WO2015192714A1 - Dérivé de cycle pyrrolo-imidazole et son usage médical - Google Patents

Dérivé de cycle pyrrolo-imidazole et son usage médical Download PDF

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WO2015192714A1
WO2015192714A1 PCT/CN2015/080570 CN2015080570W WO2015192714A1 WO 2015192714 A1 WO2015192714 A1 WO 2015192714A1 CN 2015080570 W CN2015080570 W CN 2015080570W WO 2015192714 A1 WO2015192714 A1 WO 2015192714A1
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group
alkyl
formula
compound
cycloalkyl
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PCT/CN2015/080570
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English (en)
Chinese (zh)
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范江
张晨
彭飞
吴也
冯建川
王健民
郑苏欣
魏用刚
叶飞
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四川海思科制药有限公司
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Priority to CN201580001870.3A priority Critical patent/CN105531277B/zh
Publication of WO2015192714A1 publication Critical patent/WO2015192714A1/fr
Priority to HK16105529.1A priority patent/HK1217491A1/zh

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—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 a pyrroloimidazole ring derivative and its use in medicine, in particular to a pyrrolomidazole ring derivative of the formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof and the same
  • DPP-IV dipeptidyl peptidase IV
  • Diabetes is a major medical problem worldwide. According to the International Diabetes Federation (IDF), the number of people with diabetes worldwide reached 382 million in 2013, and global medical expenses reached 548 billion US dollars, accounting for 11% of global medical expenditure. The global medical cost associated with diabetes is expected to reach $627.3 billion by 2035.
  • Insulin is a hormone required to convert sucrose, starch and other foods into energy. Diabetes is usually caused by the inability of the body to secrete or properly utilize insulin. Diabetes is usually classified into type 1 diabetes (or insulin-dependent diabetes mellitus, IDDM) and type 2 diabetes (or non-insulin-dependent diabetes mellitus, NIDDM). The most common type of diabetes is type 2 diabetes, which accounts for approximately 90% of all diabetes worldwide. The incidence of type 2 diabetes is gradually increasing due to modern unhealthy lifestyles such as reduced exercise and high-calorie diets. The huge market potential has attracted a large number of pharmaceutical companies and research centers to develop new anti-diabetic targets and drugs.
  • the currently approved drugs for the treatment of type 2 diabetes are insulin and its analogues, sulfonylureas, biguanides, thiazolidinediones (TZDs), alpha-glucosidase inhibitors, and amylin analogues.
  • Incretin hormone analogue dipeptidyl peptidase inhibitor (DPP-IV), and the like.
  • HbA1c glycated hemoglobin
  • these hypoglycemic agents have side effects such as hypoglycemia, weight gain and cardiovascular risk. These side effects add to the burden on diabetics. Therefore, there is an urgent need to develop a new type of hypoglycemic agent with high efficacy and few side effects for type 2 diabetes.
  • Dipeptidyl Peptidase IV (DPP-IV, EC 3.4.14.5) is a serine protease that hydrolyzes N-terminally from the N-position of the N-terminus of L-valine and L-alanine-containing peptides. Peptide. Although the function of DPP-IV has not been fully elucidated, it is considered to be a major physiological regulator of certain regulatory polypeptides, neuropeptides, circulating hormones, and chemokines. DPP-IV, although a multi-effect enzyme, has many substrates, but is best known as incretin, which includes glucagon-like peptide-1 (GLP-1) and glycoprotein-dependent insulin releasing peptide (GIP). ).
  • GLP-1 glucagon-like peptide-1
  • GIP glycoprotein-dependent insulin releasing peptide
  • Incretin is an intestinal hormone that secretes and promotes the intake of nutrients within minutes of ingestion of nutrients.
  • GLP-1 and GIP have the same effect on beta cells, which can improve beta cell function, including promoting glucose-dependent insulin secretion, inducing beta cell proliferation, and enhancing anti-apoptotic effects (Diabetes and Vascular Disease Research 20063: 159).
  • GLP-1 Unlike GIP, GLP-1 still promotes insulin secretion in type 2 diabetes, and therefore, increasing GLP-1 is a promising means of treating type 2 diabetes (Pharmacol Rev 60: 470–512, 2008).
  • the use of GLP-1 in patients with type 2 diabetes can significantly lower blood glucose (Lancet, 2002, 359: 824-830).
  • GLP-1, as a substrate for DPP-IV is rapidly hydrolyzed and inactivated in vivo, so DPP- IV inhibitors are of great importance for the treatment of diabetes.
  • DPP-IV inhibitor research has made great progress, and DPP-IV inhibitors including sitagliptin, saxagliptin and alogliptin have been approved for marketing and entered clinical use.
  • DPP-IV inhibitors including sitagliptin, saxagliptin and alogliptin have been approved for marketing and entered clinical use.
  • the most striking feature of DPP-IV inhibitors is that since incretin is secreted only after eating in the body, DPP-IV inhibitors are not easy to increase insulin levels when inappropriate, resulting in many side effects of hypoglycemic drugs.
  • Recent clinical data have shown that inhibition of DPP-IV increases insulin secretion, lowers blood glucose levels, and improves islet beta cell function (Diabetes, 1998, 47: 1253-1258).
  • Common side effects of DPP-IV inhibitors are respiratory infections, sore throat, diarrhea, flu-like symptoms, headache and dizziness.
  • diabetes mainly type 2 diabetes
  • the incidence of diabetes is increasing year by year in the world, becoming the third non-communicable disease that threatens people's health and life after cardiovascular disease and cancer.
  • the treatment of diabetes poses a heavy burden on families and society. Therefore, there is an urgent need to develop more updated and better DPP-IV inhibitor drugs to meet the needs of patients in clinical medicine.
  • Ar is selected from phenyl substituted with 1 to 5 substituents selected from the group consisting of halogen, hydroxy, C 1-6 alkyl;
  • V is selected from And the like, and R 3a and R 3b are independently selected from hydrogen, C 1-4 alkyl substituted by 1 to 5 fluorine atoms; R 2 is selected from the group consisting of hydrogen, hydroxy, halogen, carboxyl and the like; R 8 is selected A group such as hydrogen, -(CH 2 ) p -phenyl, but no methylsulfonyl; is not considered to be a part of the present invention.
  • DPP-IV dipeptidyl peptidase IV
  • Ar is selected from the group consisting of hydrogen, alkyl, and the like;
  • R 3a and R 3b are selected from C 1-4 alkyl groups independently selected from hydrogen and substituted by 1 to 5 fluorine atoms;
  • R 2 is selected from the group consisting of hydrogen, hydroxyl, halogen, carboxyl and the like;
  • R 8 is selected A group such as -S(O) 2 -C 1-6 cycloalkyl, -S(O) 2 -C 1-6 alkyl; is not considered to be a part of the invention.
