WO2017031918A1 - Long-acting dipeptidyl peptidase-iv inhibitor, applications, and preparation method for intermediate thereof - Google Patents

Long-acting dipeptidyl peptidase-iv inhibitor, applications, and preparation method for intermediate thereof Download PDF

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Publication number
WO2017031918A1
WO2017031918A1 PCT/CN2016/000478 CN2016000478W WO2017031918A1 WO 2017031918 A1 WO2017031918 A1 WO 2017031918A1 CN 2016000478 W CN2016000478 W CN 2016000478W WO 2017031918 A1 WO2017031918 A1 WO 2017031918A1
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group
compound
alkyl
tert
pyran
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PCT/CN2016/000478
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French (fr)
Chinese (zh)
Inventor
谢益农
游泽金
何云
宋占波
王亚军
张绍华
李路
王浩东
张继超
朱军
曾宏
宋宏梅
齐伟
王利春
王晶翼
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四川科伦药物研究院有限公司
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Priority to CN201680008006.0A priority Critical patent/CN107250135B/en
Publication of WO2017031918A1 publication Critical patent/WO2017031918A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to compounds as dipeptidyl peptidase-IV (DPP-4) inhibitors and their use in the treatment and prevention of DPP-4 related diseases including diabetes, especially type II diabetes.
  • the invention further relates to a process for the preparation of the above compounds and intermediates thereof.
  • the present invention relates to pharmaceutical compositions comprising these compounds, and the use of these compositions in the prevention or treatment of diseases associated with DPP-4.
  • Diabetes is a chronic metabolic disease caused by various factors such as genetic factors, immune dysfunction, microbial infection and its toxins, free radical toxins, and mental factors. Clinically, hyperglycemia is the main symptom. It can be divided into type I diabetes (insulin dependent), type II diabetes (non-insulin dependent), gestational diabetes and other special types of diabetes. In diabetic patients, the proportion of type 2 diabetes is about 90%.
  • Non-Patent Document 1 Non-Patent Document 1
  • Dipeptidyl peptidase-IV is a serine protease.
  • DPP-4 can block the secretion of glucagon-like peptide (GLP)-1, in particular, it can cleave the N-terminal group-propadipeptide enzyme of GLP-1 from the active form of GLP- 1 (7-36) NH 2 degrades into inactive GLP-1 (9-36) NH 2 (Non-Patent Document 2).
  • GLP-1 Glucagon-like peptide-1
  • GLP-1 is a hormone secreted by islet ⁇ -cells and intestinal L-cells, which has glucose-dependent insulin secretion and increases insulin biosynthesis. Therefore, GLP- is used.
  • GLP-1 The treatment of diabetes has caused great interest among scientists. In addition to promoting insulin secretion, GLP-1 also promotes ⁇ -cell proliferation, anti- ⁇ -cell apoptosis, inhibits glucagon and glycogen production, suppresses appetite, reduces gastrointestinal emptying rate, and protects nerve cells. And other physiological functions. These characteristics of GLP-1 make it an ideal treatment for diabetes. However, GLP-1 has a half-life in vivo of only a few minutes, and is rapidly degraded by endogenous dipeptidyl peptidase-IV (DPP-4) (removing the N-terminal dipeptide), thereby losing insulin secretion-promoting activity (Non-Patent Document 3) ).
  • DPP-4 endogenous dipeptidyl peptidase-IV
  • DPP-4 is widely distributed in human body and is the main metabolic enzyme of GLP-1, which plays an important role in regulating GLP-1 activity.
  • a DPP-4 inhibitor enhances the action of GLP-1.
  • DPP-4 inhibitors also promote ⁇ -cell proliferation, anti- ⁇ -cell apoptosis, inhibit glucagon and glycogen production, suppress appetite, increase body weight, reduce gastrointestinal emptying rate, Protect nerve cells and other effects. Therefore, DPP-4 inhibitors can also be used for the treatment of various diseases associated with dipeptidyl peptidases such as obesity and hyperlipidemia (Non-Patent Document 4).
  • DPP-4 inhibitors Since the crystal structure of DPP-4 was reported in 2003, a number of new structural types of DPP-4 inhibitors have been listed in recent years, such as sitagliptin phosphate developed by Merck (sitagliptin phosphate, in the United States in October 2006). Listing).
  • Non-Patent Document 1 Medicinal Research Review, 2009, 29(1), 125-195
  • Non-Patent Document 3 Expert Opin. Investing. Drugs, 2004, 13(9): 1091-1102
  • An object of the present invention is to provide a compound as a dipeptidyl peptidase-IV (DPP-4) inhibitor, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form thereof or Prodrugs, which are useful in the treatment and prevention of DPP-4 related diseases including the treatment of diabetes, especially type 2 diabetes.
  • the present invention provides a novel compound having a novel substituted 3-aminotetrahydropyran structure, a high inhibitory activity against dipeptidyl peptidase-IV, and excellent drug metabolism properties.
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable carrier or excipient for treating various diseases associated with dipeptidyl peptidase-IV. .
  • the therapeutic agent in particular the dipeptidyl peptidase-IV inhibitor, has an excellent activity for treating diabetes, has markedly improved solubility, and has good activity and bioavailability in animals, and low toxicity, and is suitable for use in A preparation for treating diabetes is prepared.
  • the present inventors have conducted intensive studies in order to achieve the above object, and as a result, have found that a specific compound having a 3-aminotetrahydropyran structure, that is, a compound represented by the following formula (I) has a higher
  • a specific compound having a 3-aminotetrahydropyran structure that is, a compound represented by the following formula (I) has a higher
  • the advantage of a glucose-dependent mechanism, thus reducing the risk of hypoglycemia, in addition to the existing DPP-4 inhibitors, the compounds of the invention have more favorable pharmacokinetic properties, longer durations
  • the present invention has been completed.
  • Ring A is an unsaturated ring, in the B ring Represents a single or double bond;
  • a 3 , A 4 , A 5 and A 6 are each independently selected from a carbon atom or a nitrogen atom, and at least 2 of A 3 , A 4 , A 5 and A 6 are carbon atoms;
  • R 3 is selected from a hydroxyl group, an alkyl group optionally substituted with a group selected from the substituent group a, a cycloalkyl group optionally substituted with a group selected from the substituent group a, optionally selected from a substituent a group-substituted amino group of group a, an amino C2-6 alkanoyl group optionally substituted with a group selected from substituent group a, an aminocarbonylamino group optionally substituted with a group selected from substituent group a, optionally a C6-10 aryl group substituted with a group selected from the substituent group a, a 5-11 membered heterocyclic group optionally substituted with a group selected from the substituent group a;
  • R 5 is a single bond or a C1-6 alkylene group, a C2-6 alkenylene group, or a C2-6 alkynylene group;
  • R 6 is C1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
  • R 7 and R 8 are each independently hydrogen, hydroxy, C 1-6 alkyl optionally substituted with a group selected from substituent group a, C 3-8 optionally substituted with a group selected from substituent group a a cycloalkyl group, optionally substituted with a group selected from the group of substituent group a (provided that R 7 and R 8 are not hydrogen at the same time);
  • R 9 is a single bond, a C1-6 alkylene group, a C2-6 alkenylene group, or a C2-6 alkynylene group.
  • R 1 and R 2 are not simultaneously a hydrogen atom; and when the B ring is a saturated ring and one of R 1 and R 2 is a hydrogen atom, the other of R 1 and R 2
  • One of the groups is not a C1-6 alkyl group optionally substituted with a substituent selected from a halogen atom and a C1-6 alkoxy group, a cyano group, an optionally substituted C1-6 alkoxy group, or an optionally substituted C3. -8 cycloalkyl, optionally substituted 5-11 membered heterocyclic group;
  • Ar is a C6-10 aryl group optionally substituted by 1 to 5 groups selected from the substituent group a;
  • a 3 is N, A 4 is C, A 5 is N, A 6 is C, or
  • a 3 is N, A 4 is C, A 5 is C, A 6 is C, or
  • a 3 is C
  • a 4 is C
  • a 5 is N
  • a 6 is C
  • a 3 is N, A 4 is C, A 5 is C, A 6 is N, or
  • a 3 is C
  • a 4 is C
  • a 5 is C
  • a 6 is C.
  • the ring A is an unsaturated ring
  • the ring B is a saturated ring.
  • a 3 is N, A 4 is C, A 5 is N, A 6 is C, or
  • a 3 is N, A 4 is C, A 5 is C, A 6 is C, or
  • a 3 is C
  • a 4 is C
  • a 5 is N
  • a 6 is C
  • a 3 is N, A 4 is C, A 5 is C, A 6 is N, or
  • a 3 is C
  • a 4 is C
  • a 5 is C
  • a 6 is C.
  • a compound of the present invention which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof.
  • the ring A is an unsaturated ring
  • the ring B is a ring.
  • unsaturated ring As an unsaturated ring,
  • a 3 is N, A 4 is C, A 5 is N, A 6 is C, or
  • a 3 is N, A 4 is C, A 5 is C, A 6 is C, or
  • a 3 is C
  • a 4 is C
  • a 5 is N
  • a 6 is C
  • a 3 is N, A 4 is C, A 5 is C, A 6 is N, or
  • a 3 is C
  • a 4 is C
  • a 5 is C
  • a 6 is C.
  • the compound of the present invention which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or a prodrug thereof, wherein R 1 and R 2 are each independently a hydrogen atom or an amino group.
  • R 1 and R 2 are each independently a hydrogen atom or an amino group.
  • a compound of the present invention a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein Both represent a single button.
  • a compound according to the invention a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein Ar is optionally 1 to 5 selected from the group of substituents A group substituted with a phenyl group of a.
  • the compound of the present invention which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein the compound is selected from the following formula (a), ( Any one of b), (c), (d), (e) and (f),
  • Ar is a phenyl group optionally substituted by 1 to 5 halogen atoms
  • the compound of the present invention which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein the compound is a compound selected from the group consisting of
  • a compound of the present invention a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form thereof or a prodrug thereof, for use as a dipeptidyl peptidase-IV inhibitor.
  • composition comprising a compound of the invention, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, and a pharmaceutically acceptable carrier or form Agent.
  • composition of the present invention further comprising other compounds which can be used in combination with the compound, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof Active substance.
  • composition according to the present invention wherein the other active substance is metformin or a salt thereof, or pioglitazone or the like.
  • the composition according to the invention contains 0.01 to 1000 mg of the compound according to the invention, suitably 0.5 to 800 mg, preferably 1 to 400 mg, more preferably 5 to 200 mg, particularly preferably 10-100 mg, most preferably 15-50 mg, for example 20 mg, 25 mg, 30 mg.
  • the pharmaceutical preparation of the present invention or the like may be in a unit dosage form, and the unit dose contains 0.01 to 1000 mg of the compound of the present invention, suitably 0.5 to 800 mg, preferably 1 to 400 mg, more preferably 5 to 200 mg, particularly preferably 10 to 100 mg, most It is preferably 15-50 mg, for example, 20 mg, 25 mg, 30 mg.
  • a pharmaceutical preparation suitable for administration to an animal, especially a mammal wherein the preparation comprises a compound of the invention, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or
  • the prodrug thereof is used as an active ingredient, and the preparation includes a solid preparation, a semisolid preparation, a liquid preparation, and a gaseous preparation.
  • a therapeutic or prophylactic agent for a disease associated with dipeptidyl peptidase-IV which comprises the compound, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof As an active ingredient.
  • the compound of the present invention a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form thereof or a prodrug thereof, or a combination thereof with other active substances, is used for the preparation of a treatment Use in drugs for diseases associated with dipeptidyl peptidase-IV.
  • the compound of the present invention has high inhibitory activity and selectivity to dipeptidyl peptidase-IV, has excellent drug metabolism properties, and has less toxic and side effects, and can be used as a long-acting dipeptidyl peptidase-IV inhibitor.
  • Dipeptidyl peptidase-IV related diseases include diabetes, obesity, insulin resistance or hyperlipidemia.
  • the compound of the present invention a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form thereof or a prodrug thereof, or a combination thereof with other active substances, is used for treatment and A method of peptidyl peptidase-IV related diseases.
  • the amount of the compound according to the invention is from 0.01 to 1000 mg, suitably from 0.5 to 800 mg, preferably from 1 to 400 mg, more preferably from 5 to 200 mg, particularly preferably from 10 to 100 mg, most preferably from 15 to 50 mg, for example It is 20 mg, 25 mg, 30 mg.
  • the pharmaceutical preparation of the present invention or the like may be in a unit dosage form, and the unit dose contains 0.01 to 1000 mg of the compound of the present invention, suitably 0.5 to 800 mg, preferably 1 to 400 mg, more preferably 5 to 200 mg, particularly preferably 10 to 100 mg, most It is preferably 15-50 mg, for example, 20 mg, 25 mg, 30 mg.
  • the "optionally substituted with a group selected from the substituent group a” means that it may be substituted at any position with one or two or more identical or different substituents selected from the substituent group a.
  • C1-6 alkyl group-substituted means substituted at one position with one or two or more identical or different substituents selected from a C1-6 alkyl group.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • the "C1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a n-propyl group, an isopropyl group and a n-butyl group. a group such as a benzyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a neopentyl group, a tert-amyl group or the like.
  • the "C2-6 alkenyl group” means a linear or branched alkenyl group having 2 to 6 carbon atoms, and examples thereof include a vinyl group, a n-propenyl group, an isopropenyl group, and a n-butenyl group.
  • a group such as isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, isopentenyl, neopentenyl, tert-pentenyl or the like.
  • the "C2-6 alkynyl group” means a linear or branched alkynyl group having 2 to 6 carbon atoms, and examples thereof include an ethynyl group, a n-propynyl group, an isopropynyl group, and a n-butyne group. a group such as a benzyl group, an isobutynyl group, a sec-butynyl group, a tert-butynyl group, a n-pentynyl group, an isopentenyl group, a neopentynyl group, a tert-pentynyl group, and the like.
  • the "C3-8 cycloalkyl group” may, for example, be a group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group.
  • the "C1-6 alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, and examples thereof include a methoxy group, an ethoxy group, a n-propoxy group, and a different form. a group such as propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-amyloxy, and the like group.
  • C1-6 alkylene C2-6 alkenylene
  • C2-6 alkynylene refer to the above “C1-6 alkyl” and “C2-6 alkenyl”, respectively.
  • C2-6 alkynyl group a divalent group of one hydrogen atom is removed.
  • C2-6 alkanoyl group means a linear or branched alkanoyl group having 2 to 6 carbon atoms, and examples thereof include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, and a valeryl group.
  • a group such as isovaleryl or pivaloyl.
  • the "mono C1-6 alkylaminocarbonyl group” means a carbonyl group substituted with an amino group having one of the above-mentioned "C1-6 alkyl group” as a substituent, and examples thereof include a methylaminocarbonyl group and an ethylaminocarbonyl group.
  • N-propylaminocarbonyl isopropylaminocarbonyl, n-butylaminocarbonyl, isobutyl Alkylaminocarbonyl, sec-butylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, isopentylaminocarbonyl, neopentylaminocarbonyl, and the like.
  • the "diC1-6 alkylaminocarbonyl group” means a carbonyl group substituted with two amino groups having the same or different "C1-6 alkyl group” as a substituent, and examples thereof include a dimethylaminocarbonyl group. Diethylaminocarbonyl, di(n-propyl)aminocarbonyl, bis(isopropyl)aminocarbonyl, ethylmethylaminocarbonyl, methyl(n-propyl)aminocarbonyl, methyl(isopropyl)aminocarbonyl Wait.
  • the "C6-10 aryl group” means a monocyclic or polycyclic aryl group having 6 to 10 carbon atoms.
  • a partially saturated group is also included.
  • a phenyl group, a naphthyl group, an anthracenyl group, a fluorenyl group, an indanyl group, a tetrahydronaphthyl group, etc. are mentioned.
  • the "C6-10 aryl C1-6 alkyl group” means a group in which the following C6-10 aryl group is bonded to the above C1-6 alkyl group.
  • Examples thereof include a benzyl group, a phenethyl group, a 3-phenyl-n-propyl group, a 4-phenyl-n-butyl group, a 5-phenyl-n-pentyl group, an 8-phenyl-n-hexyl group, a naphthylmethyl group, and the like.
  • the "5-11 membered heterocyclic group” means 5 to 7 which is an atom constituting the ring and contains, in addition to the carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • a heteroaromatic heterocyclic ring, a saturated heterocyclic ring, an unsaturated heterocyclic ring or a fused heterocyclic ring obtained by condensing these heterocyclic rings with a benzene ring.
  • the "C6-10 aryl C1-6 alkoxy group” means a group in which the above “C6-10 aryl C1-6 alkyl group” is bonded to an oxygen atom.
  • a benzyloxy group, a phenethyloxy group, a naphthylmethyloxy group, etc. are mentioned.
  • the "C1-6 alkylthio group” may, for example, be a methylthio group, an ethylthio group, a n-propylthio group, an isopropylthio group, a n-butylthio group, an isobutylthio group, a sec-butylthio group or a tertiary group.
  • the "C1-6 alkylsulfinyl group” may, for example, be a methylsulfinyl group, an ethylsulfinyl group, a n-propylsulfinyl group, an isopropylsulfinyl group or a n-butylsulfinic acid.
  • Preferred embodiments of the present invention include the following.
  • R 3 is preferably a C1-6 alkyl group such as a methyl group, an ethyl group or an isopropyl group, or a cyclopropyl group.
  • R 5 is preferably a single bond.
  • R 5 is preferably a single bond
  • R 6 is preferably a C1-6 alkyl group, more preferably a methyl group.
  • R 7 and R 8 are each independently preferably a C1-6 alkyl group, more preferably a methyl group or a different group. Propyl.
  • R 9 is preferably a single bond.
  • a 3 is N
  • a 4 is C
  • a 5 is N
  • a 6 is C
  • a 3 is N
  • a 4 is C
  • a 5 is C
  • a 6 is C
  • a 3 is C
  • a 4 is C
  • a 5 is N
  • a 6 is C
  • a 3 is N
  • a 4 is C
  • a 5 is C
  • a 6 is N
  • a 3 is C
  • a 4 is C
  • a 5 is C
  • a 6 is C
  • the ring A is preferably an unsaturated ring, and the ring B is a saturated ring; preferably, the ring A is an unsaturated ring, and the ring B is an unsaturated ring.
  • the ring A is an unsaturated ring
  • the ring B is a saturated ring
  • a 3 is N
  • a 4 is C
  • a 5 is N
  • a 6 is C.
  • the ring A is an unsaturated ring
  • the ring B is a saturated ring
  • a 3 is N
  • a 4 is C
  • a 5 is C
  • a 6 is C.
  • the ring A is an unsaturated ring
  • the ring B is a saturated ring
  • a 3 is C
  • a 4 is C
  • a 5 is N
  • a 6 is C.
  • the ring A is an unsaturated ring
  • the ring B is a saturated ring
  • a 3 is N
  • a 4 is C
  • a 5 is C
  • a 6 is N.
  • the ring A is an unsaturated ring
  • the ring B is a saturated ring
  • a 3 is C
  • a 4 is C
  • a 5 is C
  • a 6 is C.
  • the ring A is an unsaturated ring
  • the ring B is an unsaturated ring
  • a 3 is N
  • a 4 is C
  • a 5 is N
  • a 6 is C.
  • the ring A is an unsaturated ring
  • the ring B is an unsaturated ring
  • a 3 is N
  • a 4 is C
  • a 5 is C
  • a 6 is C.
  • the ring A is an unsaturated ring
  • the ring B is an unsaturated ring
  • a 3 is C
  • a 4 is C
  • a 5 is N
  • a 6 is C.
  • the ring A is an unsaturated ring
  • the ring B is an unsaturated ring
  • a 3 is N
  • a 4 is C
  • a 5 is C
  • a 6 is N.
  • the ring A is an unsaturated ring
  • the ring B is an unsaturated ring
  • a 3 is C
  • a 4 is C
  • a 5 is C
  • a 6 is C.
  • Ar is preferably a phenyl group optionally substituted by 1 to 5 halogen atoms, and more preferably a phenyl group substituted by 2 fluorine atoms.
  • the "pharmaceutically acceptable salt” in the present specification includes a salt with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, or nitric acid, or with acetic acid, benzoic acid, oxalic acid, lactic acid, malic acid, tartaric acid, and fumaric acid.
  • an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, or nitric acid
  • acetic acid such as acetic acid, benzoic acid, oxalic acid, lactic acid, malic acid, tartaric acid, and fumaric acid.
  • a salt of a metal ion a salt with an amine such as ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcyclohexylamine, 2-aminoethanol, benzathine or the like. It is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • the conversion of the free base of the compound of the present invention to the salt can be carried out by a conventional method.
  • the compound of the present invention may also exist as various solvates.
  • the compounds of the present invention may contain one or more asymmetric centers, thereby being capable of racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomers, and the like.
  • the term "crystalline" includes various crystals of the compounds of the invention, such as single crystals, polymorphs, and the like.
  • the compounds of the invention may be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical formulation.
  • pharmaceutically acceptable carriers, excipients and diluents refer to inactive ingredients in pharmaceutical compositions which do not cause significant irritation to the organism and which do not interfere with the biological activity of the administered compound.
  • excipient and diluent comprising water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, rubber, gel, alginate, calcium silicate , calcium phosphate, cellulose, aqueous syrup, methyl cellulose, polyvinyl pyrrolidone, alkyl p-hydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil Various oils, etc.
  • excipient or diluent in the above carrier, excipient or diluent, it may be mixed as needed.
  • Additives such as extenders, binders, disintegrants, pH adjusters, solubilizers, etc., can be used as tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions by conventional formulation techniques.
  • Oral or parenteral drugs such as agents, ointments, injections, and skin patches are prepared.
  • the compounds of the invention may be administered orally or parenterally to an adult patient.
  • the composition or compound of the present invention is generally administered once every 3-12 days, preferably once every 5-10 days, more preferably once a week, and the total amount of administration is 0.01 to 1000 mg/time.
  • the dose of the compound of the present invention can be appropriately increased or decreased depending on the type of the disease to be treated, the age, body weight, symptoms, and the like of the patient.
  • the compound of the present invention further contains a compound in which one or more hydrogen atoms, fluorine atoms, carbon atoms, nitrogen atoms, oxygen atoms, and sulfur atoms are replaced by a radioisotope or a stable isotope.
  • a radioisotope or a stable isotope can be used for metabolic or pharmacokinetic studies, ligands as receptors, and the like for biological analysis and the like.
  • the compounds of the invention may be used in combination with one or more other drugs (e.g., metformin) to treat, prevent, inhibit or ameliorate a disease or condition, wherein the combined use of the drug is safer or more secure than the separate use of any of the drugs. effective.
  • other drugs may be administered simultaneously or sequentially with the compounds of the present invention in the routes and amounts conventionally used for this purpose.
  • a pharmaceutical composition comprising the other agent and a compound of the invention in a unit dosage form is preferred, especially in combination with a pharmaceutically acceptable carrier.
  • combination therapy can also include treatment of a compound of the invention and one or more other drugs in different overlapping schedules.
  • the compounds of the invention and the other active ingredients may be employed in lower doses than when each is used alone.
  • the pharmaceutical compositions of the invention also include those compositions containing one or more additional active ingredients.
  • the compound of the present invention can be produced, for example, by the method shown below.
  • the compound of the present invention represented by the formula (1) can be produced by the synthesis method shown in Scheme 1.
  • the ketone represented by the formula (2) and the amine represented by the formula (3) are subjected to reductive amination at a temperature of 0 to 50 ° C, preferably 10 to 40 ° C for 0.5 to 30 hours, preferably 1 to 12 hours.
  • a reductive amination product as shown, and the obtained product is further subjected to an amino-protecting group under acidic conditions of pH 2 to 6, to obtain a compound of the formula (1).
  • an oxidation product in the case where the B ring is a saturated ring in the compound represented by the formula (4), an oxidation product can be obtained by an oxidation reaction of DDQ at 10 to 40 ° C for 4 to 10 hours, followed by a halogenated carboxylic acid, preferably trifluoromethane. Under the action of acetic acid at 10-40 ° C, the reaction was removed for 10-16 hours to remove Boc protection, and the corresponding compound having two double bonds in the B ring was obtained.
  • the reaction scheme is as follows:
  • the amine compound represented by the formula (3) in the above ⁇ Scheme 1> is In time, it can be produced by the synthesis method shown in Scheme 2.
  • 3-N-Boc-pyrrolidone is reacted with DMF-DMA at 0-50 ° C, preferably 10-40 ° C for 1-24 hours, preferably 2-12 hours, to give 1-tert-butoxycarbonyl-3-((2) Methylamino)methenyl)-4-pyrrolidone.
  • an alkali metal alkoxide preferably sodium ethoxide, methylthiocyanate and 1-tert-butoxycarbonyl-3-((dimethylamino)methenyl)-4-pyrrolidone are at 10-100 ° C, It is preferably refluxed at 30 to 50 ° C for 0.5 to 48 hours, preferably 2 to 24 hours, to give 2-(methylthio)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester.
  • the amine compound represented by the formula (3) in the above ⁇ Scheme 1> is In time, it can be produced by the synthesis method shown in Scheme 3.
  • the thiourea and 1-tert-butoxycarbonyl-3-((dimethylamino)methenyl)-4-pyrrolidone are subjected to 10-100 ° C, preferably 30-50, under the action of an alkali metal alkoxide, preferably sodium ethoxide.
  • the mixture is refluxed at ° C for 0.5-48 hours, preferably 2-24 hours, to give the desired product 2-mercapto-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester.
  • 2-mercapto-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester is reacted with a halogenated hydrocarbon at a concentration of 5-45 ° C, preferably 10-40 ° C in the presence of a base 0.5-24
  • the alkylation product is obtained in hours, preferably from 1 to 12 hours.
  • the resulting alkylated product and m-chloroperoxybenzophenone The oxidizing agent such as an acid is reacted at 10 to 40 ° C, preferably at room temperature to obtain an oxidation product, and then the Boc protecting group is removed by a halogenated carboxylic acid, preferably trifluoroacetic acid, to obtain an amino compound of the desired product.
  • the amine compound represented by the formula (3) in the above ⁇ Scheme 1> is In time, it can be produced by the synthesis method shown in Scheme 4.
  • R 1 and R 2 are each independently hydrogen or any group selected from the aforementioned substituent group a.
  • the 2-mercapto-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester is oxidized with chlorine gas for 1 to 20 hours, preferably 2 to 6 hours, and then quenched with an amine compound to obtain a sulfonate. Amide product.
  • the Boc protecting group is then removed by the action of a halogenated carboxylic acid, preferably trifluoroacetic acid, to give the amino compound.
  • the nuclear magnetic resonance ( 1 H NMR) measuring instrument uses a JEOL Eclipse 400 nuclear magnetic instrument; the measuring solvent is deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ), hexamethylene dimethyl sulfoxide (DMSO-d6); The internal standard substance is tetramethylsilane (TMS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometer
  • ESI Agilent 6120B
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
  • the compound n' represents a salt form of the compound n.
  • Example 1-1 (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole [3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-amine (Compound 1-1) and its ditrifluoroacetic acid Preparation of salt (compound 1-1')
  • Step 3 Synthesis of 2-(methylsulfonyl)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester
  • Step 7 Free compound (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidine-6 (Preparation of 7H)-yl)tetrahydro-2H-pyran-3-amine (Compound 1-1)
  • (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl) Tetrahydro-2H-pyran-3-amine ditrifluoroacetate is sonicated with 2M sodium carbonate aqueous solution, and then filtered to obtain the free compound (2R, 3S, 5R)-2-(2,5-difluoro Phenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-amine.
  • Example 1-2 (2R,3S,5S)-2-(2,5-Difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole [3,4-d]pyrimidine-6 ( 7H) - yl) tetrahydro -2H-pyran-3-amine (compound 1-2) and its dihydrochloride (compound 1-2 ') of
  • reaction solution was concentrated to dryness to give a semi-solid crude product, which was purified to crude (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-6H-pyrrole [3,4-d]Pyridin-6-yl)tetrahydro-2H-pyran-3-amine trifluoroacetate (38 mg, yellow solid), yield: 75%.
  • Boc-5H-pyrrole [3,4-d]pyrimidin-6(7H)-2-carboxamide instead of (2-(methylsulfonyl)-5H-pyrrole[3,4-d]pyrimidine-6 (7H - tert-butyl carboxylate
  • the Boc-5H-pyrrole[3,4-d]pyrimidin-6(7H)-2-carboxamide was charged in an amount of 200 mg, and the same operation as in the fourth step of Example 1.
  • the title product was obtained in 190 mg in a yield of 90%.
  • the second step synthesis of 2-ethylsulfonyl-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate
  • Example 12 6-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3- 6,7-7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-sulfonylisopropylamine ditrifluoroacetate (combination Preparation of substance 12')
  • Example 10 The same as Example 10 except that isopropylamine was used instead of dimethylamine, and the amount of 2-mercapto-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate was 1 g. The same procedure was carried out in one step to give 720 mg of title product.
  • Step 4 (2R, 3S, 5R)-5-(2-(sec-butylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidine Synthesis of tert-butyl-6-(7H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-carbamate
  • Step 5 ((2R,3S,5R)-5-(2-(sec-butylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-2-( Synthesis of 2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ditrifluoroacetate
  • Step 5 ((2R,3S,5R)-5-(2-(Isobutylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-2-( Synthesis of 2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ditrifluoroacetate
  • the title product was obtained in the same manner as in the first step of Example 10 except that tetrahydropyrrole was used instead of dimethylamine, and the amount of the tetrahydropyrrole was 1 g.
  • the title product was obtained in the same manner as in the first step of Example 10, except that dimethyl hydrazine was used instead of dimethylamine, and the amount of dimethyl hydrazine was 1 g.
  • the feed was 110 mg, and 32 mg of the product was obtained, and the yield was 25%.
  • the third step ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-sulfamoyl-5H-pyrrole [3,4-d]pyrimidine-6(7H)-yl)tetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester
  • Step 3 2-(N-(propylformamide)sulfamoyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester
  • the reaction liquid of the second step was heated to 45 ° C, and then 1.1 mL of n-propylamine was added. After reacting for 2 hours, the reaction system was concentrated and purified by column chromatography to obtain 2-(N-(propylformamide)sulfamoyl)- 5H-Pyrolo[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester (0.39 g, yellow solid, yield, 76.1%).
  • Step 5 ((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-(N-(propylformamide)sulfamoyl)-5H-pyrrolo[ 3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester
  • Step 6 6-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyranyl-N-propylformamide-5H-pyrrole And [3,4-d]pyrimidin-6(7H)-2-sulfonamide ditrifluoroacetate
  • the fourth step 6-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-(N-A Base group)-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidine-2-sulfonamide trifluoroacetate
  • Step 3 tert-Butyl ((2R,3S,5R)-5-(2-(N-decylsulfamoyl)-5,7-dihydro-6H-pyrrole[3,4-d]pyrimidine- 6-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate
  • the third step ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(6-(methylsulfonyl)-1H-pyrrolo[3,4-c]pyridine-2 (3H)-yl)tetrahydro-2H-pyran-3-yl)amino-tert-butylformate
  • Glycinamide hydrochloride (107 g, 0.968 mol), methanol (500 ml) was added to the reaction flask.
  • the reaction was maintained at -35 ° C for 2 h and then allowed to rise to room temperature overnight. The TLC was monitored until the starting material was completely reacted.
  • the third step synthesis of 2,3-dimethyl-5-(methylsulfonyl)pyrazine
  • 2,3-Dibromomethyl-5-(methylsulfonyl)pyrazine (6 g, 17.4 mmol), triphenylmethylamine (4.5 g, 17.4 mmol), N,N-diisopropylethylamine (6.75 g, 52.3 mmol), N,N-dimethylformamide (60 ml) was added to the reaction flask.
  • the reaction solution was heated to 60 ° C under nitrogen atmosphere, stirred for 1 h, and monitored by TLC until the reaction of the starting material was completed. Water was added to the reaction mixture, and the mixture was evaporated.
  • Step 7 ((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-(methylsulfonyl)-5H-pyrrolo[3,4-b]pyrazine Synthesis of -6(7H)-yl)tetrahydro-2H-pyran-3-yl)carbamic acid tert-butyl ester
  • Step 8 (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-(methylsulfonyl)-5H-pyrrolo[3,4-b]pyrazine- Synthesis of 6(7H)-yl)tetrahydro-2H-pyran-3-amine, ditrifluoroacetate
  • reaction mixture was concentrated and purified ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2- (N-(propylformamide)sulfamoyl)-6H-pyrrolo[3,4-d]pyrimidin-6-yl)tetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester (38 mg, Yellow solid, yield 64%).
  • the fourth step isoporphyrin-5-sulfonamide
  • Step 5 ((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-sulfonamideisoindoline-2-yl)tetrahydropyran-3-yl ) tert-butyl formate.
  • Step 6 2-((2R,3S,5R)-5-Amino-6-(2,5-difluorophenyl)-tetrahydropyran-3-yl)isoindoline-5-sulfonamide
  • EtOAc EtOAc
  • tert-Butyl 5-(chlorosulfonyl)isoindoline-2-carboxylate (0.7 g, 2.203 mmol) was added dropwise to dimethylamine hydrochloride (1.79 g, 22.03 mmol) and triethylamine. (2.23 g, 22.03 mmol), the reaction was carried out for three hours at room temperature. A 56 um solid of yellow solid was filtered and taken directly to the next.
  • the third step is tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(N,N-dimethylsulfamoyl)isoindoline- 2-yl)tetrahydro-2H-pyran-3-yl)carbamate
  • Step 2 Synthesis of 5-(chlorosulfonyl)isoindoline-2-carbonate tert-butyl ester
  • Step 3 Synthesis of 5-(N-methylaminesulfonyl)isoindoline-2-carbonate tert-butyl ester
  • Step 2 Synthesis of 5-(isopropylaminosulfonyl)isoindoline-2-carbonate tert-butyl ester
  • 5-sulfonamide isoindole-2-carboxylic acid tert-butyl ester (0.584 g, 1.96 mmol) was dissolved in 10 mL of acetonitrile under ice-cooling, then 0.57 mL of triethylamine was added, (0.367 g, 2.35 mmol) of chlorine
  • the phenyl formate was dissolved in 2 mL of acetonitrile and slowly added dropwise to the reaction system. After the reaction was completed, the reaction solution was directly used for the next reaction.
  • the reaction liquid of the second step was heated to 45 ° C, and then 1.5 mL of n-propylamine was added. After reacting for 2 hours, the reaction system was concentrated and purified by column chromatography to obtain 5-(N-(propylformamide)sulfamoyl) Tert-butyl phthalate-2-carboxylate (0.375 g, 50% yield in two steps).
  • the third step product and ((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester (0.382 g, 1.17 mmol) was dissolved in THF/DMA (8 mL / 4 mL), and reacted at 60 ° C for 1 h under argon. After cooling, sodium cyanoborohydride (0.307 g, 4.9 mmol) was added and the reaction was continued for 25 min. The reaction was quenched and extracted with ethyl acetate and brine. Purification by column chromatography gave 325 mg of crude material.
  • Step 2 Synthesis of 5-(decylsulfonyl)isoindoline-2-carbonate tert-butyl ester
  • tert-Butyl 5-(methylsulfonamido)isoindoline-2-carbonate (420 mg, 1.35 mmol) was added to a solution of 15 ml of a 4 mol/L hydrochloric acid dioxane in an ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The title compound (260 mg, 78%). MS m/z (ESI): 21:21.
  • tert-Butyl 5-(sec-butylsulfonyl)isoindoline-2-carbonate 500 mg, 1.47 mmol was added to a solution of 15 ml of a 4 mol/L hydrochloric acid dioxane in an ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The reaction mixture was concentrated to give crystall MS m/z (ESI): 242.
  • Test Example 1 Detection of inhibition of DPP-2/4/8/9 enzyme activity by compound
  • Enzyme DPP-2/4/8/9 Recombinant Human DPP-4/CD26; manufacturer: R&D Company;
  • DPP-4/8/9 substrate H-Gly-Pro-AMC ⁇ HBr
  • DPP-2 substrate Lys-Pro-AMC
  • manufacturer Bachem
  • test compound was dissolved in assay buffer (25 mM Tris-HCl, 140 mM NaCl, 10 mM KCl, 0.1% BSA, pH 7.4) at various concentrations.
  • DPP-4 and the test compound were added to a 384-well plate, and the mixture was incubated at 37 ° C for 15 minutes.
  • the reaction was initiated by the addition of a substrate (H-Gly-Pro-AMC.HBr).
  • the well plate was placed in a microplate reader, and in the enzyme kinetic mode, the excitation light wavelength was selected to be 380 nm, and the emission light wavelength was 460 nm to read the fluorescence value.
  • the slope of the change in fluorescence value of each experimental group was calculated during the linear reaction period, and the half-inhibitory concentration IC 50 value of the compound was fitted using SigmaPlot or GraphPad Prism 5 software.
  • Detection method for inhibition of DPP-2 enzyme activity The test compound is dissolved in the detection buffer at different concentrations. Add DPP-2 and the test compound to the multi-well plate, mix and add the substrate (Lys-Pro-AMC) and test under the microplate reader. Calculate the slope of the fluorescence value of each experimental group during the linear reaction period, using SigmaPlot or fitting software GraphPad Prism 5 50 value of the compound IC.
  • Detection method for inhibition of DPP-8/9 enzyme activity The test compound was dissolved in a detection buffer (25 mM Tris-HCl, 140 mM NaCl, 10 mM KCl, 0.1% BSA, pH 7.4) at various concentrations. DPP-8/9 and the test compound were added to a 384-well plate, and the mixture was incubated at 37 ° C for 15 minutes. The reaction was initiated by the addition of a substrate (H-Gly-Pro-AMC.HBr). The well plate was placed in a microplate reader, and in the enzyme kinetic mode, the excitation light wavelength was selected to be 380 nm, and the emission light wavelength was 460 nm to read the fluorescence value. The slope of the change in fluorescence value of each experimental group was calculated during the linear reaction period, and the IC 50 value of the compound was fitted using SigmaPlot or GraphPad Prism 5 software.
  • Compound DPP-4IC 50 1-1 0.45 111’ 0.50 5’ 1.24 7’ 0.46 8' 1.00 twenty two 0.52 10’ 0.36 11’ 0.65 12’ 0.82 26’ 0.95 29’ 0.45 30’ 0.67 28 1.10 28’ 1.38 20’ 0.69 31’ 0.43 19 0.85 19’ 0.90 14’ 0.47 16’ 1.20 17’ 0.97 twenty one' 0.33 twenty two' 0.52 twenty three' 0.56 36 0.81 37 0.43 38’ 0.35 39’ 0.83 41’ 0.65 42’ 1.37 46’ 1.02 47’ 1.16 48’ 0.67
  • the compounds of the present invention showed substantially no inhibitory effect on DPP-2, DPP-8, and DPP-9.
  • the compounds of the present application differ in selectivity for different DPPs, and the compounds of the present invention have a significant inhibitory effect on DPP-4 relative to DPP-2, DPP-8 and DPP-9.
  • the compound of the present invention has a similar inhibitory effect as the above compound, and the inhibitory effect on DPP-4 is significantly higher than that on DPP-2, DPP-8, and DPP-9, indicating that the compound of the present invention has excellent DPP subtype selectivity. .
  • the free base of the compound of the present invention or a salt thereof has a similar inhibitory effect as the above compound, and the inhibitory effect on DPP-4 is significantly higher than that on DPP-2, DPP-8, and DPP-9, indicating that the compound of the present invention is excellent.
  • DPP subtype selectivity DPP subtype selectivity.
  • DPP-4 substrate H-Gly-Pro-AMC ⁇ HBr; manufacturer: Bachem.
  • In vivo DPP-4 enzyme activity inhibition detection method a plasma sample and a detection buffer are mixed in a multi-well plate, and then a DPP-4 substrate is added to initiate the reaction. The well plate was placed in a microplate reader for detection. The slope of the fluorescence value of each experimental group was calculated during the linear reaction period, and the inhibition rate of the enzyme activity was calculated.
  • This experiment primarily investigates the long-acting effects of the compounds of the invention, such as DPP-4 inhibition over 48 hours (e.g., 2-4 days).
  • Table 7 shows the inhibition rate of plasma DPP-4 after compound 19' and Ogedetine intravenous (iv) administration
  • the compound 39' of the present invention was administered intravenously (iv) in dogs, and the inhibition rate of plasma DPP-4 at a low dose of 0.5 mg/kg was significantly higher than that of the positive control alogliptin 1 mg/kg.
  • the inhibition rate at high doses and the 87.5% inhibition rate at 96 hours indicates that the compound has an excellent inhibitory effect.
  • the compound 19' of the present invention was administered intravenously (iv) in dogs, and the inhibition rate of plasma DPP-4 at a low dose of 0.73 mg/kg was significantly higher than that of the positive control alogliptin 1 mg/kg.
  • the inhibition rate at high doses and the 81.6% inhibition rate at 96 hours indicates that the compound has an excellent inhibitory effect.
  • the compound of the present invention 19 was administered intravenously (iv) in dogs, and the inhibition rate of plasma DPP-4 at a low dose of 0.73 mg/kg was significantly higher than that of the positive control alogliptin 1 mg/kg.
  • the inhibition rate at the dose and still had an inhibition rate of 85.4% at 96 hours, indicating that the compound has an excellent inhibitory effect.
  • the compound 39' of the present invention was administered by intragastric administration (po) in dogs, and the inhibition rate of plasma DPP-4 at a low dose of 1 mg/kg was significantly higher than that of the positive control alogliptin 2 mg/kg.
  • the inhibition rate at high doses and the 91.7% inhibition rate at 96 hours indicates that the compound has an excellent inhibitory effect.
  • the compound 19' of the present invention was administered by intragastric administration (po) in dogs, and at a low dose of 1.25 mg/kg, there was still 86.8% inhibition rate of plasma DPP-4 at 96 hours, which was significantly higher than that.
  • the inhibition rate of the positive control alogliptin at a high dose of 2 mg/kg indicates that the compound has an excellent inhibitory effect.
  • the compound 19 of the present invention was administered by intragastric administration (PO) in dogs, and at a low dose of 1.25 mg/kg, there was still 86.5% inhibition of plasma DPP-4 at 96 hours, which was significantly higher than that of the positive one.
  • the inhibition rate of the high dose of the control of alogliptin at 2 mg/kg, indicates that the compound has an excellent inhibitory effect.
  • the compound of the present invention has a similar inhibitory effect on plasma DPP-4 and a longer potency when administered intravenously (iv) or intragastrically (po) in dogs.
  • the free base of the compound of the present invention or a salt thereof has a plasma DPP-4 inhibitory effect and a longer pharmacodynamic time similar to those of the above compounds when administered intravenously (iv) or intragastrically (po) in dogs.
  • the male compounds of the present invention were administered intravenously and intragastrically, respectively, to examine the pharmacokinetic characteristics.
  • the respective doses of iv and po were 5% DMSO: 5% solutol: 90% Saline.
  • Blood was collected at different time points after iv administration and po administration for PK/PD studies. Plasma samples were processed by precipitation protein and analyzed by LC-MS/MS. The results are shown in the table below.
  • the compound of the present invention has similar pharmacokinetic effects as the above compounds.
  • the free base of the compound of the present invention or a salt thereof is administered by intravenous (IV) administration or intragastric administration (po), it exhibits a similar pharmacological parameter exposure to the above-mentioned compound than the body, and exhibits excellent bioavailability.
  • the potassium channel encoded by the human Ether-a-go-go Related Gene mediates a delayed rectifier potassium current (IKr). IKr inhibition is the most important mechanism for drug-induced QT interval prolongation.
  • the manual patch clamp method was judged to be that if the compound IC 50 > 30 ⁇ M, it was judged that the compound had no inhibitory effect on hERG.
  • test cells were CHO cell lines transfected with hERG cDNA and stably expressing hERG channels. The cells were placed in an electrophysiological recording cell under an inverted microscope. The extracellular fluid was continuously perfused in the recording tank. The experimental procedure uses conventional whole-cell patch clamp current recording techniques. The test results are shown in Table 15:
  • the compounds of the invention have similar safety to the compounds described above.
  • the free base of the compound of the present invention or a salt thereof has similar safety to the above compounds.
  • liver microsome solution (the final concentration of liver microsomes in the reaction system was 0.2 mg/mL) was added to a 1.1 mL centrifuge tube. No positive inhibitor and test compound were added to the blank sample, 2 ⁇ L of DMSO was added, 200 ⁇ L of internal standard methanol solution was added, vortexed for 1 min (ie, minutes), and finally 20 ⁇ L of NADPH solution was added. For non-blank samples, add 2 ⁇ L of inhibitor or stock solution of the test compound (10 ⁇ M) to a 1.1 mL centrifuge tube, vortex and mix for 5 min at 37 °C, and add 20 ⁇ L of NADPH solution to start the reaction (NADPH in the reaction system).
  • the final concentration was 1 mM) and incubated for 20 min at 37 ° C with shaking. After the incubation, the reaction was terminated by adding an internal standard methanol solution, and the sample was centrifuged at 4000 rpm for 5 min, and the supernatant was taken to LC/MS/MS for analysis.
  • the compounds of the present invention have similar safety to the above-mentioned compounds, and the risk of drug interactions in clinical combination is small.
  • the free base or a salt thereof of the compound of the present invention has similar safety to the above-mentioned compound, and the clinical combination drug has a lower risk of drug interaction.
  • a 100 mg titer tablet consisting of the following ingredients was produced.
  • the active substance, microcrystalline cellulose and croscarmellose are mixed, and then the mixture is lubricated with magnesium stearate and compressed into tablets.
  • a granule for capsule filling containing the following components was produced.
  • the compound represented by the formula (1) and lactose were passed through a sieve of 60 mesh.
  • the corn flour was passed through a 120 mesh sieve. These were mixed, and the HPC-L solution was added to the mixed powder, kneaded, granulated, and dried. After the obtained dried granules were sized, 150 mg of the obtained dried granules were filled in a No. 4 hard gelatin capsule.
  • the compound of formula (1) and lactose were passed through a 60 mesh sieve.
  • the corn flour was passed through a sieve of 120 mesh. They were mixed using a V-type mixer.
  • An HPC-L (low viscosity hydroxypropylcellulose) aqueous solution is added to the mixed powder, and kneading, granulation (extrusion granulation pore diameter: 0.5 to 1 mm), and drying are carried out.
  • the obtained dried granules were sieved with a shaking sieve (12/60 mesh) to obtain granules.
  • a compound which is a dipeptidyl peptidase-IV inhibitor which has high inhibitory activity against dipeptidyl peptidase-IV and has excellent drug metabolism properties can be used for treatment and prevention including treatment of diabetes, Especially DPP-4 related diseases of type II diabetes.

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Abstract

The present invention relates to a long-acting dipeptidyl peptidase-IV inhibitor, applications, and a preparation method for an intermediate thereof. Specifically, the present invention relates to a compound represented by general formula (1) and a preparation method therefor, applications of the compound in treating and preventing diseases comprising diabetes mellitus and diseases related to DPP-4 of the type II diabetes mellitus, and a pharmaceutical composition and a pharmaceutical preparation comprising the compound represented by general formula (1), definitions of symbols in the general formula being same as those in the descriptions.

Description

长效二肽基肽酶-IV抑制剂、用途及其中间体的制备方法Long-acting dipeptidyl peptidase-IV inhibitor, use thereof and preparation method thereof 技术领域Technical field
本发明涉及作为二肽基肽酶-IV(DPP-4)抑制剂的化合物及其在治疗和预防包括糖尿病尤其是II型糖尿病的DPP-4相关疾病中的应用。本发明还涉及制备上述化合物及其中间体的制备方法。另外，本发明还涉及包含这些化合物的药物组合物，以及这些组合物在与DPP-4有关的疾病的预防或治疗中的用途。The present invention relates to compounds as dipeptidyl peptidase-IV (DPP-4) inhibitors and their use in the treatment and prevention of DPP-4 related diseases including diabetes, especially type II diabetes. The invention further relates to a process for the preparation of the above compounds and intermediates thereof. Further, the present invention relates to pharmaceutical compositions comprising these compounds, and the use of these compositions in the prevention or treatment of diseases associated with DPP-4.
背景技术Background technique
糖尿病是由遗传因素、免疫功能紊乱、微生物感染及其毒素、自由基毒素、精神因素等各种致病因子作用而引起的慢性代谢疾病，临床上以高血糖为主要症状。其可分为I型糖尿病(胰岛素依赖型)、II型糖尿病(非胰岛素依赖型)、妊娠糖尿病及其他特殊类型的糖尿病。在糖尿病患者中，II型糖尿病所占的比例约为90％。Diabetes is a chronic metabolic disease caused by various factors such as genetic factors, immune dysfunction, microbial infection and its toxins, free radical toxins, and mental factors. Clinically, hyperglycemia is the main symptom. It can be divided into type I diabetes (insulin dependent), type II diabetes (non-insulin dependent), gestational diabetes and other special types of diabetes. In diabetic patients, the proportion of type 2 diabetes is about 90%.
传统的口服降糖药种类繁多，包括磺脲类(SU)、双胍类药物等，但是一般都伴有体重增加，耐受性有限，低血糖等副作用以及药效逐渐降低等问题，因此，人们正在寻找新的治疗药物，许多新的治疗靶点正在研究中，其中以二肽基肽酶-IV(DPP-4)为靶点的药物研究取得的成果尤为突出(非专利文献1)。Traditional oral hypoglycemic agents, including sulfonylureas (SU) and biguanides, are generally associated with weight gain, limited tolerance, side effects such as hypoglycemia, and gradual reduction in efficacy. New therapeutic drugs are being sought, and many new therapeutic targets are under investigation, and the results of drug research targeting dipeptidyl peptidase-IV (DPP-4) are particularly outstanding (Non-Patent Document 1).
二肽基肽酶-IV(DPP-4)是一种丝氨酸蛋白酶。有研究表明DPP-4可以阻止胰高血糖素样肽(GLP)-1的分泌，尤其，它可以裂解GLP-1中N-末端的组-丙二肽酶，使其从活性形式的GLP-1(7-36)NH2降解为无活性GLP-1(9-36)NH2(非专利文献2)。胰高血糖素样肽-1(GLP-1)是由胰岛α-细胞和肠道L-细胞分泌的一种激素，具有葡萄糖依赖性促胰岛素分泌以及增加胰岛素生物合成的作用，因此使用GLP-1治疗糖尿病引起科学家极大兴趣。GLP-1除了具有促进胰岛素分泌作用外，还具有促进β-细胞增生、抗β-细胞凋亡、抑制胰高血糖素和肝糖的生成、抑制食欲、降低胃肠排空速度、保护神经细胞等生理功能。GLP-1这些特点使其成为理想的糖尿病治疗药物。然而，GLP-1在体内的半衰期仅数分钟，迅速被内源性二肽基肽酶-IV(DPP-4)降解(除去N端二肽)，而失去促胰岛素分泌活性(非专利文献3)。 Dipeptidyl peptidase-IV (DPP-4) is a serine protease. Studies have shown that DPP-4 can block the secretion of glucagon-like peptide (GLP)-1, in particular, it can cleave the N-terminal group-propadipeptide enzyme of GLP-1 from the active form of GLP- 1 (7-36) NH 2 degrades into inactive GLP-1 (9-36) NH 2 (Non-Patent Document 2). Glucagon-like peptide-1 (GLP-1) is a hormone secreted by islet α-cells and intestinal L-cells, which has glucose-dependent insulin secretion and increases insulin biosynthesis. Therefore, GLP- is used. 1 The treatment of diabetes has caused great interest among scientists. In addition to promoting insulin secretion, GLP-1 also promotes β-cell proliferation, anti-β-cell apoptosis, inhibits glucagon and glycogen production, suppresses appetite, reduces gastrointestinal emptying rate, and protects nerve cells. And other physiological functions. These characteristics of GLP-1 make it an ideal treatment for diabetes. However, GLP-1 has a half-life in vivo of only a few minutes, and is rapidly degraded by endogenous dipeptidyl peptidase-IV (DPP-4) (removing the N-terminal dipeptide), thereby losing insulin secretion-promoting activity (Non-Patent Document 3) ).
DPP-4在人体内广泛分布，是GLP-1的主要代谢酶，在调控GLP-1活性中发挥着重要作用。因此抑制DPP-4的活性化合物、即DPP-4抑制剂，可增强GLP-1的作用。除此之外，DPP-4抑制剂还具有促进β-细胞增生、抗β-细胞凋亡、抑制胰高血糖素和肝糖的生成、抑制食欲、不增加体重，降低胃肠排空速度、保护神经细胞等作用。因此，DPP-4抑制剂还可用于与二肽基肽酶相关的各种疾病例如肥胖症和高血脂的治疗(非专利文献4)。DPP-4 is widely distributed in human body and is the main metabolic enzyme of GLP-1, which plays an important role in regulating GLP-1 activity. Thus, inhibition of the active compound of DPP-4, a DPP-4 inhibitor, enhances the action of GLP-1. In addition, DPP-4 inhibitors also promote β-cell proliferation, anti-β-cell apoptosis, inhibit glucagon and glycogen production, suppress appetite, increase body weight, reduce gastrointestinal emptying rate, Protect nerve cells and other effects. Therefore, DPP-4 inhibitors can also be used for the treatment of various diseases associated with dipeptidyl peptidases such as obesity and hyperlipidemia (Non-Patent Document 4).
自2003年DPP-4的晶体结构报道之后，近年来多种新结构类型的DPP-4抑制剂相继上市，如默克公司研发的磷酸西他列汀等(sitagliptin phosphate，2006年10月在美国上市)。Since the crystal structure of DPP-4 was reported in 2003, a number of new structural types of DPP-4 inhibitors have been listed in recent years, such as sitagliptin phosphate developed by Merck (sitagliptin phosphate, in the United States in October 2006). Listing).
