WO2011140936A1 - Dérivés de 2-imino-pyrrolidine disubstitués en 5,5, leurs procédés de préparation et utilisations pharmaceutiques - Google Patents

Dérivés de 2-imino-pyrrolidine disubstitués en 5,5, leurs procédés de préparation et utilisations pharmaceutiques Download PDF

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WO2011140936A1
WO2011140936A1 PCT/CN2011/073550 CN2011073550W WO2011140936A1 WO 2011140936 A1 WO2011140936 A1 WO 2011140936A1 CN 2011073550 W CN2011073550 W CN 2011073550W WO 2011140936 A1 WO2011140936 A1 WO 2011140936A1
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group
aryl
alkyl
cycloalkyl
heteroaryl
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吕贺军
邓炳初
陈一千
王胜蓝
王�华
张蕾
李军
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上海恒瑞医药有限公司
江苏恒瑞医药股份有限公司
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Priority to CN201180002959.3A priority Critical patent/CN102471264B/zh
Priority to TW100126134A priority patent/TW201242964A/zh
Publication of WO2011140936A1 publication Critical patent/WO2011140936A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed 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
    • A61K31/40—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a novel 5,5-disubstituted-2-iminopyrrolidine derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly as a thrombin receptor antagonist the use of. Background technique
  • Thrombotic diseases are currently the leading cause of high rates of cardiovascular disease and high mortality worldwide.
  • Arterial thrombosis can cause a variety of acute symptoms including acute coronary syndrome, ischemic stroke / transient cerebral ischemia and peripheral arterial disease. These symptoms are caused by vascular damage caused by atherosclerotic plaque damage or vascular endothelial cell damage, which in turn induces arterial thromboembolism, resulting in insufficient blood supply. Platelets play a very important role in the formation of arterial thrombosis.
  • thrombin is the most potent platelet activator, and activates platelets and induces aggregation by interacting with members of the PAR family in the G protein-coupled receptor family, thereby realizing blood coagulation and other organisms. Learning role.
  • PARs Proteinase-activated receptors
  • the PARs family is involved in the coagulation under normal physiological conditions, maintaining the stability of the intravascular environment, as well as various physiological processes such as inflammatory reactions under pathological conditions, thrombosis and atherosclerosis, and plays a key role in it.
  • thrombin thrombin
  • This family of receptors uses a unique mechanism to achieve the activation process: thrombin (thrombin) that binds to PARs hydrolyzes the original N-terminus of the extracellular domain of the PARs receptor and forms a new N-terminus, new The formed N-terminus binds to PARs in a "tethered ligand" manner to induce receptor activation, thereby enabling signal transduction.
  • PARs family contains four receptor subtypes including PARI, PAR2, PAR3 and PAR4.
  • PAR2 is removed as a receptor for trypsin and tryptase, and the other three subtypes are activated by binding to thrombin and are therefore considered to be the major thrombin receptors (thrombin re Ce pt 0rS ).
  • PARI is a high-affinity thrombin receptor that is activated at lower concentrations (less than nanomolar) of thrombin conditions.
  • PAR4 is a low-affinity thrombin receptor involved in the activation and delivery of thrombin signals only at higher concentrations of thrombin.
  • PAR3 is also a high-affinity receptor, it usually does not activate the signaling alone, but acts as a co-receptor to synergize with PAR4 to increase PAR4 activity and achieve corresponding biological functions (see Ho-Sam et al). ; Current Pharmaceutical Design, 2003, 9, 2349-2365).
  • PARI is widely expressed in many cells and tissues in human body, including platelets, endothelial cells, vascular or tracheal smooth muscle, inflammatory cells (macrophages, lymphocytes), fibroblasts. , nerve cells, cardiovascular and skeletal muscle cells.
  • PARI can also activate receptor tyrosine kinase activity and affect the corresponding signal cascade through G protein signal cross-linking, thereby regulating cell proliferation and metastasis (see Derian CK, et al; Expert Opin. Investig Drugs , 2003, 12: 209-21). These further herald the potential of PARI as a therapeutic target for a variety of diseases.
  • PARI-targeted antagonists do not affect Thrombin's own normal clotting activity. In special emergency situations, thrombin can still induce platelet activation and aggregation through PAR4 signaling, which is normal. Coagulation. Therefore, antiplatelet drugs developed with the target of inhibiting PARI not only improve the therapeutic effect and specificity, but also reduce the possible side effects, and thus become an ideal drug for treating arterial thrombosis diseases.
