WO2018108156A1 - Rock抑制剂及其应用 - Google Patents

Rock抑制剂及其应用 Download PDF

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WO2018108156A1
WO2018108156A1 PCT/CN2017/116493 CN2017116493W WO2018108156A1 WO 2018108156 A1 WO2018108156 A1 WO 2018108156A1 CN 2017116493 W CN2017116493 W CN 2017116493W WO 2018108156 A1 WO2018108156 A1 WO 2018108156A1
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group
substituted
hydrogen
alkyl
compound
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French (fr)
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李进
张登友
冯静超
谷浩
兰燕
李偲
陈伟
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成都先导药物开发有限公司
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    • A61K31/4375—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 six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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Definitions

  • the present invention relates to a ROCK inhibitor and its use.
  • Rho belongs to the small molecule monomeric GTPase superfamily and is a mammalian gene homolog of the Ras superfamily. It regulates cell muscle through its downstream major Rho-associated coiled-coil containing protein kinase (ROCK).
  • ROCK protein kinase
  • the reorganization of the kinesin backbone is widely involved in a series of biological processes such as cell mitosis, cytoskeletal regulation, smooth muscle cell contraction, nerve regeneration, tumor cell infiltration, and apoptosis regulation.
  • Rho/ROCK When Rho/ROCK is activated, it can act on a variety of substrates to produce biological processes.
  • MLC myosin light chain
  • MLCP myosin light chain phosphatase
  • Rho kinase activity in animal models exhibits a variety of benefits in the treatment of human diseases, including cardiovascular diseases such as pulmonary hypertension, hypertension, atherosclerosis, cardiac hypertrophy, ocular hypertension, cerebral ischemia, cerebral vasospasm, etc. , and central nervous system disorders such as neuronal degeneration, etc., as well as tumors.
  • cardiovascular diseases such as pulmonary hypertension, hypertension, atherosclerosis, cardiac hypertrophy, ocular hypertension, cerebral ischemia, cerebral vasospasm, etc.
  • central nervous system disorders such as neuronal degeneration, etc.
  • ROCK expression and activity are elevated in spontaneously hypertensive rats, indicating that it is associated with the development of hypertension in these animals (Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension [J] .FASEB J., 2001, 15(6): 1062-4).
  • the ROCK inhibitor Y-27632 can significantly reduce blood pressure in three rat hypertension models (spontaneous hypertension, renal hypertension, deoxycorticosterone acetate hypertension), while the blood pressure of control rats is higher.
  • ROCK inhibitors have a good effect on pulmonary hypertension (Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension [J]. Heart, 2005: 91 (3): 391-2) .
  • Isoquinolines These compounds are structurally characterized by having an isoquinoline structure and a piperazine ring, both of which are linked by a sulfonyl group. Representatives are Faithil (Uehata M, Ishizaki T, Satoh H, et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension [J]. Nature, 1997, 389: 990-994), H-1152P (Tamura M, Nakao H, Yoshizaki H, et al. Development of specific Rho-kinase inhibitors and their clinical application [J].
  • ROCK inhibitor drugs are Elisa (for the treatment of cerebral vasospasm) from Asahi Kasei and Glanatec (for the treatment of ocular hypertension and glaucoma) from Kowa.
  • Glanatec is only available for sale in Japan. Therefore, it is of great social and economic significance to develop a targeted small molecule drug research for ROCK to obtain a ROCK inhibitor with better activity, higher selectivity, lower toxicity and side effects, and more economical.
  • One of the objects of the present invention is to provide a ROCK inhibitor.
  • the present invention provides a compound of the formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof:
  • A is selected from a substituted or unsubstituted aromatic heterocyclic ring
  • B is selected from a substituted or unsubstituted aromatic ring, a substituted or unsubstituted aromatic heterocyclic ring; wherein B 1 and B 2 are each independently selected from a substituted or unsubstituted aromatic ring, a substituted or unsubstituted aromatic heterocyclic ring;
  • R 1 is selected from hydrogen, C 1 -C 6 alkyl
  • R 2 and R 3 are each independently selected from hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or substituted C 3 -C 6 Cycloalkyl;
  • R 2 and R 3 are bonded to form a C 3 -C 6 cycloalkyl group, a C 3 -C 6 cycloheteroalkyl group, a substituted C 3 -C 6 cycloalkyl group or a substituted C 3 -C 6 cycloheteroalkyl group;
  • R 1 and R 2 or R 3 are bonded to form a C 3 -C 6 cycloheteroalkyl group or a substituted C 3 -C 6 cycloheteroalkyl group;
  • n 1, 2, 3 or 4;
  • R 4 is independently selected from the group consisting of hydrogen, nitro, cyano, halogen, carboxyl, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 Alkynyl group, substituted C2 to C6 alkynyl group, C3 to C10 cycloalkyl group, substituted C3 to C10 cycloalkyl group, C3 to C10 heterocyclic group, substituted C3 to C10 heterocyclic group, C5 to C10 aromatic ring, substitution C5-C10 aromatic ring, C5-C10 aromatic heterocyclic ring, substituted C5-C10 aromatic heterocyclic ring, Wherein R 41 and R 42 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkyn
  • A is selected from a substituted or unsubstituted C9-C10 aromatic heterocyclic ring
  • B is selected from a substituted or unsubstituted C9-C10 aromatic ring, a substituted or unsubstituted C9-C10 aromatic heterocyclic ring; wherein B 1 and B 2 are each independently selected from a substituted or unsubstituted C5-C6 aromatic ring, substituted or Unsubstituted C5-C6 aromatic heterocyclic ring;
  • R 1 is selected from the group consisting of hydrogen and C1-C6 alkyl
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and substituted C1-C6 alkyl;
  • R 1 is bonded to R 2 or R 3 to form a C 3 -C 6 cycloheteroalkyl group
  • n 1 or 2;
  • R 4 is independently selected from hydrogen, wherein R 41 and R 42 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C3-C6 heterocyclic, Substituted C3-C6 heterocyclic group, C5-C10 aromatic ring, substituted C5-C10 aromatic ring, C5-C10 aromatic heterocyclic ring, substituted C5-C10 aromatic heterocyclic ring.
  • R 1 is selected from the group consisting of hydrogen, methyl, and ethyl
  • R 2 and R 3 are each independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, isobutyl, t-butyl;
  • R 1 is bonded to R 2 or R 3 to form a C 3 -C 6 cycloheteroalkyl group
  • n 1;
  • R 4 is selected from hydrogen, wherein R 41 and R 42 are each independently selected from hydrogen,
  • a 1 is selected from a substituted or unsubstituted C9-C10 aromatic heterocyclic ring
  • X 12 , X 13 , X 14 , X 15 , X 17 , X 18 are each independently selected from N, CR a4 ; wherein R a4 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, halogen, Hydroxyl group, amino group;
  • X 16 is selected from the group consisting of S, O, NR a6 ; wherein R a6 is selected from hydrogen, C1-C6 alkyl;
  • R a1 is selected from the group consisting of hydrogen and C1-C6 alkyl
  • R a2 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl;
  • R a3 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C3-C6 heterocyclic, substituted C3-C6 heterocyclic a group, a C5-C10 aromatic ring, a substituted C5-C10 aromatic ring, a C5-C10 aromatic heterocyclic ring, or a substituted C5-C10 aromatic heterocyclic ring.
  • a 11 is selected from Wherein X 11 is selected from the group consisting of N and CH.
  • a 11 is selected from
  • X 12 , X 13 , X 14 , X 15 , X 17 , X 18 are each independently selected from N, CR a4 ; wherein R a4 is selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, amino;
  • X 16 is selected from S
  • R a1 is selected from the group consisting of hydrogen, methyl, and ethyl
  • R a2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, isobutyl, tert-butyl;
  • R a3 is selected from hydrogen
  • the compound is selected from the group consisting of:
  • a 12 is selected from Wherein Y 1 , Y 2 and Y 3 are each independently selected from N and CH.
  • a 12 is selected from
  • X 12 , X 13 , X 14 , X 15 , X 17 , X 18 are each independently selected from N, CH;
  • X 16 is selected from S
  • R a1 is selected from the group consisting of hydrogen, methyl, and ethyl
  • R a2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, isobutyl, tert-butyl;
  • R a3 is selected from hydrogen
  • the compound is selected from the group consisting of:
  • Y 4 is selected from N, CH;
  • Y 5 is selected from the group consisting of NR c and S; wherein R c is selected from the group consisting of hydrogen and C1-C6 alkyl.
  • Y 4 is selected from N;
  • Y 5 is selected from the group consisting of NH and S;
  • X 12 , X 13 , X 14 , X 15 , X 17 , X 18 are each independently selected from N, CH;
  • X 16 is selected from S
  • R a1 is selected from the group consisting of hydrogen, methyl, and ethyl
  • R a2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, isobutyl, tert-butyl;
  • R a3 is selected from hydrogen
  • the compound is selected from the group consisting of:
  • a 2 is selected from Wherein X 21 is selected from the group consisting of N and CH;
  • X 22 , X 23 , X 24 , X 25 , X 26 , X 27 , X 28 , X 29 are each independently selected from N, CR b4 ; wherein R b4 is selected from hydrogen, C 1 -C 6 alkyl, substituted C 1 - C6 alkyl, halogen, hydroxyl, amino;
  • R b1 is selected from the group consisting of hydrogen and C1-C6 alkyl
  • R b2 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl;
  • R b3 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C3-C6 heterocyclic, substituted C3-C6 heterocyclic a group, a C5-C10 aromatic ring, a substituted C5-C10 aromatic ring, a C5-C10 aromatic heterocyclic ring, or a substituted C5-C10 aromatic heterocyclic ring.
  • a 2 is selected from
  • X 22 , X 23 , X 24 , X 25 , X 26 , X 27 , X 28 , X 29 are each independently selected from N, CR b4 ; wherein R b4 is selected from hydrogen, amino;
  • R b1 is selected from the group consisting of hydrogen, methyl, and ethyl
  • R b2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, isobutyl, tert-butyl;
  • R b3 is selected from hydrogen
  • the compound is selected from the group consisting of:
  • a 3 is selected from Wherein X 31 is selected from the group consisting of N and CH;
  • X 33 , X 34 , X 36 , X 37 are each independently selected from N, CR c5 ; wherein R c5 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, halogen, hydroxy, amino;
  • X 32 and X 35 are each independently selected from the group consisting of S, O, and NR c4 ; wherein R c4 is selected from hydrogen, C 1 -C 6 alkyl;
  • R c1 is selected from the group consisting of hydrogen and C1-C6 alkyl
  • R c2 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl;
  • R c3 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C3-C6 heterocyclic, substituted C3-C6 heterocycle a group, a C5-C10 aromatic ring, a substituted C5-C10 aromatic ring, a C5-C10 aromatic heterocyclic ring, or a substituted C5-C10 aromatic heterocyclic ring.
  • a 3 is selected from
  • X 33 , X 34 , X 36 , X 37 are respectively selected from N, CH;
  • X 32 and X 35 are respectively selected from S and O;
  • R c1 is selected from the group consisting of hydrogen, methyl, and ethyl
  • R c2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, isobutyl, tert-butyl;
  • R c3 is selected from hydrogen
  • the compound is selected from the group consisting of:
  • X 41 , X 42 , X 43 , X 44 , X 45 are each independently selected from N, CH;
  • X 46 is selected from the group consisting of S, O, NR d6 ; wherein R d6 is selected from hydrogen, C 1 -C 6 alkyl;
  • R d1 is selected from the group consisting of hydrogen and C1-C6 alkyl
  • R d2 , R d4 and R d5 are each independently selected from hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl;
  • R d3 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C3-C6 heterocyclic, substituted C3-C6 heterocyclic a group, a C5-C10 aromatic ring, a substituted C5-C10 aromatic ring, a C5-C10 aromatic heterocyclic ring, or a substituted C5-C10 aromatic heterocyclic ring.
  • X 41 , X 42 , X 43 , X 44 , X 45 are each independently selected from N, CH;
  • X 46 is selected from S
  • R d1 is selected from the group consisting of hydrogen, methyl, and ethyl
  • R d2 , R d4 , R d5 are each selected from the group consisting of hydrogen, methyl, ethyl, cyclopropyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl;
  • R d3 is selected from hydrogen
  • the compound is selected from the group consisting of:
  • X 51 , X 52 , X 53 , X 54 , X 55 , X 56 , X 57 are each independently selected from N, CH;
  • R e1 is selected from the group consisting of hydrogen and C1-C6 alkyl
  • R e2 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl;
  • R e3 is selected from hydrogen or NHR e4 ; wherein R e4 is selected from hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, substituted C 3 -C 6 cycloalkyl, C 3 -C 6 hetero a cyclic group, a substituted C3 to C6 heterocyclic group, a C5-C10 aromatic ring, a substituted C5-C10 aromatic ring, a C5-C10 aromatic heterocyclic ring, or a substituted C5-C10 aromatic heterocyclic ring.
  • X 51 , X 52 , X 53 , X 54 , X 55 , X 56 , X 57 are respectively selected from N, CH;
  • R e1 is selected from the group consisting of hydrogen, methyl, and ethyl
  • R e2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, isobutyl, tert-butyl;
  • R e3 is selected from hydrogen or NHR e4 ; wherein R e4 is selected from hydrogen,
  • the compound is selected from the group consisting of:
  • a 6 is selected from Wherein X 61 is selected from the group consisting of N and CH;
  • X 63 , X 64 , X 65 , X 66 , X 67 , X 68 are each independently selected from N, CR f4 ; wherein R f4 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, halogen, Hydroxyl group, amino group;
  • X 62 is selected from the group consisting of S, O, NR f6 ; wherein R f6 is selected from hydrogen, C 1 -C 6 alkyl;
  • R f1 is selected from the group consisting of hydrogen and C1-C6 alkyl
  • R f2 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl;
  • R f3 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C3-C6 heterocyclyl, substituted C3-C6 heterocycle a group, a C5-C10 aromatic ring, a substituted C5-C10 aromatic ring, a C5-C10 aromatic heterocyclic ring, or a substituted C5-C10 aromatic heterocyclic ring.
  • a 6 is selected from
  • X 63 , X 64 , X 65 , X 66 , X 67 , X 68 are each selected from N, CR a4 ; wherein R a4 is selected from hydrogen and amino;
  • X 61 is selected from S;
  • R f1 is selected from the group consisting of hydrogen, methyl, and ethyl
  • R f2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, isobutyl, tert-butyl;
  • R f3 is selected from hydrogen
  • the compound is selected from the group consisting of:
  • a 7 is selected from Wherein X 71 is selected from the group consisting of N and CH;
  • n 0, 1, 2, 3, 4;
  • X 72 , X 73 , X 74 , X 75 , X 77 , X 78 are each independently selected from N, CR g4 ; wherein R g4 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, halogen, Hydroxyl group, amino group;
  • X 76 is selected from the group consisting of S, O, NR g6 ; wherein R g6 is selected from the group consisting of hydrogen, C1-C6 alkyl;
  • R g3 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C3-C6 heterocyclic, substituted C3-C6 heterocyclic a group, a C5-C10 aromatic ring, a substituted C5-C10 aromatic ring, a C5-C10 aromatic heterocyclic ring, or a substituted C5-C10 aromatic heterocyclic ring.
  • a 7 is selected from
  • X 72 , X 73 , X 74 , X 75 , X 77 , X 78 are each selected from N, CR g4 ; wherein R g4 is selected from the group consisting of hydrogen, methyl, halogen, amino;
  • X 76 is selected from S
  • R g3 is selected from hydrogen
  • the compound is selected from the group consisting of:
  • a 8 is selected from Wherein X 81 is selected from the group consisting of N and CH;
  • X 82 , X 83 , X 84 , X 85 , X 87 , X 88 are each independently selected from N, CR h4 ; wherein R h4 is selected from hydrogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, halogen, Hydroxyl group, amino group;
  • X 86 is selected from the group consisting of S, O, and NR h6 ; wherein R h6 is selected from the group consisting of hydrogen and C1-C6 alkyl;
  • R h1 is selected from the group consisting of hydrogen and C1-C6 alkyl
  • R h2 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl;
  • R h3 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C3-C6 heterocyclic, substituted C3-C6 heterocyclic a group, a C5-C10 aromatic ring, a substituted C5-C10 aromatic ring, a C5-C10 aromatic heterocyclic ring, or a substituted C5-C10 aromatic heterocyclic ring.
  • a 8 is selected from
  • X 82 , X 83 , X 84 , X 85 , X 87 , X 88 are each selected from N, CR h4 ; wherein R h4 is selected from the group consisting of hydrogen, methyl, halogen, amino;
  • X 86 is selected from S;
  • R h1 is selected from the group consisting of hydrogen, methyl, and ethyl
  • R h2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, isobutyl, tert-butyl;
  • R h3 is selected from hydrogen
  • the compound is selected from the group consisting of:
  • a 9 is selected from Wherein X 91 is selected from the group consisting of N and CH;
  • X 92 , X 93 , X 94 , X 95 , X 97 , X 98 are each independently selected from N, CR i4 ; wherein R i4 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, halogen, Hydroxyl group, amino group;
  • X 96 is selected from the group consisting of S, O, NR i6 ; wherein R i6 is selected from hydrogen, C1-C6 alkyl;
  • R i1 is selected from the group consisting of hydrogen and C1-C6 alkyl
  • R i2 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl;
  • R i3 is selected from the group consisting of hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C3-C6 heterocyclic, substituted C3-C6 heterocyclic a group, a C5-C10 aromatic ring, a substituted C5-C10 aromatic ring, a C5-C10 aromatic heterocyclic ring, or a substituted C5-C10 aromatic heterocyclic ring.
  • a 9 is selected from
  • X 92 , X 93 , X 94 , X 95 , X 97 , X 98 are each selected from N, CR i4 ; wherein R i4 is selected from the group consisting of hydrogen, methyl, halogen, amino;
  • X 96 is selected from S;
  • R i1 is selected from hydrogen, methyl, ethyl
  • R i2 is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, cyclopropyl, isopropyl, n-butyl, isobutyl, tert-butyl;
  • R i3 is selected from hydrogen
  • the compound is selected from the group consisting of:
  • the present invention also provides the aforementioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of a ROCK inhibitor drug use.
  • the ROCK inhibitor drug is a ROCK1 and/or ROCK2 inhibitor drug.
  • the present invention also provides the aforementioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of a treatment associated with abnormal ROCK activity Use in medicines for diseases.
  • the disease associated with abnormal ROCK activity is mitosis, cytoskeletal adjustment, smooth muscle cell harvesting Any one or more of diseases related to contraction, nerve regeneration, tumor cell infiltration, and apoptosis.
  • the present invention also provides the aforementioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of a cardiovascular disease, high eye Use in compression, pulmonary hypertension, glaucoma or cancer medications.
  • the present invention also provides a pharmaceutical composition which is a compound of the foregoing, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof
  • a pharmaceutical composition which is a compound of the foregoing, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof
  • the test proves that the novel compound of the formula I disclosed in the present invention exhibits a good ROCK inhibitory activity, and provides a new medicinal possibility for clinical treatment of diseases associated with abnormal ROCK activity.
  • ROCK inhibitors are useful in the treatment of cardiovascular diseases, neurological diseases, fibrotic diseases, tumors and the like. For example, it can reduce myocardial ischemia/reperfusion injury, fight hypertension, etc.; at the same time, it can promote neurite outgrowth, promote the recovery of nerve function after injury; and can inhibit liver, lung and kidney fibrosis; and can effectively inhibit tumors. Transfer.
  • the present invention demonstrates its potency in the treatment of various diseases described above by verifying the inhibitory activity of the compound of formula I on ROCK.