然而，尽管存在上述若干DPP-4抑制剂，但是这些化合物对DPP-4的抑制活性还不够令人满意，缺乏对DPP-2/8/9酶的选择性，且目前还缺乏长效的药物。因此，人们迫切希望开发药物代谢等的性质得到改善、活性更高、毒副作用更小、可用于长效的结构新颖的DPP-4抑制剂，以便治疗与DPP-4相关的各种疾病。However, despite the presence of several of the above DPP-4 inhibitors, the inhibitory activity of these compounds on DPP-4 is not satisfactory, lacks selectivity for the DPP-2/8/9 enzyme, and currently lacks long-acting drugs. . Therefore, there is an urgent need to develop a novel DPP-4 inhibitor which is improved in properties such as drug metabolism, has higher activity, and has less toxic side effects, and can be used for long-acting, in order to treat various diseases associated with DPP-4.
现有技术文献Prior art literature
[非专利文献1]Medicinal Research Review，2009，29(1)，125-195[Non-Patent Document 1] Medicinal Research Review, 2009, 29(1), 125-195
[非专利文献2]Endocrinology，1999，140：5356～5363[Non-Patent Document 2] Endocrinology, 1999, 140: 5356 to 5363
[非专利文献3]Expert Opin.Investing.Drugs，2004，13(9)：1091-1102[Non-Patent Document 3] Expert Opin. Investing. Drugs, 2004, 13(9): 1091-1102
[非专利文献4]Diabetologia，2007，50(6)：1148-1155[Non-Patent Document 4] Diabetologia, 2007, 50(6): 1148-1155
发明内容Summary of the invention
本发明的目的是提供一种作为二肽基肽酶-IV(DPP-4)抑制剂的化合物、其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，它们可用于治疗和预防包括治疗糖尿病、尤其是II型糖尿病的DPP-4相关疾病。进一步详细地，本发明提供具有新型取代的3-氨基四氢吡喃结构，对二肽基肽酶-IV具有高的抑制活性和具有优异的药物代谢性质的新的化合物。An object of the present invention is to provide a compound as a dipeptidyl peptidase-IV (DPP-4) inhibitor, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form thereof or Prodrugs, which are useful in the treatment and prevention of DPP-4 related diseases including the treatment of diabetes, especially type 2 diabetes. In further detail, the present invention provides a novel compound having a novel substituted 3-aminotetrahydropyran structure, a high inhibitory activity against dipeptidyl peptidase-IV, and excellent drug metabolism properties.
另外，本发明目的还在于提供用于治疗与二肽基肽酶-IV相关的各种疾病的、含有治疗有效量的本发明化合物以及药学上可以接受的载体或赋形剂的药用组合物。Further, it is an object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable carrier or excipient for treating various diseases associated with dipeptidyl peptidase-IV. .
另外，本发明的目的还在于提供含有该化合物药学上可接受的盐 的治疗剂，特别是二肽基肽酶-IV抑制剂，该成盐形式具有优异的治疗糖尿病的活性，溶解度明显改善，且在动物体内的活动及其生物利用度良好，毒性低，适用于制备治疗糖尿病的制剂。Further, it is an object of the present invention to provide a pharmaceutically acceptable salt containing the compound The therapeutic agent, in particular the dipeptidyl peptidase-IV inhibitor, has an excellent activity for treating diabetes, has markedly improved solubility, and has good activity and bioavailability in animals, and low toxicity, and is suitable for use in A preparation for treating diabetes is prepared.
本发明人为了实现上述目的进行了深入地研究，结果发现：具有3-氨基四氢吡喃结构的特定化合物、即，后述通式(I)所示的化合物与现有技术相比，具有经葡萄糖依赖性机制起作用，因此减少低血糖的风险的优点，另外与现有的DPP-4抑制剂相比，本发明的所述化合物具有更有利的药物动力学性能，更久的持续时间，从而完成了本发明。The present inventors have conducted intensive studies in order to achieve the above object, and as a result, have found that a specific compound having a 3-aminotetrahydropyran structure, that is, a compound represented by the following formula (I) has a higher The advantage of a glucose-dependent mechanism, thus reducing the risk of hypoglycemia, in addition to the existing DPP-4 inhibitors, the compounds of the invention have more favorable pharmacokinetic properties, longer durations Thus, the present invention has been completed.
具体地，本发明的实施方式可以列举以下的内容。Specifically, the following embodiments of the present invention can be cited.
下述通式(1)表示的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，a compound represented by the following formula (1), a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof,
Figure PCTCN2016000478-appb-000001
Figure PCTCN2016000478-appb-000001
式中，In the formula,
A环为不饱和环，B环中的
Figure PCTCN2016000478-appb-000002
表示单键或双键；Ring A is an unsaturated ring, in the B ring
Figure PCTCN2016000478-appb-000002
Represents a single or double bond;
A3、A4、A5和A6各自独立地选自碳原子或氮原子，并且A3、A4、A5和A6中至少2个是碳原子；A 3 , A 4 , A 5 and A 6 are each independently selected from a carbon atom or a nitrogen atom, and at least 2 of A 3 , A 4 , A 5 and A 6 are carbon atoms;
R1、R2分别独立地与A3、A4、A5或A6中的碳原子结合，且独立地选自氢原子、氰基、硝基、-S(＝O)2R3、-R5-COOH、-R5COOR6、任选被选自取代基组a的基团取代的巯基、任选被选自取代基组a的基团取代的氨基、任选被选自取代基组a的基团取代的亚磺酰基、任选被选自取代基组a的基团取代的C1-6烷基、任选被选自取代基组a的基团取代的C1-6烷氧基、任选被选自取代基组a的基团取代的C2-6烷酰基、任选被选自取代基组a的基团取代的C3-8环烷基、任选被选自取代基组a的基团取代的C6-10芳基、任选被选自取代基组a的基团取代的5-11元杂环基、-R9(C＝O)-NR7R8、或-R9(C＝O)-NH2；R 1 and R 2 are each independently bonded to a carbon atom in A 3 , A 4 , A 5 or A 6 , and are independently selected from a hydrogen atom, a cyano group, a nitro group, -S(=O) 2 R 3 , -R 5 -COOH, -R 5 COOR 6 , a fluorenyl group optionally substituted by a group selected from the substituent group a, an amino group optionally substituted with a group selected from the substituent group a, optionally selected from the group consisting of a group-substituted sulfinyl group of the group a, a C1-6 alkyl group optionally substituted with a group selected from the substituent group a, a C1-6 alkane optionally substituted with a group selected from the substituent group a An oxy group, a C2-6 alkanoyl group optionally substituted with a group selected from the substituent group a, a C3-8 cycloalkyl group optionally substituted with a group selected from the substituent group a, optionally selected from the group consisting of a C6-10 aryl group substituted with a group of the group a, a 5-11 membered heterocyclic group optionally substituted with a group selected from the substituent group a, -R 9 (C=O)-NR 7 R 8 , Or -R 9 (C=O)-NH 2 ;
其中，R3选自羟基、任选被选自取代基组a的基团取代的烷基、任选被选自取代基组a的基团取代的环烷基、任选被选自取代基组a 的基团取代的氨基、任选被选自取代基组a的基团取代的氨基C2-6烷酰基、任选被选自取代基组a的基团取代的氨基羰基氨基、任选被选自取代基组a的基团取代的C6-10芳基、任选被选自取代基组a的基团取代的5-11元杂环基；Wherein R 3 is selected from a hydroxyl group, an alkyl group optionally substituted with a group selected from the substituent group a, a cycloalkyl group optionally substituted with a group selected from the substituent group a, optionally selected from a substituent a group-substituted amino group of group a, an amino C2-6 alkanoyl group optionally substituted with a group selected from substituent group a, an aminocarbonylamino group optionally substituted with a group selected from substituent group a, optionally a C6-10 aryl group substituted with a group selected from the substituent group a, a 5-11 membered heterocyclic group optionally substituted with a group selected from the substituent group a;
R5为单键或C1-6亚烷基、C2-6亚烯基、或C2-6亚炔基；R 5 is a single bond or a C1-6 alkylene group, a C2-6 alkenylene group, or a C2-6 alkynylene group;
R6为C1-6烷基、C2-6烯基、或C2-6炔基；R 6 is C1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
R7和R8各自独立地为氢、羟基、任选被选自取代基组a的基团取代的C1-6烷基、任选被选自取代基组a的基团取代的C3-8环烷基、任选被选自取代基组a的基团取代的氨基(前提是R7和R8不同时为氢)；R 7 and R 8 are each independently hydrogen, hydroxy, C 1-6 alkyl optionally substituted with a group selected from substituent group a, C 3-8 optionally substituted with a group selected from substituent group a a cycloalkyl group, optionally substituted with a group selected from the group of substituent group a (provided that R 7 and R 8 are not hydrogen at the same time);
R9为单键、C1-6亚烷基、C2-6亚烯基、或C2-6亚炔基，R 9 is a single bond, a C1-6 alkylene group, a C2-6 alkenylene group, or a C2-6 alkynylene group.
前提是当B环为饱和环时，R1、R2不同时为氢原子；和当B环为饱和环且R1和R2中的一方为氢原子时，R1和R2中的另一方不为任选被选自卤素原子和C1-6烷氧基中的取代基取代的C1-6烷基、氰基、任选被取代的C1-6烷氧基、任选被取代的C3-8环烷基、任选被取代的5-11元杂环基；Provided that when the B ring is a saturated ring, R 1 and R 2 are not simultaneously a hydrogen atom; and when the B ring is a saturated ring and one of R 1 and R 2 is a hydrogen atom, the other of R 1 and R 2 One of the groups is not a C1-6 alkyl group optionally substituted with a substituent selected from a halogen atom and a C1-6 alkoxy group, a cyano group, an optionally substituted C1-6 alkoxy group, or an optionally substituted C3. -8 cycloalkyl, optionally substituted 5-11 membered heterocyclic group;
Ar是任选被1～5个选自取代基组a的基团取代的C6-10芳基；Ar is a C6-10 aryl group optionally substituted by 1 to 5 groups selected from the substituent group a;
取代基组a：由C1-6烷基、C2-6烯基、C2-6炔基、卤化的C1-6烷基、卤素、-CN、NHOH、-OH、-O-C1-6烷基、-NH-C1-6烷基、-N(C1-6烷基)2、-NH2、-C(＝NH)-NH-CH3、-C(＝NH)-N(CH3)2、-C(＝NH)-NH2、-C(＝NH)-NH-C1-6烷基、-C(O)NH2、-C(O)NH-C1-6烷基、-C(O)N(C1-6烷基)2、-NHC(O)-C1-6烷基、-NHC(O)-C3-8环烷基、-N(C1-6烷基)C(O)H、-N(C1-6烷基)C(O)-C1-6烷基、-NHC(O)NH2、-SO2-C1-6烷基组成。Substituent group a: from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogenated C1-6 alkyl, halogen, -CN, NHOH, -OH, -O-C1-6 alkyl , -NH-C1-6 alkyl, -N(C1-6alkyl) 2 , -NH 2 , -C(=NH)-NH-CH 3 , -C(=NH)-N(CH 3 ) 2 , -C(=NH)-NH 2 , -C(=NH)-NH-C1-6 alkyl, -C(O)NH 2 , -C(O)NH-C1-6 alkyl, -C( O) N(C1-6 alkyl) 2 , -NHC(O)-C1-6 alkyl, -NHC(O)-C3-8 cycloalkyl, -N(C1-6alkyl)C(O) H, -N(C1-6alkyl)C(O)-C1-6 alkyl, -NHC(O)NH 2 , -SO 2 -C1-6 alkyl.
本发明所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，a compound of the present invention, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein
A3为N，A4为C，A5为N，A6为C，或A 3 is N, A 4 is C, A 5 is N, A 6 is C, or
A3为N，A4为C，A5为C，A6为C，或A 3 is N, A 4 is C, A 5 is C, A 6 is C, or
A3为C，A4为C，A5为N，A6为C，或A 3 is C, A 4 is C, A 5 is N, A 6 is C, or
A3为N，A4为C，A5为C，A6为N，或A 3 is N, A 4 is C, A 5 is C, A 6 is N, or
A3为C，A4为C，A5为C，A6为C。A 3 is C, A 4 is C, A 5 is C, and A 6 is C.
所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、 异构体、晶型或其前药，通式(I)中，A环为不饱和环，B环为饱和环，a pharmaceutically acceptable salt or ester, solvate, hydrate thereof, Isomer, crystal form or prodrug thereof, in the formula (I), the ring A is an unsaturated ring, and the ring B is a saturated ring.
A3为N，A4为C，A5为N，A6为C，或A 3 is N, A 4 is C, A 5 is N, A 6 is C, or
A3为N，A4为C，A5为C，A6为C，或A 3 is N, A 4 is C, A 5 is C, A 6 is C, or
A3为C，A4为C，A5为N，A6为C，或A 3 is C, A 4 is C, A 5 is N, A 6 is C, or
A3为N，A4为C，A5为C，A6为N，或A 3 is N, A 4 is C, A 5 is C, A 6 is N, or
A3为C，A4为C，A5为C，A6为C。A 3 is C, A 4 is C, A 5 is C, and A 6 is C.
本发明所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，通式(I)中，A环为不饱和环，B环为不饱和环，A compound of the present invention, which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof. In the formula (I), the ring A is an unsaturated ring, and the ring B is a ring. As an unsaturated ring,
A3为N，A4为C，A5为N，A6为C，或A 3 is N, A 4 is C, A 5 is N, A 6 is C, or
A3为N，A4为C，A5为C，A6为C，或A 3 is N, A 4 is C, A 5 is C, A 6 is C, or
A3为C，A4为C，A5为N，A6为C，或A 3 is C, A 4 is C, A 5 is N, A 6 is C, or
A3为N，A4为C，A5为C，A6为N，或A 3 is N, A 4 is C, A 5 is C, A 6 is N, or
A3为C，A4为C，A5为C，A6为C。A 3 is C, A 4 is C, A 5 is C, and A 6 is C.
本发明所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，a compound of the present invention, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein
R1、R2分别独立地为氢原子、-S(＝O)2-C1-6烷基、-S(＝O)2-C3-8环烷基、-S(＝O)2-N(C1-6烷基)2、-S(＝O)2-NH(C1-6烷基)、任选被C1-6烷基取代的磺酰氨基、-S(＝O)2-C2-6烷酰基、C6-10芳基C1-6烷基、被C1-6烷基取代的-S(＝O)2-氨基羰基氨基、-COO-C1-6烷基、被C1-6烷基取代的氨基、C1-6烷基、C1-6烷氧基、C3-8环烷基、C6-10芳基、C6-10芳基C1-8烷氧基、C1-6烷硫基、5-11元杂环基、-(C＝O)-NH-C1-6烷基、-(C＝O)-N(C1-6烷基)2、-(C＝O)-NH-C3-8环烷基、-(C＝O)-N(C3-8环烷基)2、C1-6烷基亚磺酰基或单C1-6烷基氨基羰基、或二C1-6烷基氨基羰基。R 1 and R 2 are each independently a hydrogen atom, -S(=O) 2 -C1-6 alkyl, -S(=O) 2 -C3-8 cycloalkyl, -S(=O) 2 -N (C1-6 alkyl) 2 , -S(=O) 2 -NH(C1-6 alkyl), sulfonylamino optionally substituted by C1-6 alkyl, -S(=O) 2 -C2- 6 alkanoyl, C6-10 aryl C1-6 alkyl, -S(=O) 2 -aminocarbonylamino substituted by C1-6 alkyl, -COO-C1-6 alkyl, C1-6 alkyl Substituted amino, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, C6-10 aryl, C6-10 aryl C1-8 alkoxy, C1-6 alkylthio, 5 -11 membered heterocyclic group, -(C=O)-NH-C1-6 alkyl, -(C=O)-N(C1-6alkyl) 2 , -(C=O)-NH-C3- 8-cycloalkyl, -(C=O)-N(C3-8 cycloalkyl) 2 , C1-6 alkylsulfinyl or mono C1-6 alkylaminocarbonyl, or di-C1-6 alkylaminocarbonyl .
本发明所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，R1、R2分别独立地为氢原子、氨基、-S(＝O)2-CH3、-S(＝O)2-CH2CH3、-S(＝O)2-CH(CH3)2、-S(＝O)2-OH、-S(＝O)2-环丙基、-S(＝O)2-NH2、-S(＝O)2-N(CH3)2、-S(＝O)2-NHCH3、-S(＝O)2-NH-CHCH3)2、-S(＝O)2-CH2-CHCH3)2、-S(＝O)2-CH(CH3)-CH2CH3、-S(＝O)2-NH-C(＝NH)-NH-CH3、-S(＝O)2-NH-C(＝O)-NH-(CH2)2CH3、-S(＝O)2-NH-C(＝NH)-NH2、-NH-C(＝NH)-NH-CH3、-NH-S(＝O)2-CH3、 -S(＝O)2-NH-C(＝NH)-N(CH3)2、-COOH、-COOCH3、-NH2、-N(CH3)2、或-(C＝O)-NH2。The compound of the present invention, which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or a prodrug thereof, wherein R 1 and R 2 are each independently a hydrogen atom or an amino group. -S(=O) 2 -CH 3 , -S(=O) 2 -CH 2 CH 3 , -S(=O) 2 -CH(CH 3 ) 2 , -S(=O) 2 -OH,- S(=O) 2 -cyclopropyl, -S(=O) 2 -NH 2 , -S(=O) 2 -N(CH 3 ) 2 , -S(=O) 2 -NHCH 3 , -S (=O) 2 -NH-CHCH 3 ) 2 , -S(=O) 2 -CH 2 -CHCH 3 ) 2 , -S(=O) 2 -CH(CH 3 )-CH 2 CH 3 , -S (=O) 2 -NH-C(=NH)-NH-CH 3 , -S(=O) 2 -NH-C(=O)-NH-(CH 2 ) 2 CH 3 , -S(=O 2 -NH-C(=NH)-NH 2 , -NH-C(=NH)-NH-CH 3 , -NH-S(=O) 2 -CH 3 , -S(=O) 2 -NH -C(=NH)-N(CH 3 ) 2 , -COOH, -COOCH 3 , -NH 2 , -N(CH 3 ) 2 , or -(C=O)-NH 2 .
本发明所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，B环中的
Figure PCTCN2016000478-appb-000003
都表示单键。a compound of the present invention, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein
Figure PCTCN2016000478-appb-000003
Both represent a single button.
所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，B环中的
Figure PCTCN2016000478-appb-000004
都表示双键。a compound, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form thereof or a prodrug thereof, wherein
Figure PCTCN2016000478-appb-000004
Both represent double keys.
本发明所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，Ar是任选被1～5个选自取代基组a的基团取代的苯基。A compound according to the invention, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein Ar is optionally 1 to 5 selected from the group of substituents A group substituted with a phenyl group of a.
本发明所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，所述化合物为选自下述式(a)、(b)、(c)、(d)、(e)和(f)中的任意一种化合物，The compound of the present invention, which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein the compound is selected from the following formula (a), ( Any one of b), (c), (d), (e) and (f),
Figure PCTCN2016000478-appb-000005
Figure PCTCN2016000478-appb-000005
其中，Ar是任选被1～5个卤素原子取代的苯基，Wherein Ar is a phenyl group optionally substituted by 1 to 5 halogen atoms,
R4选自氢原子、氰基、硝基、-S(＝O)2R3、-R5-COOH、-R5COOR6、任选被选自取代基组a的基团取代的巯基、任选被选自取代基组a的基团取代的氨基、任选被选自取代基组a的基团取代的亚磺酰基、任选被选自取代基组a的基团取代的C1-6烷基、任选被选自取代基组a的基团取代的C1-6烷氧基、任选被选自取代基组a的基团取代的C2-6烷酰基、任选被选自取代基组a的基团取代的C3-8环烷基、任选被选自取代基组a的基团取代的C6-10芳基、任选被选自取代基组a的基团 取代的5-11元杂环基、-R9(C＝O)-NR7R8、或-R9(C＝O)-NH2，其中R3、R5、R6、R7、R8、R9和取代基组a与权利要求1中的定义相同。R 4 is selected from a hydrogen atom, a cyano group, a nitro group, -S(=O) 2 R 3 , -R 5 -COOH, -R 5 COOR 6 , a fluorenyl group optionally substituted with a group selected from the substituent group a An amino group optionally substituted with a group selected from the substituent group a, a sulfinyl group optionally substituted with a group selected from the substituent group a, a C1 optionally substituted with a group selected from the substituent group a a 1-6 alkyl group, a C1-6 alkoxy group optionally substituted with a group selected from the substituent group a, a C2-6 alkanoyl group optionally substituted with a group selected from the substituent group a, optionally selected a C3-8 cycloalkyl group substituted with a group of the substituent group a, a C6-10 aryl group optionally substituted with a group selected from the substituent group a, optionally substituted with a group selected from the substituent group a 5-11 membered heterocyclyl, -R 9 (C=O)-NR 7 R 8 , or -R 9 (C=O)-NH 2 , wherein R 3 , R 5 , R 6 , R 7 , R 8. R 9 and the substituent group a are the same as defined in claim 1.
本发明所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，R4为氢原子、-S(＝O)2-C1-6烷基、-S(＝O)2-C3-8环烷基、-S(＝O)2-N(C1-6烷基)2、-S(＝O)2-NH(C1-6烷基)、任选被C1-6烷基取代的磺酰氨基、-S(＝O)2-C2-6烷酰基、C6-10芳基C1-6烷基、被C1-6烷基取代的-S(＝O)2-氨基羰基氨基、-COO-C1-6烷基、被C1-6烷基取代的氨基、C1-6烷基、C1-6烷氧基、C3-8环烷基、C6-10芳基、C6-10芳基C1-8烷氧基、C1-6烷硫基、5-11元杂环基、-(C＝O)-NH-C1-6烷基、-(C＝O)-N(C1-6烷基)2、-(C＝O)-NH-C3-8环烷基、-(C＝O)-N(C3-8环烷基)2、C1-6烷基亚磺酰基或单C1-6烷基氨基羰基、或二C1-6烷基氨基羰基。A compound of the present invention, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein R 4 is a hydrogen atom, -S(=O) 2 - C1-6 alkyl, -S(=O) 2 -C3-8 cycloalkyl, -S(=O) 2 -N(C1-6alkyl) 2 , -S(=O) 2 -NH(C1 -6 alkyl), sulfonylamino group optionally substituted by C1-6 alkyl group, -S(=O) 2 -C2-6 alkanoyl group, C6-10 aryl C1-6 alkyl group, C1-6 alkane -S(=O) 2 -aminocarbonylamino, -COO-C1-6 alkyl, amino substituted by C1-6 alkyl, C1-6 alkyl, C1-6 alkoxy, C3-8 Cycloalkyl, C6-10 aryl, C6-10 aryl C1-8 alkoxy, C1-6 alkylthio, 5-11 membered heterocyclic, -(C=O)-NH-C1-6 , -(C=O)-N(C1-6alkyl) 2 , -(C=O)-NH-C3-8 cycloalkyl, -(C=O)-N(C3-8 cycloalkyl 2 ) a C1-6 alkylsulfinyl group or a mono C1-6 alkylaminocarbonyl group or a di C1-6 alkylaminocarbonyl group.
本发明所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，R4为氨基、-S(＝O)2-CH3、-S(＝O)2-CH2CH3、-S(＝O)2-CH(CH3)2、-S(＝O)2-OH、-S(＝O)2-环丙基、-S(＝O)2-NH2、-S(＝O)2-CH3)2、-S(＝O)2-NHCH3、-S(＝O)2-NH-CH(CH3)2、-S(＝O)2-CH2-CH(CH3)2、-S(＝O)2-CH(CH3)-CH2CH3、-S(＝O)2-NH-C(＝NH)-NH-CH3、-S(＝O)2-NH-C(＝O)-NH-(CH2)2CH3、-S(＝O)2-NH-C(＝NH)-NH2、-NH-C(＝NH)-NH-CH3、-NH-S(＝O)2-CH3、-S(＝O)2-NH-C(＝NH)-N(CH3)2、-COOH、-COOCH3、-NH2、-N(CH3)2或-(C＝O)-NH2。A compound according to the invention, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein R 4 is amino, -S(=O) 2 -CH 3 , -S(=O) 2 -CH 2 CH 3 , -S(=O) 2 -CH(CH 3 ) 2 , -S(=O) 2 -OH, -S(=O) 2 -cyclopropane , -S(=O) 2 -NH 2 , -S(=O) 2 -CH 3 ) 2 , -S(=O) 2 -NHCH 3 , -S(=O) 2 -NH-CH(CH 3 ) 2 , -S(=O) 2 -CH 2 -CH(CH 3 ) 2 , -S(=O) 2 -CH(CH 3 )-CH 2 CH 3 , -S(=O) 2 -NH -C(=NH)-NH-CH 3 , -S(=O) 2 -NH-C(=O)-NH-(CH 2 ) 2 CH 3 , -S(=O) 2 -NH-C( =NH)-NH 2 , -NH-C(=NH)-NH-CH 3 , -NH-S(=O) 2 -CH 3 , -S(=O) 2 -NH-C(=NH)- N(CH 3 ) 2 , -COOH, -COOCH 3 , -NH 2 , -N(CH 3 ) 2 or -(C=O)-NH 2 .
本发明所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，所述化合物是选自下述的化合物，The compound of the present invention, which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein the compound is a compound selected from the group consisting of
Figure PCTCN2016000478-appb-000006
Figure PCTCN2016000478-appb-000006
Figure PCTCN2016000478-appb-000007
Figure PCTCN2016000478-appb-000007
Figure PCTCN2016000478-appb-000008
Figure PCTCN2016000478-appb-000008
本发明所述的化合物、其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其用作二肽基肽酶-IV抑制剂。A compound of the present invention, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form thereof or a prodrug thereof, for use as a dipeptidyl peptidase-IV inhibitor.
药物组合物，其含有本发明所述的化合物、其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，以及药学上可以接受的载体或赋形剂。a pharmaceutical composition comprising a compound of the invention, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, and a pharmaceutically acceptable carrier or form Agent.
本发明所述的药物组合物，其中，进一步包含可与所述的化合物、其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药联用的其它活性物质。The pharmaceutical composition of the present invention, further comprising other compounds which can be used in combination with the compound, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof Active substance.
本发明所述的药物组合物，其中，所述其它活性物质为二甲双胍或其盐、或匹格列酮等。The pharmaceutical composition according to the present invention, wherein the other active substance is metformin or a salt thereof, or pioglitazone or the like.
本发明所述的组合物含有本发明所述的化合物0.01-1000mg，适宜为0.5-800mg，优选为1-400mg，更优选为5-200mg，特别优选 10-100mg，最优选15-50mg，例如是20mg、25mg、30mg。本发明药物制剂等可以是单位剂量形式，单位剂量含有本发明所述的化合物0.01-1000mg，适宜为0.5-800mg，优选为1-400mg，更优选为5-200mg，特别优选10-100mg，最优选15-50mg，例如是20mg、25mg、30mg。The composition according to the invention contains 0.01 to 1000 mg of the compound according to the invention, suitably 0.5 to 800 mg, preferably 1 to 400 mg, more preferably 5 to 200 mg, particularly preferably 10-100 mg, most preferably 15-50 mg, for example 20 mg, 25 mg, 30 mg. The pharmaceutical preparation of the present invention or the like may be in a unit dosage form, and the unit dose contains 0.01 to 1000 mg of the compound of the present invention, suitably 0.5 to 800 mg, preferably 1 to 400 mg, more preferably 5 to 200 mg, particularly preferably 10 to 100 mg, most It is preferably 15-50 mg, for example, 20 mg, 25 mg, 30 mg.
一种适合施用给动物，尤其是哺乳动物的药物制剂，其中，该制剂包含本发明所述的化合物、其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药作为有效成分，该制剂包括固体制剂、半固体制剂、液体制剂、气态制剂。A pharmaceutical preparation suitable for administration to an animal, especially a mammal, wherein the preparation comprises a compound of the invention, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or The prodrug thereof is used as an active ingredient, and the preparation includes a solid preparation, a semisolid preparation, a liquid preparation, and a gaseous preparation.
与二肽基肽酶-IV相关的疾病的治疗或预防剂，其含有所述的化合物、其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药作为有效成分。A therapeutic or prophylactic agent for a disease associated with dipeptidyl peptidase-IV, which comprises the compound, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof As an active ingredient.
本发明所述的化合物、其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，或其与其它活性物质联用的组合物在用于制备治疗与二肽基肽酶-IV相关的疾病的药物中的应用。The compound of the present invention, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form thereof or a prodrug thereof, or a combination thereof with other active substances, is used for the preparation of a treatment Use in drugs for diseases associated with dipeptidyl peptidase-IV.
本发明的化合物对二肽基肽酶-IV具有很高的抑制活性和选择性、具有非常优异的药物代谢性质、且毒副作用较小，可用作长效的二肽基肽酶-IV抑制剂，以治疗与二肽基肽酶-IV相关的各种疾病。The compound of the present invention has high inhibitory activity and selectivity to dipeptidyl peptidase-IV, has excellent drug metabolism properties, and has less toxic and side effects, and can be used as a long-acting dipeptidyl peptidase-IV inhibitor. Agent for treating various diseases associated with dipeptidyl peptidase-IV.
二肽基肽酶-IV相关的疾病包括糖尿病、肥胖症、胰岛素抵抗症或高血脂。Dipeptidyl peptidase-IV related diseases include diabetes, obesity, insulin resistance or hyperlipidemia.
本发明所述的化合物、其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，或其与其它活性物质联用的组合物用于治疗与二肽基肽酶-IV相关疾病的方法。The compound of the present invention, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form thereof or a prodrug thereof, or a combination thereof with other active substances, is used for treatment and A method of peptidyl peptidase-IV related diseases.
本发明所述的方法中，本发明化合物的量为0.01-1000mg，适宜为0.5-800mg，优选为1-400mg，更优选为5-200mg，特别优选10-100mg，最优选15-50mg，例如是20mg、25mg、30mg。本发明药物制剂等可以是单位剂量形式，单位剂量含有本发明所述的化合物0.01-1000mg，适宜为0.5-800mg，优选为1-400mg，更优选为5-200mg，特别优选10-100mg，最优选15-50mg，例如是20mg、25mg、30mg。In the process according to the invention, the amount of the compound according to the invention is from 0.01 to 1000 mg, suitably from 0.5 to 800 mg, preferably from 1 to 400 mg, more preferably from 5 to 200 mg, particularly preferably from 10 to 100 mg, most preferably from 15 to 50 mg, for example It is 20 mg, 25 mg, 30 mg. The pharmaceutical preparation of the present invention or the like may be in a unit dosage form, and the unit dose contains 0.01 to 1000 mg of the compound of the present invention, suitably 0.5 to 800 mg, preferably 1 to 400 mg, more preferably 5 to 200 mg, particularly preferably 10 to 100 mg, most It is preferably 15-50 mg, for example, 20 mg, 25 mg, 30 mg.
具体实施方式detailed description
以下说明在本说明书中使用的各术语的意思。各术语以统一的意思使用，单独使用时，或与其它术语组合使用时，都以相同的意思使 用。The meaning of each term used in the present specification is explained below. Each term is used in a uniform sense, used alone or in combination with other terms to have the same meaning use.
本发明中，“任选被选自取代基组a的基团取代”是指可在任意的位置用选自取代基组a的1或2个以上的相同或不同的取代基取代。In the present invention, the "optionally substituted with a group selected from the substituent group a" means that it may be substituted at any position with one or two or more identical or different substituents selected from the substituent group a.
本发明中，“C1-6烷基取代”是指在任意的位置用选自C1-6烷基的1或2个以上的相同或不同的取代基取代。In the present invention, the "C1-6 alkyl group-substituted" means substituted at one position with one or two or more identical or different substituents selected from a C1-6 alkyl group.
本发明中，“卤素原子”表示氟原子、氯原子、溴原子、或碘原子。In the present invention, the "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
本发明中，“C1-6烷基”表示直链状、或支链状的碳原子数为1～6的烷基，可以列举甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基等的基团。In the present invention, the "C1-6 alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a n-propyl group, an isopropyl group and a n-butyl group. a group such as a benzyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a neopentyl group, a tert-amyl group or the like.
本发明中，“C2-6烯基”表示直链状、或支链状的碳原子数为2～6的烯基，可以列举乙烯基、正丙烯基、异丙烯基、正丁烯基、异丁烯基、仲丁烯基、叔丁烯基、正戊烯基、异戊烯基、新戊烯基、叔戊烯基等的基团。In the present invention, the "C2-6 alkenyl group" means a linear or branched alkenyl group having 2 to 6 carbon atoms, and examples thereof include a vinyl group, a n-propenyl group, an isopropenyl group, and a n-butenyl group. A group such as isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, isopentenyl, neopentenyl, tert-pentenyl or the like.
本发明中，“C2-6炔基”表示直链状、或支链状的碳原子数为2～6的炔基，可以列举乙炔基、正丙炔基、异丙炔基、正丁炔基、异丁炔基、仲丁炔基、叔丁炔基、正戊炔基、异戊炔基、新戊炔基、叔戊炔基等的基团。In the present invention, the "C2-6 alkynyl group" means a linear or branched alkynyl group having 2 to 6 carbon atoms, and examples thereof include an ethynyl group, a n-propynyl group, an isopropynyl group, and a n-butyne group. a group such as a benzyl group, an isobutynyl group, a sec-butynyl group, a tert-butynyl group, a n-pentynyl group, an isopentenyl group, a neopentynyl group, a tert-pentynyl group, and the like.
本发明中，“C3-8环烷基”可以列举环丙基、环丁基、环戊基、环己基、环庚基等的基团。In the present invention, the "C3-8 cycloalkyl group" may, for example, be a group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or a cycloheptyl group.
本发明中，“C1-6烷氧基”是指直链状或支链状的碳原子数为1～6的烷氧基，可以列举甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊基氧基、异戊基氧基、新戊基氧基、叔戊基氧基等的基团。In the present invention, the "C1-6 alkoxy group" means a linear or branched alkoxy group having 1 to 6 carbon atoms, and examples thereof include a methoxy group, an ethoxy group, a n-propoxy group, and a different form. a group such as propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-amyloxy, and the like group.
本发明中，“C1-6亚烷基”、“C2-6亚烯基”、“C2-6亚炔基”分别是指从上述“C1-6烷基”、“C2-6烯基”、“C2-6炔基”中除去了1个氢原子的二价基团。In the present invention, "C1-6 alkylene", "C2-6 alkenylene", and "C2-6 alkynylene" refer to the above "C1-6 alkyl" and "C2-6 alkenyl", respectively. In the "C2-6 alkynyl group", a divalent group of one hydrogen atom is removed.
本发明中，“C2-6烷酰基”是指直链状或支链状的碳原子数为2～6的烷酰基，可以列举乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、特戊酰基等的基团。In the present invention, the "C2-6 alkanoyl group" means a linear or branched alkanoyl group having 2 to 6 carbon atoms, and examples thereof include an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, and a valeryl group. A group such as isovaleryl or pivaloyl.
本发明中，“单C1-6烷基氨基羰基”是指用具有1个上述“C1-6烷基”作为取代基的氨基取代了的羰基，可以列举甲基氨基羰基、乙基氨基羰基、正丙基氨基羰基、异丙基氨基羰基、正丁基氨基羰基、异丁 基氨基羰基、仲丁基氨基羰基、叔丁基氨基羰基、正戊基氨基羰基、异戊基氨基羰基、新戊基氨基羰基等。In the present invention, the "mono C1-6 alkylaminocarbonyl group" means a carbonyl group substituted with an amino group having one of the above-mentioned "C1-6 alkyl group" as a substituent, and examples thereof include a methylaminocarbonyl group and an ethylaminocarbonyl group. N-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutyl Alkylaminocarbonyl, sec-butylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, isopentylaminocarbonyl, neopentylaminocarbonyl, and the like.
本发明中，“二C1-6烷基氨基羰基”是指用具有2个相同或不同的上述“C1-6烷基”作为取代基的氨基取代了的羰基，可以列举二甲基氨基羰基、二乙基氨基羰基、二(正丙基)氨基羰基、二(异丙基)氨基羰基、乙基甲基氨基羰基、甲基(正丙基)氨基羰基、甲基(异丙基)氨基羰基等。In the present invention, the "diC1-6 alkylaminocarbonyl group" means a carbonyl group substituted with two amino groups having the same or different "C1-6 alkyl group" as a substituent, and examples thereof include a dimethylaminocarbonyl group. Diethylaminocarbonyl, di(n-propyl)aminocarbonyl, bis(isopropyl)aminocarbonyl, ethylmethylaminocarbonyl, methyl(n-propyl)aminocarbonyl, methyl(isopropyl)aminocarbonyl Wait.
本发明中，“C6-10芳基”是指单环或多环的碳原子数为6-10的芳基。其中，对于多环芳基的情况，除了完全不饱和之外，也包含部分饱和的基团。例如可举出苯基、萘基、薁基、茚基、茚满基、四氢化萘基等。In the present invention, the "C6-10 aryl group" means a monocyclic or polycyclic aryl group having 6 to 10 carbon atoms. Among them, in the case of a polycyclic aryl group, in addition to being completely unsaturated, a partially saturated group is also included. For example, a phenyl group, a naphthyl group, an anthracenyl group, a fluorenyl group, an indanyl group, a tetrahydronaphthyl group, etc. are mentioned.
本发明中，“C6-10芳基C1-6烷基”是指下述C6-10芳基与上述C1-6烷基键合的基团。例如可举出苄基、苯乙基、3-苯基-正丙基、4-苯基-正丁基、5-苯基-正戊基、8-苯基-正己基、萘甲基等。In the present invention, the "C6-10 aryl C1-6 alkyl group" means a group in which the following C6-10 aryl group is bonded to the above C1-6 alkyl group. Examples thereof include a benzyl group, a phenethyl group, a 3-phenyl-n-propyl group, a 4-phenyl-n-butyl group, a 5-phenyl-n-pentyl group, an 8-phenyl-n-hexyl group, a naphthylmethyl group, and the like. .
本发明中，“5-11元杂环基”是指：作为构成环的原子，除碳原子之外还包含选自氮原子、氧原子和硫原子的1～4个杂原子的5～7元芳族杂环、饱和杂环、不饱和杂环或这些杂环与苯环稠合得到的稠合杂环。例如可举出：2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、吡咯-1-基、吡咯-2-基、吡咯-3-基、吡啶-2-基、吡啶-3-基、吡啶-4-基、吡嗪-2-基、吡嗪-3-基、嘧啶-2-基、嘧啶-4-基、嘧啶-5-基、嘧啶-6-基、哒嗪-3-基、哒嗪-4-基、1，3-苯并二氧杂环戊烯-4-基、1，3-苯并二氧杂环戊烯-5-基、2，3-二氢苯并呋喃-4-基、2，3-二氢苯并呋喃-5-基、2，3-二氢苯并呋喃-6-基、2，3-二氢苯并呋喃-7-基、苯并呋喃-2-基、苯并呋喃-3-基、苯并呋喃-4-基、苯并呋喃-5-基、苯并呋喃-6-基、苯并呋喃-7-基、苯并噻吩-2-基、苯并噻吩-3-基、苯并噻吩-4-基、苯并噻吩-5-基、苯并噻吩-6-基、苯并噻吩-7-基、喹喔啉-2-基、喹喔啉-5-基、喹喔啉-6-基、吲哚-1-基、吲哚-2-基、吲哚-3-基、吲哚-4-基、吲哚-5-基、吲哚-6-基、吲哚-7-基、异吲哚-1-基、异吲哚-2-基、异吲哚-4-基、异吲哚-5-基、异吲哚-6-基、异吲哚-7-基、异苯并呋喃-1-基、异苯并呋喃-4-基、异苯并呋喃-5-基、异苯并呋喃-6-基、异苯并呋喃-7-基、色烯-2-基、色烯-3-基、色烯-4-基、色烯-5-基、色烯-6-基、色烯-7-基、色烯-8-基、咪唑-1-基、咪唑-2-基、咪唑-4-基、咪唑-5-基、吡唑-1-基、吡唑-3-基、吡唑-4- 基、吡唑-5-基、噻唑-2-基、噻唑-4-基、噻唑-5-基、
Figure PCTCN2016000478-appb-000009
唑-2-基、
Figure PCTCN2016000478-appb-000010
唑-4-基、
Figure PCTCN2016000478-appb-000011
唑-5-基、异
Figure PCTCN2016000478-appb-000012
唑-3-基、异
Figure PCTCN2016000478-appb-000013
唑-4-基、异
Figure PCTCN2016000478-appb-000014
唑-5-基、吡咯烷-2-基、吡咯烷-3-基、苯并咪唑-1-基、苯并咪唑-2-基、苯并咪唑-4-基、苯并咪唑-5-基、苯并噻唑-2-基、苯并噻唑-4-基、苯并噻唑-5-基、苯并
Figure PCTCN2016000478-appb-000015
唑-2-基、苯并
Figure PCTCN2016000478-appb-000016
唑-4-基、苯并
Figure PCTCN2016000478-appb-000017
唑-5-基、喹啉-2-基、喹啉-3-基、喹啉-4-基、喹啉-5-基、喹啉-6-基、喹啉-7-基、喹啉-8-基、异喹啉-1-基、异喹啉-3-基、异喹啉-4-基、异喹啉-5-基、异喹啉-6-基、异喹啉-7-基、异喹啉-8-基、1，3，4-噻二唑-2-基、吗啉代基、1，2，3-三唑-1-基、1，2，3-三唑-4-基、1，2，3-三唑-5-基、1，2，4-三唑-1-基、1，2，4-三唑-3-基、1，2，4-三唑-5-基、四唑-1-基、四唑-2-基、二氢吲哚-4-基、二氢吲哚-5-基、二氢吲哚-6-基、二氢吲哚-7-基、1，2，3，4-四氢喹啉-5-基、1，2，3，4-四氢喹啉-6-基、1，2，3，4-四氢喹啉-7-基、1，2，3，4-四氢喹啉-8-基、1，2，3，4-四氢异喹啉-5-基、1，2，3，4-四氢异喹啉-6-基、1，2，3，4-四氢异喹啉-7-基、1，2，3，4-四氢异喹啉-8-基等。In the present invention, the "5-11 membered heterocyclic group" means 5 to 7 which is an atom constituting the ring and contains, in addition to the carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. A heteroaromatic heterocyclic ring, a saturated heterocyclic ring, an unsaturated heterocyclic ring or a fused heterocyclic ring obtained by condensing these heterocyclic rings with a benzene ring. For example, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, pyrrol-1-yl, pyrrol-2-yl, pyrrol-3-yl, pyridin-2-yl, pyridine 3-yl, pyridin-4-yl, pyrazin-2-yl, pyrazin-3-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, hydrazine Pyrazin-3-yl, pyridazin-4-yl, 1,3-benzodioxol-4-yl, 1,3-benzodioxol-5-yl, 2,3 -dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7 -yl,benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl, benzofuran-7-yl , benzothiophen-2-yl, benzothiophen-3-yl, benzothiophen-4-yl, benzothiophen-5-yl, benzothiophen-6-yl, benzothiophen-7-yl, quin Porphyrin-2-yl, quinoxalin-5-yl, quinoxalin-6-yl, indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl , indol-5-yl, indol-6-yl, indol-7-yl, isoindolin-1-yl, isoindolin-2-yl, isoindole-4-yl, isoindole- 5-based, isoindole-6-yl, different哚-7-yl, isobenzofuran-1-yl, isobenzofuran-4-yl, isobenzofuran-5-yl, isobenzofuran-6-yl, isobenzofuran-7-yl , chromen-2-yl, chromen-3-yl, chromen-4-yl, chromene-5-yl, chromen-6-yl, chromen-7-yl, chromen-8-yl, Imidazolyl-1-yl, imidazol-2-yl, imidazol-4-yl, imidazol-5-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazole-5- Base, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,
Figure PCTCN2016000478-appb-000009
Zin-2-yl,
Figure PCTCN2016000478-appb-000010
Zin-4-yl,
Figure PCTCN2016000478-appb-000011
Azole-5-based, different
Figure PCTCN2016000478-appb-000012
Zyrom-3-yl, different
Figure PCTCN2016000478-appb-000013
Azol-4-yl, different
Figure PCTCN2016000478-appb-000014
Zyrid-5-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazole-5- , benzothiazol-2-yl, benzothiazol-4-yl, benzothiazole-5-yl, benzo
Figure PCTCN2016000478-appb-000015
Zin-2-yl, benzo
Figure PCTCN2016000478-appb-000016
Zin-4-yl, benzo
Figure PCTCN2016000478-appb-000017
Zyrid-5-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinoline-6-yl, quino-7-yl, quinoline -8-yl, isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinoline-7 -yl,isoquinolin-8-yl, 1,3,4-thiadiazol-2-yl, morpholino, 1,2,3-triazol-1-yl, 1,2,3-tri Zin-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4 - triazol-5-yl, tetrazol-1-yl, tetrazol-2-yl, indan-4-yl, indan-5-yl, indoline-6-yl, two Hydroquinone-7-yl, 1,2,3,4-tetrahydroquinolin-5-yl, 1,2,3,4-tetrahydroquinolin-6-yl, 1,2,3,4- Tetrahydroquinolin-7-yl, 1,2,3,4-tetrahydroquinolin-8-yl, 1,2,3,4-tetrahydroisoquinolin-5-yl, 1,2,3, 4-tetrahydroisoquinolin-6-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl, 1,2,3,4-tetrahydroisoquinolin-8-yl and the like.
本发明中，“C6-10芳基C1-6烷氧基”是指上述“C6-10芳基C1-6烷基”与氧原子键合的基团。例如可举出苄基氧基、苯乙基氧基、萘甲基氧基等。In the present invention, the "C6-10 aryl C1-6 alkoxy group" means a group in which the above "C6-10 aryl C1-6 alkyl group" is bonded to an oxygen atom. For example, a benzyloxy group, a phenethyloxy group, a naphthylmethyloxy group, etc. are mentioned.
本发明中，“C1-6烷硫基”例如可举出甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、异丁硫基、仲丁硫基、叔丁硫基、正戊硫基、异戊硫基、新戊硫基、1-甲基丁硫基、1-乙基丙硫基、正己硫基、异己硫基、3-甲基戊硫基、2-甲基戊硫基、1-甲基戊硫基、3，3-二甲基丁硫基、2，2-二甲基丁硫基、1，1-二甲基丁硫基、1，2-二甲基丁硫基、1，3-二甲基丁硫基、2，3-二甲基丁硫基、1-乙基丁硫基、2-乙基丁硫基等。In the present invention, the "C1-6 alkylthio group" may, for example, be a methylthio group, an ethylthio group, a n-propylthio group, an isopropylthio group, a n-butylthio group, an isobutylthio group, a sec-butylthio group or a tertiary group. Butylthio, n-pentylthio, isopentylthio, neopentylthio, 1-methylbutylthio, 1-ethylpropylthio, n-hexylthio, isohexylthio, 3-methylpentylthio , 2-methylpentylthio, 1-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio, and the like.
本发明中，“C1-6烷基亚磺酰基”例如可举出：甲基亚磺酰基、乙基亚磺酰基、正丙基亚磺酰基、异丙基亚磺酰基、正丁基亚磺酰基、异丁基亚磺酰基、仲丁基亚磺酰基、叔丁基亚磺酰基、正戊基亚磺酰基、异戊基亚磺酰基、新戊基亚磺酰基、1-甲基丁基亚磺酰基、1-乙基丙基亚磺酰基、正己基亚磺酰基、异己基亚磺酰基、3-甲基戊基亚磺酰基、2-甲基戊基亚磺酰基、1-甲基戊基亚磺酰基、3，3-二甲基丁基亚磺酰基、2，2-二甲基丁基亚磺酰基、1，1-二甲基丁基亚磺酰基、1，2-二甲基丁基亚磺酰基、1，3-二甲基丁基亚磺酰基、2，3-二甲基丁基亚磺酰基、1-乙基丁基亚磺酰基、2-乙基丁基亚磺酰基等。 In the present invention, the "C1-6 alkylsulfinyl group" may, for example, be a methylsulfinyl group, an ethylsulfinyl group, a n-propylsulfinyl group, an isopropylsulfinyl group or a n-butylsulfinic acid. Acyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, n-pentylsulfinyl, isopentylsulfinyl, neopentylsulfinyl, 1-methylbutyl Sulfonyl, 1-ethylpropylsulfinyl, n-hexylsulfinyl, isohexylsulfinyl, 3-methylpentylsulfinyl, 2-methylpentylsulfinyl, 1-methyl Butylsulfinyl, 3,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl, 1,1-dimethylbutylsulfinyl, 1,2-di Methylbutylsulfinyl, 1,3-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutyl Sulfonyl and the like.
除此之外，这里未定义的基团遵照通常的定义。In addition to this, groups not defined here follow the usual definitions.
本发明优选的方式可以列举以下方式。Preferred embodiments of the present invention include the following.
通式(I)中，在作为R1、R2的-S(＝O)2R3中，R3优选是甲基、乙基、异丙基等的C1-6烷基、环丙基等的C3-8环烷基、羟基、氨基、被1个或2个C1-6烷基取代的氨基、-NH-C(＝O)-NH-(CH2)2CH3、-NH-C(＝NH)-NH2、-NH-C(＝NH)-N(CH3)2。In the formula (I), in -S(=O) 2 R 3 which is R 1 and R 2 , R 3 is preferably a C1-6 alkyl group such as a methyl group, an ethyl group or an isopropyl group, or a cyclopropyl group. Equivalent C3-8 cycloalkyl, hydroxy, amino, amino substituted by 1 or 2 C1-6 alkyl, -NH-C(=O)-NH-(CH 2 ) 2 CH 3 , -NH- C(=NH)-NH 2 , -NH-C(=NH)-N(CH 3 ) 2 .
通式(I)中，在作为R1、R2的-R5-COOH中，R5优选是单键。In the formula (I), in -R 5 -COOH as R 1 and R 2 , R 5 is preferably a single bond.
通式(I)中，在作为R1、R2的-R5COOR6中，R5优选是单键，R6优选是C1-6烷基，更优选甲基。In the formula (I), in -R 5 COOR 6 as R 1 and R 2 , R 5 is preferably a single bond, and R 6 is preferably a C1-6 alkyl group, more preferably a methyl group.
通式(I)中，在作为R1、R2的-(C＝O)-NR7R8中，R7和R8各自独立地优选是C1-6烷基，更优选甲基、异丙基。In the formula (I), in -(C=O)-NR 7 R 8 as R 1 and R 2 , R 7 and R 8 are each independently preferably a C1-6 alkyl group, more preferably a methyl group or a different group. Propyl.
通式(I)中，在作为R1、R2的-R9(C＝O)-NH2中，R9优选是单键。In the formula (I), in -R 9 (C=O)-NH 2 which is R 1 and R 2 , R 9 is preferably a single bond.
通式(I)中，优选A3为N，A4为C，A5为N，A6为C。In the formula (I), it is preferred that A 3 is N, A 4 is C, A 5 is N, and A 6 is C.
通式(I)中，优选A3为N，A4为C，A5为C，A6为C。In the formula (I), it is preferred that A 3 is N, A 4 is C, A 5 is C, and A 6 is C.
通式(I)中，优选A3为C，A4为C，A5为N，A6为C。In the formula (I), it is preferred that A 3 is C, A 4 is C, A 5 is N, and A 6 is C.
通式(I)中，优选A3为N，A4为C，A5为C，A6为N。In the formula (I), it is preferred that A 3 is N, A 4 is C, A 5 is C, and A 6 is N.
通式(I)中，优选A3为C，A4为C，A5为C，A6为C。In the formula (I), it is preferred that A 3 is C, A 4 is C, A 5 is C, and A 6 is C.
通式(I)中，优选A环为不饱和环，B环为饱和环；优选A环为不饱和环，B环为不饱和环。In the formula (I), the ring A is preferably an unsaturated ring, and the ring B is a saturated ring; preferably, the ring A is an unsaturated ring, and the ring B is an unsaturated ring.
通式(I)中，更优选A环为不饱和环，B环为饱和环，A3为N，A4为C，A5为N，A6为C。In the formula (I), it is more preferred that the ring A is an unsaturated ring, the ring B is a saturated ring, A 3 is N, A 4 is C, A 5 is N, and A 6 is C.
通式(I)中，更优选A环为不饱和环，B环为饱和环，A3为N，A4为C，A5为C，A6为C。In the formula (I), it is more preferred that the ring A is an unsaturated ring, the ring B is a saturated ring, A 3 is N, A 4 is C, A 5 is C, and A 6 is C.
通式(I)中，更优选A环为不饱和环，B环为饱和环，A3为C，A4为C，A5为N，A6为C。In the formula (I), it is more preferred that the ring A is an unsaturated ring, the ring B is a saturated ring, A 3 is C, A 4 is C, A 5 is N, and A 6 is C.
通式(I)中，更优选A环为不饱和环，B环为饱和环，A3为N，A4为C，A5为C，A6为N。In the formula (I), it is more preferred that the ring A is an unsaturated ring, the ring B is a saturated ring, A 3 is N, A 4 is C, A 5 is C, and A 6 is N.
通式(I)中，更优选A环为不饱和环，B环为饱和环，A3为C，A4为C，A5为C，A6为C。In the formula (I), it is more preferred that the ring A is an unsaturated ring, the ring B is a saturated ring, A 3 is C, A 4 is C, A 5 is C, and A 6 is C.
通式(I)中，更优选A环为不饱和环，B环为不饱和环，A3为N，A4为C，A5为N，A6为C。In the formula (I), it is more preferred that the ring A is an unsaturated ring, the ring B is an unsaturated ring, A 3 is N, A 4 is C, A 5 is N, and A 6 is C.
通式(I)中，更优选A环为不饱和环，B环为不饱和环，A3为N， A4为C，A5为C，A6为C。In the formula (I), it is more preferred that the ring A is an unsaturated ring, the ring B is an unsaturated ring, A 3 is N, A 4 is C, A 5 is C, and A 6 is C.
通式(I)中，更优选A环为不饱和环，B环为不饱和环，A3为C，A4为C，A5为N，A6为C。In the formula (I), it is more preferred that the ring A is an unsaturated ring, the ring B is an unsaturated ring, A 3 is C, A 4 is C, A 5 is N, and A 6 is C.
通式(I)中，更优选A环为不饱和环，B环为不饱和环，A3为N，A4为C，A5为C，A6为N。In the formula (I), it is more preferred that the ring A is an unsaturated ring, the ring B is an unsaturated ring, A 3 is N, A 4 is C, A 5 is C, and A 6 is N.
