WO2024046223A1 - 吲唑甲酰胺类衍生物及其制备方法和用途 - Google Patents

吲唑甲酰胺类衍生物及其制备方法和用途 Download PDF

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WO2024046223A1
WO2024046223A1 PCT/CN2023/114866 CN2023114866W WO2024046223A1 WO 2024046223 A1 WO2024046223 A1 WO 2024046223A1 CN 2023114866 W CN2023114866 W CN 2023114866W WO 2024046223 A1 WO2024046223 A1 WO 2024046223A1
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migraine
pain
alkyl
ring
deuterated
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French (fr)
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应永铖
李国春
原晓辉
余尚海
顾厉明
娄万乔
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熙源安健医药（上海）有限公司
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems

Definitions

  • the present application relates to an indazole carboxamide derivative, its preparation method and a pharmaceutical composition containing the derivative or deuterated derivative, as well as its use as a therapeutic agent, especially as a calcitonin gene-related peptide. , CGRP) receptor antagonists.
  • Migraine is a common trigeminal neurovascular headache.
  • the pain may last from 4 to 72 hours, and is characterized by throbbing moderate or severe pain on one or both sides of the head with recurring attacks, or accompanied by nausea and vomiting.
  • Symptoms of sensitivity to light, sound, smell, or touch can seriously affect the patient's life (Steiner TJ et al., J Neurosurg Psychiatry 2004,75:808–811).
  • the World Health Organization (WHO) has listed migraine as one of the ten most disabling diseases. Compared with other groups of people, migraine patients are more likely to suffer from depression, anxiety, sleep disorders, other pain and fatigue.
  • migraine affects 1.3 billion patients around the world, about 11% of adults, of which female patients are three times more likely than male patients. There are about 40 million patients in the United States, about 8 million in Japan, and 13 million in China. patient. In the United States, migraines cost an estimated $80 billion in medical expenses and lost productivity each year, representing a huge drain on resources. At present, the pathogenesis of migraine is still not very clear internationally. The more recognized theory is the trigeminal vascular reflex theory, which effectively combines nerves, blood vessels and neurotransmitters to better explain the pathogenesis of migraine. At present, It has been widely accepted and recognized.
  • migraine is clinically divided into symptomatic treatment and preventive treatment.
  • the first-line therapy for symptomatic treatment is still the use of non-steroidal anti-inflammatory drugs, ergotamines or triptans.
  • opioids and other drugs are even used. joint use.
  • Triptans are currently the first-line therapy for the treatment of migraine, but some patients are insensitive to them and the therapeutic effect is not obvious.
  • triptans have side effects that cause cardiovascular risks. These problems also limit the use of triptans. use of similar drugs.
  • the commonly used prescriptions for preventive treatment are anti-epileptic drugs, tricyclic antidepressants, and beta-blockers, only some of which can prevent migraines.
  • preventive drugs were originally used to treat other diseases, are not specific for the prevention of migraine, and have obvious side effects, they are not the first choice for preventive treatment of migraine. It is conceivable that in the field of migraine, continuous exploration is still needed to find drugs with better therapeutic effects.
  • Calcitonin gene-related peptide is a neuropeptide containing 37 amino acid residues discovered by Amara and other scholars in 1982. It is widely present in the central and peripheral nervous systems, especially sensory nerves.
  • the cell body and terminals of the cell (Amara SG et al., Science 1982, 298:240-244).
  • Peripheral CGRP is in the dorsal root ganglion, and central CGRP is in the trigeminal ganglion. Both are synthesized in the body of sensory neurons and then rapidly transported to the center. end and peripheral end.
  • the central terminal terminals serve as sensory neuron afferent fibers and are mainly responsible for the conduction of pain and temperature sensations.
  • CGRP-containing sensory nerve fibers are widely distributed in various tissues and organs and are released through axonal reflexes in response to various stimuli.
  • CGRP is currently the most powerful endogenous vasodilator substance. In the field of pain, especially migraine, CGRP has become a research focus and hotspot. A number of clinical studies have confirmed that plasma CGRP levels increase during migraine attacks, and the intensity and duration of migraine are positively correlated with plasma CGRP levels (Han TH et al., Arch Drug Inf 2010, 3:55-62). In addition, Goadsby et al. found that the CGRP content in the external jugular vein increased during a migraine attack, but not in the cubital vein, indicating that CGRP is released intracranially during migraine (Goadsby PJ et al., Ann Neurol 1990, 28:183-187).
  • CGRP released by trigeminal nerve activation can cause brain and meningeal blood vessels to dilate, mast cells to release inflammatory mediators, and intracranial blood vessels to release noxious biological information to the central nervous system (Williamson D et al., Microsc Res Tech 2001, 53:167 -178).
  • Various studies have shown that migraine is closely related to the abnormal release and elevated content of CGRP.
  • the molecular weight of CGRP is about 3800 Da and consists of 2800 base pairs. In its 37 amino acid sequence, the 2nd and 7th positions of the N-terminal are connected by a disulfide bond, and the C-terminal is a phenylalanine residue.
  • This structure is an essential group for CGRP to have biological activity.
  • Human CGRP is currently known to have two types: ⁇ -CGRP and ⁇ -CGRP.
  • ⁇ -CGRP is mainly expressed in the nervous system, such as in the hypothalamus, cerebellum, brainstem and trigeminal nervous system, and ⁇ -CGRP is mainly expressed in the intestinal sensory system. expressed in the system.
  • ⁇ -CGRP is formed by splicing of the calcitonin (CT) gene, while ⁇ -CGRP is encoded by a separate gene. Although the two forms of CGRP differ by three amino acids, they have similar biological effects in the circulation system ( Edvinsson L,Expert Opinion on Therapeutic Targets 2007,11:1179-1188).
  • CGRP receptor is a G protein-coupled receptor, which consists of 7 transmembrane protein complexes (calcitonin receptor like receptor like receptor, CLR) and 1 transmembrane protein receptor activity modifying protein (receptor activity modifying protein).
  • protein 1, RAMP1 and an intracellular protein (receptor component protein, RCP) (Evans BN et al., J Biology Chem 2000, 275:38-43).
  • RAMP1 is a type of small molecule transmembrane protein that mediates the membrane translocation of CLR in the form of a molecular chaperone.
  • RCP is a type of small molecule polypeptide that mediates the transduction of downstream signals of CLR.
  • CGRP as a multifunctional neuropeptide, participates in the process of neurogenic inflammation, peripheral and central sensitization, and cortical spreading depression, thereby inducing migraine.
  • Atogepant developed by Abbvie was approved by the FDA for the preventive treatment of episodic migraine.
  • the successful launch of these three small molecule drugs has brought hope to migraine patients around the world. However, they also have side effects such as constipation, nausea, and drowsiness. Therefore, it is necessary to find safer and more effective CGRP small molecule drugs.
  • Ring A is selected from heterocyclyl or cycloalkyl
  • Ring B is selected from heterocyclyl or cycloalkyl
  • two R 1 together with the atoms to which they are connected form a 5- to 7-membered cycloalkyl group or a fused ring, and the 5- to 7-membered cycloalkyl group or fused ring is further substituted by one or more R a substituted by base;
  • n 1, 2 or 3;
  • n 1 or 2;
  • p 0, 1 or 2.
  • Ring A is cyclopentyl
  • Ring B is selected from heterocyclyl or cycloalkyl
  • two R 1 together with the atoms to which they are connected form a 5- to 7-membered cycloalkyl group or a fused ring, and the 5- to 7-membered cycloalkyl group or fused ring is further substituted by one or more R a substituted by base;
  • n 1, 2 or 3;
  • n 1 or 2;
  • p 0, 1 or 2.
  • Ring B is piperazinyl
  • Ring A is selected from heterocyclyl or cycloalkyl
  • two R 1 together with the atoms to which they are connected form a 5- to 7-membered cycloalkyl group or a fused ring, and the 5- to 7-membered cycloalkyl group or fused ring is further substituted by one or more R a substituted by base;
  • n 1, 2 or 3;
  • n 1 or 2;
  • p 0, 1 or 2.
  • two R 1 together with the atoms to which they are connected form a 5 to 7-membered cycloalkyl group or a fused ring, and the above fused ring is a pyrrolopyridine,
  • Ring A is selected from heterocyclyl or cycloalkyl
  • Ring B is selected from heterocyclyl or cycloalkyl
  • n 1, 2 or 3;
  • n 1 or 2;
  • p 0, 1 or 2.
  • R 2 is piperidine
  • Ring A is selected from heterocyclyl or cycloalkyl
  • Ring B is selected from heterocyclyl or cycloalkyl
  • two R 1 together with the atoms to which they are connected form a 5- to 7-membered cycloalkyl group or a fused ring, and the 5- to 7-membered cycloalkyl group or fused ring is further substituted by one or more R a substituted by base;
  • n 1, 2 or 3;
  • n 1 or 2;
  • p 0, 1 or 2.
  • n 1,
  • Ring A is selected from heterocyclyl or cycloalkyl
  • Ring B is selected from heterocyclyl or cycloalkyl
  • two R 1 together with the atoms to which they are connected form a 5- to 7-membered cycloalkyl group or a fused ring, and the 5- to 7-membered cycloalkyl group or fused ring is further substituted by one or more R a substituted by base;
  • n 1, 2 or 3;
  • p 0, 1 or 2.
  • n 2
  • Ring A is selected from heterocyclyl or cycloalkyl
  • Ring B is selected from heterocyclyl or cycloalkyl
  • two R 1 together with the atoms to which they are connected form a 5- to 7-membered cycloalkyl group or a fused ring, and the 5- to 7-membered cycloalkyl group or fused ring is further substituted by one or more R a substituted by base;
  • n 1 or 2;
  • p 0, 1 or 2.
  • the preferred embodiment of the present application provides a compound described in the general formula (I) or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, which is of the general formula (I) II)
  • Ring A is selected from heterocyclyl or cycloalkyl
  • two R 1 together with the atoms to which they are connected form a 5- to 7-membered cycloalkyl group or a fused ring, and the 5- to 7-membered cycloalkyl group or fused ring is further substituted by one or more R a substituted by base;
  • n 1, 2 or 3.
  • two R 1 and the atoms to which they are connected together form a 5- to 7-membered cycloalkyl group or a fused ring, the above fused ring is a pyrrolopyridine, and ring A is selected from a heterocyclic group or ring Alkyl; m is 1, 2 or 3.
  • two R 1 together with the atoms to which they are connected form a 5- to 7-membered cycloalkyl group or a fused ring, and the 5- to 7-membered cycloalkyl group or fused ring is further substituted by one or more R a substituted by base;
  • two R 1 together with the atoms to which they are connected form a 5- to 7-membered cycloalkyl group or fused Ring, the above-mentioned fused ring is pyrrolopyridine, ring A is selected from heterocyclyl or cycloalkyl; m is 2.
  • the preferred embodiment of the present application provides a compound described in the general formula (II) or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, which is of the general formula (II) III)
  • two R 1 together with the atoms to which they are connected form a 5- to 7-membered cycloalkyl group or a fused ring, and the 5- to 7-membered cycloalkyl group or fused ring is further substituted by one or more R a substituted by base;
  • n 1, 2 or 3.
  • two R 1 and the atoms to which they are connected together form a 5- to 7-membered cycloalkyl group or a fused ring, the above fused ring is a pyrrolopyridine, and ring A is selected from a heterocyclic group or ring Alkyl; m is 1, 2 or 3.
  • two R 1 together with the atoms to which they are connected form a 5- to 7-membered cycloalkyl group or a fused ring, and the 5- to 7-membered cycloalkyl group or fused ring is further substituted by one or more R a substituted by base;
  • Ring A is selected from heterocyclyl or cycloalkyl; m is 2.
  • two R 1 and the atoms to which they are connected together form a 5- to 7-membered cycloalkyl group or a fused ring, the above fused ring is a pyrrolopyridine, and ring A is selected from a heterocyclic group or ring Alkyl; m is 2.
  • the present application provides a compound described in the general formula (III) or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, which is of the general formula (III) IV)
  • the compound or its stereoisomers or tautomers Forms, deuterated derivatives or pharmaceutically acceptable salts thereof:
  • two R 1 together with the atoms to which they are connected form a 5- to 7-membered cycloalkyl group or a fused ring, and the 5- to 7-membered cycloalkyl group or fused ring is further substituted by one or more R a substituted by base;
  • n 1, 2 or 3;
  • two R 1 together with the atoms to which they are connected form a 5- to 7-membered cycloalkyl group or a fused ring.
  • the above fused ring is a pyrrolopyridine, and m is 1, 2 or 3.
  • two R 1 together with the atoms to which they are connected form a 5- to 7-membered cycloalkyl group or a fused ring, and the 5- to 7-membered cycloalkyl group or fused ring is further substituted by one or more R a substituted by base;
  • two R 1 and the atoms to which they are connected together form a 5- to 7-membered cycloalkyl group or a fused ring.
  • the above fused ring is a pyrrolopyridine, and m is 2.
  • the present application provides a compound described in the general formula (III) or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, which is of the general formula (III)
  • two R 1 together with the atoms to which they are connected form a 5- to 7-membered cycloalkyl group or a fused ring, and the 5- to 7-membered cycloalkyl group or fused ring is further substituted by one or more R a substituted by base;
  • n 1, 2 or 3;
  • two R 1 together with the atoms to which they are connected form a 5- to 7-membered cycloalkyl group or a fused ring.
  • the above fused ring is a pyrrolopyridine, and m is 1, 2 or 3.
  • two R 1 together with the atoms to which they are connected form a 5- to 7-membered cycloalkyl group or a fused ring, and the 5- to 7-membered cycloalkyl group or fused ring is further substituted by one or more R a substituted by base;
  • two R 1 and the atoms to which they are connected together form a 5- to 7-membered cycloalkyl group or a fused ring.
  • the above fused ring is a pyrrolopyridine, and m is 2.
  • the present application provides a substituted indazole carboxamide derivative represented by the general formula (IA) or its stereoisomer, tautomer, deuterated derivative or its pharmaceutically acceptable salt:
  • Ring A is selected from heterocyclyl
  • n 0 or 1
  • p 0, 1 or 2.
  • Ring A is pyrrolyl
  • n 0 or 1
  • p 0, 1 or 2.
  • Ring A is oxazinyl
  • n 0 or 1
  • p 0, 1 or 2.
  • R 1 O, and ring A is selected from heterocyclyl;
  • n 0 or 1
  • p 0, 1 or 2.
  • R 1 O, and Ring A is selected from pyrrolyl;
  • n 0 or 1
  • p 0, 1 or 2.
  • R 1 O, and ring A is selected from oxazinyl;
  • n 0 or 1
  • p 0, 1 or 2.
  • n 1 and Ring A is selected from heterocyclyl
  • p 0, 1 or 2.
  • n 1 and ring A is selected from pyrrolyl
  • p 0, 1 or 2.
  • n 1 and ring A is selected from oxazinyl
  • p 0, 1 or 2.
  • p is 1 and ring A is selected from heterocyclyl
  • m 0 or 1.
  • p is 1 and ring A is selected from pyrrolyl
  • m 0 or 1.
  • p is 1 and ring A is selected from oxazinyl
  • p is 1 and ring A is selected from heterocyclyl
  • p is 1 and ring A is selected from pyrrolyl
  • p is 1 and ring A is selected from oxazinyl
  • p is 2 and ring A is selected from heterocyclyl
  • m 0 or 1.
  • p is 2 and ring A is selected from pyrrolyl
  • m 0 or 1.
  • p is 2 and ring A is selected from oxazinyl
  • p is 2 and ring A is selected from heterocyclyl
  • p is 2 and ring A is selected from pyrrolyl
  • p is 2 and ring A is selected from oxazinyl
  • the present application provides a substituted indazole carboxamide derivative represented by the general formula (IB) or its stereoisomer, tautomer, deuterated derivative or its pharmaceutically acceptable salt:
  • Ring A is selected from heterocyclyl
  • X is selected from C or N;
  • n 0 or 1
  • p 0, 1 or 2.
  • X is C
  • ring A is selected from tetrahydropyridyl
  • p is 2;
  • m 0 or 1.
  • X is N and Ring A is selected from heterocyclyl
  • n 0 or 1
  • p 0, 1 or 2.
  • Ring A is tetrahydropyridinyl
  • X is selected from C or N;
  • m 0 or 1.
  • Ring A is imidazolidinyl
  • X is selected from N;
  • n 0 or 1
  • p 0, 1 or 2.
  • Ring A is tetrahydropyridinyl
  • X is selected from C
  • p 2;
  • n 0 or 1.
  • R 1 O
  • Ring A is selected from heterocyclyl
  • X is selected from C or N;
  • m 0 or 1.
  • R 1 O; Ring A is selected from tetrahydropyridinyl;
  • X is selected from C or N;
  • n 0 or 1
  • p 0, 1 or 2.
  • R 1 O; Ring A is selected from imidazolidinyl;
  • X is selected from N;
  • n 0 or 1
  • p 0, 1 or 2.
  • n 1 and ring A is selected from heterocyclyl
  • X is selected from C or N;
  • p 0, 1 or 2.
  • n 1 and Ring A is selected from heterocyclyl
  • X is selected from C or N;
  • p 0, 1 or 2.
  • n is 1, and ring A is selected from tetrahydropyridinyl;
  • X is selected from C or N;
  • p 0, 1 or 2.
  • n 1 and ring A is selected from imidazolidinyl
  • X is selected from N;
  • p 0, 1 or 2.
  • n 1 and ring A is selected from heterocyclyl
  • X is selected from C or N;
  • p 0, 1 or 2.
  • n 1 and ring A is selected from heterocyclyl
  • X is selected from C or N;
  • p 0, 1 or 2.