  • the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
  • the minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix (C a - C b ) alkyl group indicates any alkyl group having "a" to "b” carbon atoms.
  • (C 1 -C 4 )alkyl means an alkyl group containing from 1 to 4 carbon atoms.
  • the C1-C6 alkyl group means an alkyl group of C1, C2, C3, C4, C5, C6, that is, a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, or a C group.
  • Base isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl and the like.
  • C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C3-C10 heterocyclic, C5-C10 aromatic ring, C5-C10 aromatic ring, C5-C10 aromatic heterocyclic ring also have a corresponding group The meaning.
  • the C3 to C10 cycloalkyl group means a C3, C4, C5, C6, C7, C8, C9, C10 cycloalkyl group, that is, a cyclic alkyl group having 3 to 10 carbon atoms, such as a cyclopropyl group.
  • pharmaceutically acceptable means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form, and is physiologically Compatible with the receptor.
  • salts and pharmaceutically acceptable salt refer to the above-mentioned compounds or stereoisomers thereof, acid and/or basic salts formed with inorganic and/or organic acids and bases, and also includes zwitterionic salts ( Internal salts) also include quaternary ammonium salts such as alkyl ammonium salts. These salts can be Obtained directly in the final isolation and purification of the compound. It can also be obtained by mixing the above compound, or a stereoisomer thereof, with a certain amount of an acid or a base as appropriate (for example, an equivalent amount).
  • the salt in the present invention may be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate or a dibutyl compound.
  • the invention includes isotopically labeled compounds, which are the same as the compounds listed herein, but wherein one or more of the atoms are replaced by another atom, the atomic
  • the atomic mass or mass number is different from the atomic mass or mass number that is common in nature.
  • Isotopes which may be introduced into the compounds of formula (I) include hydrogen, carbon, nitrogen, oxygen, sulfur, i.e., 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 35 S.
  • the key intermediates and compounds in the present invention are isolated and purified in a manner common to separation and purification methods in organic chemistry and examples of such methods include filtration, extraction, drying, spin drying, and various types of chromatography. Alternatively, the intermediate can be subjected to the next reaction without purification.
  • one or more compounds of the invention may be used in combination with one another.
  • the compounds of the invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition that modulates cellular function or treats a disease. If a group of compounds is used, the compounds can be administered to the subject simultaneously, separately or sequentially.
  • treatment also includes relapse prevention or phase prevention, as well as treatment of acute or chronic signs, symptoms and/or dysfunction.
  • Treatment can be symptomatic treatment, such as inhibition of symptoms. It can be achieved in the short term, adjusted in the medium term, or it can be said to be long-term treatment, for example in maintenance therapy.
  • the prophylaxis includes delaying and/or preventing the onset of a condition, disease or condition and/or its associated symptoms; preventing the subject from contracting the condition, disease or condition; or reducing the risk of the subject being infected with the condition, disease or condition.
  • the raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.
  • 1-(5-Bromo-2-pyridinyl)propan-1-one (700 mg, 3.27 mmol) was dissolved in methanol (10.0 mL), and hydroxylamine hydrochloride (108 mg, 3.27 mmol) was added and stirred at room temperature for 1 hour. After distilling off the solvent, trifluoroacetic acid (5.00 mL) and zinc powder (600 mg, 3.27 mmol) were added, and the mixture was stirred at room temperature for 30 minutes, then filtered, and the solvent was evaporated under reduced pressure to give 1-(5-bromo-2-pyridyl)propane. 1-Ammonia (600 mg, 2.79 mmol, yield 85%).
  • the carbazole-5-formate (270 mg, 1.67 mmol) was dissolved in N,N-dimethylformamide (5.00 mL), and then 1-(5-bromo-2-pyridyl) Propane-1-ammonia (300 mg, 1.39 mmol), N,N-diisopropylethylamine (897 mg, 6.95 mmol), 1-hydroxy-7-azobenzotriazole (33.4 mg, 1.67 mmol) And 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (319 mg, 1.67 mmol). After stirring at room temperature for 1 hour, the solvent was evaporated under reduced pressure to give purified crystals. m. m. 640 ⁇ mol, yield 46%).
  • N-(1-(5-Bromo-2-pyridyl)propyl)-1H-indazole-5-carboxamide 90.0 mg, 252 ⁇ mol was dissolved in dioxane (2.00 mL), , 1'-bis(diphenylphosphino)ferrocene)palladium dichloride (9.16 mg, 12.0 ⁇ mol), potassium carbonate (104 mg, 752 ⁇ mol) and N-tetrahydropyridinium Butan-4-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxamide (92.9 mg, 276 ⁇ mol), After stirring at 100 ° C for 1 hour under nitrogen atmosphere, the solvent was evaporated under reduced pressure to give a crude material, which was purified by column chromatography and purified by HPLC to obtain N-(5-(5-(tetrahydropyran-4-ylamine) Formyl)-3-thienyl-2
  • N-(1-(6-5((tetrahydropyran-2H-pyran-4-yl)formylamino) was prepared according to the similar procedure in Example 1 using 6-bromopyridine 2-carboxylic acid as starting material.
  • Thiophen-3-yl)pyridin-2-yl)propyl)-1H-indazole-5-carboxamide was prepared according to the similar procedure in Example 1 using 6-bromopyridine 2-carboxylic acid as starting material.
  • N-(1-(4-(5-tetrahydropyranothioamide)pyridin-2-yl)propyl) was prepared according to the similar procedure of Example 1 using 4-chloro-pyridine 2-carboxylic acid as starting material. -1H-carbazole-5-amide (total yield 0.90%).
  • N-(tetrahydropyran-4-yl)-3-(4) was obtained according to Step 2 in Example 1. , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (yield 65%).
  • N-(tetrahydropyran-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane- N-(5-(3-(tetrahydropyran-4-ylamine) was prepared according to the steps 3, 4, 5, 6, and 7 in Example 1 using 2-yl)benzamide as a starting material.
  • N-(1-(4-(3-(tetrahydropyran-4-yl)amido)phenyl) was prepared according to the similar procedure in Example 4 using 4-chloro-pyridine 2-carboxylic acid as starting material. Pyridin-2-yl)propyl)-1H-indazole-5-amide (total yield 0.92%).
  • 1-(1-Isoquinolinyl)isopropanol-1-amine was prepared according to the steps 3, 4 and 5 in Example 1 using isoquinoline-1-carboxylic acid as a starting material (total yield: 7.2%) .
  • N-1-(1-isoquinolinyl)isopropanol-1H- was obtained according to the procedure 6 in Example 1. Oxazole-5-carboxamide (yield 2.8%).
  • Methyl 6-chloropyrimidine-4-carboxylate (2.00 g, 11.6 mmol) was dissolved in 1,4-dioxane (40.0 mL), water (4.00 mL), sodium carbonate (4.91 g), N -tetrahydropyran-4-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxamide (3.90 g , 11.6 mmol), tetrakis-(triphenylphosphine palladium, 200 mg), reacted at 100 ° C overnight under nitrogen. The reaction mixture was evaporated under reduced pressure and purified to purified crystals,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ).
  • N was prepared according to steps 3, 4, 5, and 6 in Example 1. -(1-(6-Tetrahydropyranothioamide)pyrimidin-4-yl)propyl-1H-indazole 5-amide (total yield 0.025%).
  • 6-Bromopyridine-2-carbaldehyde (2.00 g, 10.8 mmol) and N-(tetrahydro-2H-pyran)-4-(4,4,5,5-tetramethyl-1,3,2- Borate ester thiophene-2-carboxamide (4.35 g, 12.9 mmol) was dissolved in N,N-dimethylformamide (20.0 mL) and water (500 ⁇ L), then (1,1'-bis (two) Phenylphosphino)ferrocene)palladium dichloride (157 mg, 215 ⁇ mol) and potassium carbonate (4.45 g, 32.3 mmol) were reacted at 110 ° C for 3 hours under nitrogen atmosphere, and the solvent was evaporated under reduced pressure and purified by column chromatography. 4-(5-Acylpyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamide (2.01 g, 6.32 mmol
  • 5-oxazolinecarboxylic acid (18.8 mg, 116 ⁇ mol) and N,N-diisopropylethylamine (59.7 mg, 463 ⁇ mol) were dissolved in N,N-dimethylformamide (1.00 mL), then 2- (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (502 mg, 1.32 mmol), reacted at room temperature for 15 minutes, added 4-(5-( 1-propylamine)pyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-2-carboxamide (40.0 mg, 115 ⁇ mol) was further reacted for 2 hr.
  • Step 5 in Example 8 gave N-(1-(5-((tetrahydro-2H-pyran-4-yl)ethyl)thiophen-3-yl)pyridin-3-yl)-6-iso Quinoline-5-carboxamide (total yield 1.6%).
  • 1,3-benzothiazole-6-carboxylic acid and 4-(5-(1-propylamine)pyridin-3-yl)-N-(tetrahydro-2H-pyran-4-yl)thiophene-2- Starting from the formamide, N-(1-(5-((tetrahydro-2H-pyran-4-yl)ethyl)thiophen-3-yl)pyridine-3-, obtained according to Step 5 in Example 8. Base)-1,3-benzothiazole-6-carboxamide (total yield 5.1%).
  • N-(1) was prepared according to the procedure 5 in Example 8 using aniline and 4-(3-(1-(isoquinolin-6-carboxamide)propyl)phenyl)thiophene-2-carboxylic acid as starting materials. -(3-(5-anilinoylthiophen-3-yl)phenyl)propyl)isoquinolin-6-carboxamide (total yield 9.5%).
  • 4-bromo-N-(1-methyl-1H-pyrazole) was prepared according to the procedure 1 in Example 1 using 4-bromothiazole-2-carboxylic acid and N-methyl-4-aminopyrazole as starting materials. 4-yl)thiazole-2-carboxamide (yield 60%).
  • 4-bromothiazole-2-carboxylic acid, N-methyl-4-aminopiperidine and N-(1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxo) 4-(1-(1-(isoquinoline)-) was prepared according to steps 1 and 2 of Example 20, using hexylborane-2-yl)phenyl)propyl)isoquinolin-6-carboxamide as starting material. 6-carboxamide)propyl)phenyl)-N-(1-methylpiperidin-4-yl)thiazole-2-carboxamide (total yield 30%)
  • 4-bromothiazole-2-carboxylic acid, 4-amino-tetrahydro-2H-pyran and N-(1-(3-(4,4,5,5-tetramethyl-1,3,2-di) 4-(3-(1-(isoquinoline) was prepared according to steps 1 and 2 of Example 20 using oxahexylboran-2-yl)phenyl)propyl)isoquinolin-6-carboxamide as starting material. -6-carboxamide)propyl)phenyl)-N-(tetrahydro-2H-pyran-4-yl)thiazole-2-carboxamide (total yield 24%).
  • N-(1-(2-(5-((tetrahydro-2H-pyran-4-yl))carbamoyl)thiophene was prepared according to the similar procedure of Example 35 using isoquinoline-6-carboxylic acid as a starting material. 3-yl)thiazol-5-yl)propyl)-isoquinoline-5-carboxamide (total yield 3.3%).
  • N-Methoxy-N-methyl-oxazole-2-carboxamide (2.00 g, 12.2 mmol) was dissolved in tetrahydrofuran (10.0 mL), and a solution of ethyl chloride in tetrahydrofuran (24.5 mmol, 16.3) (mL), the reaction is carried out for 20 minutes at room temperature under nitrogen atmosphere. The reaction solution is extracted with dilute hydrochloric acid in an ice-bath, and extracted with ethyl acetate three times, and the organic phase is evaporated to give a crude product. Oxazolyl)propan-1-one (800 mg, 3.50 mmol, yield 39%).
  • N-(2H-4-Tetrahydropyran)-4-bromothiophene-2-carboxamide (1.67 g, 5.75 mmol) and 1-(2-oxazolyl)propan-1-one (800 mg, 6.39 mmol) Dissolved in N,N-dimethylformamide (2.00 mL), palladium acetate (71.6 mg, 320 ⁇ mol), potassium carbonate (2.65 g, 19.2 mmol) and cuprous iodide (1.22 g, 6.39 mmol).
  • N-1-(5-bromo-3-pyridyl)propyl)-1H-carbazole was prepared according to the steps 3, 4, 5 and 6 in Example 1 using 3-bromopyridine-5-carboxylic acid as the starting material. -5-carboxamide (total yield 12%).
  • N-1-(5-bromo-3-pyridyl)propyl)-1H-indazole-5-carboxamide (350 mg, 970 ⁇ mol) was dissolved in dichloromethane (5.00 mL) Toluenesulfonic acid (83.9 mg, 790 ⁇ mol) and 3,4-dihydro-2H-pyran (164 mg, 1.95 mmol) were reacted at room temperature for 1 hour. Preparation of (5-bromo-3-pyridyl)propyl)-4H-pyran-2-indazole-5-carboxamide (300 mg, 673 ⁇ mol, yield 86%).
  • N-(1-(5-(5-thiophenemethyl)-3-pyridyl)propanyl)-1H-indazole-5-carboxamide (2.40 g, 4.63 mmol) was dissolved in tetrahydrofuran (8.00 mL) , methanol (2.00 mL) and water (2.00 mL), then add lithium hydroxide (665 mg, 27.8 mmol), react at 25 ° C for 1 hour, adjust the pH to 2 ⁇ 3, extract with ethyl acetate and then distill off under reduced pressure The solvent gave N-(1-(5-(5-thiophene)-3-pyridyl)propanyl)-1H-indazole-5-carboxamide (1.80 g, 3.30 mmol, yield 71%).
  • N-(1-(5-(5-thiophene)-3-pyridyl)propanyl)-1H-indazole-5-carboxamide (49.0 mg, 100 ⁇ mol) was dissolved in N,N-dimethyl In the amide (500 ⁇ L), N,N-diisopropylethylamine (26.0 mg, 200 ⁇ mol), 1-hydroxy-7-azobenzotriazole (16.3 mg, 120 ⁇ mol) and 1- (3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (23.0 mg, 120 ⁇ mol). After reacting for 30 minutes at room temperature, 4-amino-1-methylpyrazole (10.7 mg, 110 ⁇ mol) was added.
  • N-(1-(5-(5-((2-piperidin-4-yl)carbamoyl)thiophene was prepared according to the similar procedure of Example 38 using 4-amino-2-piperidone as the starting material. 3-yl)pyridin-3-yl)propyl)-1H-indazole-5-carboxamide (total yield 1.8%).
  • N-(1-(5-(5-((4,4-difluorocyclohexyl)carbamoyl)thiophene) was prepared according to the similar procedure of Example 38 using 4,4-difluorocyclohexylamine as the starting material. 3-yl)pyridin-3-yl)propyl)-1H-indazole-5-carboxamide (total yield 0.92%).
  • N-(1-(5-(5-((cyclohexyl)carbamoyl)thiophen-3-yl)pyridin-3-yl)propyl was prepared according to the similar procedure of Example 38 using cyclohexylamine as starting material. -1H-indazole-5-carboxamide (total yield 2.5%).
  • N-(5-(5-((1-methylpiperidin-4-yl))carboxamide was prepared according to the similar procedure of Example 38 using 1-methyl-4-aminopiperidine as starting material.
  • Thiophen-3-yl)pyridin-3-yl)propyl)-1H-indazole-5-carboxamide (total yield 3.1%).
  • N-(1-(5-(5-(cyclobutylcarbamoyl)thiophen-3-yl)pyridin-3-yl)propyl) was prepared according to the similar procedure of Example 38. -1H-carbazole-5-carboxamide (total yield 1.4%).
  • N-(1-(5-(5-(3,3-difluorocyclobutyl)carbamoyl)thiophene was prepared according to the similar procedure of Example 38 using 3,3-difluorocyclobutylamine as the starting material. 3-yl)pyridin-3-yl)propyl)-1H-indazole-5-carboxamide (total yield 1.8%).
  • N-(1-(5-(5-(1-acetylpiperidin-4-yl)carbamoyl) was prepared according to the similar procedure of Example 38 using 1-acetyl-4-aminopiperidine as starting material.
  • Thiophen-3-yl)pyridin-3-yl)propyl)-1H-indazole-5-carboxamide (total yield 0.72%).
  • N-(5-(5-((1-methoxyformyl)piperidin-4-yl) was prepared according to the similar procedure of Example 38 using 1-methoxycarbonyl-4-aminopiperidine as starting material.
  • N-(1-(5-(piperidin-4-ylcarbamoyl)thiophene) was prepared by the similar procedure of Example 38 using 1-tert-butoxycarbonyl-4-aminopiperidine as starting material. 3-yl)pyridin-3-yl)propyl)-1H-indazole-5-carboxamide (total yield 2.5%).
  • step 2 The diethylzinc and methylmagnesium bromide in step 2 were replaced with dimethylzinc and isopropylmagnesium bromide according to the method of Example 49 to give (R)-N-(2-methyl-1). -(3-(4-methyl-5-((4-methyl-1H-pyrazol-4-yl))carbamoyl)thiophen-3-yl)phenyl)propyl)isoquinoline-6- Formamide (total yield 10%).
  • step 1 The 3-bromobenzaldehyde in step 1 was changed to 3-bromo-5-aldehyde pyridine according to the method of Example 49, and 4-bromo-3-methylthiophene-2-carboxylic acid in step 6 was replaced with 2 -Bromo-thiophene-4-carboxylic acid to give (R)-N-(1-(5-(4-((1-methyl-1H-pyrazol-4-yl)carbamoyl)thiophen-2-yl) Pyridin-3-yl)propyl)isoquinolin-6-carboxamide (total yield 12%).
  • the compound of the present invention was tested for ROCK2 inhibitory activity.
  • ROCK2 is capable of phosphorylating S6K (KRRRLASLR) polypeptide substrates and converting ATP to ADP.
  • ADP-Glo TM Reagent kinase reaction was terminated, and consumed the remaining ATP.
  • Kinase assay reagents were added, so that it converts ADP into ATP at the same time, ATP is then converted Ultra-Glo TM luciferase light emission signal to the light emitting signal positively correlated with kinase activity.
  • the ROCK2 inhibitory activity was tested as follows:
  • Example ROCK2 Example ROCK2 1 ++ 2 ++ 3 +++ 4 +++ 5 ++ 6 + 7 + 8 +++ 9 +++ 10 ++ 11 ++ 12 ++ 13 +++ 14 ++ 15 ++ 16 +++ 17 +++ 18 +++ 19 ++ 20 ++ twenty one ++ twenty two ++ twenty three +++ twenty four +++ 25 +++ 26 +++ 27 +++ 28 +++ 29 ++ 30 +++ 31 +++ 32 +++ 33 +++ 34 + 35 +++ 36 + 37 + 38 +++ 39 +++ 40 +++ 41 +++ 42 +++ 43 +++ 44 +++ 45 +++ 46 +++ 47 +++ 48 +++ 49 +++ 50 +++ 51 +++ 52 +++++
  • ND Data is being analyzed and analyzed.
  • Tests have shown that the compounds of the examples of the present invention have good ROCK inhibitory activity and can be effectively used for the treatment of diseases with abnormal ROCK activity.
  • novel compound of the formula I disclosed in the present invention exhibits a good ROCK inhibitory activity, and provides a new medicinal possibility for clinical treatment of diseases associated with abnormal ROCK activity.

