WO2015192701A1 - 氨基吡喃环衍生物及其组合物和应用 - Google Patents

氨基吡喃环衍生物及其组合物和应用 Download PDF

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WO2015192701A1
WO2015192701A1 PCT/CN2015/078923 CN2015078923W WO2015192701A1 WO 2015192701 A1 WO2015192701 A1 WO 2015192701A1 CN 2015078923 W CN2015078923 W CN 2015078923W WO 2015192701 A1 WO2015192701 A1 WO 2015192701A1
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group
alkyl
heterocycloalkyl
cycloalkyl
alkoxy
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PCT/CN2015/078923
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French (fr)
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张晨
王健民
李财虎
魏用刚
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四川海思科制药有限公司
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Priority to ES15809919T priority Critical patent/ES2963299T3/es
Priority to US15/319,591 priority patent/US10065962B2/en
Priority to JP2016574055A priority patent/JP6535034B2/ja
Priority to CN201580001776.8A priority patent/CN105518008B/zh
Priority to EP15809919.2A priority patent/EP3159344B1/en
Publication of WO2015192701A1 publication Critical patent/WO2015192701A1/zh

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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical

Definitions

  • the present invention relates to an aminopyran ring derivative, and compositions and uses thereof, and in particular to an aminopyran ring derivative of the formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof and the same
  • DPP-IV dipeptidyl peptidase IV
  • Diabetes is a major medical problem worldwide. According to the International Diabetes Federation (IDF), the number of people with diabetes worldwide reached 382 million in 2013, and global medical expenses reached 548 billion US dollars, accounting for 11% of global medical expenditure. The global medical cost associated with diabetes is expected to reach $627.3 billion by 2035.
  • Insulin is a hormone required to convert sucrose, starch and other foods into energy. Diabetes is usually caused by the inability of the body to secrete or properly utilize insulin. Diabetes is usually classified into type 1 diabetes (or insulin-dependent diabetes mellitus, IDDM) and type 2 diabetes (or non-insulin-dependent diabetes mellitus, NIDDM). The most common type of diabetes is type 2 diabetes, which accounts for approximately 90% of all diabetes worldwide. The incidence of type 2 diabetes is gradually increasing due to modern unhealthy lifestyles such as reduced exercise and high-calorie diets. The huge market potential has attracted a large number of pharmaceutical companies and research centers to develop new anti-diabetic targets and drugs.
  • the currently approved drugs for the treatment of type 2 diabetes are insulin and its analogues, sulfonylureas, biguanides, thiazolidinediones (TZDs), alpha-glucosidase inhibitors, and amylin analogues.
  • Incretin hormone analogue dipeptidyl peptidase inhibitor (DPP-IV), and the like.
  • HbA1c glycated hemoglobin
  • these hypoglycemic agents have side effects such as hypoglycemia, weight gain and cardiovascular risk. These side effects add to the burden on diabetics. Therefore, there is an urgent need to develop a new type of hypoglycemic agent with high efficacy and few side effects for type 2 diabetes.
  • Dipeptidyl Peptidase IV (DPP-IV, EC 3.4.14.5) is a serine protease that hydrolyzes N-terminally from the N-position of the N-terminus of L-valine and L-alanine-containing peptides. Peptide. Although the function of DPP-IV has not been fully elucidated, it is considered to be a major physiological regulator of certain regulatory polypeptides, neuropeptides, circulating hormones, and chemokines. DPP-IV, although a multi-effect enzyme, has many substrates, but is best known as incretin, which includes glucagon-like peptide-1 (GLP-1) and glycoprotein-dependent insulin releasing peptide (GIP). ).
  • GLP-1 glucagon-like peptide-1
  • GIP glycoprotein-dependent insulin releasing peptide
  • Incretin is an intestinal hormone that secretes and promotes the intake of nutrients within minutes of ingestion of nutrients.
  • GLP-1 and GIP have the same effect on beta cells, which can improve beta cell function, including promoting glucose-dependent insulin secretion, inducing beta cell proliferation, and enhancing anti-apoptotic effects (Diabetes and Vascular Dis ethyl acetate se Res ethyl acetate rch 2006 3: 159).
  • GLP-1 Unlike GIP, GLP-1 still promotes insulin secretion in type 2 diabetes, and therefore, increasing GLP-1 is a promising means of treating type 2 diabetes (Pharmacol Rev 60: 470–512, 2008).
  • the use of GLP-1 in patients with type 2 diabetes can significantly lower blood glucose (Lancet, 2002, 359: 824-830).
  • GLP-1, as a substrate for DPP-IV is rapidly hydrolyzed and inactivated in vivo, so DPP- IV inhibitors are of great importance for the treatment of diabetes.
  • DPP-IV inhibitor research has made great progress, and DPP-IV inhibitors including sitagliptin, saxagliptin and alogliptin have been approved for marketing and entered clinical use.
  • DPP-IV inhibitors including sitagliptin, saxagliptin and alogliptin have been approved for marketing and entered clinical use.
  • the most striking feature of DPP-IV inhibitors is that since incretin is secreted only after eating in the body, DPP-IV inhibitors are not easy to increase insulin levels when inappropriate, resulting in many side effects of hypoglycemic drugs.
  • Recent clinical data have shown that inhibition of DPP-IV increases insulin secretion, lowers blood glucose levels, and improves islet beta cell function (Diabetes, 1998, 47: 1253-1258).
  • Common side effects of DPP-IV inhibitors are respiratory infections, sore throat, diarrhea, flu-like symptoms, headache and dizziness.
  • diabetes mainly type 2 diabetes
  • the incidence of diabetes is increasing year by year in the world, becoming the third non-communicable disease that threatens people's health and life after cardiovascular disease and cancer.
  • the treatment of diabetes poses a heavy burden on families and society. Therefore, there is an urgent need to develop more updated and better DPP-IV inhibitor drugs to meet the needs of patients in clinical medicine.
  • Ar is selected from phenyl substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkyl;
  • V is selected from And the like, and R 3a and R 3b are independently selected from hydrogen, C 1-4 alkyl substituted by 1 to 5 fluorine atoms;
  • R 2 is selected from the group consisting of hydrogen, hydroxy, halogen, carboxyl and the like;
  • R 8 is selected A group such as hydrogen, -(CH 2 ) p -phenyl, but no methylsulfonyl; is not specifically described in this patent as part of the present invention.
  • DPP-IV dipeptidyl peptidase IV
  • Ar is selected from the group consisting of hydrogen, alkyl, and the like;
  • R 3a and R 3b are selected from C 1-4 alkyl groups independently selected from hydrogen and substituted by 1 to 5 fluorine atoms;
  • R 2 is selected from the group consisting of hydrogen, hydroxyl, halogen, carboxyl and the like;
  • R 8 is selected A group such as -S(O) 2 -C 1-6 cycloalkyl, -S(O) 2 -C 1-6 alkyl; is not considered to be a part of the invention.
  • WO2011103256 discloses a compound having a structure having a DPP-IV inhibitor action as a prophylactic and/or therapeutic drug for diabetes, wherein:
  • Ar is phenyl optionally substituted by 1 to 5 groups independently selected from the group consisting of halogen, cyano, hydroxy, and the like;
  • V is selected from And the like, and R 2 is selected from the group consisting of hydrogen, hydroxy, cyano, halogen, alkyl, alkoxy, carbonyl, etc.; R 3a , R 3b are selected from hydrogen or optionally substituted with from 1 to 5 fluorine atoms.
  • WO2007126745 discloses a DPP-IV inhibitor compound of the following structure for the treatment of diabetes, wherein:
  • Ar is selected from a substituted or unsubstituted phenyl group, and when substituted, the phenyl group is substituted with 1-3 selected from a halogen, a hydroxyl group, a C 1-6 alkyl group or the like;
  • V is selected from And the like, and R 2 is selected from the group consisting of hydrogen, hydroxy, halogen, alkenyl, alkynyl, aryl, heteroaryl, etc.; R 3a , R 3b are selected from hydrogen, C 1- substituted by 1 to 5 fluorine atoms 4 alkyl; R8 is selected from the group consisting of H, cycloalkyl, phenyl, alkyl, etc.; the specific description in this patent is not considered to be part of the present invention.
  • WO2011103256, WO2008060488, WO2007087231, WO2011037793, WO2011028455, WO2009025784, etc. also disclose about DPP-IV inhibitor compounds for the treatment of diabetes.
  • the object of the present invention is to introduce a novel class of DPP-IV inhibitors, in particular having the compounds of the formula (I), which have been shown to have good dipeptidyl peptidase IV (DPP- IV) Inhibition of activity and selectivity, with prospects for the treatment or alleviation of type 2 diabetes and similar diseases.
  • DPP- IV dipeptidyl peptidase IV
  • the present invention relates to an aminopyran ring derivative of the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof:
  • V is selected from the following groups:
  • Ar is a benzene ring substituted with 0 to 5 R 1 groups, preferably 2,5-difluorophenyl or 2,4,5-trifluorophenyl;
  • R 3a and R 3b are each independently selected from H, F, Cl, Br, I, hydroxy, cyano or C 1-8 alkyl, wherein the alkyl group is optionally further from 0 to 5 selected from F, Cl, Substituted by a substituent of Br, I, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3a and R 3b are each independently preferably from H or C 1-2 alkyl, wherein the alkyl group is optionally further substituted with 0 to 3 substituents selected from F, hydroxy or C 1-4 alkoxy; further preferably, R 3a and R 3b are each independently selected From H;
  • R 4a and R 4b are each independently selected from H, F, Cl, Br, I, hydroxy, cyano or C 1-8 alkyl, wherein said alkyl group is optionally further further selected from 0 to 5 selected from F, Cl, Substituted with a substituent of Br, I, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, C 1-4 alkyl or C 1-4 alkoxy, and R 4a and R 4b are not simultaneously H;
  • R 5 is selected from the group consisting of hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 3-15 cycloalkyl, C 6-10 aryl, 6 to 10 membered heteroaryl, -OC 3-15 ring
  • R 6 , R 7 and R 9 are each independently selected from H, C 1-8 alkyl, C 3-15 cycloalkyl, C 6-10 aryl, 6 to 10 membered heteroaryl or 3 to 15 membered heterocyclic ring.
  • Alkyl preferably each independently selected from H or C 1-8 alkyl;
  • n is selected from 0, 1 or 2, preferably 0 or 1, further preferably 0;
  • n is selected from 0, 1 or 2, preferably 0 or 2, further preferably 2.
  • Preferred embodiments of the invention include an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein:
  • R 1 is selected from H or F
  • R 2a and R 2b are each independently preferably H, C 1-6 alkyl or a C 3-6 cycloalkyl group, wherein the alkyl or cycloalkyl group is optionally further substituted with 0 to 3 substituents selected from the group consisting of F, hydroxy, C 1-4 alkyl or C 1-4 alkoxy ;
  • R 3a and R 3b are each independently selected from H or C 1-2 alkyl, wherein the alkyl group is optionally further substituted with 0 to 3 substituents selected from F, hydroxy or C 1-4 alkoxy; Each is preferably H independently;
  • Preferred embodiments of the invention include an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein:
  • V is selected from the following groups:
  • Ar is selected from 2,5-difluorophenyl or 2,4,5-trifluorophenyl;
  • R 2a is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl group is further further selected from 0 to 3 selected from F, hydroxy, C 1-4 alkyl Or substituted with a C 1-4 alkoxy substituent; preferably H, C 1-2 alkyl or -C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally further from 0 to 3 Substituted with a substituent selected from F, hydroxy, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3a and R 3b are each independently selected from H or C 1-2 alkyl, wherein the alkyl group is optionally further substituted with 0 to 3 substituents selected from F, hydroxy or C 1-4 alkoxy; Each is independently H;
  • Preferred embodiments of the invention include an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein:
  • R 2a is selected from H, C 1-2 alkyl or -C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl group is further further selected from 0 to 3 selected from F, hydroxy, C 1-4 alkane Substituted with a substituent of a C 1-4 alkoxy group;
  • R 2a is preferably H or C 1-2 alkyl, wherein the alkyl group is optionally further from 0 to 3 selected from the group consisting of F, hydroxy, C 1-4 Substituted with a substituent of an alkyl group or a C 1-4 alkoxy group;
  • R 2a is further preferably H or a methyl group.
  • Preferred embodiments of the invention include an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein:
  • V is selected from
  • Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl
  • R 2a is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl group is further further selected from 0 to 3 selected from F, hydroxy, C 1-4 alkyl Or substituted with a C 1-4 alkoxy substituent; preferably H, C 1-2 alkyl or -C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally further from 0 to 3 Substituted with a substituent selected from F, hydroxy, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3a and R 3b are each independently selected from H or C 1-2 alkyl, wherein the alkyl group is optionally further substituted with 0 to 3 substituents selected from F, hydroxy or C 1-4 alkoxy; Each is independently H;
  • Preferred embodiments of the invention include an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein:
  • V is selected from
  • Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl
  • R 2a is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl group is further further selected from 0 to 3 selected from F, hydroxy, C 1-4 alkyl Or substituted with a C 1-4 alkoxy substituent; preferably H, C 1-2 alkyl or -C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally further from 0 to 3 Substituted with a substituent selected from F, hydroxy, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3a and R 3b are each independently selected from H or C 1-2 alkyl, wherein the alkyl group is optionally further substituted with 0 to 3 substituents selected from F, hydroxy or C 1-4 alkoxy; Each is independently H;
  • Preferred embodiments of the invention include an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein:
  • R 8 is selected from the group consisting of methyl, ethyl, Cyclopropyl, cyclobutyl or cyclopentyl, preferably methyl, and said groups are optionally further substituted by from 0 to 5 F.
  • Preferred embodiments of the invention include an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein:
  • R 8 is selected from the group consisting of methyl, ethyl, Cyclopropyl, cyclobutyl or cyclopentyl.
  • Preferred embodiments of the invention include an aminopyran ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein:
  • V is selected from
  • Ar is 2,5-difluorophenyl or 2,4,5-trifluorophenyl
  • R 2a is selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl group is further optionally 0 to 3 selected from F, hydroxy, C 1-4 alkyl Or substituted with a C 1-4 alkoxy substituent; preferably H, C 1-2 alkyl or -C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally further from 0 to 3 Substituted with a substituent selected from F, hydroxy, C 1-4 alkyl or C 1-4 alkoxy;
  • R 3a and R 3b are each independently selected from H or C 1-2 alkyl, wherein the alkyl group is optionally further substituted with 0 to 3 substituents selected from F, hydroxy or C 1-4 alkoxy; Each is independently H;
  • R 8 is selected from the group consisting of methyl, ethyl, Cyclopropyl, cyclobutyl or cyclopentyl.
  • the invention relates to a compound selected from, but not limited to:
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising: an effective amount of an aminopyran ring derivative represented by the formula (I) according to any one of the preceding claims, or a stereoisomer thereof, A pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier or excipient.
  • the invention further relates to the use of a compound of the formula (I), or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and a composition thereof, or a prodrug thereof, for the preparation of a dipeptidyl peptidase-IV inhibitor.
  • the dipeptidyl peptidase-IV inhibitor is used for the preparation of a medicament for treating a metabolic disease, wherein the metabolic disease is selected from the group consisting of diabetes, diabetic retinopathy, and diabetic neuropathy. , diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, arteries Atherosclerosis or high blood pressure.
  • the diabetes is type II diabetes.
  • the present invention also relates to a method for treating a metabolic disease, which comprises administering an aminopyran ring derivative of the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, Or a pharmaceutical composition according to any of the inventions.
  • the metabolic diseases include diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevation of fatty acids or glycerol Level, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications, atherosclerosis or hypertension.
  • diabetes is type II diabetes.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention.
  • the nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C, and 14 C, and the hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen ), ⁇ (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes including 14 N and 15 N, the fluorine isotope 19 F, the chlorine isotope includes 35 Cl and 37 Cl, and the bromine isotopes include 79 Br and 81 Br.
  • Alkyl means a straight-chain or branched saturated aliphatic hydrocarbon group, and the main chain includes 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, further preferably 1 to 8 carbon atoms, more preferably The linear and branched groups of 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms, and most preferably 1 to 2 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl Base, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3 -hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3- Pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl , 5-methylhexyl, 2,2-dimethylpentyl, 2,2-
  • R a and R d are each independently selected from the group consisting of aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged, spiro, and cyclylene.
  • Alkoxy means an -O-alkyl group wherein alkyl is as defined above. Alkoxy groups may be substituted or unsubstituted, and alkoxy embodiments include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, undertiary Butoxy, sec-butoxy, n-pentyloxy and n-hexyloxy.