  • WO2011103256 discloses a compound having a structure having a DPP-IV inhibitor action as a prophylactic and/or therapeutic drug for diabetes, wherein:
  • Ar is phenyl optionally substituted by 1 to 5 groups independently selected from the group consisting of halogen, cyano, hydroxy, and the like;
  • V is selected from And the like, and R 2 is selected from the group consisting of hydrogen, hydroxy, cyano, halogen, alkyl, alkoxy, carbonyl, etc.; R 3a , R 3b are selected from hydrogen or optionally substituted with from 1 to 5 fluorine atoms.
  • WO2007126745 discloses a DPP-IV inhibitor compound of the following structure for the treatment of diabetes, wherein:
  • Ar is selected from a substituted or unsubstituted phenyl group, and when substituted, the phenyl group is substituted with 1-3 selected from a halogen, a hydroxyl group, a C 1-6 alkyl group or the like;
  • V is selected from And the like, and R 2 is selected from the group consisting of hydrogen, hydroxy, halogen, alkenyl, alkynyl, aryl, heteroaryl, etc.; R 3a , R 3b are selected from hydrogen, C 1- substituted by 1 to 5 fluorine atoms 4 alkyl; R 8 is selected from the group consisting of H, cycloalkyl, phenyl, alkyl, and the like; it is not considered to be a part of the invention as specifically described in this patent.
  • WO2011103256, WO2008060488, WO2007087231, WO2011037793, WO2011028455, WO2009025784, etc. also disclose about DPP-IV inhibitor compounds for the treatment of diabetes.
  • the main object of the present invention is to provide a novel class of DPP-IV inhibitors, in particular having the compounds of the formula (I), which have been shown to have good dipeptidyl peptidase IV (DPP).
  • DPP dipeptidyl peptidase IV
  • the present invention relates to a pyrroloimidazole ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof:
  • R 1 and R 2 are formed together with the atoms to which they are attached
  • R 3 is selected from H, F, Cl, Br or I, preferably H or F, further preferably H;
  • R 4 and R 5 are each independently selected from H, F, Cl, Br, I or C 1-8 alkyl, optionally further substituted by 0 to 5 substituents selected from F, Cl or hydroxy Substituting; preferably R 4 and R 5 are each independently selected from H, F, Cl, Br, I or -CF 3 ; further preferably R 4 and R 5 are each independently selected from H, -CF 3 or F;
  • R 2 cannot be -CF 3 ;
  • R 6 are each independently selected from H, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, C 3-15 cycloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl, - OC 3-15 cycloalkyl, -OC 6-10 aryl or -O- (5 to 10 membered heteroaryl);
  • R 7 , R 8 and R 10 are each independently selected from H, C 1-8 alkyl, C 3-15 cycloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl or 3 to 15 membered hetero a ring group; preferably R 7 and R 8 are each independently selected from H, C 1-4 alkyl or C 3-10 cycloalkyl, further preferably R 7 and R 8 are each independently selected from H, C 1-2 alkane a 3-membered heterocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group or a 6-membered heterocyclic group;
  • R 9 are each independently selected from C 1-8 alkyl, C 3-15 cycloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl or 3 to 15 membered heterocyclic; preferably C 1-8 An alkyl group, a C 3-10 cycloalkyl group or a 3- to 10-membered heterocyclic group, further preferably a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a 3-membered heterocyclic group, a 4-membered heterocyclic group, 5 members a heterocyclic group or a 6-membered heterocyclic group;
  • R 11 and R 12 are each independently selected from a hydroxyl group, a C 1-8 alkyl group or a C 1-8 alkoxy group;
  • An atom or group wherein the heterocyclic group is optionally further substituted with from 0 to 3 substituents of F, Cl, Br, I, hydroxy, 0 or amino;
  • n is selected from 0, 1 or 2, preferably 0 or 1, further preferably 0;
  • r is selected from 0, 1 or 2, preferably 0 or 1, further preferably 1;
  • n is selected from 0, 1 or 2, preferably 1 or 2, further preferably 2.
  • Preferred embodiments of the present invention include a pyrroloimidazole ring derivative represented by the formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein:
  • R 1 and R 2 are formed together with the atoms to which they are attached
  • R 3 is selected from H or F
  • R 4 and R 5 are each independently selected from H, F or -CF 3 ; preferably R 4 is selected from H or F, and R 5 is selected from H or -CF 3 ;
  • R 2 cannot be -CF 3 ;
  • R 6 are each independently selected from H, hydroxy, C 1-4 alkyl or C 1-6 alkoxy; preferably H, hydroxy, C 1-4 alkyl or C 1-4 alkoxy;
  • R 7 and R 8 are each independently selected from H, C 1-4 alkyl or C 3-10 cycloalkyl, preferably R 7 and R 8 are each independently selected from H, C 1-2 alkyl, 3 membered hetero a cyclo group, a 4-membered heterocyclic group, a 5-membered heterocyclic group or a 6-membered heterocyclic group;
  • R 7 and R 8 together with the nitrogen atom to which they are attached form a 3- to 6-membered heterocyclic group, preferably a 3-membered heterocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group or a 6-membered heterocyclic group.
  • R 9 is each independently selected from C 1-8 alkyl, C 3-10 cycloalkyl or 3 to 10 membered heterocyclic, preferably C 1-6 alkyl, C 3-6 cycloalkyl, 3 membered heterocyclic ring a 4-membered heterocyclic group, a 5-membered heterocyclic group or a 6-membered heterocyclic group;
  • n is selected from 0, 1 or 2;
  • r is selected from 0, 1 or 2, preferably 0 or 1, further preferably 1;
  • n is selected from 0, 1 or 2, preferably n is selected from 1 or 2.
  • Preferred embodiments of the present invention include a pyrroloimidazole ring derivative represented by the formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein:
  • the base, alkoxy, alkenyl, alkynyl, cycloalkyl, heteroaryl or heterocyclic group is optionally further substituted by 0 to 3 selected from the group consisting of F, hydroxy
  • R 1 and R 2 are formed together with the atoms to which they are attached
  • R 3 is selected from H or F, preferably H;
  • R 4 and R 5 are each independently selected from H, F or -CF 3 ; preferably R 4 is selected from H or F, R 5 is selected from H or -CF 3 ; further preferably R 4 is selected from H and R 5 is selected from H Or -CF 3 , still more preferably R 5 is selected from H;
  • R 4 and R 5 are selected from H, R 2 cannot be -CF 3 ;
  • R 6 are each independently selected from H, hydroxy, C 1-4 alkyl or C 1-4 alkoxy, preferably hydroxy or C 1-2 alkoxy;
  • R 7 and R 8 are each independently selected from H, C 1-3 alkyl or C 3-10 cycloalkyl, preferably H, C 1-3 alkyl or C 3-6 cycloalkyl;
  • R 7 and R 8 together with the nitrogen atom to which they are attached form a 3- to 6-membered heterocyclic group, preferably a 3-membered heterocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group or a 6-membered heterocyclic group.
