metaglidasen, (2) biguanide class, such as buformin, N1,N1-Dimethylbiguanide, and phenformin, etc., (3) Protein tyrosine phosphatase-1B (PTP-1B) inhibitor, such as, ISIS 113715, A-401674, A-364504, IDD-3, IDD 2846, KP-40046, KR61639, MC52445, MC52453, C7, OC-060062, OC-86839, OC29796, TTP-277BC1, and be disclosed in those medicaments in WO 04/041799,04/050646,02/26707,02/26743,04/092146,03/048140,04/089918,03/002569,04/065387,04/127570 and US 2004/167183, (4) sulfonylurea such as Acetohexamide, P-607, P-607, Glyburide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide, etc., (5) meglitinides, such as repaglinide, metiglinide (GLUFAST) and Na Gelie naphthalene, etc., (6) α glucoside hydrolase inhibitor, such as acarbose, adiposine, Camiglibose, emiglitate, miglitol, Fu Gelie alcohol, paldimycin (pradimicin)-Q, salazodine (salbostatin), CKD-711, MDL-25,637, MDL-73,945, with MOR 14, etc., (7) alpha-amylase inhibitor, such as tendamistat, extract his fourth (trestatin) and Al-3688, etc., (8) Insulin secretagogues, such as linogliride (linogliride), Na Gelie naphthalene, mitiglinide (GLUFAST), ID1101 A-4166, etc., (9) fatty acid oxidation inhibitors, such as clomoxir and etomoxir, etc., (10) A2 antagonist, such as midaglizole (midaglizole), isaglidole (isaglidole), Deriglidole, Racemic idazoxan, earoxan, and fluparoxan, etc., (11) Regular Insulin or insulin-mimickers, such as, biota, LP-100, novarapid, insulin detemir, Insulin lispro, Lantus, lente insulin (long-acting and super long effective), Lys-Pro Regular Insulin, GLP-1 (17-36), GLP-1 (73-7) (Regular Insulin growth-promoting peptide (insulintropin)), GLP-1 (7-36)-NH
2) Exenatide (exenatide)/Exendin-4, Exenatide (Exenatide) LAR, Linaglutide, AVE0010, CJC 1131, BIM51077, CS 872, THO318, BAY-694326, GP010, ALBUGON (with the GLP-1 of Albumin fusion), HGX-007 (Epac agonist), S-23521 and the compound be disclosed in WO 04/022004, WO 04/37859, etc., (12) nonthiazolidinedione class, such as JT-501 and Fa Gelietazha (GW-2570/GI-262579), etc., (13) PPAR α/γ dual agonists, such as AVE 0847, CLX-0940, GW-1536, GW1929, GW-2433, KRP-297, L-796449, LBM 642, LR-90, LY510919, MK-0767, ONO 5129, SB 219994, TAK-559, TAK-654, 677954 (GlaxoSmithkline), E-3030 (Eisai), LY510929 (Lilly), AK109 (Asahi), DRF2655 (Dr. Reddy), DRF8351 (Dr. Reddy), MC3002 (Maxocore), TY51501 (ToaEiyo), Fa Gelietazha, Na Geliezha (naveglitazar), Mo Geta azoles (muraglitazar), Pei Geliezha (peliglitazar), for Sai Gelieta (tesaglitazar) (GALIDA), Rui Geliezha (reglitazar) (JT-501), chiglitazar (chiglitazar), with be disclosed in WO 99/16758, WO 99/19313, WO 99/20614, WO 99/38850, WO 00/23415, WO 00/23417, WO 00/23445, WO 00/50414, WO 01/00579, WO 01/79150, WO 02/062799, WO 03/033481, WO 03/033450, those in WO 03/033453, (14) Regular Insulin, insulin-mimickers and other insulin sensitizing pharmaceutical, (15) VPAC2 receptor stimulant, (16) GLK conditioning agent, such as PSN105, RO 281675, RO 274375, with be disclosed in WO 03/015774, WO 03/000262, WO 03/055482, WO 04/046139, WO 04/045614, WO 04/063179, WO 04/063194, WO 04/050645 those, etc., (17) retinoid conditioning agent, such as, be disclosed in WO 03/000249 those, (18) GSK 3beta/GSK 3 inhibitor, such as, 4-[2-(2-bromophenyl)-4-(4-fluorophenyl-1H-imidazoles-5-base] pyridine, CT21022, CT20026, CT-98023, SB-216763, SB410111, SB-675236, CP-70949, XD4241, with be disclosed in WO 03/037869,03/03877,03/037891,03/024447,05/000192,05/019218 those, etc., (19) glycogen phosphorylase (HGLPa) inhibitor, such as, AVE 5688, PSN 357, GPi-879, be disclosed in WO 03/037864, WO 03/091213, WO 04/092158, WO 05/013975, WO 05/013981, US 2004/0220229 and JP 2004-196702 those, etc., (20) ATP consumes promotor, such as, be disclosed in WO 03/007990 those, (21) the fixing coupling form of PPAR gamma agonist and N1,N1-Dimethylbiguanide, such as AVANDAMET, (22) PPAR pan agonist, such as GSK 677954, (23) GPR40 (G-protein linked receptor 40), is also called SNORF 55, such as BG 700, and be disclosed in WO 04/041266,04/022551,03/099793 this those, (24) (G-protein linked receptor 119, is also called RUP3 to GPR119, SNORF 25), such as RUP3, HGPRBMY26, PFI 007, SNORF 25, (25) Adenosine Receptors 2B antagonist, such as ATL-618, ATl-802, E3080, etc., (26) carnitine palmitoyltransferase inhibitor, such as ST 1327 and ST 1326, etc., (27) fructose 1,6-diphosphatase inhibitor, such as CS-917, MB7803, etc., (28) glucagon antagonist, such as AT77077, BAY 694326, GW 4123X, NN2501, and those being disclosed in WO 03/064404, WO 05/00781, US 2004/0209928, US 2004/029943, etc., (30) G-6-Pase inhibitor, (31) phosphoenolpyruvate carboxykinase (PEPCK) inhibitor, (32) pyruvic dehydrogenase kinase (PDK) activator, (33) rxr agonist, such as MC1036, CS00018, JNJ 10166806, and those being disclosed in WO 04/089916, US 6759546, etc., (34) SGLT inhibitor, such as AVE 2268, KGT 1251, T1095/RWJ 394718, (35) BLX-1002, (36) maltin inhibitor, (37) glucagon receptor agonist, (38) activators of glucokinase, 39) GIP-1, 40) Insulin secretagogues, 41) GPR-40 agonist, such as TAK-875, 5-[4-[[(1R)-4-[6-(3-hydroxy-3-methyl butoxy)-2-picoline-3-base]-2, 3-dihydro-1H-indenes-1-base] oxygen base] phenyl] isothiazole-3-alcohol 1-oxide compound, 5-(4-((3-(2, 6-dimethyl-4-(3-(methylsulfonyl) propoxy-) phenyl) phenyl) methoxyl group) phenyl) different, 5-(4-((3-(2-methyl-6-(3-hydroxy propyloxy group) pyridin-3-yl)-2-aminomethyl phenyl) methoxyl group) phenyl) isothiazole-3-alcohol 1-oxide compound, with 5-[4-[[3-[4-(the amino propoxy-of 3-)-2, 6-3,5-dimethylphenyl] phenyl] methoxyl group] phenyl] isothiazole-3-alcohol 1-oxide compound), with be disclosed in WO 11/078371 those.
(b) anti-lipid abnormal medicament, such as (1) bile acid chelating agent, such as, Colestyramine, colesevelem, colestipol, the dialkylaminoalkyl derivative of sephadex, Colestid
?, LoCholest
?, and Questran
?, etc., (2) HMG-CoA reductase inhibitor, such as atorvastatin, itavastatin, pitavastatin, fluvastatin, lovastatin, Pravastatin, thunder cuts down its spit of fland (rivastatin), Simvastatin, superstatin (ZD-4522), and other Statins (statins), especially Simvastatin, (3) HMG-CoA synthase inhibitor, (4) cholesterol absorption inhibitor, such as FMVP4 (Forbes Medi-Tech), KT6-971 (Kotobuki Pharmaceutical), FM-VA12 (Forbes Medi-Tech), FM-VP-24 (Forbes Medi-Tech), plant alcohol ester, β-sitosterol, phytosterolin, such as tiqueside (tiqueside), with azetidin ketone, such as, ezetimibe, and those being disclosed in WO 04/005247, etc., (5) acat transaldolase (ACAT) inhibitor, such as avasimibe (avasimibe), Yi Lumaibu (eflucimibe), handkerchief is for wheat cloth (pactimibe) (KY505), SMP 797 (Sumitomo), SM32504 (Sumitomo), and those being disclosed in WO 03/091216, etc., (6) CETP inhibitor, such as Ansai bent (anacetrapib), JTT 705 (Japan Tobacco), torcetrapib (torcetrapib), CP 532,632, BAY63-2149 (Bayer), SC 591, SC 795, etc., (7) inhibitor for squalene synthetic enzyme, (8) antioxidant, such as probucol, etc., (9) PPAR alfa agonists, such as Sgd-24774, bezafibrate, Win-35833, CLOF, etofibrate, fenofibrate, gemcabene and gemfibrozil (gemfibrozil), GW 7647, BM 170744 (Kowa), LY518674 (Lilly), GW590735 (GlaxoSmithkline), KRP-101 (Kyorin), DRF10945 (Dr. Reddy), NS-220/R1593 (Nippon Shinyaku/Roche, ST1929 (Sigma Tau) MC3001/MC3004 (Maxo Core Pharmaceuticals, gemcabene calcium, other fiber acid derivative, such as Atromid
?, Lopid
?and Tricor
?, and be disclosed in US 6,548, those in 538, etc., (10) FXR receptor modulators, such as GW 4064 (GlaxoSmithkline), SR 103912, QRX401, LN-6691 (Lion Bioscience), and those being disclosed in WO 02/064125, WO 04/045511, etc., (11) lxr receptor conditioning agent, such as GW3965 (GlaxoSmithkline), T9013137 and XTCO179628 (X-Ceptor Therapeutics/Sanyo), with be disclosed in WO 03/031408, WO 03/063796, WO 04/072041 those, etc., (12) lipoprotein synthetic inhibitor, such as nicotinic acid (niacin), (13) renin-angiotensin system inhibitor, (14) PPAR δ partial agonist, such as, be disclosed in WO 03/024395 those, (15) bile acid reabsorption inhibitor, such as BARI 1453, SC435, PHA384640, S8921, AZD7706, etc., and bile acid chelating agent, such as colesevelam (colesevelam) (WELCHOL/CHOLESTAGEL), colestipol, the dialkylaminoalkyl derivative of Colestyramine and sephadex, (16) PPAR delta agonists, such as GW 501516 (Ligand, GSK), GW 590735, GW-0742 (GlaxoSmithkline), T659 (Amgen/Tularik), LY934 (Lilly), NNC610050 (Novo Nordisk), with be disclosed in WO97/28149, WO 01/79197, WO 02/14291, WO 02/46154, WO 02/46176, WO 02/076957, WO 03/016291, WO 03/033493, WO 03/035603, WO 03/072100, WO 03/097607, WO 04/005253, those in WO 04/007439 and JP10237049, etc., (17) triglyceride level synthetic inhibitor, (18) microsomal triglyceride transhipment (MTTP) inhibitor, such as implitapide (implitapide), LAB687, JTT130 (Japan Tobacco), CP346086, and those being disclosed in WO 03/072532, etc., (19) transcriptional regulatory agent, (20) squalene epoxidase inhibitor, (21) low-density lipoprotein (LDL) receptor inducer, (22) anticoagulant, (23) 5-LO or FLAP inhibitor, (24) nicotinic acid (niacin) receptor stimulant, comprises HM74A receptor stimulant, (25) PPAR conditioning agent, such as, be disclosed in WO 01/25181, WO 01/79150, WO 02/79162, WO 02/081428, WO 03/016265, WO 03/033453 those, (26) chromium of nicotinic acid (niacin)-combination disclosed in WO 03/039535, (27) acid derivative of the replacement in WO 03/040114 is disclosed in, (28) HDL of infusion, such as LUV/ETC-588 (Pfizer), APO-A1 Milano/ETC216 (Pfizer), ETC-642 (Pfizer), ISIS301012, D4F (Bruin Pharma), the trimerization ApoA1 of synthesis, the Bioral Apo A1 of target foam cell, etc., (29) ibat inhibitor, such as BARI143/HMR145A/HMR1453 (Sanofi-Aventis, PHA384640E (Pfizer), S8921 (Shionogi) AZD7806 (AstrZeneca), AK105 (Asah Kasei), etc., (30) Lp-PLA2 inhibitor, such as SB480848 (GlaxoSmithkline), 659032 (GlaxoSmithkline), 677116 (GlaxoSmithkline), etc., (31) other medicament of lipic composition is affected, comprise ETC1001/ESP31015 (Pfizer), ESP-55016 (Pfizer), AGI1067 (AtheroGenics), AC3056 (Amylin), AZD4619 (AstrZeneca), with
(c) antihypertensive agents, such as (1) diuretic(s), such as thiazides (thiazides), comprises chlorthalidone, chlorothiazide, Antidrasi, Vergonil, indapamide and Zestoretic; Loop diuretic, such as bumetanide, Ethacrynic Acid, furosemide and torasemide (torsemide); The poor medicament of potassium, such as guanamprazine and Urocaudol; And aldosterone antagonist, such as spironolactone, eplerenone (epirenone), etc.; (2) beta-adrenergic blocking agent, such as acebutolol, atenolol USP 23, betaxolol, bevantolol, bisoprolol, Bopindolol, carteolol, carvedilol, celiprolol, esmolol, indenolol, metoprolol, nadolol, nebivolol (nebivolol), penbutolol, pindolol, Proprasylyte, sotolol, Tertatolol (tertatolol), tilisolol (tilisolol) and timolol, etc.; (3) calcium channel blocker, such as amlodipine, Aranidipine, Azelnidipine, barnidipine, benidipine, Bepridil, cilnidipineb (cinaldipine), Clevidipine, diltiazem, efonidipine, felodipine, methoxyverapamil, Isrodipine, Lacidipine (62, Lemildipine (lemildipine), lercanidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, Manidipine, pranidipine (pranidipine) and verapamil, etc.; (4) angiotensin converting enzyme (ACE) inhibitor, such as benazepril; Captopril; Yipingshu; Delapril; Enalapril; Fosinopril; Imidapril; Lisinopril (losinopril); Moexipril (moexipril); Quinapril; Quinaprilat (quinaprilat); Ramipril; Perindopril; Perindopril (perindropril); Quanipril; Spirapril; Tenocapril; Trolapril and zofenopril (zofenopril), etc.; (5) neutral endopeptidase inhibitor, such as omapatrilat (omapatrilat), candoxatril (cadoxatril), ecadotril, fosidotril, Sampatrilat (sampatrilat), AVE7688, ER4030, etc.; (6) endothelin antagonists, such as tezosentan (tezosentan), A308165 and YM62899, etc.; (7) vasodilator, such as hydralazine, clonidine, minoxidil and nicotinic alcohol, nicotinic acid or its salt, etc.; (8) angiotensin II receptor antagonists, such as Candesartan, Eprosartan, Irb, losartan, Pratosartan (pratosartan), Tasosartan, telmisartan, third Valsartan and EXP-3137, FI6828K and RNH6270, etc.; (9) α/β adrenergic blocking drug, such as Nip Luo Er, Arottnolol, etc.; (10) α 1 blocker, such as terazosin, urapidil, Prazosin, bunazosin, trimazosin, Doxazosin, naphthalene group ground that, Indoramine, WHIP 164 and XEN010, etc.; (11) α 2 agonist, such as lofexidine (lofexidine), thiamenidine (tiamenidine), moxonidine (moxonidine), rilmenidine (rilmenidine) and guanobenz, etc.; (12) aldosterone inhibitor, etc.; (13) angiogenin (angiopoietin)-2-tackiness agent, such as, be disclosed in WO 03/030833 those; With
(d) anti-obesity medicament, for example (1) 5HT (thrombocytin) transporter inhibitors, for example Paxil, Prozac, fenfluramine, Fluvoxamine, Sertraline and imipramine, with be disclosed in those in WO 03/00663, and thrombocytin/noradrenaline reuptake inhibitor, for example sibutramine (MERIDIA/REDUCTIL) and dopamine absorption inhibitor/norepinephrine absorption inhibitor, for example radafaxine hydrochloride, 353162 (GlaxoSmithkline), etc., (2) NE (norepinephrine) transporter inhibitors, for example GW 320659, desipramine (despiramine), talsupram (talsupram) and nomefensine, (3) CB1 (cannboid-1 acceptor) antagonists/inverse agonists, for example its La Naban (taranabant), Rimonabant (ACCOMPLIA Sanofi Synthelabo), SR-147778 (Sanofi Synthelabo), AVE1625 (Sanofi-Aventis), BAY 65-2520 (Bayer), SLV 319 (Solvay), SLV326 (Solvay), CP945598 (Pfizer), E-6776 (Esteve), O1691 (Organix), ORG14481 (Organon), VER24343 (Vernalis), NESS0327 (Univ of Sassari/Univ of Cagliari), with be disclosed in those in following: United States Patent(USP) Nos. 4, 973, 587, 5, 013, 837, 5, 081, 122, 5, 112, 820, 5, 292, 736, 5, 532, 237, 5, 624, 941, 6, 028, 084 and 6, 509367, with WO 96/33159, WO97/29079, WO98/31227, WO 98/33765, WO98/37061, WO98/41519, WO98/43635, WO98/43636, WO99/02499, WO00/10967, WO00/10968, WO 01/09120, WO 01/58869, WO 01/64632, WO 01/64633, WO 01/64634, WO 01/70700, WO 01/96330, WO 02/076949, WO 03/006007, WO 03/007887, WO 03/020217, WO 03/026647, WO 03/026648, WO 03/027069, WO 03/027076WO 03/027114, WO 03/037332, WO 03/040107, WO 04/096763, WO 04/111039, WO 04/111033, WO 04/111034, WO 04/111038, WO 04/013120, WO 05/000301, WO 05/016286, WO 05/066126 and EP-658546, etc., (4) ghrelin agonist/antagonist, for example BVT81-97 (BioVitrum), RC1291 (Rejuvenon), SRD-04677 (Sumitomo), the ghrelin (TheraTechnologies) of non-acidylate, with be disclosed in those in WO 01/87335, WO 02/08250, WO 05/012331, etc., (5) H3 (histamine H 3) antagonists/inverse agonists, for example thioperamide (thioperamide), 3-(1H-imidazol-4 yl) propyl group N-(4-pentenyl) carbamate), clobenpropit, iodophenpropit, imoproxifan, GT2394 (Gliatech) and A331440, and those that are disclosed in WO 02/15905, and O-[3-(1H-imidazol-4 yl) propyl alcohol] carbamate (Kiec-Kononowicz, K. people is waited, Pharmazie, 55:349-55 (2000)), contain the histamine H 3-receptor antagonist (Lazewska of piperidines, D. people is waited, Pharmazie, 56:927-32 (2001), benzophenone derivates and related compound (Sasse, A. people is waited, Arch. Pharm. (Weinheim) 334:45-52 (2001)), N-carbanilate (the Reidemeister replacing, S. people is waited, Pharmazie, 55:83-6 (2000)) and proxifan derivative (Sasse, A. people is waited, J. Med. Chem.43:3335-43 (2000)) and histamine H 3 receptor modulators, for example, be disclosed in those in WO 03/024928 and WO 03/024929, (6) melanin-concentrating hormone 1 acceptor (MCH1R) antagonist, for example T-226296 (Takeda), T71 (Takeda/Amgen), AMGN-608450, AMGN-503796 (Amgen), 856464 (GlaxoSmithkline), A224940 (Abbott), A798 (Abbott)ATC0175/AR224349 (Arena Pharmaceuticals), GW803430 (GlaxoSmithkine), NBI-1A (Neurocrine Biosciences), NGX-1 (Neurogen), SNP-7941 (Synaptic), SNAP9847 (Synaptic), T-226293 (Schering Plough), TPI-1361-17 (Saitama Medical School/University of California Irvine), with be disclosed in those in following: WO 01/21169, WO 01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO 02/076929, WO 02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO 02/094799, WO 03/004027, WO 03/13574, WO 03/15769, WO 03/028641, WO 03/035624, WO 03/033476, WO 03/033480, WO 04/004611, WO 04/004726, WO 04/011438, WO 04/028459, WO 04/034702, WO 04/039764, WO 04/052848, WO 04/087680, with Japanese patent application Nos. JP 13226269, JP 1437059, JP 2004315511, etc., (7) MCH2R (melanin concentration hormone 2R) agonist/antagonist, (8) NPY1 (neuropeptide tyrosine Y1) antagonist, for example BMS205749, BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906 and GI-264879A, with be disclosed in those in following: U.S. Patent No. 6,001,836, with WO 96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO 01/85173 and WO 01/89528, (9) NPY5 (neuropeptide tyrosine Y5) antagonist, for example 152,804, S2367 (Shionogi), E-6999 (Esteve), GW-569180A, GW-594884A (GlaxoSmithkline), GW-587081X, GW-548118X,FR 235,208, FR226928, FR 240662, FR252384, 1229U91, GI-264879A, CGP71683A, C-75 (Fasgen) LY-377897, LY366377, PD-160170, SR-120562A, SR-120819A, S2367 (Shionogi), JCF-104 and H409/22, with those compounds that are disclosed in following: United States Patent(USP) Nos. 6,140,354,6,191,160,6,258,837,6,313,298,6,326,375,6,329,395,6,335,345,6,337,332,6,329,395 and 6,340,683, and EP-01010691, EP-01044970, and FR252384, with PCT publication Nos. WO 97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO 98/27063, WO 00/107409, WO 00/185714, WO 00/185730, WO 00/64880, WO 00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO 01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO 01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO 02/20488, WO 02/22592, WO 02/48152, WO 02/49648, WO 02/051806, WO 02/094789, WO 03/009845, WO 03/014083, WO 03/022849, WO 03/028726, WO 05/014592, WO 05/01493, with the people such as Norman, J. Med. Chem.43:4288-4312 (2000), (10) leptin, for example, recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl mankind leptins (Amgen), (11) leptin derivative, for example, is disclosed in those in following: patent Nos. 5,552,524, 5,552,523, 5,552,522, 5,521,283, with WO 96/23513, WO 96/23514, WO 96/23515,WO 96/23516; WO 96/23517; WO 96/23518; WO 96/23519; With WO 96/23520; (12) opioid antagonists, for example nalmefene (nalmefene) (Revex), 3-methoxyl group naltrexone, naloxone and naltrexone; Be disclosed in those in WO 00/21509; (13) orexin antagonists, for example SB-334867-A (GlaxoSmithkline); Be disclosed in those in following: WO 01/96302,01/68609,02/44172,02/51232,02/51838,02/089800,02/090355,03/023561,03/032991,03/037847,04/004733,04/026866,04/041791,04/085403, etc.; (14) BRS3 (bombysin receptor subtype 3) activator; (15) CCK-A (pancreozymin-A) activator, for example AR-R 15849, GI 181771, JMV-180, A-71378, A-71623, PD170292, PD 149164, SR146131, SR125180, butabindide, and be disclosed in US 5, those in 739,106; (16) CNTF (CNTF), for example GI-181771 (Glaxo-SmithKline), SR146131 (Sanofi Synthelabo), butabindide; With PD 170,292, PD 149164 (Pfizer); (17) CNTF derivative, for example Axokine (Regeneron); Be disclosed in those in WO 94/09134, WO 98/22128 and WO 99/43813; (18) GHS (the short acceptor of secreting of growth hormone) activator, for example NN703, Hexarelin (hexarelin), MK-0677, SM-130686, CP-424,391, L-692,429 and L-163,255 and be disclosed in U.S. Patent No. 6358951, U.S. Patent application Nos. 2002/049196 and 2002/022637; With those in WO 01/56592 and WO 02/32888; (19) 5HT2c (serotonin receptor 2c) activator, for example APD3546/AR10A (Arena Pharmaceuticals), ATH88651 (Athersys), ATH88740 (Athersys), BVT933 (Biovitrum/GSK), DPCA37215 (BMS)IK264, LY448100 (Lilly), PNU 22394, WAY 470 (Wyeth), WAY629 (Wyeth), WAY161503 (Biovitrum), R-1065, VR1065 (Vernalis/Roche) YM 348, with be disclosed in those in following: U.S. Patent No. US 3,914,250, with PCT publication 01/66548,02/36596,02/48124,02/10169,02/44152, 02/51844,02/40456,02/40457,03/057698,05/000849, etc., (20) Mc3r (melanocortin 3 acceptor) activator, (21) Mc4r (melanocortin 4 acceptor) activator, for example CHIR86036 (Chiron), CHIR915 (Chiron), ME-10142 (Melacure), ME-10145 (Melacure), HS-131 (Melacure), NBI72432 (Neurocrine Biosciences), NNC 70-619 (Novo Nordisk), TTP2435 (Transtech) and be disclosed in those in following: PCT publication WO 99/64002, 00/74679, 01/991752, 01/0125192, 01/52880, 01/74844, 01/70708, 01/70337, 01/91752, 01/010842, 02/059095, 02/059107, 02/059108, 02/059117, 02/062766, 02/069095, 02/12166, 02/11715, 02/12178, 02/15909, 02/38544, 02/068387, 02/068388, 02/067869, 02/081430, 03/06604, 03/007949, 03/009847, 03/009850, 03/013509, 03/031410, 03/094918, 04/028453, 04/048345, 04/050610, 04/075823, 04/083208, 04/089951, 05/000339 and EP 1460069 and US 2005049269 and JP2005042839, etc., (22) MARI, for example sibutramine (Meridia/Reductil) and its salt, and those compounds that are disclosed in following: United States Patent(USP) Nos. 4,746,680,4,806,570 and 5,436,272,With United States patent publication No. 2002/0006964, and WO 01/27068, and WO 01/62341, (23) serotonin reuptake inhibitors, for example Dexfenfluramine, Prozac, and be disclosed in U.S. Patent No. US 6,365,633 and WO 01/27060 and WO 01/162341 in those, (24) GLP-1 (glucagon-like peptide 1) activator, (25) Topiramate (Topimax), (26) phytopharm compound 57 (CP 644,673), (27) ACC2 (acetyl-CoA carboxylase-2) inhibitor, (28) β 3 (Beta-3 adrenergic receptor 3) activator, for example rafebergron/AD9677/TAK677 (Dainippon/Takeda), CL-316, 243, SB 418790, BRL-37344, L-796568, BMS-196085, BRL-35135A, CGP12177A, BTA-243, GRC1087 (Glenmark Pharmaceuticals) GW 427353 (hydrochloric acid Suo Labeilong (solabegron)), trecadrine (Trecadrine), Zeneca D7114, N-5984 (Nisshin Kyorin), LY-377604 (Lilly), KT07924 (Kissei), SR 59119A, with be disclosed in those in following: United States Patent(USP) Nos. US 5, 705, 515, US 5, 451, 677, with WO 94/18161, WO 95/29159, WO 97/46556, WO 98/04526, WO 98/32753, WO 01/74782, WO 02/32897, WO 03/014113, WO 03/016276, WO 03/016307, WO 03/024948, WO 03/024953, WO 03/037881, WO 04/108674, etc., (29) DGAT1 (diacylglycerol acyltransferase 1) inhibitor, (30) DGAT2 (diacylglycerol acyltransferase 2) inhibitor, (31) FAS (fatty acid synthase) inhibitor, for example cerulenin and C75, (32) PDE (phosphodiesterase) inhibitor, for example theophylline, BL-191, zaprinast, silaenafil, Amrinone, Milrinone, cilostamide, Lip river profit Puli (rolipram) and cilomilast (cilomilast), and those that are described in WO 03/037432, WO 03/037899, (33) thyroid hormone beta-agonists, for example KB-2611 (KaroBioBMS),With be disclosed in WO 02/15845, with those in Japanese patent application No. JP 2000256190, (34) UCP-1 (albumen 1 is not coupled), 2 or 3 activator, for example phytanic acids, 4-[(E)-2-(5,6,7,8-tetrahydrochysene-5,5,8,8-tetramethyl-2-naphthyl)-1-acrylic] benzoic acid (TTNPB), and retinoic acid, with be disclosed in those in WO 99/00123, (35) acyl-estrogen class, for example, is disclosed in the oleoyl-oestrone in following: del Mar-Grasa, the people such as M., Obesity Research, 9:202-9 (2001), (36) glucocorticoid receptor antagonists, for example CP472555 (Pfizer), KB 3305, and those that are disclosed in WO 04/000869, WO 04/075864, etc., (37) 11 β HSD-1 (11-β hydroxy steroid dehydrogenase type 1 type) inhibitor, for example BVT 3498 (AMG 331), BVT 2733, 3-(1-adamantyl)-4-ethyl-5-(ethylmercapto group)-4H-1, 2, 4-triazole, 3-(1-adamantyl)-5-(3, 4, 5-trimethoxyphenyl)-4-methyl-4H-1, 2, 4-triazole, 3-adamantyl-4, 5, 6, 7, 8, 9, 10, 11, 12, 3a-decahydro-1, 2, 4-triazol [4, 3-a] [11] annulene, with those compounds that are disclosed in following: WO 01/90091, 01/90090, 01/90092, 02/072084, 04/011410, 04/033427, 04/041264, 04/027047, 04/056744, 04/065351, 04/089415, 04/037251, etc., (38) SCD-1 (stearyl-coa dehydrogenase-1) inhibitor, (39) dipeptidyl peptidase-IV (DPP-4) inhibitor, for example isoleucine thiazolidide (isoleucine thiazolidide), valine pyrrolidide, sitagliptin (Januvia), BMS-477118 (saxagliptin), Alogliptin (alogliptin), NVP-DPP728, LAF237 (vildagliptin (vildagliptin)), P93/01, TSL 225, TMC-2A/2B/2C, FE 999011, P9310/K364, VIP 0177, SDZ 274-444, GSK 823093, E 3024, SYR 322, TS021, SSR 162369, GRC 8200, K579, NN7201, CR 14023, PHX 1004, PHX 1149,PT-630, SK-0403, with the compound being disclosed in following: WO 02/083128, WO 02/062764, WO 02/14271, WO 03/000180, WO 03/000181, WO 03/000250, WO 03/002530, WO 03/002531, WO 03/002553, WO 03/002593, WO 03/004498, WO 03/004496, WO 03/005766, WO 03/017936, WO 03/024942, WO 03/024965, WO 03/033524, WO 03/055881, WO 03/057144, WO 03/037327, WO 04/041795, WO 04/071454, WO 04/0214870, WO 04/041273, WO 04/041820, WO 04/050658, WO 04/046106, WO 04/067509, WO 04/048532, WO 04/099185, WO 04/108730, WO 05/009956, WO 04/09806, WO 05/023762, US 2005/043292, with EP 1 258 476, (40) lipase inhibitor, for example, orlistat (tetrahydrolipstatin) (orlistat/XENICAL), ATL962 (Alizyme/Takeda), GT389255 (Genzyme/Peptimmune) Triton WR1339, RHC80267, Lipstatin (lipstatin), Tea Saponin (teasaponin), with di(2-ethylhexyl)phosphate ethyl umbelliferone, FL-386, WAY-121898, Bay-N-3176, figured silk fabrics ammonia lactone (valilactone), esteracin, strategic point is than lactone (ebelactone) A, strategic point is than lactone (ebelactone) B and RHC 80267, with be disclosed in those in following: WO 01/77094, WO 04/111004, United States Patent(USP) Nos. 4, 598, 089, 4, 452, 813, 5, 512, 565, 5, 391, 571, 5, 602, 151, 4, 405, 644, 4, 189, 438 and 4, 242, 453, etc., (41) fatty acid transport body inhibitor, (42) dicarboxylic ester transporter inhibitors, (43) glucose transporter inhibitor, (44) phosphate cotransporter body inhibitor, (45) anoretics dicyclic compound,For example 1426 (Aventis) and 1954 (Aventis), and the compound that is disclosed in following: WO 00/18749, WO 01/32638, WO 01/62746, WO 01/62747 and WO 03/015769; (46) PYY and PYY activator, for example PYY336 (Nastech/Merck), AC162352 (IC Innovations/Curis/Amylin), TM30335/TM30338 (7TM Pharma), PYY336 (Emisphere Tehcnologies), the PYY3-36 of PEGization, is disclosed in those in WO 03/026591,04/089279, etc.; (47) lipid metabolism conditioning agent, for example crataegolic acid, erythrodiol, ursolic acid uvaol, betulinic acid, betulinol, etc., and the compound being disclosed in WO 03/011267; (48) transcription factor conditioning agent, for example, is disclosed in those in WO 03/026576; (49) Mc5r (melanocortin 5 acceptor) conditioning agent, for example, is disclosed in those in following: WO 97/19952, WO 00/15826, WO 00/15790, US 20030092041, etc.; (50) the brain derived neutotropic factor (BDNF), (51) Mc1r (melanocortin 1 receptor modulators, for example LK-184 (Proctor & Gamble), etc.; (52) 5HT6 antagonist, for example BVT74316 (BioVitrum), BVT5182c (BioVitrum), E-6795 (Esteve), E-6814 (Esteve), SB399885 (GlaxoSmithkline), SB271046 (GlaxoSmithkline), RO-046790 (Roche), etc.; (53) fatty acid transport protein 4 (FATP4); (54) acetyl-CoA carboxylase (ACC) inhibitor, for example CP640186, CP610431, CP640188 (Pfizer); (55) C-terminal growth hormone fragment, for example AOD9604 (Monash Univ/Metabolic Pharmaceuticals), etc.; (56) oxyntomodulin (oxyntomodulin); (57) neuropeptide FF receptor antagonists, for example, is disclosed in those in WO 04/083218, etc.; (58) amylin agonist, for example Symlin/ pramlintide/AC137 (Amylin); (59) Hoodia and trichocaulon extract;(60) BVT74713 and other tripe tallow matter appetite inhibitor; (61) dopamine agonist, for example Bupropion (WELLBUTRIN/GlaxoSmithkline); (62) Zonisamide (ZONEGRAN/Dainippon/Elan), etc.; With
E () to be applicable to the anoretics of compound coupling of the present invention including, but not limited to aminorex, Amphechloral (amphechloral), amphetamine, Benzphetamine, chlorphentermine, clobenzorex, cloforex, MeN-1107, clortermine, isopropylhexedrine., dexfenfluramine, Dextroamphetamine, Diethylpropion, diphemethoxidine, N-ethyl Amphetamine, Phenbutrazate, Phenfluoramine, fenisorex, Perphoxene, Win 11464, McN 1231, furcellaran, Levamphetamine, Levophacetoperane, SaH-42548, mefenorex, Mephogarbital, desoxyephedrine, pseudonorephedrine, phenpentermine, phendimetrazine, Preludin, PHENTERMINE, Phenylpropanolamine, picilorex and sibutramine, with its pharmacologically acceptable salt.Especially a suitable class anoretics is halogeno-benzene propanamine derivatives, comprises chlorphentermine, cloforex, clortermine, dexfenfluramine, Phenfluoramine, picilorex and sibutramine; With its pharmacologically acceptable salt.Comprise with the concrete halogeno-benzene propanamine derivatives of compound coupling of the present invention: Phenfluoramine and dexfenfluramine, and its pharmacologically acceptable salt.