  • the present invention has been designed to have a compound represented by the general formula (I), and it has been found that a compound having such a structure exhibits excellent thrombin receptor inhibitory activity. Summary of the invention
  • Ar is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is optionally further substituted with one or more substituents of R a ;
  • Y is selected from -CR 12 - or N atom
  • L is selected from -CR 13 R 14 - or -(CH 2 ) m -;
  • I 1 , R 2 and R 3 are each independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, a blocked group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heterocyclic group.
  • R 1 and R 2 or R 2 and R 3 together with the carbon atom to which they are attached form an aryl group, wherein said aryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy Alkyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR 15 , -OC(0)R 15 , -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15 , -S(0)pR 15 , -NR 16 R 17 , -OC(0)NR 16 Substituted by a substituent of R 17 , —C(0)NR 16 R 17 or —S(0)ONR 16 R 17 ;
  • R 4 and R 5 are each independently selected from cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, hetero
  • the cyclo, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, aryl, heteroaryl, -C(0)OR 15 , -OC ( 0) R 15 , -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15 , -S (0) Substituting a substituent of p R 15 , —NR 16 R 17 , —OC(0)NR 16 R 17 , —C(0)NR 16 R 17 or —S(0)ONR 16 R 17 ;
  • R 4 and R 5 together with the carbon atom to which they are attached form a cycloalkyl group, wherein said cycloalkyl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, alkane Substituted by an oxy group, a cycloalkyl group, a heterocyclic group or a substituent of -NR 16 R 17 ;
  • R 6 is selected from a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, a heteroaryl group, -C(0)OR 15 , -C(0)R 15 or -C(0)NR 16 R 17 wherein the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, alkoxy Substituted by a substituent of a cycloalkyl or heterocyclic group; R a may be the same or different and each independently selected from a hydrogen atom, a hydroxyl group, a halogen, a cyano group, a nitro group, a silane group, an alkoxy group, an alkyl group, an alkenyl group, a blocked group, a cycloalkyl group, a heterocyclic
  • R 12 is selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, a aryl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(0) OR 15 , -OC(0)R 15 , -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0 R 15 , -S(0) p R 15 -NR 16 R 17 , -OC(0)NR 16 R 17 , -C(0)NR 16 R 17 or -S(0)ONR 16 R 17 , where The alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of
  • R 13 and R 14 are each independently selected from alkyl or halo, wherein said alkyl group is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano or nitro;
  • R 15 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further Substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, alkoxy or alkyl;
  • R 16 and R 17 are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group Or a heterocyclic group, an aryl group or a heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, hetero Aryl, -C(0)OR 15 , -OC(0)R 15 , -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0 R 15 , -NHC(0)R 15 , -S(0)pR 15 , -NR 18 R 19 , -OC(0)NR 18 R 19
  • R 16 and R 17 together with the nitrogen atom are attached form a heterocyclic group containing one or more N, 0 or S (0) p hetero atoms in the heterocyclic group, and wherein any heterocyclyl group Further selected by one or more of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyalkyl, -C(0)OR 15 -OC(0)R 15 , -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15, -S (0) pR 15 , -NR 18 R 19, -OC (0) NR 18 R 19, -C (0) NR 18 R 19 or -S (0) ONR 18 R 19 group substituted with a substituent ;
  • R 18 and R 19 are each independently selected from a hydrogen atom, a halogen, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group; m is selected from 1, 2 or 3;
  • n is selected from 1, 2 or 3;
  • p is selected from 0, 1 or 2.
  • Y is selected from -CR 12 - or N atom
  • L is selected from -CR 13 R 14 - or -(CH 2 ) m -;
  • RR 2 and R 3 are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, a blocked group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(0)OR 15 , -OC(0)R 15 , -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15 , -S(0) p R 15 , -NR 16 R 17 , -OC(0)NR 16 R 17 , -C(0)NR 16 R 17 or -S(0)ONR 16 R 17 wherein the alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting
  • R 1 and R 2 or R 2 and R 3 together with the attached carbon form an aryl group, wherein said aryl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy , alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(0)OR 15 , -OC(0)R 15 , -0(CH 2 ) n C(0)OR 15 , (CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15 , -S(0)pR 15 , -NR 16 R 17 , -OC(0)NR 16 R 17, -C (0) NR 16 R 17 , or -S (0) ONR 16 R 17 substituents a;
  • R 4 and R 5 are each independently selected from cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, hetero
  • the cyclo, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, aryl, heteroaryl, -C(0)OR 15 , -OC ( 0) R 15 , -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15 , -S (0) Substituting a substituent of p R 15 , —NR 16 R 17 , —OC(0)NR 16 R 17 , —C(0)NR 16 R 17 or —S(0)ONR 16 R 17 ;
  • R 4 and R 5 together with the carbon atom to which they are attached form a cycloalkyl group, wherein said cycloalkyl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, alkane Substituted by an oxy group, a cycloalkyl group, a heterocyclic group or a substituent of -NR 16 R 17 ;
  • R 6 is selected from a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, a heteroaryl group, -C(0)OR 15 , -C(0)R 15 or -C(0)NR 16 R 17 wherein the alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, al
  • RR 8 , R 9 , R 1Q and R 11 are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a halogen, a cyano group, a nitro group, a silyl group, an alkoxy group, an alkyl group, an alkenyl group, a blocked group, a cycloalkyl group, and a heterocyclic ring.