  • R 9 is each independently selected from C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 6 membered heterocyclic group, preferably C 1-4 alkyl, C 3-6 cycloalkyl, 3 membered heterocyclic ring a 4-membered heterocyclic group, a 5-membered heterocyclic group or a 6-membered heterocyclic group;
  • n is selected from 0 or 1, preferably 0;
  • r is selected from 0 or 1, further preferably 1;
  • n is selected from 1 or 2, preferably 2.
  • Preferred embodiments of the present invention include a pyrroloimidazole ring derivative represented by the formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein:
  • R 1 is selected from the group consisting of H, methyl, ethyl, -CHF 2 , -CF 3 , isopropyl, tert-butyl, 2-hydroxyethyl, 2-hydroxypropyl, vinyl, propenyl, n-butenyl , 2-butenyl, ethynyl, propynyl, n-butynyl, 2-butynyl, cyclopropyl, cyclobutyl, cyclopentyl, methylsulfonyl, ethylsulfonyl, cyclopropyl Sulfonyl,
  • R 2 is selected from the group consisting of H, cyano, methyl, ethyl, 1-hydroxyethyl, 1-fluoroethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, cyclopropyl, Cyclobutyl, methylsulfonyl, methylsulfinyl, ethylsulfonyl, cyclopropylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, -CH 2 F, -CHF 2 , -CH 2 OH, -CH 2 OCOCH 3 ,
  • R 1 and R 2 are formed together with the atoms to which they are attached
  • R 3 is selected from H or F
  • R 4 is selected from H or F
  • R 5 is selected from H or -CF 3 ;
  • R 14, R 15 are each independently selected from H, C 1-4 alkyl or 1-5 C 1-4 alkyl substituted with F;
  • q is selected from 0, 1, 2, 3 or 4.
  • Preferred embodiments of the present invention include a pyrroloimidazole ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof, wherein:
  • R 1 is selected from the group consisting of H, methyl, ethyl, -CHF 2 , -CF 3 , isopropyl, tert-butyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-butynyl, cyclopropyl, Methylsulfonyl, ethylsulfonyl, cyclopropylsulfonyl, Preferred is H, methyl, ethyl, methylsulfonyl or
  • R 2 is selected from the group consisting of H, cyano, methyl, ethyl, 1-hydroxyethyl, 1-fluoroethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, cyclopropyl, Cyclobutyl, methylsulfonyl, methylsulfinyl, ethylsulfonyl, cyclopropylsulfonyl, isopropylsulfonyl, -CH 2 F, -CHF 2 , -CH 2 OH, -CH 2 OCOCH 3 , Preferred are cyano, methyl, ethoxy, cyclopropyl, methylsulfonyl, methylsulfinyl, cyclopropylsulfonyl,
  • R 1 and R 2 are formed together with the atoms to which they are attached Optimal
  • R 3 is H
  • R 4 is H, and R 5 is selected from H or -CF 3 , and preferably R 5 is H.
  • the compound includes, but is not limited to:
  • the present invention relates to an intermediate for synthesizing a pyrroloimidazole ring derivative represented by the formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof as shown in the following formula (II) Or its stereoisomer:
  • R 1 is selected from the group consisting of H, methyl, ethyl, -CH 2 F, -CHF 2 , -CF 3 , isopropyl, tert-butyl, cyclopropyl, 2-butynyl, methylsulfonyl,
  • R 1 and R 2 are formed together with the atoms to which they are attached
  • Q is selected from H or an amino protecting group
  • R 6 is selected from the group consisting of H, hydroxy, C 1-8 alkyl, C 1-8 alkoxy, C 3-15 cycloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl, -OC 3- 15 cycloalkyl, -OC 6-10 aryl or -O- (5 to 10 membered heteroaryl);
  • R 7 and R 8 are each independently selected from H, C 1-8 alkyl, C 3-15 cycloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl or 3 to 15 membered heterocyclic;
  • R 9 is selected from C 1-8 alkyl, C 3-15 cycloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl or 3 to 15 membered heterocyclic;
  • n is selected from 0, 1 or 2;
  • r is selected from 0, 1 or 2;
  • q is selected from 0, 1, 2, 3 or 4;
  • R 14 and R 15 are each independently selected from C 1-4 alkyl, C 3-6 cycloalkyl or C 1-4 alkyl substituted by 1 to 5 F.
  • R 1 is selected from the group consisting of H, methyl, ethyl, -CF 3 , isopropyl, -CH 2 F, -CHF 2 , methylsulfonyl,
  • R 1 and R 2 are formed together with the atoms to which they are attached
  • Q is selected from the group consisting of H, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl or benzyloxycarbonyl;
  • R 6 is selected from H, hydroxy, C 1-6 alkyl, C 1-6 alkoxy or C 3-10 cycloalkyl;
  • R 7 and R 8 are each independently selected from H, C 1-6 alkyl or C 3-10 cycloalkyl;
  • R 9 is selected from C 1-6 alkyl or C 3-10 cycloalkyl
  • n is selected from 0, 1, or 2.
  • the pyrrolomidazole ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug intermediate represented by the formula (I) or Its stereoisomer is selected from:
  • Q is selected from the group consisting of H, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl or benzyloxycarbonyl.
  • the present invention also relates to a pyrrolimidazole ring derivative represented by the general formula (I), or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof, represented by the following formula (II-B) Intermediate or its stereoisomer:
  • R 1 , R 2 , R 3 , R 4 and R 5 are consistent with the above;
  • P is an amino protecting group.
  • R 1 and R 2 are formed together with the atoms to which they are attached
  • R 3 is selected from H
  • R 4 and R 5 are each independently selected from H, F or -CF 3 ;
  • R 2 cannot be -CF 3 ;
  • R 6 is selected from H, hydroxy, C 1-4 alkyl or C 1-4 alkoxy
  • R 7 and R 8 are each independently selected from H, C 1-3 alkyl or C 3-10 cycloalkyl;
  • R 9 is selected from C 1-6 alkyl, C 3-7 cycloalkyl or 3 to 6 membered heterocyclic;
  • n is selected from 0 or 1;
  • r is selected from 0 or 1;
  • n is selected from 0, 1 or 2, preferably 1 or 2.