Can comprise with the particular compound of the compounds of this invention conbined usage: Simvastatin, mevastatin, ezetimibe, atorvastatin, sitagliptin (sitagliptin), N1,N1-Dimethylbiguanide, sibutramine, orlistat, Qnexa, topiramate, TREXUPONT, bupriopion, PHENTERMINE, and losartan, losartan and Zestoretic.Comprise with the concrete CB1 antagonists/inverse agonists of the compounds of this invention coupling: be described in WO03/077847 those, comprise: N-[3-(4-chloro-phenyl-)-2 (S)-phenyl-1 (S)-methyl-propyl]-2-(4-trifluoromethyl-2-pyrimidyl oxygen base)-2-methyl propanamide, N-[3-(4-chloro-phenyl-)-2-(3-cyano-phenyl)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyl oxygen base)-2-methyl propanamide, N-[3-(4-chloro-phenyl-)-2-(5-chloro-3-pyridyl base)-1-methyl-propyl]-2-(5-trifluoromethyl-2-pyridyl oxygen base)-2-methyl propanamide, with its pharmacologically acceptable salt, and those in WO05/000809, it comprises following: 3-{1-[two (4-chloro-phenyl-) methyl] azetidine-3-subunit }-3-(3, 5-difluorophenyl)-2, 2-dimethyl propionitrile, 1-{1-[1-(4-chloro-phenyl-) amyl group] azetidine-3-base }-1-(3, 5-difluorophenyl)-2-methyl propan-2-ol, 3-((S)-(4-chloro-phenyl-) { 3-[(1S)-1-(3, 5-difluorophenyl)-2-hydroxy-2-methyl propyl group] azetidine-1-base } methyl) benzonitrile, 3-((S)-(4-chloro-phenyl-) { 3-[(1S)-1-(3, 5-difluorophenyl) the fluoro-2-methyl-propyl of-2-] azetidine-1-base } methyl) benzonitrile, 3-((4-chloro-phenyl-) { 3-[1-(3, 5-difluorophenyl)-2, 2-dimethylpropyl] azetidine-1-base } methyl) benzonitrile, 3-((1S)-1-{1-[(S)-(3-cyano-phenyl) (4-cyano-phenyl) methyl] azetidine-3-base } the fluoro-2-methyl-propyl of-2-)-5-fluorobenzonitrile, 3-[(S)-(4-chloro-phenyl-) (the fluoro-1-of 3-{ (1S)-2-[fluoro-5-(4H-1 of 3-, 2, 4-triazole-4-yl) phenyl]-2-methyl-propyl } azetidine-1-base) methyl] benzonitrile, with 5-((4-chloro-phenyl-) { 3-[(1S)-1-(3, 5-difluorophenyl) the fluoro-2-methyl-propyl of-2-] azetidine-1-base } methyl) thiophene-3-nitrile, with its pharmacologically acceptable salts, and: 3-[(S)-(4-chloro-phenyl-) (the fluoro-1-of 3-{ (1S)-2-[the fluoro-5-of 3-(5-oxo-4, 5-dihydro-1, 3, 4-oxadiazole-2-base) phenyl]-2-methyl-propyl } azetidine-1-base) methyl] benzonitrile, 3-[(S)-(4-chloro-phenyl-) (the fluoro-1-of 3-{ (1S)-2-[the fluoro-5-(1 of 3-, 3, 4-oxadiazole-2-base) phenyl]-2-methyl-propyl } azetidine-1-base) methyl] benzonitrile, 3-[(S)-(3-{ (1S)-1-[3-(5-amino-1, 3, 4-oxadiazole-2-base)-5-fluorophenyl] the fluoro-2-methyl-propyl of-2-} azetidine-1-base) (4-chloro-phenyl-) methyl] benzonitrile, 3-[(S)-(4-cyano-phenyl) (the fluoro-1-of 3-{ (1S)-2-[the fluoro-5-of 3-(5-oxo-4, 5-dihydro-1, 3, 4-oxadiazole-2-base) phenyl]-2-methyl-propyl } azetidine-1-base) methyl] benzonitrile, 3-[(S)-(3-{ (1S)-1-[3-(5-amino-1, 3, 4-oxadiazole-2-base)-5-fluorophenyl] the fluoro-2-methyl-propyl of-2-} azetidine-1-base) (4-cyano-phenyl) methyl] benzonitrile, 3-[(S)-(4-cyano-phenyl) (the fluoro-1-of 3-{ (1S)-2-[the fluoro-5-(1 of 3-, 3, 4-oxadiazole-2-base) phenyl]-2-methyl-propyl } azetidine-1-base) methyl] benzonitrile, 3-[(S)-(4-chloro-phenyl-) (the fluoro-1-of 3-{ (1S)-2-[the fluoro-5-(1 of 3-, 2, 4-oxadiazole-3-base) phenyl]-2-methyl-propyl } azetidine-1-base) methyl] benzonitrile, 3-[(1S)-1-(1-{ (S)-(4-cyano-phenyl) [3-(1, 2, 4-oxadiazole-3-base) phenyl]-methyl } azetidine-3-base) the fluoro-2-methyl-propyl of-2-]-5-fluorobenzonitrile, 5-(3-{1-[1-(diphenyl-methyl) azetidine-3-base] the fluoro-2-methyl-propyl of-2-}-5-fluorophenyl)-1H-TETRAZOLE, 5-(3-{1-[1-(diphenyl-methyl) azetidine-3-base] the fluoro-2-methyl-propyl of-2-}-5-fluorophenyl)-1-methyl isophthalic acid H-tetrazolium, 5-(3-{1-[1-(diphenyl-methyl) azetidine-3-base] the fluoro-2-methyl-propyl of-2-}-5-fluorophenyl)-2-methyl-2H-tetrazolium, 3-[(4-chloro-phenyl-) (the fluoro-1-of 3-{2-[the fluoro-5-of 3-(2-methyl-2H-tetrazolium-5-base) phenyl]-2-methyl-propyl } azetidine-1-base) methyl] benzonitrile, 3-[(4-chloro-phenyl-) (the fluoro-1-of 3-{2-[the fluoro-5-of 3-(1-methyl isophthalic acid H-tetrazolium-5-base) phenyl]-2-methyl-propyl } azetidine-1-base) methyl] benzonitrile, 3-[(4-cyano-phenyl) (the fluoro-1-of 3-{2-[the fluoro-5-of 3-(1-methyl isophthalic acid H-tetrazolium-5-base) phenyl]-2-methyl-propyl } azetidine-1-base) methyl] benzonitrile, 3-[(4-cyano-phenyl) (the fluoro-1-of 3-{2-[the fluoro-5-of 3-(2-methyl-2H-tetrazolium-5-base) phenyl]-2-methyl-propyl } azetidine-1-base) methyl] benzonitrile, 5-{3-[(S)-{ 3-[(1S)-1-(3-bromo-5-fluorophenyl) the fluoro-2-methyl-propyl of-2-] azetidine-1-base } (4-chloro-phenyl-) methyl] phenyl }-1, 3, 4-oxadiazole-2 (3H)-one, 3-[(1S)-1-(1-{ (S)-(4-chloro-phenyl-) [3-(5-oxo-4, 5-dihydro-1, 3, 4-oxadiazole-2-base) phenyl] methyl } azetidine-3-base) the fluoro-2-methyl-propyl of-2-]-5-fluorobenzonitrile, 3-[(1S)-1-(1-{ (S)-(4-cyano-phenyl) [3-(5-oxo-4, 5-dihydro-1, 3, 4-oxadiazole-2-base) phenyl] methyl } azetidine-3-base) the fluoro-2-methyl-propyl of-2-]-5-fluorobenzonitrile, 3-[(1S)-1-(1-{ (S)-(4-cyano-phenyl) [3-(1, 3, 4-oxadiazole-2-base) phenyl] methyl } azetidine-3-base) the fluoro-2-methyl-propyl of-2-]-5-fluorobenzonitrile, 3-[(1S)-1-(1-{ (S)-(4-chloro-phenyl-) [3-(1, 3, 4-oxadiazole-2-base) phenyl] methyl } azetidine-3-base) the fluoro-2-methyl-propyl of-2-]-5-fluorobenzonitrile, 3-((1S)-1-{1-[(S)-[3-(5-amino-1, 3, 4-oxadiazole-2-base) phenyl] (4-chloro-phenyl-) methyl] azetidine-3-base } the fluoro-2-methyl-propyl of-2-)-5-fluorobenzonitrile, 3-((1S)-1-{1-[(S)-[3-(5-amino-1, 3, 4-oxadiazole-2-base) phenyl] (4-cyano-phenyl) methyl] azetidine-3-base } the fluoro-2-methyl-propyl of-2-)-5-fluorobenzonitrile, 3-[(1S)-1-(1-{ (S)-(4-cyano-phenyl) [3-(1, 2, 4-oxadiazole-3-base) phenyl] methyl } azetidine-3-base) the fluoro-2-methyl-propyl of-2-]-5-fluorobenzonitrile, 3-[(1S)-1-(1-{ (S)-(4-chloro-phenyl-) [3-(1, 2, 4-oxadiazole-3-base) phenyl] methyl } azetidine-3-base) the fluoro-2-methyl-propyl of-2-]-5-fluorobenzonitrile, 5-[3-((S)-(4-chloro-phenyl-) { 3-[(1S)-1-(3, 5-difluorophenyl) the fluoro-2-methyl-propyl of-2-] azetidine-1-base } methyl) phenyl]-1, 3, 4-oxadiazole-2 (3H)-one, 5-[3-((S)-(4-chloro-phenyl-) { 3-[(1S)-1-(3, 5-difluorophenyl) the fluoro-2-methyl-propyl of-2-] azetidine-1-base } methyl) phenyl]-1, 3, 4-oxadiazole-2 (3H)-one, 4-{ (S)-{ 3-[(1S)-1-(3, 5-difluorophenyl) the fluoro-2-methyl-propyl of-2-] azetidine-1-base } [3-(5-oxo-4, 5-dihydro-1, 3, 4-oxadiazole-2-base) phenyl] methyl }-benzonitrile, with its pharmacologically acceptable salt.
Comprise with the concrete NPY5 antagonist of compound coupling of the present invention: 3-oxo-N-(5-phenyl-2-pyrazinyl)-spiral shell [isobenzofuran-1 (3H), 4'-piperidines]-1'-methane amide, 3-oxo-N-(7-5-flumethiazine also [3, 2-b] pyridine-2-base) spiral shell-[isobenzofuran-1 (3H), 4'-piperidines]-1'-methane amide, N-[5-(3-fluorophenyl)-2-pyrimidyl]-3-oxo spiral shell-[isobenzofuran-1 (3H), 4'-piperidines]-1'-methane amide, trans-3'-oxo-N-(5-phenyl-2-pyrimidyl) spiral shell [hexanaphthene-1, 1'(3'H)-isobenzofuran]-4-methane amide, trans-3'-oxo-N-[1-(3-quinolyl)-4-imidazolyl] spiral shell [hexanaphthene-1, 1'(3'H)-isobenzofuran]-4-methane amide, trans-3-oxo-N-(5-phenyl-2-pyrazinyl) spiral shell [4-azaisobenzofuran-1 (3H), 1'-hexanaphthene]-4'-methane amide, trans-N-[5-(3-fluorophenyl)-2-pyrimidyl]-3-oxo spiral shell [5-azaisobenzofuran-1 (3H), 1'-hexanaphthene]-4'-methane amide, trans-N-[5-(2-fluorophenyl)-2-pyrimidyl]-3-oxo spiral shell [5-azaisobenzofuran-1 (3H), 1'-hexanaphthene]-4'-methane amide, trans-N-[1-(3, 5-difluorophenyl)-4-imidazolyl]-3-oxo spiral shell [7-azaisobenzofuran-1 (3H), 1'-hexanaphthene]-4'-methane amide, trans-3-oxo-N-(1-phenyl-4-pyrazolyl) spiral shell [4-azaisobenzofuran-1 (3H), 1'-hexanaphthene]-4'-methane amide, trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxo spiral shell [6-azaisobenzofuran-1 (3H), 1'-hexanaphthene]-4'-methane amide, trans-3-oxo-N-(1-phenyl-3-pyrazolyl) spiral shell [6-azaisobenzofuran-1 (3H), 1'-hexanaphthene]-4'-methane amide, trans-3-oxo-N-(2-phenyl-1, 2, 3-triazole-4-yl) spiral shell [6-azaisobenzofuran-1 (3H), 1'-hexanaphthene]-4'-methane amide, with its pharmacologically acceptable salt and ester.
Comprise with the concrete ACC-1/2 inhibitor of compound coupling of the present invention: 1'-[(4,8-dimethoxy-quinoline-2-base) carbonyl]-6-(1H-TETRAZOLE-5-base) spiral shell [chroman-2,4'-piperidines]-4-ketone; PIVALIC ACID CRUDE (25) ((5-{1'-[(4,8-dimethoxy-quinoline-2-base) carbonyl]-4-oxo spiral shell [chroman-2,4'-piperidines]-6-base }-2H-tetrazolium-2-base) methyl) ester; 5-{1'-[(8-cyclopropyl-4-methoxy quinoline-2-base) carbonyl]-4-oxo spiral shell [chroman-2,4'-piperidines]-6-base } nicotinic acid; 1'-(8-methoxyl group-4-morpholine-4-base-2-naphthoyl)-6-(1H-TETRAZOLE-5-base) spiral shell [chroman-2,4'-piperidines]-4-ketone; With 1'-[(4-oxyethyl group-8-ethyl quinolinium-2-base) carbonyl]-6-(1H-TETRAZOLE-5-base) spiral shell [chroman-2,4'-piperidines]-4-ketone; With its pharmacologically acceptable salt and ester.
Comprise with the concrete MCH1R agonist compounds of compound coupling of the present invention: 1-{4-[(1-ethyl azetidine-3-base) oxygen base] phenyl-4-[(4-luorobenzyl) oxygen base] pyridine-2 (1H)-one, 4-[(4-luorobenzyl) oxygen base]-1-{4-[(1-sec.-propyl azetidine-3-base) oxygen base] phenyl } pyridine-2 (1H)-one, 1-[4-(azetidine-3-base oxygen base) phenyl]-4-[(5-chloro-pyridine-2-base) methoxyl group] pyridine-2 (1H)-one, 4-[(5-chloro-pyridine-2-base) methoxyl group]-1-{4-[(1-ethyl azetidine-3-base) oxygen base] phenyl } pyridine-2 (1H)-one, 4-[(5-chloro-pyridine-2-base) methoxyl group]-1-{4-[(1-propyl group azetidine-3-base) oxygen base] phenyl } pyridine-2 (1H)-one, with 4-[(5-chloro-pyridine-2-base) methoxyl group]-1-(4-{ [(2S)-1-ethyl azetidine-2-base] methoxyl group } phenyl) pyridine-2 (1H)-one, or its pharmacologically acceptable salt.
Be selected from the concrete DP-IV inhibitor of compound coupling of the present invention: Januvia, 7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl) butyryl radicals]-3-(trifluoromethyl)-5; 6,7,8-tetrahydrochysene-1; 2,4-triazolo [4,3-a] pyrazine.Especially, preferably, the compound of formula I and 7-[(3R)-3-amino-4-(2,4; 5-trifluorophenyl) butyryl radicals]-3-(trifluoromethyl)-5,6,7,8-tetrahydrochysene-1; 2,4-triazolo [4,3-a] pyrazine and its pharmacologically acceptable salt coupling.
Comprise with concrete H3 (histamine H 3) antagonists/inverse agonists of the compounds of this invention conbined usage: be described in WO05/077905 those, comprise: 3-{4-[(1-cyclobutyl-4-piperidyl) oxygen base] phenyl-2-ethylpyridine also [2, 3-d]-pyrimidine-4 (3H)-one, 3-{4-[(1-cyclobutyl-4-piperidyl) oxygen base] phenyl }-2-picoline also [4, 3-d] pyrimidine-4 (3H)-one, 2-ethyl-3-(4-{3-[(3S)-3-methyl piperidine-1-base] propoxy-} phenyl) pyrido [2, 3-d] pyrimidine-4 (3H)-one, 2-methyl-3-(4-{3-[(3S)-3-methyl piperidine-1-base] propoxy-} phenyl) pyrido [4, 3-d] pyrimidine-4 (3H)-one, 3-{4-[(1-cyclobutyl-4-piperidyl) oxygen base] phenyl }-2, 5-dimethyl-4 (3H)-quinazolinone, 3-{4-[(1-cyclobutyl-4-piperidyl) oxygen base] phenyl }-2-methyl-5-trifluoromethyl-4 (3H)-quinazolinone, 3-{4-[(1-cyclobutyl-4-piperidyl) oxygen base] phenyl }-5-methoxyl group-2-methyl-4 (3H)-quinazolinone, 3-{4-[(1-cyclobutyl piperidin-4-yl) oxygen base] phenyl } the fluoro-2-methyl-4 of-5-(3H)-quinazolinone, 3-{4-[(1-cyclobutyl piperidin-4-yl) oxygen base] phenyl } the fluoro-2-methyl-4 of-7-(3H)-quinazolinone, 3-{4-[(1-cyclobutyl piperidin-4-yl) oxygen base] phenyl }-6-methoxyl group-2-methyl-4 (3H)-quinazolinone, 3-{4-[(1-cyclobutyl piperidin-4-yl) oxygen base] phenyl } the fluoro-2-methyl-4 of-6-(3H)-quinazolinone, 3-{4-[(1-cyclobutyl piperidin-4-yl) oxygen base] phenyl } the fluoro-2-methyl-4 of-8-(3H)-quinazolinone, 3-{4-[(1-cyclopentyl-4-piperidyl) oxygen base] phenyl }-2-picoline also [4, 3-d] pyrimidine-4 (3H)-one, 3-{4-[(1-cyclobutyl piperidin-4-yl) oxygen base] phenyl } the fluoro-2-picoline of-6-also [3, 4-d] pyrimidine-4 (3H)-one, 3-{4-[(1-cyclobutyl-4-piperidyl) oxygen base] phenyl }-2-ethylpyridine also [4, 3-d] pyrimidine-4 (3H)-one, 6-methoxyl group-2-methyl-3-{4-[3-(piperidino) propoxy-] phenyl } pyrido [3, 4-d] pyrimidine-4 (3H)-one, 6-methoxyl group-2-methyl-3-{4-[3-(1-pyrrolidyl) propoxy-] phenyl } pyrido [3, 4-d] pyrimidine-4 (3H)-one, 2, 5-dimethyl-3-{4-[3-(1-pyrrolidyl) propoxy-] phenyl }-4 (3H)-quinazolinones, 2-methyl-3-{4-[3-(1-pyrrolidyl) propoxy-] phenyl }-5-trifluoromethyl-4 (3H)-quinazolinone, the fluoro-2-methyl of 5--3-{4-[3-(piperidino) propoxy-] phenyl }-4 (3H)-quinazolinones, 6-methoxyl group-2-methyl-3-{4-[3-(piperidino) propoxy-] phenyl }-4 (3H)-quinazolinones, 5-methoxyl group-2-methyl-3-(4-{3-[(3S)-3-methyl piperidine-1-base] propoxy-} phenyl)-4 (3H)-quinazolinones, 7-methoxyl group-2-methyl-3-(4-{3-[(3S)-3-methyl piperidine-1-base] propoxy-} phenyl)-4 (3H)-quinazolinones, 2-methyl-3-(4-{3-[(3S)-3-methyl piperidine-1-base] propoxy-} phenyl) pyrido [2, 3-d] pyrimidine-4 (3H)-one, the fluoro-2-methyl of 5--3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl] propoxy-} phenyl)-4 (3H)-quinazolinones, 2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl] propoxy-} phenyl) pyrido [4, 3-d] pyrimidine-4 (3H)-one, 6-methoxyl group-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl] propoxy-} phenyl)-4 (3H)-quinazolinones, 6-methoxyl group-2-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl] propoxy-} phenyl)-4 (3H)-quinazolinones, with its pharmacologically acceptable salt.
Comprise with the concrete CCK1R agonist of compound coupling of the present invention: 3-(4-{ [1-(3-ethoxyl phenenyl)-2-(4-aminomethyl phenyl)-1H-imidazol-4 yl] carbonyl }-1-piperazinyl)-1-naphthoic acid; 3-(4-{ [1-(3-ethoxyl phenenyl)-2-(the fluoro-4-aminomethyl phenyl of 2-)-1H-imidazol-4 yl] carbonyl }-1-piperazinyl)-1-naphthoic acid; 3-(4-{ [1-(3-ethoxyl phenenyl)-2-(4-fluorophenyl)-1H-imidazol-4 yl] carbonyl }-1-piperazinyl)-1-naphthoic acid; 3-(4-{ [1-(3-ethoxyl phenenyl)-2-(2,4 difluorobenzene base)-1H-imidazol-4 yl] carbonyl }-1-piperazinyl)-1-naphthoic acid; With 3-(4-{ [1-(2,3-dihydro-Isosorbide-5-Nitrae-Ben Bing dioxin-6-base)-2-(4-fluorophenyl)-1H-imidazol-4 yl] carbonyl }-1-piperazinyl)-1-naphthoic acid; With its pharmacologically acceptable salt.
Comprise with the concrete MC4R agonist of compound coupling of the present invention: 1) (5S)-1'-{ [(3R, the 4R)-1-tertiary butyl-3-(2,3,4-trifluorophenyl) piperidin-4-yl] carbonyl }-3-chloro-2-methyl-5-[1-methyl isophthalic acid-(1-methyl isophthalic acid H-1,2,4-triazole-5-base) ethyl]-5H-spiral shell [furo [3,4-b] pyridine-7,4'-piperidines]; 2) (5R)-1'-{ [(3R, the 4R)-1-tertiary butyl-3-(2,3,4-trifluorophenyl)-piperidin-4-yl] carbonyl }-3-chloro-2-methyl-5-[1-methyl isophthalic acid-(1-methyl isophthalic acid H-1,2,4-triazole-5-base) ethyl]-5H-spiral shell [furo [3,4-b] pyridine-7,4'-piperidines]; 3) 2-(1'-{ [(3S, the 4R)-1-tertiary butyl-4-(2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl }-3-chloro-2-methyl-5H-spiral shell [furo [3,4-b] pyridine-7,4'-piperidines]-5-base)-2-methyl propionitrile; 4) 1'-{ [(3S, the 4R)-1-tertiary butyl-4-(2,4-difluorophenyl) pyrrolidin-3-yl] carbonyl }-3-chloro-2-methyl-5-[1-methyl isophthalic acid-(1-methyl isophthalic acid H-1,2,4-triazole-5-base) ethyl]-5H-spiral shell [furo [3,4-b] pyridine-7,4'-piperidines]; 5) N-[(3R, 4R)-3-({ 3-chloro-2-methyl-5-[1-methyl isophthalic acid-(1-methyl isophthalic acid H-1,2,4-triazole-5-base) ethyl]-1'H, 5H-spiral shell [furo-[3,4-b] pyridine-7,4'-piperidines]-1'-base } carbonyl)-4-(2,4 difluorobenzene base)-cyclopentyl]-N-methyl tetrahydrochysene-2H-pyrans-4-amine; 6) 2-[the chloro-1'-({ (1R of 3-, 2R)-2-(2,4-difluorophenyl)-4-[methyl (tetrahydrochysene-2H-pyrans-4-base) is amino]-cyclopentyl }-carbonyl)-2-methyl-5H-spiral shell [furo [3,4-b] pyridine-7,4'-piperidines]-5-base]-2-methyl-propan-nitrile; With its pharmacologically acceptable salt.
Suitable neurokinine-1 (NK-1) receptor antagonist can preferably use together with AMP-kinase activation of the present invention agent.The nk 1 receptor antagonist used in the present invention has carried out abundant description in this area.The concrete antagonists of neurokinine-1 receptor used in the present invention comprises: (±)-(2R3R, 2S3S)-N-{ [2-ring propoxy--5-(trifluoromethoxy)-phenyl] methyl }-2-Phenylpiperidine-3-amine; 2-(R)-(1-(R)-(3, two (the trifluoromethyl)-phenyl of 5-) oxyethyl group)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H, 4H-1,2,4-triazolo) methyl) morpholine; Aprepitant (aperpitant); CJ17493; GW597599; GW679769; R673; RO67319; R1124; R1204; SSR146977; SSR240600; T-2328; And T2763; Or its pharmacologically acceptable salt.
More than combine and not only comprise combining of compound of the present invention and other active compound a kind of, but also comprise combining of compound of the present invention and two or more other active compounds.When compound of the present invention is combined with two or more active compounds, the non-limitative example of two or more active compounds described is selected from: biguanides, sulfonylurea, HMG-CoA reductase inhibitor class, PPAR gamma agonist class, DPP-4 inhibitor class, anti-obesity compound and antihypertensive agents.