通式(I)中，更优选A环为不饱和环，B环为不饱和环，A3为C，A4为C，A5为C，A6为C。In the formula (I), it is more preferred that the ring A is an unsaturated ring, the ring B is an unsaturated ring, A 3 is C, A 4 is C, A 5 is C, and A 6 is C.
通式(I)中，优选Ar是任选被1～5个卤素原子取代的苯基，更优选是被2个氟原子取代的苯基。In the formula (I), Ar is preferably a phenyl group optionally substituted by 1 to 5 halogen atoms, and more preferably a phenyl group substituted by 2 fluorine atoms.
作为本发明化合物中的优选化合物的例子，可以列举下述的化合物：As examples of preferred compounds in the compounds of the present invention, the following compounds can be mentioned:
Figure PCTCN2016000478-appb-000018
Figure PCTCN2016000478-appb-000018
Figure PCTCN2016000478-appb-000019
Figure PCTCN2016000478-appb-000019
Figure PCTCN2016000478-appb-000020
Figure PCTCN2016000478-appb-000020
本说明书中“药物上可接受的盐”包含与硫酸、盐酸、氢溴酸、磷酸、或硝酸等无机酸的盐、或与乙酸、苯甲酸、草酸、乳酸、苹果酸、酒石酸、富马酸、马来酸、柠檬酸、丙二酸、扁桃酸、葡萄糖酸、半乳糖二酸、葡庚糖酸、乙醇酸、谷氨酸、三氟醋酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、樟脑磺酸、或萘-2-磺酸等有机酸的盐、与锂离子、钠离子、钾离子、钙离子、镁离子、锌离子、铝离子等1种或多种金属离子的盐、与氨、精氨酸、赖氨酸、哌嗪、胆碱、二乙基胺、4-苯基环己基胺、2-氨基乙醇、苄星青霉素等胺的盐。只要是药学上可接受的盐即可，没有特别限定。由本发明化合物游离碱向该盐的转换可以用现有的方法来进行。应予说明，本发明的化合物也可作为各种溶剂化物而存在。另外，从作为药物的适用性的角度考虑，有为水合物的情况。The "pharmaceutically acceptable salt" in the present specification includes a salt with an inorganic acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, or nitric acid, or with acetic acid, benzoic acid, oxalic acid, lactic acid, malic acid, tartaric acid, and fumaric acid. , maleic acid, citric acid, malonic acid, mandelic acid, gluconic acid, galactose diacid, glucoheptonic acid, glycolic acid, glutamic acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid a salt of an organic acid such as p-toluenesulfonic acid, camphorsulfonic acid or naphthalene-2-sulfonic acid, and one or more of lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, and aluminum ion. a salt of a metal ion, a salt with an amine such as ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcyclohexylamine, 2-aminoethanol, benzathine or the like. It is not particularly limited as long as it is a pharmaceutically acceptable salt. The conversion of the free base of the compound of the present invention to the salt can be carried out by a conventional method. Incidentally, the compound of the present invention may also exist as various solvates. In addition, from the viewpoint of applicability as a drug, there is a case of being a hydrate.
本发明的化合物可以含有一个或多个不对称中心，由此能够以外消旋物、外消旋混合物、单一对映异构体、非对映异构体混合物和单一非对映异构体等的形式存在。术语“晶型”包括本发明化合物的各种晶体，例如单晶、多晶型等。The compounds of the present invention may contain one or more asymmetric centers, thereby being capable of racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereomers, and the like. The form exists. The term "crystalline" includes various crystals of the compounds of the invention, such as single crystals, polymorphs, and the like.
本发明的化合物可以与一个或二个以上的药学上可接受的载体、赋形剂或稀释剂组合来形成药物制剂。作为上述载体、赋形剂和稀释剂指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性的性质的药物组合物中的非活性成分。The compounds of the invention may be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to form a pharmaceutical formulation. The above-mentioned carriers, excipients and diluents refer to inactive ingredients in pharmaceutical compositions which do not cause significant irritation to the organism and which do not interfere with the biological activity of the administered compound.
作为上述载体、赋形剂和稀释剂，包含水、乳糖、葡萄糖、果糖、蔗糖、山梨糖醇、甘露醇、聚乙二醇、丙二醇、淀粉、橡胶、凝胶、藻酸盐、硅酸钙、磷酸钙、纤维素、水性糖浆、甲基纤维素、聚乙烯基吡咯烷酮、对羟基苯并山梨酸烷基酯、滑石、硬脂酸镁、硬脂酸、甘油、芝麻油、橄榄油、大豆油等的各种油等。As the above carrier, excipient and diluent, comprising water, lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, rubber, gel, alginate, calcium silicate , calcium phosphate, cellulose, aqueous syrup, methyl cellulose, polyvinyl pyrrolidone, alkyl p-hydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil Various oils, etc.
另外，在上述的载体、赋形剂或稀释剂中根据需要可混合一般使 用的增量剂、粘合剂、崩解剂、pH调节剂、溶解剂等的添加剂，可以利用常用的制剂技术作为片剂、丸剂、胶囊剂、颗粒剂、粉剂、液剂、乳剂、悬浮剂、软膏剂、注射剂、皮肤贴剂等的口服或非口服用药物来制备。In addition, in the above carrier, excipient or diluent, it may be mixed as needed. Additives such as extenders, binders, disintegrants, pH adjusters, solubilizers, etc., can be used as tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions by conventional formulation techniques. Oral or parenteral drugs such as agents, ointments, injections, and skin patches are prepared.
本发明的化合物对于成人患者而言，可以以口服或非口服来进行给予。本发明的组合物或化合物一般为每3-12天给药1次，优选每5-10天给药1次，更优选1周给药1次，并且给药总量0.01～1000mg/次。应予说明，本发明的化合物的给药量可根据作为治疗对象的疾病的种类、患者的年龄、体重、症状等而适当增减。The compounds of the invention may be administered orally or parenterally to an adult patient. The composition or compound of the present invention is generally administered once every 3-12 days, preferably once every 5-10 days, more preferably once a week, and the total amount of administration is 0.01 to 1000 mg/time. In addition, the dose of the compound of the present invention can be appropriately increased or decreased depending on the type of the disease to be treated, the age, body weight, symptoms, and the like of the patient.
本发明的化合物还包含一个以上的氢原子、氟原子、碳原子、氮原子、氧原子、硫原子被置换为放射性同位素或稳定同位素的化合物。这些标记化合物可用于代谢或药代动力学研究、作为受体的配体等进行生物学分析等。The compound of the present invention further contains a compound in which one or more hydrogen atoms, fluorine atoms, carbon atoms, nitrogen atoms, oxygen atoms, and sulfur atoms are replaced by a radioisotope or a stable isotope. These labeled compounds can be used for metabolic or pharmacokinetic studies, ligands as receptors, and the like for biological analysis and the like.
本发明的化合物可以与一种或多种其它药物(例如二甲双胍)联合用于治疗、预防、抑制或者改善疾病或者病状，其中药物的联合使用比任何一种药物的单独使用更为安全或者更为有效。这种其它药物可以以对此通常使用的途径和量与本发明的化合物同时或者依次给药。当本发明的化合物与一种或者多种其它药物同时使用时，在单位剂型中含有该其它药物和本发明的化合物的药物组合物是优选的，特别是与药学可接受的载体联合。然而，联合治疗还可以包括在不同重叠日程中给予本发明的化合物和一种或者多种其它药物的治疗。还可以预期，当与一种或者多种其它活性成分联合使用时，本发明化合物和其它活性成分可以以比各自单独使用时更低的剂量使用。因此，除了本发明的化合物外，本发明药物组合物还包括含有一种或者多种其它活性成分的那些组合物。The compounds of the invention may be used in combination with one or more other drugs (e.g., metformin) to treat, prevent, inhibit or ameliorate a disease or condition, wherein the combined use of the drug is safer or more secure than the separate use of any of the drugs. effective. Such other drugs may be administered simultaneously or sequentially with the compounds of the present invention in the routes and amounts conventionally used for this purpose. When a compound of the invention is used contemporaneously with one or more other drugs, a pharmaceutical composition comprising the other agent and a compound of the invention in a unit dosage form is preferred, especially in combination with a pharmaceutically acceptable carrier. However, combination therapy can also include treatment of a compound of the invention and one or more other drugs in different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the invention and the other active ingredients may be employed in lower doses than when each is used alone. Thus, in addition to the compounds of the invention, the pharmaceutical compositions of the invention also include those compositions containing one or more additional active ingredients.
本发明的化合物例如可以按照下述所示的方法进行制造。式(1)所示的本发明化合物可以利用方案1所示的合成方法制造。The compound of the present invention can be produced, for example, by the method shown below. The compound of the present invention represented by the formula (1) can be produced by the synthesis method shown in Scheme 1.
<方案1><Scheme 1>
Figure PCTCN2016000478-appb-000021
Figure PCTCN2016000478-appb-000021
(式中，A3～A6、Ar、R1和R2均与前述具有相同的意思)。(wherein A 3 to A 6 , Ar, R 1 and R 2 have the same meanings as defined above).
使式(2)所示的酮和式(3)所示的胺在0-50℃、优选10-40℃的温度下进行0.5-30小时、优选1-12小时的还原胺化，得到式(4)所示的还原胺化产物，将所述得到的产物进一步在pH为2～6的酸性条件下脱去氨基保护基，获得通式化合物(1)。The ketone represented by the formula (2) and the amine represented by the formula (3) are subjected to reductive amination at a temperature of 0 to 50 ° C, preferably 10 to 40 ° C for 0.5 to 30 hours, preferably 1 to 12 hours. (4) A reductive amination product as shown, and the obtained product is further subjected to an amino-protecting group under acidic conditions of pH 2 to 6, to obtain a compound of the formula (1).
其中，在式(4)所示的化合物中B环为饱和环的情况下，可以通过DDQ在10-40℃下氧化反应4-10小时获得氧化产物，然后在卤代羧酸、优选三氟乙酸作用下10-40℃，反应10-16小时脱掉Boc保护，得到B环中具有两个双键的对应化合物。反应方案如下：Wherein, in the case where the B ring is a saturated ring in the compound represented by the formula (4), an oxidation product can be obtained by an oxidation reaction of DDQ at 10 to 40 ° C for 4 to 10 hours, followed by a halogenated carboxylic acid, preferably trifluoromethane. Under the action of acetic acid at 10-40 ° C, the reaction was removed for 10-16 hours to remove Boc protection, and the corresponding compound having two double bonds in the B ring was obtained. The reaction scheme is as follows:
Figure PCTCN2016000478-appb-000022
Figure PCTCN2016000478-appb-000022
上述<方案1>中的式(3)所示的胺化合物为
Figure PCTCN2016000478-appb-000023
时，可以利用方案2所示的合成方法制造。The amine compound represented by the formula (3) in the above <Scheme 1> is
Figure PCTCN2016000478-appb-000023
In time, it can be produced by the synthesis method shown in Scheme 2.
<方案2><Scheme 2>
Figure PCTCN2016000478-appb-000024
Figure PCTCN2016000478-appb-000024
使3-N-Boc-吡咯烷酮与DMF-DMA在0-50℃、优选10-40℃下反应1-24小时、优选2-12小时，得到1-叔丁氧基羰基-3-((二甲氨基)甲烯基)-4-吡咯烷酮。在碱金属醇盐、优选乙醇钠的作用下，使硫酸甲硫基脒与1-叔丁氧基羰基-3-((二甲氨基)甲烯基)-4-吡咯烷酮在10-100℃、优选30-50℃下回流0.5-48小时、优选2-24小时，得到2-(甲硫基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯。2-(甲硫基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯与间氯过氧苯甲酸等的氧化试剂在10-40℃、优选 室温下反应，得到2-(甲砜基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯，然后在卤代羧酸、优选三氟乙酸的作用下脱去Boc保护基，获得目标产物2-(甲砜基)-6，7-二氢-5H-吡咯[3，4-d]嘧啶。3-N-Boc-pyrrolidone is reacted with DMF-DMA at 0-50 ° C, preferably 10-40 ° C for 1-24 hours, preferably 2-12 hours, to give 1-tert-butoxycarbonyl-3-((2) Methylamino)methenyl)-4-pyrrolidone. Under the action of an alkali metal alkoxide, preferably sodium ethoxide, methylthiocyanate and 1-tert-butoxycarbonyl-3-((dimethylamino)methenyl)-4-pyrrolidone are at 10-100 ° C, It is preferably refluxed at 30 to 50 ° C for 0.5 to 48 hours, preferably 2 to 24 hours, to give 2-(methylthio)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester. Oxidation reagent of 2-(methylthio)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester and m-chloroperoxybenzoic acid at 10-40 ° C, preferably Reaction at room temperature to give 2-(methylsulfonyl)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester, then under the action of a halogenated carboxylic acid, preferably trifluoroacetic acid Removal of the Boc protecting group gave the desired product 2-(methylsulfonyl)-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidine.
利用上述
Figure PCTCN2016000478-appb-000025
可以进而利用下述方案得到
Figure PCTCN2016000478-appb-000026
Use the above
Figure PCTCN2016000478-appb-000025
Can be further obtained by the following scheme
Figure PCTCN2016000478-appb-000026
Figure PCTCN2016000478-appb-000027
Figure PCTCN2016000478-appb-000027
使2-(甲砜基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯与四正丁基氰化胺在5-45℃、优选10-40℃下反应0.5-24小时、优选1-12小时，得到2-(氰基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯，该得到的2-(氰基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯在酸的存在下，进行氰基醇解和脱Boc反应，获得目标产物。2-(Methylsulfonyl)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester with tetra-n-butyl cyanamide at 5-45 ° C, preferably 10-40 ° C The lower reaction is carried out for 0.5-24 hours, preferably 1-12 hours, to give 2-(cyano)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester, which gives 2-( The cyano)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester is subjected to cyano alcoholysis and de Boc reaction in the presence of an acid to obtain the desired product.
上述<方案1>中的式(3)所示的胺化合物为
Figure PCTCN2016000478-appb-000028
时，可以利用方案3所示的合成方法制造。The amine compound represented by the formula (3) in the above <Scheme 1> is
Figure PCTCN2016000478-appb-000028
In time, it can be produced by the synthesis method shown in Scheme 3.
<方案3><Scheme 3>
Figure PCTCN2016000478-appb-000029
Figure PCTCN2016000478-appb-000029
(式中，R与前述R3具有相同的意思)。(wherein R has the same meaning as the above R 3 ).
在碱金属醇盐、优选乙醇钠作用下，使硫脲与1-叔丁氧基羰基-3-((二甲氨基)甲烯基)-4-吡咯烷酮在10-100℃、优选30-50℃下回流0.5-48小时、优选2-24小时，得到目标产物2-巯基-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯。2-巯基-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯在碱存在下与卤代烃在5-45℃、优选10-40℃下反应0.5-24小时、优选1-12小时，获得烷基化产物。使该得到的烷基化产物与间氯过氧苯甲 酸等的氧化试剂在10-40℃、优选室温下反应，得到氧化产物，然后在卤代羧酸、优选三氟乙酸作用下脱去Boc保护基，得到目标产物氨基化合物。The thiourea and 1-tert-butoxycarbonyl-3-((dimethylamino)methenyl)-4-pyrrolidone are subjected to 10-100 ° C, preferably 30-50, under the action of an alkali metal alkoxide, preferably sodium ethoxide. The mixture is refluxed at ° C for 0.5-48 hours, preferably 2-24 hours, to give the desired product 2-mercapto-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester. 2-mercapto-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester is reacted with a halogenated hydrocarbon at a concentration of 5-45 ° C, preferably 10-40 ° C in the presence of a base 0.5-24 The alkylation product is obtained in hours, preferably from 1 to 12 hours. The resulting alkylated product and m-chloroperoxybenzophenone The oxidizing agent such as an acid is reacted at 10 to 40 ° C, preferably at room temperature to obtain an oxidation product, and then the Boc protecting group is removed by a halogenated carboxylic acid, preferably trifluoroacetic acid, to obtain an amino compound of the desired product.
上述<方案1>中的式(3)所示的胺化合物为
Figure PCTCN2016000478-appb-000030
时，可以利用方案4所示的合成方法制造。The amine compound represented by the formula (3) in the above <Scheme 1> is
Figure PCTCN2016000478-appb-000030
In time, it can be produced by the synthesis method shown in Scheme 4.
<方案4><Scheme 4>
Figure PCTCN2016000478-appb-000031
Figure PCTCN2016000478-appb-000031
(式中，R1和R2各自独立地为氢或选自前述取代基组a中的任意基团。)(wherein R 1 and R 2 are each independently hydrogen or any group selected from the aforementioned substituent group a.)
将2-巯基-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯用氯气氧化1-20小时、优选2-6小时后，用胺化合物淬灭，获得磺酰胺产物。然后在卤代羧酸、优选三氟乙酸作用下脱去Boc保护基，获得氨基化合物。The 2-mercapto-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester is oxidized with chlorine gas for 1 to 20 hours, preferably 2 to 6 hours, and then quenched with an amine compound to obtain a sulfonate. Amide product. The Boc protecting group is then removed by the action of a halogenated carboxylic acid, preferably trifluoroacetic acid, to give the amino compound.
实施例Example
以下列举实施例和试验例，进而详细地说明本发明，但它们不限定本发明，另外在不脱离本发明的范围下可进行变化。The present invention will be described in detail below with reference to the examples and the examples of the invention, but the invention is not limited thereto, and may be modified without departing from the scope of the invention.
以下的实施例中记载的化合物的结构通过核磁共振(1HNMR)或质谱(MS)来确定。The structure of the compound described in the following examples was determined by nuclear magnetic resonance ( 1 H NMR) or mass spectrometry (MS).
核磁共振(1HNMR)的测定仪器使用JEOL Eclipse 400核磁仪；测定溶剂为氘代甲醇(CD3OD)、氘代氯仿(CDCl3)，六氘代二甲基亚砜(DMSO-d6)；内标物质为四甲基硅烷(TMS)。The nuclear magnetic resonance ( 1 H NMR) measuring instrument uses a JEOL Eclipse 400 nuclear magnetic instrument; the measuring solvent is deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ), hexamethylene dimethyl sulfoxide (DMSO-d6); The internal standard substance is tetramethylsilane (TMS).
实施例中使用的核磁共振(NMR)图谱中的缩写示于以下。Abbreviations in the nuclear magnetic resonance (NMR) spectrum used in the examples are shown below.
s：单峰、d：二重峰、t：三重峰、q：四重峰、dd：双二重峰、qd：四二重峰、ddd：双双二重峰、ddt：双双三重峰、dddd：双双双二重峰、m：多重峰、br：宽峰(broad)、J：偶合常数、Hz：赫兹、DMSO-d6：氘化二甲基亚砜。s: single peak, d: doublet, t: triplet, q: quartet, dd: doublet, qd: quadruple, ddd: doublet, ddt: doublet, dddd : double doublet doublet, m: multiplet, br: broad, J: coupling constant, Hz: Hertz, DMSO-d6: deuterated dimethyl sulfoxide.
将全部δ值用ppm值表示。All δ values are expressed in ppm values.
质谱(MS)的测定仪器使用Agilent(ESI)质谱仪，型号为Agilent 6120B。 The mass spectrometer (MS) assay instrument used an Agilent (ESI) mass spectrometer, model Agilent 6120B.
在常规的合成法以及实施例、和中间体合成例中，各缩写的意思如以下所示。In the conventional synthesis methods, examples, and intermediate synthesis examples, the meanings of the respective abbreviations are as follows.
DMF：N，N-二甲基甲酰胺DMF: N,N-dimethylformamide
DMA：N，N-二甲基乙酰胺DMA: N,N-dimethylacetamide
NMP：N-甲基吡咯烷酮NMP: N-methylpyrrolidone
THF：四氢呋喃THF: tetrahydrofuran
Boc：叔丁氧基羰基Boc: tert-butoxycarbonyl
NBS；N-溴琥珀酰亚胺NBS; N-bromosuccinimide
M-CPBA：间氯过氧苯甲酸M-CPBA: m-chloroperoxybenzoic acid
TFA：三氟醋酸TFA: trifluoroacetic acid
Et2O：二乙基醚、Et 2 O: diethyl ether,
EtOH：乙醇EtOH: ethanol
Dioxane：1，4-二氧六环Dioxane: 1,4-dioxane
TLC：薄层色谱TLC: thin layer chromatography
HATU：O-(7-氮杂苯并三唑-1-基)-N，N，N’，N’-四甲基脲六氟磷酸盐HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate
Me：甲基Me: methyl
DCM：二氯甲烷DCM: dichloromethane
EA：乙酸乙酯EA: ethyl acetate
DDQ：2，3-二氯-5，6-二氰-1，4-苯醌。DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
应予说明，在以下内容中，化合物n′表示化合物n的盐形式。Incidentally, in the following, the compound n' represents a salt form of the compound n.
实施例1-1：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯Example 1-1: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole [3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺(化合物1-1)及其二三氟乙酸[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-amine (Compound 1-1) and its ditrifluoroacetic acid 盐(化合物1-1’)的制备Preparation of salt (compound 1-1')
Figure PCTCN2016000478-appb-000032
Figure PCTCN2016000478-appb-000032
第一步：1-叔丁氧基羰基-3-((二甲氨基)甲烯基)-4-吡咯烷酮的合成First step: Synthesis of 1-tert-butoxycarbonyl-3-((dimethylamino)methenyl)-4-pyrrolidone
向3-N-Boc-吡咯烷酮(56.2g)中加入DMF-DMA 300mL，65℃下搅拌12小时。浓缩，洗涤，过滤，将固体干燥，得到目标产物1-叔丁氧基羰基-3-((二甲氨基)甲烯基)-4-吡咯烷酮(47.2g，黄色固体)，收率：64％。To 3-N-Boc-pyrrolidone (56.2 g), 300 mL of DMF-DMA was added, and the mixture was stirred at 65 ° C for 12 hours. Concentration, washing, filtration and drying the solid to give the desired product 1-t-butoxycarbonyl-3-((dimethylamino)methyl)-4-pyrrolidone (47.2 g, yellow solid), yield: 64% .
MS m/z(ESI)：241.1[M+1]。MS m/z (ESI): 242.
第二步：2-(甲硫基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯的合成Step 2: Synthesis of 2-(methylthio)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester
室温下，向乙醇钠(6.6g，93mmol)的250mL乙醇溶液中加入硫酸甲硫基脒(7.8g，41.6mmol)，搅拌30分钟后，加入1-叔丁氧基羰基-3-((二甲氨基)甲烯基)-4-吡咯烷酮(5g，20.8mmol)并回流搅拌6小时后。加水淬灭，浓缩除去乙醇，水相用乙酸乙酯(50mL*4)萃取，合并有机相，无水硫酸钠干燥，旋干后得到目标分子2-(甲硫基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯(3.3g，淡黄色固体)，收率：59％。To a solution of sodium ethoxide (6.6 g, 93 mmol) in 250 mL of ethanol was added methyl thiosulfate (7.8 g, 41.6 mmol) at room temperature, and after stirring for 30 minutes, 1-tert-butoxycarbonyl-3-((2) Methylamino)methenyl)-4-pyrrolidone (5 g, 20.8 mmol) was stirred at reflux for 6 h. After quenching with water, the ethanol was concentrated, and the aqueous phase was extracted with ethyl acetate (50mL*4). The organic phase was combined, dried over anhydrous sodium sulfate and dried to give the desired compound 2-(methylthio)-5H-pyrrole [3 , 4-d]pyrimidine-6(7H)-carboxylic acid tert-butyl ester (3.3 g, pale yellow solid), yield: 59%.
MS m/z(ESI)：268.1[M+1]。MS m/z (ESI): 268.1 [M+1].
第三步：2-(甲砜基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯的合成Step 3: Synthesis of 2-(methylsulfonyl)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester
0℃下，向2-(甲硫基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯(3.3g，12.3mmol)的50mL二氯甲烷中加入间氯过氧苯甲酸(6.3g，37.1mmol)，自然升至室温，反应10小时后，向反应液中加入10％亚硫酸钠溶液，搅拌30分钟后再加入饱和碳酸钠溶液，用二氯甲烷(50mL*4)萃取，合并有机相，无水硫酸钠干燥，旋干后得到目标分子2-(甲砜基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯(3.2g，淡黄色固体)，收率： 86.7％。To a solution of 2-(methylthio)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester (3.3 g, 12.3 mmol) in 50 mL of dichloromethane at 0 ° C Chloroperoxybenzoic acid (6.3 g, 37.1 mmol), naturally raised to room temperature, after 10 hours of reaction, 10% sodium sulfite solution was added to the reaction mixture, stirred for 30 minutes, then saturated sodium carbonate solution was added, with dichloromethane (50 mL) *4) Extraction, combining organic phases, drying over anhydrous sodium sulfate, and spinning to obtain the target molecule 2-(methylsulfonyl)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl Ester (3.2 g, pale yellow solid), yield: 86.7%.
MS m/z(ESI)：300.3[M+1]。MS m/z (ESI): 300.3 [M + 1].
第四步：2-(甲砜基)-6，7-二氢-5H-吡咯[3，4-d]嘧啶三氟乙酸盐的合成Step 4: Synthesis of 2-(methylsulfonyl)-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidine trifluoroacetate
室温下，向2-(甲砜基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯(0.4g)的10mL二氯甲烷溶液中加入2mL三氟乙酸，然后搅拌2小时。将反应液浓缩至干，得到纯品2-(甲砜基)-6，7-二氢-5H-吡咯[3，4-d]嘧啶三氟乙酸盐(0.35g，棕色固体)。To a solution of 2-(methylsulfonyl)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester (0.4 g) in 10 mL of dichloromethane Then stirred for 2 hours. The reaction mixture was concentrated to dryness to give purified crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal
第五步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的合成Step 5: (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H) Synthesis of tert-butyl tetrahydro-2H-pyran-3-carbamate
室温下，向2-(甲砜基)-6，7-二氢-5H-吡咯[3，4-d]嘧啶三氟乙酸盐(170mg，0.54mmol)的20mL四氢呋喃体系中加入三乙胺(56mg，0.54mmol)，醋酸(97mg，1.62mmol)及(3R，5S，6R)-5-Boc-氨基-6-(2，5-二氟苯基)2H-四氢吡喃-3-酮(175mg，0.5mmol)，反应液搅拌4小时，然后向反应液中加入NaBH3CN(70mg，1.08mmol)并搅拌3小时。反应液用水淬灭后，浓缩，TLC分离纯化得到目标产物(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯(60mg，白色固体)，收率：22％。Add triethylamine to a 20 mL tetrahydrofuran system of 2-(methylsulfonyl)-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidine trifluoroacetate (170 mg, 0.54 mmol) at room temperature (56 mg, 0.54 mmol), acetic acid (97 mg, 1.62 mmol) and (3R,5S,6R)-5-Boc-amino-6-(2,5-difluorophenyl)2H-tetrahydropyran-3- The ketone (175 mg, 0.5 mmol) was stirred for 4 hours, then NaBH 3 CN (70 mg, 1.08 mmol) was added to the mixture and stirred for 3 hr. The reaction mixture was quenched with water, concentrated, and then purified and purified to afford the desired product (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole [3 , 4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester (60 mg, white solid), yield: 22%.
在此合成过程中，还分离得到了一个立体异构产物(2R，3S，5S)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯(20mg，白色固体)，收率：7.4％。In this synthesis, a stereoisomeric product (2R,3S,5S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole [3] was also isolated. , 4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester (20 mg, white solid), yield: 7.4%.
MS m/z(ESI)：511.1[M+1]。MS m/z (ESI): 511.1 [M + 1].
第六步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二三氟乙酸盐的合成Step 6: (2R, 3S, 5R)-2-(2,5-Difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H) -Synthesis of tetrahydro-2H-pyran-3-amine ditrifluoroacetate
室温下，向(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯(150mg)的二氯甲烷(4mL)溶液中加入三氟乙酸(4mL)，搅拌16小时后。将反应液浓缩至干后得半固体粗品，用甲基叔丁基醚打浆过滤。滤饼干燥后得纯品(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二三氟乙酸盐(138mg，淡黄色固体)，收率：73％。To (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H) at room temperature To a solution of tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester (150 mg) in dichloromethane (4 mL) The reaction mixture was concentrated to dryness to give a semi-solid crude product, which was filtered and filtered with methyl t-butyl ether. The filter cake is dried to obtain pure (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidine-6 (7H)-yl)tetrahydro-2H-pyran-3-amine ditrifluoroacetate (138 mg, pale yellow solid), yield: 73%.
第七步：游离化合物(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺(化合物1-1)的制备 Step 7: Free compound (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidine-6 ( Preparation of 7H)-yl)tetrahydro-2H-pyran-3-amine (Compound 1-1)
将(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二三氟乙酸盐用2M碳酸钠水溶液超声洗涤，然后过滤，即可获得游离化合物(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺。(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl) Tetrahydro-2H-pyran-3-amine ditrifluoroacetate is sonicated with 2M sodium carbonate aqueous solution, and then filtered to obtain the free compound (2R, 3S, 5R)-2-(2,5-difluoro Phenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-amine.
实施例1-2：(2R，3S，5S)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯 [3，4-d]嘧啶-6(7H)-基)四氢-2H吡喃-3-胺(化合物1-2)及其二盐酸盐(化 合物1-2’)的制备 Example 1-2: (2R,3S,5S)-2-(2,5-Difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole [3,4-d]pyrimidine-6 ( 7H) - yl) tetrahydro -2H-pyran-3-amine (compound 1-2) and its dihydrochloride (compound 1-2 ') of
Figure PCTCN2016000478-appb-000033
Figure PCTCN2016000478-appb-000033
按照与实施例1-1类似的第一至六步的方法，但在第六步骤中用盐酸代替三氟乙酸，将在实施例1-1的第五步中得到的立体异构体(2R，3S，5S)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯脱保护后，得到立体异构的目标产物(2R，3S，5S)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二盐酸盐(14mg，淡黄色固体)(化合物1-2′)，收率：73％。The stereoisomer obtained in the fifth step of Example 1-1 (2R) was subjected to the first to sixth steps similar to Example 1-1 except that hydrochloric acid was used in place of trifluoroacetic acid in the sixth step. ,3S,5S)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl)tetrahydro- Deprotection of tert-butyl 2H-pyran-3-carbamate gives the desired product (2R,3S,5S)-2-(2,5-difluorophenyl)-5-(2-A Sulfone-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-amine dihydrochloride (14 mg, pale yellow solid) (Compound 1-2' ), yield: 73%.
将(2R，3S，5S)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二盐酸盐用2M碳酸钠水溶液超声洗涤，然后过滤，即可获得游离化合物(2R，3S，5S)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺(化合物1-2)。(2R,3S,5S)-2-(2,5-Difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl) Tetrahydro-2H-pyran-3-amine dihydrochloride was ultrasonically washed with 2M aqueous sodium carbonate solution, followed by filtration to obtain the free compound (2R, 3S, 5S)-2-(2,5-difluorophenyl) -5-(2-Methylsulfonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-amine (Compound 1-2).
实施例2：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-6H-吡咯[3，4-d]Example 2: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-6H-pyrrole[3,4-d] 嘧啶-6-基)四氢-2H-吡喃-3-胺三氟乙酸盐(化合物2’)的制备Preparation of pyrimidin-6-yl)tetrahydro-2H-pyran-3-amine trifluoroacetate (Compound 2')
第一步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-6H-吡咯[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-Boc-胺的合成First step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-6H-pyrrole[3,4-d]pyrimidin-6-yl) Synthesis of tetrahydro-2H-pyran-3-Boc-amine
室温下，向(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d] 嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯(100mg，0.2mmol)的15mL二氧六环中加入DDQ(54mg，0.23mmol)，反应6小时后，向反应液中加入10％碳酸钠溶液，然后用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，浓缩，柱层析得到目标产品(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-6H-吡咯[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-Boc-胺(50mg，淡黄色固体)，收率：50％。To (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d] at room temperature Add DDQ (54 mg, 0.23 mmol) to 15 mL of dioxane, pyrimidine-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester (100 mg, 0.2 mmol). To the reaction mixture, a 10% sodium carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, and concentrated to give the desired product (2R,3S,5R)-2-(2, 5-difluorophenyl)-5-(2-methylsulfonyl-6H-pyrrole[3,4-d]pyrimidin-6-yl)tetrahydro-2H-pyran-3-Boc-amine (50 mg, light Yellow solid), yield: 50%.
MS m/z(ESI)：509.2[M+1]。MS m/z (ESI): 509.2 [M+].
第二步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-6H-吡咯[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-胺三氟乙酸盐的合成Second step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-6H-pyrrole[3,4-d]pyrimidin-6-yl) Synthesis of tetrahydro-2H-pyran-3-amine trifluoroacetate
室温下，向(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-6H-吡咯[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-Boc-胺(50mg)的二氯甲烷(3mL)溶液中加入三氟乙酸(1mL)，搅拌16小时后。将反应液浓缩至干后得半固体粗品，粗品洗涤得纯品(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-6H-吡咯[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-胺三氟乙酸盐(38mg，黄色固体)，收率：75％。To (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-6H-pyrrole[3,4-d]pyrimidin-6-yl) at room temperature To a solution of tetrahydro-2H-pyran-3-Boc-amine (50 mg) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) and stirred for 16 hr. The reaction solution was concentrated to dryness to give a semi-solid crude product, which was purified to crude (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-6H-pyrrole [3,4-d]Pyridin-6-yl)tetrahydro-2H-pyran-3-amine trifluoroacetate (38 mg, yellow solid), yield: 75%.
实施例3：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲氧基羰基-5H-吡咯Example 3: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methoxycarbonyl-5H-pyrrole [3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二三氟乙酸盐(化合物3’)的[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-amine ditrifluoroacetate (compound 3') 制备preparation
Figure PCTCN2016000478-appb-000035
Figure PCTCN2016000478-appb-000035
第一步：2-(氰基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯的合成First step: Synthesis of 2-(cyano)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester
室温下，向2-(甲砜基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯(1.8g，6mmol)的40mL二氯甲烷中加入四正丁基氰化胺(2g，7.4mmol)，搅拌15小时后。向反应液中加入饱和碳酸氢钠溶液，然后用二氯甲烷(40mL*3)萃取，合并二氯甲烷，无水硫酸钠干燥，浓缩后柱层析纯化，得到2-(氰基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯(1.3g，白色固体)，收率：85％。 Add tetra-n-butyl group to 40 mL dichloromethane of 2-(methylsulfonyl)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester (1.8 g, 6 mmol) at room temperature The amine cyanamide (2 g, 7.4 mmol) was stirred for 15 hours. A saturated sodium hydrogencarbonate solution was added to the reaction mixture, and then extracted with dichloromethane (40 mL*3), dichloromethane was combined, dried over anhydrous sodium sulfate, and concentrated, and then purified by column chromatography to give 2-(cyano)-5H Pyrrolo[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester (1.3 g, white solid), yield: 85%.
第二步：6，7-二氢-5H-吡咯[3，4-d]嘧啶-2-羧酸甲酯盐酸盐的合成The second step: synthesis of 6,7-dihydro-5H-pyrrole [3,4-d]pyrimidine-2-carboxylic acid methyl ester hydrochloride
向2-(氰基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯(1.3g，5.28mmol)的20mL甲醇溶液中加入10mL浓盐酸，然后升温至80℃搅拌4小时后，直接浓缩反应液，得到1g粗品。To a solution of 2-(cyano)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester (1.3 g, 5.28 mmol) in 20 mL MeOH After stirring at 80 ° C for 4 hours, the reaction mixture was directly concentrated to give 1 g of crude material.
第三步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲氧基羰基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的合成The third step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-methoxycarbonyl-5H-pyrrole[3,4-d]pyrimidine-6 (7H Synthesis of tert-butyl tetrahydro-2H-pyran-3-carbamate
室温下，向6，7-二氢-5H-吡咯[3，4-d]嘧啶-2-羧酸甲酯盐酸盐(1.0g，4.65mmol)的40mL四氢呋喃体系中加入三乙胺(3.3mL，23.3mmol)及(3R，5S，6R)-5-Boc-氨基-6-(2，5-二氟苯基)2H-四氢吡喃-3-酮(1.8g，5.58mmol)，室温搅拌13小时后。向反应液中加入NaBH3CN(580mg，9.3mmol)并搅拌6小时。反应液用水淬灭后，乙酸乙酯萃取，干燥，浓缩，柱纯化分离，得到目标产物(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲氧基羰基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯(250mg，白色固体)，收率：11％。To a 40 mL tetrahydrofuran system of 6,7-dihydro-5H-pyrrole[3,4-d]pyrimidine-2-carboxylic acid methyl ester hydrochloride (1.0 g, 4.65 mmol) was added triethylamine (3.3). mL, 23.3 mmol) and (3R,5S,6R)-5-Boc-amino-6-(2,5-difluorophenyl) 2H-tetrahydropyran-3-one (1.8 g, 5.58 mmol), After stirring at room temperature for 13 hours. NaBH 3 CN (580 mg, 9.3 mmol) was added to the reaction mixture and stirred for 6 hr. After the reaction mixture was quenched with water, ethyl acetate was evaporated, dried, concentrated, and purified by column to give the desired product (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2- oxycarbonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester (250 mg, white solid), yield: 11% .
第四步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲氧基羰基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二三氟乙酸盐的合成The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-methoxycarbonyl-5H-pyrrole[3,4-d]pyrimidine-6 (7H Synthesis of tetrahydro-2H-pyran-3-amine ditrifluoroacetate
除了使用(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲氧基羰基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯代替(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯，使(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲氧基羰基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的投料量为100mg之外，其它与实施例1第六步同样操作，得到标题产物80mg，收率为83.5％。In addition to using (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methoxycarbonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H)- Substituting tert-butyl tetrahydro-2H-pyran-3-carbamate for (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-5H- Pyrrole [3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester, (2R,3S,5R)-2-(2,5-di Fluorophenyl)-5-(2-methoxycarbonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester The same procedure as in the sixth step of Example 1 was carried out except that the amount of the mixture was 100 mg, to give the title product: 80 mg, yield: 83.5%.
实施例4：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-羧基-5H-吡咯[3，4-d]Example 4: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-carboxy-5H-pyrrole[3,4-d] 嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二三氟乙酸盐(化合物4’)的制备Preparation of pyrimidine-6(7H)-yl)tetrahydro-2H-pyran-3-amine ditrifluoroacetate (Compound 4')
Figure PCTCN2016000478-appb-000036
Figure PCTCN2016000478-appb-000036
第一步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-羧基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的合成 First step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-carboxy-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl Synthesis of tert-butyl tetrahydro-2H-pyran-3-carbamate
室温下，向7(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲氧基羰基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯(110mg，0.22mmol)的四氢呋喃(2mL)溶液中加入氢氧化锂(30mg，0.56mmol)的10mL水溶液，搅拌8小时后。用1N稀盐酸调节反应的pH＝6，然后浓缩得粗品，直接用于下一步反应。To 7(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methoxycarbonyl-5H-pyrrole[3,4-d]pyrimidin-6 (at room temperature) Add a solution of lithium hydroxide (30 mg, 0.56 mmol) in 10 mL of a solution of THF (2 mL). Rear. The pH of the reaction was adjusted with 1N diluted hydrochloric acid and then concentrated to give a crude material which was directly used for the next step.
第二步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-羧基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二三氟乙酸盐的合成Second step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-carboxy-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl Synthesis of tetrahydro-2H-pyran-3-amine ditrifluoroacetate
室温下，将7(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-羧基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯粗品溶于二氯甲烷(5mL)中，然后向其中加入三氟乙酸(1mL)并搅拌12小时后，浓缩反应液得半固体状粗品。将此粗品用乙酸乙酯溶解后，过滤，滤液旋干，重结晶得(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-羧基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二三氟乙酸盐(5.5mg，黄色固体)，两步收率4％。7(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-carboxy-5H-pyrrole[3,4-d]pyrimidin-6(7H)- The crude tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester was dissolved in dichloromethane (5 mL), then trifluoroacetic acid (1 mL) was added and stirred for 12 hr. Rough. This crude product was dissolved in ethyl acetate, filtered, and the filtrate was evaporated to give (2,,,,,,,,,,,,,,,,,,,,,, [3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-amine ditrifluoroacetate (5.5 mg, yellow solid).
实施例5：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-Example 5: 6-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3- 基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-2-羧酸酰胺二三氟乙酸盐(化合物6,7-7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-carboxylic acid amide ditrifluoroacetate (compound) 5’)的制备Preparation of 5')
Figure PCTCN2016000478-appb-000037
Figure PCTCN2016000478-appb-000037
第一步：Boc-5H-吡咯[3，4-d]嘧啶-6(7H)-2-甲酰胺的合成First step: Synthesis of Boc-5H-pyrrole [3,4-d]pyrimidin-6(7H)-2-carboxamide
0℃下，向2-(氰基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯(250mg，1mmol)的2mL DMF溶液中加入碳酸钾(0.11g，0.8mmol)，然后滴加双氧水(3mL)。3小时后，向反应液中加入饱和亚硫酸氢钠溶液，用二氯甲烷(20mL*3)萃取，合并二氯甲烷，无水硫酸钠干燥，浓缩后柱层析纯化，得到Boc-5H-吡咯[3，4-d]嘧啶-6(7H)-2-甲酰胺(0.2g，白色固体)，收率：75％。 Potassium carbonate (0.11 g) was added to a solution of 2-(cyano)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester (250 mg, 1 mmol) in 2 mL DMF. , 0.8 mmol), then hydrogen peroxide (3 mL) was added dropwise. After 3 hours, a saturated sodium hydrogen sulfite solution was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 mL*3). Pyrrole [3,4-d]pyrimidin-6(7H)-2-carboxamide (0.2 g, white solid), yield: 75%.
第二步：5H-吡咯[3，4-d]嘧啶-6(7H)-2-甲酰胺三氟乙酸盐的合成Step 2: Synthesis of 5H-pyrrole[3,4-d]pyrimidin-6(7H)-2-carboxamide trifluoroacetate
除了使用Boc-5H-吡咯[3，4-d]嘧啶-6(7H)-2-甲酰胺代替(2-(甲砜基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯，使Boc-5H-吡咯[3，4-d]嘧啶-6(7H)-2-甲酰胺的投料量为200mg之外，其它与实施例1第四步同样操作，得到标题产物190mg，收率为90％。In addition to using Boc-5H-pyrrole [3,4-d]pyrimidin-6(7H)-2-carboxamide instead of (2-(methylsulfonyl)-5H-pyrrole[3,4-d]pyrimidine-6 (7H - tert-butyl carboxylate, the Boc-5H-pyrrole[3,4-d]pyrimidin-6(7H)-2-carboxamide was charged in an amount of 200 mg, and the same operation as in the fourth step of Example 1. The title product was obtained in 190 mg in a yield of 90%.
第三步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-胺甲酰基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的合成The third step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-carbamoyl-5H-pyrrole[3,4-d]pyrimidin-6(7H) Synthesis of tert-butyl tetrahydro-2H-pyran-3-carbamate
除了使用5H-吡咯[3，4-d]嘧啶-6(7H)-2-甲酰胺三氟乙酸盐代替(2-(甲砜基)-6，7-二氢-5H-吡咯[3，4-d]嘧啶三氟乙酸盐，使5H-吡咯[3，4-d]嘧啶-6(7H)-2-甲酰胺三氟乙酸盐的投料量为120mg之外，其它与实施例1第五步同样操作，得到标题产物100mg，收率为48.8％。In addition to using 5H-pyrrole[3,4-d]pyrimidin-6(7H)-2-carboxamide trifluoroacetate instead of (2-(methylsulfonyl)-6,7-dihydro-5H-pyrrole [3 , 4-d]pyrimidine trifluoroacetate, the amount of 5H-pyrrole[3,4-d]pyrimidin-6(7H)-2-carboxamide trifluoroacetate is 120 mg, and other implementation The same procedure as in the fifth step of Example 1 gave the title product, 100 mg, yield: 48.8%.
第四步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-胺甲酰基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二三氟乙酸盐的合成The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-carbamoyl-5H-pyrrole[3,4-d]pyrimidin-6(7H) -Synthesis of tetrahydro-2H-pyran-3-amine ditrifluoroacetate
除了使用(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-胺甲酰基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯代替(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯，使(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-胺甲酰基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的投料量为90mg之外，其它与实施例1第六步同样操作，得到标题产物103mg，收率为90％。In addition to using (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-carbamoyl-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl Replacement of (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole) with tert-butyl-2H-pyran-3-carbamate [3,4-d]pyrimidine-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester, (2R,3S,5R)-2-(2,5-difluoro Feeding amount of phenyl)-5-(2-carbamoyl-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester The same procedure as in the sixth step of Example 1 was carried out except for 90 mg to give the title product (yield: 90%).
实施例6：(2R，3S，5R)-2-(2，4，5-三氟苯基)-5-(2-甲砜基-5H-吡咯Example 6: (2R,3S,5R)-2-(2,4,5-trifluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole [3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二三氟乙酸盐(化合物6’)的[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-amine ditrifluoroacetate (compound 6') 制备preparation
Figure PCTCN2016000478-appb-000038
Figure PCTCN2016000478-appb-000038
第一步：(2R，3S，5R)-2-(2，4，，5-三氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的合成First step: (2R, 3S, 5R)-2-(2,4,,5-trifluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidine-6 Synthesis of (7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester
除了使用(2R，3S)-5-氧带-2-(2，4，5-三氟苯基)四氢-2H-吡喃-3-基)氨基羧酸叔丁酯代替(2R，3S)-5-氧带-2-(2，5-三氟苯基)四氢-2H-吡喃-3- 基)氨基羧酸叔丁酯，使2-(甲砜基)-6，7-二氢-5H-吡咯[3，4-d]嘧啶三氟乙酸盐的投料量为450mg之外，其它与实施例1第五步同样操作，得到标题产物420mg，收率为55％。In addition to using (2R,3S)-5-oxo-2-(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-yl)aminocarboxylic acid tert-butyl ester instead (2R, 3S -5-oxygen-2-(2,5-trifluorophenyl)tetrahydro-2H-pyran-3- Tert-butyl aminocarboxylate, the amount of 2-(methylsulfonyl)-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidine trifluoroacetate is 450 mg, other The same procedure as in the fifth step of Example 1 gave 420 mg of the title product.
第二步：(2R，3S，5R)-2-(2，4，5-三氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二三氟乙酸盐的合成Second step: (2R, 3S, 5R)-2-(2,4,5-trifluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidine-6 ( Synthesis of 7H)-yl)tetrahydro-2H-pyran-3-amine ditrifluoroacetate
除了使用(2R，3S，5R)-2-(2，4，，5-三氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯代替(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯，使(2R，3S，5R)-2-(2，4，，5-三氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的投料量为100mg之外，其它与实施例1第六步同样操作，得到标题产物120mg，收率为96.7％。In addition to using (2R,3S,5R)-2-(2,4,5-trifluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidine-6 (7H) )-yl) tert-butyl-2H-pyran-3-carbamate instead of (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl- 5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester, (2R,3S,5R)-2-(2,4 ,5-trifluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid The same procedure as in the sixth step of Example 1 was carried out except that the amount of the tert-butyl ester was 100 mg, and the title product was obtained in a yield of 96.7%.
实施例7：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙砜基)-5H-吡咯并Example 7: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-isopropylsulfonyl)-5H-pyrrole [3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二盐酸盐(化合物7’)的制备Preparation of [3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-amine dihydrochloride (Compound 7')
Figure PCTCN2016000478-appb-000039
Figure PCTCN2016000478-appb-000039
第一步：2-异丙硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的合成First step: Synthesis of 2-isopropylthio-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate
室温条件下，将2-巯基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯(1g，4mmol)和DMF(10mL)加入到反应瓶中，加入Cs2CO3(1.95g，6mmol)和异丙基溴(0.74g，4.8mmol)。室温下搅拌15小时。将反应液倒入50mL水中，过滤，滤饼分别用20mL水和石油醚洗涤。干燥后得到目标产物2-异丙硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯(0.8g，黄色固体)收率：67.8％。2-Mercapto-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate (1 g, 4 mmol) and DMF (10 mL) were added to the reaction flask at room temperature, and Cs 2 was added. CO 3 (1.95 g, 6 mmol) and isopropyl bromide (0.74 g, 4.8 mmol). Stir at room temperature for 15 hours. The reaction solution was poured into 50 mL of water, filtered, and the filter cake was washed with 20 mL of water and petroleum ether. After drying, the desired product 2-isopropylthio-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate (0.8 g, yellow solid) yield: 67.8%.
第二步：2-异丙砜基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的合成 Step 2: Synthesis of 2-isopropylsulfonyl-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate
除了使用2-异丙硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯代替2-(甲硫基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯，使2-异丙硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的投料量为800mg之外，其它与实施例1第三步同样操作，得到标题产物750mg，收率为74.6％。In addition to using 2-isopropylthio-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate instead of 2-(methylthio)-5H-pyrrole [3,4-d] Pyrimidine-6(7H)-carboxylic acid tert-butyl ester, the amount of 2-isopropylthio-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate is 800 mg The same procedure as in the third step of Example 1 gave the title product 750 mg (yield: 74.6%).
第三步：2-(异丙砜基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶的合成Step 3: Synthesis of 2-(isopropylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine
室温条件下，将2-异丙砜基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯(0.75g，2.5mmol)和HCl/EA(3M)加入到反应瓶中，室温下搅拌1小时，过滤，滤饼分别用20mL EA和石油醚清洗两次。干燥后得到目标产物2-(异丙砜基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶(0.41g，黄色固体)收率：65.5％。2-Pepylsulfonyl-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate (0.75 g, 2.5 mmol) and HCl/EA (3M) were added at room temperature to The reaction flask was stirred at room temperature for 1 hour, filtered, and the filter cake was washed twice with 20 mL of EA and petroleum ether. After drying, the desired product 2-(isopropylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine (0.41 g, yellow solid) yield: 65.5%.
第四步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的合成Fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-isopropylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidine-6 Synthesis of (7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester
除了使用2-(异丙砜基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶代替2-(甲砜基)-6，7-二氢-5H-吡咯[3，4-d]嘧啶三氟乙酸盐，使2-(异丙砜基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶的投料量为410mg之外，其它与实施例1第五步同样操作，得到标题产物540mg，收率为66.2％。In addition to 2-(isopropylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine instead of 2-(methylsulfonyl)-6,7-dihydro-5H-pyrrole [ 3,4-d]pyrimidine trifluoroacetate, the amount of 2-(isopropylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine is 410 mg, Other procedures were carried out in the same manner as in the fifth step of Example 1 to give the title product 540 mg (yield: 66.2%).
第五步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二盐酸盐的合成Step 5: (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-isopropylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidine-6 Synthesis of (7H)-yl)tetrahydro-2H-pyran-3-amine dihydrochloride
除了使用(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯代替(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯，使(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的投料量为200mg之外，其它与实施例1第六步同样操作，得到标题产物120mg，收率为60.2％。In addition to using (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-isopropylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidine-6 (7H )-yl) tert-butyl-2H-pyran-3-carbamate instead of (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl- 5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester, (2R,3S,5R)-2-(2,5 -difluorophenyl)-5-(2-isopropylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid The same procedure as in the sixth step of Example 1 was carried out except that the amount of the tert-butyl ester was 200 mg, and the title product was obtained in a yield of 60.2%.
实施例8：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-乙砜基)-5H-吡咯并Example 8: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-ethylsulfonyl)-5H-pyrrole [3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二盐酸盐(化合物8’)的制备Preparation of [3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-amine dihydrochloride (Compound 8')
Figure PCTCN2016000478-appb-000040
Figure PCTCN2016000478-appb-000040
第一步：2-乙硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的合成First step: Synthesis of 2-ethylthio-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate
除了使用碘乙烷代替异丙基溴，使2-巯基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的投料量为1g之外，其它与实施例7第一步同样操作，得到标题产物750mg，收率为66.6％。Except for the use of iodoethane instead of isopropyl bromide, the amount of 2-mercapto-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate was 1 g, and other examples 7 The same procedure as the first step gave 750 mg of the title product.
第二步：2-乙砜基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的合成The second step: synthesis of 2-ethylsulfonyl-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate
除了使用2-乙硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯代替2-异丙硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯，使2-乙硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的投料量为750mg之外，其它与实施例7第二步同样操作，得到标题产物750mg，收率为92％。In addition to 2-ethylthio-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate instead of 2-isopropylthio-5H-pyrrolo[3,4-d]pyrimidine -6(7H)-tert-butyl carbonate, the amount of 2-ethylthio-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate was 750 mg, and the other The same procedure as in the second step of Example 7 gave 750 mg of the title product.
第三步：2-(乙砜基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶的合成Step 3: Synthesis of 2-(ethylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine
除了使用2-乙硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯代替2-异丙硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯，使2-乙硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的投料量为750mg之外，其它与实施例7第三步同样操作，得到标题产物500mg，收率为98％。In addition to 2-ethylthio-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate instead of 2-isopropylthio-5H-pyrrolo[3,4-d]pyrimidine -6(7H)-tert-butyl carbonate, the amount of 2-ethylthio-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate was 750 mg, and the other The same procedure as in the third step of Example 7 gave the title product (yield:
第四步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-乙砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的合成The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-ethylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidine-6 ( Synthesis of 7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester
除了使用2-(乙砜基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶代替2-(异丙砜基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶，使2-(乙砜基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶的投料量为500mg之外，其它与实施例7第四步同样操作，得到标题产物410mg，收率为39％。In addition to 2-(ethylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine instead of 2-(isopropylsulfonyl)-6,7-dihydro-5H-pyrrole [3,4-d]pyrimidine, the amount of 2-(ethylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine is 500 mg, and the same as in Example 7 The fourth step was carried out in the same manner to give the title product 410 mg, yield 39%.
第五步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-乙砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二盐酸盐的合成The fifth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-ethylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidine-6 ( Synthesis of 7H)-yl)tetrahydro-2H-pyran-3-amine dihydrochloride
除了使用(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-乙砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯代替(2R，3S，5R) -2-(2，5-二氟苯基)-5-(2-异丙砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯，使(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-乙砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的投料量为160mg之外，其它与实施例7第五步同样操作，得到标题产物55mg，收率为40.3％。In addition to using (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-ethylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6 (7H) -based) tert-butyl tetrahydro-2H-pyran-3-carbamate instead of (2R, 3S, 5R) -2-(2,5-Difluorophenyl)-5-(2-isopropylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H- tert-Butylpyran-3-carbamate, (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-ethylsulfonyl)-5H-pyrrolo[3, 4-d]pyrimidine-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester was charged in the same manner as in the fifth step of Example 55 mg, the yield was 40.3%.
