WO2020030107A1 - Pharmaceutical composition containing amide derivatives, preparation method therefor, and application thereof - Google Patents

Pharmaceutical composition containing amide derivatives, preparation method therefor, and application thereof Download PDF

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Publication number
WO2020030107A1
WO2020030107A1 PCT/CN2019/099971 CN2019099971W WO2020030107A1 WO 2020030107 A1 WO2020030107 A1 WO 2020030107A1 CN 2019099971 W CN2019099971 W CN 2019099971W WO 2020030107 A1 WO2020030107 A1 WO 2020030107A1
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Prior art keywords
group
alkyl
heteroaryl
cycloalkyl
alkoxy
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PCT/CN2019/099971
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French (fr)
Chinese (zh)
Inventor
高鹏
孙广俊
王少宝
张福军
包如迪
Original Assignee
江苏豪森药业集团有限公司
上海翰森生物医药科技有限公司
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Application filed by 江苏豪森药业集团有限公司, 上海翰森生物医药科技有限公司 filed Critical 江苏豪森药业集团有限公司
Priority to CN201980004523.4A priority Critical patent/CN111107848B/en
Publication of WO2020030107A1 publication Critical patent/WO2020030107A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of pharmaceutical synthesis, and particularly relates to a pharmaceutical composition containing an amide derivative, and a preparation method and application thereof.
  • the mitogen-activated protein kinase (MAPK) signaling pathway mediates many different cell functions, including cell growth, differentiation, inflammation, survival, and apoptosis, and is a key signaling pathway for cell mitosis and apoptosis.
  • MAPK mitogen-activated protein kinase kinase kinase
  • MAP3K mitogen-activated protein kinase kinase kinase
  • MAP2K mitogen-activated protein kinase kinase
  • MAPK mitogen-activated protein kinase kinase
  • MAP3K is activated by environmental signals, which activates MAP2K and MAP2K.
  • MAPK which mediates the corresponding cellular effects by phosphorylating its downstream substrates such as transcription factors.
  • Apoptosis signal-regulated kinase 1 (ASK1) is also called mitogen-activated protein kinase kinase kinase 5 (MAP3K5). It belongs to the MAPK family and mediates the activation of MAPK signaling pathways.
  • ASK1 can be used in stress responses including oxidative stress, endoplasmic It is activated by autophosphorylation under conditions such as network stress and calcium influx, thereby activating its downstream MAP2K (such as MKK3 / 6 and MKK4 / 7), further activating c-Jun N-terminal kinase (JNK) and p38 mitosis-activated protein kinase, leading to Related cellular effects such as apoptosis, ASK1 activation and its signaling pathways play important roles in neuroretirement diseases, cardiovascular diseases, inflammation, autoimmune and metabolic diseases.
  • MAP2K such as MKK3 / 6 and MKK4 / 7
  • JNK c-Jun N-terminal kinase
  • p38 mitosis-activated protein kinase leading to Related cellular effects such as apoptosis, ASK1 activation and its signaling pathways play important roles in neuroretirement diseases, cardiovascular diseases, inflammation, autoimmune and metabolic diseases.
  • NASH non-alcoholic steatohepatitis
  • ASK1 inhibitors have great potential for clinical treatment of NASH, and also have potential application value in the treatment of other disease areas including neuroretirement diseases, cardiovascular diseases, inflammation, autoimmune and metabolic diseases.
  • ASK1 inhibitors have good application prospects as medicines in the pharmaceutical industry.
  • the present invention will provide a novel structure of selective ASK1 inhibitor compositions, and it is found that compounds having such structures exhibit pharmacological and pharmacological activity Excellent effect and function.
  • An object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and its structure is as follows:
  • M 1 , M 2 , M 3 and M 4 are each independently selected from N or -CR 6 ;
  • X and Y are each independently selected from a bond, -NR 7- , -CR 7 R 8- , -S (O) m- ,
  • Ring A is selected from aryl or heteroaryl, wherein said aryl and heteroaryl are optionally further selected from deuterium, alkyl, deuterated alkyl, halogen, amino, nitro, hydroxyl, cyano, Alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O ) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C ( O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R
  • R 1 is the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, an amino group, a nitro group, a hydroxy group, a cyano group, a cyclic group Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-( CH 2 ) n C (O) NHR 10 ,-(CH 2
  • R 2 is the same or different, and each is independently selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, and a ring Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-( CH 2 ) n C (O) NHR 10 ,
  • R 3 is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; Alkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkane Group, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-( CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m
  • R 3 and M 3 , M 3 and M 4 are respectively linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is described
  • cycloalkyl, heterocyclyl, aryl or heteroaryl is described
  • haloalkyl, halogen amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ⁇ -(CH 2 ) n C (O) OR 9 ⁇ -(CH 2 ) n S (O) m R 9 ⁇ -(CH 2 ) n NR 10 R 11
  • R 1 and X or Y, M 1 and X or Y are respectively linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or Heteroaryl is optionally further selected from deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cyclic Alkyl, heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C ( O) R 9, - (CH 2) n C (O) OR 9, - (CH 2) n S (O) m R 9, - (CH 2) n NR 10 R 11, - (CH 2)
  • R 6 , R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, Hydroxyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n
  • R 9 is selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; Said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 , -(CH 2 ) n C (O) OR 12 ,-
  • R 10 and R 11 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group
  • said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of a deuterium atom, an alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkoxy group, Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 , -(
  • R 12 and R 13 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, an ester group, a cycloalkyl group, a heterocyclic group, an aryl group, and Heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, halogen, hydroxyl, amino, nitro, cyano, ester Substituted with one or more substituents of aryl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
  • x is an integer of 0, 1, 2, 3, or 4;
  • y is an integer of 0, 1, or 2;
  • n is an integer of 0, 1, or 2;
  • n is an integer of 0, 1, 2, 3, 4 or 5.
  • the pharmaceutical composition is characterized in that the weight percentage of the active ingredient is 1% to 95%, preferably 5% to 85%, more preferably 10% to 60%, even more preferably 10% to 50%.
  • the pharmaceutical composition is characterized in that the dosage range is 0.5-120 mg, preferably 1-100 mg, further preferably 1-50 mg, and even more preferably 1-30 mg.
  • the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the following compounds of the general formula (II):
  • R 4 is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxy group, a cyano group, a cycloalkyl group, a heterocyclic group, and an aromatic group.
  • heteroaryl -(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 , -(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ; the alkyl, haloalkyl, cycloalkyl, heterocyclic ring Aryl, aryl and heteroaryl are optionally further selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, halo
  • R 3 and R 4 are linked to form a heterocyclic ring or heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen group, an amino group, and a nitrate group.
  • R 3 and R 4 are linked to form a heterocyclic ring or heteroaryl ring, and any two substituents on the heterocyclic ring or heteroaryl ring may form a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein
  • the cycloalkyl, aromatic ring, heterocyclyl or heteroaryl ring group is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, Alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-( CH 2 ) n SR 9
  • Rings A, M 1 , M 2 , X, Y, R 1 -R 3 , x, y, m and n are as described in the general formula (I).
  • the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (III):
  • Ring B is selected from heterocyclyl or heteroaryl; wherein, heterocyclyl preferably contains 3 to 20 ring atoms, of which one or more ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, and the remaining rings
  • the atom is carbon
  • the heterocyclic group further preferably contains 3 to 12 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen, and phosphorus, and the remaining ring atoms are carbon
  • the heterocyclic group more preferably contains 3 to 8 ring atoms. Wherein 1 to 3 ring atoms are selected from nitrogen and oxygen, and the remaining ring atoms are carbon.
  • heterocyclic group most preferably contains 5 to 7 ring atoms, of which 1 to 2 ring atoms are selected from nitrogen and oxygen, and the remaining ring atoms
  • heterocyclyl is further preferably selected from pyrrole, piperidine, azacycloheptane, morpholine, piperazine;
  • heteroaryl preferably contains 5 to 14 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen , Phosphorus or S (O) t, the remaining ring atoms are carbon, and the heteroaryl group further preferably contains 5 to 10 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, and the rest
  • the ring atom is carbon
  • the heteroaryl group more preferably contains 5 to 10 ring atoms, of which 1 to 3 ring atoms are selected from nitrogen, oxygen, and phosphorus, the remaining ring atoms are carbon
  • R a is selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, and a heterocyclic ring.
  • R a is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cyclic group Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-( CH 2 ) n C (O) NHR
  • any two R a substituents on ring B form a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the hetero atom is 1 to 4 selected from nitrogen, oxygen, sulfur, and phosphorus, preferably any
  • the two R a substituents form a C 3-8 cycloalkyl group, a C 3-8 heterocyclyl group, a C 6-14 aryl group, and a C 5-14 heteroaryl group, wherein the hetero atom is selected from nitrogen, oxygen, sulfur, 1 to 3, more preferably any two R a substituents in phosphorus form C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, and C 5-10 heteroaryl, wherein Heteroatoms are 1 to 2 selected from nitrogen and oxygen, most preferably any two R a substituents form cyclopropyl, cyclobutyl, cyclopentyl, C 3-5 heterocyclyl, C 6-7
  • the ring formed by any two R a substituents is optionally further selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, and an alkenyl group.
  • z is an integer of 0, 1, 2, 3, 4 or 5;
  • t 0, 1, or 2.
  • the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (IV):
  • M 5 is O, -CR 6 or -NR 7 ;
  • R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyanide Group, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-( CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 )
  • R 6 and R 7 are optionally further selected from a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, and a cyclic Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-( CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O)
  • q 0, 1, or 2.
  • the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (V):
  • o is an integer of 0, 1, 2, 3, 4 or 5.
  • the pharmaceutical composition is characterized by:
  • M 1 and M 2 are each independently selected from N or -CR 6 , and optional M 1 and M 2 are different;
  • X and Y are each independently selected from a bond, -NR 7- , -CR 7 R 8- , -S (O) m- , The optional X and Y are different;
  • Ring A is selected from aryl or heteroaryl; the aryl is 6 to 14 membered full carbon monocyclic or fused polycyclic, preferably 6 to 10 members, more preferably phenyl or naphthyl; the heteroaryl The group preferably contains 5 to 14 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, the remaining ring atoms are carbon, and the heteroaryl group further preferably contains 5 to 10 ring atoms, Wherein 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, the remaining ring atoms are carbon, and the heteroaryl group more preferably contains 5 to 10 ring atoms, of which 1 to 3 ring atoms are selected from nitrogen , Oxygen, phosphorus, the remaining ring atoms are carbon, most preferably imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl,
  • Heteroaryl is further most preferably comprising 5 or 6 ring atoms, of which 1 to 2 atoms are selected from nitrogen and oxygen;
  • the ring A is optionally further selected from a deuterium atom, an alkyl group, a deuterated alkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group , Aryl and heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ⁇ -(CH 2 ) n S (O) m R 9 ⁇ -(CH 2 ) n NR 10 R 11 ⁇ -(CH 2 ) n C (O) NR 10 R 11 ⁇ -(CH 2 ) n C ( O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CHCH 2
  • R 2 is the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, an amino group, a nitro group, a hydroxy group, a cyano group, a cyclic Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-( CH 2 ) n C (O) NHR 10 ,-(CH 2 )
  • the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (III-A):
  • the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (III-A1) or the general formula (III-A2):
  • Ring C is a 4-7 membered heterocyclyl or heteroaryl group, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S (O) t, and the remaining ring atoms are carbon, preferably containing 1-2 5-membered heterocyclic group of nitrogen or oxygen atom; the heteroaryl group preferably contains 1 to 4 heteroatoms, wherein the heteroatom is selected from the group consisting of oxygen, sulfur and nitrogen, preferably a heteroatom containing 1 to 2 nitrogen or oxygen 5- or 6-membered heteroaryl; preferably, ring C has the following structure:
  • R b is selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 deuterated alkyl group, or a C 1-8 haloalkyl group
  • t 0, 1, or 2.
  • the pharmaceutical composition is characterized in that: R 1 is the same or different and each is independently selected from a hydrogen atom, a deuterium atom, and a C 1-8 alkyl group , Deuterated C 1-8 alkyl, halo C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl, C 5-14 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-( CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,- (CH 2 ) n C (O) NR 10 R 11 ,-((CH 2 ) n C (
  • R 1 is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a halogenated alkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • the pharmaceutical composition is characterized in that R 1 is the same or different, and each is independently selected from the group consisting of a hydrogen atom, a deuterium atom, a C 1-3 alkyl group, and deuterium.
  • the pharmaceutical composition is characterized in that: R 1 is selected from a hydrogen atom, a deuterium atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, Deuterated methyl, deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, Chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropyl Oxygen, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrol
  • the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (VI-A) or the general formula (VI-B):
  • R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cyano group, a cycloalkyl group, a heterocyclic group, Aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O ) NHR 10 ,-(CH 2 )
  • R 5 is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group.
  • x-1 is an integer of 1, 2, 3, or 4.
  • the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (VI-A1) or the general formula (VI-B1):
  • M 5 is O, -CR 6 or -NR 7 ;
  • R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyanide Group, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-( CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 )
  • R 6 and R 7 are optionally further selected from a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, and a cyclic Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-( CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O)
  • q 0, 1, or 2.
  • the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (VI-A2) or the general formula (VI-B2):
  • o is an integer of 0, 1, 2, 3, 4 or 5.
  • the pharmaceutical composition is characterized in that the compound of general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the following compounds of general formula (VII):
  • Ring B is selected from heterocyclyl or heteroaryl
  • R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cyano group, a cycloalkyl group, a heterocyclic group, Aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O ) NHR 10 ,-(CH 2 )
  • R a is selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, and a cycloalkyl group , Heterocyclyl, aryl, heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O ) NR 10 R
  • any two R a substituents on the B ring may form a new cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said forming a new cycloalkyl, aromatic ring, heterocyclyl or
  • the heteroaryl ring group is optionally further selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkoxy group, a hydroxyalkyl group, and a cycloalkyl group.
  • x-1 is an integer of 1, 2, 3, or 4;
  • z is an integer of 0, 1, 2, 3, 4 or 5;
  • Rings A, M 1 , M 2 , X, Y, R 1 -R 5 , x, y, m and n are as described in the general formula (I).
  • the pharmaceutical composition is characterized in that when ring B is selected from a heterocyclic group, it preferably contains 3 to 20 ring atoms, wherein one or more ring atoms are selected from A heteroatom of nitrogen, oxygen or S (O) t, t is 0, 1 or 2, and the remaining ring atoms are carbon; more preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms selected from nitrogen and oxygen Atom; most preferably contains 5 to 7 ring atoms, of which 1 to 2 are heteroatoms selected from nitrogen and oxygen; when ring B is selected from heteroaryl, it preferably contains 1 to 4 heteroatoms and 5 to 14 rings Atom heteroaryl, wherein the heteroatom is selected from the group consisting of oxygen, sulfur, and nitrogen, more preferably a 5- to 10-membered heteroaryl containing 1 to 2 heteroatoms, wherein the heteroatom is selected from the group consisting of oxygen and nitrogen, and most preferably 1 A 5- or 6-membered heteroaryl group to
  • the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compounds of the general formula (VIII):
  • the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compounds of the general formula (IX):
  • Ring B, R 1, R 5, R a, x-1 , and z are as in formula (I) said.
  • the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compounds of the following general formula (X-A):
  • M 5 is O, -CR 6 or -NR 7 ;
  • R 1 is selected from a hydrogen atom, a C 1-8 alkyl group or a halogen
  • R 5 is selected from C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, or 3-6 membered heterocyclic group;
  • R a is the same or different and each is independently selected from the group consisting of a hydrogen atom, a cyano group, a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 1-8 haloalkyl group, and a C 1-8 hydroxy group Alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl,-(CH 2 ) n OR 9 ,-(CR 9 R 10 ) n -or-(CH 2 ) n C (O) R 9 , wherein the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 alkane
  • An oxy group and a C 3-8 cycloalkyl group are optionally further selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group,
  • R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 hydroxyalkyl group, or a C 1-8 alkoxy group;
  • x-1 is an integer of 1, 2, 3 or 4;
  • q 0, 1, or 2;
  • z is an integer of 0, 1, 2, 3, 4 or 5.
  • the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compounds of the general formula (XI):
  • o is an integer of 0, 1, 2, 3, 4 or 5;
  • R 1, R 5, R a , x and z are as formula (VI) said.
  • the pharmaceutical composition is characterized in that the compound of general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the following compounds of general formula (XII):
  • R a is the same or different and each is independently selected from the group consisting of hydrogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkane Oxy, C 3-6 cycloalkyl,-(CH 2 ) n OR 9 or-(CR 9 R 10 ) n- , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-6 cycloalkyl are optionally further selected from hydrogen atom, halogen, cyano, hydroxy, C 1-6 alkyl or Substituted with one or more substituents in C 1-6 alkoxy; or any two R a substituents may form a 3-6 membered cycloalkyl, and
  • z is an integer of 0, 1, 2 or 3.
  • the pharmaceutical composition is characterized in that the compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following general formula (XIII-A) Compound:
  • M 5 is selected from S or CH;
  • R 3 is selected from C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, and 3-10 membered heterocyclic ring Group, wherein said C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl and 3-10 member
  • the heterocyclyl is optionally further selected from a hydrogen atom, a deuterium atom, a C 1-8 alkyl group, a C 1-8 deuterated alkyl group, a C 1-8 haloalkyl group, a halogen group, an amino group, a hydroxyl group, a cyano group, and C 1 One or more of -8alkoxy , C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5
  • R 4 is selected from a hydrogen atom, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, or 3-10 Heterocyclic
  • a 3-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring formed by linking R 3 and R 4 wherein the 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring is optionally further selected from a deuterium atom , Alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and hetero Aryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11
  • R b is selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 deuterated alkyl group, or a C 1-8 haloalkyl group; wherein R b may be substituted on the oxo ring or the M 5 ring;
  • p is an integer of 0, 1, 2, 3, or 4;
  • q is an integer of 0 or 1.
  • the pharmaceutical composition is characterized in that ring C is a 4- to 7-membered heterocyclic group or a heteroaryl group, preferably a 5-membered heterocyclic group.
  • ring C is a 4- to 7-membered heterocyclic group or a heteroaryl group, preferably a 5-membered heterocyclic group.
  • the most preferred structure of the ring, C is as follows:
  • the pharmaceutical composition is characterized in that the compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following general formula (XIII-B ) Compound:
  • Ring C is a 4- to 7-membered heterocyclic group or a heteroaryl group, preferably a 5-membered heterocyclic group;
  • R a each independently selected from hydrogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, - (CH 2 ) n OR 9 ,-(CR 9 R 10 ) n -or-(CH 2 ) n C (O) R 9 , or any two R a substituents may form a 3-6 membered cycloalkyl group;
  • R b is selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 deuterated alkyl group, or a C 1-8 haloalkyl group;
  • R 9 and R 10 are independently selected from a hydrogen atom or a C 1-8 alkyl group
  • z is an integer of 0, 1, 2, 3, or 4;
  • p 0, 1, or 2.
  • each of the general formulas, stereoisomers, or pharmaceutically acceptable salts thereof is shown, wherein R 1 is selected from C 1-8 alkyl, C 3-8 Cycloalkyl, 5- to 10-membered heteroaryl, and halogen, preferably 5- to 6-membered heteroaryl, halogen, and C 1-6 alkyl, more preferably pyrazole, fluorine atom, and methyl.
  • each of the general formulas, stereoisomers, or pharmaceutically acceptable salts thereof is shown, wherein Ra is selected from a hydrogen atom, a cyano group, and a C 1-8 alkane.
  • each of the general formulas, stereoisomers, or pharmaceutically acceptable salts thereof shown is characterized in that any two of R a optionally form a 3-6 membered ring Alkyl is preferably cyclopropyl.
  • each of the formulas, stereoisomers, or pharmaceutically acceptable salts thereof is shown, wherein R 5 is selected from a hydrogen atom, a C 1-8 alkyl group, and C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, halogen, C 3-8 cycloalkyl, 3-10 membered heterocyclic group, preferably From hydrogen atom, C 1-6 alkyl, hydroxy C 1-6 alkyl C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group; R 5 is most preferably cyclopropyl, Isopropyl, hydroxyisopropyl, t-butyl, trifluoromethyl or
  • the present invention also relates to a method of treating and / or treating a disease preventing ASK1-mediated pathological features, which comprises administering to a patient a therapeutically effective dose of a pharmaceutical composition.
  • the invention further relates to the pharmaceutical composition, which is characterized in that the compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is used in the preparation of an ASK1 inhibitor medicine.
  • the pharmaceutical composition which is characterized in that the compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is used in the preparation of an ASK1 inhibitor medicine.
  • the invention further relates to the application of the pharmaceutical composition in the preparation of a medicament for treating neurodegenerative disorder, cardiovascular disorder, inflammatory disorder, metabolic disorder and ASK1.
  • the inflammatory disorder is preferably non-alcoholic steatohepatitis (NASH ).
  • the present invention further relates to the pharmaceutical composition for preparing a method for treating non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • the present invention also relates to a method for treating prevention and / or treatment of a pre-prepared treatment of neurodegenerative, cardiovascular, inflammatory, and metabolic disorders, which comprises administering a therapeutically effective dose of a pharmaceutical composition to a patient.
  • the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, dragees, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
  • Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives, To provide pleasing and delicious medicinal preparations. Tablets contain the active ingredients and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
  • excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc.
  • These tablets can be uncoated or they can be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release over a longer period.
  • water-soluble taste-masking substances such as hydroxypropyl methyl cellulose or hydroxypropyl cellulose, or prolonged substances, such as ethyl cellulose, cellulose acetate butyrate, can be used.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil
  • Soft gelatin capsules are provided as an oral preparation.
  • Aqueous suspensions contain the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
  • excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and gum arabic; dispersants or wetting agents may be naturally occurring Phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecyloxycetyl alcohol (heptadecaethyleneoxycetanol), or the condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with a derivative of fatty acid and hexitol anhydride Condensation products of partial esters, such as polyethylene oxide sorbitan
  • the aqueous suspension may also contain one or more preservatives such as ethyl paraben or n-propyl paraben, one or more colorants, one or more flavoring agents, and one or more sweeteners.
  • preservatives such as ethyl paraben or n-propyl paraben
  • colorants such as ethyl paraben or n-propyl paraben
  • flavoring agents such as sucrose, saccharin or aspartame.
  • Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
  • the oil suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • the sweeteners and flavoring agents described above can be added to provide a palatable formulation. These compositions can be preserved by the addition of an antioxidant such as fenoxyfen or alpha-tocopherol.
  • dispersible powders and granules suitable for preparing aqueous suspensions can be provided with active ingredients and dispersing or wetting agents, suspending agents or one or more preservatives for mixing. Suitable dispersing or wetting agents and suspending agents can illustrate the above examples. Other excipients such as sweeteners, flavors and colorants can also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.
  • the pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion.
  • the oily phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and the condensation products of said partial esters and ethylene oxide, For example, polyethylene oxide sorbitol monooleate.
  • Emulsions may also contain sweeteners, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs can be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
  • the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
  • acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is then added to a mixture of water and glycerol to form a microemulsion. Injections or microemulsions can be injected into a patient's bloodstream by local, large injections.
  • solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of a compound of the invention.
  • continuous intravenous drug delivery devices can be used.
  • An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.
  • the pharmaceutical composition may be in the form of a sterile injectable water or oily suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent, for example, a solution prepared in 1,3-butanediol.
  • a sterile fixed oil can be conveniently used as a solvent or suspension medium.
  • any blended fixing oil including synthetic mono- or diesters can be used.
  • fatty acids such as oleic acid can also be prepared for injection.
  • the compounds of the invention may be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and therefore will dissolve in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerin gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
  • the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient Quilt, patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc .;
  • the best treatment methods such as the mode of treatment, the daily dosage of the general compound (I) or a pharmaceutically acceptable salt The type can be verified according to traditional treatment protocols.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms Alkyl, most preferably 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 2,2-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-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhex
  • the alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkane Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups, methyl, ethyl, isopropyl, t-butyl, haloalkyl are preferred in the present invention , Deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.
  • alkylene means that a hydrogen atom of an alkyl group is further substituted, for example: "methylene” means -CH 2- , “ethylene” means-(CH 2 ) 2- , “propylene” Refers to-(CH 2 ) 3- , “butylene” refers to-(CH 2 ) 4- , etc., the above substituents may be connected to different carbon atoms to form a carbon chain, or may be connected to one carbon atom to form a cycloalkyl group.
  • alkenyl refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl and the like. Alkenyl may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 Carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl includes spiro, fused and bridged cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that contains 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S (O) A heteroatom of m (where m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; and most preferably 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., and tetrahydrofuranyl, pyrazolyl, morpholinyl, piperazinyl, and pyranyl are preferred.
  • Polycyclic heterocyclyls include spiro, fused, and bridged heterocyclic groups; the involved spiro, fused, and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further connected with other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups in a ring; the heterocyclyl may be optionally substituted or unsubstituted, when substituted
  • the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano , Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carb
  • aryl refers to a 6 to 14 membered, all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 members, such as benzene And naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
  • an aryl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • Heteroaryl is preferably 5- to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrrolyl, thienyl , Thiazolyl and pyrimidinyl.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or
  • Heteroaryl may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is as defined above.
  • An alkoxy group containing 1 to 8 carbon atoms is preferred, an alkoxy group having 1 to 6 carbon atoms is more preferred, and an alkoxy group having 1 to 3 carbon atoms is most preferred.
  • Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
  • Haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
  • Haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • Hydroalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • Alkenyl means an alkenyl group, also known as an alkenyl group, preferably an alkenyl group containing 2 to 8 carbon atoms, more preferably an alkenyl group containing 2 to 6 carbon atoms, and most preferably an alkenyl group containing 2 to 3 carbon atoms ; Where the alkenyl group may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano , Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • Alkynyl means (CH ⁇ C-), preferably an alkynyl group containing 2 to 8 carbon atoms, more preferably an alkynyl group having 2 to 6 carbon atoms, and most preferably an alkynyl group having 2 to 3 carbon atoms.
  • the alkynyl group may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • other related groups such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Amino means -NH 2.
  • Cyano refers to -CN.
  • Niro refers to -NO 2.
  • Carboxy refers to -C (O) OH.
  • THF tetrahydrofuran
  • EtOAc means ethyl acetate
  • MeOH means methanol
  • DMF N, N-dimethylformamide
  • DIPEA diisopropylethylamine
  • TFA trifluoroacetic acid
  • DMA refers to N, N-dimethylacetamide.
  • Et 2 O refers to diethyl ether
  • DCE refers to 1,2-dichloroethane.
  • DIPEA N, N-diisopropylethylamine
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide
  • Cbz-Cl refers to benzyl chloroformate
  • Pd 2 (dba) 3 refers to tris (dibenzylideneacetone) dipalladium.
  • Dppf refers to 1,1'-bisdiphenylphosphine ferrocene.
  • HATU refers to 2- (7-benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate.
  • KHMDS refers to potassium hexamethyldisilazide
  • LiHMDS refers to lithium bistrimethylsilylamine.
  • MeLi means methyl lithium
  • N-BuLi refers to n-butyllithium
  • NaBH (OAc) 3 refers to sodium triacetoxyborohydride.
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, or C
  • other terms all express the same Meaning, meaning that X can be any one or several of A, B, and C.
  • Stepoisomerism includes three types of geometric isomerism (cis-trans isomerism), optical isomerism, and conformational isomerism.
  • the hydrogen atom according to the present invention may be replaced by its isotope deuterium, and any hydrogen atom in the compound of the embodiment according to the present invention may also be replaced by a deuterium atom.
  • an heterocyclic group optionally substituted with an alkyl group means that the alkyl group may but need not exist, and this description includes a case where the heterocyclic group is substituted with an alkyl group and a case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted refers to one or more hydrogen atoms in a group, preferably up to 5 and more preferably 1 to 3 hydrogen atoms independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiological / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the present invention. Such salts are safe and effective when used in mammals, and have due biological activity.
  • the compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid-mass chromatography (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
  • the NMR measurement was performed with Bruker AVANCE-400 nuclear magnetic analyzer. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ). The internal standard was four. Methylsilane (TMS).
  • Liquid chromatography-mass spectrometry LC-MS was measured using an Agilent 1200 Infinity Series mass spectrometer.
  • Agilent 1200 DAD high-pressure liquid chromatography (Sunfire C18 150 ⁇ 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatography (Gimini C18 150 ⁇ 4.6 mm column) were used.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specifications adopted by TLC are 0.15mm ⁇ 0.20mm, and the specifications adopted by thin layer chromatography purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or they can be synthesized or synthesized according to methods known in the art.
  • Step 2 Preparation of 5-((2-cyclopropyl-2-carbonylethyl) amino) -2-fluoro-4-methylbenzonitrile
  • Step 6 Synthesis of 6- (6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-amine
  • 6-aminomethylpyridylhydrazide 300mg, 1.97mmol was dissolved in 2-pentanol (5mL) and acetic acid (1mL), and 5-methoxy-3,4-dihydro-2H- Pyrrole (195 mg, 1.97 mmol).
  • the reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and then concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL ⁇ 2) was extracted.
  • Step 7 Synthesis of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride
  • 6-aminomethylpyridylhydrazide (2.35g, 15.4mmol) was dissolved in 2-pentanol (15mL) and acetic acid (2mL), and (R) -5-methoxy-2-methyl was added -3,4-dihydro-2H-pyrrole (1.93 g, 17.1 mmol).
  • the reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and then concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL ⁇ 2) was extracted.
  • 6-aminomethylpyridylhydrazide (435mg, 2.86mmol) was dissolved in 2-pentanol (15mL) and acetic acid (2mL), and 5-methoxy-2,2-dimethyl-3 was added.
  • 4-dihydro-2H-pyrrole (404 mg, 3.2 mmol).
  • the reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL ⁇ 2) was extracted.
  • the third step 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5,5-dimethyl-6,7-dihydro-5H-pyrrolo [2,1 -c] [1,2,4] Triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
  • Step 1 Synthesis of (S) -5-methoxy-2-vinyl-3,4-dihydro-2H-pyrrole
  • 6-aminomethylpyridinyl hydrazide (321 mg, 2.11 mmol) was dissolved in a mixed solvent of 2-pentanol (10 mL) and acetic acid (1 mL), and (S) -5-methoxy-2- Vinyl-3,4-dihydro-2H-pyrrole (293 mg, 2.34 mmol).
  • the reaction was heated to 125 ° C and stirred at this temperature for 12 hours.
  • the organic solvent was concentrated under reduced pressure, and then a saturated NaHCO 3 aqueous solution (5 mL) was added, and extracted with dichloromethane (50 mL ⁇ 2).
  • the organic phase was saturated with common salt.
  • Step 1 Synthesis of (S) -5-methoxy-2- (trifluoromethyl) -3,4-dihydro-2H-pyrrole
  • 6-aminomethylpyridylhydrazide (620 mg, 3.71 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (1 mL), and (S) -5-methoxy-2- (trifluoro (Methyl) -3,4-dihydro-2H-pyrrole (650 mg, 3.89 mmol).
  • the reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL ⁇ 2) was extracted.
  • Step 1 Synthesis of S-ethyl (S) -5-carbonylpyrrolidine-2-methylsulfate
  • Step 2 Synthesis of tert-butyl (S) -2-((ethylthio) carbonyl) -5-carbonylpyrrolidine-1-carboxylic acid ester
  • Step 3 Synthesis of tert-butyl (S) -2-formyl-5-carbonylpyrrolidine-1-carboxylic acid ester
  • Step 4 Synthesis of (S) -5-carbonylpyrrolidine-2-carboxaldehyde
  • t-butyl (S) -2-formyl-5-carbonylpyrrolidine-1-carboxylic acid ester (0.72 g, 3.38 mmol) was dissolved in CH 2 Cl 2 (10 mL), and then sequentially added TFA (2.5 mL). The reaction was slowly raised to room temperature, and after stirring at this temperature for 2 hours, the crude product (400 mg) was obtained after concentration under reduced pressure and used directly in the next step.
  • Step 5 Synthesis of (S) -5-ethynylpyrrolidin-2-one
  • 6-aminomethylpyridyl hydrazide (320 mg, 2.1 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (1 mL), and (S) -2-ethynyl-5-methoxy- 3,4-dihydro-2H-pyrrole (315 mg, crude product from previous step).
  • the reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL ⁇ 2) was extracted.
  • Step 1 Synthesis of (S) -2- (fluoromethyl) -5-methoxy-3,4-dihydro-2H-pyrrole
  • 6-aminomethylpyridylhydrazide (900mg, 6.0mmol) was dissolved in 2-pentanol (15mL) and acetic acid (1mL), and (S) -2- (fluoromethyl) -5-formaldehyde was added.
  • Oxy-3,4-dihydro-2H-pyrrole (783 mg, 6.0 mmol). The reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and then concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL ⁇ 2) was extracted.
  • cuprous iodide (1.06g, 5.6mmol) was dissolved in tetrahydrofuran (6mL), replaced with nitrogen three times, and methyl lithium (7.4mL, 11.1mmol) was added dropwise.
  • the reaction was stirred at 0 ° C for 45min, and cooled At -20 ° C, a solution of (S)-(5-carbonylpyrrolidin-2-yl) methyl 4-methylbenzenesulfonate (500 mg, 1.9 mmol) in tetrahydrofuran (6 mL) was added dropwise to the reaction system. After stirring at -20 ° C for 45 min, the temperature was gradually raised to room temperature to react overnight.
  • 6-aminomethylpyridyl hydrazide 243 mg, 1.59 mmol was dissolved in 2-pentanol (5 mL) and acetic acid (2 mL), and (R) -2-ethyl-5-methoxy- 3,4-dihydro-2H-pyrrole (202 mg, 1.59 mmol).
  • the reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and then concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL ⁇ 2) was extracted.
  • Step 6 Synthesis of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride
  • 6-aminomethylpyridylhydrazide 500mg, 4.5mmol was dissolved in 2-pentanol (15mL) and acetic acid (1mL), and 5-methoxy-4-azaspiro [2.4] heptane was added 4-ene (930 mg, 6.3 mmol).
  • the reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and then concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL ⁇ 2) was extracted.
  • Methyl 5-amino-2-bromo-4-methylbenzoate (900 mg, 3.69 mmol), CuCN (657 mg, 7.38 mmol) were mixed in NMP (10 mL), stirred at 180 ° C for 2 hours, and added to water after cooling , Filtered, and the filter cake was dried to obtain the crude methyl 5-amino-2-cyano-4-methylbenzoate (1.5 g) as the title compound, which was directly used in the next step.
  • 6-amino-5-methylisoindolin-1-one (370mg, 2.28mmol), 2-bromo-1-cyclopropylethane-1-one (409mg, 2.51mmol), KI (38.0mg , 0.228 mmol), K 2 CO 3 (378 mg, 2.74 mmol) was mixed in DMF (5 mL), and stirred at 55 ° C. for 2 hours. Cool, add water to the mixture, and extract twice with dichloromethane. After the organic phases were combined, the organic phase was washed three times with saturated brine, and after drying, the organic solvent was removed under reduced pressure, and the crude product was directly used in the next step.
  • Step 4 Preparation of 6- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -5-methylisodihydroindol-1-one
  • the crude product from the third step was dissolved in AcOH (10 mL), and then KSCN (442 mg, 4.56 mmol) was added to the solution, followed by stirring at 120 ° C for 2 hours. After cooling, the reaction solution was concentrated and the crude product was used directly in the next step.
  • Step 5 Preparation of 6- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylisodihydroindol-1-one
  • the crude product in the fourth step was dissolved in a mixed solvent of AcOH (10 mL) and water (2 mL), stirred, and hydrogen peroxide (30 wt%, 10.0 g, 87.8 mmol) was slowly added dropwise to the solution at 50 ° C. After completion of the dropwise addition, stirring was continued at this temperature for 1 hour. The reaction solution was cooled, and a 20 wt% aqueous Na 2 SO 3 solution (30 mL) was slowly added, followed by stirring at room temperature for 30 minutes. The organic solvent was removed under reduced pressure, and the aqueous phase was extracted twice with dichloromethane.
  • Step 6 Preparation of 3- (6-chloropyridin-2-yl) -6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazole
  • 6- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylisodihydroindol-1-one (50 mg, 0.197 mmol), 2-chloro-6- (4-isopropyl -4H-1,2,4-triazol-3-yl) pyridine (48 mg, 0.22 mmol) and cesium carbonate (86 mg, 0.30 mml) were mixed in 1,4-dioxane (4 mL), and nitrogen was used to remove oxygen 5 minutes, add Pd 2 (dba) 3 (18mg, 0.02mmol), deoxidize with nitrogen for 5 minutes, add Xantphos (23mg, 0.04mmol), continue deoxidizing with nitrogen for 5 minutes, and then stir at 120 ° C for two days .
  • TR-FRET fluorescence resonance energy transfer
  • Adding 1 to 5 uL of the substrate mixed solution contains a final concentration of the substrate polypeptide of 100 to 5000 nM and a final concentration of ATP of 100 to 1000 uM.
  • the microplate reader measures the fluorescence signal values of about 615nm and 665nm of each plate well.
  • Example 15 1.4 Example 16 4.1 Example 30 11.4 Example 31 10.9 Example 32 4.9 Example 33 7.2 Example 34 5.2 Example 36 9.1 Example 37 3.5 Example 38 4.1 Example 40 1.9 Example 41 7.7 Example 43 1.9 Example 44 3.6 Example 48 6.1 Example 50 9.6 Example 51 4.9 Example 53 8.2 Example 55 1.9 Example 56 5.0 Example 59 2.9 Example 60 6.6 Example 61 1.9 Example 62 3.0 Example 63 8.4 Example 64 5.5 Example 65 9.4
  • the compounds of the above examples can significantly inhibit the enzymatic activity of ASK1 kinase, some compounds show a strong inhibitory effect on ASK1 kinase, and the IC 50 of kinase enzyme activity inhibition is less than 10 nM. These compounds are effective inhibitors of ASK1 for the treatment of NASH Has huge application potential.
  • the mouse pharmacokinetic test of the preferred embodiment of the present invention is performed using a Balb / c male mouse (Shanghai Jiesijie Experimental Animal Co., Ltd.).
  • Orbital blood was collected from 0.1 mL, placed in a K 2 EDTA test tube, and the plasma was separated by centrifugation at 1000 to 3000 ⁇ g at room temperature for 5 to 20 minutes, and stored at -80 ° C.
  • a liquid is 0.1% formic acid aqueous solution
  • B liquid is acetonitrile
  • the rat pharmacokinetic test of the preferred embodiment of the present invention is performed by using SD male rats (Shanghai Jiesijie Experimental Animal Co., Ltd.).
  • Mass spectrometry AB Sciex API 4000 mass spectrometer
  • a liquid is 0.1% formic acid aqueous solution
  • B liquid is acetonitrile
  • the purpose of this test case is to test whether the compound of the present invention can down-regulate the levels of ALT and AST in the serum of non-alcoholic steatohepatitis mice.
  • ALT / GPT alanine aminotransferase
  • mice were adaptively reared in the SPF (No Specific Pathogens) barrier for 3-7 days, they were replaced with HFD feeds. The rearing period was 8 weeks, and the HFD was raised for the fifth week.
  • Mice were randomly divided into groups and induced by oral administration of CCl 4 twice a week for 4 weeks. Oral administration was started on the day of CCl 4 modelling. The frequency of administration was once a day for 28 consecutive days. The administration volume was 10 mL / kg; 48 hours after the last administration of CCl 4 , the mice were euthanized with CO 2 , and non-anticoagulated venous blood was collected from the heart. The whole blood was left at room temperature for at least 30 minutes. Centrifuge under the conditions of centrifugation at 4 ° C, 5000 rpm for 5 minutes, separate the serum, aliquot it into two aliquots, place them in 1.5mL EP tubes, store at -80 ° C, and reserve.
  • ALT / GPT alanine aminotransferase
  • AST / GOT aspartate aminotransferase
  • Absolute OD value OD value of the measurement well-OD value of the control well; bring the absolute OD value into the standard curve to obtain the ALT (or AST) content in the sample.
  • the serum should be diluted to a suitable concentration and restarted. Detection.
  • Example 34 67% 60%
  • Example 37 57% 62%
  • Example 40 50% 65%
  • Example 43 65% 58%
  • Example 55 56%
  • Example 61 50% 54%
  • Example 64 51% 47%
  • Example 65 46% 52%
  • the compound of the present invention shows a good effect in down-regulating the levels of ALT and AST in the serum of non-alcoholic steatohepatitis mice.
  • Examples 9 and 43 of the present invention at 10, 30, and 100 mg / kg doses, male SD rats were repeatedly administered orally once a day for 7 consecutive days to evaluate possible toxic reactions and metabolism in the body.
  • the compound prepared with the vehicle 0.5% CMC-Na (control group) was placed on a magnetic stirrer and stirred for at least 15 minutes, and continuously stirred during the administration.
  • the required volume of the compound / control is accurately orally administered according to the measured weight.
  • the observations include but are not limited to mental state, behavioral activity, skin, coat, eyes, ears, nose, Abdomen, external genitalia, anus, limbs, feet, breathing; animals in each group were weighed twice a week.
  • the toxicokinetic blood samples were collected before the first and last administration, 0.5h, 1h, 2h, 4h, 8h, 12h, and 24h after the administration.
  • centrifuge tubes containing EDTA-K 2 were placed in a refrigerator at 2-8 ° C. Store temporarily in an ice bath; collect the blood into the labeled centrifuge tube, invert it manually at least 5 times, temporarily store in the ice bath; centrifugation conditions: 4 °C, 1500g, centrifugation for 10min, complete the centrifugation within 2 hours, The centrifuged plasma was transferred to a new labeled centrifuge tube and stored below -70 ° C.
  • Example 43 showed a fluffy coat on individual animals at the dose of 100mg / kg on the 7th to 8th days after administration, and there were no abnormal changes in the clinical observations of the animals in each time period.
  • 4Clinical pathology Compared with the vehicle control group on the eighth day, at the doses of 10, 30, and 100 mg / kg in Examples 9 and 43, the blood cell count, coagulation function, and blood biochemical indexes of male rats showed no toxicological significance.
  • Toxicology In the dose range of 10-100 mg / kg, no accumulation of Examples 9 and 43 was observed in the plasma of male rats.
  • Examples 9 and 43 were administered to male SD rats repeatedly at a dose of 10, 30, and 100 mg / kg, respectively, once a day for 7 consecutive days.
  • the animals were well tolerated, and the maximum tolerated dose (MTD) was 100 mg. / kg, and good safety.
  • MTD maximum tolerated dose

Abstract

A pharmaceutical composition containing amide derivatives, a preparation method therefor, and an application thereof. Particularly involved are a pharmaceutical composition, comprising a compound of formula (I) and a stereoisomer or pharmacologically acceptable salt thereof, a pharmacologically acceptable carrier, and use thereof as an ASK1 inhibitor in treatment of neurodegenerative diseases, cardiovascular diseases, inflammations, and autoimmune and metabolic diseases.

Description

一种含有酰胺类衍生物的药物组合物及其制备方法和应用Pharmaceutical composition containing amide derivatives, preparation method and application thereof 技术领域Technical field
本发明属于药物合成领域，具体涉及一种含有酰胺类衍生物的药物组合物及其制备方法和应用。The invention belongs to the field of pharmaceutical synthesis, and particularly relates to a pharmaceutical composition containing an amide derivative, and a preparation method and application thereof.
背景技术Background technique
有丝***激活蛋白激酶(MAPK)信号通路介导多种不同的细胞功能，包括细胞生长、分化、炎症、生存和凋亡，是细胞有丝***和凋亡的关键信号通路。MAPK分为三大类型，分别为有丝***激活蛋白激酶激酶激酶(MAP3K)、有丝***激活蛋白激酶激酶(MAP2K)和有丝***激活蛋白激酶(MAPK)，MAP3K在环境信号刺激下激活，从而激活MAP2K，MAP2K进一步激活MAPK，MAPK通过磷酸化其下游底物如转录因子等介导相应的细胞效应。The mitogen-activated protein kinase (MAPK) signaling pathway mediates many different cell functions, including cell growth, differentiation, inflammation, survival, and apoptosis, and is a key signaling pathway for cell mitosis and apoptosis. There are three major types of MAPK: mitogen-activated protein kinase kinase kinase (MAP3K), mitogen-activated protein kinase kinase (MAP2K), and mitogen-activated protein kinase (MAPK). MAP3K is activated by environmental signals, which activates MAP2K and MAP2K. Activates MAPK, which mediates the corresponding cellular effects by phosphorylating its downstream substrates such as transcription factors.
凋亡信号调节激酶1(ASK1)也叫有丝***激活蛋白激酶激酶激酶5(MAP3K5)，属于MAPK家族中的一员，介导MAPK信号通路激活，ASK1可在应激反应包括氧化应激、内质网应激和钙流入等状态下通过自身磷酸化激活，从而激活其下游MAP2K(如MKK3/6 and MKK4/7)，进一步激活c-Jun N端激酶(JNK)和p38有丝***激活蛋白激酶，导致细胞凋亡等相关细胞效应，ASK1激活及其信号通路在神经退休性疾病、心血管疾病、炎症、自身免疫和代谢性疾病等过程中起着重要作用。Apoptosis signal-regulated kinase 1 (ASK1) is also called mitogen-activated protein kinase kinase kinase 5 (MAP3K5). It belongs to the MAPK family and mediates the activation of MAPK signaling pathways. ASK1 can be used in stress responses including oxidative stress, endoplasmic It is activated by autophosphorylation under conditions such as network stress and calcium influx, thereby activating its downstream MAP2K (such as MKK3 / 6 and MKK4 / 7), further activating c-Jun N-terminal kinase (JNK) and p38 mitosis-activated protein kinase, leading to Related cellular effects such as apoptosis, ASK1 activation and its signaling pathways play important roles in neuroretirement diseases, cardiovascular diseases, inflammation, autoimmune and metabolic diseases.