  • the invention further relates to a process for the preparation of a pyrrolomidazole ring derivative intermediate of the formula (II), the process comprising:
  • the compound (II-A1) is reacted with the formula (II-A2) to give the compound of the formula (II-A3); the formula (II-A3) is oxidized to give the formula (II-A4); A4) Alkylation or acylation with R 1 -X 1 to give a compound of the formula (II-A5); hydrolysis of the formula (II-A5) gives a compound of the formula (II-A6); -A6) the condensation reaction of the compound to obtain the compound of the formula (II);
  • R 2a is selected from H or C 1-8 alkyl
  • R 2b is selected from C 1-8 alkoxy, -SC 1-8 alkyl or -NR 7 R 8 ;
  • R 1 is selected from the group consisting of H, methyl, ethyl, -CH 2 F, -CHF 2 , -CF 3 , isopropyl, tert-butyl, cyclopropyl, 2-butynyl, methylsulfonyl,
  • R 7 and R 8 are each independently selected from H, C 1-8 alkyl, C 3-15 cycloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl or 3 to 15 membered heterocyclic;
  • Q is an amino protecting group
  • n is selected from 0, 1 or 2;
  • X 1 is a leaving group, preferably a halogen.
  • R 1 is selected from H, methyl, ethyl, -CH 2 F, -CHF 2 , -CF 3 , isopropyl, tert-butyl, cyclopropyl, 2-butynyl, methylsulfonyl or
  • R 7 and R 8 are each independently selected from H, methyl, ethyl, isopropyl or t-butyl;
  • R 7 and R 8 together with the nitrogen atom to which they are attached form a five-membered heterocyclic or six-membered heterocyclic group;
  • Q is a tert-butoxycarbonyl group
  • X 1 is selected from the group consisting of I, Cl, Br or F.
  • the present invention relates to a process for the preparation of a pyrrolomidazole ring derivative intermediate of the formula (II), which comprises:
  • R 1 , R 9 , n are as defined above;
  • Q is an amino protecting group
  • L 1 is a leaving group
  • R 1 is selected H, C 1-4 alkyl or 1-3 C 1-4 alkyl substituted with F;
  • Q is selected from the group consisting of t-butoxycarbonyl, benzyloxycarbonyl, benzyl or 9-fluorenylmethoxycarbonyl;
  • R 9 is selected from C 1-4 alkyl or -C 3-10 cycloalkyl, wherein the alkyl or cycloalkyl group is optionally further substituted with 0 to 3 F;
  • n is selected from 0, 1 or 2, preferably 2;
  • L 1 is selected from the group consisting of F, Cl, Br, I or imidazolyl.
  • the present invention relates to an intermediate for synthesizing a pyrroloimidazole ring derivative represented by the formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof as shown in the following formula (III) Or its stereoisomer:
  • R 3 is selected from H, F, Cl, Br or I;
  • P is an amino protecting group.
  • the present invention relates to a process for producing an intermediate of a synthetic pyrrolomidazole ring derivative represented by the formula (III), which is a method
  • the law includes:
  • the compound of the formula (IA-9) is reacted with a secondary amine compound NHR 20 R 21 to give a compound of the formula (IA-10);
  • R 3 is selected from H, F, Cl, Br or I;
  • P is an amino protecting group
  • R 20 and R 21 are each independently selected from H or C 1-8 alkyl
  • n is selected from 0, 1, or 2.
  • R 3 is selected from H or F
  • P is selected from the group consisting of t-butoxycarbonyl, benzyloxycarbonyl, benzyl or 9-fluorenylmethoxycarbonyl;
  • R 20 and R 21 form a morpholine ring with the attached nitrogen atom.
  • the present invention relates to a process for the preparation of a pyrroloimidazole ring derivative of the formula (I), which comprises:
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above;
  • P is an amino protecting group.
  • the present invention relates to a process for the preparation of a pyrroloimidazole ring derivative of the formula (I), which comprises:
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above;
  • X 1 is selected from a leaving group, preferably a halogen
  • P is an amino protecting group.
  • R 3 is selected from H or F
  • R 4 is selected from H
  • R 5 is selected from H or -CF 3 ;
  • R 6 is selected from H, hydroxy, C 1-8 alkyl or C 1-8 alkoxy;
  • R 7 and R 8 are each independently selected from H or C 1-8 alkyl
  • R 9 is selected from C 1-8 alkyl or C 3-15 cycloalkyl
  • n is selected from 0, 1 or 2, preferably 2;
  • P is selected from the group consisting of t-butoxycarbonyl, benzyloxycarbonyl, benzyl or 9-fluorenylmethoxycarbonyl.
  • the present invention relates to a process for the preparation of a pyrroloimidazole ring derivative of the formula (I), which comprises:
  • R 1 , R 7 , R 8 are identical to those described above;
  • R 3 is selected from H or F
  • R 4 is H
  • R 5 is selected from H or -CF 3 ;
  • R 13 is a C 1-8 alkoxy group
  • P is an amino protecting group.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising: an effective amount of a pyrroloimidazole ring derivative represented by the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt or a prodrug thereof Or further comprising one or more additional therapeutic agents; and a pharmaceutically acceptable carrier or excipient.
  • the present invention also relates to a method for treating a metabolic disease, which comprises administering to a subject an effective amount of the pyrrolomidazole ring derivative represented by the above formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof.
  • a prodrug or the pharmaceutical composition wherein the metabolic disease includes diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, fatty acid or glycerol Elevated levels, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, diabetic complications, atherosclerosis or hypertension.
  • the diabetes is type II diabetes.
  • the present invention also relates to a compound of the formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, and a composition thereof or The use of a prodrug thereof for the preparation of a dipeptidyl peptidase-IV inhibitor, wherein the dipeptidyl peptidase-IV inhibitor is used for the preparation of a medicament for treating a metabolic disease, wherein the metabolic disease is selected from the group consisting of Diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia , X syndrome, diabetic complications, atherosclerosis or hypertension.
  • the diabetes is type II diabetes.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur, and the groups and compounds involved in the present invention.
  • the nitrogen or halogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C, and 14 C, and the hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen ), ⁇ (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes including 14 N and 15 N, the fluorine isotope 19 F, the chlorine isotope includes 35 Cl and 37 Cl, and the bromine isotopes include 79 Br and 81 Br.
  • Alkyl means a straight-chain or branched saturated aliphatic hydrocarbon group, and the main chain includes 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, further preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, still more preferably 1 to 4 C atoms of a straight chain and a branched chain, and most preferably 1 to 2 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl Base, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3 -hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3- Pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl , 5-methylhexyl, 2,2-dimethylpentyl, 2,3-d
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group, and a cyclo group.
  • Alkoxy means an -O-alkyl group wherein alkyl is as defined above. Alkoxy groups may be substituted or unsubstituted, and alkoxy embodiments include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, undertiary Butoxy, sec-butoxy, n-pentyloxy and n-hexyloxy.
  • Alkoxyalkyl means an alkyl group attached to an alkoxy group.