实施例9：(2R，3S，5R)-2-(2，5-二氟苯基)-5(2-异丙砜基)-6H-吡咯并Example 9: (2R,3S,5R)-2-(2,5-difluorophenyl)-5(2-isopropylsulfonyl)-6H-pyrrole [3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-胺二盐酸盐(化合物9’)的制备Preparation of [3,4-d]pyrimidin-6-yl)tetrahydro-2H-pyran-3-amine dihydrochloride (Compound 9')
Figure PCTCN2016000478-appb-000041
Figure PCTCN2016000478-appb-000041
第一步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙砜基)-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的合成First step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-isopropylsulfonyl)-6H-pyrrolo[3,4-d]pyrimidine-6 Synthesis of tert-butyl tetrahydro-2H-pyran-3-carbamate
除了使用(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯代替(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯，使(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的投料量为340mg之外，其它与实施例2第一步同样操作，得到标题产物160mg，收率为47％。In addition to using (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-isopropylsulfonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H)- Substituting tert-butyl tetrahydro-2H-pyran-3-carbamate for (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-5H- Pyrrole [3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester, (2R,3S,5R)-2-(2,5-di Fluorophenyl)-5-(2-isopropylsulfonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester The title product was obtained in the same manner as in the first step of Example 2 to give a yield of 47%.
第二步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙砜基)-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-胺二盐酸盐的合成Second step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-isopropylsulfonyl)-6H-pyrrolo[3,4-d]pyrimidine-6 Synthesis of 4-hydro-2H-pyran-3-amine dihydrochloride
除了使用(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙砜基)-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯代替(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基)-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯，使(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙砜基)-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的投料量为160mg之外，其它与实施例2第二步同样操作，得到标题产物54mg，收率为37.2％。In addition to using (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-isopropylsulfonyl)-6H-pyrrolo[3,4-d]pyrimidin-6-yl ) tert-butyl tetrahydro-2H-pyran-3-carbamate instead of (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl)-6H- (2R,3S,5R)-2-(2,5-difluorobenzene) The amount of 5-(2-isopropylsulfonyl)-6H-pyrrolo[3,4-d]pyrimidin-6-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester is The same procedure as in the second step of Example 2, except for 160 mg, gave the title product, 54 mg, yield: 37.2%.
实施例10：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-Example 10: 6-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3- 基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-2-磺酰二甲胺二三氟乙酸盐(化合6,7-7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-sulfonyldimethylamine ditrifluoroacetate (combination 物10’)的制备Preparation of matter 10')
Figure PCTCN2016000478-appb-000042
Figure PCTCN2016000478-appb-000042
第一步：2-N，N-二甲氨基磺酰基-5H-吡咯并[3，4-d]嘧啶-6(7H)-氨甲酸叔丁酯的合成First step: Synthesis of 2-N,N-dimethylaminosulfonyl-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbamate
室温条件下，将2-巯基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯(1g，4mmol)和H2O/DCM(10mL/5mL)加入到反应瓶中搅拌。冰水浴条件下，向反应体系中通入氯气0.5小时。加入二甲胺(40mmL，2.2mL)淬灭反应。搅拌1h后依次加入10mL水和20mL DCM萃取三次，合并有机相用无水硫酸钠干燥。过滤浓缩，柱层析(PE∶EA＝2∶1)纯化得2-N，N-二甲氨基磺酰基-5H-吡咯并[3，4-d]嘧啶-6(7H)-氨甲酸叔丁酯(500mg，黄色固体)收率：38％。2-mercapto-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate (1 g, 4 mmol) and H 2 O/DCM (10 mL/5 mL) were added to the reaction at room temperature. Stir in the bottle. Under ice water bath conditions, chlorine gas was introduced into the reaction system for 0.5 hour. The reaction was quenched by the addition of dimethylamine (40 mL, 2.2 mL). After stirring for 1 h, 10 mL of water and 20 mL of DCM were added and extracted three times, and the combined organic phases were dried over anhydrous sodium sulfate. Concentrated by filtration and purified by column chromatography (PE:EA=2:1) to give 2-N,N-dimethylaminosulfonyl-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carbamic acid Yield of butyl ester (500 mg, yellow solid): 38%.
第二步：2-(N，N-二甲氨基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐的合成Step 2: Synthesis of 2-(N,N-dimethylaminosulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine trifluoroacetate
室温条件下，将2-N，N-二甲氨基磺酰基-5H-吡咯并[3，4-d]嘧啶-6(7H)-氨甲酸叔丁酯(0.25g，0.76mmol)和DCM/TFA(2mL/1mL)加入到反应瓶中，室温下搅拌2小时。反应完成后，加入乙醚5mL，搅拌析出固体，固体过滤，洗涤，干燥后得到目标产物2-(N，N-二甲氨基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐(0.20g，灰色固体)收率：80％。2-N,N-Dimethylaminosulfonyl-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-carbamic acid tert-butyl ester (0.25 g, 0.76 mmol) and DCM/ TFA (2 mL / 1 mL) was added to a reaction flask and stirred at room temperature for 2 hours. After completion of the reaction, 5 mL of diethyl ether was added, and the solid was precipitated, solid filtered, washed and dried to give the desired product 2-(N,N-dimethylaminosulfonyl)-6,7-dihydro-5H-pyrrolo[3, 4-d] Pyrimidine trifluoroacetate (0.20 g, gray solid) Yield: 80%.
第三步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-N，N-二甲氨基磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的合成The third step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-N,N-dimethylaminosulfonyl)-5H-pyrrolo[3,4- Synthesis of d]pyrimidine-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester
室温条件下，将2-(N，N-二甲氨基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐(170mg，0.52mmL)和(2R，3S)-2-(2，5-二氟苯基)-5-羰基-2H-吡喃-3-氨基甲酸叔丁酯(199mg，0.6mmL)溶于 MeOH(3mL)中。搅拌4小时后，加入氰基硼氢化钠(93mg，1.5mmL)搅拌13小时，固体析出，固体过滤，滤饼分别用甲醇(5mL*2)，乙酸乙酯(5mL*2)洗涤。干燥后得到目标产物(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-N，N-二甲氨基磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯(150mg，白色固体)，收率：55.6％。2-(N,N-Dimethylaminosulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine trifluoroacetate (170 mg, 0.52 mm L) and at room temperature (2R,3S)-2-(2,5-Difluorophenyl)-5-carbonyl-2H-pyran-3-carbamic acid tert-butyl ester (199 mg, 0.6 mmL) was dissolved In MeOH (3 mL). After stirring for 4 hours, sodium cyanoborohydride (93 mg, 1.5 mmL) was added and the mixture was stirred for 13 hr, and the solid was precipitated and filtered, and the filter cake was washed with methanol (5mL*2) and ethyl acetate (5mL*2). After drying, the title product (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-N,N-dimethylaminosulfonyl)-5H-pyrrolo[3,4 -d] Pyrimidine-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester (150 mg, white solid), yield: 55.6%.
第四步：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-2-磺酰二甲胺二三氟乙酸盐的合成Fourth step: 6-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-6,7-dihydrogen Synthesis of -5H-pyrrolo[3,4-d]pyrimidine-2-sulfonyldimethylamine ditrifluoroacetate
室温条件下，将(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-N，N-二甲氨基磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯(50mg，0.09mmL)和HCl/EA(3M)加入到反应瓶中，室温下搅拌1小时，除去溶剂，乙酸乙酯洗涤后，用HPLC制备纯化，最后得到目标产物6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-2-磺酰二甲胺二三氟乙酸盐(0.010g，白色固体)收率：24.5％。(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-N,N-dimethylaminosulfonyl)-5H-pyrrolo[3,4 at room temperature -d]pyrimidine-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester (50mg, 0.09mmL) and HCl/EA (3M) were added to the reaction flask and stirred at room temperature 1 After the solvent was removed, the ethyl acetate was washed and purified by HPLC to give the desired product 6-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro- 2H-pyran-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-sulfonyldimethylamine ditrifluoroacetate (0.010 g, white solid) Yield: 24.5%.
实施例11：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-Example 11: 6-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3- 基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-2-磺酰甲胺二三氟乙酸盐(化合物6,7-7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-sulfonylmethylamine ditrifluoroacetate (compound) 11’)的制备Preparation of 11')
Figure PCTCN2016000478-appb-000043
Figure PCTCN2016000478-appb-000043
第一步：2-甲氨基磺酰基-5H-吡咯并[3，4-d]嘧啶-6(7H)-氨甲酸叔丁酯的合成First step: Synthesis of 2-methylaminosulfonyl-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbamate
室温条件下，将2-巯基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯(1g，4mmol)和H2O/DCM(10mL/5mL)加入到反应瓶中搅拌。冰水浴条件下，向反应体系中通入氯气1小时，加入甲胺水溶液淬灭反应。搅拌1h后依次加入10mL水和20mL DCM萃取，合并有机相，无水硫酸钠干燥。过滤浓缩，柱层析(PE∶EA＝2∶1)纯化得2-甲氨基磺酰基 -5H-吡咯并[3，4-d]嘧啶-6(7H)-氨甲酸叔丁酯(0.52g，1.6mmol，收率41％)。2-mercapto-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate (1 g, 4 mmol) and H 2 O/DCM (10 mL/5 mL) were added to the reaction at room temperature. Stir in the bottle. Under ice water bath conditions, chlorine gas was introduced into the reaction system for 1 hour, and a methylamine aqueous solution was added to quench the reaction. After stirring for 1 h, 10 mL of water and 20 mL of DCM were added, and the organic phases were combined and dried over anhydrous sodium sulfate. Concentrated by filtration and purified by column chromatography (PE: EA=2:1) to give 2-methylaminosulfonyl-5H-pyrrolo[3,4-d]pyrimidine-6(7H)--------- , 1.6 mmol, yield 41%).
第二步：2-(甲氨基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐的合成Step 2: Synthesis of 2-(methylaminosulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine trifluoroacetate
室温条件下，将2-甲氨基磺酰基-5H-吡咯并[3，4-d]嘧啶-6(7H)-氨甲酸叔丁酯(0.4g，1.27mmol)和DCM/TFA(10mL/5mL)加入到反应瓶中，室温下搅拌2小时。除去溶剂，加入乙醚5mL，过滤、洗涤。干燥后得到目标产物2-(甲氨基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐(0.48g，灰色固体)收率：89％。2-Methylaminosulfonyl-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-carbamic acid tert-butyl ester (0.4 g, 1.27 mmol) and DCM/TFA (10 mL/5 mL) ) was added to the reaction flask and stirred at room temperature for 2 hours. The solvent was removed, and 5 mL of diethyl ether was added, filtered and washed. After drying, the desired product 2-(methylaminosulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine trifluoroacetate (0.48 g, m. .
第三步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲氨基磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的合成The third step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-methylaminosulfonyl)-5H-pyrrolo[3,4-d]pyrimidine-6 Synthesis of (7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester
除了使用2-(甲氨基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐代替2-(N，N-二甲氨基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐，使2-(甲氨基磺酰基)-6，7-一氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐的投料量为480mg之外，其它与实施例10第三步同样操作，得到标题产物310mg，收率为52％。In addition to 2-(methylaminosulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine trifluoroacetate instead of 2-(N,N-dimethylaminosulfonyl)- 6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidine trifluoroacetate, 2-(methylaminosulfonyl)-6,7-monohydro-5H-pyrrolo[3,4 The same procedure as in the third step of Example 10 was carried out to give the titled product (yield: 52%).
第四步：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-2-磺酰甲胺二三氟乙酸盐的合成Fourth step: 6-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-6,7-dihydrogen Synthesis of -5H-pyrrolo[3,4-d]pyrimidine-2-sulfonylmethylamine ditrifluoroacetate
除了使用(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲氨基磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯代替(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-N，N-二甲氨基磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯，使(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲氨基磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的投料量为310mg之外，其它与实施例10第四步同样操作，得到标题产物200mg，收率为51％。In addition to using (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylaminosulfonyl)-5H-pyrrolo[3,4-d]pyrimidine-6 (7H )-yl) tert-butyl-2H-pyran-3-carbamate instead of (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-N,N- Dimethylaminosulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester, (2R, 3S, 5R )-2-(2,5-difluorophenyl)-5-(2-methylaminosulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H The same procedure as in the fourth step of Example 10 was carried out to give the titled product (yield: 51%).
实施例12：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-Example 12: 6-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3- 基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-2-磺酰异丙胺二三氟乙酸盐(化合6,7-7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-sulfonylisopropylamine ditrifluoroacetate (combination 物12’)的制备Preparation of substance 12')
Figure PCTCN2016000478-appb-000044
Figure PCTCN2016000478-appb-000044
第一步：2-异丙氨基磺酰基-5H-吡咯并[3，4-d]嘧啶-6(7H)-氨甲酸叔丁酯的合成First step: Synthesis of 2-isopropylaminosulfonyl-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbamate
除了使用异丙胺代替二甲胺，使2-巯基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的投料量为1g之外，其它与实施例10第一步同样操作，得到标题产物720mg，收率为53％。The same as Example 10 except that isopropylamine was used instead of dimethylamine, and the amount of 2-mercapto-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate was 1 g. The same procedure was carried out in one step to give 720 mg of title product.
第二步：2-(异丙氨基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐的合成Step 2: Synthesis of 2-(isopropylaminosulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine trifluoroacetate
除了使用2-异丙氨基磺酰基-5H-吡咯并[3，4-d]嘧啶-6(7H)-氨甲酸叔丁酯代替2-N，N-二甲氨基磺酰基-5H-吡咯并[3，4-d]嘧啶-6(7H)-氨甲酸叔丁酯，使2-异丙氨基磺酰基-5H-吡咯并[3，4-d]嘧啶-6(7H)-氨甲酸叔丁酯的投料量为0.6g之外，其它与实施例10第二步同样操作，得到标题产物510mg，收率为84％。In addition to 2-isopropylaminosulfonyl-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-carbamic acid tert-butyl ester in place of 2-N,N-dimethylaminosulfonyl-5H-pyrrole [3,4-d]pyrimidine-6(7H)-tert-butyl carbamate, 2-(2-isopropylaminosulfonyl-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-carbamic acid The same procedure as in the second step of Example 10 was carried out except that the amount of the butyl ester was 0.6 g, and the title product was obtained in a yield of 84%.
第三步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙氨基磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的合成The third step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-isopropylaminosulfonyl)-5H-pyrrolo[3,4-d]pyrimidine- Synthesis of 6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester
除了使用2-(异丙氨基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐代替2-(N，N-二甲氨基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐，使2-(异丙氨基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐的投料量为0.51g之外，其它与实施例10第三步同样操作，得到标题产物360mg，收率为46％。In addition to using 2-(isopropylaminosulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine trifluoroacetate instead of 2-(N,N-dimethylaminosulfonyl) -6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidine trifluoroacetate, 2-(isopropylaminosulfonyl)-6,7-dihydro-5H-pyrrolo[3 The title product was obtained in the same manner as in the third step of Example 10 to give a title product (yield: 46%).
第四步：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-2-磺酰异丙胺二三氟乙酸盐二三氟醋酸盐的合成Fourth step: 6-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-6,7-dihydrogen Synthesis of -5H-pyrrolo[3,4-d]pyrimidine-2-sulfonylisopropylamine ditrifluoroacetate ditrifluoroacetate
除了使用(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙氨基磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯代替(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-N，N-二甲氨基磺酰基)-5H-吡咯并 [3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯，使(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙氨基磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的投料量为0.2g之外，其它与实施例10第四步同样操作，得到标题产物90mg，收率为37％。In addition to using (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-isopropylaminosulfonyl)-5H-pyrrolo[3,4-d]pyrimidine-6 ( 7H)-yl) tert-butyl-2H-pyran-3-ylcarboxylate instead of (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-N,N -dimethylaminosulfonyl)-5H-pyrrole [3,4-d]pyrimidine-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester, (2R,3S,5R)-2-(2,5-difluoro Phenyl)-5-(2-isopropylaminosulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl The same procedure as in the fourth step of Example 10 was carried out, except that the amount of the ester charged was 0.2 g, to give the title product, 90 mg, yield 37%.
实施例13：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-环戊砜基)-5H-吡咯Example 13: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-cyclopentanesulfonyl)-5H-pyrrole 并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二盐酸盐(化合物26’)的制And [3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-amine dihydrochloride (compound 26') 备Prepare
Figure PCTCN2016000478-appb-000045
Figure PCTCN2016000478-appb-000045
第一步：2-环戊基硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的合成First step: Synthesis of 2-cyclopentylthio-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate
除了使用环戊基溴代替异丙基溴，其它与实施例7第一步同样操作，得到标题产物800mg，收率为63％。Other than the use of cyclopentyl bromide in place of isopropyl bromide, the same procedure as in the first step of Example 7 gave the title product (yield:
第二步：2-环戊基砜基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的合成Step 2: Synthesis of 2-cyclopentylsulfone-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate
除了使用2-环戊基硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯代替2-异丙氨基磺酰基-5H-吡咯并[3，4-d]嘧啶-6(7H)-氨甲酸叔丁酯，使2-环戊基硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的投料量为0.8g之外，其它与实施例7第二步同样操作，得到标题产物800mg，收率为92％。In addition to using 2-cyclopentylthio-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate instead of 2-isopropylaminosulfonyl-5H-pyrrolo[3,4- d] pyrimidine-6(7H)-tert-butyl carbamate, the amount of 2-cyclopentylthio-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate is The same procedure as in the second step of Example 7 was carried out, except for 0.8 g, to give the title product 800 mg.
第三步：2-(环戊基砜基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶的合成Step 3: Synthesis of 2-(cyclopentylsulfone)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine
除了使用2-环戊基砜基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯代替2-异丙基砜基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯，使2-环戊基砜基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的投料量为0.4g之外，其它与实施例7第三步同样操作，得到标题产物320mg，收率为 92％。In addition to using 2-cyclopentylsulfone-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate instead of 2-isopropylsulfone-5H-pyrrolo[3,4- d] pyrimidine-6(7H)-tert-butyl carbonate, the amount of 2-cyclopentylsulfone-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate was 0.4 Other than the third step of Example 7, except for g, the title product 320 mg was obtained. 92%.
第四步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-环戊基砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的合成Fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-cyclopentylsulfone)-5H-pyrrolo[3,4-d]pyrimidine- Synthesis of 6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester
除了使用2-(环戊基砜基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶代替2-异丙氨基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐，使2-(环戊基砜基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶的投料量为0.32g之外，其它与实施例7第四步同样操作，得到标题产物200mg，收率为34％。In addition to using 2-(cyclopentylsulfone)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine instead of 2-isopropylaminosulfonyl)-6,7-dihydro-5H- Pyrrolo[3,4-d]pyrimidine trifluoroacetate, the amount of 2-(cyclopentylsulfone)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine is The same procedure as in the fourth step of Example 7 was carried out, except for 0.32 g, to give the title product (200 mg, yield: 34%).
第五步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-环戊基砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-胺二盐酸盐的合成Step 5: (2R, 3S, 5R)-2-(2,5-Difluorophenyl)-5-(2-cyclopentylsulfone)-5H-pyrrolo[3,4-d]pyrimidine- Synthesis of 6(7H)-yl)tetrahydro-2H-pyran-3-amine dihydrochloride
除了使用(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-环戊基砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯代替(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙基砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯，使(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-环戊基砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的投料量为0.16g之外，其它与实施例7第五步同样操作，得到标题产物80mg，收率为61％。In addition to using (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-cyclopentylsulfone)-5H-pyrrolo[3,4-d]pyrimidine-6 ( 7H)-yl) tert-butyl-2H-pyran-3-ylcarboxylate instead of (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-isopropyl Sulfhydryl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester, (2R,3S,5R)-2 -(2,5-difluorophenyl)-5-(2-cyclopentylsulfone)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyridyl The title product was obtained in the same manner as in the fifth step of Example 7 to give the title product (yield: 61%).
实施例14：1-(6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃Example 14: 1-(6-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran -3-基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-2-基)-3-甲基胍二三氟乙酸酸盐3-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-3-methylindole ditrifluoroacetate (化合物27’)的制备Preparation of (Compound 27')
Figure PCTCN2016000478-appb-000046
Figure PCTCN2016000478-appb-000046
第一步：1-(6-((3R，5S，6R)-5-Boc-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-2-基)-3-甲基胍的合成First step: 1-(6-((3R,5S,6R)-5-Boc-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-6 Synthesis of 7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-3-methylindole
室温条件下将(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲砜基-5H-吡咯[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯(0.1g，0.19mmol)和乙腈(5mL)加入到反应瓶中，加入Cs2CO3(127g，0.39mmol)和异丙基溴(0.37g，2.4mmol)。80℃下搅拌2小时，过滤，滤液浓缩得到的粗品，用HPLC制备纯化得到目标产物1-(6-((3R，5S，6R)-5-Boc-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-6，7-二氢-5H-吡咯并[3，4-d] 嘧啶-2-基)-3-甲基胍(0.035g，白色固体)收率：34％。(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-methylsulfonyl-5H-pyrrole[3,4-d]pyrimidin-6(7H) at room temperature -Based) tert-Butyl tetrahydro-2H-pyran-3-carbamate (0.1 g, 0.19 mmol) and acetonitrile (5 mL) were added to a reaction flask, and Cs 2 CO 3 (127 g, 0.39 mmol) and isopropyl Bromo (0.37 g, 2.4 mmol). The mixture was stirred at 80 ° C for 2 hours, filtered, and the filtrate was concentrated to give a crude product which was purified by HPLC to give the desired product 1-(6-((3R,5S,6R)-5-Boc-amino-6-(2,5- Fluorophenyl)tetrahydro-2H-pyran-3-yl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-3-methylindole (0.035g , white solid) Yield: 34%.
第二步：1-(6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-2-基)-3-甲基胍的合成The second step: 1-(6-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-6,7 Synthesis of dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-3-methylindole
除了使用1-(6-((3R，5S，6R)-5-Boc-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-2-基)-3-甲基胍代替(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙基砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯，使(1-(6-((3R，5S，6R)-5-Boc-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-2-基)-3-甲基胍的投料量为0.35g之外，其它与实施例7第五步同样操作，得到标题产物250mg，收率为89％。In addition to using 1-(6-((3R,5S,6R)-5-Boc-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-6,7 -Dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)-3-methylindole instead of (2R,3S,5R)-2-(2,5-difluorophenyl)-5 -(2-isopropylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester, (1 -(6-((3R,5S,6R)-5-Boc-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-6,7-dihydro The same procedure as in the fifth step of Example 7 was carried out except that the amount of -5H-pyrrolo[3,4-d]pyrimidin-2-yl)-3-methylindole was 0.35 g. The rate is 89%.
实施例15：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲磺酰氨基)-6H-吡Example 15: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methanesulfonylamino)-6H-pyridyl 咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-胺及其二三氟乙酸盐(化合物[3,4-d]pyrimidin-6-yl)tetrahydro-2H-pyran-3-amine and its ditrifluoroacetate (compound) 28’)的制备Preparation of 28')
Figure PCTCN2016000478-appb-000047
Figure PCTCN2016000478-appb-000047
第一步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲磺酰氨基)-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的合成First step: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methanesulfonylamino)-6H-pyrrolo[3,4-d]pyrimidine-6 Synthesis of tert-butyl tetrahydro-2H-pyran-3-carbamate
除了使用甲磺酰胺代替甲基胍之外，其它与实施例14第一步同样操作，得到标题产物20mg，收率为18％。The same procedure as in the first step of Example 14 was carried out except that methanesulfonamide was used instead of methyl hydrazide to give the title product 20 mg.
第二步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲磺酰氨基)-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-胺二三氟乙酸盐的合成Second step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-methanesulfonylamino)-6H-pyrrolo[3,4-d]pyrimidine-6 -Synthesis of tetrahydro-2H-pyran-3-amine ditrifluoroacetate
除了使用(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲磺酰氨基)-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯代替(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙基砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯，使(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲磺酰氨基)-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的投料量为0.02g之外，其它与实施例7第五步同样操作，得到标题产物14mg，收率为85％。In addition to the use of (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methanesulfonylamino)-6H-pyrrolo[3,4-d]pyrimidin-6-yl Substituting tert-butyl-2H-pyran-3-carbamate for (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-isopropylsulfonyl)- 5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester, (2R,3S,5R)-2-(2, 5-difluorophenyl)-5-(2-methanesulfonylamino)-6H-pyrrolo[3,4-d]pyrimidin-6-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl The same procedure as in the fifth step of Example 7 was carried out except that the amount of the ester charged was 0.02 g, to afford the title product (yield: 85%).
第三步：游离化合物(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲磺酰氨 基)-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-胺(化合物34)的制备。The third step: free compound (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-methanesulfonamide Preparation of -6H-pyrrolo[3,4-d]pyrimidin-6-yl)tetrahydro-2H-pyran-3-amine (Compound 34).
将(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲磺酰氨基)-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-胺二三氟乙酸盐用2M碳酸钠水溶液超声洗涤，然后过滤，即可获得游离化合物(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-甲磺酰氨基)-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-胺。(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-methanesulfonylamino)-6H-pyrrolo[3,4-d]pyrimidin-6-yl) Tetrahydro-2H-pyran-3-amine ditrifluoroacetate is sonicated with 2M sodium carbonate aqueous solution, and then filtered to obtain the free compound (2R, 3S, 5R)-2-(2,5-difluoro Phenyl)-5-(2-methanesulfonylamino)-6H-pyrrolo[3,4-d]pyrimidin-6-yl)tetrahydro-2H-pyran-3-amine.
实施例16：(2R，3S，5R)-5-(2-(仲丁基砜基)-5H-吡咯并[3，4-d]嘧啶Example 16: (2R,3S,5R)-5-(2-(sec-butylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidine -6(7H)-基)-2-(2，5-二氟苯基)四氢-2H-吡喃-3-胺二三氟乙酸盐(化合物-6(7H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ditrifluoroacetate (compound) 29’)的制备Preparation of 29')
Figure PCTCN2016000478-appb-000048
Figure PCTCN2016000478-appb-000048
除了使用2-碘丁烷代替异丙基溴，其它与实施例7第一步同样操作，得到标题产物1.5g，收率为61％。Other than the use of 2-iodobutane in place of isopropyl bromide, the same procedure as in the first step of Example 7 gave 1.5 g of the title product.
第二步：2-仲丁基砜基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的合成Step 2: Synthesis of 2-sec-butylsulfonyl-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate
除了使用2-仲丁基硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯代替2-异丙氨基磺酰基-5H-吡咯并[3，4-d]嘧啶-6(7H)-氨甲酸叔丁酯，使2-仲丁基硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的投料量为1.5g之外，其它与实施例7第二步同样操作，得到标题产物1.5g，收率为91％。In addition to using 2-sec-butylthio-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate instead of 2-isopropylaminosulfonyl-5H-pyrrolo[3,4- d] pyrimidine-6(7H)-tert-butyl carbamate, the amount of 2-sec-butylthio-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate is The same procedure as in the second step of Example 7 was carried out, except for 1.5 g, to give the title product 1.5 g, yield 91%.
第三步：2-(仲丁基砜基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶的合成Step 3: Synthesis of 2-(sec-butylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine
除了使用2-仲丁基砜基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯代替2-异丙基砜基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯，使2-仲丁基砜基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的投料量为0.5g之外，其它与实施例7第三步同样操作，得到标题产物450mg，收率为86％。In addition to using 2-sec-butylsulfonyl-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate instead of 2-isopropylsulfone-5H-pyrrolo[3,4- d] pyrimidine-6(7H)-tert-butyl carbonate, the amount of 2-sec-butylsulfonyl-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate is 0.5 Other than the third step of Example 7, except for g, the title product was obtained (yield: 86%).
第四步：(2R，3S，5R)-5-(2-(仲丁基砜基)-5H-吡咯并[3，4-d]嘧啶 -6(7H)-基)-2-(2，5-二氟苯基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的合成Step 4: (2R, 3S, 5R)-5-(2-(sec-butylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidine Synthesis of tert-butyl-6-(7H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-carbamate
除了使用2-(仲丁基砜基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶代替2-异丙氨基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐，使2-(仲丁基砜基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶的投料量为0.45g之外，其它与实施例7第四步同样操作，得到标题产物300mg，收率为52％。In addition to using 2-(sec-butylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine instead of 2-isopropylaminosulfonyl)-6,7-dihydro-5H- Pyrrolo[3,4-d]pyrimidine trifluoroacetate, the amount of 2-(sec-butylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine is The same procedure as in the fourth step of Example 7 was carried out, except for 0.45 g, to give the title product, 300 mg, yield 52%.
第五步：((2R，3S，5R)-5-(2-(仲丁基砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-2-(2，5-二氟苯基)四氢-2H-吡喃-3-胺二三氟乙酸盐的合成Step 5: ((2R,3S,5R)-5-(2-(sec-butylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-2-( Synthesis of 2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ditrifluoroacetate
除了使用(2R，3S，5R)-5-(2-(仲丁基砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-2-(2，5-二氟苯基)四氢-2H-吡喃-3-氨基甲酸叔丁酯代替(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙基砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯，使(2R，3S，5R)-5-(2-(仲丁基砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-2-(2，5-二氟苯基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的投料量为0.15g之外，其它与实施例7第五步同样操作，得到标题产物33mg，收率为27％。In addition to using (2R,3S,5R)-5-(2-(sec-butylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-2-(2,5 -Difluorophenyl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester in place of (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-isopropyl (sulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester, (2R,3S,5R)- 5-(2-(sec-butylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H The same procedure as in the fifth step of Example 7 was carried out except that the amount of the tert-butylpyran-3-carbamate was 0.15 g, and the title product was obtained in a yield of 27%.
实施例17：(2R，3S，5R)-5-(2-(异丁基砜基)-5H-吡咯并[3，4-d]嘧啶Example 17: (2R,3S,5R)-5-(2-(isobutylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidine -6(7H)-基)-2-(2，5-二氟苯基)四氢-2H-吡喃-3-胺二三氟乙酸盐(化合物-6(7H)-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ditrifluoroacetate (compound) 30’)的制备Preparation of 30')
Figure PCTCN2016000478-appb-000049
Figure PCTCN2016000478-appb-000049
除了使用异丁基碘代替异丙基溴，其它与实施例7第一步同样操作，得到标题产物2.5g，收率为58％。Other than the use of isobutyl iodide in place of isopropyl bromide, the same procedure as in the first step of Example 7 gave 2.5 g of the title product.
第二步：2-异丁基砜基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的合成Step 2: Synthesis of 2-isobutylsulfone-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate
除了使用2-异丁基硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯代替2-异丙氨基磺酰基-5H-吡咯并[3，4-d]嘧啶-6(7H)-氨甲酸叔丁酯，使2-异丁基硫基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的投料量为 1.5g之外，其它与实施例7第二步同样操作，得到标题产物1.5g，收率为91％。In addition to using 2-isobutylthio-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate instead of 2-isopropylaminosulfonyl-5H-pyrrolo[3,4- d] pyrimidine-6(7H)-tert-butyl carbamate, the amount of 2-isobutylthio-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate is The same procedure as in the second step of Example 7 was carried out, except for 1.5 g, to give the title product 1.5 g, yield 91%.
第三步：2-(异丁基砜基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶的合成Step 3: Synthesis of 2-(isobutylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine
除了使用2-异丁基砜基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯代替2-异丙基砜基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯，使2-异丁基砜基-5H-吡咯并[3，4-d]嘧啶-6(7H)-碳酸叔丁酯的投料量为0.5g之外，其它与实施例7第三步同样操作，得到标题产物500mg，收率为96％。In addition to using 2-isobutylsulfonyl-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate instead of 2-isopropylsulfone-5H-pyrrolo[3,4- d] pyrimidine-6(7H)-tert-butyl carbonate, the amount of 2-isobutylsulfone-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-tert-butyl carbonate is 0.5 Other than the third step of Example 7, except for g, the title product was obtained (yield: 96%).
第四步：(2R，3S，5R)-5-(2-(异丁基砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-2-(2，5-二氟苯基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的合成The fourth step: (2R, 3S, 5R)-5-(2-(isobutylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-2-(2 Synthesis of 5-Butylfluorophenyl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester
除了使用2-(异丁基砜基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶代替2-异丙氨基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐，使2-(异丁基砜基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶的投料量为0.3g之外，其它与实施例7第四步同样操作，得到标题产物120mg，收率为25％。In addition to using 2-(isobutylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine instead of 2-isopropylaminosulfonyl)-6,7-dihydro-5H- Pyrrolo[3,4-d]pyrimidine trifluoroacetate, the amount of 2-(isobutylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine is The same procedure as in the fourth step of Example 7 was carried out, except for 0.3 g, to give the title product 120 mg.
第五步：((2R，3S，5R)-5-(2-(异丁基砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-2-(2，5-二氟苯基)四氢-2H-吡喃-3-胺二三氟乙酸盐的合成Step 5: ((2R,3S,5R)-5-(2-(Isobutylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-2-( Synthesis of 2,5-difluorophenyl)tetrahydro-2H-pyran-3-amine ditrifluoroacetate
除了使用(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丁基砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯代替(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丙基砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯，使(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-异丁基砜基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的投料量为0.12g之外，其它与实施例7第五步同样操作，得到标题产物33mg，收率为33％。In addition to using (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-isobutylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidine-6 ( 7H)-yl) tert-butyl-2H-pyran-3-ylcarboxylate instead of (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-isopropyl Sulfhydryl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester, (2R,3S,5R)-2 -(2,5-difluorophenyl)-5-(2-isobutylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyridyl The title product was obtained in the same manner as in the fifth step of Example 7 to give the title product (yield: 33%).
实施例18：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(四氢吡咯基磺酰基)-5H-Example 18: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(tetrahydropyrrolylsulfonyl)-5H- 吡咯并[3，4-d]嘧啶-6(7H)-基)-四氢-2H-吡喃-3-胺二三氟醋酸盐(化合物Pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-tetrahydro-2H-pyran-3-amine ditrifluoroacetate (compound) 31’)的制备Preparation of 31')
Figure PCTCN2016000478-appb-000050
Figure PCTCN2016000478-appb-000050
第一步：2-(四氢吡咯-1-基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-氨甲酸叔丁酯的合成First step: Synthesis of 2-(tetrahydropyrrole-1-ylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-carbamic acid tert-butyl ester
除了使用四氢吡咯代替二甲胺，使四氢吡咯的投料量为1g之外，其它与实施例10第一步同样操作，得到标题产物0.85g，收率为60.7％。The title product was obtained in the same manner as in the first step of Example 10 except that tetrahydropyrrole was used instead of dimethylamine, and the amount of the tetrahydropyrrole was 1 g.
第二步：2-(四氢吡咯-1-基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐的合成Step 2: Synthesis of 2-(tetrahydropyrrole-1-ylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine trifluoroacetate
除了使用2-(四氢吡咯-1-基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-氨甲酸叔丁酯代替2-(二甲氨基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-氨甲酸叔丁酯，使2-(四氢吡咯-1-基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-氨甲酸叔丁酯的投料量为0.45g之外，其它与实施例10第二步同样操作，得到标题产物0.4g，收率为89.6％。In addition to 2-(dihydropyrrol-1-ylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-carbamic acid tert-butyl ester instead of 2-(dimethylaminosulfonyl) a tert-butyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-carbamic acid to give 2-(tetrahydropyrrole-1-ylsulfonyl)-6,7-dihydro- The title product was obtained in the same manner as in the second step of Example 10, except that 5H-pyrrolo[3,4-d]pyrimidine-carbamic acid tert-butyl ester was added in an amount of 0.45 g.
第三步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(四氢吡咯-1-基磺酰基))-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-四氢-2H-吡喃-3-氨基甲酸叔丁酯的合成The third step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-(tetrahydropyrrole-1-ylsulfonyl))-5H-pyrrolo[3, Synthesis of 4-d]pyrimidine-6(7H)-yl)-tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester
除了使用2-(四氢吡咯-1-基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐代替2-(二甲氨基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐，使2-(四氢吡咯-1-基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐的投料量为0.4g之外，其它与实施例10第三步同样操作，得到标题产物0.31g，收率为48.9％。In addition to 2-(tetrahydropyrrole-1-ylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine trifluoroacetate instead of 2-(dimethylaminosulfonyl) -6,7-Dihydro-5H-pyrrolo[3,4-d]pyrimidine trifluoroacetate, 2-(tetrahydropyrrole-1-ylsulfonyl)-6,7-dihydro-5H- The title product was obtained in the same manner as in the third step of Example 10, except that the amount of the pyrrolo[3,4-d]pyrimidine trifluoroacetate was 0.4 g.
第四步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(四氢吡咯-1-基磺酰基))-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-四氢-2H-吡喃-3-胺双三氟醋酸盐的合成The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-(tetrahydropyrrol-1-ylsulfonyl))-5H-pyrrolo[3, Synthesis of 4-d]pyrimidine-6(7H)-yl)-tetrahydro-2H-pyran-3-amine bistrifluoroacetate
除了使用(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(四氢吡咯-1-基磺酰基))-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-四氢-2H-吡喃-3-氨基甲酸叔丁酯 代替(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(二甲氨基磺酰基))-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-四氢-2H-吡喃-3-氨基甲酸叔丁酯，使(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(四氢吡咯-1-基磺酰基))-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-四氢-2H-吡喃-3-氨基甲酸叔丁酯的投料量为0.3g之外，其它与实施例10第四步同样操作，得到标题产物0.108g，收率为30.8％。In addition to using (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(tetrahydropyrrole-1-ylsulfonyl))-5H-pyrrolo[3,4- d]pyrimidine-6(7H)-yl)-tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester Instead of (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(dimethylaminosulfonyl))-5H-pyrrolo[3,4-d]pyrimidine-6 (7H)-yl)-tert-butyl tetrahydro-2H-pyran-3-carbamate, (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2- (tetrahydropyrrole-1-ylsulfonyl))-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester The title product was obtained in the same manner as in the fourth step of Example 10 except that the amount of the mixture was 0.3 g, and the yield was 30.8%.
实施例19：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲磺酰基)异吲哚-2-Example 19: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonyl)isoindole-2- 基)四氢-2H-吡喃-3-胺及其二盐酸盐(化合物19’)的制备Preparation of tetrahydro-2H-pyran-3-amine and its dihydrochloride (compound 19')
Figure PCTCN2016000478-appb-000051
Figure PCTCN2016000478-appb-000051
第一步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲磺酰基)异吲哚-2-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的制备First step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonyl)isoindol-2-yl)tetrahydro-2H-pyran Preparation of tert-butyl 3-carbamic acid
除了使用5-(甲磺酰基)异吲哚三氟醋酸盐代替2-(二甲氨基磺酰基)-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐，使5-(甲磺酰基)异吲哚三氟醋酸盐的投料量为0.1g之外，其它与实施例10第三步同样操作，得到标题产物29mg，收率为17.8％。In addition to using 5-(methylsulfonyl)isoindole trifluoroacetate instead of 2-(dimethylaminosulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine trifluoroacetic acid The title product was obtained in the same manner as in the third step of Example 10 to give the title product (yield: 17.8%).
第二步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲磺酰基)异吲哚-2-基)四氢-2H-吡喃-3-胺二盐酸盐的制备The second step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonyl)isoindol-2-yl)tetrahydro-2H-pyran Preparation of 3-Amine Dihydrochloride
除了使用(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲磺酰基)异吲哚-2-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯代替(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(二甲氨基磺酰基))-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-四氢-2H-吡喃-3-氨基甲酸叔丁酯，使(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲磺酰基)异吲哚-2-基)四氢-2H-吡喃-3-氨基甲酸叔丁酯的投料量为29mg之外，其它与实施例10第四步同样操作，得到标题产物18mg，收率为64.3％。In addition to using (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonyl)isoindol-2-yl)tetrahydro-2H-pyran-3 - tert-butyl carbamate instead of (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(dimethylaminosulfonyl))-5H-pyrrolo[3,4 -d]pyrimidine-6(7H)-yl)-tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester, (2R,3S,5R)-2-(2,5-difluorophenyl) -5-(5-(methylsulfonyl)isoindol-2-yl)tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester was charged in an amount of 29 mg, and the fourth step of Example 10 In the same manner, 18 mg of the title product was obtained in a yield of 64.3%.
第三步：游离化合物(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲磺酰基)异吲哚-2-基)四氢-2H-吡喃-3-胺(化合物19)的制备。The third step: free compound (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonyl)isoindol-2-yl)tetrahydro-2H- Preparation of pyran-3-amine (Compound 19).
将(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲磺酰基)异吲哚-2-基)四氢-2H-吡喃-3-胺二盐酸盐用2M碳酸钠水溶液超声洗涤，然后过滤，即可获得游离化合物(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲磺酰基)异吲哚 -2-基)四氢-2H-吡喃-3-胺。(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-(methylsulfonyl)isoindol-2-yl)tetrahydro-2H-pyran-3- The amine dihydrochloride salt was ultrasonically washed with a 2M aqueous solution of sodium carbonate, and then filtered to obtain the free compound (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonate) Acyl)isoindole -2-yl)tetrahydro-2H-pyran-3-amine.
实施例20：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(二甲基胍基磺酰Example 20: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(dimethylsulfonylsulfonyl) 基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-四氢-2H-吡喃-3-胺二三氟醋酸盐-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-tetrahydro-2H-pyran-3-amine ditrifluoroacetate (化合物20’)的制备Preparation of (Compound 20')
Figure PCTCN2016000478-appb-000052
Figure PCTCN2016000478-appb-000052
第一步：2-二甲基胍基磺酰基-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-氨甲酸叔丁酯的合成First step: Synthesis of 2-dimethylsulfonylsulfonyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-tert-butyl carbamate
除了使用二甲基胍代替二甲胺，使二甲基胍的投料量为1g之外，其它与实施例10第一步同样操作，得到标题产物1.05g，收率为71.9％。The title product was obtained in the same manner as in the first step of Example 10, except that dimethyl hydrazine was used instead of dimethylamine, and the amount of dimethyl hydrazine was 1 g.
第二步：2-二甲基胍基磺酰基-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐的合成Step 2: Synthesis of 2-dimethylsulfonylsulfonyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine trifluoroacetate
除了使用2-二甲基胍基磺酰基-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-氨甲酸叔丁酯代替2-二甲氨基磺酰基-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-氨甲酸叔丁酯，使2-二甲基胍基磺酰基-6，7-二氢-5H-吡咯并[3，4-d]嘧啶-氨甲酸叔丁酯的投料量为150mg之外，其它与实施例10第二步同样操作，得到标题产物135mg，收率为91.2％。In addition to 2-dimethylmercaptosulfonyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-carbamic acid tert-butyl ester in place of 2-dimethylaminosulfonyl-6,7- Dihydro-5H-pyrrolo[3,4-d]pyrimidine-tert-butyl carbamate, 2-dimethylmercaptosulfonyl-6,7-dihydro-5H-pyrrolo[3,4-d The title product 135 mg was obtained in a yield of 91.2%, except that the yield of the pyrimidine-tert-butyl carbamate was 150 mg.
第三步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-二甲基胍基磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-四氢-2H-吡喃-3-氨基甲酸叔丁酯的合成The third step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-dimethylsulfonylsulfonyl)-5H-pyrrolo[3,4-d] Synthesis of pyrimidine-6(7H)-yl)-tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester
除了使用2-二甲基胍基磺酰基-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐代替2-二甲氨基磺酰基-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐，使2-二甲基胍基磺酰基-6，7-二氢-5H-吡咯并[3，4-d]嘧啶三氟醋酸盐的投料量为135mg之外，其它与实施例10第三步同样操作，得到标题产物110mg，收率为51.6％。In addition to 2-dimethylmercaptosulfonyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine trifluoroacetate instead of 2-dimethylaminosulfonyl-6,7-di Hydrogen-5H-pyrrolo[3,4-d]pyrimidine trifluoroacetate to give 2-dimethyldecylsulfonyl-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine The title product was obtained in the same manner as in the third step of Example 10 except that the amount of the trifluoroacetate was 135 mg.
第四步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-二甲基胍基磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-四氢-2H-吡喃-3-胺二三氟醋酸盐的合成 Step 4: (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-dimethylsulfonylsulfonyl)-5H-pyrrolo[3,4-d] Synthesis of Pyrimidine-6(7H)-yl)-tetrahydro-2H-pyran-3-amine Ditrifluoroacetate
除了使用(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-二甲基胍基磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-四氢-2H-吡喃-3-氨基甲酸叔丁酯代替(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-二甲氨基磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-四氢-2H-吡喃-3-氨基甲酸叔丁酯，使(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-二甲基胍基磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-四氢-2H-吡喃-3-氨基甲酸叔丁酯的投料量为110mg之外，其它与实施例10第四步同样操作，得到标题产物32mg，收率为25％。In addition to the use of (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-dimethylsulfonylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidine- 6(7H)-yl)-tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester in place of (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2- Dimethylaminosulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-tetrahydro-2H-pyran-3-carbamic acid tert-butyl ester, (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-dimethylsulfonylsulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl) The same procedure as in the fourth step of Example 10 was carried out to give the titled product (yield: 25%).
按实施例10第四步，投料：110mg，得32mg产品，收率：25％。According to the fourth step of Example 10, the feed was 110 mg, and 32 mg of the product was obtained, and the yield was 25%.
实施例21：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)-四氢-2H-吡喃Example 21: 6-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran -3-基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-2-磺酰胺二三氟醋酸盐(化合物-3-yl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-2-sulfonamide ditrifluoroacetate (compound) 14’)14’)
Figure PCTCN2016000478-appb-000053
Figure PCTCN2016000478-appb-000053
第一步：2-磺酰胺-5H-吡咯并[3，4-d]嘧啶-6(7H)-甲酸叔丁酯First step: 2-sulfonamide-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester
室温条件下，将2-巯基-5H-吡咯并[3，4-d]嘧啶-6(7H)-甲酸叔丁酯(3g，11.8mmol)和H2O/DCM(30mL/15mL)加入到反应瓶中搅拌。冰水浴条件下，向反应体系中通入氯气，反应体系溶清后停止通氯气。加入氨水至体系PH为9-10，淬灭反应。室温搅拌15min后将反应体系倒入50mL水中，乙酸乙酯萃取，有机层用饱和食盐水洗涤，无水硫酸钠干燥。浓缩拌样，柱层析纯化得2-磺酰胺-5H-吡咯并[3，4-d]嘧啶-6(7H)-甲酸叔丁酯(0.61g，白色固体)收率：17.2％。Add 2-mercapto-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester (3 g, 11.8 mmol) and H 2 O/DCM (30 mL / 15 mL) to room temperature Stir in the reaction flask. Under ice water bath conditions, chlorine gas is introduced into the reaction system, and the chlorine gas is stopped after the reaction system is dissolved. Ammonia water was added until the pH of the system was 9-10, and the reaction was quenched. After stirring at room temperature for 15 minutes, the reaction mixture was poured into 50 mL of water, and ethyl acetate was evaporated. The mixture was concentrated and purified by column chromatography tolululululululululululu
第二步：6，7-二氢-5H-吡咯并[3，4-d]嘧啶-2-磺酰胺三氟醋酸盐Second step: 6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine-2-sulfonamide trifluoroacetate
室温条件下，将2-磺酰胺-5H-吡咯并[3，4-d]嘧啶-6(7H)-甲酸叔丁酯(0.60g，2mmol)和DCM/TFA(18mL/6mL)加入到反应瓶中，室温下搅30min。浓缩干燥。2-sulfonamide-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester (0.60 g, 2 mmol) and DCM/TFA (18 mL / 6 mL) were added to the reaction at room temperature. Stir in the bottle for 30 min at room temperature. Concentrated and dried.
第三步：((2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-氨磺酰基-5H-吡咯并 [3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-基)甲酸叔丁酯The third step: ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-sulfamoyl-5H-pyrrole [3,4-d]pyrimidine-6(7H)-yl)tetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester
将第二步产物和((2R，3S)-2-(2，5-二氟苯基)-5-氧代四氢-2H-吡喃-3-基)甲酸叔丁酯(0.785g，2.4mmol)用THF/DMA(10mL/5mL)溶解，60℃搅拌1h，冷却后，加入氰基硼氢化钠(0.628g，10mmol，然后继续搅拌25min，加入水淬灭反应，并用乙酸乙酯萃取，合并有机相用饱和食盐水洗涤。柱层析纯化，得420mg的产品。The second step product and ((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester (0.785 g, 2.4 mmol) was dissolved in THF / DMA (10 mL / 5 mL), and stirred at 60 ° C for 1 h. After cooling, sodium cyanoborohydride (0.628 g, 10 mmol) was added, and stirring was continued for 25 min, then quenched with water and extracted with ethyl acetate The combined organic phases were washed with saturated brine and purified by column chromatography to yield 420 g.
第四步：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)-四氢-2H-吡喃-3-基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-2-磺酰胺二三氟醋酸盐Fourth step: 6-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[ 3,4-d]pyrimidin-6(7H)-yl)-2-sulfonamide ditrifluoroacetate
将第五步的产品(200mg)和DCM/TFA(6mL/2mL)加入反应瓶中，室温搅拌30min，旋干，制备分离得到6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)-四氢-2H-吡喃-3-基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)-2-磺酰胺二三氟醋酸盐(85mg)。The product of the fifth step (200 mg) and DCM/TFA (6 mL/2 mL) were added to the reaction flask, stirred at room temperature for 30 min, and dried to obtain 6-((3R,5S,6R)-5-amino-6-. (2,5-difluorophenyl)-tetrahydro-2H-pyran-3-yl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-2-sulfonamide Trifluoroacetate (85 mg).
1H NMR(400MHz，CD3OD)δ：8.78(s，1H)，7.33-7.29(m，1H)，7.26-7.19(m，2H)，4.62(d，J＝10.0Hz，1H)，4.41-4.36(m，1H)，4.27(s，2H)，4.23(d，J＝3.6Hz，2H)，3.58-3.51(m，2H)，3.22-3.16(m，1H)，2.66-2.63(m，1H)，1.81(q，J＝12.0Hz，1H).MS m/z(ESI)：412.1(M+1)。 1 H NMR (400 MHz, CD 3 OD) δ: 8.78 (s, 1H), 7.33 - 7.29 (m, 1H), 7.26-7.19 (m, 2H), 4.62 (d, J = 10.0 Hz, 1H), 4.41 -4.36(m,1H), 4.27(s,2H), 4.23(d,J=3.6Hz,2H),3.58-3.51(m,2H),3.22-3.16(m,1H),2.66-2.63(m , 1H), 1.81 (q, J = 12.0 Hz, 1H). MS m/z (ESI): 4121.
实施例22：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-Example 22: 6-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3- 基)-N-丙基甲酰胺-5H-吡咯并[3，4-d]嘧啶-6(7H)-2-磺酰胺二三氟乙酸盐-N-propylformamide-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-2-sulfonamide ditrifluoroacetate (化合物22’)(compound 22’)
Figure PCTCN2016000478-appb-000054
Figure PCTCN2016000478-appb-000054
第一步：2-磺酰胺-5H-吡咯并[3，4-d]嘧啶-6(7H)-甲酸叔丁酯First step: 2-sulfonamide-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester
室温下，将2-巯基-5H-吡咯并[3，4-d]嘧啶-6(7H)-甲酸叔丁酯(3.0g， 11.8mmol)和H2O/DCM(30mL/15mL)加入反应瓶中搅拌。冰浴下，向反应体系中通入自制氯气，反应体系溶清后停止通氯气，加入氨水至体系pH为9-10，猝灭反应，室温搅拌15min后，将反应体系倒入50mL水中，用乙酸乙酯(150mL*3)萃取，并用饱和食盐水洗涤，无水硫酸钠干燥，浓缩拌样，柱层析纯化得到2-磺酰胺-5H-吡咯并[3，4-d]嘧啶-6(7H)-甲酸叔丁酯(0.61g，白色固体)，收率为17.2％。Add 2-oxyl-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester (3.0 g, 11.8 mmol) and H 2 O/DCM (30 mL / 15 mL) at room temperature. Stir in the bottle. Under ice bath, self-made chlorine gas was introduced into the reaction system. After the reaction system was dissolved, the chlorine gas was stopped. Ammonia water was added until the pH of the system was 9-10. The reaction was quenched. After stirring at room temperature for 15 minutes, the reaction system was poured into 50 mL of water. Ethyl acetate (150 mL * 3) was extracted, washed with brine, dried over anhydrous sodium sulfate, dried over anhydrous sodium sulfate, and purified by column chromatography to give 2-sulfonamide-5H-pyrrolo[3,4-d]pyrimidine-6 (7H)-tert-butyl formate (0.61 g, white solid), yield 17.2%.
第二步：2-(N-(苯氧羰基)胺磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-甲酸叔丁酯Second step: 2-(N-(phenoxycarbonyl)aminesulfonyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester
冰浴下，将2-磺酰胺-5H-吡咯并[3，4-d]嘧啶-6(7H)-甲酸叔丁酯(0.40g，1.33mmol)和10mL乙腈加入反应瓶中搅拌，然后加入0.74mL三乙胺，将0.22mL氯甲酸苯酯溶于2mL乙腈中，混匀后滴加至反应体系。反应完全后，反应液直接投下步反应。2-sulfonamide-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester (0.40 g, 1.33 mmol) and 10 mL of acetonitrile were added to the reaction flask under ice-cooling, and then added 0.74 mL of triethylamine, 0.22 mL of phenyl chloroformate was dissolved in 2 mL of acetonitrile, mixed and added dropwise to the reaction system. After the reaction is completed, the reaction solution is directly subjected to a step reaction.