非酒精性脂肪性肝炎(NASH)发病率高，全球或国内大约有2％～5％的NASH患者，市场规模在2025年预计将达到350亿～400亿美元。目前NASH临床上没有批准上市的药物，早期在研的治疗NASH靶点包括FXR、PPAR和GLP等，但FXR和PPAR靶点存在较大的安全性问题，而GLP属于早期的糖尿病治疗靶点，疗效还没有得到确切的临床终点验证，且属于肽类药物需每天皮下注射给药。ASK1正成为是NASH治疗领域的新机制和新靶点，其信号通路通过促进肝组织炎症和纤维化，在NASH发生发展过程中起重要作用。ASK1抑制剂对NASH的临床治疗具有巨大的潜力，对其他疾病领域包括神经退休性疾病、心血管疾病、炎症、自身免疫和代谢性疾病等的治疗也具有潜在的应用价值。The incidence of non-alcoholic steatohepatitis (NASH) is high. There are approximately 2% to 5% of NASH patients worldwide or domestically. The market size is expected to reach 35 billion to 40 billion US dollars by 2025. At present, NASH does not have a clinically approved drug in the market. The targets for early treatment of NASH include FXR, PPAR, and GLP. However, there are major safety issues with FXR and PPAR targets. GLP is an early target for diabetes treatment. Efficacy has not been verified by exact clinical endpoints, and peptide drugs need to be administered daily by subcutaneous injection. ASK1 is becoming a new mechanism and new target in the field of NASH treatment. Its signaling pathway plays an important role in the development of NASH by promoting inflammation and fibrosis of liver tissue. ASK1 inhibitors have great potential for clinical treatment of NASH, and also have potential application value in the treatment of other disease areas including neuroretirement diseases, cardiovascular diseases, inflammation, autoimmune and metabolic diseases.
公开的选择性抑制ASK1的抑制剂专利申请包括WO2011008709、WO2016025474、WO2012003387、WO2016105453、WO2016106384和WO2008008375等。Published patent applications for inhibitors that selectively inhibit ASK1 include WO2011008709, WO2016025474, WO2012003387, WO2016105453, WO2016106384, and WO2008008375 and the like.
ASK1抑制剂作为药物在医药行业具有良好的应用前景，本发明将提供一种新型结构的选择性ASK1抑制剂组合物，并发现具有此类结构的化合物在药代活性和药效活性方面表现出优异的效果和作用。ASK1 inhibitors have good application prospects as medicines in the pharmaceutical industry. The present invention will provide a novel structure of selective ASK1 inhibitor compositions, and it is found that compounds having such structures exhibit pharmacological and pharmacological activity Excellent effect and function.
发明内容Summary of the invention
本发明的目的在于提供一种药物组合物，包含通式(I)所示的化合物、其立体异构体或其药学上可接受盐，其结构如下：An object of the present invention is to provide a pharmaceutical composition comprising a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and its structure is as follows:
Figure PCTCN2019099971-appb-000001
Figure PCTCN2019099971-appb-000001
其中：among them:
M 1、M 2、M 3和M 4各自独立地选自N或-CR 6； M 1 , M 2 , M 3 and M 4 are each independently selected from N or -CR 6 ;
X和Y各自独立地选自键、
Figure PCTCN2019099971-appb-000002
-NR 7-、-CR 7R 8-、-S(O) m-、
Figure PCTCN2019099971-appb-000003
Figure PCTCN2019099971-appb-000004
X and Y are each independently selected from a bond,
Figure PCTCN2019099971-appb-000002
-NR 7- , -CR 7 R 8- , -S (O) m- ,
Figure PCTCN2019099971-appb-000003
Figure PCTCN2019099971-appb-000004
环A选自芳基或杂芳基，其中所述的芳基和杂芳基任选进一步被选自氘原子、烷基、氘代烷基、卤素、氨基、硝基、羟基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代； Ring A is selected from aryl or heteroaryl, wherein said aryl and heteroaryl are optionally further selected from deuterium, alkyl, deuterated alkyl, halogen, amino, nitro, hydroxyl, cyano, Alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O ) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C ( O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 With one or more substituents;
R 1相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代； R 1 is the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, an amino group, a nitro group, a hydroxy group, a cyano group, a cyclic group Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-( CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ; the alkyl and haloalkane described therein Group, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy , Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 Substituted with one or more substituents;
R 2相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、 -(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9； R 2 is the same or different, and each is independently selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, and a ring Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-( CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ;
R 3选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、环烷基、杂环基、芳基和杂芳基，所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9； R 3 is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; Alkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkane Group, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-( CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ;
或者，R 3和M 3、M 3和M 4链接分别形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基或杂芳基任选进一步被选自氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代； Alternatively, R 3 and M 3 , M 3 and M 4 are respectively linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is described Optionally further selected from deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, Heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 、-(CH 2 ) n C (O) OR 9 、-(CH 2 ) n S (O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 Substituted with one or more substituents;
又或者，R 1和X或Y、M 1和X或Y链接分别形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基或杂芳基任选进一步被选自氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代； Alternatively, R 1 and X or Y, M 1 and X or Y are respectively linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or Heteroaryl is optionally further selected from deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cyclic Alkyl, heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C ( O) R 9, - (CH 2) n C (O) OR 9, - (CH 2) n S (O) m R 9, - (CH 2) n NR 10 R 11, - (CH 2) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R Substituted by one or more substituents of 9 ;
R 6、R 7和R 8相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代； R 6 , R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, Hydroxyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ; Said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkane Oxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 is substituted by one or more substituents;
R 9选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤素、氨基、 硝基、氰基、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代； R 9 is selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; Said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 , -(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 or Substituted with multiple substituents;
R 10和R 11相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代； R 10 and R 11 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group Wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of a deuterium atom, an alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkoxy group, Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 , -(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 or Substituted with multiple substituents;
R 12和R 13相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、酯基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤素、羟基、氨基、硝基、氰基、酯基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 12 and R 13 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, an ester group, a cycloalkyl group, a heterocyclic group, an aryl group, and Heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, halogen, hydroxyl, amino, nitro, cyano, ester Substituted with one or more substituents of aryl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
x为0、1、2、3或4的整数；x is an integer of 0, 1, 2, 3, or 4;
y为0、1或2的整数；y is an integer of 0, 1, or 2;
m为0、1或2的整数；且m is an integer of 0, 1, or 2; and
n为0、1、2、3、4或5的整数。n is an integer of 0, 1, 2, 3, 4 or 5.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于活性成分的重量百分比为1％～95％，优选5％～85％，更优选10％～60％，进一步优选10％～50％。In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the weight percentage of the active ingredient is 1% to 95%, preferably 5% to 85%, more preferably 10% to 60%, even more preferably 10% to 50%.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于，剂量范围为0.5-120mg，优选为1-100mg，进一步优选为1-50mg，更进一步优选为1-30mg。In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the dosage range is 0.5-120 mg, preferably 1-100 mg, further preferably 1-50 mg, and even more preferably 1-30 mg.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(II)化合物：In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the following compounds of the general formula (II):
Figure PCTCN2019099971-appb-000005
Figure PCTCN2019099971-appb-000005
其中：among them:
R 4选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧 基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代； R 4 is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxy group, a cyano group, a cycloalkyl group, a heterocyclic group, and an aromatic group. Group, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 , -(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ; the alkyl, haloalkyl, cycloalkyl, heterocyclic ring Aryl, aryl and heteroaryl are optionally further selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 are substituted by one or more substituents;
R 3和R 4链接形成一个杂环或杂芳环，其中所述的杂环或杂芳环任选进一步被选自氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代； R 3 and R 4 are linked to form a heterocyclic ring or heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen group, an amino group, and a nitrate group. Radical, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 are substituted by one or more substituents;
或者，R 3和R 4链接形成的杂环或杂芳环，所述杂环或杂芳环上的任意两个取代基可以形成环烷基、杂环基、芳基和杂芳基，其中所述环烷基、芳环基、杂环基或杂芳环基任选进一步被选自氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代； Alternatively, R 3 and R 4 are linked to form a heterocyclic ring or heteroaryl ring, and any two substituents on the heterocyclic ring or heteroaryl ring may form a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein The cycloalkyl, aromatic ring, heterocyclyl or heteroaryl ring group is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, Alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-( CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 And-(CH 2 ) n NR 10 S (O) m R 9 are substituted by one or more substituents;
环A、M 1、M 2、X、Y、R 1-R 3、x、y、m和n如通式(I)所述。 Rings A, M 1 , M 2 , X, Y, R 1 -R 3 , x, y, m and n are as described in the general formula (I).
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于，通式(I)化合物如通式(III)所示：In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (III):
Figure PCTCN2019099971-appb-000006
Figure PCTCN2019099971-appb-000006
环B选自杂环基或杂芳基；其中，杂环基优选包含3至20个环原子，其中一个或多个环原子为选自氮、氧、磷或S(O)t，其余环原子为碳，杂环基进一步优选包含3至12个环原子，其中1～4个环原子选自氮、氧和磷，其余环原子为碳，杂环基更优选包含3至8个环原子，其中1～3个环原子选自氮、氧，其余环原子为碳，杂环基最优选包含5至7个环原子，其中1～2个环原子选自氮、 氧，其余环原子为碳，杂环基进一步最优选自吡咯、哌啶、氮杂环庚烷、吗啉、哌嗪；杂芳基优选包含5至14个环原子，其中1至4个环原子选自氮、氧、磷或S(O)t，其余环原子为碳，杂芳基进一步优选包含5至10个环原子，其中1至4个环原子选自氮、氧、磷或S(O)t，其余环原子为碳，杂芳基更优选包含5至10个环原子，其中1至3个环原子选自氮、氧、磷，其余环原子为碳，杂芳基最优选为包含5个或6个环原子，其中1至2个原子选自氮、氧；Ring B is selected from heterocyclyl or heteroaryl; wherein, heterocyclyl preferably contains 3 to 20 ring atoms, of which one or more ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, and the remaining rings The atom is carbon, and the heterocyclic group further preferably contains 3 to 12 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen, and phosphorus, and the remaining ring atoms are carbon, and the heterocyclic group more preferably contains 3 to 8 ring atoms. Wherein 1 to 3 ring atoms are selected from nitrogen and oxygen, and the remaining ring atoms are carbon. The heterocyclic group most preferably contains 5 to 7 ring atoms, of which 1 to 2 ring atoms are selected from nitrogen and oxygen, and the remaining ring atoms Carbon, heterocyclyl is further preferably selected from pyrrole, piperidine, azacycloheptane, morpholine, piperazine; heteroaryl preferably contains 5 to 14 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen , Phosphorus or S (O) t, the remaining ring atoms are carbon, and the heteroaryl group further preferably contains 5 to 10 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, and the rest The ring atom is carbon, and the heteroaryl group more preferably contains 5 to 10 ring atoms, of which 1 to 3 ring atoms are selected from nitrogen, oxygen, and phosphorus, the remaining ring atoms are carbon, and the heteroaryl group most preferably contains 5 or 6 ring atoms, of which 1 to 2 atoms are selected from nitrogen and oxygen;
R a选自氢原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，优选自氢原子、C 1-8烷基、氘代C 1-8烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、卤素、氨基、硝基、羟基、氰基、C 1-8烯基、C 1-8炔基、C 3-8环烷基、C 3-12杂环基、C 6-14芳基、C 5-14杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，更优选自氢原子、C 1-3烷基、氘代C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、卤素、氨基、硝基、羟基、氰基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，最优选自氢原子、甲基、乙基、正丙基、异丙基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、乙烯、丙烯、丁烯、乙炔、丙炔、丁炔、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基、C(O)CH 3； R a is selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, and a heterocyclic ring. , Aryl, heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 , -(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 , preferably from hydrogen Atom, C 1-8 alkyl, deuterated C 1-8 alkyl, halo C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy, halogen, amino, nitrate Group, hydroxy, cyano, C 1-8 alkenyl, C 1-8 alkynyl, C 3-8 cycloalkyl, C 3-12 heterocyclyl, C 6-14 aryl, C 5-14 heteroaryl Base,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 , - (CH 2) n NR 10 C (O) R 9 and - (CH 2) n NR 10 S (O) m R 9, and more preferably from hydrogen Sub, C 1-3 alkyl, deuterated C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, a C 1-3 alkoxy group, haloalkyl, halo, amino, nitro Group, hydroxy, cyano, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, C 5-10 heteroaryl Base,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 , optimally selected from hydrogen atom, methyl, ethyl Methyl, n-propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, Trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy , Chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, ethylene, propylene, butene, acetylene, propyne, butyne, cyclic Base, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydro Pyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl Oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, C (O) CH 3 ;
其中，R a任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，优选被氘原子、C 1-8烷基、卤代C 1-8烷基、卤素、氨基、硝基、氰基、羟基、C 2-8烯 基、C 2-8炔基、C 1-8烷氧基、卤代C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基、C 5-14杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，更优选被氘原子、C 1-3烷基、卤代C 1-3烷基、卤素、氨基、硝基、氰基、羟基、C 2-4烯基、C 2-4炔基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，最优选被氘原子、甲基、乙基、正丙基、异丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、乙烯、丙烯、丁烯、乙炔、丙炔、丁炔、羟基取代的甲基、羟基取代的乙基、羟基取代的丙基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基中的一个或多个取代基所取代； Wherein R a is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cyclic group Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-( CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 Substitution, preferably by deuterium, C 1-8 alkyl, halo C 1-8 alkyl, halogen, amino, nitro, cyano, hydroxyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, halo C 1-8 alkoxy, C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl, C 5 -14 heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 , -(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 is substituted by one or more substituents, more preferably by deuterium atom, C 1-3 alkyl, halo C 1-3 alkyl, halogen, amino, nitro, cyano, Hydroxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, C 5-10 heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O ) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C ( O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 Substituted by one or more substituents, most preferably by deuterium, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl , Dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy , Chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, ethylene, Ene, butene, acetylene, propyne, butyne, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrole Alkyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thio Morpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, Substituted by one or more substituents of pyrimidinyl, thiadiazole, pyrazinyl;
或者，环B上任意两个R a取代基形成环烷基、杂环基、芳基和杂芳基，其中杂原子为选自氮、氧、硫、磷中的1至4个，优选任意两个R a取代基形成C 3-8环烷基、C 3-8杂环基、C 6-14芳基和C 5-14杂芳基，其中杂原子为选自氮、氧、硫、磷中的1至3个，更优选任意两个R a取代基形成C 3-6环烷基、C 3-6杂环基、C 6-10芳基和C 5-10杂芳基，其中杂原子为选自氮、氧中的1至2个，最优选任意两个R a取代基形成环丙基、环丁基、环戊基、C 3-5杂环基、C 6-7芳基和C 5-7杂芳基，其中杂原子为选自氮、氧中的1至2个； Alternatively, any two R a substituents on ring B form a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the hetero atom is 1 to 4 selected from nitrogen, oxygen, sulfur, and phosphorus, preferably any The two R a substituents form a C 3-8 cycloalkyl group, a C 3-8 heterocyclyl group, a C 6-14 aryl group, and a C 5-14 heteroaryl group, wherein the hetero atom is selected from nitrogen, oxygen, sulfur, 1 to 3, more preferably any two R a substituents in phosphorus form C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, and C 5-10 heteroaryl, wherein Heteroatoms are 1 to 2 selected from nitrogen and oxygen, most preferably any two R a substituents form cyclopropyl, cyclobutyl, cyclopentyl, C 3-5 heterocyclyl, C 6-7 aromatic And C 5-7 heteroaryl, wherein the hetero atom is 1 to 2 selected from nitrogen and oxygen;
其中，所述任意两个R a取代基形成的环任选进一步被选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代，优选被选自氢原子、氘原子、C 1-8烷基、氘代C 1-8烷基、卤代C 1-8烷基、卤素、氨基、硝基、羟基、氰基、C 2-8烯基、C 2-8炔基、C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基和C 5-14杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、 -(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代，更优选被选自氢原子、氘原子、C 1-3烷基、氘代C 1-3烷基、卤代C 1-3烷基、卤素、氨基、硝基、羟基、氰基、C 2-4烯基、C 2-4炔基、C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、C 3-6杂环基、C 6-7芳基和C 5-7杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代；最优选被氢原子、氘原子、甲基、乙基、正丙基、异丙基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、乙烯、丙烯、丁烯、乙炔、丙炔、丁炔、甲氧基、乙氧基、丙氧基、羟基取代的甲基、羟基取代的乙基、羟基取代的丙基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基中的一个或多个取代基所取代； Wherein, the ring formed by any two R a substituents is optionally further selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, and an alkenyl group. , Alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and -(CH 2 ) n NR 10 S (O) m R 9 is substituted with one or more substituents, preferably selected from a hydrogen atom, a deuterium atom, a C 1-8 alkyl group, a deuterated C 1-8 alkane Alkyl, halo C 1-8 alkyl, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 1-8 hydroxy Alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl and C 5-14 heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O ) m R 9 is substituted with one or more substituents, more preferably selected from a hydrogen atom, a deuterium atom, a C 1-3 alkyl group, a deuterated C 1-3 alkyl group, a halogenated C 1-3 alkyl group , Halogen, amino, nitro, hydroxyl, cyano, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl , C 3-6 heterocyclyl, C 6-7 aryl and C 5-7 heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 、-(CH 2 ) n C (O) R 9 、-(CH 2 ) n C (O) OR 9 、-(CH 2 ) n S (O) m R 9 、-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 is substituted by one or more substituents; most preferably by a hydrogen atom, deuterium atom, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, Deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, Fluoromethoxy, Fluoroethoxy, Fluoro Propoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, ethylene, propylene, butene, acetylene, propane Alkyne, butyne, methoxy, ethoxy, propoxy, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxe Butane, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholine Base, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, pyrazinyl or one or more substituents;
z为0、1、2、3、4或5的整数；z is an integer of 0, 1, 2, 3, 4 or 5;
t为0、1或2。t is 0, 1, or 2.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于通式(I)化合物如通式(IV)所示：In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (IV):
Figure PCTCN2019099971-appb-000007
Figure PCTCN2019099971-appb-000007
其中：among them:
M 5为O、-CR 6或-NR 7； M 5 is O, -CR 6 or -NR 7 ;
R 6、R 7相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，优选自氢原子、C 1-8烷基、氘代C 1-8烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、卤素、氨基、硝基、羟基、 氰基、C 3-8环烷基、C 3-12杂环基、C 6-14芳基、C 5-14杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，更优选自氢原子、C 1-3烷基、氘代C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、卤素、氨基、硝基、羟基、氰基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，最优选自氢原子、甲基、乙基、正丙基、异丙基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基； R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyanide Group, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-( CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 , preferably from a hydrogen atom, C 1-8 alkyl, deuterated C 1-8 alkyl, halo C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy, halogen, amino, nitro, Hydroxyl, cyano, C 3-8 cycloalkyl, C 3-12 heterocyclyl, C 6-14 aryl, C 5-14 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-( CH 2 ) n NR 10 S (O) m R 9 , more preferably from hydrogen atom, C 1-3 alkyl, deuterated C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 3-6 ring Alkyl, C 3-6 heterocyclyl, C 6-10 aryl, C 5-10 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 , optimally selected from hydrogen atom, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluorine Ethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethyl Oxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, cyclopropyl, cyclo Butyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl Dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furan Base, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
其中，所述的R 6、R 7任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；优选被选自氘原子、C 1-8烷基、卤代C 1-8烷基、卤素、氨基、硝基、羟基、氰基、C 1-8烷氧基、卤代C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基和C 5-14杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，更优选被选自氘原子、C 1-3烷基、卤代C 1-3烷基、卤素、氨基、硝基、羟基、氰基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基和C 5-10杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，最优选被甲基、乙基、正丙基、异丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、羟基取代的甲基、羟基取代的乙基、羟基取代的丙基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、 四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基中的一个或多个取代基所取代； Wherein, R 6 and R 7 are optionally further selected from a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, and a cyclic Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-( CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 Substitution; preferably selected from deuterium atom, C 1-8 alkyl, halo C 1-8 alkyl, halogen, amino, nitro, hydroxyl, cyano, C 1-8 alkoxy, halo C 1- 8 alkoxy, C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl and C 5-14 heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C (O) NR 12 R 13 、-(CH 2 ) n C (O) NHR 13 、-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 Substituted with one or more substituents, more preferably selected from deuterium atom, C 1-3 alkyl, halo C 1-3 alkyl, halogen, amino, nitro, hydroxyl, cyano, C 1-3 alkoxy Alkyl, halo C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, and C 5-10 heteroaryl ,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-( CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 are substituted with one or more substituents, most preferably methyl, ethyl, n-propyl Methyl, isopropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, Ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, Iodine, amino, nitro, hydroxyl, cyano, hydroxyl substituted methyl, hydroxyl substituted ethyl, hydroxyl substituted propyl , Cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl , Dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazole Substituted with one or more substituents of phenyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
q为0、1或2。q is 0, 1, or 2.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于通式(I)化合物如通式(V)所示：In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (V):
Figure PCTCN2019099971-appb-000008
Figure PCTCN2019099971-appb-000008
其中：among them:
o为0、1、2、3、4或5的整数。o is an integer of 0, 1, 2, 3, 4 or 5.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于：In a preferred embodiment of the present invention, the pharmaceutical composition is characterized by:
M 1、M 2各自独立地选自N或-CR 6，可选的M 1、M 2不相同； M 1 and M 2 are each independently selected from N or -CR 6 , and optional M 1 and M 2 are different;
X和Y各自独立地选自键、
Figure PCTCN2019099971-appb-000009
-NR 7-、-CR 7R 8-、-S(O) m-、
Figure PCTCN2019099971-appb-000010
Figure PCTCN2019099971-appb-000011
可选的X和Y不相同； X and Y are each independently selected from a bond,
Figure PCTCN2019099971-appb-000009
-NR 7- , -CR 7 R 8- , -S (O) m- ,
Figure PCTCN2019099971-appb-000010
Figure PCTCN2019099971-appb-000011
The optional X and Y are different;
环A选自芳基或杂芳基；所述芳基为6至14元全碳单环或稠合多环，优选为6至10元，更优选为苯基或萘基；所述杂芳基优选包含5至14个环原子，其中1至4个环原子选自氮、氧、磷或S(O)t，其余环原子为碳，杂芳基进一步优选包含5至10个环原子，其中1至4个环原子选自氮、氧、磷或S(O)t，其余环原子为碳，杂芳基更优选包含5至10个环原子，其中1至3个环原子选自氮、氧、磷，其余环原子为碳，最优选为咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑或吡嗪基，Ring A is selected from aryl or heteroaryl; the aryl is 6 to 14 membered full carbon monocyclic or fused polycyclic, preferably 6 to 10 members, more preferably phenyl or naphthyl; the heteroaryl The group preferably contains 5 to 14 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, the remaining ring atoms are carbon, and the heteroaryl group further preferably contains 5 to 10 ring atoms, Wherein 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, the remaining ring atoms are carbon, and the heteroaryl group more preferably contains 5 to 10 ring atoms, of which 1 to 3 ring atoms are selected from nitrogen , Oxygen, phosphorus, the remaining ring atoms are carbon, most preferably imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl , Thiadiazole or pyrazinyl,
Figure PCTCN2019099971-appb-000012
Figure PCTCN2019099971-appb-000013
Figure PCTCN2019099971-appb-000012
Figure PCTCN2019099971-appb-000013
杂芳基进一步最优选为包含5个或6个环原子，其中1至2个原子选自氮、氧；Heteroaryl is further most preferably comprising 5 or 6 ring atoms, of which 1 to 2 atoms are selected from nitrogen and oxygen;
其中，所述环A任选进一步被选自氘原子、烷基、氘代烷基、卤素、氨基、硝基、羟基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代，优选被选自氘原子、C 1-8烷基、氘代C 1-8烷基、卤素、氨基、硝基、羟基、氰基、C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基和C 5-14杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代，更优选被选自氘原子、C 1-3烷基、氘代C 1-3烷基、卤素、氨基、硝基、羟基、氰基、C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基和C 5-10杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代，最优选被选自氘原子、甲基、乙基、正丙基、异丙基、氘代甲基、氘代乙基、氘代丙基、甲氧基、乙氧基、丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、甲氧基、乙氧基、丙氧基、羟基取代的甲基、羟基取代的乙基、羟基取代的丙基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基、
Figure PCTCN2019099971-appb-000014
Figure PCTCN2019099971-appb-000015
Figure PCTCN2019099971-appb-000016
中的一个或多个取代基所取代； Wherein, the ring A is optionally further selected from a deuterium atom, an alkyl group, a deuterated alkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group , Aryl and heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 、-(CH 2 ) n S (O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C (O) NR 10 R 11 、-(CH 2 ) n C ( O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 are substituted with one or more substituents, preferably selected from Deuterium atom, C 1-8 alkyl, deuterated C 1-8 alkyl, halogen, amino, nitro, hydroxyl, cyano, C 1-8 alkoxy, C 1-8 hydroxyalkyl, C 3- 8 -cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl and C 5-14 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S ( O) m R 9 is substituted with one or more substituents, more preferably selected from a deuterium atom, C 1- 3 alkyl, deuterated C 1-3 alkyl, halogen, amino, nitro, hydroxy, cyano, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl and C 5-10 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O ) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 Substituted with one or more substituents, most preferably selected from deuterium, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, methoxy , Ethoxy, propoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxy, cyano, methoxy, ethoxy, propoxy, hydroxy-substituted methyl, hydroxy-substituted ethyl , Hydroxy-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl , Dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, Base, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, pyrazinyl,
Figure PCTCN2019099971-appb-000014
Figure PCTCN2019099971-appb-000015
Figure PCTCN2019099971-appb-000016
With one or more substituents;
R 2相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；优选自氢原子、氘原子、C 1-8烷基、氘代C 1-8烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、卤素、氨基、硝基、羟基、氰基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基、C 5-14杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；更优选自氢原子、氘原子、C 1-6烷基、氘代C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、卤素、氨基、硝基、羟基、氰基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；最优选自氢原子、氘原子、甲基、乙基、正丙基、异丙基、、正丁基、异丁基、叔丁基、仲丁基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、羟基取代的甲基、羟基取到的乙基、羟基取代的丙基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基。 R 2 is the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, an amino group, a nitro group, a hydroxy group, a cyano group, a cyclic Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-( CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ; preferably from a hydrogen atom, a deuterium atom, C 1-8 alkyl, deuterated C 1-8 alkyl, halo C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy, halogen, amino, nitro, Hydroxy, cyano, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl, C 5-14 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-( CH 2) n NR 10 S ( O) m R 9; more preferably from hydrogen atom, deuterium atom, C 1-6 Group, deuterated C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halo, amino, nitro, hydroxy, cyano, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, C 5-10 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,- (CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 , -(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ; optimally selected from hydrogen atom, deuterium atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, deuterium Methyl, deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chlorine Propyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy Methyl, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxy , Cyano, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydro Pyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furanyl, thienyl, thiazolyl , Pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于通式(I)化合物如通式(III-A)所示：In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (III-A):
Figure PCTCN2019099971-appb-000017
Figure PCTCN2019099971-appb-000017
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于通式(I)化合物如通式(III-A1)或通式(III-A2)所示：In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (III-A1) or the general formula (III-A2):
Figure PCTCN2019099971-appb-000018
Figure PCTCN2019099971-appb-000018
其中，among them,
环C为4-7元杂环基或杂芳基，其中一个或多个环原子为选自氮、氧或S(O)t的杂原子，其余环原子为碳，优选包含1-2个氮或氧原子的5元杂环基；所述杂芳基优选包含1至4个杂原子，其中杂原子选自氧、硫和氮，优选为包含1至两个氮或氧的杂原子的5元或6元杂芳基；优选的，环C为以下结构：Ring C is a 4-7 membered heterocyclyl or heteroaryl group, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S (O) t, and the remaining ring atoms are carbon, preferably containing 1-2 5-membered heterocyclic group of nitrogen or oxygen atom; the heteroaryl group preferably contains 1 to 4 heteroatoms, wherein the heteroatom is selected from the group consisting of oxygen, sulfur and nitrogen, preferably a heteroatom containing 1 to 2 nitrogen or oxygen 5- or 6-membered heteroaryl; preferably, ring C has the following structure:
Figure PCTCN2019099971-appb-000019
Figure PCTCN2019099971-appb-000019
R b选自氢原子、C 1-8烷基、C 1-8氘代烷基或C 1-8卤代烷基 R b is selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 deuterated alkyl group, or a C 1-8 haloalkyl group
t为0、1或2。t is 0, 1, or 2.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于：其特征在于：R 1相同或不同，且各自独立地选自氢原子、氘原子、C 1-8烷基、氘代C 1-8烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、卤素、氨基、硝基、羟基、氰基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基、C 5-14杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9； In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that: R 1 is the same or different and each is independently selected from a hydrogen atom, a deuterium atom, and a C 1-8 alkyl group , Deuterated C 1-8 alkyl, halo C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl, C 5-14 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-( CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,- (CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ;
其中所述的R 1任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，优选被选自氢原子、氘原子、C 1-8烷基、氘代C 1-8烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、C 1-8羟烷基、卤素、氨基、硝基、羟基、氰基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基、C 5-14杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代，更优选被选自氢原子、氘原子、C 1-6烷基、氘代C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、卤素、氨基、硝基、羟基、氰基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、 -(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代，最优选被选自氢原子、氘原子、甲基、乙基、正丙基、异丙基、、正丁基、异丁基、叔丁基、仲丁基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、羟基取代的甲基、羟基取到的乙基、羟基取代的丙基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基中的一个或多个取代。 Wherein R 1 is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a halogenated alkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group. Cyclic, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O ) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 is substituted by one or more substituents in C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 , preferably by Selected from hydrogen atom, deuterium atom, C 1-8 alkyl, deuterated C 1-8 alkyl, halo C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy , C 1-8 hydroxyalkyl, halogen, amino, nitro, hydroxyl, cyano, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl, C 5-14 heteroaryl Base,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,- (CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 is substituted with one or more substituents, and is more preferably selected from a hydrogen atom, a deuterium atom, a C 1-6 alkyl group, a deuterated C 1-6 alkyl group, a halogenated C 1-6 alkyl group, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, halogen, amino, nitro, hydroxyl, cyano, C 3-6 cycloalkyl, C 3-6 hetero Cyclic group, C 6-10 aryl group, C 5-10 heteroaryl group,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,- (CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 Substituted with a substituent, most preferably selected from hydrogen atom, deuterium atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, deuterated Methyl, deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloro Propyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy Chloroethoxy, chloropropoxy, hydroxy-substituted methyl, hydroxy-derived ethyl, hydroxy-substituted propyl, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, cyclic Propyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, di Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, One or more of oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, and pyrazinyl are substituted.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于：R 1相同或不同，且各自独立地选自选自氢原子、氘原子、C 1-3烷基、氘代C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、卤素、氨基、硝基、羟基、氰基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的R 1任选进一步被取代。 In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that R 1 is the same or different, and each is independently selected from the group consisting of a hydrogen atom, a deuterium atom, a C 1-3 alkyl group, and deuterium. C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 3- 6 -cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, C 5-10 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S ( O) m R 9 ; wherein R 1 is optionally further substituted.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于：其特征在于：R 1选自氢原子、氘原子、甲基、乙基、正丙基、异丙基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基；任选被选自氢原子、氘原子、甲基、乙基、正丙基、异丙基、、正丁基、异丁基、叔丁基、仲丁基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、羟基取代的甲基、羟基取到的乙基、羟基取代的丙基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、环丙基、 环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基中的一个或多个取代。 In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that: R 1 is selected from a hydrogen atom, a deuterium atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, Deuterated methyl, deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, Chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropyl Oxygen, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, Tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyridine Ranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl ; Optional Selected from hydrogen atom, deuterium atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, deuterated methyl, deuterated ethyl, deuterium Propyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy Group, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, hydroxy-substituted methyl, hydroxy To ethyl, hydroxy substituted propyl, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxy, cyano, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl , Imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine Base, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl , Thiadiazole, pyrazine One or more substituents.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于通式(I)化合物如通式(VI-A)或通式(VI-B)所示：In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (VI-A) or the general formula (VI-B):
Figure PCTCN2019099971-appb-000020
Figure PCTCN2019099971-appb-000020
R 5选自氢原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、羟烷基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，优选自氢原子、C 1-8烷基、氘代C 1-8烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、卤素、氨基、硝基、羟基、C 1-8羟烷基、氰基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基、C 5-14杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，更优选自氢原子、C 1-6烷基、氘代C 1-6烷基、卤代C 1-6烷基、C 1-8烷氧基、卤代C 1-8烷氧基、卤素、氨基、硝基、羟基、C 1-6羟烷基、氰基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，最优选自氢原子、甲基、乙基、正丙基、异丙基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、羟基取代的甲基、羟基取代的乙基、羟基取代的丙基、羟基取代的丁基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基； R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cyano group, a cycloalkyl group, a heterocyclic group, Aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O ) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 , preferably from hydrogen atom, C 1-8 alkyl, deuterated C 1-8 alkyl, halo C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy, halogen, amino, nitro, hydroxyl, C 1-8 hydroxyalkyl, Cyano, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl, C 5-14 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 、-(CH 2 ) n C (O) R 9 、-(CH 2 ) n C (O) OR 9 、-(CH 2 ) n S (O) m R 9 、-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9, and more preferably from hydrogen atoms, C 1-6 alkyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl , C 1-8 alkoxy, halo C 1-8 alkoxy, halo, amino, nitro, hydroxy, C 1-6 hydroxyalkyl, cyano, C 3-6 cycloalkyl, C 3- 6 heterocyclyl, C 6-10 aryl, C 5-10 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 , most preferred From hydrogen atom, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoro Propyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropyl Oxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxy, cyano, hydroxy-substituted methyl, hydroxy-substituted ethyl , Hydroxy-substituted propyl, hydroxy-substituted butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane , Pyrrolidinyl, imidazolyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, Thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridine Group, pyrimidinyl, thiadiazole, pyrazinyl;
其中，R 5任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，优选被氘原子、C 1-8烷基、卤代C 1-8烷基、卤素、氨基、硝基、氰基、羟基、C 1-8烷氧基、卤代C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基、C 5-14杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；更优选被氘原子、C 1-6烷基、卤代C 1-6烷基、卤素、氨基、硝基、氰基、羟基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；最优选被氘原子、甲基、乙基、正丙基、异丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、羟基取代的甲基、羟基取代的乙基、羟基取代的丙基、羟基取代的丁基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基中的一个或多个取代； Wherein R 5 is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group. , Aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C ( O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 are substituted with one or more substituents, preferably a deuterium atom , C 1-8 alkyl, halo C 1-8 alkyl, halogen, amino, nitro, cyano, hydroxyl, C 1-8 alkoxy, halo C 1-8 alkoxy, C 1- 8 -hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl, C 5-14 heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-( in a 12 CH 2) n NR 13 S (O) m R or more substituents Generation; more preferably a deuterium atom, C 1-6 alkyl, halo C 1-6 alkyl, halo, amino, nitro, cyano, hydroxy, C 1-6 alkoxy, halo C 1-6 Alkoxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, C 5-10 heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C ( O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 are substituted by one or more substituents; most preferably by a deuterium atom, methyl, ethyl, n-propyl, isopropyl , Difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propyl Oxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitrate Hydroxy, cyano, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, hydroxy-substituted Butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyridine Oxazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, One or more substitutions of pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
x-1为1、2、3或4的整数。x-1 is an integer of 1, 2, 3, or 4.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于通式(I)化合物如通式(VI-A1)或通式(VI-B1)所示：In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (VI-A1) or the general formula (VI-B1):
Figure PCTCN2019099971-appb-000021
Figure PCTCN2019099971-appb-000021
M 5为O、-CR 6或-NR 7； M 5 is O, -CR 6 or -NR 7 ;
R 6、R 7相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、 -(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，优选自氢原子、C 1-8烷基、氘代C 1-8烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、卤素、氨基、硝基、羟基、氰基、C 3-8环烷基、C 3-12杂环基、C 6-14芳基、C 5-14杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，更优选自氢原子、C 1-3烷基、氘代C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、卤素、氨基、硝基、羟基、氰基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，最优选自氢原子、甲基、乙基、正丙基、异丙基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基； R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyanide Group, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-( CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 , preferably from a hydrogen atom, C 1-8 alkyl, deuterated C 1-8 alkyl, halo C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy, halogen, amino, nitro, Hydroxyl, cyano, C 3-8 cycloalkyl, C 3-12 heterocyclyl, C 6-14 aryl, C 5-14 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-( CH 2 ) n NR 10 S (O) m R 9 , more preferably from hydrogen atom, C 1-3 alkyl, deuterated C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 3-6 ring Alkyl, C 3-6 heterocyclyl, C 6-10 aryl, C 5-10 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 , optimally selected from hydrogen atom, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluorine Ethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethyl Oxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, cyclopropyl, cyclo Butyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl Dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furan Base, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
其中，所述的R 6、R 7任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；优选被选自氘原子、C 1-8烷基、卤代C 1-8烷基、卤素、氨基、硝基、羟基、氰基、C 1-8烷氧基、卤代C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基和C 5-14杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，更优选被选自氘原子、C 1-3烷基、卤代C 1-3烷基、卤素、氨基、硝基、羟基、氰基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基和C 5-10杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，最优选被甲基、乙基、正丙基、异丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲 氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、羟基取代的甲基、羟基取代的乙基、羟基取代的丙基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基中的一个或多个取代基所取代； Wherein, R 6 and R 7 are optionally further selected from a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, and a cyclic Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-( CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 Substitution; preferably selected from deuterium atom, C 1-8 alkyl, halo C 1-8 alkyl, halogen, amino, nitro, hydroxyl, cyano, C 1-8 alkoxy, halo C 1- 8 alkoxy, C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl and C 5-14 heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C (O) NR 12 R 13 、-(CH 2 ) n C (O) NHR 13 、-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 Substituted with one or more substituents, more preferably selected from deuterium atom, C 1-3 alkyl, halo C 1-3 alkyl, halogen, amino, nitro, hydroxyl, cyano, C 1-3 alkoxy Alkyl, halo C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, and C 5-10 heteroaryl ,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-( CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 are substituted with one or more substituents, most preferably methyl, ethyl, n-propyl Methyl, isopropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, Ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, Iodine, amino, nitro, hydroxyl, cyano, hydroxyl substituted methyl, hydroxyl substituted ethyl, hydroxyl substituted propyl , Cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl , Dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazole Substituted with one or more substituents of phenyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
q为0、1或2。q is 0, 1, or 2.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于通式(I)化合物如通式(VI-A2)或通式(VI-B2)所示：In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of the general formula (I) is represented by the general formula (VI-A2) or the general formula (VI-B2):
Figure PCTCN2019099971-appb-000022
Figure PCTCN2019099971-appb-000022
o为0、1、2、3、4或5的整数。o is an integer of 0, 1, 2, 3, 4 or 5.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(VII)化合物：In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the following compounds of general formula (VII):
Figure PCTCN2019099971-appb-000023
Figure PCTCN2019099971-appb-000023
其中：among them:
环B选自杂环基或杂芳基；Ring B is selected from heterocyclyl or heteroaryl;
R 5选自氢原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、羟烷基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和 -(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；优选环丙基； R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cyano group, a cycloalkyl group, a heterocyclic group, Aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O ) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ; the alkyl, haloalkyl, cycloalkyl, hetero The cyclic group, aryl group and heteroaryl group are optionally further selected from the group consisting of a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, and a cycloalkane group. Group, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 ; Cyclopropyl is preferred;
R a选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、烯基、炔基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；优选C 1-8烷基、C 1-8烷氧基、C 1-8环烷基； R a is selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, and a cycloalkyl group , Heterocyclyl, aryl, heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O ) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ; The alkyl group, alkenyl group, alkynyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are optionally further selected from deuterium atom, alkyl group, haloalkyl group, halogen, amino group, nitrate Group, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 is substituted by one or more substituents; preferably C 1-8 alkyl, C 1-8 alkoxy, C 1-8 cycloalkyl;
或者，B环上任意两个R a取代基可以形成新的环烷基、杂环基、芳基和杂芳基，其中所述的形成新的环烷基、芳环基、杂环基或杂芳环基任选进一步被选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代； Alternatively, any two R a substituents on the B ring may form a new cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said forming a new cycloalkyl, aromatic ring, heterocyclyl or The heteroaryl ring group is optionally further selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkoxy group, a hydroxyalkyl group, and a cycloalkyl group. , Heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O ) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 With one or more substituents;
x-1为1、2、3或4的整数；且x-1 is an integer of 1, 2, 3, or 4; and
z为0、1、2、3、4或5的整数；z is an integer of 0, 1, 2, 3, 4 or 5;
环A、M 1、M 2、X、Y、R 1-R 5、x、y、m和n如通式(I)所述。 Rings A, M 1 , M 2 , X, Y, R 1 -R 5 , x, y, m and n are as described in the general formula (I).
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于，环B选自杂环基时，优选包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O)t的杂原子，t为0、1或2，其余环原子为碳；更优选包含3至12个环原子，其中1至4个是选自氮、氧的杂原子；最优选包含5至7个环原子，其中1至2个是选自氮、氧的杂原子；环B选自杂芳基时，优选包含1至4个杂原子、5至14个环原子的杂芳基，其中杂原子选自氧、硫和氮，更优选为包含1至2个杂原子的5至10元杂芳基，其中杂原子选自氧和氮，最优选为包含1至2个杂原子的5元或6元杂芳基，其中杂原子选自氧和氮；In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that when ring B is selected from a heterocyclic group, it preferably contains 3 to 20 ring atoms, wherein one or more ring atoms are selected from A heteroatom of nitrogen, oxygen or S (O) t, t is 0, 1 or 2, and the remaining ring atoms are carbon; more preferably 3 to 12 ring atoms, of which 1 to 4 are heteroatoms selected from nitrogen and oxygen Atom; most preferably contains 5 to 7 ring atoms, of which 1 to 2 are heteroatoms selected from nitrogen and oxygen; when ring B is selected from heteroaryl, it preferably contains 1 to 4 heteroatoms and 5 to 14 rings Atom heteroaryl, wherein the heteroatom is selected from the group consisting of oxygen, sulfur, and nitrogen, more preferably a 5- to 10-membered heteroaryl containing 1 to 2 heteroatoms, wherein the heteroatom is selected from the group consisting of oxygen and nitrogen, and most preferably 1 A 5- or 6-membered heteroaryl group to 2 heteroatoms, wherein the heteroatoms are selected from oxygen and nitrogen;
进一步环B优选的结构如下：Further preferred structure of ring B is as follows:
Figure PCTCN2019099971-appb-000024
Figure PCTCN2019099971-appb-000024
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(VIII)化合物：In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compounds of the general formula (VIII):
Figure PCTCN2019099971-appb-000025
Figure PCTCN2019099971-appb-000025
其中：环A、环B、M 1、M 2、R 1、R 2、R 5、R a、x-1、y和z如通式(I)所述。 Wherein: ring A, ring B, M 1, M 2, R 1, R 2, R 5, R a, x-1, y and z of the general formula (I).
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(IX)化合物：In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compounds of the general formula (IX):
Figure PCTCN2019099971-appb-000026
Figure PCTCN2019099971-appb-000026
其中：among them:
环B、R 1、R 5、R a、x-1和z如通式(I)所述。 Ring B, R 1, R 5, R a, x-1 , and z are as in formula (I) said.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(X-A)化合物：In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compounds of the following general formula (X-A):
Figure PCTCN2019099971-appb-000027
Figure PCTCN2019099971-appb-000027
其中：among them:
M 5为O、-CR 6或-NR 7； M 5 is O, -CR 6 or -NR 7 ;
R 1选自氢原子、C 1-8烷基或卤素； R 1 is selected from a hydrogen atom, a C 1-8 alkyl group or a halogen;
R 5选自C 1-8烷基、C 3-8环烷基、C 1-8卤代烷基、C 1-8羟烷基或3-6元杂环基； R 5 is selected from C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, or 3-6 membered heterocyclic group;
R a相同或不同，各自独立的选自氢原子、氰基、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 1-8卤代烷基、C 1-8羟代烷基、C 1-8烷氧基、C 3-8环烷基、-(CH 2) nOR 9、-(CR 9R 10) n-或-(CH 2) nC(O)R 9，其中所述的C 1-8烷基、C 2-8烯基、C 2-8炔基、卤代C 1-8烷基、C 1-8羟代烷基、C 1-8烷氧基和C 3-8环烷基任选进一步被选自氢原子、氘原子、卤素、氰基、羟基、C 1-8烷基、C 1-8羟烷基或C 1-8烷氧基中的一个或多个取代基所取代；或者任意两个R a取代基形成C 3-8环烷基或C 3-8杂环基； R a is the same or different and each is independently selected from the group consisting of a hydrogen atom, a cyano group, a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 1-8 haloalkyl group, and a C 1-8 hydroxy group Alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl,-(CH 2 ) n OR 9 ,-(CR 9 R 10 ) n -or-(CH 2 ) n C (O) R 9 , wherein the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 alkane An oxy group and a C 3-8 cycloalkyl group are optionally further selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, a C 1-8 alkyl group, a C 1-8 hydroxyalkyl group, or a C 1-8 alkoxy group. Substituted with one or more substituents in the group; or any two R a substituents form a C 3-8 cycloalkyl or a C 3-8 heterocyclyl;
R 9和R 10相同或不同，各自独立的选自氢原子、C 1-8烷基、C 1-8卤代烷基、C 1-8羟代烷基或C 1-8烷氧基； R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 hydroxyalkyl group, or a C 1-8 alkoxy group;
x-1为1、2、3或4的整数；x-1 is an integer of 1, 2, 3 or 4;
q为0、1或2；且q is 0, 1, or 2; and
z为0、1、2、3、4或5的整数。z is an integer of 0, 1, 2, 3, 4 or 5.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(XI)化合物：In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compounds of the general formula (XI):
Figure PCTCN2019099971-appb-000028
Figure PCTCN2019099971-appb-000028
o为0、1、2、3、4或5的整数；且o is an integer of 0, 1, 2, 3, 4 or 5; and
R 1、R 5、R a、x和z如通式(VI)所述。 R 1, R 5, R a , x and z are as formula (VI) said.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(XII)化合物：In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the following compounds of general formula (XII):
Figure PCTCN2019099971-appb-000029
Figure PCTCN2019099971-appb-000029
其中：among them:
R a相同或不同，各自独立的选自氢原子、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 3-6环烷基、-(CH 2) nOR 9或-(CR 9R 10) n-，其中所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基和C 3-6环烷基任选进一步被选自氢原子、卤素、氰基、羟基、C 1-6烷基或C 1-6烷氧基中的一个或多个取代基所取代；或者任意两个R a取代基可以形成3-6元环烷基，且 R a is the same or different and each is independently selected from the group consisting of hydrogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkane Oxy, C 3-6 cycloalkyl,-(CH 2 ) n OR 9 or-(CR 9 R 10 ) n- , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-6 cycloalkyl are optionally further selected from hydrogen atom, halogen, cyano, hydroxy, C 1-6 alkyl or Substituted with one or more substituents in C 1-6 alkoxy; or any two R a substituents may form a 3-6 membered cycloalkyl, and
z为0、1、2或3的整数。z is an integer of 0, 1, 2 or 3.