The method of the disease that the present invention also provides a kind for the treatment of or prevention G-protein linked receptor 40 (GPR40) to mediate, the method comprises the patient's a certain amount of GPR40 agonist and one or more activeconstituentss a certain amount of that need this treatment or be among the disease risk forming GPR40 mediation, and they provide effective relief together like this.
In another aspect of this invention, the invention provides the pharmaceutical composition comprising GPR40 agonist and one or more activeconstituentss and the pharmaceutically acceptable carrier of at least one or vehicle.
Therefore, according to another aspect of the present invention, the invention provides GPR40 agonist and the purposes of one or more activeconstituentss for the preparation of medicine, the disease that described medicine is used for the treatment of or prevents GPR40 to mediate.Therefore, in another aspect of this invention or in alternative aspect, the invention provides a kind of product, it comprises GPR40 agonist and one or more activeconstituentss as combined preparation, for simultaneously, separately or the disease being used for the treatment of successively or preventing GPR40 to mediate.Such combined preparation such as can with the form of packing in pairs.
What it will be understood that is, for treatment or the prevention of diabetes, obesity, hypertension, metabolism syndrome, hyperlipemia, cancer, atherosclerosis and associated disorders thereof, compound of the present invention can use with to treating the effective drug combination in addition of this obstacle.
The present invention also provides a kind of method for the treatment of or prevent diabetes, obesity, hypertension, metabolism syndrome, hyperlipemia, cancer, atherosclerosis and associated disorders thereof, the method comprises needs a certain amount of compound of the present invention of the patient of this treatment and a certain amount of medicament effectively other to this obstacle for the treatment of, and they can provide effective relief together like this.
The present invention also provides a kind of method for the treatment of or prevent diabetes, obesity, hypertension, metabolism syndrome, hyperlipemia, cancer, atherosclerosis and associated disorders thereof, the method comprises needs a certain amount of compound of the present invention of the patient of this treatment and the effectively other medicament of this specific illness of a certain amount for the treatment of, and they can provide effective relief together like this.
Term " treatment significant quantity " refers to the consumption by causing tissue, system, the biology of animal or human or the Compounds of structural formula I of medical response sought by researchist, animal doctor, attending doctor or other clinicist, and it comprises alleviating of institute's disease therapy symptom.New treatment of the present invention is for the known disease of those skilled in the art.Term " Mammals " comprises people and pet such as dog and cat.
The compound of formula I and the weight ratio of second active ingredient can change and will depend on the effective dose of each composition.Usually, each effective dose will be used.Therefore, such as, when the compound of formula I is combined with a kind of DPIV inhibitor, the compound of described formula I and the weight ratio of described DPIV inhibitor by usual in the scope of about 1000:1 to about 1:1000, preferably in the scope of about 200:1 to about 1:200.The drug combination of the compound of formula I and other activeconstituents usually also within above-mentioned scope, but in each case, will should use the effective dose of often kind of activeconstituents.
the synthetic method of the compounds of this invention:
Following reaction scheme and embodiment illustrate the method that can be used for synthesizing Compounds of structural formula I described in the present invention.There is provided these reaction scheme and embodiment to be for illustrating the present invention, but be not be understood as to limit the invention by any way.Unless otherwise stated, all substituting groups all as defined above.In order to prepare the compound of structural formula I, the some strategies transformed based on the known in the literature synthesis in organic synthesis can be used.Scope of the present invention defined by appended claims.
Compound of the present invention can use suitable raw material preparation according to the step of the following example.But illustrational compound should not be understood to that formation is considered to a unique class of the present invention in an embodiment.Described embodiment illustrates the preparation details of the compounds of this invention further.Those skilled in the art will easily understand, and the described protecting group below in preparation process and the known variant of condition and technique may be used for preparing these compounds.Should also be understood that, if a kind of chemical reagent such as boric acid or boric acid ester commercially can't buy, so this chemical reagent can easily be prepared according to one of many methods described in document.Unless otherwise noted, otherwise all temperature is all centigradetemperature.Mass spectrum (MS) or by electron spray(ES) ion-mass spectrum (ESMS) measure, or by atmospheric pressure chemical ion massspectrum (APCI) measure.
list of abbreviations
Ac is ethanoyl; AcO is acetoxyl group; Alk is alkyl; APCI is atmospheric pressure chemical ionization; Aq or aq. is moisture; Ar is aryl; Boc is tertbutyloxycarbonyl; Br is wide; T-BuOK is potassium tert.-butoxide; DEG C be centigradetemperature; Cbz is carbobenzoxy-(Cbz); CH
2cl
2it is methylene dichloride; CO is carbon monoxide; Conc or conc. is dense; D is bimodal; DAST is (diethylin) sulfur trifluoride; DIAD is diisopropyl azodiformate; DCM is methylene dichloride; DIPEA is DIPEA; DMAP is 4-dimethylaminopyridine; DMF is DMF; DMSO is methyl-sulphoxide; Dppf is 1,1
'-two (diphenyl-phosphino) ferrocene; ESI is electrospray ionization; EA or EtOAc is ethyl acetate; Et is ethyl; EtMgBr is ethyl-magnesium-bromide; EtOH is ethanol; G is gram (Zhu Ke); H or hr or hrs is hour (all a hour); HPLC is high pressure liquid chromatography; HOAc or AcOH is acetic acid; Kg is kilogram (all a kilogram); KOH is potassium hydroxide; KOAc is potassium acetate; L rises; LC-MS is liquid chromatography-mass spectrography; LDA is diisopropylamide lithium; LiOH is lithium hydroxide; M is multiplet; M-CPBA, MCPBA or mCPBA are metachloroperbenzoic acids; ML is milliliter; Min or mins is minute (all a minute); Mol is mole (all a mole); Mmol is mmole (all mmole); Mg is milligram (all milligram); MeMgBr is methylmagnesium-bromide; MeOH is methyl alcohol; MgSO
4magnesium sulfate; MS is mass spectrum; MsCl or Ms-Cl is methylsulfonyl chloride; N is standard; Na (AcO)
3bH is sodium triacetoxy borohydride; NaHMDS is hexamethyldisilazane sodium salt; NaOH is sodium hydroxide; Na
2sO
4sodium sulfate; NH
4oAc is ammonium acetate; NBS is N-bromination succinic diamide; NIS is N-iodosuccinamide; NMO is 4-methylmorpholine N-oxide; NMP is 1-Methyl-2-Pyrrolidone; NMR is NMR (Nuclear Magnetic Resonance) spectrum; PE is sherwood oil; PG is protecting group; P (Cy)
3it is tricyclohexyl phosphine; Pd
2(dba)
3it is three (dibenzalacetone) two palladium (0); Pd [P (
t-Bu)
3]
2it is two (three-tertiary butyl phosphine) palladium (0); Pd (dppf) Cl
2it is [1,1'-bis-(diphenylphosphino) ferrocene] two chloro-palladium (II); PMB is to methoxy-benzyl; PMBCl is to methoxy-benzyl chlorine; Prep is preparation property; Prep. TLC or prep-TLC or prep TLC is preparative thin layer chromatography; RBF is round-bottomed flask; RCM is that ring closes replacement(metathesis)reaction; Rt or r.t. or RT is room temperature; S is unimodal; SFC is supercritical fluid chromatography; S-phos is 2-bis-cyclohexyl phosphino--2', 6'-dimethoxy-biphenyl; T is triplet; TBTU be N, N, N ', N '-tetramethyl--O-(benzotriazole-1-base)
a tetrafluoro borate; TEA is triethylamine; THF is tetrahydrofuran (THF); Ti (OiPr)
4it is titanium isopropoxide; TFA is trifluoroacetic acid; TLC is tlc; TMSCl is trimethylsilyl chloride; TsCl or TosCl is Tosyl chloride; TsOH is tosic acid, and xphos be 2-bis-cyclohexyl phosphino--2 ', 4 ', 6 '-tri isopropyl biphenyl.
Several preparation methods of the compounds of this invention are illustrated below in scheme and embodiment.Initial substance or commercially available or can be prepared according to method known in the literature or by following illustrational method.The present invention also provides the preparation method of the compound of a kind of structural formula I as defined above.In some cases, the order of carrying out above-mentioned reaction scheme can change promote reaction or avoid unwanted reaction product.There is provided the following example to be only used to illustrational object, and should not be understood to disclosed restriction of the present invention.Unless otherwise noted, otherwise all temperature is all centigradetemperature.
Scheme 1
As in scheme 1 summarize; amino in 2-amino-4-bromopyridine (1-1) is by two-p-methoxy-benzyl (PMB) radical protections; reacted under highly basic exists by (1-1) and PMB-Cl, obtain (1-2).This protected pyridinyl derivatives (1-2) and N-iodosuccinimide (NIS) react, and obtain 5-iodo-pyridin (1-3).Under the Suzuki reaction conditions of gentleness, this iodo derivative (1-3) is converted into 5-vinylpyridine with vinyl-tin reagent and forms sediment (1-4).Under more violent Suzuki reaction conditions, (1-4) and tributyl-3-propenyl tin react, and obtain 4-allyl group, 5-vinyl pyridine based compound (1-5).Under ring closing metathesis (RCM) condition, use Grubbs catalyzer, (1-5) is converted into azepine-indene derivative (1-6).(1-6) double bond in and ethyl diazoacetate react under rhodium catalyst exists, and obtain azepine-tricyclic derivatives (1-7).PMB protecting group in removing (1-7), carries out diazotization/hydrolysis reaction subsequently, obtains the hydroxyl-azepine-tricyclic compound (1-9) of target.
Scheme 2.
Other method for the preparation of compound 1-9 is summarised in scheme 2.2-methoxyl group-5-bromopyridine LDA lithiumation, and use DMF cancellation, obtain aldehyde 39-1.Compound 39-1 and Pd (dppf) Cl in MeOH
2react in CO atmosphere, obtain ester 39-2.By the aldehyde homologization in 39-2, obtain vinyl ester 39-3.Double bond hydrogenation in 39-3, obtains pyridyl-propionic acid diester 39-4.39-4 hexamethyldisilazane (disilazide) sodium salt process, obtains azepine-indone 39-6.Ketone body powder in 39-6, then carries out eliminative reaction, obtains azepine-indenes 39-8.39-8 ethyl diazoacetate process, obtains the cyclopropyl derivatives 39-9 condensed.Subsequently, 39-9 and trimethylsilyl iodide are reacted, and obtain compound 1-9.
Embodiment
Reference example 1-9
4-hydroxyl-1,1a, 6,6a-tetrahydrochysene-3-azepine-cyclopropane also [a] indenes-1-ethyl formate (1-9)
Steps A: (the bromo-pyridine of 4--2-base)-two-(4-methyoxy-benzyl)-amine (1-2)
At 0 DEG C, in the suspension of sodium hydride (60% in oil, 93 g, 2.32 mol) in DMF (1.8 L), be added in the compound 1-1 (100 g, 0.58 mol) in DMF (500 mL) lentamente.Then, at N
2under protection, gained mixture is at room temperature stirred 0.5 h.PMBCl (227 g, 1.45 mol) is joined in said mixture, and described temperature is remained between 0-10 DEG C.After finishing, described mixture at room temperature stirs 2h.Described mixture is poured in frozen water carefully, collects gained solid precipitation, filter, wash with PE (150 mL x 3).Described filtrate is concentrated, obtains compound 1-2.MS(ESI)m/e(M+H
+): 414.1/416.1。
The iodo-pyridine of the bromo-5-of step B:(4--2-base)-two-(4-methyoxy-benzyl)-amine (1-3)
Add NIS (115 g, 0.51 mmol) in the solution of compound 1-2 (140 g, 0.34 mol) in DMF (2.8 L) under stirring in batches.Then, gained mixture be heated to 40 DEG C and stir 24 h.Described mixture is cooled, is poured in frozen water and also constantly stirs.Collect the solid of gained precipitation, filter, wash with PE (100 mL x 3).Described filtrate is concentrated in a vacuum, obtains compound 1-3.MS(ESI)m /e(M+H
+): 540,541(M+H
+)。
The bromo-5-vinyl-pyridin of step C:(4--2-base)-two-(4-methyoxy-benzyl)-amine (1-4)
Tributyl (vinyl) tin (85 g, 267 mmol), Pd (PPh is added in the solution of compound 1-3 (144 g, 267 mmol) in toluene (2 L) under stirring
3)
4(15.4 g, 13.4 mmol), and KF (31 g, 534 mmol).Gained mixture is at N
2middle reflux 18 h.Cooled by described mixture, add KF (300 mL, 2 mol L), described mixture stirs 20 minutes.Then, described mixture is filtered, and separating filtrate.Collected organic layer, and it is evaporated in a vacuum, obtain crude product, it is purified (PE:EA=20:1) with silica gel column chromatography, obtains compound 1-4.MS(ESI)m/e(M+H
+): 439.8/441 8。
Step D:(4-allyl group-5-vinyl-pyridin-2-base)-two-(4-methyoxy-benzyl)-amine (1-5)
Cs is added in the solution of compound 1-4 (90 g, 205 mmol) in THF (2 L) under stirring
2cO
3(134 g, 410 mmol), Pd (dppf) Cl
2(7.5 g, 10.3 mmol) and allyl tributyltin (136 g, 410 mmol).Then, gained mixture is at N
2middle reflux 18 h.Cooled by described mixture, add KF (300 mL, 2 mol/L), described mixture stirs 20min.Described mixture is filtered, and separating filtrate.Collected organic layer, and it is evaporated in a vacuum, obtain crude product, it is purified (PE:EA=30:1) with silica gel column chromatography, obtains compound 1-5.MS(ESI)m /e(M+H
+): 440.1。
Step e: two-(4-methyoxy-benzyl)-(5H-[2] pyridin-3-yl)-amine (1-6)
Disposablely in the solution of compound 1-5 (55 g, 138 mmol) in DCM (700 mL) under stirring add Grubbs reagent (II) (3.5 g, 4.14 mmol).Gained mixture is at N
2in heat 3 h under reflux.Then, cooling mixture, gains matter is directly used in next step.MS(ESI)m /e(M+H
+): 373.2。
Step F: 4-[two-(4-methyoxy-benzyl)-amino]-1,1a, 6,6a-tetrahydrochysene-3-azepine-cyclopropane also [a]-indenes-1-ethyl formate (1-7)
Disposablely in the solution of thick 1-6 (52 g, 138 mmol) in DCM (0.7 L) under stirring add Rh (OAc)
2(1.6 g, 6.9 mmol).Described mixture stirs 15 minutes, then, under the reflux conditions of gentleness, in 3 h, is joined in this mixture by ethyl diazoacetate (126 g, 1.1 mol) lentamente.Gained mixture is stirred 1h under r.t.Described mixture evaporates in a vacuum, obtains crude product, and it is purified (PE:EA=10:1) with silica gel column chromatography, obtains the trans-isomer mixture of 1-7.The trans-isomer mixture of described 1-7 is undertaken being separated (SFC splitting condition: instrument: Thar 200 by chiral column chromatography; Post: AD 250mm x 50mm, 10um; Moving phase: A supercritical CO
2, B EtOH (0.05%NH
3.H
2o), A/B=60/40 is with 200mL/min; Column temperature: 38 DEG C; Nozzle pressure: 100 bar; Nozzle temperature: 60 DEG C; Evaporator temperature: 20 DEG C; Trimmer temperature: 25 DEG C; Wavelength: 220nm), obtain required enantiomer 1-7.MS(ESI)m/e(M+H
+): 459.1。
Amino-1,1a, 6, the 6a-tetrahydrochysene-3-azepine-cyclopropane of step G:4-also [a] indenes-1-ethyl formate (1-8)
Disposablely in the solution of compound 1-7 (19 g, 41.4 mmol) in DCM (130 mL) under stirring add TFA (130 mL).Gained mixture is stirred under r.t and spends the night.Described mixture evaporates in a vacuum, and obtain compound 1-8, it is directly used in next step.MS(ESI)m /e(M+H
+): 219.1。
Step H:4-hydroxyl-1,1a, 6,6a-tetrahydrochysene-3-azepine-cyclopropane also [a] indenes-1-ethyl formate
(1-9)
At 0 DEG C, to the compound 1-8 (23 g, crude product) under stirring at H
2sO
4divide several in solution in (200 mL, 15%) and add NaNO
2(14.4 g, 209 mmol).Gained mixture is stirred 2 h under r.t.Described mixture 2N NaOH alkalizes to pH value=5-6, then adds NaHCO
3the aqueous solution, is adjusted to 7 by the pH value of described filtrate.Then, described suspension DCM (300 mL x 3) extracts, and the organic layer washed with brine of merging, at Na
2sO
4middle drying, then concentrates.Gained residue over silica gel chromatography over CC (DCM/MeOH=50/1-20/1), obtains 1-9.
for the preparation of the other method of reference compound 1-9
Steps A: (5-bromo-2-methoxyl group isonicotine aldehyde
(39-1)
At N
2in atmosphere, at-78 DEG C, to Diisopropylamine (63 g, 642 mmol) drip in solution in anhydrous THF (500 ml) n-BuLi (2.5 M, in hexane, 256 mL, 642 mmol), then described mixture is stirred 30 min.The bromo-2-methoxypyridine of 5-(100 g, the 535 mmol) solution in 100 mL THF is added in described reaction mixture.Described reaction mixture stirs 1h at-78 DEG C, then adds DMF (50 ml, 642 mmol).After stirring 30 min, described reaction mixture shrend is gone out and extracts with EtOAc.Organic layers with water and salt water washing, then at Na
2sO
4middle drying.After filtering and concentrating, described residue over silica gel chromatography over CC (using sherwood oil: ethyl acetate=10:1 wash-out), obtains solid 39-1.MS(ESI)m/e(M+H
+): 216.0/218.0。
Step B:4-formyl radical-6-methoxynicotinate (39-2)
To compound 39-1 (30 g, 139 mmol) and Et
3pd (dppf) Cl is added in the solution of N (27 g, 280 mmol) in 100 mL methyl alcohol
2(10.5 g, 139 mmol).Gained mixture stirs 12 hours in CO (50 Psi) at 70 DEG C.After cooling, filter and concentrate, gained residue over silica gel chromatography over CC (using sherwood oil: ethyl acetate=3:1 wash-out), obtains 39-2.MS(ESI)m/e(M+H
+): 196.0。
Step C:(E)-4-(3-oxyethyl group-3-oxo third-1-alkene-1-base)-6-methoxynicotinate (39-3)
At room temperature; to NaH (5.6 g; 139 mmol) add 2-(diethoxy phosphoryl) ethyl acetate (31 g in solution in 200 mL THF; 137 mmol); gained mixture stirs 1 hour; then add 39-2 (22.5 g, 116 mmol), then described reaction mixture is stirred 1h.Then, described reaction mixture distributes between ethyl acetate and water.By organic layer washed with brine, then at Na
2sO
4middle drying.After concentrated, gained residue over silica gel chromatography over CC (using sherwood oil: ethyl acetate=10:1 wash-out), obtains 39-3.MS(ESI)m/e(M+H
+): 266.1。
Step D:4-(3-oxyethyl group-3-oxopropyl)-6-methoxynicotinate
(39-4)
In the solution of 39-3 (24 g, 91 mmol) in MeOH (100 ml), adding Pd/C, (2 g).Described mixture is at room temperature at H
2stir 2.5 hours in atmosphere (30 psi).After filtration, described filtrate concentrated, obtain crude compound 39-4, it is not purified namely for next step.MS(ESI)m/e(M+H
+): 268.1。
Step e: 3-methoxyl group-7-oxo-6,7-dihydro-5H-cyclopenta [c] pyridine-6-ethyl formate
(39-5)
At-78 DEG C, in the solution of 39-4 (18.8 g, 71 mmol) in THF (300 mL), add NaHMDS (141 mL, 141 mmol), then gained mixture is stirred 2h at this temperature.Described reaction mixture shrend is gone out, and is extracted with ethyl acetate.Organic layer washed with brine, then at Na
2sO
4middle drying.After filtering and concentrating, described residue over silica gel chromatography over CC (using sherwood oil: ethyl acetate=10:1 wash-out), obtains 39-5.MS(ESI)m/e(M+H
+): 236.1。
Step F: 3-methoxyl group-5H-cyclopenta [c] pyridine-7 (6H)-one (39-6)
To compound 39-5 (12 g, 51 mmol) at DMSO/H
2(1 g) to add p-TsOH in solution in O (15 mL/1 mL).Gained mixture is heated to 150 DEG C and reaches 2 hours.After cooling, described reaction shrend is gone out, and is extracted with ethyl acetate twice.The organic layer washed with brine merged, at Na
2sO
4middle drying.After filtering and concentrating, gained residue over silica gel chromatography over CC, obtains 39-6.MS(ESI)m/e(M+H
+): 164.1。
Step G:3-methoxyl group-6,7-dihydro-5H-cyclopenta [c] pyridine-7-alcohol
(39-7)
At 0 DEG C, in the solution of 39-6 (8 g, 48 mmol) in MeOH (50 mL), add NaBH in batches
4(1.8 g, 48 mmol).Mixture is at room temperature stirred 2 hours.Described reaction shrend is gone out, and is extracted with ethyl acetate twice.By the organic layer washed with brine merged, then at Na
2sO
4middle drying.After filtering and concentrating, described residue over silica gel chromatography over CC (using sherwood oil: ethyl acetate=2:1 wash-out), obtains 39-7.MS(ESI)m/e(M+H
+): 166.1。
Step H:3-methoxyl group-5H-cyclopenta [c] pyridine (39-8)
To 39-7 (7 g, 42.4 mmol) and MgSO
41-methylsulfonyl-4-methyl-benzene (0.73 g, 4.24 mmol) is added in (11.6 g, 84.8mmol) solution in 100 mL toluene.Gained mixture is heated to 110 DEG C and reaches 2 hours.After being cooled to room temperature, described reaction shrend is gone out, and is extracted with ethyl acetate twice.By the organic layer washed with brine merged, then at Na
2sO
4middle drying.After filtering and concentrating, gained residue over silica gel chromatography over CC (using sherwood oil: ethyl acetate=10:1 wash-out), obtains 39-8.MS(ESI)m/e(M+H
+): 148.1。
Step I:3-methoxyl group-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate also
(39-9)
Rh is added in solution in anhydrous DCM (30 mL) of the mixture (1.6 g, 10.7 mmol) of 39-8
2(OAc)
4(0.5 g, 1.07 mmol).Then, in 8 hours, add ethyl diazoacetate (2.5 g, the 21.4 mmol) solution in anhydrous DCM (10 mL) by syringe pump.After adding, described reaction shrend is gone out, described water layer DCM extracting twice.By the organic layer washed with brine merged, then at Na
2sO
4middle drying.After filtering and concentrating, gained residue over silica gel chromatography over CC (using sherwood oil: ethyl acetate=5:1 wash-out), obtains 39-9.MS(ESI)m/e(M+H
+): 234.1。
Step J:3-hydroxyl-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate also
(1-9)
To 39-9 (0.2 g, 0.86 mmol) and NaI (0.17 g, 1.12mmol) at 10 mL CH
3add TMSCl (0.47 g, 4.29 mmol) in solution in CN, then gained mixture is refluxed 2 hours.After being cooled to room temperature, described reaction shrend is gone out, and described water layer is extracted with ethyl acetate twice.By the organic layer washed with brine merged, then at Na
2sO
4middle drying.After filtering and concentrating, gained residue over silica gel chromatography over CC (using DCM:MeOH=30:1 wash-out), obtains compound 1-9.MS(ESI)m/e(M+H
+): 220.1。
Reference example 2-4
4-[the fluoro-5-of 2-(4,4,5,5-tetramethyl--[1,3,2] dioxaborinate-2-base)-benzyloxy]-1,1a, 6,6a-tetrahydrochysene-3-azepine-cyclopropane also [a] indenes-1-ethyl formate (2-4)
Steps A: [the fluoro-5-of 2-(4,4,5,5-tetramethyl--[1,3,2] dioxaborinate-2-base)-phenyl]-methyl alcohol
(2-2)
Compound 2-1 (25 g under stirring, two (tetramethyl ethylene ketone is (pinacolato) also) two boron (45 g, 180 mmol), Pd (dppf) Cl is added in solution in 120 mmol) dioxs (400 mL)
2(4.4 g, 6.0 mmol) and KOAc (23.5 g, 240 mmol).Gained mixture is at N
2in be heated to 110 DEG C and spend the night.Then, concentrated by described mixture, obtain crude product, it is purified (PE:EA=20:1) with silica gel column chromatography, obtains compound 2-2.MS(ESI)m/z: 253(M+H
+)。
Step B:2-(the fluoro-phenyl of 3-brooethyl-4-)-4,4,5,5-tetramethyl-s-[1,3,2] dioxaborinate (2-3)
At 0 DEG C, in the solution of compound 2-2 (7 g, 28 mmol) in THF (80 mL) under stirring, drip PBr
3(7.6 g, 28 mmol).Gained mixture stirs 1h at 0 DEG C.By H
2o (50 mL) joins in described mixture, and then gained mixture EtOAc (50 mL x 3) extracts.The organic layer washed with brine merged, at Na
2sO
4middle drying, concentrated, obtain crude product, it is purified (PE:EA=20:1) by silica gel column chromatography, obtains compound 2-3.MS(ESI)m/z: 315, 316(M+H
+)。
Step C:4-[the fluoro-5-of 2-(4,4,5,5-tetramethyl--[1,3,2] dioxaborinate-2-base)-benzyloxy]-1,1a, 6,6a-tetrahydrochysene-3-azepine-cyclopropane also [a] indenes-1-ethyl formate
(2-4)
Disposablely Ag is added in the compound 2-3 (863 mg, 2.74 mmol) under stirring and the solution of 1-9 (500 mg, 2.28 mmol) in toluene (35 mL)
2cO
3(1.30 g, 4.56 mmol).Gained mixture is at N
2be heated to 110 DEG C under protection spend the night.TLC shows that compound 2-3 is exhausted.Filtered by described mixture, filtrate concentrates, and obtain crude product, this crude product purified by silica gel chromatography over CC (PE:EA=5:1), obtains 2-4.
Reference example 2-5 is prepared according to the mode being similar to reference example 2-4, uses suitable commercially available starting raw material.
Reference example 2-5:
。
Reference example 3-3
bromo-2, the 4-dimethyl-6-of 3-(3-(methyl sulphonyl) propoxy-) pyridine (3-3)
Chloro-2, the 4-lutidine (3-1) of the bromo-6-of steps A: 3-
To 2-amino-5-bromo-4,6-lutidine (5.03 g, 25 mmol) in mixture in dense HCl (30 mL), it is cooled to-5 DEG C, in 30 min, drip Sodium Nitrite (5.18 g, the 75 mmol) solution in water (20 mL), keep described temperature of reaction simultaneously between-5 DEG C to 5 DEG C.After finishing, 1h is stirred in reaction.Then, removing cooling bath, described reaction is warmed to room temperature and stirs 24 h.Then, described reaction is poured in ice, adds 5N NaOH, so that the pH value of gained mixture is adjusted to pH 7.Described mixture EtOAc extracts three times.By the organic layer of merging in anhydrous Na
2sO
4middle drying, filters, concentrated.Gained residue over silica gel Flash chromatography, uses PE:EA=20:1 wash-out, obtains chloro-2, the 4-lutidine of the bromo-6-of 3-.MS(ESI)m/e(M+H
+): 222.0/220.0。
Bromo-2, the 4-dimethyl-6-of step B:3-(3-(methylthio group) propoxy-) pyridine (3-2)
By 3-methylsulfanyl-propyl-1-alcohol (212 mg, 2.0 mmol) and the bromo-6-of 3-chloro-2,4-lutidine (440 mg, 2.0 mmol) and t-BuOK (250 mg, 2.2 mmol) the mixture reflux 2h in anhydrous THF.Described mixture water and EtOAc distribute, then separate aqueous layer and organic layer, described aqueous solution EtOAc extracting twice.The organic layer of merging is concentrated, obtains a kind of resistates, this residue over silica gel Flash chromatography, obtain bromo-2, the 4-dimethyl-6-of 3-(3-(methylthio group) propoxy-) pyridine.MS(ESI)m/e(M+H
+): 292.0/290.0。
Bromo-2, the 4-dimethyl-6-of step C:3-(3-(methyl sulphonyl) propoxy-) pyridine (3-3)
To 3-bromo-2, in the solution of 4-dimethyl-6-(3-(methylthio group) propoxy-) pyridine (378 mg, 1.3 mmol) in dry DCM (12 mL), it cools in ice bath, add MCPBA (580 mg, 2.86 mmol).Gained mixture stirs 2h at 0 DEG C.Then, described reaction NaHSO
3aqueous solution cancellation.Be separated DCM layer, use Na
2cO
3(aqueous solution), water and salt water washing, then concentrate, and obtains a kind of resistates, this residue over silica gel Flash chromatography, obtains bromo-2, the 4-dimethyl-6-of 3-(3-(methyl sulphonyl) propoxy-) pyridine.
Reference example 4-10 is prepared by the mode being similar to reference example 3, uses suitable commercially available starting raw material:
Reference example 11 (compound 34-5)
3'-(brooethyl)-2,6-dimethyl-4-(3-(methyl sulphonyl) propoxy-)-1,1'-biphenyl (34-5)
Steps A: 4-toluene sulfonic acide (3-(methylthio group) propyl group) ester (34-1)
At 0 DEG C, add TsCl (90 g, 0.47 mol) to 3-(methylthio group) third-1-alcohol (50 g, 0.47 mol) and TEA (95 g, 0.94 mol) in the solution in DCM (500 mL) in batches.After finishing, described reaction mixture be warmed to lentamente room temperature and stir 16h at this temperature.Then, described reaction 1N HCl cancellation, so that pH value is adjusted to pH 7-8, is then extracted with ethyl acetate three times by described mixture.The organic layer washed with brine merged, at Na
2sO
4middle drying, filters, concentrates in a vacuum, obtain a kind of resistates.Described residue purified over silica chromatography purity (sherwood oil: ethyl acetate 5/1), obtains compound 34-1.