  • R 9 and R 1Q together with the carbon atom to which they are attached form a heterocyclic group, an aryl group or a heteroaryl group, wherein the heterocyclic group, aryl group or heteroaryl group is optionally further selected from one or more selected from one or more Halogen, hydroxy, cyano, nitro, silyl, alkoxy, alkyl, alkenyl, aryl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR 15 , - OC(0)R 15 , -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15 , -S(0) p R 15 , -NR 16 R 17 , -OC(0)NR 16 R 17 , -C(0)NR 16 R 17 or -S(0)ONR 16 R 17 substituted;
  • R 12 is selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, a aryl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(0) OR 15 , -OC(0)R 15 , -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0 R 15 , -S(0) p R 15 -NR 16 R 17 , -OC(0)NR 16 R 17 , -C(0)NR 16 R 17 or -S(0)ONR 16 R 17 , where The alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group optionally further selected from one or more selected from the group consisting of
  • R 13 and R 14 are each independently selected from alkyl or halo, wherein said alkyl group is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano or nitro;
  • R 15 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further Substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, alkoxy or alkyl;
  • R 16 and R 17 are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group Or a heterocyclic group, an aryl group or a heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, hetero Aryl, -C(0)OR 15 , -OC(0)R 15 , -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15 , -S(0)pR 15 , -NR 18 R 19 , -OC(0)NR 18 R 19
  • R 16 and R 17 form a heterocyclic group with a nitrogen atom to which the ring is bonded, wherein the heterocyclic group contains one or more N, 0 or S(0) p heteroatoms, and the heterocyclic group is Further selected by one or more of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, hydroxyalkyl, -C(0)OR 15 -OC(0)R 15 , -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15, -S (0) pR 15 , -NR 18 R 19, -OC (0) NR 18 R 19, -C (0) NR 18 R 19 or -S (0) ONR 18 R 19 group substituted with a substituent ;
  • R 18 and R 19 are each independently selected from a hydrogen atom, a halogen, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group.
  • n is selected from 1, 2 or 3;
  • n is selected from 1, 2 or 3;
  • p is selected from 0, 1 or 2.
  • Ar is selected from a 5- or 6-membered heteroaryl group, preferably a pyrrolyl group or a pyridyl group.
  • a preferred embodiment of the invention a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are selected from alkyl or aryl.
  • a preferred embodiment of the invention a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon atom to which they are attached form a cyclopropyl group.
  • a preferred embodiment of the invention a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from a hydrogen atom.
  • a preferred embodiment of the invention a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein R 12 is selected from a hydrogen atom or a halogen.
  • a preferred embodiment of the invention a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein L is selected from -(CH 2 ) m -, m is 1.
  • Typical compounds of the invention include, but are not limited to:
  • the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) is present in the form of a free or pharmaceutically acceptable acid addition salt, said pharmaceutically acceptable Acid addition salts include hydrochloride, hydrobromide, methanesulfonate, sulfate, phosphate, maleate, malate, citrate, acetate or trifluoroacetate, preferably It is a hydrobromide salt and a hydrochloride salt.
  • the present invention relates to a method for synthesizing a compound of the formula (I), which comprises:
  • X is selected from a halogen, preferably a chlorine atom or a bromine atom;
  • L, Y, R ⁇ R 11 are as defined in the compound of the formula.