第三步：2-(N-(丙基甲酰胺)氨磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-甲酸叔丁酯Step 3: 2-(N-(propylformamide)sulfamoyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester
将第二步的反应液加热至45℃，然后加入1.1mL的正丙胺，反应2h后，将反应体系浓缩，柱层析纯化得到2-(N-(丙基甲酰胺)氨磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-甲酸叔丁酯(0.39g，黄色固体，两步收率76.1％)。The reaction liquid of the second step was heated to 45 ° C, and then 1.1 mL of n-propylamine was added. After reacting for 2 hours, the reaction system was concentrated and purified by column chromatography to obtain 2-(N-(propylformamide)sulfamoyl)- 5H-Pyrolo[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester (0.39 g, yellow solid, yield, 76.1%).
第四步：N-(丙基甲酰胺)-5H-吡咯并[3，4-d]嘧啶-6(7H)-2-磺酰胺三氟乙酸盐Step 4: N-(propylformamide)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-2-sulfonamide trifluoroacetate
室温下，将2-(N-(丙基甲酰胺)氨磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-甲酸叔丁酯(0.44g，1.14mmol)和DCM/TFA(15mL/5mL)加入反应瓶中，搅拌30min后浓缩后的纯品直接用于下一步。2-(N-(propylformamide)sulfamoyl)-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester (0.44 g, 1.14 mmol) DCM/TFA (15 mL/5 mL) was added to the reaction flask, and after stirring for 30 minutes, the concentrated pure product was directly used in the next step.
第五步：((2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(N-(丙基甲酰胺)氨磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-基)甲酸叔丁酯Step 5: ((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-(N-(propylformamide)sulfamoyl)-5H-pyrrolo[ 3,4-d]pyrimidin-6(7H)-yl)tetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester
将第四步产物和((2R，3S)-2-(2，5-二氟苯基)-5-氧代四氢-2H-吡喃-3-基)甲酸叔丁酯(0.448g，1.37mmol)用THF/DMA(8mL/4mL)溶解，60℃搅拌1h，冷却后，加入氰基硼氢化钠(0.358g，5.70mmol)，继续搅拌25min，加入水淬灭反应，并用乙酸乙酯萃取，合并收集有机相用饱和食盐水洗涤。柱层析纯化，得410mg的产品。The product of the fourth step and ((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester (0.448 g, 1.37 mmol) was dissolved in THF / DMA (8 mL / 4 mL), EtOAc (EtOAc) EtOAc (EtOAc) The organic phase was washed and washed with saturated brine. Purification by column chromatography gave 410 mg of product.
第六步：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃基-N-丙基甲酰胺-5H-吡咯并[3，4-d]嘧啶-6(7H)-2-磺酰胺二三氟乙酸盐 Step 6: 6-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyranyl-N-propylformamide-5H-pyrrole And [3,4-d]pyrimidin-6(7H)-2-sulfonamide ditrifluoroacetate
将第五步的产品(400mg)和DCM/TFA(12mL/4mL)加入反应瓶中，室温搅拌30min，浓缩后制备分离纯化得到6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃基-N-丙基甲酰胺-5H-吡咯并[3，4-d]嘧啶-6(7H)-2-磺酰胺二三氟乙酸盐(180mg，白色固体)。H NMR(400Hz，CD3OD)，δ：8.80(s，1H)，7.33-7.29(m，1H)，7.26-7.17(m，2H)，4.62(d，J＝10.0Hz，1H)，4.39-4.35(m，1H)，4.26(s，2H)，4.20(s，2H)，3.58-3.50(m，2H)，3.19-3.13(m，1H)，3.07(t，J＝7.2Hz，2H)，2.64(d，J＝11.6Hz，1H)，1.79(q，J＝11.6Hz，1H)，1.52-1.43(m，2H)，0.88(t，J＝7.2Hz，3H).MS m/z(ESI)：497.2(M+1)。The product of the fifth step (400 mg) and DCM/TFA (12 mL/4 mL) were added to the reaction flask, stirred at room temperature for 30 min, concentrated and purified to obtain 6-((3R,5S,6R)-5-amino-6- (2,5-difluorophenyl)tetrahydro-2H-pyranyl-N-propylformamide-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-2-sulfonamide Fluoroacetate (180 mg, white solid). H NMR (400 Hz, CD 3 OD), δ: 8.80 (s, 1H), 7.33 - 7.29 (m, 1H), 7.26-7.17 (m, 2H), 4.62 ( d, J = 10.0 Hz, 1H), 4.39-4.35 (m, 1H), 4.26 (s, 2H), 4.20 (s, 2H), 3.58-3.50 (m, 2H), 3.19-3.13 (m, 1H) , 3.07 (t, J = 7.2 Hz, 2H), 2.64 (d, J = 11.6 Hz, 1H), 1.79 (q, J = 11.6 Hz, 1H), 1.52-1.43 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H). MS m/z (ESI): 497.2 (M + 1).
实施例23：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-Example 23: 6-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3- 基)-6H-吡咯并[3，4-d]嘧啶-2-磺酰胺三氟乙酸盐(化合物25’)-6H-pyrrolo[3,4-d]pyrimidine-2-sulfonamide trifluoroacetate (compound 25')
Figure PCTCN2016000478-appb-000055
Figure PCTCN2016000478-appb-000055
第一步：((2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-氨磺酰基-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-基)甲酸叔丁酯First step: ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-sulfamoyl-6H-pyrrolo[3,4-d]pyrimidine-6- Tert-butyl tetrahydro-2H-pyran-3-yl)carboxylate
室温下，将((2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-胺磺酰基-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-基)甲酸叔丁酯(0.103g，0.2mmol)和2mL的二氧六环加入反应瓶中搅拌，然后加入DDQ(55mg，0.24mmol)，TLC监测反应完全后，反应液浓缩后制备纯化得到((2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-氨磺酰基-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-基)甲酸叔丁酯(58mg，黄色固体，收率56％)((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-aminesulfonyl-5H-pyrrolo[3,4-d]pyrimidin-6 7H)-yl)tetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester (0.103 g, 0.2 mmol) and 2 mL of dioxane were added to the reaction flask and stirred, then DDQ (55 mg, 0.24 mmol) was added. After TLC monitors the reaction, the reaction mixture is concentrated and purified to obtain ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-sulfamoyl-6H-pyrrole[ Tert-butyl 3,4-d]pyrimidin-6-yl)tetrahydro-2H-pyran-3-yl)carboxylate (58 mg, yellow solid, yield 56%)
第二步：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-6H-吡咯并[3，4-d]嘧啶-2-磺酰胺三氟乙酸盐Second step: 6-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-6H-pyrrolo[3 ,4-d]pyrimidine-2-sulfonamide trifluoroacetate
室温下，将((2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-氨磺酰基-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-基)甲酸叔丁酯(58mg，0.114mmol)和DCM/TFA(1.5mL/0.5mL)加入反应瓶中搅拌30min，浓缩后加入水，冻干得到6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-6H-吡咯并[3，4-d]嘧啶-2-磺酰胺三氟乙酸盐(42mg，黄色固体)1H NMR(400MHz，CD3OD)δ：9.37(s，1H)，7.93(d，J＝2.0Hz，1H)，7.83(d，J＝1.2Hz，1H)，7.41-7.37(m，1H)，7.28-7.23(m，2H)，5.10-5.02 (m，1H)，4.84(br，1H)，4.44-4.39(m，1H)，4.05(t，J＝11.2Hz，1H)，3.80-3.74(m，1H)，2.86-2.83(m，1H)，2.48(q，J＝12.0Hz，1H).MS m/z(ESI)：410.1(M+1)。((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-sulfamoyl-6H-pyrrolo[3,4-d]pyrimidin-6- at room temperature Tert-butyl tetrahydro-2H-pyran-3-yl)carboxylate (58mg, 0.114mmol) and DCM/TFA (1.5mL / 0.5mL) were added to the reaction flask and stirred for 30min, concentrated, added water, and lyophilized 6-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-6H-pyrrolo[3,4-d Pyrimidine-2-sulfonamide trifluoroacetate (42 mg, yellow solid) 1 H NMR (400 MHz, CD 3 OD) δ: 9.37 (s, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 1.2 Hz, 1H), 7.41-7.37 (m, 1H), 7.28-7.23 (m, 2H), 5.10-5.02 (m, 1H), 4.84 (br, 1H), 4.44 - 4.39 (m , 1H), 4.05 (t, J = 11.2 Hz, 1H), 3.80-3.74 (m, 1H), 2.86-2.83 (m, 1H), 2.48 (q, J = 12.0 Hz, 1H). MS m/z (ESI): 410.1 (M+1).
实施例24：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-Example 24: 6-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3- 基)-N-(N-甲基胍基)-6，7-二氢-5H-吡咯[3，4-d]嘧啶-2-磺胺三氟乙酸盐-N-(N-methylindenyl)-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidine-2-sulfonamide trifluoroacetate (化合物23’)(compound 23')
Figure PCTCN2016000478-appb-000056
Figure PCTCN2016000478-appb-000056
第一步：叔丁基l 2-(N-(N-甲基胍基)氨磺酰基)-5，7-二氢-6H-吡咯[3，4-d]嘧啶-6-羧酸盐First step: tert-butyl l 2-(N-(N-methylindolyl)sulfamoyl)-5,7-dihydro-6H-pyrrole[3,4-d]pyrimidine-6-carboxylate
A：将盐酸甲基胍(17g，158mmol)溶于水(80ml)中，-5℃～0℃分批加入碳酸钾(22g，158mmol)，保温搅拌反应，备用；A: methylhydrazine hydrochloride (17 g, 158 mmol) was dissolved in water (80 ml), potassium carbonate (22 g, 158 mmol) was added portionwise at -5 ° C to 0 ° C, and the reaction was stirred while stirring;
B：室温下将化合物2-巯基-5H-吡咯并[3，4-d]嘧啶-6(7H)-羧酸叔丁酯(4g，15.8mmol)加入至二氯甲烷(80ml)、水(80ml)中，加入氯化钙(16g，144mmol)，将体系冷却至-5℃，保持-5℃～0℃将氯气导入其中，反应10分钟，TLC监控反应，原料消失，停止通入氯气，体系静置分层，温度保持于-5℃～0℃；B: The compound 2-mercapto-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester (4 g, 15.8 mmol) was added to dichloromethane (80 ml), water ( In 80 ml), calcium chloride (16 g, 144 mmol) was added, the system was cooled to -5 ° C, chlorine gas was introduced thereto at -5 ° C to 0 ° C, and the reaction was carried out for 10 minutes. The reaction was monitored by TLC, the starting material disappeared, and chlorine gas was stopped. The system is allowed to stand layering, and the temperature is maintained at -5 ° C to 0 ° C;
C：将B反应中下层二氯甲烷相移加至A溶液中，移加过程，保持充分搅拌，加完后，自然升温至10℃反应10分钟，TLC监控反应，原料消失，将反应液静置分层，体系浑浊，过滤，干燥，所滤得黄色固体便是化合物b(1.5g，4.2mmol)，MS(ESI)m/z：357(M+1)+，收率Y＝27％。C: The lower layer of methylene chloride in the B reaction is phase-shifted and added to the A solution, and the process is further stirred. After the addition, the temperature is naturally raised to 10 ° C for 10 minutes. The reaction is monitored by TLC, the starting material disappears, and the reaction solution is allowed to stand still. The layers were separated, the system was cloudy, filtered, and dried. The yellow solid was obtained as compound b (1.5 g, 4.2 mmol), MS (ESI) m/z: 357 (M+1) + , yield Y=27% .
第二步：N-(N-甲基胍基)-6，7-二氢-5H-吡咯[3，4-d]嘧啶-2-磺胺三氟乙酸盐 Second step: N-(N-methylindenyl)-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidine-2-sulfonamide trifluoroacetate
室温下将化合物2-(N-(N-甲基胍基)氨磺酰基)-5，7-二氢-6H-吡咯[3，4-d]嘧啶-6-羧酸叔丁酯(1.0g，2.8mmol)溶于二氯甲烷(15ml)和三氟乙酸(5ml)的混合溶剂中，搅拌反应一小时，TLC监控反应，原料消失，将反应液于30℃减压浓缩干，得黄棕色固体化合物c(2.0g，2.8mmol)。MS(ESI)m/z：257(M+1)+。The compound 2-(N-(N-methylindolyl)sulfamoyl)-5,7-dihydro-6H-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (1.0) g, 2.8 mmol) was dissolved in a mixed solvent of dichloromethane (15 ml) and trifluoroacetic acid (5 ml), and the reaction was stirred for one hour. The reaction was monitored by TLC, the material disappeared, and the reaction mixture was concentrated under reduced pressure at 30 ° C to yield yellow. Brown solid compound c (2.0 g, 2.8 mmol). MS (ESI) m / z: 257 (M + 1) +.
第三步：叔丁基((2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(N-(N-甲基胍基)氨磺酰基)-5，7-二氢-6H-吡咯[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-基)氨基甲酸酯Third step: tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(N-(N-methylindenyl)sulfamoyl)- 5,7-Dihydro-6H-pyrrole[3,4-d]pyrimidin-6-yl)tetrahydro-2H-pyran-3-yl)carbamate
室温下将化合物N-(N-甲基胍基)-6，7-二氢-5H-吡咯[3，4-d]嘧啶-2-磺胺三氟乙酸盐(2.0g，2.8mmol)加入至甲醇(12ml)中，加入化合物((2R，3S)-2-(2，5-二氟苯基)-5-氧代四氢-2H-吡喃-3-基)甲酸叔丁酯(1.0g，2.8mmol)，搅拌反应3小时后，加入氰基硼氢化钠(0.5g，8.4mmol)反应三小时，TLC监控反应，将反应液浓缩倒入水(50ml)中，碳酸氢钾调节PH≈7～8，氯化钠饱和水相，乙酸乙酯萃取，硫酸钠干燥，制备板分离得淡黄色固体化合物e(0.1g，0.17mmol)，MS(ESI)m/z：568(M+1)+，收率Y＝6％。The compound N-(N-methylindenyl)-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidin-2-sulfonamide trifluoroacetate (2.0 g, 2.8 mmol) was added at room temperature. To methanol (12 ml), the compound ((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester ( 1.0 g, 2.8 mmol), after stirring for 3 hours, sodium cyanoborohydride (0.5 g, 8.4 mmol) was added for three hours, the reaction was monitored by TLC, and the reaction mixture was concentrated and poured into water (50 ml). ≈7～8, a saturated aqueous phase of sodium chloride, ethyl acetate, and dried over sodium sulfate. +1) + , yield Y = 6%.
第四步：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-N-(N-甲基胍基)-6，7-二氢-5H-吡咯[3，4-d]嘧啶-2-磺胺三氟乙酸盐The fourth step: 6-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-(N-A Base group)-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidine-2-sulfonamide trifluoroacetate
室温下将化合物叔丁基((2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(N-(N-甲基胍基)氨磺酰基)-5，7-二氢-6H-吡咯[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-基)氨基甲酸酯(0.1g，0.17mmol)加入至二氯甲烷(1.5ml)和三氟乙酸(0.5ml)的混合溶剂中，搅拌反应一小时，TLC监控反应，原料消失，将反应液于30℃减压浓缩至快干时，浓缩液用乙醚洗涤，析出固体，固体干燥得黄色化合物6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-N-(N-甲基胍基)-6，7-二氢-5H-吡咯[3，4-d]嘧啶-2-磺胺三氟乙酸盐(100mg，0.15mmol)，MS(ESI)m/z：468(M+1)+，收率Y＝88％，1H NMR(400MHz，MeOD)δ8.77(s，1H)，7.36-7.28(m，1H)，7.22(dt，J＝7.3，4.6Hz，2H)，4.64(d，J＝9.9Hz，1H)，4.40(dd，J＝11.1，2.5Hz，1H)，4.35-4.25(m，3H)，3.62-3.52(m，2H)，3.49(q，J＝7.0Hz，1H)，2.80(d，J＝15.4Hz，3H)，2.67(d，J＝11.8Hz，1H)，1.85(q，J＝11.7Hz，1H)，1.17(t，J＝7.0Hz，1H)。The compound tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(N-(N-methylmercapto))sulfonyl)- 5,7-Dihydro-6H-pyrrole[3,4-d]pyrimidin-6-yl)tetrahydro-2H-pyran-3-yl)carbamate (0.1 g, 0.17 mmol) was added to dichloro In a mixed solvent of methane (1.5 ml) and trifluoroacetic acid (0.5 ml), the reaction was stirred for one hour, the reaction was monitored by TLC, and the material was evaporated. The mixture was concentrated to dryness at 30 ° C. The solid is precipitated and the solid is dried to give the yellow compound 6-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N- (N-methylindenyl)-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidine-2-sulfonamide trifluoroacetate (100 mg, 0.15 mmol), MS (ESI) m/z : 468 (M+1) + , Yield Y = 88%, 1 H NMR (400 MHz, MeOH) δ 8.77 (s, 1H), 7.36-7.28 (m, 1H), 7.22 (dt, J = 7.3, 4.6 Hz, 2H), 4.64 (d, J = 9.9 Hz, 1H), 4.40 (dd, J = 11.1, 2.5 Hz, 1H), 4.35-4.25 (m, 3H), 3.62-3.52 (m, 2H), 3.49 (q, J=7.0 Hz, 1H), 2.80 (d, J = 15.4 Hz, 3H), 2.67 (d, J = 11.8 Hz, 1H), 1.85 (q, J = 11.7 Hz, 1H), 1.17 ( t, J = 7.0 Hz, 1H).
实施例25：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-Example 25: 6-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3- 基)-N-胍基-6，7-二氢-5H-吡咯[3，4-d]嘧啶-2-磺胺三氟乙酸盐(化合物-N-mercapto-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidine-2-sulfonamide trifluoroacetate (compound) 21’)twenty one')
Figure PCTCN2016000478-appb-000057
Figure PCTCN2016000478-appb-000057
第一步：叔丁基2-(N-胍基氨磺酰)-5，7-二氢-6H-吡咯[3，4-d]嘧啶-6-羧酸盐First step: tert-butyl 2-(N-mercaptosulfonyl)-5,7-dihydro-6H-pyrrole[3,4-d]pyrimidine-6-carboxylate
A：将盐酸胍(15g，158mmol)溶于水(80ml)中，-5℃～0℃分批加入碳酸钾(22g，158mmol)，保温搅拌反应，备用；A: hydrazine hydrochloride (15 g, 158 mmol) was dissolved in water (80 ml), potassium carbonate (22 g, 158 mmol) was added portionwise at -5 ° C to 0 ° C, and the reaction was stirred while stirring;
B：室温下将化合物2-巯基-5H-吡咯并[3，4-d]嘧啶-6(7H)-羧酸叔丁酯(4g，15.8mmol)加入至二氯甲烷(80ml)、水(80ml)中，加入氯化钙(16g，144mmol)，将体系冷却至-5℃，保持-5℃～0℃将氯气导入其中，反应10分钟，TLC监控反应，原料反应完全后，停止通入氯气，体系静置分层，温度保持于-5℃～0℃；B: The compound 2-mercapto-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester (4 g, 15.8 mmol) was added to dichloromethane (80 ml), water ( Calcium chloride (16g, 144mmol) was added to 80ml), the system was cooled to -5 °C, chlorine gas was introduced into the mixture at -5 °C to 0 °C, and the reaction was carried out for 10 minutes. The reaction was monitored by TLC, and the reaction was stopped after the reaction of the raw materials was completed. Chlorine gas, the system is allowed to stand layering, and the temperature is maintained at -5 ° C ~ 0 ° C;
C：将B反应中下层二氯甲烷相移加至A溶液中，移加过程，保持充分搅拌，加完后，自然升温至10℃反应10分钟，TLC监控反应，原料消失，将反应液静置分层，水相用乙酸乙酯萃取，合并有机相，硫酸钠干燥，过滤，滤液浓缩至快干时加入异丙醚(20ml)重结晶，得黄色固体化合物2-(N-胍基氨磺酰)-5，7-二氢-6H-吡咯[3，4-d]嘧啶-6-羧酸叔丁酯(1g，2.9mmol)，MS(ESI)m/z：343(M+1)+，收率Y＝18％。C: The lower layer of methylene chloride in the B reaction is phase-shifted and added to the A solution, and the process is further stirred. After the addition, the temperature is naturally raised to 10 ° C for 10 minutes. The reaction is monitored by TLC, the starting material disappears, and the reaction solution is allowed to stand still. The layers were separated and the aqueous phase was extracted with EtOAc. EtOAc (EtOAc m. Sulfonyl)-5,7-dihydro-6H-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (1 g, 2.9 mmol), MS (ESI) m. ) + , yield Y = 18.8%.
第二步：N-胍基-6，7-二氢-5H-吡咯[3，4-d]嘧啶-2-磺胺Step 2: N-Mercapto-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidine-2-sulfonamide
室温下将化合物2-(N-胍基氨磺酰)-5，7-二氢-6H-吡咯[3，4-d]嘧啶-6-羧酸叔丁酯(0.7g，2.0mmol)溶于二氯甲烷(10.5ml)和三氟乙酸(3.5ml)的混合溶剂中，搅拌反应一小时，TLC监控反应，原料消失，将反应液于30℃减压浓缩干，得黑色固体化合物N-胍基-6，7-二氢-5H-吡咯[3，4-d]嘧啶-2-磺胺(1.2g，2.0mmol)。MS(ESI)m/z：243 (M+1)+。The compound 2-(N-mercaptosulfonyl)-5,7-dihydro-6H-pyrrole[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (0.7 g, 2.0 mmol) was dissolved at room temperature. The reaction was stirred for one hour in a mixed solvent of dichloromethane (10.5 ml) and trifluoroacetic acid (3.5 ml). The reaction was monitored by TLC, and the material was evaporated. The reaction mixture was concentrated to dryness. Mercapto-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidine-2-sulfonamide (1.2 g, 2.0 mmol). MS (ESI) m / z: 243 (M + 1) +.
第三步：叔丁基((2R，3S，5R)-5-(2-(N-胍基氨磺酰)-5，7-二氢-6H-吡咯[3，4-d]嘧啶-6-基)-2-(2，5-二氟苯基)四氢-2H-吡喃-3-基)氨基甲酸酯Step 3: tert-Butyl ((2R,3S,5R)-5-(2-(N-decylsulfamoyl)-5,7-dihydro-6H-pyrrole[3,4-d]pyrimidine- 6-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate
室温下将化合物N-胍基-6，7-二氢-5H-吡咯[3，4-d]嘧啶-2-磺胺(1.2g，2.0mmol)加入至甲醇(12ml)中，加入化合物((2R，3S)-2-(2，5-二氟苯基)-5-氧代四氢-2H-吡喃-3-基)甲酸叔丁酯(0.74g，2.0mmol)，搅拌反应3小时后，加入氰基硼氢化钠(0.4g，6.0mmol)，搅拌三小时，TLC监控反应，所余原料无明显转换，将反应液浓缩倒入水(50ml)中，碳酸氢钾调节PH≈7～8，氯化钠饱和水相，乙酸乙酯萃取，硫酸钠干燥，制备板分离得淡黄色固体化合物叔丁基((2R，3S，5R)-5-(2-(N-胍基氨磺酰)-5，7-二氢-6H-吡咯[3，4-d]嘧啶-6-基)-2-(2，5-二氟苯基)四氢-2H-吡喃-3-基)氨基甲酸酯(0.1g，0.18mmol)，MS(ESI)m/z：554(M+1)+，收率Y＝9％。The compound N-mercapto-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidine-2-sulfonamide (1.2 g, 2.0 mmol) was added to methanol (12 ml) at room temperature, and compound (( 2R,3S)-2-(2,5-Difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester (0.74 g, 2.0 mmol), stirring for 3 hours After that, sodium cyanoborohydride (0.4 g, 6.0 mmol) was added, and the mixture was stirred for three hours. The reaction was monitored by TLC, and the remaining materials were not converted, and the reaction mixture was concentrated and poured into water (50 ml), and potassium hydrogencarbonate was adjusted to pH ≈7. ～8, saturated aqueous phase of sodium chloride, extracted with ethyl acetate, dried over sodium sulfate, and then purified to give a pale yellow solid compound t-butyl ((2R,3S,5R)-5-(2-(N-decylamino) Sulfonyl)-5,7-dihydro-6H-pyrrole[3,4-d]pyrimidin-6-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3- yl) carbamate (0.1g, 0.18mmol), MS ( ESI) m / z: 554 (m + 1) +, yield Y = 9%.
第四步：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-N-胍基-6，7-二氢-5H-吡咯[3，4-d]嘧啶-2-磺胺三氟乙酸盐Fourth step: 6-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-indenyl-6 ,7-Dihydro-5H-pyrrole[3,4-d]pyrimidine-2-sulfonamide trifluoroacetate
室温下将化合物叔丁基((2R，3S，5R)-5-(2-(N-胍基氨磺酰)-5，7-二氢-6H-吡咯[3，4-d]嘧啶-6-基)-2-(2，5-二氟苯基)四氢-2H-吡喃-3-基)氨基甲酸酯(0.1g，0.18mmol)加入至二氯甲烷(1.5ml)和三氟乙酸(0.5ml)的混合溶剂中，搅拌反应一小时，TLC监控反应完全后，将反应液减压浓缩，浓缩液用乙醚洗涤，析出固体，固体干燥得黄色化合物6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-N-胍基-6，7-二氢-5H-吡咯[3，4-d]嘧啶-2-磺胺三氟乙酸盐100mg，0.15mmol)，MS(ESI)m/z：454(M+1)+，收率Y＝83％，1H NMR(400MHz，MeOD)δ8.78(s，1H)，7.35-7.29(m，1H)，7.27-7.16(m，2H)，4.65(d，J＝9.9Hz，1H)，4.37(ddd，J＝29.5，16.4，2.2Hz，4H)，3.65-3.52(m，2H)，3.49(q，J＝7.0Hz，1H)，2.69(d，J＝10.4Hz，1H)，1.87(q，J＝11.7Hz，1H)，1.17(t，J＝7.0Hz，1H)。The compound tert-butyl ((2R,3S,5R)-5-(2-(N-mercaptosulfonyl)-5,7-dihydro-6H-pyrrole[3,4-d]pyrimidine- 6-yl)-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate (0.1 g, 0.18 mmol) was added to dichloromethane (1.5 ml) In a mixed solvent of trifluoroacetic acid (0.5 ml), the reaction was stirred for one hour. After the reaction was completed by TLC, the reaction mixture was concentrated under reduced pressure, and the mixture was washed with diethyl ether to precipitate a solid, which was dried to give a yellow compound 6-(3R, 5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-indolyl-6,7-dihydro-5H-pyrrole [ 3,4-d]pyrimidine-2-sulfonamide trifluoroacetate 100 mg, 0.15 mmol), MS (ESI) m/z: 454 (M+1) + , yield Y=83%, 1 H NMR (400 MHz , MeOD) δ 8.78 (s, 1H), 7.35-7.29 (m, 1H), 7.27-7.16 (m, 2H), 4.65 (d, J = 9.9 Hz, 1H), 4.37 (ddd, J = 29.5, 16.4, 2.2 Hz, 4H), 3.65-3.52 (m, 2H), 3.49 (q, J = 7.0 Hz, 1H), 2.69 (d, J = 10.4 Hz, 1H), 1.87 (q, J = 11.7 Hz, 1H), 1.17 (t, J = 7.0 Hz, 1H).
实施例26：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(6-(甲基Example 26: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(6-(methyl) 磺酰基)-1H-吡咯并[3，4-c]吡啶-2(3H)-基)四氢-2H-吡喃-3-胺二盐Sulfonyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-yl)tetrahydro-2H-pyran-3-amine diphosphate 酸盐(化合物17’)Acid salt (compound 17')
Figure PCTCN2016000478-appb-000058
Figure PCTCN2016000478-appb-000058
第一步 叔丁基-6-(甲基磺酰基)-1H吡咯并[3，4-c]吡啶-2(3H)-羧酸叔丁酯First step tert-butyl-6-(methylsulfonyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylic acid tert-butyl ester
将6-氯-1H-吡咯并[3，4-c]吡啶-2(3H)-碳酸叔丁酯(0.137g，0.539mmol)、甲烷亚磺酸钠(0.138g，1.35mmol)、(CuOTf)2PhH(0.109g，0.216mmol)、N，N’-二甲基乙二胺(0.086g，0.97mmol)加入DMSO(3mL)中，N环境下120℃反应24h。反应完全后将反应液加入水中，用EA萃取，合并有机相，干燥浓缩得450mg粗品。经柱层析纯化，得到275mg固体。MS m/z(ESI)：239.1[M+1]。6-Chloro-1H-pyrrolo[3,4-c]pyridine-2(3H)-tert-butyl carbonate (0.137 g, 0.539 mmol), sodium methanesulfinate (0.138 g, 1.35 mmol), (CuOTf 2PhH (0.109 g, 0.216 mmol), N,N'-dimethylethylenediamine (0.086 g, 0.97 mmol) was added to DMSO (3 mL), and reacted at 120 ° C for 24 h under N atmosphere. After completion of the reaction, the reaction mixture was poured into water and extracted with EtOAc. Purification by column chromatography gave 275 mg of solid. MS m/z (ESI): 239.1 [M + 1].
第二步 6-(甲基磺酰基)-2，3-二氢-1H-吡咯并[3，4-c]吡啶The second step 6-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine
将6-(甲基磺酰基)-1H吡咯并[3，4-c]吡啶-2(3H)-羧酸叔丁酯(275mg)加入三氟醋酸(1mL)和二氧六环(0.5mL)中，室温下反应24h。将反应液过滤，滤饼用DCM洗三次，得227mg黄白色固体。MS m/z(ESI)：199.08[M+1]。Add 6-(methylsulfonyl)-1Hpyrrolo[3,4-c]pyridine-2(3H)-carboxylic acid tert-butyl ester (275 mg) to trifluoroacetic acid (1 mL) and dioxane (0.5 mL) In the reaction at room temperature for 24 h. The reaction solution was filtered, and the filtered cake was washed with EtOAc EtOAc EtOAc MS m/z (ESI): 195.08 [M + 1].
第三步 ((2R，3S，5R)-2-(2，5-二氟苯基)-5-(6-(甲基磺酰基)-1H吡咯并[3，4-c]吡啶-2(3H)-基)四氢-2H-吡喃-3-基)氨基叔丁基甲酸酯The third step ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(6-(methylsulfonyl)-1H-pyrrolo[3,4-c]pyridine-2 (3H)-yl)tetrahydro-2H-pyran-3-yl)amino-tert-butylformate
将6-(甲基磺酰基)-2，3-二氢-1H-吡咯并[3，4-c]吡啶(0.227g，0.838mmol)、酮(0.288g，0.879mmol)加入甲醇中，室温下搅拌1h，后加入醋酸硼氢化钠(0.621g，2.93mmol)，LCMS监测反应完全后过滤，滤饼用冷甲醇少量洗两次，干燥得361mg。MS m/z(ESI)：510.16[M+1]，直接用于下一步。6-(Methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine (0.227 g, 0.838 mmol), ketone (0.288 g, 0.879 mmol) was added to methanol at room temperature After stirring for 1 h, sodium borohydride (0.621 g, 2.93 mmol) was added, and the mixture was filtered and filtered, and then filtered, and then filtered, and then filtered. MS m/z (ESI): 510.16 [M + 1].
第四步 (2R，3S，5R)-2-(2，5-二氟苯基)-5-(6-(甲基磺酰基)-1H-吡咯并[3，4-c]吡啶-2(3H)-基)四氢-2H-吡喃-3-胺The fourth step (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(6-(methylsulfonyl)-1H-pyrrolo[3,4-c]pyridine-2 (3H)-yl)tetrahydro-2H-pyran-3-amine
将((2R，3S，5R)-2-(2，5-二氟苯基)-5-(6-(甲基磺酰基)-1H吡咯并[3，4-c]吡啶-2(3H)-基)四氢-2H-吡喃-3-基)氨基叔丁基甲酸 酯(361mg)于冰浴下加入6mL HCl乙酸乙酯中，室温下反应1h。反应液经浓缩得到标题化合物白色固体160mg(73.1％)。MS m/z(ESI)：410.13[M+1]((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(6-(methylsulfonyl)-1H-pyrrolo[3,4-c]pyridine-2 (3H )-yl)tetrahydro-2H-pyran-3-yl)amino-tert-butylformic acid The ester (361 mg) was added to 6 mL of EtOAc EtOAc. The reaction mixture was concentrated to give the title compound Compound Compound Compound Compound Compound MS m/z (ESI): 410.13 [M+1]
1H NMR(400MHz，CD3OD)δ：8.85(1H，s)，8.23(1H，s)，7.38-7.35(1H，m)，7.30-7.23(1H，m)，7.33(1H，s)，5.08(4H，s)，4.80-4.78(1H，m)，4.60-4.56(1H，m)，4.11-4.13(1H，m)，3.98-3.95(1H，m)，3.72-3.62(1H，m)，3.30(3H，s)，2.91(1H，m)，2.34-2.261(1H，m)。 1 H NMR (400 MHz, CD 3 OD) δ: 8.85 (1H, s), 8.23 (1H, s), 7.38-7.35 (1H, m), 7.30-7.23 (1H, m), 7.33 (1H, s) , 5.08 (4H, s), 4.80-4.78 (1H, m), 4.60-4.56 (1H, m), 4.11-4.13 (1H, m), 3.98-3.95 (1H, m), 3.72-3.62 (1H, m), 3.30 (3H, s), 2.91 (1H, m), 2.34 - 2.261 (1H, m).
实施例27：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(甲基Example 27: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(methyl) 磺酰基)-5-吡咯并[3，4-b]吡啶6(7h)-基)四氢-2H-吡喃-3-胺(化合Sulfonyl)-5-pyrrolo[3,4-b]pyridine 6(7h)-yl)tetrahydro-2H-pyran-3-amine (combination 物16)Matter 16)
Figure PCTCN2016000478-appb-000059
Figure PCTCN2016000478-appb-000059
第一步 6-(2，4-二甲氧基苄基)-2-(甲基磺酰基)-6，7-二氢-5H-吡咯并[3，4-b]吡啶First step 6-(2,4-Dimethoxybenzyl)-2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine
将2-氯-6-(2，4-二甲氧基苄基)-6，7-二氢-5H-吡咯并[3，4-b]吡啶(0.05g，0.164mmol)、甲烷亚磺酸钠(0.042g，0.411mmol)、(CuOTf)2PhH(0.033g，0.066mmol)、N，N’-二甲基乙二胺(0.009g，0.099mmol)加入DMSO(2mL)中，氮气环境下120℃反应24h。将反应液加入水，用EA萃取水层三次，合并有机相，干燥浓缩得150mg粗品。经柱层析纯化，得到34mg灰黑色固体(59.6％)。MS m/z(ESI)：211.6[M+1]。2-Chloro-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (0.05 g, 0.164 mmol), methanesulfin Sodium (0.042g, 0.411mmol), (CuOTf)2PhH (0.033g, 0.066mmol), N,N'-dimethylethylenediamine (0.009g, 0.099mmol) was added to DMSO (2mL) under nitrogen The reaction was carried out at 120 ° C for 24 h. The reaction mixture was poured into water, and the aqueous layer was extracted with EtOAc EtOAc. Purification by column chromatography gave 34 mg (yield: 59. MS m/z (ESI): 211.6 [M+1].
第二步 2-(甲基磺酰基)-6，7-二氢-5H-吡咯并[3，4-b]吡啶The second step 2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine
将6-(2，4-二甲氧基苄基)-2-(甲基磺酰基)-6，7-二氢-5H-吡咯并[3，4-b]吡啶(34mg)加入三氟醋酸(1mL)和二氧六环(0.5mL)中，于90℃下反应24h。后处理：反应液浓缩后加入3mL EA，于冰浴下滴加3mL HCl二氧六环溶液，室温下搅拌1h，过滤，用乙醚重结晶得9mg黑色固体。MS m/z(ESI)：199.05[M+1]。Add 6-(2,4-dimethoxybenzyl)-2-(methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (34 mg) to trifluoro Acetic acid (1 mL) and dioxane (0.5 mL) were reacted at 90 ° C for 24 h. After the reaction mixture was concentrated, 3 mL of EA was added, and 3 mL of HCl dioxane solution was added dropwise to the ice bath. MS m/z (ESI): 195.05 [M + 1].
第三步 叔丁基((2R，3S，5R)-2-(2，5-二氟苯基1)-5-(2-(甲基磺酰基)-5H吡咯并[3，4-b]吡啶-6(7H)-基)四氢-2h-吡喃-3-基) 氨基甲酸酯The third step tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl 1)-5-(2-(methylsulfonyl)-5Hpyrrolo[3,4-b Pyridine-6(7H)-yl)tetrahydro-2h-pyran-3-yl) Carbamate
将2-(甲基磺酰基)-6，7-二氢-5H-吡咯并[3，4-b]吡啶(0.155g，0.572mmol)、酮(0.281g，0.858mmol)加入甲醇中，室温下搅拌1h，于冰浴下加入醋酸硼氢化钠(0.18g，2.86mmol)，LCMS监测反应完全后过滤，滤饼经洗涤，干燥得0.149g。MS m/z(ESI)：510.18[M+1]，直接用于下一步。2-(Methylsulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (0.155 g, 0.572 mmol), ketone (0.281 g, 0.858 mmol) in methanol, room temperature After stirring for 1 h, sodium borohydride (0.18 g, 2.86 mmol) was added, and the mixture was filtered, and then filtered, and then filtered and dried. MS m/z (ESI): 510.18 [M + 1].
第四步 (2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(甲基磺酰基)-5-吡咯并[3，4-b]吡啶-6(7H)-基)四氢-2H-吡喃-3-胺The fourth step (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-5-pyrrolo[3,4-b]pyridine-6 (7H)-yl)tetrahydro-2H-pyran-3-amine
将叔丁基((2R，3S，5R)-2-(2，5-二氟苯基1)-5-(2-(甲基磺酰基)-5H吡咯并[3，4-b]吡啶-6(7H)-基)四氢-2h-吡喃-3-基)氨基甲酸酯(0.149g)于冰浴下加入3.7mL HCl乙酸乙酯中，室温下反应1h。LCMS监测反应完全反应液经HPLC分离纯化得到白色固体117mg(63.9％)。MS m/z(ESI)：410.18[M+1]tert-Butyl ((2R,3S,5R)-2-(2,5-difluorophenyl 1)-5-(2-(methylsulfonyl)-5Hpyrrolo[3,4-b]pyridine -6(7H)-yl)tetrahydro-2h-pyran-3-yl)carbamate (0.149 g) was added to 3.7 mL EtOAc EtOAc. The reaction was completely purified by HPLC to give 117 mg (yield: 63.9%) of white solid. MS m/z (ESI): 410.18 [M+1]
1H NMR(400MHz，CD3OD)δ：8.23-8.21(1H，m)，8.16-8.14(1H，m)，7.34(1H，s)，7.26(1H，s)，5.14(2H，s)，5.04(2H，s)，4.82-4.80(1H，m)，4.63-4.61(1H，m)，4.11(1H，m)，4.00(1H，m)，3.61(1H，m)，3.60(2H，m)，3.28(3H，s)，2.98(1H，m)，2.36-2.33(1H，m)，2.03(1H，m)。 1 H NMR (400 MHz, CD 3 OD) δ: 8.23 - 8.21 (1H, m), 8.16-8.14 (1H, m), 7.34 (1H, s), 7.26 (1H, s), 5.14 (2H, s) , 5.04 (2H, s), 4.82-4.80 (1H, m), 4.63-4.61 (1H, m), 4.11 (1H, m), 4.00 (1H, m), 3.61 (1H, m), 3.60 (2H) m), 3.28 (3H, s), 2.98 (1H, m), 2.36-2.33 (1H, m), 2.03 (1H, m).
实施例28：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(甲磺酰基)-5H-吡咯Example 28: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-5H-pyrrole 并[3，4-b]吡嗪-6(7H)-基)四氢-2H-吡喃-3-胺，二三氟乙酸盐(化合物And [3,4-b]pyrazine-6(7H)-yl)tetrahydro-2H-pyran-3-amine, ditrifluoroacetate (compound 18’)18’)
Figure PCTCN2016000478-appb-000060
Figure PCTCN2016000478-appb-000060
第一步：5，6-二甲基吡嗪-2-醇的合成First step: synthesis of 5,6-dimethylpyrazin-2-ol
将甘氨酰胺盐酸盐(107g，0.968mol)，甲醇(500ml)加入到反应瓶中。降温至-35℃时滴加15mol/L氢氧化钠(121g)水溶液和2，3-丁二酮(100g，1.162mol)的甲醇溶液。滴毕，保持在-35℃反应2h后升至室温反应过夜。TLC监测至原料反应完全。于冰浴下加入6mol/L盐酸水溶液(350ml)调至PH＝7-8，过滤，将滤液浓缩并加入1.5L甲醇搅拌30min，过滤，滤液减压浓缩后加入甲醇和无水乙醚重结晶得到淡黄白色固体目标化合物(65g，54％)。MS m/z(ESI)：125(M+1)。Glycinamide hydrochloride (107 g, 0.968 mol), methanol (500 ml) was added to the reaction flask. A cooling solution of 15 mol/L sodium hydroxide (121 g) and a solution of 2,3-butanedione (100 g, 1.162 mol) in methanol were added dropwise while cooling to -35 °C. After completion of the dropwise addition, the reaction was maintained at -35 ° C for 2 h and then allowed to rise to room temperature overnight. The TLC was monitored until the starting material was completely reacted. After adding 6 mol/L hydrochloric acid aqueous solution (350 ml) to pH=7-8, the mixture was filtered, and the filtrate was concentrated and added to 1.5 L of methanol, stirred for 30 min, filtered, and the filtrate was concentrated under reduced pressure. Pale yellow-white solid title compound (65 g, 54%). MS m/z (ESI): 125 (M + 1).
第二步：5-氯-2，3-二甲基吡嗪的合成Step 2: Synthesis of 5-chloro-2,3-dimethylpyrazine
将5，6-二甲基吡嗪-2-醇(65g，0.524mol)，三氯氧磷(600ml)加入到反应瓶中。加热回流搅拌3h。LC-MS监测至原料反应完全。减压蒸馏除掉三氯氧磷，残留物中加入二氯甲烷(1.5L)后缓慢倒入水(1.5L)中。用氢氧化钠水溶液调至PH＝7-8，用二氯甲烷萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩至干后，经硅胶柱层析色谱分离得到无色油状物的标题化合物(44g，59％)MS m/z(ESI)：143(M+1)。5,6-Dimethylpyrazin-2-ol (65 g, 0.524 mol), phosphorus oxychloride (600 ml) was added to the reaction flask. Heat and reflux for 3 h. LC-MS was monitored until the starting material was completely reacted. The phosphorus oxychloride was removed by distillation under reduced pressure, and dichloromethane (1.5 L) was added to the residue, which was then slowly poured into water (1.5 L). The mixture was adjusted to pH = 7-8 with aqueous sodium hydroxide, and extracted with dichloromethane. The organic phase was combined, dried over anhydrous sodium sulfate, filtered and evaporated. The title compound (44 g, 59%) MS m.
第三步：2，3-二甲基-5-(甲磺酰基)吡嗪的合成The third step: synthesis of 2,3-dimethyl-5-(methylsulfonyl)pyrazine
将5-氯-2，3-二甲基吡嗪(23g，161mmol)，焦亚硫酸钾(71.7g，322.6mmol)，甲酸钠(24.1g，354.8mmol)，醋酸钯(1.8g，8mmol)，1，10-菲罗林(4.8g，24mmol)以及二甲基亚砜(250ml)加入到反应瓶中。将反应液氮气环境下加热回流搅拌16h，TLC监测至原料反应完全。向反应液加入水，用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩至干，经硅胶柱层析色谱分离纯化得到浅黄色固体的标题化合物(23g，77％)。MS m/z(ESI)：187(M+1)。5-Chloro-2,3-dimethylpyrazine (23 g, 161 mmol), potassium pyrosulfite (71.7 g, 322.6 mmol), sodium formate (24.1 g, 354.8 mmol), palladium acetate (1.8 g, 8 mmol), 1,10-Pyroline (4.8 g, 24 mmol) and dimethyl sulfoxide (250 ml) were added to the reaction flask. The reaction solution was heated and refluxed under a nitrogen atmosphere for 16 h, and then was taken to the reaction mixture. Water was added to the reaction mixture, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 77%). MS m/z (ESI): 187 (MH).
第四步：2，3-二溴甲基-5-(甲磺酰基)吡嗪的合成Step 4: Synthesis of 2,3-dibromomethyl-5-(methylsulfonyl)pyrazine
将2，3-二甲基-5-(甲磺酰基)吡嗪(10g，53.8mmol)，N-溴代丁二酰亚胺(20.1g，113mmol)，偶氮二异丁腈(0.88g，5.38mmol)，以及四氯化碳(400ml)加入到反应瓶中。加热回流搅拌16h，TLC监测至原料反应完全。反应液过滤，滤液减压浓缩至干，经硅胶柱层析色谱分离纯化得到黄色油状物的标题化合物的粗品12g。MS m/z(ESI)：345(M+1)。2,3-Dimethyl-5-(methylsulfonyl)pyrazine (10 g, 53.8 mmol), N-bromosuccinimide (20.1 g, 113 mmol), azobisisobutyronitrile (0.88 g) , 5.38 mmol), and carbon tetrachloride (400 ml) were added to the reaction flask. The mixture was stirred under heating and refluxed for 16 h, and then the mixture was monitored by TLC. The reaction mixture was filtered, and the~~~~~~ MS m/z (ESI): 345 (M + 1).
第五步：2-(甲磺酰基)-6-三苯甲基-6，7-二氢-5H-吡咯并(3，4-b)吡嗪的合成 Step 5: Synthesis of 2-(methylsulfonyl)-6-trityl-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine
将2，3-二溴甲基-5-(甲磺酰基)吡嗪(6g，17.4mmol)，三苯甲胺(4.5g，17.4mmol)，N，N-二异丙基乙胺(6.75g，52.3mmol)，N，N-二甲基甲酰胺(60ml)加入反应瓶中。反应液在氮气环境下加热至60℃搅拌拌1h，TLC监测至原料反应完。向反应液加入水，用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩至干得到棕色油状物的标题化合物粗品12g。2,3-Dibromomethyl-5-(methylsulfonyl)pyrazine (6 g, 17.4 mmol), triphenylmethylamine (4.5 g, 17.4 mmol), N,N-diisopropylethylamine (6.75 g, 52.3 mmol), N,N-dimethylformamide (60 ml) was added to the reaction flask. The reaction solution was heated to 60 ° C under nitrogen atmosphere, stirred for 1 h, and monitored by TLC until the reaction of the starting material was completed. Water was added to the reaction mixture, and the mixture was evaporated.
第六步：2-(甲磺酰基)-6，7-氢-5H-吡咯并[3，4-b]吡嗪盐酸盐的合成Step 6: Synthesis of 2-(methylsulfonyl)-6,7-hydro-5H-pyrrolo[3,4-b]pyrazine hydrochloride
将2-(甲磺酰基)-6-三苯甲基-6，7-二氢-5H-吡咯并(3，4-b)吡嗪粗品(12g)于冰浴下加入50ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。反应液浓缩后经HPLC色谱分离纯化得到黄色油状物的标题化合物600mg。MS m/z(ESI)：200(M+1)。The crude 2-(methylsulfonyl)-6-trityl-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine (12 g) was added to 50 ml of 4 mol/L hydrochloric acid under ice bath. In a dioxane solution. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The reaction mixture was concentrated and purified by EtOAcjjjjli MS m/z (ESI): 200 (M + 1).
第七步：((2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(甲磺酰基)-5H-吡咯并[3，4-b]吡嗪-6(7H)-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯的合成Step 7: ((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-(methylsulfonyl)-5H-pyrrolo[3,4-b]pyrazine Synthesis of -6(7H)-yl)tetrahydro-2H-pyran-3-yl)carbamic acid tert-butyl ester
将2-(甲磺酰基)-6，7-二氢-5H-吡咯并[3，4-b]吡嗪盐酸盐(100mg，0.42mmol)和N-[(2R，3S)-2-(2，5-二氟苯基)四氢-5-氧代-2H-吡喃-3-基]氨基甲酸叔丁酯(208mg，0.635mmol)加入4ml无水甲醇中。于环境温度下搅拌1h后加入三乙酰氧基硼氢化钠(198mg，0.933mmol)，室温下搅拌1h，LC-MS检测原料反应完全。反应液过滤，滤饼分别用无水甲醇和无水乙醚洗涤，干燥，得到灰白色固体的标题化合物(40mg，19％)。MS m/z(ESI)：511(M+1)。2-(Methanesulfonyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine hydrochloride (100 mg, 0.42 mmol) and N-[(2R,3S)-2- (2,5-Difluorophenyl)tetrahydro-5-oxo-2H-pyran-3-yl]carbamic acid tert-butyl ester (208 mg, 0.635 mmol) was added to 4 mL anhydrous methanol. After stirring at ambient temperature for 1 h, sodium triacetoxyborohydride (198 mg, 0.933 mmol) was added and stirred at room temperature for 1 h. The reaction mixture was filtered, EtOAcjjjjjjjj MS m/z (ESI): 511 (M + 1).
第八步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(甲磺酰基)-5H-吡咯并[3，4-b]吡嗪-6(7H)-基)四氢-2H-吡喃-3-胺，二三氟乙酸盐的合成Step 8: (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-(methylsulfonyl)-5H-pyrrolo[3,4-b]pyrazine- Synthesis of 6(7H)-yl)tetrahydro-2H-pyran-3-amine, ditrifluoroacetate
将((2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(甲磺酰基)-5H-吡咯并[3，4-b]吡嗪-6(7H)-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯(40mg，0.078mmol)和二氯甲烷4ml加入反应瓶中，反应液加入三氟乙酸(4ml)。室温反应1h，LC-MS检测原料反应完全。直接旋干反应液，制备纯化得到白色固体的标题化合物(4mg，8％)。MS m/z(ESI)：411(M+1)。((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-(methylsulfonyl)-5H-pyrrolo[3,4-b]pyrazine-6 ( To the reaction flask was added 7H)-yl-tetrahydro-2H-pyran-3-yl)carbamic acid tert-butyl ester (40 mg, 0.078 mmol) and dichloromethane (4 ml). The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The title compound (4 mg, 8%) was obtained. MS m/z (ESI): 411 (M + 1).
1H NMR(400MHz，CD3OD)δ：9.05(s，1H)，7.35-7.31(m，1H)，7.25-7.21(m，2H)，4.65-4.62(d，J＝12Hz 1H)，4.44-4.40(m，1H)，4.26-4.25(d，J＝8Hz，4H)，3.60-3.52(m，2H)，3.27(s，3H)，3.22-3.14(m，1H)，2.68-2.63(m，1H)，1.85-1.79(m，1H)。 1H NMR (400MHz, CD3OD) δ: 9.05 (s, 1H), 7.35-7.31 (m, 1H), 7.25-7.21 (m, 2H), 4.65-4.62 (d, J = 12 Hz 1H), 4.44 - 4.40 ( m,1H), 4.26-4.25 (d, J=8Hz, 4H), 3.60-3.52 (m, 2H), 3.27 (s, 3H), 3.22-3.14 (m, 1H), 2.68-2.63 (m, 1H) ), 1.85-1.79 (m, 1H).
实施例29：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯)四氢-2H-吡喃-3-Example 29: 6-((3R,5S,6R)-5-Amino-6-(2,5-difluorobenzene)tetrahydro-2H-pyran-3- 基)-N-(丙基甲酰胺)-6H-吡咯并[3，4-d]嘧啶-2-磺酰胺三氟乙酸盐(化合-N-(propylformamide)-6H-pyrrolo[3,4-d]pyrimidine-2-sulfonamide trifluoroacetate (combination 物32’)Object 32’)
Figure PCTCN2016000478-appb-000061
Figure PCTCN2016000478-appb-000061
第一步：((2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(N-(丙基甲酰胺)氨磺酰基)-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-基)甲酸叔丁酯First step: ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(N-(propylformamide)sulfamoyl)-6H-pyrrolo[ 3,4-d]pyrimidin-6-yl)tetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester
室温下，将((2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(N-(丙基甲酰胺)氨磺酰基)-5H-吡咯并[3，4-d]嘧啶-6(7H)-基)四氢-2H-吡喃-3-基)甲酸叔丁酯(0.06g，0.1mmol)和1.5mL的二氧六环加入反应瓶中搅拌，然后加入DDQ(28mg，0.12mmol)TLC监测反应完全后，反应液浓缩经纯化得到((2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(N-(丙基甲酰胺)氨磺酰基)-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-基)甲酸叔丁酯(38mg，黄色固体，收率64％)。((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-(N-(propylcarboxamide)sulfamoyl)-5H-pyrrolo[ 3,4-d]pyrimidine-6(7H)-yl)tetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester (0.06 g, 0.1 mmol) and 1.5 mL of dioxane were added to the reaction flask. After stirring, the reaction was completed by adding DDQ (28 mg, 0.12 mmol) TLC. The reaction mixture was concentrated and purified ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2- (N-(propylformamide)sulfamoyl)-6H-pyrrolo[3,4-d]pyrimidin-6-yl)tetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester (38 mg, Yellow solid, yield 64%).
第二步：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-N-(丙基甲酰胺)-6H-吡咯并[3，4-d]嘧啶-2-磺酰胺三氟乙酸盐Second step: 6-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-(propyl-propyl) Amide)-6H-pyrrolo[3,4-d]pyrimidine-2-sulfonamide trifluoroacetate
将((2R，3S，5R)-2-(2，5-二氟苯基)-5-(2-(N-(丙基甲酰胺)氨磺酰基)-6H-吡咯并[3，4-d]嘧啶-6-基)四氢-2H-吡喃-3-基)甲酸叔丁酯(38mg，0.06mmol)和DCM/TFA(1.5mL/0.5mL)加入反应瓶中搅拌30min钟后，旋干，加水冻干得到((3R，5S，6R)-5-氨基-6-(2，5-二氟苯)四氢-2H-吡喃-3-基)-N-(丙基甲酰胺)-6H-吡咯并[3，4-d]嘧啶-2-磺酰胺三氟乙酸盐(12mg，黄色固体)。((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(2-(N-(propylformamide)sulfamoyl)-6H-pyrrolo[3,4 -d]pyrimidin-6-yl)tetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester (38 mg, 0.06 mmol) and DCM/TFA (1.5 mL / 0.5 mL) were added to the reaction flask and stirred for 30 min. , spin dry, add water to freeze-dry to obtain ((3R,5S,6R)-5-amino-6-(2,5-difluorobenzene)tetrahydro-2H-pyran-3-yl)-N-(propyl Formamide)-6H-pyrrolo[3,4-d]pyrimidine-2-sulfonamide trifluoroacetate (12 mg, yellow solid).