Step B:4-toluene sulfonic acide (3-(methyl sulphonyl) propyl group) ester (34-2)
To in the solution of 34-1 (35 g, 135 mmol) in dry DCM (400 mL), it is cooled with an ice bath, and adds MCPBA (46.5 g, 270 mmol) in batches.Gained mixture is stirred 1h at 0 DEG C, is then warmed to room temperature and stirs 20 h.By adding NaHSO
3aqueous solution quencher is reacted, and then described DCM layer is used Na respectively
2cO
3(aqueous solution), water and salt water washing, concentrated, obtain a kind of resistates, this residue over silica gel chromatography purity (sherwood oil: ethyl acetate=3/1), obtains compound 34-2.
Bromo-1, the 3-dimethyl-5-of step C:2-(3-(methyl sulphonyl) propoxy-) benzene (34-3)
The bromo-MX of 4-(20.1 g, 100 mmol) and K is added in the solution of compound 34-2 (32.1 g, 110 mmol) in DMF (300 mL)
2cO
3(16.5 g, 120 mmol).Gained mixture is stirred 18 hours at 100 DEG C.Then, add water, described mixture ethyl acetate (150 mL x 3) extracts.The organic layer washed with brine merged, dry, concentrated, obtain a kind of resistates.Described residue over silica gel chromatography purity (sherwood oil: ethyl acetate=3/1), obtains compound 34-3.MS(ESI)m/z(M+H)
+: 321.0/323.0。
Step D:(2', 6'-dimethyl-4'-(3-(methyl sulphonyl) propoxy-)-[1,1
'-biphenyl]-3-base) methyl alcohol
(34-4)
In nitrogen atmosphere, to compound 34-3 (10 g, 31.1 mmol), (3-(4,4,5,5-tetramethyl--1,3,2-dioxaborinate-2-base) phenyl) methyl alcohol (7.64 g, 32.6 mmol) and K
3pO
4(15.7 g, 77.9 mmol) are at altogether-solvent THF/H
2pd (dppf) is added in mixture in O (120/30 mL)
2cl
2(1.27 g, 1.56 mmol).Gained mixture reflux 16h.After being cooled to room temperature, described mixture passes through Celite
tMpad filters, and described filtrate is extracted with ethyl acetate twice.The organic layer washed with water of described merging, dry, concentrate in a vacuum, obtain a kind of resistates, this residue over silica gel chromatography over CC (sherwood oil: ethyl acetate=3/1), obtains compound 34-4.MS(ESI)m/z(M+H)
+: 349.1。
Step e:
3'-(brooethyl)-2,6-dimethyl-4-(3-(methyl sulphonyl) propoxy-)-1,1'-biphenyl (34-5)
To in the solution of crude compound 34-4 (20 g, 73 mmol) in dry THF (300 mL), it is with ice-cooled, drips PBr
3(6.8 g, 25.2 mmol).Described reaction soln is stirred 1h at 0 DEG C, and then described mixture is warmed to 20 DEG C and stirs 16h.Then, to go out described mixture with shrend, in described mixture, add NaHCO
3saturated aqueous solution, so that described mixture is neutralized to pH 7.Be separated organic layer, with water, salt water washing, at Na
2sO
4middle drying, then filters.Described filtrate concentrates, and obtains a kind of resistates, and it, with purified by silica gel chromatography (PE/EA=5/1), obtains 34-5.MS(ESI)m /e(M+H
+): 341.1/343.1。
Embodiment 1 (compound 3-4)
(5aR, 6S, 6aS)-3-((2', 6'-dimethyl-4'-((3-methy oxetane-3-base) methoxyl group)-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (3-4) also
Steps A:
3-((bromo-3, the 5-dimethyl phenoxies of 4-) methyl)-3-methy oxetane (3-2)
By compound 3-1 (1 g, 5.0 mmol), 3-(chloromethyl)-3-methy oxetane (1.2 g, 9.95 mmol) and K
2cO
3(2.74 g, 19.9 mmol) solution in DMF (10 mL) is heated to 100 DEG C and reaches 12 h.After having reacted, described reaction mixture salt solution (100 mL) processes, and extracts with EtOAc (50 mL × 3).Merge organic phase, with water (50 mL), salt solution (50 mL) washing, dry also concentrated, obtain crude compound 3-2, its when purifying further just for next step.MS(ESI)
m/z: 285,287(M+H)。
Step B:
(5aR, 6S, 6aS)-3-((2', 6'-dimethyl-4'-((3-methy oxetane-3-base) methoxyl group)-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (3-3) also
By compound 3-2 (90 mg, 0.31mmol), boric acid ester (205 mg, 0.47 mmol), Pd from reference example 2-4
2(dba)
3(27.48 mg, 0.03 mmol), P (Cy)
3(16.8 mg, 0.06 mmol) and K
2cO
3(86.94 mg, 0.63 mmol) diox/H
2mixture in O (3 mL/0.6 mL) at 100 DEG C under microwave condition at N
2middle stirring 10 min.After having reacted, described mixture is filtered and concentrates.Gained crude product is purified with preparation property silicon-dioxide TLC on silica gel, with sherwood oil: ethyl acetate=(3:1) wash-out, obtains ester 3-3.MS(ESI)m/z: 513(M+H)
+。
Step C:
(5aR, 6S, 6aS)-3-((2', 6'-dimethyl-4'-((3-methy oxetane-3-base) methoxyl group)-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (3-4) also
To compound 3-3 (130 mg, 0.25 mmol) at MeOH/H
2liOH (63 mg, 1.5 mmol) is added in solution in O (5/1 mL).Described solution is at room temperature stirred and spends the night.After having reacted, HCl (1 mol/L) is joined in described solution, so that its pH value is adjusted to pH 5.Then, described solution EtOAc (5 mL x 3) extracts, and concentrated.Gained crude compound preparation property HPLC purifies, and (preparation property HPLC is on GILSON 281 instrument, YMC-Actus Triart 18 C (100 x 30mm x 4um) is housed, use water and acetonitrile as eluent, mobile phase A: water is (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 36-66% B, 0-10min; 100% B, 10.5-12.5min; 5% B, 13-15min), obtain compound 3-4.
The following example 2 (compound 3-5) is prepared according to the mode being similar to compound 3-4, uses suitable commercially available raw material.
Embodiment 3 (compound 4-5)
(5aR, 6S, 6aS)-3-((4'-(2-(1-hydroxycyclopropyl) oxyethyl group)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (4-5) also
Steps A:
3-(bromo-3, the 5-dimethyl phenoxies of 4-) methyl propionate (4-2)
CH is added in the solution of compound 4-1 (2.0 g, 0.01 mol) in methyl acrylate (8.6 g, 0.1 mol)
3oNa (1.1 g, 0.02 mol).Gained mixture is stirred 20 hours at 50 DEG C.By concentrated for described solution with except desolventizing, then add H
2o.Then, described solution HCl (1M) is acidified to pH 2.5, and extracts with EtOAc (15 mL x 3).The organic layer washed with brine merged, dry, concentrated, obtain compound 4-2.MS(ESI)
m/z: 287, 289(M+H)
+。
Step B:
1-(2-(bromo-3, the 5-dimethyl phenoxies of 4-) ethyl) ring propyl alcohol (4-3)
Titanium isopropylate (IV) (0.04 g, 1.4 mmol) is added in the solution of compound 4-2 (0.5 g, 3.5 mmol) in THF (10 mL).Then, ethyl-magnesium-bromide (3.3 mL, 3M) is dissolved in THF (2 mL), then at 0 DEG C, described solution is dropped in described reaction.Described reaction HCl (1 M) cancellation, then uses EtOAc (15 mL x 3) to extract.The organic layer washed with brine merged, dry also concentrated, obtain crude product, it is purified by silica gel preparative TLC, with sherwood oil: ethyl acetate (5:1) wash-out, obtains compound 4-3.
Step C:(
5aR, 6S, 6aS)-3-((4'-(2-(1-hydroxycyclopropyl) oxyethyl group)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (4-4) also
Compound 4-4 uses to be similar to and prepares the step that compound 3-3 uses and be prepared.MS(ESI)
m/z: 287, 289(M+H)
+。
Step D:
(5aR, 6S, 6aS)-3-((4'-(2-(1-hydroxycyclopropyl) oxyethyl group)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (4-5) also
Compound 4-6 uses to be similar to and prepares the step that compound 3-4 uses and be prepared.
The following example 4 (compound 4-6) is prepared according to the mode being similar to compound 4-5, uses suitable commercially available starting raw material.
Embodiment 5 (compound 5-3)
Steps A:
4-(bromo-3, the 5-dimethyl phenoxies of 4-)-2-methyl fourth-2-alcohol (5-1)
At 0 DEG C, in the solution of compound 4-2 (3.4 g, 0.01 mol) in THF (20 mL), drip CH lentamente
3mgBr (3 M, 13 mL).Reaction mixture is warmed to room temperature, and stirs 2 hours.Described reaction HCl (1 M) cancellation, then uses EtOAc (15 mL x 3) to extract.The organic layer washed with brine merged, dry, concentrated, obtain compound 4-3.
Step B and C:(5aR, 6S, 6aS)-3-((4'-(3-hydroxy-3-methyl butoxy)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (5-3) also
Compound 5-3 use is similar to the step preparing compound 3-3 and 3-4 and is prepared.
The following example 6-8 (compound 5-4,5-5 and 5-6) is prepared according to the mode being similar to compound 5-3, uses suitable commercially available starting raw material.
Embodiment 6 (compound 5-4):
。
Embodiment 7 (compound 5-5):
。
Embodiment 8 (compound 5-6):
。
Embodiment 9 (compound 6-4)
(5aR, 6S, 6aS)-3-((the fluoro-4'-of 4-((S)-2-hydroxy propyloxy group)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (6-4) also
Steps A:
(S)-1-(bromo-3, the 5-dimethyl phenoxies of 4-) propan-2-ol (6-2)
K is added in solution in DMF (3 mL) to compound 6-1 (100 mg, 0.5 mmol) and (S)-(-)-propylene oxide (120 mg, 2 mmol)
2cO
3(280 mg, 2 mmol).By described mixture heated overnight at 100 DEG C, then filter.Described filtrate concentrates in a vacuum, and the gained residue over silica gel property prepared TLC purifies, with sherwood oil: ethyl acetate (2:1) wash-out, obtains compound 6-2.MS(ESI)
m/z: 241(M+H-18)
+。
Step B:(
5aR, 6S, 6aS)-3-((the fluoro-4'-of 4-((S)-2-hydroxy propyloxy group)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (6-3) also
At N
2in, to compound 6-2 (15.5 mg, 0.06 mmol) and reference example 2-4 (30 mg, 0.066 mmol) diox (2 mL) and 2M K
2cO
3pd is added in suspension in the aqueous solution (1 mL)
2(dba)
3(10 mg, 0.01 mmol) and tricyclohexyl phosphine (8.4 mg, 0.03 mmol).Described reaction is heated to 130 DEG C in microwave reactor and reaches 10 minutes, be then separated described diox layer, purify with silica gel preparative TLC, with sherwood oil: ethyl acetate (2:1) wash-out, obtains compound 6-3.MS(ESI)
m/z: 506(M+H)
+。
Step C:(
5aR, 6S, 6aS)-3-((the fluoro-4'-of 4-((S)-2-hydroxy propyloxy group)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (6-4) also
The 2 M NaOH aqueous solution (1 mL) are added in the solution of compound 6-3 (10 mg, 0.02 mmol) in MeOH (2 mL).Described mixture is heated to 50 DEG C and reaches 30 minutes, be then poured in 10 mL water, be acidified to pH 4 with rare HCl.Described mixture ethyl acetate (5 mL x 3) extracts, and described ethyl acetate layer is separated, and concentrates in a vacuum, obtains compound 6-4.
Embodiment 10 (compound 7-4)
Steps A:
4-((the bromo-6-picoline of 5--2-base) oxygen base)-2-methyl fourth-2-alcohol (7-2)
At 0 DEG C in 10mins, in the solution of compound 1a (4 g, 38 mmol) in DMF (30 mL) under stirring, add NaH (60% in mineral oil for 3.3 g, 8.4 mmol).Described mixture is stirred half an hour under r.t., is then cooled to 0 DEG C.Then, the compound 7-1 (6 g, 32 mmol) in DMF (20 mL) is joined in reaction, and described reaction is stirred 12 h under r.t..Described reaction is poured in water (100 mL), then gained mixture is stirred 10 min.Then, described mixture EtOAc (60 mL x 3) extraction.Merge organic layer, use the washing of water (60 mL), salt solution (60 mL), drying is also concentrated, and obtain crude product, it is just directly used in next step when not purifying further.MS(ESI)m/z: 274.1。
Step B:(
5aR, 6S, 6aS)-3-((3-(6-(3-hydroxy-3-methyl butoxy)-2-picoline-3-base) benzyl) oxygen base)-5, a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (7-3) also
To the compound 7-2 (22 mg, 0.08 mmol) under stirring, reference example 2-5 (35 mg, 0.08 mmol), Na
2cO
3(40 mg) and Pd (PPh
3)
4(in the solution in 5 mg) dioxs (3 mL), add H
2o (1 mL).By gained mixture at N
2in be heated to 100 DEG C and reach 2h.Then, filtered by described mixture, filtrate concentrates, and obtain crude product, it is purified by silica gel preparative TLC, with sherwood oil: ethyl acetate (2:1) wash-out, obtains compound 7-3.MS(ESI)m/z: 503(M+H)
+。
Step C:(
5aR, 6S, 6aS)-3-((3-(6-(3-hydroxy-3-methyl butoxy)-2-picoline-3-base) benzyl) oxygen base)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid
Compound 7-4 uses and is similar to preparation embodiment 1 (compound 3-4) step that uses and is prepared.
The following example 11-14 (compound 7-5,7-6,7-7 and 7-8) is prepared by the mode being similar to compound 7-4, uses suitable commercially available starting raw material and reference example 2-4.
Embodiment 11 (compound 7-5):
。
Embodiment 12 (compound 7-6):
。
Embodiment 13 (compound 7-7)
。
Embodiment 14 (compound 7-8)
。
Embodiment 15 (compound 8-5)
(5aR, 6S, 6aS)-3-((the fluoro-4'-of 4-(2-(1-hydroxycyclopropyl) oxyethyl group)-2'-(trifluoromethyl)-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (8-5)
Steps A:
3-(the bromo-3-of 4-(trifluoromethyl) phenoxy group) methyl propionate (8-2)
Add MeONa (2.1 g, 37.2 mmol) in the solution of the compound 8-1 that stirred (3 g, 12.4 mmol) in methyl acrylate (25 ml) in batches.At N
2middlely described mixture is heated to backflow spends the night.HCl (2N, 30 mL) is joined in described mixture.Then, described mixture EA extracts, use salt water washing, drying is also concentrated, obtain crude product, it is purified with preparation property HPLC, and (on GILSON 281 instrument, it is equipped with YMC-Actus Triart C18 (150 x 30mm x 5um) to preparation property HPLC, uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 50-80% B, 0-10min; 100% B, 10.5-12.5 min; 5% B, 13-15 min), obtain compound 8-2.MS (ESI) m/z: do not observe MS.
Step B:
1-(2-(the bromo-3-of 4-(trifluoromethyl) phenoxy group) ethyl) ring propyl alcohol (8-3)
Disposablely in the solution of compound 8-2 (250 mg, 0.76 mmol) in THF (10 mL) under stirring add Ti (OiPr)
4(86 mg, 0.31 mmol).Described mixture is stirred 10 minutes, then at 0 DEG C, in described mixture, drips EtMgBr (0.31 mL, 0.93 mmol).Gained mixture is stirred 1 h under r.t.Then, the 2 N HCl cancellation of described mixture, with EtOAc (20 mL x 3) extraction, use salt water washing, at Na
2sO
4middle drying, and concentrated, obtain crude product, it is purified with silica gel preparative TLC, with sherwood oil: ethyl acetate (3:1) wash-out, obtains compound 8-3.
Step C:(
5aR, 6S, 6aS)-3-((the fluoro-4'-of 4-(2-(1-hydroxycyclopropyl) oxyethyl group)-2'-(trifluoromethyl)-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5]-cyclopenta [1,2-c] pyridine-6-ethyl formate (8-4)
Compound 8-3 (20 mg, 0.06 mmol), reference example 2-4 (33 mg, 0.07 mmol), Pd (dppf) Cl will be housed
2(5 mg), K
3pO
4(25 mg, 0.12 mmol), THF (2 mL) and H
2the microwave container of O (0.5 mL) is heated to 100 DEG C and reaches 30 minutes in microwave.Reaction mixture is cooled and filters.Described filtrate concentrated, gained resistates preparation property silicon-dioxide TLC purifies (PE/EA=1/1), obtains compound 8-4.MS(ESI)m/z: 572(M+H
+)。
Step D:
(5aR, 6S, 6aS)-3-((the fluoro-4'-of 4-(2-(1-hydroxycyclopropyl) oxyethyl group)-2'-(trifluoromethyl)-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (8-5)
To the compound 8-4 (12 mg) under stirring at MeOH (2 mL) and H
2disposablely in solution in O (2 mL) add LiOH (100 mg).Reaction mixture is stirred 1h under r.t.Described reaction mixture is poured in 10 mL water, with 1N HCl acidified aqueous solution to pH 4.Described mixture ethyl acetate (5 mL x 3) extracts, and the ethyl acetate layer merged is separated, concentrate in a vacuum, obtain crude compound, with prep.HPLC, (preparation property HPLC is on GILSON 281 instrument for it, it is equipped with YMC-Actus Triart C18 (150 x 30 mm x 4 um) and purifies, and uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 45-65% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min), obtain compound 8-5.
The following example 16 (compound 8-6) is prepared according to the mode being similar to compound 8-5, uses suitable commercially available starting raw material.
Embodiment 16 (compound 8-6):
。
Embodiment 17 (compound 9-7)
(5aR, 6S, 6aS)-3-((the fluoro-4'-of 4-((4-fluorine tetrahydrochysene-2H-pyrans-4-base) methoxyl group)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (9-7) also
Steps A:
4-((ethyl peroxide) methyl)-4-fluorine tetrahydrochysene-2H-pyrans (9-2)
At-78 DEG C, in the solution of compound 9-1 (2 g, 14 mmol) in THF (20 mL), drip LDA (2M, 14 mL).Reaction mixture is stirred 1h under rt.Then, at-78 DEG C, FN (SO is dripped
2ph)
2(446 mg, 11.7 mmol) solution in THF (10 mL), then stirs 12 h by described mixture under rt.Then, the saturated NH of described reaction mixture
4cl cancellation, then uses EtOAc (10 mL × 3) to extract.Merge organic layer, at Na
2sO
4middle drying, filters and concentrates, and obtain compound 9-2, it is directly used in next step.
Step B:
(4-fluorine tetrahydrochysene-2H-pyrans-4-base) methyl alcohol (9-3)
At 0 DEG C, to compound 9-2 (500 mg, 3.1 mmol) at CH
3naBH is added in solution in OH
4(352 mg, 9.3 mmol).Reaction mixture is stirred 3h under rt.Then, reaction mixture concentrates in a vacuum, and salt solution (20 mL) process of gained resistates, then uses EtOAc (5 mL × 4) to extract.Merge organic layer, at Na
2sO
4middle drying, filters and concentrates, and obtains the compound 9-3 as solid.
Step C:
4-toluene sulfonic acide ((
4-fluorine tetrahydrochysene-2H-pyrans-4-base) methyl) ester (9-4)
At 0 DEG C, in the solution of compound 9-3 (320 mg, 2.4 mmol) in pyridine (2 mL), points several add TosCl (1.36 g, 7.2 mmol), and reaction is stirred 1h under rt.Then, reaction mixture concentrates in a vacuum, with salt solution (30 mL) process, and extracts with EtOAc (10 mL × 3).Merge organic layer, at Na
2sO
4middle drying, filters and concentrates, and obtains the compound 9-4 as solid.MS(ESI)
m/z: 298(M+H)
+。
Step D:
4-((bromo-3, the 5-dimethyl phenoxies of 4-) methyl)-4-fluorine tetrahydrochysene-2H-pyrans (9-5)
NaH (72 mg, 3 mmol) is added in solution in DMF (2 mL) to compound 9-4 (150 mg, 0.52 mmol) and 4-bromo-3,5-dimethyl-phenol (210 mg, 1.04 mmol).Reaction mixture is stirred 3h under rt.After having reacted, add H
2o (5 mL), described mixture EtOAc (3 mL x 3) extract.Merge organic layer, use salt water washing, at Na
2sO
4middle drying, then concentrates.The gained residue over silica gel property prepared TLC purifies (using sherwood oil: ethyl acetate=5:1 wash-out), obtains compound 9-5.MS (ESI)
m/z: 318 and 320 (M+H)
+.
Step e:
3-((the fluoro-4'-of 4-((4-fluorine tetrahydrochysene-2H-pyrans-4-base) methoxyl group)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (9-6) also
By compound 9-5 (30 mg, 0.092 mmol), boric acid ester (62 mg, 0.138 mmol), Pd from reference example 2-4
2(dba)
3(11 mg, 0.0092 mmol), P (Cy)
3(5 mg, 0.0018 mmol) and K
2cO
3(25 mg, 0.184 mmol) diox (2 mL) and H
2solution in O (0.4 mL) is heated to backflow and reaches 1h.Then, remove described solvent, the gained residue over silica gel property prepared TLC purifies, with sherwood oil: ethyl acetate (5:1) wash-out, obtains compound 9-6.MS(ESI)
m/z: 564(M+H)
+。
Step F: (
5aR, 6S, 6aS)-3-((the fluoro-4'-of 4-((4-fluorine tetrahydrochysene-2H-pyrans-4-base) methoxyl group)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (9-7) also
To compound 9-6 (20 mg, 0.035 mmol) at CH
3oH and H
2liOH.H is added in solution in O (2 mL/0.5 mL)
2o(4 mg, 0.1 mmol), and described mixture is heated to 40 DEG C reaches 2h.Then, described reaction mixture concentrates in a vacuum, obtains a kind of resistates, and it is purified with silica gel preparative TLC, with DCM:MeOH (2:1) wash-out, obtains compound 9-7.
The following example 18 (compound 9-8) is prepared according to the mode being similar to compound 9-7, uses suitable commercially available starting raw material and the boric acid ester from reference example 2-5.
Embodiment 18 (compound 9-8):
。
Embodiment 19 (compound 10-5)
(5aR; 6S; 6aS)-3-((2'; the fluoro-4'-of 4-bis-(3-(methyl sulphonyl) propoxy-)-6'-(trifluoromethyl)-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a; 6; 6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (10-5) also
Steps A:
the fluoro-3-of 1-(3-(methyl sulphonyl) propoxy-)-5-(trifluoromethyl) benzene (10-2)
Compound 1a (973 mg, 3.33 mmol) and K is added in the solution of compound 10-1 (400 mg, 2.22 mmol) in DMF (5.0 mL)
2cO
3(613 mg, 4.44 mmol).Gained mixture is stirred 18 hours at 100 DEG C.Add H
2o, then gained mixture EtOAc (15 mL x 3) extracts.The organic layer washed with brine merged, dry also concentrated, obtain a kind of resistates, it is purified by silica gel preparative TLC, with sherwood oil: ethyl acetate (5:1) wash-out, obtains compound 10-2.
Step B:
the fluoro-5-of the bromo-1-of 2-(3-(methyl sulphonyl) propoxy-)-3-(trifluoromethyl) benzene (10-3)
Br is added in the solution of compound 10-2 (300 mg, 1.0 mmol) in HOAc (5.0 mL)
2(2.0 mL).Gained mixture is stirred 4 hours under rt.Then, described solution NaHCO
3alkalization, uses saturated Na
2sO
3cancellation, extracts with EtOAc (10mL x 3).The organic layer washed with brine merged, dry also concentrated, obtain a kind of resistates, it is purified by silica gel preparative TLC, with sherwood oil: ethyl acetate (3:1) wash-out, obtains compound 10-3.MS(ESI)
m/z: 378, 380(M+H)
+。
Step C:
2 (5aR; 6S; 6aS)-3-((2'; the fluoro-4'-of 4-bis-(3-(methyl sulphonyl) propoxy-)-6'-(trifluoromethyl)-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a; 6; 6a-tetrahydrochysene cyclopropane is [4,5]-cyclopenta [1,2-c] pyridine-6-ethyl formate (10-4) also
At N
2in, to compound 10-3 (40 mg, 0.11 mmol) at THF (9.0 mL) and H
2boric acid ester (57 mg, 0.13 mmol), the K from reference example 2-4 is added in solution in O (3.0 mL)
3pO
4(70 mg, 0.33 mmol) and Pd (dppf)
2cl
2(8 mg, 0.01 mmol).Gained mixture is sealed, then reaches 10 minutes with microwave heating to 100 DEG C.Then, filtered by described solution, filtrate concentrates, and obtains a kind of resistates, and it is purified with silica gel preparative TLC, with sherwood oil: ethyl acetate (1:1) wash-out, obtains compound 10-4.MS(ESI)
m/z: 626(M+H)
+。
Step D:(
5aR; 6S; 6aS)-3-((2'; the fluoro-4'-of 4-bis-(3-(methyl sulphonyl) propoxy-)-6'-(trifluoromethyl)-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a; 6; 6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (10-5) also
To compound 10-4 (30 mg, 0.05 mmol) at THF (9.0 mL), MeOH (3.0 mL) and H
2liOH.H is added in solution in O (3.0 mL)
2o (8 mg, 0.20 mmol).Gained mixture is stirred 4 hours under rt.Add H
2o, then described solution HCl (1 M) is acidified to pH value 2.5, then uses EtOAc (10mL x 3) to extract.The organic layer washed with brine merged, drying is also concentrated, obtain a kind of resistates, it is purified with preparation property HPLC, and (preparation property HPLC is on GILSON 281 instrument, it is equipped with YMC-Actus Triart C18 (150 x 30 mm x4um), uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 35-65% B, 0-10min; 100% B, 10.5-12.5 min; 5% B, 13-15 min), obtain compound 10-5.
Embodiment 20 (compound 10-6) and embodiment 21 (compound 10-7)
Steps A: (
5aR; 6S; 6aS)-3-((2'; 6'-dimethyl-4'-(3-(methyl sulphonyl) propoxy-)-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a; 6; 6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (34-6) and enantiomer (34-6a) thereof also
To reference example 1-9 (0.12 g, 0.55 mmol) and Ag
2cO
3add the compound 34-5 (0.3 g, 0.73 mmol) from reference example 11 in (0.4 g, 1.46 mmol) suspension in 3 mL toluene, then gained mixture is heated 3 hours at 110 DEG C.After being cooled to room temperature, described reaction shrend is gone out, described aqueous layer with ethyl acetate extracting twice.The organic layer washed with brine merged, at Na
2sO
4middle drying.After filtering and concentrating, gained residue over silica gel chromatography over CC (with DCM: MeOH=30:1 wash-out), obtains the mixture of enantiomer.The mixture of this enantiomer is split by SFC under following SFC splitting condition, obtains compound 34-6, and enantiomer compound 34-6a: instrument: Thar 80, post: AD 250 mm x 20mm, 20 um; Moving phase: A: supercritical CO
2, B: ethanol (0.05%NH
3h
2o, A:B=60:40 are with the flow velocity of 80mL/min; Column temperature: 38 DEG C, nozzle pressure: 100 bar, nozzle temperature: 60 DEG C, evaporator temperature: 20 DEG C, regulator temperature: 25 DEG C, wavelength: 220 nm.MS(ESI)m/e(M+H
+): 550.2。
Step B:(
5aR; 6S; 6aS)-3-((2'; 6'-dimethyl-4'-(3-(methyl sulphonyl) propoxy-)-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a; 6; 6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (10-6)
LiOH (36 mg, 0.9 mmol) is added in the solution of compound 34-6 (100 mg, 0.182 mmol) in methyl alcohol (3 mL) and water (1 mL).Gained mixture is at room temperature stirred 2h.After pH value being adjusted to pH ~ 3 with 1N HCl, described reaction mixture distributes between ethyl acetate and water.Separate aqueous layer, is extracted with ethyl acetate twice.By the organic layer washed with brine merged, at Na
2sO
4middle drying, and concentrated.Gained resistates preparation property HPLC purifies, and (preparation property HPLC carries out on GILSON 281 instrument, it is equipped with Phenomenex Synergi C18 post (150 x 30 mm x 5um), use water and acetonitrile as eluent: mobile phase A: water is (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile; Gradient: 20-60% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15min, obtain compound 10-6.
Equally; compound 34-6a and lithium hydroxide react as described in step B; obtain (5aS; 6R; 6aR)-3-((2'; 6'-dimethyl-4'-(3-(methyl sulphonyl)-propoxy-)-[1; 1'-biphenyl]-3-base) methoxyl group)-5; 5a, 6,6a-tetrahydrochysene cyclopropane also [4; 5] cyclopenta [1; 2-c] pyridine-6-formic acid (embodiment 21, compound 10-7), it shows the spectrum property identical with compound 10-6.
The following example 22-26 (compound 10-8 to 10-12) is prepared according to the mode being similar to embodiment 19 (compound 10-5), uses suitable starting raw material and the boric acid ester from reference example 2-4 or the boric acid ester from reference example 2-5.
Embodiment 27 (compound 11-6)
Steps A:
3-(bromo-3, the 5-dimethyl phenoxies of 4-) propionic acid (11-1)
To compound 4-2 (330 mg, 1.15 mmol) at MeOH/H
2liOH (144.8 mg, 3.45 mmol) is added in solution in O (4/1 mL).Described solution is stirred 2h at 100 DEG C.After having reacted, HCl (1 mol/L, 1 mL) is joined in described solution, so that its pH value is adjusted to pH 5.Then, described solution EtOAc (5 mL x 3) extracts, and is separated organic layer and concentrates, obtaining compound 11-1.