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Abstract

式（I）所示的ROCK抑制剂及其制备方法和应用。试验表明，所述化合物具有良好的ROCK抑制活性，可以有效用于与ROCK活性异常疾病的治疗。

Description

[根据细则37.2由ISA制定的发明名称]　ROCK抑制剂及其应用 技术领域
本发明涉及一种ROCK抑制剂及其应用。
背景技术
Rho属于小分子单聚体GTPase超家族，是Ras超家族的哺乳动物基因同系物，通过其下游最主要的效应分子Rho激酶(Rho-associated coiled-coil containing protein kinase，ROCK)，来调节细胞肌动蛋白骨架的重组，从而广泛参与细胞有丝分裂、细胞骨架调整、平滑肌细胞收缩、神经再生、肿瘤细胞浸润、细胞凋亡的调节等一系列生物学过程。Rho/ROCK激活后可以作用于多种底物，从而产生生物学过程。最主要的两种底物是肌球蛋白轻链(MLC)和肌球蛋白轻链磷酸酶(MLCP)，MLC的磷酸化水平是决定平滑肌收缩程度的一个重要因素。肌球蛋白轻链激酶(MLCK)磷酸化MLC的Ser-19位点，导致平滑肌收缩；MLCP的抑制可以使MLC的磷酸化和平滑肌的收缩进一步增强。ROCK被激活以后，本身可以将MLC磷酸化而发生肌丝收缩作用；同时也能将MLCP磷酸化，使MLCP失活，导致细胞胞浆内MLC磷酸化程度增高，间接促进肌丝收缩。
在动物模型中Rho激酶活性的抑制展现出治疗人类疾病的多种益处，包括心血管疾病如肺动脉高压、高血压、动脉粥样硬化、心脏肥大、高眼压、脑缺血、脑血管痉挛等，和中枢神经系统病症如神经元变性等，以及肿瘤。研究表明ROCK表达和活性在自发性高血压大鼠中有所升高，说明其与这些动物高血压的发生具有关联(Involvement of Rho-kinase in hypertensive vascular disease:a novel therapeutic target in hypertension[J].FASEB J.,2001,15(6):1062-4)。ROCK抑制剂Y-27632可使三种大鼠高血压模型(自发性高血压、肾性高血压、醋酸脱氧皮质酮盐型高血压)中的血压显著降低，而对对照大鼠的血压作用较小(Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension[J].Nature,1997,389(6654):990-4)。也有研究表明ROCK抑制剂对肺动脉高压具有较好的作用(Acute vasodilator effects of a Rho-kinase inhibitor,fasudil,in patients with severe pulmonary hypertension[J].Heart,2005:91(3):391-2)。
目前已经研究开发的ROCK抑制剂可分为五大类：(1)异喹啉类：此类化合物结构特点是具有一个异喹啉结构和哌嗪环，两者通过磺酰基相连。代表物有法苏地尔(Uehata M,Ishizaki T,Satoh H,et al.Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension[J].Nature,1997,389:990-994)、H-1152P(Tamura M,Nakao H,Yoshizaki H,et al.Development of specific Rho-kinase inhibitors and their clinical application[J].Biochim Biophys Acta,2005,1754:245-252)；(2)4-氨基吡啶类：此类化合物结构除4-氨基吡啶母核外，在分子的中心位置还含有一个环己烷或苯环结构，在环己烷的4位具有侧链结构。代表物有Y-30141(Takami A,Iwakubo M,Okada Y,et al.Design and synthesis of Rho kinase inhibitors[J].Bioorg Med Chem,2004,12:2115-2137)；(3)吲唑类：此类化合物 将5-氨基或5-烷氧基-1H吲唑作为骨架；(4)酰胺和脲类：此类化合物具有一个邻苯二甲酰亚胺和一个脲基构成的绞和结构。(5)其它类：其它不包含上述结构的ROCK抑制剂，代表物有Rockout(Yarrow JC,Totsukawa G,Charras GT,et al.Screening for cell migration inhibitors via automated microscopy reveals a Rho-kinase inhibitor[J].Chem Biol,2005,12:385-395)。
目前已上市的ROCK抑制剂药物有Asahi Kasei公司的Eril(适用于脑血管痉挛的治疗)和Kowa公司的Glanatec(适用于高眼压症和青光眼的治疗)。其中Glanatec仅在日本上市销售。因此进行开发作用于ROCK的靶向小分子药物研究，得到活性更好、选择性更高、更低毒性和副作用、更经济的ROCK抑制剂，具有十分重要的社会和经济意义。
发明内容
本发明目的之一在于提供一种ROCK抑制剂。
本发明提供了式Ⅰ所示的化合物化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物：
Figure PCTCN2017116493-appb-000001
其中，
A选自取代或未取代的芳杂环；
B选自
Figure PCTCN2017116493-appb-000002
取代或未取代的芳环、取代或未取代的芳杂环；其中B1、B2分别独立地选自取代或未取代的芳环、取代或未取代的芳杂环；
R1选自氢、C1-C6烷基；R2、R3分别独立地选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基或取代的C3～C6环烷基；
或者，R2与R3相连构成C3～C6环烷基、C3～C6环杂烷基、取代的C3～C6环烷基或取代的C3～C6环杂烷基；
或者，R1与R2或R3相连构成C3～C6环杂烷基或取代的C3～C6环杂烷基；
n为1、2、3或4；
R4分别独立地选自氢、硝基、氰基、卤素、羧基、C1～C6烷基、取代的C1～C6烷基、C2～C6烯基、取代的C2～C6烯基、C2～C6炔基、取代的C2～C6炔基、C3～C10环烷基、取代的C3～C10环烷基、C3～C10杂环基、取代的C3～C10杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10 芳杂环、取代的C5～C10芳杂环、
Figure PCTCN2017116493-appb-000003
Figure PCTCN2017116493-appb-000004
其中R41、R42分别独立地选自氢、C1～C6烷基、取代的C1～C6烷基、C2～C6烯基、取代的C2～C6烯基、C2～C6炔基、取代的C2～C6炔基、C3～C10环烷基、取代的C3～C10环烷基、C3～C10杂环基、取代的C3～C10杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
进一步地，
A选自取代或未取代的C9～C10的芳杂环；
B选自
Figure PCTCN2017116493-appb-000005
取代或未取代的C9～C10的芳环、取代或未取代的C9～C10的芳杂环；其中B1、B2分别独立地选自取代或未取代的C5～C6的芳环、取代或未取代的C5～C6的芳杂环；
R1选自氢、C1～C6烷基；
R2、R3分别独立地选自氢、C1～C6烷基、取代的C1～C6烷基；
或者，R1与R2或R3相连构成C3～C6环杂烷基；
n为1或2；
R4分别独立地选自氢、
Figure PCTCN2017116493-appb-000006
其中R41、R42分别独立地选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
进一步地，
A选自
Figure PCTCN2017116493-appb-000007
Figure PCTCN2017116493-appb-000008
B选自
Figure PCTCN2017116493-appb-000009
Figure PCTCN2017116493-appb-000010
Figure PCTCN2017116493-appb-000011
R1选自氢、甲基、乙基；
R2、R3分别独立地选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
或者，R1与R2或R3相连构成C3～C6环杂烷基；
n为1；
R4选自氢、
Figure PCTCN2017116493-appb-000012
其中R41、R42分别独立地选自氢、
Figure PCTCN2017116493-appb-000013
Figure PCTCN2017116493-appb-000014
进一步地，所述式I化合物如式IIa所示：
Figure PCTCN2017116493-appb-000015
Figure PCTCN2017116493-appb-000016
其中，
A1选自取代或未取代的C9～C10的芳杂环；
X12、X13、X14、X15、X17、X18分别独立地选自N、CRa4；其中Ra4选自氢、C1～C6烷基、取代的C1～C6烷基、卤素、羟基、氨基；
X16选自S、O、NRa6；其中Ra6选自氢、C1-C6烷基；
Ra1选自氢、C1～C6烷基；
Ra2选自氢、C1～C6烷基、取代的C1～C6烷基；
Ra3选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
进一步地，
所述式IIa化合物如式IIIa所示：
Figure PCTCN2017116493-appb-000017
其中，
A11选自
Figure PCTCN2017116493-appb-000018
其中X11选自N、CH。
进一步地，
A11选自
Figure PCTCN2017116493-appb-000019
X12、X13、X14、X15、X17、X18分别选自独立地选自N、CRa4；其中Ra4选自氢、C1～C6烷基、卤素、氨基；
X16选自S；
Ra1选自氢、甲基、乙基；
Ra2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
Ra3选自氢、
Figure PCTCN2017116493-appb-000020
Figure PCTCN2017116493-appb-000021
进一步地，所述化合物选自下述化合物：
Figure PCTCN2017116493-appb-000022
Figure PCTCN2017116493-appb-000023
Figure PCTCN2017116493-appb-000024
Figure PCTCN2017116493-appb-000025
进一步地，所述式IIa化合物如式IIIb所示：
Figure PCTCN2017116493-appb-000026
其中，
A12选自
Figure PCTCN2017116493-appb-000027
其中Y1、Y2、Y3分别独立地选自N、CH。
进一步地，
A12选自
Figure PCTCN2017116493-appb-000028
X12、X13、X14、X15、X17、X18分别独立地选自N、CH；
X16选自S；
Ra1选自氢、甲基、乙基；
Ra2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
Ra3选自氢、
Figure PCTCN2017116493-appb-000029
进一步地，所述化合物选自下述化合物：
Figure PCTCN2017116493-appb-000030
进一步地，所述式IIa化合物如式IIIc所示：
Figure PCTCN2017116493-appb-000031
其中，
Y4选自N、CH；
Y5选自NRc、S；其中，Rc选自氢、C1～C6烷基。
进一步地，
Y4选自N；
Y5选自NH、S；
X12、X13、X14、X15、X17、X18分别独立地选自N、CH；
X16选自S；
Ra1选自氢、甲基、乙基；
Ra2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
Ra3选自氢、
Figure PCTCN2017116493-appb-000032
进一步地，所述化合物选自下述化合物：
Figure PCTCN2017116493-appb-000033
进一步地，所述式I化合物如式IIb所示：
Figure PCTCN2017116493-appb-000034
其中，
A2选自
Figure PCTCN2017116493-appb-000035
其中X21选自N、CH；
X22、X23、X24、X25、X26、X27、X28、X29分别独立地选自N、CRb4；其中Rb4选自氢、C1～C6 烷基、取代的C1～C6烷基、卤素、羟基、氨基；
Rb1选自氢、C1～C6烷基；
Rb2选自氢、C1～C6烷基、取代的C1～C6烷基；
Rb3选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
进一步地，
A2选自
Figure PCTCN2017116493-appb-000036
X22、X23、X24、X25、X26、X27、X28、X29分别独立地选自N、CRb4；其中Rb4选自氢、氨基；
Rb1选自氢、甲基、乙基；
Rb2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
Rb3选自氢、
Figure PCTCN2017116493-appb-000037
进一步地，所述化合物选自下述化合物：
Figure PCTCN2017116493-appb-000038
进一步地，所述式I化合物如式IIc所示：
Figure PCTCN2017116493-appb-000039
Figure PCTCN2017116493-appb-000040
其中，
A3选自
Figure PCTCN2017116493-appb-000041
其中X31选自N、CH；
X33、X34、X36、X37分别独立地选自N、CRc5；其中Rc5选自氢、C1～C6烷基、取代的C1～C6烷基、卤素、羟基、氨基；
X32、X35分别独立地选自S、O、NRc4；其中Rc4选自氢、C1-C6烷基；
Rc1选自氢、C1～C6烷基；
Rc2选自氢、C1～C6烷基、取代的C1～C6烷基；
Rc3选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
进一步地，
A3选自
Figure PCTCN2017116493-appb-000042
X33、X34、X36、X37分别选自N、CH；
X32、X35分别选自S、O；
Rc1选自氢、甲基、乙基；
Rc2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
Rc3选自氢、
Figure PCTCN2017116493-appb-000043
进一步地，所述化合物选自如下化合物：
Figure PCTCN2017116493-appb-000044
Figure PCTCN2017116493-appb-000045
进一步地，所述式I化合物如式IId所示：
Figure PCTCN2017116493-appb-000046
其中，
X41、X42、X43、X44、X45分别独立地选自N、CH；
X46选自S、O、NRd6；其中Rd6选自氢、C1-C6烷基；
Rd1选自氢、C1～C6烷基；
Rd2、Rd4、Rd5分别独立地选自氢、C1～C6烷基、取代的C1～C6烷基；
Rd3选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
进一步地，
X41、X42、X43、X44、X45分别独立地选自N、CH；
X46选自S；
Rd1选自氢、甲基、乙基；
Rd2、Rd4、Rd5分别选自氢、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、叔丁基；
Rd3选自氢、
Figure PCTCN2017116493-appb-000047
进一步地，所述化合物选自如下化合物：
Figure PCTCN2017116493-appb-000048
进一步地，所述式I化合物如式IIe所示：
Figure PCTCN2017116493-appb-000049
其中，
X51、X52、X53、X54、X55、X56、X57分别独立地选自N、CH；
Re1选自氢、C1～C6烷基；
Re2选自氢、C1～C6烷基、取代的C1～C6烷基；
Re3选自氢或NHRe4；其中Re4选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
进一步地，
X51、X52、X53、X54、X55、X56、X57分别选自N、CH；
Re1选自氢、甲基、乙基；
Re2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
Re3选自氢或NHRe4；其中Re4选自氢、
Figure PCTCN2017116493-appb-000050
进一步地，所述化合物选自如下化合物：
Figure PCTCN2017116493-appb-000051
进一步地，所述式I化合物如式IIf所示：
Figure PCTCN2017116493-appb-000052
Figure PCTCN2017116493-appb-000053
其中，
A6选自
Figure PCTCN2017116493-appb-000054
其中X61选自N、CH；
X63、X64、X65、X66、X67、X68分别独立地选自N、CRf4；其中Rf4选自氢、C1～C6烷基、取代的C1～C6烷基、卤素、羟基、氨基；
X62选自S、O、NRf6；其中Rf6选自氢、C1-C6烷基；
Rf1选自氢、C1～C6烷基；
Rf2选自氢、C1～C6烷基、取代的C1～C6烷基；
Rf3选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
进一步地，
A6选自
Figure PCTCN2017116493-appb-000055
X63、X64、X65、X66、X67、X68分别选自N、CRa4；其中Ra4选自氢、氨基；
X61选自S；
Rf1选自氢、甲基、乙基；
Rf2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
Rf3选自氢、
Figure PCTCN2017116493-appb-000056
进一步地，所述化合物选自如下化合物：
Figure PCTCN2017116493-appb-000057
进一步地，所述式I化合物如式IIg所示：
Figure PCTCN2017116493-appb-000058
其中，
A7选自
Figure PCTCN2017116493-appb-000059
其中X71选自N、CH；
m为0、1、2、3、4；
X72、X73、X74、X75、X77、X78分别独立地选自N、CRg4；其中Rg4选自氢、C1～C6烷基、取代的C1～C6烷基、卤素、羟基、氨基；
X76选自S、O、NRg6；其中Rg6选自氢、C1-C6烷基；
Rg3选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
进一步地，
A7选自
Figure PCTCN2017116493-appb-000060
X72、X73、X74、X75、X77、X78分别选自N、CRg4；其中Rg4选自氢、甲基、卤素、氨基；
X76选自S；
Rg3选自氢、
Figure PCTCN2017116493-appb-000061
进一步地，所述化合物选自如下化合物：
Figure PCTCN2017116493-appb-000062
进一步地，所述式I化合物如式IIh所示：
Figure PCTCN2017116493-appb-000063
其中，
A8选自
Figure PCTCN2017116493-appb-000064
其中X81选自N、CH；
X82、X83、X84、X85、X87、X88分别独立地选自N、CRh4；其中Rh4选自氢、C1～C6烷基、取代的C1～C6烷基、卤素、羟基、氨基；
X86选自S、O、NRh6；其中Rh6选自氢、C1-C6烷基；
Rh1选自氢、C1～C6烷基；
Rh2选自氢、C1～C6烷基、取代的C1～C6烷基；
Rh3选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
进一步地，
A8选自
Figure PCTCN2017116493-appb-000065
X82、X83、X84、X85、X87、X88分别选自N、CRh4；其中Rh4选自氢、甲基、卤素、氨基；
X86选自S；
Rh1选自氢、甲基、乙基；
Rh2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
Rh3选自氢、
Figure PCTCN2017116493-appb-000066
进一步地，所述化合物选自如下化合物：
Figure PCTCN2017116493-appb-000067
进一步地，所述式I化合物如式IIi所示：
Figure PCTCN2017116493-appb-000068
其中，
A9选自
Figure PCTCN2017116493-appb-000069
其中X91选自N、CH；
X92、X93、X94、X95、X97、X98分别独立地选自N、CRi4；其中Ri4选自氢、C1～C6烷基、取代的C1～C6烷基、卤素、羟基、氨基；
X96选自S、O、NRi6；其中Ri6选自氢、C1-C6烷基；
Ri1选自氢、C1～C6烷基；
Ri2选自氢、C1～C6烷基、取代的C1～C6烷基；
Ri3选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