H NMR(400Hz，CD3OD)：9.35(s，1H)，7.93(s，1H)，7.86(s，1H)，7.41-7.36(m，1H)，7.28-7.23(m，2H)，5.06(br，2H)，4.40(d，J＝7.2Hz，1H)，4.04(t，J＝10.8Hz，1H)，3.79-3.74(m，1H)，3.09(br，1H)，3.04(t，J＝7.2Hz，1H)，2.84(d，J＝11.6Hz，1H)，2.48(q，J＝12.0Hz，1H)，1.51-1.46(m，2H)，0.87(t，J＝7.6Hz，3H).MS m/z(ESI)：495.1(M+1)H NMR (400 Hz, CD 3 OD): 9.35 (s, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 7.41-7.36 (m, 1H), 7.28-7.23 (m, 2H), 5.06 (br, 2H), 4.40 (d, J = 7.2 Hz, 1H), 4.04 (t, J = 10.8 Hz, 1H), 3.79-3.74 (m, 1H), 3.09 (br, 1H), 3.04 (t, J = 7.2 Hz, 1H), 2.84 (d, J = 11.6 Hz, 1H), 2.48 (q, J = 12.0 Hz, 1H), 1.51-1.46 (m, 2H), 0.87 (t, J = 7.6 Hz, 3H).MS m/z (ESI): 495.1 (M+1)
实施例30：2-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)-四氢吡喃-3-基)Example 30: 2-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)-tetrahydropyran-3-yl) 异吲哚啉-5-磺酰胺(化合物34)Isoporphyrin-5-sulfonamide (compound 34)
Figure PCTCN2016000478-appb-000062
Figure PCTCN2016000478-appb-000062
第一步：5-(苯甲硫基)异吲哚啉-2-甲酸叔丁酯First step: 5-(phenylthio)isoindoline-2-carboxylic acid tert-butyl ester
氩气保护下，5-溴异吲哚啉-2-甲酸叔丁酯(2.0g，6.70mmol)、苄硫醇(0.87mL，7.40mmol)、Pd2(dba)3(154mg，0.17mmol)、X-phos(194mg，0.34mmol)、二异丙基乙基胺(2.3mL)的二氧六环(15mL)溶液在90℃下，搅拌反应16小时。反应液浓缩后经柱层析纯化的黄色油状物2.0g。Under the protection of argon, 5-bromoisoindoline-2-carboxylic acid tert-butyl ester (2.0 g, 6.70 mmol), benzyl mercaptan (0.87 mL, 7.40 mmol), Pd2 (dba) 3 (154 mg, 0.17 mmol), A solution of X-phos (194 mg, 0.34 mmol) and diisopropylethylamine (2.3 mL) in dioxane (15 mL) was stirred at 90 ° C for 16 hours. After the reaction mixture was concentrated, the title compound was obtained.
第二步：5-(磺酰氯)异吲哚啉-2-甲酸叔丁酯Second step: 5-(sulfonyl chloride) isoindoline-2-carboxylic acid tert-butyl ester
室温、氩气保护下，向5-(苯甲硫基)异吲哚啉-2-甲酸叔丁酯(1.9g，0.23mmol)的醋酸/水＝25mL/3mL溶液中分批次加入N-氯代丁二酰亚胺(2.3g，16.80mmol)后，室温搅拌反应1小时。然后加水稀释，乙酸乙酯萃取，收集有机相经干燥浓缩得产品1.5g，无需纯化直接用于下一步骤。Add N- in batches to a solution of 5-(benzylthio)isoindoline-2-carboxylic acid tert-butyl ester (1.9 g, 0.23 mmol) in acetic acid/water = 25 mL / 3 mL at room temperature under argon. After chlorosuccinimide (2.3 g, 16.80 mmol), the reaction was stirred at room temperature for 1 hour. It was then diluted with water and extracted with ethyl acetate. The organic phase was collected and dried and evaporated to ethylamine.
第三步：5-磺酰胺异吲哚啉-2-甲酸叔丁酯The third step: 5-sulfonamide isoindoline-2-carboxylic acid tert-butyl ester
向5-(磺酰氯)异吲哚啉-2-甲酸叔丁酯(1.5g，第二步粗品)的四氢呋喃(10mL)溶液中加入氨水(3mL)，然后室温搅拌反应0.5小时。液质检测反应完毕。反应液经柱层析纯化得到红色固体1.2g。To a solution of 5-(sulfonyl chloride)isoindoline-2-carboxylic acid tert-butyl ester (1.5 g, crude product of the second step) in THF (3 mL). The liquid quality test reaction is completed. The reaction solution was purified by column chromatography to yieldd white solid.
第四步：异吲哚啉-5-磺酰胺The fourth step: isoporphyrin-5-sulfonamide
5-磺酰胺异吲哚啉-2-甲酸叔丁酯(400mg，1.34mmol)的二氯甲烷/三氟醋酸＝2mL/mL溶液在室温下搅拌反应2小时。检测反应完毕后将反应液浓缩得到黑色粘稠物410mg，即产物的三氟醋酸盐。 A solution of 5-sulfonamide isoindoline-2-carboxylic acid tert-butyl ester (400 mg, 1.34 mmol) in dichloromethane / trifluoroacetic acid = 2 mL / mL was stirred at room temperature for 2 hr. After the completion of the reaction, the reaction solution was concentrated to give a black viscous material: 410 mg, the product trifluoroacetate.
第五步：((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-磺酰胺异吲哚啉-2-基)四氢吡喃-3-基)甲酸叔丁酯。Step 5: ((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-sulfonamideisoindoline-2-yl)tetrahydropyran-3-yl ) tert-butyl formate.
异吲哚啉-5-磺酰胺(410mg，1.30mmol)、N-[(2R，3S)-2-(2，5-二氟苯基)四氢-5-氧代-2H-吡喃-3-基]氨基甲酸叔丁酯(646mg，1.98mmol)的甲醇溶液在室温下搅拌反应过夜。然后加入氰基硼氢化钠(245mg，4mmol)，室温继续搅拌10分钟。检测反应完毕。反应液经柱层析纯化得到纯的目标产物88mg。Isoindoline-5-sulfonamide (410 mg, 1.30 mmol), N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5-oxo-2H-pyran- A solution of tert-butyl 3-carbamomate (646 mg, 1.98 mmol) in methanol was stirred at room temperature overnight. Sodium cyanoborohydride (245 mg, 4 mmol) was then added and stirring was continued at room temperature for 10 min. The reaction was detected. The reaction solution was purified by column chromatography to yieldd the desired product.
第六步：2-((2R，3S，5R)-5-氨基-6-(2，5-二氟苯基)-四氢吡喃-3-基)异吲哚啉-5-磺酰胺Step 6: 2-((2R,3S,5R)-5-Amino-6-(2,5-difluorophenyl)-tetrahydropyran-3-yl)isoindoline-5-sulfonamide
((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-磺酰胺异吲哚啉-2-基)四氢吡喃-3-基)甲酸叔丁酯的二氯甲烷/甲醇(2/1)溶液在室温下搅拌反应一小时，检测反应完毕。反应液浓缩加乙酸乙酯稀释，过滤即得目标产物的三氟醋酸盐90mg。((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-sulfonamideisoindoline-2-yl)tetrahydropyran-3-yl)carboxylic acid tert-butyl The ester dichloromethane/methanol (2/1) solution was stirred at room temperature for one hour, and the reaction was completed. The reaction mixture was concentrated and diluted with ethyl acetate.
1H-NMR(400MHz，MeOD)：δ＝7.95-7.93(d，J＝8Hz，2H)，δ＝7.59-7.57(d，J＝8Hz，1H)，δ＝7.31(s，1H)，δ＝7.25-7.22(m，2H)，δ＝4.83-4.77(m，4H)，δ＝4.73-4.71(d，J＝8Hz，1H)，δ＝4.54-4.52(d，J＝8Hz，1H)，δ＝3.96-3.88(m，1H)，δ＝3.83-3.78(t，J＝12Hz，1H)，δ＝3.68-3.63(m，1H)，δ＝2.88-2.85(d，J＝12Hz，1H)，δ＝2.18-2.09(dd，J＝24，1H)1H-NMR (400MHz, MeOD): δ=7.95-7.93 (d, J=8Hz, 2H), δ=7.59-7.57 (d, J=8Hz, 1H), δ=7.31(s,1H),δ= 7.25-7.22 (m, 2H), δ = 4.83-4.77 (m, 4H), δ = 4.73-4.71 (d, J = 8 Hz, 1H), δ = 4.54-4.52 (d, J = 8 Hz, 1H), δ=3.96-3.88(m,1H),δ=3.83-3.78(t,J=12Hz,1H),δ=3.68-3.63(m,1H),δ=2.88-2.85(d,J=12Hz,1H ), δ=2.18-2.09 (dd, J=24, 1H)
MS m/z(ESI)：410.1(M+1)。MS m/z (ESI): 4121.
实施例31(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲基磺酰基)-2H-异吲哚Example 31 (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonyl)-2H-isoindole 啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐(化合物35’)Benzan-2-yl)tetrahydro-2H-pyran-3-amine dihydrochloride (compound 35')
Figure PCTCN2016000478-appb-000063
Figure PCTCN2016000478-appb-000063
第一步：((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲基磺酰基)-2H-异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯的合成First step: ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonyl)-2H-isoindol-2-yl)tetra Synthesis of tert-butyl hydrogen-2H-pyran-3-yl)carbamate
将((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲基磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯(2g，3.94mmol)，醋酸钯(88mg，0.394mmol)和环己烯(2.42g，19.7mmol)加入20ml DMF中。升温至110℃下搅拌过夜，LC-MS检测原料反应完全。过滤，固体分别用20ml无水甲醇洗涤，干燥，得到灰白色固体的标题化合物粗品 ((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲基磺酰基)-2H-异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯(2g)。MS m/z(ESI)：507.2(M+1)。((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-(methylsulfonyl)isoindolin-2-yl)tetrahydro-2H-pyran tert-Butyl 3-methyl)carbamate (2 g, 3.94 mmol), palladium acetate (88 mg, 0.394 mmol) and cyclohexene (2.42 g, 19.7 mmol) were added to 20 ml DMF. The mixture was heated to 110 ° C and stirred overnight, and the reaction of the starting material was confirmed by LC-MS. Filtration and washing with EtOAc (EtOAc) ((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-(methylsulfonyl)-2H-isoindol-2-yl)tetrahydro-2H- tert-Butyl pyran-3-yl)carbamate (2 g). MS m/z (ESI): 507.2 (M + 1).
第二步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲基磺酰基)-2H-异吲哚啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐的合成Second step: (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonyl)-2H-isoindol-2-yl)tetrahydro Synthesis of -2H-pyran-3-amine dihydrochloride
将((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲基磺酰基)-2H-异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯(2g)于冰浴下加入4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。直接减压浓缩至干，纯化得到白色固体的标题化合物(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲基磺酰基)-2H-异吲哚啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐(320mg)。1H NMR(400MHz，CD3OD)δ：7.93(s，1H)，7.87-7.85(m，2H)，7.28-7.23(m，2H)，6.89(s，1H)，6.46(s，2H)，5.10-5.02(m，1H)，4.84(br，1H)，4.44-4.39(m，1H)，4.05(m，1H)，3.80-3.74(m，1H)，2.86-2.83(m，1H)，2.48(m，1H)，3.33(s，3H).MS m/z(ESI)：407.2(M+1)。((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-(methylsulfonyl)-2H-isoindol-2-yl)tetrahydro-2H tert-Butyl pyran-3-yl)carbamate (2 g) was added to a 4 mol/L hydrochloric acid dioxane solution in an ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The title compound (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonyl)-2H- Porphyrin-2-yl)tetrahydro-2H-pyran-3-amine dihydrochloride (320 mg). 1 H NMR (400MHz, CD 3 OD) δ: 7.93 (s, 1H), 7.87-7.85 (m, 2H), 7.28-7.23 (m, 2H), 6.89 (s, 1H), 6.46 (s, 2H) , 5.10-5.02 (m, 1H), 4.84 (br, 1H), 4.44-4.39 (m, 1H), 4.05 (m, 1H), 3.80-3.74 (m, 1H), 2.86-2.83 (m, 1H) , 2.48 (m, 1H), 3.33 (s, 3H). MS m/z (ESI): 407.2 (M+1).
实施例32 2-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)Example 32 2-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl) 四氢-2H-吡喃-3-基)-N，N-二甲基氨磺酰-5-磺酰胺(化合物36)Tetrahydro-2H-pyran-3-yl)-N,N-dimethylsulfamoyl-5-sulfonamide (Compound 36)
Figure PCTCN2016000478-appb-000064
Figure PCTCN2016000478-appb-000064
第一步 叔丁基5-(N，N-二甲基氨磺酰)异吲哚啉-2-甲酸酯First step tert-butyl 5-(N,N-dimethylsulfamoyl)isoindoline-2-carboxylate
将叔丁基5-(氯磺酰)异吲哚啉-2-甲酸酯(0.7g，2.203mmol)于冰浴下滴加到盐酸二甲胺(1.79g，22.03mmol)和三乙胺(2.23g，22.03mmol)中，室温下反应三小时。过滤得黄色固体56omg固体，直接投下一步。tert-Butyl 5-(chlorosulfonyl)isoindoline-2-carboxylate (0.7 g, 2.203 mmol) was added dropwise to dimethylamine hydrochloride (1.79 g, 22.03 mmol) and triethylamine. (2.23 g, 22.03 mmol), the reaction was carried out for three hours at room temperature. A 56 um solid of yellow solid was filtered and taken directly to the next.
第二步 N，N-二甲基吲哚啉-5-磺酰胺Second step N,N-dimethyl porphyrin-5-sulfonamide
除了使用5-(N，N-二甲基氨磺酰异吲哚啉-2-羧酸酰叔丁酯代替5-甲基砜异吲哚啉，使5-(N，N-二甲基氨磺酰异吲哚啉-2-羧酸酰叔丁酯的投料量为0.312g之外，其它与操作同实施例26第二步同样操作，得到标题产物白色固体0.226g，收率为74.9％。 In addition to using 5-(N,N-dimethylsulfamoylisoindoline-2-carboxylic acid tert-butyl ester instead of 5-methylsulfone isoindoline, 5-(N,N-dimethyl) The same procedure as in the second step of Example 26 was carried out to give the title product as a white solid (yield: 74.9). %.
第三步 叔丁基((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(N，N-二甲基氨磺酰)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸酯The third step is tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(N,N-dimethylsulfamoyl)isoindoline- 2-yl)tetrahydro-2H-pyran-3-yl)carbamate
除了使用N，N-二甲基异吲哚啉-5-磺酰胺代替5-甲基砜异吲哚啉，使N，N-二甲基异吲哚啉-5-磺酰胺的投料量为0.226g之外，其它与操作实施例26第三步同样操作，得到标题产物白色固体187mg，收率为76.9％。MS m/z(ESI)：538.21[M+1]In addition to using N,N-dimethylisoindoline-5-sulfonamide instead of 5-methylsulfone isoindoline, the amount of N,N-dimethylisoindoline-5-sulfonamide is The same procedure as in the third step of Working Example 26 was afforded to give the title product 187 mg (yield: 76.9%). MS m/z (ESI): 538.21.[M+1]
第四步 2-((3R，5S，6R)-5-胺基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-N，N-二甲基氨磺酰-5-磺酰胺The fourth step 2-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N,N-dimethyl Sulfonamide-5-sulfonamide
除了使用叔丁基((2R，3S，5R)-2-(2-氟苯基)-5-(5-(N，N-二甲基氨磺酰)异吲哚啉-2-)四氢-2-吡喃3-基)氨基甲酸酯代替叔丁基((2R，3S，5R)-2-(2-氟苯基)-5-(5-(甲基砜)异吲哚啉-2-)四氢-2-吡喃3-基)氨基甲酸酯，使叔丁基((2R，3S，5R)-2-(2-氟苯基)-5-(5-(N，N-二甲基氨磺酰)异吲哚啉-2-)四氢-2-吡喃3-基)氨基甲酸酯为187mg之外，其它与操作同实施例26第四步同样操作，得到标题产物白色固体161mg，收率为72.3％。MS m/z(ESI)：438.21[M+1]In addition to the use of tert-butyl ((2R,3S,5R)-2-(2-fluorophenyl)-5-(5-(N,N-dimethylsulfamoyl)isoindoline-2-)tetra Hydrogen-2-pyran-3-yl)carbamate instead of tert-butyl ((2R,3S,5R)-2-(2-fluorophenyl)-5-(5-(methylsulfone)isoindole Porphyrin-2-)tetrahydro-2-pyran-3-yl)carbamate, tert-butyl((2R,3S,5R)-2-(2-fluorophenyl)-5-(5-( The N,N-dimethylsulfamoyl)isoindoline-2-)tetrahydro-2-pyran-3-yl)carbamate was 187 mg, and the operation was the same as the fourth step of Example 26 The title product was obtained as a white solid (yield: 161 g). MS m/z (ESI): 438.21 [M+1]
1H NMR(400MHz，CD3OD)δ：7.89(1H，s)，7.86-7.84(1H，m)，7.71-7.69(1H，m)，7.34(1H，m)，7.25-7.23(1H，m)，4.98(4H，m)，4.79-4.77(1H，m)，4.57-4.55(1H，m)，4.13(1H，m)，3.93(1H，m)，3.72(1H，m)，3.31(3H，s)，2.91(1H，m)，2.71(6H，s)，2.33-2.27(1H，m)， 1 H NMR (400MHz, CD 3 OD) δ: 7.89 (1H, s), 7.86-7.84 (1H, m), 7.71-7.69 (1H, m), 7.34 (1H, m), 7.25-7.23 (1H, m), 4.98 (4H, m), 4.79-4.77 (1H, m), 4.57-4.55 (1H, m), 4.13 (1H, m), 3.93 (1H, m), 3.72 (1H, m), 3.31 (3H, s), 2.91 (1H, m), 2.71 (6H, s), 2.33-2.27 (1H, m),
实施例33(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(异吲Example 33 (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(isoindole) 哚啉乙磺酰基)-2-基)四氢-2H-吡喃-3-胺(化合物37)Porphyrin Ethylsulfonyl)-2-yl)tetrahydro-2H-pyran-3-amine (Compound 37)
Figure PCTCN2016000478-appb-000065
Figure PCTCN2016000478-appb-000065
第一步 叔丁基((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(乙基砜)异吲哚啉-2-基)呋喃-2H-吡喃-3-基)氨基甲酸酯First step tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(ethylsulfone)isoindoline-2-yl)furan-2H -pyran-3-yl)carbamate
除了使用5-乙基砜异吲哚啉代替5-甲基砜异吲哚啉，使5-乙基砜异吲哚啉的投料量为1.1g之外，其它与操作同实施例27第三步同样操作，得到标题产物白色固体1.58g，收率为83.5％。Except that 5-ethylsulfone isoindolin was used instead of 5-methylsulfone isoporphyrin, the amount of 5-ethylsulfone isoindoline was 1.1 g, and the other operation was the same as in Example 27 The same procedure was carried out to give the title product as a white solid.
第二步 (2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(异吲哚啉 乙磺酰基)-2-基)四氢-2H-吡喃-3-胺Second step (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(isoporphyrin) Ethylsulfonyl)-2-yl)tetrahydro-2H-pyran-3-amine
除了使用叔丁基((2R，3S，5R)-2-(2-氟苯基)-5-(5-(乙基砜)异吲哚啉-2-)四氢-2-吡喃3-基)氨基甲酸酯代替叔丁基((2R，3S，5R)-2-(2-氟苯基)-5-(5-(甲基砜)异吲哚啉-2-)四氢-2-吡喃3-基)氨基甲酸酯，使5-乙基砜异吲哚啉的投料量为1.58g之外，其它与操作同实施例27第四步同样操作，得到标题产物白色固体643mg，收率为61.5％。In addition to the use of tert-butyl ((2R,3S,5R)-2-(2-fluorophenyl)-5-(5-(ethylsulfone)isoindoline-2-)tetrahydro-2-pyran 3 -yl)carbamate instead of tert-butyl ((2R,3S,5R)-2-(2-fluorophenyl)-5-(5-(methylsulfone)isoindoline-2-)tetrahydrol -2-pyran-3-yl)carbamate, except that the amount of 5-ethylsulfone isoindoline charged was 1.58 g, and the same operation as in the fourth step of Example 27 gave the title product white. The solid was 643 mg, and the yield was 61.5%.
MS m/z(ESI)：423.15[M+1]MS m/z (ESI): 423.15 [M+1]
1H NMR(400MHz，CD3OD)δ：8.02(1H，s)，8.00-7.98(1H，m)，7.74-7.72(1H，m)，7.35(1H，m)，7.25(1H，s)，5.01(4H，s)，4.77(1H，m)，4.58-4.56(1H，m)，4.14(1H，m)，3.96-3.94(1H，m)，3.68-3.62(1H，m)，3.26-3.24(2H，m)，2.91(1H，m)，2.30-2.27(1H，m)，1.25-1.22(3H，m)。 1 H NMR (400 MHz, CD 3 OD) δ: 8.02 (1H, s), 8.00-7.98 (1H, m), 7.74-7.72 (1H, m), 7.35 (1H, m), 7.25 (1H, s) , 5.01 (4H, s), 4.77 (1H, m), 4.58-4.56 (1H, m), 4.14 (1H, m), 3.96-3.94 (1H, m), 3.68-3.62 (1H, m), 3.26 - 3.24 (2H, m), 2.91 (1H, m), 2.30-2.27 (1H, m), 1.25-1.22 (3H, m).
实施例34(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲胺磺酰基)异吲哚啉-2-Example 34 (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-(methylaminesulfonyl)isoindoline-2- 基)四氢-2H-吡喃-3-胺二盐酸盐(化合物38’)Tetrahydro-2H-pyran-3-amine dihydrochloride (compound 38')
Figure PCTCN2016000478-appb-000066
Figure PCTCN2016000478-appb-000066
第一步：5-(苯甲硫基)异吲哚啉-2-碳酸叔丁酯的合成First step: synthesis of 5-(phenylthio)isoindoline-2-carbonate tert-butyl ester
将5-溴异吲哚啉-2-碳酸叔丁酯(4g，13.4mmol)，苄硫醇(1.82g，14.7mmol)，三(二亚苄基丙酮)二钯(306mg，0.33mmol)，4，5-双二苯基膦-9，9-二甲基氧杂蒽(390mg，0.67mmol)，N，N-二异丙基乙胺(4.6ml，26.8mmol)以及二氧六环(50ml)加入到反应瓶中。氮气环境下回流搅拌16h，TLC监测至原料反应完全。反应液经硅胶柱层析色谱分离纯化得到浅黄色油状物的标题化合物4.5g，98％。MS m/z(ESI)：342.1(M+1)。tert-Butyl 5-bromoisoindoline-2-carboxylate (4 g, 13.4 mmol), benzyl mercaptan (1.82 g, 14.7 mmol), tris(dibenzylideneacetone) dipalladium (306 mg, 0.33 mmol), 4,5-bisdiphenylphosphino-9,9-dimethyloxaxan (390 mg, 0.67 mmol), N,N-diisopropylethylamine (4.6 ml, 26.8 mmol) and dioxane ( 50 ml) was added to the reaction flask. The mixture was stirred under a nitrogen atmosphere for 16 h, and was subjected to TLC. The reaction mixture was purified to mjjjjjjjjj MS m/z (ESI): 3421. (M + 1).
第二步：5-(氯磺酰基)异吲哚啉-2-碳酸叔丁酯的合成Step 2: Synthesis of 5-(chlorosulfonyl)isoindoline-2-carbonate tert-butyl ester
将5-(苯甲硫基)异吲哚啉-2-碳酸叔丁酯(1g，2.93mmol)和N-氯代丁二酰亚胺(1.17g，8.8mmol)加入20ml乙酸与2.2ml水的混合液中。室温搅拌30min，TLC监测至原料反应完全。向反应液中加入水， 用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩至干，得到浅黄色油状物的标题化合物粗品1.4g。MS m/z(ESI)：318.1(M+1)。tert-Butyl 5-(benzylthio)isoindoline-2-carboxylate (1 g, 2.93 mmol) and N-chlorosuccinimide (1.17 g, 8.8 mmol) were added to 20 ml of acetic acid and 2.2 ml of water. In the mixture. After stirring at room temperature for 30 min, TLC was monitored until the starting material was completely reacted. Adding water to the reaction solution, The mixture was extracted with EtOAc EtOAc. MS m/z (ESI): 318.1 (M + 1).
第三步：5-(N-甲胺磺酰基)异吲哚啉-2-碳酸叔丁酯的合成Step 3: Synthesis of 5-(N-methylaminesulfonyl)isoindoline-2-carbonate tert-butyl ester
将5-(氯磺酰基)异吲哚啉-2-碳酸叔丁酯(700mg，1.46mmol)，甲胺盐酸盐(500mg，7.33mmol)和三乙胺(1.48g，14.65mmol)加入30ml二氯甲烷中。室温搅拌过夜，TLC监测至原料反应完全。反应液用水洗两次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩至干，得到浅黄色油状物的标题化合物粗品450mg。MS m/z(ESI)：313.1(M+1)。Add 5-(chlorosulfonyl)isoindoline-2-carbonate tert-butyl ester (700 mg, 1.46 mmol), methylamine hydrochloride (500 mg, 7.33 mmol) and triethylamine (1.48 g, 14.65 mmol) to 30 ml In dichloromethane. Stir at room temperature overnight and TLC was monitored until the starting material was completed. The reaction mixture was washed with EtOAc EtOAc. MS m/z (ESI): 31:21.
第四步：5-(N-甲胺磺酰基)异吲哚啉盐酸盐的合成Step 4: Synthesis of 5-(N-methylaminesulfonyl)isoindoline hydrochloride
将5-(N-甲胺磺酰基)异吲哚啉-2-碳酸叔丁酯粗品(450mg)于冰浴下加入15ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。直接浓缩反应液，得到灰白色固体的标题化合物300mg。MS m/z(ESI)：213.1(M+1)。The crude tert-butyl 5-(N-methylaminesulfonyl)isoindoline-2-carboxylate (450 mg) was added to a solution of &lt The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The reaction mixture was concentrated to give the title compound m. MS m/z (ESI): 21:21.
第五步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲胺磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯的合成The fifth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(5-(methylaminesulfonyl)isoindol-2-yl)tetrahydro-2H- Synthesis of tert-butyl pyran-3-yl)carbamate
将5-(N-甲胺磺酰基)异吲哚啉盐酸盐(300mg，1.2mmol)和N-[(2R，3S)-2-(2，5-二氟苯基)四氢-5-氧代-2H-吡喃-3-基]氨基甲酸叔丁酯(590mg，1.8mmol)加入6ml无水甲醇中。室温下搅拌1h后加入三乙酰氧基硼氢化钠(636mg，3mmol)，室温下反应1h后送LC-MS检测原料反应完全。过滤，固体用无水甲醇和无水乙醚洗涤，干燥，得到白色固体的标题化合物230mg，37％。MS m/z(ESI)：524.2(M+1)。5-(N-Methylaminesulfonyl)isoindoline hydrochloride (300 mg, 1.2 mmol) and N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5 -Oxo-2H-pyran-3-yl]carbamic acid tert-butyl ester (590 mg, 1.8 mmol) was added to 6 mL anhydrous methanol. After stirring at room temperature for 1 h, sodium triacetoxyborohydride (636 mg, 3 mmol) was added, and the mixture was reacted at room temperature for 1 hour, and then subjected to LC-MS to detect the reaction. Filtration and EtOAc (EtOAc)EtOAc. MS m/z (ESI): 524.2 (M + 1).
第六步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲胺磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐的合成The sixth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(5-(methylaminesulfonyl)isoindol-2-yl)tetrahydro-2H- Synthesis of pyran-3-amine dihydrochloride
将((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲胺磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯(230mg，0.44mmol)于冰浴下加入10ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。浓缩反应液，制备纯化得到白色固体的标题化合物50mg，23％。MS m/z(ESI)：424.2(M+1)。((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-(methylaminesulfonyl)isoindolin-2-yl)tetrahydro-2H-pyran tert-Butyl -3-yl)carbamate (230 mg, 0.44 mmol) was added to a solution of 10 ml of a 4 mol/L hydrochloric acid dioxane under ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The reaction mixture was concentrated to purified crystal crystal crystal crystal crystal crystal crystal MS m/z (ESI): 424.2 (M + 1).
1H NMR(400MHz，CD3OD)δ：7.93(s，1H)，7.92-7.90(d，J＝8Hz，1H)，7.67-7.65(d，J＝8Hz，1H)，7.36-7.32(m，1H)，7.27-7.24(m，2H)，4.97(s，4H)，4.79-4.77(d，J＝8Hz，1H)，4.58-4.55(m，1H)，4.17-4.10(m， 1H)，3.99-3.94(m，1H)，3.74-3.71(m，1H)，2.94-2.91(m，1H)，2.55(s，3H)，2.32-2.24(m，1H)。1H NMR (400MHz, CD3OD) δ: 7.93 (s, 1H), 7.92-7.90 (d, J = 8 Hz, 1H), 7.67-7.65 (d, J = 8 Hz, 1H), 7.36-7.32 (m, 1H) , 7.27-7.24 (m, 2H), 4.97 (s, 4H), 4.79-4.77 (d, J = 8 Hz, 1H), 4.58-4.55 (m, 1H), 4.17-4.10 (m, 1H), 3.99-3.94 (m, 1H), 3.74-3.71 (m, 1H), 2.94-2.91 (m, 1H), 2.55 (s, 3H), 2.32 - 2.24 (m, 1H).
实施例35(2R3S，5R)-5-(5-异吲哚啉(甲磺酰基)-2-基)-2-Example 35 (2R3S,5R)-5-(5-isoindoline (methanesulfonyl)-2-yl)-2- (2，4，5-三氟苯基)四氢-2H-吡喃-3-胺二盐酸盐(化合物39’)(2,4,5-trifluorophenyl)tetrahydro-2H-pyran-3-amine dihydrochloride (compound 39')
Figure PCTCN2016000478-appb-000067
Figure PCTCN2016000478-appb-000067
第一步 叔丁基(2R，3S，5R)-5-(5-(甲基磺酰基)异吲哚啉-2-基)-2-(2，4，5-三氟苯基)四氢-2H-吡喃-3-基)氨基甲酸酯First step tert-butyl(2R,3S,5R)-5-(5-(methylsulfonyl)isoindol-2-yl)-2-(2,4,5-trifluorophenyl)tetra Hydrogen-2H-pyran-3-yl)carbamate
除了使用叔丁基((2R，3S)-5-氧代-2-(2，4，5-三氟苯基)四氢-2-吡喃3-基)氨基甲酸酯代替叔丁基((2R，3S)-5-氧代-2-(2，5-二氟苯基)四氢-2-吡喃3-基)氨基甲酸酯，使叔丁基((2R，3S)-5-氧代-2-(2，4，5-三氟苯基)四氢-2-吡喃3-基)氨基甲酸酯的投料量为0.489g之外，其它与操作实施例27第三步同样操作，得到标题产物白色固体0.78g，收率为87.2％。In addition to the use of tert-butyl ((2R,3S)-5-oxo-2-(2,4,5-trifluorophenyl)tetrahydro-2-pyran-3-yl)carbamate in place of tert-butyl ((2R,3S)-5-oxo-2-(2,5-difluorophenyl)tetrahydro-2-pyran-3-yl)carbamate, tert-butyl ((2R,3S) The amount of -5-oxo-2-(2,4,5-trifluorophenyl)tetrahydro-2-pyran-3-yl)carbamate was 0.489 g, and the same operation example 27 The third step was carried out in the same manner to give the title product as a white solid (yield: 0.78 g).
第二步 (2R，3S，5R)-5-(5-异吲哚啉(甲磺酰基)-2-基)-2-(2，4，5-三氟苯基)四氢-2H-吡喃-3-胺二盐酸盐The second step (2R, 3S, 5R)-5-(5-isoporphyrin (methanesulfonyl)-2-yl)-2-(2,4,5-trifluorophenyl)tetrahydro-2H- Pyran-3-amine dihydrochloride
除了使用叔丁基((2R，3S，5R)-5-(5-(甲基磺酰基)异吲哚啉-2-基)-2-(2，4，5-三氟苯基)四氢-2-吡喃3-基)氨基甲酸酯代替叔丁基((2R，3S，5R)-5-(5-(甲基磺酰基)异吲哚啉-2-基)-2-(2，5-二氟苯基)四氢-2-吡喃3-基)氨基甲酸酯，使叔丁基((2R，3S，5R)-5-(5-(甲基磺酰基)异吲哚啉-2-基)-2-(2，4，5-三氟苯基)四氢-2-吡喃3-基)氨基甲酸酯的投料量为0.429g之外，其它与操作实施例27第四步同样操作，得到标题产物白色固体320mg，收率为77.3％。MS m/z(ESI)：427.12[M+1]In addition to the use of tert-butyl ((2R,3S,5R)-5-(5-(methylsulfonyl)isoindol-2-yl)-2-(2,4,5-trifluorophenyl)tetra Hydrogen-2-pyran-3-yl)carbamate in place of tert-butyl ((2R,3S,5R)-5-(5-(methylsulfonyl)isoindoline-2-yl)-2- (2,5-Difluorophenyl)tetrahydro-2-pyran-3-yl)carbamate, tert-butyl ((2R,3S,5R)-5-(5-(methylsulfonyl)) The isoxalin-2-yl)-2-(2,4,5-trifluorophenyl)tetrahydro-2-pyran-3-yl)carbamate was fed in an amount of 0.429 g, The same procedure as in the fourth step of Example 27 was afforded to give the title product as a white solid (yield: MS m/z (ESI): 427.12 [M+1]
1H NMR(400MHz，CD3OD)δ：8.06(1H，s)，8.03-8.01(1H，m)，7.70(1H，m)，7.58-7.54(1H，m)，7.33-7.29(1H，m)，5.02(4H，s)，4.77(1H，m)，4.57-4.55(1H，m)，4.18(1H，m)，3.95(1H，m)，3.73-3.71(1H，m)，3.17(3H，s)，3.00-2.93(1H，m)，2.36-2.27(1H，m)。 1 H NMR (400MHz, CD 3 OD) δ: 8.06 (1H, s), 8.03-8.01 (1H, m), 7.70 (1H, m), 7.58-7.54 (1H, m), 7.33-7.29 (1H, m), 5.02 (4H, s), 4.77 (1H, m), 4.57-4.55 (1H, m), 4.18 (1H, m), 3.95 (1H, m), 3.73-3.71 (1H, m), 3.17 (3H, s), 3.00-2.93 (1H, m), 2.36-2.27 (1H, m).
实施例36(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(异丙基磺酰基)异吲Example 36 (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(isopropylsulfonyl)isoindole 哚啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐(化合物40’)Porphyrin-2-yl)tetrahydro-2H-pyran-3-amine dihydrochloride (compound 40')
Figure PCTCN2016000478-appb-000068
Figure PCTCN2016000478-appb-000068
第一步：5-(异丙基磺酰基)异吲哚啉-2-碳酸叔丁酯的合成First step: Synthesis of 5-(isopropylsulfonyl)isoindoline-2-carbonate tert-butyl ester
将5-溴异吲哚啉-2-碳酸叔丁酯(1.2g，4mmol)，异丙基亚磺酸钠(1.59g，12mmol)，碘化亚铜(0.23g，1.2mmol)，L-脯氨酸钠(0.11g，0.8mmol)以及二甲基亚砜(20ml)加入到反应瓶中。反应液氮气环境下加热回流搅拌16h，TLC监测至原料反应完全。向反应液加入水，用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩至干，经柱层析分离纯化得到浅黄色油状物的标题化合物(1g，77％)。MS m/z(ESI)：326.1(M+1)(270)(M+1-56)。tert-Butyl 5-bromoisoindoline-2-carboxylate (1.2 g, 4 mmol), sodium isopropylsulfinate (1.59 g, 12 mmol), cuprous iodide (0.23 g, 1.2 mmol), L- Sodium proline (0.11 g, 0.8 mmol) and dimethyl sulfoxide (20 ml) were added to the reaction flask. The reaction solution was heated and refluxed under a nitrogen atmosphere for 16 h, and was subjected to TLC to the reaction mixture. Water was added to the reaction mixture, and the mixture was evaporated. %). MS m/z (ESI): 326.1 (M + 1) (270) (M+1 - 56).
第二步：5-(异丙基磺酰基)异吲哚啉盐酸盐的合成Step 2: Synthesis of 5-(isopropylsulfonyl)isoindoline hydrochloride
将5-(异丙基磺酰基)异吲哚啉-2-碳酸叔丁酯(1g，3.07mmol)于冰浴下加入15ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。直接旋干反应液，得到白色固体的标题化合物(740mg，95％)。MS m/z(ESI)：226.1(M+1)。tert-Butyl 5-(isopropylsulfonyl)isoindoline-2-carboxylate (1 g, 3.07 mmol) was added to 15 mL of a 4 mol/L aqueous solution of dioxane under ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The title compound (740 mg, 95%) MS m/z (ESI): 226.1 (M + 1).
第三步：((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(异丙基磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯的合成Third step: ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(isopropylsulfonyl)isoindol-2-yl)tetrahydro- Synthesis of tert-butyl 2H-pyran-3-yl)carbamate
将5-(异丙基磺酰基)异吲哚啉盐酸盐(740mg，2.84mmol)和N-[(2R，3S)-2-(2，5-二氟苯基)四氢-5-氧代-2H-吡喃-3-基]氨基甲酸叔丁酯(1.2g，3.68mmol)加入15ml无水甲醇中。于环境温度下搅拌1h后加入三乙酰氧基硼氢化钠(1.5g，7.1mmol)，室温下反应1h后送LC-MS检测原料反应完全。过滤，固体分别用无水甲醇和无水乙醚洗涤，干燥，得到白色固体的标题化合物(740mg，48％)。MS m/z(ESI)：537.2(M+1)。5-(Isopropylsulfonyl)isoindoline hydrochloride (740 mg, 2.84 mmol) and N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5- tert-Butyl oxo-2H-pyran-3-yl]carbamate (1.2 g, 3.68 mmol) was added to 15 mL anhydrous methanol. After stirring at ambient temperature for 1 h, sodium triacetoxyborohydride (1.5 g, 7.1 mmol) was added, and the mixture was reacted at room temperature for 1 hour, and then subjected to LC-MS to detect the reaction. The title compound (740 mg, 48%) elute MS m/z (ESI): 537.2 (M + 1).
第四步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(异丙基磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐的合成The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(5-(isopropylsulfonyl)isoindol-2-yl)tetrahydro-2H -Synthesis of pyran-3-amine dihydrochloride
将((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(异丙基磺酰基)异吲哚啉-2- 基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯(740mg，1.38mmol)于冰浴下加入20ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。直接旋干反应液，制备纯化得到白色固体的标题化合物(504mg，72％)。MS m/z(ESI)：437.2(M+1)。((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-(isopropylsulfonyl)isoindoline-2- tert-Butyl tetrahydro-2H-pyran-3-yl)carbamate (740 mg, 1.38 mmol) was added to a solution of 20 ml of a 4 mol/L hydrochloric acid dioxane in an ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The title compound (504 mg, 72%) MS m/z (ESI): 437.2 (M + 1).
1H NMR(400MHz，CD3OD)δ：7.99(s，1H)，7.96-7.94(d，J＝8Hz，1H)，7.73-7.71(d，J＝8Hz，1H)，7.36-7.33(m，1H)，7.26-7.23(m，2H)，5.02-5.00(d，J＝8Hz，4H)，4.79-4.77(d，J＝8Hz，1H)，4.58-4.55(m，1H)，4.19-4.11(m，1H)，3.99-3.94(m，1H)，3.74-3.68(m，1H)，3.41-3.33(m，1H)，2.94-2.91(m，1H)，2.33-2.25(m，1H)，1.27-1.25(d，J＝8Hz，6H)。1H NMR (400MHz, CD3OD) δ: 7.99 (s, 1H), 7.96-7.94 (d, J=8Hz, 1H), 7.73-7.71 (d, J=8Hz, 1H), 7.36-7.33 (m, 1H) , 7.26-7.23 (m, 2H), 5.02-5.00 (d, J = 8 Hz, 4H), 4.79 - 4.77 (d, J = 8 Hz, 1H), 4.58 - 4.55 (m, 1H), 4.19 - 4.11 (m , 1H), 3.99-3.94 (m, 1H), 3.74-3.68 (m, 1H), 3.41-3.33 (m, 1H), 2.94-2.91 (m, 1H), 2.33-2.25 (m, 1H), 1.27 -1.25 (d, J = 8 Hz, 6H).
实施例37(2R，3S，5R)-2-(2，4，5-三氟苯基)-5-(5-(乙基磺酰基)异吲哚Example 37 (2R,3S,5R)-2-(2,4,5-trifluorophenyl)-5-(5-(ethylsulfonyl)isoindole 啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐(化合物41’)Benzan-2-yl)tetrahydro-2H-pyran-3-amine dihydrochloride (compound 41')
Figure PCTCN2016000478-appb-000069
Figure PCTCN2016000478-appb-000069
第一步：5-(乙基磺酰基)异吲哚啉-2-碳酸叔丁酯的合成First step: Synthesis of 5-(ethylsulfonyl)isoindoline-2-carbonate tert-butyl ester
将5-溴异吲哚啉-2-碳酸叔丁酯(2.5g，8.4mmol)，异丙基亚磺酸钠(1.46g，12.6mmol)，碘化亚铜(0.48g，2.5mmol)，L-脯氨酸钠(0.35g，2.5mmol)以及二甲基亚砜(20ml)加入到反应瓶中。反应液氮气环境下加热回流搅拌16h，TLC监测至原料反应完全。向反应液加入水，用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩至干，经柱层析分离纯化得到浅黄色油状物的标题化合物(2g，76％)。MS m/z(ESI)：312.1(M+1)。tert-Butyl 5-bromoisoindoline-2-carboxylate (2.5 g, 8.4 mmol), sodium isopropylsulfinate (1.46 g, 12.6 mmol), cuprous iodide (0.48 g, 2.5 mmol), Sodium L-valine (0.35 g, 2.5 mmol) and dimethyl sulfoxide (20 ml) were added to the reaction flask. The reaction solution was heated and refluxed under a nitrogen atmosphere for 16 h, and was subjected to TLC to the reaction mixture. Water was added to the reaction mixture, and the mixture was evaporated. %). MS m/z (ESI): 3121. (M + 1).
第二步：5-(乙基磺酰基)异吲哚啉盐酸盐的合成Step 2: Synthesis of 5-(ethylsulfonyl)isoindoline hydrochloride
将5-(乙基磺酰基)异吲哚啉-2-碳酸叔丁酯(2g，6.4mmol)于冰浴下加入30ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。直接旋干反应液，得到白色固体的标题化合物(1.5g，94％)。MS m/z(ESI)：212.1(M+1)。tert-Butyl 5-(ethylsulfonyl)isoindoline-2-carbonate (2 g, 6.4 mmol) was added to 30 mL of a 4 mol/L aqueous solution of dioxane under ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The title compound (1.5 g, 94%) MS m/z (ESI): 2121. (M + 1).
第三步：((2R，3S，5R)-2-(2，4，5-三氟苯基)-5-(5-(乙基磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯的合成 Third step: ((2R,3S,5R)-2-(2,4,5-trifluorophenyl)-5-(5-(ethylsulfonyl)isoindoline-2-yl)tetrahydrogen Synthesis of tert-butyl-2H-pyran-3-yl)carbamate
将5-(乙基磺酰基)异吲哚啉盐酸盐(780mg，3.15mmol)和N-[(2R，3S)-2-(2，4，5-三氟苯基)四氢-5-氧代-2H-吡喃-3-基]氨基甲酸叔丁酯(1.4g，4.1mmol)加入10ml无水甲醇中。于室温下搅拌1h后加入三乙酰氧基硼氢化钠(1.7g，7.9mmol)，继续反应1h后送LC-MS检测原料反应完全。过滤，固体分别用无水甲醇和无水乙醚洗涤，干燥，得到白色固体的标题化合物(1.3g，76％)。MS m/z(ESI)：541.2(M+1)。5-(Ethylsulfonyl)isoindoline hydrochloride (780 mg, 3.15 mmol) and N-[(2R,3S)-2-(2,4,5-trifluorophenyl)tetrahydro-5 tert-Butyl oxo-2H-pyran-3-yl]carbamate (1.4 g, 4.1 mmol) was added to 10 mL anhydrous methanol. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (1.7 g, 7.9 mmol) was added, and the reaction was continued for 1 hour, and then the mixture was subjected to LC-MS to confirm the reaction. The title compound (1.3 g, 76%) elute MS m/z (ESI): 541.2 (M + 1).
第四步：(2R，3S，5R)-2-(2，4，5-三氟苯基)-5-(5-(乙基磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐的合成Fourth step: (2R, 3S, 5R)-2-(2,4,5-trifluorophenyl)-5-(5-(ethylsulfonyl)isoindol-2-yl)tetrahydro- Synthesis of 2H-pyran-3-amine dihydrochloride
将((2R，3S，5R)-2-(2，4，5-三氟苯基)-5-(5-(乙基磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯(1.3g，2.4mmol)于冰浴下加入20ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。直接旋干反应液，制备纯化得到白色固体的标题化合物(577mg，47％)。MS m/z(ESI)：441.2(M+1)。((2R,3S,5R)-2-(2,4,5-Trifluorophenyl)-5-(5-(ethylsulfonyl)isoindol-2-yl)tetrahydro-2H- tert-Butyl pyran-3-yl)carbamate (1.3 g, 2.4 mmol) was added to a solution of 4 mol/L hydrochloric acid dioxane in an ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The title compound (577 mg, 47%) MS m/z (ESI): 4421.
1H NMR(400MHz，CD3OD)δ：8.02(s，1H)，8.00-7.98(d，J＝8Hz，1H)，7.74-7.72(d，J＝8Hz，1H)，7.60-7.54(m，1H)，7.36-7.29(m，1H)，5.02-5.00(d，J＝8Hz，4H)，4.79-4.77(d，J＝8Hz，1H)，4.58-4.55(m，1H)，4.19-4.11(m，1H)，3.99-3.94(m，1H)，3.75-3.70(m，1H)，3.28-3.24(m，2H)，2.94-2.92(m，1H)，2.34-2.25(m，1H)，1.25-1.22(t，J＝8Hz，3H)。1H NMR (400MHz, CD3OD) δ: 8.02 (s, 1H), 8.00-7.98 (d, J=8Hz, 1H), 7.74-7.72 (d, J=8Hz, 1H), 7.60-7.54 (m, 1H) , 7.36-7.29 (m, 1H), 5.02-5.00 (d, J = 8 Hz, 4H), 4.79 - 4.77 (d, J = 8 Hz, 1H), 4.58 - 4.55 (m, 1H), 4.19 - 4.11 (m , 1H), 3.99-3.94 (m, 1H), 3.75-3.70 (m, 1H), 3.28-3.24 (m, 2H), 2.94 - 2.92 (m, 1H), 2.34 - 2.25 (m, 1H), 1.25 -1.22 (t, J = 8 Hz, 3H).
实施例38(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(异丙基胺基磺酰基)Example 38 (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-(isopropylaminosulfonyl) 异吲哚啉-2-基)四氧-2H-吡喃-3-胺二盐酸盐(化合物42’)Isoindol-2-yl)tetraoxo-2H-pyran-3-amine dihydrochloride (compound 42')
Figure PCTCN2016000478-appb-000070
Figure PCTCN2016000478-appb-000070
第一步：5-(氯磺酰基)异吲哚啉-2-碳酸叔丁酯的合成First step: Synthesis of 5-(chlorosulfonyl)isoindoline-2-carbonate tert-butyl ester
将5-(苯甲硫基)异吲哚啉-2-碳酸叔丁酯(600mg，1.76mmol)和N-氯代丁二酰亚胺(705mg，5.28mmol)加入15ml乙酸与1.6ml水的混合液中。氮气环境室温搅拌30min，TLC监测至原料反应完全。向反应液中加入50ml水，用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩至干，得到浅黄色油状物的标题化合物粗品 (800mg)。MS m/z(ESI)：318.1(M+1)。tert-Butyl 5-(benzylthio)isoindoline-2-carboxylate (600 mg, 1.76 mmol) and N-chlorosuccinimide (705 mg, 5.28 mmol) were added to 15 ml of acetic acid and 1.6 ml of water. In the mixture. The mixture was stirred at room temperature for 30 min under a nitrogen atmosphere, and was taken by TLC until the starting material was completely reacted. The reaction mixture was combined with 50 ml of EtOAc. (800mg). MS m/z (ESI): 318.1 (M + 1).
第二步：5-(异丙基胺基磺酰基)异吲哚啉-2-碳酸叔丁酯的合成Step 2: Synthesis of 5-(isopropylaminosulfonyl)isoindoline-2-carbonate tert-butyl ester
将5-(氯磺酰基)异吲哚啉-2-碳酸叔丁酯(800mg，1.8mmol)，异丙基胺(532mg，9mmol)和三乙胺(545mg，5.4mmol)加入30ml二氯甲烷中。室温搅拌过夜，TLC监测至原料反应完全。反应液用水洗两次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩至干，得到灰白色固体的标题化合物粗品(560mg)。MS m/z(ESI)：341.1(M+1)。tert-Butyl 5-(chlorosulfonyl)isoindoline-2-carboxylate (800 mg, 1.8 mmol), isopropylamine (532 mg, 9 mmol) and triethylamine (545 mg, 5.4 mmol) in. Stir at room temperature overnight and TLC was monitored until the starting material was completed. The reaction mixture was washed with EtOAc EtOAc. MS m/z (ESI): 341.1 (M + 1).
第三步：5-(异丙基胺基磺酰基)异吲哚啉盐酸盐的合成Step 3: Synthesis of 5-(isopropylaminosulfonyl)isoindoline hydrochloride
将5-(异丙基胺基磺酰基)异吲哚啉-2-碳酸叔丁酯粗品(560mg)于冰浴下加入15ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。过滤，固体用无水乙醚洗涤，得到灰白色固体的标题化合物(270mg)。MS m/z(ESI)：241.1(M+1)。The crude tert-butyl 5-(isopropylaminosulfonyl)isoindoline-2-carboxylate (560 mg) was added to a solution of 15 ml of a 4 mol/L hydrochloric acid dioxane under ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The title compound (270 mg) was obtained. MS m/z (ESI): 242.
第四步：((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(异丙基胺基磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯的合成Fourth step: ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(isopropylaminosulfonyl)isoindoline-2-yl)tetra Synthesis of tert-butyl hydrogen-2H-pyran-3-yl)carbamate
将5-(异丙基胺基磺酰基)异吲哚啉盐酸盐(270mg，1mmol)和N-[(2R，3S)-2-(2，5-二氟苯基)四氢-5-氧代-2H-吡喃-3-基]氨基甲酸叔丁酯(416mg，1.27mmol)加入6ml无水甲醇中。于环境温度下搅拌1h后加入三乙酰氧基硼氢化钠(530mg，2.5mmol)，继续反应1h后送LC-MS检测原料反应完全。过滤，固体用无水甲醇和无水乙醚洗涤，干燥，得到白色固体的标题化合物(500mg，90％)。MS m/z(ESI)：552.2(M+1)。5-(Isopropylaminosulfonyl)isoindoline hydrochloride (270 mg, 1 mmol) and N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5 tert-Butyl oxo-2H-pyran-3-yl]carbamate (416 mg, 1.27 mmol) was added to 6 mL anhydrous methanol. After stirring at ambient temperature for 1 h, sodium triacetoxyborohydride (530 mg, 2.5 mmol) was added, and the reaction was continued for 1 h, and then the mixture was subjected to LC-MS. The title compound (500 mg, EtOAc) MS m/z (ESI):552.
第五步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(异丙基胺基磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐的合成Step 5: (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-(isopropylaminosulfonyl)isoindoline-2-yl)tetrahydrogen Synthesis of -2H-pyran-3-amine dihydrochloride
将(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(异丙基胺基磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯(500mg，0.9mmol)于冰浴下加入10ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。直接旋干反应液，纯化得到白色固体的标题化合物(270mg，60％)。MS m/z(ESI)：452.2(M+1)。(2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-(isopropylaminosulfonyl)isoindol-2-yl)tetrahydro-2H- tert-Butyl pyran-3-yl)carbamate (500 mg, 0.9 mmol) was added to 10 ml of a 4 mol/L hydrochloric acid dioxane solution in an ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The title compound (270 mg, 60%) MS m/z (ESI): 4521.
1H NMR(400MHz，CD3OD)δ：7.95(s，1H)，7.94-7.92(d，J＝8Hz，1H)，7.65-7.63(d，J＝8Hz，1H)，7.36-7.33(m，1H)，7.26-7.23(m，2H)，4.97(s，4H)，4.79-4.77(d，J＝8Hz，1H)，4.57-4.54(m，1H)，4.17-4.11(m，1H)，3.98-3.93(m，1H)，3.76-3.68(m，1H)，3.42-3.35(m，1H)，2.94-2.92(m， 1H)，2.33-2.24(m，1H)，1.04-1.02(d，J＝8Hz，6H)。1H NMR (400MHz, CD3OD) δ: 7.95 (s, 1H), 7.94-7.92 (d, J=8Hz, 1H), 7.65-7.63 (d, J=8Hz, 1H), 7.36-7.33 (m, 1H) , 7.26-7.23 (m, 2H), 4.97 (s, 4H), 4.79-4.77 (d, J = 8 Hz, 1H), 4.57-4.54 (m, 1H), 4.17-4.11 (m, 1H), 3.98- 3.93 (m, 1H), 3.76-3.68 (m, 1H), 3.42-3.35 (m, 1H), 2.94-2.92 (m, 1H), 2.33 - 2.24 (m, 1H), 1.04-1.02 (d, J = 8 Hz, 6H).