  • the alkoxyalkyl group can be substituted or unsubstituted, non-limiting examples of which include methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxy , propoxyethyl, 2-propoxymethyl, butoxypropyl, tert-butoxyethyl, pentyloxyethyl, hexyloxyethyl, cyclopropoxymethyl, cyclopropyl Oxyethyl, cyclopropyloxypropyl and cyclohexyloxymethyl; when substituted, the substituent is preferably from 1 to 5 selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkane Oxyl, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano, isocyano,
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • Alkenyl means an alkyl group as defined herein above containing at least one carbon-carbon double bond, preferably having from 2 to 20 carbon atoms, further preferably from 2 to 12 carbon atoms, more preferably 2 on the backbone Up to 8 carbon atoms, the alkenyl group may be substituted or unsubstituted.
  • Non-limiting examples include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentyl Alkenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1- Hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-decenyl, 3-decenyl, 1- Decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, 1,4-hexadiene, 3-
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • Alkynyl means an alkyl group as defined herein above containing at least one carbon-carbon triple bond, preferably containing from 2 to 20 carbon atoms, further preferably from 2 to 8 carbon atoms, more preferably 2 on the backbone Alkynyl group up to 4 carbon atoms.
  • An alkynyl group can be substituted or unsubstituted.
  • Non-limiting examples include ethynyl, 1-propynyl, 2-propynyl, butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 4- Pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl , 3-octynyl, 3-decynyl, 4-decynyl, 3-undynyl and 4-dodecynyl, etc.; when substituted, the substituent is preferably one or more of the following groups , independently selected from the group consisting of F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, decyl, amino, cyano, isocyano,
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • Alkylthio means -S-alkyl or -S-(unsubstituted cycloalkyl), and non-limiting examples include methylthio, ethylthio, propylthio, butylthio and the like.
  • Halogen means fluorine, chlorine, bromine, or iodine.
  • Niro means -NO 2 .
  • Haloalkyl means a halogen-substituted alkyl group as defined herein above, and non-limiting examples include monofluoromethyl, difluoromethyl, trifluoromethyl, monobromomethyl, dibromomethyl, tribromo.
  • Mercaptan refers to a hydrocarbon in which one or more hydrogen atoms in the alkyl group are replaced by a thiol group, and non-limiting examples include methyl mercaptan, ethanethiol, 1,2-dithiol.
  • Hydroxyalkyl means that the alkyl group is substituted by one or more hydroxyl groups, preferably by 1, 2 or 3 hydroxyl groups, and the alkyl group is preferably a lower alkyl group.
  • Non-limiting examples include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl, and 2,3-dihydroxypropyl, and the like.
  • Cycloalkyl means a saturated or unsaturated monocyclic cyclic hydrocarbon group which may be substituted or unsubstituted, and the ring carbon atom includes 3 to 20 carbon atoms, preferably 3 to 10 carbon atoms, further preferably 3 to 8 Carbon atoms, non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexene A group, a cycloheptenyl group, a 1,5-cyclooctadienyl group, a 1,4-cyclohexadienyl group, a cycloheptatrienyl group, and the like.
  • R b and R c may form a five- or six-membered cycloalkyl group or a heterocyclic group.
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • Heterocyclyl means substituted or unsubstituted saturated or unsaturated and contains at least 1 to 5 non-aromatic rings selected from N, O, P or S heteroatoms, and the non-aromatic ring may be 3 to 10 members.
  • a monocyclic, 4 to 20 membered spiro, ring or bridged ring, the selectively substituted N, S in the heterocyclyl ring can be oxidized to various oxidation states.
  • a 3- to 12-membered heterocyclic ring is preferred.
  • Non-limiting examples include oxiranyl, oxetanyl, oxearyl, oxetan, oxacyclooctyl, aziridine, azetidinyl, azacyclocycle Pentyl, azacyclohexyl, azacyclopropenyl, 1,3 dioxocyclopentyl, 1,4-dioxocyclopentyl, 1,3-dioxocyclohexyl, 1,3-dithiocyclohexyl , azacycloheptenyl, dihydropyran, thiadiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, 1,4-dioxadienyl, Wait.
  • R b and R c may form a five- or six-membered cycloalkyl group or a heterocyclic group.
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • R b and R c may form a five- or six-membered cycloalkyl group or a heterocyclic group.
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • Non-limiting examples include:
  • R b and R c may form a five- or six-membered cycloalkyl group or a heterocyclic group.
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • the ring atom contains 5 to 20 atoms, preferably 5 to 14 atoms, further preferably 5 to 12, and further preferably 5 to 10.
  • Non-limiting examples include And adamantane.
  • R b and R c may form a five- or six-membered cycloalkyl group or a heterocyclic group.
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • Benzyl refers to -CH 2 - phenyl, substituted or unsubstituted of substituted, non-limiting examples include -CH 2 - phenyl, -CH 2 - p-methylphenyl and the like.
  • Aryl means a substituted or unsubstituted 6 to 14 membered cyclic aromatic group, including monocyclic aromatic groups and fused ring aromatic groups.
  • a 6 to 14 membered aromatic ring is preferred, a 6 to 10 membered aromatic ring is further preferred, and non-limiting examples thereof include a phenyl group, a naphthyl group, an anthracenyl group, a phenanthryl group and the like.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
  • R b and R c may form a five- or six-membered cycloalkyl group or a heterocyclic group.
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • the ring is further preferably 5 to 6 yuan.
  • heteroaryl groups include, but are not limited to, pyridinyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Piperidinyl, morpholine, thiomorpholine, 1,3-dithiane, benzimidazole, piperidinyl, benzimidazole, benzopyridine, pyrrolopyridine and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include
  • R b and R c may form a five- or six-membered cycloalkyl group or a heterocyclic group.
  • R a and R d are each independently selected from the group consisting of an aryl group, a heteroaryl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, a carbonyl group, an ester group, a bridged ring group, a spiro group or a cyclo group.
  • Arylthio means an -S-aryl or -S-heteroaryl group as defined herein.
  • arylthio groups include, but are not limited to, phenylthio, pyridylthio, furylthio, thienylthio, and pyrimidinylthio, and the like.
  • silica refers to a group formed by the substitution of one or more hydrogen atoms in a silicon methane with an alkyl group, examples including, but not limited to, trimethylsilyl, triethylsilyl, tert-butyldimethyl Silyl and tert-butyldiphenylsilyl and the like.
  • single bond refers to a chemical single bond, such as "a single bond between A and B” means that there is a chemical single bond between A and B, namely: A-B.
  • alkyl group optionally substituted by F means that the alkyl group may, but need not, be substituted by F, indicating a case where the alkyl group is substituted by F and a case where the alkyl group is not substituted by F.
  • Carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance that is added to a pharmaceutical composition to further depend on the administration of the compound.
  • excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, Granules, lubricants, binders, disintegrants, and the like.
  • Prodrug means a compound which can be converted to a biologically active compound of the invention under physiological conditions or by solvolysis. Compound.