  • Alkoxyalkyl means an alkyl group attached to an alkoxy group.
  • the alkoxyalkyl group can be substituted or unsubstituted, non-limiting examples of which include methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxy , propoxyethyl, 2-propoxymethyl, butoxypropyl, tert-butoxyethyl, pentyloxyethyl, hexyloxyethyl, cyclopropoxymethyl, cyclopropyl Oxyethyl, cyclopropyloxypropyl and cyclohexyloxymethyl; when substituted, the substituent is preferably from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkane Oxyl, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano, isocyano,
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.
  • Alkenyl means an alkyl group as defined herein above containing at least one carbon-carbon double bond, preferably having from 2 to 20 carbon atoms, further preferably from 2 to 12 carbon atoms, more preferably 2 on the backbone Up to 8 carbon atoms, the alkenyl group may be substituted or unsubstituted.
  • Non-limiting examples include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentyl Alkenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1- Hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-decenyl, 3-decenyl, 1- Decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, 1,4-hexadiene, 3-
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.
  • Alkynyl means an alkyl group as defined herein above containing at least one carbon-carbon triple bond, preferably containing from 2 to 20 carbon atoms, further preferably from 2 to 8 carbon atoms, more preferably 2 on the backbone Alkynyl group up to 4 carbon atoms.
  • An alkynyl group can be substituted or unsubstituted.
  • Non-limiting examples include ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4- Pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl , 3-octynyl, 3-decynyl, 4-decynyl, 3-undynyl and 4-dodecynyl, etc.; when substituted, the substituent is preferably one or more of the following groups , independently selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano, isocyano,
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.
  • Alkylthio means -S-alkyl or -S-(unsubstituted cycloalkyl), and non-limiting examples include methylthio, ethylthio, propylthio, butylthio and the like.
  • Halogen means fluorine, chlorine, bromine, or iodine.
  • Niro means -NO 2 .
  • Haloalkyl means a halogen-substituted alkyl group as defined herein above, and non-limiting examples include monofluoromethyl, difluoromethyl, trifluoromethyl, monobromomethyl, dibromomethyl, tribromo.
  • Mercaptan refers to a hydrocarbon in which one or more hydrogen atoms in the alkyl group are replaced by a thiol group, and non-limiting examples include methyl mercaptan, ethanethiol, 1,2-dithiol.
  • Hydroxyalkyl means that the alkyl group is substituted by one or more hydroxyl groups, preferably by 1, 2 or 3 hydroxyl groups, and the alkyl group is preferably a lower alkyl group.
  • Non-limiting examples include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl, and 2,3-dihydroxypropyl, and the like.
  • Cycloalkyl means a saturated or unsaturated non-aromatic ring group which may be substituted or unsubstituted, and the ring carbon atom includes 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, further preferably 3 to 8 Carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexene A group, a cycloheptenyl group, a 1,5-cyclooctadienyl group, a 1,4-cyclohexadienyl group, a cycloheptatrienyl group, and the like.
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.
  • Heterocycloalkyl means a substituted or unsubstituted saturated or unsaturated and contains at least 1 to 5 non-aromatic rings selected from N, O or S heteroatoms, and the non-aromatic ring may be a 3 to 10 membered single Rings, 4 to 20 membered spiro, ring or bridged ring, and optionally substituted N, S in the heterocycloalkyl ring can be oxidized to various oxidation states. A 3- to 12-membered heterocyclic ring is preferred.
  • Non-limiting examples include oxiranyl, oxetanyl, oxearyl, oxetan, oxacyclohexyl, oxetanyl, aziridine, azetidin , azacyclopentyl, azacyclohexyl, azacyclopropenyl, 1,3 dioxocyclopentyl, 1,4-dioxocyclopentyl, 1,3-dioxocyclopentyl, 1, 3-Dioxocyclohexyl, 1,3-dithiocyclohexyl, azepanyl, morpholinyl, piperazinyl, pyridyl, furyl, thienyl, pyrrolyl, pyranyl, N-alkane Pyryryl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, thiomorpholiny
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.
  • Non-limiting examples include
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.
  • the ring atom contains 5 to 20 atoms, preferably 5 to 14 atoms, further preferably 5 to 12, and further preferably 5 to 10.
  • Non-limiting examples include And adamantane.
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.
  • Benzyl refers to -CH 2 - phenyl, substituted or unsubstituted of substituted, non-limiting examples include -CH 2 - phenyl and -CH 2 - p-methylphenyl and the like.
  • Aryl means a substituted or unsubstituted 6 to 14 membered cyclic aromatic group, including monocyclic aromatic groups and fused ring aromatic groups.
  • a 6 to 14 membered aromatic ring is preferred, and a 6 to 10 membered aromatic ring is further preferred, non-limiting examples of which include phenyl, naphthyl, ⁇ .
  • the aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.
  • the ring is further preferably 5 to 6 yuan.
  • heteroaryl groups include, but are not limited to, pyridinyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Piperidinyl, morpholine, thiomorpholine, 1,3-dithiane, benzimidazole, piperidinyl, benzimidazole, benzopyridine, pyrrolopyridine and the like.
  • the heteroaryl ring can be fused to an aryl, heterocycloalkyl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include
  • R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, carbonyl, ester, bridged ring, spiro or a cis- ring group.
  • Arylthio means an -S-aryl or -S-heteroaryl group as defined herein.
  • arylthio groups include, but are not limited to, phenylthio, pyridylthio, furylthio, thienylthio, and pyrimidinylthio, and the like.
  • silica refers to a group formed by the substitution of one or more hydrogen atoms in a silicon methane with an alkyl group, examples including, but not limited to, trimethylsilyl, triethylsilyl, tert-butyldimethyl Silyl and tert-butyldiphenylsilyl and the like.
  • single bond refers to a chemical single bond, such as "a single bond between A and B” means that there is a chemical single bond between A and B, namely: A-B.
  • alkyl group optionally substituted by F means that the alkyl group may, but need not, be substituted by F, indicating a case where the alkyl group is substituted by F and a case where the alkyl group is not substituted by F.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” refers to maintaining the biological effectiveness and properties of the free acid or free base, and the free acid is passed through a non-toxic inorganic or organic base. Or those salts obtained by reacting the free acid with a non-toxic inorganic or organic acid.
  • Carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound.
  • excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, Granules, lubricants, binders, disintegrators, and the like.
  • Prodrug means a compound that can be converted to a biologically active compound of the invention under physiological conditions or by solvolysis.
  • Prodrugs of the invention are prepared by modifying a phenolic group in the compound which can be removed by conventional procedures or in vivo to provide the parent compound.
  • prodrug of the invention is administered to a mammalian subject, the prodrug is cleaved to form free hydroxyl groups, respectively.
  • Examples of prodrugs include, but are not limited to, phenolic hydroxyl groups and phosphoric acid sodium salt derivatives of the compounds of the invention.
  • Certain of the compounds described herein can exist as tautomers with different hydrogen attachment points with the transfer of one or more double bonds.
  • keto-enol tautomers Both single tautomers and mixtures thereof are included within the scope of the compounds of the invention.
  • Tautomers within the scope of the compounds of the invention include, but are not limited to:
  • the compounds described herein may contain one or more asymmetric centers and may thus be racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereoisomers. presence.
  • Co-crystal or “eutectic” refers to a crystal in which an active pharmaceutical ingredient (API) and a cocrystal former (CCF) are combined by hydrogen bonding or other non-covalent bonds.
  • API active pharmaceutical ingredient
  • CCF cocrystal former
  • the pure state of API and CCF is solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-component eutectic formed by a neutral solid with a salt or solvate.
  • X Syndrome refers to conditions, diseases, and conditions of metabolic syndrome.
  • X Syndrome refers to conditions, diseases, and conditions of metabolic syndrome.
  • Effective dose refers to an amount of a compound that causes a physiological or medical translation of a tissue, system or subject, which amount is sought, and includes one or more of the conditions or conditions sufficient to prevent treatment when administered to a subject. The amount of a compound that occurs or reduces it to some extent.
  • Solvate means a compound of the invention or a salt thereof, which also includes a stoichiometric or non-stoichiometric amount of solvent bound by intermolecular non-covalent forces.
  • solvent is water, it is a hydrate.
  • IC50 refers to the half-inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.
  • the compounds of the present invention can be prepared by the following scheme:
  • intermediates I-A and I-B are reacted by reductive amination conditions to give intermediates I-C which are obtained by further removal of the amino protecting group to give the compound of formula (I).
  • the intermediate I-A can be prepared by referring to the documents WO2010056708 and US2007232676, the method of which is described as follows:
  • Ar, R 1 and V are as defined above, and P is an amino protecting group such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or 9-fluorenylmethoxycarbonyl (Fmoc).
  • P is an amino protecting group such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or 9-fluorenylmethoxycarbonyl (Fmoc).
  • Figure 1 is a 1 H- 1 H COSY spectrum of Compound 1.
  • Figure 2 is a 1 H- 1 H NOESY map of Compound 1.
  • Figure 3 is a 1 H- 1 H J-resolved spectrum of Compound 1.
  • Figure 4 is a 1 H- 1 H COSY spectrum of Compound 2.
  • Figure 5 is a 1 H- 1 H NOESY map of Compound 2.
  • Figure 6 is a 1H-1H J-resolved spectrum of Compound 2.
  • Figure 7 is a 1 H- 1 H COSY spectrum of Compound 3.
  • Figure 8 is a 1 H- 1 H NOESY map of Compound 3.
  • Figure 9 is a 1H-1H J-resolved spectrum of Compound 3.
  • Figure 10 is a 1 H- 1 H COSY spectrum of Compound 6.
  • Figure 11 is a 1 H- 1 H NOESY map of Compound 6.
  • Figure 12 is a 1H-1H J-resolved spectrum of Compound 6.
  • Figure 13 is a graph showing the effect of a single oral administration on DPP4 activity in ob/ob mice.
  • Figure 14 is a graph showing the results of the experiment of compound 3 on monkey plasma DPP-IV enzymatic screening.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • the NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR tetramethylsilane
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS tetramethylsilane
  • 1H NMR information is listed in the following format: chemical shift (multiple peaks (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), Number of protons).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorba x SB-C18 100x 4.6 mm).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon having a volume of about 2 L.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature.
  • the room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.
  • Dibenzylidene glycine ethyl ester 1A (50 g, 0.187 mol) was dissolved in methyl tert-butyl ether (300 mL) at room temperature to give propargyl besylate (44 g, 0.224 mol), tetrabutyl Ammonium bromide (6.1 g, 0.019 mol) was added to the reaction liquid, the temperature was raised to 50 ° C, and cesium carbonate (121.8 g, 0.374 mol) was added thereto, and the reaction was carried out at 50 ° C overnight.
  • reaction solution was filtered, and the filter cake was washed with methyl tert-butyl ether (40 mL ⁇ 2), and the organic phase was combined, and concentrated to a half volume by rotary distillation.
  • Hydrochloric acid solution (3 mol/L, 100 mL) was added, and the mixture was stirred at room temperature for 1 hour. The layers were separated, and the aqueous phase was extracted with methyl tert-butyl ether (70 mL ⁇ 2), and the aqueous phase was collected to obtain 1B.
  • the layers were allowed to stand, the aqueous phase was washed with methyl tert-butyl ether (80 mL ⁇ 2), the aqueous phase was adjusted to pH 3 with 3 mol/L hydrochloric acid solution, and extracted with methyl tert-butyl ether (100 mL ⁇ 2). The combined organic phases were washed with EtOAc EtOAc m.
  • 2,5-difluorobromobenzene (15.05g, 78mmol) was dissolved in dry toluene (50mL) under nitrogen, and the ice salt bath was cooled to below -10 °C.
  • Isopropylmagnesium chloride/lithium chloride tetrahydrofuran solution was added dropwise. (66 mL, 1.3 mol/L), kept stirring at about -10 ° C for 1 hour.
  • 1D (10 g, 39 mmol) was dissolved in dry tetrahydrofuran (100 mL), and added dropwise to the reaction mixture, maintaining the temperature at -10 ° C, and the reaction was carried out at room temperature for 4 hours.
  • Step 5 tert-Butyl ((1R,2S)-1-(2,5-difluorophenyl)-1-hydroxypentyl-4-yn-2-yl)carbamate (1F)
  • Step 7 tert-Butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-hydroxytetrahydro-2H-pyran-3-yl)carbamate (1H)
  • Step 8 tert-Butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-carbonyltetrahydro-2H-pyran-3-yl)carbamate (1I)
  • Step 9 tert-Butyl N-[(2R,3S)2-(2,5-difluorophenyl)-5-morpholine-3,4-dihydro-2H-pyran-3-yl]amino Formate (1J)
  • Step 10 tert-Butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-carbonyl-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl Carbamate (intermediate 1)
  • Petroleum ether / ethyl acetate (v / v) 10:1), obtained as a yellow solid.
  • the solid was added to a 7 mL tetrahydrofuran solution, and hydrochloric acid (3 mL, 1 mol/L) was added, and the mixture was stirred at room temperature for 3 hours.
  • the pH of the reaction mixture was adjusted to 7 with 2 mol/L sodium hydroxide solution, and extracted with ethyl acetate (30 mL ⁇ 3).
  • 2,3,5-trifluorobromobenzene (42.2g, 200mmol) was dissolved in dry toluene (130mL) under nitrogen, and the ice salt bath was cooled to below -10 °C. Isopropylmagnesium chloride/lithium chloride was added dropwise. A tetrahydrofuran solution (100 mL, 2.2 mol/L) was stirred at about -10 ° C for 1 hour. 1D (25.6 g, 100 mmol) was dissolved in dry tetrahydrofuran (250 mL), and added dropwise to the reaction mixture, maintaining the temperature at -10 ° C, and the reaction was carried out at room temperature for 4 hours.
  • Step 2 tert-Butyl ((1R,2S)-1-hydroxy-1-(2,4,5-trifluorophenyl)pentyl-4-yn-2-yl)carbamate (3B)
  • Step 4 tert-Butyl ((2R,3S)-5-hydroxy-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate (3D )
  • Step 5 tert-Butyl ((2R,3S)-5-carbonyl-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate (3E )
  • Step 6 tert-Butyl ((2R,3S)-5-morpholin-2-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran-3-yl) Carbamate (3F)
  • Step 7 tert-Butyl ((2R,3S)-5-carbonyl-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3 -based) carbamate (intermediate 3)
  • Step 3 tert-Butyl ((2R,3S,5R,6S)-5-(2-(cyclopropylsulfonyl)pyrrolo[3,4-c]pyrazole-5(2H,4H,6H) -yl)-2-(2,5-difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate (1c)
  • tert-Butyl intermediate 1 (305 mg, 0.77 mmol) and 2-(cyclopropylsulfonate)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole 1b (197 mg, 0.93 mmol) was added to 5 mL of toluene, and the mixture was exposed to an oil bath temperature of 140 ° C until the solvent was evaporated to dryness. The residue was cooled to room temperature under nitrogen atmosphere, redissolved in 1,2-dichloroethane (10 mL), and sodium tris(acetoxy)borohydride (650 mg, 3.08 mmol) and acetic acid (92.5 mg, 1.54 mmol), reacted at room temperature for 3 hours. The reaction mixture was diluted with EtOAc EtOAc EtOAc. It was separated and purified by silica gel column chromatography (EtOAc(EtOAc)
  • Step 4 (2R, 3S, 5R, 6S)-5-(2-(cyclopropylsulfonyl)pyrrolo[3,4-c]pyrazole-5(2H,4H,6H)-yl)- 2-(2,5-Difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine (Compound 1)
  • Step 3 tert-Butyl ((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-pyrrolo[3,4- c]pyrazole-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate (3c)
  • Step 3 tert-Butyl ((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(((R))-tetrahydrofuran-3-yl)sulfonyl) Pyrrolo[3,4-c]pyrazole-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate ( 5c)
  • the third step tert-butyl ((2R, 3S, 5R, 6S)-5-(2-(cyclopentylsulfonyl)pyrrolo[3,4-c]pyrazole-5 (2H, 4H, 6H )-yl)-2-(2,5-difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate (6c)
  • the compounds of the present invention have higher maximum concentrations and exposures, longer half-lives, and smaller clearance rates in rats compared to the positive control (Omarigliptin).
  • mice The hypoglycemic effect of the compounds of the present invention in mice was evaluated using an oral glucose tolerance test (OGTT).
  • the animals used were C57 mice, eight weeks old, male, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and the animal production certificate number: SCXK (Beijing) 2012-0001.
  • SCXK Beijing 2012-0001.
  • the test compound was formulated into a suspension of 1 mg/mL.
  • the drug was administered by intragastric administration at a dose of 10 mg/kg.