在本发明的一个优选实施例方案中，所述的药物组合物，其特征在于通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(XIII-A)化合物：In a preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following general formula (XIII-A) Compound:
Figure PCTCN2019099971-appb-000030
Figure PCTCN2019099971-appb-000030
其中：among them:
M 5选自S或CH； M 5 is selected from S or CH;
R 3选自C 1-8烷基、C 1-8氘代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基和3-10元杂环基，其中所述的C 1-8烷基、C 1-8氘代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基和3-10元杂环基任选进一步被被选自氢原子、氘原子、C 1-8烷基、C 1-8氘代烷基、C 1-8卤代烷基、卤素、氨基、羟基、氰基、C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基中的一个或多个取代基所取代； R 3 is selected from C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, and 3-10 membered heterocyclic ring Group, wherein said C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl and 3-10 member The heterocyclyl is optionally further selected from a hydrogen atom, a deuterium atom, a C 1-8 alkyl group, a C 1-8 deuterated alkyl group, a C 1-8 haloalkyl group, a halogen group, an amino group, a hydroxyl group, a cyano group, and C 1 One or more of -8alkoxy , C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl Substituted by a substituent;
R 4选自氢原子、C 1-8烷基、C 1-8氘代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、C 3-8环烷基或3-10元杂环基； R 4 is selected from a hydrogen atom, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 3-8 cycloalkyl, or 3-10 Heterocyclic
或者R 3和R 4链接形成的3-10元杂环或5-10元杂芳环，其中所述的3-10元杂环或5-10元杂芳环任选进一步被选自氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取 代基所取代； Or a 3-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring formed by linking R 3 and R 4 , wherein the 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring is optionally further selected from a deuterium atom , Alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and hetero Aryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ;
R b选自氢原子、C 1-8烷基、C 1-8氘代烷基或C 1-8卤代烷基；其中R b可以在氧代环取代也可以在M 5环上取代； R b is selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 deuterated alkyl group, or a C 1-8 haloalkyl group; wherein R b may be substituted on the oxo ring or the M 5 ring;
p为0、1、2、3或4的整数；且p is an integer of 0, 1, 2, 3, or 4; and
q为0或1的整数。q is an integer of 0 or 1.
在本发明的一个更优选实施例方案中，所述的药物组合物，通式(XIII-A)其特征在于，环C为4-7元杂环基或杂芳基，优选5元杂环基，环C最优选结构如下：In a more preferred embodiment of the present invention, the pharmaceutical composition, the general formula (XIII-A) is characterized in that ring C is a 4- to 7-membered heterocyclic group or a heteroaryl group, preferably a 5-membered heterocyclic group. The most preferred structure of the ring, C is as follows:
Figure PCTCN2019099971-appb-000031
Figure PCTCN2019099971-appb-000031
在本发明的一个更优选实施例方案中，所述的药物组合物，其特征在于通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(XIII-B)化合物：In a more preferred embodiment of the present invention, the pharmaceutical composition is characterized in that the compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following general formula (XIII-B ) Compound:
Figure PCTCN2019099971-appb-000032
Figure PCTCN2019099971-appb-000032
其中：among them:
环C为4至7元杂环基或杂芳基，优选5元杂环基；Ring C is a 4- to 7-membered heterocyclic group or a heteroaryl group, preferably a 5-membered heterocyclic group;
R a相同或不同，各自独立的选自氢原子、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-6环烷基、-(CH 2) nOR 9、-(CR 9R 10) n-或-(CH 2) nC(O)R 9，或者任意两个R a取代基可以形成3-6元环烷基； They are the same or different R a, each independently selected from hydrogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, - (CH 2 ) n OR 9 ,-(CR 9 R 10 ) n -or-(CH 2 ) n C (O) R 9 , or any two R a substituents may form a 3-6 membered cycloalkyl group;
R b选自氢原子、C 1-8烷基、C 1-8氘代烷基或C 1-8卤代烷基； R b is selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 deuterated alkyl group, or a C 1-8 haloalkyl group;
R 9和R 10独立地选自氢原子或C 1-8烷基； R 9 and R 10 are independently selected from a hydrogen atom or a C 1-8 alkyl group;
z为0、1、2、3或4的整数；且z is an integer of 0, 1, 2, 3, or 4; and
p为0、1或2。p is 0, 1, or 2.
在本发明的一个优选实施例方案中，所示各通式、其立体异构体或其药学上可接受的盐，其特征在于，R 1选自C 1-8烷基、C 3-8环烷基、5-10元杂芳基和卤素，优选5-6元杂芳基、卤素、C 1-6烷基，更优选吡唑、氟原子、甲基。 In a preferred embodiment of the present invention, each of the general formulas, stereoisomers, or pharmaceutically acceptable salts thereof is shown, wherein R 1 is selected from C 1-8 alkyl, C 3-8 Cycloalkyl, 5- to 10-membered heteroaryl, and halogen, preferably 5- to 6-membered heteroaryl, halogen, and C 1-6 alkyl, more preferably pyrazole, fluorine atom, and methyl.
在本发明的一个优选实施例方案中，所示各通式、其立体异构体或其药学上可接受的盐，其特征在于，R a选自氢原子、氰基、C 1-8烷基、C 2-8烯基、C 2-8炔 基、C 1-8卤代烷基、C 1-8羟代烷基、氰基取代的C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、-(CH 2) nOR 9、-(CR 9R 10) n-或-(CH 2) nC(O)R 9，优选自氢原子、氰基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、羟代C 1-6烷基、C 1-6卤代烷基、3-6元杂环基、C 3-6环烷基；最优选甲基、乙基、乙烯基、乙炔基或三氟甲基。 In a preferred embodiment of the present invention, each of the general formulas, stereoisomers, or pharmaceutically acceptable salts thereof is shown, wherein Ra is selected from a hydrogen atom, a cyano group, and a C 1-8 alkane. Alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, cyano-substituted C 1-8 alkyl, C 1-8 alkoxy , C 3-8 cycloalkyl,-(CH 2 ) n OR 9 ,-(CR 9 R 10 ) n -or-(CH 2 ) n C (O) R 9 , preferably from hydrogen atom, cyano, hydroxyl , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxy C 1-6 alkyl, C 1-6 haloalkyl, 3-6 membered heterocyclyl, C 3-6 Cycloalkyl; most preferably methyl, ethyl, vinyl, ethynyl or trifluoromethyl.
在本发明的一个优选实施例方案中，所示各通式、其立体异构体或其药学上可接受的盐，其特征在于，可选的其中任意两个R a形成3-6元环烷基，优选为环丙基。 In a preferred embodiment of the present invention, each of the general formulas, stereoisomers, or pharmaceutically acceptable salts thereof shown is characterized in that any two of R a optionally form a 3-6 membered ring Alkyl is preferably cyclopropyl.
在本发明的一个优选实施例方案中，所示各通式、其立体异构体或其药学上可接受的盐，其特征在于，R 5选自氢原子、C 1-8烷基、C 1-8卤代烷基、C 1-8羟代烷基、C 1-8烷氧基、C 1-8卤代烷氧基、卤素、C 3-8环烷基、3-10元杂环基，优选自氢原子、C 1-6烷基、羟代C 1-6烷基C 1-6卤代烷基、C 3-6环烷基，3-6元杂环基；R 5最优选环丙基、异丙基、羟基异丙基、叔丁基、三氟甲基或
Figure PCTCN2019099971-appb-000033
In a preferred embodiment of the present invention, each of the formulas, stereoisomers, or pharmaceutically acceptable salts thereof is shown, wherein R 5 is selected from a hydrogen atom, a C 1-8 alkyl group, and C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, halogen, C 3-8 cycloalkyl, 3-10 membered heterocyclic group, preferably From hydrogen atom, C 1-6 alkyl, hydroxy C 1-6 alkyl C 1-6 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group; R 5 is most preferably cyclopropyl, Isopropyl, hydroxyisopropyl, t-butyl, trifluoromethyl or
Figure PCTCN2019099971-appb-000033
本发明还涉及一种治疗预防和/或治疗预防ASK1介导的病理学特征的疾病的方法，其包括向患者施用治疗有效剂量的药物组合物。The present invention also relates to a method of treating and / or treating a disease preventing ASK1-mediated pathological features, which comprises administering to a patient a therapeutically effective dose of a pharmaceutical composition.
本发明进一步涉及所述的药物组合物，其特征在于通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，或其药物组合物在制备ASK1抑制剂药物中的应用。The invention further relates to the pharmaceutical composition, which is characterized in that the compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is used in the preparation of an ASK1 inhibitor medicine. Applications.
本发明进一步涉及所述的药物组合物，在制备治疗神经变性障碍、心血管障碍、炎性障碍、代谢障碍和ASK1的药物中的应用，所述的炎症障碍优选非酒精性脂肪性肝炎(NASH)。The invention further relates to the application of the pharmaceutical composition in the preparation of a medicament for treating neurodegenerative disorder, cardiovascular disorder, inflammatory disorder, metabolic disorder and ASK1. The inflammatory disorder is preferably non-alcoholic steatohepatitis (NASH ).
本发明进一步涉及所述的药物组合物，在制备治疗非酒精性脂肪性肝炎(NASH)的方法。The present invention further relates to the pharmaceutical composition for preparing a method for treating non-alcoholic steatohepatitis (NASH).
本发明还涉及一种治疗预防和/或治疗预制备治疗神经变性障碍、心血管障碍、炎性障碍、代谢障碍疾病的方法，其包括向患者施用治疗有效剂量的药物组合物。The present invention also relates to a method for treating prevention and / or treatment of a pre-prepared treatment of neurodegenerative, cardiovascular, inflammatory, and metabolic disorders, which comprises administering a therapeutically effective dose of a pharmaceutical composition to a patient.
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或***胶；和润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包 衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。The active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, dragees, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives, To provide pleasing and delicious medicinal preparations. Tablets contain the active ingredients and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing. These excipients can be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; binders such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. These tablets can be uncoated or they can be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release over a longer period. For example, water-soluble taste-masking substances, such as hydroxypropyl methyl cellulose or hydroxypropyl cellulose, or prolonged substances, such as ethyl cellulose, cellulose acetate butyrate, can be used.
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。Hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin, or olive oil Soft gelatin capsules are provided as an oral preparation.
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂，例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和***胶；分散剂或湿润剂可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxy cetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。Aqueous suspensions contain the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, and gum arabic; dispersants or wetting agents may be naturally occurring Phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as heptadecyloxycetyl alcohol (heptadecaethyleneoxycetanol), or the condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with a derivative of fatty acid and hexitol anhydride Condensation products of partial esters, such as polyethylene oxide sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl paraben or n-propyl paraben, one or more colorants, one or more flavoring agents, and one or more sweeteners. Flavoring agents such as sucrose, saccharin or aspartame.
油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油悬浮液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The sweeteners and flavoring agents described above can be added to provide a palatable formulation. These compositions can be preserved by the addition of an antioxidant such as fenoxyfen or alpha-tocopherol.
通过加入水可使适用于制备水混悬也的可分散粉末和颗粒提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂可说明上述的例子。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。By adding water, dispersible powders and granules suitable for preparing aqueous suspensions can be provided with active ingredients and dispersing or wetting agents, suspending agents or one or more preservatives for mixing. Suitable dispersing or wetting agents and suspending agents can illustrate the above examples. Other excipients such as sweeteners, flavors and colorants can also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂和由脂肪酸和己糖醇酐衍生的酯或偏酯例如山梨坦单油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and the condensation products of said partial esters and ethylene oxide, For example, polyethylene oxide sorbitol monooleate. Emulsions may also contain sweeteners, flavoring agents, preservatives and antioxidants. Syrups and elixirs can be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装 置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerol to form a microemulsion. Injections or microemulsions can be injected into a patient's bloodstream by local, large injections. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of a compound of the invention. To maintain this constant concentration, continuous intravenous drug delivery devices can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.
药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液，例如1,3-丁二醇中制备的溶液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用包括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸例如油酸也可以制备注射剂。The pharmaceutical composition may be in the form of a sterile injectable water or oily suspension for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent, for example, a solution prepared in 1,3-butanediol. In addition, a sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixing oil including synthetic mono- or diesters can be used. In addition, fatty acids such as oleic acid can also be prepared for injection.
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。The compounds of the invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and therefore will dissolve in the rectum to release the drug. Such materials include cocoa butter, glycerin gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行被、患者的饮食、给药时间、给药方式、***的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、通式化合物(I)的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient Quilt, patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc .; In addition, the best treatment methods such as the mode of treatment, the daily dosage of the general compound (I) or a pharmaceutically acceptable salt The type can be verified according to traditional treatment protocols.
发明的详细说明Detailed description of the invention
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, terms used in the specification and claims have the following meanings.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至8个碳原子的烷基，更优选1至6个碳原子的烷基，最更优选1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基及其各种支链异构体等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、 杂环烷硫基、氧代基、羧基或羧酸酯基，本发明优选甲基、乙基、异丙基、叔丁基、卤代烷基、氘代烷基、烷氧基取代的烷基和羟基取代的烷基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms Alkyl, most preferably 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 2,2-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-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Amyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 , 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2- Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups, which are independently selected from alkane Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate groups, methyl, ethyl, isopropyl, t-butyl, haloalkyl are preferred in the present invention , Deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl.
术语“亚烷基”是指烷基的一个氢原子进一步被取代，例如：“亚甲基”指-CH 2-、“亚乙基”指-(CH 2) 2-、“亚丙基”指-(CH 2) 3-、“亚丁基”指-(CH 2) 4-等，上述取代基可以连接在不同的碳原子形成碳链，也可以连接在一个碳原子上形成环烷基。术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。 The term "alkylene" means that a hydrogen atom of an alkyl group is further substituted, for example: "methylene" means -CH 2- , "ethylene" means-(CH 2 ) 2- , "propylene" Refers to-(CH 2 ) 3- , "butylene" refers to-(CH 2 ) 4- , etc., the above substituents may be connected to different carbon atoms to form a carbon chain, or may be connected to one carbon atom to form a cycloalkyl group. The term "alkenyl" refers to an alkyl group, as defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl and the like. Alkenyl may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至8个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基，优选环丙基、环丁基、环己基、环戊基和环庚基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 Carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl includes spiro, fused and bridged cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至8个环原子；最优选包含3至8个环原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选四氢呋喃基、吡唑烷基、吗啉基、哌嗪基和吡喃基。多环杂环基包括螺环、稠环和桥环的杂环基；其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接，或者通过环上的任意两个或者两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接；杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent that contains 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen, or S (O) A heteroatom of m (where m is an integer from 0 to 2), excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; and most preferably 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., and tetrahydrofuranyl, pyrazolyl, morpholinyl, piperazinyl, and pyranyl are preferred. Polycyclic heterocyclyls include spiro, fused, and bridged heterocyclic groups; the involved spiro, fused, and bridged heterocyclic groups are optionally connected to other groups through a single bond, or through a ring Any two or more of the above atoms are further connected with other cycloalkyl, heterocyclyl, aryl, and heteroaryl groups in a ring; the heterocyclyl may be optionally substituted or unsubstituted, when substituted The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano , Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy, or carboxylate.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The term "aryl" refers to a 6 to 14 membered, all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 members, such as benzene And naphthyl. More preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include:
Figure PCTCN2019099971-appb-000034
Figure PCTCN2019099971-appb-000034
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。An aryl group may be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，更优选为5元或6元，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为***基、噻吩基、咪唑基、吡唑基或嘧啶基、噻唑基；更有选***基、吡咯基、噻吩基、噻唑基和嘧啶基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5- to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrrolyl, thienyl , Thiazolyl and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:
Figure PCTCN2019099971-appb-000035
Figure PCTCN2019099971-appb-000035
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。优选含有1至8个碳原子的烷氧基，更优选1至6个碳原子的烷氧基，最更优选1至3个碳原子的烷氧基。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is as defined above. An alkoxy group containing 1 to 8 carbon atoms is preferred, an alkoxy group having 1 to 6 carbon atoms is more preferred, and an alkoxy group having 1 to 3 carbon atoms is most preferred. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, and alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxyl or carboxylate.
“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。"Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。"Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。"Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
“烯基”指链烯基，又称烯烃基，优选含有2至8个碳原子的烯基，更优选2至6个碳原子的烯基，最更优选2至3个碳原子的烯基；其中所述的烯基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。"Alkenyl" means an alkenyl group, also known as an alkenyl group, preferably an alkenyl group containing 2 to 8 carbon atoms, more preferably an alkenyl group containing 2 to 6 carbon atoms, and most preferably an alkenyl group containing 2 to 3 carbon atoms ; Where the alkenyl group may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano , Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
“炔基”指(CH≡C-)，优选含有2至8个碳原子的炔基，更优选2至6个碳原子的炔基，最更优选2至3个碳原子的炔基。其中所述的炔基可以进一步被其他相关基团取代，例如：烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。"Alkynyl" means (CH≡C-), preferably an alkynyl group containing 2 to 8 carbon atoms, more preferably an alkynyl group having 2 to 6 carbon atoms, and most preferably an alkynyl group having 2 to 3 carbon atoms. The alkynyl group may be further substituted by other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, Cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.
“羟基”指-OH基团。"Hydroxy" refers to the -OH group.
“卤素”指氟、氯、溴或碘。"Halogen" means fluorine, chlorine, bromine or iodine.
“氨基”指-NH 2。 "Amino" means -NH 2.
“氰基”指-CN。"Cyano" refers to -CN.
“硝基”指-NO 2。 "Nitro" refers to -NO 2.
“羧基”指-C(O)OH。"Carboxy" refers to -C (O) OH.
“THF”指四氢呋喃。"THF" means tetrahydrofuran.
“EtOAc”指乙酸乙酯。"EtOAc" means ethyl acetate.
“MeOH”指甲醇。"MeOH" means methanol.
“DMF”指N、N-二甲基甲酰胺。"DMF" refers to N, N-dimethylformamide.
“DIPEA”指二异丙基乙胺。"DIPEA" means diisopropylethylamine.
“TFA”指三氟乙酸。"TFA" means trifluoroacetic acid.
“MeCN”指乙晴。"MeCN" means Yiqing.
“DMA”指N,N-二甲基乙酰胺。"DMA" refers to N, N-dimethylacetamide.
“Et 2O”指***。 "Et 2 O" refers to diethyl ether.
“DCE”指1,2二氯乙烷。"DCE" refers to 1,2-dichloroethane.
“DIPEA”指N，N-二异丙基乙胺。"DIPEA" refers to N, N-diisopropylethylamine.
“NBS”指N-溴代琥珀酰亚胺。"NBS" refers to N-bromosuccinimide.
“NIS”指N-碘代丁二酰亚胺。"NIS" refers to N-iodosuccinimide.
“Cbz-Cl”指氯甲酸苄酯。"Cbz-Cl" refers to benzyl chloroformate.
“Pd 2(dba) 3”指三(二亚苄基丙酮)二钯。 "Pd 2 (dba) 3 " refers to tris (dibenzylideneacetone) dipalladium.
“Dppf”指1,1’-双二苯基膦二茂铁。"Dppf" refers to 1,1'-bisdiphenylphosphine ferrocene.
“HATU”指2-(7-氧化苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯。"HATU" refers to 2- (7-benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate.
“KHMDS”指六甲基二硅基胺基钾。"KHMDS" refers to potassium hexamethyldisilazide.
“LiHMDS”指双三甲基硅基胺基锂。"LiHMDS" refers to lithium bistrimethylsilylamine.
“MeLi”指甲基锂。"MeLi" means methyl lithium.
“n-BuLi”指正丁基锂。"N-BuLi" refers to n-butyllithium.
“NaBH(OAc) 3”指三乙酰氧基硼氢化钠。 "NaBH (OAc) 3 " refers to sodium triacetoxyborohydride.
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义，即表示X可以是A、B、C中的任意一种或几种。"X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", "X is A, B, or C" and other terms all express the same Meaning, meaning that X can be any one or several of A, B, and C.
“立体异构”包含几何异构(顺反异构)、旋光异构、构象异构三类。"Stereoisomerism" includes three types of geometric isomerism (cis-trans isomerism), optical isomerism, and conformational isomerism.
本发明所述的氢原子均可被其同位素氘所取代，本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。The hydrogen atom according to the present invention may be replaced by its isotope deuterium, and any hydrogen atom in the compound of the embodiment according to the present invention may also be replaced by a deuterium atom.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the event or environment described later can, but need not, occur, and the description includes situations where the event or environment occurs or does not occur. For example, "an heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not exist, and this description includes a case where the heterocyclic group is substituted with an alkyl group and a case where the heterocyclic group is not substituted with an alkyl group .
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5 and more preferably 1 to 3 hydrogen atoms independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group having free hydrogen may be unstable when combined with a carbon atom having an unsaturated (eg, olefinic) bond.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiological / pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as physiological / pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and then exerts the biological activity.
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。"Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention. Such salts are safe and effective when used in mammals, and have due biological activity.
具体实施方式detailed description
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。The present invention is further described below with reference to examples, but these examples do not limit the scope of the present invention.
实施例Examples
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代甲醇(CD 3OD)和氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。 The compound structure of the present invention is determined by nuclear magnetic resonance (NMR) or / and liquid-mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). The NMR measurement was performed with Bruker AVANCE-400 nuclear magnetic analyzer. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ). The internal standard was four. Methylsilane (TMS).
液质联用色谱LC-MS的测定用Agilent 1200 Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。Liquid chromatography-mass spectrometry LC-MS was measured using an Agilent 1200 Infinity Series mass spectrometer. For HPLC measurement, an Agilent 1200 DAD high-pressure liquid chromatography (Sunfire C18 150 × 4.6 mm column) and a Waters 2695-2996 high-pressure liquid chromatography (Gimini C18 150 × 4.6 mm column) were used.
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，TLC采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specifications adopted by TLC are 0.15mm ～ 0.20mm, and the specifications adopted by thin layer chromatography purification products are 0.4mm ～ 0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
本发明实施例中的起始原料是已知的并且可以在市场上买到，或者可以采用或按照本领域已知的方法来合成。The starting materials in the examples of the present invention are known and commercially available, or they can be synthesized or synthesized according to methods known in the art.
在无特殊说明的情况下，本发明的所有反应均在连续的磁力搅拌下，在干燥氮气或氩气氛下进行，溶剂为干燥溶剂，反应温度单位为摄氏度。Unless otherwise specified, all the reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent is a dry solvent, and the reaction temperature unit is degrees Celsius.
实施例1Example 1
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺的制备5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] Preparation of azole-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000036
Figure PCTCN2019099971-appb-000036
第一步：5-氨基-2-氟-4-甲基苯甲腈的制备Step 1: Preparation of 5-amino-2-fluoro-4-methylbenzonitrile
Figure PCTCN2019099971-appb-000037
Figure PCTCN2019099971-appb-000037
5-溴-4-氟-2-甲基苯胺(10.0g,49.0mmol),氰化亚铜(8.78g,98.0mmol)混合于NMP(50mL)中，氮气保护下，在180℃下搅拌1小时，然后在100℃下搅拌过夜。冷却后，加入28wt％的氨水溶液，搅拌15分钟，用EtOAc萃取三次。合并有机相，用饱和食盐水洗涤三次，然后有机相用无水硫酸钠干燥，减压浓缩后柱层析得到标题化合物5-氨基-2-氟-4-甲基苯甲腈(5.70g,78％)。5-Bromo-4-fluoro-2-methylaniline (10.0g, 49.0mmol), cuprous cyanide (8.78g, 98.0mmol) were mixed in NMP (50mL), and stirred at 180 ° C under nitrogen protection for 1 Hours and then stirred at 100 ° C overnight. After cooling, a 28 wt% aqueous ammonia solution was added, stirred for 15 minutes, and extracted three times with EtOAc. The organic phases were combined, washed three times with saturated brine, and then the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography was performed to give the title compound 5-amino-2-fluoro-4-methylbenzonitrile (5.70 g, 78%).
MS m/z(ESI):151.1[M+H] +. MS m / z (ESI): 151.1 [M + H] + .
第二步：5-((2-环丙基-2-羰基乙基)氨基)-2-氟-4-甲基苯甲腈的制备Step 2: Preparation of 5-((2-cyclopropyl-2-carbonylethyl) amino) -2-fluoro-4-methylbenzonitrile
Figure PCTCN2019099971-appb-000038
Figure PCTCN2019099971-appb-000038
5-氨基-2-氟-4-甲基苯甲腈(5.70g,38.0mmol),K 2CO 3(6.30g,45.6mmol),KI(0.630g,3.80mmol),2-溴-1-环丙基乙烷-1-酮(7.43g,45.6mmol)混合于DMF(50mL)中，氮气保护下，80℃下搅拌90分钟。反应冷却后，补加2-溴-1-环丙基乙烷-1-酮(3.00g,18.4mmol),K 2CO 3(2.54g,18.4mmol)，再在75℃下搅拌1小时。冷却至室温，向反应瓶中加入水，静置15分钟后，过滤，滤饼用水洗涤，干燥后得标题化合物5-((2-环丙基-2-羰基乙基)氨基)-2-氟-4-甲基苯甲腈粗品(6.80g,77％)。 5-amino-2-fluoro-4-methylbenzonitrile (5.70 g, 38.0 mmol), K 2 CO 3 (6.30 g, 45.6 mmol), KI (0.630 g, 3.80 mmol), 2-bromo-1- Cyclopropylethane-1-one (7.43 g, 45.6 mmol) was mixed in DMF (50 mL) and stirred at 80 ° C. for 90 minutes under a nitrogen blanket. After the reaction was cooled, 2-bromo-1-cyclopropylethane-1-one (3.00 g, 18.4 mmol) and K 2 CO 3 (2.54 g, 18.4 mmol) were added thereto, followed by stirring at 75 ° C. for 1 hour. After cooling to room temperature, water was added to the reaction flask. After standing for 15 minutes, the filter cake was washed with water and dried to obtain the title compound 5-((2-cyclopropyl-2-carbonylethyl) amino) -2- Crude fluoro-4-methylbenzonitrile (6.80 g, 77%).
MS m/z(ESI):233.1[M+H] +. MS m / z (ESI): 233.1 [M + H] + .
第三步：5-(4-环丙基-2-巯基-1H-咪唑-1-基)-2-氟-4-甲基苯甲腈的制备Step 3: Preparation of 5- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -2-fluoro-4-methylbenzonitrile
Figure PCTCN2019099971-appb-000039
Figure PCTCN2019099971-appb-000039
5-((2-环丙基-2-羰基乙基)氨基)-2-氟-4-甲基苯甲腈(6.80g,29.3mmol),KSCN(5.69g,58.6mmol)的醋酸溶液(100mL)在110℃下搅拌4小时，冷却后，浓缩，加入CH 2Cl 2和水，分出有机相，水相再用CH 2Cl 2萃取一次。合并有机相，用无水硫酸钠干燥，减压浓缩后得5-(4-环丙基-2-巯基-1H-咪唑-1-基)-2-氟-4-甲基苯甲腈粗品8.00g，直接用于下一步反应。 5-((2-Cyclopropyl-2-carbonylethyl) amino) -2-fluoro-4-methylbenzonitrile (6.80g, 29.3mmol), KSCN (5.69g, 58.6mmol) in acetic acid ( (100 mL) was stirred at 110 ° C for 4 hours. After cooling, it was concentrated. CH 2 Cl 2 and water were added to separate the organic phase. The aqueous phase was extracted once more with CH 2 Cl 2 . The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 5- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -2-fluoro-4-methylbenzonitrile. 8.00g, used directly in the next reaction.
MS m/z(ESI):274.1[M+H] +. MS m / z (ESI): 274.1 [M + H] + .
第四步：5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲腈的制备Step 4: Preparation of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzonitrile
Figure PCTCN2019099971-appb-000040
Figure PCTCN2019099971-appb-000040
50℃下，向上述粗品的醋酸(160mL)和水(32mL)的溶液中，缓慢滴加入双氧水(30wt％,10.0mL)，滴加完毕，再在该温度下搅拌一小时。冷却至室温，再缓慢加入Na 2SO 3水溶液(20wt％,100mL)，然后搅拌30分钟。浓缩除去有机溶剂，水相用CH 2Cl 2萃取两次。合并有机相，依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后柱层析得到标题化合物5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲腈(3.3g,两步收率47％)。 To a solution of the crude acetic acid (160 mL) and water (32 mL) at 50 ° C, hydrogen peroxide (30 wt%, 10.0 mL) was slowly added dropwise. After the dropwise addition was completed, the mixture was stirred at this temperature for one hour. Cooled to room temperature, then slowly added Na 2 SO 3 solution (20wt%, 100mL), then stirred for 30 minutes. The organic solvent was removed by concentration, and the aqueous phase was extracted twice with CH 2 Cl 2 . The organic phases were combined, washed successively with a saturated sodium bicarbonate aqueous solution and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Column chromatography was performed to give the title compound 5- (4-cyclopropyl-1H-imidazol-1-yl). 2-fluoro-4-methylbenzonitrile (3.3 g, 47% yield over two steps).
MS m/z(ESI):242.1[M+H] +. MS m / z (ESI): 242.1 [M + H] + .
第五步：6-氨基甲基吡啶酰肼的合成Step 5: Synthesis of 6-aminomethylpyridyl hydrazide
Figure PCTCN2019099971-appb-000041
Figure PCTCN2019099971-appb-000041
室温下，将甲基6-氨基甲基吡啶酸酯(2.0g,13mmol)溶于乙醇(60mL)中，加入水合肼(4.1g,66mmol)。反应加热至80℃，在此温度下搅拌5小时，缓慢冷却至室温后，将反应液中析出的固体过滤，收集滤饼，得到标题化合物6-氨基甲基吡啶酰肼(1.6g,80％)。At room temperature, methyl 6-aminomethylpicolinate (2.0 g, 13 mmol) was dissolved in ethanol (60 mL), and hydrazine hydrate (4.1 g, 66 mmol) was added. The reaction was heated to 80 ° C, stirred at this temperature for 5 hours, and slowly cooled to room temperature. The solid precipitated in the reaction solution was filtered, and the filter cake was collected to obtain the title compound 6-aminomethylpyridylhydrazide (1.6g, 80%). ).
MS m/z(ESI):153.2[M+H] +. MS m / z (ESI): 153.2 [M + H] + .
第六步：6-(6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺的合成Step 6: Synthesis of 6- (6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-amine
Figure PCTCN2019099971-appb-000042
Figure PCTCN2019099971-appb-000042
室温下，将6-氨基甲基吡啶酰肼(300mg,1.97mmol)溶于2-戊醇(5mL)和 乙酸(1mL)中，加入5-甲氧基-3,4-二氢-2H-吡咯(195mg,1.97mmol)。反应加热至125℃，在此温度下搅拌12小时，冷却至室温后，减压浓缩。然后加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经柱层析得标题化合物6-(6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺(360mg,91％)。 At room temperature, 6-aminomethylpyridylhydrazide (300mg, 1.97mmol) was dissolved in 2-pentanol (5mL) and acetic acid (1mL), and 5-methoxy-3,4-dihydro-2H- Pyrrole (195 mg, 1.97 mmol). The reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and then concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL × 2) was extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 6- (6,7- Dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-amine (360 mg, 91%).
MS m/z(ESI):202.1[M+H] +. MS m / z (ESI): 202.1 [M + H] + .
第七步：5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酰氯的合成Step 7: Synthesis of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride
Figure PCTCN2019099971-appb-000043
Figure PCTCN2019099971-appb-000043
将5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲腈(1.8g,7.47mmol)溶于30mL浓盐酸中，加热回流下搅拌过夜，冷却后浓缩，干燥后得到5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酸盐酸盐(2g,粗产品)直接用于下一步。Dissolve 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzonitrile (1.8 g, 7.47 mmol) in 30 mL of concentrated hydrochloric acid, and stir under heating and reflux overnight. After cooling and concentrating, after drying, 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoate hydrochloride (2g, crude product) was directly used in the next step .
室温下，将上述5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酸盐酸盐(100mg,上述粗产品),溶于二氯亚砜(5mL)中，加热回流下搅拌2小时，冷却后减压浓缩，得到浅黄色固体产品直接用于下一步反应。At room temperature, the above 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoate hydrochloride (100 mg, the above crude product) was dissolved in dichloromethane The sulfone (5 mL) was stirred under heating and refluxing for 2 hours. After cooling, it was concentrated under reduced pressure to obtain a pale yellow solid product which was directly used in the next reaction.
第八步：5-(4-环丙基-1H-咪唑-1-基)-N-(6-(6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺的合成The eighth step: 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6,7-dihydro-5H-pyrrolo [2,1-c] [1,2 Synthesis of 4,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000044
Figure PCTCN2019099971-appb-000044
室温下，将6-(6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺(43mg,0.22mmol)加入5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酰氯(100mg,上步粗产品)的THF(5mL)和吡啶(5mL)溶液中，然后加入4-二甲氨基吡啶(11mg,0.09mmol)。将反应加热至45℃，并在该温度下搅拌2小时,然后滴加水(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析得标题化合物5-(4-环丙基-1H-咪唑-1-基)-N-(6-(6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺(60mg,63％)。At room temperature, 6- (6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-amine (43 mg, 0.22 mmol) Add 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (100 mg, crude product from the previous step) in THF (5 mL) and pyridine (5 mL). , Then 4-dimethylaminopyridine (11 mg, 0.09 mmol) was added. The reaction was heated to 45 ° C and stirred at this temperature for 2 hours, and then water (5 mL) and dichloromethane (50 mL x 2) were added dropwise. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Chromatography gave the title compound 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6,7-dihydro-5H-pyrrolo [2,1-c] [1, 2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide (60 mg, 63%).
1H NMR(400MHz,CDCl 3)δ9.05(d,J＝15.1Hz,1H),8.34(d,J＝8.2Hz,1H),8.13-8.02(m,2H),7.88(t,J＝8.0Hz,1H),7.48(m,1H),7.20(d,J＝12.4Hz,1H),6.80(m,1H),4.53-4.34(m,2H),3.04(t,J＝7.7Hz,2H),2.96-2.74(m,2H),2.30(s,3H),1.98-1.82(m,1H),0.90(m,2H),0.88-0.76(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 9.05 (d, J = 15.1 Hz, 1 H), 8.34 (d, J = 8.2 Hz, 1 H), 8.13-8.02 (m, 2 H), 7.88 (t, J = 8.0Hz, 1H), 7.48 (m, 1H), 7.20 (d, J = 12.4 Hz, 1H), 6.80 (m, 1H), 4.53-4.34 (m, 2H), 3.04 (t, J = 7.7Hz, 2H), 2.96-2.74 (m, 2H), 2.30 (s, 3H), 1.98-1.82 (m, 1H), 0.90 (m, 2H), 0.88-0.76 (m, 2H);
MS m/z(ESI):444.1[M+H] +. MS m / z (ESI): 444.1 [M + H] + .
实施例2Example 2
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(6,7,8,9-四氢-5H-[1,2,4]***并[4,3-a]吖庚英-3-基)吡啶-2-基)苯酰胺5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (6,7,8,9-tetrahydro-5H- [1,2 , 4] triazolo [4,3-a] azepine-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000045
Figure PCTCN2019099971-appb-000045
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(6,7,8,9-四氢-5H-[1,2,4]***并[4,3-a]吖庚英-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例1。5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (6,7,8,9-tetrahydro-5H- [1,2 Refer to Example 1 for the method for preparing 4,4] triazolo [4,3-a] azepine-3-yl) pyridin-2-yl) benzamide.
1H NMR(400MHz,CDCl 3)δ9.00(d,J＝14.9Hz,1H),8.29(d,J＝0.8Hz,1H),7.99(d,J＝7.3Hz,1H),7.92-7.90(m,1H),7.83(t,J＝7.9Hz,1H),7.43(d,J＝1.0Hz,1H),7.12(d,J＝12.3Hz,1H),6.73(m,1H),4.57(m,2H),3.03-3.01(m,2H),2.22(s,3H),1.85(m,3H),1.81(m,2H),1.74(m,2H),0.85-0.82(m,2H),0.79-0.76(m,2H)； 1 H NMR (400MHz, CDCl 3 ) 9.00 (d, J = 14.9 Hz, 1H), 8.29 (d, J = 0.8 Hz, 1H), 7.99 (d, J = 7.3 Hz, 1H), 7.92-7.90 (m, 1H), 7.83 (t, J = 7.9 Hz, 1H), 7.43 (d, J = 1.0 Hz, 1H), 7.12 (d, J = 12.3 Hz, 1H), 6.73 (m, 1H), 4.57 (m, 2H), 3.03-3.01 (m, 2H), 2.22 (s, 3H), 1.85 (m, 3H), 1.81 (m, 2H), 1.74 (m, 2H), 0.85-0.82 (m, 2H) ), 0.79-0.76 (m, 2H);
MS m/z(ESI):472.2[M+H] +. MS m / z (ESI): 472.2 [M + H] + .
实施例3Example 3
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5,6,7,8-四氢-[1,2,4]***并[4,3-a]吡啶-3-基)吡啶-2-基)苯酰胺5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5,6,7,8-tetrahydro- [1,2,4 ] Triazolo [4,3-a] pyridin-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000046
Figure PCTCN2019099971-appb-000046
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5,6,7,8-四氢-[1,2,4]***并[4,3-a]吡啶-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例1。5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5,6,7,8-tetrahydro- [1,2,4 The method for preparing] triazolo [4,3-a] pyridin-3-yl) pyridin-2-yl) benzamide is described in Example 1.
1H NMR(400MHz,CDCl 3)δ8.98(d,J＝14.6Hz,1H),8.27(d,J＝8.2Hz,1H),7.99(t,J＝7.5Hz,2H),7.81(t,J＝8.0Hz,1H),7.39(s,1H),7.12(d,J＝12.3Hz,1H),6.72(s,1H),4.41(t,J＝6.0Hz,2H),3.00(t,J＝6.4Hz,2H),2.22(s,3H),2.03-1.95(m,2H),1.93-1.87(m,2H),1.85-1.79(m,1H),0.88-0.79(m,2H),0.78-0.70(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 8.98 (d, J = 14.6 Hz, 1 H), 8.27 (d, J = 8.2 Hz, 1 H), 7.99 (t, J = 7.5 Hz, 2 H), 7.81 (t , J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.12 (d, J = 12.3 Hz, 1H), 6.72 (s, 1H), 4.41 (t, J = 6.0 Hz, 2H), 3.00 (t , J = 6.4Hz, 2H), 2.22 (s, 3H), 2.03-1.95 (m, 2H), 1.93-1.87 (m, 2H), 1.85-1.79 (m, 1H), 0.88-0.79 (m, 2H ), 0.78-0.70 (m, 2H);
MS m/z(ESI):458.2[M+H] +. MS m / z (ESI): 458.2 [M + H] + .
实施例4Example 4
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5,6-二氢-8H-[1,2,4]***并[3,4-c][1,4]噁嗪-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5,6-dihydro-8H- [1,2,4] triazolo [3,4-c] [1,4] oxazin-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000047
Figure PCTCN2019099971-appb-000047
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5,6-二氢-8H-[1,2,4]***并[3,4-c][1,4]噁嗪-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺的制备方法参照实施例1。5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5,6-dihydro-8H- [1,2,4] triazolo [3,4-c] Refer to Example 1 for the method for preparing [1,4] oxazin-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide.
1H NMR(400MHz,CDCl 3)δ9.08(d,J＝14.7Hz,1H),8.41-8.35(m,1H), 8.13-8.07(m,1H),8.05(d,J＝7.3Hz,1H),7.91(t,J＝8.0Hz,1H),7.48(d,J＝1.2Hz,1H),7.20(d,J＝12.3Hz,1H),6.80(d,J＝1.2Hz,1H),5.06(s,2H),4.59(t,J＝5.2Hz,2H),4.09(t,J＝5.3Hz,2H),2.30(s,3H),1.95-1.86(m,1H),0.95-0.87(m,2H),0.87-0.78(m,2H)； 1 H NMR (400MHz, CDCl 3 ) δ9.08 (d, J = 14.7Hz, 1H), 8.41-8.35 (m, 1H), 8.13-8.07 (m, 1H), 8.05 (d, J = 7.3Hz, 1H), 7.91 (t, J = 8.0 Hz, 1H), 7.48 (d, J = 1.2 Hz, 1H), 7.20 (d, J = 12.3 Hz, 1H), 6.80 (d, J = 1.2 Hz, 1H) , 5.06 (s, 2H), 4.59 (t, J = 5.2Hz, 2H), 4.09 (t, J = 5.3Hz, 2H), 2.30 (s, 3H), 1.95-1.86 (m, 1H), 0.95- 0.87 (m, 2H), 0.87-0.78 (m, 2H);
MS m/z(ESI):460.2[M+H] +. MS m / z (ESI): 460.2 [M + H] + .
实施例5Example 5
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5,6,7,8-四氢-[1,2,4]***并[4,3-a]吡嗪-3-基)吡啶-2-基)苯酰胺5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5,6,7,8-tetrahydro- [1,2,4 ] Triazolo [4,3-a] pyrazin-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000048
Figure PCTCN2019099971-appb-000048
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5,6,7,8-四氢-[1,2,4]***并[4,3-a]吡嗪-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例1。5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5,6,7,8-tetrahydro- [1,2,4 The method for preparing] triazolo [4,3-a] pyrazin-3-yl) pyridin-2-yl) benzamide is described in Example 1.
1H NMR(400MHz,CDCl 3)δ9.01(d,J＝14.5Hz,1H),8.29(d,J＝8.3Hz,1H),7.99(t,J＝8.3Hz,2H),7.83(d,J＝8.0Hz,1H),7.42(s,1H),7.12(d,J＝12.3Hz,1H),6.73(s,1H),4.45(t,J＝5.5Hz,2H),4.27(s,2H),3.24(t,J＝5.5Hz,2H),2.33(s,1H),2.22(s,3H),1.84-1.82(m,1H),0.87-0.80(m,2H),0.78-0.75(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 9.01 (d, J = 14.5 Hz, 1 H), 8.29 (d, J = 8.3 Hz, 1 H), 7.99 (t, J = 8.3 Hz, 2 H), 7.83 (d , J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.12 (d, J = 12.3 Hz, 1H), 6.73 (s, 1H), 4.45 (t, J = 5.5 Hz, 2H), 4.27 (s , 2H), 3.24 (t, J = 5.5Hz, 2H), 2.33 (s, 1H), 2.22 (s, 3H), 1.84-1.82 (m, 1H), 0.87-0.80 (m, 2H), 0.78- 0.75 (m, 2H);
MS m/z(ESI):459.2[M+H] +. MS m / z (ESI): 459.2 [M + H] + .
实施例6Example 6
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(7-甲基-5,6,7,8-四氢-[1,2,4]***并[4,3-a]吡嗪-3-基)吡啶-2-基)苯酰胺5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (7-methyl-5,6,7,8-tetrahydro- [ 1,2,4] triazolo [4,3-a] pyrazin-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000049
Figure PCTCN2019099971-appb-000049
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(7-甲基-5,6,7,8-四氢-[1,2,4]***并[4,3-a]吡嗪-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例1。5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (7-methyl-5,6,7,8-tetrahydro- [ Refer to Example 1 for the preparation method of 1,2,4] triazolo [4,3-a] pyrazin-3-yl) pyridin-2-yl) benzamide.
1H NMR(400MHz,CDCl 3)δ8.98(d,J＝14.8Hz,1H),8.29(d,J＝8.2Hz,1H),8.01(m,2H),7.82(t,J＝8.0Hz,1H),7.44(s,1H),7.12(d,J＝12.3Hz,1H),6.73(s,1H),4.49(t,J＝5.5Hz,2H),3.80(s,2H),2.83(t,J＝5.5Hz,2H),2.48(s,3H),2.22(s,3H),1.85(m,1H),0.85-0.82(m,2H),0.79-077(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 8.98 (d, J = 14.8 Hz, 1 H), 8.29 (d, J = 8.2 Hz, 1 H), 8.01 (m, 2 H), 7.82 (t, J = 8.0 Hz , 1H), 7.44 (s, 1H), 7.12 (d, J = 12.3Hz, 1H), 6.73 (s, 1H), 4.49 (t, J = 5.5Hz, 2H), 3.80 (s, 2H), 2.83 (t, J = 5.5Hz, 2H), 2.48 (s, 3H), 2.22 (s, 3H), 1.85 (m, 1H), 0.85-0.82 (m, 2H), 0.79-077 (m, 2H);
MS m/z(ESI):473.2[M+H] +. MS m / z (ESI): 473.2 [M + H] + .
实施例7Example 7
4-(4-环丙基-1H-咪唑-1-基)-N-(3-(6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)苯基)甲基吡啶酰胺4- (4-cyclopropyl-1H-imidazol-1-yl) -N- (3- (6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] Azol-3-yl) phenyl) methylpyridinamide
Figure PCTCN2019099971-appb-000050
Figure PCTCN2019099971-appb-000050
4-(4-环丙基-1H-咪唑-1-基)-N-(3-(6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)苯基)甲基吡啶酰胺的制备方法参照实施例1。4- (4-cyclopropyl-1H-imidazol-1-yl) -N- (3- (6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] The method for preparing azole-3-yl) phenyl) methylpyridinamide is described in Example 1.
1H NMR(400MHz,CDCl 3)δ10.16(s,1H),8.68(d,J＝5.4Hz,1H),8.49(s,1H),8.27(d,J＝2.1Hz,1H),8.01(d,J＝1.0Hz,1H),7.92-7.64(m,2H),7.63-7.41(m,2H),7.22(d,J＝1.0Hz,1H),4.35(t,J＝7.1Hz,2H),3.08-3.04(m,2H),2.89-2.84(m,2H),1.94-1.90(m,1H),0.95-0.91(m,2H),0.87-0.84(m,2H)； 1 H NMR (400MHz, CDCl 3 ) δ 10.16 (s, 1H), 8.68 (d, J = 5.4 Hz, 1H), 8.49 (s, 1H), 8.27 (d, J = 2.1 Hz, 1H), 8.01 (d, J = 1.0 Hz, 1H), 7.92-7.64 (m, 2H), 7.63-7.41 (m, 2H), 7.22 (d, J = 1.0 Hz, 1H), 4.35 (t, J = 7.1 Hz, 2H), 3.08-3.04 (m, 2H), 2.89-2.84 (m, 2H), 1.94-1.90 (m, 1H), 0.95-0.91 (m, 2H), 0.87-0.84 (m, 2H);
MS m/z(ESI):412.2[M+H] +. MS m / z (ESI): 412.2 [M + H] + .
实施例8Example 8
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000051
Figure PCTCN2019099971-appb-000051
第一步 (R)-5-甲氧基-2-甲基-3,4-二氢-2H-吡咯的合成Step 1 Synthesis of (R) -5-methoxy-2-methyl-3,4-dihydro-2H-pyrrole
Figure PCTCN2019099971-appb-000052
Figure PCTCN2019099971-appb-000052
冰浴下，向(R)-5-甲基吡咯烷-2-酮(1.7g,17.2mmol)的二氯甲烷(40mL)溶液中，分批加入三甲基氧鎓四氟硼酸(3.55g,24.0mmol)。反应缓慢升至室温，在此温度下搅拌5小时，然后加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，加入冰醋酸(5mL)，减压浓缩，得到粗品直接用于下一步反应。 To a solution of (R) -5-methylpyrrolidin-2-one (1.7 g, 17.2 mmol) in dichloromethane (40 mL) under ice bath, trimethyloxonium tetrafluoroborate (3.55 g) was added in portions. , 24.0 mmol). The reaction was slowly raised to room temperature, stirred at this temperature for 5 hours, and then added saturated aqueous NaHCO 3 solution (5 mL), and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and added with ice. Acetic acid (5 mL) was concentrated under reduced pressure to obtain the crude product, which was directly used in the next reaction.