进一步地，
A9选自
Figure PCTCN2017116493-appb-000070
X92、X93、X94、X95、X97、X98分别选自N、CRi4；其中Ri4选自氢、甲基、卤素、氨基；
X96选自S；
Ri1选自氢、甲基、乙基；
Ri2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
Ri3选自氢、
Figure PCTCN2017116493-appb-000071
进一步地，所述化合物选自如下化合物：
Figure PCTCN2017116493-appb-000072
本发明还提供了前述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备ROCK抑制剂类药物中的用途。
进一步地，所述ROCK抑制剂类药物为ROCK1和/或ROCK2抑制剂类药物。
本发明还提供了前述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗与ROCK活性异常相关的疾病的药物中的用途。
进一步地，所述与ROCK活性异常相关的疾病是与细胞有丝分裂、细胞骨架调整、平滑肌细胞收 缩、神经再生、肿瘤细胞浸润、细胞凋亡相关的疾病中的任一种或几种。
本发明还提供了前述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗心血管疾病、高眼压症、肺动脉高压、青光眼或癌症药物中的用途。
本发明还提供了一种药物组合物，它是以前述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物为活性成分，加上药学上可接受的辅料制备而成的制剂。
试验证明，本发明公开的式I所示的新化合物，表现出了良好的ROCK抑制活性，为临床治疗与ROCK活性异常相关的疾病提供了一种新的药用可能。
ROCK抑制剂可用于治疗心血管疾病、神经系统疾病、纤维化疾病、肿瘤等。例如，能够减轻心肌缺血/再灌注损伤，对抗高血压等；同时能够促进神经突起生长，促进损伤后神经功能的恢复；并且能够抑制肝脏、肺、肾脏纤维化；还有能够有效抑制肿瘤的转移。本发明通过验证式I化合物对ROCK的抑制活性，说明了其具有治疗上述多种疾病的效果。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社，Columbus，OH)命名系统命名。
关于本发明的使用术语的定义：除非另有说明，本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语；对于本文没有具体定义的术语，应该根据公开内容和上下文，给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示，例如，前缀(Ca～Cb)烷基表明任何含“a”至“b”个碳原子的烷基。因此，例如，(C1～C4)烷基是指包含1～4个碳原子的烷基。
所述C1～C6烷基是指C1、C2、C3、C4、C5、C6的烷基，即具有1～6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、己基等等。C2～C6烯基、C2～C6炔基、C3～C10环烷基、C3～C10杂环基、C5～C10芳环、C5～C10芳环、C5～C10芳杂环也具有与其基团相应的含义。例如，所述C3～C10的环烷基是指C3、C4、C5、C6、C7、C8、C9、C10的环烷基，即具有3～10个碳原子的环状烷基，例如环丙基、环丁基、环戊基、己基、庚基、辛基、环壬基、环癸基、甲基取代的环丙基、乙基取代的环丁基等等。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
术语“盐”和“药学上可接受的盐”是指上述化合物或其立体异构体，与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是 在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物，或其立体异构体，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明的某些实施方式中，本发明包括了同位素标记的化合物，所述同位素标记化合物是指与本文中所列化合物相同，但是其中的一个或多个原子被另一个原子取代，该原子的原子质量或质量数不同于自然界中常见的原子质量或质量数。可以引入式(I)化合物中的同位素包括氢、碳、氮、氧、硫，即2H,3H、13C、14C、15N、17O、18O、35S。含有上述同位素和/或其它原子同位素的式(I)的化合物及其立体异构体，以及该化合物、立体异构体的可药用的盐均应包含在本发明范围之内。
本发明中的关键中间体和化合物进行分离和纯化，所使用的方式是有机化学中常用的分离和纯化方法且所述方法的实例包括过滤、萃取、干燥、旋干和各种类型的色谱。可选择地，可以使中间体不经纯化即进行下一步反应。
在某些实施方式中，本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其它的活性试剂结合使用，用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物，则可将这些化合物同时、分别或有序地对受试对象进行给药。
在本发明的含义之内，“治疗”也包括复发性(relapse)预防或阶段性(phase)预防，以及急性或慢性体征、症状和/或功能失常的治疗。治疗可以是对症治疗，例如抑制症状。它可以在短期内实现，在中期内调整，或者可以说是长期治疗，例如在维持疗法里面。所述预防包括延迟和/或阻止病症、疾病或病况和/或其伴发症状的发作；防止对象染上病症、疾病或病况；或降低对象染上病症、疾病或病况的风险的方法。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
实施例1 N-(1-(5-(5-(四氢吡喃-4-基胺甲酰基)-3-噻吩基)-2-吡啶基)丙基)-1H-吲唑-5-甲酰胺的制备
1. 4-溴-N-(四氢吡喃-4-基)噻吩-2-甲酰胺的制备
Figure PCTCN2017116493-appb-000073
将4-溴噻吩-2-羧酸(17.0g)、N,N-二甲基甲酰胺(0.50mL)溶于二氯甲烷(250mL)中，冰浴下滴加入草酰氯(18.4g)。滴加完毕后升至室温搅拌4小时。将反应液减压浓缩得4-溴噻吩-2-酰氯粗品(21.0g)。
将4-氨基-四氢吡喃盐酸盐(9.10g)、三乙胺(21.9g)加入到二氯甲烷(250mL)中，冰浴下加入4-溴噻吩-2-酰氯粗品的二氯甲烷溶液(50.0mL)。升至室温搅拌1小时后，减压浓缩得到粗品，加水荡洗后50℃真空干燥得到4-溴-N-(四氢吡喃-4-基)噻吩-2-甲酰胺(19.3g,产率91％)。
MS(ESI)m/z＝290/292(M+1)+。
2. N-四氢吡喃-4-基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)噻吩-2-甲酰胺的制备
Figure PCTCN2017116493-appb-000074
将4-溴-N-(四氢吡喃-4-基)噻吩-2-甲酰胺(10.0g)溶于1,4-二氧六环(200mL)中，依次加入乙酸钾(13.5g)，双联硼频那醇硼酸酯(11.7g)，1,1-双三苯基磷二茂铁二氯化钯(500mg)。氮气保护下于100℃反应2小时，加水淬灭后乙酸乙酯萃取，减压蒸除溶剂，经柱层析得N-四氢吡喃-4-基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)噻吩-2-甲酰胺(8.60g，产率74％)。
MS(ESI)m/z＝338(M+1)+。
3. 5-溴-N-甲氧基-N-甲基-吡啶-2-甲酰胺的制备
Figure PCTCN2017116493-appb-000075
将5-溴-2-吡啶羧酸(5.30g,26.2mmol)溶于四氢呋喃(60.0mL)中，冰浴下依次加入苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(7.99g,31.5mmol)，N,N-二异丙基乙胺(16.9g,131mmol)和盐酸二甲羟胺(1.92g,31.5mmol)，升至室温搅拌1小时后减压蒸除溶剂得粗品，经柱层析纯化得5-溴-N-甲氧基-N-甲基-吡啶-2-甲酰胺(6.10g,24.9mmol,产率95％)。
MS(ESI)m/z＝245/247(M+1)+。
4. 1-(5-溴-2-吡啶基)丙烷-1-酮的制备
Figure PCTCN2017116493-appb-000076
将5-溴-N-甲氧基-N-甲基-吡啶-2-甲酰胺(3.00g,12.2mmol)溶于四氢呋喃(10.0mL)中，冰浴下加入乙基氯化镁四氢呋喃溶液(24.5mmol,16.3mL)，氮气保护下室温下搅拌20分钟，反应液用稀盐酸在冰浴下萃灭后用乙酸乙酯萃取三次，合并有机相减压蒸除溶剂后得粗品。经柱层析纯化得1-(5-溴-2-吡啶基)丙烷-1-酮(750mg,3.50mmol,产率29％)。
MS(ESI)m/z＝214(M+1)+。
5. 1-(5-溴-2-吡啶基)丙烷-1-氨的制备
Figure PCTCN2017116493-appb-000077
将1-(5-溴-2-吡啶基)丙烷-1-酮(700mg,3.27mmol)溶于甲醇(10.0mL)中，加入盐酸羟胺(108mg,3.27mmol)后室温搅拌1小时，减压蒸除溶剂后加入三氟乙酸(5.00mL)和锌粉(600mg,3.27mmol)，室温搅拌30分钟后过滤，滤液减压蒸除溶剂后得到1-(5-溴-2-吡啶基)丙烷-1-氨(600mg,2.79mmol,产率85％)。
MS(ESI)m/z＝215(M+1)+。
6. N-1-(5-溴-2-吡啶基)丙基)-1H-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000078
将吲唑-5-甲酸盐酸盐(270mg,1.67mmol)溶于N,N-二甲基甲酰胺(5.00mL)中，冰浴下依次加入1-(5-溴-2-吡啶基)丙烷-1-氨(300mg,1.39mmol)，N,N-二异丙基乙胺(897mg,6.95mmol)，1-羟基-7-偶氮苯并三氮唑(33.4mg,1.67mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(319mg,1.67mmol)。室温下搅拌1小时后减压蒸除溶剂得粗品，经柱层析纯化得N-(1-(5-溴-2-吡啶基)丙基)-1H-吲唑-5-甲酰胺(230mg,640μmol，产率46％)。
MS(ESI)m/z＝359(M+1)+。
7. N-(-1-(5-(5-(四氢吡喃-4-基胺甲酰基)-3-噻吩基)-2-吡啶基)丙基)-1H-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000079
将N-(1-(5-溴-2-吡啶基)丙基)-1H-吲唑-5-甲酰胺(90.0mg,252μmol)溶于二氧六环(2.00mL)中，加入(1,1'-双(二苯基膦基)二茂铁)二氯化钯(9.16mg,12.0μmol)，碳酸钾(104mg,752μmol)和N-四氢吡 喃-4-基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)噻吩-2-甲酰胺(92.9mg,276μmol)，氮气保护下100℃搅拌1小时后减压蒸除溶剂得粗品，经柱层析及制备高效液相纯化得N-(-1-(5-(5-(四氢吡喃-4-基胺甲酰基)-3-噻吩基)-2-吡啶基)丙烷基)-1H-吲唑-5-甲酰胺(13.7mg,26.9μmol,产率11％)。
MS(ESI)m/z＝490(M+1)+。
1H NMR(400MHz,DMSO):δ＝8.89(d,J＝2.0Hz,,1H),8.79(d,J＝8.0Hz,1H),8.46(s,1H),8.39(d,J＝7.6Hz,1H),8.29(d,J＝1.6Hz,1H),8.24(s,1H),8.19(d,J＝1.2Hz,1H),8.07(dd,J＝2.4,8.0Hz,1H),7.92(d,J＝7.2Hz 1H),7.60(d,J＝8.8Hz,1H),7.53(d,J＝8.0,1H)5.10-5.04(m,1H),4.05-3.95(m,1H),3.91(d,J＝9.2Hz,2H),3.43-3.3-37(m,2H),2.10-1.88(m,2H),1.82-1.79(m,2H),1.63-1.53(m,2H),0.98(t,J＝7.2Hz,3H)。
实施例2 N-(1-(6-5((四氢吡喃-2H-吡喃-4-基)甲酰氨基)噻吩-3-基)吡啶-2-基)丙基)-1H-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000080
以6-溴吡啶2-甲酸为原料，按照实施例1中的类似步骤制得N-(1-(6-5((四氢吡喃-2H-吡喃-4-基)甲酰氨基)噻吩-3-基)吡啶-2-基)丙基)-1H-吲唑-5-甲酰胺(总产率1.1％)。
MS(ESI)m/z＝490(M+1)+。
1H NMR(400MHz,DMSO):δ＝13.31(s,1H),8.79(d,J＝8.0Hz,1H),8.56(d,J＝8.0Hz,1H),8.46(d,J＝6.4Hz,2H),8.38(s,1H),8.24(s,1H),7.93(d,J＝8.8Hz,1H),7.85(t,J＝8.0Hz，1H),7.71(d,J＝8.0Hz,1H),7.60(d,J＝8.8Hz,1H),7.39(d,J＝8.0Hz,1H),5.14-5.08(m,1H),4.01-3.98(m,1H),3.93-3.90(m,2H),3.4(t,J＝12.0Hz,2H),2.10-2.04(m,1H),1.96-1.88(m,1H),1.81-1.78(m,2H),1.67-1.57(m,2H),1.02(t,J＝7.2Hz,3H)。
实施例3 N-(1-(4-(5-四氢吡喃噻吩酰胺)吡啶-2-基)丙基)-1H-吲唑-5-酰胺的制备
Figure PCTCN2017116493-appb-000081
以4-氯-吡啶2-羧酸为原料，按照实施例1中的类似步骤制得N-(1-(4-(5-四氢吡喃噻吩酰胺)吡啶-2-基)丙基)-1H-吲唑-5-酰胺(总产率0.90％)。
MS(ESI)m/z＝490(M+1)+
1H NMR(400MHz,DMSO):δ＝13.29(s,1H),8.76(d,J＝8.0Hz,1H),8.59(d,J＝4.0Hz,1H),8.49(d,J＝8.0Hz,1H),8.45(s,1H),8.34-8.35(m,2H),8.22(s,1H),7.90-7.92(m,1H),7.78(s,1H),7.56-7.59(m, 2H),5.09-5.12(m,1H),3.95-4.04(m,1H),3.88-3.91(m,2H),3.39-3.42(m,2H),1.93-2.02(m,2H),1.78-1.81(m,2H),1.53-1.63(m,2H),0.95(t,J＝8.0Hz,3H)。
实施例4 N-(1-(5-(3-(四氢吡喃-4-基胺甲酰基)苯基)-3-吡啶基)丙基)-1H-吲唑-5-甲酰胺的制备
1. 3-溴-N-(四氢吡喃-4-基)苯甲酰胺的制备
Figure PCTCN2017116493-appb-000082
以3-溴苯甲酸为原料，按照实施例1中的步骤1制得3-溴-N-(四氢吡喃-4-基)苯甲酰胺(产率90％)。
MS(ESI)m/z＝284/286(M+1)+
2. N-(四氢吡喃-4-基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯甲酰胺的制备
Figure PCTCN2017116493-appb-000083
以3-溴-N-(四氢吡喃-4-基)苯甲酰胺为原料，按照实施例1中的步骤2制得N-(四氢吡喃-4-基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯甲酰胺(产率65％)。
MS(ESI)m/z＝332(M+1)+
3. N-(1-(5-(3-(四氢吡喃-4-基胺甲酰基)苯基)-3-吡啶基)丙基)-1H-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000084
以5-溴-3-吡啶羧酸、N-(四氢吡喃-4-基)-3-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苯甲酰胺为原料，按照实施例1中的步骤3、4、5、6、7制得N-(1-(5-(3-(四氢吡喃-4-基胺甲酰基)苯基)-3-吡啶基)异丙基)-1H-吲唑-5-甲酰胺(总产率1.2％)。
MS(ESI)m/z＝484(M+1)+。
1H NMR(400MHz,MeOD):δ＝8.82(d,J＝2.1Hz,1H),8.68(d,J＝1.9Hz,1H),8.41(m,1H),8.23-8.21(m,2H),8.17-8.16(m,1H),7.94-7.88(m,3H),7.66-7.62(m,2H),5.17(q,J＝2.0,8.8Hz,1H),4.17-4.10(m,1H),4.02-3.99(m,2H),3.56-3.50(m,2H),2.14-2.10(m,1H),2.04-2.00(m,1H),1.94-1.88(m,2H)1.76-1.66(m,2H),1.10(t,J＝7.2Hz,3H)。
实施例5 N-(1-(4-(3-(四氢吡喃-4-基)酰胺基)苯基)吡啶-2-基)丙基)-1H-吲唑-5-酰胺的制备
Figure PCTCN2017116493-appb-000085
以4-氯-吡啶2-羧酸为原料，按照实施例4中的类似步骤制得N-(1-(4-(3-(四氢吡喃-4-基)酰胺基)苯基)吡啶-2-基)丙基)-1H-吲唑-5-酰胺(总产率0.92％)。
MS(ESI)m/z＝484(M+1)+
1H NMR(400MHz,DMSO):δ＝13.27(s,1H),8.79(d,J＝8.0Hz,1H),8.64(d,J＝8.0Hz,1H),8.44-8.46(m,2H),8.23(s,1H),8.18(s,1H),7.90-7.94(m,3H),7.83(s,1H),7.57-7.66(m,3H),5.12-5.18(m,1H),3.98-4.07(m,1H),3.87-3.90(m,2H),3.36-3.42(m,2H),1.90-2.05(m,2H),1.74-1.80(m,2H),1.52-1.63(m,2H),0.99(t,J＝8.0Hz,3H)。
实施例6 N-(1-(1-异喹啉基)丙基)-1H-吲唑-5-甲酰胺的制备
1. 1-(1-异喹啉基)丙-1-胺的制备
Figure PCTCN2017116493-appb-000086
以异喹啉-1-羧酸为原料，按照实施例1中的步骤3、4、5制得1-(1-异喹啉基)异丙醇-1-胺(总产率7.2％)。
MS(ESI)m/z＝187(M+1)+
2. N-1-(1-异喹啉基)丙基)-1H-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000087
以1-(1-异喹啉基)异丙醇-1-胺为原料，按照实施例1中的步骤6制得N-1-(1-异喹啉基)异丙醇)-1H-吲唑-5-甲酰胺(产率2.8％)。
MS(ESI)m/z＝331(M+1)+
1H NMR(400MHz,DMSO):δ＝13.26(s,1H,),8.98(d,J＝6.4Hz,1H),8.64(d,J＝8.4Hz,1H),8.50(d,J＝6.0Hz,1H),8.45(m,1H),8.21(m,1H),8.13(d,J＝8.6Hz,1H),8.00-7.92(m,2H),7.89-7.82(m,2H),7.57(d,J＝8.8Hz,1H),5.97(q,J＝6.4,13.6Hz,1H),2.17-2.08(m,2H),1.00(t,J＝7.2Hz,3H)。
实施例7 N-(1-(6-四氢吡喃噻吩酰胺)嘧啶-4-基)丙基-1H-吲唑5-酰胺的制备
1. 6-(5((四氢吡喃-4-基)酰胺)噻吩-3-基)嘧啶-4-羧酸的制备
Figure PCTCN2017116493-appb-000088
将6-氯嘧啶-4-甲酸甲酯(2.00g，11.6mmol)溶于1,4-二氧六环(40.0mL)中，依次加入水(4.00mL)，碳酸钠(4.91g)，N-四氢吡喃-4-基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)噻吩-2-甲酰胺(3.90g，11.6mmol)，四-(三苯基磷钯，200mg)，氮气保护下于100℃反应过夜。反应液减压蒸除溶剂，经柱层析得到6-(5((四氢吡喃-4-基)酰胺)噻吩-3-基)嘧啶-4-羧酸(1.30g,产率30％)。
MS(ESI)m/z＝334(M+1)+
2. N-(1-(6-四氢吡喃噻吩酰胺)嘧啶-4-基)丙基-1H-吲唑5-酰胺的制备
Figure PCTCN2017116493-appb-000089
以6-(5((四氢吡喃-4-基)酰胺)噻吩-3-基)嘧啶-4-羧酸为原料，按照实施例1中的步骤3、4、5、6制得N-(1-(6-四氢吡喃噻吩酰胺)嘧啶-4-基)丙基-1H-吲唑5-酰胺(总产率0.025％)。
MS(ESI)m/z＝491(M+1)+
1H NMR(400MHz,MeOD):δ＝9.12(d,J＝1.2Hz,1H),8.51(d,J＝4Hz,1H),8.45(s,1H),8.42(d,J＝1.2Hz,1H),8.21(s,1H),7.93-7.96(m,1H),7.89(d,J＝1.2Hz,1H),7.62-7.65(m,1H),5.12-5.15(m,1H),4.06-4.13(m,1H),3.99-4.02(m,2H),3.50-3.57(m,2H),2.00-2.17(m,2H),1.90-1.93(m,2H),1.65-1.75(m,2H),1.11(t,J＝8.0Hz,3H)。
实施例8 N-(1-(5-((四氢-2H-吡喃-4-基)乙基)噻吩-3-基)吡啶-3-基)-1H-吲唑-5-甲酰胺的制备
1、 4-(5-醛基吡啶-3-基)-N-(四氢-2H-吡喃-4-基)噻吩-2-甲酰胺的制备.