  • the prodrugs of the present invention are prepared by modifying an amino group, a hydroxyl group in the compound, which can be removed by conventional procedures or in vivo to give the parent compound.
  • a prodrug of the invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or hydroxyl group, respectively.
  • Certain of the compounds described herein can exist as tautomers with different hydrogen attachment points with the transfer of one or more double bonds.
  • keto-enol tautomers Both single tautomers and mixtures thereof are included within the scope of the compounds of the invention.
  • the ring may contain one or more double bonds to form an aromatic ring.
  • the compounds described herein may contain one or more asymmetric centers and may thus be racemates, racemic mixtures, single enantiomers, diastereomeric mixtures, and single diastereoisomers. presence.
  • X Syndrome refers to conditions, diseases, and conditions of metabolic syndrome.
  • X Syndrome refers to conditions, diseases, and conditions of metabolic syndrome.
  • Effective dose refers to an amount of a compound that causes a physiological or medical translation of a tissue, system or subject, which amount is sought, and includes one or more of the conditions or conditions sufficient to prevent treatment when administered to a subject. The amount of a compound that occurs or reduces it to some extent.
  • IC 50 refers to the half-inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above;
  • P is an amino protecting group.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined above;
  • X 1 is selected from a leaving group, preferably a halogen
  • P is an amino protecting group.
  • the compound of the formula (II-D) is hydrolyzed to obtain a compound of the formula (II-E); the condensation of the formula (II-E) is carried out to obtain a compound of the formula (II-F); and the compound of the formula (II-F) is removed.
  • R 1 , R 7 , R 8 are identical to those described above;
  • R 3 is selected from H or F
  • R 4 is H
  • R 5 is selected from H or -CF 3 ;
  • R 13 is a C 1-8 alkoxy group
  • P is an amino protecting group.
  • R 1 , R 2 and R 3 are as defined above, and P is an amino protecting group such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or 9-fluorenylmethoxycarbonyl (Fmoc). .
  • the intermediate IA can be prepared as follows:
  • the compound of the formula (IA-9) is reacted with a secondary amine compound NHR 20 R 21 to give a compound of the formula (IA-10);
  • R 3 is selected from H, F, Cl, Br or I;
  • P is an amino protecting group such as tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or 9-fluorenylmethoxycarbonyl (Fmoc);
  • R 20 and R 21 are each independently selected from H or C 1-8 alkyl
  • n is selected from 0, 1, or 2.
  • the compound of the present invention The compound of the formula (II) can be produced as follows:
  • the compound (II-A1) is reacted with the formula (II-A2) to give the compound of the formula (II-A3); the formula (II-A3) is oxidized to give the formula (II-A4); A4) Alkylation or acylation with R 1 -X1 to give a compound of the formula (II-A5); hydrolysis of the formula (II-A5) gives a compound of the formula (II-A6); A6) the compound is subjected to a condensation reaction to obtain a compound of the formula (II), or the formula (II-A5) is subjected to an aminolysis reaction to obtain a compound of the formula (II);
  • R 2a is selected from H or C 1-8 alkyl
  • R 2b is selected from C 1-8 alkoxy, -SC 1-8 alkyl or -NR 7 R 8 ;
  • R 1 is selected from the group consisting of H, ethyl, -CH 2 F, -CHF 2 , -CF 3 , isopropyl, tert-butyl, cyclopropyl, 2-butynyl, methylsulfonyl,
  • R 7 and R 8 are each independently selected from H, C 1-8 alkyl, C 3-15 cycloalkyl, C 6-10 aryl, 5 to 10 membered heteroaryl or 3 to 15 membered heterocyclic;
  • Q is an amino protecting group
  • X 1 is a leaving group, preferably a halogen.
  • R 1 , R 9 , n are as defined above;
  • Q is an amino protecting group
  • L 1 is a leaving group
  • NMR NMR was measured using a (Bruker ADVANCE III 400) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), internal standard. It is tetramethylsilane (TMS). For the determination of MS (Agilent 6120B (ESI)).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorba x SB-C18100x 4.6 mm).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • methyl tert-butyl ether, tetrabutylammonium bromide, sodium hydride, triphenylphosphine, trifluoroacetic acid were purchased from Chengdu Kelon Chemical Reagent Factory; di-tert-butyl dicarbonate, ethyl acetyl Imine hydrochloride, trimethyl orthoformate, N,N'-dicarbonyldiimidazole, N,O-dimethylhydroxylamine hydrochloride purchased from Ester (Chengdu) Pharmaceutical Technology Co., Ltd.; cesium carbonate, N -Hydroxysuccinimide, N,N-diisopropylethylamine, dibenzylidene glycine ethyl ester purchased from Anike Chemical; ethyl cyanoformate, 2,5-difluorobromobenzene, between Chloroperoxybenzoic acid purchased from Shanghai Demer Pharmaceutical Technology Co., Ltd.;
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon having a volume of about 2 L.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times. Unless otherwise stated in the examples, the solution means an aqueous solution.
  • the reaction temperature is room temperature. The room temperature is 20 ° C ⁇ 30 ° C.
  • Dibenzylidene glycine ethyl ester (1A) (50 g, 0.187 mol) was dissolved in methyl tert-butyl ether (300 mL) at room temperature to give propargyl besylate (44 g, 0.224 mol), four Ammonium bromide (6.1 g, 0.019 mol) was added to the reaction mixture, the temperature was raised to 50 ° C, and cesium carbonate (121.8 g, 0.374 mol) was added thereto, and the reaction was carried out at 50 ° C overnight.
  • the reaction solution was filtered, and the filter cake was washed with methyl tert-butyl ether (40 mL ⁇ 2), and the organic phase was combined, and concentrated to a half volume by rotary evaporation.
  • the liquid (3 mol/L, 100 mL) was stirred at room temperature for 1 hour, and the mixture was allowed to stand for separation.
  • the aqueous phase was extracted with methyl tert-butyl ether (70 mL ⁇ 2), and the aqueous phase was collected to obtain 1B.
  • the layers were allowed to stand, the aqueous phase was washed with methyl tert-butyl ether (80 mL ⁇ 2), the aqueous phase was adjusted to pH 3 with 3 mol/L hydrochloric acid solution, and extracted with methyl tert-butyl ether (100 mL ⁇ 2). The combined organic phases were washed with EtOAc EtOAc m.
  • 2,5-difluorobromobenzene (15.05g, 78mmol) was dissolved in dry toluene (50mL) under nitrogen, and the ice salt bath was cooled to below -10 °C.
  • Isopropylmagnesium chloride/lithium chloride tetrahydrofuran solution was added dropwise. (66 mL, 1.3 mol/L), kept stirring at about -10 ° C for 1 hour.