MS m/z(ESI):114.1[M+H] +. MS m / z (ESI): 114.1 [M + H] + .
第二步 (R)-6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺的合成Second step (R) -6- (5-methyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridine-2 -Amine synthesis
Figure PCTCN2019099971-appb-000053
Figure PCTCN2019099971-appb-000053
室温下，将6-氨基甲基吡啶酰肼(2.35g,15.4mmol)溶于2-戊醇(15mL)和乙酸(2mL)中，加入(R)-5-甲氧基-2-甲基-3,4-二氢-2H-吡咯(1.93g,17.1mmol)。反应加热至125℃，在此温度下搅拌12小时，冷却至室温后，减压浓缩。然后加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经柱层析得到标题化合物(R)-6-(5-甲 基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺(1.62g,两步产率49％)。 At room temperature, 6-aminomethylpyridylhydrazide (2.35g, 15.4mmol) was dissolved in 2-pentanol (15mL) and acetic acid (2mL), and (R) -5-methoxy-2-methyl was added -3,4-dihydro-2H-pyrrole (1.93 g, 17.1 mmol). The reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and then concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL × 2) was extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (R) -6- ( 5-methyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-amine (1.62 g, two-step yield 49%).
1H NMR(400MHz,CDCl 3)δ7.65(m,1H),7.61-7.42(m,1H),6.54(m,1H),5.17-4.88(m,1H),3.18-2.77(m,3H),2.43-2.31(m,1H),1.53-1.37(m,3H)； 1 H NMR (400MHz, CDCl 3 ) δ 7.65 (m, 1H), 7.61-7.42 (m, 1H), 6.54 (m, 1H), 5.17-4.88 (m, 1H), 3.18-2.77 (m, 3H ), 2.43-2.31 (m, 1H), 1.53-1.37 (m, 3H);
MS m/z(ESI):216.1[M+H] +. MS m / z (ESI): 216.1 [M + H] + .
第三步 (R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的合成The third step (R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6,7-di Synthesis of hydrogen-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000054
Figure PCTCN2019099971-appb-000054
室温下，将(R)-6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺(139mg,0.65mmol)加入5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酰氯(298mg,1.07mmol)的THF(10mL)和吡啶(10mL)溶液中，然后加入4-二甲氨基吡啶(12mg,0.097mmol)。将反应加热至45℃，并在该温度下搅拌2小时,然后加入水(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析得标题化合物(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(151mg,产率51％)。(R) -6- (5-methyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridine- 2-amine (139 mg, 0.65 mmol) was added 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (298 mg, 1.07 mmol) in THF (10 mL) And pyridine (10 mL) solution, then 4-dimethylaminopyridine (12 mg, 0.097 mmol) was added. The reaction was heated to 45 ° C. and stirred at this temperature for 2 hours, and then water (5 mL) and dichloromethane (50 mL × 2) were added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Chromatography gave the title compound (R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6,7 -Dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide (151 mg, yield 51%).
1H NMR(400MHz,CDCl 3)δ9.06(d,J＝15.6Hz,1H),8.36-8.34(m,1H),8.10(t,J＝7.2Hz,2H),7.89(t,J＝8.0Hz,1H),7.48(s,1H),7.20(d,J＝12.6Hz,1H),6.80(s,1H),5.03(s,1H),3.16-2.94(m,3H),2.48-2.41(m,1H),2.30(s,3H),1.94-1.90(m,1H),1.56(d,J＝6.4Hz,3H),0.92-0.90(m,2H),0.86-0.73(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 9.06 (d, J = 15.6 Hz, 1 H), 8.36-8.34 (m, 1 H), 8.10 (t, J = 7.2 Hz, 2H), 7.89 (t, J = 8.0Hz, 1H), 7.48 (s, 1H), 7.20 (d, J = 12.6Hz, 1H), 6.80 (s, 1H), 5.03 (s, 1H), 3.16-2.94 (m, 3H), 2.48- 2.41 (m, 1H), 2.30 (s, 3H), 1.94-1.90 (m, 1H), 1.56 (d, J = 6.4Hz, 3H), 0.92-0.90 (m, 2H), 0.86-0.73 (m, 2H);
MS m/z(ESI):458.1[M+H] +. MS m / z (ESI): 458.1 [M + H] + .
实施例9Example 9
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000055
Figure PCTCN2019099971-appb-000055
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例8。(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6,7-dihydro-5H -For the preparation method of pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide, refer to Example 8.
1H NMR(400MHz,CDCl 3)δ9.06(d,J＝15.6Hz,1H),8.36-8.34(m,1H),8.10(t,J＝7.2Hz,2H),7.89(t,J＝8.0Hz,1H),7.48(s,1H),7.20(d,J＝12.6Hz,1H),6.80(s,1H),5.03(s,1H),3.16-2.94(m,3H),2.48-2.41(m,1H),2.30(s,3H),1.94-1.90(m,1H),1.56(d,J＝6.4Hz,3H),0.92-0.90(m,2H),0.86-0.73(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 9.06 (d, J = 15.6 Hz, 1 H), 8.36-8.34 (m, 1 H), 8.10 (t, J = 7.2 Hz, 2H), 7.89 (t, J = 8.0Hz, 1H), 7.48 (s, 1H), 7.20 (d, J = 12.6Hz, 1H), 6.80 (s, 1H), 5.03 (s, 1H), 3.16-2.94 (m, 3H), 2.48- 2.41 (m, 1H), 2.30 (s, 3H), 1.94-1.90 (m, 1H), 1.56 (d, J = 6.4Hz, 3H), 0.92-0.90 (m, 2H), 0.86-0.73 (m, 2H);
MS m/z(ESI):458.1[M+H] +. MS m / z (ESI): 458.1 [M + H] + .
实施例10Example 10
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5,5-二甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]三 唑-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5,5-dimethyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000056
Figure PCTCN2019099971-appb-000056
第一步 5-甲氧基-2,2-二甲基-3,4-二氢-2H-吡咯的合成Step 1 Synthesis of 5-methoxy-2,2-dimethyl-3,4-dihydro-2H-pyrrole
Figure PCTCN2019099971-appb-000057
Figure PCTCN2019099971-appb-000057
冰浴下，向5,5-二甲基吡咯烷-2-酮(0.36g,3.2mmol)的二氯甲烷溶液(30mL)中，分批加入三甲基氧鎓四氟硼酸(0.66g,4.45mmol)。然后将反应缓慢升至室温，并在此温度下搅拌5小时，接着加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，加入冰醋酸(5mL)，减压浓缩，得到粗品直接用于下一步反应。 To a solution of 5,5-dimethylpyrrolidin-2-one (0.36 g, 3.2 mmol) in dichloromethane (30 mL) under ice bath, trimethyloxonium tetrafluoroborate (0.66 g, 4.45 mmol). The reaction was then slowly warmed to room temperature and stirred at this temperature for 5 hours. Then, saturated aqueous NaHCO 3 solution (5 mL) was added, and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Add glacial acetic acid (5 mL) and concentrate under reduced pressure to obtain the crude product which is directly used in the next reaction.
MS m/z(ESI):128.2[M+H] +. MS m / z (ESI): 128.2 [M + H] + .
第二步 6-(5,5-二甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺的合成The second step 6- (5,5-dimethyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridine-2- Synthesis of amines
Figure PCTCN2019099971-appb-000058
Figure PCTCN2019099971-appb-000058
室温下，将6-氨基甲基吡啶酰肼(435mg,2.86mmol)溶于2-戊醇(15mL)和乙酸(2mL)中，加入5-甲氧基-2,2-二甲基-3,4-二氢-2H-吡咯(404mg,3.2mmol)。反应加热至125℃，在此温度下搅拌12小时，冷却至室温后,减压浓缩。然后加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析得到标题化合物6-(5,5-二甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺(380mg，两步产率52％)。 At room temperature, 6-aminomethylpyridylhydrazide (435mg, 2.86mmol) was dissolved in 2-pentanol (15mL) and acetic acid (2mL), and 5-methoxy-2,2-dimethyl-3 was added. , 4-dihydro-2H-pyrrole (404 mg, 3.2 mmol). The reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL × 2) was extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound 6- (5,5-di Methyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-amine (380 mg, 52% in two steps) .
MS m/z(ESI):230.1[M+H] +. MS m / z (ESI): 230.1 [M + H] + .
第三步 5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5,5-二甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺的合成The third step 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5,5-dimethyl-6,7-dihydro-5H-pyrrolo [2,1 -c] [1,2,4] Triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000059
Figure PCTCN2019099971-appb-000059
室温下，将6-(5,5-二甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺(35mg,0.15mmol)加入5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酰氯(70mg,0.25mmol)的THF(5mL)和吡啶(5mL)溶液中，加入4-二甲氨基吡啶(4.6mg,0.04mmol)。将反应加热至45℃，并在该温度下搅拌2小时，然后加入水(5mL)淬灭，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸 钠干燥，浓缩后柱层析得标题化合物5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5,5-二甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺(39mg,产率54％)。At room temperature, 6- (5,5-dimethyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridine-2 -Amine (35 mg, 0.15 mmol) was added 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (70 mg, 0.25 mmol) in THF (5 mL) and To a solution of pyridine (5 mL), 4-dimethylaminopyridine (4.6 mg, 0.04 mmol) was added. The reaction was heated to 45 ° C and stirred at this temperature for 2 hours, and then quenched by adding water (5 mL), and extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Post-column chromatography gave the title compound 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5,5-dimethyl-6,7-dihydro-5H-pyrrolo) [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide (39 mg, yield 54%).
1H NMR(400MHz,CDCl 3)δ9.05(d,J＝16.6Hz,1H),8.29-8.27(m,1H),8.09-7.94(m,2H),7.82(t,J＝8.0Hz,1H),7.44(s,1H),7.12(d,J＝12.2Hz,1H),6.73(s,1H),3.10-2.86(m,2H),2.60-2.45(m,2H),2.22(s,3H),1.88-1.82(m,1H),1.72(s,6H),0.87-0.82(m,2H),0.78-0.75(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 9.05 (d, J = 16.6 Hz, 1 H), 8.29-8.27 (m, 1H), 8.09-7.94 (m, 2H), 7.82 (t, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.12 (d, J = 12.2Hz, 1H), 6.73 (s, 1H), 3.10-2.86 (m, 2H), 2.60-2.45 (m, 2H), 2.22 (s , 3H), 1.88-1.82 (m, 1H), 1.72 (s, 6H), 0.87-0.82 (m, 2H), 0.78-0.75 (m, 2H);
MS m/z(ESI):472.2[M+H] +. MS m / z (ESI): 472.2 [M + H] + .
实施例11Example 11
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-(甲氧基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺(S) -5- (4-Cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (methoxymethyl) -6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-appb-000060
Figure PCTCN2019099971-appb-000060
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-(甲氧基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺的制备方法参照实施例8。(S) -5- (4-Cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (methoxymethyl) -6,7-dihydro-5H -For the preparation method of pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide, refer to Example 8.
1H NMR(400MHz,CDCl 3)δ9.05(d,J＝15.6Hz,1H),8.35(m,1H),8.10(m,2H),7.89(t,J＝8.0Hz,1H),7.49(s,1H),7.20(d,J＝12.4Hz,1H),6.81(m,1H),5.09-4.94(m,1H),3.81(m,1H),3.78-3.66(m,1H),3.28(s,3H),3.17-3.02(m,1H),3.02-2.89(m,2H),2.82-2.69(m,1H),2.30(s,3H),1.92(m,1H),0.91(m,2H),0.89-0.77(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 9.05 (d, J = 15.6 Hz, 1 H), 8.35 (m, 1 H), 8.10 (m, 2 H), 7.89 (t, J = 8.0 Hz, 1 H), 7.49 (s, 1H), 7.20 (d, J = 12.4 Hz, 1H), 6.81 (m, 1H), 5.09-4.94 (m, 1H), 3.81 (m, 1H), 3.78-3.66 (m, 1H), 3.28 (s, 3H), 3.17-3.02 (m, 1H), 3.02-2.89 (m, 2H), 2.82-2.69 (m, 1H), 2.30 (s, 3H), 1.92 (m, 1H), 0.91 ( m, 2H), 0.89-0.77 (m, 2H);
MS m/z(ESI):488.2[M+H] +. MS m / z (ESI): 488.2 [M + H] + .
实施例12Example 12
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-(甲氧基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (methoxymethyl) -6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-appb-000061
Figure PCTCN2019099971-appb-000061
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-(甲氧基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺的制备方法参照实施例8。(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (methoxymethyl) -6,7-dihydro-5H -For the preparation method of pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide, refer to Example 8.
1H NMR(400MHz,CDCl 3)δ9.05(d,J＝15.6Hz,1H),8.35(m,1H),8.10(m,2H),7.89(t,J＝8.0Hz,1H),7.49(s,1H),7.20(d,J＝12.4Hz,1H),6.81(m,1H),5.09-4.94(m,1H),3.81(m,1H),3.78-3.66(m,1H),3.28(s,3H),3.17-3.02(m,1H),3.02-2.89(m,2H),2.82-2.69(m,1H),2.30(s,3H),1.92(m,1H),0.91(m,2H),0.89-0.77(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 9.05 (d, J = 15.6 Hz, 1 H), 8.35 (m, 1 H), 8.10 (m, 2 H), 7.89 (t, J = 8.0 Hz, 1 H), 7.49 (s, 1H), 7.20 (d, J = 12.4 Hz, 1H), 6.81 (m, 1H), 5.09-4.94 (m, 1H), 3.81 (m, 1H), 3.78-3.66 (m, 1H), 3.28 (s, 3H), 3.17-3.02 (m, 1H), 3.02-2.89 (m, 2H), 2.82-2.69 (m, 1H), 2.30 (s, 3H), 1.92 (m, 1H), 0.91 ( m, 2H), 0.89-0.77 (m, 2H);
MS m/z(ESI):488.2[M+H] +. MS m / z (ESI): 488.2 [M + H] + .
实施例13Example 13
(R)-2-氟-5-(4-异丙基-1H-咪唑-1-基)-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(R) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000062
Figure PCTCN2019099971-appb-000062
(R)-2-氟-5-(4-异丙基-1H-咪唑-1-基)-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例8。(R) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6,7-dihydro-5H -For the preparation method of pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide, refer to Example 8.
1H NMR(400MHz,CD 3OD)δ9.22(d,J＝1.4Hz,1H),8.45(d,J＝8.2Hz,1H),8.10(t,J＝8.0Hz,1H),8.05-7.97(m,2H),7.66(s,1H),7.50(d,J＝10.9Hz,1H),5.57-5.45(m,1H),3.47-3.36(m,1H),3.28-3.16(m,3H),2.65-2.57(m,1H),2.36(s,3H),1.59(d,J＝6.5Hz,3H),1.43(d,J＝6.9Hz,6H)； 1 H NMR (400 MHz, CD 3 OD) δ 9.22 (d, J = 1.4 Hz, 1 H), 8.45 (d, J = 8.2 Hz, 1 H), 8.10 (t, J = 8.0 Hz, 1 H), 8.05 7.97 (m, 2H), 7.66 (s, 1H), 7.50 (d, J = 11.0Hz, 1H), 5.57-5.45 (m, 1H), 3.47-3.36 (m, 1H), 3.28-3.16 (m, 3H), 2.65-2.57 (m, 1H), 2.36 (s, 3H), 1.59 (d, J = 6.5Hz, 3H), 1.43 (d, J = 6.9Hz, 6H);
MS m/z(ESI):460.2[M+H] +. MS m / z (ESI): 460.2 [M + H] + .
实施例14Example 14
(S)-2-氟-5-(4-异丙基-1H-咪唑-1-基)-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(S) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000063
Figure PCTCN2019099971-appb-000063
(S)-2-氟-5-(4-异丙基-1H-咪唑-1-基)-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例8。(S) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6,7-dihydro-5H -For the preparation method of pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide, refer to Example 8.
1H NMR(400MHz,CD 3OD)δ9.21(s,1H),8.55-8.30(m,1H),8.18-7.96(m,3H),7.67(s,1H),7.51(d,J＝9.8Hz,1H),5.54-5.34(m,1H),3.34(s,1H),3.28-3.16(m,3H),2.65-2.57(m,1H),2.36(s,3H),1.57(d,J＝5.8Hz,3H),1.42(d,J＝6.9Hz,6H)； 1 H NMR (400MHz, CD 3 OD) δ9.21 (s, 1H), 8.55-8.30 (m, 1H), 8.18-7.96 (m, 3H), 7.67 (s, 1H), 7.51 (d, J = 9.8Hz, 1H), 5.54-5.34 (m, 1H), 3.34 (s, 1H), 3.28-3.16 (m, 3H), 2.65-2.57 (m, 1H), 2.36 (s, 3H), 1.57 (d , J = 5.8Hz, 3H), 1.42 (d, J = 6.9Hz, 6H);
MS m/z(ESI):460.2[M+H] +. MS m / z (ESI): 460.2 [M + H] + .
实施例15Example 15
(R)-5-(4-(叔-丁基)-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(R) -5- (4- (tert-butyl) -1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6,7-di Hydrogen-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000064
Figure PCTCN2019099971-appb-000064
(R)-5-(4-(叔-丁基)-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例8。(R) -5- (4- (tert-butyl) -1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6,7-di For the preparation method of hydrogen-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide, refer to Example 8.
1H NMR(400MHz,CD 3OD)δ9.34(s,1H),8.48(d,J＝8.3Hz,1H),8.14(t,J＝7.9Hz,1H),8.08-8.01(m,2H),7.74(s,1H),7.52(d,J＝10.8Hz,1H),5.64(s,1H), 3.58-3.44(m,1H),3.30-3.21(m,2H),2.71-2.63(m,1H),2.39(s,3H),1.63(d,J＝5.5Hz,3H),1.48(s,9H)； 1 H NMR (400MHz, CD 3 OD) δ 9.34 (s, 1H), 8.48 (d, J = 8.3 Hz, 1H), 8.14 (t, J = 7.9 Hz, 1H), 8.08-8.01 (m, 2H ), 7.74 (s, 1H), 7.52 (d, J = 10.8 Hz, 1H), 5.64 (s, 1H), 3.58-3.44 (m, 1H), 3.30-3.21 (m, 2H), 2.71-2.63 ( m, 1H), 2.39 (s, 3H), 1.63 (d, J = 5.5Hz, 3H), 1.48 (s, 9H);
MS m/z(ESI):474.2[M+H] +. MS m / z (ESI): 474.2 [M + H] + .
实施例16Example 16
(S)-5-(4-(叔-丁基)-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(S) -5- (4- (tert-butyl) -1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6,7-di Hydrogen-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000065
Figure PCTCN2019099971-appb-000065
(S)-5-(4-(叔-丁基)-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例8。(S) -5- (4- (tert-butyl) -1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-methyl-6,7-di For the preparation method of hydrogen-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide, refer to Example 8.
1H NMR(400MHz,CD 3OD)δ9.34(s,1H),8.48(d,J＝8.3Hz,1H),8.14(t,J＝7.9Hz,1H),8.08-8.01(m,2H),7.74(s,1H),7.52(d,J＝10.8Hz,1H),5.64(s,1H),3.58-3.44(m,1H),3.30-3.21(m,2H),2.71-2.63(m,1H),2.39(s,3H),1.63(d,J＝5.5Hz,3H),1.48(s,9H)； 1 H NMR (400MHz, CD 3 OD) δ 9.34 (s, 1H), 8.48 (d, J = 8.3 Hz, 1H), 8.14 (t, J = 7.9 Hz, 1H), 8.08-8.01 (m, 2H ), 7.74 (s, 1H), 7.52 (d, J = 10.8 Hz, 1H), 5.64 (s, 1H), 3.58-3.44 (m, 1H), 3.30-3.21 (m, 2H), 2.71-2.63 ( m, 1H), 2.39 (s, 3H), 1.63 (d, J = 5.5Hz, 3H), 1.48 (s, 9H);
MS m/z(ESI):474.2[M+H] +. MS m / z (ESI): 474.2 [M + H] + .
实施例17Example 17
(S)-2-氟-5-(4-异丙基-1H-咪唑-1-基)-N-(6-(5-(甲氧基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺(S) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -N- (6- (5- (methoxymethyl) -6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-appb-000066
Figure PCTCN2019099971-appb-000066
(S)-2-氟-5-(4-异丙基-1H-咪唑-1-基)-N-(6-(5-(甲氧基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺的制备方法参照实施例8。(S) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -N- (6- (5- (methoxymethyl) -6,7-dihydro-5H -For the preparation method of pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide, refer to Example 8.
MS m/z(ESI):490.2[M+H] +. MS m / z (ESI): 490.2 [M + H] + .
实施例18Example 18
(R)-2-氟-5-(4-异丙基-1H-咪唑-1-基)-N-(6-(5-(甲氧基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺(R) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -N- (6- (5- (methoxymethyl) -6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-appb-000067
Figure PCTCN2019099971-appb-000067
(R)-2-氟-5-(4-异丙基-1H-咪唑-1-基)-N-(6-(5-(甲氧基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺的制备方法参照实施例8。(R) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -N- (6- (5- (methoxymethyl) -6,7-dihydro-5H -For the preparation method of pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide, refer to Example 8.
MS m/z(ESI):490.2[M+H] +. MS m / z (ESI): 490.2 [M + H] + .
实施例19Example 19
(S)-5-(4-(叔-丁基)-1H-咪唑-1-基)-2-氟-N-(6-(5-(甲氧基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺(S) -5- (4- (tert-butyl) -1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (methoxymethyl) -6,7-di Hydrogen-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-appb-000068
Figure PCTCN2019099971-appb-000068
(S)-5-(4-(叔-丁基)-1H-咪唑-1-基)-2-氟-N-(6-(5-(甲氧基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺的制备方法参照实施例8。(S) -5- (4- (tert-butyl) -1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (methoxymethyl) -6,7-di For the preparation method of hydrogen-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide, refer to Example 8.
MS m/z(ESI):504.2[M+H] +. MS m / z (ESI): 504.2 [M + H] + .
实施例20Example 20
(R)-5-(4-(叔-丁基)-1H-咪唑-1-基)-2-氟-N-(6-(5-(甲氧基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺(R) -5- (4- (tert-butyl) -1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (methoxymethyl) -6,7-di Hydrogen-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-appb-000069
Figure PCTCN2019099971-appb-000069
(R)-5-(4-(叔-丁基)-1H-咪唑-1-基)-2-氟-N-(6-(5-(甲氧基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺的制备方法参照实施例8。(R) -5- (4- (tert-butyl) -1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (methoxymethyl) -6,7-di For the preparation method of hydrogen-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide, refer to Example 8.
MS m/z(ESI):504.2[M+H] +. MS m / z (ESI): 504.2 [M + H] + .
实施例21Example 21
(R)-2-氟-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-(4-(三氟甲基)-1H-咪唑-1-基)苯酰胺(R) -2-fluoro-4-methyl-N- (6- (5-methyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] Azol-3-yl) pyridin-2-yl) -5- (4- (trifluoromethyl) -1H-imidazol-1-yl) benzamide
Figure PCTCN2019099971-appb-000070
Figure PCTCN2019099971-appb-000070
(R)-2-氟-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-(4-(三氟甲基)-1H-咪唑-1-基)苯酰胺的制备方法参照实施例8。(R) -2-fluoro-4-methyl-N- (6- (5-methyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] The method for preparing azole-3-yl) pyridin-2-yl) -5- (4- (trifluoromethyl) -1H-imidazol-1-yl) benzamide is described in Example 8.
MS m/z(ESI):486.2[M+H] +. MS m / z (ESI): 486.2 [M + H] + .
实施例22Example 22
(S)-2-氟-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-(4-(三氟甲基)-1H-咪唑-1-基)苯酰胺(S) -2-fluoro-4-methyl-N- (6- (5-methyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] Azol-3-yl) pyridin-2-yl) -5- (4- (trifluoromethyl) -1H-imidazol-1-yl) benzamide
Figure PCTCN2019099971-appb-000071
Figure PCTCN2019099971-appb-000071
(S)-2-氟-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-(4-(三氟甲基)-1H-咪唑-1-基)苯酰胺的制备方法参照实施例8。(S) -2-fluoro-4-methyl-N- (6- (5-methyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] The method for preparing azole-3-yl) pyridin-2-yl) -5- (4- (trifluoromethyl) -1H-imidazol-1-yl) benzamide is described in Example 8.
MS m/z(ESI):486.2[M+H] +. MS m / z (ESI): 486.2 [M + H] + .
实施例23Example 23
(R)-2-氟-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-(4-(噁丁环-3-基)-1H-咪唑-1-基)苯酰胺(R) -2-fluoro-4-methyl-N- (6- (5-methyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] Azole-3-yl) pyridin-2-yl) -5- (4- (oxetan-3-yl) -1H-imidazol-1-yl) benzamide
Figure PCTCN2019099971-appb-000072
Figure PCTCN2019099971-appb-000072
(R)-2-氟-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-(4-(噁丁环-3-基)-1H-咪唑-1-基)苯酰胺的制备方法参照实施例8。(R) -2-fluoro-4-methyl-N- (6- (5-methyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] The method for preparing azole-3-yl) pyridin-2-yl) -5- (4- (oxetan-3-yl) -1H-imidazol-1-yl) benzamide is described in Example 8.
MS m/z(ESI):474.2[M+H] +. MS m / z (ESI): 474.2 [M + H] + .
实施例24Example 24
(S)-2-氟-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-(4-(噁丁环-3-基)-1H-咪唑-1-基)苯酰胺(S) -2-fluoro-4-methyl-N- (6- (5-methyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] Azole-3-yl) pyridin-2-yl) -5- (4- (oxetan-3-yl) -1H-imidazol-1-yl) benzamide
Figure PCTCN2019099971-appb-000073
Figure PCTCN2019099971-appb-000073
(S)-2-氟-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-(4-(噁丁环-3-基)-1H-咪唑-1-基)苯酰胺的制备方法参照实施例8。(S) -2-fluoro-4-methyl-N- (6- (5-methyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] The method for preparing azole-3-yl) pyridin-2-yl) -5- (4- (oxetan-3-yl) -1H-imidazol-1-yl) benzamide is described in Example 8.
MS m/z(ESI):474.2[M+H] +. MS m / z (ESI): 474.2 [M + H] + .
实施例25Example 25
(R)-2-氟-5-(4-(2-羟基丙烷-2-基)-1H-咪唑-1-基)-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(R) -2-fluoro-5- (4- (2-hydroxypropane-2-yl) -1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6 , 7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000074
Figure PCTCN2019099971-appb-000074
(R)-2-氟-5-(4-(2-羟基丙烷-2-基)-1H-咪唑-1-基)-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例8。(R) -2-fluoro-5- (4- (2-hydroxypropane-2-yl) -1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6 Refer to Example 8 for the method for preparing 7,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide.
MS m/z(ESI):476.2[M+H] +. MS m / z (ESI): 476.2 [M + H] + .
实施例26Example 26
(S)-2-氟-5-(4-(2-羟基丙烷-2-基)-1H-咪唑-1-基)-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(S) -2-fluoro-5- (4- (2-hydroxypropane-2-yl) -1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6 , 7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000075
Figure PCTCN2019099971-appb-000075
(S)-2-氟-5-(4-(2-羟基丙烷-2-基)-1H-咪唑-1-基)-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例8。(S) -2-fluoro-5- (4- (2-hydroxypropane-2-yl) -1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6 Refer to Example 8 for the preparation method of 7,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide.
MS m/z(ESI):476.2[M+H] +. MS m / z (ESI): 476.2 [M + H] + .
实施例27Example 27
N-(6-(7-乙酰基-5,6,7,8-四氢-[1,2,4]***并[4,3-a]吡嗪-3-基)吡啶-2-基)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯酰胺N- (6- (7-acetyl-5,6,7,8-tetrahydro- [1,2,4] triazolo [4,3-a] pyrazin-3-yl) pyridine-2- ) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000076
Figure PCTCN2019099971-appb-000076
N-(6-(7-乙酰基-5,6,7,8-四氢-[1,2,4]***并[4,3-a]吡嗪-3-基)吡啶-2-基)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯酰胺的制备同实施例1。N- (6- (7-acetyl-5,6,7,8-tetrahydro- [1,2,4] triazolo [4,3-a] pyrazin-3-yl) pyridine-2- The preparation of the group) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide was the same as in Example 1.
1H NMR(400MHz,CDCl 3)δ9.00(d,J＝15.0Hz,1H),8.31(m,1H),8.15-7.94(m,2H),7.84(t,J＝8.0Hz,1H),7.47-7.37(m,1H),7.14(m,1H),6.74(s,1H),4.95(m,2H),4.62-4.44(m,2H),3.93(m,2H),2.22(s,3H),2.19(s,3H),1.85(m,1H),0.88-0.81(m,2H),0.78-0.75(m,2H)； 1 H NMR (400MHz, CDCl 3 ) 9.00 (d, J = 15.0 Hz, 1H), 8.31 (m, 1H), 8.15-7.94 (m, 2H), 7.84 (t, J = 8.0 Hz, 1H) , 7.47-7.37 (m, 1H), 7.14 (m, 1H), 6.74 (s, 1H), 4.95 (m, 2H), 4.62-4.44 (m, 2H), 3.93 (m, 2H), 2.22 (s , 3H), 2.19 (s, 3H), 1.85 (m, 1H), 0.88-0.81 (m, 2H), 0.78-0.75 (m, 2H);
MS m/z(ESI):501.2[M+H] +. MS m / z (ESI): 501.2 [M + H] + .
实施例28Example 28
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(7-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (7-methyl-6,7-dihydro-5H-pyrrolo [ 2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000077
Figure PCTCN2019099971-appb-000077
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(7-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例8。5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (7-methyl-6,7-dihydro-5H-pyrrolo [ Refer to Example 8 for the preparation method of 2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide.
1H NMR(400MHz,CD 3OD)δ8.20(d,J＝8.1Hz,1H),7.87(t,J＝7.9Hz,1H),7.83-7.78(m,1H),7.68-7.62(m,2H),7.25(d,J＝11.2Hz,1H),6.96(s,1H),4.58-4.50(m,1H),4.34-4.23(m,1H),3.35-3.26(m,1H),2.94-2.86(m,1H),2.38-2.28(m,1H),2.17(s,3H),1.84-1.77(m,1H),1.35(d,J＝7.0Hz,3H), 0.81-0.77(m,2H),0.68-0.62(m,2H)； 1 H NMR (400 MHz, CD 3 OD) δ 8.20 (d, J = 8.1 Hz, 1 H), 7.87 (t, J = 7.9 Hz, 1 H), 7.83-7.78 (m, 1H), 7.68-7.62 (m , 2H), 7.25 (d, J = 11.2 Hz, 1H), 6.96 (s, 1H), 4.58-4.50 (m, 1H), 4.34-4.23 (m, 1H), 3.35-3.26 (m, 1H), 2.94-2.86 (m, 1H), 2.38-2.28 (m, 1H), 2.17 (s, 3H), 1.84-1.77 (m, 1H), 1.35 (d, J = 7.0Hz, 3H), 0.81-0.77 ( m, 2H), 0.68-0.62 (m, 2H);
MS m/z(ESI):458.2[M+H] +. MS m / z (ESI): 458.2 [M + H] + .
实施例29Example 29
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(6-甲氧基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (6-methoxy-6,7-dihydro-5H-pyrrolo [2,1- c) [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-appb-000078
Figure PCTCN2019099971-appb-000078
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(6-甲氧基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺的制备方法参照实施例8。5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (6-methoxy-6,7-dihydro-5H-pyrrolo [2,1- c] [1,2,4] Triazol-3-yl) pyridin-2-yl) -4-methylbenzamide is prepared by referring to Example 8.
1H NMR(400MHz,CD 3OD)δ9.11(s,1H),8.35(s,1H),8.11-7.90(m,3H),7.60(s,1H),7.50(d,J＝10.3Hz,1H),4.71-4.62(m,2H),3.46(s,3H),3.39-3.35(m,2H),3.15-3.03(m,1H),2.35(s,3H),2.13-2.06(m,1H),1.19-1.13(m,2H),0.97-0.88(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ9.11 (s, 1H), 8.35 (s, 1H), 8.11-7.90 (m, 3H), 7.60 (s, 1H), 7.50 (d, J = 10.3Hz , 1H), 4.71-4.62 (m, 2H), 3.46 (s, 3H), 3.39-3.35 (m, 2H), 3.15-3.03 (m, 1H), 2.35 (s, 3H), 2.13-2.06 (m , 1H), 1.19-1.13 (m, 2H), 0.97-0.88 (m, 2H);
MS m/z(ESI):474.2[M+H] +. MS m / z (ESI): 474.2 [M + H] + .
实施例30Example 30
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(6-环丙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6-cyclopropyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1 , 2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000079
Figure PCTCN2019099971-appb-000079
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(6-环丙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺的制备方法参照实施例8。5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6-cyclopropyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1 Refer to Example 8 for the method for preparing 2,2] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide.
1H NMR(400MHz,CD 3OD)δ8.22(d,J＝8.1Hz,1H),7.88(t,J＝7.9Hz,1H),7.84-7.79(m,1H),7.64(d,J＝6.6Hz,1H),7.58(d,J＝1.2Hz,1H),7.27(d,J＝11.1Hz,1H),6.94(d,J＝1.1Hz,1H),4.70-4.63(m,1H),4.18-4.14(m,1H),3.13-3.07(m,1H),2.79-2.72(m,1H),2.55-2.43(m,1H),2.17(s,3H),1.82-1.77(m,1H),1.01-0.91(m,1H),0.81-0.74(m,2H),0.67-0.62(m,2H),0.53-0.47(m,2H),0.28-0.16(m,2H)； 1 H NMR (400 MHz, CD 3 OD) δ 8.22 (d, J = 8.1 Hz, 1 H), 7.88 (t, J = 7.9 Hz, 1 H), 7.84-7.79 (m, 1H), 7.64 (d, J = 6.6 Hz, 1H), 7.58 (d, J = 1.2 Hz, 1H), 7.27 (d, J = 11.1 Hz, 1H), 6.94 (d, J = 1.1 Hz, 1H), 4.70-4.63 (m, 1H ), 4.18-4.14 (m, 1H), 3.13-3.07 (m, 1H), 2.79-2.72 (m, 1H), 2.55-2.43 (m, 1H), 2.17 (s, 3H), 1.82-1.77 (m , 1H), 1.01-0.91 (m, 1H), 0.81-0.74 (m, 2H), 0.67-0.62 (m, 2H), 0.53-0.47 (m, 2H), 0.28-0.16 (m, 2H);
MS m/z(ESI):484.2[M+H] +. MS m / z (ESI): 484.2 [M + H] + .
实施例31Example 31
N-(6-(5'H,7'H-螺[环丙烷-1,6'-吡咯并[2,1-c][1,2,4]***]-3'-基)吡啶-2-基)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯酰胺N- (6- (5'H, 7'H-spiro [cyclopropane-1,6'-pyrrolo [2,1-c] [1,2,4] triazole] -3'-yl) pyridine 2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000080
Figure PCTCN2019099971-appb-000080
N-(6-(5'H,7'H-螺[环丙烷-1,6'-吡咯并[2,1-c][1,2,4]***]-3'-基)吡啶-2-基)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯酰胺的制备方法参照实施例8。N- (6- (5'H, 7'H-spiro [cyclopropane-1,6'-pyrrolo [2,1-c] [1,2,4] triazole] -3'-yl) pyridine Refer to Example 8 for the method for preparing 2--2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide.
MS m/z(ESI):470.2[M+H] +. MS m / z (ESI): 470.2 [M + H] + .
实施例32Example 32
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(6,6-二甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6,6-dimethyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000081
Figure PCTCN2019099971-appb-000081
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(6,6-二甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺的制备方法参照实施例8。5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6,6-dimethyl-6,7-dihydro-5H-pyrrolo [2,1-c] Refer to Example 8 for the method for preparing [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide.
1H NMR(400MHz,CD 3OD)δ8.36-8.28(m,2H),8.00-7.86(m,2H),7.77(d,J＝5.9Hz,1H),7.37(d,J＝10.8Hz,1H),7.12(s,1H),4.31(s,2H),2.87(s,2H),2.29(s,3H),1.97-1.88(m,1H),1.35(s,6H),0.96-0.89(m,2H),0.80-0.74(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 8.36-8.28 (m, 2H), 8.00-7.86 (m, 2H), 7.77 (d, J = 5.9Hz, 1H), 7.37 (d, J = 10.8Hz , 1H), 7.12 (s, 1H), 4.31 (s, 2H), 2.87 (s, 2H), 2.29 (s, 3H), 1.97-1.88 (m, 1H), 1.35 (s, 6H), 0.96- 0.89 (m, 2H), 0.80-0.74 (m, 2H);
MS m/z(ESI):472.2[M+H] +. MS m / z (ESI): 472.2 [M + H] + .
实施例33Example 33
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(6-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (6-methyl-6,7-dihydro-5H-pyrrolo [ 2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000082
Figure PCTCN2019099971-appb-000082
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(6-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例8。5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (6-methyl-6,7-dihydro-5H-pyrrolo [ Refer to Example 8 for the preparation method of 2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide.
1H NMR(400MHz,CD 3OD)δ9.21(s,1H),8.48(d,J＝8.3Hz,1H),8.13(t,J＝8.0Hz,1H),8.05-7.98(m,2H),7.66(s,1H),7.50(d,J＝10.7Hz,1H),5.11-5.07(m,1H),4.40-3.35(m,1H),3.59-3.47(m,2H),3.07-2.94(m,1H),2.37(s,3H),2.13-2.06(m,1H),1.43(d,J＝5.5Hz,3H),1.21-1.14(m,2H),1.00-0.88(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ9.21 (s, 1H), 8.48 (d, J = 8.3Hz, 1H), 8.13 (t, J = 8.0Hz, 1H), 8.05-7.98 (m, 2H ), 7.66 (s, 1H), 7.50 (d, J = 10.7 Hz, 1H), 5.11-5.07 (m, 1H), 4.40-3.35 (m, 1H), 3.59-3.47 (m, 2H), 3.07- 2.94 (m, 1H), 2.37 (s, 3H), 2.13-2.06 (m, 1H), 1.43 (d, J = 5.5Hz, 3H), 1.21-1.14 (m, 2H), 1.00-0.88 (m, 2H);
MS m/z(ESI):458.2[M+H] +. MS m / z (ESI): 458.2 [M + H] + .
实施例34Example 34
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(6-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (6-methyl-6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000083
Figure PCTCN2019099971-appb-000083
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(6-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例8。(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (6-methyl-6,7-dihydro-5H -For the preparation method of pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide, refer to Example 8.
1H NMR(400MHz,CD 3OD)δ9.21(s,1H),8.48(d,J＝8.3Hz,1H),8.13(t,J＝8.0Hz,1H),8.05-7.98(m,2H),7.66(s,1H),7.50(d,J＝10.7Hz,1H),5.11-5.07(m,1H),4.40-3.35(m,1H),3.59-3.47(m,2H),3.07-2.94(m,1H),2.37(s,3H),2.13-2.06(m,1H),1.43(d,J＝5.5Hz,3H),1.21-1.14(m,2H),1.00-0.88(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ9.21 (s, 1H), 8.48 (d, J = 8.3Hz, 1H), 8.13 (t, J = 8.0Hz, 1H), 8.05-7.98 (m, 2H ), 7.66 (s, 1H), 7.50 (d, J = 10.7 Hz, 1H), 5.11-5.07 (m, 1H), 4.40-3.35 (m, 1H), 3.59-3.47 (m, 2H), 3.07- 2.94 (m, 1H), 2.37 (s, 3H), 2.13-2.06 (m, 1H), 1.43 (d, J = 5.5Hz, 3H), 1.21-1.14 (m, 2H), 1.00-0.88 (m, 2H);
MS m/z(ESI):458.2[M+H] +. MS m / z (ESI): 458.2 [M + H] + .
实施例35Example 35
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(6-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (6-methyl-6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000084
Figure PCTCN2019099971-appb-000084
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(6-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例8。(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (6-methyl-6,7-dihydro-5H -For the preparation method of pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide, refer to Example 8.
1H NMR(400MHz,CD 3OD)δ9.21(s,1H),8.48(d,J＝8.3Hz,1H),8.13(t,J＝8.0Hz,1H),8.05-7.98(m,2H),7.66(s,1H),7.50(d,J＝10.7Hz,1H),5.11-5.07(m,1H),4.40-3.35(m,1H),3.59-3.47(m,2H),3.07-2.94(m,1H),2.37(s,3H),2.13-2.06(m,1H),1.43(d,J＝5.5Hz,3H),1.21-1.14(m,2H),1.00-0.88(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ9.21 (s, 1H), 8.48 (d, J = 8.3Hz, 1H), 8.13 (t, J = 8.0Hz, 1H), 8.05-7.98 (m, 2H ), 7.66 (s, 1H), 7.50 (d, J = 10.7 Hz, 1H), 5.11-5.07 (m, 1H), 4.40-3.35 (m, 1H), 3.59-3.47 (m, 2H), 3.07- 2.94 (m, 1H), 2.37 (s, 3H), 2.13-2.06 (m, 1H), 1.43 (d, J = 5.5Hz, 3H), 1.21-1.14 (m, 2H), 1.00-0.88 (m, 2H);
MS m/z(ESI):458.2[M+H] +. MS m / z (ESI): 458.2 [M + H] + .
实施例36Example 36
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-((R)-5-((R)-1-甲氧基乙基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6-((R) -5-((R) -1-methoxyethyl) -6, 7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-appb-000085
Figure PCTCN2019099971-appb-000085
5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-((R)-5-((R)-1-甲氧基乙基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺的制备参照实施例8。5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6-((R) -5-((R) -1-methoxyethyl) -6, Refer to Example 8 for the preparation of 7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide.
1H NMR(400MHz,CDCl 3)δ8.96(d,J＝15.6Hz,1H),8.31(m,1H),8.01(m,2H),7.83(t,J＝8.0Hz,1H),7.41(s,1H),7.12(d,J＝12.6Hz,1H),6.73(s,1H),5.08(m,1H),4.03-3.92(m,1H),3.36(s,3H),2.96-2.87(m,2H),2.87-2.64(m,3H),2.21(s,3H),0.85-0.79(m,7H)； 1 H NMR (400 MHz, CDCl 3 ) δ 8.96 (d, J = 15.6 Hz, 1 H), 8.31 (m, 1 H), 8.01 (m, 2 H), 7.83 (t, J = 8.0 Hz, 1 H), 7.41 (s, 1H), 7.12 (d, J = 12.6Hz, 1H), 6.73 (s, 1H), 5.08 (m, 1H), 4.03-3.92 (m, 1H), 3.36 (s, 3H), 2.96- 2.87 (m, 2H), 2.87-2.64 (m, 3H), 2.21 (s, 3H), 0.85-0.79 (m, 7H);
MS m/z(ESI):502.2[M+H] +. MS m / z (ESI): 502.2 [M + H] + .
实施例37Example 37
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-乙烯基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-vinyl-6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000086
Figure PCTCN2019099971-appb-000086
(S)-5-乙烯基吡咯烷-2-酮的合成参见J.Org.Chem.,2017,82,532–540.For the synthesis of (S) -5-vinylpyrrolidin-2-one, see J. Org. Chem., 2017, 82, 532-540.
MS m/z(ESI):112.2[M+H] +. MS m / z (ESI): 112.2 [M + H] + .
第一步：(S)-5-甲氧基-2-乙烯基-3,4-二氢-2H-吡咯的合成Step 1: Synthesis of (S) -5-methoxy-2-vinyl-3,4-dihydro-2H-pyrrole
Figure PCTCN2019099971-appb-000087
Figure PCTCN2019099971-appb-000087
冰浴下，向(S)-5-乙烯基吡咯烷-2-酮(0.26g,2.34mmol)溶于二氯甲烷(60mL)中，分批加入三甲基氧鎓四氟硼酸(0.48g,3.28mmol)。反应缓慢升至室温，在此温度下搅拌5小时，然后加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，加入冰醋酸(5mL)，减压浓缩有机溶剂，得到粗品直接用于下一步反应。 In an ice bath, (S) -5-vinylpyrrolidin-2-one (0.26 g, 2.34 mmol) was dissolved in dichloromethane (60 mL), and trimethyloxonium tetrafluoroborate (0.48 g) was added in portions. , 3.28 mmol). The reaction was slowly raised to room temperature, stirred at this temperature for 5 hours, and then added saturated aqueous NaHCO 3 solution (5 mL), and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and added with ice. Acetic acid (5 mL), and the organic solvent was concentrated under reduced pressure to obtain a crude product, which was directly used in the next reaction.
MS m/z(ESI):126.1[M+H] +. MS m / z (ESI): 126.1 [M + H] + .
第二步：(S)-6-(5-乙烯基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺的合成Second step: (S) -6- (5-vinyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridine- Synthesis of 2-amine
Figure PCTCN2019099971-appb-000088
Figure PCTCN2019099971-appb-000088
室温下，将6-氨基甲基吡啶酰肼(321mg,2.11mmol)溶于2-戊醇(10mL)和乙酸(1mL)的混合溶剂中，加入(S)-5-甲氧基-2-乙烯基-3,4-二氢-2H-吡咯(293mg,2.34mmol)。反应加热至125℃，在此温度下搅拌12小时，冷却至室温后，减压浓缩有机溶剂，然后加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩有机溶剂后柱层析分离得标题化合物(S)-6-(5-乙烯基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺(240mg,两步产率50％)。 At room temperature, 6-aminomethylpyridinyl hydrazide (321 mg, 2.11 mmol) was dissolved in a mixed solvent of 2-pentanol (10 mL) and acetic acid (1 mL), and (S) -5-methoxy-2- Vinyl-3,4-dihydro-2H-pyrrole (293 mg, 2.34 mmol). The reaction was heated to 125 ° C and stirred at this temperature for 12 hours. After cooling to room temperature, the organic solvent was concentrated under reduced pressure, and then a saturated NaHCO 3 aqueous solution (5 mL) was added, and extracted with dichloromethane (50 mL × 2). The organic phase was saturated with common salt. Wash with water, dry over anhydrous sodium sulfate, and concentrate the organic solvent to isolate the title compound (S) -6- (5-vinyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-amine (240 mg, 50% yield in two steps).
MS m/z(ESI):228.1[M+H] +. MS m / z (ESI): 228.1 [M + H] + .