Step B:
3-(bromo-3, the 5-dimethyl phenoxies of 4-)-N-methoxy-. N-methyl propionic acid amide (11-2)
To compound 11-1 (346 mg, 1.27 mmol) add TBTU (490 mg in solution in DCM (3 mL), 1.53 mmol), then TEA (154.5 mg are added, 1.53 mmol), then N-methoxyl group methylamine (149 mg, 1.53 mmol) is added.Described reaction is at room temperature stirred and spends the night.After having reacted, described reaction mixture washes with water and uses DCM (5 mL x 3) to extract.Be separated organic layer, merge and concentrate, obtaining crude product, it is purified by silica gel preparative TLC, with sherwood oil: ethyl acetate (5:1) wash-out, obtains compound 11-2.MS(ESI)
m/z: 316,318(M+H)
+。
Step C:
4-(bromo-3, the 5-dimethyl phenoxies of 4-) fourth-2-ketone (11-3)
MeMgBr (1 mL) is dripped in the solution of compound 11-2 (100 mg, 0.317 mmol) in THF (2 mL) under cooling in ice bath.Described reaction is at room temperature stirred 2h.After having reacted, described reaction mixture at 0 DEG C with 2 mol/L HCl cancellation.Described reaction mixture washes with water and uses EtOAc (5 mL x 3) to extract.Merge organic layer and concentrated, obtain crude product, it is purified by silica gel column chromatography, with sherwood oil: ethyl acetate (5:1) wash-out, obtains compound 11-3.MS(ESI)
m/z: 271(M+H)
+。
Step D:
4-(bromo-3, the 5-dimethyl phenoxies of 4-) fourth-2-alcohol (11-4)
NaBH is added in the solution of compound 11-3 (80 mg, 0.332 mmol) in MeOH (1 mL)
4(61.44 mg, 1.66 mmol).Described solution is at room temperature stirred 20 min.After having reacted, described reaction EtOAc (5 mL x 3) extracts, and is concentrated by the organic layer of merging, obtains compound 11-4.
Step e: (
5aR, 6S, 6aS)-3-((the fluoro-4'-of 4-(3-hydroxybutoxy)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (11-5) also
Compound 11-5 uses to be similar to and prepares the step that compound 10-4 uses and be prepared.MS(ESI)
m/z: 520(M+H)
+。
Step F:
(5aR, 6S, 6aS)-3-((the fluoro-4'-of 4-(3-hydroxybutoxy)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (11-6) also
Compound 11-6 uses to be similar to and prepares the step that compound 10-5 uses and be prepared.
Embodiment 28 (compound 12-7)
(5aR, 6S, 6aS)-3-((3-(2-methoxypyridine-4-base)-4-methyl-benzyl) oxygen base)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (12-7)
Steps A:
(the bromo-4-aminomethyl phenyl of 3-) methyl alcohol (12-2)
At 0 DEG C, in the solution of compound 12-1 (5.0 g, 0.02 mol) in THF (40 mL), drip BH lentamente
3-(CH
3)
2s (14 mL, 10M).Gained mixture is stirred 18 hours under rt.Described solution HCl (1 M) cancellation, then uses EtOAc (30 mL x 3) to extract.The organic layer washed with brine merged, drying is also concentrated, and obtain a kind of resistates, it is purified by silica gel column chromatography, sherwood oil: ethyl acetate (8:1) wash-out, obtains compound 12-2.
Step B:(
4-methyl-3-(4,4,5,5-tetramethyl--1,3,2-dioxaborinate-2-base) phenyl) methyl alcohol (12-3)
At N
2in atmosphere, to compound 12-2 (200 mg, compound 1a (381 mg, 1.5 mmol), KOAc (196 mg, 2.0 mmol) and Pd (dppf) is added in solution in 1.0 mmol) dioxs (5.0 mL)
2cl
2(146 mg, 2.0 mmol).Gained mixture is stirred 18 hours at 100 DEG C.Then, described solution filters, and filtrate concentrated, obtain resistates, it is purified by silica gel preparative TLC, with sherwood oil: ethyl acetate (5:1) wash-out, obtains compound 12-3.
Step C:(
3-(2-methoxypyridine-4-base)-4-aminomethyl phenyl) methyl alcohol (12-4)
At N
2in, to compound 12-3 (220 mg, 0.89 mmol) diox (9.0 mL) and H
2compound 2a (139 mg, 0.74 mmol), Na is added in solution in O (3.0 mL)
2cO
3(204 mg, 1.48 mmol) and Pd (PPh
3)
2cl
2(54 mg, 0.07 mmol).Gained mixture is sealed, then reaches 10 minutes with microwave heating to 100 DEG C.Filtered by described mixture, filtrate concentrates, and obtain a kind of resistates, it is purified by silica gel preparative TLC, with sherwood oil: ethyl acetate (3:1) wash-out, obtains compound 12-4.MS(ESI)
m/z: 230(M+H)
+。
Step D:
4-(5-(brooethyl)-2-aminomethyl phenyl)-2-methoxypyridine (12-5)
At 0 DEG C, in the solution of compound 12-4 (80 mg, 0.35 mmol) in THF (5.0 mL), add PBr lentamente
3(95 mg, 0.35 mmol).Gained mixture is stirred 1 hour.Then H is added
2o, then described solution EtOAc (10mL x 3) extraction.The organic layer washed with brine merged, dry also concentrated, obtain a kind of resistates, it is purified by silica gel preparative TLC, with sherwood oil: ethyl acetate (5:1) wash-out, obtains compound 12-5.MS(ESI)
m/z: 292, 294(M+H)
+。
Step e:
(5aR, 6S, 6aS)-3-((3-(2-methoxypyridine-4-base)-4-methyl-benzyl) oxygen base)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (12-6)
Reference example 1-9 (60 mg, 0.28 mmol) and Ag is added in the solution of compound 12-5 (67 mg, 0.23 mmol) in toluene (5 mL)
2cO
3(127 mg, 0.46 mmol).Gained mixture is stirred 20 hours at 100 DEG C.Then, filtered by described mixture, filtrate extracts with EtOAc (10 mL x 3).The organic layer washed with brine merged, dry, concentrated, obtain a kind of resistates, it is purified by silica gel column chromatography, sherwood oil: ethyl acetate (3:1) wash-out, obtains compound 12-6.MS(ESI)
m/z: 431(M+H)
+。
Step F: (
5aR, 6S, 6aS)-3-((3-(2-methoxypyridine-4-base)-4-methyl-benzyl) oxygen base)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (12-7)
To compound 12-6 (80 mg, 0.19 mmol) at THF (9.0 mL), MeOH (3.0 mL) and H
2liOH.H is added in solution in O (3.0 mL)
2o (32 mg, 0.76 mmol).Gained mixture is stirred 4 hours under rt.Then H is added
2o, is then acidified to pH value 2.5 by described solution HCl (1 M), extracts with EtOAc (10mL x 3).The organic layer washed with brine merged, drying is also concentrated, obtain a kind of resistates, it is purified with preparation property HPLC, and (preparation property HPLC is on GILSON 281 instrument, it is equipped with YMC-Actus Triart C18 (150 x 30 mm x5um), uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 35-65% B, 0-10min; 100% B, 10.5-12.5 min; 5% B, 13-15 min), obtain compound 12-7.
The following example 29-31 (compound 12-8,12-9 and 12-10) is prepared according to the mode being similar to compound 10-5, uses suitable commercially available starting raw material and boric acid ester.
Embodiment 32 (compound 13-7)
(5aR, 6S, 6aS)-3-((3-(6-(2-hydroxy-2-methyl propoxy-)-4-(trifluoromethyl) pyridin-3-yl) benzyl) oxygen base)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (13-7) also
Steps A:
4-(trifluoromethyl) pyridine-2-alcohol (13-2)
To compound 13-1 (8.0 g, 0.04 mol) at H
2dense HCl (20 mL) is added in solution in O (20 mL).Gained mixture is stirred 20 hours at 110 DEG C.Then, described solution NaHCO
3alkalization, extracts with EtOAc (40 mL x 3).The organic layer washed with brine merged, dry, and concentrated, obtain compound 13-2.
Step B:2-((4-(trifluoromethyl) pyridine-2-base) oxygen base) ethyl acetate (13-3)
Ethyl bromoacetate (3.1 g, 0.02 mol) and Ag is added in the solution of compound 13-2 (1.0 g, 6.1 mmol) in toluene (10 mL)
2cO
3(5.1 g, 0.02 mol).Gained mixture is stirred 20 hours at 100 DEG C.Then, filtered by described solution, filtrate extracts with EtOAc (15 mL x 3).The organic layer washed with brine merged, dry, concentrated, obtain a kind of resistates, it is purified by silica gel column chromatography, sherwood oil: ethyl acetate (5:1) wash-out, obtains compound 13-3.MS(ESI)
m/z: 250(M+H)
+。
Step C:
2-methyl isophthalic acid-((4-(trifluoromethyl) pyridine-2-base) oxygen base) propan-2-ol (13-4)
At 0 DEG C, in the solution of compound 13-3 (1.0 g, 4.02 mmol) in THF (10 mL), drip CH lentamente
3mgBr (3 M, 8 mL).Reaction mixture is warmed to rt., and stirs 2 hours.Then, described reaction HCl (1 M) cancellation, then uses EtOAc (15 mL x 3) to extract.The organic layer washed with brine merged, dry, and concentrated, obtain compound 13-4.
Step D:
1-((the bromo-4-of 5-(trifluoromethyl) pyridine-2-base) oxygen base)-2-methyl propan-2-ol (13-5)
Br is added in the solution of compound 13-4 (200 mg, 0.85 mmol) in HOAc (5.0 mL)
2(5.0 mL).Gained mixture is stirred 2 hours under rt.Then, described mixture NaHCO
3alkalization, uses saturated Na
2sO
3cancellation, then uses EtOAc (10mL x 3) to extract.The organic layer washed with brine merged, dry also concentrated, obtain a kind of resistates, it is purified by silica gel preparative TLC, with sherwood oil: ethyl acetate (4:1) wash-out, obtains compound 13-5.MS(ESI)
m/z: 313, 315(M+H)
+。
Step e: (
5aR, 6S, 6aS)-3-((3-(6-(2-hydroxy-2-methyl propoxy-)-4-(trifluoromethyl) pyridin-3-yl) benzyl) oxygen base)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (13-6) also
At N
2in, to compound 13-5 (40 mg, 0.14 mmol) at THF (9.0 mL) and H
2reference example 2-5 (72 mg, 0.16 mmol), K is added in solution in O (3.0 mL)
3pO
4(89 mg, 0.42 mmol) and Pd (dppf)
2cl
2(7 mg, 0.01 mmol).Gained mixture is sealed, then reaches 10 minutes with microwave heating to 100 DEG C.Filtered by described mixture, and filtrate concentrated, obtain a kind of resistates, it is purified with silica gel preparative TLC, with sherwood oil: ethyl acetate (1:1) wash-out, obtains compound 13-6.MS(ESI)
m/z: 543(M+H)
+。
Step F:
(5aR, 6S, 6aS)-3-((3-(6-(2-hydroxy-2-methyl propoxy-)-4-(trifluoromethyl) pyridin-3-yl) benzyl) oxygen base)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (13-7) also
To compound 13-6 (40 mg, 0.07 mmol) at THF (9.0 mL), MeOH (3.0 mL) and H
2liOH.H is added in solution in O (3.0 mL)
2o (12 mg, 0.28 mmol).Gained mixture is stirred 4 hours under rt.Then H is added
2o, is then acidified to pH value 2.5 by described solution HCl (1 M), extracts with EtOAc (5 mL x 3).The organic layer washed with brine merged, drying is also concentrated, obtain a kind of resistates, it is purified with preparation property HPLC, and (preparation property HPLC is on GILSON 281 instrument, it is equipped with YMC-Actus Triart C18 (150 x 30 mm x5um), uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 47-67% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min), obtain compound 13-7.
The following example 33 (compound 13-8) is prepared according to the mode being similar to compound 13-7, uses suitable commercially available starting raw material.
Embodiment 33 (compound 13-8):
。
Embodiment 34 (compound 14-4)
(5aR, 6S, 6aS)-3-((fluoro-2', the 6'-dimethyl-[1 of 4'-(2,3-dihydroxyl propoxy-)-4-, 1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (14-4)
Steps A:
3-(bromo-3, the 5-dimethyl phenoxies of 4-) propane-1,2-glycol (14-2)
At 0 DEG C, to compound 14-1 (200 mg, 0.83 mmol) and OsO
4nMO (116.5 mg, 0.996 mmol) is added in batches in (21.1 mg, 0.083 mmol) solution in acetone (2 mL).Then, described reaction mixture is stirred 0.5 h at 0 DEG C.After having reacted, described reaction mixture EtOH (4 mL) cancellation, then uses EtOAc (5 mL × 3) to extract.The washing of the organic layers with water (10 mL) merged, salt solution (10 mL), drying is also concentrated, obtains compound 14-2.MS(ESI)
m/z: 275,277(M+H)。
Step B:(
5aR, 6S, 6aS)-3-((fluoro-2', the 6'-dimethyl-[1 of 4'-(2,3-dihydroxyl propoxy-)-4-, 1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (14-3)
Compound 14-3 uses to be similar to and prepares the step that compound 13-6 uses and be prepared.MS(ESI)
m/z: 522(M +H)
+。
Step C:(
5aR, 6S, 6aS)-3-((4'-(2,3-dihydroxyl propoxy-) the fluoro-2' of-4-, 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid also
Compound 14-4 uses to be similar to and prepares the step that compound 13-7 uses and be prepared.
Embodiment 35 (compound 15-5)
(5aR, 6S, 6aS)-3-((4'-(3-hydroxyl-2-(methylol)-2-methyl propoxy-)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (15-5) also
Steps A:
3-((bromo-3, the 5-dimethyl phenoxies of 4-) methyl)-3-methy oxetane (15-2)
By compound 15-1 (1 g, 5.0 mmol), 3-(chloromethyl)-3-methy oxetane (1.2 g, 9.95 mmol) and K
2cO
3(2.74 g, 19.9 mmol) solution in DMF (10 mL) is heated to 100 DEG C and reaches 12 h.After having reacted, described reaction mixture salt solution (100 mL) processes, and then uses EtOAc (50 mL × 3) to extract.The washing of the organic layers with water (10 mL) merged, salt solution (10 mL), drying is also concentrated, obtains compound 15-2.MS(ESI)
m/z: 285,287(M+H)。
Step B:
2-((bromo-3, the 5-dimethyl phenoxies of 4-) methyl)-2-methylpropane-1,3-glycol (15-3)
Compound 15-2 (100 mg, 0.35 mmol) is added in the solution of HCl (5 mL, 2 mol/L).Described solution is stirred 3h under reflux.After described reaction completes, described solution EtOAc (10 mL x 3) extracts and concentrates, and obtains compound 15-3.MS(ESI)
m/z: 303,305(M+H)
+。
Step C:(
5aR, 6S, 6aS)-3-((4'-(3-hydroxyl-2-(methylol)-2-methyl propoxy-)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (15-4) also
Compound 15-4 uses to be similar to and prepares the step that compound 13-6 uses and be prepared.MS(ESI)
m/z: 532(M+H)
+。
Step D:(
5aR, 6S, 6aS)-3-((4'-(3-hydroxyl-2-(methylol)-2-methyl propoxy-)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (15-5) also
Compound 15-5 uses to be similar to and prepares the step that compound 13-7 uses and be prepared.
The following example 36 (compound 15-6) is prepared according to the mode being similar to compound 15-5, uses suitable starting raw material and the boric acid ester from reference example 2-4.
Embodiment 37 (compound 16-8)
(5aR, 6S, 6aS)-3-((4'-((3,3-difluoro cyclobutyl) methoxyl group)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (16-8)
Steps A:
3-(methylol) cyclobutanol (16-2)
At-78 DEG C, in the solution of compound 16-1 (500 mg, 4.24 mmol) in THF (5 mL), drip BH lentamente
3-(CH
3)
2s (0.6 mL, 10M).Gained mixture is warmed to rt., and stirs 18 hours.Described solution HCl (1 M) cancellation, then uses EtOAc (30 mL x 3) to extract.The organic layer washed with brine merged, dry, and concentrated, obtain compound 16-2.
Step B:
4-toluene sulfonic acide ((3-hydroxycyclobutyl) methyl) ester (16-3)
At 0 DEG C, in the solution of compound 16-2 (300 mg, 3.0 mmol) in DCM (5 mL), add Et lentamente
3n (606 mg, 6.0 mmol) and TosCl (573 mg, 3.0 mmol).Gained mixture is warmed to rt., and stirs 4 hours.Described solution HCl (1 M) cancellation, then uses EtOAc (30 mL x 3) to extract.Add H
2o, then described solution DCM (10 mL x 3) extraction.The organic layer merged is dry also concentrated, and obtain a kind of resistates, it is purified by silica gel preparative TLC, with sherwood oil: ethyl acetate (5:1) wash-out, obtains compound 16-3.MS(ESI)
m/z: 257(M+H)
+。
Step C:
3-((bromo-3, the 5-dimethyl phenoxies of 4-) methyl) cyclobutanol (16-4)
The bromo-MX of 4-(350 mg, 1.37 mmol) and K is added in the solution of compound 16-3 (330 mg, 1.64 mmol) in DMF (10.0 mL)
2cO
3(378 mg, 2.74 mmol).Gained mixture is stirred 18 hours at 100 DEG C.Then H is added
2o, then described solution EtOAc (15 mL x 3) extraction.The organic layer washed with brine merged, dry also concentrated, obtain a kind of resistates, it is purified by silica gel preparative TLC, with sherwood oil: ethyl acetate (3:1) wash-out, obtains compound 16-4.
Step D:
3-((bromo-3, the 5-dimethyl phenoxies of 4-) methyl) cyclobutanone (16-5)
At-78 DEG C, in the solution of oxalyl dichloro (170 mg, 1.34 mmol) in DCM (5.0 mL), add DMSO (209 mg, 2.68 mmol).Described solution is stirred 15 minutes at-78 DEG C, at-78 DEG C, is then added in the compound 16-4 (190 mg, 0.67 mmol) in DCM (2 mL) lentamente, by described reaction stirring 15 minutes, then adds Et
3n (338 mg, 3.35 mmol), at room temperature reacts described reaction to 2h again.Then H is added
2o, then described reaction DCM (15 mL x 3) extraction.The organic layer washed with brine merged, dry also concentrated, obtain a kind of resistates, it is purified by silica gel preparative TLC, with sherwood oil: ethyl acetate (5:1) wash-out, obtains compound 16-5.
Step e:
the bromo-5-of 2-((3,3-difluoro cyclobutyl) methoxyl group)-1.3-dimethyl benzene (16-6)
Compound 16-5 (90 mg, 0.32 mmol) is dissolved in solution stirring in DAST (2 mL) 2 hours.Reaction ice-shrend is gone out, then extracts with EtOAc.The organic layer washed with brine merged, dry also concentrated, obtain a kind of resistates, it is purified by silica gel preparative TLC, with sherwood oil: ethyl acetate (5:1) wash-out, obtains compound 16-6.
Step F: (
5aR, 6S, 6aS)-3-((4'-((3,3-difluoro cyclobutyl) methoxyl group)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (16-8)
By Suzuki reaction reference example 2-5, carry out ester hydrolysis reaction subsequently, obtain compound 16-8; The step using described step to be similar to prepare compound 13-7 to use is prepared.
The following example 38-40 (compound 16-9 to 16-11) is prepared according to the mode being similar to compound 16-8, uses suitable starting raw material and the boric acid ester from reference example 2-4 or the boric acid ester from reference example 2-5.
Embodiment 40 (compound 17-5)
(5aR, 6S, 6aS)-3-((4'-(((E)-4-(methoxyimino) amyl group) oxygen base)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (17-5) also
Steps A:
5-(bromo-3, the 5-dimethyl phenoxies of 4-) penta-2-ketone (17-2)
At N
2in, at 0 DEG C, to compound 17-1 (100 mg, 0.5 mmol), 5-hydroxyl-Skellysolve A-2-ketone (100 mg, 1 mmol) and triphenyl-phosphine alkane (262 mg, 1 mmol) drip DIAD (200 mg, 1 mmol) in solution in THF (5 mL).Described mixture is at room temperature stirred 2 hours.Described reaction shrend is gone out, and extracts with EtOAc.By the organic layer washed with brine merged, drying is also concentrated.The described crude product purified by silica gel property prepared TLC purifies, with sherwood oil: ethyl acetate (3:1) wash-out, obtains compound 17-2.
Step B:
5-(bromo-3, the 5-dimethyl phenoxies of 4-) penta-2-ketone O-methyloxime (17-3)
O-methyl-hydroxylamine (25 mg, 0.3 mmol) is added in the solution of compound 17-2 (50 mg, 0.17 mmol) in EtOH (2 mL).Reaction mixture is heated to backflow and reaches 1 hour.Then, described mixture is poured in water (10 mL), then uses ethyl acetate (5 mL x 2) to extract.Separating ethyl acetate layer, concentrates in a vacuum, obtains compound 17-3.MS(ESI)
m/z: 314(M+H)
+。
Step C:(
5aR, 6S, 6aS)-3-((4'-(((E)-4-(methoxyimino) amyl group) oxygen base)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (17-5) also
Be used for the boric acid ester of self-reference embodiment 2-5, reacted by Suzuki, carry out Ester hydrolysis subsequently, obtained compound 17-5; The step using described step to be similar to prepare compound 13-7 to use is prepared.
The following example 41 (compound 17-6) is prepared according to the mode being similar to compound 17-5, uses suitable starting raw material.
Embodiment 42 (compound 18-4)
(5aR, 6S, 6aS)-3-((4'-(3-(3,3-difluoro azetidine-1-base) propoxy-)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (18-4)
Steps A:
3-(bromo-3, the 5-dimethyl phenoxies of 4-)-1-(3,3-difluoro azetidine-1-base) the third-1-ketone (18-1)
Et is added in the compound 11-1 (500 mg, 1.85 mmol) under stirring and the solution of compound 11-1a (715 mg, 5.55 mmol) in DMF (10 mL)
3n (0.52 mL, 3.7 mmol).By described reaction stirring 15 minutes, then TBTU (900 mg, 2.8 mmol) is joined in this reaction in batches.Gained mixture is stirred at 40 DEG C and spends the night.Then H is added
2o, described mixture EtOAc (20 mL x 2) extract, at Na
2sO
4middle drying, and concentrated, obtain crude product, it is purified with silica gel preparative TLC, with sherwood oil: ethyl acetate (3:1) wash-out, obtains compound 18-1.MS(ESI)m/z：348,350(M+H)+。
Step B:
1-(3-(bromo-3, the 5-dimethyl phenoxies of 4-) propyl group)-3,3-difluoro azetidines (18-2)
BH is dripped in the solution of compound 18-1 (50mg, 0.14 mmol) in THF (5 mL) under stirring
3.THF (0.42 mL, 1mol/L).Described reaction mixture is heated to backflow and reaches 10 h, then cool, with MeOH (0.1 mL) and NaOH (0.2 mL, 2mol/L) cancellation.Be separated organic layer, purify with silica gel preparative TLC, with sherwood oil: ethyl acetate (3:1) wash-out, obtains compound 18-2.MS(ESI)m/z: 334,336(M+H
+)。
Step C:(
5aR, 6S, 6aS)-3-((4'-(3-(3,3-difluoro azetidine-1-base) propoxy-)-2 ', 6 '-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (18-3)
Compound 18-2 (40 mg, 0.12 mmol), reference example 2-5 (52 mg, 0.12 mmol), Pd (dppf) Cl will be housed
2(5 mg), K
3pO
4(51 mg, 0.24 mmol), THF (2 mL) and H
2the microwave container microwave heating to 100 DEG C of O (0.5 mL) reaches 30 minutes.Cooling reaction, is separated organic layer, purifies, with DCM:MeOH (20:1) wash-out, obtain compound 18-3 with silica gel preparative TLC.MS(ESI)m/z: 563(M+H
+)。
Step D:(
5aR, 6S, 6aS)-3-((4'-(3-(3,3-difluoro azetidine-1-base) propoxy-)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (18-4)
Compound 18-4 uses to be similar to and prepares the step that compound 13-7 uses and be prepared.
Embodiment 43 (compound 19-6)
(5aR, 6S, 6aS)-3-((the fluoro-4'-of 4-(3-hydroxy-3-methyl butyl)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (19-6) also
Steps A: (
e)-3-(bromo-3, the 5-3,5-dimethylphenyls of 4-) ethyl propenoate (19-2)
At 0 DEG C, in the solution of phosphine acyl acetic acid three ethyl (2.1 g, 9.4 mmol) in THF (20 mL), add NaH (0.38 g, 9.4 mmol) in batches.Described mixture is stirred 30 minutes at 0 DEG C, then adds compound 19-1 (1 g, 4.7 mmol), then react and stir 30 minutes again at 0 DEG C.Described reaction mixture is poured in 100 mL water, then uses ethyl acetate (50 ml x 2) to extract.Ethyl acetate layer concentrates in a vacuum, gained residue over silica gel chromatography over CC, with sherwood oil: ethyl acetate (10:1) wash-out, obtains compound 19-2.MS(ESI)
m/z: 283(M+H)
+。
Step B:
3-(bromo-3, the 5-3,5-dimethylphenyls of 4-) ethyl propionate (19-3)
Pd/C (20 mg) is added in the solution of compound 19-2 (140 mg, 0.5 mmol) in THF (5 mL), then that described mixture is degassed in a vacuum and use H
2purge several times.By described mixture at H
21 hour is at room temperature stirred in balloon.Then, described mixture is filtered, filtrate is concentrated, obtain compound 19-3.MS(ESI)
m/z: 285(M+H)
+。
Step C:
4-(bromo-3, the 5-3,5-dimethylphenyls of 4-)-2-methyl fourth-2-alcohol (19-4)
At-60 DEG C, in the solution of compound 19-3 (130 mg, 0.46 mmol) in THF (3 mL), drip MeBrMg (0.5 mL, 1.5 mmol).Mixture is at room temperature stirred 1 hour, is then poured in 20 mL frozen water, extract by ethyl acetate (5 mL x 4).Separating ethyl acetate layer, concentrates in a vacuum, obtains compound 19-4.MS(ESI)
m/z: 253(M-18+H)
+。
Step D:(
5aR, 6S, 6aS)-3-((the fluoro-4'-of 4-(3-hydroxy-3-methyl butyl)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (19-6) also
Compound 19-6 reacts by Suzuki the acquisition that is then hydrolyzed; Use described step to be similar to prepare the step used in compound 6-4 and be prepared.
Embodiment 44 (compound 19-16)
(5aR; 6S; 6aS)-3-((the fluoro-2' of 4-; 6'-dimethyl-4'-(4-(methyl sulphonyl) butyl)-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a; 6; 6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (19-16) also
Steps A:
3-(bromo-3, the 5-3,5-dimethylphenyls of 4-) the third-1-alcohol (19-7)
Add NaBH in the solution of compound 19-3 (1.4 g, 4.9 mmol) in MeOH (30 mL) in batches
4(0.57 g, 15 mmol).Described mixture is at room temperature stirred 2 hours.Then, 50 mL water are joined in this mixture, then removes MeOH in a vacuum.Described aqueous layer with ethyl acetate (20 mL x 3) extracts.Combined ethyl acetate layer, uses salt water washing, at Na
2sO
4middle drying, and concentrated, obtain compound 19-7.MS(ESI)
m/z: 243(M+H)
+。
Step B:
methylsulfonic acid (3-(bromo-3, the 5-3,5-dimethylphenyls of 4-) propyl group) ester (19-8)
MsCl (68 mg, 0.6 mmol) is dripped in solution in DCM (3 mL) to compound 19-7 (100 mg, 0.4 mmol) and TEA (120 mg, 1.2 mmol).Described mixture is at room temperature stirred 2 hours.Then add 3 mL water, be separated DCM layer, concentrate in a vacuum, obtain compound 19-8.
Step C:
4-(bromo-3, the 5-3,5-dimethylphenyls of 4-) butane nitrile (19-9)
In the solution of compound 19-8 (32 mg, 0.37 mmol) in DMF (1 mL), add NaCN (10 mg, 0.2 mmol), and described mixture is heated to 80 DEG C reaches 2 hours.Then, add 10 mL water, described mixture ethyl acetate (3 mL x 3) extracts.Combined ethyl acetate layer, concentrates in a vacuum, obtains compound 19-9.
Step D:
4-(bromo-3, the 5-3,5-dimethylphenyls of 4-) methyl-butyrate (19-10)
Compound 19-9 (0.5 g, 2 mmol) is dissolved in 4 M HCl/MeOH solution (5 mL), and is heated to backflow and reaches 1 hour.Then, in a vacuum except desolventizing, compound 19-10 is obtained.MS(ESI)
m/z: 285(M+H)
+。
Step e:
4-(bromo-3, the 5-3,5-dimethylphenyls of 4-) fourth-1-alcohol (19-11)
Add NaBH in the solution of compound 19-10 (0.3 g, 1.05 mmol) in MeOH (10 mL) in batches
4(0.19 g, 5 mmol), then at room temperature stir 2 hours by described mixture.Then, add 20 mL water, then remove MeOH in a vacuum.Described aqueous layer with ethyl acetate (10 mL x 3) extracts.Combined ethyl acetate layer, uses salt water washing, at Na
2sO
4middle drying, and concentrated, obtain compound 19-11.MS(ESI)
m/z: 257(M+H)
+。
Step F:
methylsulfonic acid (4-(bromo-3, the 5-3,5-dimethylphenyls of 4-) butyl) ester (19-12)
MsCl (34 mg, 0.3 mmol) is dripped in solution in DCM (2 mL) to compound 19-11 (50 mg, 0.2 mmol) and TEA (60 mg, 0.6 mmol).Described mixture is at room temperature stirred 2 hours, then adds 10 mL water.Described water layer DCM (3 mL x 3) extracts, and this DCM layer concentrates in a vacuum, obtains compound 19-12.
Step G:(
4-(bromo-3, the 5-3,5-dimethylphenyls of 4-) butyl) (methyl) sulfane (19-13)
In the solution of compound 19-12 (300 mg, 0.89 mmol) in MeOH (10 mL), add NaSMe (140 mg, 2 mmol), then described mixture is at room temperature stirred 2 hours.Then, 30 mL water are added.Described aqueous layer with ethyl acetate (10 mL x 2) extracts, and this ethyl acetate layer concentrates in a vacuum, obtains compound 19-13.