Figure PCTCN2017116493-appb-000090
将6-溴吡啶-2-甲醛(2.00g,10.8mmol)和N-(四氢-2H-吡喃)-4-(4,4,5,5-四甲基-1,3,2-硼酸酯)噻吩-2-甲酰胺(4.35g,12.9mmol)溶于N,N-二甲基甲酰胺(20.0mL)和水(500μL)中，然后加入(1,1'-双(二苯基膦基)二茂铁)二氯化钯(157mg,215μmol)和碳酸钾(4.45g,32.3mmol),在氮气保护下110℃反应3小时后减压蒸除溶剂，经柱层析纯化得4-(5-醛基吡啶-3-基)-N-(四氢-2H-吡喃-4-基)噻吩-2-甲酰胺(2.01g,6.32mmol,产率59％)。
MS(ESI)m/z＝317(M+1)+。
2、 4-(5-(1-羟基丙烷)吡啶-3-基)-N-(四氢-2H-吡喃-4-基)噻吩-2-甲酰胺的制备
Figure PCTCN2017116493-appb-000091
将4-(5-醛基吡啶-3-基)-N-(四氢-2H-吡喃-4-基)噻吩-2-甲酰胺(2.00g,6.32mmol)溶于四氢呋喃(20.0mL)中，冰浴下滴加乙基溴化镁(8.40ml,12.6mmol,1.5mol/L)，滴加完毕后，室温反应1小时后,反应液加入饱和氯化铵淬灭,然后用乙酸乙酯和水萃取，合并有机相，减压蒸除溶剂后经柱层析纯化得4-(5-(1-羟基丙烷)吡啶-3-基)-N-(四氢-2H-吡喃-4-基)噻吩-2-甲酰胺(800mg,2.10mmol,产率33％)。
MS(ESI)m/z＝347(M+1)+。
3、 4-(5丙酮吡啶-3-基)-N-(四氢-2H-4-基)噻吩-2-甲酰胺的制备
Figure PCTCN2017116493-appb-000092
将4-(5-(1-羟基丙烷)吡啶-3-基)-N-(四氢-2H-吡喃-4-基)噻吩-2-甲酰胺(400mg,1.15mmol)溶于二氯甲烷(5.00mL)中,然后在0℃下加入戴斯-马丁氧化剂(332mg,870μmol)，室温下反应2小时后减压蒸除溶剂得粗品，经柱层析纯化得到4-(5丙酮吡啶-3-基)-N-(四氢-2H-4-基)噻吩-2-甲酰胺(300mg,760μmol,产率67％)
MS(ESI)m/z＝351(M+1)+。
4、 4-(5-(1-丙胺)吡啶-3-基)-N-(四氢-2H-吡喃-4-基)噻吩-2-甲酰胺的制备
Figure PCTCN2017116493-appb-000093
将4-(5丙酮吡啶-3-基)-N-(四氢-2H-4-基)噻吩-2-甲酰胺(300mg,870μmol)加入甲醇(3.00mL)中,然后在0℃下加入盐酸羟胺(332mg,871μmol)，室温下反应2小时后减压蒸除溶剂，将残余物用三氟乙酸(5.00mL)溶解,在冰浴下加入锌粉(140mg,2.18mmol)，室温反应过夜后用硅藻土过滤，减压蒸除溶剂得到4-(5-(1-丙胺)吡啶-3-基)-N-(四氢-2H-吡喃-4-基)噻吩-2-甲酰胺(100mg,230μmol,产率21％)
MS(ESI)m/z＝352(M+1)+。
5、 N-(1-(5-((四氢-2H-吡喃-4-基)乙基)噻吩-3-基)吡啶-3-基)-1H吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000094
将5-吲唑甲酸(18.8mg,116μmol)和N,N-二异丙基乙胺(59.7mg,463μmol)溶于N,N-二甲基甲酰胺(1.00mL)中，然后加入2-(7-偶氮苯并三氮唑)-N,N,N’,N’-四甲基脲六氟磷酸酯(502mg,1.32mmol)，室温下反应15分钟，加入4-(5-(1-丙胺)吡啶-3-基)-N-(四氢-2H-吡喃-4-基)噻吩-2-甲酰胺(40.0mg,115μmol)后继续反应2小时，减压蒸除溶剂得粗品，经柱层析及制备高效液相纯化得N-(1-(5-((四氢-2H-吡喃-4-基)乙基)噻吩-3-基)吡啶-3-基)-1H吲唑-5-甲酰胺(2.40mg,3.58μmol,产率1.6％)。
MS(ESI)m/z＝490(M+1)+。
1H NMR(400MHz,DMSO):δ＝8.89(s,1H),8.66(s,1H),8.47(s,1H),8.36(s,1H),8.23(d,J＝12Hz,1H),7.82-7.84(d,J＝8Hz,1H),7.59-7.62(d,J＝12Hz,1H),5.07(m,1H),3.38-3.47(m,6H),1.91-1.98(m,2H),1.75-1.79(m,2H),1.55-1.58(m,2H),0.96(t,J＝7.2Hz,3H).
实施例9 N-(1-(5-((四氢-2H-吡喃-4-基)乙基)噻吩-3-基)吡啶-3-基)-6-异喹啉-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000095
以6-异喹啉甲酸和4-(5-(1-丙胺)吡啶-3-基)-N-(四氢-2H-吡喃-4-基)噻吩-2-甲酰胺为原料，按照实施例8中的步骤5制得N-(1-(5-((四氢-2H-吡喃-4-基)乙基)噻吩-3-基)吡啶-3-基)-6-异喹啉-5-甲酰胺(总产率1.6％)。
MS(ESI)m/z＝501(M+1)+。
1H NMR(400MHz,MeOD):δ＝9.81(s,1H),9.07(s,1H),8.85-8.87(d,J＝7.2Hz,2H),8.36(s,1H),8.66-8.68(d,J＝6.8,Hz,1H),8.54-8.59(m,2H),8.30-8.31(d,J＝1.2Hz,1H),3.38-3.47(m,6H),1.91-1.98(m,2H),1.75-1.79(m,2H),1.55-1.58(m,2H),0.96(t,J＝7.2Hz,3H)。
实施例10 N-(1-(5-((四氢-2H-吡喃-4-基)乙基)噻吩-3-基)吡啶-3-基)-咪唑[1,5-A]吡啶-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000096
以咪唑[1,5-A]吡啶-6-羧酸和4-(5-(1-丙胺)吡啶-3-基)-N-(四氢-2H-吡喃-4-基)噻吩-2-甲酰胺为原料，按照实施例8中的步骤5制得N-(1-(5-((四氢-2H-吡喃-4-基)乙基)噻吩-3-基)吡啶-3-基)-咪唑[1,5-A]吡啶-6-甲酰胺(总产率6.2％)。
MS(ESI)m/z＝490(M+1)+。
1H NMR(400MHz,DMSO-D2O):δ＝9.23(s,1H),8.95(s,1H),8.88(s,2H),8.63(s,1H),8.41(s,1H),8.24-8.21(d,J＝11.6Hz,2H),7.87(s,1H),7.80-7.78(d,J＝9.6Hz,1H),7.41-7.38(d,J＝9.6Hz,1H),5.04-5.00(m,1H),3.94-3.93(m,1H),3.87-3.85(d,J＝8.8Hz,2H),3.39-3.34(m,2H),1.99-1.86(m,2H),1.79-1.74(m,2H),1.58-1.50(m,2H),1.12-1.01(m,1H),0.94(t,J＝6.8Hz,3H)。
实施例11 N-(1-(5-((四氢-2H-吡喃-4-基)乙基)噻吩-3-基)吡啶-3-基)-[1,2,4]三唑[4,3-A]嘧啶-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000097
以[1,2,4]三唑[4,3-A]嘧啶-6-羧酸和4-(5-(1-丙胺)吡啶-3-基)-N-(四氢-2H-吡喃-4-基)噻吩-2-甲酰胺为原料，按照实施例8中的步骤5制得N-(1-(5-((四氢-2H-吡喃-4-基)乙基)噻吩-3-基)吡啶-3-基)-[1,2,4]三唑[4,3-A]嘧啶-6-甲酰胺(总产率5.6％)。
MS(ESI)m/z＝491(M+1)+。
1H NMR(400MHz,DMSO-D2O):δ＝9.31(s,1H),9.06(s,1H),8.88(s,1H),8.63(s,1H),8.43(s,1H),8.24(s,1H),8.20(s,1H),7.82-7.76(m,2H),5.04-5.00(m,1H),3.87-3.85(d,J＝9.2Hz,2H),3.45-3.34(m,3H),1.97-1.88(m,2H),1.77-1.74(m,2H),1.59-1.53(m,2H),1.03(t,J＝14.0Hz,1H),0.94(t,J＝6.8Hz,3H)。
实施例12 N-(1-(5-((四氢-2H-吡喃-4-基)乙基)噻吩-3-基)吡啶-3-基)-1H-吡咯并[2,3-C]吡啶-2-甲酰胺的制备
Figure PCTCN2017116493-appb-000098
以1H-吡咯并[2,3-C]吡啶-2-羧酸和4-(5-(1-丙胺)吡啶-3-基)-N-(四氢-2H-吡喃-4-基)噻吩-2-甲酰胺为原料，按照实施例8中的步骤5制得N-(1-(5-((四氢-2H-吡喃-4-基)乙基)噻吩-3-基)吡啶-3-基)-1H-吡咯并[2,3-C]吡啶-2-甲酰胺(总产率6.1％)。
MS(ESI)m/z＝490(M+1)+。
1H NMR(400MHz,DMSO-D2O):δ＝9.06(s,1H),8.87(s,1H),8.64(s,1H),8.40(s,1H),8.24-8.21(m,4H),7.60(s,1H),5.10-5.06(m,1H),3.87-3.84(m,2H),3.41-3.34(m,2.4H),3.06-3.01(m,0.6H),2.02-1.92(m,2H),1.77-1.74(m,2H),1.59-1.49(m,2H),0.95(t,J＝7.2Hz,3H)。
实施例13 N-(1-(5-((四氢-2H-吡喃-4-基)乙基)噻吩-3-基)吡啶-3-基)-噻吩并[2,3-c]吡啶-2-甲酰胺的制备
Figure PCTCN2017116493-appb-000099
以噻吩并[2,3-c]吡啶-2-羧酸和4-(5-(1-丙胺)吡啶-3-基)-N-(四氢-2H-吡喃-4-基)噻吩-2-甲酰胺为原料，按照实施例8中的步骤5制得N-(1-(5-((四氢-2H-吡喃-4-基)乙基)噻吩-3-基)吡啶-3-基)-噻吩并[2,3-c]吡啶-2-甲酰胺(总产率4.6％)。
MS(ESI)m/z＝507(M+1)+。
1H NMR(400MHz,DMSO-D2O):δ＝9.57(s,1H),8.90(s,1H),8.67(s,1H),8.61-8.59(d,J＝6.4Hz,1H),8.47(s,1H),8.40-8.37(m,2H),8.25(s,1H),8.21(m,1H),5.05(t,J＝7.6Hz,1H),3.96-3.91(m,1H),3.97-3.84(m,2H),3.40-3.34(m,2H),2.03-1.92(m,2H),1.77-1.74(m,2H),1.60-1.50(m,2H),1.16-1.01(m,1H),0.95(t,J＝7.2Hz,3H)。
实施例14 N-(1-(5-((四氢-2H-吡喃-4-基)乙基)噻吩-3-基)吡啶-3-基)-咪唑[1,2-A]吡啶-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000100
以咪唑[1,2-A]吡啶-6-甲酸和4-(5-(1-丙胺)吡啶-3-基)-N-(四氢-2H-吡喃-4-基)噻吩-2-甲酰胺为原料，按照实施例8中的步骤5制得N-(1-(5-((四氢-2H-吡喃-4-基)乙基)噻吩-3-基)吡啶-3-基)-咪唑[1,2-A]吡啶-6-甲酰胺(总产率7.9％)。
MS(ESI)m/z＝490(M+1)+。
1H NMR(400MHz,DMSO-D2O):δ＝9.30(s,1H),8.90(s,1H),8.66(s,1H),8.46(s,1H),8.28-8.22(m,4H),8.10(s,1H),7.97-7.75(d,J＝9.6Hz,1H),5.05(t,J＝7.6Hz,1H),3.96-3.92(m,1H),3.87-3.85(m,2H),3.43-3.34(m,2H),1.98-1.90(m,2H),1.77-1.74(m,2H),1.60-1.51(m,2H),1.12-1.01(m,1H),0.94(t,J＝6.8Hz,3H)。
实施例15 N-(1-(5-((四氢-2H-吡喃-4-基)乙基)噻吩-3-基)吡啶-3-基)-1,3-苯并噻唑-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000101
以1,3-苯并噻唑-6-羧酸和4-(5-(1-丙胺)吡啶-3-基)-N-(四氢-2H-吡喃-4-基)噻吩-2-甲酰胺为原料，按照实施例8中的步骤5制得N-(1-(5-((四氢-2H-吡喃-4-基)乙基)噻吩-3-基)吡啶-3-基)-1,3-苯并噻唑-6-甲酰胺(总产率5.1％)。
MS(ESI)m/z＝507(M+1)+。
1H NMR(400MHz,DMSO-D2O):δ＝9.44(s,1H),8.88(s,1H),8.61(s,1H),8.49(s,1H),8.25(m,1H),8.20(s,1H),8.15-8.06(m,2H),7.99-7.96(m,1H),5.06(t,J＝7.6Hz,1H),3.97-3.90(m,2H),3.87-3.84(m,2H),3.39-3.34(m,2H),2.03-1.87(m,2H),1.77-1.74(m,2H),1.60-1.50(m,2H),0.95(t,J＝7.2Hz,3H)。
实施例16 N-(1-(3-(5-((1-甲基-1H-吡唑-4-基)甲酰胺基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
1、 1-(3-溴苯基)丙基-1-酮的制备
Figure PCTCN2017116493-appb-000102
以二甲基羟胺盐酸盐和3-溴苯甲酸为原料，按照实施例1中的步骤3和4制得1-(3-溴苯基)丙基-1-酮(产率43％)。
MS(ESI)m/z＝213/215(M+1)+。
2、 1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基-1-酮的制备
Figure PCTCN2017116493-appb-000103
将1-(3-溴苯基)丙基-1-酮(1.30g,6.10mmol)溶于1,4-二氧六环(10.0mL)中，依次加入醋酸钾(1.30g,6.10mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(233mg,305umol)、联硼酸频那醇酯(2.32g,9.15mmol)，氮气保护下100℃反应2小时后减压蒸除溶剂得粗品，经柱层析纯化得1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基-1-酮(1.50g,5.48mmol,产率90％)。
MS(ESI)m/z＝261(M+1)+。
3、 1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-)苯丙基-1-胺的制备
Figure PCTCN2017116493-appb-000104
将1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基-1-酮(1.50g,5.48mmol)溶于甲醇(10.0mL)中，加入盐酸羟胺(401mg,5.77mmol)，室温下反应1小时，然后加入钯碳，在氢气下室温下反应1小时，过滤后得1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基丙基-1-胺(1.40g,5.36mmol,产率93％)。
MS(ESI)m/z＝262(M+1)+。
4、 N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000105
以6-溴异喹啉甲酸和1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯丙基-1-胺为原料，按照实施例1中的步骤6的方法制得N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰 胺(产率67％)。
MS(ESI)m/z＝417(M+1)+。
5、 4-(3-(1-(异喹啉-6-甲酰胺)丙基)苯基)噻吩-2-羧酸甲酯的制备
Figure PCTCN2017116493-appb-000106
将N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺(200mg,480μmol)溶于二氧六环(5.00mL)中，加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(17.6mg,24.0μmol)、碳酸钾(199mg,1.44mmol)和4-溴噻吩-2-羧酸甲酯(117mg，528μmol)，氮气保护下于100℃反应1小时后减压蒸除溶剂得粗品，经柱层析纯化得4-(3-(1-(异喹啉-6-甲酰胺)丙基)苯基)噻吩-2-羧酸甲酯(130mg,302μmol,产率63％。
MS(ESI)m/z＝431(M+1)+。
6、 4-(3-(1-(异喹啉-6-甲酰胺)丙基)苯基)噻吩-2-羧酸的制备
Figure PCTCN2017116493-appb-000107
将4-(3-(1-(异喹啉-6-甲酰胺)丙基)苯基)噻吩-2-羧酸甲酯(130mg,302μmol)溶于甲醇：水：四氢呋喃＝1：1：4的溶液(5.00mL)中，然后加入氢氧化锂(126mg,3.02mmol)，室温下反应1小时，反应液用稀盐酸在冰浴下调节pH至中性后用乙酸乙酯萃取三次，合并有机相减压蒸除溶剂得4-(3-(1-(异喹啉-6-甲酰胺)丙基)苯基)噻吩-2-羧酸(120mg,288μmol,产率95％)。
MS(ESI)m/z＝417(M+1)+。
7、 N-(1-(3-(5-((1-甲基-1H-吡唑-4-基)甲酰胺基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000108
以1-甲基-1H-吡唑-4-胺和4-(3-(1-(异喹啉-6-甲酰胺)丙基)苯基)噻吩-2-羧酸为原料，按照实施例8中的步骤5制得N-(1-(3-(5-((1-甲基-1H-吡唑-4-基)甲酰胺基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺(产率33％)。
MS(ESI)m/z＝496(M+1)+。
1HNMR(400MHz,MeOD):δ＝9.73(s,1H),8.65-8.62(m,2H),8.52-8.49(m,1H),8.44-8.43(m,1H),8.32-8.30(m,1H),8.20-8.19(m,1H),8.00(s,1H),7.92-7.91(m,1H),7.77(s,1H),7.64-7.60(m,2H),7.47-7.42(m,2H),5.51(s,1H),5.13(t,J＝7.6Hz,1H),3.90(s,3H),2.11-2.00(m,2H),1.08(t,J＝7.2Hz, 3H)。
实施例17 N-(1-(3-(5-((1-甲基哌啶-4-基)甲酰胺基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000109
以1-甲基哌啶-4-胺和4-(3-(1-(异喹啉-6-甲酰胺)丙基)苯基)噻吩-2-羧酸为原料，按照实施例8中的步骤5制得N-(1-(3-(5-((1-甲基哌啶-4-基)甲酰胺基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺(总产率为1.5％)。
MS(ESI)m/z＝513(M+1)+。
1HNMR(400MHz,MeOD):δ＝9.34-9.33(m,1H),8.55-8.53(m,1H),8.44(s,1H),8.24-8.20(m,1H),8.16(s,1H),8.10-8.08(m,1H),7.97-7.95(m,1H),7.92-7.91(m,1H),7.75(s,1H),7.60-7.59(m,1H),7.45-7.44(m,2H),5.12-5.09(m,1H),4.17-4.09(m,1H),3.55-3.51(m,2H),3.18-3.12(m,3H),2.87(s,3H),2.25-2.22(m,2H),2.13-1.94(m,4H),1.36-1.31(m,1H),1.17(t,J＝7.2Hz,3H)。
实施例18 N-(1-(3-(5-((四氢-2H-吡喃-4-基)甲酰胺基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000110
以4-氨基四氢吡喃和4-(3-(1-(异喹啉-6-甲酰胺)丙基)苯基)噻吩-2-羧酸为原料，按照实施例8中的步骤5制得N-(1-(3-(5-((四氢-2H-吡喃-4-基)甲酰胺基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺(总产率为9.5％)。
MS(ESI)m/z＝500(M+1)+。
1HNMR(400MHz,MeOD):δ＝9.64(s,1H),8.63-8.60(m,2H),8.46-8.43(m,1H),8.35-8.33(m,1H),8.27-8.25(m,1H),8.15(s,1H),7.90-7.89(m,1H),7.77(s,1H),7.62-7.60(m,1H),7.47-7.42(m,2H),5.14-5.11(m,1H),4.14-4.08(m,1H),4.02-4.00(m,2H),3.57-3.51(m,2H),2.11-2.02(m,2H),1.94-1.91(m,2H),1.74-1.66(m,2H),1.08(t,J＝7.2Hz,3H)。
实施例19 N-(1-(3-(5-苯胺甲酰基噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000111
以苯胺和4-(3-(1-(异喹啉-6-甲酰胺)丙基)苯基)噻吩-2-羧酸为原料，按照实施例8中的步骤5制得N-(1-(3-(5-苯胺甲酰基噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺(总产率为9.5％)。
MS(ESI)m/z＝492(M+1)+。
1HNMR(400MHz,DMSO-D2O):δ＝9.64(s,1H),8.64-8.61(m,2H),8.45-8.41(m,2H),8.30-8.29(m,1H),8.22-8.19(m,1H),8.14-8.13(m,1H),7.80(s,1H),7.73-7.71(m,2H),7.64-7.62(m,1H),7.48-7.36(m,4H),7.16-7.12(m,1H),5.06-5.02(m,1H),2.02-1.87(m,2H),0.98(t,J＝7.2Hz,3H)。
实施例20 4-(3-(1-(异喹啉-6-甲酰胺)丙基)苯基)-N-(1-甲基-1H-吡唑-4-基)噻唑-2-甲酰胺的制备
1、 4-溴-N-(1-甲基-1H-吡唑-4-基)噻唑-2-甲酰胺的制备
Figure PCTCN2017116493-appb-000112
以4-溴噻唑-2-甲酸和N-甲基-4-氨基吡唑为原料，按照实施例1中的步骤1制得4-溴-N-(1-甲基-1H-吡唑-4-基)噻唑-2-甲酰胺(产率60％)。
MS(ESI)m/z＝287/289(M+1)+。
2、 4-(3-(1-(异喹啉-6-甲酰胺)丙基)苯基)-N-(1-甲基-1H-吡唑-4-基)噻唑-2-甲酰胺的制备
Figure PCTCN2017116493-appb-000113
以4-溴-N-(1-甲基-1H-吡唑-4-基)噻唑-2-甲酰胺和N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺为原料，按照实施例1中的步骤7制得4-(3-(1-(异喹啉-6-甲酰胺)丙基)苯基)-N-(1-甲基-1H-吡唑-4-基)噻唑-2-甲酰胺(65％)。
MS(ESI)m/z＝497(M+1)+。
实施例21 4-(3-(1-(异喹啉-6-甲酰胺)丙基)苯基)-N-(1-甲基哌啶-4-基)噻唑-2-甲酰胺的制备
Figure PCTCN2017116493-appb-000114
以4-溴噻唑-2-甲酸、N-甲基-4-氨基哌啶和N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺为原料，按照实施例20的步骤1和2制得4-(3-(1-(异喹啉-6-甲酰胺)丙基)苯基)-N-(1-甲基哌啶-4-基)噻唑-2-甲酰胺(总产率30％)
MS(ESI)m/z＝514(M+1)+。
实施例22 4-(3-(1-(异喹啉-6-甲酰胺)丙基)苯基)-N-(四氢-2H-吡喃-4-基)噻唑-2-甲酰胺的制备
Figure PCTCN2017116493-appb-000115
以4-溴噻唑-2-甲酸、4-氨基-四氢-2H-吡喃和N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺为原料，按照实施例20的步骤1和2制得4-(3-(1-(异喹啉-6-甲酰胺)丙基)苯基)-N-(四氢-2H-吡喃-4-基)噻唑-2-甲酰胺(总产率24％)。
MS(ESI)m/z＝514(M+1)+。