  • the blank control group was given a blank reagent.
  • the compound of the present invention has a significant hypoglycemic effect, and the blood glucose can be significantly reduced after a single oral administration in mice.
  • the test compound was formulated into a solution of 0.3 mg/mL, 1.0 mg/mL or 3.0 mg/mL with 0.5% CMC-Na.
  • the ob/ob mice from the Shanghai Institute of Medicine were fasted for 16 hours in advance, and could not help but be watered. The next day, they were evenly divided into 5 groups according to their body weight.
  • the test group was given different doses of the compound, and the control group was given a blank solvent at a volume of 10 mL/kg. Blood was then collected from the eyelids at 0h, 2h, 4h, 10h, 24h, 34h, 48h, 58h and 72h.
  • the experimental animals were SD rats, 8 weeks old, male, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and the animal production certificate number: SCXK (Beijing) 2012-0001. Rats after fasting were grouped by weight. The rats were given blood by eyelids, and the test compound was orally administered to the EDTA-2Na anticoagulation test group at a dose of 3.0 mg/kg; the control group was orally administered with a blank reagent. Blood was taken at different time points after administration. The blood sample was centrifuged at 2500 rpm for 15 min, and the plasma was taken out and stored at -20 °C.
  • the compound of the present invention can significantly inhibit the plasma DPPIV enzyme activity in rats, especially the duration of inhibition of plasma DPP-IV enzyme activity ⁇ 70% by compound 4 is significantly longer than that of the control compound.
  • the experimental animals were provided by the male beagle dog, Chengdu Dashuo Biotechnology Co., Ltd.
  • the fasted Beagle dogs are grouped by weight.
  • the test group was orally administered with a test compound at a dose of 10.0 mg/kg.
  • Blood was taken at different time points after administration, and EDTA-2Na was anticoagulated.
  • the blood sample was centrifuged at 2500 rpm for 15 min, and the plasma was taken out and stored at -20 °C.
  • the compounds of the present invention inhibit the activity of DPPIV enzyme in dogs plasma significantly longer than the control compounds, and have better long-term potential.
  • the experimental animals were rhesus monkeys of about 5 kg in healthy males, provided by Sichuan Plymei Biotechnology Co., Ltd.
  • the fasting rhesus monkeys are grouped by weight.
  • the test group was orally administered with a test compound at a dose of 10.0 mg/kg.
  • Blood was taken at different time points after administration, and EDTA-2Na was anticoagulated.
  • the blood sample was centrifuged at 2500 rpm for 15 min, and the plasma was taken out and stored at -20 °C.
  • the once-oral administration of the compound of the present invention can inhibit the activity of DPPIV enzyme in monkey plasma for more than 11 days, and has a very good long-term potential.

Abstract

通式（I）所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐、前药、含有该衍生物的药物组合物以及在制备二肽基肽酶IV（DPP-IV）抑制剂的医药上的用途，。

Description

氨基吡喃环衍生物及其组合物和应用 技术领域
本发明涉及一种氨基吡喃环衍生物及其组合物和应用，具体说涉及通式(I)所示氨基吡喃环衍生物或其可用药用的盐或其立体异构体及含有该衍生物或其可用药用的盐或其立体异构体的药物组合物，以及其作为治疗剂特别是作为二肽基肽酶IV(DPP-IV)抑制剂的用途。
背景技术
糖尿病是一个世界范围内的重大医疗问题，据国际糖尿病联盟(IDF)统计，2013年全球糖尿病患者人数已达3.82亿，全球医疗花费达5480亿美元，占全球医疗支出的11％。预计到2035年，与糖尿病相关的全球医疗花费将达到6273亿美元。胰岛素是将蔗糖、淀粉及其他食物转化为能量时所需的激素，糖尿病通常是由于自机体不能分泌或适当利用胰岛素而引起的。糖尿病通常被分为I型糖尿病(或胰岛素依赖型糖尿病,IDDM)和Ⅱ型糖尿病(或非胰岛素依赖型糖尿病,NIDDM)。最常见的糖尿病类型是Ⅱ型糖尿病，在世界范围内，Ⅱ型糖尿病约占所有糖尿病的90％。由于现代不健康的生活方式，如锻炼减少和高热量饮食等原因，Ⅱ型糖尿病的发病率呈逐渐增加的趋势。巨大的市场潜力吸引了大量的制药公司和研究中心开发新的抗糖尿病靶点和药物。
目前已批准的用于治疗Ⅱ型糖尿病上市的药物主要有胰岛素及其类似物、磺酰脲类、双胍类、噻唑烷二酮类(TZDs)、α-葡萄糖苷酶抑制剂、糊精类似物、肠促胰岛素激素类似物、二肽基肽酶抑制剂(DPP-IV)等。然而，患者长期服用这些降糖药仍不能达到预期的糖化血红蛋白(HbA1c)降低指标，而且这些降糖药均有副作用，如低血糖、体重增加和心血管风险等。这些副作用加重了糖尿病患者的负担。因此，迫切需要针对Ⅱ型糖尿病开发具有高效、副作用少的新型降糖药。
二肽基肽酶IV(Dipeptidyl Peptidase,DPP-IV,EC3.4.14.5)是一个丝氨酸蛋白酶，从含有L-脯氨酸和L-丙氨酸的多肽N端倒数第二位水解N端二肽。尽管DPP-IV的功能未被完全阐明，它被认为是某些调节多肽、神经肽、循环激素和趋化因子的主要生理性调节因子。尽管作为多效酶，DPP-IV有诸多底物，但最为人所知的是肠促胰素，它包括胰高血糖素样肽-1(GLP-1)和糖依赖性胰岛素释放肽(GIP)。肠促胰素是在摄入营养物的几分钟内分泌并促进摄入营养物的处置的肠道激素。GLP-1和GIP对β细胞的作用相同，可改善β细胞功能，包括促进葡萄糖依赖的胰岛素分泌、诱导β细胞增殖、增强抗凋亡作用(Diabetes and  Vascular Dis乙酸乙酯se Res乙酸乙酯rch 20063：159)。
与GIP不同，GLP-1在Ⅱ型糖尿病中仍是促进胰岛素分泌的，因此，提高GLP-1是一种有前景的治疗Ⅱ型糖尿病的手段(Pharmacol Rev 60:470–512,2008)。Ⅱ型糖尿病患者中使用GLP-1可明显降低血糖(Lancet，2002,359:824-830),然而GLP-1作为DPP-IV的底物在体内会迅速被水解而失活，因此研制DPP-Ⅳ抑制剂对治疗糖尿病具有非常重要的意义。
目前，DPP-IV抑制剂的研究取得了较大的进展，包括西他列汀、沙格列汀、阿格列汀在内的DPP-IV抑制剂已经批准上市，进入临床使用。DPP-IV抑制剂最显著的特点是，由于肠促胰岛素只在机体进食后分泌，DPP-IV抑制剂不易在不适当的时候增加胰岛素水平，产生许多降糖药共同的副作用低血糖。近期的临床数据已经显示，抑制DPP-IV可使胰岛素分泌增加，降低血糖浓度并改善胰岛beta细胞功能(Diabetes,1998,47:1253-1258)。常见的DPP-IV抑制剂的副作用有呼吸道感染、喉咙痛、腹泻、感冒样症状、头痛头晕等。但总体具有较好的安全性和耐受性，目前还没有发现使用的病人有严重的体重增加或者潜在的体重减少以及水肿等症状。近几年，长效DPP-IV抑制剂特别引人注目。长效DPP-IV抑制剂使用更方便，同时具备理想的降糖效果，这会使其在Ⅱ型糖尿病患者中更受欢迎。Ⅱ期临床数据显示，由默克公司开发的一周一次DPP-IV抑制剂Omarigliptin，可明显降低血糖。Trelagliptin是由武田制药有限公司开发的另一个一周一次DPP-IV抑制剂，该药的安全性和有效性在Ⅲ期临床中得到了确认，目前已在日本提交新药申请。
糖尿病(主要是Ⅱ型糖尿病)的发病率在全球范围内呈逐年增高趋势，成为继心血管疾病和肿瘤之后，第3位威胁人们健康和生命的非传染性疾病。糖尿病的治疗给家庭和社会带来了沉重的负担。因此，急需开发更多更新更好的DPP-IV抑制药物以满足广大患者临床用药的需要。
目前，关于DPP-IV抑制剂相关研究的文献被相继报道：
(1)US2007232676公布了如下结构的化合物作为DPP-IV抑制剂，其中：
Figure PCTCN2015078923-appb-000001
Ar选自被1-5个选自卤素、羟基、C1-6烷基等取代基取代的苯基；
V选自
Figure PCTCN2015078923-appb-000002
等基团，且R3a、R3b独立地选自氢、被1-5个氟原子取代的C1-4烷基；R2选自氢、羟基、卤素、羧基等基团；R8选自氢、-(CH2)p-苯基等基团，但无甲基磺酰基；不认为此专利中具体描述是本发明的一部分。
(2)US20100120863公布了如下结构的化合物作为二肽基肽酶IV(DPP-IV)抑制剂，在治疗、预防II型糖尿病的用途，其中：
Figure PCTCN2015078923-appb-000003
Ar选自氢、烷基等基团；
V选自
Figure PCTCN2015078923-appb-000004
等，且R3a、R3b选自独立地选自氢、被1-5个氟原子取代的C1-4烷基；R2选自氢、羟基、卤素、羧基等基团；R8选自-S(O)2-C1-6环烷基、-S(O)2-C1-6烷基等基团；不认为此专利中具体描述是本发明的一部分。
(3)WO2011103256公开了如下结构的化合物具有DPP-IV抑制剂作用，作为糖尿病的预防和/或治疗药的用途，其中：
Figure PCTCN2015078923-appb-000005
Ar为任选被1-5个独立地选自卤素、氰基、羟基等基团取代的苯基；
V选自
Figure PCTCN2015078923-appb-000006
等基团，且R2选自氢、羟基、氰基、卤素、烷基、烷氧基、羰基等基团；R3a、R3b选自氢或任选被1-5个氟原子取代的C1-4烷基；R8选自氢、烷基、芳基、环烷基、杂芳基、-SO2-C1-6烷基等基团；不认为此专利中具体描述是本发明的一部分。
(4)WO2007126745公布了DPP-IV抑制剂如下结构的化合物用于治疗糖尿病，其中：
Figure PCTCN2015078923-appb-000007
Ar选自取代或未取代的苯基，当取代时，苯基被1-3个选自卤素、羟基、C1-6烷基等取代；
V选自
Figure PCTCN2015078923-appb-000008
等基团，且R2选自氢、羟基、卤素、烯基、炔基、芳基、杂芳基等；R3a、R3b选自氢、被1-5个氟原子取代的C1-4烷基；R8 选自H、环烷基、苯基、烷基等基团；不认为此专利中具体描述是本发明的一部分。
还有WO2011103256、WO2008060488、WO2007087231、WO2011037793、WO2011028455、WO2009025784等也公开了有关DPP-IV抑制剂化合物用于糖尿病治疗。
发明内容
本发明的目的是介绍一类新型DPP-IV抑制剂，具体而言具有通式(I)所示的化合物，经研究表明，此类结构的化合物具有良好的二肽基肽酶IV(DPP-IV)抑制活性和选择性，具有用于治疗或缓解II型糖尿病及类似疾病的前景。
本发明涉及一种通式(I)的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药：
Figure PCTCN2015078923-appb-000009
其中：
V选自以下基团：
Figure PCTCN2015078923-appb-000010
Ar为0至5个R1基团取代的苯环，优选2,5-二氟苯基或2,4,5-三氟苯基；
R1选自H、F、Cl、Br、I、羟基、氰基、C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、-(CH2)m-C3-15环烷基、-(CH2)m-3至15元杂环烷基、-(CH2)m-C6-10芳基、-(CH2)m-6至10元杂芳基、-(CH2)m-C(＝O)-R5、-(CH2)m-NR6R7、-(CH2)m-C(＝O)-NR6R7、-(CH2)m-O-C(＝O)-NR6R7、-(CH2)m-S(＝O)n-R8、-(CH2)m-NR9-S(＝O)n-R8、-(CH2)m-NR9-C(＝O)-NR6R7或-(CH2)m-NR9-C(＝O)-R5，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至5个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或 C1-4烷氧基的取代基所取代，所述杂环烷基含有1至5个选自N、O或S(＝O)n的原子或基团；R1优选为H或F；
R2a和R2b各自独立选自H、F、Cl、Br、I、羟基、氰基、C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、-(CH2)m-C3-15环烷基、-(CH2)m-3至15杂环烷基、-(CH2)m-C6-10芳基、-(CH2)m-6至10元杂芳基、-(CH2)m-C(＝O)-R5、-(CH2)m-NR6R7、-(CH2)m-C(＝O)-NR6R7、-(CH2)m-O-C(＝O)-NR6R7、-(CH2)m-S(＝O)n-R8、-(CH2)m-NR9-S(＝O)n-R8、-(CH2)m-NR9-C(＝O)-NR6R7或-(CH2)m-NR9-C(＝O)-R5，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至3个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环烷基含有1至5个选自N、O或S(＝O)n的原子或基团；优选R2a和R2b各自独立选自H、C1-6烷基、-(CH2)m-C3-6环烷基或-(CH2)m-3至8元杂环烷基，其中所述烷基、环烷基或杂环烷基任选进一步被0至3个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环烷基含有1至3个选自N、O或S(＝O)n的原子或基团；进一步优选，R2b选自H，R2a选自H、C1-6烷基或-(CH2)m-C3-6环烷基，其中所述烷基或环烷基任选进一步被0至3个选自F、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；
R3a和R3b各自独立选自H、F、Cl、Br、I、羟基、氰基或C1-8烷基，其中所述烷基任选进一步被0至5个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；R3a和R3b各自独立优选自H或C1-2烷基，其中所述烷基任选进一步被0至3个选自F、羟基或C1-4烷氧基的取代基所取代；进一步优选，R3a和R3b各自独立选自H；
R4a和R4b各自独立选自H、F、Cl、Br、I、羟基、氰基或C1-8烷基，其中所述烷基任选进一步被0至5个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代，且R4a和R4b不同时为H；
R4选自H、氰基、C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、-(CH2)m-C3-15环烷基、-(CH2)m-3至15元杂环烷基、-(CH2)m-C6-10芳基、-(CH2)m-6至10元杂芳基、-(CH2)m-C(＝O)-R5、-(CH2)m-NR6R7、-(CH2)m-C(＝O)-NR6R7、-(CH2)m-O-C(＝O)-NR6R7、-(CH2)m-S(＝O)n-R8、-(CH2)m-NR9-S(＝O)n-R8、-(CH2)m-NR9-C(＝O)-NR6R7或-(CH2)m-NR9-C(＝O)-R5，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至3个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环烷基含有1至5个选自N、O或S(＝O)n的原子或基团；R4优选自H或-(CH2)m-S(＝O)n-R8；进一步优选为-S(＝O)2-CH3；
R5选自羟基、C1-8烷基、C1-8烷氧基、C3-15环烷基、C6-10芳基、6至10元杂芳基、-O-C3-15环烷基、-O-C6-10芳基或-O-(6至10元杂芳基)，优选C1-8烷基或C1-8烷氧基，进一步优选 C1-8烷氧基；
R6、R7和R9各自独立选自H、C1-8烷基、C3-15环烷基、C6-10芳基、6至10元杂芳基或3至15元杂环烷基；优选各自独立选自H或C1-8烷基；
R8选自C1-8烷基、C3-15环烷基、C6-10芳基、6至10元杂芳基或3至15元杂环烷基；优选C1-8烷基、C3-15环烷基或3至15元杂环烷基，进一步优选C1-8烷基；其中所述烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至5个F所取代，所述杂环烷基或杂芳基含有1至5个选自N、O或S(＝O)n的原子或基团；