Step H:
bromo-1, the 3-dimethyl-5-of 2-(4-(methyl sulphonyl) butyl) benzene (19-4)
In the solution of compound 19-13 (100 mg, 0.35 mmol) in DCM (5 mL), add m-CPBA (215 mg, 1 mmol), then this mixture is at room temperature stirred 2 hours.Then, the 2 mL 10% NaOH aqueous solution are added.Be separated DCM layer, purify with silica gel preparative TLC, with sherwood oil: ethyl acetate (1:1) wash-out, obtains compound 19-14.
Step I:(
5aR; 6S; 6aS)-3-((the fluoro-2' of 4-; 6'-dimethyl-4'-(4-(methyl sulphonyl) butyl)-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a; 6; 6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (19-16) also
Reacted by the Suzuki of compound 19-14 and reference example 2-4, hydrolysis reaction subsequently, obtain compound 19-16; Use described step to be similar to prepare the step used in compound 6-4 and be prepared.
Embodiment 45 (compound 19-19)
(5aR, 6S, 6aS)-3-((the fluoro-4'-of 4-(4-hydroxy-4-methyl amyl group)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (19-19) also
Steps A:
5-(bromo-3, the 5-3,5-dimethylphenyls of 4-)-2-methylpentane-2-alcohol (19-17)
At-70 DEG C, in the solution of compound 19-10 (100 mg, 0.35 mmol) in THF (3 mL), drip MeBrMg (1 mL, 3 mmol).Mixture is at room temperature stirred 30 minutes, is then poured in 10 mL frozen water, extract by ethyl acetate (5 mL x 3).Combined ethyl acetate layer, concentrates in a vacuum, obtains compound 19-17.
Step B:(
5aR, 6S, 6aS)-3-((the fluoro-4'-of 4-(4-hydroxy-4-methyl amyl group)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (19-19) also
Reacted by the Suzuki of compound 19-17 and reference example 2-4, hydrolysis reaction subsequently, obtain compound 19-19, use described step to be similar to prepare the step used in compound 6-4 and be prepared.
Embodiment 46 (compound 20-5)
3-((the fluoro-5-of 2-(6-(3-hydroxy-3-methyl butoxy)-4-(trifluoromethyl) pyridin-3-yl) benzyl) oxygen base)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (20-5)
Steps A:
2-methyl-4-((4-(trifluoromethyl) pyridine-2-base) oxygen base) butane-2-alcohol (20-2)
In the solution of 3-methyl-butan-1,3-glycol (1.6 g, 15 mmol) in DMF (50 mL), add NaH (1.2 g, 30 mmol) in batches, then described mixture is at room temperature stirred 30 minutes.Then, described mixture is poured in 300 mL water, extracts with EtOAc (100 mL x 2).Merge EtOAc layer, and concentrated, gained residue over silica gel chromatography over CC, with sherwood oil: ethyl acetate (2:1) wash-out, obtains compound 20-2.
Step B:
4-((the bromo-4-of 5-(trifluoromethyl) pyridine-2-base) oxygen base)-2-methylbutane-2-alcohol (20-3)
Br is added in the solution of compound 20-2 (100 mg, 0.4 mmol) in AcOH (0.5 mL)
2(0.5 mL), then at room temperature stirs 2 hours by described mixture.Then, described mixture is poured into 20 mL NaHCO
3in the aqueous solution, add Na
2s
2o
3, until solution becomes colorless.Described mixture ethyl acetate (5 mL x 3) extracts.The ethyl acetate layer of merging is concentrated, purifies with silica gel preparative TLC, with sherwood oil: ethyl acetate (2:1) wash-out, obtains compound 20-3.
Step C:
3-((the fluoro-5-of 2-(6-(3-hydroxy-3-methyl butoxy)-4-(trifluoromethyl) pyridin-3-yl) benzyl) oxygen base)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate) (20-4)
At N
2in, to compound 20-3 (20 mg, 0.06 mmol) and reference example 2-4 (30 mg, 0.066 mmol) diox (2 mL) and 2 M Na
2cO
3pd (PPh is added in mixture in the aqueous solution (1 mL)
3)
4(10 mg, 0.008 mmol).By described reaction heated overnight at 100 DEG C.Be separated described diox layer, purify with silica gel preparative TLC, with sherwood oil: ethyl acetate (2:1) wash-out, obtains compound 20-4.MS(ESI)
m/z: 575(M+H)
+。
Step D:
3-((the fluoro-5-of 2-(6-(3-hydroxy-3-methyl butoxy)-4-(trifluoromethyl) pyridin-3-yl) benzyl) oxygen base)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (20-5)
The 2 M NaOH aqueous solution (1 mL) are added in the solution of compound 20-4 (10 mg, 0.017 mmol) in MeOH (2 mL).Described mixture is at room temperature stirred 2 hours.Then, described mixture is poured in 10 mL water, is acidified to pH 4 with rare HCl.Described mixture ethyl acetate (5 mL x 2) extracts, and the ethyl acetate layer of merging concentrates in a vacuum.Gained resistates preparation property HPLC purifies, and (preparation property HPLC carries out on GILSON 281 instrument, and it is equipped with Phenomenex Synergi C18 (150 x 30 mm x 5um), uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 40-70% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min), obtain compound 20-5.
The following example 47-49 (compound 20-6 to 20-8) is prepared according to the mode being similar to compound 20-5, uses suitable starting raw material and reference example 2-4 or reference example 2-5.
Embodiment 50 (compound 21-7)
3-((the fluoro-5-of 2-(6-((4-hydroxy-4-methyl amyl group) oxygen base)-4-(trifluoromethyl) pyridin-3-yl) benzyl) oxygen base)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (21-7)
Steps A:
4-(trifluoromethyl) pyridine-2-alcohol (21-2)
To compound 21-1 (8 g, 0.04 mol) at H
2concentrated hydrochloric acid (30 mL) is added in solution in O (30 mL).Gained mixture is stirred 18 hours at 110 DEG C.Described solution NaHCO
3alkalization, to separate out a kind of white solid.Filter this white solid, obtain compound 21-2.
Step B:
4-((4-(trifluoromethyl) pyridine-2-base) oxygen base) methyl-butyrate (21-3)
4-bromobutyrate (2.3 g, 12.3 mmol) and Ag is added in the solution of compound 21-2 (1.0 g, 6.13 mmol) in DMF (10 mL)
2cO
3(3.3 g, 12.3 mmol).Gained mixture is stirred 18 hours at 100 DEG C.Then H is added
2o, then described solution EtOAc (15 mL x 3) extraction.The organic layer washed with brine merged, dry and concentrated, obtain a kind of resistates, it is purified by silica gel column chromatography, with sherwood oil: ethyl acetate (5:1) wash-out, obtains compound 21-3.
Step C:
2-methyl-5-((4-(trifluoromethyl) pyridine-2-base) oxygen base) penta-2-alcohol (21-4)
At 0 DEG C, in the solution of compound 21-3 (1.1 g, 3.97 mmol) in THF (10.0 mL), drip methylmagnesium-bromide (8 mL, 3 M) lentamente.Reaction mixture is warmed to rt., and stirs 2 hours.Then, described reaction HCl (1 M) cancellation, then uses EtOAc (15 mL x 3) to extract.The organic layer washed with brine merged, dry, concentrated, obtain a kind of resistates, it is purified by silica gel column chromatography, with sherwood oil: ethyl acetate (5:1) wash-out, obtains compound 21-4.
Step D:
5-((the bromo-4-of 5-(trifluoromethyl) pyridine-2-base) oxygen base)-2-methylpent-2-alcohol (21-5)
Br is added in the solution of compound 21-4 (200 mg) in HOAc (10.0 mL)
2(10.0 mL).Gained mixture is stirred 2 hours under rt.Described solution NaHCO
3alkalization, uses Na
2sO
3cancellation, then uses EtOAc (10mL x 3) to extract.The organic layer washed with brine merged, dry also concentrated, obtain a kind of resistates, it is purified by silica gel preparative TLC, with sherwood oil: ethyl acetate (3:1) wash-out, obtains compound 21-5.
Step e: (
5aR, 6S, 6aS)-3-((the fluoro-5-of 2-(6-((4-hydroxy-4-methyl amyl group) oxygen base)-4-(trifluoromethyl) pyridin-3-yl) benzyl) oxygen base)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (21-6) also
To compound 21-5 (15 mg, 0.04 mmol) at THF (5.0 mL) and H
2boric acid ester (24 mg, 0.05 mmol), Pd (dppf) Cl from reference example 2-4 is added in solution in O (1mL)
2(5 mg, 0.004 mmol) and K
3pO
4(11 mg, 0.08 mmol).Gained mixture is stirred 2 hours at 100 DEG C.Described mixture filters, and filtrate extracts with EtOAc (15 mL x 3).The organic layer washed with brine merged, drying is also concentrated, and obtain a kind of resistates, it is purified by silica gel preparative TLC, with DCM:MeOH (25:1) wash-out, obtains compound 21-6.MS(ESI)
m/z: 589(M+H)
+。
Step F:
3-((the fluoro-5-of 2-(6-((4-hydroxy-4-methyl amyl group) oxygen base)-4-(trifluoromethyl) pyridin-3-yl) benzyl) oxygen base)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (2-7)
To compound 21-6 (10 mg, 0.02 mmol) at THF (3.0 mL), MeOH (1.0 mL) and H
2liOH.H is added in solution in O (1.0 mL)
2o (4 mg, 0.08 mmol).Gained mixture is stirred 4 hours under rt.Then H is added
2o, is then acidified to pH value 2.5 by described solution HCl (1 M), extracts with EtOAc (5 mL x 3).The organic layer washed with brine merged, drying is also concentrated, obtain a kind of resistates, it is purified with preparation property HPLC, and (preparation property HPLC is on GILSON 281 instrument, it is equipped with Phenomenex Synergi C18 (150 x 30 mm x 5um), uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 45-65% B, 0-10min; 100% B, 10.5-12.5min; 5% B, 13-15min), obtain embodiment 21-7.
The following example 51 (compound 21-8) is prepared according to the mode being similar to compound 21-7, uses suitable starting raw material and the boric acid ester from reference example 2-5.
Embodiment 52 (compound 22-2)
(5aR, 6S, 6aS)-3-((fluoro-2', 6'-dimethyl-[1 of 4-, 1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (22-2) also
Steps A: (
5aR, 6S, 6aS)-3-((fluoro-2', the 6'-dimethyl-[1 of 4-, 1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (22-1) also
At N
2in, the compound (90 mg, 0.2 mmol) of reference example 2-4,2-bromo-1,3-dimethyl-benzene (36 mg, 0.2 mmol), Pd (dppf) Cl
2(15 mg, 0.02 mmol), K
3pO
3(120 g, 0.6 mmol) is at THF/H
2suspension in O (4:1,2.5 mL) heats 30 min at 100 DEG C in microwave.After cooling, filtering mixt, described filtrate ethyl acetate and water dispenser.Described aqueous layer with ethyl acetate extracting twice.The organic layer washed with brine merged, dry in anhydrous sodium sulphate, then concentrate in a vacuum.The gained residue over silica gel property prepared TLC purifies, and with DCM:MeOH (25:1) wash-out, obtains compound 22-1.MS(ESI)m/e(M+H
+): 432.2(M+H
+)。
Step B:(
5aR, 6S, 6aS)-3-((fluoro-2', the 6'-dimethyl-[1 of 4-, 1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (22-2) also
By compound 22-1 (71 mg, 0.16 mmol) and LiOH (32 mg, 0.8 mmol) at THF/H
2mixture in O/MeOH (1:1:1,3 mL) stirs 5 hours under r.t.Described mixture 1N HCl is acidified to pH value 5-6.Obtained aqueous solution is extracted with ethyl acetate twice.The organic layer washed with brine merged, in anhydrous Na
2sO
3middle drying, then concentrates.Gained resistates preparation property HPLC purifies, and (on GILSON 281 instrument, it is equipped with YMC-Actus Triart C18 (150 x 30mm x 5um) to preparation property HPLC, uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 65-85% B, 0-10min; 100% B, 10.5-12.5 min; 5% B, 13-1min, obtain compound 22-2.
The following example 53-59 (compound 22-3 to 22-9) is prepared according to the mode being similar to compound 22-2, uses suitable starting raw material and the boric acid ester from reference example 2-4 or the boric acid ester from reference example 2-5.
Embodiment 60 (compound 23-8)
the fluoro-5-of 4-{2-[6-(3-methylsulfonyl-propoxy-)-4-methvl-pyridinium-3-base]-benzyloxy }-1,1a, 6,6a-tetrahydrochysene-3-azepine-cyclopropane also [a] indenes-1-formic acid (23-8)
Steps A:
the bromo-4-methyl of 5--2-(3-(methylthio group) propoxy-) pyridine (3-2)
Compound 23-1 (6.30 g, 33 mmol), 3-methylsulfanyl-propyl-1-alcohol (5.26 g, 49.5 mmol) and t-BuOK (5.54 g, the 49.5 mmol) mixture in anhydrous THF are heated 4 hours under reflux.Then, described mixture water and EtOAc distribute, and separating layer.Described aqueous extracted with EtOAc twice.Merge organic layer and concentrated, obtain a kind of resistates, it is purified with silica gel flash column chromatography, with sherwood oil: ethyl acetate (10:1) wash-out, obtains compound 23-2.MS(ESI)m /e(M+H
+): 276.0/278.0。
Step B:
the bromo-4-methyl of 5--2-(3-(methyl sulphonyl) propoxy-) pyridine (23-3)
To in the solution of compound 23-2 (9.23 g, 33 mmol) in dry DCM (150 mL), it is cooled with an ice bath, and adds MCPBA (80%, 15.15 g, 70.2 mmol).Gained mixture is stirred 2 hours at 0 DEG C, then adds NaHSO
3the aqueous solution.Be separated DCM layer, use Na successively
2cO
3(aq.), water and then use salt water washing, and concentrated, obtain a kind of resistates, it is purified with silica gel flash column chromatography, with sherwood oil: ethyl acetate (20:1) wash-out, obtains compound 23-3.MS(ESI)m/e(M+H
+): 308.0/310.0。
Step C:
the fluoro-5-of 2-(4-methyl-6-(3-(methyl sulphonyl) propoxy-) pyridin-3-yl) phenylformic acid (23-4)
In nitrogen atmosphere, by compound 23-3 (924 mg, 3.0 mmol), 5-borono-(borono)-2-fluorobenzoic acid (827 mg, 4.5 mmol), Cs
2cO
3(2.94 g, 9.0 mmol) and Pd [P (t-Bu)
3]
2(153 mg, 0.3 mmol) diox (12 mL)/H
2mixture microwave radiation to 100 DEG C in the cosolvent of O (3 mL) reaches 30 min.Described mixture is cooled to room temperature, then filters.Described filtrate extracts with EA, and the ethyl acetate washed with water washing of merging, drying also concentrates in a vacuum, obtains crude product 23-4.MS(ESI)m /e(M+H
+): 368.1。
Step D:(
the fluoro-5-of 2-(4-methyl-6-(3-(methyl sulphonyl) propoxy-) pyridin-3-yl) phenyl) methyl alcohol (23-5)
To crude compound 23-4, (in 2.45 solution g) in dry THF (50 mL), it cools in ice bath, drips Me
2s-BH
3(10 M, 6mL).Described reaction soln is stirred 1h at 0 DEG C, is then warmed to 20 DEG C and stirs 16 hours.Described mixture is cooled to 0 DEG C again, then adds MeOH and reacts with quencher, until do not have gas to overflow.Concentrated by described mixture, obtain a kind of resistates, it is purified with silica gel flash column chromatography, with sherwood oil: ethyl acetate (12:1) wash-out, obtains 23-5.MS(ESI)m /e(M+H
+): 354.1。
Step e:
5-(3-(brooethyl)-4-fluorophenyl)-4-methyl-2-(3-(methyl sulphonyl) propoxy-) pyridine (23-6)
To in the solution of crude compound 23-5 (353 mg, 1.0 mmol) in dry THF (5 mL), it cools in ice bath, drips PBr
3(216 mg, 0.8 mmol).Described reaction mixture is stirred 1h at 0 DEG C, is then warmed to 20 DEG C and stirs 16 hours.To go out described reaction with shrend, in described reaction, add NaHCO
3(aq), with by the pH regulator of described mixture to pH 7.Concentrated by described reaction soln, obtain a kind of resistates, it is purified with silica gel flash column chromatography, with sherwood oil: ethyl acetate (12:1) wash-out, obtains 23-6.MS(ESI)m/e(M+H
+): 416.0/418.0。
Step F:
the fluoro-5-of 4-{2-[6-(3-methylsulfonyl-propoxy-)-4-methvl-pyridinium-3-base]-benzyloxy }-1,1a, 6,6a-tetrahydrochysene-3-azepine-cyclopropane also [a] indenes-1-ethyl formate (23-7)
By compound 23-6 (227 mg, 0.54 mmol), compound 1-9 (120 mg, 1.64 mmol) and Ag
2cO
3(451 mg, 1.64 mmol) mixture in toluene (5 mL) is heated to 100 DEG C and reaches 12 hours.Described mixture filters, and filtrate is concentrated, obtains a kind of resistates, and it is purified with silica gel flash column chromatography, with sherwood oil: ethyl acetate (5.7:1) wash-out, obtains compound 23-7.MS(ESI)m/e(M+H
+): 555.2。
Step G:
the fluoro-5-of 4-{2-[6-(3-methylsulfonyl-propoxy-)-4-methvl-pyridinium-3-base]-benzyloxy }-1,1a, 6,6a-tetrahydrochysene-3-azepine-cyclopropane also [a] indenes-1-formic acid (23-8)
To 23-7 (160 mg, 0.29 mmol) at altogether-solvent THF (2 mL), MeOH (2 mL) and H
2add NaOH (150 mg, 3.7 mmol) in mixture in O (2 mL), then described mixture is at room temperature stirred 2 hours.Gained mixture HCl (2 N) is acidified to pH=2, then uses ethyl acetate (10 mL) extracting twice.The organic layers with water merged, salt water washing, at Na
2sO
4middle drying, concentrate in a vacuum, obtain crude product, it is purified with preparation property-HPLC, and (preparation property HPLC is on GILSON 281 instrument, it is equipped with YMC-Actus Triart C18 (150 x 30 mm x 5um), uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 20-70% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15min, obtain 23-8.
The following example 61-70 (compound 23-9 to 23-18) is prepared according to the mode being similar to compound 23-8, uses suitable starting raw material and the boric acid ester from reference example 2-4 or the boric acid ester from reference example 2-5.
Embodiment 71 (compound 24-4)
3-((the fluoro-5-of 2-(2-methyl-6-(3-(methyl sulphonyl) propoxy-) pyridin-3-yl) benzyl) is amino)-5; 5a; 6; 6a-tetrahydrochysene cyclopropane also [4; 5] cyclopenta [1,2-c] pyridine-6-formic acid (24-4)
the fluoro-5-of steps A: 2-(2-methyl-6-(3-(methyl sulphonyl) propoxy-) pyridin-3-yl) phenyl aldehyde (24-2)
MnO is added to stirring in the solution of lower compound 24-1 (500 mg, 1.41 mmol, use the step being similar to the step preparing compound 13-5 obtained) in THF (10 ml)
2(1.23 g, 14.15 mmol).Reaction mixture is stirred 1h at 60 DEG C, then filters, and wash with EA.Concentrated by the ethyl acetate layer of merging, obtain pure product, it is not purified just for next step further.MS(ESI)m /e(M+H
+)352.1。
Step B:
3-((the fluoro-5-of 2-(2-methyl-6-(3-(methyl sulphonyl) propoxy-) pyridin-3-yl) benzyl) is amino)-5; 5a; 6; 6a-tetrahydrochysene cyclopropane also [4; 5] cyclopenta [1,2-c] pyridine-6-ethyl formate (24-3)
Triethylamine (34 mg, 341 μm of ol) and TiCl is added in the solution of amine 1-8 (28 mg, 128 μm of ol) in the DCM (3 mL) of drying
4(27 mg, 142 μm of ol).Then, at-40 DEG C, add compound 24-2 (30 mg, 85 μm of ol) carefully.Gained suspension stirs 16h at ambient temperature.Then, steaming desolventizes, and remaining powder crushes in ethyl acetate (20 mL).Leach gained solid, filtrate is evaporated to dry, obtain described crude product.Described crude product is dissolved in EtOH (3 mL), adds Na (AcO)
3bH (36mg, 170 μm of ol).Described mixture stirs 1h at ambient temperature, and gained reaction mixture is directly used in next step.MS(ESI)m /e(M+H
+)554.2。
Step C:
3-((the fluoro-5-of 2-(2-methyl-6-(3-(methyl sulphonyl) propoxy-) pyridin-3-yl) benzyl) is amino)-5; 5a; 6; 6a-tetrahydrochysene cyclopropane also [4; 5] cyclopenta [1,2-c] pyridine-6-formic acid (24-4)
H is added in the mixture of compound 24-3 (20 mg, 36 μm of ol) in THF (1 mL) and EtOH (0.5 mL)
2o (0.5 mL) and LiOH (28 mg).Described reaction mixture is stirred at ambient temperature and spends the night, then use HCl (1N) that pH value is adjusted to pH 4.Described reaction mixture salt solution (30 mL) and 50 mL EA wash.Be separated organic layer, at Na
2sO
4middle drying is also concentrated.Gained resistates preparation property HPLC purifies, and (preparation property HPLC carries out on GILSON 281 instrument, and it is equipped with YMC-pack ODS-AQ C18 (150 x 30 mm x 5 um), uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 16-36% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min), obtain described pure product 24-4.MS(ESI)m /e(M+H
+)526.2。
Embodiment 72 (compound 25-2)
4-[the fluoro-5-of 2-(2-tri fluoromethy I-phenoxy)-benzyloxy]-1,1a, 6,6a-tetrahydrochysene-3-azepine-cyclopropane also [a] indenes-1-formic acid
Steps A:
4-[the fluoro-5-of 2-(2-tri fluoromethy I-phenoxy)-benzyloxy]-1,1a, 6,6a-tetrahydrochysene-3-azepine-cyclopropane also [a] indenes-1-ethyl formate (25-1)
To compound 2-4 (100 mg, 0.22 mmol) and 2-triffuoromethyl-phenol (71 mg, 0.44 mmol) at CH
3dMAP (54 mg, 0.33 mmol) and Cu (OAc) is added in mixture in CN (3 mL)
2(170 mg, 0.33 mmol).By degassed for described mixture and use N
2recharge three times.Then, described mixture is heated to 80 DEG C, and stirring is spent the night.Then, described mixture is cooled to room temperature, then filters.Described filtrate sodium hydrogen carbonate solution and salt water washing, in anhydrous Na
2sO
4middle drying, and concentrated, and obtain crude product, it is purified with preparation property HPLC, obtains crude compound 25-1.MS(ESI)m /e(M+H
+): 488.0。
Step B:
4-[the fluoro-5-of 2-(2-tri fluoromethy I-phenoxy)-benzyloxy]-1,1a, 6,6a-tetrahydrochysene-3-azepine-cyclopropane also [a] indenes-1-formic acid (25-2)
At room temperature, to compound 25-1 (60 mg, 0.123mmol) at cosolvent THF (2 mL), MeOH (2 mL) and H
2add NaOH (25 mg, 0.62 mmol) in mixture in O (2 mL), then described mixture is stirred 3 h.Gained mixture HCl (1 N) is acidified to pH=5 ~ 6, then uses ethyl acetate (10 mL) to extract three times.The organic layer washed with brine merged, at Na
2sO
4middle drying, concentrate in a vacuum, obtain crude product, it is purified with preparation property HPLC, and (preparation property HPLC is on GILSON 281 instrument, it is equipped with YMC-Actus Triart C18 (150 x 30 mm x 5um), uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 45-75% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min), obtain compound 25-2.
The following example 73 and 74 (compound 25-3 and 25-4) is prepared according to the mode being similar to compound 25-2, uses suitable starting raw material.
Embodiment 75 (compound 26-7)
3-((6-(2,6-3,5-dimethylphenyl)-3-fluorine pyridine-2-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (26-7)
Steps A:
the fluoro-2-picoline (26-2) of 6-(2,6-3,5-dimethylphenyl)-3-
By bromo-for 6-3-fluoro-2-picoline 26-1 (570 mg, 3.0 mmol), 2,6-dimethylphenylboronic acid (675 mg, 4.5mmol), K
3pO
4(2.34 g, 9.0 mmol), Pd
2(dba)
3(274 mg, 0.3 mmol) and s-phos (246 mg, 0.6mmol) are at altogether-solvent THF (10 mL)/H
2mixture in O (2.5 mL) reaches 30 min by microwave radiation to 100 DEG C in nitrogen atmosphere.Described mixture is cooled to room temperature, and filter, then described filtrate extracts with EA.The washing of described ethyl acetate washed with water, dry, and concentrate in a vacuum, obtain crude product, this crude product purified by silica gel flash column chromatography is purified, with sherwood oil: ethyl acetate (97:3) wash-out, obtains compound 26-2.MS(ESI)m/e(M+H
+): 216.1。
Step B:
6-(2,6-3,5-dimethylphenyl)-3-fluorine picoline aldehyde (26-3)
SeO is added in the mixture of 26-2 (242 mg, 1.1 mmol) in Isosorbide-5-Nitrae-diox (3 mL)
2(276 mg, 2.4 mmol).Gained mixture is stirred 12 hours at 100 DEG C, then concentrates.Gained residue over silica gel flash column chromatography is purified, with sherwood oil: ethyl acetate (95:5) wash-out, obtains compound 26-3.MS(ESI)m/e(M+H
+): 230.1。
Step C:
(6-(2,6-3,5-dimethylphenyl)-3-fluorine pyridine-2-base) methyl alcohol (26-4)
To in the solution of crude compound 26-3 (166 mg) in MeOH (5 mL), it cools in ice bath, disposablely adds NaBH
4(76 mg, 2.0 mmol).Described reaction soln is stirred 1h at 0 DEG C.Then, described reaction mixture shrend is gone out, and is extracted with ethyl acetate three times.Concentrated by the organic layer of merging, obtain a kind of resistates, it is purified with silica gel flash column chromatography, with sherwood oil: ethyl acetate (92:8) wash-out, obtains compound 26-4.MS(ESI)m /e(M+H
+): 232.1。
Step D:
2-(brooethyl)-6-(2,6-3,5-dimethylphenyl)-3-fluorine pyridine (26-5)
To in the solution of crude compound 26-4 (113 mg, 0.49 mmol) in dry THF (3 mL), it cools in ice bath, drips PBr
3(106 mg, 0.39 mmol).Described reaction soln is stirred 1h at 0 DEG C, is then warmed to 20 DEG C and stirs 2 hours.Then, to go out described mixture with shrend, in described mixture, add NaHCO
3the aqueous solution, so that described mixture is neutralized to pH 7.Concentrated by described mixture, obtain a kind of resistates, it is purified with silica gel flash column chromatography, with sherwood oil: ethyl acetate (95:5) wash-out, obtains compound 26-5.MS(ESI)m/e(M+H
+): 294.0/296.0。
Step e: 3-((6-(2,6-3,5-dimethylphenyl)-3-fluorine pyridine-2-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate
(26-6)
By compound 26-5 (90 mg, 0.3 mmol), compound 1-9 (66 mg, 0.3 mmol) and Ag
2cO
3(249 mg, 0.9 mmol) mixture in toluene (3 mL) is heated to 100 DEG C and reaches 12 hours.Then, filtered by described mixture, and filtrate concentrated, obtain thick 26-6, it is not purified just for next step.MS(ESI)m /e(M+H
+): 433.2。
Step F:
3-((6-(2,6-3,5-dimethylphenyl)-3-fluorine pyridine-2-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (26-7)
To thick 26-6 (120 mg) at altogether-solvent THF (2 mL), MeOH (2 mL) and H
2add NaOH (100 mg) in mixture in O (2 mL), then described mixture is at room temperature stirred 2 hours.Gained mixture HCl (2 N) is acidified to pH 3, then uses ethyl acetate (2 x 10 mL) to extract.The organic layers with water merged, salt water washing, at Na
2sO
4middle drying, concentrate in a vacuum, obtain crude product, it is purified with preparation property HPLC, and (preparation property HPLC is on GILSON 281 instrument, it is equipped with YMC-pack ODS-AQ C18 (150 x 30 mm x 5 um), uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 40-70% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min), obtain compound 26-7.
The following example 76-78 (compound 26-8 to 26-10) is prepared according to the mode being similar to compound 26-7, uses suitable starting raw material.