第三步：(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-乙烯基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的合成Third step: (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-vinyl-6,7- Synthesis of dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000089
Figure PCTCN2019099971-appb-000089
室温下，将(S)-6-(5-乙烯基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺(44mg,0.19mmol)加入5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酰氯(90mg,0.33mmol)的THF(5mL)和吡啶(5mL)溶液中，然后加入4-二甲氨基吡啶(5.9mg,0.048mmol)。将反应加热至45℃，并在该温度下搅拌2小时，然后滴加水(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩有机溶剂后柱层析得标题化合物(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-乙烯基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(53mg,产率58％)。(S) -6- (5-vinyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridine- 2-amine (44 mg, 0.19 mmol) was added to 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (90 mg, 0.33 mmol) in THF (5 mL) And pyridine (5 mL) solution, then 4-dimethylaminopyridine (5.9 mg, 0.048 mmol) was added. The reaction was heated to 45 ° C. and stirred at this temperature for 2 hours, and then water (5 mL) and dichloromethane (50 mL × 2) were added dropwise, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was concentrated Post-column chromatography gave the title compound (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-vinyl-6 , 7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide (53 mg, yield 58%).
1H NMR(400MHz,CD 3OD)δ9.08(s,1H),8.36(d,J＝8.4Hz,1H),8.02-7.97(m,1H),7.90-7.85(m,2H),7.50(s,1H),7.40-7.38(m,1H),6.00-5.95(m,2H),5.26-5.22(m,1H),5.16-5.13(m,1H),3.39-3.31(m,1H),3.24-3.20(m,2H),2.68-2.60(m,1H),2.22(s,3H),2.03-1.95(m,1H),1.07-1.02(m,2H),0.87-0.82(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 9.08 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.02-7.97 (m, 1H), 7.90-7.85 (m, 2H), 7.50 (s, 1H), 7.40-7.38 (m, 1H), 6.00-5.95 (m, 2H), 5.26-5.22 (m, 1H), 5.16-5.13 (m, 1H), 3.39-3.31 (m, 1H) , 3.24-3.20 (m, 2H), 2.68-2.60 (m, 1H), 2.22 (s, 3H), 2.03-1.95 (m, 1H), 1.07-1.02 (m, 2H), 0.87-0.82 (m, 2H);
MS m/z(ESI):470.1[M+H] +. MS m / z (ESI): 470.1 [M + H] + .
实施例38Example 38
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-乙烯基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-vinyl-6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000090
Figure PCTCN2019099971-appb-000090
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-乙烯基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备参照实施例37。5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-vinyl-6,7-dihydro-5H-pyrrolo [ Refer to Example 37 for the preparation of 2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide.
1H NMR(400MHz,CD 3OD)δ9.08(s,1H),8.36(d,J＝8.4Hz,1H),8.02-7.97(m,1H),7.90-7.85(m,2H),7.50(s,1H),7.40-7.38(m,1H),6.00-5.95(m,2H),5.26-5.22(m,1H),5.16-5.13(m,1H),3.39-3.31(m,1H),3.24-3.20(m,2H),2.68-2.60(m,1H),2.22(s,3H),2.03-1.95(m,1H),1.07-1.02(m,2H),0.87-0.82(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 9.08 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.02-7.97 (m, 1H), 7.90-7.85 (m, 2H), 7.50 (s, 1H), 7.40-7.38 (m, 1H), 6.00-5.95 (m, 2H), 5.26-5.22 (m, 1H), 5.16-5.13 (m, 1H), 3.39-3.31 (m, 1H) , 3.24-3.20 (m, 2H), 2.68-2.60 (m, 1H), 2.22 (s, 3H), 2.03-1.95 (m, 1H), 1.07-1.02 (m, 2H), 0.87-0.82 (m, 2H);
MS m/z(ESI):470.1[M+H] +. MS m / z (ESI): 470.1 [M + H] + .
实施例39Example 39
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-乙烯基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-vinyl-6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000091
Figure PCTCN2019099971-appb-000091
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-乙烯基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备参照实施例37。(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-vinyl-6,7-dihydro-5H -Preparation of pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide Refer to Example 37.
1H NMR(400MHz,CD 3OD)δ9.08(s,1H),8.36(d,J＝8.4Hz,1H),8.02-7.97(m,1H),7.90-7.85(m,2H),7.50(s,1H),7.40-7.38(m,1H),6.00-5.95(m,2H),5.26-5.22(m,1H),5.16-5.13(m,1H),3.39-3.31(m,1H),3.24-3.20(m,2H),2.68-2.60(m,1H),2.22(s,3H),2.03-1.95(m,1H),1.07-1.02(m,2H),0.87-0.82(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 9.08 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.02-7.97 (m, 1H), 7.90-7.85 (m, 2H), 7.50 (s, 1H), 7.40-7.38 (m, 1H), 6.00-5.95 (m, 2H), 5.26-5.22 (m, 1H), 5.16-5.13 (m, 1H), 3.39-3.31 (m, 1H) , 3.24-3.20 (m, 2H), 2.68-2.60 (m, 1H), 2.22 (s, 3H), 2.03-1.95 (m, 1H), 1.07-1.02 (m, 2H), 0.87-0.82 (m, 2H);
MS m/z(ESI):470.1[M+H] +. MS m / z (ESI): 470.1 [M + H] + .
实施例40Example 40
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-(三氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5- (trifluoromethyl) -6,7- Dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000092
Figure PCTCN2019099971-appb-000092
第一步：(S)-5-甲氧基-2-(三氟甲基)-3,4-二氢-2H-吡咯的合成Step 1: Synthesis of (S) -5-methoxy-2- (trifluoromethyl) -3,4-dihydro-2H-pyrrole
Figure PCTCN2019099971-appb-000093
Figure PCTCN2019099971-appb-000093
冰浴下，将(S)-5-(三氟甲基)吡咯烷-2-酮(0.6g,3.92mmol)溶于二氯甲烷(40mL)溶液中，分批加入三甲基氧鎓四氟硼酸(0.81g,5.5mmol)。反应缓慢升至室温，在此温度下搅拌5小时，然后加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，加入冰醋酸(5mL)，减压浓缩有机溶剂，得到粗品直接用于下一步反应。 In an ice bath, (S) -5- (trifluoromethyl) pyrrolidin-2-one (0.6 g, 3.92 mmol) was dissolved in a solution of dichloromethane (40 mL), and trimethyloxonium tetrachloride was added in portions. Fluoroboric acid (0.81 g, 5.5 mmol). The reaction was slowly raised to room temperature, stirred at this temperature for 5 hours, and then added saturated aqueous NaHCO 3 solution (5 mL), and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and added with ice. Acetic acid (5 mL), and the organic solvent was concentrated under reduced pressure to obtain a crude product, which was directly used in the next reaction.
MS m/z(ESI):168.2[M+H] +. MS m / z (ESI): 168.2 [M + H] + .
第二步：(S)-6-(5-(三氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺的合成Second step: (S) -6- (5- (trifluoromethyl) -6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazole-3- Of Pyridyl) -2-amine
Figure PCTCN2019099971-appb-000094
Figure PCTCN2019099971-appb-000094
室温下，将6-氨基甲基吡啶酰肼(620mg,3.71mmol)溶于2-戊醇(15mL)和乙酸(1mL)中，加入(S)-5-甲氧基-2-(三氟甲基)-3,4-二氢-2H-吡咯(650mg，3.89mmol)。反应加热至125℃，在此温度下搅拌12小时，冷却至室温后,减压浓缩。然后加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩有机溶剂后柱层析分离得标题化 合物(S)-6-(5-(三氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺(560mg,两步产率56％)。 At room temperature, 6-aminomethylpyridylhydrazide (620 mg, 3.71 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (1 mL), and (S) -5-methoxy-2- (trifluoro (Methyl) -3,4-dihydro-2H-pyrrole (650 mg, 3.89 mmol). The reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL × 2) was extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was concentrated to isolate the title compound (S) -6. -(5- (trifluoromethyl) -6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-amine (560mg , 56% yield in two steps).
MS m/z(ESI):270.2[M+H] +. MS m / z (ESI): 270.2 [M + H] + .
第三步：(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-(三氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的合成Third step: (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5- (trifluoromethyl)- Synthesis of 6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000095
Figure PCTCN2019099971-appb-000095
室温下，将(S)-6-(5-(三氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺(43mg,0.22mmol)加入5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酰氯(100mg,0.36mmol)的THF(5mL)和吡啶(5mL)溶液中，然后加入4-二甲氨基吡啶(11mg,0.09mmol)。将反应加热至45℃，并在该温度下搅拌2小时，然后加入水(5mL)淬灭反应,二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩有机溶剂后柱层析分离得标题化合物(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-(三氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(51mg,产率62％)。(S) -6- (5- (trifluoromethyl) -6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazole-3- Pyridyl-2-amine (43 mg, 0.22 mmol) was added to 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (100 mg, 0.36 mmol). To a solution of THF (5 mL) and pyridine (5 mL), then 4-dimethylaminopyridine (11 mg, 0.09 mmol) was added. The reaction was heated to 45 ° C and stirred at this temperature for 2 hours, and then the reaction was quenched by adding water (5 mL), and extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. After concentrating the organic solvent, the title compound (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5- (Trifluoromethyl) -6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide (51 mg, Yield: 62%).
1H NMR(400MHz,CDCl 3)δ8.99(d,J＝15.6Hz,1H),8.32-8.30(m,1H),8.01-7.98(m,2H),7.83(t,J＝8.0Hz,1H),7.53(s,1H),7.12(d,J＝13.6Hz,1H),6.74(s,1H),5.56-5.51(m,1H),3.21-3.01(m,3H),2.92-2.85(m,1H),2.21(s,3H),1.89-1.82(m,1H),0.89-0.81(m,4H)； 1 H NMR (400 MHz, CDCl 3 ) δ 8.99 (d, J = 15.6 Hz, 1 H), 8.32-8.30 (m, 1H), 8.01-7.98 (m, 2H), 7.83 (t, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.12 (d, J = 13.6Hz, 1H), 6.74 (s, 1H), 5.56-5.51 (m, 1H), 3.21-3.01 (m, 3H), 2.92-2.85 (m, 1H), 2.21 (s, 3H), 1.89-1.82 (m, 1H), 0.89-0.81 (m, 4H);
MS m/z(ESI):512.2[M+H] +. MS m / z (ESI): 512.2 [M + H] + .
实施例41Example 41
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-(三氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5- (trifluoromethyl) -6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000096
Figure PCTCN2019099971-appb-000096
5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-(三氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备参照实施例40。5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5- (trifluoromethyl) -6,7-dihydro-5H -Preparation of pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide Refer to Example 40.
1H NMR(400MHz,CDCl 3)δ8.99(d,J＝15.6Hz,1H),8.32-8.30(m,1H),8.01-7.98(m,2H),7.83(t,J＝8.0Hz,1H),7.53(s,1H),7.12(d,J＝13.6Hz,1H),6.74(s,1H),5.56-5.51(m,1H),3.21-3.01(m,3H),2.92-2.85(m,1H),2.21(s,3H),1.89-1.82(m,1H),0.89-0.81(m,4H)； 1 H NMR (400 MHz, CDCl 3 ) δ 8.99 (d, J = 15.6 Hz, 1 H), 8.32-8.30 (m, 1H), 8.01-7.98 (m, 2H), 7.83 (t, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.12 (d, J = 13.6Hz, 1H), 6.74 (s, 1H), 5.56-5.51 (m, 1H), 3.21-3.01 (m, 3H), 2.92-2.85 (m, 1H), 2.21 (s, 3H), 1.89-1.82 (m, 1H), 0.89-0.81 (m, 4H);
MS m/z(ESI):512.2[M+H] +. MS m / z (ESI): 512.2 [M + H] + .
实施例42Example 42
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-(三氟甲基)-6,7-二氢-5H-吡咯 并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5- (trifluoromethyl) -6,7- Dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000097
Figure PCTCN2019099971-appb-000097
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-(三氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备参照实施例40。(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5- (trifluoromethyl) -6,7- Refer to Example 40 for the preparation of dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide.
1H NMR(400MHz,CDCl 3)δ8.99(d,J＝15.6Hz,1H),8.32-8.30(m,1H),8.01-7.98(m,2H),7.83(t,J＝8.0Hz,1H),7.53(s,1H),7.12(d,J＝13.6Hz,1H),6.74(s,1H),5.56-5.51(m,1H),3.21-3.01(m,3H),2.92-2.85(m,1H),2.21(s,3H),1.89-1.82(m,1H),0.89-0.81(m,4H)； 1 H NMR (400 MHz, CDCl 3 ) δ 8.99 (d, J = 15.6 Hz, 1 H), 8.32-8.30 (m, 1H), 8.01-7.98 (m, 2H), 7.83 (t, J = 8.0 Hz, 1H), 7.53 (s, 1H), 7.12 (d, J = 13.6Hz, 1H), 6.74 (s, 1H), 5.56-5.51 (m, 1H), 3.21-3.01 (m, 3H), 2.92-2.85 (m, 1H), 2.21 (s, 3H), 1.89-1.82 (m, 1H), 0.89-0.81 (m, 4H);
MS m/z(ESI):512.2[M+H] +. MS m / z (ESI): 512.2 [M + H] + .
实施例43Example 43
(S)-5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-乙炔基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethynyl-6,7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000098
Figure PCTCN2019099971-appb-000098
叔-丁基(S)-2-甲酰基-5-羰基吡咯烷-1-羧酸酯的合成参见Org.Lett.2011,13,2634-2637For the synthesis of tert-butyl (S) -2-formyl-5-carbonylpyrrolidine-1-carboxylic acid ester, see Org. Lett. 2011, 13, 2634-2637
第一步：S-乙基(S)-5-羰基吡咯烷-2-甲硫酸酯的合成Step 1: Synthesis of S-ethyl (S) -5-carbonylpyrrolidine-2-methylsulfate
Figure PCTCN2019099971-appb-000099
Figure PCTCN2019099971-appb-000099
冰浴下，将(S)-5-羰基吡咯烷-2-羧酸(20g,150mmol)溶于CH 2Cl 2(300mL)和DMF(160mL)中，然后依次加入DMAP(1.85g,15.0mmol)及乙硫醇(13.8mL,180mmol)，DCC(40.5g,180mmol)。反应缓慢升至室温，在此温度下搅拌16小时，加入饱和NaHCO 3水溶液(20mL)，二氯甲烷(100mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后柱层析得标题化合物S-乙基(S)-5-羰基吡咯烷-2-甲硫酸酯(18.5g,69％)。 Under an ice bath, (S) -5-carbonylpyrrolidine-2-carboxylic acid (20 g, 150 mmol) was dissolved in CH 2 Cl 2 (300 mL) and DMF (160 mL), and then DMAP (1.85 g, 15.0 mmol) was added in this order. ) And ethyl mercaptan (13.8 mL, 180 mmol), DCC (40.5 g, 180 mmol). The reaction was slowly raised to room temperature, and stirred at this temperature for 16 hours. A saturated NaHCO 3 aqueous solution (20 mL) was added, and extracted with dichloromethane (100 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Post-column chromatography gave the title compound S-ethyl (S) -5-carbonylpyrrolidine-2-methyl sulfate (18.5 g, 69%).
MS m/z(ESI):174.1[M+H] +. MS m / z (ESI): 174.1 [M + H] + .
第二步：叔-丁基(S)-2-((乙硫基)羰基)-5-羰基吡咯烷-1-羧酸酯的合成Step 2: Synthesis of tert-butyl (S) -2-((ethylthio) carbonyl) -5-carbonylpyrrolidine-1-carboxylic acid ester
Figure PCTCN2019099971-appb-000100
Figure PCTCN2019099971-appb-000100
冰浴下，将S-乙基(S)-5-羰基吡咯烷-2-甲硫酸酯(6g,34.6mmol)溶于MeCN(35mL)中，然后依次加入Boc 2O(8.28mL,35.0mmol)，DMAP(470mg,3.46mmol)。反应缓慢升至室温，在此温度下搅拌2小时，加入饱和NaHCO 3水 溶液(20mL)，乙酸乙酯(100mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后柱层析分离得标题化合物S-乙基(S)-5-羰基吡咯烷-2-甲硫酸酯(7.3g,77％)。 In an ice bath, S-ethyl (S) -5-carbonylpyrrolidine-2-methylsulfate (6g, 34.6mmol) was dissolved in MeCN (35mL), and then Boc 2 O (8.28mL, 35.0mmol) was added sequentially. ), DMAP (470 mg, 3.46 mmol). The reaction was slowly raised to room temperature, and stirred at this temperature for 2 hours. A saturated NaHCO 3 aqueous solution (20 mL) was added, followed by extraction with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Post-column chromatography gave the title compound S-ethyl (S) -5-carbonylpyrrolidine-2-methyl sulfate (7.3 g, 77%).
MS m/z(ESI):296.1[M+Na] +. MS m / z (ESI): 296.1 [M + Na] + .
第三步：叔-丁基(S)-2-甲酰基-5-羰基吡咯烷-1-羧酸酯的合成Step 3: Synthesis of tert-butyl (S) -2-formyl-5-carbonylpyrrolidine-1-carboxylic acid ester
Figure PCTCN2019099971-appb-000101
Figure PCTCN2019099971-appb-000101
冰浴下，将S-乙基(S)-5-羰基吡咯烷-2-甲硫酸酯(1.0g,3.66mmol)溶于丙酮(15mL)中，然后依次加入Pd/C(160mg)，EtSiH(1.28g,10.98mmol)。反应缓慢升至室温，在此温度下搅拌1小时后，硅藻土过滤，滤液减压浓缩后得到油状产品(0.72g)直接用于下一步。In an ice bath, S-ethyl (S) -5-carbonylpyrrolidine-2-methylsulfate (1.0g, 3.66mmol) was dissolved in acetone (15mL), and then Pd / C (160mg), EtSiH (1.28 g, 10.98 mmol). The reaction was slowly raised to room temperature. After stirring at this temperature for 1 hour, the celite was filtered, and the filtrate was concentrated under reduced pressure to obtain an oily product (0.72 g), which was directly used in the next step.
1H NMR(400MHz,CDCl 3)δ9.58(s,1H),4.63-4.41(m,1H),2.54-2.48(m,2H),2.28-2.15(m,1H),2.07-2.01(m,1H),1.46(s,9H)； 1 H NMR (400MHz, CDCl 3 ) δ9.58 (s, 1H), 4.63-4.41 (m, 1H), 2.54-2.48 (m, 2H), 2.28-2.15 (m, 1H), 2.07-2.01 (m , 1H), 1.46 (s, 9H);
MS m/z(ESI):214.1[M+H] +. MS m / z (ESI): 214.1 [M + H] + .
第四步：(S)-5-羰基吡咯烷-2-甲醛的合成Step 4: Synthesis of (S) -5-carbonylpyrrolidine-2-carboxaldehyde
Figure PCTCN2019099971-appb-000102
Figure PCTCN2019099971-appb-000102
冰浴下，将叔-丁基(S)-2-甲酰基-5-羰基吡咯烷-1-羧酸酯(0.72g,3.38mmol)溶于CH 2Cl 2(10mL)中，然后依次加入TFA(2.5mL)。反应缓慢升至室温，在此温度下搅拌2小时后，减压浓缩后得到油状粗产品(400mg)直接用于下一步。 In an ice bath, t-butyl (S) -2-formyl-5-carbonylpyrrolidine-1-carboxylic acid ester (0.72 g, 3.38 mmol) was dissolved in CH 2 Cl 2 (10 mL), and then sequentially added TFA (2.5 mL). The reaction was slowly raised to room temperature, and after stirring at this temperature for 2 hours, the crude product (400 mg) was obtained after concentration under reduced pressure and used directly in the next step.
MS m/z(ESI):114.1[M+H] +. MS m / z (ESI): 114.1 [M + H] + .
第五步：(S)-5-乙炔基吡咯烷-2-酮的合成Step 5: Synthesis of (S) -5-ethynylpyrrolidin-2-one
Figure PCTCN2019099971-appb-000103
Figure PCTCN2019099971-appb-000103
冰浴下，将(S)-5-羰基吡咯烷-2-甲醛(400mg,上步粗产品)溶于MeOH(15mL)中，然后依次加入K 2CO 3(931mg,6.74mmol)，(1-重氮基-2-氧代丙基)膦酸二甲酯(1.01g,4.04mmol)。反应缓慢升至室温，在此温度下搅拌12小时，加入饱和食盐水(20mL)，用CH 2Cl 2(100mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后柱层析分离得标题化合物(S)-5-乙炔基吡咯烷-2-酮(260mg,71％)。 Under an ice bath, (S) -5-carbonylpyrrolidine-2-carboxaldehyde (400 mg, crude product from the previous step) was dissolved in MeOH (15 mL), and then K 2 CO 3 (931 mg, 6.74 mmol) was added in sequence, (1 -Dimethyl diazo-2-oxopropyl) phosphonate (1.01 g, 4.04 mmol). The reaction slowly rose to room temperature, stirred at this temperature for 12 hours, added saturated brine (20 mL), and extracted with CH 2 Cl 2 (100 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and decompressed. After concentration, the title compound (S) -5-ethynylpyrrolidin-2-one (260 mg, 71%) was isolated by column chromatography.
1H NMR(400MHz,CDCl 3)δ6.68(s,1H),4.38-4.35(m,1H),2.50-2.40(m,2H),2.37(d,J＝2.2Hz,1H),2.33-2.26(m,1H),2.22-2.15(m,1H)； 1 H NMR (400MHz, CDCl 3 ) δ6.68 (s, 1H), 4.38-4.35 (m, 1H), 2.50-2.40 (m, 2H), 2.37 (d, J = 2.2Hz, 1H), 2.33 2.26 (m, 1H), 2.22-2.15 (m, 1H);
MS m/z(ESI):110.1[M+H] +. MS m / z (ESI): 110.1 [M + H] + .
第六步：(S)-2-乙炔基-5-甲氧基-3,4-二氢-2H-吡咯的合成Step 6: Synthesis of (S) -2-ethynyl-5-methoxy-3,4-dihydro-2H-pyrrole
Figure PCTCN2019099971-appb-000104
Figure PCTCN2019099971-appb-000104
冰浴下，将(S)-5-乙炔基吡咯烷-2-酮(0.26g,2.38mmol)溶于CH 2Cl 2(10mL)溶液中，分批加入三甲基氧鎓四氟硼酸(0.67g,4.53mmol)。反应缓慢升至室温，在此温度下搅拌5小时，然后加入饱和NaHCO 3水溶液(5mL)，用CH 2Cl 2(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，加入冰醋酸(5mL)，减压浓缩有机溶剂，得到粗品(315mg)直接用于下一步反应。 Under an ice bath, (S) -5-ethynylpyrrolidin-2-one (0.26 g, 2.38 mmol) was dissolved in a solution of CH 2 Cl 2 (10 mL), and trimethyloxonium tetrafluoroborate ( 0.67 g, 4.53 mmol). The reaction was slowly raised to room temperature, stirred at this temperature for 5 hours, and then a saturated aqueous NaHCO 3 solution (5 mL) was added, and extracted with CH 2 Cl 2 (50 mL × 2). The organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. Glacial acetic acid (5 mL) was added, and the organic solvent was concentrated under reduced pressure to obtain a crude product (315 mg), which was directly used in the next reaction.
MS m/z(ESI):124.2[M+H] +. MS m / z (ESI): 124.2 [M + H] + .
第七步：(S)-6-(5-乙炔基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺的合成Seventh step: (S) -6- (5-ethynyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridine- Synthesis of 2-amine
Figure PCTCN2019099971-appb-000105
Figure PCTCN2019099971-appb-000105
室温下，将6-氨基甲基吡啶酰肼(320mg,2.1mmol)溶于2-戊醇(15mL)和乙酸(1mL)中，加入(S)-2-乙炔基-5-甲氧基-3,4-二氢-2H-吡咯(315mg,上步粗产品)。反应加热至125℃，在此温度下搅拌12小时，冷却至室温后,减压浓缩。然后加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩有机溶剂后柱层析分离得标题化合物(S)-6-(5-乙炔基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺(362mg,两步产率46％)。 At room temperature, 6-aminomethylpyridyl hydrazide (320 mg, 2.1 mmol) was dissolved in 2-pentanol (15 mL) and acetic acid (1 mL), and (S) -2-ethynyl-5-methoxy- 3,4-dihydro-2H-pyrrole (315 mg, crude product from previous step). The reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL × 2) was extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was concentrated to isolate the title compound (S) -6. -(5-Ethynyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-amine (362 mg, produced in two steps Rate 46%).
MS m/z(ESI):226.2[M+H] +. MS m / z (ESI): 226.2 [M + H] + .
第八步：(S)-5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-乙炔基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺的合成The eighth step: (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethynyl-6,7-dihydro-5H-pyrrolo [2 Synthesis of 1,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000106
Figure PCTCN2019099971-appb-000106
室温下，(S)-6-(5-乙炔基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺(80mg,0.36mmol)加入5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酰氯(220mg,0.79mmol)的THF(25mL)和吡啶(35mL)溶液中，然后加入4-二甲氨基吡啶(15mg,0.12mmol)。将反应加热至45℃，并在该温度下搅拌2小时，然后加入水(5mL)淬灭反应，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩有机溶剂后柱层析分离得标题化合物(S)-5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-乙炔基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺(122mg,产率73％)。(S) -6- (5-ethynyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridine-2 at room temperature -Amine (80 mg, 0.36 mmol) was added 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (220 mg, 0.79 mmol) in THF (25 mL) and Pyridine (35 mL) solution, then 4-dimethylaminopyridine (15 mg, 0.12 mmol) was added. The reaction was heated to 45 ° C and stirred at this temperature for 2 hours, and then the reaction was quenched by adding water (5 mL), and extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. After concentrating the organic solvent, the title compound (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethynyl-6,7-dihydro) was separated by column chromatography. -5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide (122 mg, yield 73% ).
1H NMR(400MHz,CDCl 3)δ9.09(d,J＝15.0Hz,1H),8.42-8.28(m,1H), 8.08-7.94(m,2H),7.81(t,J＝7.0Hz,1H),7.49(s,1H),7.14(d,J＝12.6Hz,1H),6.74(s,1H),5.49-5.47(m,1H),3.16-3.10(m,2H),3.0-2.95(m,1H),2.93-2.80(m,1H),2.34(d,J＝2.4Hz,1H),2.22(s,3H),1.91-1.77(m,1H),0.87-0.83(m,2H),0.79-0.77(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 9.09 (d, J = 15.0 Hz, 1 H), 8.42-8.28 (m, 1H), 8.08-7.94 (m, 2H), 7.81 (t, J = 7.0 Hz, 1H), 7.49 (s, 1H), 7.14 (d, J = 12.6Hz, 1H), 6.74 (s, 1H), 5.49-5.47 (m, 1H), 3.16-3.10 (m, 2H), 3.0-2.95 (m, 1H), 2.93-2.80 (m, 1H), 2.34 (d, J = 2.4Hz, 1H), 2.22 (s, 3H), 1.91-1.77 (m, 1H), 0.87-0.83 (m, 2H ), 0.79-0.77 (m, 2H);
MS m/z(ESI):468.2[M+H] +. MS m / z (ESI): 468.2 [M + H] + .
实施例44Example 44
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-乙炔基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethynyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1, 2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000107
Figure PCTCN2019099971-appb-000107
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-乙炔基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺参照实施例43。5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethynyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1, 2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide Refer to Example 43.
1H NMR(400MHz,CDCl 3)δ9.09(d,J＝15.0Hz,1H),8.42-8.28(m,1H),8.08-7.94(m,2H),7.81(t,J＝7.0Hz,1H),7.49(s,1H),7.14(d,J＝12.6Hz,1H),6.74(s,1H),5.49-5.47(m,1H),3.16-3.10(m,2H),3.0-2.95(m,1H),2.93-2.80(m,1H),2.34(d,J＝2.4Hz,1H),2.22(s,3H),1.91-1.77(m,1H),0.87-0.83(m,2H),0.79-0.77(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 9.09 (d, J = 15.0 Hz, 1 H), 8.42-8.28 (m, 1H), 8.08-7.94 (m, 2H), 7.81 (t, J = 7.0 Hz, 1H), 7.49 (s, 1H), 7.14 (d, J = 12.6Hz, 1H), 6.74 (s, 1H), 5.49-5.47 (m, 1H), 3.16-3.10 (m, 2H), 3.0-2.95 (m, 1H), 2.93-2.80 (m, 1H), 2.34 (d, J = 2.4Hz, 1H), 2.22 (s, 3H), 1.91-1.77 (m, 1H), 0.87-0.83 (m, 2H ), 0.79-0.77 (m, 2H);
MS m/z(ESI):468.2[M+H] +. MS m / z (ESI): 468.2 [M + H] + .
实施例45Example 45
(R)-5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-乙炔基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethynyl-6,7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000108
Figure PCTCN2019099971-appb-000108
(R)-5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-乙炔基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺参照实施例43。(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethynyl-6,7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide Refer to Example 43.
1H NMR(400MHz,CDCl 3)δ9.09(d,J＝15.0Hz,1H),8.42-8.28(m,1H),8.08-7.94(m,2H),7.81(t,J＝7.0Hz,1H),7.49(s,1H),7.14(d,J＝12.6Hz,1H),6.74(s,1H),5.49-5.47(m,1H),3.16-3.10(m,2H),3.0-2.95(m,1H),2.93-2.80(m,1H),2.34(d,J＝2.4Hz,1H),2.22(s,3H),1.91-1.77(m,1H),0.87-0.83(m,2H),0.79-0.77(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 9.09 (d, J = 15.0 Hz, 1 H), 8.42-8.28 (m, 1H), 8.08-7.94 (m, 2H), 7.81 (t, J = 7.0 Hz, 1H), 7.49 (s, 1H), 7.14 (d, J = 12.6Hz, 1H), 6.74 (s, 1H), 5.49-5.47 (m, 1H), 3.16-3.10 (m, 2H), 3.0-2.95 (m, 1H), 2.93-2.80 (m, 1H), 2.34 (d, J = 2.4Hz, 1H), 2.22 (s, 3H), 1.91-1.77 (m, 1H), 0.87-0.83 (m, 2H ), 0.79-0.77 (m, 2H);
MS m/z(ESI):468.2[M+H] +. MS m / z (ESI): 468.2 [M + H] + .
实施例46Example 46
(S)-N-(6-(5-氰基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯酰胺(S) -N- (6- (5-cyano-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridine-2 -Yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000109
Figure PCTCN2019099971-appb-000109
(S)-N-(6-(5-氰基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯酰胺的制备方法参照实施例8。(S) -N- (6- (5-cyano-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridine-2 The method for preparing -yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide is described in Example 8.
1H NMR(400MHz,CD 3OD)δ9.06(s,1H),8.30(d,J＝8.2Hz,1H),7.99(t,J＝7.9Hz,1H),7.95-7.89(m,2H),7.52(s,1H),7.39(d,J＝10.8Hz,1H),6.17-6.06(m,1H),3.43-3.34(m,2H),3.17-3.08(m,2H),2.25(s,3H),2.00-1.95(m,1H),1.08-1.02(m,2H),0.85-0.79(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 9.06 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.95-7.89 (m, 2H ), 7.52 (s, 1H), 7.39 (d, J = 10.8 Hz, 1H), 6.17-6.06 (m, 1H), 3.43-3.34 (m, 2H), 3.17-3.08 (m, 2H), 2.25 ( s, 3H), 2.00-1.95 (m, 1H), 1.08-1.02 (m, 2H), 0.85-0.79 (m, 2H);
MS m/z(ESI):469.1[M+H] +. MS m / z (ESI): 469.1 [M + H] + .
实施例47Example 47
(R)-N-(6-(5-氰基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯酰胺(R) -N- (6- (5-cyano-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridine-2 -Yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000110
Figure PCTCN2019099971-appb-000110
(R)-N-(6-(5-氰基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯酰胺的制备方法参照实施例8。(R) -N- (6- (5-cyano-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridine-2 The method for preparing -yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide is described in Example 8.
1H NMR(400MHz,CD 3OD)δ9.06(s,1H),8.30(d,J＝8.2Hz,1H),7.99(t,J＝7.9Hz,1H),7.95-7.89(m,2H),7.52(s,1H),7.39(d,J＝10.8Hz,1H),6.17-6.06(m,1H),3.43-3.34(m,2H),3.17-3.08(m,2H),2.25(s,3H),2.00-1.95(m,1H),1.08-1.02(m,2H),0.85-0.79(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ 9.06 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.99 (t, J = 7.9 Hz, 1H), 7.95-7.89 (m, 2H ), 7.52 (s, 1H), 7.39 (d, J = 10.8 Hz, 1H), 6.17-6.06 (m, 1H), 3.43-3.34 (m, 2H), 3.17-3.08 (m, 2H), 2.25 ( s, 3H), 2.00-1.95 (m, 1H), 1.08-1.02 (m, 2H), 0.85-0.79 (m, 2H);
MS m/z(ESI):469.1[M+H] +. MS m / z (ESI): 469.1 [M + H] + .
实施例48Example 48
(S)-N-(6-(5-(氰基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯酰胺(S) -N- (6- (5- (cyanomethyl) -6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl ) Pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000111
Figure PCTCN2019099971-appb-000111
(S)-N-(6-(5-(氰基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯酰胺的制备方法参照实施例8。(S) -N- (6- (5- (cyanomethyl) -6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl ) Pyridine-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide is prepared by referring to Example 8.
1H NMR(400MHz,CD 3OD)δ9.19(s,1H),8.39(d,J＝8.1Hz,1H),8.15(t,J＝7.8Hz,1H),8.11-8.07(m,1H),8.06-7.99(m,1H),7.64(s,1H),7.50(d,J＝10.6 Hz,1H),5.80(s,1H),3.65-3.53(m,1H),3.49-3.38(m,4H),3.03-2.92(m,1H),2.36(s,3H),2.15-2.07(m,1H),1.22-1.11(m,2H),0.98-0.91(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ9.19 (s, 1H), 8.39 (d, J = 8.1Hz, 1H), 8.15 (t, J = 7.8Hz, 1H), 8.11-8.07 (m, 1H ), 8.06-7.99 (m, 1H), 7.64 (s, 1H), 7.50 (d, J = 10.6 Hz, 1H), 5.80 (s, 1H), 3.65-3.53 (m, 1H), 3.49-3.38 ( m, 4H), 3.03-2.92 (m, 1H), 2.36 (s, 3H), 2.15-2.07 (m, 1H), 1.22-1.11 (m, 2H), 0.98-0.91 (m, 2H);
MS m/z(ESI):483.2[M+H] +. MS m / z (ESI): 483.2 [M + H] + .
实施例49Example 49
(S)-N-(6-(5-(氰基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯酰胺(S) -N- (6- (5- (cyanomethyl) -6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl ) Pyridin-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000112
Figure PCTCN2019099971-appb-000112
(R)-N-(6-(5-(氰基甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯酰胺的制备方法参照实施例8。(R) -N- (6- (5- (cyanomethyl) -6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl ) Pyridine-2-yl) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzamide is prepared by referring to Example 8.
1H NMR(400MHz,CD 3OD)δ9.19(s,1H),8.39(d,J＝8.1Hz,1H),8.15(t,J＝7.8Hz,1H),8.11-8.07(m,1H),8.06-7.99(m,1H),7.64(s,1H),7.50(d,J＝10.6Hz,1H),5.80(s,1H),3.65-3.53(m,1H),3.49-3.38(m,4H),3.03-2.92(m,1H),2.36(s,3H),2.15-2.07(m,1H),1.22-1.11(m,2H),0.98-0.91(m,2H)； 1 H NMR (400MHz, CD 3 OD) δ9.19 (s, 1H), 8.39 (d, J = 8.1Hz, 1H), 8.15 (t, J = 7.8Hz, 1H), 8.11-8.07 (m, 1H ), 8.06-7.99 (m, 1H), 7.64 (s, 1H), 7.50 (d, J = 10.6Hz, 1H), 5.80 (s, 1H), 3.65-3.53 (m, 1H), 3.49-3.38 ( m, 4H), 3.03-2.92 (m, 1H), 2.36 (s, 3H), 2.15-2.07 (m, 1H), 1.22-1.11 (m, 2H), 0.98-0.91 (m, 2H);
MS m/z(ESI):483.2[M+H] +. MS m / z (ESI): 483.2 [M + H] + .
实施例50Example 50
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-(羟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺(S) -5- (4-Cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (hydroxymethyl) -6,7-dihydro-5H-pyrrole Benzo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-appb-000113
Figure PCTCN2019099971-appb-000113
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-(羟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺的制备参照实施例8。(S) -5- (4-Cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (hydroxymethyl) -6,7-dihydro-5H-pyrrole Refer to Example 8 for the preparation of [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide.
1H NMR(400MHz,CDCl 3)δ9.06(d,J＝15.6Hz,1H),8.28-8.16(m,1H),8.04(d,J＝7.2Hz,1H),7.79-7.65(m,2H),7.42(t,J＝4.0Hz,1H),7.19(d,J＝12.2Hz,1H),6.79(s,1H),4.97-4.83(m,1H),4.47(m,1H),4.05-3.87(m,1H),3.30-3.15(m,1H),3.00-2.75(m,3H),2.29(s,3H),1.94-1.75(m,2H),0.94-0.86(m,2H),0.86-0.70(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 9.06 (d, J = 15.6 Hz, 1 H), 8.28-8.16 (m, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.79-7.65 (m, 2H), 7.42 (t, J = 4.0 Hz, 1H), 7.19 (d, J = 12.2 Hz, 1H), 6.79 (s, 1H), 4.97-4.83 (m, 1H), 4.47 (m, 1H), 4.05-3.87 (m, 1H), 3.30-3.15 (m, 1H), 3.00-2.75 (m, 3H), 2.29 (s, 3H), 1.94-1.75 (m, 2H), 0.94-0.86 (m, 2H ), 0.86-0.70 (m, 2H);
MS m/z(ESI):474.1[M+H] +. MS m / z (ESI): 474.1 [M + H] + .
实施例51Example 51
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-(氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (fluoromethyl) -6,7-dihydro-5H-pyrrole Benzo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-appb-000114
Figure PCTCN2019099971-appb-000114
第一步:(S)-2-(氟甲基)-5-甲氧基-3,4-二氢-2H-吡咯的合成Step 1: Synthesis of (S) -2- (fluoromethyl) -5-methoxy-3,4-dihydro-2H-pyrrole
Figure PCTCN2019099971-appb-000115
Figure PCTCN2019099971-appb-000115
冰浴下，向(S)-5-(氟甲基)吡咯烷-2-酮(0.7g,6.0mmol)溶于二氯甲烷(60mL)中，分批加入三甲基氧鎓四氟硼酸(1.24g,8.4mmol)。反应缓慢升至室温，在此温度下搅拌5小时，然后加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，加入冰醋酸(5mL)，减压浓缩有机溶剂，得到粗品直接用于下一步反应。 In an ice bath, (S) -5- (fluoromethyl) pyrrolidin-2-one (0.7 g, 6.0 mmol) was dissolved in dichloromethane (60 mL), and trimethyloxonium tetrafluoroborate was added in portions. (1.24 g, 8.4 mmol). The reaction was slowly raised to room temperature, stirred at this temperature for 5 hours, and then added saturated aqueous NaHCO 3 solution (5 mL), and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and added with ice. Acetic acid (5 mL), and the organic solvent was concentrated under reduced pressure to obtain a crude product, which was directly used in the next reaction.
MS m/z(ESI):132.2[M+H] +. MS m / z (ESI): 132.2 [M + H] + .
第二步:(S)-6-(5-(氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺的合成Step 2: (S) -6- (5- (fluoromethyl) -6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl ) Synthesis of pyridin-2-amine
Figure PCTCN2019099971-appb-000116
Figure PCTCN2019099971-appb-000116
室温下，将6-氨基甲基吡啶酰肼(900mg,6.0mmol)溶于2-戊醇(15mL)和乙酸(1mL)中，加入(S)-2-(氟甲基)-5-甲氧基-3,4-二氢-2H-吡咯(783mg,6.0mmol)。反应加热至125℃，在此温度下搅拌12小时，冷却至室温后，减压浓缩。然后加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩有机溶剂后经柱层析得标题化合物(S)-6-(5-(氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺(430mg,两步产率55％)。 At room temperature, 6-aminomethylpyridylhydrazide (900mg, 6.0mmol) was dissolved in 2-pentanol (15mL) and acetic acid (1mL), and (S) -2- (fluoromethyl) -5-formaldehyde was added. Oxy-3,4-dihydro-2H-pyrrole (783 mg, 6.0 mmol). The reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and then concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL × 2) was extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was concentrated to obtain the title compound (S) -6 by column chromatography. -(5- (fluoromethyl) -6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-amine (430 mg, 25% yield).
1H NMR(400MHz,CDCl 3)δ7.69(m,1H),7.66-7.51(m,1H),6.60-6.47(m,1H),5.21-5.04(m,1H),4.94(m,0.5H),4.82(m,1H),4.70(m,0.5H),3.20-2.92(m,3H),2.85-2.70(m,1H)； 1 H NMR (400MHz, CDCl 3 ) δ7.69 (m, 1H), 7.66-7.51 (m, 1H), 6.60-6.47 (m, 1H), 5.21-5.04 (m, 1H), 4.94 (m, 0.5 H), 4.82 (m, 1H), 4.70 (m, 0.5H), 3.20-2.92 (m, 3H), 2.85-2.70 (m, 1H);
MS m/z(ESI):234.2[M+H] +. MS m / z (ESI): 234.2 [M + H] + .
第三步:(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-(氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺的合成Third step: (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (fluoromethyl) -6,7-dihydro Of 5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-appb-000117
Figure PCTCN2019099971-appb-000117
室温下，将(S)-6-(5-(氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡 啶-2-胺(195mg,0.84mmol)加入5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酰氯(390mg,1.4mmol)的THF(15mL)和吡啶(15mL)溶液中，然后加入4-二甲氨基吡啶(26mg,0.21mmol)。将反应加热至45℃，并在该温度下搅拌2小时,然后加入水(5mL)淬灭,二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩有机溶剂后柱层析分离得标题化合物(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-(氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺(179mg,产率45％)。(S) -6- (5- (fluoromethyl) -6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl Pyridine-2-amine (195 mg, 0.84 mmol) was added to 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (390 mg, 1.4 mmol) in THF (15 mL) and pyridine (15 mL) solution, then 4-dimethylaminopyridine (26 mg, 0.21 mmol) was added. The reaction was heated to 45 ° C and stirred at this temperature for 2 hours, and then quenched by adding water (5 mL), and extracted with dichloromethane (50 mL x 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, The organic solvent was concentrated under pressure, and the title compound (S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (fluoromethyl) was isolated by column chromatography. ) -6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide (179mg, Yield 45%).
1H NMR(400MHz,CDCl 3)δ9.06(d,J＝15.6Hz,1H),8.30-8.28(m,1H),8.16-7.96(m,2H),7.87(t,J＝8.0Hz,1H),7.45-7.43(m,1H),7.16(d,J＝12.6Hz,1H),6.77(s,1H),5.17-5.00(m,1H),4.96-4.93(m,0.5H),4.84-4.79(m,1H),4.71-4.68(m,0.5H),3.19-2.87(m,3H),2.87-2.68(m,1H),2.26(s,3H),1.93-1.81(m,1H),0.92-0.74(m,4H)； 1 H NMR (400MHz, CDCl 3 ) δ9.06 (d, J = 15.6Hz, 1H), 8.30-8.28 (m, 1H), 8.16-7.96 (m, 2H), 7.87 (t, J = 8.0Hz, 1H), 7.45-7.43 (m, 1H), 7.16 (d, J = 12.6Hz, 1H), 6.77 (s, 1H), 5.17-5.00 (m, 1H), 4.96-4.93 (m, 0.5H), 4.84-4.79 (m, 1H), 4.71-4.68 (m, 0.5H), 3.19-2.87 (m, 3H), 2.87-2.68 (m, 1H), 2.26 (s, 3H), 1.93-1.81 (m, 1H), 0.92-0.74 (m, 4H);
MS m/z(ESI):476.2[M+H] +. MS m / z (ESI): 476.2 [M + H] + .
实施例52Example 52
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-(氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (fluoromethyl) -6,7-dihydro-5H-pyrrole Benzo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-appb-000118
Figure PCTCN2019099971-appb-000118
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-(氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺的制备参照实施例51。(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5- (fluoromethyl) -6,7-dihydro-5H-pyrrole Refer to Example 51 for the preparation of benzo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide.
1H NMR(400MHz,CDCl 3)δ9.06(d,J＝15.6Hz,1H),8.30-8.28(m,1H),8.16-7.96(m,2H),7.87(t,J＝8.0Hz,1H),7.45-7.43(m,1H),7.16(d,J＝12.6Hz,1H),6.77(s,1H),5.17-5.00(m,1H),4.96-4.93(m,0.5H),4.84-4.79(m,1H),4.71-4.68(m,0.5H),3.19-2.87(m,3H),2.87-2.68(m,1H),2.26(s,3H),1.93-1.81(m,1H),0.92-0.74(m,4H)； 1 H NMR (400MHz, CDCl 3 ) δ9.06 (d, J = 15.6Hz, 1H), 8.30-8.28 (m, 1H), 8.16-7.96 (m, 2H), 7.87 (t, J = 8.0Hz, 1H), 7.45-7.43 (m, 1H), 7.16 (d, J = 12.6Hz, 1H), 6.77 (s, 1H), 5.17-5.00 (m, 1H), 4.96-4.93 (m, 0.5H), 4.84-4.79 (m, 1H), 4.71-4.68 (m, 0.5H), 3.19-2.87 (m, 3H), 2.87-2.68 (m, 1H), 2.26 (s, 3H), 1.93-1.81 (m, 1H), 0.92-0.74 (m, 4H);
MS m/z(ESI):476.2[M+H] +. MS m / z (ESI): 476.2 [M + H] + .
实施例53Example 53
(R)-2-氯-5-(4-环丙基-1H-咪唑-1-基)-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(R) -2-chloro-5- (4-cyclopropyl-1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000119
Figure PCTCN2019099971-appb-000119
(R)-2-氯-5-(4-环丙基-1H-咪唑-1-基)-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例8。(R) -2-chloro-5- (4-cyclopropyl-1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6,7-dihydro-5H -For the preparation method of pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide, refer to Example 8.