  • n is 1, and ring A is selected from tetrahydropyridinyl;
  • X is selected from C or N;
  • p 0, 1 or 2.
  • n 1 and ring A is selected from imidazolidinyl
  • X is selected from N;
  • p 0, 1 or 2.
  • p is 1 and ring A is selected from heterocyclyl
  • X is selected from N;
  • m 0 or 1.
  • p is 1 and ring A is selected from heterocyclyl
  • X is selected from N;
  • m 0 or 1.
  • p is 1 and ring A is selected from tetrahydropyridinyl
  • X is selected from N;
  • m 0 or 1.
  • p is 1 and ring A is selected from imidazolidinyl
  • X is selected from N;
  • m 0 or 1.
  • p is 1 and ring A is selected from heterocyclyl
  • X is selected from N;
  • m 0 or 1.
  • p is 1 and ring A is selected from heterocyclyl
  • X is selected from N;
  • m 0 or 1.
  • p is 1 and ring A is selected from tetrahydropyridinyl
  • X is selected from N;
  • m 0 or 1.
  • p is 1 and ring A is selected from imidazolidinyl
  • X is selected from N;
  • m 0 or 1.
  • p is 1 and ring A is selected from heterocyclyl
  • X is selected from N;
  • p is 1 and ring A is selected from heterocyclyl
  • X is selected from N;
  • p is 1 and ring A is selected from tetrahydropyridinyl
  • X is selected from N;
  • p is 1 and ring A is selected from imidazolidinyl
  • X is selected from N;
  • p is 1 and ring A is selected from heterocyclyl
  • X is selected from N;
  • p is 1 and ring A is selected from heterocyclyl
  • X is selected from N;
  • p is 1 and ring A is selected from tetrahydropyridinyl
  • X is selected from N;
  • p is 1 and ring A is selected from imidazolidinyl
  • X is selected from N;
  • p is 2 and ring A is selected from heterocyclyl
  • X is selected from C or N; provided that when X is selected from C, ring A is selected from tetrahydropyridinyl;
  • m 0 or 1.
  • p is 2 and ring A is selected from heterocyclyl
  • X is selected from C or N; provided that when X is selected from C, ring A is selected from tetrahydropyridinyl;
  • m 0 or 1.
  • p is 2, and ring A is selected from tetrahydropyridinyl;
  • X is selected from C or N; provided that when X is selected from C, ring A is selected from tetrahydropyridinyl;
  • m 0 or 1.
  • p is 2 and ring A is selected from imidazolidinyl
  • X is selected from N;
  • m 0 or 1.
  • p is 2 and ring A is selected from heterocyclyl
  • X is selected from C or N; provided that when X is selected from C, ring A is selected from tetrahydropyridinyl;
  • m 0 or 1.
  • p is 2 and ring A is selected from heterocyclyl
  • X is selected from C or N; provided that when X is selected from C, ring A is selected from tetrahydropyridinyl;
  • m 0 or 1.
  • p is 2, and ring A is selected from tetrahydropyridinyl;
  • X is selected from C or N; provided that when X is selected from C, ring A is selected from tetrahydropyridinyl;
  • m 0 or 1.
  • p is 2 and ring A is selected from imidazolidinyl
  • X is selected from N;
  • m 0 or 1.
  • p is 2 and ring A is selected from heterocyclyl
  • X is selected from C or N; provided that when X is selected from C, ring A is selected from tetrahydropyridinyl;
  • p is 2 and ring A is selected from heterocyclyl
  • X is selected from C or N; provided that when X is selected from C, ring A is selected from tetrahydropyridinyl;
  • p is 2, and ring A is selected from tetrahydropyridinyl;
  • X is selected from C or N; provided that when X is selected from C, ring A is selected from tetrahydropyridinyl;
  • p is 2 and ring A is selected from imidazolidinyl
  • X is selected from N;
  • p is 2 and ring A is selected from heterocyclyl
  • X is selected from C or N; provided that when X is selected from C, ring A is selected from tetrahydropyridinyl;
  • p is 2 and ring A is selected from heterocyclyl
  • X is selected from C or N; provided that when X is selected from C, ring A is selected from tetrahydropyridinyl;
  • p is 2, and ring A is selected from tetrahydropyridinyl;
  • X is selected from C or N; provided that when X is selected from C, ring A is selected from tetrahydropyridinyl;
  • p is 2 and ring A is selected from imidazolidinyl
  • X is selected from N;
  • this application provides a pharmaceutical composition containing an effective dose of general formula (I), The compound described in (II), (III), (IV), (V), (IA) or (IB) or its stereoisomer, tautomer, deuterated derivative or its pharmaceutically acceptable salts, and pharmaceutically acceptable carriers, excipients or combinations thereof.
  • This application provides a compound described in general formula (I), (II), (III), (IV), (V), (I-A) or (I-B) or its stereoisomers and tautomers , deuterated derivatives or pharmaceutically acceptable salts thereof, or the use of pharmaceutical compositions thereof in the preparation of CGRP receptor antagonists.
  • This application also provides a compound described in general formula (I), (II), (III), (IV), (V), (I-A) or (I-B) or its stereoisomers and tautomers.
  • the use of the body, deuterated derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for preventing and/or treating diseases mediated by CGRP wherein the diseases mediated by CGRP are preferably brain Blood vessels or vascular disorders; wherein the CGRP-mediated cerebrovascular or vascular disorders are selected from the group consisting of episodic migraine, migraine without aura, chronic migraine, purely menstrual migraine, and menstrual-related migraine.
  • migraine with aura migraine in children/adolescents
  • hemiplegic migraine sporadic hemiplegic migraine
  • basilar migraine cyclic vomiting, abdominal migraine, benign paroxysmal vertigo of childhood
  • retinal migraine cluster headache, dialysis headache, unexplained chronic headache, tension/stress-induced headache, allergy-induced headache, osteoarthritis and related osteoporotic fracture pain, related to menopause or caused by surgery or medication
  • Medically induced menopausal-related hot flashes, cyclic vomiting syndrome opioid withdrawal, psoriasis, asthma, obesity, morphine tolerance, neurodegenerative diseases, epilepsy, allergic rhinitis, rosacea, toothache , earache, otitis media, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, gout, trigeminal neuralgia, nasal polyps, chronic sinusitis
  • the present application further provides a compound described in general formula (I), (II), (III), (IV), (V), (I-A) or (I-B) or its stereoisomers and tautomers.
  • This application provides a compound described in general formula (I), (II), (III), (IV), (V), (IA) or (IB) or its stereoisomers and tautomers , deuterated derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for the preparation of prevention and/or treatment of episodic migraine, migraine without aura, chronic migraine, pure menstrual migraine, menstruation-related migraine , migraine with aura, migraine in children/adolescents, hemiplegic migraine, sporadic hemiplegic migraine, basilar migraine, cyclic vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine , cluster headache, dialysis headache, unexplained chronic headache, tension/stress-induced headache, allergy-induced headache, osteoarthritis and related osteoporotic fracture pain, related to menopause or caused by surgery or medication Medically induced menopausal-related hot flashes, cyclic vomiting syndrome, opioid withdrawal, psoriasis, asthma, obesity,
  • the present application further provides a method for preventing and/or treating diseases mediated by CGRP, comprising administering to a subject general formulas (I), (II), (III), (IV), (V), (I-A ) or the compound described in (I-B) or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, or its pharmaceutical composition, wherein the disease mediated by CGRP It is a cerebrovascular or vascular disorder type disease.
  • the cerebrovascular or vascular disorder disease mediated by CGRP is selected from the group consisting of episodic migraine, migraine without aura, chronic migraine, purely menstrual migraine, menstrual-related migraine, and migraine with aura.
  • Headache childhood/adolescent migraine, hemiplegic migraine, sporadic hemiplegic migraine, basilar migraine, cyclic vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine, cluster headache , dialysis headache, unexplained chronic headache, tension/stress-induced headache, allergy-induced headache, neurogenic inflammation, postherpetic neuralgia, ovarian pain, menopausal migraine, eye pain, diarrhea, osteoarthritis and pain associated with osteoporotic fractures, hot flashes associated with menopause or medically induced menopause caused by surgery or medication, cyclic vomiting syndrome, opioid withdrawal, psoriasis, asthma, obesity, Morphine tolerance, neurodegenerative diseases, epilepsy, allergic rhinitis,
  • the present application further provides a compound described in general formula (I), (II), (III), (IV), (V), (I-A) or (I-B) or its stereoisomers and tautomers.
  • the present application provides a compound described in the general formula (I), (II), (III), (IV), (V), (IA) or (IB) or its stereoisomers and tautomers.
  • Conforms, deuterated derivatives or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof are useful in preventing and/or treating episodic migraine, migraine without aura, chronic migraine, purely menstrual migraine, and menstrual-related migraine.
  • Headache migraine with aura, migraine in children/adolescents, hemiplegic migraine, sporadic hemiplegic migraine, basilar migraine, cyclic vomiting, abdominal migraine, benign paroxysmal vertigo of childhood, retinal migraine Headache, cluster headache, dialysis headache, unexplained chronic headache, tension/stress-induced headache, allergy-induced headache, neurogenic inflammation, post-herpetic neuralgia, ovarian pain, menopausal migraine, eye pain, Diarrhea, osteoarthritis and associated osteoporotic fracture pain, hot flashes associated with menopause or medically induced menopause due to surgery or medication, cyclic vomiting syndrome, Opioid withdrawal, psoriasis, asthma, obesity, morphine tolerance, neurodegenerative diseases, epilepsy, allergic rhinitis, rosacea, toothache, earache, otitis media, sunburn, osteoarthritis and the like Rheumatoid arthritis-related joint pain, cancer
  • the compounds of the present application are optionally in the form of single optical isomers, single enantiomers or racemic mixtures, in the form of tautomeric forms and in the form of free bases or with pharmacologically acceptable Acids form the corresponding acid addition salts.
  • Alkyl when used as a group or part of a group means a C 1 -C 20 linear or branched aliphatic hydrocarbon group. Preferably it is a C 1 -C 10 alkyl group, more preferably a C 1 -C 6 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl wait.
  • Alkyl groups may be substituted or unsubstituted.
  • Cycloalkyl refers to saturated or partially saturated monocyclic, fused, bridged and spiro carbon rings. Preferred is C 3 -C 12 cycloalkyl, more preferred is C 3 -C 8 cycloalkyl, and most preferred is C 5 -C 7 cycloalkyl.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyltri Alkenyl group, cyclooctyl group, etc., preferably cyclopropyl group and cyclohexenyl group. Cycloalkyl groups may be optionally substituted or unsubstituted.
  • Heterocyclyl “heterocycloalkyl”, “heterocycle” or “heterocyclic” are used interchangeably in this application and all refer to non-aromatic heterocyclyl groups in which one or more ring-forming atoms It is heteroatoms, such as oxygen, nitrogen, sulfur atoms, etc., including single ring, polycyclic ring, fused ring, bridged ring and spiro ring. It is preferably a 5- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, oxazinyl, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyridyl, tetrahydrofuryl, tetrahydropyranyl, 1,1- Dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, imidazolidinyl, 2-oxo-imidazolidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperidinyl Azin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, hexahydropyrimidine. Heterocyclyl groups may be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic 5 to 6 membered monocyclic ring or 8 to 10 membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzoyl Dioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-is
  • “Fused ring” refers to a polycyclic group in which two or more cyclic structures share a pair of atoms with each other.
  • One or more rings may contain one or more double bonds, but at least one ring is not fully conjugated.
  • the fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclyl group or a monocyclic cycloalkyl group. It is preferably 7 to 14 yuan, more preferably 8 to 10 yuan. Examples of "fused rings" include, but are not limited to:
  • Alkoxy refers to the group (alkyl-O-). Among them, alkyl group is as defined in this article. C 1 -C 6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO 2 .
  • Carboxy refers to -C(O)OH.
  • DMSO dimethyl sulfoxide
  • BOC refers to tert-butoxycarbonyl
  • TFA trifluoroacetic acid
  • PMB refers to p-methoxybenzyl
  • SEM refers to (trimethylsilyl)ethoxymethyl.
  • Hydroalkyl refers to a hydroxyl-substituted alkyl group.
  • Haloalkyl refers to a halogen-substituted alkyl group.
  • aminoalkyl refers to an amino-substituted alkyl group.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art is able to determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • Substituted or “substituted” mentioned in this specification, unless otherwise specified, means that the group can be substituted by one or more groups selected from the following: alkyl, alkoxy, alkylthio, alkyl Amino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkyl Substituted with thio, amino, haloalkyl, and hydroxyalkyl substituents.
  • Deuterated means that at least one hydrogen (“H”) is replaced by a deuterium (“D").
  • Deuterated alkyl means an alkyl group in which at least one hydrogen (“H”) is replaced by a deuterium (“D").
  • “Pharmaceutically acceptable salts” refer to certain salts of the above compounds that can maintain their original biological activity and are suitable for medical use.
  • Pharmaceutically acceptable salts of the compound represented by the general formula (I) may be metal salts or amine salts formed with a suitable acid.
  • salts including pharmaceutically acceptable salts, of compounds of general formula (I), (II), (III), (IV), (V), (I-A) or (I-B) can be prepared. These salts may be prepared in situ during the final isolation and purification of the compound, or by independently reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
  • Can form pharmaceutically acceptable acid addition salts with inorganic and organic acids for example, acetates, aspartates, benzoates, benzenesulfonates, bromides/hydrobromides, bicarbonates /Carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate, Glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonic acid Salt, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, stearate, oleate, oxalate, palmitate , pamoate, phosphate/hydrogen
  • Inorganic acids that can form salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids that can form salts include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, Ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic or organic bases.
  • Inorganic bases from which salts can be formed include, for example, ammonium salts and metals from Groups I to XII of the Periodic Table of Elements.
  • the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts .
  • Organic bases that can form salts include, for example, primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, alkali ion exchange resins, and the like. Some organic amines include isopropylamine, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.
  • the pharmaceutically acceptable salts of the present application can be synthesized from basic or acidic moieties by conventional chemical methods. Generally, these salts can be obtained by reacting the free acid form of these compounds with a stoichiometric amount of a suitable base (hydroxides, carbonates, bicarbonates of Na, Ca, Mg or K, etc.) or by The free base form is prepared by reacting a stoichiometric amount of the appropriate acid. These reactions are usually carried out in water or in organic solvents, or in mixtures of the two. Typically, where appropriate, non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile are used.
  • Deuterated derivatives refer to compounds in which the above-mentioned compounds contain deuterium bonded to carbon at at least one position, and the content of deuterium bonded to carbon exceeds its natural content.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or physiologically acceptable salts or prodrugs thereof, and other chemical components, together with other ingredients such as physiologically acceptable carriers and excipients. form agent.
  • the purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.
  • compositions involved in the present application can be formulated for specific routes of administration, such as oral administration, parenteral administration, rectal administration, etc.
  • pharmaceutical compositions of the present application can be in solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories) or in liquid form (including without limitation solutions, suspensions or emulsion).
  • Pharmaceutical compositions can be subjected to conventional pharmaceutical operations (e.g., sterilization) and/or can contain conventional inert diluents, lubricants or buffers as well as excipients, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc. .
  • compositions are tablets or capsules containing the active ingredient and
  • Diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, etc.
  • Lubricants such as silicon dioxide, talc, stearic acid, its magnesium or calcium salts and/or polyethylene glycol; for tablets also included
  • Binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; and if necessary
  • Disintegrating agents such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or
  • Tablets may be film-coated or enteric-coated according to methods known in the art.
  • compositions for oral administration include an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which Take the form of tablets, dragees, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions for oral use are prepared according to any method known in the art for the preparation of pharmaceutical compositions, and in order to provide a refined and palatable preparation the composition can contain one or more selected from the group consisting of sweeteners, flavoring agents agents, colorants and preservatives. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients are, for example, inert diluents (such as calcium carbonate, sodium carbonate, lactose, calcium or sodium phosphate); granulating and disintegrating agents (such as corn starch, or alginic acid); binders (such as starch) , gelatin or gum arabic); and lubricants (such as magnesium stearate, stearic acid or talc). Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over an extended period of time. For example, time delay materials such as glyceryl monostearate or glyceryl distearate can be used.
  • Formulations for oral administration can be presented in hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or in soft gelatin capsules, in which the active ingredient is mixed with an aqueous or oily vehicle, such as peanut oil, liquid paraffin or olive oil).
  • an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin
  • an aqueous or oily vehicle such as peanut oil, liquid paraffin or olive oil
  • compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously made from fatty emulsions or suspensions.
  • the compositions may be sterilized and/or contain adjuvants such as preservatives, stabilizing, wetting or emulsifying agents, dissolution accelerators, salts for adjusting osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances.
  • the compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75% or about 1-50% of the active ingredients.
  • the present application also provides anhydrous pharmaceutical compositions and dosage forms, which contain the compounds of the present application as active ingredients.
  • Anhydrous pharmaceutical compositions and dosage forms of the present application can be prepared using anhydrous or low water content ingredients and low water content or low humidity conditions.
  • Anhydrous pharmaceutical compositions can be prepared and stored so as to maintain their anhydrous properties. Therefore, anhydrous compositions are packaged using materials known to prevent contact with water so that they can be included in a suitable formulation kit. Examples of suitable packaging include, without limitation, airtight foil, plastic, unit dose containers (eg, vials), blister packs, and strip packs.
  • compositions and dosage forms which contain one or more agents that reduce the decomposition rate of the compound of the present application as an active ingredient.
  • agents include, without limitation, antioxidants (eg, ascorbic acid), pH buffers or salt buffers, and the like.
  • the pharmaceutical composition or combination product of the present application can be a unit dose of about 1-1000 mg of active ingredient, or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg, Or approximately 1-50mg active ingredient.