Embodiment 79 (compound 27-7)
4-(2,2', 6'-trimethylammonium-biphenyl-3-ylmethoxy)-1,1a, 6,6a-tetrahydrochysene-3-azepine-cyclopropane also [a] indenes-1-formic acid (27-5)
Steps A:
(2,2', 6'-trimethylammonium-biphenyl-3-base)-methyl alcohol (27-2)
2-bromo-1,3-dimethyl-benzene (700 mg, 3.7 mmol), compound 27-1 (938 mg, 3.7 mmol), Na
2cO
3(1.12 g, 11.1 mmol), Pd
2(dba)
3(346 mg, 0.37 mmol), P (Cy)
3(207 mg, 0.74 mmol) is being total to-Rong Ji diox (12 mL)/H
2mixture in O (3 mL) reaches 30 min by microwave radiation to 100 DEG C in nitrogen atmosphere.Described mixture is cooled to room temperature, and filter, then described filtrate extracts with EA.Described ethyl acetate washed with water washing, dry, concentrate in a vacuum, obtain crude compound 27-2.MS(ESI)m/e(M+H
+): 226.3/227.1。
Step B:
3-brooethyl-2,2', 6'-trimethylammoniums-biphenyl (27-3)
To in the solution of crude compound 27-2 (200 mg, 0.88 mmol) in dry THF (5 mL), it cools in ice bath, drips PBr
3(191 mg, 0.70 mmol).Described reaction soln is stirred 1h at 0 DEG C, is then warmed to 20 DEG C and stirs 16 hours.Then, to go out described mixture with shrend, in described mixture, add NaHCO
3the aqueous solution, so that described mixture is neutralized to pH 7.Then, concentrated by described mixture, obtain a kind of resistates, it is purified with silica gel flash column chromatography, with sherwood oil: ethyl acetate (94:6) wash-out, obtains compound 27-3.MS(ESI)m/e(M+H
+): 289.2/289.1。
Step C:
(2,2', 6'-trimethylammonium-biphenyl-3-methoxyl group)-1,1a, 6,6a-tetrahydrochysene-3-azepine-cyclopropane also [a] indenes-1-formic acid, ethyl ester (27-4)
By compound 27-3 (50 mg, 0.18 mmol) and compound 1-9 (40 mg, 0.18 mmol) and Ag
2cO
3(148 mg, 0.54 mmol) mixture in toluene (5 mL) is heated to 100 DEG C and reaches 12 hours.Filtered by described mixture, filtrate concentrates, and obtains a kind of resistates, and it is purified with silica gel flash column chromatography, with sherwood oil: ethyl acetate (92:8) wash-out, obtains compound 27-4.MS(ESI)m/e(M+H
+): 427.5/428.2。
Step D:
4-(2,2', 6'-trimethylammonium-biphenyl-3-ylmethoxy)-1,1a, 6,6a-tetrahydrochysene-3-azepine-cyclopropane also [a] indenes-1-formic acid (27-5)
By compound 27-4 (50 mg, 0.11 mmol) and LiOH (40 mg, 1 mmol) at THF/H
2mixture in O/MeOH (3:3:3 mL) stirs 2 hours under r.t; Then described mixture is acidified to pH value 5-6, then extracts with EA.By the water washing of described ethyl acetate layer salt, in anhydrous Na
2sO
4middle drying, and concentrated.Gained resistates preparation property HPLC purifies, and (preparation property HPLC carries out on GILSON 281 instrument, and it is equipped with Waters XSELECT C18 (150 x 30 mm x 5 um), uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 6-79% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min), obtain 27-5.
The following example 80 (compound 27-6) is prepared according to the mode being similar to compound 27-5, uses suitable starting raw material.
Embodiment 81 (compound 28-6)
(5aR, 6S, 6aR)-3-((4'-((4-cyano group-4-methyl amyl) oxygen base)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid also
Steps A:
1-(3-bromine propoxy-)-3,5-dimethyl benzenes (28-2)
By compound 28-1 (3.6 g, 30 mmol), 1,3-dibromopropane (12 g, 60 mmol) and K
2cO
3(8.4 g, 60 mmol) mixture in 80 mL acetone refluxes 18 h.Then, described mixture is cooled to room temperature, filters, purify, with sherwood oil with silica gel flash column chromatography: ethyl acetate (15:1) wash-out.MS(ESI)m /e(M+H
+): 243.0。
Step B:
5-(3,5-dimethyl phenoxy)-2,2-dimethylpentane nitrile (28-3)
At-78 DEG C, at N
2in atmosphere, in the solution of compound 28-2 (6.55 g, 95 mmol) in dry THF (100 mL), slowly add LDA (2 M, 10 mL, 70 mmol).Stirring, more than after 30 min, drips 1-(3-bromine propoxy-)-3,5-dimethyl benzenes (24 g, 95 mmol) in described reaction soln.Described reaction is warmed to room temperature, and stirring is spent the night, and adds 150 mL NH
4cl (aqueous solution) quencher is reacted.Described mixture ethyl acetate (3 × 60 mL) extracts, and organic layer washed with brine (60 mL) washing of merging, at Na
2sO
4middle drying, and concentrated.Gained crude product purified by silica gel flash column chromatography is purified, with sherwood oil: ethyl acetate (10:1) wash-out, obtains 28-3.MS(ESI)m/e(M+H
+): 232.1。
Step C:
5-(bromo-3, the 5-dimethyl phenoxies of 4-)-2,2-dimethylpentane nitriles (28-4)
Compound 28-3 (690 mg, 3 mmol) and NBS (564 mg, the 3.15 mmol) mixture in 8 mL DCM are stirred 18 h at 15 DEG C.Then, described mixture directly concentrates, and to obtain a kind of crude product, it is purified with silica gel flash column chromatography, with sherwood oil: ethyl acetate (10:1) wash-out, obtains compound 28-4.MS(ESI)m /e(M+H
+): 310.1。
Step D:
(5aR, 6S, 6aR)-3-((4'-((4-cyano group-4-methyl amyl) oxygen base)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (28-5) also
By compound 28-4 (30 mg, 0.1 mmol), reference example 2-5 (43 mg, 0.1 mmol), Na
2cO
3(32 mg, 0.3 mmol), Pd (dppf) Cl
2the mixture of (7 mg, 0.01 mmol), THF (2 mL) and water (0.5 mL) is at N
2at 100 DEG C, 18 h are heated in atmosphere.Then, add water (20 mL), described mixture ethyl acetate (3 × 20 mL) extracts.Organic layer washed with brine (20 mL) washing merged, in anhydrous Na
2sO
4middle drying, concentrated, obtain compound 28-5, it is not purified just for next step further.MS(ESI)m /e(M+H
+): 539.3。
Step e:
(5aR, 6S, 6aR)-3-((4'-((4-cyano group-4-methyl amyl) oxygen base)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (28-6) also
By compound 28-5 (27 mg, 0.05 mmol) and LiOH (12 mg, 0.5 mmol) at THF/MeOH/H
2mixture in O (3/0.5/0.5 mL) at room temperature stirs 1h, then adds NH
4cl (aqueous solution), to make its pH regulator to pH 5.Described mixture DCM (3 × 10 mL) extracts, and organic layer washed with brine (10 mL) washing of merging, at Na
2sO
4middle drying, and concentrated.Gained crude compound preparation property HPLC purifies, and (on GILSON 281 instrument, it is equipped with YMC-Actus Triart C18 (150 x 30 mm x 5 um) to preparation property HPLC, uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 50-70% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min, obtains compound 28-6.
The following example 82 (compound 28-7) is prepared according to the mode being similar to compound 28-6, uses suitable starting raw material.
Embodiment 83 (compound 29-7)
(5aR, 6S, 6aR)-3-((4'-((1s, 3s)-3-cyano group-3-methyl cyclobutoxy group)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (29-7)
Steps A:
methylsulfonic acid (3-cyano group cyclobutyl) ester (29-2)
At 0 DEG C, disposablely in the solution of compound 29-1 (200 mg, 2 mmol) in DCM (4 mL) add TEA (606 mg, 6 mmol).Then, MsCl (273 mg, 2.4 mmol) is added.Described mixture is stirred 2h at this temperature, then, adds 10 mL H
2o quencher is reacted, and extracts by ethyl acetate (3 × 10 mL).Organic layer washed with brine (30 mL) washing merged, at Na
2sO
4middle drying, then concentrates, and obtain crude product 29-2, it is directly used in next step.
Step B:
3-(3,5-dimethyl phenoxy) tetramethylene nitrile (29-3)
By compound 29-2 (350 mg, 2 mmol), MX (244 mg, 2 mmol) and K
2cO
3(834 mg, 6 mmol) mixture in 5 mL DMSO stirs 18 h at 120 DEG C.Described mixture is cooled to room temperature, then adds 10 mL H
2o, then extracts described mixture ethyl acetate (3 × 10 mL).Organic layer washed with brine (30 mL) washing merged, at Na
2sO
4middle drying, and concentrated, obtain a kind of crude product.Described crude product purified by silica gel flash column chromatography is purified, with sherwood oil: ethyl acetate (10:1) wash-out, obtains 29-3.MS(ESI)m /e(M+H
+): 202.1.
Step C:(
1s, 3s)-3-(3,5-dimethyl phenoxy)-1-methyl cyclobutane nitrile (29-4)
At-78 DEG C, at N
2in atmosphere, in the solution of compound 29-3 (200 mg, 1 mmol) in dry THF (5 mL), slowly add LDA (2 M, 1 mL, 2 mmol).After stirring 30 min, drip methyl iodide (284 mg, 2 mmol), then reaction is warmed to room temperature, and stirring is spent the night.Then, 10 mL NH are added
4cl (aq) quencher is reacted, and extracts by ethyl acetate (3 × 10 mL).Organic layer washed with brine (10 mL) washing merged, at Na
2sO
4middle drying, concentrated, purify with silica gel flash column chromatography, with sherwood oil: ethyl acetate (10:1) wash-out, obtains 29-4.MS(ESI)m /e(M+H
+): 216.0。
Step D:(
(1s, 3s)-3-(bromo-3, the 5-dimethyl phenoxies of 4-)-1-methyl cyclobutane nitrile (29-5)
By compound 29-4 (60 mg, 0.3 mmol) and NBS (54 mg, 0.3 mmol) mixture in 3 mL DCM stirs 18 h at 15 DEG C, then, described mixture is directly concentrated, crude product purified by silica gel flash column chromatography is purified, with sherwood oil: ethyl acetate (8:1) wash-out.MS(ESI)m /e(M+H
+): 294.1。
Step e: (
5aR, 6S, 6aR)-3-((4'-((1s, 3s)-3-cyano group-3-methyl cyclobutoxy group)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (29-6)
By compound 29-5 (29 mg, 0.1 mmol), reference example 2-5 (43 mg, 0.1 mmol), Na
2cO
3(32 mg, 0.3 mmol), Pd (dppf) Cl
2the mixture of (7 mg, 0.01 mmol), THF (2 mL) and water (0.5 mL) is at N
2at 100 DEG C, 18 h are heated in atmosphere.Then, add water (20 mL), and described mixture ethyl acetate (3 × 20 mL) is extracted.Organic layer washed with brine (20 mL) washing merged, in anhydrous Na
2sO
4middle drying, concentrated, obtain crude product, it does not process just for next step further.MS(ESI)m /e(M+H
+): 523.0。
Step F: (
5aR, 6S, 6aR)-3-((4'-((1s, 3s)-3-cyano group-3-methyl cyclobutoxy group)-2', 6'-dimethyl-[1,1'-biphenyl]-3-base) methoxyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (29-7)
By compound 29-6 (26 mg, 0.05 mmol) and LiOH (12 mg, 0.5 mmol) at THF/MeOH/H
2mixture in O (3/0.5/0.5 mL) at room temperature stirs 1h, then adds NH
4cl (aq), makes its pH reach 5.Gained mixture DCM (3 × 10 mL) extracts.Organic layer washed with brine (10 mL) washing merged, at Na
2sO
4middle drying, then concentrates.Gained crude product preparation property HPLC purifies, and (on GILSON 281 instrument, it is equipped with YMC-Actus Triart C18 (150 x 30 mm x 5 um) to preparation property HPLC, uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 47-67% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min), obtain compound 29-7.
Embodiment 84 (compound 30-5)
(5aR; 6S; 6aS)-3-(1-(the fluoro-2' of 4-; 6'-dimethyl-4'-(3-(methyl sulphonyl) propoxy-)-[1,1'-biphenyl]-3-base) oxyethyl group)-5,5a; 6; 6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (30-5) also
Steps A:
the bromo-2-of 4-(1-bromotrifluoromethane)-1-fluorobenzene ( 30-2)
Tribromo phosphine (0.26 mL, 2.74 mmol) is added in the solution of 1-(the bromo-2-fluorophenyl of 5-) ethanol 30-1 (1.2 g, 5.48 mmol) in DCM (15 ml) under stirring.Reaction mixture is stirred 1h at 0 DEG C, then uses DCM (50 mL) to dilute.Then, in described mixture, saturated NaHCO is dripped
3solution, is then separated each layer.The saturated NaHCO of described organic layer
3solution (30mL), salt solution (30 mL) wash, then at Na
2sO
4middle drying, and concentrated, and obtain crude product 30-2, it is not purified just for next step.
Step B:(
5aR, 6S, 6aS)-3-(1-(the bromo-2-fluorophenyl of 5-) oxyethyl group)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (30-3)
Compound 1-9 (209 mg, 2.98 mmol) and Ag is added in the solution of compound 30-2 (150 mg, 533 μm of ol) in toluene (3 ml)
2cO
3(294 mg, 1.07 mmol).Reaction mixture is stirred 16 h at 110 DEG C, then uses DCM (30 mL) to dilute, then filter.Described filtrate concentrated, the gained residue over silica gel property prepared TLC purifies, with sherwood oil: ethyl acetate (2:1) wash-out, obtains pure product 30-3.MS(ESI)m /e(M+H
+)421。
Step C:(
5aR; 6S; 6aS)-3-(1-(the fluoro-2' of 4-; 6'-dimethyl-4'-(3-(methyl sulphonyl) propoxy-)-[1,1'-biphenyl]-3-base) oxyethyl group)-5,5a; 6; 6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (30-4) also
Compound 30-3 (57 mg, 135.7 μm of ol), boric acid ester B1 (50 mg, 135.7 μm of ol use traditional Miyaura boranation method to obtain by described bromide), Na is loaded in one 40 mL bottles
2cO
3(28 mg, 271.5 μm of ol), dioxs (1.5 mL), H
2o (0.5 mL) and PdCl
2dppfCH
2cl
2(5 mg).This bottle is placed on 100 DEG C of vibrators and spends the night, be then cooled to envrionment temperature.Described reaction mixture ethyl acetate (30 mL) is diluted, and is then separated organic layer, uses salt water washing, and concentrated, obtains crude product 30-4, and it is not purified just for next step further.MS(ESI)m /e(M+H
+)582。
Step D:(
5aR; 6S; 6aS)-3-(1-(the fluoro-2' of 4-; 6'-dimethyl-4'-(3-(methyl sulphonyl) propoxy-)-[1,1'-biphenyl]-3-base) oxyethyl group)-5,5a; 6; 6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (30-5) also
H is added in the mixture of compound 30-4 (50 mg, 86 μm of ol) in THF (1 mL) and EtOH (0.5 mL)
2o (0.5 mL) and LiOH (10 mg, 429 μm of ol).Described reaction mixture is stirred at ambient temperature and spends the night, then use HCl (1N) that pH value is adjusted to pH 4.Reaction mixture salt solution (30 mL) and 50 mL EA wash, and are separated organic layer, at Na
2sO
4middle drying, and concentrated.Gained resistates preparation property HPLC purifies, and (preparation property HPLC carries out on GILSON 281 instrument, and it is equipped with YMC-pack ODS-AQ (150 x 30 mm x 5 um), uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 41-61% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min), obtain described pure product 30-5.
Embodiment 85 (compound 31-8)
(5aR; 6S; 6aS)-3-((the fluoro-5-of 2-(2-methyl-6-(3-((methyl sulphonyl) methyl) azetidine-1-base) pyridin-3-yl) benzyl) oxygen base)-5; 5a; 6; 6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (31-8) also
Steps A:
3-((methyl sulphonyl oxygen base) methyl) azetidine-1-t-butyl formate(31-2)
Compound 31-1 (1.0 g under stirring, 5.34 mmol) add triethylamine (810 mg in solution in DCM (10 mL), 8.01 mmol), then drip methylsulfonyl chloride (734 mg, 6.41 mmol).Reaction mixture is stirred 1h at ambient temperature, then uses DCM (50 mL) to dilute.Described mixture water (20 mL), rare HCl solution (20 mL x 3) and salt water washing, then at Na
2sO
4middle drying, and concentrated, and obtain crude product 31-2, it is not purified just for next step.
Step B:
3-(methylthiomethyl) azetidine-1-t-butyl formate (31-3)
Sodium methyl mercaptide (317 mg, 4.52 mmol) is added in the solution of compound 31-2 (800 mg, 3.02 mmol) in EtOH (10 mL) under stirring.Described bottle is placed on 100 DEG C of vibrators and reaches 1h, monitored by TLC (PE/EA=2/1).Then, described reaction mixture is cooled to room temperature, and dilutes by ethyl acetate (60 mL).Described mixture water (20 mL x 3) and salt solution (30 mL) washing, at Na
2sO
4middle drying, and concentrated, and obtain crude product, it is not purified just for next step.
Step C:
3-(methylthiomethyl) azetidine (31-4)
TFA (2 mL) is added in the solution of compound 31-3 (500 mg, 2.46 mmol) in DCM (2 mL).Reaction mixture is at room temperature stirred 10min.Then concentrate, obtain the thick azetidine 31-4 as trifluoroacetate.
Step D:
the bromo-2-methyl of 3--6-(3-(methylthiomethyl) azetidine-1-base) pyridine (31-5)
TEA (656 mg, 6.49 mmol) and the fluoro-2-picoline of the bromo-6-of 3-(410 mg, 2.16 mmol) is added in the solution of compound 31-4 (500 mg, 2.16 mmol) in NMP (5 mL).In nitrogen atmosphere, stirring is descended to spend the night at 120 DEG C reaction mixture.Described reaction mixture ethyl acetate (50 mL) is diluted, with water (10 mL x 3) and salt solution (20 mL) washing, at Na
2sO
4middle drying, and concentrated, obtain crude product 31-5, it is purified with silica gel flash column chromatography, with sherwood oil: ethyl acetate (5:1) wash-out, obtains pure product.MS(ESI)m /e(M+H+)288。
Step e:
the bromo-2-methyl of 3--6-(3-(sulfonyloxy methyl ylmethyl) azetidine-1-base) pyridine (31-6)
Add m-CPBA (85%, 89 mg, 439 μm of ol) in the solution of ice-cooled compound 31-5 (200 mg, 696.3 μm of ol) in the DCM (10 mL) of drying in batches.Reaction mixture is stirred 1h at 0 DEG C, then uses DCM (50 mL) to dilute.The saturated Na of described mixture
2sO
3solution (20 mL), NaHCO
3(20 mL) solution and salt solution (20 mL) washing, then at Na
2sO
4middle drying, and concentrated, obtain crude product, it is purified with silica gel preparative TLC, with sherwood oil: ethyl acetate (3:1) wash-out, obtains pure product 31-6.MS(ESI)m/e(M+H+)522。
Step F:
(5aR; 6S; 6aS)-3-((the fluoro-5-of 2-(2-methyl-6-(3-((methyl sulphonyl) methyl) azetidine-1-base) pyridin-3-yl) benzyl) oxygen base)-5; 5a; 6; 6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (31-7) also
Compound 31-6 (20 mg, 62 μm of ol), boric acid ester (28 mg, 62 μm of ol), Na from reference example 2-4 is loaded in one 40 mL bottles
2cO
3(13 mg, 124 μm of ol), dioxs (1.5 mL), H
2o (0.5 mL) and PdCl
2dppf CH
2cl
2(5 mg).The vibrator described bottle being placed on 100 DEG C spends the night, is cooled to envrionment temperature, then uses ethyl acetate (30 mL) to dilute.The water washing of described mixture salt, and concentrated, and obtain a kind of crude product, it is not purified just for next step further.MS(ESI)m /e(M+H
+)566。
Step F: (
5aR; 6S; 6aS)-3-((the fluoro-5-of 2-(2-methyl-6-(3-((methyl sulphonyl) methyl) azetidine-1-base) pyridin-3-yl) benzyl) oxygen base)-5; 5a; 6; 6a-tetrahydrochysene cyclopropane is [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (31-8) also
H is added in the mixture of compound 31-7 (35 mg, 62 μm of ol) in THF (2 mL) and EtOH (1 mL)
2o (1 mL) and LiOH (15 mg).Described reaction mixture is stirred at ambient temperature and spends the night, then use HCl (1N) that pH value is adjusted to pH 4.Reaction mixture salt solution (30 mL) and ethyl acetate (50 mL) washing, be separated organic layer, at Na
2sO
4middle drying, and concentrated.Gained resistates preparation property HPLC purifies, and (preparation property HPLC carries out on GILSON 215 instrument, and it is equipped with Diamonsil C18 (150 x 20 mm x 5 um), uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 25-55% B, 0-10 min; 100% B, 10.5-12.5min; 5% B, 13-15 min), obtain pure product 31-8.
Embodiment 86-90 (compound 31-9 to 31-13) is prepared according to the mode being similar to compound 31-8, uses suitable commercially available starting raw material.
Embodiment 91 (compound 32-8)
(5aR, 6S, 6aS)-3-((3-(6, the fluoro-2-of 7-bis-(trifluoromethyl)-1H-benzo [d] imidazoles-1-base)-2-methyl-benzyl) oxygen base)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (32-8)
Steps A:
3-(the fluoro-6-nitro-phenylamino of 2,3-bis-)-2-methyl-toluate (32-2)
By compound 32-1 (7 g, 40 mmol), the bromo-2-methyl-toluate of 3-(11 g, 48 mmol), K
3pO
4(25 g, 120 mmol), Pd
2(dba)
3(915 mg, 1 mmol), the mixture of X-phos (952 mg, 2 mmol) in 100 mL dry toluene are at N
2at 100 DEG C, 18 h are heated in atmosphere.Then, add water (200 mL), then described mixture ethyl acetate (3 x 100 mL) is extracted.Organic layer washed with brine (100 mL) washing merged, in anhydrous Na
2sO
4middle drying, concentrated, obtain a kind of crude product.Described crude product purified by silica gel flash column chromatography is purified, with sherwood oil: ethyl acetate (3:1) wash-out, obtains 32-2.MS(ESI)m /e(M+H
+): 323.1。
Step B:
3-(amino-2, the 3-Difluorophenylamino of 6-)-2-methyl-toluate (32-3)
By the mixture of compound 32-2 (5 g, 15.5 mmol) in THF/MeOH (20/40 mL) at H
2stir at 25 DEG C in atmosphere (50 psi).Then, described mixture passes through Celite
tMfilter, then concentrate.Gained crude product is not purified further and is just directly used in next step.MS(ESI)m /e(M+H
+): 293.0。
Step C:
3-(the fluoro-2-of 6,7-bis-(trifluoromethyl)-1H-benzo [d] imidazoles-1-base)-2-methyl-toluate (32-4)
By compound 32-3 (1.1 g, 3.8 mmol) at (CF
3cO)
2o/CF
3mixture in COOH (2/8 mL) refluxes 18 h, then concentrates.Gained resistates is dissolved in 20 mL EA again, uses NaHCO
3(aqueous solution, 20 mL) and salt solution (20 mL) wash, then in anhydrous Na
2sO
4middle drying, and concentrated, obtain described crude product.Required product silica gel flash column chromatography is purified, with sherwood oil: ethyl acetate (5:1) wash-out.MS(ESI)m /e(M+H
+): 371.2。
Step D:(3-(the fluoro-2-of 6,7-bis-(trifluoromethyl)-1H-benzo [d] imidazoles-1-base)-2-aminomethyl phenyl) methyl alcohol
( 32-5)
At 0 DEG C, in the solution of compound 32-4 (1.15 g, 3.1 mmol) in dry THF (30 mL), add LiBH lentamente
4(136 mg, 6.2 mmol).Stir 3 h under rt after, at 0 DEG C, add MeOH (10 mL), then except desolventizing.Described crude product is dissolved in ethyl acetate (20 mL) again, with water (10 mL) washing, then uses salt solution (10 mL) to wash, at Na
2sO
4middle drying, and concentrated, obtain compound 32-5.MS(ESI)m/e(M+H
+): 343.1。
Step e:
1-(3-(brooethyl)-2-aminomethyl phenyl)-6,7-bis-fluoro-2-(trifluoromethyl)-1H-benzo [d] imidazoles (32-6)
Tribromide phosphine (427 mg, 1.6 mmol) is added in the solution of compound 32-5 (684 mg, 2 mmol) in dry THF (10 mL).After stirring 180 min, add ethyl acetate (20 mL).By described mixture NaHCO
3(aqueous solution, 20 mL) and salt solution (20 mL) wash, then in anhydrous Na
2sO
4middle drying, and concentrated, obtain described crude product.Described pure product silica gel flash column chromatography is purified, with sherwood oil: ethyl acetate (10:1) wash-out.MS(ESI)m /e(M+H
+): 404.8。
Step F:
(5aR, 6S, 6aS)-3-((3-(6, the fluoro-2-of 7-bis-(trifluoromethyl)-1H-benzo [d] imidazoles-1-base)-2-methyl-benzyl) oxygen base)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-ethyl formate (32-7)
By compound 32-6 (419 mg, 1.04 mmol), reference example 1-9 (227 mg, 1.04 mmol), Ag
2cO
3the mixture of (1.0 g, 3.69 mmol) and toluene (6 mL) is at N
2at 100 DEG C, 18 h are heated in atmosphere.Then, described mixture is cooled to room temperature, then passes through Celite
tMfilter, and concentrated, obtain described crude product.Pure product is by obtaining with silica gel preparative TLC purification (with sherwood oil: ethyl acetate=3:1 wash-out).MS(ESI)m /e(M+H
+): 544.2。
Step G:
(5aR, 6S, 6aS)-3-((3-(6, the fluoro-2-of 7-bis-(trifluoromethyl)-1H-benzo [d] imidazoles-1-base)-2-methyl-benzyl) oxygen base)-5,5a, 6,6a-tetrahydrochysene cyclopropane also [4,5] cyclopenta [1,2-c] pyridine-6-formic acid (32-8)
By compound 32-7 (54 mg, 0.1 mmol) and LiOH (23 mg, 1 mmol) at THF/MeOH/H
2mixture in O (3/0.5/0.5 mL) at room temperature stirs 1h, then adds NH
4cl (aqueous solution), makes its pH reach 5.Described mixture DCM (3 × 10 mL) extracts.Organic layer washed with brine (10 mL) washing merged, in anhydrous Na
2sO
4middle drying, concentrated, obtain a kind of crude product.Described pure product 32-8 is separated by preparation property HPLC and obtains that (preparation property HPLC carries out on GILSON 281 instrument, and it is equipped with YMC-Actus Triart C18 (150 x 30mm x 5um), uses water and acetonitrile as eluent.Mobile phase A: water (containing 0.1%TFA, v/v), Mobile phase B: acetonitrile.Gradient: 42-82% B, 0-10 min; 100% B, 10.5-12.5 min; 5% B, 13-15 min).
The following example 92 (compound 32-9) is prepared according to the mode being similar to compound 32-8, uses suitable starting raw material.
Embodiment 93 (compound 33-5)
Steps A:
(the bromo-propyl group of 3-)-diethyl phosphonate (33-2)
By the compound 33-1 (10 g, 0.06 mol) under stirring and mixture heated overnight at 140 DEG C of 1,3-dibromo-propane (18.2 g, 0.09 mol).Then, described reaction is cooled to R.T., concentrates in a vacuum, obtains crude product, and it is purified (using PE/EA=50/1 wash-out) with silica gel column chromatography, obtains the compound 33-2 as colourless oil.(ESI)m /e(M+H
+): 259.0/261.0。
Step B:
[3-(bromo-3, the 5-Dimehtyl-phenoxy of 4-)-propyl group]-diethyl phosphonate (33-3)
At 0 DEG C, to 4-bromo-3,5-dimethyl-phenol (0.3 g, 1.5 mmol) add NaH (60% in oil, 80 mg, 2.0 mmol) in solution in anhydrous THF (3 mL), then described mixture stirs 10 min at this temperature, then drip compound 33-2 (520 mg, the 2.0 mmol) solution in THF (0.5 mL), gained mixture is at room temperature stirred 5 h.Then, reaction NH
4cl cancellation also extracts three times with EtOAc.By the organic layer washed with brine merged, in anhydrous Na
2sO
4middle drying, and concentrated.Gained residue over silica gel Flash chromatography (5% EA, in PE), obtains compound 33-3.(ESI)m/e(M+H
+): 379.1/381.1。
Step C:
compound (33-4)
By compound 33-3 (80 mg, 0.211 mmol), reference compound 2-5 (110 mg, 1.2 eq), Pd (dppf) Cl
2(15 mg, 0.1 eq) and K
3pO
4(110 mg, 3 eq) are at THF/H
2mixture in O (2/0.4 mL) at 110 DEG C at N
2in atmosphere, backflow is spent the night.Then, described mixture is cooled to room temperature, dilutes by ethyl acetate (15 mL).Then, described mixture water and salt water washing, in anhydrous Na
2sO
4middle drying, and concentrated, and obtain crude product, it uses preparation property silicon-dioxide TLC purification (CH
2cl
2/ MeOH=20/1), obtain compound 33-4.(ESI)m /e(M+H
+): 625.1。
Step D:
compound (33-5)
At room temperature, be total to-solvent THF (1.0 mL), MeOH (1.0 mL) and H to compound 33-4 (50 mg, 0.082 mmol)
2naOH (17 mg, 0.412 mmol) is added in mixture in O (0.5 mL).Described reaction is at room temperature stirred and spends the night.Gained mixture HCl (1 N) is acidified to pH=5 ~ 6, then uses ethyl acetate (10 mL) to extract three times.The organic layer washed with brine merged, at Na
2sO
4middle drying, concentrates in a vacuum, obtains described crude product, and it is purified with preparation property-HPLC, obtains compound 33-5.(ESI)m/e(M+H+): 597.1。
The embodiment of pharmaceutical composition
As a kind of specific embodiments of combination of oral medication, the effective tablet of 100 mg is made up of any one the compound of embodiment, 268 mg Microcrystalline Celluloses, 20 mg AC-DI-SOLs and 4 mg Magnesium Stearates of 100 mg the present invention.First active ingredient, Microcrystalline Cellulose and croscarmellose are mixed.Then, described mixture is lubricated by Magnesium Stearate, is then pressed into tablet.
biological characteristis
the generation of GPR40-express cell:
The mankind and the stable clone of mouse GPR40 result from the Chinese hamster ovary celI of stably express NFAT BLA (β-lactamase).The clone that mankind GPR40 is stable results from the HEK cell of the reporter molecule that stably express aequorin is expressed.Utilize lipofection amine (Life Technologies), according to the specification sheets of manufacturers, transfection is carried out to expression plasmid.According to medicament selection, create stable clone.
fLIPR measures:
Carry out FLIPR (Fluorometric Imaging Plate reader, Molecular Devices) to measure, thus measure the calcium mobilization (mobilization) of the stable clone of agonist-bring out.FLIPR is measured, one day before the assay, with μ L medium/hole, 1.4 × 10 e, 4 cell/20, GPR40/CHO NFAT BLA cell is sowed in black wall clear bottom 384-orifice plate (Costar).At room temperature, contain 8 μMs of fluo-4, AM with 20 μ l/ holes, the mensuration damping fluid (HBSS, 0.1%BSA, 20mM HEPES, 2.5mM probenecid, pH7.4) of 0.08% Pluronic acid was by cell cultures 100 minutes.Utilize FLIPR to export fluorescence to measure.Compound to be dissolved in DMSO and by the concentration measuring damping fluid and be diluted to expectation.Add wherein with the compound solution in 13.3 μ L/ holes.In above-mentioned FLIPR measures, the compound in embodiment 1-93 has the EC50 value being less than 100 nmoles (nM) and is listed in table 1.
inositol monophosphate upset (IP1) measures:
This is determined in 96-orifice plate and carries out.Fabric swatch is carried out to the HEK cell of stably express mankind GPR40, to converge 60-80% in 72 hours.After 72 hours, plate is aspirated, and with the DMEM (ICN) without inositol, cell is washed.Washing medium is replaced with the medium of 150uL 3H-inositol mark (containing 0.4% human albumin or 0.4% mouse albumin, 1X pen/ strep antibiotic, glutamine, 25mM HEPES without inositol medium, add 3H-myo-inositol NEN #NET114A 1mCi/mL wherein, in supporting medium, dilution is 25Ci/mmol 1: 150, and final specific activity is 1 μ Ci/150 μ L).Alternatively, before adding LiCl, after markers step of spending the night, the mankind and mouse albumin can be added wherein.