1H NMR(400MHz,CD 3OD)δ8.19(d,J＝8.1Hz,1H),7.89(t,J＝7.9Hz,1H),7.84-7.79(m,1H),7.68(s,1H),7.56-7.49(m,2H),7.12(s,1H),6.27-6.22(m,2H),5.19-5.09(m,1H),3.08-2.80(m,3H),2.39-2.31(m,1H),2.18(s,3H),1.78-1.73(m,3H),1.36-1.31(m,3H)； 1 H NMR (400MHz, CD 3 OD) δ 8.19 (d, J = 8.1 Hz, 1H), 7.89 (t, J = 7.9 Hz, 1H), 7.84-7.79 (m, 1H), 7.68 (s, 1H ), 7.56-7.49 (m, 2H), 7.12 (s, 1H), 6.27-6.22 (m, 2H), 5.19-5.09 (m, 1H), 3.08-2.80 (m, 3H), 2.39-2.31 (m , 1H), 2.18 (s, 3H), 1.78-1.73 (m, 3H), 1.36-1.31 (m, 3H);
MS m/z(ESI):474.1[M+H] +. MS m / z (ESI): 474.1 [M + H] + .
实施例54Example 54
(S)-2-氯-5-(4-环丙基-1H-咪唑-1-基)-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(S) -2-chloro-5- (4-cyclopropyl-1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000120
Figure PCTCN2019099971-appb-000120
(S)-2-氯-5-(4-环丙基-1H-咪唑-1-基)-4-甲基-N-(6-(5-甲基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例8。(S) -2-chloro-5- (4-cyclopropyl-1H-imidazol-1-yl) -4-methyl-N- (6- (5-methyl-6,7-dihydro-5H -For the preparation method of pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide, refer to Example 8.
1H NMR(400MHz,CD 3OD)δ8.19(d,J＝8.1Hz,1H),7.89(t,J＝7.9Hz,1H),7.84-7.79(m,1H),7.68(s,1H),7.56-7.49(m,2H),7.12(s,1H),6.27-6.22(m,2H),5.19-5.09(m,1H),3.08-2.80(m,3H),2.39-2.31(m,1H),2.18(s,3H),1.78-1.73(m,3H),1.36-1.31(m,3H)； 1 H NMR (400MHz, CD 3 OD) δ 8.19 (d, J = 8.1 Hz, 1H), 7.89 (t, J = 7.9 Hz, 1H), 7.84-7.79 (m, 1H), 7.68 (s, 1H ), 7.56-7.49 (m, 2H), 7.12 (s, 1H), 6.27-6.22 (m, 2H), 5.19-5.09 (m, 1H), 3.08-2.80 (m, 3H), 2.39-2.31 (m , 1H), 2.18 (s, 3H), 1.78-1.73 (m, 3H), 1.36-1.31 (m, 3H);
MS m/z(ESI):474.1[M+H] +. MS m / z (ESI): 474.1 [M + H] + .
实施例55Example 55
(R)-5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-乙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺(R) -5- (4-Cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethyl-6,7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000121
Figure PCTCN2019099971-appb-000121
第一步：(S)-(5-羰基吡咯烷-2-基)甲基4-甲基苯磺酸酯的制备Step 1: Preparation of (S)-(5-carbonylpyrrolidin-2-yl) methyl 4-methylbenzenesulfonate
Figure PCTCN2019099971-appb-000122
Figure PCTCN2019099971-appb-000122
室温下，依次将(S)-5-(羟甲基)吡咯烷-2-酮(5.0g,43.5mmol)、对甲苯磺酰氯(13.3g,71.7mmol)、三乙胺(13.2g,130.6mmol)溶于二氯甲烷(60mL)中，室温反应过夜，加入二氯甲烷(80mL)稀释，用1N HCl洗涤，有机相用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，粗品柱层析纯化后得(S)-(5-羰基吡咯烷-2-基)甲基4-甲基苯磺酸酯(8.3g,收率：71％)。At room temperature, (S) -5- (hydroxymethyl) pyrrolidin-2-one (5.0 g, 43.5 mmol), p-toluenesulfonyl chloride (13.3 g, 71.7 mmol), and triethylamine (13.2 g, 130.6) (mmol) was dissolved in dichloromethane (60mL), reacted at room temperature overnight, diluted with dichloromethane (80mL), washed with 1N HCl, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure. After analysis and purification, (S)-(5-carbonylpyrrolidin-2-yl) methyl 4-methylbenzenesulfonate (8.3 g, yield: 71%) was obtained.
1H NMR(400MHz，CDCl 3)δ7.79(d,J＝8.3Hz,2H),7.37(d,J＝8.2Hz,2H),6.26(s,1H),4.06-4.03(m,1H),3.97-3.84(m,2H),2.46(s,3H),2.36-2.19(m,3H),1.83-1.72(m,1H)； 1 H NMR (400 MHz, CDCl 3 ) δ 7.79 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 6.26 (s, 1H), 4.06-4.03 (m, 1H) , 3.97-3.84 (m, 2H), 2.46 (s, 3H), 2.36-2.19 (m, 3H), 1.83-1.72 (m, 1H);
MS m/z(ESI):270.1[M+H] +. MS m / z (ESI): 270.1 [M + H] + .
第二步：(R)-5-乙基吡咯烷-2-酮的制备Step 2: Preparation of (R) -5-ethylpyrrolidin-2-one
Figure PCTCN2019099971-appb-000123
Figure PCTCN2019099971-appb-000123
冰浴条件下，碘化亚铜(1.06g,5.6mmol)溶于四氢呋喃(6mL)中，氮气置换三次，滴加甲基锂(7.4mL,11.1mmol)，反应在0℃下搅拌45min，冷却至-20℃，滴加(S)-(5-羰基吡咯烷-2-基)甲基4-甲基苯磺酸酯(500mg,1.9mmol)的四氢呋喃(6mL)的溶液至反应体系中，-20℃下继续搅拌45min后，逐渐升至室温反应过夜，加入饱和氯化铵，用乙酸乙酯萃取，有机相用无水硫酸钠干燥，过滤后减压浓缩有机溶剂，粗品柱层析纯化后得(R)-5-乙基吡咯烷-2-酮(185mg,收率：86％)。In an ice bath, cuprous iodide (1.06g, 5.6mmol) was dissolved in tetrahydrofuran (6mL), replaced with nitrogen three times, and methyl lithium (7.4mL, 11.1mmol) was added dropwise. The reaction was stirred at 0 ° C for 45min, and cooled At -20 ° C, a solution of (S)-(5-carbonylpyrrolidin-2-yl) methyl 4-methylbenzenesulfonate (500 mg, 1.9 mmol) in tetrahydrofuran (6 mL) was added dropwise to the reaction system. After stirring at -20 ° C for 45 min, the temperature was gradually raised to room temperature to react overnight. Saturated ammonium chloride was added and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate. After filtration, the organic solvent was concentrated under reduced pressure and purified by crude column chromatography (R) -5-ethylpyrrolidin-2-one (185 mg, yield: 86%) was obtained.
1H NMR(400MHz，CD 3OD)δ3.54-3.45(m,1H),2.24-2.19(m,2H),2.18-2.09(m,1H),1.66-1.57(m,1H),1.53-1.43(m,1H),1.42-1.32(m,1H),0.84(t，J＝7.5Hz,3H)； 1 H NMR (400MHz, CD 3 OD) δ3.54-3.45 (m, 1H), 2.24-2.19 (m, 2H), 2.18-2.09 (m, 1H), 1.66-1.57 (m, 1H), 1.53- 1.43 (m, 1H), 1.42-1.32 (m, 1H), 0.84 (t, J = 7.5Hz, 3H);
MS m/z(ESI):114.2[M+H] +. MS m / z (ESI): 114.2 [M + H] + .
第三步：(R)-2-乙基-5-甲氧基-3,4-二氢-2H-吡咯的制备Step 3: Preparation of (R) -2-ethyl-5-methoxy-3,4-dihydro-2H-pyrrole
Figure PCTCN2019099971-appb-000124
Figure PCTCN2019099971-appb-000124
冰浴下，向(R)-5-乙基吡咯烷-2-酮(180mg,1.59mmol)的二氯甲烷(10mL)溶液中，分批加入三甲基氧鎓四氟硼酸(226mg,1.59mmol)。反应缓慢升至室温，在此温度下搅拌5小时，然后加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，加入冰醋酸(5mL)，减压浓缩，得到粗品直接用于下一步反应。 To a solution of (R) -5-ethylpyrrolidin-2-one (180 mg, 1.59 mmol) in dichloromethane (10 mL) under ice bath, trimethyloxonium tetrafluoroborate (226 mg, 1.59) was added in portions. mmol). The reaction was slowly raised to room temperature, stirred at this temperature for 5 hours, and then added saturated aqueous NaHCO 3 solution (5 mL), and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and added with ice. Acetic acid (5 mL) was concentrated under reduced pressure to obtain the crude product, which was directly used in the next reaction.
MS m/z(ESI):128.2[M+H] +. MS m / z (ESI): 128.2 [M + H] + .
第四步：6-氨基甲基吡啶酰肼的合成Step 4: Synthesis of 6-aminomethylpyridyl hydrazide
Figure PCTCN2019099971-appb-000125
Figure PCTCN2019099971-appb-000125
室温下，将甲基6-氨基甲基吡啶酸酯(2.0g,13mmol)溶于乙醇(60mL) 中，加入水合肼(4.1g,66mmol)。反应加热至80℃，在此温度下搅拌5小时，缓慢冷却至室温后，将反应液中析出的固体过滤，收集滤饼，得到标题化合物6-氨基甲基吡啶酰肼(1.6g,80％)。At room temperature, methyl 6-aminomethylpicolinate (2.0 g, 13 mmol) was dissolved in ethanol (60 mL), and hydrazine hydrate (4.1 g, 66 mmol) was added. The reaction was heated to 80 ° C, stirred at this temperature for 5 hours, and slowly cooled to room temperature. The solid precipitated in the reaction solution was filtered, and the filter cake was collected to obtain the title compound 6-aminomethylpyridylhydrazide (1.6g, 80%). ).
MS m/z(ESI):153.2[M+H] +. MS m / z (ESI): 153.2 [M + H] + .
第五步：(R)-6-(5-乙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺的制备Step 5: (R) -6- (5-ethyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridine- Preparation of 2-amine
Figure PCTCN2019099971-appb-000126
Figure PCTCN2019099971-appb-000126
室温下，将6-氨基甲基吡啶酰肼(243mg,1.59mmol)溶于2-戊醇(5mL)和乙酸(2mL)中，加入(R)-2-乙基-5-甲氧基-3,4-二氢-2H-吡咯(202mg,1.59mmol)。反应加热至125℃，在此温度下搅拌12小时，冷却至室温后，减压浓缩。然后加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后经柱层析得到标题化合物(R)-6-(5-乙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺(70mg，产率19％)。 At room temperature, 6-aminomethylpyridyl hydrazide (243 mg, 1.59 mmol) was dissolved in 2-pentanol (5 mL) and acetic acid (2 mL), and (R) -2-ethyl-5-methoxy- 3,4-dihydro-2H-pyrrole (202 mg, 1.59 mmol). The reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and then concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL × 2) was extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the title compound (R) -6- ( 5-ethyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-amine (70 mg, yield 19%) .
MS m/z(ESI):230.2[M+H] +. MS m / z (ESI): 230.2 [M + H] + .
第六步：5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酰氯的合成Step 6: Synthesis of 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride
Figure PCTCN2019099971-appb-000127
Figure PCTCN2019099971-appb-000127
室温下，将上述5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酸盐酸盐(154mg,0.594mmol)，溶于二氯亚砜(5mL)中，加热回流下搅拌2小时，冷却后减压浓缩，得到浅黄色固体产品直接用于下一步反应。At room temperature, the above 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoate hydrochloride (154mg, 0.594mmol) was dissolved in dichlorosulfoxide (5 mL), stirred under heating and refluxing for 2 hours, cooled and concentrated under reduced pressure to obtain a pale yellow solid product which was directly used in the next reaction.
第七步：(R)-5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-乙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺的制备Seventh step: (R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethyl-6,7-dihydro-5H-pyrrolo [2 Preparation of 1,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000128
Figure PCTCN2019099971-appb-000128
室温下，将(R)-6-(5-乙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-胺(68mg，0.297mmol)加入5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酰氯(165mg,0.594mmol)的THF(6mL)和吡啶(4mL)溶液中，然后加入4-二甲氨 基吡啶(15mg,0.119mmol)。将反应加热至45℃，并在该温度下搅拌2小时，然后加入水(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩后柱层析得标题化合物(R)-5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-乙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺(26mg,产率19％)。(R) -6- (5-ethyl-6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridine- 2-amine (68 mg, 0.297 mmol) was added to 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (165 mg, 0.594 mmol) in THF (6 mL) And pyridine (4 mL) solution, then 4-dimethylaminopyridine (15 mg, 0.119 mmol) was added. The reaction was heated to 45 ° C. and stirred at this temperature for 2 hours, and then water (5 mL) and dichloromethane (50 mL × 2) were added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. Chromatography gave the title compound (R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethyl-6,7-dihydro-5H-pyrrolo [ 2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide (26 mg, yield 19%).
1H NMR(400MHz,CDCl 3)δ9.04(d,J＝15.8Hz,1H),8.40-8.33(m,1H),8.14-8.07(m,2H),7.89(t,J＝8.0Hz,1H),7.52(s,1H),7.21(d,J＝12.6Hz,1H),6.82-6.79(m,1H),4.87-4.81(m,1H),3.08-2.89(m,3H),2.61-2.50(m,1H),2.30(s,3H),2.15-2.05(m,1H),1.96-1.90(m,1H),1.79-1.71(m,1H),1.00(t,J＝7.5Hz,3H),0.95-0.89(m,2H),0.88-0.79(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 9.04 (d, J = 15.8 Hz, 1 H), 8.40-8.33 (m, 1H), 8.14-8.07 (m, 2H), 7.89 (t, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.21 (d, J = 12.6Hz, 1H), 6.82-6.79 (m, 1H), 4.87-4.81 (m, 1H), 3.08-2.89 (m, 3H), 2.61 -2.50 (m, 1H), 2.30 (s, 3H), 2.15-2.05 (m, 1H), 1.96-1.90 (m, 1H), 1.79-1.71 (m, 1H), 1.00 (t, J = 7.5Hz , 3H), 0.95-0.89 (m, 2H), 0.88-0.79 (m, 2H);
MS m/z(ESI):472.2[M+H] +. MS m / z (ESI): 472.2 [M + H] + .
实施例56Example 56
(S)-5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-乙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺(S) -5- (4-Cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethyl-6,7-dihydro-5H-pyrrolo [2,1-c ] [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000129
Figure PCTCN2019099971-appb-000129
(S)-5-(4-环丙基-1H-咪唑-1-基)-N-(6-(5-乙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-2-氟-4-甲基苯酰胺的制备方法参照实施例55。(S) -5- (4-Cyclopropyl-1H-imidazol-1-yl) -N- (6- (5-ethyl-6,7-dihydro-5H-pyrrolo [2,1-c The method for preparing [1,2,4] triazol-3-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide is described in Example 55.
1H NMR(400MHz,CDCl 3)δ9.04(d,J＝15.8Hz,1H),8.40-8.33(m,1H),8.14-8.07(m,2H),7.89(t,J＝8.0Hz,1H),7.52(s,1H),7.21(d,J＝12.6Hz,1H),6.82-6.79(m,1H),4.87-4.81(m,1H),3.08-2.89(m,3H),2.61-2.50(m,1H),2.30(s,3H),2.15-2.05(m,1H),1.96-1.90(m,1H),1.79-1.71(m,1H),1.00(t,J＝7.5Hz,3H),0.95-0.89(m,2H),0.88-0.79(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 9.04 (d, J = 15.8 Hz, 1 H), 8.40-8.33 (m, 1H), 8.14-8.07 (m, 2H), 7.89 (t, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.21 (d, J = 12.6Hz, 1H), 6.82-6.79 (m, 1H), 4.87-4.81 (m, 1H), 3.08-2.89 (m, 3H), 2.61 -2.50 (m, 1H), 2.30 (s, 3H), 2.15-2.05 (m, 1H), 1.96-1.90 (m, 1H), 1.79-1.71 (m, 1H), 1.00 (t, J = 7.5Hz , 3H), 0.95-0.89 (m, 2H), 0.88-0.79 (m, 2H);
MS m/z(ESI):472.2[M+H] +. MS m / z (ESI): 472.2 [M + H] + .
实施例57Example 57
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-异丙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5-isopropyl-6,7-dihydro-5H-pyrrolo [ 2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-appb-000130
Figure PCTCN2019099971-appb-000130
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-异丙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺的制备参照实施例8。(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5-isopropyl-6,7-dihydro-5H-pyrrolo [ Refer to Example 8 for the preparation of 2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide.
1H NMR(400MHz,CDCl 3)δ9.00(d,J＝15.6Hz,1H),8.46-8.26(m,1H),8.10-7.99(m,2H),7.80(m,1H),7.43(t,J＝8.8Hz,1H),7.14(d,J＝12.6Hz,1H),6.73(s,1H),4.86-4.61(m,1H),3.00-2.81(m,2H),2.76(m,1H),2.60-2.47(m,2H), 2.22(s,3H),1.85(m,1H),1.01(d,J＝7.0Hz,3H),0.84(m,2H),0.80-0.74(m,2H),0.60(m,3H)； 1 H NMR (400 MHz, CDCl 3 ) 9.00 (d, J = 15.6 Hz, 1 H), 8.46-8.26 (m, 1H), 8.10-7.99 (m, 2H), 7.80 (m, 1H), 7.43 ( t, J = 8.8Hz, 1H), 7.14 (d, J = 12.6Hz, 1H), 6.73 (s, 1H), 4.86-4.61 (m, 1H), 3.00-2.81 (m, 2H), 2.76 (m , 1H), 2.60-2.47 (m, 2H), 2.22 (s, 3H), 1.85 (m, 1H), 1.01 (d, J = 7.0Hz, 3H), 0.84 (m, 2H), 0.80-0.74 ( m, 2H), 0.60 (m, 3H);
MS m/z(ESI):486.2[M+H] +. MS m / z (ESI): 486.2 [M + H] + .
实施例58Example 58
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-异丙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5-isopropyl-6,7-dihydro-5H-pyrrolo [ 2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide
Figure PCTCN2019099971-appb-000131
Figure PCTCN2019099971-appb-000131
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-N-(6-(5-异丙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-4-甲基苯酰胺的制备参照实施例8。(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-N- (6- (5-isopropyl-6,7-dihydro-5H-pyrrolo [ Refer to Example 8 for the preparation of 2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -4-methylbenzamide.
1H NMR(400MHz,CDCl 3)δ9.00(d,J＝15.6Hz,1H),8.46-8.26(m,1H),8.10-7.99(m,2H),7.80(m,1H),7.43(t,J＝8.8Hz,1H),7.14(d,J＝12.6Hz,1H),6.73(s,1H),4.86-4.61(m,1H),3.00-2.81(m,2H),2.76(m,1H),2.60-2.47(m,2H),2.22(s,3H),1.85(m,1H),1.01(d,J＝7.0Hz,3H),0.84(m,2H),0.80-0.74(m,2H),0.60(m,3H)； 1 H NMR (400 MHz, CDCl 3 ) 9.00 (d, J = 15.6 Hz, 1 H), 8.46-8.26 (m, 1H), 8.10-7.99 (m, 2H), 7.80 (m, 1H), 7.43 ( t, J = 8.8Hz, 1H), 7.14 (d, J = 12.6Hz, 1H), 6.73 (s, 1H), 4.86-4.61 (m, 1H), 3.00-2.81 (m, 2H), 2.76 (m , 1H), 2.60-2.47 (m, 2H), 2.22 (s, 3H), 1.85 (m, 1H), 1.01 (d, J = 7.0Hz, 3H), 0.84 (m, 2H), 0.80-0.74 ( m, 2H), 0.60 (m, 3H);
MS m/z(ESI):486.2[M+H] +. MS m / z (ESI): 486.2 [M + H] + .
实施例59Example 59
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-丙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-propyl-6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000132
Figure PCTCN2019099971-appb-000132
(R)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-丙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例55。(R) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-propyl-6,7-dihydro-5H -For the preparation method of pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide, refer to Example 55.
1H NMR(400MHz,CDCl 3)δ9.03(d,J＝15.3Hz,1H),8.37(d,J＝8.0Hz,1H),8.15-8.06(m,2H),7.89(t,J＝8.0Hz,1H),7.51(s,1H),7.21(d,J＝12.5Hz,1H),6.84-6.78(m,1H),4.95-4.86(m,1H),3.09-2.89(m,3H),2.60-2.50(m,1H),2.30(s,3H),2.04-1.99(m,1H),1.95-1.89(m,1H),1.71-1.63(m,1H),1.49-1.36(m,2H),0.97(t,J＝7.3Hz,3H),0.93-0.88(m,2H),0.87-0.82(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 9.03 (d, J = 15.3 Hz, 1 H), 8.37 (d, J = 8.0 Hz, 1 H), 8.15-8.06 (m, 2 H), 7.89 (t, J = 8.0Hz, 1H), 7.51 (s, 1H), 7.21 (d, J = 12.5Hz, 1H), 6.84-6.78 (m, 1H), 4.95-4.86 (m, 1H), 3.09-2.89 (m, 3H ), 2.60-2.50 (m, 1H), 2.30 (s, 3H), 2.04-1.99 (m, 1H), 1.95-1.89 (m, 1H), 1.71-1.63 (m, 1H), 1.49-1.36 (m , 2H), 0.97 (t, J = 7.3Hz, 3H), 0.93-0.88 (m, 2H), 0.87-0.82 (m, 2H);
MS m/z(ESI):486.2[M+H] +. MS m / z (ESI): 486.2 [M + H] + .
实施例60Example 60
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-丙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-propyl-6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide
Figure PCTCN2019099971-appb-000133
Figure PCTCN2019099971-appb-000133
(S)-5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基-N-(6-(5-丙基-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)苯酰胺的制备方法参照实施例55。(S) -5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methyl-N- (6- (5-propyl-6,7-dihydro-5H -For the preparation method of pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) benzamide, refer to Example 55.
1H NMR(400MHz,CDCl 3)δ9.03(d,J＝15.3Hz,1H),8.37(d,J＝8.0Hz,1H),8.15-8.06(m,2H),7.89(t,J＝8.0Hz,1H),7.51(s,1H),7.21(d,J＝12.5Hz,1H),6.84-6.78(m,1H),4.95-4.86(m,1H),3.09-2.89(m,3H),2.60-2.50(m,1H),2.30(s,3H),2.04-1.99(m,1H),1.95-1.89(m,1H),1.71-1.63(m,1H),1.49-1.36(m,2H),0.97(t,J＝7.3Hz,3H),0.93-0.88(m,2H),0.87-0.82(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 9.03 (d, J = 15.3 Hz, 1 H), 8.37 (d, J = 8.0 Hz, 1 H), 8.15-8.06 (m, 2 H), 7.89 (t, J = 8.0Hz, 1H), 7.51 (s, 1H), 7.21 (d, J = 12.5Hz, 1H), 6.84-6.78 (m, 1H), 4.95-4.86 (m, 1H), 3.09-2.89 (m, 3H ), 2.60-2.50 (m, 1H), 2.30 (s, 3H), 2.04-1.99 (m, 1H), 1.95-1.89 (m, 1H), 1.71-1.63 (m, 1H), 1.49-1.36 (m , 2H), 0.97 (t, J = 7.3Hz, 3H), 0.93-0.88 (m, 2H), 0.87-0.82 (m, 2H);
MS m/z(ESI):486.2[M+H] +. MS m / z (ESI): 486.2 [M + H] + .
实施例61Example 61
5-(4-环丙基-1H-咪唑-1-基)-N-(6-(6',7'-二氢螺[环丙烷-1,5'-吡咯并[2,1-c][1,2,4]***]-3'-基)吡啶-2-基)-2-氟-4-甲基苯酰胺5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6 ', 7'-dihydrospiro [cyclopropane-1,5'-pyrrolo [2,1-c ] [1,2,4] triazole] -3'-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000134
Figure PCTCN2019099971-appb-000134
第一步：5-甲氧基-4-氮杂螺[2.4]庚-4-烯的合成Step 1: Synthesis of 5-methoxy-4-azaspiro [2.4] hept-4-ene
Figure PCTCN2019099971-appb-000135
Figure PCTCN2019099971-appb-000135
冰浴下，向4-氮杂螺[2.4]庚烷-5-酮(1.7g,17.2mmol)的二氯甲烷(60mL)溶液中，分批加入三甲基氧鎓四氟硼酸(3.55g,24.0mmol)。反应缓慢升至室温，在此温度下搅拌5小时，然后加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，加入冰醋酸(5mL)，减压浓缩，得到粗品直接用于下一步反应。 To a solution of 4-azaspiro [2.4] heptane-5-one (1.7 g, 17.2 mmol) in dichloromethane (60 mL) under ice bath, trimethyloxonium tetrafluoroborate (3.55 g) was added in portions. , 24.0 mmol). The reaction was slowly raised to room temperature, stirred at this temperature for 5 hours, and then added saturated aqueous NaHCO 3 solution (5 mL), and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and added with ice. Acetic acid (5 mL) was concentrated under reduced pressure to obtain the crude product, which was directly used in the next reaction.
MS m/z(ESI):126.2[M+H] +. MS m / z (ESI): 126.2 [M + H] + .
第二步：6-(6',7'-二氢螺[环丙烷-1,5'-吡咯并[2,1-c][1,2,4]***]-3'-基)吡啶-2-胺的合成Second step: 6- (6 ', 7'-dihydrospiro [cyclopropane-1,5'-pyrrolo [2,1-c] [1,2,4] triazole] -3'-yl) Synthesis of pyridin-2-amine
Figure PCTCN2019099971-appb-000136
Figure PCTCN2019099971-appb-000136
室温下，将6-氨基甲基吡啶酰肼(500mg,4.5mmol)溶于2-戊醇(15mL)和乙酸(1mL)中，加入5-甲氧基-4-氮杂螺[2.4]庚-4-烯(930mg,6.3mmol)。反应加热至125℃，在此温度下搅拌12小时，冷却至室温后，减压浓缩。然后加入饱和NaHCO 3水溶液(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食 盐水洗涤，无水硫酸钠干燥，有机溶剂浓缩后经柱层析分离得标题化合物6-(6',7'-二氢螺[环丙烷-1,5'-吡咯并[2,1-c][1,2,4]***]-3'-基)吡啶-2-胺(515mg,两步产率50％)。 At room temperature, 6-aminomethylpyridylhydrazide (500mg, 4.5mmol) was dissolved in 2-pentanol (15mL) and acetic acid (1mL), and 5-methoxy-4-azaspiro [2.4] heptane was added 4-ene (930 mg, 6.3 mmol). The reaction was heated to 125 ° C, stirred at this temperature for 12 hours, cooled to room temperature, and then concentrated under reduced pressure. Then, a saturated NaHCO 3 aqueous solution (5 mL) was added, and dichloromethane (50 mL × 2) was extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was concentrated to obtain the title compound 6- (6 ', 7'-Dihydrospiro [cyclopropane-1,5'-pyrrolo [2,1-c] [1,2,4] triazole] -3'-yl) pyridin-2-amine (515mg, 50% yield in two steps).
1H NMR(400MHz,CDCl 3)δ7.60-7.44(m,2H),6.57-6.47(m,1H),4.31(s,2H),3.21-3.05(m,2H),2.79-2.67(m,2H),2.13-2.05(m,2H),0.86-0.79(m,2H)； 1 H NMR (400MHz, CDCl 3 ) δ 7.60-7.44 (m, 2H), 6.57-6.47 (m, 1H), 4.31 (s, 2H), 3.21-3.05 (m, 2H), 2.79-2.67 (m , 2H), 2.13-2.05 (m, 2H), 0.86-0.79 (m, 2H);
MS m/z(ESI):228.2[M+H] +. MS m / z (ESI): 228.2 [M + H] + .
第三步：5-(4-环丙基-1H-咪唑-1-基)-N-(6-(6',7'-二氢螺[环丙烷-1,5'-吡咯并[2,1-c][1,2,4]***]-3'-基)吡啶-2-基)-2-氟-4-甲基苯酰胺的合成Third step: 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6 ', 7'-dihydrospiro [cyclopropane-1,5'-pyrrolo [2 Synthesis of 1,1-c] [1,2,4] triazole] -3'-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide
Figure PCTCN2019099971-appb-000137
Figure PCTCN2019099971-appb-000137
室温下，将6-(6',7'-二氢螺[环丙烷-1,5'-吡咯并[2,1-c][1,2,4]***]-3'-基)吡啶-2-胺(39mg,0.17mmol)加入5-(4-环丙基-1H-咪唑-1-基)-2-氟-4-甲基苯甲酰氯(80mg,0.29mmol)的THF(5mL)和吡啶(5mL)溶液中，然后加入4-二甲氨基吡啶(5.3mg,0.043mmol)。将反应加热至45℃，并在该温度下搅拌2小时，然后加入水(5mL)，二氯甲烷(50mL×2)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，有机溶剂浓缩后柱层析分离得标题化合物5-(4-环丙基-1H-咪唑-1-基)-N-(6-(6',7'-二氢螺[环丙烷-1,5'-吡咯并[2,1-c][1,2,4]***]-3'-基)吡啶-2-基)-2-氟-4-甲基苯酰胺(51mg,产率63％)。At room temperature, 6- (6 ', 7'-dihydrospiro [cyclopropane-1,5'-pyrrolo [2,1-c] [1,2,4] triazole] -3'-yl) Pyridine-2-amine (39 mg, 0.17 mmol) was added to 5- (4-cyclopropyl-1H-imidazol-1-yl) -2-fluoro-4-methylbenzoyl chloride (80 mg, 0.29 mmol) in THF ( 5 mL) and pyridine (5 mL), then 4-dimethylaminopyridine (5.3 mg, 0.043 mmol) was added. The reaction was heated to 45 ° C and stirred at this temperature for 2 hours, and then water (5 mL) and dichloromethane (50 mL x 2) were added to extract. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was concentrated The title compound 5- (4-cyclopropyl-1H-imidazol-1-yl) -N- (6- (6 ', 7'-dihydrospiro [cyclopropane-1,5'- Pyrrolo [2,1-c] [1,2,4] triazole] -3'-yl) pyridin-2-yl) -2-fluoro-4-methylbenzamide (51 mg, yield 63%) .
1H NMR(400MHz,CDCl 3)δ9.05(d,J＝16.6Hz,1H),8.33-8.31(m,1H),8.09(d,J＝7.4Hz,1H),8.06-7.99(m,1H),7.86(t,J＝8.0Hz,1H),7.46(s,1H),7.21(d,J＝12.6Hz,1H),6.80(s,1H),3.17(t,J＝7.6Hz,2H),2.80(t,J＝7.8Hz,2H),2.30(s,3H),2.19-2.05(m,2H),1.98-1.84(m,1H),1.00-0.87(m,4H),0.87-0.78(m,2H)； 1 H NMR (400MHz, CDCl 3 ) δ 9.05 (d, J = 16.6 Hz, 1H), 8.33-8.31 (m, 1H), 8.09 (d, J = 7.4 Hz, 1H), 8.06-7.99 (m, 1H), 7.86 (t, J = 8.0Hz, 1H), 7.46 (s, 1H), 7.21 (d, J = 12.6Hz, 1H), 6.80 (s, 1H), 3.17 (t, J = 7.6Hz, 2H), 2.80 (t, J = 7.8Hz, 2H), 2.30 (s, 3H), 2.19-2.05 (m, 2H), 1.98-1.84 (m, 1H), 1.00-0.87 (m, 4H), 0.87 -0.78 (m, 2H);
MS m/z(ESI):470.2[M+H] +. MS m / z (ESI): 470.2 [M + H] + .
实施例62Example 62
N-(6-(6',7'-二氢螺[环丙烷-1,5'-吡咯并[2,1-c][1,2,4]***]-3'-基)吡啶-2-基)-2-氟-5-(4-异丙基-1H-咪唑-1-基)-4-甲基苯酰胺N- (6- (6 ', 7'-dihydrospiro [cyclopropane-1,5'-pyrrolo [2,1-c] [1,2,4] triazole] -3'-yl) pyridine 2-yl) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -4-methylbenzamide
Figure PCTCN2019099971-appb-000138
Figure PCTCN2019099971-appb-000138
N-(6-(6',7'-二氢螺[环丙烷-1,5'-吡咯并[2,1-c][1,2,4]***]-3'-基)吡啶-2-基)-2-氟-5-(4-异丙基-1H-咪唑-1-基)-4-甲基苯酰胺的制备参照实施例61。N- (6- (6 ', 7'-dihydrospiro [cyclopropane-1,5'-pyrrolo [2,1-c] [1,2,4] triazole] -3'-yl) pyridine -2-yl) -2-fluoro-5- (4-isopropyl-1H-imidazol-1-yl) -4-methylbenzamide was prepared as described in Example 61.
1H NMR(400MHz,CDCl 3)δ9.06(d,J＝16.6Hz,1H),8.31(m,1H),8.05(m,2H),7.86(t,J＝8.0Hz,1H),7.57(s,1H),7.22(d,J＝12.4Hz,1H),6.77(s,1H),3.17(t,J＝7.6Hz,2H),2.99(m,1H),2.80(t,J＝7.8Hz,2H),2.31(s,3H),2.19-2.12(m,2H),1.33(d,J＝6.8Hz,6H),0.98(m,2H)； 1 H NMR (400MHz, CDCl 3 ) δ 9.06 (d, J = 16.6 Hz, 1H), 8.31 (m, 1H), 8.05 (m, 2H), 7.86 (t, J = 8.0 Hz, 1H), 7.57 (s, 1H), 7.22 (d, J = 12.4 Hz, 1H), 6.77 (s, 1H), 3.17 (t, J = 7.6 Hz, 2H), 2.99 (m, 1H), 2.80 (t, J = 7.8Hz, 2H), 2.31 (s, 3H), 2.19-2.12 (m, 2H), 1.33 (d, J = 6.8Hz, 6H), 0.98 (m, 2H);
MS m/z(ESI):472.2[M+H] +. MS m / z (ESI): 472.2 [M + H] + .
实施例63Example 63
6-(4-环丙基-1H-咪唑-1-基)-2-(6-(6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-甲基异二氢吲哚-1-酮6- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6- (6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] Azole-3-yl) pyridin-2-yl) -5-methylisodihydroindol-1-one
Figure PCTCN2019099971-appb-000139
Figure PCTCN2019099971-appb-000139
第一步：甲基5-氨基-2-氰基-4-甲基苯酸酯的制备Step 1: Preparation of methyl 5-amino-2-cyano-4-methylbenzoate
Figure PCTCN2019099971-appb-000140
Figure PCTCN2019099971-appb-000140
甲基5-氨基-2-溴-4-甲基苯酸酯(900mg,3.69mmol)，CuCN(657mg,7.38mmol)混合于NMP(10mL)中，180℃下搅拌2小时，冷却后加入水，过滤，滤饼干燥得到标题化合物甲基5-氨基-2-氰基-4-甲基苯酸酯粗品(1.5g)，直接用于下一步。Methyl 5-amino-2-bromo-4-methylbenzoate (900 mg, 3.69 mmol), CuCN (657 mg, 7.38 mmol) were mixed in NMP (10 mL), stirred at 180 ° C for 2 hours, and added to water after cooling , Filtered, and the filter cake was dried to obtain the crude methyl 5-amino-2-cyano-4-methylbenzoate (1.5 g) as the title compound, which was directly used in the next step.
MS m/z(ESI):191.1[M+H] +. MS m / z (ESI): 191.1 [M + H] + .
第二步：6-氨基-5-甲基异二氢吲哚-1-酮的制备Second step: Preparation of 6-amino-5-methylisoindolin-1-one
Figure PCTCN2019099971-appb-000141
Figure PCTCN2019099971-appb-000141
将上述粗品溶于甲醇(20mL)中，加入Raney Ni(约100mg)，在H 2氛(2～3atm)、常温的条件下，搅拌过夜。用硅藻土过滤除去催化剂，滤液浓缩，柱层析，得到标题化合物6-氨基-5-甲基异二氢吲哚-1-酮(800mg,粗产品)。 The above crude product was dissolved in methanol (20 mL), Raney Ni (about 100 mg) was added, and stirred under H 2 atmosphere (2 to 3 atm) and normal temperature overnight. The catalyst was removed by filtration through Celite, the filtrate was concentrated, and column chromatography was performed to give the title compound 6-amino-5-methylisoindolin-1-one (800 mg, crude product).
MS m/z(ESI):163.1[M+H] +. MS m / z (ESI): 163.1 [M + H] + .
第三步：6-((2-环丙基-2-羰基乙基)氨基)-5-甲基异二氢吲哚-1-酮的制备Third step: Preparation of 6-((2-cyclopropyl-2-carbonylethyl) amino) -5-methylisodihydroindol-1-one
Figure PCTCN2019099971-appb-000142
Figure PCTCN2019099971-appb-000142
6-氨基-5-甲基异二氢吲哚-1-酮(370mg,2.28mmol),2-溴-1-环丙基乙烷-1-酮(409mg,2.51mmol),KI(38.0mg,0.228mmol),K 2CO 3(378mg,2.74mmol)混合于DMF(5mL)中，55℃下搅拌2小时。冷却，往混合物中加入水，再用二氯甲烷萃取两次。有机相合并后，用饱和食盐水洗涤三次，干燥后减压除去有机溶剂，粗品直接用于下一步。 6-amino-5-methylisoindolin-1-one (370mg, 2.28mmol), 2-bromo-1-cyclopropylethane-1-one (409mg, 2.51mmol), KI (38.0mg , 0.228 mmol), K 2 CO 3 (378 mg, 2.74 mmol) was mixed in DMF (5 mL), and stirred at 55 ° C. for 2 hours. Cool, add water to the mixture, and extract twice with dichloromethane. After the organic phases were combined, the organic phase was washed three times with saturated brine, and after drying, the organic solvent was removed under reduced pressure, and the crude product was directly used in the next step.
MS m/z(ESI):245.1[M+H] +. MS m / z (ESI): 245.1 [M + H] + .
第四步：6-(4-环丙基-2-巯基-1H-咪唑-1-基)-5-甲基异二氢吲哚-1-酮的制备Step 4: Preparation of 6- (4-cyclopropyl-2-mercapto-1H-imidazol-1-yl) -5-methylisodihydroindol-1-one
Figure PCTCN2019099971-appb-000143
Figure PCTCN2019099971-appb-000143
将第三步的粗品溶于AcOH(10mL)，然后再往溶液中加入KSCN(442mg,4.56mmol)，然后在120℃下搅拌2小时。冷却后反应液浓缩，粗品直接用于下一步。The crude product from the third step was dissolved in AcOH (10 mL), and then KSCN (442 mg, 4.56 mmol) was added to the solution, followed by stirring at 120 ° C for 2 hours. After cooling, the reaction solution was concentrated and the crude product was used directly in the next step.
MS m/z(ESI):286.1[M+H] +. MS m / z (ESI): 286.1 [M + H] + .
第五步：6-(4-环丙基-1H-咪唑-1-基)-5-甲基异二氢吲哚-1-酮的制备Step 5: Preparation of 6- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylisodihydroindol-1-one
Figure PCTCN2019099971-appb-000144
Figure PCTCN2019099971-appb-000144
将第四步粗品溶于AcOH(10mL)和水(2mL)的混合溶剂中，搅拌，在50℃下，往该溶液中缓慢滴加入双氧水(30wt％,10.0g,87.8mmol)。滴加完毕后，在该温度下继续搅拌1小时。冷却反应液，缓慢加入20wt％的Na 2SO 3水溶液(30mL)，在室温下搅拌30分钟。减压除去有机溶剂，水相用二氯甲烷萃取两次。有机相合并后，依次用饱和碳酸氢钠水溶液、饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩后柱层析分离，得到标题化合物6-(4-环丙基-1H-咪唑-1-基)-5-甲基异二氢吲哚-1-酮(180mg,五步收率:42％)。 The crude product in the fourth step was dissolved in a mixed solvent of AcOH (10 mL) and water (2 mL), stirred, and hydrogen peroxide (30 wt%, 10.0 g, 87.8 mmol) was slowly added dropwise to the solution at 50 ° C. After completion of the dropwise addition, stirring was continued at this temperature for 1 hour. The reaction solution was cooled, and a 20 wt% aqueous Na 2 SO 3 solution (30 mL) was slowly added, followed by stirring at room temperature for 30 minutes. The organic solvent was removed under reduced pressure, and the aqueous phase was extracted twice with dichloromethane. After the organic phases were combined, the organic phase was sequentially washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. -Yl) -5-methylisoindolin-1-one (180 mg, five-step yield: 42%).
MS m/z(ESI):254.1[M+H] +. MS m / z (ESI): 254.1 [M + H] + .
第六步：3-(6-氯吡啶-2-基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***的制备Step 6: Preparation of 3- (6-chloropyridin-2-yl) -6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazole
Figure PCTCN2019099971-appb-000145
Figure PCTCN2019099971-appb-000145
3-(6-氯吡啶-2-基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***的制备参照实施例1的第五步和第六步。Preparation of 3- (6-chloropyridin-2-yl) -6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazole Refer to the fifth step of Example 1 And step six.
MS m/z(ESI):221.1[M+H] +. MS m / z (ESI): 221.1 [M + H] + .
第七步：6-(4-环丙基-1H-咪唑-1-基)-2-(6-(6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-甲基异二氢吲哚-1-酮的制备Seventh step: 6- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6- (6,7-dihydro-5H-pyrrolo [2,1-c] [1,2 , 4] Preparation of triazol-3-yl) pyridin-2-yl) -5-methylisodihydroindol-1-one
Figure PCTCN2019099971-appb-000146
Figure PCTCN2019099971-appb-000146
6-(4-环丙基-1H-咪唑-1-基)-5-甲基异二氢吲哚-1-酮(50mg,0.197mmol),2-氯-6-(4-异丙基-4H-1,2,4-***-3-基)吡啶(48mg,0.22mmol)，碳酸铯(86mg, 0.30mml)混合于1,4-二氧六环(4mL)中，氮气除氧5分钟，加入Pd 2(dba) 3(18mg,0.02mmol),氮气再除氧5分钟，再加入Xantphos(23mg,0.04mmol)，继续用氮气除氧5分钟，然后在120℃下搅拌两天。冷却，浓缩，用二氯甲烷和水分层。分出有机相，用饱和食盐水洗涤，无水硫酸钠干燥，浓缩有机溶剂后用制备薄层析纯化，得到标题化合物6-(4-环丙基-1H-咪唑-1-基)-2-(6-(6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)-5-甲基异二氢吲哚-1-酮(43mg，收率：50％)。 6- (4-cyclopropyl-1H-imidazol-1-yl) -5-methylisodihydroindol-1-one (50 mg, 0.197 mmol), 2-chloro-6- (4-isopropyl -4H-1,2,4-triazol-3-yl) pyridine (48 mg, 0.22 mmol) and cesium carbonate (86 mg, 0.30 mml) were mixed in 1,4-dioxane (4 mL), and nitrogen was used to remove oxygen 5 minutes, add Pd 2 (dba) 3 (18mg, 0.02mmol), deoxidize with nitrogen for 5 minutes, add Xantphos (23mg, 0.04mmol), continue deoxidizing with nitrogen for 5 minutes, and then stir at 120 ° C for two days . Cool and concentrate, and dichloromethane and water layer. The organic phase was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The organic solvent was concentrated and purified by preparative thin chromatography to obtain the title compound 6- (4-cyclopropyl-1H-imidazol-1-yl) -2 -(6- (6,7-dihydro-5H-pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) -5-methylisodi Indolin-1-one (43 mg, yield: 50%).
1H NMR(400MHz,CDCl 3)δ8.63(d,J＝8.0Hz,1H),8.04(d,J＝8.0Hz,1H),7.84(t,J＝8.0Hz,1H),7.76(s,1H),7.48(s,1H),6.84(s,1H),5.08(s,2H),4.48(t,J＝7.2Hz,2H),2.88(m,2H),2.35(s,3H),1.93(m,1H),0.91(m,2H),0.85(m,2H)； 1 H NMR (400 MHz, CDCl 3 ) δ 8.63 (d, J = 8.0 Hz, 1 H), 8.04 (d, J = 8.0 Hz, 1 H), 7.84 (t, J = 8.0 Hz, 1 H), 7.76 (s , 1H), 7.48 (s, 1H), 6.84 (s, 1H), 5.08 (s, 2H), 4.48 (t, J = 7.2Hz, 2H), 2.88 (m, 2H), 2.35 (s, 3H) , 1.93 (m, 1H), 0.91 (m, 2H), 0.85 (m, 2H);
MS m/z(ESI):438.2[M+H] +. MS m / z (ESI): 438.2 [M + H] + .
实施例64Example 64
6-(4-环丙基-1H-咪唑-1-基)-2-(6-(6',7'-二氢螺[环丙烷-1,5'-吡咯并[2,1-c][1,2,4]***]-3'-基)吡啶-2-基)-5-甲基异二氢吲哚-1-酮6- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6- (6 ', 7'-dihydrospiro [cyclopropane-1,5'-pyrrolo [2,1-c ] [1,2,4] triazole] -3'-yl) pyridin-2-yl) -5-methylisodihydroindol-1-one
Figure PCTCN2019099971-appb-000147
Figure PCTCN2019099971-appb-000147
6-(4-环丙基-1H-咪唑-1-基)-2-(6-(6',7'-二氢螺[环丙烷-1,5'-吡咯并[2,1-c][1,2,4]***]-3'-基)吡啶-2-基)-5-甲基异二氢吲哚-1-酮的制备参照实施例63。6- (4-cyclopropyl-1H-imidazol-1-yl) -2- (6- (6 ', 7'-dihydrospiro [cyclopropane-1,5'-pyrrolo [2,1-c [1,2,4] triazole] -3'-yl) pyridin-2-yl) -5-methylisodihydroindol-1-one was prepared as described in Example 63.
1H NMR(400MHz,CDCl 3)δ8.70(d,J＝8.0Hz,1H),7.95(d,J＝7.2Hz,1H),7.87(t,J＝8.0Hz,1H),7.78(s,1H),7.56(s,1H),7.49(s,1H),6.63(s,1H),5.13(s,2H),3.19(t,J＝7.6Hz,2H),2.80(t,J＝7.6Hz,2H),2.35(s,3H),1.93(m,3H),1.01(m,2H),0.88(m,4H)； 1 H NMR (400 MHz, CDCl 3 ) δ 8.70 (d, J = 8.0 Hz, 1 H), 7.95 (d, J = 7.2 Hz, 1 H), 7.87 (t, J = 8.0 Hz, 1 H), 7.78 (s , 1H), 7.56 (s, 1H), 7.49 (s, 1H), 6.63 (s, 1H), 5.13 (s, 2H), 3.19 (t, J = 7.6Hz, 2H), 2.80 (t, J = 7.6Hz, 2H), 2.35 (s, 3H), 1.93 (m, 3H), 1.01 (m, 2H), 0.88 (m, 4H);
MS m/z(ESI):464.2[M+H] +. MS m / z (ESI): 464.2 [M + H] + .