  • the present invention relates to a compound of the formula (IA) or (IB) which is used as a intermediate for the preparation of a compound of the formula (I)
  • Y is selected from -CR 12 - or N atom
  • RR 2 and R 3 are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, a blocked group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(0)OR 15 , -OC(0)R 15 , -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15 , -S(0) p R 15 , -NR 16 R 17 , -OC(0)NR 16 R 17 , -C(0)NR 16 R 17 or -S(0)ONR 16 R 17 wherein the alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting
  • R 1 and R 2 or R 2 and R 3 together with the carbon atom to which they are attached form an aryl group, wherein said aryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy Alkyl, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR 15 , -OC(0)R 15 , -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15 , -S(0) p R 15 -NR 16 R 17 , -OC(0)NR 16 Substituted by a substituent of R 17 , —C(0)NR 16 R 17 or —S(0)ONR 16 R 17 ;
  • R 4 and R 5 are each independently selected from cyano, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, hetero
  • the cyclo, aryl or heteroaryl group is further optionally further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, aryl, heteroaryl, -C(0)OR 15 , -OC ( 0) R 15 , -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15 , -S (0) Substituting a substituent of p R 15 , —NR 16 R 17 , —OC(0)NR 16 R 17 , —C(0)NR 16 R 17 or —S(0)ONR 16 R 17 ;
  • R 4 and R 5 together with the carbon atom to which they are attached form a cycloalkyl group, wherein said cycloalkyl group is optionally further further selected from one or more selected from the group consisting of halogen, hydroxy, nitro, cyano, alkyl, alkane Substituted by an oxy group, a cycloalkyl group, a heterocyclic group or a substituent of -NR 16 R 17 ;
  • R 6 is selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, an aryl group, a heteroaryl group, -C(0)OR 15 ,
  • alkyl, alkoxy, cycloalkyl, aryl or heteroaryl group is further optionally further selected from one or more halogens Substituted with a substituent of a hydroxyl group, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group or a heterocyclic group;
  • R 12 is selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a nitro group, an alkoxy group, an alkyl group, an alkenyl group, a aryl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -C(0) OR 15 , -OC(0)R 15 -0(CH 2 ) n C(0)OR 15 -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15 , -S(0) p R 15 -NR 16 R 17 , -OC(0)NR 16 R 17 , -C(0)NR 16 R 17 or -S(0)ONR 16 R 17 , wherein the alkoxy group, alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further Or a plurality selected from halogen,
  • R 15 is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further Substituted by one or more substituents selected from halogen, hydroxy, cyano, nitro, alkoxy or alkyl;
  • R 16 and R 17 are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group Or a heterocyclic group, an aryl group or a heteroaryl group, optionally further selected from one or more selected from the group consisting of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, hetero Aryl, -C(0)OR 15 , -OC(0)R 15 , -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0 R 15 , -NHC(0)R 15 , -S(0)pR 15 , -NR 18 R 19 , -OC(0)NR 18 R 19
  • R 16 and R 17 form a heterocyclic group with a nitrogen atom to which the ring is bonded, wherein the heterocyclic group contains one or more N, 0 or S(0) p heteroatoms, and the heterocyclic group is Further selected by one or more of halogen, hydroxy, cyano, nitro, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(0)OR 15 , -OC ( 0) R 15 , -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15 , -S (0) Substituting a substituent of p R 15 , -NR 18 R 19 , -OC(0)NR 18 R 19 , -C(0)NR 18 R 19 or -S(0)ONR 18 R 19 ;
  • R 18 and R 19 are each independently selected from a hydrogen atom, a halogen, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group;
  • n is selected from 1, 2 or 3;
  • p is selected from 0, 1 or 2.
  • a preferred embodiment of the invention is a compound of the formula (IA) or (IB) or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 together with the carbon atom to which they are attached form a cyclopropyl group.
  • R 6 is selected from a hydrogen atom.
  • a preferred embodiment of the invention is a compound of the formula (IA) or (IB) or a pharmaceutically acceptable salt thereof, wherein R 12 is selected from a hydrogen atom or a halogen.
  • compound (IA) may also exist in the form of tautomers.
  • the tautomeric form of the compound (IA) may include, but is not limited to, a structure represented by the following formula (IB):
  • Typical compounds of the compounds of formula (IA) or (IB) include, but are not limited to:
  • the present invention relates to a process for the preparation of a compound of the formula (1) or (IB), which comprises:
  • the dimethyl sulfoxide solution of the compound of the formula (III) is heated in the presence of cuprous cyanide and cuprous iodide to obtain a compound of the formula (IA) or (IB);
  • the compound of the formula (IV) is mixed with a format reagent and a titanate under ice bath, and the reaction is stirred at room temperature to obtain a compound of the formula (IA) or (IB);
  • a compound of the formula (V) is reacted with concentrated aqueous ammonia and t-butoxy hydrogen peroxide to give a compound of the formula (IA) or (IB);
  • a tetrahydrofuran solution of the compound of the formula (VI) can be stirred in the presence of water and triphenylphosphine at room temperature to obtain a compound of the formula (IA) or (IB).
  • Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • Another aspect of the invention relates to a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof Use of a pharmaceutical composition for the preparation of a calcium ion transport inhibitor.
  • Another aspect of the invention relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a thrombin receptor antagonist, wherein said thrombin receptor antagonism Agent is
  • the present invention relates to the use of a compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the preparation of a platelet aggregation inhibitor.
  • the present invention relates to the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for inhibiting smooth muscle cell proliferation.