  • the therapeutically effective dose of a compound, pharmaceutical composition or combination thereof depends on the species, weight, age and individual condition of the individual, the condition or disease for which he or she is being treated, or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of a condition or disease.
  • stereoisomers and stereoisomers of a compound having a given stereochemical configuration refers to the opposite enantiomer of the compound and refers to any non-geometric isomer (Z/E) of the compound.
  • Enantiomers for example, if a compound has the S,R,Z stereochemical configuration, then its stereoisomers will include its opposite enantiomer having the R,S,Z configuration, as well as its S,S,Z configuration, The R,R,Z configuration, the S,R,E configuration, the R,S,E configuration, the S,S,E configuration, and the diastereomers of the R,R,E configuration. If the stereochemical configuration of a compound is not specified, then “stereoisomer" refers to any of the possible stereochemical configurations of the compound.
  • Compounds of general formula (I), (II), (III), (IV), (V), (I-A) or (I-B), their stereoisomers, or general formulas (I), (II), ( Tautomeric forms of compounds III), (IV), (V), (I-A) or (I-B) or complexes of stereoisomers thereof may be administered alone or in combination with one or more pharmaceutically active compounds.
  • one or more of these compounds are administered in the form of a pharmaceutical composition (formulation) in combination with one or more pharmaceutically acceptable excipients.
  • the choice of excipient depends on the specific mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form, among others.
  • Useful pharmaceutical compositions and methods for their preparation can be found, for example, in A. R. Gennaro (Ed.), Remington: Pharmaceutical Science and Practice (20th ed., 2000)
  • the compounds of the present application may contain asymmetric centers or chiral centers and therefore exist in different stereoisomer forms. It is contemplated that all stereoisomeric forms of the compounds of the present application, including, but not limited to, diastereoisomers, enantiomers, and atropisomers and geometric (conformational) isomers, and Mixtures thereof, such as racemic mixtures, are within the scope of this application.
  • structures described herein also include all isomeric (e.g., diastereomeric, enantiomeric, and atropisomer and geometric (conformational) isomeric forms of this structure; e.g., , the R and S configurations of each asymmetric center, the (Z) and (E) double bond isomers, and the (Z) and (E) conformational isomers. Therefore, the single stereoisomers of the compounds of the present application and the Enantiomeric mixtures, diastereomeric mixtures and geometric (conformational) isomer mixtures are all within the scope of this application.
  • stereoisomer refers to the isomers produced by the different spatial arrangements of atoms in the molecule. It can be divided into cis-trans isomers and enantiomers, and can also be divided into enantiomers. There are two categories: isomers and diastereomers. Stereoisomers are a type of isomers. Isomers in a molecule in which atoms or groups of atoms are connected in the same order but have different spatial arrangements are called stereoisomers.
  • substantially enantiomerically pure means greater than 90% enantiomeric purity for a given stereocenter.
  • substantially enantiomerically pure means greater than 80% ee (enantiomeric excess).
  • stereoisomers may be substantially enantiomerically pure at the stereocenter, or preferably may have greater than 97% enantiomeric purity, or more preferably greater than 99% enantiomeric purity. Enantiomeric purity.
  • the present application provides a method for preparing a compound of general formula (I) or its stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof.
  • the method includes:
  • the compound represented by the general formula (Ia) undergoes a nucleophilic substitution reaction with N,N'-disuccinimidyl carbonate and the compound represented by the general formula (Ib) under alkaline conditions to obtain the compound represented by the general formula (I) compound of;
  • Ring A, Ring B, R 1 , R 2 , p, m and n are as defined in general formula (I).
  • the compound represented by the general formula (Ic) undergoes a nucleophilic substitution reaction with N,N'-disuccinimidyl carbonate and the compound represented by the general formula (Id) under alkaline conditions to obtain the compound represented by (I-A) compound of;
  • Ring A, R 1 , m and p are as defined in general formula (IA).
  • the compound represented by the general formula (Ic) undergoes a nucleophilic substitution reaction with N,N'-disuccinimidyl carbonate and the compound represented by the general formula (Ie) under alkaline conditions to obtain the compound represented by the general formula (IB) compound of;
  • Ring A, R 1 , X, m and p are as defined in general formula (IB).
  • the examples provide the preparation and related structural identification data of representative compounds represented by formula (I). It must be noted that the following examples are used to illustrate the present application but not to limit the present application.
  • the 1 H NMR spectrum was measured with a Bruker instrument (400MHz), and the chemical shift was expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used.
  • the mass spectrum is measured with an LC/MS instrument, and the ionization method can be ESI or APCI.
  • Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm ⁇ 0.2mm.
  • the specifications used for thin layer chromatography separation and purification products are 0.4mm. -0.5mm.
  • CD 3 OD deuterated methanol.
  • DMSO-d 6 Deuterated dimethyl sulfoxide.
  • Argon atmosphere means that the reaction bottle is connected to an argon balloon with a volume of about 1L.
  • the solution in the reaction refers to an aqueous solution.
  • the compound is purified using C18 reversed-phase column preparative or semi-preparative purification, silica gel column chromatography eluent system and thin layer chromatography, where the eluent system is selected from: A: petroleum ether and tetrahydrofuran system; B: acetonitrile and Water system; C: petroleum ether and ethyl acetate system; D: methylene chloride and methanol system; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents can also be added to adjust, such as Trifluoroacetic acid, acetic acid or triethylamine, etc.
  • the eluent system is selected from: A: petroleum ether and tetrahydrofuran system; B: acetonitrile and Water system; C: petroleum ether and ethyl acetate system; D: methylene chloride and methanol system; the volume ratio of the
  • reaction solution was poured into ice-cold saturated aqueous ammonium chloride solution (200 mL), extracted with dichloromethane (200 mL ⁇ 3), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the obtained residue was separated and purified by column chromatography (eluent: C system) to obtain (3-bromopyridin-2-yl)carbamic acid tert-butyl ester 4b (13.59g), yield: 71.4%.
  • reaction solution was quenched with 50 mL of ice-cold saturated aqueous ammonium chloride solution. Concentrate under reduced pressure to obtain 4-(2-((tert-butoxycarbonyl)amino)pyridin-3-yl)-4-hydroxyazepane-1-carboxylic acid tert-butyl ester 4d (4.48g), yield :99.6%, proceed directly to the next reaction without purification.
  • Butyl ester 4e (0.918mg, 2.75mmol) was chiral resolved by SFC (column model: Waters SFC-150, Dnicel IG, 20 ⁇ 250mm, 10 ⁇ m; mobile phase: A for CO2and B for Ethanol; detection wavelength: 214nm; column After purification (temperature: 40°C), compounds with a single configuration (shorter retention time) and compounds with a single configuration (longer retention time) were obtained.
  • Test Example 1 Determination of the inhibitory effect of the compound of the present application on the CGRP signaling pathway in CHO-K1 cells expressing human CGRP receptors
  • the inhibitory effect of the CGRP signaling pathway in vitro is evaluated by indirectly measuring cAMP levels.
  • the principle is that after CGRP binds to the CGRP receptor, it activates the CGRP signaling pathway and induces an increase in cAMP levels. Reports that cAMP can induce regulation by CRE (cAMP response element)
  • CRE cAMP response element
  • the specific experimental methods are as follows:
  • CHO-K1 CGRPR/CHO-K1, PerkinElmer, ES-420-C cells expressing human CGRP receptor were transfected with pGL4.29[luc2P/CRE/Hygro] (Promega, 9PIE847) using Lipofectamine 2000 (Invitrogen, 11668019) ) plasmid, culture in F12K+10% FBS+400 ⁇ g/mL G418+10 ⁇ g/mL Blasticidin+350 ⁇ g/mL Hygromycin B medium, and collect cells in the logarithmic growth phase. Add 20 ⁇ L of cell suspension to each well of a 384-well white microplate (Nest, 761601), and the cell density is 8000 cells/well.
  • the biological activity of the compound of the present application was measured through the above test.
  • the compound of this application has a significant inhibitory effect on the CGRP signaling pathway in CHO-K1 cells expressing human CGRP receptors.
  • Test Example 2 Determination of the inhibitory effect of the compound of the present application on the CGRP signaling pathway in SK-N-MC cells
  • the inhibitory effect of the CGRP signaling pathway in vitro is evaluated by measuring cAMP levels.
  • the principle is that after CGRP binds to the CGRP receptor, it activates the CGRP signaling pathway and induces an increase in cAMP levels. Therefore, a decrease in cAMP levels means that the CGRP signaling pathway is inhibited.
  • cAMP was measured using CAMP-GS DYNAMIC KIT detection kit (Cisbio, 62AM4PEB).
  • SK-N-MC (ATCC, HTB-10) cells endogenously expressing CGRP receptors were cultured in EMEM+10% FBS medium, and the cells were collected in the logarithmic growth phase. According to the instructions of the kit, the cells were resuspended in Stimulation Buffer containing 0.5mM IBMX, and 5 ⁇ L of cell suspension was added to each well of a 96-well microplate (Cisbio, 66PL96025). The cell density was 15,000 cells/well.
  • the biological activity of the compound of the present application was measured through the above test.
  • the compound of this application has a significant inhibitory effect on the CGRP signaling pathway in SK-N-MC cells.

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Abstract

本申请涉及一种取代的吲唑甲酰胺类衍生物、其制备方法及含有该衍生物或氘代衍生物的药物组合物在医药上的应用。具体而言，本申请涉及一种通式(I)所示的取代的吲唑甲酰胺类衍生物、其制备方法及其可药用的盐，以及它们作为CGRP受体拮抗剂，在预防和/或治疗CGRP相关疾病中的用途，特别是偏头痛领域。其中通式(I)中的各取代基的定义与说明书中的定义相同。

Description

吲唑甲酰胺类衍生物及其制备方法和用途 技术领域
本申请涉及一种吲唑甲酰胺类衍生物、其制备方法及含有该衍生物或氘代衍生物的药物组合物以及其作为治疗剂特别是作为降钙素基因相关肽(calcitonin gene-related peptide，CGRP)受体拮抗剂的用途。
背景技术
偏头痛是一种常见的三叉神经血管性头痛，疼痛可能持续4至72个小时，表现为头部一侧或双侧出现跳动性中度或重度疼痛且反复发作，或伴有恶心、呕吐，对光线、声音、气味或触觉敏感的症状，严重影响患者的生活(Steiner TJ等人，J Neurol Neurosurg Psychiatry 2004,75:808–811)。世界卫生组织WHO已将偏头痛列为十大最致残疾病之一，与其他人群相比，偏头痛患者更可能发生抑郁、焦虑、睡眠障碍、其他疼痛及疲劳。据统计，偏头痛影响全世界13亿患者，约11％的成年人，其中女性患者是男性患者的三倍，美国约有4000万例患者，日本约有800万例，然而中国也有1300万名患者。在美国，每年由偏头痛导致的医疗费用和生产力损失估计在800亿美元，这是一笔巨额的资源损耗。目前国际上对于偏头痛的发病机制仍不十分明确，较为公认的为三叉神经血管反射学说，它将神经、血管和神经递质三者有效结合，较好的解释了偏头痛的发病机制，目前已经被广泛接受认可。