实施例23 N-(1-(3-(4-甲基-5-((4-甲基-1H-吡唑-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000116
以4-溴-3-甲基噻吩-2-甲酸、N-甲基-4-氨基吡唑和N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺为原料，按照实施例20的步骤1和2制得N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺(总产率18％)。
MS(ESI)m/z＝510(M+1)+。
1HNMR(400MHz,DMSO):δ＝10.19(s,1H),9.39-9.32(m,1H),9.11-8.98(m,1H),8.59-8.57(m,1H),8.49(s,1H),8.22-8.20(m,1H),8.09-8.07(m,1H),7.98-7.95(m,2H),7.65(s,1H),7.52-7.41(m,3H),7.29-7.27(m,1H),5.06-5.01(m,1H),3.81(s,2H),2.37(s,3H),1.99-1.80(m,2H),0.97(t,J＝7.2Hz,3H)。
实施例24 N-(1-(3-(4-甲基-5-((1-甲基哌啶-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000117
以4-溴-3-甲基噻吩-2-甲酸、N-甲基-4-氨基哌啶和N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺为原料，按照实施例20的步骤1和2制得N-(1-(3-(4-甲基-5-((1-甲基哌啶-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-胺甲酰(总产率19％)。
MS(ESI)m/z＝527(M+1)+。
1HNMR(400MHz,DMSO-D2O):δ＝9.58(s,1H),8.63-8.61(m,1H),8.56(s,1H),8.37-8.35(m,1H),8.21-8.14(m,2H),7.80(s,0.3H),7.58(m,0.7H),7.43-7.40(m,3H),7.26-7.24(m,1H),5.01(t,J＝4.8Hz1H),4.12-4.10(m,0.5H),3.97-3.91(m,1.5H),3.45-3.42(m,2H),3.31-3.16(m,1H),3.09-3.03(m,2H), 2.76-2.75(m,4H),2.32-2.30(m,3H),2.04-2.00(m,2H),1.98-1.83(m,3H),1.78-1.68(m,2H),0.95(t,J＝7.2Hz,3H)。
实施例25 N-(1-(3-(4-甲基-5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000118
以4-溴-3-甲基噻吩-2-甲酸、4-氨基吡喃和N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺为原料，按照实施例20的步骤1和2制得N-(1-(3-(4-甲基-5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺(总产率24％)。
MS(ESI)m/z＝514(M+1)+。
1HNMR(400MHz,DMSO):δ＝9.41(s,1H),9.12(d,J＝7.6Hz,1H),8.60-8.59(m,1H),8.50(s,1H),8.24-8.21(m,1H),8.10-8.06(m,2H),7.97-7.96(m,1H),7.59(s,1H),7.47-7.43(m,3H),7.28-7.26(m,1H),5.07-5.01(m,1H),4.00-3.93(m,1H),3.88-3.86(m,2H),3.41-3.36(m,4H),2.33(s,3H),1.97-1.87(m,2H),1.78-1.75(m,2H),1.62-1.55(m,2H),0.98(t,J＝7.2Hz,3H)。
实施例26 N-(1-(3-(4-氟-5-((4-甲基-1H-吡唑-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000119
以4-溴-3-氟噻吩-2-甲酸、N-甲基-4-氨基吡唑和N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺为原料，按照实施例20的步骤1和2制得N-(1-(3-(4-氟-5-((1甲基-1H-吡唑-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-胺甲酰(总产率18％)。
MS(ESI)m/z＝514(M+1)+。
1HNMR(400MHz,DMSO):δ＝10.10(s,1H),9.41(s,1H),9.13(d,J＝8.0,1H),8.59(d,J＝5.6,1H),8.51(s,1H),8.22(d,J＝8.8,1H),8.08(m,2H),7.98(m,2H),7.73(s,1H),7.59(s,1H),7.51(m,3H),5.05(m,1H),3.83(s,3H),1.93(m,2H),0.98(t,J＝7.2Hz,3H)。
实施例27 N-(1-(3-(4-氟-5-((1-甲基哌啶-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000120
以4-溴-3-氟噻吩-2-甲酸、N-甲基-4-氨基哌啶和N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺为原料，按照实施例20的步骤1和2制得N-(1-(3-(4-氟-5-((1-甲基哌啶-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-胺甲酰(总产率21％)。
MS(ESI)m/z＝531(M+1)+。
1HNMR(400MHz,MeOD):δ＝9.35(s,1H),9.55(d,J＝6.0,1H),9.15(s,1H),8.44(s,1H),8.23(d,J＝8.4,1H),8.08(m,1H),7.97(d,J＝6.0,1H),7.87(d,J＝4.4,1H),7.70(s,1H),7.54(m,2H),5.11(m,1H),4.19(m,1H),3.55(m,2H),3.20(m,2H),2.91(s,3H),2.66(m,2H),2.06(m,4H),1.08(t,J＝7.2Hz,3H)。
实施例28 N-(1-(3-(4-氟-5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000121
以4-溴-3-氟噻吩-2-甲酸、4-氨基吡喃和N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺为原料，按照实施例20的步骤1和2制得N-(1-(3-(4-氟-5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺(总产率19％)。
MS(ESI)m/z＝518(M+1)+。
1HNMR(400MHz,DMSO):δ＝9.40(s,1H),9.13(d,J＝8.4Hz,1H),8.60(d,J＝5.6,1H),8.50(s,1H),8.22(d,J＝8.8Hz,1H),8.08(m,1H),8.03(s,1H),8.02(s,1H),7.91(m,1H),7.71(s,1H),7.50(m,2H),5.03(m,1H),4.00(m,1H),3.86(m,2H),3.38(m,2H),1.92(m,2H),1.77(m,2H),1.63(m,2H),0.98(t,J＝7.2Hz,3H)。
实施例29 N-(1-(3-(4-氟-5-苯基胺甲酰基噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000122
以4-溴-3-氟噻吩-2-甲酸、苯胺和N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺为原料，按照实施例20的步骤1和2制得N-(1-(3-(4-氟-5-苯基胺甲酰基噻吩-3-基)苯基)丙基)异喹啉-6-胺甲酰(总产率17％)+。
MS(ESI)m/z＝510(M+1)。
1HNMR(400MHz,DMSO):δ＝10.10(s,1H),9.40(s,1H),9.15(s,1H),8.60(d,J＝5.6,1H),8.51(s, 1H),8.23(d,J＝8.8,1H),8.11(m,2H),7.97(d,J＝5.6Hz,1H),7.75(s,1H),7.69(d,J＝7.6,2H),7.52(m,3H),7.36(m,2H),7.14(m,1H),5.06(m,1H),1.95(m,1H),0.99(t,J＝7.2Hz,3H)。
实施例30 N-(1-(3-(1-氟-5-((4-甲基-1H-吡唑-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000123
以4-溴-5-氟噻吩-2-甲酸、N-甲基-4-氨基吡唑和N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺为原料，按照实施例20的步骤1和2制得N-(1-(3-(1-氟-5-((1甲基-1H-吡唑-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-胺甲酰(总产率18％)。
MS(ESI)m/z＝514(M+1)+。
1HNMR(400MHz,MeOD):δ＝9.39(s,1H),8.56-8.54(m,1H),8.46(s,1H),8.27-8.25(m,1H),8.13-8.10(m,1H),8.03-8.01(m,1H),7.97(s,1H),7.92(d,J＝4.0Hz,1H),7.73(s,1H),7.61(m,1H),7.56-7.55(m,1H),7.51-7.47(m,2H),5.13-5.09(m,1H),3.90(s,3H),2.11-1.98(m,2H),1.08(t,J＝7.2Hz,3H)。
实施例31 N-(1-(3-(1-氟-5-((1-甲基哌啶-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000124
以4-溴-5-氟噻吩-2-甲酸、N-甲基-4-氨基哌啶和N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺为原料，按照实施例20的步骤1和2制得N-(1-(3-(1-氟-5-((1-甲基哌啶-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-胺甲酰(总产率17％)。
MS(ESI)m/z＝531(M+1)+。
1HNMR(400MHz,DMSO-D2O):δ＝9.95(s,1H),8.81(m,5H),8.59(m,2H),8.47(s,1H),8.34(d,J＝8.4,1H),8.25(s,1H),5.17(m,1H),3.99(m,1H),3.45(m,2H),3.11(m,2H),2.82(s,3H),1.97(m,6H),1.01(t,J＝7.2Hz,3H)。
实施例32 N-(1-(3-(1-氟-5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000125
以4-溴-5-氟噻吩-2-甲酸、4-氨基吡喃和N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺为原料，按照实施例20的步骤1和2制得N-(1-(3-(1-氟-5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺(总产率19％)。
MS(ESI)m/z＝518(M+1)+。
1HNMR(400MHz,MeOD):δ＝9.41(s,1H),8.75(s,1H),8.65(s,1H),8.57(s,1H),8.49(s,1H),8.30(d,J＝8.4,1H),8.13(m,3H),7.94(d,J＝4.0,1H),5.17(m,1H),3.99(m,3H),3.53(m,2H),2.10(m,2H),1.91(d,J＝11.2,2H),1.70(m,2H),1.12(t,J＝7.2Hz,3H)。
实施例33 N-(1-(3'-((1-甲基哌啶-4-基)胺甲酰基)-[1,1'-联苯]-3-基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000126
以3-溴苯甲酸、4-氨基-N-甲基吡唑和N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺为原料，按照实施例20的步骤1和2制得N-(1-(3'-((1-甲基哌啶-4-基)胺甲酰基)-[1,1'-联苯]-3-基)丙基)异喹啉-6-甲酰胺(总产率22％)。
MS(ESI)m/z＝490(M+1)+。
1HNMR(400MHz,DMSO):δ＝10.78(s,1H),9.99(s,1H),9.59-9.57(m,1H),8.92(s,1H),8.74-8.72(m,1H),8.63-8.60(m,2H),8.44-8.42(m,1H),8.36(s,1H),8.08-8.06(m,2H),7.95(d,J＝7.6Hz,1H),7.87(d,J＝8.0Hz,1H),7.69-7.64(m,2H),7.62-7.58(m,1H),7.50-7.47(m,2H),5.10(q,J＝8.4,11.4Hz,1H),3.83(s,3H),2.06-1.89(m,2H),0.98(t,J＝7.2Hz,3H)。
实施例34 N-(1-(4'-((1-甲基哌啶-4-基)胺甲酰基)-[1,1'-联苯]-3-基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000127
以4-溴苯甲酸、4-氨基-N-甲基吡唑和N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺为原料，按照实施例20的步骤1和2制得N-(1-(4'-((1-甲基哌啶-4-基)胺甲酰基)-[1,1'-联苯]-3-基)丙基)异喹啉-6-甲酰胺(总产率22％)。
MS(ESI)m/z＝490(M+1)+。
实施例35 N-(1-(2-(5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)噻唑-5-基)丙基)-1H-吲唑-5-甲酰胺的制备
1、 2-(5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)噻唑-5-甲酸乙酯的制备
Figure PCTCN2017116493-appb-000128
将2-溴噻唑-5-甲酸乙酯(2.00g,8.47mmol)和N-(四氢-2H-吡喃)-4-(4,4,5,5-四甲基-1,3,2-硼酸酯)噻吩-2-甲酰胺(3.14g,9.32mmol)溶于N,N-二甲基甲酰胺(20.0mL)和水(500μL)中，然后加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(157mg,215μmol)和碳酸钾(4.45g,32.3mmol),氮气保护下110℃反应3小时后减压蒸除溶剂，经柱层析纯化得2-(5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)噻唑-5-甲酸乙酯(1.20g,2.62mmol,产率31％)。
MS(ESI)m/z＝367(M+1)+
2、 2-(5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)噻唑-5-甲酸的制备
Figure PCTCN2017116493-appb-000129
将2-(5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)噻唑-5-甲酸乙酯(2.00g,8.47mmol)溶于四氢呋喃(4.00mL)和乙醇(1.00mL)中，滴加5.00mL氢氧化锂(203mg,8.47mmol)的水溶液，室温反应两小时。稀盐酸调节pH＝3～4，然后用乙酸乙酯和水萃取，再将水相用乙酸乙酯洗两次，合并有机相，减压蒸除溶剂得2-(5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)噻唑-5-甲酸(1.80g,6.92mmol,产率78％)。
MS(ESI)m/z＝339(M+1)+。
3、 N-(1-(2-(5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)噻唑-5-基)丙基)-1H-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000130
以2-(5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)噻唑-5-甲酸、吲唑5-甲酸为原料，按照实施例1的步骤3、4、5、6制得N-(1-(2-(5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)噻唑-5-基)丙基)-1H-吲唑-5-甲酰胺(产率2.2％)。
MS(ESI)m/z＝496(M+1)+。
1H NMR(400MHz,DMSO):δ＝8.38(s,1H),8.19(s,1H),8.14(d,J＝4Hz,2H),7.91-7.93(m,1H), 7.77(s,1H),7.63(d,J＝8Hz,1H),5.40(t,J＝7.2Hz 1H),3.98-4.09(m,3H),3.50-3.57(m,2H),2.13-2.17(m,2H),1.91(d,J＝12.4Hz,2H),1.68-1.74(m,2H),1.36(t,J＝7.6Hz,3H)。
实施例36 N-(1-(2-(5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)噻唑-5-基)丙基)-异喹啉-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000131
以异喹啉-6-甲酸为原料，按照实施例35的类似步骤制得N-(1-(2-(5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)噻唑-5-基)丙基)-异喹啉-5-甲酰胺(总产率为3.3％)。
MS(ESI)m/z＝507(M+1)+。
1H NMR(400MHz,MeOD):δ＝9.81(s,1H),9.07(s,1H),8.86(J＝7.2Hz,d,2H),8.79(s,1H),8.69(d,J＝7.2Hz,1H),8.54-8.59(m,2H),8.30(d,J＝8.4Hz,1H),8.30(s,2H),5.28(t,J＝7.8Hz,1H),3.98-4.09(m,3H),3.52-3.53(m,2H),2.14-2.23(m,2H),1.91-1.94(m,2H),1.69-1.74(m,2H),1.15(t,J＝7.2Hz,3H)。
实施例37 N-(1-(2-(5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)噁唑-5-基)丙基)-异喹啉-5-甲酰胺的制备
1、 N-甲氧基-N-甲基-噁唑-2-甲酰胺的制备
Figure PCTCN2017116493-appb-000132
将2-噁唑羧酸(2.00g,17.7mmol)溶于二氯甲烷(20.0mL)中，在冰浴下依次加入苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(7.39g,19.5mmol)，N,N-二异丙基乙胺(9.15g,70.8mmol)和盐酸二甲羟胺(1.08g,17.7mmol)，室温反应1小时后蒸除溶剂得粗品，经柱层析纯化得N-甲氧基-N-甲基-噁唑-2-甲酰胺(2.76g,24.9mmol,产率95％).
MS(ESI)m/z＝157(M+1)+。
2、 1-(2-噁唑基)丙烷-1-酮的制备
Figure PCTCN2017116493-appb-000133
将N-甲氧基-N-甲基-噁唑-2-甲酰胺(2.00g,12.2mmol)溶于四氢呋喃(10.0mL)中，在冰浴下加入乙基氯化镁四氢呋喃溶液(24.5mmol,16.3mL)，氮气保护下室温下反应20分钟，反应液用稀盐酸在冰浴下萃灭，乙酸乙酯萃取三次，合并有机相蒸除溶剂得粗品，经柱层析纯化得1-(2-噁唑基)丙烷-1-酮 (800mg,3.50mmol,产率39％)。
MS(ESI)m/z＝126(M+1)+。
3、 5-(四氢吡喃-4-甲酰基)-3-噻吩基]噁唑-丙烷-1-酮的制备
Figure PCTCN2017116493-appb-000134
将N-(2H-4-四氢吡喃)-4-溴噻吩-2-甲酰胺(1.67g,5.75mmol)和1-(2-噁唑基)丙烷-1-酮(800mg,6.39mmol)溶于N,N-二甲基甲酰胺(2.00mL)中，加入醋酸钯(71.6mg,320μmol)，碳酸钾(2.65g,19.2mmol)和碘化亚铜(1.22g,6.39mmol)，氮气保护下100℃反应1小时后减压蒸除溶剂得粗品，经柱层析及制备高效液相纯化得5-(四氢吡喃-4-甲酰基)-3-噻吩基]噁唑-丙烷-1-酮(200mg,480μmol,产率7.8％).
MS(ESI)m/z＝335(M+1)+。
4、 N-(1-(2-(5-((四氢-2H-吡喃-4-基)胺甲酰基)噻吩-3-基)噁唑-5-基)丙基)-异喹啉-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000135
以5-(四氢吡喃-4-甲酰基)-3-噻吩基]噁唑-丙烷-1-酮、异喹啉-6-甲酸为原料，按照实施例1的步骤5和6制得N-(1-(2-(5-((四氢-2H-吡喃-4-基)胺甲酰基)恶吩-3-基)噁唑-5-基)丙基)-异喹啉-5-甲酰胺(产率为3.3％)。
MS(ESI)m/z＝491(M+1)+。
1H NMR(400MHz,MeOD):δ＝9.72(s,1H),8.66(t,J＝8.4Hz,2H),8.51(d,J＝7.2Hz,1H),8.42(d,J＝8.4Hz,1H),8.31(d,J＝1.2Hz,1H),8.24-8.25(m,1H),8.17-8.24(m,1H),7.22-7.23(m,1H),5.38(t,J＝7.2Hz,1H),4.06-4.11(m,1H),2.98-4.01(m,2H),3.53(t,J＝7.2Hz,2H),2.08-2.24(m,2H),1.88-1.92(m,2H),1.68-1.72(m,2H),1.37-1.41(m,2H),1.14(t,J＝7.6Hz,3H)。
实施例38 N-(1-(5-(5-((1-甲基-1H-吡唑-4-基)胺甲酰基)噻吩-3-基)吡啶-3-基)丙基)吲唑-5-甲酰胺的制备
1、 N-1-(5-溴-3-吡啶基)丙基)-1H-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000136
以3-溴吡啶-5-甲酸为原料，按照实施例1中的步骤3、4、5、6制得N-1-(5-溴-3-吡啶基)丙基)-1H-吲唑-5-甲酰胺(总收率为12％)。
MS(ESI)m/z＝358(M+1)+＝359/361。
2、 N-1-(5-溴-3-吡啶基)丙基)-4H-吡喃-2-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000137
将N-1-(5-溴-3-吡啶基)丙基)-1H-吲唑-5-甲酰胺(350mg,970μmol)溶于二氯甲烷(5.00mL)中，冰浴下依次加入对甲苯磺酸(83.9mg,790μmol)和3,4-二氢-2H-吡喃(164mg,1.95mmol)，室温反应1小时后减压蒸除溶剂得粗品，经柱层析纯化得N-1-(5-溴-3-吡啶基)丙基)-4H-吡喃-2-吲唑-5-甲酰胺的制备(300mg,673μmol，产率86％)。
MS(ESI)m/z＝443/445(M+1)+。
3、 N-(1-(5-(5-噻吩甲酸甲脂基)-3-吡啶基)丙基)-4H-吡喃2-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000138
将N-1-(5-溴-3-吡啶基)丙基)-4H-吡喃-2-吲唑-5-甲酰胺(3.00g,6.73mmol)溶于二氧六环(20.0mL)中，然后加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(91.6mg,130μmol)，碳酸钾(2.80g,20.2mmol)和(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)噻吩-2-甲酸甲脂(5.40g,26.9mmol)，氮气保护下100℃反应1小时后减压蒸除溶剂得粗品，经柱层析及制备高效液相纯化得N-(1-(5-(5-噻吩甲酸甲脂基)-3-吡啶基)丙烷基)-1H-吲唑-5-甲酰胺(3.20g,5.36mmol,产率79％).