  • the present invention relates to the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, for the preparation of a medicament for treating a thrombin receptor-related disease, wherein said thrombin Receptor-related diseases are selected from thrombosis, vascular restenosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, heart disease, sowing intravascular coagulation syndrome, hypertension, inflammatory disease, rheumatism, asthma, kidney Small ball nephritis, osteoporosis, neurological disease and/or malignancy.
  • thrombin Receptor-related diseases are selected from thrombosis, vascular restenosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, heart disease, sowing intravascular coagulation syndrome, hypertension, inflammatory disease, rheumatism, asthma, kidney Small ball nephritis, osteoporosis, neurological disease
  • the present invention relates to a method of inhibiting calcium ion transport comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.
  • the present invention relates to a method of inhibiting a thrombin receptor comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein said The thrombin receptor is a PARI receptor.
  • the present invention relates to a method of inhibiting platelet aggregation comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.
  • the present invention relates to a method for inhibiting proliferation of smooth muscle cells, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.
  • the present invention relates to a method for treating a thrombin receptor-related disease, which comprises administering to a patient in need of treatment a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same
  • a thrombin receptor-related disease is selected from the group consisting of thrombosis, vascular restenosis, deep venous thrombosis, pulmonary embolism, cerebral infarction, heart disease, sowing intravascular coagulation syndrome, hypertension, inflammation Sexual diseases, rheumatism, asthma, glomerulonephritis, osteoporosis, neurological diseases and/or malignancies.
  • the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same as a medicament for inhibiting calcium ion transport.
  • the present invention relates to a compound of the formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, wherein the thrombin receptor is a PARI receptor.
  • the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same as a medicament for inhibiting platelet aggregation.
  • the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same as a medicament for inhibiting proliferation of smooth muscle cells.
  • the present invention relates to a compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same as a treatment
  • a medicament for treating a thrombin receptor-related disease wherein the thrombin receptor-related disease is selected from the group consisting of thrombosis, vascular restenosis, deep venous thrombosis, pulmonary embolism, cerebral infarction, heart disease, sowing Intravascular coagulation syndrome, hypertension, inflammatory disease, rheumatism, asthma, glomerulonephritis, osteoporosis, neurological disease and/or malignancy.
  • Alkyl means a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to alkyl groups having 1 to 12 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl 1,1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methyl Butyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 3-
  • lower alkyl groups having 1 to 6 carbon atoms More preferred are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl, alkenyl, Block group, alkoxy group, alkylthio group, alkylamino group, halogen, thiol, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, hetero Cycloalkoxy, cycloalkylthio, heterocycloalkylthio, carbonyl, -C(0)OR 15 , -OC(0)R 15 , -0(CH 2 ) n C(0)OR 15 , -( CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15 , -S(0) p R 15 -NR 16 R 17 , -OC(0)NR 16 R 17
  • Cycloalkyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cycloalkyl ring comprises from 3 to 10 One carbon atom.
  • monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Alkenyl, cyclooctyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
  • “Spirocycloalkyl” means a polycyclic group of 5 to 20 members which shares a carbon atom (referred to as a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings are fully conjugated. ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the ring and the ring. . More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospirocycloalkyl.
  • fused cycloalkyl refers to 5 to 20 members, each ring in the system sharing an adjacent carbon atom of an all-carbon polycyclic group with other rings in the system, wherein one or more rings may contain one or more Two double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the number of the constituent rings may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or a 5-membered/6-membered bicycloalkyl group.
  • fused cycloalkyl groups include
  • “Bridge cycloalkyl” means 5 to 20 members, any two rings sharing two carbon-free all-carbon polycyclic groups, which may contain one or more double bonds, but none of the rings have a total The ⁇ -electron system of the yoke. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, more preferably a bicyclic ring or a tricyclic ring. Unrestricted
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydrogen Naphthyl, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carbonyl, -C(0)OR 15 , -OC(0)R 15 , -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15 , -S(0) p R 15 -NR 16 R 17 , -OC(0)NR 16 R 17 , -C(0)NR 16 R 17 or
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. For example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, alkane.
  • Block group refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. For example, an ethyl group, a 1-propyl block group, a 2-propyl block group, a 1-, 2- or 3-butyl block group, and the like.
  • the block group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, alkane.
  • Heterocyclyl means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(0) n ( Wherein n is a hetero atom of the integer 0 to 2), but does not include a ring moiety of -0-0-, -0-S- or -SS-, and the remaining ring atoms are carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms, more preferably the cycloalkyl ring contains from 3 to 10 ring atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
  • Polycyclic cycloalkyl groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclyl means a polycyclic heterocyclic group of 5 to 20 members in which one atom (called a spiro atom) is shared between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(0) p The hetero atom (where p is an integer from 0 to 2) and the remaining ring atoms are carbon.