目前对于偏头痛临床上分为对症治疗和预防治疗，其中对症治疗的一线疗法仍是使用非甾体消炎药、麦角胺类或曲坦类药物，对严重的患者甚至采用阿片类药物和其它药物的联合使用。曲坦类药物是目前偏头痛治疗的一线疗法，但是某些患者对该类不敏感，治疗效果并不明显，另外，曲坦类药物存在引发心血管风险的副作用，这些问题也限制了曲坦类药物的使用。而预防治疗常用的处方是抗癫痫类药物、三环类抗抑郁药、β受体阻滞剂，其中只有部分药物有预防偏头痛的作用。由于这些预防性药物原本是被用来治疗其它疾病，对偏头痛的预防不具有专一性，且副作用明显，所以并不是偏头痛预防性治疗的优选。可想而知，在偏头痛领域，仍需要不断探索，以寻求有更佳治疗效果的药物。
降钙素基因相关肽(calcitonin gene-related peptide，CGRP)是Amara等学者在1982年发现的中含有37个氨基酸残基的神经多肽，它广泛存在于中枢和外周神经系统内，特别是感觉神经元的胞体和末梢(Amara SG等人，Science 1982,298:240-244)。外周的CGRP在背根神经节，中枢的CGRP在三叉神经节，都是在感觉神经元胞体内合成，然后快速运输到中枢 端和外周端末梢。中枢端末梢作为感觉神经元传入纤维，主要负责痛温觉的传导。在外周，含CGRP的感觉神经纤维广泛分布于各种组织和器官，并因多种刺激通过轴突反射的方式释放。
CGRP是目前最为强大的内源性血管舒张物质，在疼痛，尤其是偏头痛领域中，CGRP已经成为一个研究的重点和热点。多项临床研究证实在偏头痛的发作中，血浆中CGRP水平增高，而且偏头痛的强度和持续时间与血浆CGRP水平呈正相关(Han TH等人，Arch Drug Inf 2010,3:55-62)。另外Goadsby等人发现偏头痛发作时，颈外静脉中的CGRP含量增加，但是肘静脉中没有增加，表明偏头痛时颅内释放CGRP(Goadsby PJ等人，Ann Neurol1990,28:183-187)。动物研究也发现三叉神经活化释放的CGRP可以引起脑及脑膜血管扩张、肥大细胞释放炎症介质、颅内血管释放的伤害性生物信息传递至中枢(Williamson D等人，Microsc Res Tech 2001,53:167-178)。种种研究表明，偏头痛与CGRP的异常释放和含量升高息息相关。
CGRP的分子量约3800Da，由2800个碱基对组成，在它的37个氨基酸序列中，N端的第2位和第7位由二硫键连接，C端是苯丙氨酸残基，这两个结构是CGRP具有生物活性的必需基团。人的CGRP目前已知有α-CGRP和β-CGRP两种类型，其中α-CGRP主要在神经系统中表达，例如在下丘脑、小脑、脑干和三叉神经系统，β-CGRP主要在肠道感觉系统中表达。α-CGRP由降钙素(calcitonin，CT)基因剪接形成，而β-CGRP则由分离基因编码，尽管两种形式的CGRP相差三个氨基酸，但是在循环系统中却有着相似的生物学效应(Edvinsson L,Expert Opinion on Therapeutic Targets 2007,11:1179-1188)。
CGRP受体属于G蛋白偶联受体，由7个跨膜蛋白复合体(降钙素受体样受体calcitonin receptor like receptor，CLR)、1个跨膜蛋白受体活性修饰蛋白(receptor activity modifying protein 1，RAMP1)和1个胞内蛋白(受体组分蛋白receptor component protein，RCP)组成(Evans BN等人，J Biology Chem 2000,275:38-43)。RAMP1是一类小分子跨膜蛋白，以分子伴侣的形式介导CLR的膜转位，RCP是一类小分子多肽，介导CLR的下游信号的转导。目前关于CGRP参与偏头痛的机制没有明确，大部分学者认为，CGRP作为多功能神经肽参与到神经源性炎症、外周及中枢敏化和皮质扩散性抑制的过程中，从而诱发偏头痛。
随着对CGRP及其受体的研究越来越多，我们对它的了解也与日俱增，从1983年首次分离出CGR到2018年美国批准三款CGRP单抗药物上市，历时35年之久。目前已经有四款CGRP单抗药物上市，除了CGRP单克隆抗体外，CGRP受体拮抗剂的研发也备受关注，毕竟在给药方式的友好性方面，小分子类化合物具有明显优势，至今也有三款小分子CGRP受体拮抗剂上市。
在CGRP受体拮抗剂的开发过程中，有惊喜也有挫败，以Olcegepant、Telcagepant、MK-3207为例，尽管多项临床试验均证实了这类药物的有效性，但由于临床应用中多个患者出现肝脏毒性等严重不良反应，这几款化合物只能被暂停。通过不断地优化筛选，以寻 找更合适的化合物，幸运地是，2019年12月FDA批准了Ubrogepant的上市，这款药物由Abbvie公司开发，用于治疗急性偏头痛。次年2月，Biohaven公司研发的Rimegepant也成功获批，用于治疗急性偏头痛，2021年5月，Rimegepant又获批扩展适应症，用于发作性偏头痛的预防性治疗。2021年9月，Abbvie公司开发的Atogepant被FDA批准，用于发作性偏头痛的预防性治疗。这三款小分子药物的成功上市给全球偏头痛患者带来了希望，但是同时也有便秘、恶心、嗜睡等副作用，所以寻求更加安全有效的CGRP小分子药物十分有必要。
发明内容
针对上述的技术问题，本申请提供一种通式(I)所示的一种取代的吲唑甲酰胺类衍生物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐：
其中：
环A选自杂环基或环烷基；
环B选自杂环基或环烷基；
R1选自＝O、杂芳基或稠合环，所述的杂芳基或稠合环任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
或者，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，所述的5～7元环烷基或稠合环进一步被一个或多个Ra的取代基所取代；
每个Ra相同或不同，各自独立地选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
R2选自杂环基或环烷基，所述的杂环基或环烷基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
m为1，2或3；
n为1或2；
p为0，1或2。
在一个具体的实施方式中，环A为环戊烷基，
环B选自杂环基或环烷基；
R1选自＝O、杂芳基或稠合环，所述的杂芳基或稠合环任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
或者，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，所述的5～7元环烷基或稠合环进一步被一个或多个Ra的取代基所取代；
每个Ra相同或不同，各自独立地选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
R2选自杂环基或环烷基，所述的杂环基或环烷基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
m为1，2或3；
n为1或2；
p为0，1或2。
在一个具体的实施方式中，环B为哌嗪基，
环A选自杂环基或环烷基；
R1选自＝O、杂芳基或稠合环，所述的杂芳基或稠合环任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
或者，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，所述的5～7元环烷基或稠合环进一步被一个或多个Ra的取代基所取代；
每个Ra相同或不同，各自独立地选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
R2选自杂环基或环烷基，所述的杂环基或环烷基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
m为1，2或3；
n为1或2；
p为0，1或2。
在一个具体的实施方式中，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，上述稠合环为吡咯并吡啶，
环A选自杂环基或环烷基；
环B选自杂环基或环烷基；
R2选自杂环基或环烷基，所述的杂环基或环烷基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
m为1，2或3；
n为1或2；
p为0，1或2。
在一个具体的实施方式中，R2为哌啶，
环A选自杂环基或环烷基；
环B选自杂环基或环烷基；
R1选自＝O、杂芳基或稠合环，所述的杂芳基或稠合环任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
或者，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，所述的5～7元环烷基或稠合环进一步被一个或多个Ra的取代基所取代；
每个Ra相同或不同，各自独立地选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1，2或3；
n为1或2；
p为0，1或2。
在一个具体的实施方式中，n为1，
环A选自杂环基或环烷基；
环B选自杂环基或环烷基；
R1选自＝O、杂芳基或稠合环，所述的杂芳基或稠合环任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
或者，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，所述的5～7元环烷基或稠合环进一步被一个或多个Ra的取代基所取代；
每个Ra相同或不同，各自独立地选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
R2选自杂环基或环烷基，所述的杂环基或环烷基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
m为1，2或3；
p为0，1或2。
在一个具体的实施方式中，m为2，
环A选自杂环基或环烷基；
环B选自杂环基或环烷基；
R1选自＝O、杂芳基或稠合环，所述的杂芳基或稠合环任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
或者，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，所述的5～7元环烷基或稠合环进一步被一个或多个Ra的取代基所取代；
每个Ra相同或不同，各自独立地选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
R2选自杂环基或环烷基，所述的杂环基或环烷基任选进一步被一个或多个选自羟基、 卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
n为1或2；
p为0，1或2。
本申请的优选方案，本申请提供一种通式(I)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，其为通式(II)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐：
其中：
环A选自杂环基或环烷基；
R1选自＝O、杂芳基或稠合环，所述的杂芳基或稠合环任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
或者，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，所述的5～7元环烷基或稠合环进一步被一个或多个Ra的取代基所取代；
每个Ra相同或不同，各自独立地选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1，2或3。
在一个具体的实施方式中，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，上述稠合环为吡咯并吡啶，环A选自杂环基或环烷基；m为1，2或3。
在一个具体的实施方式中，R1选自＝O、杂芳基或稠合环，所述的杂芳基或稠合环任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
或者，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，所述的5～7元环烷基或稠合环进一步被一个或多个Ra的取代基所取代；
每个Ra相同或不同，各自独立地选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；环A选自杂环基或环烷基；
m为2。
在一个具体的实施方式中，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合 环，上述稠合环为吡咯并吡啶，环A选自杂环基或环烷基；m为2。本申请的优选方案，本申请提供一种通式(II)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，其为通式(III)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐：
其中：
R1选自＝O、杂芳基或稠合环，所述的杂芳基或稠合环任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
或者，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，所述的5～7元环烷基或稠合环进一步被一个或多个Ra的取代基所取代；
每个Ra相同或不同，各自独立地选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1，2或3。
在一个具体的实施方式中，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，上述稠合环为吡咯并吡啶，环A选自杂环基或环烷基；m为1，2或3。
在一个具体的实施方式中，R1选自＝O、杂芳基或稠合环，所述的杂芳基或稠合环任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
或者，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，所述的5～7元环烷基或稠合环进一步被一个或多个Ra的取代基所取代；
每个Ra相同或不同，各自独立地选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
环A选自杂环基或环烷基；m为2。
在一个具体的实施方式中，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，上述稠合环为吡咯并吡啶，环A选自杂环基或环烷基；m为2。
本申请的优选方案，本申请提供一种通式(III)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，其为通式(IV)所述的化合物或其立体异构体、互变异 构体、氘代衍生物或其可药用的盐：
其中：
R1选自＝O、杂芳基或稠合环，所述的杂芳基或稠合环任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
或者，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，所述的5～7元环烷基或稠合环进一步被一个或多个Ra的取代基所取代；
每个Ra相同或不同，各自独立地选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1，2或3；
在一个具体的实施方式中，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，上述稠合环为吡咯并吡啶，m为1，2或3。
在一个具体的实施方式中，R1选自＝O、杂芳基或稠合环，所述的杂芳基或稠合环任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
或者，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，所述的5～7元环烷基或稠合环进一步被一个或多个Ra的取代基所取代；
每个Ra相同或不同，各自独立地选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基，m为2。
在一个具体的实施方式中，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，上述稠合环为吡咯并吡啶，m为2。本申请的优选方案，本申请提供一种通式(III)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，其为通式(V)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐：
其中：
R1选自＝O、杂芳基或稠合环，所述的杂芳基或稠合环任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
或者，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，所述的5～7元环烷基或稠合环进一步被一个或多个Ra的取代基所取代；
每个Ra相同或不同，各自独立地选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1，2或3；
在一个具体的实施方式中，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，上述稠合环为吡咯并吡啶，m为1，2或3。
在一个具体的实施方式中，R1选自＝O、杂芳基或稠合环，所述的杂芳基或稠合环任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
或者，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，所述的5～7元环烷基或稠合环进一步被一个或多个Ra的取代基所取代；
每个Ra相同或不同，各自独立地选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基，m为2。
在一个具体的实施方式中，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，上述稠合环为吡咯并吡啶，m为2。
本申请提供一种通式(I-A)所示的一种取代的吲唑甲酰胺类衍生物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐：
其中：
环A选自杂环基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1；
p为0，1或2。
在一个具体的实施方式中，环A为吡咯基，R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1；
p为0，1或2。
在一个具体的实施方式中，环A为噁嗪基，R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1；
p为0，1或2。
在一个具体的实施方式中，R1为＝O，环A选自杂环基；
m为0或1；
p为0，1或2。
在一个具体的实施方式中，R1为＝O，环A选自吡咯基；
m为0或1；
p为0，1或2。
在一个具体的实施方式中，R1为＝O，环A选自噁嗪基；
m为0或1；
p为0，1或2。
在一个具体的实施方式中，m为1，环A选自杂环基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
p为0，1或2。
在一个具体的实施方式中，m为1，环A选自吡咯基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
p为0，1或2。
在一个具体的实施方式中，m为1，环A选自噁嗪基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
p为0，1或2。
在一个具体的实施方式中，p为1，环A选自杂环基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1。
在一个具体的实施方式中，p为1，环A选自吡咯基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1。
在一个具体的实施方式中，p为1，环A选自噁嗪基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1。
在一个具体的实施方式中，p为1，环A选自杂环基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1。
在一个具体的实施方式中，p为1，环A选自吡咯基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1。
在一个具体的实施方式中，p为1，环A选自噁嗪基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1。
在一个具体的实施方式中，p为2，环A选自杂环基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、 羟基烷基或氨基烷基；
m为0或1。
在一个具体的实施方式中，p为2，环A选自吡咯基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1。
在一个具体的实施方式中，p为2，环A选自噁嗪基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1。
在一个具体的实施方式中，p为2，环A选自杂环基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1。
在一个具体的实施方式中，p为2，环A选自吡咯基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1。
在一个具体的实施方式中，p为2，环A选自噁嗪基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1。
本申请提供一种通式(I-B)所示的一种取代的吲唑甲酰胺类衍生物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐：
其中：
环A选自杂环基；
X选自C或N；
条件是，当X选自C时，环A选自四氢吡啶，p为2；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1；
p为0，1或2。
在一个具体的实施方式中，X为C，环A选自四氢吡啶基，p为2；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1。
在一个具体的实施方式中，X为N，环A选自杂环基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1；
p为0，1或2。
在一个具体的实施方式中，环A为四氢吡啶基；
X选自C或N；
条件是，当X选自C时，环A选自四氢吡啶基，p为2；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1。
在一个具体的实施方式中，环A为咪唑烷基；
X选自N；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1；
p为0，1或2。
在一个具体的实施方式中，环A为四氢吡啶基；
X选自C；
p为2；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1。在一个具体的实施方式中，R1为＝O；环A选自杂环基；
X选自C或N；
条件是，当X选自C时，环A选自四氢吡啶，p为2；
m为0或1。
在一个具体的实施方式中，R1为＝O；环A选自四氢吡啶基；
X选自C或N；
条件是，当X选自C时，环A选自四氢吡啶，p为2；
m为0或1；
p为0，1或2。
在一个具体的实施方式中，R1为＝O；环A选自咪唑烷基；
X选自N；
m为0或1；
p为0，1或2。
在一个具体的实施方式中，m为1，环A选自杂环基；
X选自C或N；
条件是，当X选自C时，环A选自四氢吡啶，p为2；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
p为0，1或2。
在一个具体的实施方式中，m为1，环A选自杂环基；
X选自C或N；
条件是，当X选自C时，环A选自四氢吡啶，p为2；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
p为0，1或2。
在一个具体的实施方式中，m为1，环A选自四氢吡啶基；
X选自C或N；
条件是，当X选自C时，环A选自四氢吡啶，p为2；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