MS(ESI)m/z＝519(M+1)+。
4、 N-(1-(5-(5-噻吩甲酸基)-3-吡啶基)丙基)-4H-吡喃2-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000139
将N-(1-(5-(5-噻吩甲酸甲脂基)-3-吡啶基)丙烷基)-1H-吲唑-5-甲酰胺(2.40g,4.63mmol)溶于四氢呋喃(8.00mL)，甲醇(2.00mL)和水(2.00mL)中，然后加入氢氧化锂(665mg,27.8mmol)，25℃下反应1小时后调节pH至2～3，乙酸乙酯萃取后减压蒸除溶剂得到N-(1-(5-(5-噻吩甲酸)-3-吡啶基)丙烷基)-1H-吲唑-5-甲酰胺(1.80g,3.30mmol,产率71％).
MS(ESI)m/z＝491(M+1)+。
5、 N-(1-(5-(5-((1-甲基-1H-吡唑-4-基)胺甲酰基)噻吩-3-基)吡啶-3-基)丙基)吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000140
将N-(1-(5-(5-噻吩甲酸)-3-吡啶基)丙烷基)-1H-吲唑-5-甲酰胺(49.0mg,100μmol)溶于N,N-二甲基甲酰胺(500μL)中，冰浴下依次加入N,N-二异丙基乙胺(26.0mg,200μmol)，1-羟基-7-偶氮苯并三氮唑(16.3mg,120μmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(23.0mg,120μmol)。室温反应30分钟后加入4-氨基-1-甲基吡唑(10.7mg,110μmol)。继续反应3小时后用乙酸乙酯和水萃取，合并有机相，减压蒸除溶剂，将残留物溶于1.00mL二氯甲烷和三氟乙酸(1：1)的混合溶剂中反应1小时。减压蒸除溶剂后经制备高效液相纯化得N-(1-(5-(5-((1-甲基-1H-吡唑-4-基)胺甲酰基)噻吩-3-基)吡啶-3-基)丙基)吲唑-5-甲酰胺(9.21mg,19μmol，产率19％)。
MS(ESI)m/z＝486(M+1)+
1H NMR(400MHz,MeOD):δ＝8.81(d,J＝2.0Hz,1H),8.60(d,J＝2.0Hz,2H),8.40(s,1H),8.25-8.24(m,1H),8.20(s,1H),8.12-8.12(m,1H),8.01(s,1H),7.93-7.90(m,1H),7.65-7.62(m,2H),5.16-5.12(m,1H),3.91(m,3H),2.14-2.01(m,2H),1.11(t,J＝7.2Hz,3H)。
实施例39 N-(1-(5-(5-((2-哌啶酮-4-基)胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000141
以4-氨基-2-哌啶酮为原料，按照实施例38的类似步骤制得N-(1-(5-(5-((2-哌啶酮-4-基)胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺(总产率1.8％)。
MS(ESI)m/z＝503(M+1)+。
1HNMR(400MHz,DMSO-D2O):δ＝8.94-8.93(m,1H),8.71(s,1H),8.52(s,1H),8.38(s,1H),8.31(s,1H),8.27(s,1H),8.22(s,1H),7.86-7.83(m,1H),7.60-7.59(m,1H),5.11-5.07(m,1H),4.19-4.14(m,1H),3.24-3.14(m,2H),2.28-2.22(m,1H),2.02-1.89(m,3.6H),1.76-1.70(m,1.4H),0.96(d,J＝7.2Hz,3H)。
实施例40 N-(1-(5-(5-((4,4-二氟环己基)胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000142
以4,4-二氟环己胺为原料，按照实施例38的类似步骤制得N-(1-(5-(5-((4,4-二氟环己基)胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺(总产率0.92％)。
MS(ESI)m/z＝524(M+1)+。
1HNMR(400MHz,MeOD):δ＝8.94-8.93(m,1H),8.72-8.71(m,1H),8.54(s,1H),8.41(s,1H),8.22-8.20(m,3H),7.93-7.90(m,1H),7.64-7.62(m,1H),5.20-5.16(m,1H),4.06-4.00(m,1H),2.21-1.89(m,8H),1.79-1.69(m,2H),1.13(t,J＝7.2Hz,3H)。
实施例41 N-(1-(5-(5-((环己基)胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000143
以环己胺为原料，按照实施例38的类似步骤制得N-(1-(5-(5-((环己基)胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺(总产率2.5％)。
MS(ESI)m/z＝488(M+1)+。
1HNMR(400MHz,DMSO):δ＝13.31(s,1H),8.93-8.91(m,1H),8.82-8.81(m,1H),8.58-8.57(m,1H),8.40(s,1H),8.36-8.34(m,1H),8.31(s,1H),8.22(s,1H),8.18-8.15(m,2H),7.88-7.85(m,1H),7.58-7.56(m,1H),5.06-5.00(m,1H),3.73(s,1H),2.03-1.96(m,1H),1.88-1.85(m,2H),1.75-7.73(m,2H),1.67-1.60(m,2H),1.36-1.25(m,4H),1.19-1.11(m,1H),0.95(d,J＝7.2Hz,3H)。
实施例42 N-(1-(5-(5-((1-甲基哌啶-4-基)胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000144
以1-甲基-4-氨基哌啶为原料，按照实施例38的类似步骤制得N-(1-(5-(5-((1-甲基哌啶-4-基)胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺(总产率3.1％)。
MS(ESI)m/z＝503(M+1)+。
1HNMR(400MHz,DMSO-D2O):δ＝9.00-8.95(m,1H),8.77-8.73(m,1H),8.54-8.50(m,1H),8.42-8.40(m,1H),8.35-8.34(m,2H),8.23(s,1H),7.88-7.85(m,1H),7.62-7.59(m,1H),5.12-5.08(m,1H),4.02-3.97 (m,3H),3.48-3.44(m,1.5H),3.35-3.32(m,0.5H),3.12-3.05(m,2H),2.81-2.75(m,3H),2.07-1.93(m,4H),1.86-1.77(m,2H),1.27-1.24(m,2H),0.97(d,J＝7.2Hz,3H)。
实施例43 N-(1-(5-(5-(环丁基胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000145
以环丁胺为原料，按照实施例38的类似步骤制得N-(1-(5-(5-(环丁基胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺(总产率1.4％)。
MS(ESI)m/z＝460(M+1)+。
实施例44 N-(1-(5-(5-((3,3-二氟环丁基)胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000146
以3,3-二氟环丁胺为原料，按照实施例38的类似步骤制得N-(1-(5-(5-((3,3-二氟环丁基)胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺(总产率1.8％)。
MS(ESI)m/z＝496(M+1)+。
实施例45 N-(1-(5-(5-((1-乙酰基哌啶-4-基)胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000147
以1-乙酰基-4-氨基哌啶为原料，按照实施例38的类似步骤制得N-(1-(5-(5-((1-乙酰基哌啶-4-基)胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺(总产率0.72％)。
MS(ESI)m/z＝531(M+1)+。
1HNMR(400MHz,MeOD):δ＝8.79-8.78(m,1H),8.59-8.58(m,1H),8.39(s,1H),8.20-8.18(m,3H),8.08-8.07(m,1H),7.92-7.90(m,1H),7.63-7.61(m,1H),5.13-5.11(m,1H),4.58-4.55(m,1H),4.18-4.10(m,1H),4.02-3.98(m,1H),3.27-3.24(m,1H),2.85-2.78(m,1H),2.15(s,3H),2.11-1.96(m,4H),1.964-1.46(m,2H),1.10(t,J＝7.2Hz,3H)。
实施例46 N-(1-(5-(5-((1-甲氧甲酰基哌啶-4-基)胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺的 制备
Figure PCTCN2017116493-appb-000148
以1-甲氧甲酰基-4-氨基哌啶为原料，按照实施例38的类似步骤制得N-(1-(5-(5-((1-甲氧甲酰基哌啶-4-基)胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺(总产率3.2％)。
MS(ESI)m/z＝547(M+1)+。
1HNMR(400MHz,MeOD):δ＝8.79-8.78(m,1H),8.59-8.58(m,1H),8.39(s,1H),8.20-8.18(m,3H),8.08-8.07(m,1H),7.92-7.90(m,1H),7.63-7.61(m,1H),5.15-5.11(m,1H),4.62(s,1H),4.19-4.03(m,3H),3.72(s,3H),2.99(s,2H),2.17-1.97(m,4H),1.60-1.50(m,2H),1.10(t,J＝7.2Hz,3H)。
实施例47 N-(1-(5-(5-(哌啶-4-基胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺的制备
Figure PCTCN2017116493-appb-000149
以1-叔丁氧甲酰基-4-氨基哌啶为原料，按照实施例38的类似步骤制得N-(1-(5-(5-(哌啶-4-基胺甲酰)噻吩-3-基)吡啶-3-基)丙基)-1H-吲唑-5-甲酰胺(总产率2.5％)。
MS(ESI)m/z＝489(M+1)+。
1HNMR(400MHz,MeOD):δ＝8.79-8.78(m,1H),8.59-8.58(m,1H),8.39(s,1H),8.20-8.18(m,3H),8.08-8.07(m,1H),7.92-7.90(m,1H),7.63-7.61(m,1H),5.13-5.11(m,1H),4.58-4.55(m,1H),4.18-4.10(m,1H),4.02-3.98(m,1H),3.27-3.24(m,1H),2.85-2.78(m,1H),2.15(s,3H),2.11-1.96(m,4H),1.964-1.46(m,2H),1.10(t,J＝7.2Hz,3H)。
实施例48 5-氟-4-(3-(1-(异喹啉-6-甲酰)四氢吡咯-2-基)苯基)-N-(1-甲基-1H-吡唑-4-基)噻吩-2-甲酰胺的制备
1、叔丁基2-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)四氢吡咯-1-甲酰胺的制备
Figure PCTCN2017116493-appb-000150
以叔丁基2-(3-溴苯基)四氢吡咯-1-甲酰胺为原料，按照实施例1中的步骤6的方法制得叔丁基2-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)四氢吡咯-1-甲酰胺(产率57％)。
MS(ESI)m/z＝374(M+1)+。
2、 2-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)四氢吡咯的制备
Figure PCTCN2017116493-appb-000151
将叔丁基2-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)四氢吡咯-1-甲酰胺(1.40g,3.75mmol)溶于2M的盐酸二氧六环溶液，室温搅拌1小时，然后减压蒸馏除去溶剂，得到化合物2-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)四氢吡咯盐酸盐(1.1g,产率为96％)
MS(ESI)m/z＝274(M+1)+。
3、异喹啉-6-基(2-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)四氢吡咯-1-基)甲酮的制备
Figure PCTCN2017116493-appb-000152
以6-溴异喹啉甲酸和2-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)四氢吡咯盐酸盐为原料，按照实施例1中的步骤6的方法制得异喹啉-6-基(2-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)四氢吡咯-1-基)甲酮(产率84％)。
MS(ESI)m/z＝429(M+1)+。
4、 5-氟-4-(3-(1-(异喹啉-6-甲酰)四氢吡咯-2-基)苯基)-N-(1-甲基-1H-吡唑-4-基)噻吩-2-甲酰胺的制备
Figure PCTCN2017116493-appb-000153
以4-溴-5-氟噻酚-2-甲酸、N-甲基-4-氨基吡唑和异喹啉-6-基(2-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)四氢吡咯-1-基)甲酮为原料，按照实施例20的步骤1和2制得5-氟-4-(3-(1-(异喹啉-6-甲酰)四氢吡咯-2-基)苯基)-N-(1-甲基-1H-吡唑-4-基)噻吩-2-甲酰胺(总产率8.3％)。
MS(ESI)m/z＝526(M+1)+
实施例49 N-(1-(3-(4-甲基-5-((4-甲基-1H-吡唑-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
1、(R)-N-(3-溴苯亚甲基)-2-甲基丙烷-2-亚磺酰胺的制备
Figure PCTCN2017116493-appb-000154
将3-溴苯甲醛(11.0g,59.5mmol)加入(R)-叔丁基亚磺酰胺(9.01g,74.3mmol)的四氢呋喃(100mL)溶液中，在室温下加入钛酸四乙酯(30.6g，134mmol)。回流搅拌2小时。反应完成后降至室温，并加入水淬灭。然后过滤除去固体，并用乙酸乙酯冲洗固体。再用乙酸乙酯和水萃取。水相再用乙酸乙酯洗两遍，合并有机相，并减压蒸馏除去溶剂。再通过柱层析纯化残留物得到白色固体(R)-N-(3-溴苯亚甲基)-2-甲基丙烷-2-亚磺酰胺(15.00g,52.05mmol,产率87％)
MS(ESI)m/z＝288，290(M+1)+。
2、(R)-N-((R)-1-(3-溴苯基)丙基)-2-甲基丙烷-2-亚磺酰胺的制备
Figure PCTCN2017116493-appb-000155
将二乙基锌的四氢呋喃溶液(70.8mmol,70.0mL)慢慢加入甲基溴化镁(62.5mmol,62.0mL)的四氢呋喃溶液中，再将该混合溶液缓慢滴入-78℃的(R)-N-(3-溴苯亚甲基)-2-甲基丙烷-2-亚磺酰胺(12.0g,41.6mmol)四氢呋喃(120mL)溶液，并在该温度下搅拌2小时。待反应完成后在冰浴下加入饱和氯化铵溶液淬灭，再用乙酸乙酯和水萃取，并将水相用乙酸乙酯洗两次，合并有机相，减压蒸馏除去溶剂。再将残余物柱层析得到白色固体。最后用乙酸乙酯和石油醚重结晶得到单一异构体(R)-N-((R)-1-(3-溴苯基)丙基)-2-甲基丙烷-2-亚磺酰胺(5.00g,15.7mmol,产率37.7％)。
MS(ESI)m/z＝318,320(M+1)+。
3、(R)-2-甲基-N-((R)-1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)苯基)丙烷-2-亚磺酰胺的制备
Figure PCTCN2017116493-appb-000156
以(R)-N-((R)-1-(3-溴苯基)丙基)-2-甲基丙烷-2-亚磺酰胺为原料，按照实施例1中的步骤6的方法制得(R)-2-甲基-N-((R)-1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)苯基)丙烷-2-亚磺酰胺(产率58％)。
MS(ESI)m/z＝366(M+1)+。
4、(R)-1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)苯基)丙烷-2-胺的制备
Figure PCTCN2017116493-appb-000157
以(R)-2-甲基-N-((R)-1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)苯基)丙烷-2-亚磺酰胺为原料，按照实施例48中的步骤2的方法制得(R)-1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)苯基)丙烷-2-胺(产率98％)。
MS(ESI)m/z＝262(M+1)+。
5、(R)-N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000158
以6-溴异喹啉甲酸和(R)-1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)苯基)丙烷-2-胺为原料，按照实施例1中的步骤6的方法制得(R)-N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺(产率59％)。
MS(ESI)m/z＝417(M+1)+。
6、(R)-N-(1-(3-(4-甲基-5-((4-甲基-1H-吡唑-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000159
以4-溴-3-甲基噻吩-2-甲酸、N-甲基-4-氨基吡唑和(R)-N-(1-(3-(4,4,5,5-四甲基-1,3,2-二氧杂己硼烷-2-基)苯基)丙基)异喹啉-6-甲酰胺为原料，按照实施例20的步骤1和2制得(R)-N-(1-(3-(4-甲基-5-((4-甲基-1H-吡唑-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺(总产率25％)。
MS(ESI)m/z＝510(M+1)+。
1HNMR(400MHz,MeOD):δ＝9.91(s,1H),8.73(s,1H),8.68(s,1H),8.63(m,2H),8.61(m,2H),8.38(d,J＝8.8Hz,1H),7.46(m,4H),7.32(m,1H),5.12(t,J＝7.2Hz,1H),4.01(m,1H),3.98(m,2H),3.54(m,2H),2.39(s,3H),2.05(m,2H),1.94(m,2H),1.70(m,2H),1.09(t,J＝7.2Hz,3H)。
实施例50(R)-N-(2-甲基-1-(3-(4-甲基-5-((4-甲基-1H-吡唑-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000160
按照实施例49的方法，将步骤2中的二乙基锌和甲基溴化镁换成二甲基锌和异丙基溴化镁，得到(R)-N-(2-甲基-1-(3-(4-甲基-5-((4-甲基-1H-吡唑-4-基)胺甲酰基)噻吩-3-基)苯基)丙基)异喹啉-6-甲酰胺(总产率10％)。
MS(ESI)m/z＝538(M+1)+
实施例51(R)-N-(1-(5-(4-((1-甲基-1H-吡唑-4-基)氨基甲酰基)噻吩-2-基)吡啶-3-基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000161
按照实施例49的方法，将步骤1中的3-溴苯甲醛换成3-溴-5-醛基吡啶，将步骤6中的4-溴-3-甲基噻吩-2-甲酸换成2-溴-噻吩-4-甲酸，得到(R)-N-(1-(5-(4-((1-甲基-1H-吡唑-4-基)氨基甲酰基)噻吩-2-基)吡啶-3-基)丙基)异喹啉-6-甲酰胺(总产率12％)。
MS(ESI)m/z＝497(M+1)+
1HNMR(400MHz,MeOD):δ＝9.34(s,1H),8.81-8.80(m,1H),8.63-8.62(m,1H),8.56-8.54(m,1H),8.46(s,1H),8.31(s,1H),8.25-8.23(m,2H),8.20-8.18(m,1H),8.11-8.08(m,1H),8.02-8.01(m,2H),7.98-7.97(m,1H),7.64(s,1H),5.19-5.15(m,1H),3.91(s,3H),2.17-2.02(m,2H),1.12(t,J＝7.2Hz,3H)。
实施例52(R)-N-(1-(3-(5-((1-甲基-1H-吡唑-4-基)氨基甲酰基)噻吩-2-基)苯基)丙基)异喹啉-6-甲酰胺的制备
Figure PCTCN2017116493-appb-000162
按照实施例49的方法，将步骤6中的4-溴-3-甲基噻吩-2-甲酸换成2-溴-噻吩-5-甲酸，得到(R)-N-(1-(3-(5-((1-甲基-1H-吡唑-4-基)氨基甲酰基)噻吩-2-基)苯基)丙基)异喹啉-6-甲酰胺(总产率11％)。
MS(ESI)m/z＝496(M+1)+
为了说明本发明的有益效果，本发明提供以下试验例：
试验例 本发明化合物的生物活性
对本发明的化合物进行了ROCK2抑制活性的检测。
(1)方法
ROCK2抑制活性的检测
ROCK2能够磷酸化S6K(KRRRLASLR)多肽底物，将ATP转化成ADP。在激酶反应后，加入ADP-GloTM试剂，使激酶反应终止，并消耗完剩余的ATP。加入激酶检测试剂，它在使ADP转化成ATP的同时，ATP再被Ultra-GloTM萤光素酶转化成光发光信号，发光信号与激酶活性正相关。
按以下步骤进行ROCK2抑制活性的检测：
1.Assay Buffer:40mM Tris pH 7.5，20mM MgCl2，0.1％BSA(w/v)，50μM DTT；
2.加12μL2.5x0.1μg/ml ROCK2工作液进入96孔PCR板；
3.加6μL6x化合物工作液进入96孔PCR板混匀，25℃预孵育10min；
4.加入12μL 2.5x 37.5μg/mlS6K底物和12.5μMATP混合工作液，30℃孵育60min；
5.取25μL反应混合物到一个新96孔PCR板，并加入25μL ADP-GloTM试剂混匀，25℃孵育40min终止反应；
6.取40μL终止反应混合物到一个新96孔PCR板，并加入40μL激酶检测试剂混匀，25℃孵育40min；
7.读取luminescence(冷光)信号值，计算抑制率。
(2)结果
试验结果见表1，其中测定各化合物的IC50按照说明分类，表1中：
“+”表示IC50测定值大于500nM；
“++”表示IC50测定值小于500nM大于50nM；