  • 1D (10 g, 39 mmol) was dissolved in dry tetrahydrofuran (100 mL), and added dropwise to the reaction mixture, maintaining the temperature at -10 ° C, and the reaction was carried out at room temperature for 4 hours.
  • Step 5 tert-Butyl ((1R,2S)-1-(2,5-difluorophenyl)-1-hydroxypentyl-4-yn-2-yl)carbamate (1F)
  • Step 7 tert-Butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-hydroxytetrahydro-2H-pyran-3-yl)carbamate (1H)
  • Step 8 tert-Butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-carbonyltetrahydro-2H-pyran-3-yl)carbamate (Intermediate 1 )
  • N-tert-Butoxycarbonyl-pyrroline (2A) (100 g, 0.59 mol) was dissolved in dichloromethane (600 mL), and m-chloroperoxybenzoic acid (198.70 g, 0.88 mol) was added portionwise and stirred at room temperature. hour.
  • reaction solution was slowly added to a 17% sodium thiosulfate solution (46.64 g, 0.29 mol), stirred well, filtered over Celite, and the filtrate was separated and the aqueous phase was extracted with dichloromethane (400 mL ⁇ 3)
  • the organic phase was combined and washed with a saturated aqueous solution of potassium carbonate (500 mL ⁇ 1) and a saturated sodium chloride solution (1000 mL ⁇ 1), and the organic phase was dried over anhydrous sodium sulfate. , used directly in the next step.
  • Oxalyl chloride (2.85 g, 22.5 mmoL) was dissolved in dry dichloromethane (15 mL), cooled to -78 ° C with dry ice acetone bath, and dried dimethyl sulfoxide (3.284 g, 42 mmoL) was added dropwise with stirring. Stirring was continued for 30 minutes.
  • 4A (2.11g, 10mmoL) of dichloromethane (5mL) solution was added dropwise to the reaction solution, the reaction was stirred for 20 minutes, triethylamine (10.1g, 100mmoL) was added dropwise at -78 °C, and the reaction was stirred up to room temperature. 2 hours.
  • Oxalyl chloride (652.5 mg, 5.14 mmoL) was dissolved in dry dichloromethane (15 mL), cooled to -78 ° C with dry ice acetone bath, and dried dimethyl sulfoxide (803.96 mg, 10.29mmoL) was added dropwise with stirring. Stir for 30 minutes. Reverse A solution of 5C (970 mg, 3.43 mmol) in dichloromethane (5 mL) was then evaporated. Diisopropylethylamine (2.216 g, 17.15 mmol) was added dropwise at -78 ° C, and naturally allowed to react to room temperature for 2 hours.
  • Oxyl chloride (1.24 g, 9.80 mmol) was dissolved in dichloromethane (10 mL) at room temperature under nitrogen atmosphere, cooled to -78 ° C, and dichloromethane (20 mL) dissolved dimethyl sulfoxide (1.53). g, 19.6 mmol), and the reaction was maintained at -78 ° C for 30 minutes.
  • a solution of 6B (1.26 g, 4.90 mmol) in dichloromethane (20 mL) was slowly added dropwise and the mixture was reacted at -78 ° C for 15 min.
  • Triethylamine (4.95 g, 49.0 mmol) was added to the reaction liquid, and the mixture was allowed to react to room temperature for 3 hours.
  • Step 4 tert-Butyl 2-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate (Intermediate 6)
  • Oxalyl chloride (0.749 g, 5.9 mmol) was dissolved in dichloromethane (10 mL) at room temperature under nitrogen, cooled to -78 ° C, and dimethyl sulfoxide dissolved in dichloromethane (10 mL) was slowly added dropwise. (0.914 g, 11.7 mmol), and the mixture was stirred at -78 ° C for 30 minutes.
  • 7A (1g, 3.9mmol) of dichloromethane (10mL) was added dropwise, and stirred at -78 °C for 15 minutes, N,N-diisopropylethylamine (2.5 g, 9.5 mmol) was added dropwise. The reaction was naturally raised to room temperature for 3 hours.
  • Dichloromethane 300 mL was added to the reaction mixture, and the mixture was diluted with EtOAc EtOAc (EtOAc) Concentration under reduced pressure gave a white solid 7B (1.0 g).
  • Step 3 tert-Butyl 2-cyano-1-methyl-4,6-dihydropyrrolo[3,4-d]imidazol-5(1H)-formate (Intermediate 8)
  • 3-Bromopropanol was dissolved in dichloromethane (150 mL) at room temperature, and then triethylamine (14.5 g, 14.4 mmol), acetic anhydride (14.7 g, 14.4 mmol) was added, and the mixture was reacted at room temperature for 12 hours. .
  • Saturated sodium bicarbonate solution 100 mL was added dropwise to the reaction mixture until no bubble production, liquid separation, and the organic phase was adjusted to pH 7 with 0.5 mol/L dilute hydrochloric acid solution (20 mL), and the organic phase was separated again, and the organic phase was saturated.
  • the aqueous solution was washed with brine (100 mL ⁇ 1), dried over anhydrous magnesium sulfate, filtered, and evaporated.
  • Second step tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-d]imidazole -5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate (1b)
  • the third step tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(methylsulfonyl)pyrrolo[3, 4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate (2c)
  • Step 3 tert-Butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-(methylsulfonyl)pyrrolo[3,4-d]imidazole -5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate (5c)
  • Second step ethyl 5-((3R,5S,6S)-5-((tert-butoxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3 -yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate (6b)
  • Oxalyl chloride (1.49 g, 11.75 mol) was dissolved in dichloromethane (30 mL) in a nitrogen atmosphere, cooled to -78 ° C, dimethyl sulfoxide (1.84 g, 23.50 mol) was added dropwise, and stirred at -70 ° C.
  • a solution of 9a (2.00 g, 7.83 mol) in dichloromethane (10 mL) was added dropwise, and the mixture was stirred at -70 ° C for 30 min, and N'N-diisopropylethylamine (5.06 g, 39.17 mol) was added dropwise. ), naturally, the reaction was stirred at room temperature for 4 hours.
  • Step 5 tert-Butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-ethoxy-1-methylpyrrolo[3,4-d Imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate (9e)
  • Step 6 (2R, 3S, 5R)-2-(2,5-Difluorophenyl)-5-(2-ethoxy-1-methylpyrrolo[3,4-d]imidazole-5 (1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine (Compound 9)
  • Step 4 tert-Butyl ((2R,3S,5R)-5-(2-carbamoyl-1-ethylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl )-2-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate (10d)
  • Step 5 5-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-ethyl-1 ,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxamide (Compound 10)
  • Second step ethyl 5-((3R,5S,6R)-5-((tert-butyloxycarbonyl)amino)-6-(2,5-difluorophenyl)tetrahydro-2H-pyran- 3-yl)-1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate (11b)
  • the third step tert-butyl ((2R,3S,5R)-5-(2-carbamoylpyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)-2-( 2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)carbamate (11c)
  • the intermediate 8 (500 mg, 2.016 mmol) was dissolved in ethanol (5 mL), and hydroxylamine hydrochloride (158.9 mg, 2.218 mmol) and potassium carbonate (695.5 mg, 5.04 mmol) were added at room temperature, and the mixture was heated to 80 ° C for 1 hour.