m选自0、1或2，优选0或1，进一步优选0；
n选自0、1或2，优选0或2，进一步优选2。
本发明优选方案，包括通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中：
R1选自H或F；
R2a和R2b各自独立地选自H、C1-6烷基、C3-6环烷基或3至8元杂环烷基，其中所述烷基、环烷基或杂环烷基任选进一步被0至3个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环烷基含有1至3个选自N、O或S(＝O)2的原子或基团；R2a和R2b各自独立地优选H、C1-6烷基或C3-6环烷基，其中所述烷基或环烷基任选进一步被0至3个选自F、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；
R3a和R3b各自独立选自H或C1-2烷基，其中所述烷基任选进一步被0至3个选自F、羟基或C1-4烷氧基的取代基所取代；各自独立地优选H；
R4选自H或-S(＝O)2-R8，优选-S(＝O)2-R8；
R8选自C1-6烷基、C3-6环烷基、C6-10芳基、6至10元杂芳基或3至8元杂环烷基，优选C1-2烷基、4至6元杂环烷基或C3-6环烷基，进一步优选C1-2烷基，其中所述烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至5个F所取代，所述杂环烷基或杂芳基含有1至5个选自N、O或S(＝O)2的原子或基团。
本发明优选方案，包括通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中：
V选自以下基团：
Figure PCTCN2015078923-appb-000011
Ar选自2,5-二氟苯基或2,4,5-三氟苯基；
R2a选自H、C1-6烷基或C3-6环烷基，其中所述烷基或环烷基任选进一步被0至3个选自F、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；优选H、C1-2烷基或-C3-6环烷基，其中所述烷基或环烷基任选进一步被0至3个选自F、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；
R3a和R3b各自独立选自H或C1-2烷基，其中所述烷基任选进一步被0至3个选自F、羟基或C1-4烷氧基的取代基所取代；各自独立优选H；
R4为-S(＝O)2-R8，优选为-S(＝O)2-CH3；
R8选自C1-2烷基、3至6元杂环烷基或C3-6环烷基，其中所述烷基、杂环烷基或环烷基任选进一步被0至5个F所取代，所述杂环烷基含有1至3个选自N、O或S(＝O)2的原子或基团。
本发明优选方案，包括通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中：
R2a选自H、C1-2烷基或-C3-6环烷基，其中所述烷基或环烷基任选进一步被0至3个选自F、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；R2a优选H或C1-2烷基，其中所述烷基任选进一步被0至3个选自F、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；R2a进一步优选H或者甲基。
本发明优选方案，包括通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中：
V选自
Figure PCTCN2015078923-appb-000012
Ar为2,5-二氟苯基或2,4,5-三氟苯基；
R2a选自H、C1-6烷基或C3-6环烷基，其中所述烷基或环烷基任选进一步被0至3个选自F、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；优选H、C1-2烷基或-C3-6环烷基，其中所述烷基或环烷基任选进一步被0至3个选自F、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；
R3a和R3b各自独立选自H或C1-2烷基，其中所述烷基任选进一步被0至3个选自F、羟基或C1-4烷氧基的取代基所取代；各自独立优选H；
R4为-S(＝O)2-R8，优选为-S(＝O)2-CH3；
R8选自C1-2烷基、3至6元杂环烷基或C3-6环烷基，其中所述烷基、杂环烷基或环烷基任选进一步被0至5个F所取代，所述杂环烷基含有1至3个选自N、O或S(＝O)2的原子或基团。
本发明优选方案，包括通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中：
V选自
Figure PCTCN2015078923-appb-000013
Ar为2,5-二氟苯基或2,4,5-三氟苯基；
R2a选自H、C1-6烷基或C3-6环烷基，其中所述烷基或环烷基任选进一步被0至3个选自F、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；优选H、C1-2烷基或-C3-6环烷基，其中所述烷基或环烷基任选进一步被0至3个选自F、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；
R3a和R3b各自独立选自H或C1-2烷基，其中所述烷基任选进一步被0至3个选自F、羟基或C1-4烷氧基的取代基所取代；各自独立优选H；
R4为-S(＝O)2-R8；
R8选自C1-2烷基、4至6元杂环烷基或C3-6环烷基，其中所述烷基、杂环烷基或环烷基任选进一步被0至5个F所取代，所述杂环烷基含有1至3个选自N、O或S(＝O)2的原子或基团。
本发明优选方案，包括通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中：
R8选自甲基、乙基、
Figure PCTCN2015078923-appb-000014
环丙基、环丁基或者环戊基，优选甲基，且所述的基团任选进一步被0至5个F所取代。
本发明优选方案，包括通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中：
R8选自甲基、乙基、
Figure PCTCN2015078923-appb-000015
环丙基、环丁基或者环戊基。
本发明优选方案，包括通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中：
V选自
Figure PCTCN2015078923-appb-000016
Ar为2,5-二氟苯基或2,4,5-三氟苯基；
R2a选自H、C1-6烷基或C3-6环烷基，其中所述烷基或环烷基任选进一步被0至3个选 自F、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；优选H、C1-2烷基或-C3-6环烷基，其中所述烷基或环烷基任选进一步被0至3个选自F、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；
R3a和R3b各自独立选自H或C1-2烷基，其中所述烷基任选进一步被0至3个选自F、羟基或C1-4烷氧基的取代基所取代；各自独立优选H；
R4为-S(＝O)2-R8；
R8选自甲基、乙基、
Figure PCTCN2015078923-appb-000017
环丙基、环丁基或者环戊基。
本发明优选方案，包括通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中该氨基吡喃环衍生物选自：
Figure PCTCN2015078923-appb-000018
优选
Figure PCTCN2015078923-appb-000019
进一步优选
Figure PCTCN2015078923-appb-000020
本发明优选方案，本发明涉及化合物选自，但不限于：
Figure PCTCN2015078923-appb-000021
Figure PCTCN2015078923-appb-000022
Figure PCTCN2015078923-appb-000023
优选
Figure PCTCN2015078923-appb-000024
进一步优选
Figure PCTCN2015078923-appb-000025
本发明还涉及一种药物组合物，所述的组合物包括：有效剂量的根据本发明前面任一项所述通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，以及药学上可接受的载体或赋形剂。
本发明还涉及通式(I)所述的化合物或其立体异构体、药学上可接受的盐及其组合物或其前药在制备二肽基肽酶-IV抑制剂中的应用。
根据本发明所述的应用，其中所述的二肽基肽酶-IV抑制剂用于制备治疗代谢性疾病的药物，其中所述的代谢性疾病选自糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性、高血糖、高胰岛素血症、脂肪酸或甘油的升高的水平、高脂血症、肥胖症、高甘油三脂血症、X综合症、糖尿病并发症、动脉粥样硬化或高血压。
根据本发明所述的应用，所述的糖尿病为II型糖尿病。
本发明还涉及一种治疗代谢性疾病的方法，所述方法包括给药通式(I)所述的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，或本发明任意所述的药物组合物。
根据本发明所述的方法，其中所述的代谢性疾病包括糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性、高血糖、高胰岛素血症、脂肪酸或甘油的升高的水平、高脂血症、肥胖症、高甘油三脂血症、X综合症、糖尿病并发症、动脉粥样硬化或高血压。
根据本发明所述的方法，其中所述的糖尿病为II型糖尿病。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括12C、13C和14C，氢的同位素包括氕(H)、氘(D，又称为重氢)、氚(T，又称为超重氢)，氧的同位素包括16O、17O和18O，硫的同位素包括32S、33S、34S和36S，氮的同位素包括14N和15N，氟的同位素19F，氯的同位素包括35Cl和37Cl，溴的同位素包括79Br和81Br。
“烷基”是指直链和支链的饱和脂肪族烃基团，主链包括1至20个碳原子，优选为1至12个碳原子，进一步优选为1至8个碳原子，更优选为1至6个碳原子，再进一步优选1至4个碳原子的直链与支链基团，最优选1至2个碳原子。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,2-二甲基己基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基和正癸基等。烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，取代基优选为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb 与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基、并环基。
“烷氧基”是指-O-烷基，其中烷基如本文上述定义。烷氧基可以是取代的或未取代的，烷氧基实施例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基和正己氧基等。当被取代时，取代基优选为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环烷基Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“烷氧基烷基”指与烷氧基相连的烷基。烷氧基烷基可以是取代的或未取代的，其非限制性实施例包括，甲氧基甲基、甲氧基乙基、乙氧基甲基、乙氧基乙基、丙氧基甲基、丙氧基乙基、2-丙氧基甲基、丁氧基丙基、叔丁氧基乙基、戊氧基乙基、己氧基乙基、环丙氧基甲基、环丙氧基乙基、环丙氧基丙基和环己氧基甲基；当被取代时，取代基优选为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“烯基”是指至少含一个碳-碳双键组成的如本文上述定义的烷基，优选含有2至20个碳原子，进一步优选2至12个碳原子，更优选在主链上有2至8个碳原子，烯基可以是取代的或未取代的。非限制性实施例包括乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯、1,4- 己二烯、3-十一烯基、4-十二烯基和4,8,12-十四碳三烯基等。当被取代时，取代基为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“炔基”是指包含至少一个碳-碳三键组成的如本文上述定义的烷基，优选含有2至20个碳原子，进一步优选2至8个碳原子，更优选在主链上有2至4个碳原子的炔基。炔基可以是取代的或未取代的。非限制性实施例包括乙炔基、1-丙炔基、2-丙炔基、丁炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、4-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-己炔基、3-己炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基、4-癸炔基、3-十一炔基和4-十二炔基等；当被取代时，取代基优选为一个或多个以下基团，独立地选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“氨基”是指-NH2，可以是取代的或未取代的，当被取代时，取代基优选为1至3个以下基团，独立地选自烷基、环烷基、卤代烷基、硫醇、羟基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“烷硫基”是指-S-烷基或-S-(未被取代环烷基)，非限制性实施例包括甲硫基、乙硫基、丙硫基和丁硫基等。
“酰基”或“羰基”是指-C(＝O)-Ra基团，其中Ra如上文定义。
“醛”是指-C(＝O)-H。
“卤素”是指氟、氯、溴、碘。
“羟基”是指-OH。
“氰基”是指-C≡N。
“异氰基”是指-N≡C。
“硝基”是指-NO2。
“羧酸”是指-C(＝O)-OH。
“羧酸酯”是指-C(＝O)-O-Rd，Rd选自烷基、环烷基或杂环烷基。
“卤代烷基”是指卤素取代的如本文上述定义的烷基，非限制性实施例包括一氟甲基、二氟甲基、三氟甲基、一溴甲基、二溴甲基、三溴甲基、1-氟乙基-2-基、2-氟乙基-2-基、1,1-二氟乙基-2-基、1,2-二氟乙基-2-基、1,1,1-氟乙基-2-基、1-溴乙基-2-基、2-溴乙基-2-基和1,1,1-三溴乙基-2-基等。
“巯基”是指-SH。
“硫醇”是指烷基中的一个或多个氢原子被巯基取代的烃，非限制性实施例包括甲硫醇、乙硫醇、1,2-二硫醇。
“硫酰基”或“硫代羰基”是指-C(＝S)-Ra基团，其中Ra如上文定义。
“羟烷基”是指烷基被一个或多个羟基取代，优选为被1、2或3个羟基取代，烷基优选为低级烷基。非限制性实施例包括羟甲基、2-羟乙基、1-羟乙基、1,2-二羟基丙基、1,3-二羟基丙基和2,3-二羟基丙基等。
“环烷基”是指饱和或不饱和的非芳香环基，可以是取代的或未取代的，环碳原子包括3至20个碳原子，优选3至10个碳原子，进一步优选3至8个碳原子，非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、1,5-环辛二烯基、1,4-环己二烯基和环庚三烯基等。当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、 三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“杂环烷基”是指取代的或未取代的饱和或者不饱和且至少含有1至5个选自N、O或S杂原子的非芳香环，非芳香环可以是3至10元的单环，4至20元的螺环、并环或桥环，杂环烷基环中选择性取代的N、S可被氧化成各种氧化态。优选3至12元杂环。非限制性实施例包括氧杂环丙烷基、氧杂环丁基、氧杂环戊基、氧杂环己基、氧杂环己基、氧杂环辛基、氮杂环丙烷基、氮杂环丁基、氮杂环戊基、氮杂环己基、氮杂环丙烯基、1,3二氧环戊基、1,4-二氧环戊基、1,3-二氧环戊基、1,3-二氧环己基、1,3-二硫环己基、氮杂环庚烯基、吗啉基、哌嗪基、吡啶基、呋喃基、噻吩基、吡咯基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、硫代吗啉基、二氢吡喃、噻二唑基、噁唑基、噁二唑基、吡唑基、1,4-二氧杂环己二烯基、
Figure PCTCN2015078923-appb-000026
等。当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“螺环”是指取代的或未取代的单环之间共用一个碳原子(称螺原子)的5至20元多环基团，其可以包含0至5个双键，且可以含有0至5个选自N、O或S(＝O)n的杂原子。优选为6至14元，进一步优选为6至12元，更有选6至10元，其非限定性实例包括
Figure PCTCN2015078923-appb-000027
当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“并环”是指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的多环基团，其中一个或多个环可以含有0个或多个双键，且可以是取代的或未取代，并环体系中的各个环可以含0至5个选自N、S(＝O)n或O的杂原子。优选为5至20元，进一步优选为5至14元，更有选5至12元，再进一步优选5至10元。非限定性实例包括
Figure PCTCN2015078923-appb-000028
当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(＝O)-Ra、 -O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“桥环”是指任意两个不直接连接的碳原子的多环基团，可以含有0个或多个双键，且可以是取代的或未取代的，并环体系中的任意环可以含0至5个选自N、S(＝O)n或O杂原子或基团(其中n为1、1、2)。环原子包含5至20个原子，优选为5至14个原子，进一步优选5至12个，在进一步优选5至10个。非限定性实例包括
Figure PCTCN2015078923-appb-000029
和金刚烷。当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“苄基”是指-CH2-苯基，所述苯基为取代的或未取代的，其非限制性实施例包括-CH2-苯基和-CH2-对甲基苯基等。
“芳基”是指取代的或未取代的6至14元环状芳香基团，包括单环芳香基和稠环芳香基。优选6至14元芳香环，进一步优选6至10元芳香环，其非限制性实例包括苯基、萘基、 蒽基和菲基等。所述芳基环可以稠合于杂芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含：
Figure PCTCN2015078923-appb-000030
当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“杂芳基”是指取代或未取代的5至14元芳香环，且含有1至5个选自N、O或S(＝O)n杂原子或基团，优选5至10元杂芳香环，进一步优选5至6元。杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉、硫代吗啉、1,3-二噻烷、苯并咪唑、哌叮基、苯并咪唑、苯并吡啶、吡咯并吡啶等。所述杂芳基环可以稠合于芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含
Figure PCTCN2015078923-appb-000031
当被取代时，取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“芳基硫基”是指如本文定义的-S-芳基或-S-杂芳基。芳基硫基实例包括但不限于苯硫基、吡啶基硫基、呋喃基硫基、噻吩基硫基和嘧啶基硫基等。