Typically after 18 hour-symbols, ran at second day and measure.Mensuration the same day, 5 μ L 300mM LiCl are joined institute porose in and at 37 DEG C, cultivated 20 minutes.The 200X compound of 0.75 μ L is added wherein, and cultivated 60 minutes with cell at 37 DEG C.Then by medium sucking-off and by adding 60 μ L 10mM formic acid termination mensuration.At room temperature by cytolysis 60 minutes.In clear bottom Isoplates, 15-30 μ L lysate is mixed with 70 μ L/1mg YSi SPA bead (Amersham).At room temperature by above-mentioned plate jolting 2 hours.Make bead sedimentation and in Wallac Microbeta, plate counted.In above-mentioned inositol monophosphate upset (IP1) measures, the compound in embodiment 1-93 has the EC50 value being less than 3000 nmoles (nM) and is listed in table 1.
in vivo study:
With 10/case, stable breeding is carried out to male C57BL/6N mouse (7-12 age in week), and reserve the path leading to normal diet mouse group food and supply water arbitrarily.Above-mentioned mouse is divided into each treatment group at random and by its fasting 4-6 hour.By saccharometer, from afterbody cut blood, benchmark blood sugar concentration is determined.Then, by oral vehicle (0.25% methylcellulose gum) or test compounds, above-mentioned animal is processed.Process (t=0min) to setting-up time point blood sugar concentration is measured, then, with glucose (2g/kg), intraperitoneal stimulation (challenged) is carried out to mouse.With salt solution, one of vehicle process group of mouse is stimulated, as negative control.Glucose stimulate after 20,40 and 60 minutes time the glucose level of tail blood is measured.For each process, the blood glucose excursions pattern from t=0 to t=60min is used for the area (AUC) under integrated curve.By being normalized by the control group of AUC data relative to salt solution-stimulation, obtain the suppression percent value for each process.
Table 1. is for the EC of each embodiment in GPR40 FLIPR and IP1 mensuration
50value (nM).
The scope of claims should by the restriction of preferred embodiment set forth in an embodiment, and should provide and meet specification sheets the widest explanation integrally.
Although by quoting some specific embodiment of the invention scheme, invention has been described and illustrate, but those skilled in the art will be understood that, when not departing from scope of the present invention, various change, change, modification, replacement, deletion or increase can be carried out to method of the present invention and scheme.Such as, can effective dose be used, as the result of the change of the mammiferous response by any indication of compounds for treating of the present invention pointed above, instead of the foregoing concrete dosage of this paper.According to depend on selected concrete active compound or whether there is type and the mode of administration of pharmaceutical carrier and preparation used, the response of viewed concrete pharmacology can change, and change desired by these in all results or difference expection and object of the present invention with put into practice consistent.
Claims (31)
1. the compound of structural formula I:
Or its pharmacy acceptable salt; Wherein
X is selected from:
(1) oxygen, and
(2) NH；
T is selected from: CH, N and N-oxide compound;
U is selected from: CH, N and N-oxide compound;
V is selected from: CH, N and N-oxide compound;
Condition is one or two in T, U and V is N or N-oxide compound;
A is selected from:
(1) aryl, and
(2) heteroaryl,
Wherein A is unsubstituted or is selected from R by 1-5
asubstituting group replace;
B is selected from:
(1) aryl,
(2) aryl-O-,
(3) C
3-6cycloalkyl-,
(4) C
3-6cycloalkyl-C
1-10alkyl-,
(5) C
3-6cycloalkyl-C
1-10alkyl-O-,
(6) C
2-5ring mix alkyl-,
(7) heteroaryl,
(8) heteroaryl-O-,
(9) aryl-C
1-10alkyl-, and
(10) heteroaryl-C
1-10alkyl-;
Wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace;
R
1be selected from:
(1) halogen,
(2) -OR
e，
(3) -CN，
(4)-C
1-6alkyl, and
(5)-C
3-6cycloalkyl,
Wherein each-C
1-6alkyl and-C
3-6cycloalkyl is unsubstituted or is selected from R by 1-3
isubstituting group replace;
R
2be selected from:
(1) hydrogen,
(2)-C
1-6alkyl, and
(3)-C
3-6cycloalkyl,
Wherein each-C
1-6alkyl and-C
3-6cycloalkyl is unsubstituted or is selected from R by 1-3
jsubstituting group replace;
R
3be selected from:
(1) hydrogen,
(2) halogen,
(3) -OR
e，
(4)-C
1-6alkyl,
(5)-C
2-6alkenyl,
(6)-C
2-6alkynyl, and
(7)-C
3-6cycloalkyl,
Wherein each C
1-6alkyl, C
2-6alkenyl, C
2-6alkynyl and C
3-6cycloalkyl is unsubstituted or is selected from R by 1-3
lsubstituting group replace;
R
4be selected from:
(1) hydrogen,
(2) halogen,
(3) -OR
e，
(4)-C
1-6alkyl,
(5)-C
2-6alkenyl,
(6)-C
2-6alkynyl, and
(7)-C
3-6cycloalkyl,
Wherein each-C
1-6alkyl ,-C
2-6alkenyl ,-C
2-6alkynyl and-C
3-6cycloalkyl is unsubstituted or is selected from R by 1-3
lsubstituting group replace;
R
5be selected from:
(1) hydrogen,
(2)-C
1-3alkyl, and
(3) halogen;
R
6be selected from:
(1) hydrogen,
(2)-C
1-3alkyl, and
(3) halogen, or
R
5and R
6oxo can be formed together;
R
abe selected from:
(1)-C
1-6alkyl,
(2) halogen,
(3) -OR
e，
(4) -NR
cS(O)mR
e，
(5) -S(O)mR
e，
(6) -S(O)mNR
cR
d，
(7) -NR
cR
d，
(8) -C(O)R
e，
(9) -OC(O)R
e，
(10) -CO
2R
e,
(11) -CN,
(12) -C(O)NR
cR
d,
(13) -NR
cC(O)R
e,
(14) -NR
cC(O)OR
e,
(15) -NR
cC(O)NR
cR
d,
(16) -CF
3,
(17) -OCF
3,
(18) -OCHF
2,
(19)-C
3-6cycloalkyl, and
(20)-C
2-5ring is mixed alkyl;
R
bindependently selected from:
(1)-C
1-10alkyl,
(2)-C
2-10alkenyl,
(3) halogen,
(4) -OH，
(5)-OC
1-10alkyl,
(6)-OC
2-10alkenyl,
(7)-O (CH
2) pOC
1-10alkyl,
(8)-O (CH
2) pC
3-6cycloalkyl,
(9)-O (CH
2) pC
3-6cycloalkyl-C
1-10alkyl-,
(10)-O (CH
2) pC
2-10ring is mixed alkyl,
(11)-O (CH
2) pC
2-5ring is mixed alkyl-C
1-10alkyl-,
(12)-O-aryl,
(13)-O-heteroaryl,
(14)-O-aryl-C
1-10alkyl-,
(15)-O-heteroaryl-C
1-10alkyl-,
(16) -NR
cS(O)
mR
e,
(17) -S(O)
mR
e,
(18) -S(O)
mNR
cR
d,
(19) -NR
cR
d,
(20) -C(O)R
e ,
(21) -OC(O)R
e ,
(22) -CO
2R
e,
(23) -CN,
(24) -C(O)NR
cR
d,
(25) -NR
cC(O)R
e,
(26) -NR
cC(O)OR
e,
(27) -NR
cC(O)NR
cR
d,
(28)-O (CH
2) pO-C
3-6cycloalkyl,
(29)-O (CH
2) pO-C
2-10ring is mixed alkyl,
(30) -CF
3,
(31) -OCF
3,
(32) -OCHF
2,
(33)-(CH
2) p-C
3-6cycloalkyl,
(34)-(CH
2) p-C
2-10ring is mixed alkyl,
(35) aryl,
(36) heteroaryl,
(37) aryl-C
1-10alkyl-, and
(38) heteroaryl-C
1-10alkyl-,
Wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace;
R
cand R
deach independently selected from:
(1) hydrogen,
(2) C
1-10alkyl,
(3) C
2-10alkenyl,
(4) C
3-6cycloalkyl,
(5) C
3-6cycloalkyl-C
1-10alkyl-,
(6) ring is mixed alkyl,
(7) ring is mixed alkyl-C
1-10alkyl-,
(8) aryl,
(9) heteroaryl,
(10) aryl-C
1-10alkyl-, and
(11) heteroaryl-C
1-10alkyl-, or
R
cand R
dformed together with the atom (all atoms) that they connect containing 0-2 extra heteroatomic 4-7 membered cycloheteroalkyl group ring, described heteroatoms is independently selected from oxygen, sulphur and N-R
g, and wherein each R
cand R
dunsubstituted or individual independently selected from R by 1-3
fsubstituting group replace;
Each R
eindependently selected from:
(1) hydrogen,
(2)-C
1-10alkyl,
(3)-C
2-10alkenyl,
(4)-C
3-6cycloalkyl,
(5)-C
3-6cycloalkyl-C
1-10alkyl-,
(6)-C
2-5ring is mixed alkyl,
(7)-C
2-5ring is mixed alkyl-C
1-10alkyl-,
(8) aryl,
(9) heteroaryl,
(10) aryl-C
1-10alkyl-, and
(11) heteroaryl-C
1-10alkyl-,
Wherein each R
ebe unsubstituted or be selected from R by 1-3
hsubstituting group replace;
Each R
fbe selected from:
(1) halogen,
(2) C
1-10alkyl,
(3) -OH，
(4)-O-C
1-4alkyl,
(5)-S (O) m-C
1-4alkyl,
(6) -CN，
(7) -CF
3，
(8)-OCHF
2, and
(9) -OCF
3，
Wherein each C
1-10alkyl be unsubstituted or by 1-3 independently selected from-OH, halogen, cyano group and-S (O)
2cH
3substituting group replace;
Each R
gbe selected from:
(1) hydrogen,
(2)-C (O) R
e, and
(3)-C
1-10alkyl,
Wherein-C
1-10alkyl is unsubstituted or is replaced by 1-5 fluorine;
Each R
hbe selected from:
(1) halogen,
(2) C
1-10alkyl,
(3) -OH，
(4)-O-C
1-4alkyl,
(5)-S (O) m-C
1-4alkyl,
(6) -CN，
(7) -CF
3，
(8)-OCHF
2, and
(9) -OCF
3，
Wherein each C
1-10alkyl be unsubstituted or by 1-3 independently selected from-OH, halogen, cyano group and-S (O)
2cH
3substituting group replace;
R
iindependently selected from:
(1)-C
1-6alkyl,
(2) -OR
e,
(3) -NR
cS(O)
mR
e,
(4) halogen,
(5) -S(O)
mR
e,
(6) -S(O)
mNR
cR
d,
(7) -NR
cR
d,
(8) -C(O)R
e ,
(9) -OC(O)R
e ,
(10) -CO
2R
e,
(11) -CN,
(12) -C(O)NR
cR
d,
(13) -NR
cC(O)R
e,
(14) -NR
cC(O)OR
e,
(15) -NR
cC(O)NR
cR
d,
(16) -CF
3,
(17) -OCF
3,
(18) -OCHF
2,
(19)-C
3-6cycloalkyl, and
(20)-C
2-5ring is mixed alkyl;
R
jindependently selected from:
(1)-C
1-6alkyl,
(2) -OR
e,
(3) -NR
cS(O)
mR
e,
(4) halogen,
(5) -S(O)
mR
e,
(6) -S(O)
mNR
cR
d,
(7) -NR
cR
d,
(8) -C(O)R
e ,
(9) -OC(O)R
e ,
(10) -CO
2R
e,
(11) -CN,
(12) -C(O)NR
cR
d,
(13) -NR
cC(O)R
e,
(14) -NR
cC(O)OR
e,
(15) -NR
cC(O)NR
cR
d,
(16) -CF
3,
(17) -OCF
3,
(18) -OCHF
2,
(19)-C
3-6cycloalkyl, and
(20)-C
2-5ring is mixed alkyl;
Each R
kindependently selected from:
(1) halogen,
(2)-C
1-10alkyl,
(3) -OH，
(4) oxo,
(5) halogen,
(6)-O-C
1-4alkyl,
(7)-SO
2-C
1-6alkyl,
(8)-C
1-6alkyl-SO
2c
1-6alkyl,
(9) -CN,
(10) -CF
3,
(11) -OCHF
2,
(12) -OCF
3,
(13) -NH
2,
(14)-NHSO
2c
1-6alkyl,
(15)-NHCOC
1-6alkyl,
(16) =N(OCH
3),
(17)-P (O) (OH)
2, and
(18)-P (O) (OC
1-6alkyl)
2,
Wherein each C
1-10alkyl be unsubstituted or by 1-3 independently selected from-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6the substituting group of alkyl replaces;
R
lbe selected from:
(1)-C
1-6alkyl,
(2) halogen,
(3) -OR
e,
(4) -NR
cS(O)
mR
e,
(5) -S(O)
mR
e,
(6) -S(O)
mNR
cR
d,
(7) -NR
cR
d,
(8) -C(O)R
e ,
(9) -OC(O)R
e ,
(10) -CO
2R
e,
(11) -CN,
(12) -C(O)NR
cR
d,
(13) -NR
cC(O)R
e,
(14) -NR
cC(O)OR
e,
(15) -NR
cC(O)NR
cR
d,
(16) -CF
3,
(17) -OCF
3,
(18) -OCHF
2,
(19)-C
3-6cycloalkyl, and
(20)-C
2-5ring is mixed alkyl;
Each n independently selected from: 0,1,2,3 or 4;
Each m independently selected from: 0,1 or 2; With
Each p independently selected from: 0,1,2,3,4,5,6,7,8,9 or 10.
2. the compound of claim 1, wherein n is 1; Or its pharmacy acceptable salt.
3. the compound of claim 1 or 2, wherein X is oxygen; Or its pharmacy acceptable salt.
4. the compound of claim 1-3, wherein T is CH, U is N or N-oxide compound, and V is CH; Or its pharmacy acceptable salt.
5. the compound of claim 1-3, wherein T is CH, U is N, and V is CH; Or its pharmacy acceptable salt.
6. the compound of claim 1-5, wherein A is selected from: phenyl and pyridine, and wherein A is unsubstituted or is selected from R by 1-5
asubstituting group replace; Or its pharmacy acceptable salt.
7. the compound of claim 1-5, wherein A is phenyl, and wherein phenyl is unsubstituted or is selected from R by 1-5
asubstituting group replace; Or its pharmacy acceptable salt.
8. the compound of claim 1-7, wherein B is selected from: aryl and heteroaryl, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace; Or its pharmacy acceptable salt.
9. the compound of claim 1-7, wherein B is selected from: phenyl, pyridine, pyrimidine, thiazole, benzoglyoxaline, benzothiazole, benzoxazole and benzoisoxazole, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace; Or its pharmacy acceptable salt.
10. the compound of claim 1-7, wherein B is selected from: phenyl and pyridine, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace; Or its pharmacy acceptable salt.
The compound of 11. claim 1-10, wherein R
1, R
2, R
5and R
6hydrogen; Or its pharmacy acceptable salt.
The compound of 12. claim 1-11, wherein R
3and R
4be selected from: hydrogen, halogen and-C
1-6alkyl, wherein each C
1-6alkyl is unsubstituted or is selected from R by 1-3
lsubstituting group replace; Or its pharmacy acceptable salt.
The compound of 13. claim 1-11, wherein R
3and R
4hydrogen; Or its pharmacy acceptable salt.
The compound of 14. claim 1-13, wherein R
abe selected from :-C
1-6alkyl, halogen and-CF
3, or its pharmacy acceptable salt.
The compound of 15. claim 1-14, wherein R
bindependently selected from:
(1)-C
1-10alkyl,
(2) halogen,
(3) -OH,
(4)-OC
1-10alkyl,
(5)-O (CH
2) pOC
1-10alkyl,
(6)-O (CH
2) pC
3-6cycloalkyl,
(7)-O (CH
2) pC
2-10ring is mixed alkyl,
(8)-O (CH
2) pO-C
3-6cycloalkyl,
(9)-O (CH
2) pO-C
2-10ring is mixed alkyl,
(10) -CF
3,
(11) -OCF
3,
(12) -OCHF
2,
(13)-(CH
2) p-C
2-10ring is mixed alkyl, and
(14)-S (O)
2c
1-10alkyl,
Wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace; Or its pharmacy acceptable salt.
The compound of 16. claim 1-14, wherein R
bindependently selected from:
(1)-C
1-10alkyl,
(2) halogen,
(3) -OH,
(4)-OC
1-10alkyl,
(5)-O (CH
2) pC
2-10ring is mixed alkyl,
(6)-CF
3, and
(7)-(CH
2) p-C
2-10ring is mixed alkyl,
Wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace; Or its pharmacy acceptable salt.
The compound of 17. claim 1-16, wherein each R
kindependently selected from:
(1)-C
1-10alkyl,
(2)-O-C
1-4alkyl,
(3) -OH,
(4) halogen,
(5)-SO
2-C
1-6alkyl,
(6)-C
1-6alkyl-SO
2c
1-6alkyl,
(7) -CN,
(8)-NHSO
2c
1-6alkyl,
(9)=N (OCH
3), and
(10)-P (O) (OC
1-6alkyl)
2,
Wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl; Or its pharmacy acceptable salt.
The compound of 18. claim 1-16, wherein each R
kindependently selected from:
(1)-C
1-10alkyl,
(2) -OH,
(3) halogen,
(4)-SO
2-C
1-6alkyl,
(5)-C
1-6alkyl-SO
2c
1-6alkyl, and
(6) -CN,
Wherein each C
1-10alkyl is unsubstituted or is replaced independently selected from substituting group below by 1-3 :-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6alkyl; Or its pharmacy acceptable salt.
The compound of 19. claim 1-18, wherein as follows at the absolute stereochemical at two places of three-dimensional carbon center:
Or its pharmacy acceptable salt.
The compound of 20. claims 1, wherein:
N is 1;
X is oxygen;
T is CH;
U is N;
V is CH;
A is selected from: aryl and heteroaryl, and wherein A is unsubstituted or is selected from R by 1-5
asubstituting group replace;
B is selected from: aryl and heteroaryl, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace;
R
1, R
2, R
5and R
6hydrogen; And
R
3and R
4be selected from: hydrogen, halogen and-C
1-6alkyl, wherein each C
1-6alkyl is unsubstituted or is selected from R by 1-3
lsubstituting group replace;
Or its pharmacy acceptable salt.
The compound of 21. claims 1, wherein:
N is 1;
X is oxygen;
T is CH;
U is N;
V is CH;
A is selected from: phenyl and pyridine, and wherein A is unsubstituted or is selected from R by 1-5
asubstituting group replace;
B is selected from: phenyl, pyridine, pyrimidine, thiazole, benzoglyoxaline, benzothiazole, benzoxazole and benzoisoxazole, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace;
R
1, R
2, R
3, R
4, R
5and R
6hydrogen;
R
abe selected from :-C
1-6alkyl, halogen and-CF
3;
R
bindependently selected from:
(1)-C
1-10alkyl,
(2) halogen,
(3) -OH,
(4)-OC
1-10alkyl,
(5)-O (CH
2) pOC
1-10alkyl,
(6)-O (CH
2) pC
3-6cycloalkyl,
(7)-O (CH
2) pC
2-10ring is mixed alkyl,
(8)-O (CH
2) pO-C
3-6cycloalkyl,
(9)-O (CH
2) pO-C
2-10ring is mixed alkyl,
(10) -CF
3,
(11) -OCF
3,
(12) -OCHF
2,
(13)-(CH
2) p-C
2-10ring is mixed alkyl, and
(14)-S (O)
2c
1-10alkyl,
Wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace; With
Each R
kindependently selected from:
(1)-C
1-10alkyl,
(2)-O-C
1-4alkyl,
(3) -OH,
(4) halogen,
(5)-SO
2-C
1-6alkyl,
(6)-C
1-6alkyl-SO
2c
1-6alkyl,
(7) -CN,
(8)-NHSO
2c
1-6alkyl,
(9)=N (OCH
3), and
(10)-P (O) (OC
1-6alkyl)
2,
Wherein each C
1-10alkyl be unsubstituted or by 1-3 independently selected from-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6the substituting group of alkyl replaces;
Or its pharmacy acceptable salt.
The compound of 22. claims 1, wherein
N is 1;
X is oxygen;
T is CH;
U is N;
V is CH;
A is phenyl, and wherein phenyl is unsubstituted or is selected from R by 1-5
asubstituting group replace;
B is selected from: phenyl and pyridine, and wherein B is unsubstituted or is selected from R by 1-5
bsubstituting group replace;
R
1, R
2, R
3, R
4, R
5and R
6hydrogen;
R
abe selected from :-C
1-6alkyl, halogen and-CF
3;
R
bindependently selected from:
(1)-C
1-10alkyl,
(2) halogen,
(3) -OH,
(4)-OC
1-10alkyl,
(5)-O (CH
2) pC
2-10ring is mixed alkyl,
(6)-CF
3, and
(7)-(CH
2) p-C
2-10ring is mixed alkyl,
Wherein each R
bbe unsubstituted or be selected from R by 1-5
ksubstituting group replace; With
Each R
kindependently selected from:
(1)-C
1-10alkyl,
(2) -OH,
(3) halogen,
(4)-SO
2-C
1-6alkyl,
(5)-C
1-6alkyl-SO
2c
1-6alkyl, and
(6) -CN,
Wherein each C
1-10alkyl be unsubstituted or by 1-3 independently selected from-OH ,-OC
1-6alkyl, halogen, cyano group and-S (O)
2c
1-6the substituting group of alkyl replaces;
Or its pharmacy acceptable salt.
The compound of 23. claims 22, it is selected from:
with
Or its pharmacy acceptable salt.
24. pharmaceutical compositions, it comprises the compound of claim 1-23, or its pharmacy acceptable salt, and pharmaceutically acceptable carrier.
The compound of 25. claim 1-23 or its pharmacy acceptable salt are for the preparation of the purposes for the treatment of in the Mammals having this to need in the medicine of the obstacle, illness or the disease that the agonism of G-protein-coupled receptor 40 are had to response.
The compound of 26. claim 1-23 or the purposes of its pharmacy acceptable salt in the medicine for the preparation for the treatment of type ii diabetes.
The compound of 27. claim 1-23 or its pharmacy acceptable salt, during it is used for the treatment of.
28. in the patient having this to need treatment or prevention have the method for the obstacle of response, illness or disease to the agonism of G-protein-coupled receptor 40, the method comprises the compound or its pharmacy acceptable salt that give the claim 1 for the treatment of significant quantity.
29. methods for the treatment of type ii diabetes in a patient in need for the treatment of, the method comprises compound or its pharmacy acceptable salt of the claim 1 giving this bacterium.
30. pharmaceutical compositions, it comprises
(1) compound of claim 1 or its pharmacy acceptable salt;
(2) one or more are selected from following compound:
(a) PPAR gamma agonist and partial agonist;
(b) biguanides;
(c) Protein Tyrosine Phosphatases-1B (PTP-1B) inhibitor;
(d) DPP IV (DP-IV) inhibitor;
(e) Regular Insulin or insulin-mimickers;
(f) sulfonylurea;
(g) alpha-glucosidase inhibitor;
H () improves the medicament of patient's lipid profile, described medicament is selected from (i) HMG-CoA reductase inhibitor, (ii) bile acid chelating agent, (iii) nicotinic alcohol, nicotinic acid or its salt, (iv) PPAR alfa agonists, (v) cholesterol absorption inhibitor, (vi) acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor, (vii) CETP inhibitor, and (viii) phenolic antioxidant;
(i) PPAR α/γ dual agonists,
(j) PPAR delta agonists,
(k) antiobesity compounds,
(l) ileal bile acid transporter inhibitor;
(m) anti-inflammatory agents;
(n) glucagon receptor antagonist;
(o) GLP-1；
(p) GIP-1；
(q) GLP-1 analogue;
(r) HSD-1 inhibitor;
(s) SGLT 1 inhibitor; With
(t) SGLT 2 inhibitor; With
(3) pharmaceutically acceptable carrier.
31. pharmaceutical compositions, it comprises compound or its pharmacy acceptable salt of claim 1, and a kind of compound being selected from Simvastatin, ezetimibe and sitagliptin; And pharmaceutically acceptable carrier.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNPCT/CN2012/079558 | 2012-08-02 | ||
| US201261696572P | 2012-09-04 | 2012-09-04 | |
| US61/696572 | 2012-09-04 | ||
| PCT/US2013/052961 WO2014022528A1 (en) | 2012-08-02 | 2013-07-31 | Antidiabetic tricyclic compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104684907A true CN104684907A (en) | 2015-06-03 |
Family
ID=53318759
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201380051773.6A Pending CN104684907A (en) | 2012-08-02 | 2013-07-31 | Antidiabetic tricyclic compounds |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104684907A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110088089A (en) * | 2016-10-25 | 2019-08-02 | 勃林格殷格翰国际有限公司 | Benzylamino pyridyl cyclopropane formic acid, medical composition and its use |
| CN110177773B (en) * | 2017-01-26 | 2023-08-25 | 勃林格殷格翰国际有限公司 | Benzyl aminopyridine cyclopropanecarboxylic acid, pharmaceutical composition and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007136572A2 (en) * | 2006-05-15 | 2007-11-29 | Merck & Co., Inc. | Antidiabetic bicyclic compounds |
| CN101106991A (en) * | 2005-01-28 | 2008-01-16 | 默克公司 | Antidiabetic bicyclic compounds |
| WO2009058237A1 (en) * | 2007-10-29 | 2009-05-07 | Merck & Co., Inc. | Antidiabetic tricyclic compounds |
-
2013
- 2013-07-31 CN CN201380051773.6A patent/CN104684907A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101106991A (en) * | 2005-01-28 | 2008-01-16 | 默克公司 | Antidiabetic bicyclic compounds |
| WO2007136572A2 (en) * | 2006-05-15 | 2007-11-29 | Merck & Co., Inc. | Antidiabetic bicyclic compounds |
| WO2009058237A1 (en) * | 2007-10-29 | 2009-05-07 | Merck & Co., Inc. | Antidiabetic tricyclic compounds |
Non-Patent Citations (1)
| Title |
|---|
| 欧春艳: "生物电子等排及其在新药设计中的应用综述", 《湛江海洋大学学报》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110088089A (en) * | 2016-10-25 | 2019-08-02 | 勃林格殷格翰国际有限公司 | Benzylamino pyridyl cyclopropane formic acid, medical composition and its use |
| CN110088089B (en) * | 2016-10-25 | 2023-08-29 | 勃林格殷格翰国际有限公司 | Benzyl amino pyridyl cyclopropane carboxylic acid, pharmaceutical composition and application thereof |
| CN110177773B (en) * | 2017-01-26 | 2023-08-25 | 勃林格殷格翰国际有限公司 | Benzyl aminopyridine cyclopropanecarboxylic acid, pharmaceutical composition and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2880028B1 (en) | Antidiabetic tricyclic compounds | |
| EP3055288B1 (en) | Antidiabetic tricyclic compounds | |
| CN102361857B (en) | Can be used as the ring-type benzimidizole derivatives of antidiabetic | |
| EP2362731B1 (en) | Novel cyclic benzimidazole derivatives useful anti-diabetic agents | |
| EP3102198B1 (en) | Antidiabetic compounds | |
| EP2906040B1 (en) | Novel benzimidazole tetrahydropyran derivatives | |
| WO2014019186A1 (en) | Antidiabetic tricyclic compounds | |
| EP3068768B1 (en) | Antidiabetic tricyclic compounds | |
| CN102264228A (en) | Novel cyclic benzimidazole derivatives useful for anti-diabetic agents | |
| EP3076959B1 (en) | Antidiabetic bicyclic compounds | |
| CN105001219A (en) | Novel cyclic azabenzimidazole derivatives useful as anti-diabetic agents | |
| EP3436003B1 (en) | Antidiabetic bicyclic compounds | |
| CN104994848A (en) | Antidiabetic bicyclic compounds | |
| CN102271511A (en) | Novel cyclic benzimidazole derivatives useful anti-diabetic agents | |
| CA2786314A1 (en) | Novel cyclic benzimidazole derivatives useful anti-diabetic agents | |
| US11225471B2 (en) | Antidiabetic bicyclic compounds | |
| CN101365694A (en) | Heterocycle-substituted 3-alkyl azetidine derivatives | |
| CN104684907A (en) | Antidiabetic tricyclic compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20150603 |
|
| WD01 | Invention patent application deemed withdrawn after publication |