实施例39 2-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3- 基)-N-(丙基甲酰胺)异吲哚-5-磺酰胺(化合物43) Example 39 2-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3 -yl)-N-(propylformamide Isoindole-5-sulfonamide (compound 43)
Figure PCTCN2016000478-appb-000071
Figure PCTCN2016000478-appb-000071
第一步 5-(N-(苯氧甲酰基)磺酰胺)异吲哚-2-甲酸叔丁酯First step 5-(N-(phenoxycarbonyl)sulfonamide)isoindole-2-carboxylic acid tert-butyl ester
冰浴下，将5-磺胺异吲哚-2-甲酸叔丁酯(0.584g，1.96mmol)溶于10mL乙腈中，然后加入0.57mL的三乙胺，将(0.367g，2.35mmol)的氯甲酸苯酯溶于2mL的乙腈中，再缓慢滴加至反应体系，反应完全后，反应液直接用于下一步反应。5-sulfonamide isoindole-2-carboxylic acid tert-butyl ester (0.584 g, 1.96 mmol) was dissolved in 10 mL of acetonitrile under ice-cooling, then 0.57 mL of triethylamine was added, (0.367 g, 2.35 mmol) of chlorine The phenyl formate was dissolved in 2 mL of acetonitrile and slowly added dropwise to the reaction system. After the reaction was completed, the reaction solution was directly used for the next reaction.
第二步 5-(N-(丙基甲酰胺)氨磺酰基)异吲哚-2-甲酸叔丁酯Step 2 5-(N-(propylformamide)sulfamoyl)isoindole-2-carboxylic acid tert-butyl ester
将第二步的反应液加热至45℃，然后加入1.5mL的正丙胺，反应2h后，将反应体系浓缩，柱层析纯化得到5-(N-(丙基甲酰胺)氨磺酰基)异吲哚-2-甲酸叔丁酯(0.375g，两步收率50％)。The reaction liquid of the second step was heated to 45 ° C, and then 1.5 mL of n-propylamine was added. After reacting for 2 hours, the reaction system was concentrated and purified by column chromatography to obtain 5-(N-(propylformamide)sulfamoyl) Tert-butyl phthalate-2-carboxylate (0.375 g, 50% yield in two steps).
第三步 N-(丙基甲酰胺)异吲哚-5-磺酰胺三氟乙酸盐The third step N-(propylformamide)isoindole-5-sulfonamide trifluoroacetate
室温下，将5-(N-(丙基甲酰胺)氨磺酰基)异吲哚-2-甲酸叔丁酯5-(N-(propylformamide)sulfamoyl)isoindole-2-carboxylic acid tert-butyl ester at room temperature
(0.375g，0.98mmol)和DCM/TFA(12mL/3mL)加入反应瓶中，搅拌30min后，浓缩，粗品直接用于下一步。(0.375 g, 0.98 mmol) and DCM/TFA (12 mL / 3 mL) were added to the reaction flask, stirred for 30 min, concentrated, and the crude was taken directly to the next.
第四步 ((1S，2R，5S)-2-(2，5-二氟苯基)-5-(5-(N-(丙基甲酰胺)磺酰胺)异吲哚-2-基)环己基)甲酸叔丁酯The fourth step ((1S, 2R, 5S)-2-(2,5-difluorophenyl)-5-(5-(N-(propylformamide)sulfonamide)isoindol-2-yl) Cyclohexyl)carboxylic acid tert-butyl ester
将第三步产物和((2R，3S)-2-(2，5-二氟苯基)-5-氧代四氢-2H-吡喃-3-基)甲酸叔丁酯(0.382g，1.17mmol)用THF/DMA(8mL/4mL)溶解，氩气环境下，60℃反应1h，冷却后，加入氰基硼氢化钠(0.307g，4.9mmol)后继续反应25min，反应液加入水淬灭反应，并用乙酸乙酯萃取，并用饱和食盐水洗涤。柱层析进行纯化得到325mg的粗品。 The third step product and ((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)carboxylic acid tert-butyl ester (0.382 g, 1.17 mmol) was dissolved in THF/DMA (8 mL / 4 mL), and reacted at 60 ° C for 1 h under argon. After cooling, sodium cyanoborohydride (0.307 g, 4.9 mmol) was added and the reaction was continued for 25 min. The reaction was quenched and extracted with ethyl acetate and brine. Purification by column chromatography gave 325 mg of crude material.
第五步 2-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-N-(丙基甲酰胺)异吲哚-5-磺酰胺Step 5 2-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-(propylformamide Iso-5-sulfonamide
将第四步得到的粗品(325mg)溶于4N的盐酸异丙酯溶液，室温搅拌2h，旋干，制备分离得到2-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-N-(丙基甲酰胺)异吲哚-5-磺酰胺87mg，白色固体)。The crude product (325 mg) obtained in the fourth step was dissolved in 4N isopropyl HCl solution, stirred at room temperature for 2 hr, and dried to give 2-((3R,5S,6R)-5-amino-6-(2, 5-Difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-(propylformamide)isoindole-5-sulfonamide 87 mg (white solid).
1H NMR(400MHz，CD3OD)δ：8.08(s，1H)，8.05(d，J＝8.0Hz，1H)，7.66(d，J＝8.0Hz，1H)，7.35-7.31(m，1H)，7.27-7.24(m，2H)，4.95(br，4H)，4.75(d，J＝10.0Hz，1H)，4.58-4.54(m，1H)，4.06(br，1H)，3.87(t，J＝7.2Hz，1H)，3.71-3.65(m，1H)，3.02(t，J＝6.8Hz，2H)，2.87(d，J＝12.0Hz，1H)，2.22-2.14(m，1H)，1.43(q，J＝6.8Hz，2H)，0.85(t，J＝7.2Hz，3H).MS m/z(ESI)：495.5(M+1)。 1 H NMR (400MHz, CD 3 OD) δ: 8.08 (s, 1H), 8.05 (d, J = 8.0Hz, 1H), 7.66 (d, J = 8.0Hz, 1H), 7.35-7.31 (m, 1H ), 7.27-7.24 (m, 2H), 4.95 (br, 4H), 4.75 (d, J = 10.0 Hz, 1H), 4.58-4.54 (m, 1H), 4.06 (br, 1H), 3.87 (t, J = 7.2 Hz, 1H), 3.71-3.65 (m, 1H), 3.02 (t, J = 6.8 Hz, 2H), 2.87 (d, J = 12.00 Hz, 1H), 2.22 - 2.14 (m, 1H), 1.43 (q, J = 6.8 Hz, 2H), 0.85 (t,J = 7.2 Hz, 3H). MS m/z (ESI): 495.5 (M+1).
实施例40(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(异丁烷磺酰基)异吲Example 40 (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(isobutanesulfonyl)isoindole 哚啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐(化合物44’)Porphyrin-2-yl)tetrahydro-2H-pyran-3-amine dihydrochloride (compound 44')
Figure PCTCN2016000478-appb-000072
Figure PCTCN2016000478-appb-000072
第一步：5-(异丁烷磺酰基)异吲哚啉-2-碳酸叔丁酯的合成First step: Synthesis of 5-(isobutanesulfonyl)isoindoline-2-carbonate tert-butyl ester
将5-溴异吲哚啉-2-碳酸叔丁酯(500mg，1.68mmol)，异丙基亚磺酸钠(725mg，5mmol)，碘化亚铜(96mg，0.5mmol)，L-脯氨酸钠(46mg，0.34mmol)以及二甲基亚砜(10ml)加入到反应瓶中。反应液氮气环境下加热至100℃搅拌16h，TLC监测至原料反应完全。向反应液加入水，用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩至干，经柱层析色谱分离纯化得到灰白色固体的标题化合物(269mg，47％)。MS m/z(ESI)：340.1(M+1)。tert-Butyl 5-bromoisoindoline-2-carboxylate (500 mg, 1.68 mmol), sodium isopropylsulfinate (725 mg, 5 mmol), cuprous iodide (96 mg, 0.5 mmol), L-decylamine Sodium (46 mg, 0.34 mmol) and dimethyl sulfoxide (10 ml) were added to the reaction flask. The reaction solution was heated to 100 ° C under nitrogen atmosphere and stirred for 16 h, and was monitored by TLC until the starting material was completely reacted. Water was added to the reaction mixture, and the mixture was evaporated. ). MS m/z (ESI): 340.1 (M + 1).
第二步：5-(异丁烷磺酰基)异吲哚啉盐酸盐的合成Step 2: Synthesis of 5-(isobutanesulfonyl)isoindoline hydrochloride
将5-(异丁烷磺酰基)异吲哚啉-2-碳酸叔丁酯(269mg，0.79mmol)于冰浴下加入15ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。直接浓缩反应液，得到灰白色固体的标题化合物 (196mg，90％)。MS m/z(ESI)：240.1(M+1)。tert-Butyl 5-(isobutanesulfonyl)isoindoline-2-carboxylate (269 mg, 0.79 mmol) was added to a solution of 15 ml of a 4 mol/L hydrochloric acid dioxane under ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The reaction mixture was concentrated directly to give the title compound (196 mg, 90%). MS m/z (ESI): 242.
第三步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(异丁烷磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯的合成The third step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(5-(isobutanesulfonyl)isoindoline-2-yl)tetrahydro-2H Synthesis of tert-butyl pyran-3-yl)carbamate
将5-(异丁烷磺酰基)异吲哚啉盐酸盐(196mg，0.71mmol)和N-[(2R，3S)-2-(2，5-二氟苯基)四氢-5-氧代-2H-吡喃-3-基]氨基甲酸叔丁酯(350mg，1.07mmol)加入8ml无水甲醇中。室温下搅拌1h后加入三乙酰氧基硼氢化钠(376mg，1.77mmol)，继续反应1h后送LC-MS检测原料反应完全。过滤，固体分别用无水甲醇和无水乙醚洗涤，干燥，得到灰白色固体的标题化合物(300mg，77％)。MS m/z(ESI)：551.2(M+1)。5-(Isobutanesulfonyl)isoindoline hydrochloride (196 mg, 0.71 mmol) and N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5- tert-Butyl oxo-2H-pyran-3-yl]carbamate (350 mg, 1.07 mmol) was taken in 8 mL anhydrous methanol. After stirring at room temperature for 1 h, sodium triacetoxyborohydride (376 mg, 1.77 mmol) was added, and the reaction was continued for 1 hour, and then the mixture was subjected to LC-MS. The title compound (300 mg, 77%) eluted elute MS m/z (ESI): 5521.
第四步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(异丁烷磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐的合成The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(5-(isobutanesulfonyl)isoindol-2-yl)tetrahydro-2H -Synthesis of pyran-3-amine dihydrochloride
将((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(异丁烷磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯(300mg，0.55mmol)于冰浴下加入10ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。过滤，固体用无水乙醚洗涤，干燥，得到白色固体的标题化合物(240mg，83％)。MS m/z(ESI)：437.2(M+1)。((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-(isobutanesulfonyl)isoindol-2-yl)tetrahydro-2H-pyridyl tert-Butyl benzyl-3-yl)carbamate (300 mg, 0.55 mmol) was added to a solution of 10 ml of a 4 mol/L hydrochloric acid dioxane in an ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The title compound (240 mg, EtOAc) MS m/z (ESI): 437.2 (M + 1).
1H NMR(400MHz，CD3OD)δ：8.03(s，1H)，8.01-7.99(d，J＝8Hz，1H)，7.73-7.71(d，J＝8Hz，1H)，7.37-7.33(m，1H)，7.27-7.23(m，2H)，5.00(s，4H)，4.79-4.77(d，J＝8Hz，1H)，4.59-4.54(m，1H)，4.17-4.10(m，1H)，3.99-3.93(t，J＝12Hz，1H)，3.74-3.68(m，1H)，3.17-3.16(d，J＝4Hz，2H)，2.95-2.89(m，1H)，2.33-2.24(m，1H)，2.19-2.12(m，1H)，1.07-1.05(d，J＝8Hz，6H)。1H NMR (400MHz, CD3OD) δ: 8.03 (s, 1H), 8.01-7.99 (d, J=8Hz, 1H), 7.73-7.71 (d, J=8Hz, 1H), 7.37-7.33 (m, 1H) , 7.27-7.23 (m, 2H), 5.00 (s, 4H), 4.79-4.77 (d, J = 8 Hz, 1H), 4.59-4.54 (m, 1H), 4.17-4.10 (m, 1H), 3.99- 3.93 (t, J = 12 Hz, 1H), 3.74 - 3.68 (m, 1H), 3.17 - 3.16 (d, J = 4 Hz, 2H), 2.95 - 2.89 (m, 1H), 2.33 - 2.24 (m, 1H) , 2.19-2.12 (m, 1H), 1.07-1.05 (d, J = 8 Hz, 6H).
实施例41(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(环丙烷磺酰基)异吲Example 41 (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(cyclopropanesulfonyl)isoindole 哚啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐(化合物45’)Porphyrin-2-yl)tetrahydro-2H-pyran-3-amine dihydrochloride (compound 45')
Figure PCTCN2016000478-appb-000073
Figure PCTCN2016000478-appb-000073
第一步：5-(环丙烷磺酰基)异吲哚啉-2-碳酸叔丁酯的合成First step: Synthesis of 5-(cyclopropanesulfonyl)isoindoline-2-carbonate tert-butyl ester
将5-溴异吲哚啉-2-碳酸叔丁酯(400mg，1.34mmol)，环丙烷亚磺酸钠(223g，1.74mmol)，碘化亚铜(77mg，0.4mmol)，L-脯氨酸钠(37mg，0.27mmol)以及二甲基亚砜(10ml)加入到反应瓶中。反应液氮气环境下加热至100℃搅拌16h，TLC监测至原料反应完全。向反应液加入水，用乙酸乙酯萃取)，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩至干，经柱层析分离纯化得到棕色油状物的标题化合物(220mg，50％)。MS m/z(ESI)：324.1(M+1)。tert-Butyl 5-bromoisoindoline-2-carboxylate (400 mg, 1.34 mmol), sodium cyclopropanesulfinate (223 g, 1.74 mmol), cuprous iodide (77 mg, 0.4 mmol), L-ammonia Sodium (37 mg, 0.27 mmol) and dimethyl sulfoxide (10 ml) were added to the reaction flask. The reaction solution was heated to 100 ° C under nitrogen atmosphere and stirred for 16 h, and was monitored by TLC until the starting material was completely reacted. Water was added to the reaction mixture, and the mixture was evaporated. %). MS m/z (ESI): 324.1 (M + 1).
第二步：5-(环丙烷磺酰基)异吲哚啉盐酸盐的合成Step 2: Synthesis of 5-(cyclopropanesulfonyl)isoindoline hydrochloride
将5-(环丙烷磺酰基)异吲哚啉-2-碳酸叔丁酯(220mg，0.68mmol)于冰浴下加入15ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。反应液浓缩得到灰白色固体的标题化合物(150mg，85％)。MS m/z(ESI)：224.1(M+1)。tert-Butyl 5-(cyclopropanesulfonyl)isoindoline-2-carboxylate (220 mg, 0.68 mmol) was added to a solution of &lt The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The reaction mixture was concentrated to give crystall MS m/z (ESI): 224.1 (M + 1).
第三步：((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(环丙烷磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯的合成Third step: ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(cyclopropanesulfonyl)isoindoline-2-yl)tetrahydro-2H Synthesis of tert-butyl pyran-3-yl)carbamate
将5-(环丙烷磺酰基)异吲哚啉盐酸盐(150mg，0.58mmol)和N-[(2R，3S)-2-(2，5-二氟苯基)四氢-5-氧代-2H-吡喃-3-基]氨基甲酸叔丁酯(284mg，0.87mmol)加入6ml无水甲醇中。室温下搅拌1h后加入三乙酰氧基硼氢化钠(307mg，1.45mmol)继续反应1h后送LC-MS检测原料反应完全。过滤，固体分别用无水甲醇和无水乙醚洗涤，干燥，得到灰白色固体的标题化合物(220mg，71％)。MS m/z(ESI)：535.2(M+1)。5-(cyclopropanesulfonyl)isoindoline hydrochloride (150 mg, 0.58 mmol) and N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5-oxo tert-Butyl-2H-pyran-3-yl]carbamate (284 mg, 0.87 mmol) was added to 6 mL anhydrous methanol. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (307 mg, 1.45 mmol) was added to continue the reaction for 1 hour, and then the mixture was subjected to LC-MS to confirm the reaction. The title compound (220 mg, 71%) elute MS m/z (ESI): 535.2 (M + 1).
第四步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(环丙烷磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐的合成The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(5-(cyclopropanesulfonyl)isoindol-2-yl)tetrahydro-2H- Synthesis of pyran-3-amine dihydrochloride
将((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(环丙烷磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯(220mg，0.41mmol)于冰浴下加入10ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。过滤，固体用无水乙醚洗涤，得到白色固体的标题化合物(151mg，73％)。MS m/z(ESI)：435.2(M+1)。((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-(cyclopropanesulfonyl)isoindolin-2-yl)tetrahydro-2H-pyran tert-Butyl -3-yl)carbamate (220 mg, 0.41 mmol) was added to a solution of 10 ml of a 4 mol/L hydrochloric acid dioxane in an ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The title compound ( 151 mg, EtOAc) MS m/z (ESI): 435.2 (M + 1).
1H NMR(400MHz，CD3OD)δ：8.02(s，1H)，8.00-7.98(d，J＝8Hz，1H)，7.72-7.70(d，J＝8Hz，1H)，7.35-7.33(m，1H)，7.27-7.24(m，2H)，5.00(s，4H)，4.79-4.77(d，J＝8Hz，1H)，4.58-4.55(m，1H)， 4.18-4.13(m，1H)，3.99-3.94(m，1H)，3.75-3.68(m，1H)，2.94-2.91(m，1H)，2.76-2.70(m，1H)，2.31-2.28(m，1H)，1.29-1.25(m，2H)，1.10-1.08(m，2H)。1H NMR (400MHz, CD3OD) δ: 8.02 (s, 1H), 8.00-7.98 (d, J = 8 Hz, 1H), 7.72-7.70 (d, J = 8 Hz, 1H), 7.35-7.33 (m, 1H) , 7.27-7.24 (m, 2H), 5.00 (s, 4H), 4.79-4.77 (d, J = 8 Hz, 1H), 4.58-4.55 (m, 1H), 4.18-4.13(m,1H), 3.99-3.94(m,1H), 3.75-3.68(m,1H),2.94-2.91(m,1H), 2.76-2.70(m,1H),2.31-2.28(m , 1H), 1.29-1.25 (m, 2H), 1.10-1.08 (m, 2H).
实施例42(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(胍基磺酰基)异吲哚Example 42 (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(indolylsulfonyl)isoindole 啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐(化合物46’)Benzin-2-yl)tetrahydro-2H-pyran-3-amine dihydrochloride (compound 46')
Figure PCTCN2016000478-appb-000074
Figure PCTCN2016000478-appb-000074
第一步：5-(氯磺酰基)异吲哚啉-2-碳酸叔丁酯的合成First step: Synthesis of 5-(chlorosulfonyl)isoindoline-2-carbonate tert-butyl ester
将5-(苯甲硫基)异吲哚啉-2-碳酸叔丁酯(1g，2.93mmol)和N-氯代丁二酰亚胺(1.174g，8.8mmol)加入20ml乙酸与2ml水的混合液中。氮气环境下室温搅拌30min，TLC监测至原料反应完全。向反应液中加入水，用乙酸乙酯萃取三次，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩至干，得到浅黄色油状物的标题化合物粗品(1.6g)。MS m/z(ESI)：318.1(M+1)。tert-Butyl 5-(benzylthio)isoindoline-2-carboxylate (1 g, 2.93 mmol) and N-chlorosuccinimide (1.174 g, 8.8 mmol) were added to 20 ml of acetic acid and 2 ml of water. In the mixture. Stir at room temperature for 30 min under nitrogen, and the mixture was monitored by TLC until the starting material was completely reacted. Water was added to the reaction mixture, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ MS m/z (ESI): 318.1 (M + 1).
第二步：5-(胍基磺酰基)异吲哚啉-2-碳酸叔丁酯的合成Step 2: Synthesis of 5-(decylsulfonyl)isoindoline-2-carbonate tert-butyl ester
将5-(氯磺酰基)异吲哚啉-2-碳酸叔丁酯(1.6g)，盐酸胍(1.96g，20.5mmol)和碳酸钾(4g，29.3mmol)加入20mlTHF/10mlH2O中。室温搅拌过夜，TLC监测至原料反应完全。反应液中加入50ml水，用乙酸乙酯萃取三次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩至干，柱纯化(MeOH/DCM＝0-5％)得到白色固体的标题化合物(210mg)。MS m/z(ESI)：341.1(M+1)。tert-Butyl 5-(chlorosulfonyl)isoindoline-2-carboxylate (1.6 g), hydrazine hydrochloride (1.96 g, 20.5 mmol) and potassium carbonate (4 g, 29.3 mmol) were added to 20 ml of THF / 10 ml of H 2 O. Stir at room temperature overnight and TLC was monitored until the starting material was completed. 50 ml of water was added to the reaction mixture, and the mixture was evaporated. (210 mg). MS m/z (ESI): 341.1 (M + 1).
第三步：5-(胍基磺酰基)异吲哚啉盐酸盐的合成Step 3: Synthesis of 5-(indolylsulfonyl)isoindoline hydrochloride
将5-(胍基磺酰基)异吲哚啉-2-碳酸叔丁酯(210mg，0.62mmol)于冰浴下加入15ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。过滤，固体用无水乙醚洗涤，得到灰白色固体的标题化合物(150mg，77％)。MS m/z(ESI)：241.1(M+1)。tert-Butyl 5-(decylsulfonyl)isoindoline-2-carboxylate (210 mg, 0.62 mmol) was added to a solution of &lt The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The title compound (150 mg, 77%) MS m/z (ESI): 242.
第四步：((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(胍基磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯的合成 Fourth step: ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(indolylsulfonyl)isoindoline-2-yl)tetrahydro-2H Synthesis of tert-butyl pyran-3-yl)carbamate
将5-(胍基磺酰基)异吲哚啉盐酸盐(150mg，0.48mmol)和N-[(2R，3S)-2-(2，5-二氟苯基)四氢-5-氧代-2H-吡喃-3-基]氨基甲酸叔丁酯(218mg，0.66mmol)加入6ml无水甲醇中。室温下搅拌1h后加入三乙酰氧基硼氢化钠(270mg，1.28mmol)，反应1h后送LC-MS检测原料反应完全。反应液减压浓缩后加入20ml水，用乙酸乙酯萃取三次，合并有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，得到灰色固体的标题化合物粗品(560mg)。MS m/z(ESI)：552.2(M+1)。5-(indolylsulfonyl)isoindoline hydrochloride (150 mg, 0.48 mmol) and N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5-oxo tert-Butyl-2H-pyran-3-yl]carbamate (218 mg, 0.66 mmol) was added to 6 mL anhydrous methanol. After stirring at room temperature for 1 h, sodium triacetoxyborohydride (270 mg, 1.28 mmol) was added. After 1 h of reaction, the mixture was subjected to LC-MS to confirm the reaction. The reaction mixture was concentrated under reduced pressure. EtOAc EtOAc. MS m/z (ESI):552.
第五步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(胍基磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐的合成Step 5: (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-(indolylsulfonyl)isoindol-2-yl)tetrahydro-2H- Synthesis of pyran-3-amine dihydrochloride
将((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(胍基磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯(560mg)于冰浴下加入10ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。反应液浓缩纯化得到白色固体的标题化合物(50mg)。MS m/z(ESI)：452.2(M+1)。((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-(indolylsulfonyl)isoindol-2-yl)tetrahydro-2H-pyran tert-Butyl -3-yl)carbamate (560 mg) was added to 10 ml of a 4 mol/L hydrochloric acid dioxane solution in an ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The reaction mixture was concentrated to purified crystal crystal crystal crystal crystal MS m/z (ESI): 4521.
1H NMR(400MHz，CD3OD)δ：8.42(s，1H)，7.78(s，1H)，7.78-7.76(d，J＝8Hz，1H)，7.41-7.39(d，J＝8Hz，1H)，7.32-7.28(m，1H)，7.25-7.18(m，2H)，4.56-4.54(d，J＝8Hz，1H)，4.38-4.34(m，1H)，4.00(s，4H)，4.51-3.39(m，2H)，3.08-3.01(m，1H)，2.63-2.60(m，1H)，1.75-1.66(m，1H)。1H NMR (400MHz, CD3OD) δ: 8.42 (s, 1H), 7.78 (s, 1H), 7.78-7.76 (d, J = 8 Hz, 1H), 7.41-7.39 (d, J = 8 Hz, 1H), 7.32 -7.28 (m, 1H), 7.25-7.18 (m, 2H), 4.56-4.54 (d, J = 8 Hz, 1H), 4.38-4.34 (m, 1H), 4.00 (s, 4H), 4.51-3.39 ( m, 2H), 3.08-3.01 (m, 1H), 2.63-2.60 (m, 1H), 1.75-1.66 (m, 1H).
实施例43(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(异丁烷磺酰基)异吲Example 43 (2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-(isobutanesulfonyl)isoindole 哚啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐(化合物47’)Porphyrin-2-yl)tetrahydro-2H-pyran-3-amine dihydrochloride (compound 47')
Figure PCTCN2016000478-appb-000075
Figure PCTCN2016000478-appb-000075
第一步：5-(甲基磺酰胺基)异吲哚啉-2-碳酸叔丁酯的合成First step: Synthesis of 5-(methylsulfonylamino)isoindoline-2-carbonate tert-butyl ester
将5-溴异吲哚啉-2-碳酸叔丁酯(600mg，2mmol)，甲基磺酰胺(383mg，4mmol)，碘化亚铜(76mg，0.4mmol)，7水磷酸钾(1.69g，5mmol)，二甲氨基乙酸(41mg，0.4mmol)以及二甲基亚砜(15 ml)加入到100ml反应瓶中。反应液氮气环境下加热至150℃搅拌48h，TLC监测至原料反应完全。向反应液加入水，用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩至干，经柱层析分离纯化得到淡黄色油状物的标题化合物(420mg，67％)。MS m/z(ESI)：313.1(M+1)。tert-Butyl 5-bromoisoindoline-2-carboxylate (600 mg, 2 mmol), methanesulfonamide (383 mg, 4 mmol), cuprous iodide (76 mg, 0.4 mmol), potassium sulphate (1.69 g, 5 mmol), dimethylaminoacetic acid (41 mg, 0.4 mmol) and dimethyl sulfoxide (15 Ml) was added to a 100 ml reaction flask. The reaction solution was heated to 150 ° C under a nitrogen atmosphere for 48 h, and was monitored by TLC until the starting material was completely reacted. Water was added to the reaction mixture, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ %). MS m/z (ESI): 31:21.
第二步：5-(甲基磺酰胺基)异吲哚啉盐酸盐的合成Step 2: Synthesis of 5-(methylsulfonylamino)isoindoline hydrochloride
将5-(甲基磺酰胺基)异吲哚啉-2-碳酸叔丁酯(420mg，1.35mmol)于冰浴下加入15ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。过滤，固体用无水乙醚洗涤，得到灰白色固体的标题化合物(260mg，78％)。MS m/z(ESI)：213.1(M+1)。tert-Butyl 5-(methylsulfonamido)isoindoline-2-carbonate (420 mg, 1.35 mmol) was added to a solution of 15 ml of a 4 mol/L hydrochloric acid dioxane in an ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The title compound (260 mg, 78%). MS m/z (ESI): 21:21.
第三步：((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(异丁烷磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯的合成Third step: ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(isobutanesulfonyl)isoindoline-2-yl)tetrahydro- Synthesis of tert-butyl 2H-pyran-3-yl)carbamate
将5-(甲基磺酰胺基)异吲哚啉盐酸盐(260mg，1.05mmol)和N-[(2R，3S)-2-(2，5-二氟苯基)四氢-5-氧代-2H-吡喃-3-基]氨基甲酸叔丁酯(515mg，1.57mmol)加入8ml无水甲醇中。室温下搅拌1h后加入三乙酰氧基硼氢化钠(530mg，2.5mmol)，室温下搅拌1h后送LC-MS检测原料反应完全。过滤，固体分别用无水甲醇和无水乙醚洗涤，干燥，得到灰白色固体的标题化合物(500mg，95％)。MS m/z(ESI)：524.2(M+1)。5-(Methylsulfonylamino)isoindoline hydrochloride (260 mg, 1.05 mmol) and N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5- tert-Butyl oxo-2H-pyran-3-yl]carbamate (515 mg, 1.57 mmol) was added to 8 mL anhydrous methanol. After stirring at room temperature for 1 h, sodium triacetoxyborohydride (530 mg, 2.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour, and then subjected to LC-MS. The title compound (500 mg, 95%) eluted elute MS m/z (ESI): 524.2 (M + 1).
第四步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲基磺酰胺基)异吲哚啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐的合成Fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(5-(methylsulfonamido)isoindol-2-yl)tetrahydro-2H -Synthesis of pyran-3-amine dihydrochloride
将((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(甲基磺酰胺基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯(500mg，0.96mmol)于冰浴下加入10ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。滤液浓缩后制备纯化得到白色固体的标题化合物(195mg，41％)。MS m/z(ESI)：424.2(M+1)。((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-(methylsulfonamido)isoindol-2-yl)tetrahydro-2H-pyridyl tert-Butyl benzyl-3-yl)carbamate (500 mg, 0.96 mmol) was added to a solution of 4 ml of a 4 mol/L hydrochloric acid dioxane in an ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The title compound (195 mg, 41%) MS m/z (ESI): 424.2 (M + 1).
1H NMR(400MHz，CD3OD)δ：7.42-7.40(d，J＝8Hz，1H)，7.39(s，1H)，7.35-7.31(m，1H)，7.29-7.27(m，1H)，7.26-7.24(m，2H)，4.88-4.79(m，4H)，4.76-4.74(d，J＝8Hz，1H)，4.58-4.54(m，1H)，4.03-3.97(m，1H)，3.86-3.81(m，1H)，3.71-3.64(m，1H)，3.01(s，3H)，2.91-2.88(m，1H)，2.22-2.13(m，1H)。1H NMR (400MHz, CD3OD) δ: 7.42-7.40 (d, J=8Hz, 1H), 7.39 (s, 1H), 7.35-7.31 (m, 1H), 7.29-7.27 (m, 1H), 7.26-7.24 (m, 2H), 4.88-4.79 (m, 4H), 4.76-4.74 (d, J = 8 Hz, 1H), 4.58-4.54 (m, 1H), 4.03-3.97 (m, 1H), 3.86-3.81 ( m, 1H), 3.71-3.64 (m, 1H), 3.01 (s, 3H), 2.91-2.88 (m, 1H), 2.22 - 2.13 (m, 1H).
实施例44(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(仲丁基磺酰基)异吲Example 44 (2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(sec-butylsulfonyl)isoindole 哚啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐(化合物48’)Porphyrin-2-yl)tetrahydro-2H-pyran-3-amine dihydrochloride (compound 48')
Figure PCTCN2016000478-appb-000076
Figure PCTCN2016000478-appb-000076
第一步：5-(仲丁基磺酰基)异吲哚啉-2-碳酸叔丁酯的合成First step: Synthesis of 5-(sec-butylsulfonyl)isoindoline-2-carbonate tert-butyl ester
将5-溴异吲哚啉-2-碳酸叔丁酯(700mg，2.35mmol)，异丙基亚磺酸钠(1g，7mmol)，碘化亚铜(134mg，0.7mmol)，L-脯氨酸钠(64mg，0.5mmol)以及二甲基亚砜(10ml)加入到100ml反应瓶中。反应液在氮气环境下加热至100℃搅拌16h，TLC监测至原料反应完全。向反应液加入水，用乙酸乙酯萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩至干，经柱层析色谱分离纯化得到棕色油状物的标题化合物(500mg，63％)。MS m/z(ESI)：340.1(M+1)。tert-Butyl 5-bromoisoindoline-2-carboxylate (700 mg, 2.35 mmol), sodium isopropylsulfinate (1 g, 7 mmol), cuprous iodide (134 mg, 0.7 mmol), L-decylamine Sodium (64 mg, 0.5 mmol) and dimethyl sulfoxide (10 ml) were added to a 100 ml reaction flask. The reaction solution was heated to 100 ° C under nitrogen atmosphere and stirred for 16 h. Water was added to the reaction mixture, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ %). MS m/z (ESI): 340.1 (M + 1).
第二步：5-(仲丁基磺酰基)异吲哚啉盐酸盐的合成Step 2: Synthesis of 5-(sec-butylsulfonyl)isoindoline hydrochloride
将5-(仲丁基磺酰基)异吲哚啉-2-碳酸叔丁酯(500mg，1.47mmol)于冰浴下加入15ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。反应液浓缩得到灰白色固体的标题化合物(450mg，100％)。MS m/z(ESI)：240.1(M+1)。tert-Butyl 5-(sec-butylsulfonyl)isoindoline-2-carbonate (500 mg, 1.47 mmol) was added to a solution of 15 ml of a 4 mol/L hydrochloric acid dioxane in an ice bath. The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The reaction mixture was concentrated to give crystall MS m/z (ESI): 242.
第三步：((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(仲丁基磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯的合成Third step: ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(5-(sec-butylsulfonyl)isoindol-2-yl)tetrahydro- Synthesis of tert-butyl 2H-pyran-3-yl)carbamate
将5-(仲丁基磺酰基)异吲哚啉盐酸盐(450mg，1.47mmol)和N-[(2R，3S)-2-(2，5-二氟苯基)四氢-5-氧代-2H-吡喃-3-基]氨基甲酸叔丁酯(800mg，2.4mmol)加入10ml无水甲醇中室温下搅拌1h后加入三乙酰氧基硼氢化钠(847mg，4mmol)继续反应1h后送LC-MS检测原料反应完全。过滤，固体分别用无水甲醇和无水乙醚洗涤，干燥，得到灰白色固体的标题化合物(400mg，49％)。MS m/z(ESI)：551.2(M+1)。5-(sec-butylsulfonyl)isoindoline hydrochloride (450 mg, 1.47 mmol) and N-[(2R,3S)-2-(2,5-difluorophenyl)tetrahydro-5- tert-Butyl oxo-2H-pyran-3-yl]carbamate (800 mg, 2.4 mmol) was added to 10 ml of anhydrous methanol and stirred at room temperature for 1 h, then sodium triacetoxyborohydride (847 mg, 4 mmol) was added and the reaction was continued for 1 h. The LC-MS was sent to the reaction to detect the completion of the reaction. The title compound (400 mg, 49%) eluted elute MS m/z (ESI): 5521.
第四步：(2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(仲丁基磺酰基)异吲哚 啉-2-基)四氢-2H-吡喃-3-胺二盐酸盐的合成The fourth step: (2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(5-(sec-butylsulfonyl)isoindole Synthesis of oxa-2-yl)tetrahydro-2H-pyran-3-amine dihydrochloride
将((2R，3S，5R)-2-(2，5-二氟苯基)-5-(5-(仲丁基磺酰基)异吲哚啉-2-基)四氢-2H-吡喃-3-基)氨基甲酸叔丁酯(400mg，0.72mmol)于冰浴下加入20ml 4mol/L盐酸二氧六环溶液中。室温反应1h，LC-MS检测原料反应完全。直接旋干反应液，制备纯化得到白色固体的标题化合物(189mg，50％)。MS m/z(ESI)：437.2(M+1)。((2R,3S,5R)-2-(2,5-Difluorophenyl)-5-(5-(sec-butylsulfonyl)isoindol-2-yl)tetrahydro-2H-pyridyl tert-Butyl benzyl-3-yl)carbamate (400 mg, 0.72 mmol) was added to a solution of &lt The reaction was carried out for 1 h at room temperature, and the reaction of the starting material was confirmed by LC-MS. The title compound (189 mg, 50%) was obtained. MS m/z (ESI): 437.2 (M + 1).
1H NMR(400MHz，CD3OD)δ：8.00(s，1H)，7.98-7.96(d，J＝8Hz，1H)，7.75-7.73(d，J＝8Hz，1H)，7.38-7.35(m，1H)，7.28-7.25(m，2H)，4.99(s，4H)，4.81-4.79(d，J＝8Hz，1H)，4.59-4.57(m，1H)，4.14-4.09(m，1H)，3.99-3.94(m，1H)，3.77-3.74(m，1H)，3.22-3.16(m，1H)，2.95-2.92(m，1H)，2.33-2.24(m，1H)，2.00-1.93(m，1H)，1.50-1.42(m，1H)，1.28-1.26(d，J＝8Hz，1H)，1.04-1.00(t，J＝8Hz，3H)。1H NMR (400MHz, CD3OD) δ: 8.00 (s, 1H), 7.98-7.96 (d, J = 8 Hz, 1H), 7.75-7.73 (d, J = 8 Hz, 1H), 7.38-7.35 (m, 1H) , 7.28-7.25 (m, 2H), 4.99 (s, 4H), 4.81-4.79 (d, J = 8 Hz, 1H), 4.59-4.57 (m, 1H), 4.14 - 4.09 (m, 1H), 3.99- 3.94 (m, 1H), 3.77-3.74 (m, 1H), 3.22-3.16 (m, 1H), 2.95-2.92 (m, 1H), 2.33-2.24 (m, 1H), 2.00-1.93 (m, 1H) ), 1.50-1.42 (m, 1H), 1.28-1.26 (d, J = 8 Hz, 1H), 1.04-1.00 (t, J = 8 Hz, 3H).
实施例45 6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-Example 45 6-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3- 基)-N-(N-甲基胍基)-6H-吡咯并[3，4-d]嘧啶-2-磺酰胺三氟乙酸盐(化合-N-(N-methylindolyl)-6H-pyrrolo[3,4-d]pyrimidine-2-sulfonamide trifluoroacetate (combination 物33’)Object 33’)
Figure PCTCN2016000478-appb-000077
Figure PCTCN2016000478-appb-000077
第一步：6-((3R，5S，6R)-5-氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-N-(N-甲基胍基)-6H-吡咯并[3，4-d]嘧啶-2-磺酰胺三氟乙酸盐First step: 6-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-(N-A Base group)-6H-pyrrolo[3,4-d]pyrimidine-2-sulfonamide trifluoroacetate
室温下将化合物6-((3R，5S，6R)-5-Boc氨基-6-(2，5-二氟苯基)四氢-2H-吡喃-3-基)-N-(N-甲基胍基)-6H-吡咯并[3，4-d]嘧啶-2-磺酰胺(0.1g，0.18mmol)加入至二氯甲烷(1.5ml)和三氟乙酸(0.5ml)的混合溶剂中，搅拌反应一小时，TLC监控反应，原料消失，将反应液于减压浓缩后用乙醚洗涤，析出固体，固体干燥得黄色化合物(100mg，0.15mmol)，MS(ESI)m/z：466(M+1)+，收率Y＝83％，1H NMR(400MHz，MeOD)δ8.78(s，1H)，7.35-7.29(m，1H)，7.27-7.16(m，2H)，6.46(s，2H)4.65(d，J＝9.9Hz，1H)，3.65-3.52(m，2H)，3.49(q，J＝7.0Hz，1H)，2.81(s，3H)，2.69(d，J＝10.4Hz，1H)，1.87(q，J＝11.7Hz，1H)，1.17(t，J＝7.0Hz，1H)。 Compound 6-((3R,5S,6R)-5-Bocamino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-N-(N- Methylmercapto)-6H-pyrrolo[3,4-d]pyrimidine-2-sulfonamide (0.1 g, 0.18 mmol) was added to a mixed solvent of dichloromethane (1.5 ml) and trifluoroacetic acid (0.5 ml) The reaction was stirred for one hour, and the reaction mixture was evaporated. EtOAc m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m (M+1) + , Yield Y = 83%, 1 H NMR (400MHz, MeOH) δ 8.78 (s, 1H), 7.35-7.29 (m, 1H), 7.27-7.16 (m, 2H), 6.46 (s, 2H) 4.65 (d, J = 9.9 Hz, 1H), 3.65-3.52 (m, 2H), 3.49 (q, J = 7.0 Hz, 1H), 2.81 (s, 3H), 2.69 (d, J) = 10.4 Hz, 1H), 1.87 (q, J = 11.7 Hz, 1H), 1.17 (t, J = 7.0 Hz, 1H).
实施例46(2R，3S，5S)-2-(2，5-二氟苯基)-5-(5-(甲磺酰基)异吲哚啉Example 46 (2R,3S,5S)-2-(2,5-Difluorophenyl)-5-(5-(methylsulfonyl)isoindoline -2-基)四氢-2H-吡喃-3-胺(化合物49)-2-yl)tetrahydro-2H-pyran-3-amine (Compound 49)
Figure PCTCN2016000478-appb-000078
Figure PCTCN2016000478-appb-000078
在实施例19的终产物分离中，收集母液进行分离，获得其异构体化合物，MS(ESI)m/z：409(M+1)+，1H NMR(400MHz，MeOD)δ7.86-7.77(m，2H)，7.55-7.48(m，1H)，7.35-7.26(m，1H)，7.22-7.13(m，2H)，4.74-4.65(m，1H)，4.52-4.43(m，2H)，3.85-3.52(m，5H)，3.15(s，3H)，2.63-2.55(m，1H)，2.14-1.94(m，2H)。In the final product separation of Example 19, the mother liquid was collected for separation to obtain an isomer compound thereof, MS (ESI) m/z: 409 (M+1) + , 1 H NMR (400 MHz, MeOD) δ 7.86- 7.77 (m, 2H), 7.55-7.48 (m, 1H), 7.35-7.26 (m, 1H), 7.22-7.13 (m, 2H), 4.74-4.65 (m, 1H), 4.52-4.43 (m, 2H) ), 3.85-3.52 (m, 5H), 3.15 (s, 3H), 2.63-2.55 (m, 1H), 2.14-1.94 (m, 2H).
将本发明的优选化合物的1H-NMR、MS的测定结果示于表1。 The results of 1 H-NMR and MS measurement of preferred compounds of the present invention are shown in Table 1.
【表1】【Table 1】
Figure PCTCN2016000478-appb-000079
Figure PCTCN2016000478-appb-000079
Figure PCTCN2016000478-appb-000080
Figure PCTCN2016000478-appb-000080
Figure PCTCN2016000478-appb-000081
Figure PCTCN2016000478-appb-000081
Figure PCTCN2016000478-appb-000082
Figure PCTCN2016000478-appb-000082
Figure PCTCN2016000478-appb-000083
Figure PCTCN2016000478-appb-000083
Figure PCTCN2016000478-appb-000084
Figure PCTCN2016000478-appb-000084
Figure PCTCN2016000478-appb-000085
Figure PCTCN2016000478-appb-000085
Figure PCTCN2016000478-appb-000086
Figure PCTCN2016000478-appb-000086
Figure PCTCN2016000478-appb-000087
Figure PCTCN2016000478-appb-000087
Figure PCTCN2016000478-appb-000088
Figure PCTCN2016000478-appb-000088
Figure PCTCN2016000478-appb-000089
Figure PCTCN2016000478-appb-000089
Figure PCTCN2016000478-appb-000090
Figure PCTCN2016000478-appb-000090
试验例1：化合物对DPP-2/4/8/9酶活性的抑制作用的检测Test Example 1: Detection of inhibition of DPP-2/4/8/9 enzyme activity by compound
1.1试剂： 1.1 Reagents:
酶DPP-2/4/8/9：Recombinant Human DPP-4/CD26；厂家：R&D公司；Enzyme DPP-2/4/8/9: Recombinant Human DPP-4/CD26; manufacturer: R&D Company;
DPP-4/8/9底物：H-Gly-Pro-AMC·HBr；DPP-2底物：Lys-Pro-AMC；厂家：Bachem；DPP-4/8/9 substrate: H-Gly-Pro-AMC·HBr; DPP-2 substrate: Lys-Pro-AMC; manufacturer: Bachem;
1.2检测方法：1.2 Detection method:
1.2.1DPP-4酶活性抑制检测方法：1.2.1 DPP-4 enzyme activity inhibition detection method:
将待测化合物按不同浓度溶解于检测缓冲液(25mM Tris-HCl，140mM NaCl，10mM KCl，0.1％BSA，pH 7.4)中。在384孔板中加入DPP-4和待测化合物，混匀后37℃孵育15分钟。加入底物(H-Gly-Pro-AMC·HBr)启动反应。将孔板放入酶标仪中，在酶动力学模式下，选择激发光波长为380nm，发射光波长为460nm读取荧光值。在线性反应期内计算各实验组荧光值变化斜率，使用SigmaPlot或GraphPad Prism 5软件拟合化合物的半数抑制浓度IC50值。The test compound was dissolved in assay buffer (25 mM Tris-HCl, 140 mM NaCl, 10 mM KCl, 0.1% BSA, pH 7.4) at various concentrations. DPP-4 and the test compound were added to a 384-well plate, and the mixture was incubated at 37 ° C for 15 minutes. The reaction was initiated by the addition of a substrate (H-Gly-Pro-AMC.HBr). The well plate was placed in a microplate reader, and in the enzyme kinetic mode, the excitation light wavelength was selected to be 380 nm, and the emission light wavelength was 460 nm to read the fluorescence value. The slope of the change in fluorescence value of each experimental group was calculated during the linear reaction period, and the half-inhibitory concentration IC 50 value of the compound was fitted using SigmaPlot or GraphPad Prism 5 software.
1.2.2DPP-2酶活性抑制作用的检测方法：将待测化合物按不同浓度溶解于检测缓冲液中。多孔板中加入DPP-2和待测化合物，混匀后加入底物(Lys-Pro-AMC)并于酶标仪下检测，在线性反应期内计算各实验组荧光值变化斜率，使用SigmaPlot或GraphPad Prism 5软件拟合化合物IC50值。1.2.2 Detection method for inhibition of DPP-2 enzyme activity: The test compound is dissolved in the detection buffer at different concentrations. Add DPP-2 and the test compound to the multi-well plate, mix and add the substrate (Lys-Pro-AMC) and test under the microplate reader. Calculate the slope of the fluorescence value of each experimental group during the linear reaction period, using SigmaPlot or fitting software GraphPad Prism 5 50 value of the compound IC.
1.2.3DPP-8/9酶活性抑制作用的检测方法：将待测化合物按不同浓度溶解于检测缓冲液(25mM Tris-HCl，140mM NaCl，10mM KCl，0.1％BSA，pH 7.4)中。在384孔板中加入DPP-8/9和待测化合物，混匀后37℃孵育15分钟。加入底物(H-Gly-Pro-AMC·HBr)启动反应。将孔板放入酶标仪中，在酶动力学模式下，选择激发光波长为380nm，发射光波长为460nm读取荧光值。在线性反应期内计算各实验组荧光值变化斜率，使用SigmaPlot或GraphPad Prism 5软件拟合化合物IC50值。 1.2.3 Detection method for inhibition of DPP-8/9 enzyme activity: The test compound was dissolved in a detection buffer (25 mM Tris-HCl, 140 mM NaCl, 10 mM KCl, 0.1% BSA, pH 7.4) at various concentrations. DPP-8/9 and the test compound were added to a 384-well plate, and the mixture was incubated at 37 ° C for 15 minutes. The reaction was initiated by the addition of a substrate (H-Gly-Pro-AMC.HBr). The well plate was placed in a microplate reader, and in the enzyme kinetic mode, the excitation light wavelength was selected to be 380 nm, and the emission light wavelength was 460 nm to read the fluorescence value. The slope of the change in fluorescence value of each experimental group was calculated during the linear reaction period, and the IC 50 value of the compound was fitted using SigmaPlot or GraphPad Prism 5 software.
表2：试验化合物对DPP-4的抑制作用Table 2: Inhibition of DPP-4 by test compounds
化合物Compound DPP-4IC50(nM)DPP-4IC 50 (nM)
1-11-1 0.450.45
111’111’ 0.500.50
5’5’ 1.241.24
7’7’ 0.460.46
8’8' 1.001.00
22twenty two 0.520.52
10’10’ 0.360.36
11’11’ 0.650.65
12’12’ 0.820.82
26’26’ 0.950.95
29’29’ 0.450.45
30’30’ 0.670.67
2828 1.101.10
28’28’ 1.381.38
20’20’ 0.690.69
31’31’ 0.430.43
1919 0.850.85
19’19’ 0.900.90
14’14’ 0.470.47
16’16’ 1.201.20
17’17’ 0.970.97
21’twenty one' 0.330.33
22’twenty two' 0.520.52
23’twenty three' 0.560.56
3636 0.810.81
3737 0.430.43
38’38’ 0.350.35
39’39’ 0.830.83
41’41’ 0.650.65
42’42’ 1.371.37
46’46’ 1.021.02
47’47’ 1.161.16
48’48’ 0.670.67
由表2中的试验数据可知，本发明的上述化合物对DPP-4具有优异的抑制作用。From the test data in Table 2, the above compounds of the present invention have an excellent inhibitory effect on DPP-4.
表3：试验化合物对DPP-2的抑制作用Table 3: Inhibition of DPP-2 by test compounds
化合物Compound DPP-2IC50((μM)DPP-2IC 50 ((μM)
17’17’ 1.31.3
39’39’ ＞10>10
19’19’ ＞30>30
1919 ＞100>100
表4：试验化合物对DPP-9的抑制作用Table 4: Inhibition of DPP-9 by test compounds
化合物Compound DPP-9IC50(μM)DPP-9IC 50 (μM)
1-1’1-1’ ＞30>30
3’3’ ＞30>30
7’7’ ＞30>30
8’8' ＞30>30
6’6’ ＞30>30
17’17’ ＞100>100
39’39’ ≈100≈100
19’19’ ＞10>10
1919 ＞10>10
表5：试验化合物对DPP-8的抑制作用Table 5: Inhibition of DPP-8 by test compounds
化合物Compound DPP-8IC50(μM)DPP-8IC50 (μM)
1-1’1-1’ ＞100>100
3’3’ ＞30>30
5’5’ ＞30>30
7’7’ ＞100>100
8’8' ＞30>30
6’6’ ＞30>30
17’17’ ＞30>30
39’39’ 10～3010~30
19’19’ 3030
1919 ＞30>30
由表3-5可见，本发明化合物对DPP-2，DPP-8，DPP-9显示基本无抑制作用。本申请的化合物对于不同DPP的选择性不同，相对于DPP-2，DPP-8和DPP-9而言，本发明的化合物对DPP-4具有显著的抑制作用。本发明化合物具有与上述化合物相似的抑制效果，对DPP-4的抑制作用明显高于对DPP-2，DPP-8，DPP-9的抑制，表明本发明的化合物具有优异的DPP亚型选择性。As can be seen from Tables 3-5, the compounds of the present invention showed substantially no inhibitory effect on DPP-2, DPP-8, and DPP-9. The compounds of the present application differ in selectivity for different DPPs, and the compounds of the present invention have a significant inhibitory effect on DPP-4 relative to DPP-2, DPP-8 and DPP-9. The compound of the present invention has a similar inhibitory effect as the above compound, and the inhibitory effect on DPP-4 is significantly higher than that on DPP-2, DPP-8, and DPP-9, indicating that the compound of the present invention has excellent DPP subtype selectivity. .
本发明化合物的游离碱或其盐具有与上述化合物相似的抑制效果，对DPP-4的抑制作用明显高于对DPP-2，DPP-8，DPP-9的抑制，表明本发明的化合物具有优异的DPP亚型选择性。The free base of the compound of the present invention or a salt thereof has a similar inhibitory effect as the above compound, and the inhibitory effect on DPP-4 is significantly higher than that on DPP-2, DPP-8, and DPP-9, indicating that the compound of the present invention is excellent. DPP subtype selectivity.
试验例2：犬体内的药效动力学(PD)研究Test Example 2: Pharmacodynamics (PD) study in dogs
试剂：DPP-4底物：H-Gly-Pro-AMC·HBr；厂家：Bachem。Reagents: DPP-4 substrate: H-Gly-Pro-AMC·HBr; manufacturer: Bachem.
体内DPP-4酶活抑制检测方法：在多孔板中加入血浆样品和检测缓冲液混匀，再加入DPP-4底物启动反应。将孔板放入酶标仪中检测。在线性反应期内计算各实验组荧光值变化斜率，计算酶活性抑制率。In vivo DPP-4 enzyme activity inhibition detection method: a plasma sample and a detection buffer are mixed in a multi-well plate, and then a DPP-4 substrate is added to initiate the reaction. The well plate was placed in a microplate reader for detection. The slope of the fluorescence value of each experimental group was calculated during the linear reaction period, and the inhibition rate of the enzyme activity was calculated.
本实验主要考察本发明化合物的长效作用，例如在48小时以上(如2-4天)的DPP-4抑制作用。 This experiment primarily investigates the long-acting effects of the compounds of the invention, such as DPP-4 inhibition over 48 hours (e.g., 2-4 days).
表6化合物39’和奥格列汀(omarigliptin)犬静脉(iv)给药后的血浆DPP-4抑制率Table 6: Inhibition of plasma DPP-4 after compound 39' and omarigliptin canine (iv) administration
Figure PCTCN2016000478-appb-000091
Figure PCTCN2016000478-appb-000091
表7化合物19’和奥格列汀犬静脉(iv)给药后的血浆DPP-4抑制率Table 7 shows the inhibition rate of plasma DPP-4 after compound 19' and Ogedetine intravenous (iv) administration
Figure PCTCN2016000478-appb-000092
Figure PCTCN2016000478-appb-000092
表8化合物19和奥格列汀犬静脉(iv)给药后的血浆DPP-4抑制率Table 8: Inhibition of plasma DPP-4 by Compound 19 and Ogedetine in intravenous (iv) administration
Figure PCTCN2016000478-appb-000093
Figure PCTCN2016000478-appb-000093
如表6所示，本发明化合物39’在犬体内通过静脉(iv)给药，在0.5mg/kg低剂量下的血浆DPP-4的抑制率明显高于阳性对照奥格列汀1mg/kg高剂量下的抑制率，并且在96小时仍然有87.5％的抑制率，表明该化合物具有优异的抑制效果。As shown in Table 6, the compound 39' of the present invention was administered intravenously (iv) in dogs, and the inhibition rate of plasma DPP-4 at a low dose of 0.5 mg/kg was significantly higher than that of the positive control alogliptin 1 mg/kg. The inhibition rate at high doses and the 87.5% inhibition rate at 96 hours indicates that the compound has an excellent inhibitory effect.