“硅烷基”是指硅甲烷中的一个或多个氢原子被烷基取代所形成的基团，实施例包括但不限于三甲基硅基、三乙基硅基、叔丁基二甲基硅基和叔丁基二苯基硅基等。
术语“单键”是指化学单键，例如“A与B之间为一个单键”表示A与B之间存在一个化学单键，即：A-B。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。
“药学上可接受的盐”或“其药学上可接受的盐”指的是保持游离酸或游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或有机碱，或所述的游离酸通过与无毒的无机酸或有机酸反应获得的那些盐。
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。
“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。
“前药”是指可以在生理条件下或通过溶剂解转化为具有生物活性的本发明化合物的化合物。本发明的前药通过修饰在该化合物中的酚基团来制备，该修饰可以按常规的操作或在体内被除去，而得到母体化合物。当本发明的前体药物被施予哺乳动物个体时，前体药物被割裂而分别形成游离的羟基。前药的例子包括，但不限于本发明化合物的酚羟基和磷酸成钠盐衍生物。
某些本文所述的化合物可以作为互变异构体存在，伴随着一个或多个双键的转移，具有不同的氢连接点。例如酮-烯醇互变异构体。单一互变异构体及其混合物都包括在本发明化合物的范围。本发明化合物范围内的互变异构体包括但不限于：
Figure PCTCN2015078923-appb-000032
本文所述化合物可以含有一个或多个不对称中心，并且由此可以以外消旋物、外消旋混合物、单一对映异构体、非対映异构体混合物和单一非対映异构体存在。
本文所述某些化合物含有双键，除非另有说明，包含E和Z几何构体。
“共晶体”或“共晶”是指活性药物成分(active pharmaceutical ingredient,API)和共晶形成物(cocrystal former,CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或溶剂化物形成的多元共晶。
“X综合症”是指代谢综合症的病症、疾病和疾患。详细描述见Johannsson J.Clin.Endocrinol.Metab.,1997,82,727-734。
“有效剂量”指引起组织、系统或受试者生理或医学翻译的化合物的量，此量是所寻求的，包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。
“溶剂化物”指本发明化合物或其盐，它们还包括以分子间非共价力结合的化学计量或非化学计量的溶剂。当溶剂为水时，则为水合物。
“IC50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。
本发明化合物的合成方法：
为了完成本发明的目的，本发明化合物可以由以下方案制备而得：
方案一：
Figure PCTCN2015078923-appb-000033
中间体I-A和I-B通过还原氨基化条件反应得到中间体I-C，中间体I-C再通过脱除氨基保护基得到通式(I)化合物。
中间体I-A可以参考专利WO2010056708、US2007232676文献制备，其方法描述如下：
Figure PCTCN2015078923-appb-000034
Figure PCTCN2015078923-appb-000035
其中，Ar、R1和V如上文所定义，P为氨基保护基，比如叔丁氧基羰基(Boc)、苄氧基羰基(Cbz)或9-芴基甲氧基羰基(Fmoc)。
附图说明
图1是化合物1的1H-1H COSY图谱。
图2是化合物1的1H-1H NOESY图谱。
图3是化合物1的1H-1H J-分辨谱。
图4是化合物2的1H-1H COSY图谱。
图5是化合物2的1H-1H NOESY图谱。
图6是化合物2的1H-1H J-分辨谱。
图7是化合物3的1H-1H COSY图谱。
图8是化合物3的1H-1H NOESY图谱。
图9是化合物3的1H-1H J-分辨谱。
图10是化合物6的1H-1H COSY图谱。
图11是化合物6的1H-1H NOESY图谱。
图12是化合物6的1H-1H J-分辨谱。
图13是单次口服给药对ob/ob小鼠DPP4活性的影响。图14是化合物3对猴血浆DPP-IV酶学筛选实验结果曲线图。
具体实施方式
以下结合附图及实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。
NMR位移(δ)以10-6(ppm)的单位给出。
NMR的测定是用(Bruker ADVANCE III 400)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)，1HNMR信息以下列格式来列表：化学位移(多重峰(s,单峰；d,双重峰；t,三重峰；q,四重峰；m,多重峰),质子数)。
MS的测定用(Agilent 6120B(ESI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorba x SB-C18 100x 4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
无特殊说明，三乙胺、甲基叔丁基醚、水合联氨、四丁基溴化铵、二氯亚砜、咪唑、氢化钠、三苯基磷、三氟乙酸购买于成都市科龙化工试剂厂；二碳酸二叔丁基酯、N,N'-二羰基二咪唑、N,N-二甲基甲酰胺二甲基缩醛、N,O-二甲基羟胺盐酸盐、顺式-4-羟基-D-脯氨酸盐酸盐购买于爱斯特(成都)医药技术有限公司；碳酸铯、硼氢化锂、叔丁基二甲基氯硅烷、N-羟基丁二酰亚胺、二(三甲基硅基)氨基钠、二苯亚甲基甘氨酸乙酯、反式-L-羟基脯氨酸购买于安耐吉化学；戴斯马丁购买于上海泰坦科技股份有限公司；三氟甲磺酸甲酯、2,5-二氟溴苯、S-(三氟甲基)二苯并噻吩三氟甲基磺酸盐购买于上海德默医药科技有限公司；2-碘丙烷购买于上海毕得医药科技有限公司；异丙基氯化镁/氯化锂四氢呋喃溶液购买于百灵威科技有限公司；炔丙基苯磺酸酯、四丁基氟化铵、三(乙酰氧基)硼氢化钠、四丁基六氟磷酸铵购买于阿达玛斯试剂公司；环戊二烯基双(三苯基膦)氯化钌(II)购买于ACROS orgainics；硼烷二甲硫醚购买于韶远化学科技(上海)有限公司；四氢呋喃-3-磺酰基氯购买于南京康满林化工实业有限公司；过硼酸钠购买于天津光复精细化工研究所；[(R,R)-N-(2-氨基-1,2-二苯乙基)五氟苯磺酰胺]氯化(对伞花烃)钌(II)购买于Strem chemical；碘甲烷、甲基磺酰氯购买于国药集团药业股份有限公司。
氮气氛是指反应瓶连接一个约1L容积的氮气气球。
氢气氛是指反应瓶连接一个约2L容积的氢气气球。
氢化反应通常抽真空，充入氢气，反复操作3次。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温。
室温为最适宜的反应温度，为20℃～30℃。
中间体1：叔丁基((2R,3S)-2-(2,5-二氟苯基)-5-羰基-6-(三氟甲基)四氢-2H-吡喃-3-基)氨基甲酸酯(中间体1)
tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate
Figure PCTCN2015078923-appb-000036
第一步：2-氨基-4-炔戊酸乙酯(1B)
ethyl 2-aminopent-4-ynoate
室温下，将二苯亚甲基甘氨酸乙酯1A(50g,0.187mol)溶于甲基叔丁基醚(300mL)中，将炔丙基苯磺酸酯(44g,0.224mol)、四丁基溴化铵(6.1g,0.019mol)加至反应液中，升温至50℃，加入碳酸铯(121.8g,0.374mol)，于50℃温度下反应过夜。将反应液过滤，用甲基叔丁基醚(40mL×2)洗涤滤饼，合并有机相，旋蒸浓缩至一半体积，加入盐酸溶液(3mol/L,100mL)，室温下搅拌1小时，静置分层，水相用甲基叔丁基醚(70mL×2)萃取，收集水相，得到1B。
第二步：2-((叔丁氧羰基)氨基)-4-炔戊酸(1C)
2-((tert-butoxycarbonyl)amino)pent-4-ynoic acid
将氢氧化钠(33.7g,0.842mol)溶于水(100mL)，逐滴滴加至1B(26.4g,0.187mol)的反应液中，室温下搅拌2小时。将二碳酸二叔丁基酯(45g,0.206mol)溶于甲基叔丁基醚(125mL)，滴加至反应液中，室温下搅拌4小时。静置分层，水相用甲基叔丁基醚(80mL×2)洗涤，水相用3mol/L的盐酸溶液调节pH值至3，用甲基叔丁基醚(100mL×2)萃取，合并有机相，饱和氯化钠水溶液(30mL×2)洗涤，有机相中加入无水硫酸镁干燥，过滤，旋干，得到黄色油状液体1C(33g,产率83％)。
MS m/z(ESI)：212.0[M-1]。
第三步：叔丁基(1-(甲氧基(甲基)氨基)-1-羰基戊基-4-炔-2-基)氨基甲酸酯(1D)
tert-butyl(1-(methoxy(methyl)amino)-1-oxopent-4-yn-2-yl)carbamate
将1C(33g,0.155mol)溶于N,N-二甲基甲酰胺(200mL)中，控制温度小于10℃，将N,N'-羰基二咪唑(32.58g,0.201mol)加至反应液中，0℃下反应1小时。将N,O-二甲基羟胺盐酸盐(19.6g,0.186mol)加至反应液中，室温搅拌过夜。逐滴加入水(150mL)，搅拌1小时，用乙酸乙酯(100mL×2)萃取，合并有机相，用饱和碳酸氢钠溶液(60mL×3)、饱和氯化钠溶液(60mL×3)洗涤有机相，有机相中加入无水硫酸镁干燥。过滤，将滤液浓缩，用柱层析分离(石油醚/乙酸乙酯(v/v)＝10:1)，得到白色固体1D(35g,产率88.2％)。
MS m/z(ESI)：156.9[M-99]。
第四步：叔丁基(1-(2,5-二氟苯基)-1-羰基戊基-4-炔-2-基)氨基甲酸酯(1E)
tert-butyl(1-(2,5-difluorophenyl)-1-oxopent-4-yn-2-yl)carbamate
氮气保护下，将2,5-二氟溴苯(15.05g,78mmol)溶于干燥甲苯(50mL)，冰盐浴降温至-10℃以下，逐滴加入异丙基氯化镁/氯化锂四氢呋喃溶液(66mL,1.3mol/L)，保持在-10℃左右搅拌1小时。将1D(10g,39mmol)溶于干燥四氢呋喃(100mL)中，逐滴滴加至反应液中，保持温度-10℃，加毕，于室温下反应4小时。将温度降至-10℃左右，逐滴加入饱和氯化铵溶液(40mL)，搅拌10分钟，用3mol/L的盐酸溶液调节pH值至5～6，静置分层，水相用甲基叔丁基醚(50mL×2)萃取，合并有机相，用饱和氯化钠溶液(30mL×2)洗涤，有机相中加入无水硫酸钠干燥，过滤，浓缩，柱层析分离(石油醚/乙酸乙酯(v/v)＝50:1-8:1)，得到淡黄色固体1E(10.1g,产率83.5％)。
MS m/z(ESI)：210.1[M-99]。
第五步：叔丁基((1R,2S)-1-(2,5-二氟苯基)-1-羟基戊基-4-炔-2-基)氨基甲酸酯(1F)
tert-butyl((1R,2S)-1-(2,5-difluorophenyl)-1-hydroxypent-4-yn-2-yl)carbamate
将1E(16.07g,52mmol)溶于四氢呋喃(100mL)，加入三乙烯二胺(17.39g,155mmol)与[(R,R)-N-(2-氨基-1,2-二苯乙基)五氟苯磺酰胺]氯化(对伞花烃)钌(II)(即RuCl(p-cymene)(R,R)-FSDPEN)(0.37g,0.52mmol)，逐滴加入甲酸(14.27g,310mmol)，加毕，于40℃反应过夜。旋蒸掉反应液中的四氢呋喃和甲酸，加入水(60mL)、盐酸(3mol/L,10mL)，用甲基叔丁基醚(90mL×3)萃取，合并有机相，饱和碳酸氢钠溶液(35mL×2)洗涤，有机相中加入无水硫酸镁干燥，过滤，浓缩，柱层析分离(石油醚/乙酸乙酯(v/v)＝60:1-10:1)，得到淡黄色胶状物1F(15.37g,产率95％)。
MS m/z(ESI)：334.2[M+23]。
第六步：叔丁基((2R,3S)-2-(2,5-二氟苯基)-3,4-二氢-2H-吡喃-3-基)氨基甲酸酯(1G)
tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-3,4-dihydro-2H-pyran-3-yl)carbamate
将1F(15.37g,49.4mmol)加热条件下溶于N,N-二甲基甲酰胺(75mL)，加入四丁基六氟磷酸铵(2.49g,6.42mmol)、N-羟基丁二酰亚胺(2.84g,24.75mmol)、三苯基膦(0.86g,3.26mmol)、碳酸氢钠(2.16g,25.69mmol)，氮气置换三次，抽真空15分钟，加入环戊二烯基双(三苯基膦)氯化钌(II)(即CpRuCl(PPh3)2)(1.79g,2.47mmol)，氮气置换三次，并抽真空15分钟，氮气保护下，升温至85℃反应过夜。反应液中加入水(300mL)、甲基叔丁基醚(200mL)，用硅胶过滤，滤液静置分层，水相用甲基叔丁基醚(90mL×2)萃取，合并有机相，用饱和碳酸氢钠溶液(60mL×2)洗涤，有机相中加入无水硫酸钠干燥，过滤浓缩，柱层析分离(石油醚/乙酸乙酯(v/v)＝80:1-30:1)，得到淡黄色粉末固体1G(8.9g,产率57.9％)。
MS m/z(ESI)：256.2[M-55]。
第七步：叔丁基((2R,3S)-2-(2,5-二氟苯基)-5-羟基四氢-2H-吡喃-3-基)氨基甲酸酯(1H)
tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-5-hydroxytetrahydro-2H-pyran-3-yl)carbamate
将1G(8.9g,28.6mmol)溶解于干燥甲基叔丁基醚(90mL)中，加入干燥甲苯(9mL)，温度降至-10℃，逐滴加入硼烷二甲硫醚四氢呋喃溶液(2mol/L,35.9mL)，于0℃下反应3.5小时。缓慢加入水(4mL)，逐滴加入氢氧化钠溶液(1mol/L,89mL)，搅拌15分钟，分批加入过硼酸钠(13.2g,85.8mmol)，室温搅拌过夜。静置分层，水相用甲基叔丁基醚(50mL×2)萃取，合并有机相，饱和氯化钠溶液(20mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩，加入甲苯(50mL)，加热至90℃溶解，将正己烷(200mL)滴加至反应液中，析出白色固体，过滤，正己烷(30mL×2)洗涤滤饼，浓缩除去溶剂，得到白色固体粉末1H(7.9g，产率84％)。
MS m/z(ESI)：274.1[M-55]。
第八步：叔丁基((2R,3S)-2-(2,5-二氟苯基)-5-羰基四氢-2H-吡喃-3-基)氨基甲酸酯(1I)
tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)carbamate
将1H(11.53g,35.03mmol)溶解于二氯甲烷(130mL)，降温至0℃，将戴斯马丁氧化剂(29.72g,70.06mmol)分批加至反应液中，自然升至室温反应4小时。降温至0℃，将饱和碳酸氢钠溶液(60mL)滴加至反应液中，搅拌20分钟，过滤，滤液静置分层，水相用甲基叔丁基醚(60mL×3)萃取，合并有机相，用饱和碳酸氢钠溶液(30mL×2)洗涤，有机相中加入无水硫酸钠干燥，过滤浓缩，柱层析分离(石油醚/乙酸乙酯(v/v)＝10:1-4:1)，得到白色晶状粉末1I(10.85g,产率94.7％)。
MS m/z(ESI):272.0[M-55]；
1H NMR(400MHz,DMSO-d6)：δ7.29-7.13(m,4H),4.77–4.75(d,1H),4.22-4.02(m,3H), 2.75-2.70(m,2H),1.23(s,9H)。
第九步：叔丁基N-[(2R,3S)2-(2,5-二氟苯基)-5-吗啉-3,4-二氢-2H-吡喃-3-基]氨基甲酸酯(1J)
tert-butylN-[(2R,3S)-2-(2,5-difluorophenyl)-5-morpholino-3,4-dihydro-2H-pyran-3-yl]carbamate
将1I(2.5g,7.64mmol)加入到40mL甲苯溶液中，加入吗啉(1.30g,15.30mmol)，反应加热至回流，并用分水器分水，反应6小时。将反应液降至室温，析出固体，抽滤，甲苯洗涤，得白色固体1J(2.1g,收率70％)。
1H NMR(400MHz,DMSO-d6)：δ7.27–7.12(m,3H),6.89(d,1H),6.10(s,1H),4.55(d,1H),3.99–3.83(m,1H),3.61(t,4H),2.64(qd,4H),2.41–2.20(m,2H),1.27–1.10(m,9H)。
第十步：叔丁基((2R,3S)-2-(2,5-二氟苯基)-5-羰基-6-(三氟甲基)四氢-2H-吡喃-3-基)氨基甲酸酯(中间体1)
tert-butyl((2R,3S)-2-(2,5-difluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate
将1J(2.3g,5.80mmol)加入到30mL N,N-二甲基甲酰胺溶液中，再加入4-二甲氨基吡啶(0.070g,0.58mmol)，在无水无氧，氮气保护的条件下，加入S-(三氟甲基)二苯并噻吩三氟甲基磺酸盐(2.33g,5.80mmol)，0℃下反应2小时。向上述反应液中加入30mL水，用乙酸乙酯(30mL×3)萃取，有机层用饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩干，残留物用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝10:1)，得到的黄色固体。将其固体加入到7mL四氢呋喃溶液中，加入盐酸(3mL,1mol/L)，反应室温搅拌3小时。用2mol/L氢氧化钠溶液调节反应液pH值至7，用乙酸乙酯(30mL×3)萃取，有机层用饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩旋干，残留物用柱层析分离纯化(石油醚:乙酸乙酯(v/v)＝8:1)，得淡黄色固体中间体1(0.41g,产率18％)。
MS m/z(ESI):394.0[M-1]；
1H NMR(400MHz,DMSO-d6)：δ7.27(dd,4H),5.20(q,1H),5.07(d,1H),4.13(dd,1H),2.96(dd,1H),2.83(dd,1H),1.26–1.15(m,9H)。
中间体2：叔丁基4,6-二氢-2H-吡咯并[3,4-c]吡唑-5-甲酸酯(中间体2)
tert-butyl 4,6-dihydro-2H-pyrrolo[3,4-c]pyrazole-5-carboxylate
Figure PCTCN2015078923-appb-000037
第一步：叔丁基(3Z)-3-(二甲基氨基甲亚甲基)-4-氧代-吡咯-1-甲酸酯(2B)
tert-butyl(3Z)-3-(dimethylaminomethylene)-4-oxo-pyrrolidine-1-carboxylate
将1-叔丁氧羰基-3-吡咯烷酮2A(100g,0.54mol)溶于N,N-二甲基乙酰胺(600mL)中，加入N,N-二甲基甲酰胺二甲缩醛(83.6g,0.70mmol)，升温至105℃搅拌反应40分钟。用500mL水淬灭反应，乙酸乙酯(500mL×2)萃取反应液，用水(500mL×2)洗涤，有机相用无水硫酸钠干燥，浓缩，硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝4:1～1:1)，得到淡黄色液体状2B(50g,产率47％)。
第二步：叔丁基6a-羟基-1,3a,4,6-四氢吡咯并[3,4-c]吡唑-5-甲酸酯(2C)
tert-butyl 6a-hydroxy-1,3a,4,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carboxylate
将2B(50g,0.21mol)溶于甲醇(200mL)中，加入水合联氨(7.8g,0.16mmol)，室温下反应4小时，旋干有机溶剂直接进行下一步。
第三步：叔丁基4,6-二氢-2H-吡咯并[3,4-c]吡唑-5-甲酸酯(中间体2)