  • the spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of common spiro atoms between the rings, preferably a monospirocycloalkyl group and a bispirocycloalkyl group.
  • spirocycloalkyl groups include
  • “Fused heterocyclic group” means 5 to 20 members, and each ring in the system shares a pair of adjacent atoms with other rings in the system.
  • Polycyclic heterocyclic group one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are selected from nitrogen, oxygen or S ( 0) p (where p is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused heterocyclic groups include
  • “Bridge heterocyclyl” refers to a polycyclic heterocyclic group of 5 to 14 members in which two rings share two atoms which are not directly bonded, and these may contain one or more double bonds, but none of the rings have a complete conjugation
  • a ⁇ -electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(0) p (where ⁇ is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. 7 to 10 yuan.
  • bridged cycloalkyl groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, and the examples include:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclomethoxy, cycloalkylthio ,heterocycloalkylthio,carbonyl, -C(0)OR 15 , -OC(0)R 15 , -0(CH 2 ) n C(0)OR 15 -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15 , -S(0) p R 15 -NR 16 R 17 , -OC(0)NR 16 R 17 , -C(0)NR 16 R 17 Or -S
  • Aryl means a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms),
  • a polycyclic ring having a conjugated ⁇ -electron system i.e., a ring having an adjacent pair of carbon atoms
  • 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:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, alkane.
  • Heteroaryl means a heteroaromatic system containing from 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms include oxygen, sulfur and nitrogen. It is preferably 6 to 10 yuan.
  • the heteroaryl group is preferably a 5- or 6-membered compound such as a furyl group, a thienyl group, a pyridyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group, a tetrazolyl group and the like.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the parent structure is attached:
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio Base, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocyclomethoxy, cycloalkylthio , heterocycloalkylthio, -C(0)OR 15 , -OC(0)R 15 , -0(CH 2 ) n C(0)OR 15 -(CH 2 ) n C(0)OR 15 , C(0)R 15 , -NHC(0)R 15 , -S(0) p R 15 -NR 16 R 17 , -OC(0)NR 16 R 17 , -C(0)NR 16 R 17 or - S(0)ONR 16 R 17 .
  • Alkoxy means -O-(indenyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, when substituted, substituted
  • the group is preferably one or more of the following groups, independently selected from the group consisting of alkyl, alkenyl, blocked, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, -C(0)OR 15 , -OC(0 R 15 -0(CH 2 ) n C(0)OR 15 , -(CH 2 ) n C(0)OR 15 , -C(0)R 15 , -NHC(0)R 15 , -S(0 ) p R 15 , -NR 16 R 17 , -OC(0)NR 16 R 17 , -C(0)NR 16 R 17 or -S(0)
  • silane means an organosilane in which the hydrogen in the silane (SiH 4 ) is replaced by one or more alkyl, alkenyl, blocked, aryl, heteroaryl, alkoxy, cycloalkyl or heterocyclic groups.
  • an alkyl group, an alkenyl group, a blocked group, an aryl group, a heteroaryl group, an alkoxy group, a cycloalkyl group, a heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably Is one or more of the following groups, independently selected from alkyl, alkoxy, halogen, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, carbonyl, -C ( 0) OR 15 , -OC(0)R 15 ,
  • Non-limiting examples include trimethylsilyl, dimethylethylsilyl, tri-tert-butylsilyl, methyldiethoxysilyl, trimethoxysilyl, phenylsilyl, and the like.
  • Haldroxy means an -OH group.
  • Halogen means fluoro, chloro, bromo or iodo.
  • Amino means -NH 2 .
  • Neitro means -N0 2 .
  • Hydroalkyl means an alkyl group substituted by a hydroxy group.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, including the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity.
  • the preparation method of the compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof comprises the following steps:
  • a solution of the compound of the formula (I) or a compound of the formula (IB) in tetrahydrofuran is reacted with a compound of the formula (IC) at room temperature to obtain a compound of the formula (I) under triethylamine;
  • a compound of the formula (IV) is reacted with concentrated aqueous ammonia and t-butoxy hydrogen peroxide to give a compound of the formula (IA) or (IB).
  • a tetrahydrofuran solution of the compound of the formula (V) is stirred in the presence of water and triphenylphosphine at room temperature to obtain a compound of the formula (IA) or (IB).
  • X is selected from halogen, preferably a chlorine atom or a bromine atom; L, Y and !
  • ⁇ 1 is as described in the general formula (I). detailed description
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR shift ( ⁇ ) is given in units of parts per million (ppm).
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus.