p为0，1或2。
在一个具体的实施方式中，m为1，环A选自咪唑烷基；
X选自N；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
p为0，1或2。
在一个具体的实施方式中，m为1，环A选自杂环基；
X选自C或N；
条件是，当X选自C时，环A选自四氢吡啶，p为2；
R1为＝O；
p为0，1或2。
在一个具体的实施方式中，m为1，环A选自杂环基；
X选自C或N；
条件是，当X选自C时，环A选自四氢吡啶，p为2；
R1为＝O；
p为0，1或2。
在一个具体的实施方式中，m为1，环A选自四氢吡啶基；
X选自C或N；
条件是，当X选自C时，环A选自四氢吡啶，p为2；
R1为＝O；
p为0，1或2。
在一个具体的实施方式中，m为1，环A选自咪唑烷基；
X选自N；
R1为＝O；
p为0，1或2。
在一个具体的实施方式中，p为1，环A选自杂环基；
X选自N；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1。
在一个具体的实施方式中，p为1，环A选自杂环基；
X选自N；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1。
在一个具体的实施方式中，p为1，环A选自四氢吡啶基；
X选自N；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1。
在一个具体的实施方式中，p为1，环A选自咪唑烷基；
X选自N；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1。
在一个具体的实施方式中，p为1，环A选自杂环基；
X选自N；
R1为＝O；
m为0或1。
在一个具体的实施方式中，p为1，环A选自杂环基；
X选自N；
R1为＝O；
m为0或1。
在一个具体的实施方式中，p为1，环A选自四氢吡啶基；
X选自N；
R1为＝O；
m为0或1。
在一个具体的实施方式中，p为1，环A选自咪唑烷基；
X选自N；
R1为＝O；
m为0或1。
在一个具体的实施方式中，p为1，环A选自杂环基；
X选自N；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1。
在一个具体的实施方式中，p为1，环A选自杂环基；
X选自N；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1。
在一个具体的实施方式中，p为1，环A选自四氢吡啶基；
X选自N；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、 羟基烷基或氨基烷基；
m为1。
在一个具体的实施方式中，p为1，环A选自咪唑烷基；
X选自N；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1。
在一个具体的实施方式中，p为1，环A选自杂环基；
X选自N；
R1为＝O；
m为1。
在一个具体的实施方式中，p为1，环A选自杂环基；
X选自N；
R1为＝O；
m为1。
在一个具体的实施方式中，p为1，环A选自四氢吡啶基；
X选自N；
R1为＝O；
m为1。
在一个具体的实施方式中，p为1，环A选自咪唑烷基；
X选自N；
R1为＝O；
m为1。
在一个具体的实施方式中，p为2，环A选自杂环基；
X选自C或N；条件是，当X选自C时，环A选自四氢吡啶基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1。
在一个具体的实施方式中，p为2，环A选自杂环基；
X选自C或N；条件是，当X选自C时，环A选自四氢吡啶基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1。
在一个具体的实施方式中，p为2，环A选自四氢吡啶基；
X选自C或N；条件是，当X选自C时，环A选自四氢吡啶基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1。
在一个具体的实施方式中，p为2，环A选自咪唑烷基；
X选自N；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为0或1。
在一个具体的实施方式中，p为2，环A选自杂环基；
X选自C或N；条件是，当X选自C时，环A选自四氢吡啶基；
R1为＝O；
m为0或1。
在一个具体的实施方式中，p为2，环A选自杂环基；
X选自C或N；条件是，当X选自C时，环A选自四氢吡啶基；
R1为＝O；
m为0或1。
在一个具体的实施方式中，p为2，环A选自四氢吡啶基；
X选自C或N；条件是，当X选自C时，环A选自四氢吡啶基；
R1为＝O；
m为0或1。
在一个具体的实施方式中，p为2，环A选自咪唑烷基；
X选自N；
R1为＝O；
m为0或1。
在一个具体的实施方式中，p为2，环A选自杂环基；
X选自C或N；条件是，当X选自C时，环A选自四氢吡啶基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1。
在一个具体的实施方式中，p为2，环A选自杂环基；
X选自C或N；条件是，当X选自C时，环A选自四氢吡啶基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1。
在一个具体的实施方式中，p为2，环A选自四氢吡啶基；
X选自C或N；条件是，当X选自C时，环A选自四氢吡啶基；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1。
在一个具体的实施方式中，p为2，环A选自咪唑烷基；
X选自N；
R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
m为1。
在一个具体的实施方式中，p为2，环A选自杂环基；
X选自C或N；条件是，当X选自C时，环A选自四氢吡啶基；
R1为＝O；
m为1。
在一个具体的实施方式中，p为2，环A选自杂环基；
X选自C或N；条件是，当X选自C时，环A选自四氢吡啶基；
R1为＝O；
m为1。
在一个具体的实施方式中，p为2，环A选自四氢吡啶基；
X选自C或N；条件是，当X选自C时，环A选自四氢吡啶基；
R1为＝O；
m为1。
在一个具体的实施方式中，p为2，环A选自咪唑烷基；
X选自N；
R1为＝O；
m为1。
在本申请的优选方案中，通式(I)所述的化合物选自：


或其立体异构体、互变异构体、氘代衍生物或其可药用的盐。
注：如果在画出的结构和给出的该结构的名称之间有差异，则画出的结构将给予更大的权重。
更进一步，本申请提供一种药物组合物，所述的药物组合物含有有效剂量的通式(I)、 (II)、(III)、(IV)、(V)、(I-A)或(I-B)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，及可药用的载体、赋形剂或它们的组合。
本申请提供一种通式(I)、(II)、(III)、(IV)、(V)、(I-A)或(I-B)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，或其药物组合物在制备CGRP受体拮抗剂中的用途。
本申请还提供一种通式(I)、(II)、(III)、(IV)、(V)、(I-A)或(I-B)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，或其药物组合物在制备预防和/或治疗由CGRP介导的疾病的药物中的用途，其中所述的由CGRP介导的疾病优选脑血管或血管障碍类疾病；其中所述的由CGRP介导的脑血管或血管障碍类疾病选自发作性偏头痛、无先兆偏头痛、慢性偏头痛、纯月经性偏头痛、月经相关性偏头痛、有先兆偏头痛、儿童/青少年偏头痛、偏瘫性偏头痛、散发性偏瘫性偏头痛、基底型偏头痛、周期性呕吐、腹型偏头痛、儿童期良性阵发性眩晕、视网膜性偏头痛、丛集性头痛、透析性头痛、原因不明的慢性头痛、紧张/压力诱导的头痛、过敏诱导的头痛、骨关节炎和相关的骨质疏松性骨折疼痛、与绝经或由手术或药物治疗造成的医疗诱导的绝经相关的潮热、周期性呕吐综合征、阿片类物质戒断、银屑病、哮喘、肥胖症、吗啡耐受、神经退行性疾病、癫痫、变应性鼻炎、红斑痤疮、牙痛、耳痛、中耳炎、晒伤、与骨关节炎和类风湿性关节炎相关的关节痛、癌痛、纤维肌痛、糖尿病性神经病、痛风、三叉神经痛、鼻息肉、慢性鼻窦炎、颞下颌综合征、背痛、下腰痛、咳嗽、张力障碍性疼痛、炎性疼痛、术后切口疼痛、坐骨神经痛、复杂性区域疼痛综合征、白塞病、子宫内膜异位症、幻肢综合征、痛经、与分娩相关的疼痛、由皮肤烧伤造成的疼痛、或炎性肠病(包括克罗恩病、回肠炎和溃疡性结肠炎)、胃-食管反流病、消化不良、肠易激综合征、肾绞痛、膀胱炎、胰腺炎和前列腺炎等慢性继发性内脏疼痛。本申请进一步提供一种通式(I)、(II)、(III)、(IV)、(V)、(I-A)或(I-B)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，或其药物组合物在制备预防和/或治疗脑血管或血管障碍类疾病的药物中的用途。
本申请提供一种通式(I)、(II)、(III)、(IV)、(V)、(I-A)或(I-B)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，或其药物组合物在制备预防和/或治疗发作性偏头痛、无先兆偏头痛、慢性偏头痛、纯月经性偏头痛、月经相关性偏头痛、有先兆偏头痛、儿童/青少年偏头痛、偏瘫性偏头痛、散发性偏瘫性偏头痛、基底型偏头痛、周期性呕吐、腹型偏头痛、儿童期良性阵发性眩晕、视网膜性偏头痛、丛集性头痛、透析性头痛、原因不明的慢性头痛、紧张/压力诱导的头痛、过敏诱导的头痛、骨关节炎和相关的骨质疏松性骨折疼痛、与绝经或由手术或药物治疗造成的医疗诱导的绝经相关的潮热、周期性呕吐综合征、阿片类物质戒断、银屑病、哮喘、肥胖症、吗啡耐受、神经退行性疾病、癫痫、变应性鼻炎、红斑痤疮、牙痛、耳痛、中耳炎、晒伤、与骨关节炎和类风湿性关节炎相关的关节痛、癌痛、纤维肌痛、糖尿病性神经病、痛风、三叉神经痛、鼻息肉、慢性 鼻窦炎、颞下颌综合征、背痛、下腰痛、咳嗽、张力障碍性疼痛、炎性疼痛、术后切口疼痛、坐骨神经痛、复杂性区域疼痛综合征、白塞病、子宫内膜异位症、幻肢综合征、痛经、与分娩相关的疼痛、由皮肤烧伤造成的疼痛、或炎性肠病(包括克罗恩病、回肠炎和溃疡性结肠炎)、胃-食管反流病、消化不良、肠易激综合征、肾绞痛、膀胱炎、胰腺炎和前列腺炎等慢性继发性内脏疼痛的药物中的用途。
本申请进一步提供一种预防和/或治疗由CGRP介导的疾病的方法，包括向受试者施用通式(I)、(II)、(III)、(IV)、(V)、(I-A)或(I-B)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，或其药物组合物，其中所述的由CGRP介导的疾病为脑血管或血管障碍类疾病。
进一步的，其中所述的由CGRP介导的脑血管或血管障碍类疾病选自发作性偏头痛、无先兆偏头痛、慢性偏头痛、纯月经性偏头痛、月经相关性偏头痛、有先兆偏头痛、儿童/青少年偏头痛、偏瘫性偏头痛、散发性偏瘫性偏头痛、基底型偏头痛、周期性呕吐、腹型偏头痛、儿童期良性阵发性眩晕、视网膜性偏头痛、丛集性头痛、透析性头痛、原因不明的慢性头痛、紧张/压力诱导的头痛、过敏诱导的头痛、神经源性炎症、带状疱疹后神经痛、卵巢痛、更年期偏头痛、眼痛、腹泻、骨关节炎和相关的骨质疏松性骨折疼痛、与绝经或由手术或药物治疗造成的医疗诱导的绝经相关的潮热、周期性呕吐综合征、阿片类物质戒断、银屑病、哮喘、肥胖症、吗啡耐受、神经退行性疾病、癫痫、变应性鼻炎、红斑痤疮、牙痛、耳痛、中耳炎、晒伤、与骨关节炎和类风湿性关节炎相关的关节痛、癌痛、纤维肌痛、糖尿病性神经病、痛风、三叉神经痛、鼻息肉、慢性鼻窦炎、颞下颌综合征、背痛、下腰痛、咳嗽、张力障碍性疼痛、炎性疼痛、术后切口疼痛、坐骨神经痛、复杂性区域疼痛综合征、白塞氏病、子宫内膜异位症、幻肢综合征、痛经、与分娩相关的疼痛、由皮肤烧伤造成的疼痛、或炎性肠病(包括克罗恩病、回肠炎和溃疡性结肠炎)、胃-食管反流病、消化不良、肠易激综合征、肾绞痛、膀胱炎、胰腺炎和前列腺炎等慢性继发性内脏疼痛。
本申请进一步提供一种通式(I)、(II)、(III)、(IV)、(V)、(I-A)或(I-B)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，或其药物组合物在预防和/或治疗由CGRP介导的疾病的用途，其中所述的由CGRP介导的疾病为脑血管或血管障碍类疾病。
本申请提供一种通式通式(I)、(II)、(III)、(IV)、(V)、(I-A)或(I-B)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，或其药物组合物在预防和/或治疗发作性偏头痛、无先兆偏头痛、慢性偏头痛、纯月经性偏头痛、月经相关性偏头痛、有先兆偏头痛、儿童/青少年偏头痛、偏瘫性偏头痛、散发性偏瘫性偏头痛、基底型偏头痛、周期性呕吐、腹型偏头痛、儿童期良性阵发性眩晕、视网膜性偏头痛、丛集性头痛、透析性头痛、原因不明的慢性头痛、紧张/压力诱导的头痛、过敏诱导的头痛、神经源性炎症、带状疱疹后神经痛、卵巢痛、更年期偏头痛、眼痛、腹泻、骨关节炎和相关的骨质疏松性骨折疼痛、与绝经或由手术或药物治疗造成的医疗诱导的绝经相关的潮热、周期性呕吐综合征、 阿片类物质戒断、银屑病、哮喘、肥胖症、吗啡耐受、神经退行性疾病、癫痫、变应性鼻炎、红斑痤疮、牙痛、耳痛、中耳炎、晒伤、与骨关节炎和类风湿性关节炎相关的关节痛、癌痛、纤维肌痛、糖尿病性神经病、痛风、三叉神经痛、鼻息肉、慢性鼻窦炎、颞下颌综合征、背痛、下腰痛、咳嗽、张力障碍性疼痛、炎性疼痛、术后切口疼痛、坐骨神经痛、复杂性区域疼痛综合征、白塞氏病、子宫内膜异位症、幻肢综合征、痛经、与分娩相关的疼痛、由皮肤烧伤造成的疼痛、或炎性肠病(包括克罗恩病、回肠炎和溃疡性结肠炎)、胃-食管反流病、消化不良、肠易激综合征、肾绞痛、膀胱炎、胰腺炎和前列腺炎等慢性继发性内脏疼痛中的用途。
本申请的化合物其任选呈单个光学异构体、单个对映异构体或外消旋体的混合物的形式，呈互变异构体的形式以及呈游离碱或与药理学上可接受的酸形成的相应酸加成盐的形式。
本申请的化合物可以以互变异构体存在。本申请的化合物的所有互变异构形式被预期在本申请的范围内。
发明的详细说明
除非有相反陈述，否则本申请在说明书和权利要求书中所使用的部分术语定义如下：
“烷基”当作一基团或一基团的一部分时是指包括C1-C20直链或者带有支链的脂肪烃基团。优选为C1-C10烷基，更优选为C1-C6烷基。烷基基团的实施例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代或未取代的。
“环烷基”是指饱和或部分饱和的单环、稠环、桥环和螺环的碳环。优选为C3-C12环烷基，更优选为C3-C8环烷基，最优选为C5-C7环烷基。单环环烷基的实施例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环己烯基。环烷基可以是任选取代的或未取代的。
“杂环基”、“杂环烷基”、“杂环”或“杂环的”在本申请中可交换使用，都是指非芳香性杂环基，其中一个或多个成环的原子是杂原子，如氧、氮、硫原子等，包括单环、多环、稠环、桥环和螺环。优选具有5至7元单环或7至10元双环或三环，其可以包含1，2或3个选自氮、氧和/或硫中的原子。“杂环基”的实例包括但不限于噁嗪基、吗啉基、氧杂环丁烷基、硫代吗啉基、四氢吡啶基、四氢呋喃基、四氢吡喃基、1，1-二氧代-硫代吗啉基、哌啶基、2-氧代-哌啶基、咪唑烷基、2-氧代-咪唑烷基、吡咯烷基、2-氧代-吡咯烷基、哌嗪-2-酮、8-氧杂-3-氮杂-双环[3.2.1]辛基、哌嗪基、六氢嘧啶。杂环基可以是取代或未取代的。
“杂芳基”是指芳香族5至6元单环或8至10元双环，其可以包含1至4个选自氮、氧和/或硫中的原子。“杂芳基”的实施例包括但不限于呋喃基，吡啶基，2-氧代-1，2-二氢吡啶基，哒嗪基，嘧啶基，吡嗪基，噻吩基，异噁唑基，噁唑基，噁二唑基，咪唑基，吡咯基，吡唑基，三唑基，四氮唑基，噻唑基，异噻唑基，1，2，3-噻二唑基，苯并间二氧杂环戊烯基，苯并噻吩基、苯并咪唑基，吲哚基，异吲哚基，1，3-二氧代-异吲哚基，喹啉基，吲唑基，苯并异噻唑基，苯并噁唑基、苯并异噁唑基。杂芳基可以是取代或未取代的。
“稠合环”是指两个或两个以上环状结构彼此共用一对原子的多环基团，一个或多个环可以含有一个或多个双键，但至少一个环不具有完全共轭的π电子的芳香系统，同时，至少一个环具有完全共轭的π电子的芳香系统，其中环原子中选自0个、一个或多个环原子选自氮、氧或S的杂原子，其余环原子为碳。稠合环优选包括双环或三环的稠合环，其中双环稠合环优选为芳基或杂芳基与单环杂环基或单环环烷基的稠合环。优选为7至14元，更优选为8至10元。“稠合环”的实施例包括但不限于：
“烷氧基”是指(烷基-O-)的基团。其中，烷基见本文有关定义。C1-C6的烷氧基为优先选择。其实例包括，但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基等。
“羟基”指-OH基团。
“卤素”是指氟、氯、溴和碘。
“氨基”指-NH2。
“氰基”指-CN。
“硝基”指-NO2。
“羧基”指-C(O)OH。
“DMSO”指二甲基亚砜。
“BOC”指叔丁氧基羰基。
“TFA”指三氟醋酸。
“PMB”指对甲氧基苄基。
“SEM”指(三甲基硅)乙氧基甲基。
“羟基烷基”指羟基取代的烷基。
“卤代烷基”指卤素取代的烷基。
“氨基烷基”指氨基取代的烷基。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本说明书所述的“取代”或“取代的”，如无特别指出，均是指基团可被一个或多个选自以下的基团取代：烷基、烷氧基、烷硫基、烷基氨基、卤素、疏基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氨基、卤代烷基、羟烷基的取代基所取代。
“氘代的”指至少一个氢(“H”)被氘(“D”)取代。
“氘代烷基”指烷基中至少一个氢(“H”)被氘(“D”)取代。
“可药用的盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。通式(I)所表示的化合物的可药用的盐可以为金属盐、与合适的酸形成的胺盐。
本领域技术人员应当理解，可以制备通式(I)、(II)、(III)、(IV)、(V)、(I-A)或(I-B)的化合物的盐，包括可药用的盐。这些盐类可以在所述化合物最终分离和纯化过程中原位制备，或者通过独立地分别将以其游离酸或游离碱形式的纯化的化合物与适合的碱或酸反应制备。
可以与无机酸和有机酸形成可药用的酸加成盐，例如，乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘化物/碘化物、羟乙基磺酸盐、乳酸盐、乳糖酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、硬脂酸盐、油酸盐、草酸盐、软脂酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖醛酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。
可以生成盐的无机酸包括，例如，盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以生成盐的有机酸包括，例如，乙酸、丙酸、羟乙酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、甲苯磺酸、磺基水杨酸等。药学上可接受的碱加成盐可以与无机或有机碱形成。
可以生成盐的无机碱包括，例如，铵盐和元素周期表的I至XII族的金属。在某些实施方案中，所述盐是衍生自钠、钾、铵、钙、镁、铁、银、锌和铜；特别适合的盐包括铵盐、钾盐、钠盐、钙盐和镁盐。
可以生成盐的有机碱包括，例如，伯胺、仲胺和叔胺，取代的胺包括天然产生的取代胺类，环胺、碱离子交换树脂等。某些有机胺类包括异丙胺、二乙醇胺、二乙胺、赖氨酸、葡甲胺、哌嗪及氨基丁三醇。
本申请的可药用的盐能够通过常规的化学方法由碱性或酸性部分合成而来。通常，这些盐能够通过将这些化合物的游离酸形式与化学量的合适的碱(Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应、或者通过将这些化合物的游离碱形式与化学量的合适的酸反应而进行制备。这些反应通常在水中或在有机溶剂中、或在两者的混合物中进行。通常，在适宜时，需要使用非水介质，例如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。其它合适的盐的列表可在“Remington's Pharmaceutical Sciences”，第20版，Mack Publishing Company，Easton，Pa.，(1985)；以及Stahl和Wermuth的“Handbook of Pharmaceutical Salts：Properties，Selection，and Use”(Wiley-VCH，Weinheim，德国，2002)中找到。
“氘代衍生物”是指上述化合物至少在一个位置上含有与碳相结合的氘的化合物，与碳相连的氘的含量超过其天然含量。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
本申请涉及的药物组合物能够针对特定的给药途径进行配制，例如口服给药、肠胃外给药和直肠给药等。此外，本申请的药物组合物能够以固体形式(非限制性地包括胶囊、片剂、丸剂、颗粒剂、粉末剂或栓剂)或以液体形式(非限制性地包括溶液剂、混悬剂或乳剂)制成。药物组合物能够经历常规的制药操作(例如灭菌)和/或能够含有常规的惰性稀释剂、润滑剂或缓冲剂以及辅料，例如防腐剂、稳定剂、润湿剂、乳化剂和缓冲剂等。
通常，药物组合物是片剂或胶囊，其包含活性成分以及
a)稀释剂，例如乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素、甘氨酸等；
b)润滑剂，例如二氧化硅、滑石粉、硬脂酸、其镁或钙盐和/或聚乙二醇；对于片剂也包含
c)粘合剂，例如硅酸镁铝、淀粉糊、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮；如果需要，还有
d)崩解剂，例如淀粉、琼脂、海藻酸或其钠盐、或泡腾混合物；和/或
e)吸收剂、着色剂、调味剂和增甜剂。
根据本领域中已知的方法，片剂可以是薄膜包衣或肠溶包衣的。
用于口服给药的合适的组合物包括有效量的式(I)的化合物或其药学上可接受的盐，其 为片剂、锭剂、水或油混悬液、可分散的粉末或颗粒、乳剂、硬或软胶囊、或糖浆或酏剂的形式。根据本领域中已知的用于制备药物组合物的任意方法制备用于口服使用的组合物，并且为了提供精制和适口的制剂该组合物能够含有一种或多种选自增甜剂、调味剂、着色剂和防腐剂的试剂。片剂可以含有与适合于制备片剂的无毒的药学上可接受的赋形剂混合在一起的活性成分。这些赋形剂是例如惰性的稀释剂(例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠)；成粒剂和崩解剂(例如玉米淀粉、或海藻酸)；粘合剂(例如淀粉、明胶或阿拉伯胶)；和润滑剂(例如硬脂酸镁、硬脂酸或滑石粉)。片剂是未经包衣的或者通过已知的技术进行包衣从而延缓在胃肠道的崩解和吸收，从而在较长的时期内提供持久的作用。例如，能够使用延时材料，例如单硬脂酸甘油酯或二硬脂酸甘油酯。用于口服的制剂能够以硬明胶胶囊呈递，其中活性成分与惰性的固体稀释剂(例如碳酸钙、磷酸钙或高岭土)混合，或者以软明胶胶囊呈递，其中活性成分与水或油介质(例如花生油、液体石蜡或橄榄油)混合。
某些可注射的组合物是等渗水溶液或混悬液，栓剂有利地由脂肪乳或混悬液制得。所述的组合物可以进行灭菌和/或含有辅料，例如防腐、稳定、润湿或乳化剂、溶解促进剂、用于调节渗透压的盐和/或缓冲剂。此外，其也可以含有其他的治疗上有价值的物质。所述的组合物分别根据常规的混合、制粒或包衣法进行制备，并且含有大约0.1-75％或含有大约1-50％的活性成分。
由于水可能促进某些化合物的降解，本申请还提供无水的药物组合物和剂型，其包含作为活性成分的本申请化合物。
使用无水或低水含量的成分和低水含量或低湿度的条件能够制备本申请的无水的药物组合物和剂型。可以制备和贮存无水的药物组合物以便保持其无水的性质。因此，使用已知防止与水接触的材料包装无水的组合物以便其能够包含于合适的配方药盒中。合适的包装的实例非限制性地包括气密的箔、塑料、单位剂量容器(例如管形瓶)、泡罩包装和条带包装。
本申请进一步提供药物组合物和剂型，其包含1种或多种降低作为活性成分的本申请化合物的分解速率的试剂。该试剂(其在本文中称作“稳定剂”)非限制性地包括抗氧化剂(例如抗坏血酸)、pH缓冲剂或盐缓冲剂等。
对于大约50-70kg的个体，本申请的药物组合物或组合产品能够是大约1-1000mg活性成分的单位剂量，或者大约1-500mg或大约1-250mg或大约1-150mg或大约0.5-100mg、或大约1-50mg活性成分。化合物、药物组合物或其组合产品的治疗有效剂量取决于个体的物种、体重、年龄和个体情况、其正在接受治疗的病症或疾病或其严重程度。普通技术的内科医生、临床医师或兽医能够容易地确定为了预防、治疗或抑制病症或疾病的发展所需的每一种活性成分的有效量。