tert-butyl 4,6-dihydro-2H-pyrrolo[3,4-c]pyrazole-5-carboxylate
将上步反应得到的2C(47.5g,0.21mol)溶于二氯甲烷(300mL)和甲醇(180mL)的混合溶剂中，0℃下加入对甲苯磺酸(5.64g,0.029mmol)，反应过夜。将反应液溶剂旋干，用硅胶柱层析分离纯化(二氯甲烷)，得到淡黄色固体中间体2(20g,产率44％)。
1H NMR(400MHz,MeOD):δ7.44(d,1H),4.53–4.33(m,4H),1.54(s,9H)。
中间体3：叔丁基((2R,3S)-2-(2,3,5-三氟苯基)-5-羰基-6-(三氟甲基)四氢-2H-吡喃-3-基)氨基甲酸酯(中间体3)
tert-butyl((2R,3S)-2-(2,3,5-trifluorophenyl)-5-oxo-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate
Figure PCTCN2015078923-appb-000038
Figure PCTCN2015078923-appb-000039
第一步：叔丁基(1-羰基-1-(2,4,5-三氟苯基)戊基-4-炔-2-基)氨基甲酸酯(3A)
tert-butyl(1-oxo-1-(2,4,5-trifluorophenyl)pent-4-yn-2-yl)carbamate
氮气保护下，将2,3,5-三氟溴苯(42.2g,200mmol)溶于干燥甲苯(130mL)，冰盐浴降温至-10℃以下，逐滴加入异丙基氯化镁/氯化锂四氢呋喃溶液(100mL,2.2mol/L)，保持在-10℃左右搅拌1小时。将1D(25.6g,100mmol)溶于干燥四氢呋喃(250mL)中，逐滴滴加至反应液中，保持温度-10℃，加毕，室温下反应4小时。将温度降至-10℃左右，逐滴加入饱和氯化铵溶液(100mL)，搅拌10分钟，用3mol/L的盐酸溶液调节pH值至5～6，静置分层，水相用甲基叔丁基醚(150mL×2)萃取，合并有机相，用饱和氯化钠溶液(100mL×2)洗涤，有机相中加入无水硫酸钠干燥，过滤，浓缩，柱层析分离(石油醚/乙酸乙酯(v/v)＝50:1-8:1)，得到白色固体3A(27g,产率82.6％)。
第二步：叔丁基((1R,2S)-1-羟基-1-(2,4,5-三氟苯基)戊基-4-炔-2-基)氨基甲酸酯(3B)
tert-butyl((1R,2S)-1-hydroxy-1-(2,4,5-trifluorophenyl)pent-4-yn-2-yl)carbamate
将3A(27g,82.6mmol)溶于四氢呋喃(200mL)，加入三乙烯二胺(27.8g,248mmol)与[(R,R)-N-(2-氨基-1,2-二苯乙基)五氟苯磺酰胺]氯化(对伞花烃)钌(II)(即RuCl(p-cymene)(R,R)-FSDPEN)(0.57g,0.8mmol)，逐滴加入甲酸(22.8g,496mmol)，加毕，于40℃反应过夜。旋蒸除去反应液中的四氢呋喃和甲酸，加入水(120mL)、盐酸(3mol/L,20mL)，用甲基叔丁基醚(180mL×3)萃取，合并有机相，饱和碳酸氢钠溶液(70mL×2)洗涤，有机相中加入无水硫酸镁干燥，过滤，浓缩，柱层析分离(石油醚/乙酸乙酯(v/v)＝60:1-10:1)，得到白色固体3B(23.6g,产率87.4％)。
第三步：叔丁基((2R,3S)-2-(2,4,5-三氟苯基)-3,4-二氢-2H-吡喃-3-基)氨基甲酸酯(3C)
tert-butyl((2R,3S)-2-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran-3-yl)carbamate
将3B(23.6g,71.7mmol)加热条件下溶于N,N-二甲基甲酰胺(250mL)，加入四丁基六氟磷酸胺(3.6g,9.3mmol)、N-羟基丁二酰亚胺(4.1g,35.8mmol)、三苯基膦(1.24g,4.73mmol)、碳酸氢钠(3.13g,37.3mmol)，氮气置换三次，抽真空15分钟，加入环戊二烯基双(三苯基膦)氯化钌(II)(即CpRuCl(PPh3)2)(2.6g,3.58mmol)，氮气置换三次，并抽真空15分钟，氮气保护下，升温至85℃反应过夜。反应液中加入水(500mL)、甲基叔丁基醚(300mL)，用硅胶过滤，滤液静置分层，水相用甲基叔丁基醚(150mL×2)萃取，合并有机相，用饱和碳酸氢钠溶液(100mL×2)洗涤，有机相中加入无水硫酸钠干燥，过滤浓缩，柱层析分 离(石油醚/乙酸乙酯(v/v)＝80:1-30:1)，得到白色粉末固体3C(9.0g,产率38.1％)。
第四步：叔丁基((2R,3S)-5-羟基-2-(2,4,5-三氟苯基)四氢-2H-吡喃-3-基)氨基甲酸酯(3D)
tert-butyl((2R,3S)-5-hydroxy-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate
将3C(9.0g,27.4mmol)溶解于干燥甲基叔丁基醚(60mL)中，加入干燥甲苯(9mL)，温度降至-10℃，逐滴加入硼烷二甲硫醚四氢呋喃溶液(2mol/L,34.2mL)，于0℃下反应3.5小时。缓慢加入水(4mL)，逐滴加入氢氧化钠溶液(1mol/L,90mL)，搅拌15分钟，分批加入过硼酸钠(12.6g,82.2mmol)，室温搅拌过夜。静置分层，水相用甲基叔丁基醚(50mL×2)萃取，合并有机相，饱和氯化钠溶液(20mL×2)洗涤，有机相用无水硫酸钠干燥，过滤，浓缩，加入甲苯(50mL)，加热至90℃溶解，将正己烷(200mL)滴加至反应液中，析出白色固体，过滤，正己烷(30mL×2)洗涤滤饼，浓缩，得到白色固体粉末3D(8.6g,产率90.5％)。
第五步：叔丁基((2R,3S)-5-羰基-2-(2,4,5-三氟苯基)四氢-2H-吡喃-3-基)氨基甲酸酯(3E)
tert-butyl((2R,3S)-5-oxo-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate
将3D(8.6g,24.8mmol)溶解于二氯甲烷(100mL)，降温至0℃，将邻苯二甲酸二甲酯(21.1g,49.6mmol)分批加至反应液中，自然升至室温反应4小时。降温至0℃，将饱和碳酸氢钠溶液(50mL)滴加至反应液中，搅拌20分钟，过滤，滤液静置分层，水相用甲基叔丁基醚(50mL×3)萃取，合并有机相，用饱和碳酸氢钠溶液(30mL×2)洗涤，有机相中加入无水硫酸钠干燥，过滤，浓缩，柱层析分离(石油醚/乙酸乙酯(v/v)＝10:1～4:1)，得到白色晶状粉末3E(6.8g,产率80％)。
MS m/z(ESI):290.1[M-55]；
第六步：叔丁基((2R,3S)-5-吗啉-2-(2,4,5-三氟苯基)-3,4-二氢-2H-吡喃-3-基)氨基甲酸酯(3F)
tert-butyl((2R,3S)-5-morpholino-2-(2,4,5-trifluorophenyl)-3,4-dihydro-2H-pyran-3-yl)carbamate
将3E(6.8g,19.7mmol)加入到70mL甲苯溶液中，加入吗啉(6.8g,78.8mmol)，反应加热至138℃回流，并用分水器分水，反应6小时。将反应液降至室温，析出固体，抽滤，甲苯洗涤，得白色固体3F(6.7g,收率82％)。
MS m/z(ESI):415.1[M+1]；
第七步：叔丁基((2R,3S)-5-羰基-6-(三氟甲基)-2-(2,4,5-三氟苯基)四氢-2H-吡喃-3-基)氨基甲酸酯(中间体3)
tert-butyl((2R,3S)-5-oxo-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate
将3F(6.7g,16.2mmol)加入到N,N-二甲基甲酰胺(70mL)中，加入4-二甲氨基吡啶 (0.19g,1.62mmol)，在无水无氧，氮气保护的条件下，加入S-(三氟甲基)二苯并噻吩三氟甲基磺酸盐(6.5g,16.2mmol)，0℃下反应2小时。向上述反应液中加入水(200mL)，用乙酸乙酯(100mL×3)萃取，有机层用饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩干，残留物用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝10:1)，得到的黄色固体加入到70mL四氢呋喃中，加入盐酸(30mL,1mol/L)，室温搅拌反应3小时。用2mol/L氢氧化钠溶液调节反应液pH值至7，用乙酸乙酯(30mL×3)萃取，有机层用饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩旋干，残留物用柱层析分离纯化(石油醚:乙酸乙酯(v/v)＝8:1)，得淡黄色固体中间体3(3.0g,产率44％)。
1H NMR(400MHz,DMSO-d6):δ7.61-7.49(m,2H),7.31(d,1H),5.21-5.17(m,1H),5.05(d,1H),4.17-4.09(m,1H),2.99(dd,1H),2.85(dd,1H),1.22(s,9H)。
实施例1：
(2R,3S,5R,6S)-5-(2-(环丙基磺酰基)吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-2-(2,5-二氟苯基)-6-(三氟甲基)四氢-2H-吡喃-3-胺(化合物1)
(2R,3S,5R,6S)-5-(2-(cyclopropylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-2-(2,5-difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine
Figure PCTCN2015078923-appb-000040
第一步：叔丁基2-(环丙基磺酰基)-4,6-二氢吡咯并[3,4-c]吡唑-5-甲酸酯(1a)
tert-butyl 2-(cyclopropylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate
无水无氧处理，氮气保护，将中间体2(604mg,2.87mmol)溶解于四氢呋喃(20mL)中，降温至0℃，加入氢化钠(180mg,60wt％,4.5mmol)，搅拌30分钟，滴加入环丙基磺酰氯(1.27g,9.0mmol)，自然升温至室温下反应1小时。向反应液中加水(20mL)淬灭反应，用乙酸乙酯(20mL×2)萃取，合并有机层，无水硫酸钠干燥，浓缩，重新溶解于5mL四氢呋喃中，冷却至-10℃至0℃，加入叔丁醇钾(36mg,0.32mmol)，保持此温度下反应28小时。反应结束，加入柠檬酸水溶液(1mL,15％)，加入水(10mL)，用乙酸乙酯(20mL×3) 萃取，合并有机层，无水硫酸钠干燥，浓缩。残余物硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝2:1)，得到白色固体1a(660mg,产率73％)。
第二步：2-(环丙基磺酰基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑(1b)
2-(cyclopropylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole
将1a(645mg,2.06mmol)溶于二氯甲烷(8mL)中，加入三氟乙酸(8mL)，室温下反应2小时。将反应液旋干，加氨水(1mL)淬灭反应，用硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝10:1)，得到淡黄色固体1b(400mg,产率91％)。
1H NMR(400MHz,MeOD):δ7.85(s,1H),4.01-3.94(m,4H),3.36(s,3H)。
第三步：叔丁基((2R,3S,5R,6S)-5-(2-(环丙基磺酰基)吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-2-(2,5-二氟苯基)-6-(三氟甲基)四氢-2H-吡喃-3-基)氨基甲酸酯(1c)
tert-butyl((2R,3S,5R,6S)-5-(2-(cyclopropylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-2-(2,5-difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate
将叔丁基中间体1(305mg,0.77mmol)和2-(环丙基磺酸基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑1b(197mg,0.93mmol)加入到5mL甲苯中，在140℃油浴温度下敞口反应至溶剂蒸干。在氮气氛围中，剩余物冷却至室温，重新溶解于1,2-二氯乙烷(10mL)中，依次加入三(乙酰氧基)硼氢化钠(650mg,3.08mmol)和乙酸(92.5mg,1.54mmol)，室温下反应3小时。向反应液中加入饱和碳酸氢钠溶液(15mL)淬灭反应，分层，用乙酸乙酯(15mL×3)萃取水相，合并有机相，无水硫酸钠干燥，浓缩。硅胶柱层析(石油醚/乙酸乙酯(v/v)＝4:1)分离纯化，得到白色泡状固体1c(190mg,产率42％)。
第四步：(2R,3S,5R,6S)-5-(2-(环丙基磺酰基)吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-2-(2,5-二氟苯基)-6-(三氟甲基)四氢-2H-吡喃-3-胺(化合物1)
(2R,3S,5R,6S)-5-(2-(cyclopropylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-2-(2,5-difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine
将1c(190mg,0.32mmol)溶于二氯甲烷(4.5mL)和三氟乙酸(1.5mL)中，室温下搅拌1小时。向反应液中加入饱和碳酸氢钠水溶液(10mL)淬灭反应，分层，用乙酸乙酯(15mL×2)萃取水相。合并有机相，无水硫酸钠干燥，浓缩。硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝50:1)，得到白色粉末固体化合物1(126mg,产率80％)。
MS m/z(ESI):493.1[M+1]；
1H NMR(400MHz,DMSO-d6)δ7.98(m,1H),7.27(m,3H),4.81–4.68(qd,1H),4.50(d,1H),3.94(dd,2H),3.78(dd,2H),3.46(m,1H),3.11–3.04(m,1H),3.03–2.94(ddd,1H),2.37–2.26(m,1H),1.83(m,1H),1.28–1.21(m,4H)。
化合物1的1H-1H COSY、1H-1H NOESY和1H-1H J-分辨谱如图1-3所示，数据如表1所示，证明化合物1构型如下式所示：
Figure PCTCN2015078923-appb-000041
表1 化合物1的1HNMR、1H-1H COSY和1H-1H NOESY数据(DMSO-d6,400MHz)
Figure PCTCN2015078923-appb-000042
*根据1H-1H J-分辨谱读出
**与水峰交换的NH2质子
实施例2
(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(乙基磺酰基)吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-6-(三氟乙基)四氢-2H-吡喃-3-胺(化合物2)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(ethylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine
Figure PCTCN2015078923-appb-000043
Figure PCTCN2015078923-appb-000044
第一步：叔丁基2-(乙基磺酰基)-4,6-二氢吡咯并[3,4-c]吡唑-5-甲酸酯(2a)
tert-butyl 2-(ethylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate
无水无氧处理，氮气保护，将中间体2(627mg,3.0mmol)溶解于四氢呋喃(20mL)中，降温至0℃，加入氢化钠(180mg,60wt％,4.5mmol)，搅拌30分钟，滴加入乙基磺酰氯(1.16g,9.0mmol)，自然升温至室温下反应1小时。向反应液中加水(20mL)淬灭反应，用乙酸乙酯(20mL×2)萃取，合并有机层，无水硫酸钠干燥，浓缩，重新溶解于四氢呋喃(5mL)中，冷却至-10℃至0℃，加入叔丁醇钾(35mg,0.31mmol)，保持此温度下反应24小时。反应结束，加入饱和氯化铵水溶液(10mL)、水(10mL)，用乙酸乙酯(20mL×3)萃取，合并有机层，无水硫酸钠干燥，浓缩。残余物硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得到白色固体2a(730mg,产率81％)。
第二步：2-(乙基磺酰基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑(2b)
2-(ethylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole
将2a(710mg,2.36mmol)溶于二氯甲烷(8mL)中，加入加入三氟乙酸(8mL)，室温下反应2小时。将反应液旋干，加氨水(1mL)淬灭反应，用硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝10:1)，得到淡黄色固体2b(460mg,产率97％)。
第三步：叔丁基((2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(乙基磺酰基)吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-6-(三氟甲基)四氢-2H-吡喃-3-基)氨基甲酸酯(2c)
tert-butyl((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(ethylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate
将中间体1(350mg,0.89mmol)和2-(乙基磺酰基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑2b(244mg,1.21mmol)加入到甲苯(5mL)中，在140℃油浴温度下圆底烧瓶敞口反应至溶剂蒸干。在氮气氛围中，剩余物冷却至室温，重新溶解于1,2-二氯乙烷(10mL)中。在氮气氛围中，依次加入三(乙酰氧基)硼氢化钠(854mg,4.04mmol)和乙酸(0.115mL,2.02mmol)，室温下反应3小时。向反应液中加入饱和碳酸氢钠溶液(15mL)淬灭反应，分层，用乙酸乙酯(15mL×3)萃取水相，合并有机相，无水硫酸钠干燥，浓缩。硅胶柱层析(石油醚/乙酸乙酯(v/v)＝5:1)分离纯化，得到白色泡状固体2c(220mg,产率38％)。
第四步：(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(乙基磺酰基)吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-6-(三氟乙基)四氢-2H-吡喃-3-胺(化合物2)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(ethylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine
将2c(220mg,0.38mmol)溶于二氯甲烷(4.5mL)和三氟乙酸(1.5mL)中，室温下搅拌1小时。反应结束，加入饱和碳酸氢钠水溶液(10mL)淬灭反应，分层，用乙酸乙酯(15mL×2)萃取水相，合并有机相，无水硫酸钠干燥，浓缩。硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝50:1)，得到白色粉末固体化合物2(60mg,产率33％)。
MS m/z(ESI):481.1[M+1]；
1H NMR(400MHz,DMSO-d6)δ7.98(m,1H),7.33–7.22(m,3H),4.88–4.71(qd,1H),4.51(d,1H),3.95(dd,2H),3.78(dd,2H),3.64(q,2H),3.49–3.43(m,1H),3.05–2.97(ddd,1H),2.35–2.29(m,1H),1.82(m,1H),1.12(t,3H)。
化合物2的1H-1H COSY、1H-1H NOESY和1H-1H J-分辨谱如图4-6所示，数据如表2所示，证明化合物2构型如下式所示：
Figure PCTCN2015078923-appb-000045
表2 化合物2的1HNMR、1H-1H COSY和1H-1H NOESY数据(DMSO-d6,400MHz)
Figure PCTCN2015078923-appb-000046
*根据1H-1H J-分辨谱读出
**与水峰交换的NH2质子
实施例3：
(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(甲基磺酰基)-吡咯并[3,4]吡唑-5(2H,4H,6H)-基)-6-(三氟甲基)四氢-2H-吡喃-3-胺(化合物3)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine
Figure PCTCN2015078923-appb-000047
第一步：叔丁基2-甲基磺酸基-4,6-二氢吡咯并[3,4-c]吡唑-5-甲酸酯(3a)
tert-butyl 2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxylate
将中间体2(3.5g,16.7mmol)溶于四氢呋喃(35mL)中，0℃下加入的氢化钠(1.0g,25.4mmol,60％)，反应30分钟，加入甲基磺酰氯(2.9g,25.4mmol)反应1小时。向反应液中加水(10mL)淬灭反应，用乙酸乙酯(50mL×2)萃取，合并有机层，无水硫酸钠干燥，浓缩，用硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝1:1)，得到白色固体3a(2.1g,产率44％)。
第二步：2-甲基磺酰基-5,6-二氢-4-H-吡咯并[3,4-c]吡唑(3b)
2-methylsulfonyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole
将3a(2.1g,7.3mmol)溶于二氯甲烷(25mL)中，0℃下加入加入三氟乙酸(5mL)，0℃下反应2小时。将反应液旋干，加氨水(2mL)淬灭反应，用硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝50:1)，得到白色固体3b(1.1g,产率80.5％)。
1H NMR(400MHz,MeOD)：δ7.85(s,1H),4.01-3.94(m,4H),3.36(s,3H)。
第三步：叔丁基((2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(甲基磺酰基)-吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-6-(三氟甲基)四氢-2H-吡喃-3-基)氨基甲酸酯(3c)
tert-butyl((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate
将中间体1(490mg,1.24mmol)和3b(254mg,1.36mmol)加入到10mL甲苯中，在140℃油浴温度下圆底烧瓶敞口反应至溶剂蒸干。在氮气氛围中，剩余物冷却至室温，重新溶解于1,2-二氯乙烷(15mL)中，依次加入三(乙酰氧基)硼氢化钠(1.05mg,4.96mmol)和乙酸(149mg,2.48mmol)，室温下反应3小时。向反应液中加入饱和碳酸氢钠溶液(20mL)淬灭反应，分层，用乙酸乙酯(20mL×2)萃取水相,合并有机相，无水硫酸钠干燥，浓缩。硅胶柱层析(石油醚/乙酸乙酯(v/v)＝3:1)分离纯化，得到白色油状液体3c(455mg,产率60％)和白色固体3d(45mg,产率5.9％)。
第四步：(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(甲基磺酰基)-吡咯并[3,4]吡唑-5(2H,4H,6H)-基)-6-(三氟甲基)四氢-2H-吡喃-3-胺(化合物3)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine
将3c(410mg,0.72mmol)溶于6mL二氯甲烷和2mL三氟乙酸中，室温下搅拌1小时。反应结束后加入饱和碳酸氢钠水溶液(30mL)淬灭反应，分层后用乙酸乙酯萃取水相(30mL×2),合并有机相，无水硫酸钠干燥，浓缩。硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30:1)，得到白色粉末固体化合物3(250mg,产率75％)。
MS m/z(ESI)：467.1[M+1]；
1H NMR(400MHz,DMSO-d6):δ7.96(m,1H),7.35–7.04(m,3H),4.86–4.63(qd,1H),4.50(d,1H),3.95(dd,2H),3.78(dd,2H),3.49(s,3H),3.45(m,1H),3.00(ddd,1H),2.33(m,1H),1.82(m,1H),1.48(br,2H)。
化合物3的1H-1H COSY、1H-1H NOESY和1H-1H J-分辨谱如图7-9所示，数据如表3所示，证明化合物3构型如下式所示：
Figure PCTCN2015078923-appb-000048
表3 化合物3的1HNMR、1H-1H COSY和1H-1H NOESY数据(DMSO-d6,400MHz)
Figure PCTCN2015078923-appb-000049
*根据1H-1H J-分辨谱读出
**与水峰交换的NH2质子
实施例4：
(2R,3S,5R,6S)-5-(2-(甲基磺酰基)吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-6-(三氟甲基)-2-(2,4,5-三氟苯基)四氢-2H-吡喃-3-胺(化合物4)
(2R,3S,5R,6S)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-amine
Figure PCTCN2015078923-appb-000050
第一步：叔丁基((2R,3S,5R,6S)-5-(2-(甲基磺酰基)吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-6-(三氟甲基)-2-(2,4,5-三氟苯基)四氢-2H-吡喃-3-基)氨基甲酸酯(4a)
tert-butyl((2R,3S,5R,6S)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate
将中间体3(3g,7.26mmol)和3b(1.76g,9.44mmol)加入到100mL甲苯中，在140℃ 油浴温度下圆底烧瓶敞口反应至溶剂蒸干。在氮气氛围中，剩余物冷却至室温，剩余物重新溶解于1,2-二氯乙烷(30mL)中，依次加入三(乙酰氧基)硼氢化钠(4.62g,21.8mmol)和乙酸(0.87g,14.5mmol)，室温下反应3小时。向反应液中加入饱和碳酸氢钠溶液(30mL)淬灭反应，分层，用乙酸乙酯(30mL×2)萃取水相。合并有机相，无水硫酸钠干燥，浓缩。硅胶柱层析(石油醚/乙酸乙酯(v/v)＝3:1)分离纯化，得到白色油状液体4a(1.3g,产率30.6％)。
第二步：(2R,3S,5R,6S)-5-(2-(甲基磺酰基)吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-6-(三氟甲基)-2-(2,4,5-三氟苯基)四氢-2H-吡喃-3-胺(化合物4)
(2R,3S,5R,6S)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-amine
将4a(1.3g,2.44mmol)溶于二氯甲烷(7.8mL)和三氟乙酸(2.6mL)中，室温下搅拌1小时。反应结束后加入饱和碳酸氢钠水溶液(30mL)淬灭反应，分层，用乙酸乙酯(30mL×2)萃取水相，合并有机相，无水硫酸钠干燥，浓缩。硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30:1)，得到白色粉末固体化合物4(700mg,产率65％)。
MS m/z(ESI):485.0[M+1]；
1H NMR(400MHz,DMSO-d6):δ7.97(s,1H),7.58-7.53(m,2H),4.78-4.74(m,1H),4.47(d,1H),3.98-3.91(m,2H),3.81-3.73(m,2H),3.49(s,3H),3.46-3.43(m,1H),2.99(m,1H),2.33(m,1H),1.82(q,1H),1.50(s,2H)。
实施例5
(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(((R)-四氢呋喃-3-基)磺酰基)吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-6-(三氟甲基)四氢-2H-吡喃-3-胺(化合物5)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(((R)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine
Figure PCTCN2015078923-appb-000051
第一步：(R)-叔丁基2-((四氢呋喃-3-基)磺酰基)-4,6-二氢吡咯并[3,4-c]吡唑-5-甲酸酯(5a)
(R)-tert-butyl 2-((tetrahydrofuran-3-yl)sulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate
无水无氧处理，氮气保护，将中间体2(1000mg,4.78mmol)溶解于N,N-二甲基甲酰胺(15mL)中，降温至-15℃，加入双(三甲基硅)氨基钠(4.78mL,2mol/L,9.56mmol)，搅拌30分钟，将S-四氢呋喃-3-磺酰氯(1.39g,8.13mmol)滴加到反应液中，保持此温度反应16小时。反应结束，升温至0℃，向反应液中加水(20mL)淬灭反应，用乙酸乙酯(20mL×2)萃取，合并有机层，无水硫酸钠干燥，浓缩，重新溶解于四氢呋喃(20mL)中，冷却至-10℃至0℃。加入叔丁醇钾(85mg,0.76mmol)，保持此温度下反应24小时。反应结束，加入饱和氯化铵水溶液(10mL)、水(10mL)，用乙酸乙酯(20mL×3)萃取，合并有机层，无水硫酸钠干燥，浓缩。残余物硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得到白色固体5a(810mg,产率62.3％)。
第二步：(R)-2-((四氢呋喃-3-基)磺酰基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑(5b)
(R)-2-((tetrahydrofuran-3-yl)sulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole
将5a(400mg,1.17mmol)溶于盐酸的乙酸乙酯溶液(5mL,4mol/L)中，室温下反应1小时。反应结束，静置，除去液体，加入乙酸乙酯搅拌1分钟，静置，除去液体。残留固体柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20:1,加少许氨水)，得到淡黄色固体5b(210mg,产率74％)。
第三步：叔丁基((2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(((R)-四氢呋喃-3-基)磺酰基)吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-6-(三氟甲基)四氢-2H-吡喃-3-基)氨基甲酸酯(5c)
tert-butyl((2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(((R)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate
将中间体1(271mg,0.686mmol)和5b(200mg,0.823mmol)加入到甲苯(5mL)中，在140℃油浴温度下圆底烧瓶敞口反应至溶剂蒸干。在氮气氛围中，剩余物冷却至室温，溶解于1,2-二氯乙烷(10mL)中，依次加入三(乙酰氧基)硼氢化钠(580mg,2.744mmol)和乙酸(103mg,2.50mmol)，室温下反应3小时。向反应液中加入饱和碳酸氢钠溶液(15mL)淬灭反应，分层，用乙酸乙酯(15mL×3)萃取水相，合并有机相，无水硫酸钠干燥，浓缩。硅胶柱层析(石油醚/乙酸乙酯(v/v)＝5:1)分离纯化，得到白色泡状固体5c(255mg,产率61％)。
第四步：(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(((R)-四氢呋喃-3-基)磺酰基)吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-6-(三氟甲基)四氢-2H-吡喃-3-胺(化合物5)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(((R)-tetrahydrofuran-3-yl)sulfonyl)pyrrolo[ 3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine
将5c(255mg,0.41mmol)溶于6mL二氯甲烷和2mL三氟乙酸中，室温下搅拌1小时。反应结束后加入饱和碳酸氢钠水溶液(10mL)淬灭反应，分层，用乙酸乙酯(15mL×2)萃取水相，合并有机相，无水硫酸钠干燥，浓缩。硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝50:1)，得到白色粉末固体化合物5(175mg,产率82％)。
MS m/z(ESI):523.1[M+1]；
1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.32–7.22(m,3H),4.82–4.72(m,1H),4.49(m,2H),4.09(ddd,1H),4.00–3.80(m,4H),3.80–3.72(m,2H),3.64(dd,1H),3.49–3.42(m,1H),3.00(ddt,1H),2.36–2.28(m,1H),2.23(dt,2H),1.81(dd,1H)。
实施例6
(2R,3S,5R,6S)-5-(2-(环戊基磺酰基)吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-2-(2,5-二氟苯基)-6-(三氟甲基)四氢-2H-吡喃-3-胺(化合物6)
(2R,3S,5R,6S)-5-(2-(cyclopentylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-2-(2,5-difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine
Figure PCTCN2015078923-appb-000052
第一步：叔丁基2-(环戊基磺酰基)-4,6-二氢吡咯并[3,4-c]吡唑-5(2H)-甲酸酯(6a)
tert-butyl 2-(cyclopentylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate
无水无氧处理，氮气保护，将中间体2(1000mg,4.78mmol)溶解于N,N-二甲基甲酰胺(15mL)中，降温至-15℃，加入双(三甲基硅)氨基钠(4.78mL,2mol/L,9.56mmol)，搅拌30分钟，滴加S-环戊基磺酰基(1.37g,8.13mmol)，保持-15℃反应16小时。反应结束，升温至0℃，向反应液中加水(20mL)淬灭反应，用乙酸乙酯(20mL×2)萃取，合并有机层，无水硫酸钠干燥，浓缩。重新溶解于四氢呋喃(20mL)中，冷却至-10℃至0℃，加入叔丁醇钾(85mg,0.76mmol)，保持此温度下反应24小时。反应结束，加入饱和氯化铵水溶液(10mL)、水(10mL)，用乙酸乙酯(20mL×3)萃取，合并有机层，无水硫酸钠干燥，浓缩。残 余物硅胶柱层析分离纯化(石油醚/乙酸乙酯(v/v)＝5:1)，得到白色固体6a(800mg,产率62％)。
第二步：2-(环戊基磺酰基)-2,4,5,6-四氢吡咯并[3,4-c]吡唑(6b)
2-(cyclopentylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole
将6a(430mg,1.26mmol)溶于盐酸的乙酸乙酯溶液中(8mL,4mol/L)中，室温下反应1小时。反应结束后，静置，除去液体。加入乙酸乙酯搅拌1分钟，静置，除去液体。柱层析分离纯化(二氯甲烷/甲醇(v/v)＝20:1,加少许氨水)，得到淡黄色固体6b(290mg,产率95％)。
第三步：叔丁基((2R,3S,5R,6S)-5-(2-(环戊基基磺酰基)吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-2-(2,5-二氟苯基)-6-(三氟甲基)四氢-2H-吡喃-3-基)氨基甲酸酯(6c)
tert-butyl((2R,3S,5R,6S)-5-(2-(cyclopentylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-2-(2,5-difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-yl)carbamate
将中间体1(327mg,0.828mmol)和6b(280mg,1.16mmol)加入到甲苯(8mL)中，在140℃油浴温度下圆底烧瓶敞口反应至溶剂蒸干。在氮气氛围中，剩余物冷却至室温，溶解于1,2-二氯乙烷(10mL)中，依次加入三(乙酰氧基)硼氢化钠(700mg,3.31mmol)和乙酸(0.1ml,1.82mmol)，室温下反应3小时。向反应液中加入饱和碳酸氢钠溶液(15mL)淬灭反应，分层，用乙酸乙酯(15mL×3)萃取水相，合并有机相，无水硫酸钠干燥，浓缩。硅胶柱层析(石油醚/乙酸乙酯(v/v)＝5:1)分离纯化，得到白色泡状固体6c(210mg,产率41％)。
第四步：(2R,3S,5R,6S)-5-(2-(环戊基磺酰基)吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-2-(2,5-二氟苯基)-6-(三氟甲基)四氢-2H-吡喃-3-胺(化合物6)
(2R,3S,5R,6S)-5-(2-(cyclopentylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-2-(2,5-difluorophenyl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine
将6c(210mg,0.34mmol)溶于二氯甲烷(6mL)和三氟乙酸(2mL)中，室温下搅拌1小时。反应结束，加入饱和碳酸氢钠水溶液(10mL)淬灭反应，分层，用乙酸乙酯(15mL×2)萃取水相，合并有机相，无水硫酸钠干燥，浓缩。硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝50:1)，得到白色粉末固体化合物6(105mg,产率60％)。