  • the reaction mixture was dried with EtOAc EtOAc EtOAc m.
  • Ethyl acetate (50 mL) and a saturated sodium chloride solution (100 mL) were added to the reaction mixture, and the mixture was separated, and the aqueous phase was filtered, and the filtrate was extracted with ethyl acetate (50 mL ⁇ 3), and the organic phase was combined with 0.5 mol/L.
  • the third step tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(5-methyl-1,2,4) -oxadiazol-3-yl)pyrrolo[3,4-d]imidazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate (12c)
  • the fourth step tert-butyl ((2R, 3S, 5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-tetrazole- 5-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate (14d)
  • Step 5 (2R, 3S, 5R)-2-(2,5-Difluorophenyl)-5-(1-methyl-2-(1-methyl-1H-tetrazol-5-yl) Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-amine (Compound 14)
  • Second step tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-methyl-2-(2-methyl-2H-tetrazole)- 5-yl)pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate (15b)
  • Oxalyl chloride (652.5 mg, 5.14 mmoL) was dissolved in dry dichloromethane (15 mL), cooled to -78 ° C with dry ice acetone bath, and dried dimethyl sulfoxide (803.96 mg, 10.29mmoL) was added dropwise with stirring. Stir for 30 minutes.
  • a 5C (970 mg, 3.43 mmol) solution of dichloromethane (5 mL) was added dropwise to the mixture and the mixture was stirred for 20 min.
  • Diisopropylethylamine (2.216 g, 17.15 mmol) was added dropwise at -78 ° C, and naturally allowed to react to room temperature for 2 hours.
  • Step 5 Methyl 5-((3R,5S,6R)-5-amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-1-methyl -1,4,5,6-tetrahydropyrrolo[3,4-d]imidazole-2-carboxylate (Compound 16)
  • 18a (500mg, 1.99mmol) was dissolved in a mixed solvent of dichloromethane (20mL) and methanol (10mL), benzenesulfonic acid .1.5H 2 O (555.60mg, 3.0mmol) was added and reacted at room temperature 16 hour. The reaction solution was concentrated under reduced pressure to give 18b (yield: 650 mg, yield: 100%).
  • the third step tert-butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(1-ethyl-2-methylpyrrolo[3,4-d] Imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate (18c)
  • reaction solution was cooled to 0 ° C, and water (30 mL) and aqueous ammonia (5 mL) were successively added to the reaction liquid, and extracted with dichloromethane (40 mL ⁇ 4), and the organic phase was combined, and then water (30 mL ⁇ 2) and saturated aqueous salt solution (30mL ⁇ 1) washing, drying with anhydrous sodium sulfate, filtering, filtering
  • Step 3 tert-Butyl ((2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methyl-1-(2,2,2-trifluoroethyl) Pyrrolo[3,4-d]imidazole-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate (19c)
  • Step 5 2-((3R,5S,6R)-5-Amino-6-(2,5-difluorophenyl)tetrahydro-2H-pyran-3-yl)-2,3,7, 8-tetrahydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyrazine-5(6H)-one (Compound 23)

Abstract

L'invention concerne un dérivé de cycle pyrrolo-imidazole et son usage médical. Elle concerne en particulier un dérivé de cycle pyrrolo-imidazole représenté par la formule générale (I) ou un stéréoisomère de celui-ci, un sel pharmaceutiquement acceptable de celui-ci et un promédicament de celui-ci; une composition pharmaceutique contenant le dérivé; et l'utilisation médicale de ce dérivé dans la préparation d'un inhibiteur de la dipeptidyl-peptidase IV (DPP-IV), la définition de chaque groupe substituant dans la formule générale (I) étant identique à celle indiquée dans la description.
PCT/CN2015/080570 2014-06-16 2015-06-02 Dérivé de cycle pyrrolo-imidazole et son usage médical WO2015192714A1 (fr)

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CN109942583A (zh) * 2019-04-11 2019-06-28 广东东阳光药业有限公司 芳基取代的氨基四氢吡喃类化合物及其用途
WO2019154218A1 (fr) 2018-02-06 2019-08-15 四川海思科制药有限公司 Composition de dérivé d'aminopyrane
KR20210110204A (ko) * 2020-02-28 2021-09-07 한양대학교 에리카산학협력단 단백질 인산화 효소 저해 활성을 갖는 신규한 이미다졸 유도체 및 이의 용도

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CN106916158A (zh) * 2015-12-25 2017-07-04 四川海思科制药有限公司 一种吡喃衍生物盐酸盐水合物及其中间体的制备方法
WO2019154218A1 (fr) 2018-02-06 2019-08-15 四川海思科制药有限公司 Composition de dérivé d'aminopyrane
CN111683659A (zh) * 2018-02-06 2020-09-18 四川海思科制药有限公司 一种氨基吡喃衍生物的组合物
JP2021512900A (ja) * 2018-02-06 2021-05-20 スーチュアン ハイスーク ファーマシューティカル カンパニー リミテッド アミノピラン誘導体の組成物
TWI730289B (zh) * 2018-02-06 2021-06-11 大陸商四川海思科製藥有限公司 氨基吡喃衍生物的組合物
JP7150862B2 (ja) 2018-02-06 2022-10-11 スーチュアン ハイスーク ファーマシューティカル カンパニー リミテッド アミノピラン誘導体の組成物
CN111683659B (zh) * 2018-02-06 2023-08-29 四川海思科制药有限公司 一种氨基吡喃衍生物的组合物
US11974985B2 (en) 2018-02-06 2024-05-07 Haisco Pharmaceutical Group Co., Ltd. Composition of aminopyran derivative
CN109942583A (zh) * 2019-04-11 2019-06-28 广东东阳光药业有限公司 芳基取代的氨基四氢吡喃类化合物及其用途
CN109942583B (zh) * 2019-04-11 2023-12-08 广东东阳光药业股份有限公司 芳基取代的氨基四氢吡喃类化合物及其用途
KR20210110204A (ko) * 2020-02-28 2021-09-07 한양대학교 에리카산학협력단 단백질 인산화 효소 저해 활성을 갖는 신규한 이미다졸 유도체 및 이의 용도
KR102510351B1 (ko) 2020-02-28 2023-03-17 한양대학교 에리카산학협력단 단백질 인산화 효소 저해 활성을 갖는 신규한 이미다졸 유도체 및 이의 용도

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