具有给定立体化学构型的化合物的“立体异构体(stereoisomer和stereoisomers)”是指该化合物的相反对映异构体并且指包括该化合物的几何异构体(Z/E)的任何非对映异构体。例 如，如果化合物具有S,R,Z立体化学构型，那么其立体异构体将包括具有R,S,Z构型的其相反对映异构体，以及具有S,S,Z构型、R,R,Z构型、S,R,E构型、R,S,E构型、S,S,E构型、以及R,R,E构型的其非对映异构体。如果化合物的立体化学构型未指定，那么“立体异构体”是指该化合物的可能的立体化学构型中的任一种。
通式(I)、(II)、(III)、(IV)、(V)、(I-A)或(I-B)的化合物、其立体异构体、或通式(I)、(II)、(III)、(IV)、(V)、(I-A)或(I-B)化合物的互变异构体或其立体异构体的复合物可以单独施用或与一种或多种药学活性化合物组合施用。一般而言，一种或多种这些化合物以与一种或多种药学上可接受的赋形剂结合的药物组合物(制剂)的形式施用。赋形剂的选择取决于具体的施用模式、赋形剂对溶解度和稳定性的影响、以及剂型的性质等等。可用的药物组合物及其制备方法可见于，例如，A.R.Gennaro(编辑),雷明顿：制药科学与实践(第20版,2000)
本申请化合物可以含有不对称中心或手性中心，因此以不同的立体异构体形式存在。所预期的是，本申请化合物的所有立体异构体形式，包括但不限于非对映异构体、对映异构体和阻转异构体(atropisomer)和几何(构象)异构体及它们的混合物，如外消旋体混合物，均在本申请的范围内。
除非另外指出，本申请描述的结构还包括此结构的所有异构体(如，非对映异构体、对映异构体和阻转异构体和几何(构象)异构体形式；例如，各不对称中心的R和S构型，(Z)和(E)双键异构体，以及(Z)和(E)构象异构体。因此本申请化合物的单个立体异构体以及对映体混合物、非对映异构体混合物和几何(构象)异构体混合物均在本申请范围内。
术语“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，它可分为顺反异构体、对映异构体两种，也可分为对映异构体和非对映异构体两大类。立体异构体属于同分异构体的一种。分子中原子或原子团互相连接次序相同，但空间排列不同而引起的异构体称为立体异构体。
术语“基本上对映体纯”是指给定的立体中心的大于90％的对映体纯度。因此，术语“基本上对映体纯”是指大于80％ee(对映体过量)。对于以立体异构体存在的化合物，这种立体异构体在立体中心处可以基本上对映体纯，或者优选地可以具有大于97％对映体纯度，或更优选地具有大于99％对映体纯度。
本申请化合物的合成方法
为了完成本申请的目的，本申请采用如下技术方案：
本申请提供了一种通式(I)化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐的制备方法，所述方法包括：
方法一：
通式(Ia)所示的化合物在碱性条件下与N,N'-二琥珀酰亚胺基碳酸酯和通式(Ib)所示的化合物进行亲核取代反应，得到(I)所示的化合物；
其中：
环A、环B、R1、R2、p、m和n的定义如通式(I)中所述。
方法二：
通式(Ic)所示的化合物在碱性条件下与N,N'-二琥珀酰亚胺基碳酸酯和通式(Id)所示的化合物进行亲核取代反应，得到(I-A)所示的化合物；
其中：
环A、R1、m和p的定义如通式(I-A)中所述。
方法三：
通式(Ic)所示的化合物在碱性条件下与N,N'-二琥珀酰亚胺基碳酸酯和通式(Ie)所示的化合物进行亲核取代反应，得到(I-B)所示的化合物；
其中：
环A、R1、X、m和p的定义如通式(I-B)中所述。
具体实施方式
以下结合实施例用于进一步描述本申请，但这些实施例并非限制着本申请的范围。
实施例
实施例给出了式(I)所表示的代表性化合物的制备及相关结构鉴定数据。必须说明，下述实施例是用于说明本申请而不是对本申请的限制。1H NMR图谱是用Bruker仪器(400MHz)测定而得，化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。1H NMR的表示方法：s＝单峰，d＝双重峰，t＝三重峰，m＝多重峰，br＝变宽的，dd＝双重峰的双重峰，dt＝三重峰的双重峰。若提供偶合常数时，其单位为Hz。
质谱是用LC/MS仪测定得到，离子化方式可为ESI或APCI。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
在下列实施例中，除非另有指明，所有温度为摄氏温度，除非另有指明，各种起始原料和试剂来自市售或者是根据已知的方法合成，市售原料和试剂均不经进一步纯化直接使用，除非另有指明，市售厂家包括但不限于Aldrich Chemical Company，ABCR GmbH & Co.KG，Acros Organics，广赞化工科技有限公司和景颜化工科技有限公司等处购买。
CD3OD：氘代甲醇。
CDCl3：氘代氯仿。
DMSO-d6：氘代二甲基亚砜。
D2O：重水。
氩气氛是指反应瓶连接一个约1L容积的氩气气球。
实施例中无特殊说明，反应中的溶液是指水溶液。
对化合物进行纯化，采用C18反相柱制备或半制备纯化、硅胶柱层析洗脱剂体系和薄层色谱法，其中洗脱剂体系选自：A：石油醚和四氢呋喃体系；B：乙腈和水体系；C：石油醚和乙酸乙酯体系；D：二氯甲烷和甲醇体系；其中溶剂的体积比根据化合物的极性不同而不同，也可以加入少量的酸性或碱性试剂进行调节，如三氟乙酸、醋酸或三乙胺等。
实施例1
(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代-1',2'-二氢螺[哌啶-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-甲酰胺
第一步
1-苄基-5-溴-7-甲基-1H-吲唑
将5-溴-7-甲基-1H-吲唑1a(10g,47.38mmol)加入到四氢呋喃中(50mL)，在零摄氏度加入叔丁醇钾(26.58g,236.90mmol)，维持零摄氏搅拌1小时，然后加入溴苄(24.31g,142.14mmol)，加热到75℃，搅拌16小时，反应结束后，减压浓缩，得到的残留物经过柱层析分离纯化(洗脱剂：A体系)，得到1-苄基-5-溴-7-甲基-1H-吲唑1b(8.2g)，产率：48.27％。
MS m/z(ESI):301.1[M+1]
第二步
(R)-3-(1-苄基-7-甲基-1H-吲唑-5-基)-2-((叔丁氧基羰基)氨基)丙酸甲酯
氮气保护下，将1-苄基-5-溴-7-甲基-1H-吲唑1b(1g,3.32mmol)和(S)-2-((叔丁氧基羰基)氨基)-3-碘丙酸甲酯1c(6.56g,19.92mmol,根据专利申请WO2020074926中描述的方法制备)溶解于N,N-二甲基乙酰胺中(11mL)，降至零摄氏度，分别加入氯化镍二甲氧基乙烷(72.95mg,332.03μmol)，锰(912.04mg,16.60mmol)和2-脒基吡啶盐酸盐(36.63mg,232.42μmol)，40℃搅拌18小时，加入乙酸乙酯(100mL)和水(30mL)，用乙酸乙酯(60mL×3)萃取，合并有机相，减压浓缩，得到的残留物经过柱层析分离纯化(洗脱剂：A体系)，得到 (R)-3-(1-苄基-7-甲基-1H-吲唑-5-基)-2-((叔丁氧基羰基)氨基)丙酸甲酯1d(4.1g)，产率：100％，未经纯化，直接进行下一步反应。
MS m/z(ESI):424.3[M+1]
第三步
(R)-3-(7-甲基-1H-吲唑-5-基)-2-((叔丁氧基羰基)氨基)丙酸甲酯
氮气保护下，将(R)-3-(1-苄基-7-甲基-1H-吲唑-5-基)-2-((叔丁氧基羰基)氨基)丙酸甲酯1d(1.6g,3.78mmol)加入到甲醇中(5mL)，再加入10％钯炭(48.00g,39.52mmol)和甲酸(3.63g,75.56mmol)，加热到75℃，搅拌16小时，反应结束后，过滤，滤液减压浓缩，得到的残留物经过柱层析分离纯化(洗脱剂：A体系)，得到(R)-3-(7-甲基-1H-吲唑-5-基)-2-((叔丁氧基羰基)氨基)丙酸甲酯1e(937mg)，产率：70.40％。
MS m/z(ESI):334.2[M+1]
第四步
(R)-3-(7-甲基-1H-吲唑-5-基)-2-((叔丁氧基羰基)氨基)丙酸
将(R)-3-(7-甲基-1H-吲唑-5-基)-2-((叔丁氧基羰基)氨基)丙酸甲酯1e(1.23g,3.69mmol)溶解于21.2mL的混合溶液中(四氢呋喃：甲醇：水＝2：1：1)，加入氢氧化锂(265.09mg,11.07mmol)，25℃搅拌2小时，反应结束后，减压浓缩，加入乙酸乙酯(20mL)和水(30mL)，水层用稀盐酸调节pH至2，用乙酸乙酯(40mL×3)萃取，合并有机相，减压浓缩，得到(R)-3-(7-甲基-1H-吲唑-5-基)-2-((叔丁氧基羰基)氨基)丙酸1f(883mg)，产率：68.95％。
MS m/z(ESI):320.0[M+1]
第五步
(R)-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯
将(R)-3-(7-甲基-1H-吲唑-5-基)-2-((叔丁氧基羰基)氨基)丙酸1f(530mg,1.66mmol)，1-(1-甲基哌啶-4-基)哌嗪1g(395.45mg,2.16mmol)N,N-二异丙基乙胺(857.96mg,6.64mmol)溶解于N,N-二甲基甲酰胺中(12mL)，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(945.97mg,2.49mmol)，20℃搅拌18小时，反应结束后，减压浓缩，得到的残留物经过柱层析分离纯化(洗脱剂：D体系)，得到(R)-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯1h(750mg)，产率：89.99％。
MS m/z(ESI):485.1[M+1]
第六步
(R)-2-氨基-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)丙-1-酮
将(R)-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯1h(750mg,1.55mmol)溶解于4M的盐酸二氧六环溶液中(11mL)，25℃搅拌30分钟，反应结束后，减压浓缩，得到(R)-2-氨基-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)丙-1-酮1i(903mg)，产率：93.52％，未经纯化，直接进行下一步反应。 MS m/z(ESI):385.4[M+1]
第七步
(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代
-1',2'-二氢螺[哌啶-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-甲酰胺
将(R)-2-氨基-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)丙-1-酮1i(80mg,150.84μmol)和三乙胺(152.63mg,1.51mmol)溶解于N,N-二甲基甲酰胺中(2.5mL)，加入N,N'-二琥珀酰亚胺基碳酸酯(50.23mg,196.09μmol)，25℃搅拌4小时，加入螺[哌啶-4,4'-吡啶并[2,3-d][1,3]噁嗪]-2'(1'H)-酮1j(30.86mg,120.67μmol)，25℃搅拌18小时，反应结束后，减压浓缩，得到的残留物经过C18反相柱制备分离(洗脱剂：B体系)，得到(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代-1',2'-二氢螺[哌啶-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-甲酰胺1(28.6mg)，产率：29.51％。
MS m/z(ESI):630.5[M+1]
1HNMR(400MHz,DMSO-d6)δ13.02(s,1H),10.81(s,1H),8.19(dd,J＝4.8,1.6Hz,1H),7.96(d,J＝6.6Hz,1H),7.48(dd,J＝7.6,1.6Hz,1H),7.38(s,1H),7.05(dd,J＝7.6,4.8Hz,1H),7.01(s,1H),6.83(d,J＝8.0Hz,1H),4.81(q,J＝4.0Hz,1H),3.99(d,J＝14.4Hz,2H),3.59-3.56(m,1H),3.27-3.22(m,1H),3.13-2.86(m,5H),2.76-2.73(m,2H),2.47(s,3H),2.36-2.21(m,2H),2.13(s,3H),1.97-1.75(m,9H),1.55-1.50(m,1H),1.41-1.37(m,2H),1.25-1.14(m,2H).
实施例2
(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代-1',2'-二氢螺[哌啶-4,3'-吡咯并[2,3-b]吡啶]-1-甲酰胺
第一步
(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代-1',2'-二氢螺[哌啶-4,3'-吡咯并[2,3-b]吡啶]-1-甲酰胺
将(R)-2-氨基-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)丙-1-酮1i(50mg,94.28μmol)和三乙胺(198.12mg,1.96mmol)溶解于N,N-二甲基甲酰胺中(2mL)，加入N,N'-二琥珀酰亚胺基碳酸酯(31.40mg,122.56μmol)，20℃搅拌1小时，加螺[哌啶-4,3'-吡咯并[2,3-b]吡啶]-2'(1'H)-酮2a(17.24mg,84.85μmol)，20℃搅拌15小时，反应结束后，减压浓缩，得到的残留物经过C18反相柱制备分离(洗脱剂：B体系)，得到(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代-1',2'-二氢螺[哌啶-4,3'-吡咯并[2,3-b]吡啶]-1-甲酰胺2(4.37mg)，产率：7.08％。
MS m/z(ESI):614.5[M+1]
1H NMR(400MHz,DMSO-d6)δ13.00(s,1H),11.01(s,1H),8.05-8.03(m,1H),7.94(s,1H),7.71(d,J＝7.2Hz,1H),7.35(s,1H),6.99(s,1H),6.92-6.89(m,1H),6.77(d,J＝8.0Hz,1H),4.81-4.76(m,1H),3.74-3.72(m,2H),3.56-3.50(m,4H),3.26-3.21(m,2H),3.11-3.07(m,1H),2.97-2.73(m,4H),2.44(s,3H),2.33-2.15(m,5H),1.95-1.83(m,4H),1.67-1.38(m,6H),1.25-1.16(m,2H).
实施例3
(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺
第一步
(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺
将(R)-2-氨基-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)丙-1-酮1i(80mg,150.84μmol)和三乙胺(152.63mg,1.51mmol)溶解于N,N-二甲基甲酰胺中(2.5mL)，加入N,N'-二琥珀酰亚胺基碳酸酯(46.37mg,181.01μmol)，在20℃搅拌2小时，再加入1-(哌啶-4-基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮3a(34.58mg,135.76μmol)，20℃搅拌18小时，反应结束后，减压浓缩，得到的残留物经过C18反相柱制备分离(洗脱剂：B体系)，得到(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-4-(2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)哌啶-1-甲酰胺3(38.13mg)，产率：38.43％。
MS m/z(ESI):629.5[M+1]
1H NMR(400MHz,DMSO-d6)δ12.99(s,1H),7.93(s,1H),7.85(dd,J＝5.2,0.08Hz,1H),7.36-7.34(m,2H),6.99(s,1H),6.90-6.87(m,1H),6.75(d,J＝8.0Hz,1H),4.75(q,J＝8.0Hz,1H),4.35-4.28(m,1H),4.13-4.10(m,2H),3.59-3.56(m,2H),3.23-3.06(m,2H),2.96-2.69(m,6H),2.43(s,3H),2.35-2.20(m,3H),2.09-1.85(m,7H),1.78-1.61(m,4H),1.51-1.45(m,1H),1.37-1.34(m,2H),1.19-1.10(m,2H).
实施例4A
(R)-N-((R)-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代-1',2'-二氢螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-甲酰胺4A
实施例4B
(S)-N-((R)-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代-1',2'-二氢螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-甲酰胺4B

第一步
(3-溴吡啶-2-基)氨基甲酸叔丁酯
将1M的双(三甲基硅基)氨基钠(127.9mL,127.90mmol)溶于四氢呋喃中(80mL),温度降到零摄氏度,加入3-溴吡啶-2-胺4a(10g,58.13mmol)，维持零摄氏度反应0.5小时，然后将二碳酸二叔丁酯(16.4g,75.58mmol)溶于四氢呋喃中(20mL),零摄氏度下滴加，20℃反应1小时。反应结束后，将反应液倒入冰的饱和氯化铵水溶液中(200mL),用二氯甲烷萃取(200mL×3)，饱和食盐水洗涤(200mL)，无水硫酸钠干燥，减压浓缩，得到的残留物经过柱层析分离纯化(洗脱剂：C体系)，得到(3-溴吡啶-2-基)氨基甲酸叔丁酯4b(13.59g)，产率：71.4％。
MS m/z(ESI):273.0[M+1]
第二步
4-(2-((叔丁氧基羰基)氨基)吡啶-3-基)-4-羟基氮杂环庚烷-1-甲酸叔丁酯
氮气保护下，将(3-溴吡啶-2-基)氨基甲酸叔丁酯4b(3g,11.02mmol)溶于四氢呋喃中(20mL)，温度降到零下78℃,缓慢滴加2.5M的正丁基锂(13.2mL,33.08mmol),零下78℃反应0.5小时,然后滴加4-氧代氮杂环庚烷-1-甲酸叔丁酯4c(7.05g,33.08mmol)的四氢呋喃溶液(10mL)，20℃反应2小时。反应结束后，反应液用冰的50mL的饱和氯化铵水溶液淬灭， 减压浓缩，得到4-(2-((叔丁氧基羰基)氨基)吡啶-3-基)-4-羟基氮杂环庚烷-1-甲酸叔丁酯4d(4.48g)，产率：99.6％，未经纯化，直接进行下一步反应。
MS m/z(ESI):408.2[M+1]
第三步
2'-氧代-1',2'-二氢螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-甲酸叔丁酯向4-(2-((叔丁氧基羰基)氨基)吡啶-3-基)-4-羟基氮杂环庚烷-1-甲酸叔丁酯4d(4.48g,10.99mmol)的四氢呋喃溶液中(30mL)，加入1M的叔丁醇钾溶液(16.5mL,16.48mmol)，20℃反应16小时。反应结束后，加入100mL的二氯甲烷和100mL的水，用饱和氯化钠溶液洗涤，减压浓缩，得到的残留物经过柱层析分离纯化(洗脱剂：C体系)，得到2'-氧代-1',2'-二氢螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-甲酸叔丁酯4e(807.2mg)，产率：21.9％。
MS m/z(ESI):334.1[M+1]
1H NMR(400MHz,DMSO-d6)δ10.80(s,1H),8.19(d,J＝4.1Hz,1H),7.70(d,J＝7.5Hz,1H),7.09-7.05(m,7.6Hz,1H),3.80-3.59(m,1H),3.57-3.46(m,1H),3.43-3.33(m,1H),3.30-3.17(m,1H),2.19-1.89(m,5H),1.73-1.74(m,1H),1.42(s,9H)
第四步
(R)-2'-氧代-1',2'-二氢螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-甲酸叔丁酯4e-A
(S)-2'-氧代-1',2'-二氢螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-甲酸叔丁酯4e-B
将2'-氧代-1',2'-二氢螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-甲酸叔丁酯4e(0.918mg,2.75mmol)通过SFC手性拆分(柱型号：Waters SFC-150,Dnicel IG,20×250mm,10μm；流动相：A for CO2and B for Ethanol；检测波长：214nm；柱温：40℃)纯化后，得到单一构型的化合物(较短保留时间)和单一构型化合物(较长保留时间)。
单一构型化合物(较短保留时间)：
400mg，产率：43.6％，保留时间1.612分钟，手性纯度100％ee。
MS m/z(ESI):334.2[M+1]
单一构型化合物(较长保留时间)：
410mg，产率：44.7％，保留时间2.030分钟,手性纯度99.1％ee。
MS m/z(ESI):334.2[M+1]
第五步
(R)-螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-2'(1'H)-酮4f-A
(S)-螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-2'(1'H)-酮4f-B
将手性拆分得到的(R)-2'-氧代-1',2'-二氢螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-甲酸叔丁酯4e-A(100mg,299.96μmol)或(S)-2'-氧代-1',2'-二氢螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-甲酸叔丁酯4e-B(100mg,299.96μmol)溶解于4M的盐酸二氧六环溶液中(2mL)，30℃反应3小时,反应结束后，减压浓缩，分别得到(R)-螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-2'(1'H)-酮4f-A(100mg)，产率：100％，未经纯化，直接进行下一 步反应；(S)-螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-2'(1'H)-酮4f-B(120mg)，产率：100％，未经纯化，直接进行下一步反应。
MS m/z(ESI):234.1[M+1]
MS m/z(ESI):234.1[M+1]
第六步
(R)-N-((R)-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代-1',2'-二氢螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-甲酰胺
将(R)-2-氨基-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)丙-1-酮1i(47.08mg,88.77μmol)加入到N,N-二甲基甲酰胺中(1mL)，加入三乙胺(99.80mg,986.28μmol)和N,N'-二琥珀酰亚胺基碳酸酯(27.77mg,108.49μmol)，30℃搅拌1小时，再加入(R)-螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-2'(1'H)-酮4f-A(0.03g,98.63μmol)，30℃搅拌18小时，反应结束后，减压浓缩，得到的残留物经过C18反相柱制备分离(洗脱剂：B体系)，得到(R)-N-((R)-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代-1',2'-二氢螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-甲酰胺4A(27.87mg)，产率：41.61％。
MS m/z(ESI):644.5[M+1]
1H NMR(400MHz,DMSO-d6)δ13.00(s,1H),10.75(s,1H),8.13(dd,J＝4.8,1.6Hz,1H),7.91(s,1H),7.35-7.30(m,2H),6.98(s,1H),6.93-6.90(m,1H),6.38(d,J＝8.4Hz,1H),4.80(q,J＝8.0Hz,1H),3.79-3.76(m,2H),3.56-3.49(m,5H),3.22-3.14(m,2H),2.96-2.81(m,3H),2.43-2.40(m,4H),2.25-2.17(m,4H),2.04-1.67(m,11H),1.46-1.32(m,2H),1.24-1.20(m,2H).