MS m/z(ESI):521.1[M+1]；
1H NMR(400MHz,DMSO-d6)δ8.00(m,1H),7.34–7.19(m,3H),4.81–4.70(qd,1H),4.50(d,1H),4.09(m,1H),4.00–3.89(m,2H),3.84–3.73(m,2H),3.50–3.40(m,1H),3.00(td,1H),2.37–2.27(m,1H),1.96–1.85(m,4H),1.85–1.75(m,1H),1.63–1.56(m,4H)。
化合物6的1H-1H COSY、1H-1H NOESY和1H-1H J-分辨谱如图10-12所示，数据如表4所示，证明化合物6构型如下式所示：
Figure PCTCN2015078923-appb-000053
表4.化合物6的1HNMR、1H-1H COSY和1H-1H NOESY数据(DMSO-d6,400MHz
Figure PCTCN2015078923-appb-000054
*根据1H-1H J-分辨谱读出
**与水峰交换的NH2质子
实施例7
(2R,3S,5S,6R)-2-(2,5-二氟苯基)-5-(2-(甲基磺酰基)吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-6-(三氟甲基)四氢-2H-吡喃-3-胺(化合物7)
(2R,3S,5S,6R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine
Figure PCTCN2015078923-appb-000055
第一步：(2R,3S,5S,6R)-2-(2,5-二氟苯基)-5-(2-(甲基磺酰基)吡咯并[3,4-c]吡唑-5(2H,4H,6H)-基)-6-(三氟甲基)四氢-2H-吡喃-3-胺(化合物7)
(2R,3S,5S,6R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine
将3d(400mg,0.7mmol)溶于二氯甲烷(6mL)和三氟乙酸(2mL)中，室温下搅拌1小时。反应结束，加入饱和碳酸氢钠水溶液(30mL)淬灭反应，分层，用乙酸乙酯(30mL×2)萃取水相，合并有机相，无水硫酸钠干燥，浓缩。硅胶柱层析分离纯化(二氯甲烷/甲醇(v/v)＝30:1),得到白色粉末固体化合物7(200mg,产率61％)。
MS m/z(ESI):467.0[M+1]；
1H NMR(400MHz,DMSO-d6):δ7.94(s,1H),7.39–7.06(m,3H),4.52–4.41(m,2H),4.07(s,2H),4.01(s,2H),3.49(m,4H),3.28(d,1H),2.48(d,1H),1.75(ddd,1H),1.38(s,2H)。
生物测试
1、大鼠药代动力学评价
雄性SD大鼠(购自Vital River Laboratory Animal Technology Co.LTD，许可证号：11400700005540)200-240g，禁食过夜。实验当天3只SD大鼠分别灌胃5mg·kg-1，分别于给药前及给药后15min，30min，45min，1h，2h，4h，8h，12h和24h，由颈静脉采血0.20mL，置于EDTA试管中。血液样品采集后加入含内标(维拉帕米，5.00ng/mL和格列本脲，50.0ng/mL)的乙腈，剧烈涡旋后13000rpm离心10min。取上清进行LC-MS/MS检测。采用Pharsight Phoenix 6.3中的非房室模型计算药代动力学参数，实验结果如表5所示。
表5 大鼠药代动力学评价结果
Figure PCTCN2015078923-appb-000056
结论：本发明化合物与阳性对照(Omarigliptin)相比，在大鼠上具有更高的最大浓度和暴露量、更长的半衰期及更小的清除率。
2、口服葡萄糖耐量实验
利用口服葡萄糖耐量实验(OGTT)评价本发明化合物在小鼠中的降糖效果。使用的动物为C57小鼠，八周龄，雄性，购自北京维通利华实验动物技术有限公司，动物生产合格证号：SCXK(京)2012-0001。根据禁食后的基础血糖值分组，每组10只。受试化合物配制成1mg/mL的混悬液。灌胃给药，给药量为10mg/kg。空白对照组给予空白试剂。给药60min后给予50％的葡萄糖水溶液(5g/kg)，并在0min、15min、30min、45min、60min、120min时使用强生稳豪血糖测定仪测定各小鼠的血糖值，计算药-时曲线下面积(AUC)降低比例。
实验结果见表6。
表6 小鼠口服葡萄糖耐量实验评价结果
序号 化合物编号 AUC降低比例(％)
1 Omarigliptin 22.27
2 化合物1 27.20
3 化合物3 27.99
结论：本发明化合物有显著的降糖效果，小鼠单次口服给药后可明显降低血糖。
3、单次口服给药对ob/ob小鼠DPP-IV酶活性的影响
将待测化合物用0.5％的CMC-Na配制成0.3mg/mL、1.0mg/mL或3.0mg/mL的溶液。来源于上海药物所ob/ob小鼠提前禁食16小时，不禁水，第二天按体重均匀分成5组。受试组分别给予不同剂量的化合物，对照组给予空白溶剂，给予体积为10mL/kg。然后在0h、2h、4h、10h、24h、34h、48h、58h和72h时间点从小鼠眼眶采集血液。EDTA-2Na抗凝后取出40μl血浆，同时加入AFC(0.2mM)底物10μl，室温反应15min后酶标仪测试血浆中的DPP4酶活性，实验结果见表7和图13。
表7 单次口服给药对ob/ob小鼠DPP-IV酶活性的结果
Figure PCTCN2015078923-appb-000057
结论：ob/ob小鼠单次口服给药后，化合物3比阳性对照Omarigliptin具有更明显的抑制DPP-IV酶活性效果。化合物3与阳性对照Omarigliptin同等剂量下，对DPPIV酶活性80％抑制率的时间达到Omarigliptin的3倍以上；在化合物3仅为阳性对照Omarigliptin 1/10的剂量下，对DPP-IV酶活性抑制效果仍更加明显，具备更长效的潜质。
4、大鼠血浆DPP-IV酶学筛选实验
实验动物为SD大鼠，8周龄，雄性，购自北京维通利华实验动物技术有限公司，动物生产合格证号：SCXK(京)2012-0001。将禁食后的大鼠按体重分组。大鼠采用眼眶取血，EDTA-2Na抗凝受试组口服受试化合物，剂量为3.0mg/kg；对照组口服空白试剂。分别于给药后不同时间点处取血。将血液样本于2500rpm离心15min，取出血浆，于-20℃保存。酶活测试，每个受试样取40μl血浆，加入10μl H-Ala-Pro-AFC底物(0.2mM)，反应15min后用酶标仪测值(激发波长Excitation＝405nM；发射波长Emission＝535nM)，使用Origin 7.5进行统计分析，计算测试化合物对血浆DPP-IV酶活抑制率≥70％所持续的时间，结果见表8。
表8 大鼠血浆DPP-IV酶学筛选实验结果
序号 化合物编号 ≥70％抑制率持续时间(h)
1 Omarigliptin 55
2 化合物1 55
3 化合物4 >72
结论：本发明化合物能显著抑制大鼠血浆DPPIV酶活性，特别是化合物4对血浆DPP-IV酶活抑制率≥70％所持续的时间明显长于对照化合物。
5、犬血浆DPP-IV酶学筛选实验
实验动物为雄性比格犬，成都达硕生物科技有限公司提供。将禁食后的比格犬按体重分组。受试组口服受试化合物，剂量为10.0mg/kg。分别于给药后不同时间点取血，EDTA-2Na抗凝。将血液样本于2500rpm离心15min，取出血浆，于-20℃保存。酶活测试，每个受试样取40μl血浆，加入10μl H-Ala-Pro-AFC底物(0.2mM)，反应15min后用酶标仪测值(激发波长Excitation＝405nM；发射波长Emission＝535nM)，使用Origin 7.5进行统计分析，计算测试化合物对血浆DPP-IV酶活抑制率≥80％所持续的时间，结果见下表9：
表9 犬血浆DPP-IV酶学实验筛选结果
序号 化合物编号 ≥80％抑制率持续时间(h)
1 Omarigliptin 162
2 化合物4 192
结论：本发明化合物抑制犬血浆DPPIV酶活时间明显长于对照化合物，具有更好的长效潜质。
6、猴血浆DPP-IV酶学筛选实验
实验动物为健康雄性5公斤左右的恒河猴，四川普莱美生物科技有限公司提供。将禁食后的恒河猴按体重分组。受试组口服受试化合物，剂量为10.0mg/kg。分别于给药后不同时间点取血，EDTA-2Na抗凝。将血液样本于2500rpm离心15min，取出血浆，于-20℃保存。酶活测试，每个受试样取40μl血浆，加入10μl H-Ala-Pro-AFC底物(0.2mM)，反应15min后用酶标仪测值(激发波长Excitation＝405nM；发射波长Emission＝535nM)，使用Origin 7.5进行统计分析，计算测试化合物对血浆DPP-IV酶活抑制率≥80％所持续的时间。同时用LC-MS/MS检测血浆中化合物的浓度。结果见图14和下表10：
表10 猴血浆DPP-IV酶学筛选实验结果
Figure PCTCN2015078923-appb-000058
结论：本发明化合物一次口服给药能够抑制猴血浆DPPIV酶活长达11天以上，具有非常好的长效潜质。

Claims (18)

  1. 通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药：
    Figure PCTCN2015078923-appb-100001
    其中：
    V选自以下基团：
    Figure PCTCN2015078923-appb-100002
    Ar为0至5个R1基团取代的苯环；
    R1选自H、F、Cl、Br、I、羟基、氰基、C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、-(CH2)m-C3-15环烷基、-(CH2)m-3至15元杂环烷基、-(CH2)m-C6-10芳基、-(CH2)m-6至10元杂芳基、-(CH2)m-C(＝O)-R5、-(CH2)m-NR6R7、-(CH2)m-C(＝O)-NR6R7、-(CH2)m-O-C(＝O)-NR6R7、-(CH2)m-S(＝O)n-R8、-(CH2)m-NR9-S(＝O)n-R8、-(CH2)m-NR9-C(＝O)-NR6R7或-(CH2)m-NR9-C(＝O)-R5，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至5个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环烷基含有1至5个选自N、O或S(＝O)n的原子或基团；
    R2a和R2b各自独立选自H、F、Cl、Br、I、羟基、氰基、C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、-(CH2)m-C3-15环烷基、-(CH2)m-3至15元杂环烷基、-(CH2)m-C6-10芳基、-(CH2)m-6至10元杂芳基、-(CH2)m-C(＝O)-R5、-(CH2)m-NR6R7、-(CH2)m-C(＝O)-NR6R7、-(CH2)m-O-C(＝O)-NR6R7、-(CH2)m-S(＝O)n-R8、-(CH2)m-NR9-S(＝O)n-R8、-(CH2)m-NR9-C(＝O)-NR6R7或-(CH2)m-NR9-C(＝O)-R5，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至3个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环烷基含有1至5个 选自N、O或S(＝O)n的原子或基团；
    R3a和R3b各自独立选自H、F、Cl、Br、I、羟基、氰基或C1-8烷基，其中所述烷基任选进一步被0至5个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；
    R4a和R4b各自独立选自H、F、Cl、Br、I、羟基、氰基或C1-8烷基，其中所述烷基任选进一步被0至5个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代，且R4a和R4b不同时为H；
    R4选自H、氰基、C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、-(CH2)m-C3-15元环烷基、-(CH2)m-3至15元杂环烷基、-(CH2)m-C6-10芳基、-(CH2)m-6至10元杂芳基、-(CH2)m-C(＝O)-R5、-(CH2)m-NR6R7、-(CH2)m-C(＝O)-NR6R7、-(CH2)m-O-C(＝O)-NR6R7、-(CH2)m-S(＝O)n-R8、-(CH2)m-NR9-S(＝O)n-R8、-(CH2)m-NR9-C(＝O)-NR6R7或-(CH2)m-NR9-C(＝O)-R5，其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至3个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环烷基含有1至5个选自N、O或S(＝O)n的原子或基团；
    R5选自羟基、C1-8烷基、C1-8烷氧基、C3-15环烷基、C6-10芳基、6至10杂芳基、-O-C3-15环烷基、-O-C6-10芳基或-O-6至10元杂芳基；
    R6、R7和R9各自独立选自H、C1-8烷基、C3-15环烷基、C6-10芳基、6至10元杂芳基或3至15元杂环烷基；
    R8选自C1-8烷基、C3-15环烷基、C6-10芳基、6至10元杂芳基或3至15元杂环烷基，其中所述烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至5个F所取代，所述杂环烷基或杂芳基含有1至5个选自N、O或S(＝O)n的原子或基团；
    m选自0、1或2；
    n选自0、1或2。
  2. 根据权利要求1所述通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中：
    R1选自H或F；
    R2a和R2b各自独立地选自H、C1-6烷基、C3-6环烷基或3至8元杂环烷基，其中所述烷基、环烷基或杂环烷基任选进一步被0至3个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代，所述杂环烷基含有1至3个选自N、O或S(＝O)2的原子或基团；
    R3a和R3b各自独立选自H或C1-2烷基，其中所述烷基任选进一步被0至3个选自F、羟基或C1-4烷氧基的取代基所取代；
    R4选自H或-S(＝O)2-R8；
    R8选自C1-6烷基、C3-6环烷基、C6-10芳基、6至10元杂芳基或3至8元杂环烷基，其中所述烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至5个F所取代，所述杂环烷基含有1至5个选自N、O或S(＝O)2的原子或基团。
  3. 根据权利要求2所述通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中：
    V选自
    Figure PCTCN2015078923-appb-100003
    Ar选自2,5-二氟苯基或2,4,5-三氟苯基；
    R2a选自H、C1-6烷基或C3-6环烷基，其中所述烷基或环烷基任选进一步被0至3个选自F、羟基、C1-4烷基或C1-4烷氧基的取代基所取代；
    R3a和R3b各自独立选自H或C1-2烷基，其中所述烷基任选进一步被0至3个选自F、羟基或C1-4烷氧基的取代基所取代；
    R4为-S(＝O)2-R8；
    R8选自C1-2烷基、3至6元杂环烷基或C3-6环烷基，其中所述烷基、杂环烷基或环烷基任选进一步被0至5个F所取代，所述杂环烷基含有1至3个选自N、O或S(＝O)2的原子或基团。
  4. 根据权利要求3所述通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中：
    V选自
    Figure PCTCN2015078923-appb-100004
  5. 根据权利要求4所述通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中：
    R4为-S(＝O)2-R8；
    R8选自C1-2烷基、4至6元杂环烷基或C3-6环烷基，其中所述烷基、杂环烷基或环烷基任选进一步被0至5个F所取代，所述杂环烷基含有1至3个选自N、O或S(＝O)2的原子或基团。
  6. 根据权利要求5所述通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中：
    R8选自甲基、乙基、
    Figure PCTCN2015078923-appb-100005
    环丙基、环丁基或者环戊基。
  7. 根据权利要求1～6所述的任何一项通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中该氨基吡喃环衍生物选自：
    Figure PCTCN2015078923-appb-100006
  8. 根据权利要求7所述的通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中该氨基吡喃环衍生物选自：
    Figure PCTCN2015078923-appb-100007
  9. 根据权利要求8所述的通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中该氨基吡喃环衍生物选自：
    Figure PCTCN2015078923-appb-100008
  10. 根据权利要求1所述的通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中该氨基吡喃环衍生物选自：
    Figure PCTCN2015078923-appb-100009
    Figure PCTCN2015078923-appb-100010
  11. 根据权利要求10所述的通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，其中该氨基吡喃环衍生物选自：
    Figure PCTCN2015078923-appb-100011
  12. 一种药物组合物，所述的组合物包括：有效剂量的根据权利要求1～11中任一项所述通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，以及药学上可接受的载体或赋形剂。
  13. 权利要求1～11中任一项所述通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药或者权利要求12所述的组合物在制备二肽基肽酶-IV抑制剂中的应用。
  14. 根据权利要求13中所述的应用，其中所述的二肽基肽酶-IV抑制剂用于制备治疗代谢性疾病的药物，其中所述的代谢性疾病包括糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性、高血糖、高胰岛素血症、脂肪酸或甘油的升高的水平、高脂血症、肥胖症、高甘油三脂血症、X综合症、糖尿病并发症、动脉粥样硬化或高血压。
  15. 根据权利要求14中所述的应用，其中所述的糖尿病为II型糖尿病。
  16. 一种治疗代谢性疾病的方法，所述方法包括给药权利要求1～11任意一项所述的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药，或权利要求12所述的药物组合物。
  17. 根据权利要求16所述的方法，其中所述的代谢性疾病包括糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性、高血糖、高胰岛素血症、脂肪酸或甘油的升高的水平、高脂血症、肥胖症、高甘油三脂血症、X综合症、糖尿病并发症、动脉粥样硬化或高血压。
  18. 根据权利要求17所述的方法，其中所述的糖尿病为II型糖尿病。
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