  • the solvent was deuterated dimethyl sulfoxide (DMSO-), deuterated chloroform (CDC1 3 ), deuterated methanol (CH 3 OD), and the internal standard was tetramethyl.
  • silane (TMS) chemical shifts are 10- 6 (ppmM given in units of first glance.
  • the MS was assayed using a FINMGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINMGAN LCQAd
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the IC 50 value was determined using a NovoStar plate reader (BMG, Germany).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used for thin layer chromatography (TLC) has a specification of 0.15 mm ⁇ 0.2 mm, and the thin layer chromatography separation and purification product adopts a specification of 0.4 mm. ⁇ 0.5 mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Companies such as Dare Chemicals.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenation apparatus and a clear blue QL-500 hydrogen generator or HC2-SS type hydrogenation instrument.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction was carried out using a CEM Discover-S Model 908860 microwave reactor.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature.
  • the optimum temperature for the reaction at room temperature is from 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the systems used for the reaction were: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, petroleum ether and ethyl acetate systems, The volume ratio of acetone to solvent is adjusted depending on the polarity of the compound.
  • the system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol systems, B: n-hexane and ethyl acetate systems, C: ethyl acetate and Methanol system, D: hexamethylene, E: ethyl acetate, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of an alkaline reagent such as triethylamine or an acidic reagent such as acetic acid.
  • A dichloromethane and methanol systems
  • B n-hexane and ethyl acetate systems
  • C ethyl acetate and Methanol system
  • D hexamethylene
  • E ethyl acetate
  • the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted
  • 1,2-diethoxybenzene 7a (16.6 g, 100 mmol) was dissolved in 200 mL of dichloromethane, and bromo (10 mL, 200 mmol) was added dropwise, and the mixture was stirred at room temperature for 4 hours.
  • 100 mL of water and 1 g of sodium sulfite were added, and the organic phase was washed with saturated sodium chloride (150 mL), dried over anhydrous sodium sulfate, filtered, -Dibromo-4,5-diethoxybenzene 7b (29.8 g, white solid), Yield: 92.0%.
  • 1,2-Dibromo-4,5-diethoxybenzene 7b (13.62 g, 42 mmol) was dissolved in 150 mL of dimethyl sulfoxide, cuprous cyanide (14.97 g, 167.2 mmol) and iodinated. Cuprous (7.18 g, 37.7 mmol), and the reaction was stirred at 160 ° C for 4 hours.
  • Ethyl ketone 8b (2.0 g, 9.05 mmol) and 1,4-dibromobutane (2.54 g, 11.77 mmol) were dissolved in 20 mL of N,N-dimethylformamide and potassium carbonate (3.1 g, 22.63) Methyl) and potassium iodide (0.15 g, 0.91 mmol) were stirred at 80 ° C for 48 hours. Filtration, and the filtrate was concentrated under reduced pressure.
  • 5-bromo-2-methyl-B-pyridyl 9a (1.72 g, 10 mmol) was dissolved in 10 mL of diethyl ether under dry ice-acetone bath, and 2.5 M n-butyllithium (4.4 mL, 11 mmol) was added dropwise. The n-hexane solution was stirred for 1 hour, acetophenone (1.29 mL, 11 mmol) was added and stirring was continued for 1 hour.
  • Phenyl]ethanone 12a (1.8 g, 6.2 mmol) was dissolved in 20 mL of acetic acid, tribromopyridinium salt (2.29 g, 7.15 mmol) was added, and the reaction was stirred for 12 hours.
  • EtOAc EtOAc
  • EtOAc EtOAc
  • Acetylamine 13a (3.7 g, 14.1 mmol) was dissolved in 20 mL of acetic acid, tribromopyridinium salt (4.5 g, 14.1 mmol) was added, and the reaction was stirred for 12 hours. The organic layer was concentrated under reduced pressure. EtOAc (EtOAc m.
  • EtOAc EtOAc
  • EtOAc EtOAc
  • Ethyl ketone 17d (303 mg, 0.77 mmol) was dissolved in 15 mL of acetone, and then potassium carbonate (316.8 mg, 2.3 mmol) and io Filtration, the filter cake was washed with ethyl acetate (10 mL ⁇ 2), the filtrate was concentrated under reduced pressure, and 20 mL of ethyl acetate was added. The organic phase was combined and washed with water (20 mL ⁇ 3) and saturated sodium chloride solution (20 mL), The aqueous sodium sulfate was dried, filtered, and the filtrate was evaporated.
  • reaction mixture was poured into 30 mL of ice water and 150 mL of ethyl acetate, and the mixture was separated, and the aqueous phase was extracted with ethyl acetate (50 mL ⁇ 2). The organic phase was combined and washed with saturated sodium chloride solution (50 mL ⁇ 2) Concentration, the title product 1-[4-[3-tert-butyl- 5- (U -dimethoxyethyl)-2-methoxyphenyl]piperazine small group] ethyl ketone 20a was obtained directly. reaction.