第七步
(S)-N-((R)-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代-1',2'-二氢螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-甲酰胺
将(R)-2-氨基-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)丙-1-酮1i(53.09mg,100.10μmol)，加入到N,N-二甲基甲酰胺中(2mL)，加入三乙胺(112.55mg,1.11mmol)和N,N'-二琥珀酰亚胺基碳酸酯(31.32mg,122.35μmol)，30℃搅拌1小时，再加入(S)-螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-2'(1'H)-酮4f-B(0.03g,98.63μmol)，30℃搅拌18小时，反应结束后，减压浓缩，得到的残留物经过C18反相柱制备分离(洗脱剂：B体系)，得到(S)-N-((R)-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代-1',2'-二氢螺[氮杂环庚烷-4,4'-吡啶并[2,3-d][1,3]噁嗪]-1-甲酰胺4B(11mg)，产率：13.52％。
MS m/z(ESI):644.6[M+1]
1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.18(dd,J＝4.8,1.6Hz,1H),7.97(s,1H),7.40-7.33(m,2H),7.05-7.02(m,2H),6.41(d,J＝8.4Hz,1H),4.85(q,J＝8.0Hz,1H),3.76-3.72(m,1H),3.55-3.45(m,3H),3.23-3.10(m,4H),3.01-2.88(m,3H),2.65-2.56(m,5H), 2.47-2.42(m,6H),2.38-2.35(m,1H),2.30-2.24(m,1H),2.17-1.95(m,6H),1.75-1.53(m,4H),1.40-1.23(m,1H).
实施例5A
(3aR,5S,6aS)-N-((R)-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代-1',2',3a,4,6,6a-六氢-1H-螺[环戊[c]吡咯-5,3'-吡咯并[2,3-b]吡啶]-2(3H)-甲酰胺
实施例5B
(3aR,5R,6aS)-N-((R)-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代-1',2',3a,4,6,6a-六氢-1H-螺[环戊[c]吡咯-5,3'-吡咯并[2,3-b]吡啶]-2(3H)-甲酰胺

第一步
马来酸二苄酯
将马来酸5a(4g,34.46mmol)和苄溴(14.74g,86.15mmol)溶解于N,N-二甲基甲酰胺中(40mL)，加入碳酸钾(19.02g,137.85mmol)，25℃下搅拌48小时，加入水(40mL)，用乙酸乙酯萃取(80mL×3)，合并有机相，减压浓缩，得到粗品，得到的残留物经过柱层析分离纯化(洗脱剂：C体系)，得到马来酸二苄酯5b(2.43g)，产率：22.61％。
1H NMR(400MHz,CDCl3)δ7.38-7.31(m,10H),6.29(s,2H),5.14(s,4H).
第二步
(3S,4R)-吡咯烷-1-甲酸叔丁酯-3,4-二甲酸二苄酯
将马来酸二苄酯5b(1.6g,5.40mmol)，甘氨酸(8.11g,107.99mmol)和多聚甲醛(971.93mg,32.40mmol)溶解于甲苯中(100mL)，130℃搅拌4小时，反应结束后，减压浓缩，加入乙醇(30mL)，加入二碳酸二叔丁酯(1.41g,6.48mmol)，25℃搅拌18小时，反应结束后，过滤，滤液减压浓缩，得到的残留物经过柱层析分离纯化(洗脱剂：A体系)，得到(3S,4R)-吡咯烷-1-甲酸叔丁酯-3,4-二甲酸二苄酯5c(1.40g)，产率：47.19％。
MS m/z(ESI):462.4[M+23]
第三步
(3S,4R)-3,4-双(羟甲基)吡咯烷-1-甲酸叔丁酯
将(3S,4R)-吡咯烷-1-甲酸叔丁酯-3,4-二甲酸二苄酯5c(900mg,2.05mmol)溶解于四氢呋喃中(30mL)，在零摄氏度，加入氢化铝锂(466.89mg,12.29mmol)，维持零摄氏度搅拌30分钟，加入25％的氢氧化钠溶液淬灭反应，过滤，减压浓缩，得到(3S,4R)-3,4-双(羟甲基)吡咯烷-1-甲酸叔丁酯5d(473mg)，产率：100％，未经纯化，直接进行下一步反应。
MS m/z(ESI):254.0[M+23]
第四步
(3S,4R)-3,4-双(((甲基磺酰基)氧基)甲基)吡咯烷-1-甲酸叔丁酯
将(3S,4R)-3,4-双(羟甲基)吡咯烷-1-甲酸叔丁酯5d(473mg,2.05mmol)和三乙胺(2.07g,20.45mmol)溶解于二氯甲烷中(25mL)，在零摄氏度，加入甲磺酰氯(1.41g,12.27mmol)，维持零摄氏度搅拌30分钟，加入1M的稀盐酸调节pH＝5，用二氯甲烷萃取(30mL×3)， 合并有机相，减压浓缩，得到的残留物经过柱层析分离纯化(洗脱剂：A体系)，得到(3S,4R)-3,4-双(((甲基磺酰基)氧基)甲基)吡咯烷-1-甲酸叔丁酯5e(790mg)，产率：89.73％。1H NMR(400MHz,CDCl3)δ4.34-4.22(m,4H),3.59-3.51(m,2H),3.35-3.29(m,2H),3.05(s,6H),2.80-2.77(m,2H),1.45(s,9H).
第五步
(3aR,5S,6aS)-2'-氧代-1'-((2-(三甲基甲硅烷基)乙氧基)甲基)-1',2',3a,4,6,6a-六氢-1H-螺[环戊[c]吡咯-5,3'-吡咯并[2,3-b]吡啶]-2(3H)-甲酸叔丁酯5g-A
(3aR,5R,6aS)-2'-氧代-1'-((2-(三甲基甲硅烷基)乙氧基)甲基)-1',2',3a,4,6,6a-六氢-1H-螺[环戊[c]吡咯-5,3'-吡咯并[2,3-b]吡啶]-2(3H)-甲酸叔丁酯5g-B
将1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,3-二氢-2H-吡咯并[2,3-b]吡啶-2-酮5f(850mg,3.21mmol)和(3S,4R)-3,4-双(((甲基磺酰基)氧基)甲基)吡咯烷-1-甲酸叔丁酯5e(1.25g,3.21mmol)溶解于N,N-二甲基甲酰胺中(20mL)，加入碳酸铯(3.67g,11.25mmol)，在80摄氏度搅拌21小时，加入水(20mL)，用乙酸乙酯萃取(40mL×3)萃取，合并有机相，减压浓缩，得到的残留物经过柱层析分离纯化(洗脱剂：A体系)，分别得到(3aR,5S,6aS)-2'-氧代-1'-((2-(三甲基甲硅烷基)乙氧基)甲基)-1',2',3a,4,6,6a-六氢-1H-螺[环戊[c]吡咯-5,3'-吡咯并[2,3-b]吡啶]-2(3H)-甲酸叔丁酯5g-A(89mg),174.26μmol,产率：5.42％和(3aR,5R,6aS)-2'-氧代-1'-((2-(三甲基甲硅烷基)乙氧基)甲基)-1',2',3a,4,6,6a-六氢-1H-螺[环戊[c]吡咯-5,3'-吡咯并[2,3-b]吡啶]-2(3H)-甲酸叔丁酯5g-B(126mg)，产率：7.67％。
MS m/z(ESI):460.6[M+1]
MS m/z(ESI):460.5[M+1]
1H NMR(400MHz,CDCl3)δ8.19(dd,J＝5.2,1.6Hz,1H),7.47(dd,J＝7.2,1.6Hz,1H),7.00(dd,J＝7.2,1.2Hz,1H),5.22(s,2H),3.68-3.52(m,4H),3.41-3.16(m,4H),2.40-2.31(m,2H),1.90-1.81(m,2H),1.49(s,9H),0.99-0.95(m,2H),0.08(s,9H).
1H NMR(400MHz,CDCl3)δ8.21(dd,J＝5.2,1.2Hz,1H),7.48(dd,J＝7.6,1.6Hz,1H),6.96(d,J＝7.6,5.6Hz,1H),5.24(s,2H),3.67-3.55(m,4H),3.49-3.40(m,2H),3.06-3.01(m,2H),2.20-2.15(m,2H),2.06-2.01(m,2H),1.47(s,9H),0.97-0.93(m,2H),0.05(s,9H).
第六步
(3aR,5S,6aS)-2,3,3a,4,6,6a-六氢-1H-螺[环戊[c]吡咯-5,3'-吡咯并[2,3-b]吡啶]-2'(1'H)-酮5h-A
(3aR,5R,6aS)-2,3,3a,4,6,6a-六氢-1H-螺[环戊[c]吡咯-5,3'-吡咯并[2,3-b]吡啶]-2'(1'H)-酮5h-B
分别将(3aR,5S,6aS)-2'-氧代-1'-((2-(三甲基甲硅烷基)乙氧基)甲基)-1',2',3a,4,6,6a-六氢-1H-螺[环戊[c]吡咯-5,3'-吡咯并[2,3-b]吡啶]-2(3H)-甲酸叔丁酯5g-A(89mg,193.62μmol)和(3aR,5R,6aS)-2'-氧代-1'-((2-(三甲基甲硅烷基)乙氧基)甲基)-1',2',3a,4,6,6a-六氢-1H-螺[环戊[c]吡咯-5,3'-吡咯并[2,3-b]吡啶]-2(3H)-甲酸叔丁酯5g-B(90mg,195.80μmol)溶解于三氟乙酸中(3mL)，25℃搅拌3小时，反应结束后，减压浓缩，加入四氢呋喃(2.00mL)和氨水(1mL)，继续搅拌1小时，减压浓缩，分别得到(3aR,5S,6aS)-2,3,3a,4,6,6a-六氢-1H-螺[环戊[c] 吡咯-5,3'-吡咯并[2,3-b]吡啶]-2'(1'H)-酮5h-A(44mg)，产率：98.8％和(3aR,5R,6aS)-2,3,3a,4,6,6a-六氢-1H-螺[环戊[c]吡咯-5,3'-吡咯并[2,3-b]吡啶]-2'(1'H)-酮5h-B(44mg)，产率：97.7％，未经纯化，直接进行下一步反应。
MS m/z(ESI):230.2[M+1]
MS m/z(ESI):230.2[M+1]
第七步
(3aR,5S,6aS)-N-((R)-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代-1',2',3a,4,6,6a-六氢-1H-螺[环戊[c]吡咯-5,3'-吡咯并[2,3-b]吡啶]-2(3H)-甲酰胺
将(R)-2-氨基-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)丙-1-酮1i(40mg,75.42μmol)加入到N,N-二甲基甲酰胺中(1.2mL)，加入三乙胺(76.32mg,754.20μmol)和N,N'-二琥珀酰亚胺基碳酸酯(25.12mg,98.05μmol)，25℃搅拌2小时，再加入(3aR,5S,6aS)-2,3,3a,4,6,6a-六氢-1H-螺[环戊[c]吡咯-5,3'-吡咯并[2,3-b]吡啶]-2'(1'H)-酮5h-A(25.07mg,82.96μmol)，25℃搅拌15小时，反应结束后，减压浓缩，得到的残留物经过C18反相柱制备分离(洗脱剂：B体系)，得到(3aR,5S,6aS)-N-((R)-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代-1',2',3a,4,6,6a-六氢-1H-螺[环戊[c]吡咯-5,3'-吡咯并[2,3-b]吡啶]-2(3H)-甲酰胺5A(15mg)，产率：29.50％。
MS m/z(ESI):640.6[M+1]
1HNMR(400MHz,DMSO-d6)δ12.99(s,1H),10.85(s,1H),7.99(d,J＝6.4Hz,1H),7.92(s,1H),7.51(d,J＝8.4Hz,1H),7.33(s,1H),6.97(s,1H),6.92-6.89(m,1H),6.27(d,J＝8.0Hz,1H),4.78(q,J＝7.6Hz,1H),3.53-3.51(s,2H),3.25-2.77(m,12H),2.43(s,3H),2.32-2.14(m,7H),1.97-1.87(m,4H),1.72-1.65(m,2H),1.48-1.35(m,3H),1.21-1.15(m,1H),0.92(t,J＝7.2Hz,1H).
第八步
(3aR,5R,6aS)-N-((R)-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代-1',2',3a,4,6,6a-六氢-1H-螺[环戊[c]吡咯-5,3'-吡咯并[2,3-b]吡啶]-2(3H)-甲酰胺
将(R)-2-氨基-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)丙-1-酮1i(47.39mg,89.35μmol)加入到N,N-二甲基甲酰胺中(2mL)，加入三乙胺(100.45mg,992.72μmol)和N,N'-二琥珀酰亚胺基碳酸酯(31.32mg,122.35μmol)，30℃搅拌1小时，再加入(3aR,5R,6aS)-2,3,3a,4,6,6a-六氢-1H-螺[环戊[c]吡咯-5,3'-吡咯并[2,3-b]吡啶]-2'(1'H)-酮5h-B(0.03g,99.27μmol)，30℃搅拌16小时，反应结束后，减压浓缩，得到的残留物经过C18反相柱制备分离(洗脱剂：B体系)，得到(3aR,5R,6aS)-N-((R)-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-2'-氧代-1',2',3a,4,6,6a-六氢-1H-螺[环戊[c]吡咯-5,3'-吡咯并[2,3-b]吡啶]-2(3H)-甲酰胺5B(11mg)，产率：17.32％。
MS m/z(ESI):640.5[M+1]
1HNMR(400MHz,DMSO-d6)δ11.01(s,1H),8.03(d,J＝5.2Hz,1H),7.94(s,1H),7.64(d,J＝7.2Hz,1H),7.33(s,1H),6.97-6.92(m,2H),6.36(d,J＝7.6Hz,1H),4.75(q,J＝7.2Hz,1H), 3.59-3.48(m,1H),3.13-2.84(m,9H),2.64(s,5H),2.33-2.17(m,9H),1.97-1.91(m,5H),1.85-1.78(m,2H),1.48-1.40(m,2H),1.29-1.23(m,1H),0.92(t,J＝6.8Hz,1H).