“+++”表示IC50测定值小于50nM
表1、化合物对ROCK2的抑制活性
实施例 ROCK2 实施例 ROCK2
1 ++ 2 ++
3 +++ 4 +++
5 ++ 6 +
7 + 8 +++
9 +++ 10 ++
11 ++ 12 ++
13 +++ 14 ++
15 ++ 16 +++
17 +++ 18 +++
19 ++ 20 ++
21 ++ 22 ++
23 +++ 24 +++
25 +++ 26 +++
27 +++ 28 +++
29 ++ 30 +++
31 +++ 32 +++
33 +++ 34 +
35 +++ 36 +
37 + 38 +++
39 +++ 40 +++
41 +++ 42 +++
43 +++ 44 +++
45 +++ 46 +++
47 +++ 48 +++
49 +++ 50 +++
51 +++ 52 +++
ND:数据正在检测分析中。
试验表明，本发明实施例的化合物具有良好的ROCK抑制活性，可以有效用于与ROCK活性异常疾病的治疗。
综上所述，本发明公开的式I所示的新化合物，表现出了良好的ROCK抑制活性，为临床治疗与ROCK活性异常相关的疾病提供了一种新的药用可能。

Claims (43)

  1. 式Ⅰ所示的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物：
    Figure PCTCN2017116493-appb-100001
    其中，
    A选自取代或未取代的芳杂环；
    B选自
    Figure PCTCN2017116493-appb-100002
    取代或未取代的芳环、取代或未取代的芳杂环；其中B1、B2分别独立地选自取代或未取代的芳环、取代或未取代的芳杂环；
    R1选自氢、C1-C6烷基；R2、R3分别独立地选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基或取代的C3～C6环烷基；
    或者，R2与R3相连构成C3～C6环烷基、C3～C6环杂烷基、取代的C3～C6环烷基或取代的C3～C6环杂烷基；
    或者，R1与R2或R3相连构成C3～C6环杂烷基或取代的C3～C6环杂烷基；
    n为1、2、3或4；
    R4分别独立地选自氢、硝基、氰基、卤素、羧基、C1～C6烷基、取代的C1～C6烷基、C2～C6烯基、取代的C2～C6烯基、C2～C6炔基、取代的C2～C6炔基、C3～C10环烷基、取代的C3～C10环烷基、C3～C10杂环基、取代的C3～C10杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环、
    Figure PCTCN2017116493-appb-100003
    Figure PCTCN2017116493-appb-100004
    其中R41、R42分别独立地选自氢、C1～C6烷基、取代的C1～C6烷基、C2～C6烯基、取代的C2～C6烯基、C2～C6炔基、取代的C2～C6炔基、C3～C10环烷基、取代的C3～C10环烷基、C3～C10杂环基、取代的C3～C10杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
  2. 根据权利要求1所述的化合物，其特征在于：
    A选自取代或未取代的C9～C10的芳杂环；
    B选自
    Figure PCTCN2017116493-appb-100005
    取代或未取代的C9～C10的芳环、取代或未取代的C9～C10的芳杂环；其中B1、B2分别独立地选自取代或未取代的C5～C6的芳环、取代或未取代的C5～C6的芳杂环；
    R1选自氢、C1～C6烷基；
    R2、R3分别独立地选自氢、C1～C6烷基、取代的C1～C6烷基；
    或者，R1与R2或R3相连构成C3～C6环杂烷基；
    n为1或2；
    R4分别独立地选自氢、
    Figure PCTCN2017116493-appb-100006
    其中R41、R42分别独立地选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
  3. 根据权利要求2所述的化合物，其特征在于：
    A选自
    Figure PCTCN2017116493-appb-100007
    Figure PCTCN2017116493-appb-100008
    B选自
    Figure PCTCN2017116493-appb-100009
    Figure PCTCN2017116493-appb-100010
    Figure PCTCN2017116493-appb-100011
    R1选自氢、甲基、乙基；
    R2、R3分别独立地选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；或者，R1与R2或R3相连构成C3～C6环杂烷基；
    n为1；
    R4选自氢、
    Figure PCTCN2017116493-appb-100012
    其中R41、R42分别独立地选自氢、
    Figure PCTCN2017116493-appb-100013
    Figure PCTCN2017116493-appb-100014
    Figure PCTCN2017116493-appb-100015
  4. 根据权利要求1所述的化合物，其特征在于：所述式I化合物如式IIa所示：
    Figure PCTCN2017116493-appb-100016
    其中，
    A1选自取代或未取代的C9～C10的芳杂环；
    X12、X13、X14、X15、X17、X18分别独立地选自N、CRa4；其中Ra4选自氢、C1～C6烷基、取代的C1～C6烷基、卤素、羟基、氨基；
    X16选自S、O、NRa6；其中Ra6选自氢、C1-C6烷基；
    Ra1选自氢、C1～C6烷基；
    Ra2选自氢、C1～C6烷基、取代的C1～C6烷基；
    Ra3选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
  5. 根据权利要求4所述的化合物，其特征在于：所述式IIa化合物如式IIIa所示：
    Figure PCTCN2017116493-appb-100017
    其中，
    A11选自
    Figure PCTCN2017116493-appb-100018
    其中X11选自N、CH。
  6. 根据权利要求5所述的化合物，其特征在于：
    A11选自
    Figure PCTCN2017116493-appb-100019
    X12、X13、X14、X15、X17、X18分别选自独立地选自N、CRa4；其中Ra4选自氢、C1～C6烷基、卤素、氨基；
    X16选自S；
    Ra1选自氢、甲基、乙基；
    Ra2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
    Ra3选自氢、
    Figure PCTCN2017116493-appb-100020
    Figure PCTCN2017116493-appb-100021
  7. 根据权利要求6所述的化合物，其特征在于：所述化合物选自下述化合物：
    Figure PCTCN2017116493-appb-100022
    Figure PCTCN2017116493-appb-100023
    Figure PCTCN2017116493-appb-100024
    Figure PCTCN2017116493-appb-100025
  8. 根据权利要求4所述的化合物，其特征在于：所述式IIa化合物如式IIIb所示：
    Figure PCTCN2017116493-appb-100026
    其中，
    A12选自
    Figure PCTCN2017116493-appb-100027
    其中Y1、Y2、Y3分别独立地选自N、CH。
  9. 根据权利要求8所述的化合物，其特征在于：
    A12选自
    X12、X13、X14、X15、X17、X18分别独立地选自N、CH；
    X16选自S；
    Ra1选自氢、甲基、乙基；
    Ra2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
    Ra3选自氢、
    Figure PCTCN2017116493-appb-100029
  10. 根据权利要求9所述的化合物，其特征在于：所述化合物选自下述化合物：
    Figure PCTCN2017116493-appb-100030
  11. 根据权利要求4所述的化合物，其特征在于：所述式IIa化合物如式IIIc所示：
    Figure PCTCN2017116493-appb-100031
    其中，
    Y4选自N、CH；
    Y5选自NRc、S；其中，Rc选自氢、C1～C6烷基。
  12. 根据权利要求11所述的化合物，其特征在于：
    Y4选自N；
    Y5选自NH、S；
    X12、X13、X14、X15、X17、X18分别独立地选自N、CH；
    X16选自S；
    Ra1选自氢、甲基、乙基；
    Ra2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
    Ra3选自氢、
    Figure PCTCN2017116493-appb-100032
  13. 根据权利要求12所述的化合物，其特征在于：所述化合物选自下述化合物：
    Figure PCTCN2017116493-appb-100033
  14. 根据权利要求1所述的化合物，其特征在于：所述式I化合物如式IIb所示：
    Figure PCTCN2017116493-appb-100034
    其中，
    A2选自
    Figure PCTCN2017116493-appb-100035
    其中X21选自N、CH；
    X22、X23、X24、X25、X26、X27、X28、X29分别独立地选自N、CRb4；其中Rb4选自氢、C1～C6烷基、取代的C1～C6烷基、卤素、羟基、氨基；
    Rb1选自氢、C1～C6烷基；
    Rb2选自氢、C1～C6烷基、取代的C1～C6烷基；
    Rb3选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
  15. 根据权利要求14所述的化合物，其特征在于：
    A2选自
    Figure PCTCN2017116493-appb-100036
    X22、X23、X24、X25、X26、X27、X28、X29分别独立地选自N、CRb4；其中Rb4选自氢、氨基；
    Rb1选自氢、甲基、乙基；
    Rb2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
    Rb3选自氢、
    Figure PCTCN2017116493-appb-100037
  16. 根据权利要求15所述的化合物，其特征在于：所述化合物选自下述化合物：
    Figure PCTCN2017116493-appb-100038
  17. 根据权利要求1所述的化合物，其特征在于：所述式I化合物如式IIc所示：
    Figure PCTCN2017116493-appb-100039
    其中，
    A3选自
    Figure PCTCN2017116493-appb-100040
    其中X31选自N、CH；
    X33、X34、X36、X37分别独立地选自N、CRc5；其中Rc5选自氢、C1～C6烷基、取代的C1～C6烷基、卤素、羟基、氨基；
    X32、X35分别独立地选自S、O、NRc4；其中Rc4选自氢、C1-C6烷基；
    Rc1选自氢、C1～C6烷基；
    Rc2选自氢、C1～C6烷基、取代的C1～C6烷基；
    Rc3选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
  18. 根据权利要求17所述的化合物，其特征在于：
    A3选自
    Figure PCTCN2017116493-appb-100041
    X33、X34、X36、X37分别选自N、CH；
    X32、X35分别选自S、O；
    Rc1选自氢、甲基、乙基；
    Rc2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
    Rc3选自氢、
    Figure PCTCN2017116493-appb-100042
  19. 根据权利要求18所述的化合物，其特征在于：所述化合物选自如下化合物：
    Figure PCTCN2017116493-appb-100044
  20. 根据权利要求1所述的化合物，其特征在于：所述式I化合物如式IId所示：
    Figure PCTCN2017116493-appb-100045
    其中，
    X41、X42、X43、X44、X45分别独立地选自N、CH；
    X46选自S、O、NRd6；其中Rd6选自氢、C1-C6烷基；
    Rd1选自氢、C1～C6烷基；
    Rd2、Rd4、Rd5分别独立地选自氢、C1～C6烷基、取代的C1～C6烷基；
    Rd3选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
  21. 根据权利要求20所述的化合物，其特征在于：
    X41、X42、X43、X44、X45分别独立地选自N、CH；
    X46选自S；
    Rd1选自氢、甲基、乙基；
    Rd2、Rd4、Rd5分别选自氢、甲基、乙基、环丙基、正丙基、异丙基、正丁基、异丁基、叔丁基；
    Rd3选自氢、
    Figure PCTCN2017116493-appb-100046
  22. 根据权利要求21所述的化合物，其特征在于：所述化合物选自如下化合物：
    Figure PCTCN2017116493-appb-100047
  23. 根据权利要求1所述的化合物，其特征在于：所述式I化合物如式IIe所示：
    Figure PCTCN2017116493-appb-100048
    其中，
    X51、X52、X53、X54、X55、X56、X57分别独立地选自N、CH；
    Re1选自氢、C1～C6烷基；
    Re2选自氢、C1～C6烷基、取代的C1～C6烷基；
    Re3选自氢或NHRe4；其中Re4选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
  24. 根据权利要求23所述的化合物，其特征在于：
    X51、X52、X53、X54、X55、X56、X57分别选自N、CH；
    Re1选自氢、甲基、乙基；
    Re2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
    Re3选自氢或NHRe4；其中Re4选自氢、
    Figure PCTCN2017116493-appb-100049
  25. 根据权利要求24所述的化合物，其特征在于：所述化合物选自如下化合物：
    Figure PCTCN2017116493-appb-100050
  26. 根据权利要求1所述的化合物，其特征在于：所述式I化合物如式IIf所示：
    Figure PCTCN2017116493-appb-100051
    其中，
    A6选自
    Figure PCTCN2017116493-appb-100052
    其中X61选自N、CH；
    X63、X64、X65、X66、X67、X68分别独立地选自N、CRf4；其中Rf4选自氢、C1～C6烷基、取代的C1～C6烷基、卤素、羟基、氨基；
    X62选自S、O、NRf6；其中Rf6选自氢、C1-C6烷基；
    Rf1选自氢、C1～C6烷基；
    Rf2选自氢、C1～C6烷基、取代的C1～C6烷基；
    Rf3选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
  27. 根据权利要求26所述的化合物，其特征在于：
    A6选自
    Figure PCTCN2017116493-appb-100053
    X63、X64、X65、X66、X67、X68分别选自N、CRa4；其中Ra4选自氢、氨基；
    X61选自S；
    Rf1选自氢、甲基、乙基；
    Rf2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
    Rf3选自氢、
    Figure PCTCN2017116493-appb-100054
  28. 根据权利要求27所述的化合物，其特征在于：所述化合物选自如下化合物：
    Figure PCTCN2017116493-appb-100055
  29. 根据权利要求1所述的化合物，其特征在于：所述式I化合物如式IIg所示：
    Figure PCTCN2017116493-appb-100056
    其中，
    A7选自
    Figure PCTCN2017116493-appb-100057
    其中X71选自N、CH；
    m为0、1、2、3、4；
    X72、X73、X74、X75、X77、X78分别独立地选自N、CRg4；其中Rg4选自氢、C1～C6烷基、取代的C1～C6烷基、卤素、羟基、氨基；
    X76选自S、O、NRg6；其中Rg6选自氢、C1-C6烷基；
    Rg3选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
  30. 根据权利要求29所述的化合物，其特征在于：
    A7选自
    Figure PCTCN2017116493-appb-100058
    X72、X73、X74、X75、X77、X78分别选自N、CRg4；其中Rg4选自氢、甲基、卤素、氨基；
    X76选自S；
    Rg3选自氢、
    Figure PCTCN2017116493-appb-100059
  31. 根据权利要求求30所述的化合物，其特征在于：所述化合物选自如下化合物：
    Figure PCTCN2017116493-appb-100060
  32. 根据权利要求求1所述的化合物，其特征在于：所述式I化合物如式IIh所示：
    Figure PCTCN2017116493-appb-100061
    其中，
    A8选自
    Figure PCTCN2017116493-appb-100062
    其中X81选自N、CH；
    X82、X83、X84、X85、X87、X88分别独立地选自N、CRh4；其中Rh4选自氢、C1～C6烷基、取代的C1～C6烷基、卤素、羟基、氨基；
    X86选自S、O、NRh6；其中Rh6选自氢、C1-C6烷基；
    Rh1选自氢、C1～C6烷基；
    Rh2选自氢、C1～C6烷基、取代的C1～C6烷基；
    Rh3选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、 C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
  33. 根据权利要求32所述的化合物，其特征在于：
    A8选自
    Figure PCTCN2017116493-appb-100063
    X82、X83、X84、X85、X87、X88分别选自N、CRh4；其中Rh4选自氢、甲基、卤素、氨基；
    X86选自S；
    Rh1选自氢、甲基、乙基；
    Rh2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
    Rh3选自氢、
    Figure PCTCN2017116493-appb-100064
  34. 根据权利要求33所述的化合物，其特征在于：所述化合物选自如下化合物：
    Figure PCTCN2017116493-appb-100065
  35. 根据权利要求求1所述的化合物，其特征在于：所述式I化合物如式IIi所示：
    Figure PCTCN2017116493-appb-100066
    其中，
    A9选自
    Figure PCTCN2017116493-appb-100067
    其中X91选自N、CH；
    X92、X93、X94、X95、X97、X98分别独立地选自N、CRi4；其中Ri4选自氢、C1～C6烷基、取代的C1～C6烷基、卤素、羟基、氨基；
    X96选自S、O、NRi6；其中Ri6选自氢、C1-C6烷基；
    Ri1选自氢、C1～C6烷基；
    Ri2选自氢、C1～C6烷基、取代的C1～C6烷基；
    Ri3选自氢、C1～C6烷基、取代的C1～C6烷基、C3～C6环烷基、取代的C3～C6环烷基、C3～C6杂环基、取代的C3～C6杂环基、C5～C10芳环、取代的C5～C10芳环、C5～C10芳杂环、取代的C5～C10芳杂环。
  36. 根据权利要求35所述的化合物，其特征在于：
    A9选自
    Figure PCTCN2017116493-appb-100068
    X92、X93、X94、X95、X97、X98分别选自N、CRi4；其中Ri4选自氢、甲基、卤素、氨基；
    X96选自S；
    Ri1选自氢、甲基、乙基；
    Ri2选自氢、甲基、乙基、正丙基、环丙基、异丙基、正丁基、异丁基、叔丁基；
    Ri3选自氢、
    Figure PCTCN2017116493-appb-100069
  37. 根据权利要求36所述的化合物，其特征在于：所述化合物选自如下化合物：
    Figure PCTCN2017116493-appb-100070
  38. 权利要求1-37任一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合 物、或其前体药物、或其代谢产物在制备ROCK抑制剂类药物中的用途。
  39. 根据权利要求38所述的化合物，其特征在于：所述ROCK抑制剂类药物为ROCK1和/或ROCK2抑制剂类药物。
  40. 权利要求1-37任一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗与ROCK活性异常相关的疾病的药物中的用途。
  41. 根据权利要求40所述的用途，其特征在于：所述与ROCK活性异常相关的疾病是与细胞有丝分裂、细胞骨架调整、平滑肌细胞收缩、神经再生、肿瘤细胞浸润、细胞凋亡相关的疾病中的任一种或几种。
  42. 权利要求1-37任一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物在制备治疗心血管疾病、高眼压症、肺动脉高压、青光眼或癌症药物中的用途。
  43. 一种药物组合物，其特征在于：它是以权利要求1-37任一项所述的化合物、或其立体异构体、或其药学上可接受的盐、或其溶剂合物、或其前体药物、或其代谢产物为活性成分，加上药学上可接受的辅料制备而成的制剂。
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