  • the residue obtained was purified by silica gel column chromatography elut elut elut elut elut elut elut 5,6-Diethoxy-1,1-diethyl-4-fluoro-3-imino-isoindolin-2-yl)ethanone hydrobromide 36 (0.02 g, yellow solid), Yield: 3.0%.
  • Lithium bis(;trimethylsilyl)amine (12.7 mL, 12.7 mmol) and 1-[3-tert-butyl1-4-methoxy-5-(6-oxa-- at -78 °C 2-Azaspiro[3.3]heptan-2-yl)phenyl]ethanone 40e (3.5 g, 11.6 mmol) was dissolved in 50 mL of THF, stirred for 1 hour, then bromo (1.85 g, 11.6 mmol). The reaction was stirred for 2 hours.

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Abstract

La présente invention concerne des dérivés de 2-imino-pyrrolidine disubstitués en 5,5 de formule (I) et leurs sels pharmaceutiquement acceptables ; leurs procédés de préparation et utilisations en médecine en tant qu'antagonistes du récepteur de la thrombine, chacun des substituants de la formule (I) étant défini comme dans la description.
PCT/CN2011/073550 2010-05-11 2011-04-29 Dérivés de 2-imino-pyrrolidine disubstitués en 5,5, leurs procédés de préparation et utilisations pharmaceutiques WO2011140936A1 (fr)

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US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
WO2017108737A1 (fr) 2015-12-23 2017-06-29 Chiesi Farmaceutici S.P.A. Dérivés de 1-(3-tert-butyl-phényl)-3-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tétrahydro-naphthalèn-1-yl)-urée et leur utilisation en tant qu'inhibiteur de p38 mapk
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US10011594B2 (en) 2015-06-03 2018-07-03 Bristol-Myers Squibb Company 4-hydroxy-3-(heteroaryl)pyridine-2-one APJ agonists
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
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WO2019149205A1 (fr) * 2018-01-31 2019-08-08 江苏恒瑞医药股份有限公司 Dérivé de benzohétéroaryle et son procédé de préparation et son application médicale
CN110256342B (zh) * 2019-07-16 2022-06-07 河南省科学院化学研究所有限公司 一种2-氰基喹啉衍生物的合成方法
CN110698352B (zh) * 2019-10-29 2023-01-17 邢台学院 一种3-溴-5-氨基邻苯二酚二甲醚的合成方法
WO2024046409A1 (fr) * 2022-08-31 2024-03-07 江苏恒瑞医药股份有限公司 Composé hétérocyclique, son procédé de préparation et son utilisation pharmaceutique

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EP3640249A1 (fr) 2013-03-15 2020-04-22 Dow AgroSciences LLC 4-amino-6-(hétérocyclique)-picolinates et 6-amino-2-(hétérocyclique)-pyrimidine-4-carboxylates et leur utilisation comme herbicides
WO2014151008A1 (fr) 2013-03-15 2014-09-25 Dow Agrosciences Llc 4-amino-6-(hétérocycle)picolinates et 6-amino-2-(hétérocycle) pyrimidine-4-carboxylates et leur utilisation comme herbicides
US10047085B2 (en) 2014-02-03 2018-08-14 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US11535614B2 (en) 2014-02-03 2022-12-27 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9624217B2 (en) 2014-02-03 2017-04-18 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10807980B2 (en) 2014-02-03 2020-10-20 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US10399976B2 (en) 2014-02-03 2019-09-03 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US10087184B2 (en) 2014-10-14 2018-10-02 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of RORγ
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US11001583B2 (en) 2014-11-05 2021-05-11 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10336739B2 (en) 2015-06-03 2019-07-02 Bristol-Myers Squibb Company 4-hydroxy-3-(heteroaryl)pyridine-2-one APJ agonists
US10011594B2 (en) 2015-06-03 2018-07-03 Bristol-Myers Squibb Company 4-hydroxy-3-(heteroaryl)pyridine-2-one APJ agonists
US10829448B2 (en) 2015-08-05 2020-11-10 Vitae Pharmaceuticals, Llc Substituted benzoimidazoles as modulators of ROR-γ
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
WO2017108737A1 (fr) 2015-12-23 2017-06-29 Chiesi Farmaceutici S.P.A. Dérivés de 1-(3-tert-butyl-phényl)-3-(4-([1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-1,2,3,4-tétrahydro-naphthalèn-1-yl)-urée et leur utilisation en tant qu'inhibiteur de p38 mapk
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma

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