实施例65Example 65
(S)-6-(4-环丙基-1H-咪唑-1-基)-5-甲基-2-(6-(5-(三氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)异二氢吲哚-1-酮(S) -6- (4-cyclopropyl-1H-imidazol-1-yl) -5-methyl-2- (6- (5- (trifluoromethyl) -6,7-dihydro-5H -Pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) isoindol-1-one
Figure PCTCN2019099971-appb-000148
Figure PCTCN2019099971-appb-000148
(S)-6-(4-环丙基-1H-咪唑-1-基)-5-甲基-2-(6-(5-(三氟甲基)-6,7-二氢-5H-吡咯并[2,1-c][1,2,4]***-3-基)吡啶-2-基)异二氢吲哚-1-酮的制备参照实施例63。(S) -6- (4-cyclopropyl-1H-imidazol-1-yl) -5-methyl-2- (6- (5- (trifluoromethyl) -6,7-dihydro-5H -Preparation of pyrrolo [2,1-c] [1,2,4] triazol-3-yl) pyridin-2-yl) isoindolin-1-one Refer to Example 63.
1H NMR(400MHz,CDCl 3)δ8.67(d,J＝8.0Hz,1H),8.04(d,J＝7.6Hz,1H), 7.85(t,J＝8.0Hz,1H),7.77(s,1H),7.56(s,1H),7.50(s,1H),6.84(s,1H),5.58(m,1H),5.10(d,J＝13.2Hz,1H),4.91(d,J＝13.2Hz,1H),3.19(m,2H),3.00(m,2H),2.35(s,3H),1.94(m,1H),0.90(m,4H)； 1 H NMR (400 MHz, CDCl 3 ) δ 8.67 (d, J = 8.0 Hz, 1 H), 8.04 (d, J = 7.6 Hz, 1 H), 7.85 (t, J = 8.0 Hz, 1 H), 7.77 (s , 1H), 7.56 (s, 1H), 7.50 (s, 1H), 6.84 (s, 1H), 5.58 (m, 1H), 5.10 (d, J = 13.2 Hz, 1H), 4.91 (d, J = 13.2Hz, 1H), 3.19 (m, 2H), 3.00 (m, 2H), 2.35 (s, 3H), 1.94 (m, 1H), 0.90 (m, 4H);
MS m/z(ESI):506.2[M+H] +. MS m / z (ESI): 506.2 [M + H] + .
生物学测试评价Evaluation of biological tests
以下结合测试例进一步描述解释本发明，但这些实施例并非意味着限制本发明的范围。The present invention is further described below in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.
1.测试ASK1酶学实验1. Test ASK1 enzyme experiment
本实验采用荧光共振能量转移(TR-FRET)的方法测试化合物对ASK1激酶活性的抑制作用，并得出化合物对ASK1激酶活性的半数抑制浓度IC 50。 This experiment uses fluorescence resonance energy transfer (TR-FRET) method of test compounds on ASK1 kinase inhibitory activity and to obtain compounds of ASK1 kinase activity half inhibitory concentration IC 50.
1)在384孔板中加入1～5uL ASK1酶溶液，酶终浓度为0.2～20nM。1) Add 1 ~ 5uL ASK1 enzyme solution to 384-well plate, the final enzyme concentration is 0.2 ~ 20nM.
2)加入1～5uL梯度稀释好的化合物溶液。2) Add 1 ~ 5uL of the diluted compound solution.
3)加入1～5uL底物混合液包含底物多肽终浓度100～5000nM和ATP终浓度100～1000uM。3) Adding 1 to 5 uL of the substrate mixed solution contains a final concentration of the substrate polypeptide of 100 to 5000 nM and a final concentration of ATP of 100 to 1000 uM.
4)室温孵育0.5～5小时。4) Incubate at room temperature for 0.5 to 5 hours.
5)加入10uL EDTA和含标记抗体的检测液，室温孵育2～24小时。5) Add 10uL of EDTA and detection solution containing labeled antibody, and incubate at room temperature for 2-24 hours.
6)酶标仪测定各板孔的约615nm和665nm荧光信号值。6) The microplate reader measures the fluorescence signal values of about 615nm and 665nm of each plate well.
7)通过荧光信号值计算抑制率。7) Calculate the inhibition rate from the fluorescence signal value.
8)根据不同浓度的抑制率通过曲线拟合得出化合物的IC 50。 8) The compound obtained IC 50 inhibition rate of different concentration by curve fitting.
本发明中实施例化合物酶学活性见表1。The enzymatic activity of the compounds of the examples in the present invention is shown in Table 1.
表1本发明中实施例化合物酶学活性Table 1 Enzymatic activities of the compounds of the examples in the present invention
化合物编号Compound number ASK1 IC 50(nM) ASK1 IC 50 (nM)
实施例1Example 1 6.06.0
实施例2Example 2 9.39.3
实施例3Example 3 13.413.4
实施例4Example 4 47.847.8
实施例7Example 7 19.619.6
实施例8Example 8 1.81.8
实施例9Example 9 5.05.0
实施例10Example 10 1.01.0
实施例11Example 11 10.610.6
实施例13Example 13 2.72.7
实施例14Example 14 9.09.0
实施例15Example 15 1.41.4
实施例16Example 16 4.14.1
实施例30Example 30 11.411.4
实施例31Example 31 10.910.9
实施例32Example 32 4.94.9
实施例33Example 33 7.27.2
实施例34Example 34 5.25.2
实施例36Example 36 9.19.1
实施例37Example 37 3.53.5
实施例38Example 38 4.14.1
实施例40Example 40 1.91.9
实施例41Example 41 7.77.7
实施例43Example 43 1.91.9
实施例44Example 44 3.63.6
实施例48Example 48 6.16.1
实施例50Example 50 9.69.6
实施例51Example 51 4.94.9
实施例53Example 53 8.28.2
实施例55Example 55 1.91.9
实施例56Example 56 5.05.0
实施例59Example 59 2.92.9
实施例60Example 60 6.66.6
实施例61Example 61 1.91.9
实施例62Example 62 3.03.0
实施例63Example 63 8.48.4
实施例64Example 64 5.55.5
实施例65Example 65 9.49.4
以上实施例化合物都能显著抑制ASK1激酶的酶学活性，部分化合物对ASK1激酶表现出强效的抑制作用，激酶酶活性抑制的IC 50小于10nM，这些化合物作为ASK1的有效抑制剂对NASH的治疗具有巨大的应用潜力。 The compounds of the above examples can significantly inhibit the enzymatic activity of ASK1 kinase, some compounds show a strong inhibitory effect on ASK1 kinase, and the IC 50 of kinase enzyme activity inhibition is less than 10 nM. These compounds are effective inhibitors of ASK1 for the treatment of NASH Has huge application potential.
2.小鼠PK分析2. Mouse PK analysis
本发明优选实施例的小鼠药物代谢动力学试验采用Balb/c雄性小鼠(上海杰思捷实验动物有限公司)进行。The mouse pharmacokinetic test of the preferred embodiment of the present invention is performed using a Balb / c male mouse (Shanghai Jiesijie Experimental Animal Co., Ltd.).
■给药方式：单次灌胃给药。■ Method of administration: single intragastric administration.
■给药剂量：5毫克/10毫升/千克。■ Dose of administration: 5 mg / 10 ml / kg.
■制剂处方：0.5％CMC-Na，超声溶解。■ Formulation: 0.5% CMC-Na, ultrasonically dissolved.
■取样点：给药后0.5、1、2、4、6、8和24小时。■ Sampling points: 0.5, 1, 2, 4, 6, 8 and 24 hours after administration.
■样品处理：■ Sample processing:
1)眼眶采血0.1mL，置于K 2EDTA试管中，室温1000～3000×g离心5～20min分离血浆，于-80℃保存。 1) Orbital blood was collected from 0.1 mL, placed in a K 2 EDTA test tube, and the plasma was separated by centrifugation at 1000 to 3000 × g at room temperature for 5 to 20 minutes, and stored at -80 ° C.
2)血浆样品40uL加入160uL乙腈沉淀,混合后500～2000×g离心5～20分钟。2) 40uL of plasma sample was added to 160uL of acetonitrile to precipitate. After mixing, centrifuge at 500 ～ 2000 × g for 5 ～ 20 minutes.
取处理后上清溶液100uL进行LC/MS/MS分析待测化合物的浓度。100 uL of the treated supernatant solution was taken for LC / MS / MS analysis of the concentration of the test compound.
■LC-MS/MS分析：■ LC-MS / MS analysis:
●液相条件：Shimadzu LC-20AD泵● Liquid phase conditions: Shimadzu LC-20AD pump
●质谱条件：AB Sciex API 4000质谱仪● Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer
●色谱柱：phenomenex Gemiu 5um C18 50×4.6mm● Column: phenomenex, Gemiu, 5um, C18, 50 × 4.6mm
●移动相：A液为0.1％甲酸水溶液，B液为乙腈● Mobile phase: A liquid is 0.1% formic acid aqueous solution, B liquid is acetonitrile
●流速：0.8mL/min● Flow rate: 0.8mL / min
●洗脱时间：0-3.5分钟梯度洗脱● Elution time: 0-3.5 minutes gradient elution
■药代动力学：■ Pharmacokinetics:
主要参数用WinNonlin 6.1计算得到，小鼠药代实验结果见下表2：The main parameters were calculated using WinNonlin 6.1. The results of the pharmacokinetic experiments in mice are shown in Table 2 below:
表2Table 2
Figure PCTCN2019099971-appb-000149
Figure PCTCN2019099971-appb-000149
Figure PCTCN2019099971-appb-000150
Figure PCTCN2019099971-appb-000150
从表中小鼠药代实验结果可以看出：本发明实施例化合物表现出良好的代谢性质，暴露量AUC和最大血药浓度C max都表现良好。 It can be seen from the results of the pharmacokinetic experiments of mice in the table that the compounds of the examples of the present invention exhibit good metabolic properties, and both the exposure AUC and the maximum blood concentration C max perform well.
3.大鼠PK分析3. Rat PK analysis
本发明优选实施例的大鼠药物代谢动力学试验采用SD雄性大鼠(上海杰思捷实验动物有限公司)进行。The rat pharmacokinetic test of the preferred embodiment of the present invention is performed by using SD male rats (Shanghai Jiesijie Experimental Animal Co., Ltd.).
■给药方式：单次灌胃给药。■ Method of administration: single intragastric administration.
■给药剂量：5毫克/10毫升/千克。■ Dose of administration: 5 mg / 10 ml / kg.
■制剂处方：5％EtOH-75％PG-10％Kolliphor-10％Water，超声溶解。■ Formulation: 5% EtOH-75% PG-10% Kolliphor-10% Water, dissolved by ultrasound.
■取样点：给药后0.5、1、2、4、6、8和24小时。■ Sampling points: 0.5, 1, 2, 4, 6, 8 and 24 hours after administration.
■样品处理：■ Sample processing:
2)静脉采血0.2mL，置于K 2EDTA试管中，室温1000～3000×g离心5～20min分离血浆，于-80℃保存。 2) 0.2 mL of blood was collected from veins, placed in a K 2 EDTA test tube, and centrifuged at 1000 to 3000 × g at room temperature for 5 to 20 minutes to separate plasma, and stored at -80 ° C.
3)血浆样品40uL加入160uL乙腈沉淀，混合后500～2000×g离心5～20分钟。3) Add 40uL of plasma sample to 160uL of acetonitrile to precipitate. After mixing, centrifuge at 500-2000 × g for 5-20 minutes.
4)取处理后上清溶液100uL进行LC/MS/MS分析待测化合物的浓度。4) Take 100 uL of the treated supernatant solution and analyze the concentration of the test compound by LC / MS / MS.
■液相分析：■ Liquid phase analysis:
●液相条件：Shimadzu LC-20AD泵● Liquid phase conditions: Shimadzu LC-20AD pump
●质谱条件:AB Sciex API 4000质谱仪Mass spectrometry: AB Sciex API 4000 mass spectrometer
●色谱柱：phenomenex Gemiu 5um C18 50×4.6mm● Column: phenomenex, Gemiu, 5um, C18, 50 × 4.6mm
●移动相：A液为0.1％甲酸水溶液，B液为乙腈● Mobile phase: A liquid is 0.1% formic acid aqueous solution, B liquid is acetonitrile
●流速：0.8mL/min● Flow rate: 0.8mL / min
●洗脱时间：0-3.5分钟梯度洗脱● Elution time: 0-3.5 minutes gradient elution
■药代动力学：■ Pharmacokinetics:
主要参数用WinNonlin 6.1计算得到，大鼠药代实验结果见下表3：The main parameters were calculated using WinNonlin 6.1. The results of the pharmacokinetic experiments in rats are shown in Table 3 below:
表3table 3
Figure PCTCN2019099971-appb-000151
Figure PCTCN2019099971-appb-000151
从表中大鼠药代实验结果可以看出：本发明实施例化合物相较于现有技术表现出良好的代谢性质，暴露量AUC和最大血药浓度C max都表现良好。 From the results of the rat pharmacokinetic experiments in the table, it can be seen that, compared with the prior art, the compounds of the examples of the present invention exhibit good metabolic properties, and both the exposure AUC and the maximum blood concentration C max perform well.
4、本发明化合物对HFD(高脂饲料)+CCl 4诱导的非酒精性脂肪肝炎小鼠ALT和AST水平的影响 4. Effect of the compound of the present invention on ALT and AST levels in non-alcoholic steatohepatitis mice induced by HFD (high-fat diet) + CCl 4
1)实验目的：1) Experiment purpose:
该测试例的目的是检测本发明化合物是否能下调非酒精性脂肪肝炎小鼠血清中ALT和AST的水平。The purpose of this test case is to test whether the compound of the present invention can down-regulate the levels of ALT and AST in the serum of non-alcoholic steatohepatitis mice.
2)实验原料和仪器：2) Experimental materials and instruments:
利用谷丙转氨酶(ALT/GPT)测试盒：南京建成科技有限公司Using alanine aminotransferase (ALT / GPT) test box: Nanjing Jiancheng Technology Co., Ltd.
谷草转氨酶(AST/GOT)测试盒：南京建成科技有限公司Aspartate aminotransferase (AST / GOT) test box: Nanjing Jiancheng Technology Co., Ltd.
96孔板：Corning公司96-well plate: Corning
BioTek Synergy H1酶标仪：美国BioTek公司BioTek Synergy H1 microplate reader: BioTek, USA
3)实验步骤：3) Experimental steps:
C57BL/6小鼠在SPF(无特定病原体)屏障内进行3-7天的适应性饲养后，更换HFD饲料饲养，饲养周期为8周，HFD饲养第五周，根据动物体重将HFD诱导后的小鼠随机分组，口服给予一周两次CCl 4诱导，并持续4周；给予CCl 4建模当日开始口服给药，给药频率每天一次，连续给药28天；溶媒对照组给予供试品对应的溶媒，给药体积为10mL/kg；CCl 4最后一次给予48小时后，用CO 2将小鼠安乐死，从心脏处采集动物非抗凝静脉血，全血在常温下放置至少30分钟，在4度5000转5分钟离心条件下离心，分离血清，分装成两份，装入1.5mL的EP管中，-80℃保存，备用。 After C57BL / 6 mice were adaptively reared in the SPF (No Specific Pathogens) barrier for 3-7 days, they were replaced with HFD feeds. The rearing period was 8 weeks, and the HFD was raised for the fifth week. Mice were randomly divided into groups and induced by oral administration of CCl 4 twice a week for 4 weeks. Oral administration was started on the day of CCl 4 modelling. The frequency of administration was once a day for 28 consecutive days. The administration volume was 10 mL / kg; 48 hours after the last administration of CCl 4 , the mice were euthanized with CO 2 , and non-anticoagulated venous blood was collected from the heart. The whole blood was left at room temperature for at least 30 minutes. Centrifuge under the conditions of centrifugation at 4 ° C, 5000 rpm for 5 minutes, separate the serum, aliquot it into two aliquots, place them in 1.5mL EP tubes, store at -80 ° C, and reserve.
利用谷丙转氨酶(ALT/GPT)测试盒和谷草转氨酶(AST/GOT)测试盒检测小鼠血清ALT和AST水平。将ALT(或AST)检测基质液放入37℃恒温箱中预热；吸取20uL基质液加入96孔板中，再吸取5uL血清加入96孔板中作为测定孔，混匀后使用封口膜封板放入37℃恒温箱中孵育30min；配制ALT(或AST)标准曲线，吸取25uL加入96孔板中；再吸取20uL血浆加入96孔板中作为对照孔；各孔分别加入2,4-二硝基苯肼液20uL，混匀后使用封口膜封板放入37℃恒温箱中孵育20min，各孔加入0.4M的NaOH溶液200uL，放入摇板仪上摇动15min，在BioTek Synergy H1仪器上使用检测OD程序进行读板，波长为510nm，根据各孔OD值计算绝对OD值。绝对OD值＝测定孔OD值-对照孔OD值；将绝对OD值带入标准曲线中求得样品中ALT(或AST)的含量，超出标曲范围的样品需将血清稀释至合适浓度后重新检测。The alanine aminotransferase (ALT / GPT) test box and the aspartate aminotransferase (AST / GOT) test box were used to detect serum ALT and AST levels in mice. Pre-warm the ALT (or AST) detection matrix solution in a 37 ° C incubator; pipette 20uL of matrix solution into a 96-well plate, and then pipette 5uL of serum into a 96-well plate as a measurement well. After mixing, use a parafilm to seal the plate. Incubate in a 37 ° C incubator for 30 min; prepare an ALT (or AST) standard curve, draw 25uL into a 96-well plate; draw 20uL plasma into a 96-well plate as a control well; add 2,4-dinitrate to each well 20uL of phenyl hydrazine solution. After mixing, use a sealing film to seal the plate and incubate for 20min in a 37 ° C incubator. Add 200uL of 0.4M NaOH solution to each well, place it on a shaker for 15min, and use it on a BioTek Synergy H1 instrument Detect the OD program to read the plate, the wavelength is 510nm, and calculate the absolute OD value according to the OD value of each well. Absolute OD value = OD value of the measurement well-OD value of the control well; bring the absolute OD value into the standard curve to obtain the ALT (or AST) content in the sample. For samples outside the range of the standard curve, the serum should be diluted to a suitable concentration and restarted. Detection.
数据处理：(％ALT降低率)＝(溶媒对照组-测试化合物)/溶媒对照组╳100％；Data processing: (% ALT reduction rate) = (vehicle control group-test compound) / vehicle control group ╳ 100%;
(％AST降低率)＝(溶媒对照组-测试化合物)/溶媒对照组╳100％。(% AST reduction rate) = (vehicle control group-test compound) / vehicle control group ╳ 100%.
4)实验结果见下表4：4) The experimental results are shown in Table 4 below:
表4Table 4
 Zh ALT(U/L)降低率ALT (U / L) reduction rate AST(U/L)降低率AST (U / L) reduction rate
溶媒对照Vehicle control -- --
GS-4997GS-4997 40％40% 35％35%
实施例8Example 8 56％56% 58％58%
实施例9Example 9 69％69% 67％67%
实施例10Example 10 50％50% 46％46%
实施例15Example 15 54％54% 58％58%
实施例34Example 34 67％67% 60％60%
实施例37Example 37 57％57% 62％62%
实施例40Example 40 50％50% 65％65%
实施例43Example 43 65％65% 58％58%
实施例55Example 55 56％56% 55％55%
实施例61Example 61 50％50% 54％54%
实施例64Example 64 51％51% 47％47%
实施例65Example 65 46％46% 52％52%
5)实验结论：5) Experimental conclusions:
本发明化合物在下调非酒精性脂肪肝炎小鼠血清中ALT和AST的水平中相较于现有技术表现出良好的效果。Compared with the prior art, the compound of the present invention shows a good effect in down-regulating the levels of ALT and AST in the serum of non-alcoholic steatohepatitis mice.
5、本发明实施例化合物进行灌胃给予SD大鼠7天的剂量试验5. Dose test of the compound of the embodiment of the present invention by intragastric administration to SD rats for 7 days
1)实验目的：1) Experiment purpose:
本发明实施例9和43，在10、30、100mg/kg剂量下，每天1次重复灌胃给予雄性SD大鼠，连续7天，评价可能出现的毒性反应及体内的代谢情况。In Examples 9 and 43 of the present invention, at 10, 30, and 100 mg / kg doses, male SD rats were repeatedly administered orally once a day for 7 consecutive days to evaluate possible toxic reactions and metabolism in the body.
2)实验器材及试剂：2) Experimental equipment and reagents:
血液分析仪             
Figure PCTCN2019099971-appb-000152
系列 Blood analyzer
Figure PCTCN2019099971-appb-000152
series
自动血液凝血分析仪      
Figure PCTCN2019099971-appb-000153
Automatic blood coagulation analyzer
Figure PCTCN2019099971-appb-000153
全自动生化分析仪        TBA-120FRFully automatic biochemical analyzer TBA-120FR
电解质分析仪            EasylyteElectrolyte Analyzer Easylyte
羧甲基纤维素钠(CMC-Na)  国药集团化学试剂有限公司Sodium carboxymethyl cellulose (CMC-Na) Sinopharm Chemical Reagent Co., Ltd.
血生化采血管            江苏康健医疗用品有限公司Blood biochemical blood collection tube Jiangsu Kangjian Medical Supplies Co., Ltd.
EDTA-K 2离心管           江苏康健医疗用品有限公司 EDTA-K 2 centrifuge tube Jiangsu Kangjian Medical Supplies Co., Ltd.
3)实验方法及处理：3) Experimental method and treatment:
给药前，将溶媒0.5％CMC-Na(对照组)配制后的化合物置于磁力搅拌器上搅拌至少15分钟，并在给药过程中持续搅拌。根据测定的体重准确抽取所需体积的化合物/对照品经口灌胃给药。Prior to the administration, the compound prepared with the vehicle 0.5% CMC-Na (control group) was placed on a magnetic stirrer and stirred for at least 15 minutes, and continuously stirred during the administration. The required volume of the compound / control is accurately orally administered according to the measured weight.
试验期间每天至少观察两次(上午和下午各观察1次)，首次给药后连续观察约4小时，观察内容包括但不限于精神状态、行为活动、皮肤、被毛、眼、耳、 鼻、腹部、外生殖器、***、四肢、足、呼吸；各组动物每周称重2次。During the trial, observe at least twice a day (once in the morning and in the afternoon), and continuously observe for about 4 hours after the first dose. The observations include but are not limited to mental state, behavioral activity, skin, coat, eyes, ears, nose, Abdomen, external genitalia, anus, limbs, feet, breathing; animals in each group were weighed twice a week.
所有动物于第8天计划安乐死前腹主动脉收集血样用于血细胞计数、凝血功能、血液生化的检测，分别装在含有EDTA-K 2抗凝剂(血细胞计数)，枸橼酸钠(凝血功能)，分离胶+促凝剂(血液生化)的采样管中。血液分析仪、自动血液凝血分析仪和全自动生化分析仪分别用于血细胞计数、凝血功能和血液生化指标的检测，电解质分析仪用于电解质检测。病理学进行大体解剖观察，肝脏和肺脏固定后制作病理切片染色进一步观察。 All animals were euthanized on day 8 before planned aortic blood samples were collected for blood cell counts, coagulation, blood biochemical test, were installed in the containing EDTA-K 2 anticoagulant (blood cell count), sodium citrate (blood coagulation ), Separating the gel + coagulant (blood biochemical) sampling tube. Blood analyzer, automatic blood coagulation analyzer and automatic biochemical analyzer are used for blood cell count, blood coagulation function and blood biochemical index detection, and electrolyte analyzer is used for electrolyte detection. The pathology was grossly dissected, and the liver and lungs were fixed for pathological section staining for further observation.
毒代动力学血样分别于首、末次给药前，药后0.5h、1h、2h、4h、8h、12h、24h采集；采血前，含有EDTA-K 2的离心管置于2-8℃冰箱中或冰浴中暂存；采集的血液加入上述标记好的离心管中，手动颠倒至少5次，于冰浴中暂存；离心条件：4℃，1500g，离心10min，2小时内完成离心，离心后的血浆转移至新的标记好的离心管中，于-70℃以下保存。 The toxicokinetic blood samples were collected before the first and last administration, 0.5h, 1h, 2h, 4h, 8h, 12h, and 24h after the administration. Before blood collection, centrifuge tubes containing EDTA-K 2 were placed in a refrigerator at 2-8 ° C. Store temporarily in an ice bath; collect the blood into the labeled centrifuge tube, invert it manually at least 5 times, temporarily store in the ice bath; centrifugation conditions: 4 ℃, 1500g, centrifugation for 10min, complete the centrifugation within 2 hours, The centrifuged plasma was transferred to a new labeled centrifuge tube and stored below -70 ° C.
4)实验结果4) Experimental results
①动物死亡：试验期间，各组动物均未见死亡或濒死现象。① Animal death: During the experiment, no death or dying was observed in any group of animals.
②临床观察：试验期间，实施例43在100mg/kg剂量下分别于给药后第7-8天可见个别动物被毛蓬松，其余各时间段各组动物的临床观察均未见异常改变。②Clinical observation: During the test, Example 43 showed a fluffy coat on individual animals at the dose of 100mg / kg on the 7th to 8th days after administration, and there were no abnormal changes in the clinical observations of the animals in each time period.
③体重：试验期间，各组雄鼠的体重均呈持续增长趋势。③ Weight: During the test, the weight of male rats in each group showed a continuous increase trend.
④临床病理：第八天与溶媒对照组比较，实施例9和43在10、30、100mg/kg剂量下，雄鼠的血细胞计数、凝血功能、血液生化指标均未见毒理学意义的改变。④Clinical pathology: Compared with the vehicle control group on the eighth day, at the doses of 10, 30, and 100 mg / kg in Examples 9 and 43, the blood cell count, coagulation function, and blood biochemical indexes of male rats showed no toxicological significance.
⑤大体和组织病理学检查：本试验，实施例9和43在10、30、100mg/kg剂量下，大体观察均未见改变、肺脏和肝脏的组织病理学检查均未见相关的改变。⑤ Gross and Histopathological Examinations: In this test, Examples 9 and 43 at 10, 30, and 100 mg / kg doses showed no changes in general observations, and no histopathological examinations in lungs and livers.
⑥毒代动力学：在10-100mg/kg剂量范围内，雄鼠血浆中实施例9和43均未见蓄积。⑥ Toxicology: In the dose range of 10-100 mg / kg, no accumulation of Examples 9 and 43 was observed in the plasma of male rats.
5)实验结论：5) Experimental conclusions:
实施例9和43分别以10、30、100mg/kg的剂量重复灌胃给予SD雄鼠，每天1次，连续给药7天，动物耐受性良好，最大耐受剂量(MTD)均为100mg/kg，且安全性良好。Examples 9 and 43 were administered to male SD rats repeatedly at a dose of 10, 30, and 100 mg / kg, respectively, once a day for 7 consecutive days. The animals were well tolerated, and the maximum tolerated dose (MTD) was 100 mg. / kg, and good safety.

Claims (36)

  1. 一种药物组合物,包含通式(I)所示的化合物、其立体异构体或其药学上可接受的盐：A pharmaceutical composition comprising a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2019099971-appb-100001
    Figure PCTCN2019099971-appb-100001
    其中：among them:
    M 1、M 2、M 3和M 4各自独立地选自N或-CR 6； M 1 , M 2 , M 3 and M 4 are each independently selected from N or -CR 6 ;
    X和Y各自独立地选自键、
    Figure PCTCN2019099971-appb-100002
    -NR 7-、-CR 7R 8-、-S(O) m-、
    Figure PCTCN2019099971-appb-100003
    Figure PCTCN2019099971-appb-100004
    X and Y are each independently selected from a bond,
    Figure PCTCN2019099971-appb-100002
    -NR 7- , -CR 7 R 8- , -S (O) m- ,
    Figure PCTCN2019099971-appb-100003
    Figure PCTCN2019099971-appb-100004
    环A选自芳基或杂芳基，其中所述的芳基和杂芳基任选进一步被选自氘原子、烷基、氘代烷基、卤素、氨基、硝基、羟基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代； Ring A is selected from aryl or heteroaryl, wherein said aryl and heteroaryl are optionally further selected from deuterium, alkyl, deuterated alkyl, halogen, amino, nitro, hydroxyl, cyano, Alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O ) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C ( O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 With one or more substituents;
    R 1相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代； R 1 is the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, an amino group, a nitro group, a hydroxy group, a cyano group, a cyclic group Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-( CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ; the alkyl and haloalkane described therein Group, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy , Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 Substituted with one or more substituents;
    R 2相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、 -(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9； R 2 is the same or different, and each is independently selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, and a ring Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-( CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ;
    R 3选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、环烷基、杂环基、芳基和杂芳基，所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9； R 3 is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; Alkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkane Group, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-( CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ;
    或者，R 3和M 3、M 3和M 4链接分别形成一个环烷基、芳环基、杂环基或杂芳环基，其中所述的环烷基、芳环基、杂环基或杂芳环基任选进一步被选自氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代； Alternatively, R 3 and M 3 , M 3 and M 4 are respectively linked to form a cycloalkyl, aromatic ring, heterocyclic or heteroaryl ring, wherein the cycloalkyl, aromatic ring, heterocyclic group or The heteroaryl ring group is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxy group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, Cycloalkyl, heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m Substituted by one or more substituents in R 9 ;
    又或者，R 1和X或Y、M 1和X或Y链接分别形成一个环烷基、杂环基、芳基或杂芳基，其中所述的环烷基、杂环基、芳基或杂芳基任选进一步被选自氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代； Alternatively, R 1 and X or Y, M 1 and X or Y are respectively linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or Heteroaryl is optionally further selected from deuterium, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxyl, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cyclic Alkyl, heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C ( O) R 9, - (CH 2) n C (O) OR 9, - (CH 2) n S (O) m R 9, - (CH 2) n NR 10 R 11, - (CH 2) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R Substituted by one or more substituents of 9 ;
    R 6、R 7和R 8相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代； R 6 , R 7 and R 8 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, Hydroxyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ; Said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkane Oxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 is substituted by one or more substituents;
    R 9选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤素、氨基、 硝基、氰基、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代； R 9 is selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; Said alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, halogen, amino, nitro, cyano, hydroxy, hydroxyalkyl, Alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 , -(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 or Substituted with multiple substituents;
    R 10和R 11相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代； R 10 and R 11 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group Wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of a deuterium atom, an alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkoxy group, Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 , -(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 or Substituted with multiple substituents;
    R 12和R 13相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、羟基、氨基、酯基、环烷基、杂环基、芳基和杂芳基，其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤素、羟基、氨基、硝基、氰基、酯基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R 12 and R 13 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a hydroxyl group, an amino group, an ester group, a cycloalkyl group, a heterocyclic group, an aryl group, and Heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, halogen, hydroxyl, amino, nitro, cyano, ester Substituted with one or more substituents of aryl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
    x为0、1、2、3或4的整数；x is an integer of 0, 1, 2, 3, or 4;
    y为0、1或2的整数；y is an integer of 0, 1, or 2;
    m为0、1或2的整数；且m is an integer of 0, 1, or 2; and
    n为0、1、2、3、4或5的整数；n is an integer of 0, 1, 2, 3, 4 or 5;
    所述药物组合物还包括药学上可接受的载体。The pharmaceutical composition also includes a pharmaceutically acceptable carrier.
  2. 根据权利要求1所述的药物组合物，其特征在于，以组合物总重计，活性成分的重量百分比为1％～95％，优选5％～85％，更优选10％～60％，进一步优选10％～50％。The pharmaceutical composition according to claim 1, characterized in that, based on the total weight of the composition, the weight percentage of the active ingredient is 1% to 95%, preferably 5% to 85%, more preferably 10% to 60%, further It is preferably 10% to 50%.
  3. 根据权利要求1所述的药物组合物，其特征在于，剂量范围为0.5-120mg，优选为1-100mg，进一步优选为1-50mg，更进一步优选为1-30mg。The pharmaceutical composition according to claim 1, characterized in that the dosage ranges from 0.5 to 120 mg, preferably from 1 to 100 mg, further preferably from 1 to 50 mg, and even more preferably from 1 to 30 mg.
  4. 根据权利要求1所述的药物组合物，其特征在于，通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(II)化合物：The pharmaceutical composition according to claim 1, wherein the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compounds of the general formula (II):
    Figure PCTCN2019099971-appb-100005
    Figure PCTCN2019099971-appb-100005
    其中：among them:
    R 4选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代； R 4 is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxy group, a cyano group, a cycloalkyl group, a heterocyclic group, and an aromatic group. Group, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 , -(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ; the alkyl, haloalkyl, cycloalkyl, heterocyclic ring Aryl, aryl and heteroaryl are optionally further selected from the group consisting of deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 are substituted by one or more substituents;
    R 3和R 4链接形成一个杂环或杂芳环，其中所述的杂环或杂芳环任选进一步被选自烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代； R 3 and R 4 are linked to form a heterocyclic ring or heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring is optionally further selected from alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxyl , Cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C (O) R 9 、-(CH 2 ) n C (O) OR 9 、-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C ( O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 are substituted by one or more substituents;
    或者，R 3和R 4链接形成的杂环或杂芳环，所述杂环或杂芳环上的任意两个取代基可以形成环烷基、杂环基、芳基和杂芳基，其中所述环烷基、芳环基、杂环基或杂芳环基任选进一步被选自氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代； Alternatively, R 3 and R 4 are linked to form a heterocyclic ring or heteroaryl ring, and any two substituents on the heterocyclic ring or heteroaryl ring may form a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein The cycloalkyl, aromatic ring, heterocyclyl or heteroaryl ring group is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, Alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-( CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 And-(CH 2 ) n NR 10 S (O) m R 9 are substituted by one or more substituents;
    环A、M 1、M 2、X、Y、R 1-R 3、x、y、m和n如权利要求1所述。 Rings A, M 1 , M 2 , X, Y, R 1 -R 3 , x, y, m and n are as described in claim 1.
  5. 根据权利要求4所述的药物组合物，其特征在于，通式(I)化合物如通式(III)所示：The pharmaceutical composition according to claim 4, wherein the compound of the general formula (I) is represented by the general formula (III):
    Figure PCTCN2019099971-appb-100006
    Figure PCTCN2019099971-appb-100006
    环B选自杂环基或杂芳基；其中，杂环基优选包含3至20个环原子，其中一个或多个环原子为选自氮、氧、磷或S(O)t，其余环原子为碳，杂环基进一步优选包含3至12个环原子，其中1～4个环原子选自氮、氧和磷，其余环原子为 碳，杂环基更优选包含3至8个环原子，其中1～3个环原子选自氮、氧，其余环原子为碳，杂环基最优选包含5至7个环原子，其中1～2个环原子选自氮、氧，其余环原子为碳，杂环基进一步优选自吡咯、哌啶、氮杂环庚烷、吗啉、哌嗪；杂芳基优选包含5至14个环原子，其中1至4个环原子选自氮、氧、磷或S(O)t，其余环原子为碳，杂芳基进一步优选包含5至10个环原子，其中1至4个环原子选自氮、氧、磷或S(O)t，其余环原子为碳，杂芳基更优选包含5至10个环原子，其中1至3个环原子选自氮、氧、磷，其余环原子为碳，杂芳基最优选为包含5个或6个环原子，其中1至2个原子选自氮、氧；Ring B is selected from heterocyclyl or heteroaryl; wherein, heterocyclyl preferably contains 3 to 20 ring atoms, of which one or more ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, and the remaining rings The atom is carbon, and the heterocyclic group further preferably contains 3 to 12 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen and phosphorus, and the remaining ring atoms are carbon, and the heterocyclic group more preferably contains 3 to 8 ring atoms Wherein 1 to 3 ring atoms are selected from nitrogen and oxygen, and the remaining ring atoms are carbon. The heterocyclic group most preferably contains 5 to 7 ring atoms, of which 1 to 2 ring atoms are selected from nitrogen and oxygen, and the remaining ring atoms are Carbon, heterocyclic group is further preferably selected from pyrrole, piperidine, azacycloheptane, morpholine, piperazine; heteroaryl preferably contains 5 to 14 ring atoms, wherein 1 to 4 ring atoms are selected from nitrogen, oxygen, Phosphorus or S (O) t, the remaining ring atoms are carbon, and the heteroaryl group further preferably contains 5 to 10 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, and the remaining rings The atom is carbon, and the heteroaryl group more preferably contains 5 to 10 ring atoms, of which 1 to 3 ring atoms are selected from nitrogen, oxygen, and phosphorus, and the remaining ring atoms are carbon, and the heteroaryl group most preferably contains 5 or 6 Ring atoms, wherein 1-2 atoms selected from nitrogen, oxygen;
    R a选自氢原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，优选自氢原子、C 1-8烷基、氘代C 1-8烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、卤素、氨基、硝基、羟基、氰基、C 1-8烯基、C 1-8炔基、C 3-8环烷基、C 3-12杂环基、C 6-14芳基、C 5-14杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，更优选自氢原子、C 1-3烷基、氘代C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、卤素、氨基、硝基、羟基、氰基、C 2-4烯基、C 2-4炔基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，最优选自氢原子、甲基、乙基、正丙基、异丙基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、乙烯、丙烯、丁烯、乙炔、丙炔、丁炔、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基或C(O)CH 3； R a is selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, and a heterocyclic ring. , Aryl, heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 , -(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 , preferably from hydrogen Atom, C 1-8 alkyl, deuterated C 1-8 alkyl, halo C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy, halogen, amino, nitrate Group, hydroxy, cyano, C 1-8 alkenyl, C 1-8 alkynyl, C 3-8 cycloalkyl, C 3-12 heterocyclyl, C 6-14 aryl, C 5-14 heteroaryl Base,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 , - (CH 2) n NR 10 C (O) R 9 and - (CH 2) n NR 10 S (O) m R 9, and more preferably from hydrogen Sub, C 1-3 alkyl, deuterated C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, a C 1-3 alkoxy group, haloalkyl, halo, amino, nitro Group, hydroxy, cyano, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, C 5-10 heteroaryl Base,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 , optimally selected from hydrogen atom, methyl, ethyl Methyl, n-propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, Trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy , Chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, ethylene, propylene, butene, acetylene, propyne, butyne, cyclic Base, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydro Pyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl Oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl or C (O) CH 3 ;
    其中，R a任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、 -(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，优选被氘原子、C 1-8烷基、卤代C 1-8烷基、卤素、氨基、硝基、氰基、羟基、C 2-8烯基、C 2-8炔基、C 1-8烷氧基、卤代C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基、C 5-14杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，更优选被氘原子、C 1-3烷基、卤代C 1-3烷基、卤素、氨基、硝基、氰基、羟基、C 2-4烯基、C 2-4炔基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，最优选被氘原子、甲基、乙基、正丙基、异丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、乙烯、丙烯、丁烯、乙炔、丙炔、丁炔、羟基取代的甲基、羟基取代的乙基、羟基取代的丙基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基中的一个或多个取代基所取代； Wherein R a is optionally further selected from a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cyclic Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-( CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 Substitution, preferably by deuterium, C 1-8 alkyl, halo C 1-8 alkyl, halogen, amino, nitro, cyano, hydroxyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, halo C 1-8 alkoxy, C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl, C 5 -14 heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 , -(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 1 3 S (O) m R 12 is substituted by one or more substituents, more preferably by deuterium atom, C 1-3 alkyl, halo C 1-3 alkyl, halogen, amino, nitro, cyano , Hydroxyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, halo C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl , C 3-6 heterocyclyl, C 6-10 aryl, C 5-10 heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C ( O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 is substituted by one or more substituents, most preferably by a deuterium atom, methyl, ethyl, n-propyl, isopropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl Methyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy Group, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, ethylene, Ene, butene, acetylene, propyne, butyne, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrole Alkyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thio Morpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, Substituted by one or more substituents of pyrimidinyl, thiadiazole, pyrazinyl;
    或者，环B上任意两个R a取代基形成环烷基、杂环基、芳基和杂芳基，其中杂原子为选自氮、氧、硫、磷中的1至4个，优选任意两个R a取代基形成C 3-8环烷基、C 3-8杂环基、C 6-14芳基和C 5-14杂芳基，其中杂原子为选自氮、氧、硫、磷中的1至3个，更优选任意两个R a取代基形成C 3-6环烷基、C 3-6杂环基、C 6-10芳基和C 5-10杂芳基，其中杂原子为选自氮、氧中的1至2个，最优选任意两个R a取代基形成环丙基、环丁基、环戊基、C 3-5杂环基、C 6-7芳基和C 5-7杂芳基，其中杂原子为选自氮、氧中的1至2个； Alternatively, any two R a substituents on ring B form a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the hetero atom is 1 to 4 selected from nitrogen, oxygen, sulfur, and phosphorus, preferably any The two R a substituents form a C 3-8 cycloalkyl group, a C 3-8 heterocyclyl group, a C 6-14 aryl group, and a C 5-14 heteroaryl group, wherein the hetero atom is selected from nitrogen, oxygen, sulfur, 1 to 3, more preferably any two R a substituents in phosphorus form C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, and C 5-10 heteroaryl, wherein Heteroatoms are 1 to 2 selected from nitrogen and oxygen, most preferably any two R a substituents form cyclopropyl, cyclobutyl, cyclopentyl, C 3-5 heterocyclyl, C 6-7 aromatic And C 5-7 heteroaryl, wherein the hetero atom is 1 to 2 selected from nitrogen and oxygen;
    其中，所述任意两个R a取代基形成的环任选进一步被选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代，优选被选自氢原子、氘原子、C 1-8烷基、氘代C 1-8烷基、卤代C 1-8烷基、卤素、氨基、硝基、羟基、氰基、C 2-8 烯基、C 2-8炔基、C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基和C 5-14杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代，更优选被选自氢原子、氘原子、C 1-3烷基、氘代C 1-3烷基、卤代C 1-3烷基、卤素、氨基、硝基、羟基、氰基、C 2-4烯基、C 2-4炔基、C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、C 3-6杂环基、C 6-7芳基和C 5-7杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代；最优选被氢原子、氘原子、甲基、乙基、正丙基、异丙基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、乙烯、丙烯、丁烯、乙炔、丙炔、丁炔、甲氧基、乙氧基、丙氧基、羟基取代的甲基、羟基取代的乙基、羟基取代的丙基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基中的一个或多个取代基所取代； Wherein, the ring formed by any two R a substituents is optionally further selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, and , Alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and -(CH 2 ) n NR 10 S (O) m R 9 is substituted with one or more substituents, preferably selected from a hydrogen atom, a deuterium atom, a C 1-8 alkyl group, a deuterated C 1-8 alkane Alkyl, halo C 1-8 alkyl, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 1-8 hydroxy Alkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl and C 5-14 heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O ) m R 9 is substituted with one or more substituents, more preferably selected from a hydrogen atom, a deuterium atom, a C 1-3 alkyl group, a deuterated C 1-3 alkyl group, a halogenated C 1-3 alkyl group , Halogen, amino, nitro, hydroxyl, cyano, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl , C 3-6 heterocyclyl, C 6-7 aryl and C 5-7 heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 、-(CH 2 ) n C (O) R 9 、-(CH 2 ) n C (O) OR 9 、-(CH 2 ) n S (O) m R 9 、-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 is substituted by one or more substituents; most preferably by a hydrogen atom, deuterium atom, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, Deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, Fluoromethoxy, Fluoroethoxy, Fluoro Oxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, ethylene, propylene, butene, acetylene, propyne , Butyne, methoxy, ethoxy, propoxy, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetan Alkane, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl , Thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, Substituted by one or more substituents of pyridyl, pyrimidinyl, thiadiazole, and pyrazinyl;
    z为0、1、2、3、4或5的整数；z is an integer of 0, 1, 2, 3, 4 or 5;
    t为0、1或2。t is 0, 1, or 2.
  6. 根据权利要求5所述的药物组合物，其特征在于通式(I)化合物如通式(IV)所示：The pharmaceutical composition according to claim 5, characterized in that the compound of the general formula (I) is represented by the general formula (IV):
    Figure PCTCN2019099971-appb-100007
    Figure PCTCN2019099971-appb-100007
    其中：among them:
    M 5为O、-CR 6或-NR 7； M 5 is O, -CR 6 or -NR 7 ;
    R 6、R 7相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、 -(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，优选自氢原子、C 1-8烷基、氘代C 1-8烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、卤素、氨基、硝基、羟基、氰基、C 3-8环烷基、C 3-12杂环基、C 6-14芳基、C 5-14杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，更优选自氢原子、C 1-3烷基、氘代C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、卤素、氨基、硝基、羟基、氰基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，最优选自氢原子、甲基、乙基、正丙基、异丙基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基； R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyanide Group, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-( CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 , preferably from a hydrogen atom, C 1-8 alkyl, deuterated C 1-8 alkyl, halo C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy, halogen, amino, nitro, Hydroxyl, cyano, C 3-8 cycloalkyl, C 3-12 heterocyclyl, C 6-14 aryl, C 5-14 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-( CH 2 ) n NR 10 S (O) m R 9 , more preferably from hydrogen atom, C 1-3 alkyl, deuterated C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 3-6 ring Alkyl, C 3-6 heterocyclyl, C 6-10 aryl, C 5-10 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 , optimally selected from hydrogen atom, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluorine Ethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethyl Oxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, cyclopropyl, cyclo Butyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl Dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furan Base, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
    其中，所述的R 6、R 7任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；优选被选自氘原子、C 1-8烷基、卤代C 1-8烷基、卤素、氨基、硝基、羟基、氰基、C 1-8烷氧基、卤代C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基和C 5-14杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，更优选被选自氘原子、C 1-3烷基、卤代C 1-3烷基、卤素、氨基、硝基、羟基、氰基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基和C 5-10杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，最优选被甲基、乙基、正丙基、异丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲 氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、羟基取代的甲基、羟基取代的乙基、羟基取代的丙基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基中的一个或多个取代基所取代； Wherein, R 6 and R 7 are optionally further selected from a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, and a cyclic Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-( CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 Substitution; preferably selected from deuterium atom, C 1-8 alkyl, halo C 1-8 alkyl, halogen, amino, nitro, hydroxyl, cyano, C 1-8 alkoxy, halo C 1- 8 alkoxy, C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl and C 5-14 heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C (O) NR 12 R 13 、-(CH 2 ) n C (O) NHR 13 、-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 Substituted with one or more substituents, more preferably selected from deuterium atom, C 1-3 alkyl, halo C 1-3 alkyl, halogen, amino, nitro, hydroxyl, cyano, C 1-3 alkoxy Alkyl, halo C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, and C 5-10 heteroaryl ,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-( CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 are substituted with one or more substituents, most preferably methyl, ethyl, n-propyl Methyl, isopropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, Ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, Iodine, amino, nitro, hydroxyl, cyano, hydroxyl substituted methyl, hydroxyl substituted ethyl, hydroxyl substituted propyl , Cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl , Dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazole Substituted with one or more substituents of phenyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
    q为0、1或2。q is 0, 1, or 2.