如表7所示，本发明化合物19’在犬体内通过静脉(iv)给药，在0.73mg/kg低剂量下的血浆DPP-4的抑制率明显高于阳性对照奥格列汀1mg/kg高剂量下的抑制率，并且在96小时仍然有81.6％的抑制率，表明该化合物具有优异的抑制效果。As shown in Table 7, the compound 19' of the present invention was administered intravenously (iv) in dogs, and the inhibition rate of plasma DPP-4 at a low dose of 0.73 mg/kg was significantly higher than that of the positive control alogliptin 1 mg/kg. The inhibition rate at high doses and the 81.6% inhibition rate at 96 hours indicates that the compound has an excellent inhibitory effect.
如表8所示，本发明化合物19在犬体内通过静脉(iv)给药，在0.73mg/kg低剂量下的血浆DPP-4的抑制率明显高于阳性对照奥格列汀1mg/kg高剂量下的抑制率，并且在96小时仍然有85.4％的抑制率，表明该化合物具有优异的抑制效果。 As shown in Table 8, the compound of the present invention 19 was administered intravenously (iv) in dogs, and the inhibition rate of plasma DPP-4 at a low dose of 0.73 mg/kg was significantly higher than that of the positive control alogliptin 1 mg/kg. The inhibition rate at the dose, and still had an inhibition rate of 85.4% at 96 hours, indicating that the compound has an excellent inhibitory effect.
表9化合物39’和奥格列汀犬灌胃(po)给药后的血浆DPP-4抑制率Table 9: Inhibition rate of plasma DPP-4 after administration of compound 39' and alogliptin in gavage (po)
Figure PCTCN2016000478-appb-000094
Figure PCTCN2016000478-appb-000094
表10化合物19’和奥格列汀犬灌胃(po)给药后的血浆DPP-4抑制率Table 10: Inhibition rate of plasma DPP-4 after administration of compound 19' and alogliptin in gavage (po)
Figure PCTCN2016000478-appb-000095
Figure PCTCN2016000478-appb-000095
表11化合物19和奥格列汀犬灌胃(po)给药后的血浆DPP-4抑制率Table 11: Inhibition rate of plasma DPP-4 after administration of compound 19 and alogliptin in gavage (po)
Figure PCTCN2016000478-appb-000096
Figure PCTCN2016000478-appb-000096
如表9所示，本发明化合物39’在犬体内通过灌胃(po)给药，在1mg/kg低剂量下的血浆DPP-4的抑制率明显高于阳性对照奥格列汀2mg/kg高剂量下的抑制率，并且在96小时仍然有91.7％的抑制率，表明该化合物具有优异的抑制效果。As shown in Table 9, the compound 39' of the present invention was administered by intragastric administration (po) in dogs, and the inhibition rate of plasma DPP-4 at a low dose of 1 mg/kg was significantly higher than that of the positive control alogliptin 2 mg/kg. The inhibition rate at high doses and the 91.7% inhibition rate at 96 hours indicates that the compound has an excellent inhibitory effect.
如表10所示，本发明化合物19’在犬体内通过灌胃(po)给药，在1.25mg/kg低剂量下，96小时仍然有86.8％的血浆DPP-4的抑制率，明显高于阳性对照奥格列汀2mg/kg高剂量下的抑制率，，表明该化合物具有优异的抑制效果。As shown in Table 10, the compound 19' of the present invention was administered by intragastric administration (po) in dogs, and at a low dose of 1.25 mg/kg, there was still 86.8% inhibition rate of plasma DPP-4 at 96 hours, which was significantly higher than that. The inhibition rate of the positive control alogliptin at a high dose of 2 mg/kg indicates that the compound has an excellent inhibitory effect.
如表11所示，本发明化合物19在犬体内通过灌胃(PO)给药，在1.25mg/kg低剂量下，96小时仍然有86.5％的血浆DPP-4的抑制率，明显高于阳性对照奥格列汀2mg/kg高剂量下的抑制率，＝表明该化合物具有优异的抑制效果。As shown in Table 11, the compound 19 of the present invention was administered by intragastric administration (PO) in dogs, and at a low dose of 1.25 mg/kg, there was still 86.5% inhibition of plasma DPP-4 at 96 hours, which was significantly higher than that of the positive one. The inhibition rate of the high dose of the control of alogliptin at 2 mg/kg, = indicates that the compound has an excellent inhibitory effect.
本发明的化合物在犬体内通过静脉(iv)或灌胃(po)给药时具有上述化合物相似的血浆DPP-4的抑制效果和较长的药效时间。The compound of the present invention has a similar inhibitory effect on plasma DPP-4 and a longer potency when administered intravenously (iv) or intragastrically (po) in dogs.
本发明化合物的游离碱或其盐在犬体内通过静脉(iv)或灌胃(po)给药时具有与上述化合物相似的血浆DPP-4的抑制效果和较长的药效时间。The free base of the compound of the present invention or a salt thereof has a plasma DPP-4 inhibitory effect and a longer pharmacodynamic time similar to those of the above compounds when administered intravenously (iv) or intragastrically (po) in dogs.
试验例3：犬体内的药代动力学(PK)研究Test Example 3: Pharmacokinetics (PK) study in dogs
分别通过静脉和灌胃给予雄性犬本发明化合物，考察药代动力学特点。iv和po的分别给药，溶媒系统均为5％DMSO：5％solutol：90％ 生理盐水。iv给药和po给药后在不同时间点收集血液，用于PK/PD研究。血浆样品经沉淀蛋白处理后进行LC-MS/MS分析。结果如下表所示。The male compounds of the present invention were administered intravenously and intragastrically, respectively, to examine the pharmacokinetic characteristics. The respective doses of iv and po were 5% DMSO: 5% solutol: 90% Saline. Blood was collected at different time points after iv administration and po administration for PK/PD studies. Plasma samples were processed by precipitation protein and analyzed by LC-MS/MS. The results are shown in the table below.
表12化合物39’在犬体内的药代动力学参数Table 12 Pharmacokinetic parameters of compound 39' in dogs
给药途径Route of administration 静脉0.5mg/kgIntravenous 0.5mg/kg 灌胃1mg/kgOral 1mg/kg
AUClast(h*ng/ml)AUC last (h*ng/ml) 68906890 1300013000
表13化合物19’在犬体内的药代动力学参数Table 13 Pharmacokinetic parameters of compound 19' in dogs
给药途径Route of administration 静脉0.731mg/kgVein 0.731mg/kg 灌胃1.25mg/kgOral 1.25mg/kg
AUClast(h*ng/ml)AUC last (h*ng/ml) 45404540 92709270
表14化合物19在犬体内的药代动力学参数Table 14 Pharmacokinetic parameters of compound 19 in dogs
给药途径Route of administration 静脉0.5mg/kgIntravenous 0.5mg/kg 灌胃1mg/kgOral 1mg/kg
AUClast(h*ng/ml)AUC last (h*ng/ml) 56305630 1020010200
由表12、表13和表14试验数据可知，本发明化合物39’、19’和19通过静脉(iv)给药和灌胃(po)给药在犬体内显示出优良的药物暴露量和生物利用度。From the test data of Table 12, Table 13, and Table 14, it is known that the compounds 39', 19' and 19 of the present invention exhibit excellent drug exposure and organisms in dogs by intravenous (iv) administration and intragastric (po) administration. Utilization.
本发明化合物具有与上述化合物相似，具有优良的药代动力学效果。The compound of the present invention has similar pharmacokinetic effects as the above compounds.
本发明化合物的游离碱或其盐通过静脉(IV)给药或灌胃(po)给药时，在比体内具有与上述化合物相似的药代学参数暴露量，显示优良的生物利用度。When the free base of the compound of the present invention or a salt thereof is administered by intravenous (IV) administration or intragastric administration (po), it exhibits a similar pharmacological parameter exposure to the above-mentioned compound than the body, and exhibits excellent bioavailability.
试验例4：安全性试验Test Example 4: Safety test
在心肌细胞中，human Ether-a-go-go Related Gene(hERG)编码的钾通道介导一种延迟整流钾电流(IKr)。IKr抑制是药物导致QT间期延长最重要的机制。在hERG测试中，手动膜片钳法判定标准为如果化合物IC50＞30μM，则判定化合物对hERG无抑制作用。 In cardiomyocytes, the potassium channel encoded by the human Ether-a-go-go Related Gene (hERG) mediates a delayed rectifier potassium current (IKr). IKr inhibition is the most important mechanism for drug-induced QT interval prolongation. In the hERG test, the manual patch clamp method was judged to be that if the compound IC 50 > 30 μM, it was judged that the compound had no inhibitory effect on hERG.
采用手动膜片钳检测化合物1-1’对hERG钾离子通道的作用，测试浓度为0.1，0.3，1，3，10，30μM。在心肌细胞中，human Ether-a-go-go Related Gene(hERG)编码的钾通道介导一种延迟整流钾电流(IKr)，IKr抑制是药物导致QT间期延长最重要的机制。The effect of Compound 1-1' on the hERG potassium channel was tested using a manual patch clamp at a concentration of 0.1, 0.3, 1, 3, 10, 30 μM. In cardiomyocytes, the potassium channel encoded by the human Ether-a-go-go Related Gene (hERG) mediates a delayed rectifier potassium current (IKr), which is the most important mechanism for drug-induced QT prolongation.
试验细胞为转染有hERG cDNA与稳定表达hERG通道的CHO细胞系。细胞被放置于倒置显微镜下的电生理记录槽中。记录槽内以细胞外液作持续灌流。实验过程采用常规全细胞膜片钳电流记录技术。试验结果如表15所示：The test cells were CHO cell lines transfected with hERG cDNA and stably expressing hERG channels. The cells were placed in an electrophysiological recording cell under an inverted microscope. The extracellular fluid was continuously perfused in the recording tank. The experimental procedure uses conventional whole-cell patch clamp current recording techniques. The test results are shown in Table 15:
表15：试验化合物hERG实验结果：Table 15: Results of test compound hERG experiments:
化合物Compound 1-1’1-1’ 3’3’ 5’5’ 7’7’ 19’19’ 17’17’ 39’39’ 1919
IC50(μM)IC50 (μM) ＞30>30 ＞30>30 ＞30>30 ＞30>30 ＞30>30 ＞30>30 ＞30>30 ＞30>30
由表15中的试验数据可知，本次试验中，上述化合物对于hERG的50％抑制浓度(IC50)值均大于30μM，无导致心脏QT间期延长的安全性隐患。From the test data in Table 15, it is known that the 50% inhibitory concentration (IC 50 ) value of the above compound for hERG is greater than 30 μM in this test, and there is no safety hazard that leads to prolongation of the QT interval of the heart.
本发明的化合物具有与上述化合物相似的安全性。The compounds of the invention have similar safety to the compounds described above.
本发明化合物的游离碱或其盐具有与上述化合物相似的安全性。The free base of the compound of the present invention or a salt thereof has similar safety to the above compounds.
试验例5.CYP酶抑制实验Test Example 5. CYP enzyme inhibition experiment
向1.1mL离心管中加入178μL肝微粒体溶液(肝微粒体在反应体系的终浓度为0.2mg/mL)。空白样品中不加入阳性抑制剂及待测化合物，相应加入2μLDMSO，再加入200μL内标的甲醇溶液，涡旋混合1min(即分钟)，最后加入20μL NADPH溶液。非空白样品，向1.1mL离心管中加入2μL抑制剂或待测化合物的储备液(10μM)，涡旋混合后在37℃条件下预孵育5min，加入20μL NADPH溶液开始反应(NADPH在反应体系的终浓度为1mM)，在37℃振摇的条件下孵育20min。孵育结束后加入内标的甲醇溶液终止反应，样品4000rpm下离心5min，取上清液至LC/MS/MS进行分析。178 μL of liver microsome solution (the final concentration of liver microsomes in the reaction system was 0.2 mg/mL) was added to a 1.1 mL centrifuge tube. No positive inhibitor and test compound were added to the blank sample, 2 μL of DMSO was added, 200 μL of internal standard methanol solution was added, vortexed for 1 min (ie, minutes), and finally 20 μL of NADPH solution was added. For non-blank samples, add 2 μL of inhibitor or stock solution of the test compound (10 μM) to a 1.1 mL centrifuge tube, vortex and mix for 5 min at 37 °C, and add 20 μL of NADPH solution to start the reaction (NADPH in the reaction system). The final concentration was 1 mM) and incubated for 20 min at 37 ° C with shaking. After the incubation, the reaction was terminated by adding an internal standard methanol solution, and the sample was centrifuged at 4000 rpm for 5 min, and the supernatant was taken to LC/MS/MS for analysis.
测试化合物对不同CYP亚型的抑制结果见表16。 The inhibition results of the test compounds against different CYP subtypes are shown in Table 16.
表16：试验化合物对不同CYP亚型的抑制结果Table 16: Inhibition Results of Test Compounds on Different CYP Subtypes
  CYPCYP 1A21A2 2C92C9 2C192C19 2D62D6 3A43A4 2B62B6 2C82C8
1-1’1-1’ IC50(uM)IC 50 (uM) ＞50>50 ＞50>50 ＞50>50 ＞50>50 ＞50>50 ＞50>50 10.410.4
3’3’ IC50(uM)IC 50 (uM) ＞50>50 ＞50>50 ＞50>50 ＞50>50 ＞50>50 ＞50>50 ＞50>50
5’5’ IC50(uM)IC 50 (uM) ＞50>50 ＞50>50 ＞50>50 ＞50>50 ＞50>50 ＞50>50 ＞50>50
7’7’ IC50(uM)IC 50 (uM) ＞50>50 ＞50>50 ＞50>50 ＞50>50 ＞50>50 ＞50>50 ＞50>50
19’19’ IC50(uM)IC 50 (uM) ＞100>100 ＞100>100 ＞100>100 ＞100>100 ＞100>100 ＞100>100 ＞100>100
39’39’ IC50(uM)IC 50 (uM) ＞10>10 NANA NANA ＞10>10 ＞10>10 NANA NANA
17’17’ IC50(uM)IC 50 (uM) ＞10>10 NANA NANA ＞10>10 ＞10>10 NANA NANA
1919 IC50(uM)IC 50 (uM) ＞100>100 ＞100>100 ＞100>100 ＞100>100 ＞100>100 ＞100>100 ＞100>100
备注：NA：未检测Remarks: NA: not detected
由表16中的试验数据可知，上述本发明的化合物各自对上述CYP亚型IC50均大于10uM，大部分大于50μM，表明所述化合物具有优异的安全性，临床上联合用药产生药物相互作用的风险较小。From the test data in Table 16, it is known that the above compounds of the present invention each have an IC 50 of more than 10 uM for the above CYP subtypes, and most of them are greater than 50 μM, indicating that the compounds have excellent safety, and clinically combined drugs produce drug interactions. The risk is small.
本发明的化合物具有与上述化合物相似的安全性，临床上联合用药产生药物相互作用的风险较小。The compounds of the present invention have similar safety to the above-mentioned compounds, and the risk of drug interactions in clinical combination is small.
本发明化合物的游离碱或其盐具有与上述化合物相似的安全性，临床上联合用药产生药物相互作用的风险较小。The free base or a salt thereof of the compound of the present invention has similar safety to the above-mentioned compound, and the clinical combination drug has a lower risk of drug interaction.
制剂例1Formulation Example 1
作为口服药物组合物的具体实施方式，制造由以下成分组成的100mg效价的片剂。As a specific embodiment of the oral pharmaceutical composition, a 100 mg titer tablet consisting of the following ingredients was produced.
Figure PCTCN2016000478-appb-000097
Figure PCTCN2016000478-appb-000097
首先，将活性物质、微晶纤维素和交联羧甲基纤维素混合，然后用硬脂酸镁将混合物润滑并压为片剂。First, the active substance, microcrystalline cellulose and croscarmellose are mixed, and then the mixture is lubricated with magnesium stearate and compressed into tablets.
制剂例2Formulation Example 2
制造含有以下成分的胶囊填充用颗粒剂。A granule for capsule filling containing the following components was produced.
Figure PCTCN2016000478-appb-000098
Figure PCTCN2016000478-appb-000098
使式(1)所示的化合物、乳糖通过60筛目的筛。使玉米粉通过120筛目的筛。将它们混合，在混合粉末中添加HPC-L溶液，进行捏合、造粒、干燥。将所得的干燥颗粒整粒后，将其150mg填充到4号硬明胶胶囊中。The compound represented by the formula (1) and lactose were passed through a sieve of 60 mesh. The corn flour was passed through a 120 mesh sieve. These were mixed, and the HPC-L solution was added to the mixed powder, kneaded, granulated, and dried. After the obtained dried granules were sized, 150 mg of the obtained dried granules were filled in a No. 4 hard gelatin capsule.
制剂例3Formulation Example 3
制剂例1Formulation Example 1
制造含有以下成分的颗粒剂。A granule containing the following ingredients was produced.
Figure PCTCN2016000478-appb-000099
Figure PCTCN2016000478-appb-000099
将式(1)所示的化合物和乳糖通过60网目的筛。将玉米粉通过120网目的筛。将它们利用V型混合机混合。在混合粉末中添加HPC-L(低粘度羟丙基纤维素)水溶液，进行捏合、造粒(挤压造粒孔径0.5～1mm)、干燥的步骤。将所得的干燥颗粒用振荡筛(12/60筛目)过筛，得到颗粒剂。The compound of formula (1) and lactose were passed through a 60 mesh sieve. The corn flour was passed through a sieve of 120 mesh. They were mixed using a V-type mixer. An HPC-L (low viscosity hydroxypropylcellulose) aqueous solution is added to the mixed powder, and kneading, granulation (extrusion granulation pore diameter: 0.5 to 1 mm), and drying are carried out. The obtained dried granules were sieved with a shaking sieve (12/60 mesh) to obtain granules.
产业上的可利用性Industrial availability
根据本发明，可以提供作为二肽基肽酶-IV抑制剂的化合物，其对二肽基肽酶-IV具有高的抑制活性和具有优异的药物代谢性质，可用于治疗和预防包括治疗糖尿病、尤其是II型糖病的DPP-4相关疾病。 According to the present invention, there can be provided a compound which is a dipeptidyl peptidase-IV inhibitor which has high inhibitory activity against dipeptidyl peptidase-IV and has excellent drug metabolism properties, and can be used for treatment and prevention including treatment of diabetes, Especially DPP-4 related diseases of type II diabetes.

Claims (29)

  1. 下述通式(1)表示的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，a compound represented by the following formula (1), a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof,
    Figure PCTCN2016000478-appb-100001
    Figure PCTCN2016000478-appb-100001
    式中，In the formula,
    A环为不饱和环，B环中的
    Figure PCTCN2016000478-appb-100002
    表示单键或双键；    Ring A is an unsaturated ring, in the B ring
    Figure PCTCN2016000478-appb-100002
    Represents a single or double bond;
    A3、A4、A5和A6各自独立地选自碳原子或氮原子，并且A3、A4、A5和A6中至少2个是碳原子；A 3 , A 4 , A 5 and A 6 are each independently selected from a carbon atom or a nitrogen atom, and at least 2 of A 3 , A 4 , A 5 and A 6 are carbon atoms;
    R1、R2分别独立地与A3、A4、A5或A6中的碳原子结合，且独立地选自氢原子、氰基、硝基、-S(＝O)2R3、-R5-COOH、-R5COOR6、任选被选自取代基组a的基团取代的巯基、任选被选自取代基组a的基团取代的氨基、任选被选自取代基组a的基团取代的亚磺酰基、任选被选自取代基组a的基团取代的C1-6烷基、任选被选自取代基组a的基团取代的C1-6烷氧基、任选被选自取代基组a的基团取代的C2-6烷酰基、任选被选自取代基组a的基团取代的C3-8环烷基、任选被选自取代基组a的基团取代的C6-10芳基、任选被选自取代基组a的基团取代的5-11元杂环基、-R9(C＝O)-NR7R8、或-R9(C＝O)-NH2；R 1 and R 2 are each independently bonded to a carbon atom in A 3 , A 4 , A 5 or A 6 , and are independently selected from a hydrogen atom, a cyano group, a nitro group, -S(=O) 2 R 3 , -R 5 -COOH, -R 5 COOR 6 , a fluorenyl group optionally substituted by a group selected from the substituent group a, an amino group optionally substituted with a group selected from the substituent group a, optionally selected from the group consisting of a group-substituted sulfinyl group of the group a, a C1-6 alkyl group optionally substituted with a group selected from the substituent group a, a C1-6 alkane optionally substituted with a group selected from the substituent group a An oxy group, a C2-6 alkanoyl group optionally substituted with a group selected from the substituent group a, a C3-8 cycloalkyl group optionally substituted with a group selected from the substituent group a, optionally selected from the group consisting of a C6-10 aryl group substituted with a group of the group a, a 5-11 membered heterocyclic group optionally substituted with a group selected from the substituent group a, -R 9 (C=O)-NR 7 R 8 , Or -R 9 (C=O)-NH 2 ;
    其中，R3选自羟基、任选被选自取代基组a的基团取代的烷基、任选被选自取代基组a的基团取代的环烷基、任选被选自取代基组a的基团取代的氨基、任选被选自取代基组a的基团取代的氨基C2-6烷酰基、任选被选自取代基组a的基团取代的氨基羰基氨基、任选被选自取代基组a的基团取代的C6-10芳基、任选被选自取代基组a的基团取代的5-11元杂环基；Wherein R 3 is selected from a hydroxyl group, an alkyl group optionally substituted with a group selected from the substituent group a, a cycloalkyl group optionally substituted with a group selected from the substituent group a, optionally selected from a substituent a group-substituted amino group of group a, an amino C2-6 alkanoyl group optionally substituted with a group selected from substituent group a, an aminocarbonylamino group optionally substituted with a group selected from substituent group a, optionally a C6-10 aryl group substituted with a group selected from the substituent group a, a 5-11 membered heterocyclic group optionally substituted with a group selected from the substituent group a;
    R5为单键或C1-6亚烷基、C2-6亚烯基、或C2-6亚炔基；R 5 is a single bond or a C1-6 alkylene group, a C2-6 alkenylene group, or a C2-6 alkynylene group;
    R6为C1-6烷基、C2-6烯基、或C2-6炔基；R 6 is C1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
    R7和R8各自独立地为氢、羟基、任选被选自取代基组a的基团取代的C1-6烷基、任选被选自取代基组a的基团取代的C3-8环烷基、 任选被选自取代基组a的基团取代的氨基，前提是R7和R8不同时为氢；R 7 and R 8 are each independently hydrogen, hydroxy, C 1-6 alkyl optionally substituted with a group selected from substituent group a, C 3-8 optionally substituted with a group selected from substituent group a a cycloalkyl group, an amino group optionally substituted with a group selected from the group of substituents a, provided that R 7 and R 8 are not hydrogen at the same time;
    R9为单键、C1-6亚烷基、C2-6亚烯基、或C2-6亚炔基，R 9 is a single bond, a C1-6 alkylene group, a C2-6 alkenylene group, or a C2-6 alkynylene group.
    前提是当B环为饱和环时，R1、R2不同时为氢原子；和当B环为饱和环且R1和R2中的一方为氢原子时，R1和R2中的另一方不为任选被选自卤素原子和C1-6烷氧基中的取代基取代的C1-6烷基、氰基、任选被取代的C1-6烷氧基、任选被取代的C3-8环烷基、任选被取代的5-11元杂环基；Provided that when the B ring is a saturated ring, R 1 and R 2 are not simultaneously a hydrogen atom; and when the B ring is a saturated ring and one of R 1 and R 2 is a hydrogen atom, the other of R 1 and R 2 One of the groups is not a C1-6 alkyl group optionally substituted with a substituent selected from a halogen atom and a C1-6 alkoxy group, a cyano group, an optionally substituted C1-6 alkoxy group, or an optionally substituted C3. -8 cycloalkyl, optionally substituted 5-11 membered heterocyclic group;
    Ar是任选被1～5个选自取代基组a的基团取代的C6-10芳基；Ar is a C6-10 aryl group optionally substituted by 1 to 5 groups selected from the substituent group a;
    取代基组a：由C1-6烷基、C2-6烯基、C2-6炔基、卤化的C1-6烷基、卤素、-CN、NHOH、-OH、-O-C1-6烷基、-NH-C1-6烷基、-N(C1-6烷基)2、-NH2、-C(＝NH)-NH-CH3、-C(＝NH)-N(CH3)2、-C(＝NH)-NH2、-C(＝NH)-NH-C1-6烷基、-C(O)NH2、-C(O)NH-C1-6烷基、-C(O)N(C1-6烷基)2、-NHC(O)-C1-6烷基、-NHC(O)-C3-8环烷基、-N(C1-6烷基)C(O)H、-N(C1-6烷基)C(O)-C1-6烷基、-NHC(O)NH2、-SO2-C1-6烷基组成。Substituent group a: from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogenated C1-6 alkyl, halogen, -CN, NHOH, -OH, -O-C1-6 alkyl , -NH-C1-6 alkyl, -N(C1-6alkyl) 2 , -NH 2 , -C(=NH)-NH-CH 3 , -C(=NH)-N(CH 3 ) 2 , -C(=NH)-NH 2 , -C(=NH)-NH-C1-6 alkyl, -C(O)NH 2 , -C(O)NH-C1-6 alkyl, -C( O) N(C1-6 alkyl) 2 , -NHC(O)-C1-6 alkyl, -NHC(O)-C3-8 cycloalkyl, -N(C1-6alkyl)C(O) H, -N(C1-6alkyl)C(O)-C1-6 alkyl, -NHC(O)NH 2 , -SO 2 -C1-6 alkyl.
  2. 根据权利要求1所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，The compound according to claim 1, which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein
    A3为N，A4为C，A5为N，A6为C，或A 3 is N, A 4 is C, A 5 is N, A 6 is C, or
    A3为N，A4为C，A5为C，A6为C，或A 3 is N, A 4 is C, A 5 is C, A 6 is C, or
    A3为C，A4为C，A5为N，A6为C，或A 3 is C, A 4 is C, A 5 is N, A 6 is C, or
    A3为N，A4为C，A5为C，A6为N，或A 3 is N, A 4 is C, A 5 is C, A 6 is N, or
    A3为C，A4为C，A5为C，A6为C。A 3 is C, A 4 is C, A 5 is C, and A 6 is C.
  3. 根据权利要求1或2所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，A环为不饱和环，B环为饱和环，The compound according to claim 1 or 2, which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or a prodrug thereof, wherein the ring A is an unsaturated ring and the ring B is Saturated ring,
    A3为N，A4为C，A5为N，A6为C，或A 3 is N, A 4 is C, A 5 is N, A 6 is C, or
    A3为N，A4为C，A5为C，A6为C，或A 3 is N, A 4 is C, A 5 is C, A 6 is C, or
    A3为C，A4为C，A5为N，A6为C，或A 3 is C, A 4 is C, A 5 is N, A 6 is C, or
    A3为N，A4为C，A5为C，A6为N，或A 3 is N, A 4 is C, A 5 is C, A 6 is N, or
    A3为C，A4为C，A5为C，A6为C。A 3 is C, A 4 is C, A 5 is C, and A 6 is C.
  4. 根据权利要求1或2所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，A环为不饱和环， B环为不饱和环，The compound according to claim 1 or 2, which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or a prodrug thereof, wherein the ring A is an unsaturated ring. B ring is an unsaturated ring.
    A3为N，A4为C，A5为N，A6为C，或A 3 is N, A 4 is C, A 5 is N, A 6 is C, or
    A3为N，A4为C，A5为C，A6为C，或A 3 is N, A 4 is C, A 5 is C, A 6 is C, or
    A3为C，A4为C，A5为N，A6为C，或A 3 is C, A 4 is C, A 5 is N, A 6 is C, or
    A3为N，A4为C，A5为C，A6为N，或A 3 is N, A 4 is C, A 5 is C, A 6 is N, or
    A3为C，A4为C，A5为C，A6为C。A 3 is C, A 4 is C, A 5 is C, and A 6 is C.
  5. 根据权利要求1、2、3或4任一项所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，The compound according to any one of claims 1, 2, 3 or 4, which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein
    R1、R2分别独立地为氢原子、-S(＝O)2-C1-6烷基、-S(＝O)2-C3-8环烷基、-S(＝O)2-N(C1-6烷基)2、-S(＝O)2-NH(C1-6烷基)、任选被C1-6烷基取代的磺酰氨基、-S(＝O)2-C2-6烷酰基、C6-10芳基C1-6烷基、被C1-6烷基取代的-S(＝O)2-氨基羰基氨基、-COO-C1-6烷基、被C1-6烷基取代的氨基、C1-6烷基、C1-6烷氧基、C3-8环烷基、C6-10芳基、C6-10芳基C1-8烷氧基、C1-6烷硫基、5-11元杂环基、-(C＝O)-NH-C1-6烷基、-(C＝O)-N(C1-6烷基)2、-(C＝O)-NH-C3-8环烷基、-(C＝O)-N(C3-8环烷基)2、C1-6烷基亚磺酰基或单C1-6烷基氨基羰基、或二C1-6烷基氨基羰基。R 1 and R 2 are each independently a hydrogen atom, -S(=O) 2 -C1-6 alkyl, -S(=O) 2 -C3-8 cycloalkyl, -S(=O) 2 -N (C1-6 alkyl) 2 , -S(=O) 2 -NH(C1-6 alkyl), sulfonylamino optionally substituted by C1-6 alkyl, -S(=O) 2 -C2- 6 alkanoyl, C6-10 aryl C1-6 alkyl, -S(=O) 2 -aminocarbonylamino substituted by C1-6 alkyl, -COO-C1-6 alkyl, C1-6 alkyl Substituted amino, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, C6-10 aryl, C6-10 aryl C1-8 alkoxy, C1-6 alkylthio, 5 -11 membered heterocyclic group, -(C=O)-NH-C1-6 alkyl, -(C=O)-N(C1-6alkyl) 2 , -(C=O)-NH-C3- 8-cycloalkyl, -(C=O)-N(C3-8 cycloalkyl) 2 , C1-6 alkylsulfinyl or mono C1-6 alkylaminocarbonyl, or di-C1-6 alkylaminocarbonyl .
  6. 根据权利要求1-5任一项所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，R1、R2分别独立地为氢原子、氨基、-S(＝O)2-CH3、-S(＝O)2-CH2CH3、-S(＝O)2-CH(CH3)2、-S(＝O)2-OH、-S(＝O)2-环丙基、-S(＝O)2-NH2、-S(＝O)2-N(CH3)2、-S(＝O)2-NHCH3、-S(＝O)2-NH-CH(CH3)2、-S(＝O)2-CH2-CH(CH3)2、-S(＝O)2-CH(CH3)-CH2CH3、-S(＝O)2-NH-C(＝NH)-NH-CH3、-S(＝O)2-NH-C(＝O)-NH-(CH2)2CH3、-S(＝O)2-NH-C(＝NH)-NH2、-NH-C(＝NH)-NH-CH3、-NH-S(＝O)2-CH3、-S(＝O)2-NH-C(＝NH)-N(CH3)2、-COOH、-COOCH3、-NH2、-N(CH3)2或-(C＝O)-NH2。A compound according to any one of claims 1 to 5, which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein R 1 and R 2 are each independently The ground is a hydrogen atom, an amino group, -S(=O) 2 -CH 3 , -S(=O) 2 -CH 2 CH 3 , -S(=O) 2 -CH(CH 3 ) 2 , -S(= O) 2 -OH, -S(=O) 2 -cyclopropyl, -S(=O) 2 -NH 2 , -S(=O) 2 -N(CH 3 ) 2 , -S(=O) 2 -NHCH 3 , -S(=O) 2 -NH-CH(CH 3 ) 2 , -S(=O) 2 -CH 2 -CH(CH 3 ) 2 , -S(=O) 2 -CH( CH 3 )-CH 2 CH 3 , -S(=O) 2 -NH-C(=NH)-NH-CH 3 , -S(=O) 2 -NH-C(=O)-NH-(CH 2 ) 2 CH 3 , -S(=O) 2 -NH-C(=NH)-NH 2 , -NH-C(=NH)-NH-CH 3 , -NH-S(=O) 2 -CH 3 , -S(=O) 2 -NH-C(=NH)-N(CH 3 ) 2 , -COOH, -COOCH 3 , -NH 2 , -N(CH 3 ) 2 or -(C=O) -NH 2 .
  7. 根据权利要求1-6任一项所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、或其前药，其中，B环中的
    Figure PCTCN2016000478-appb-100003
    都表示单键。    A compound according to any one of claims 1 to 6, which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, or prodrug thereof, wherein
    Figure PCTCN2016000478-appb-100003
    Both represent a single button.
  8. 根据权利要求1-7任一项所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、或其前药，其中，B环中的
    Figure PCTCN2016000478-appb-100004
    都表 示双键。    A pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, or prodrug thereof, according to any one of claims 1 to 7, wherein
    Figure PCTCN2016000478-appb-100004
    Both indicate double keys.
  9. 根据权利要求1-8任一项所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、或其前药，其中，Ar是任选被1～5个选自取代基组a的基团取代的苯基。The compound according to any one of claims 1 to 8, which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, or prodrug thereof, wherein Ar is optionally 1 to 5 A phenyl group substituted with a group selected from the substituent group a.
  10. 根据权利要求1-9任一项所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，所述化合物为选自下述式(a)、(b)、(c)、(d)、(e)和(f)中的任意一种化合物，The compound according to any one of claims 1 to 9, which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein the compound is selected from the group consisting of a compound of any one of the formulae (a), (b), (c), (d), (e) and (f),
    Figure PCTCN2016000478-appb-100005
    Figure PCTCN2016000478-appb-100005
    其中，Ar是任选被1～5个卤素原子取代的苯基，Wherein Ar is a phenyl group optionally substituted by 1 to 5 halogen atoms,
    R4选自氢原子、氰基、硝基、-S(＝O)2R3、-R5-COOH、-R5COOR6、任选被选自取代基组a的基团取代的巯基、任选被选自取代基组a的基团取代的氨基、任选被选自取代基组a的基团取代的亚磺酰基、任选被选自取代基组a的基团取代的C1-6烷基、任选被选自取代基组a的基团取代的C1-6烷氧基、任选被选自取代基组a的基团取代的C2-6烷酰基、任选被选自取代基组a的基团取代的C3-8环烷基、任选被选自取代基组a的基团取代的C6-10芳基、任选被选自取代基组a的基团取代的5-11元杂环基、-R9(C＝O)-NR7R8、或-R9(C＝O)-NH2，R 4 is selected from a hydrogen atom, a cyano group, a nitro group, -S(=O) 2 R 3 , -R 5 -COOH, -R 5 COOR 6 , a fluorenyl group optionally substituted with a group selected from the substituent group a An amino group optionally substituted with a group selected from the substituent group a, a sulfinyl group optionally substituted with a group selected from the substituent group a, a C1 optionally substituted with a group selected from the substituent group a a 1-6 alkyl group, a C1-6 alkoxy group optionally substituted with a group selected from the substituent group a, a C2-6 alkanoyl group optionally substituted with a group selected from the substituent group a, optionally selected a C3-8 cycloalkyl group substituted with a group of the substituent group a, a C6-10 aryl group optionally substituted with a group selected from the substituent group a, optionally substituted with a group selected from the substituent group a 5-11 membered heterocyclic group, -R 9 (C=O)-NR 7 R 8 , or -R 9 (C=O)-NH 2 ,
    其中R3、R5、R6、R7、R8、R9和取代基组a与权利要求1中的定义相同。Wherein R 3 , R 5 , R 6 , R 7 , R 8 , R 9 and the substituent group a are the same as defined in claim 1.
  11. 根据权利要求1-10任一项所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，R4为氢 原子、-S(＝O)2-C1-6烷基、-S(＝O)2-C3-8环烷基、-S(＝O)2-N(C1-6烷基)2、-S(＝O)2-NH(C1-6烷基)、任选被C1-6烷基取代的磺酰氨基、-S(＝O)2-C2-6烷酰基、C6-10芳基C1-6烷基、被C1-6烷基取代的-S(＝O)2-氨基羰基氨基、-COO-C1-6烷基、被C1-6烷基取代的氨基、C1-6烷基、C1-6烷氧基、C3-8环烷基、C6-10芳基、C6-10芳基C1-8烷氧基、C1-6烷硫基、5-11元杂环基、-(C＝O)-NH-C1-6烷基、-(C＝O)-N(C1-6烷基)2、-(C＝O)-NH-C3-8环烷基、-(C＝O)-N(C3-8环烷基)2、C1-6烷基亚磺酰基或单C1-6烷基氨基羰基、或二C1-6烷基氨基羰基。The compound according to any one of claims 1 to 10, which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or a prodrug thereof, wherein R 4 is a hydrogen atom, S(=O) 2 -C1-6 alkyl, -S(=O) 2 -C3-8 cycloalkyl, -S(=O) 2 -N(C1-6alkyl) 2 , -S(= O) 2- NH(C1-6 alkyl), sulfonylamino optionally substituted by C1-6 alkyl, -S(=O) 2 -C2-6 alkanoyl, C6-10 aryl C1-6 alkane a group, a -S(=O) 2 -aminocarbonylamino group substituted by a C1-6 alkyl group, a -COO-C1-6 alkyl group, an amino group substituted by a C1-6 alkyl group, a C1-6 alkyl group, a C1-6 group Alkoxy, C3-8 cycloalkyl, C6-10 aryl, C6-10 aryl C1-8 alkoxy, C1-6 alkylthio, 5-11 membered heterocyclyl, -(C=O) -NH-C1-6 alkyl, -(C=O)-N(C1-6alkyl) 2 , -(C=O)-NH-C3-8 cycloalkyl, -(C=O)-N (C3-8 cycloalkyl) 2 , C1-6 alkylsulfinyl or mono C1-6 alkylaminocarbonyl, or di C1-6 alkylaminocarbonyl.
  12. 根据权利要求1-11任一项所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、或其前药，其中，R4为氨基、-S(＝O)2-CH3、-S(＝O)2-CH2CH3、-S(＝O)2-CH(CH3)2、-S(＝O)2-OH、-S(＝O)2-环丙基、-S(＝O)2-NH2、-S(＝O)2-N(CH3)2、-S(＝O)2-NHCH3、-S(＝O)2-NH-CH(CH3)2、-S(＝O)2-CH2-CH(CH3)2、-S(＝O)2-CH(CH3)-CH2CH3、-S(＝O)2-NH-C(＝NH)-NH-CH3、-S(＝O)2-NH-C(＝O)-NH-(CH2)2CH3、-S(＝O)2-NH-C(＝NH)-NH2、-NH-C(＝NH)-NH-CH3、-NH-S(＝O)2-CH3、-S(＝O)2-NH-C(＝NH)-N(CH3)2、-COOH、-COOCH3、-NH2、-N(CH3)2或-(C＝O)-NH2。The compound according to any one of claims 1 to 11, which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, or a prodrug thereof, wherein R 4 is an amino group, -S (= O) 2 -CH 3 , -S(=O) 2 -CH 2 CH 3 , -S(=O) 2 -CH(CH 3 ) 2 , -S(=O) 2 -OH, -S(=O 2 -cyclopropyl, -S(=O) 2 -NH 2 , -S(=O) 2 -N(CH 3 ) 2 , -S(=O) 2 -NHCH 3 , -S(=O) 2 -NH-CH(CH 3 ) 2 , -S(=O) 2 -CH 2 -CH(CH 3 ) 2 , -S(=O) 2 -CH(CH 3 )-CH 2 CH 3 , -S (=O) 2 -NH-C(=NH)-NH-CH 3 , -S(=O) 2 -NH-C(=O)-NH-(CH 2 ) 2 CH 3 , -S(=O 2 -NH-C(=NH)-NH 2 , -NH-C(=NH)-NH-CH 3 , -NH-S(=O) 2 -CH 3 , -S(=O) 2 -NH -C(=NH)-N(CH 3 ) 2 , -COOH, -COOCH 3 , -NH 2 , -N(CH 3 ) 2 or -(C=O)-NH 2 .
  13. 根据权利要求1-12任一项所述的化合物，其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其中，所述化合物是选自下述的化合物，The compound according to any one of claims 1 to 12, which is a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form or prodrug thereof, wherein the compound is selected from the group consisting of Compound,
    Figure PCTCN2016000478-appb-100006
    Figure PCTCN2016000478-appb-100006
    Figure PCTCN2016000478-appb-100007
    Figure PCTCN2016000478-appb-100007
    Figure PCTCN2016000478-appb-100008
    Figure PCTCN2016000478-appb-100008
  14. 根据权利要求1-13任一项所述的化合物、其药学上可接受的盐或酯、溶剂化物、水合物、异构体、晶型或其前药，其用作二肽基肽酶-IV抑制剂。A compound according to any one of claims 1 to 13, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer, crystal form thereof or a prodrug thereof, which is used as a dipeptidyl peptidase IV inhibitor.
  15. 根据权利要求1所述的化合物的制造方法，其包括下述方案1所示的合成方法，The method for producing a compound according to claim 1, which comprises the synthesis method shown in the following Scheme 1,
    Figure PCTCN2016000478-appb-100009
    Figure PCTCN2016000478-appb-100009
    式中，A3～A6、Ar、R1和R2均与权利要求1中具有相同的意思，Wherein A 3 to A 6 , Ar, R 1 and R 2 have the same meanings as in claim 1.
    使式(2)所示的酮和式(3)所示的胺在0-50℃、优选10-40℃的温度下进行0.5-30小时、优选1-12小时的还原胺化，得到式(4)所示的还原胺化产物，将所述得到的产物进一步在pH为2～6的酸性条件下脱去氨基保护基，获得通式(1)所示的化合物，The ketone represented by the formula (2) and the amine represented by the formula (3) are subjected to reductive amination at a temperature of 0 to 50 ° C, preferably 10 to 40 ° C for 0.5 to 30 hours, preferably 1 to 12 hours. (4) a reductive amination product as shown, and further removing the amino-protecting group under acidic conditions having a pH of 2 to 6 to obtain a compound represented by the formula (1).
    其中，在式(4)所示的化合物中B环为饱和环时，通过DDQ在10-40℃下氧化反应4-10小时获得氧化产物，然后在卤代羧酸、优选三 氟乙酸作用下10-40℃，反应10-16小时脱掉Boc保护，得到B环中具有两个双键的对应化合物，反应方案如下：Wherein, in the compound represented by the formula (4), when the ring B is a saturated ring, the oxidation product is obtained by oxidation reaction at 10-40 ° C for 4-10 hours by DDQ, and then the halogenated carboxylic acid, preferably three Under the action of fluoroacetic acid at 10-40 ° C, the reaction is removed for 10-16 hours to remove Boc protection, and the corresponding compound having two double bonds in the B ring is obtained. The reaction scheme is as follows:
    Figure PCTCN2016000478-appb-100010
    Figure PCTCN2016000478-appb-100010
  16. 根据权利要求15所述的化合物的制造方法，其中，上述方案1中的式(3)所示的胺化合物为
    Figure PCTCN2016000478-appb-100011
    其利用下述方案2所示的合成方法制造，    The method for producing a compound according to claim 15, wherein the amine compound represented by the formula (3) in the first embodiment is
    Figure PCTCN2016000478-appb-100011
    It is produced by the synthesis method shown in the following scheme 2,
    Figure PCTCN2016000478-appb-100012
    Figure PCTCN2016000478-appb-100012
    使3-N-Boc-吡咯烷酮与DMF-DMA在0-50℃、优选10-40℃下反应1-24小时、优选2-12小时，得到1-叔丁氧基羰基-3-((二甲氨基)甲烯基)-4-吡咯烷酮，在碱金属醇盐、优选乙醇钠的作用下，使硫酸甲硫基脒与1-叔丁氧基羰基-3-((二甲氨基)甲烯基)-4-吡咯烷酮在10-100℃、优选30-50℃下回流0.5-48小时、优选2-24小时，得到2-(甲硫基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯，使该2-(甲硫基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯与间氯过氧苯甲酸等的氧化试剂在10-40℃、优选室温下反应，得到2-(甲砜基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯，然后在卤代羧酸、优选三氟乙酸的作用下脱去Boc保护基，获得目标产物2-(甲砜基)-6，7--二氢-5H-吡咯[3，4-d]嘧啶。3-N-Boc-pyrrolidone is reacted with DMF-DMA at 0-50 ° C, preferably 10-40 ° C for 1-24 hours, preferably 2-12 hours, to give 1-tert-butoxycarbonyl-3-((2) Methylamino)methenyl)-4-pyrrolidone, methyl mercaptosulfate and 1-tert-butoxycarbonyl-3-((dimethylamino)methene under the action of an alkali metal alkoxide, preferably sodium ethoxide 4-pyrrolidone is refluxed at 10-100 ° C, preferably 30-50 ° C for 0.5-48 hours, preferably 2-24 hours, to give 2-(methylthio)-5H-pyrrole[3,4-d]pyrimidine -6(7H)-tert-butyl carboxylic acid, the 2-(methylthio)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester and m-chloroperoxybenzene An oxidizing reagent such as formic acid is reacted at 10-40 ° C, preferably at room temperature to obtain 2-(methylsulfonyl)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester, and then The Boc protecting group is removed by the action of a halogenated carboxylic acid, preferably trifluoroacetic acid, to give the desired product 2-(methylsulfonyl)-6,7-dihydro-5H-pyrrole[3,4-d]pyrimidine.
  17. 根据权利要求15或16所述的化合物的制造方法，其中，The method for producing a compound according to claim 15 or 16, wherein
    利用上述
    Figure PCTCN2016000478-appb-100013
    通过下述方案得到
    Figure PCTCN2016000478-appb-100014
    Use the above
    Figure PCTCN2016000478-appb-100013
    Obtained by the following scheme
    Figure PCTCN2016000478-appb-100014
    Figure PCTCN2016000478-appb-100015
    Figure PCTCN2016000478-appb-100015
    使2-(甲砜基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯与四正丁基氰化胺在5-45℃、优选10-40℃下反应0.5-24小时、优选1-12小时，得到2-(氰基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯，该得到的2-(氰基)-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯在酸的存在下，进行氰基醇解和脱Boc反应，获得目标产物。2-(Methylsulfonyl)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester with tetra-n-butyl cyanamide at 5-45 ° C, preferably 10-40 ° C The lower reaction is carried out for 0.5-24 hours, preferably 1-12 hours, to give 2-(cyano)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester, which gives 2-( The cyano)-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester is subjected to cyano alcoholysis and de Boc reaction in the presence of an acid to obtain the desired product.
  18. 根据权利要求15所述的化合物的制造方法，其中，上述方案1中的式(3)所示的胺化合物为
    Figure PCTCN2016000478-appb-100016
    其利用下述方案3所示的合成方法制造，    The method for producing a compound according to claim 15, wherein the amine compound represented by the formula (3) in the first embodiment is
    Figure PCTCN2016000478-appb-100016
    It is produced by the synthesis method shown in the following scheme 3,
    Figure PCTCN2016000478-appb-100017
    Figure PCTCN2016000478-appb-100017
    式中，R与前述R3具有相同的意思，Wherein R has the same meaning as the above R 3 ,
    在碱金属醇盐、优选乙醇钠作用下，使硫脲与1-叔丁氧基羰基-3-((二甲氨基)甲烯基)-4-吡咯烷酮在10-100℃、优选30-50℃下回流0.5-48小时、优选2-24小时，得到2-巯基-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯，使该2-巯基-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯在碱存在下与卤代烃在5-45℃、优选10-40℃下反应0.5-24小时、优选1-12小时，获得烷基化产物，使该得到的烷基化产物与间氯过氧苯甲酸等的氧化试剂在10-40℃、优选室温下反应，得到氧化产物，然后在卤代羧酸、优选三氟乙酸作用下脱去Boc保护基，得到目标产物氨基化合物。The thiourea and 1-tert-butoxycarbonyl-3-((dimethylamino)methenyl)-4-pyrrolidone are subjected to 10-100 ° C, preferably 30-50, under the action of an alkali metal alkoxide, preferably sodium ethoxide. Reflux at ° C for 0.5-48 hours, preferably 2-24 hours, to give 2-mercapto-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester, such 2-meryl-5H- Pyrrole [3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester is reacted with a halogenated hydrocarbon in the presence of a base at 5-45 ° C, preferably 10-40 ° C for 0.5-24 hours, preferably 1-12 In an hour, an alkylation product is obtained, and the obtained alkylation product is reacted with an oxidizing agent such as m-chloroperoxybenzoic acid at 10 to 40 ° C, preferably at room temperature to obtain an oxidation product, and then a halogenated carboxylic acid, preferably The Boc protecting group is removed by the action of trifluoroacetic acid to obtain the target product amino compound.
  19. 根据权利要求15所述的化合物的制造方法，其中，上述方案 1中的式(3)所示的胺化合物为
    Figure PCTCN2016000478-appb-100018
    其利用下述方案4所示的合成方法制造，    The method for producing a compound according to claim 15, wherein the amine compound represented by the formula (3) in the first embodiment is
    Figure PCTCN2016000478-appb-100018
    It is produced by the synthesis method shown in the following scheme 4,
    Figure PCTCN2016000478-appb-100019
    Figure PCTCN2016000478-appb-100019
    式中，R1和R2各自独立地为氢或选自前述取代基组a中的任意基团，Wherein R 1 and R 2 are each independently hydrogen or any group selected from the group of substituents a above,
    将2-巯基-5H-吡咯[3，4-d]嘧啶-6(7H)-羧酸叔丁酯用氯气氧化1-20小时、优选2-6小时后，用胺化合物淬灭，获得磺酰胺产物，然后在卤代羧酸、优选三氟乙酸作用下脱去Boc保护基，获得氨基化合物。The 2-mercapto-5H-pyrrole[3,4-d]pyrimidin-6(7H)-carboxylic acid tert-butyl ester is oxidized with chlorine gas for 1 to 20 hours, preferably 2 to 6 hours, and then quenched with an amine compound to obtain a sulfonate. The amide product is then deprotected with a halogenated carboxylic acid, preferably trifluoroacetic acid, to give the amino compound.
  20. 药物组合物，其含有权利要求1～14中任一项所述的化合物、其药学上可接受的盐或酯、溶剂化物、水合物、异构体、或其前药，以及药学上可以接受的载体或赋形剂。A pharmaceutical composition comprising the compound according to any one of claims 1 to 14, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer thereof, or a prodrug thereof, and a pharmaceutically acceptable Carrier or excipient.
  21. 根据权利要求20所述的药物组合物，其中，进一步包含可与权利要求1～14中任一项所述的化合物、其药学上可接受的盐或酯、溶剂化物、水合物、异构体、或其前药，联用的其它活性物质。The pharmaceutical composition according to claim 20, further comprising a compound according to any one of claims 1 to 14, a pharmaceutically acceptable salt or ester, solvate, hydrate or isomer thereof , or its prodrug, other active substances used in combination.
  22. 根据权利要求21所述的药物组合物，其中，所述其它活性物质为二甲双胍或其盐、或匹格列酮等。The pharmaceutical composition according to claim 21, wherein the other active substance is metformin or a salt thereof, or pioglitazone or the like.
  23. 根据权利要求20或21所述的药物组合物，其中，含有权利要求1～14中任一项所述的化合物0.01-1000mg，适宜为0.5-800mg，优选为1-400mg，更优选为5-200mg，特别优选10-100mg，最优选15-50mg。The pharmaceutical composition according to claim 20 or 21, which comprises 0.01 to 1000 mg of the compound according to any one of claims 1 to 14, suitably 0.5 to 800 mg, preferably 1 to 400 mg, more preferably 5 to 200 mg, particularly preferably 10-100 mg, most preferably 15-50 mg.
  24. 一种适合施用给哺乳动物的药物制剂，其中，包含权利要求1～14中任一项所述的化合物、其药学上可接受的盐或酯、溶剂化物、水合物、异构体、或其前药作为有效成分，该药物制剂包括固体制剂、半固体制剂、液体制剂、气态制剂。A pharmaceutical preparation suitable for administration to a mammal, comprising the compound according to any one of claims 1 to 14, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer thereof, or A prodrug is used as an active ingredient, and the pharmaceutical preparation includes a solid preparation, a semisolid preparation, a liquid preparation, and a gaseous preparation.
  25. 与二肽基肽酶-IV相关的疾病的治疗或预防剂，其含有权利要求1～14中任一项所述的化合物、其药学上可接受的盐或酯、溶剂化物、水合物、异构体、或其前药作为有效成分。A therapeutic or prophylactic agent for a disease associated with dipeptidyl peptidase-IV, which comprises the compound according to any one of claims 1 to 14, a pharmaceutically acceptable salt or ester, solvate, hydrate or the like The construct, or a prodrug thereof, is used as an active ingredient.
  26. 权利要求1～14中任一项所述的化合物、其药学上可接受的盐或酯、溶剂化物、水合物、异构体、或其前药，或其与其它活性物质联 用的组合物在用于制备治疗与二肽基肽酶-IV相关的疾病的药物中的应用。A compound according to any one of claims 1 to 14, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer thereof, or a prodrug thereof, or a combination thereof with other active substances Use of a composition for the preparation of a medicament for the treatment of a disease associated with dipeptidyl peptidase-IV.
  27. 根据权利要求26所述的应用，其中与二肽基肽酶-IV相关的疾病包括糖尿病、肥胖症、胰岛素抵抗症或高血脂。The use according to claim 26, wherein the disease associated with dipeptidyl peptidase-IV comprises diabetes, obesity, insulin resistance or hyperlipidemia.
  28. 权利要求1～14中任一项所述的化合物、其药学上可接受的盐或酯、溶剂化物、水合物、异构体、或其前药，或其与其它活性物质联用的组合物用于治疗与二肽基肽酶-IV相关的疾病的方法。A compound according to any one of claims 1 to 14, a pharmaceutically acceptable salt or ester, solvate, hydrate, isomer thereof, or a prodrug thereof, or a combination thereof with other active substances A method for treating a disease associated with dipeptidyl peptidase-IV.
  29. 根据权利要求28所述的方法，其中，所述权利要求1～14中任一项所述的化合物的单位剂量0.01-1000mg，适宜为0.5-800mg，优选为1-400mg，更优选为5-200mg，特别优选10-100mg，最优选15-50mg。 The method according to claim 28, wherein the compound according to any one of claims 1 to 14 has a unit dose of 0.01 to 1000 mg, suitably 0.5 to 800 mg, preferably 1 to 400 mg, more preferably 5 to 200 mg, particularly preferably 10-100 mg, most preferably 15-50 mg.
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