实施例6
N-((R)-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-4-(2-氧代-1,2-二氢喹啉-3-基)氮杂环庚烷-1-甲酰胺
第一步
4-(2-甲氧基-2-氧亚乙基)氮杂环庚烷-1-甲酸叔丁酯
将2-(二甲氧基磷酰基)乙酸甲酯6a(1.87g,10.32mmol)溶于四氢呋喃中(15mL),温度降到零摄氏度,分批加入氢化钠(518.1mg,12.95mmol)，零摄氏度反应0.5小时，然后零摄氏度加入4-氧代氮杂环庚烷-1-甲酸叔丁酯4c(2.00g,9.38mmol)的四氢呋喃溶液(5mL)，25℃反应16小时，反应结束后，将反应液倒入冰的饱和氯化铵水溶液中(100mL),用二氯甲烷萃取(100mL×3)，饱和食盐水洗涤(100mL)，无水硫酸钠干燥，减压浓缩，得到的残留物经过柱层析分离纯化(洗脱剂：C体系)，得到4-(2-甲氧基-2-氧亚乙基)氮杂环庚烷-1-甲酸叔丁酯6b(1.81g)，产率：71.4％。
MS m/z(ESI):292.1[M+23]
第二步
4-(2-甲氧基-2-氧乙基)氮杂环庚烷-1-甲酸叔丁酯
氮气保护下，将4-(2-甲氧基-2-氧亚乙基)氮杂环庚烷-1-甲酸叔丁酯6b(1.89g,7.02mmol)溶于甲醇中(20mL)，加入10％钯碳(189mg),25℃反应16小时,反应结束后，过滤，甲醇淋洗三次，滤液减压浓缩，得到4-(2-甲氧基-2-氧乙基)氮杂环庚烷-1-甲酸叔丁酯6c(1.76g)，产率：92.6％，未经纯化，直接进行下一步反应。
MS m/z(ESI):294.1[M+23]
第三步
4-(1-羟基-3-甲氧基-1-(2-硝基苯基)-3-氧代丙烷-2-基)氮杂环庚烷-1-甲酸叔丁酯
将4-(2-甲氧基-2-氧乙基)氮杂环庚烷-1-甲酸叔丁酯6c(1.76g,6.49mmol)溶于四氢呋喃中(17mL)，降温至零下78℃，滴加2M的二异丙基氨基锂溶液(4.2mL,8.43mmol)，零下78℃反应0.5小时，零下78℃滴加2-硝基苯甲醛6d(1.66g,11.03mmol)的四氢呋喃溶液(5mL)。零下78℃反应2小时，反应结束后，将反应液倒入冰的饱和氯化铵水溶液淬灭(100mL),用二氯甲烷萃取(100mL×3)，合并的有机相，用饱和氯化钠溶液洗涤(100mL)，减压浓缩，得到的残留物经过柱层析分离纯化(洗脱剂：C体系)，得到4-(1-羟基-3-甲氧基-1-(2-硝基苯基)-3-氧代丙烷-2-基)氮杂环庚烷-1-甲酸叔丁酯6e(2.38g)，产率：85.0％。
MS m/z(ESI):445.3[M+23]
第四步
4-(4-羟基-2-氧代-1,2,3,4-四氢喹啉-3-基)氮杂环庚烷-1-甲酸叔丁酯
氮气保护下，将4-(1-羟基-3-甲氧基-1-(2-硝基苯基)-3-氧代丙烷-2-基)氮杂环庚烷-1-甲酸叔丁酯6e(2.38g,6.6mmol)溶解于甲醇中(30mL)，加入10％钯碳(189.5mg)，25℃反应16小时，反应结束后，将反应液过滤，用甲醇淋洗三次，减压浓缩，加入醋酸(25mL)，80℃反应2小时，反应结束后，减压浓缩，得到4-(4-羟基-2-氧代-1,2,3,4-四氢喹啉-3-基)氮杂环庚烷-1-甲酸叔丁酯6f(3.22g)，产率：100％，未经纯化，直接进行下一步反应。
MS m/z(ESI):361.2[M+1]
第五步
3-(氮杂环庚烷-4-基)喹啉-2(1H)-酮
将4-(4-羟基-2-氧代-1,2,3,4-四氢喹啉-3-基)氮杂环庚烷-1-甲酸叔丁酯6f(3.22g,8.94mmol)溶解于甲醇中(30mL)，零摄氏度加入4M的稀盐酸(22.3mL,89.44mmol)，在25℃搅拌16小时，反应结束后，加入乙腈打浆(15mL)，过滤，得到3-(氮杂环庚烷-4-基)喹啉-2(1H)-酮6g(1.42g)，产率：88％。
MS m/z(ESI):243.1[M+1]
1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),9.14(m,1H),7.70-7.77(m,1H),7.64(d,J＝7.63Hz,1H),7.40-7.48(m,1H),7.30(d,J＝8.13Hz,1H),7.16-7.18(m,1H),3.19-3.36(m,2H),3.02-3.17(m,3H),1.67-1.92(m,2H),1.65-2.05(m,4H).
第六步
N-((R)-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-4-(2-氧代-1,2-二氢喹啉-3-基)氮杂环庚烷-1-甲酰胺
将(R)-2-氨基-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)丙-1-酮1i(64mg,120.67μmol)加入到N,N-二甲基甲酰胺中(3mL)，加入N,N'-二琥珀酰亚胺基碳酸酯(40.19mg,156.87μmol)，25℃搅拌2小时，加入3-(氮杂环庚烷-4-基)喹啉-2(1H)-酮6g(31.96mg,114.64μmol)，25℃搅拌18小时，反应结束后，减压浓缩，得到的残留物经过C18反相柱制备分离(洗脱剂：B体系)，得到N-((R)-3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙烷-2-基)-4-(2-氧代-1,2-二氢喹啉-3-基)氮杂环庚烷-1-甲酰胺6(55mg)，产率：66.47％。
MS m/z(ESI):653.6[M+1]
1H NMR(400MHz,DMSO-d6)δ12.99(s,1H),11.71(s,1H),7.93(d,J＝5.2Hz,1H),7.60-7.54(m,2H),7.41-7.22(m,3H),7.13-7.08(m,1H),6.97(s,1H),6.30-6.24(m,1H),4.84-4.79(m,1H),3.65-3.45(m,3H),3.20-2.64(m,9H),2.43-2.42(m,3H),2.30-1.15(m,21H).
生物学评价
测试例1、本申请化合物在表达人CGRP受体的CHO-K1细胞中对CGRP信号通路的抑制作用的测定
体外CGRP信号通路的抑制作用是通过间接测定cAMP水平进行评价，原理是CGRP和CGRP受体结合后，激活CGRP信号通路，诱导cAMP水平升高，cAMP可诱导受CRE(cAMP response element)调控的报告基因萤火虫荧光素酶的表达，因此萤火虫荧光素酶活性水平降低代表CGRP信号通路受到抑制，具体的实验方法如下：
将表达人CGRP受体的CHO-K1(CGRPR/CHO-K1,PerkinElmer,ES-420-C)细胞经Lipofectamine 2000(Invitrogen,11668019)转染pGL4.29[luc2P/CRE/Hygro](Promega,9PIE847)质粒后，培养在F12K+10％FBS+400μg/mL G418+10μg/mL Blasticidin+350μg/mL Hygromycin B培养基中，在对数生长期收集细胞。在384孔白色微孔板(Nest,761601)每孔加入20μL细胞悬液体，细胞密度为8000细胞/孔。每孔加入5μL梯度稀释的化合物溶液，37℃孵育30分钟后，每孔加入5μL 12ng/mL人α-CGRP(Bachem,H-1470.0500)，终浓度为2ng/mL，37℃孵育5小时后，每孔加入15μL萤火虫萤光素酶报告基因检测试剂，室温孵育15分钟，使用酶标仪(Molecular Devices)读取发光信号。用Graphpad Prism依据化合物浓度与发光信号计算化合物对萤火虫荧光素酶活性水平抑制作用的IC50值。
本申请化合物的生物活性通过以上的试验进行测定，测得在[α-CGRP]＝2ng/mL下的IC50值见下表1。
表1本申请化合物在表达人CGRP受体的CHO-K1细胞中对CGRP信号通路的抑制作用 的IC50
结论：本申请化合物在表达人CGRP受体的CHO-K1细胞中对CGRP信号通路均有明显的抑制作用。
测试例2、本申请化合物在SK-N-MC细胞中对CGRP信号通路的抑制作用的测定
体外CGRP信号通路的抑制作用是通过测定cAMP水平进行评价，原理是CGRP和CGRP受体结合后，激活CGRP信号通路，诱导cAMP水平升高，因此cAMP水平降低代表CGRP信号通路受到抑制，具体的实验方法如下：
cAMP测定使用CAMP-GS DYNAMIC KIT检测试剂盒(Cisbio,62AM4PEB)。
将内源表达CGRP受体的SK-N-MC(ATCC,HTB-10)细胞培养在EMEM+10％FBS培养基中，在对数生长期收集细胞。根据试剂盒使用说明，细胞重悬于含0.5mM IBMX的Stimulation Buffer中，在96孔微孔板(Cisbio,66PL96025)每孔加入5μL细胞悬液体，细胞密度为15000细胞/孔。每孔加入2.5μL梯度稀释的化合物溶液(化合物溶液的最高浓度为100nM，3倍稀释，共11个浓度)，37℃孵育30分钟后，每孔加入2.5μL稀释在含0.5mM IBMX的Stimulation Buffer中的40ng/mL人α-CGRP(Bachem,H-1470.0500)，终浓度为10ng/mL，37℃孵育30分钟后，每孔加入5μL Anti-cAMP-Cryptate溶液和5μL cAMP-d2溶液。室温孵育60分钟，使用酶标(Molecular Devices)读取HTRF信号。用Graphpad Prism依据化合物浓度与HTRF信号计算化合物对cAMP水平升高抑制作用的IC50值。
本申请化合物的生物活性通过以上的试验进行测定，测得在[α-CGRP]＝10ng/mL下的IC50值见下表2。
表2本申请化合物在SK-N-MC细胞中对CGRP信号通路的抑制作用的IC50
结论：本申请化合物在SK-N-MC细胞中对CGRP信号通路均有明显的抑制作用。

Claims (17)

  1. 一种通式(I)所示的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐：
    其中：
    环A选自杂环基或环烷基；
    环B选自杂环基或环烷基；
    R1选自＝O、杂芳基或稠合环，所述的杂芳基或稠合环任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
    或者，两个R1与它们相连接的原子一起形成5～7元环烷基或稠合环，所述的5～7元环烷基或稠合环进一步被一个或多个Ra的取代基所取代；
    每个Ra相同或不同，各自独立地选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
    R2选自杂环基或环烷基，所述的杂环基或环烷基任选进一步被一个或多个选自羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、＝O的取代基所取代；
    m为1，2或3；
    n为1或2；
    p为0，1或2。
  2. 根据权利要求1所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，其中，环B为哌嗪基；或者R2为哌啶；或者n为1；或者p为0。
  3. 根据权利要求1或2所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，其为通式(II)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐：
    其中：环A、R1和m的定义如权利要求1中所述。
  4. 根据权利要求3所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，其为通式(III)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐：
    其中：R1和m的定义如权利要求1中所述。
  5. 根据权利要求4所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，其为通式(IV)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐：
    其中：R1和m的定义如权利要求1中所述。
  6. 根据权利要求4所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药 用的盐，其为通式(V)所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐：
    其中：R1和m的定义如权利要求1中所述。
  7. 一种通式(I-A)所示的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐：
    其中：
    环A选自杂环基；
    R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
    m为0或1；
    p为0，1或2。
  8. 一种通式(I-B)所示的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐：
    其中：
    环A选自杂环基；
    X选自C或N；
    条件是，当X选自C时，环A选自四氢吡啶，p为2；
    R1选自＝O、羟基、卤素、硝基、氰基、烷基、氘代烷基、烷氧基、环烷基、卤代烷基、羟基烷基或氨基烷基；
    m为0或1；
    p为0，1或2。
  9. 根据权利要求1～8中任一项所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，其中所述的化合物为：
  10. 一种药物组合物，其含有：
    根据权利要求1～9中任何一项所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，及可药用的载体、赋形剂或它们的组合物。
  11. 根据权利要求1～9中任何一项所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，或根据权利要求10所述的药物组合物在制备CGRP受体拮抗剂中的用途。
  12. 根据权利要求1～9中任何一项所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，或根据权利要求10所述的药物组合物在制备预防和/或治疗由CGRP介导的疾病的药物中的用途，其中所述的由CGRP介导的疾病为脑血管或血管障碍类疾病。
  13. 根据权利要求12所述的用途，其中所述的由CGRP介导的脑血管或血管障碍类疾病选自发作性偏头痛、无先兆偏头痛、慢性偏头痛、纯月经性偏头痛、月经相关性偏头痛、有先兆偏头痛、儿童/青少年偏头痛、偏瘫性偏头痛、散发性偏瘫性偏头痛、基底型偏头痛、周期性呕吐、腹型偏头痛、儿童期良性阵发性眩晕、视网膜性偏头痛、丛集性头痛、透析性头痛、原因不明的慢性头痛、紧张/压力诱导的头痛、过敏诱导的头痛、神经源性炎症、带状疱疹后神经痛、卵巢痛、更年期偏头痛、眼痛、腹泻、骨关节炎和相关的骨质疏松性骨折疼痛、与绝经或由手术或药物治疗造成的医疗诱导的绝经相关的潮热、周期性呕吐综合征、阿片类物质戒断、银屑病、哮喘、肥胖症、吗啡耐受、神经退行性疾病、癫痫、变应性鼻炎、红斑痤疮、牙痛、耳痛、中耳炎、晒伤、与骨关节炎和类风湿性关节炎相关的关节痛、癌痛、纤维肌痛、糖尿病性神经病、痛风、三叉神经痛、鼻息肉、慢性鼻窦炎、颞下颌综合征、背痛、下腰痛、咳嗽、张力障碍性疼痛、炎性疼痛、术后切口疼痛、坐骨神经痛、复杂性区域疼痛综合征、白塞氏病、子宫内膜异位症、幻肢综合征、痛经、与分娩相关的疼痛、由皮肤烧伤造成的疼痛、或炎性肠病(包括克罗恩病、回肠炎和溃疡性结肠炎)、胃-食管反流病、消化不良、肠易激综合征、肾绞痛、膀胱炎、胰腺炎和前列腺炎等慢性继发性内脏疼痛。
  14. 一种预防和/或治疗由CGRP介导的疾病的方法，包括向受试者施用权利要求1～9中任何一项所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，或根据权利要求10所述的药物组合物，其中所述的由CGRP介导的疾病为脑血管或血管障碍类疾病。
  15. 根据权利要求14所述的方法，其中所述的由CGRP介导的脑血管或血管障碍类疾病选自发作性偏头痛、无先兆偏头痛、慢性偏头痛、纯月经性偏头痛、月经相关性偏头痛、有先兆偏头痛、儿童/青少年偏头痛、偏瘫性偏头痛、散发性偏瘫性偏头痛、基底型偏头痛、周期性呕吐、腹型偏头痛、儿童期良性阵发性眩晕、视网膜性偏头痛、丛集性头痛、透析性头痛、原因不明的慢性头痛、紧张/压力诱导的头痛、过敏诱导的头痛、神经源性炎症、带状疱疹后神经痛、卵巢痛、更年期偏头痛、眼痛、腹泻、骨关节炎和相关的骨质疏松性 骨折疼痛、与绝经或由手术或药物治疗造成的医疗诱导的绝经相关的潮热、周期性呕吐综合征、阿片类物质戒断、银屑病、哮喘、肥胖症、吗啡耐受、神经退行性疾病、癫痫、变应性鼻炎、红斑痤疮、牙痛、耳痛、中耳炎、晒伤、与骨关节炎和类风湿性关节炎相关的关节痛、癌痛、纤维肌痛、糖尿病性神经病、痛风、三叉神经痛、鼻息肉、慢性鼻窦炎、颞下颌综合征、背痛、下腰痛、咳嗽、张力障碍性疼痛、炎性疼痛、术后切口疼痛、坐骨神经痛、复杂性区域疼痛综合征、白塞氏病、子宫内膜异位症、幻肢综合征、痛经、与分娩相关的疼痛、由皮肤烧伤造成的疼痛、或炎性肠病(包括克罗恩病、回肠炎和溃疡性结肠炎)、胃-食管反流病、消化不良、肠易激综合征、肾绞痛、膀胱炎、胰腺炎和前列腺炎等慢性继发性内脏疼痛。
  16. 根据权利要求1～9中任何一项所述的化合物或其立体异构体、互变异构体、氘代衍生物或其可药用的盐，或根据权利要求10所述的药物组合物在预防和/或治疗由CGRP介导的疾病的用途，其中所述的由CGRP介导的疾病为脑血管或血管障碍类疾病。
  17. 根据权利要求16所述的用途，其中所述的由CGRP介导的脑血管或血管障碍类疾病选自发作性偏头痛、无先兆偏头痛、慢性偏头痛、纯月经性偏头痛、月经相关性偏头痛、有先兆偏头痛、儿童/青少年偏头痛、偏瘫性偏头痛、散发性偏瘫性偏头痛、基底型偏头痛、周期性呕吐、腹型偏头痛、儿童期良性阵发性眩晕、视网膜性偏头痛、丛集性头痛、透析性头痛、原因不明的慢性头痛、紧张/压力诱导的头痛、过敏诱导的头痛、神经源性炎症、带状疱疹后神经痛、卵巢痛、更年期偏头痛、眼痛、腹泻、骨关节炎和相关的骨质疏松性骨折疼痛、与绝经或由手术或药物治疗造成的医疗诱导的绝经相关的潮热、周期性呕吐综合征、阿片类物质戒断、银屑病、哮喘、肥胖症、吗啡耐受、神经退行性疾病、癫痫、变应性鼻炎、红斑痤疮、牙痛、耳痛、中耳炎、晒伤、与骨关节炎和类风湿性关节炎相关的关节痛、癌痛、纤维肌痛、糖尿病性神经病、痛风、三叉神经痛、鼻息肉、慢性鼻窦炎、颞下颌综合征、背痛、下腰痛、咳嗽、张力障碍性疼痛、炎性疼痛、术后切口疼痛、坐骨神经痛、复杂性区域疼痛综合征、白塞氏病、子宫内膜异位症、幻肢综合征、痛经、与分娩相关的疼痛、由皮肤烧伤造成的疼痛、或炎性肠病(包括克罗恩病、回肠炎和溃疡性结肠炎)、胃-食管反流病、消化不良、肠易激综合征、肾绞痛、膀胱炎、胰腺炎和前列腺炎等慢性继发性内脏疼痛。
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