  7. 根据权利要求5所述的药物组合物，其特征在于通式(I)化合物如通式(V)所示：The pharmaceutical composition according to claim 5, characterized in that the compound of the general formula (I) is represented by the general formula (V):
    Figure PCTCN2019099971-appb-100008
    Figure PCTCN2019099971-appb-100008
    其中：among them:
    o为0、1、2、3、4或5的整数。o is an integer of 0, 1, 2, 3, 4 or 5.
  8. 根据权利要求5-7任一项所述的药物组合物，其特征在于，The pharmaceutical composition according to any one of claims 5 to 7, characterized in that:
    M 1、M 2各自独立地选自N或-CR 6，可选的M 1、M 2不相同； M 1 and M 2 are each independently selected from N or -CR 6 , and optional M 1 and M 2 are different;
    X和Y各自独立地选自键、
    Figure PCTCN2019099971-appb-100009
    -NR 7-、-CR 7R 8-、-S(O) m-、
    Figure PCTCN2019099971-appb-100010
    Figure PCTCN2019099971-appb-100011
    可选的X和Y不相同；     X and Y are each independently selected from a bond,
    Figure PCTCN2019099971-appb-100009
    -NR 7- , -CR 7 R 8- , -S (O) m- ,
    Figure PCTCN2019099971-appb-100010
    Figure PCTCN2019099971-appb-100011
    The optional X and Y are different;
    环A选自芳基或杂芳基；所述芳基为6至14元全碳单环或稠合多环，优选为6至10元，更优选为苯基或萘基；所述杂芳基优选包含5至14个环原子，其中1至4个环原子选自氮、氧、磷或S(O)t，其余环原子为碳，杂芳基进一步优选包含5至10个环原子，其中1至4个环原子选自氮、氧、磷或S(O)t，其余环原子为碳，杂芳基更优选包含5至10个环原子，其中1至3个环原子选自氮、氧、磷，其余环原子为碳，最优选为咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑或吡嗪基，Ring A is selected from aryl or heteroaryl; the aryl is 6 to 14 membered full carbon monocyclic or fused polycyclic, preferably 6 to 10 members, more preferably phenyl or naphthyl; the heteroaryl The group preferably contains 5 to 14 ring atoms, of which 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, the remaining ring atoms are carbon, and the heteroaryl group further preferably contains 5 to 10 ring atoms, Wherein 1 to 4 ring atoms are selected from nitrogen, oxygen, phosphorus or S (O) t, the remaining ring atoms are carbon, and the heteroaryl group more preferably contains 5 to 10 ring atoms, of which 1 to 3 ring atoms are selected from nitrogen , Oxygen, phosphorus, the remaining ring atoms are carbon, most preferably imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl , Thiadiazole or pyrazinyl,
    Figure PCTCN2019099971-appb-100012
    Figure PCTCN2019099971-appb-100012
    杂芳基进一步最优选为包含5个或6个环原子，其中1至2个原子选自氮、氧；Heteroaryl is further most preferably comprising 5 or 6 ring atoms, of which 1 to 2 atoms are selected from nitrogen and oxygen;
    其中，所述环A任选进一步被选自氘原子、烷基、氘代烷基、卤素、氨基、硝基、羟基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代，优选被选自氘原子、C 1-8烷基、氘代C 1-8烷基、卤素、氨基、硝基、羟基、氰基、C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基和C 5-14杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代，更优选被选自氘原子、C 1-3烷基、氘代C 1-3烷基、卤素、氨基、硝基、羟基、氰基、C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基和C 5-10杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代，最优选被选自氘原子、甲基、乙基、正丙基、异丙基、氘代甲基、氘代乙基、氘代丙基、甲氧基、乙氧基、丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、甲氧基、乙氧基、丙氧基、羟基取代的甲基、羟基取代的乙基、羟基取代的丙基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基、
    Figure PCTCN2019099971-appb-100013
    Figure PCTCN2019099971-appb-100014
    Figure PCTCN2019099971-appb-100015
    中的一个或多个取代基所取代；     Wherein, the ring A is optionally further selected from a deuterium atom, an alkyl group, a deuterated alkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group , Aryl and heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 、-(CH 2 ) n S (O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C (O) NR 10 R 11 、-(CH 2 ) n C ( O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 are substituted with one or more substituents, preferably selected from Deuterium atom, C 1-8 alkyl, deuterated C 1-8 alkyl, halogen, amino, nitro, hydroxyl, cyano, C 1-8 alkoxy, C 1-8 hydroxyalkyl, C 3- 8 -cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl and C 5-14 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S ( O) m R 9 is substituted with one or more substituents, more preferably selected from a deuterium atom, C 1- 3 alkyl, deuterated C 1-3 alkyl, halogen, amino, nitro, hydroxy, cyano, C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl and C 5-10 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O ) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 Substituted with one or more substituents, most preferably selected from deuterium, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, methoxy , Ethoxy, propoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxy, cyano, methoxy, ethoxy, propoxy, hydroxy-substituted methyl, hydroxy-substituted ethyl , Hydroxy-substituted propyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl , Dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, Base, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , Pyridyl, pyrimidinyl, thiadiazole, pyrazinyl,
    Figure PCTCN2019099971-appb-100013
    Figure PCTCN2019099971-appb-100014
    Figure PCTCN2019099971-appb-100015
    With one or more substituents;
    R 2相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；优选自氢原子、氘原子、C 1-8烷基、氘代C 1-8烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、卤素、氨基、硝基、羟基、氰基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基、C 5-14杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；更优选自氢原子、氘原子、C 1-6烷基、氘代C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、卤素、氨基、硝基、羟基、氰基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；最优选自氢原子、氘原子、甲基、乙基、正丙基、异丙基、、正丁基、异丁基、叔丁基、仲丁基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、羟基取代的甲基、羟基取到的乙基、羟基取代的丙基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基。 R 2 is the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen group, an amino group, a nitro group, a hydroxy group, a cyano group, a cyclic Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-( CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ; preferably from a hydrogen atom, a deuterium atom, C 1-8 alkyl, deuterated C 1-8 alkyl, halo C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy, halogen, amino, nitro, Hydroxy, cyano, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl, C 5-14 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-( CH 2) n NR 10 S ( O) m R 9; more preferably from hydrogen atom, deuterium atom, C 1-6 Group, deuterated C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy, halo, amino, nitro, hydroxy, cyano, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, C 5-10 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,- (CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 , -(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ; optimally selected from hydrogen atom, deuterium atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, deuterium Methyl, deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chlorine Propyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy Methyl, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxy , Cyano, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydro Pyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furanyl, thienyl, thiazolyl , Pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl.
  9. 根据权利要求5所述的药物组合物，其特征在于，通式(I)化合物如通式(III-A)所示：The pharmaceutical composition according to claim 5, wherein the compound of the general formula (I) is represented by the general formula (III-A):
    Figure PCTCN2019099971-appb-100016
    Figure PCTCN2019099971-appb-100016
  10. 根据权利要求9所述的药物组合物，其特征在于，通式(I)化合物如通式(III-A1)或通式(III-A2)所示：The pharmaceutical composition according to claim 9, wherein the compound of the general formula (I) is represented by the general formula (III-A1) or the general formula (III-A2):
    Figure PCTCN2019099971-appb-100017
    Figure PCTCN2019099971-appb-100017
    其中，among them,
    环C为4-7元杂环基或杂芳基，其中一个或多个环原子为选自氮、氧或S(O)t的杂原子，其余环原子为碳，优选包含1-2个氮或氧原子的5元杂环基；所述杂芳基优选包含1至4个杂原子，其中杂原子选自氧、硫和氮，优选为包含1至两个氮或氧的杂原子的5元或6元杂芳基；优选的，环C为以下结构：Ring C is a 4-7 membered heterocyclyl or heteroaryl group, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S (O) t, and the remaining ring atoms are carbon, preferably containing 1-2 5-membered heterocyclic group of nitrogen or oxygen atom; the heteroaryl group preferably contains 1 to 4 heteroatoms, wherein the heteroatom is selected from the group consisting of oxygen, sulfur and nitrogen, preferably a heteroatom containing 1 to 2 nitrogen or oxygen 5- or 6-membered heteroaryl; preferably, ring C has the following structure:
    Figure PCTCN2019099971-appb-100018
    Figure PCTCN2019099971-appb-100018
    R b选自氢原子、C 1-8烷基、C 1-8氘代烷基或C 1-8卤代烷基； R b is selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 deuterated alkyl group, or a C 1-8 haloalkyl group;
    t为0、1或2。t is 0, 1, or 2.
  11. 根据权利要求10所述的药物组合物，其特征在于：R 1相同或不同，且各自独立地选自氢原子、氘原子、C 1-8烷基、氘代C 1-8烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、卤素、氨基、硝基、羟基、氰基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基、C 5-14杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9； The pharmaceutical composition according to claim 10, wherein R 1 is the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, a C 1-8 alkyl group, a deuterated C 1-8 alkyl group, a halogen C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 3-8 cycloalkyl, C 3-8 Heterocyclyl, C 6-14 aryl, C 5-14 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 , -(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ;
    其中所述的R 1任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，优选被选自氢原子、氘原子、C 1-8烷基、氘代C 1-8烷基、卤代C 1-8烷基、C 1-8烷氧基、 卤代C 1-8烷氧基、C 1-8羟烷基、卤素、氨基、硝基、羟基、氰基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基、C 5-14杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代，更优选被选自氢原子、氘原子、C 1-6烷基、氘代C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、卤素、氨基、硝基、羟基、氰基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代，最优选被选自氢原子、氘原子、甲基、乙基、正丙基、异丙基、、正丁基、异丁基、叔丁基、仲丁基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、羟基取代的甲基、羟基取到的乙基、羟基取代的丙基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基中的一个或多个取代。 Wherein R 1 is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, a hetero Cyclic, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O ) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 is substituted by one or more substituents in C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 , preferably by Selected from hydrogen atom, deuterium atom, C 1-8 alkyl, deuterated C 1-8 alkyl, halo C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy , C 1-8 hydroxyalkyl, halogen, amino, nitro, hydroxyl, cyano, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl, C 5-14 heteroaryl Base,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,- (CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 is substituted with one or more substituents, more preferably selected from a hydrogen atom, a deuterium atom, a C 1-6 alkyl group, a deuterated C 1-6 alkyl group, a halogenated C 1-6 alkyl group, C 1-6 alkoxy, halo C 1-6 alkoxy, C 1-6 hydroxyalkyl, halogen, amino, nitro, hydroxyl, cyano, C 3-6 cycloalkyl, C 3-6 hetero Cyclic group, C 6-10 aryl group, C 5-10 heteroaryl group,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,- (CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 Substituted with a substituent, most preferably selected from hydrogen atom, deuterium atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, deuterated Methyl, deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloro Propyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy Chloroethoxy, chloropropoxy, hydroxy-substituted methyl, hydroxy-derived ethyl, hydroxy-substituted propyl, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, cyclic Propyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, di Hydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, One or more of oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, and pyrazinyl are substituted.
  12. 根据权利要求11所述的药物组合物，其特征在于：R 1相同或不同，且各自独立地选自选自氢原子、氘原子、C 1-3烷基、氘代C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、卤素、氨基、硝基、羟基、氰基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的R 1任选进一步被取代。 The pharmaceutical composition according to claim 11, wherein R 1 is the same or different, and each is independently selected from the group consisting of a hydrogen atom, a deuterium atom, a C 1-3 alkyl group, and a deuterated C 1-3 alkyl group. , Halogenated C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 3-6 cycloalkyl, C 3 -6 heterocyclyl, C 6-10 aryl, C 5-10 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 、-(CH 2 ) n C (O) OR 9 、-(CH 2 ) n S (O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ; of which The R 1 is optionally further substituted.
  13. 根据权利要求12所述的药物组合物，其特征在于：R 1选自氢原子、氘原子、甲基、乙基、正丙基、异丙基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪 基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基；任选被选自氢原子、氘原子、甲基、乙基、正丙基、异丙基、、正丁基、异丁基、叔丁基、仲丁基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、羟基取代的甲基、羟基取到的乙基、羟基取代的丙基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基中的一个或多个取代。 The pharmaceutical composition according to claim 12, wherein: R 1 is selected from a hydrogen atom, a deuterium atom, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, ethyl deuterated, deuterium Propyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy Group, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, Amino, nitro, hydroxyl, cyano, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, di Hydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl , Thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl; optionally selected from a hydrogen atom, a deuterium atom Methyl, B , N-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, deuterated methyl, deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl , Fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluorine Ethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, hydroxy-substituted methyl, hydroxy-derived ethyl, hydroxy-substituted propyl, fluoro, Chlorine, bromine, iodine, amino, nitro, hydroxy, cyano, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, Dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl , One, or more of imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl Replaced.
  14. 根据权利要求10所述的药物组合物，其特征在于通式(I)化合物如通式(VI-A)或通式(VI-B)所示：The pharmaceutical composition according to claim 10, wherein the compound of the general formula (I) is represented by the general formula (VI-A) or the general formula (VI-B):
    Figure PCTCN2019099971-appb-100019
    Figure PCTCN2019099971-appb-100019
    R 5选自氢原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、羟烷基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，优选自氢原子、C 1-8烷基、氘代C 1-8烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、卤素、氨基、硝基、羟基、C 1-8羟烷基、氰基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基、C 5-14杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，更优选自氢原子、C 1-6烷基、氘代C 1-6烷基、卤代C 1-6烷基、C 1-8烷氧基、卤代C 1-8烷氧基、卤素、氨基、硝基、羟基、C 1-6羟烷基、氰基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，最优选自氢原子、甲基、乙基、正丙基、异丙基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲 基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、羟基取代的甲基、羟基取代的乙基、羟基取代的丙基、羟基取代的丁基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基； R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cyano group, a cycloalkyl group, a heterocyclic group, Aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O ) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 , preferably from hydrogen atom, C 1-8 alkyl, deuterated C 1-8 alkyl, halo C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy, halogen, amino, nitro, hydroxyl, C 1-8 hydroxyalkyl, Cyano, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl, C 5-14 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 、-(CH 2 ) n C (O) R 9 、-(CH 2 ) n C (O) OR 9 、-(CH 2 ) n S (O) m R 9 、-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9, and more preferably from hydrogen atoms, C 1-6 alkyl, deuterated C 1-6 alkyl, halo C 1-6 alkyl , C 1-8 alkoxy, halo C 1-8 alkoxy, halo, amino, nitro, hydroxy, C 1-6 hydroxyalkyl, cyano, C 3-6 cycloalkyl, C 3- 6 heterocyclyl, C 6-10 aryl, C 5-10 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 , most preferred From hydrogen atom, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoro Propyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropyl Oxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxy, cyano, hydroxy-substituted methyl, hydroxy-substituted ethyl , Hydroxy-substituted propyl, hydroxy-substituted butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane , Pyrrolidinyl, imidazolyl, tetrahydrofuryl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, Thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridine Group, pyrimidinyl, thiadiazole, pyrazinyl;
    其中，R 5任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，优选被氘原子、C 1-8烷基、卤代C 1-8烷基、卤素、氨基、硝基、氰基、羟基、C 1-8烷氧基、卤代C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基、C 5-14杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；更优选被氘原子、C 1-6烷基、卤代C 1-6烷基、卤素、氨基、硝基、氰基、羟基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6羟烷基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；最优选被氘原子、甲基、乙基、正丙基、异丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、羟基取代的甲基、羟基取代的乙基、羟基取代的丙基、羟基取代的丁基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基中的一个或多个取代； Wherein R 5 is optionally further selected from the group consisting of a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group. , Aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C ( O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 are substituted with one or more substituents, preferably a deuterium atom , C 1-8 alkyl, halo C 1-8 alkyl, halogen, amino, nitro, cyano, hydroxyl, C 1-8 alkoxy, halo C 1-8 alkoxy, C 1- 8 -hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl, C 5-14 heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-( in a 12 CH 2) n NR 13 S (O) m R or more substituents Generation; more preferably a deuterium atom, C 1-6 alkyl, halo C 1-6 alkyl, halo, amino, nitro, cyano, hydroxy, C 1-6 alkoxy, halo C 1-6 Alkoxy, C 1-6 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, C 5-10 heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C ( O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 are substituted by one or more substituents; most preferably by a deuterium atom, methyl, ethyl, n-propyl, isopropyl , Difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propyl Oxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitrate Hydroxy, cyano, hydroxy-substituted methyl, hydroxy-substituted ethyl, hydroxy-substituted propyl, hydroxy-substituted Butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyridine Oxazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, One or more substitutions of pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
    x-1为1、2、3或4的整数。x-1 is an integer of 1, 2, 3, or 4.
  15. 根据权利要求14所述的药物组合物，其特征在于通式(I)化合物如通式(VI-A1)或通式(VI-B1)所示：The pharmaceutical composition according to claim 14, characterized in that the compound of the general formula (I) is represented by the general formula (VI-A1) or the general formula (VI-B1):
    Figure PCTCN2019099971-appb-100020
    Figure PCTCN2019099971-appb-100020
    M 5为O、-CR 6或-NR 7； M 5 is O, -CR 6 or -NR 7 ;
    R 6、R 7相同或不同，且各自独立地选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，优选自氢原子、C 1-8烷基、氘代C 1-8烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、卤素、氨基、硝基、羟基、氰基、C 3-8环烷基、C 3-12杂环基、C 6-14芳基、C 5-14杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，更优选自氢原子、C 1-3烷基、氘代C 1-3烷基、卤代C 1-3烷基、C 1-3烷氧基、卤代C 1-3烷氧基、卤素、氨基、硝基、羟基、氰基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基、C 5-10杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9，最优选自氢原子、甲基、乙基、正丙基、异丙基、氘代甲基、氘代乙基、氘代丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基； R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyanide Group, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-( CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 , preferably from a hydrogen atom, C 1-8 alkyl, deuterated C 1-8 alkyl, halo C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy, halogen, amino, nitro, Hydroxyl, cyano, C 3-8 cycloalkyl, C 3-12 heterocyclyl, C 6-14 aryl, C 5-14 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-( CH 2 ) n NR 10 S (O) m R 9 , more preferably from hydrogen atom, C 1-3 alkyl, deuterated C 1 -3 alkyl, halo C 1-3 alkyl, C 1-3 alkoxy, halo C 1-3 alkoxy, halogen, amino, nitro, hydroxyl, cyano, C 3-6 cycloalkane , C 3-6 heterocyclyl, C 6-10 aryl, C 5-10 heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 , preferably selected from hydrogen atom, methyl, ethyl, n-propyl, isopropyl, deuterated methyl, deuterated ethyl, deuterated propyl, difluoromethyl, trifluoromethyl, fluoro Ethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, ethoxy, propoxy, fluoromethoxy, fluoroethoxy Methyl, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, iodine, amino, nitro, hydroxyl, cyano, cyclopropyl, cyclobutane Base, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl Dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furan Base, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl;
    其中，所述的R 6、R 7任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；优选被选自氘原子、C 1-8烷基、卤代C 1-8烷基、卤素、氨基、硝基、羟基、氰基、C 1-8烷氧基、卤代C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、C 3-8杂环基、C 6-14芳基和C 5-14杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、 -(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，更优选被选自氘原子、C 1-3烷基、卤代C 1-3烷基、卤素、氨基、硝基、羟基、氰基、C 1-3烷氧基、卤代C 1-3烷氧基、C 1-3羟烷基、C 3-6环烷基、C 3-6杂环基、C 6-10芳基和C 5-10杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代，最优选被甲基、乙基、正丙基、异丙基、二氟甲基、三氟甲基、氟代乙基、氟代丙基、二氯甲基、三氯甲基、氯代乙基、氯代丙基、甲氧基、乙氧基、丙氧基、氟代甲氧基、氟代乙氧基、氟代丙氧基、氯代甲氧基、氯代乙氧基、氯代丙氧基、氟、氯、溴、碘、氨基、硝基、羟基、氰基、羟基取代的甲基、羟基取代的乙基、羟基取代的丙基、环丙基、环丁基、环戊基、氧杂环丁烷、吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、苯基、咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、***基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基中的一个或多个取代基所取代； Wherein, R 6 and R 7 are optionally further selected from the group consisting of a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, and a cyclic group. Alkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-( CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 Substitution; preferably selected from deuterium atom, C 1-8 alkyl, halo C 1-8 alkyl, halogen, amino, nitro, hydroxyl, cyano, C 1-8 alkoxy, halo C 1- 8 alkoxy, C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, C 3-8 heterocyclyl, C 6-14 aryl and C 5-14 heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 、-(CH 2 ) n NR 12 R 13 、-(CH 2 ) n C (O) NR 12 R 13 、-(CH 2 ) n C (O) NHR 13 、-(CH 2 ) n NR 13 C (O) R 12 and - of (CH 2) n NR 13 S (O) m R 12 a Or more substituents, selected from more preferably a deuterium atom, C 1-3 alkyl, halo C 1-3 alkyl, halo, amino, nitro, hydroxy, cyano, C 1-3 alkoxy Alkyl, halo C 1-3 alkoxy, C 1-3 hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 heterocyclyl, C 6-10 aryl, and C 5-10 heteroaryl ,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-( CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 are substituted with one or more substituents, most preferably methyl, ethyl, n-propyl Methyl, isopropyl, difluoromethyl, trifluoromethyl, fluoroethyl, fluoropropyl, dichloromethyl, trichloromethyl, chloroethyl, chloropropyl, methoxy, Ethoxy, propoxy, fluoromethoxy, fluoroethoxy, fluoropropoxy, chloromethoxy, chloroethoxy, chloropropoxy, fluorine, chlorine, bromine, Iodine, amino, nitro, hydroxyl, cyano, hydroxyl-substituted methyl, hydroxyl-substituted ethyl, hydroxyl-substituted propyl , Cyclopropyl, cyclobutyl, cyclopentyl, oxetane, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl , Dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, phenyl, imidazolyl, furyl, thienyl, thiazolyl, pyrazole Substituted with one or more substituents of the group, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, and pyrazinyl;
    q为0、1或2。q is 0, 1, or 2.
  16. 根据权利要求14所述的药物组合物，其特征在于通式(I)化合物如通式(VI-A2)或通式(VI-B2)所示：The pharmaceutical composition according to claim 14, characterized in that the compound of the general formula (I) is represented by the general formula (VI-A2) or the general formula (VI-B2):
    Figure PCTCN2019099971-appb-100021
    Figure PCTCN2019099971-appb-100021
    o为0、1、2、3、4或5的整数。o is an integer of 0, 1, 2, 3, 4 or 5.
  17. 根据权利要求1所述的药物组合物，其特征在于通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(VII)化合物：The pharmaceutical composition according to claim 1, characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compounds of the general formula (VII):
    Figure PCTCN2019099971-appb-100022
    Figure PCTCN2019099971-appb-100022
    其中：among them:
    环B选自杂环基或杂芳基；Ring B is selected from heterocyclyl or heteroaryl;
    R 5选自氢原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、羟烷基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；优选环丙基； R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cyano group, a cycloalkyl group, a heterocyclic group, Aryl, heteroaryl,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O ) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ; the alkyl, haloalkyl, cycloalkyl, hetero The cyclic group, aryl group and heteroaryl group are optionally further selected from the group consisting of a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a hydroxyalkyl group, and a cycloalkane group. Group, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and-(CH 2 ) n NR 13 S (O) m R 12 ; Cyclopropyl is preferred;
    R a选自氢原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9；其中所述的烷基、烯基、炔基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-(CH 2) nOR 12、-(CH 2) nSR 12、-(CH 2) nC(O)R 12、-(CH 2) nC(O)OR 12、-(CH 2) nS(O) mR 12、-(CH 2) nNR 12R 13、-(CH 2) nC(O)NR 12R 13、-(CH 2) nC(O)NHR 13、-(CH 2) nNR 13C(O)R 12和-(CH 2) nNR 13S(O) mR 12中的一个或多个取代基所取代；优选C 1-8烷基、C 1-8烷氧基、C 1-8环烷基； R a is selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, and a heterocyclic ring. , Aryl, heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 , -(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 ; wherein Alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, haloalkyl, halogen, amino, nitro, cyano Group, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH 2 ) n OR 12 ,-(CH 2 ) n SR 12 ,-(CH 2 ) n C (O) R 12 ,-(CH 2 ) n C (O) OR 12 ,-(CH 2 ) n S (O) m R 12 ,-(CH 2 ) n NR 12 R 13 ,-(CH 2 ) n C (O) NR 12 R 13 ,-(CH 2 ) n C (O) NHR 13 ,-(CH 2 ) n NR 13 C (O) R 12 and- (CH 2 ) n NR 13 S (O) m R 12 is substituted by one or more substituents; preferably C 1-8 alkyl, C 1-8 alkoxy, C 1-8 cycloalkyl;
    或者，环B上任意两个R a取代基形成环烷基、杂环基、芳基和杂芳基，其中所述环烷基、芳环基、杂环基或杂芳环基任选进一步被选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代； Alternatively, any two R a substituents on ring B form a cycloalkyl, heterocyclyl, aryl, and heteroaryl group, wherein the cycloalkyl, aromatic ring group, heterocyclic group, or heteroaryl ring group is optionally further Is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a hydroxy group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, Heterocyclyl, aryl and heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 、-(CH 2 ) n C (O) OR 9 、-(CH 2 ) n S (O) m R 9 、-(CH 2 ) n NR 10 R 11 、-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 Substituted with one or more substituents;
    x-1为1、2、3或4的整数；且x-1 is an integer of 1, 2, 3, or 4; and
    z为0、1、2、3、4或5的整数；z is an integer of 0, 1, 2, 3, 4 or 5;
    环A、M 1、M 2、X、Y、R 1、R 2、y、m和n如权利要求1所述。 Rings A, M 1 , M 2 , X, Y, R 1 , R 2 , y, m and n are as described in claim 1.
  18. 根据权利要求17所述的药物组合物，其特征在于，环B选自杂环基时，优选包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O)t的杂原子，t为0、1或2，其余环原子为碳；更优选包含3至12个环原子，其中1 至4个是选自氮、氧的杂原子；最优选包含5至7个环原子，其中1至2个是选自氮、氧的杂原子；环B选自杂芳基时，优选包含1至4个杂原子、5至14个环原子的杂芳基，其中杂原子选自氧、硫和氮，更优选为包含1至2个杂原子的5至10元杂芳基，其中杂原子选自氧和氮，最优选为包含1至2个杂原子的5元或6元杂芳基，其中杂原子选自氧和氮；The pharmaceutical composition according to claim 17, wherein when ring B is selected from heterocyclic groups, it preferably contains 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O ) hetero atom of t, t is 0, 1 or 2, the remaining ring atoms are carbon; more preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms selected from nitrogen and oxygen; most preferably 5 to 7 ring atoms, of which 1 to 2 are heteroatoms selected from nitrogen and oxygen; when ring B is selected from heteroaryl, a heteroaryl group containing 1 to 4 heteroatoms and 5 to 14 ring atoms is preferred, wherein The heteroatom is selected from oxygen, sulfur and nitrogen, more preferably a 5- to 10-membered heteroaryl group containing 1 to 2 heteroatoms, wherein the heteroatom is selected from oxygen and nitrogen, and most preferably 5 to 1 to 2 heteroatoms 6-membered or 6-membered heteroaryl, wherein the heteroatom is selected from oxygen and nitrogen;
    进一步环B优选的结构如下：Further preferred structure of ring B is as follows:
    Figure PCTCN2019099971-appb-100023
    Figure PCTCN2019099971-appb-100023
  19. 根据权利要求1-2、4、17-18任一项所述的药物组合物，其特征在于通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(VIII)化合物：The pharmaceutical composition according to any one of claims 1-2, 4, 17-18, characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following general formula ( VIII) Compound:
    Figure PCTCN2019099971-appb-100024
    Figure PCTCN2019099971-appb-100024
    其中：among them:
    环A、环B、M 1、M 2、R 1、R 2、R 5、R a、x-1、y和z如权利要求17所述。 Ring A, ring B, M 1, M 2, R 1, R 2, R 5, R a, x-1, y and z are as defined in claim 17.
  20. 根据权利要求1-2、4、17、19任一项所述的药物组合物，其特征在于，通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(IX)化合物：The pharmaceutical composition according to any one of claims 1-2, 4, 17, 19, wherein the compound of general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the following general formula (IX) Compound:
    Figure PCTCN2019099971-appb-100025
    Figure PCTCN2019099971-appb-100025
    其中：among them:
    环B、R 1、R 5、R a、x-1和z如权利要求19所述。 Ring B, R 1, R 5, R a, x-1 and z as claimed in claim 19.
  21. 根据权利要求1-2、4、17、19-20所述的药物组合物，其特征在，于通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(X-A)化合物：The pharmaceutical composition according to claims 1-2, 4, 17, 19-20, wherein the compound of the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the following general formula (XA) Compound:
    Figure PCTCN2019099971-appb-100026
    Figure PCTCN2019099971-appb-100026
    其中：among them:
    M 5为O、-CR 6或-NR 7； M 5 is O, -CR 6 or -NR 7 ;
    R 1选自氢原子、C 1-8烷基或卤素； R 1 is selected from a hydrogen atom, a C 1-8 alkyl group or a halogen;
    R 5选自C 1-8烷基、C 3-8环烷基、C 1-8卤代烷基、C 1-8羟烷基或3-6元杂环基； R 5 is selected from C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, or 3-6 membered heterocyclic group;
    R a相同或不同，各自独立的选自氢原子、氰基、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 1-8卤代烷基、C 1-8羟代烷基、C 1-8烷氧基、C 3-8环烷基、-(CH 2) nOR 9、-(CR 9R 10) n-或-(CH 2) nC(O)R 9，其中所述的C 1-8烷基、C 2-8烯基、C 2-8炔基、卤代C 1-8烷基、C 1-8羟代烷基、C 1-8烷氧基和C 3-8环烷基任选进一步被选自氢原子、氘原子、卤素、氰基、羟基、C 1-8烷基、C 1-8羟烷基或C 1-8烷氧基中的一个或多个取代基所取代；或者任意两个R a取代基形成C 3-8环烷基或C 3-8杂环基； R a is the same or different and each is independently selected from the group consisting of a hydrogen atom, a cyano group, a C 1-8 alkyl group, a C 2-8 alkenyl group, a C 2-8 alkynyl group, a C 1-8 haloalkyl group, and a C 1-8 hydroxy group Alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl,-(CH 2 ) n OR 9 ,-(CR 9 R 10 ) n -or-(CH 2 ) n C (O) R 9 , wherein the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, halo C 1-8 alkyl, C 1-8 hydroxyalkyl, C 1-8 alkane An oxy group and a C 3-8 cycloalkyl group are optionally further selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a hydroxyl group, a C 1-8 alkyl group, a C 1-8 hydroxyalkyl group, or a C 1-8 alkoxy group. Substituted with one or more substituents in the group; or any two R a substituents form a C 3-8 cycloalkyl or a C 3-8 heterocyclyl;
    R 9和R 10相同或不同，各自独立的选自氢原子、C 1-8烷基、C 1-8卤代烷基、C 1-8羟代烷基或C 1-8烷氧基； R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 haloalkyl group, a C 1-8 hydroxyalkyl group, or a C 1-8 alkoxy group;
    x-1为1、2、3或4的整数；x-1 is an integer of 1, 2, 3 or 4;
    q为0、1或2；且q is 0, 1, or 2; and
    z为0、1、2、3、4或5的整数。z is an integer of 0, 1, 2, 3, 4 or 5.
  22. 根据权利要求1-2、4、17、19-21所述的药物组合物，其特征在于，通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(XI)化合物：The pharmaceutical composition according to claims 1-2, 4, 17, 19-21, wherein the compound of the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the following general formula ( XI) Compound:
    Figure PCTCN2019099971-appb-100027
    Figure PCTCN2019099971-appb-100027
    其中：among them:
    R a选自氢原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、环烷基、杂环基、芳基、杂芳基、-(CR 9R 10) n-和-(CH 2) nOR 9；其中所述的烷基、卤代烷基、环烷基、烯基、炔基、杂环基、芳基和杂芳基任选进一步被选自氘原子、烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烯基、炔基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基和-(CH 2) nOR 12中的一个或多个取代基所取代；优选C 1-8烷基、C 1-8烷氧基、C 1-8环烷基； R a is selected from the group consisting of a hydrogen atom, an alkyl group, a deuterated alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, and a heterocyclic ring Aryl, aryl, heteroaryl,-(CR 9 R 10 ) n -and-(CH 2 ) n OR 9 ; wherein the alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, heterocyclic ring Group, aryl and heteroaryl are optionally further selected from the group consisting of a deuterium atom, an alkyl group, a haloalkyl group, a halogen, an amino group, a nitro group, a cyano group, a hydroxy group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkoxy group, a hydroxy group Alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and-(CH 2 ) n OR 12 are substituted with one or more substituents; preferably C 1-8 alkyl, C 1-8 alkane Oxy, C 1-8 cycloalkyl;
    或者，任意两个R a取代基可以形成环烷基、杂环基、芳基和杂芳基，其中所述环烷基、芳环基、杂环基或杂芳环基任选进一步被选自氢原子、氘原子、烷基、氘代烷基、卤代烷基、卤素、氨基、硝基、羟基、氰基、烯基、炔基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代； Alternatively, any two R a substituents may form a cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the cycloalkyl, arylcyclyl, heterocyclyl, or heteroarylcyclyl is optionally further selected From hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclic , Aryl and heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 , -(CH 2 ) n C (O) OR 9 ,-(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 or Substituted with multiple substituents;
    o为0、1、2、3、4或5的整数；且o is an integer of 0, 1, 2, 3, 4 or 5; and
    R 1、R 5、x-1和z如权利要求21所述。 R 1 , R 5 , x-1 and z are as described in claim 21.
  23. 根据权利要求1-2、4、17、19-22所述的药物组合物，其特征在于，通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(XII)化合物：The pharmaceutical composition according to claims 1-2, 4, 17, 19-22, wherein the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the following general formula ( XII) Compound:
    Figure PCTCN2019099971-appb-100028
    Figure PCTCN2019099971-appb-100028
    其中：among them:
    R a相同或不同，各自独立的选自氢原子、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基、C 3-6环烷基、-(CH 2) nOR 9或-(CR 9R 10) n-，其中所述的C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6卤代烷基、C 1-6烷氧基和C 3-6环烷基任选进一步被选自氢原子、卤素、氰基、羟基、C 1-6烷基或C 1-6烷氧基中的一个或多个取代基所取代； R a is the same or different and each is independently selected from the group consisting of hydrogen atom, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkane Oxy, C 3-6 cycloalkyl,-(CH 2 ) n OR 9 or-(CR 9 R 10 ) n- , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2 -6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 3-6 cycloalkyl are optionally further selected from hydrogen atom, halogen, cyano, hydroxy, C 1-6 alkyl or Substituted with one or more substituents in C 1-6 alkoxy;
    或者任意两个R a取代基可以形成3-6元环烷基，且 Or any two R a substituents may form a 3-6 membered cycloalkyl group, and
    z为0、1、2或3的整数。z is an integer of 0, 1, 2 or 3.
  24. 根据权利要求1所述的药物组合物，其特征在于，通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(XIII-A)化合物：The pharmaceutical composition according to claim 1, characterized in that the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compounds of the general formula (XIII-A):
    Figure PCTCN2019099971-appb-100029
    Figure PCTCN2019099971-appb-100029
    其中：among them:
    R 3和R 4链接形成的3-10元杂环或5-10元杂芳环，其中所述的3-10元杂环或5-10元杂芳环任选进一步被选自氘原子、C 1-8烷基、C 1-8氘代烷基、C 1-8卤代烷基、卤素、氨基、硝基、羟基、氰基、C 2-8烯基、C 2-8炔基、C 1-8烷氧基、C 1-8羟烷基、C 3-8环烷基、3-10元杂环基、6-10元芳基和5-10元杂芳基、-(CR 9R 10) n-、-(CH 2) nOR 9、-(CH 2) nSR 9、-(CH 2) nC(O)R 9、-(CH 2) nC(O)OR 9、-(CH 2) nS(O) mR 9、-(CH 2) nNR 10R 11、-(CH 2) nC(O)NR 10R 11、-(CH 2) nC(O)NHR 10、-(CH 2) nNR 10C(O)R 9和-(CH 2) nNR 10S(O) mR 9中的一个或多个取代基所取代； R 3 and R 4 are linked to form a 3-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring, wherein the 3-10 membered heterocyclic ring or 5-10 membered heteroaromatic ring is optionally further selected from a deuterium atom, C 1-8 alkyl, C 1-8 deuterated alkyl, C 1-8 haloalkyl, halogen, amino, nitro, hydroxyl, cyano, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 1-8 hydroxyalkyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, and 5-10 membered heteroaryl,-(CR 9 R 10 ) n -,-(CH 2 ) n OR 9 ,-(CH 2 ) n SR 9 ,-(CH 2 ) n C (O) R 9 ,-(CH 2 ) n C (O) OR 9 , -(CH 2 ) n S (O) m R 9 ,-(CH 2 ) n NR 10 R 11 ,-(CH 2 ) n C (O) NR 10 R 11 ,-(CH 2 ) n C (O) NHR 10 ,-(CH 2 ) n NR 10 C (O) R 9 and-(CH 2 ) n NR 10 S (O) m R 9 are substituted by one or more substituents;
    R b选自氢原子、C 1-8烷基、C 1-8氘代烷基或C 1-8卤代烷基； R b is selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 deuterated alkyl group, or a C 1-8 haloalkyl group;
    R 1选自氢原子、C 1-8烷基、C 1-8氘代烷基或C 1-8卤代烷基； R 1 is selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 deuterated alkyl group, or a C 1-8 haloalkyl group;
    x-1为0、1、2或3的整数；x-1 is an integer of 0, 1, 2 or 3;
    p为0、1、2、3或4的整数。p is an integer of 0, 1, 2, 3, or 4.
  25. 根据权利要求24所述的药物组合物，其特征在于，环C为4-7元杂环基或杂芳基，优选5元杂环基，环C最优选结构如下：The pharmaceutical composition according to claim 24, wherein ring C is a 4- to 7-membered heterocyclic group or a heteroaryl group, preferably a 5-membered heterocyclic group, and the most preferred structure of ring C is as follows:
    Figure PCTCN2019099971-appb-100030
    Figure PCTCN2019099971-appb-100030
  26. 根据权利要求1所述的药物组合物，其特征在于，通式(I)化合物、其立体异构体或其药学上可接受盐选自如下通式(XIII-B)化合物：The pharmaceutical composition according to claim 1, wherein the compound of the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is selected from the compounds of the general formula (XIII-B):
    Figure PCTCN2019099971-appb-100031
    Figure PCTCN2019099971-appb-100031
    其中：among them:
    环C为5-7元杂环基或杂芳基，优选5元杂环基；Ring C is a 5- to 7-membered heterocyclic group or a heteroaryl group, preferably a 5-membered heterocyclic group;
    R a相同或不同，各自独立的选自氢原子、氰基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-6环烷基、-(CH 2) nOR 9、-(CR 9R 10) n-或-(CH 2) nC(O)R 9，或者任意两个R a取代基可以形成3-6元环烷基； They are the same or different R a, each independently selected from hydrogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, - (CH 2 ) n OR 9 ,-(CR 9 R 10 ) n -or-(CH 2 ) n C (O) R 9 , or any two R a substituents may form a 3-6 membered cycloalkyl group;
    R b选自氢原子、C 1-8烷基、C 1-8氘代烷基或C 1-8卤代烷基； R b is selected from a hydrogen atom, a C 1-8 alkyl group, a C 1-8 deuterated alkyl group, or a C 1-8 haloalkyl group;
    R 9和R 10独立地选自氢原子或C 1-8烷基； R 9 and R 10 are independently selected from a hydrogen atom or a C 1-8 alkyl group;
    z为0、1、2、3或4的整数；且z is an integer of 0, 1, 2, 3, or 4; and
    p为0、1或2。p is 0, 1, or 2.
  27. 根据权利要求1、4、17、19-22和24所述的药物组合物，其特征在于所包含的通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其中R 1选自C 1-8烷基、C 3-8环烷基、5-10元杂芳基和卤素，优选5-6元杂芳基、卤素、C 1-6烷基，更优选吡唑、氟原子或甲基。 The pharmaceutical composition according to claim 1, 4, 17, 19-22, and 24, characterized in that it comprises a compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof Wherein R 1 is selected from C 1-8 alkyl, C 3-8 cycloalkyl, 5-10 membered heteroaryl and halogen, preferably 5-6 membered heteroaryl, halogen, C 1-6 alkyl, more Pyrazole, a fluorine atom or a methyl group is preferred.
  28. 根据权利要求17、19-23、26所述的药物组合物，其特征在于，通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其中R a选自氢原子、氰基、C 1-8烷基、C 2-8烯基、C 2-8炔基、C 1-8卤代烷基、C 1-8羟代烷基、氰基取代的C 1-8烷基、C 1-8烷氧基、C 3-8环烷基、-(CH 2) nOR 9、-(CR 9R 10) n-或-(CH 2) nC(O)R 9，优选自氢原子、氰基、羟基、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6羟代烷基、卤代C 1-6烷基、3-6元杂环基、C 3-6环烷基；最优选甲基、乙基、乙烯基、乙炔基或三氟甲基。 The pharmaceutical composition according to claims 17, 19-23, and 26, wherein the compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R a is selected from Hydrogen atom, cyano, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, cyano-substituted C 1- 8 alkyl, C 1-8 alkoxy, C 3-8 cycloalkyl,-(CH 2 ) n OR 9 ,-(CR 9 R 10 ) n -or-(CH 2 ) n C (O) R 9 , preferably from a hydrogen atom, cyano, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 hydroxyalkyl, halo C 1-6 alkyl , 3-6 membered heterocyclyl, C 3-6 cycloalkyl; most preferred are methyl, ethyl, vinyl, ethynyl or trifluoromethyl.
  29. 根据权利要求17、19-23、26所述的药物组合物，其特征在于，通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，可选的其中任意两个R a形成3-6元环烷基，优选为环丙基。 The pharmaceutical composition according to claims 17, 19-23, and 26, wherein the compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is optional. Two R a form a 3-6 membered cycloalkyl, preferably cyclopropyl.
  30. 根据权利要求17、19-22所述的药物组合物，其特征在于，通式(I)所示的化合物、其立体异构体或其药学上可接受的盐，其中R 5选自氢原子、C 1-8烷基、卤代C 1-8烷基、羟代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、卤素、C 3-8 环烷基、3-10元杂环基，优选自氢原子、C 1-6烷基、羟代C 1-6烷基、卤代C 1-6烷基、3-6元杂环基或C 3-6环烷基；R 5最优选环丙基、异丙基、羟基异丙基、叔丁基、三氟甲基或
    Figure PCTCN2019099971-appb-100032
    The pharmaceutical composition according to claim 17, 19-22, wherein the compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from a hydrogen atom , C 1-8 alkyl, halo C 1-8 alkyl, hydroxy C 1-8 alkyl, C 1-8 alkoxy, halo C 1-8 alkoxy, halogen, C 3-8 Cycloalkyl, 3-10 membered heterocyclic group, preferably from a hydrogen atom, C 1-6 alkyl, hydroxy C 1-6 alkyl, halo C 1-6 alkyl, 3-6 membered heterocyclic group or C 3-6 cycloalkyl; R 5 is most preferably cyclopropyl, isopropyl, hydroxyisopropyl, t-butyl, trifluoromethyl or
    Figure PCTCN2019099971-appb-100032
  31. 根据权利要求1-30所述的药物组合物，其特征在于，通式(I)所示的化合物、其立体异构体或其药学上可接受的盐选自如下化合物：The pharmaceutical composition according to claim 1-30, wherein the compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the following compounds:
    Figure PCTCN2019099971-appb-100033
    Figure PCTCN2019099971-appb-100033
    Figure PCTCN2019099971-appb-100034
    Figure PCTCN2019099971-appb-100034
    Figure PCTCN2019099971-appb-100035
    Figure PCTCN2019099971-appb-100035
  32. 权利要求1-31所述药物组合物的制备方法，其特征在于，通式(I)所示的化合物、其立体异构体或其药学上可接受的盐与可药用的载体混合制备产物，优选的，通式(I)所示的化合物、其立体异构体或其药学上可接受的盐与赋形剂、溶剂或其它可药用的载体混合。The method for preparing a pharmaceutical composition according to claims 1 to 31, wherein a compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is mixed with a pharmaceutically acceptable carrier to prepare a product Preferably, the compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is mixed with an excipient, a solvent, or another pharmaceutically acceptable carrier.
  33. 根据权利要求1-31所述的药物组合物，其特征在于，在制备ASK1抑制剂药物中的应用。The pharmaceutical composition according to claims 1 to 31, wherein the pharmaceutical composition is used for preparing an ASK1 inhibitor medicine.
  34. 根据权利要求1-31所述的药物组合物在制备治疗神经变性障碍、心血管障碍、炎性障碍、代谢障碍和ASK1的药物中的应用；所述的炎症障碍优选非酒精性脂肪性肝炎(NASH)。The use of the pharmaceutical composition according to claims 1-31 in the preparation of a medicament for treating neurodegenerative disorder, cardiovascular disorder, inflammatory disorder, metabolic disorder and ASK1; the inflammatory disorder is preferably non-alcoholic steatohepatitis ( NASH).
  35. 根据权利要求1-31所述的药物组合物可适用的形式选自口服、肌内和皮下给药的无菌注射水或油混悬液、水包油乳剂和无菌注射水溶液。The pharmaceutical composition according to claims 1-31 is suitably used in a form selected from the group consisting of a sterile injectable water or oil suspension, an oil-in-water emulsion and a sterile injectable aqueous solution for oral, intramuscular and subcutaneous administration.
  36. 根据权利要求35所述药物组合物的口服的形式，选自片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂；所述的水包油乳剂的形式，油相为植物油或矿物油；所述的无菌注射水溶液形式，其溶媒或溶剂选自水、林格氏液和等渗氯化钠溶液；所述的肌内和皮下给药的无菌注射水或油混悬液的形式是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液，优选1,3-丁二醇中制备的溶液。The oral form of the pharmaceutical composition according to claim 35, selected from the group consisting of tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Liniment; the form of the oil-in-water emulsion, the oil phase of which is a vegetable or mineral oil; the form of the sterile injectable aqueous solution, whose solvent or solvent is selected from the group consisting of water, Ringer's solution, and isotonic sodium chloride solution; The form of the sterile injectable water or oil suspension for intramuscular and subcutaneous administration is a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent, preferably 1, 3 -A solution prepared in butanediol.
PCT/CN2019/099971 2018-08-10 2019-08-09 Pharmaceutical composition containing amide derivatives, preparation method therefor, and application thereof WO2020030107A1 (en)

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