CN117466893A - Pyridocycloheptane derivative and preparation method and application thereof - Google Patents

Pyridocycloheptane derivative and preparation method and application thereof Download PDF

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CN117466893A
CN117466893A CN202310935051.2A CN202310935051A CN117466893A CN 117466893 A CN117466893 A CN 117466893A CN 202310935051 A CN202310935051 A CN 202310935051A CN 117466893 A CN117466893 A CN 117466893A
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pain
pyridin
compound
migraine
pharmaceutically acceptable
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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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Xiyuan Anjian Medicine Shanghai Co ltd
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Abstract

The application relates to a substituted pyridocycloheptane derivative, a preparation method thereof and application of a pharmaceutical composition containing the derivative or deuterated derivative in medicine. In particular, the present application relates to substituted pyridocycloheptane derivatives represented by general formula (I), a preparation method and pharmaceutically acceptable salts thereof, and other compoundsThe use thereof as CGRP receptor antagonists in the prevention and/or treatment of CGRP related diseases, in particular in the migraine field. Wherein each substituent in the general formula (I) is defined as the specification.

Description

Pyridocycloheptane derivative and preparation method and application thereof
Technical Field
The present application relates to pyridocycloheptane derivatives, a process for their preparation and pharmaceutical compositions containing the derivatives or deuterated derivatives and their use as therapeutic agents, in particular as calcitonin gene-related peptide (CGRP) receptor antagonists.
Background
Migraine is a common trigeminal vascular headache, and pain may last from 4 to 72 hours, manifested as moderate or severe jumping pain on one or both sides of the head and recurrent episodes, or with nausea, vomiting, symptoms sensitive to light, sound, smell or touch, severely affecting the patient's life (Steiner TJ et al, J Neurol Neurosurg Psychiatry 2004, 75:808-811). Migraine sufferers are more likely to develop depression, anxiety, sleep disorders, other pain and fatigue than others. Migraine is statistically affecting 13 million patients worldwide, about 11% of adults, with female patients being three times as many as male patients. The pathogenesis of migraine is not completely defined internationally, and is known as trigeminal vasoreflex theory, the pathogenesis of migraine is well explained by effectively combining nerves, blood vessels and neurotransmitters, and the pathogenesis of migraine is widely accepted.
Currently, migraine is clinically divided into symptomatic and prophylactic treatments, wherein the first-line therapy of symptomatic treatment is still using non-steroidal anti-inflammatory drugs, ergotamines or triptans, and even using opioid and other drug combinations for severe patients. Triptans are the first-line therapy of current migraine treatments, but some patients are not sensitive to this type and the therapeutic effect is not obvious, and in addition, the problems of the triptans have side effects that cause cardiovascular risks, which limit the use of the triptans. The common prescription for preventing and treating is antiepileptic drugs, tricyclic antidepressants and beta-receptor blockers, wherein only part of the drugs have the effect of preventing migraine. Since these preventive drugs are originally used for the treatment of other diseases, they are not specific for the prevention of migraine and have remarkable side effects, they are not preferable for the preventive treatment of migraine. It is conceivable that in the migraine field, there is still a need to search for drugs with better therapeutic effects.
Calcitonin gene-related peptide (CGRP) is a neuropeptide containing 37 amino acid residues found by Amara et al in 1982 and is widely found in the central and peripheral nervous systems, particularly the cell bodies and endings of sensory neurons (Amara SG et al, science 1982, 298:240-244). Peripheral CGRP is synthesized in the dorsal root ganglion, central CGRP is synthesized in the trigeminal ganglion, both in the sensory neuron cell body, and then rapidly transported to the central and peripheral end tips. The central terminal is used as sensory neuron afferent fiber and is mainly responsible for the conduction of pain and temperature sensation. In the periphery, CGRP-containing sensory nerve fibers are widely distributed in various tissues and organs and are released by means of axonal reflex due to various stimuli.
CGRP is currently the most powerful endogenous vasodilating substance and has become an important and hot spot of research in the area of pain, especially migraine. Several clinical studies demonstrated that in the onset of migraine, the level of CGRP in the plasma increased and that the intensity and duration of migraine was positively correlated with plasma CGRP levels (Han TH et al, arch Drug Inf 2010, 3:55-62). In addition Goadsby et al found an increase in CGRP content in the external jugular vein but no increase in the elbow vein upon migraine attacks, indicating intracranial release of CGRP upon migraine (Goadsby PJ et al, ann Neurol1990, 28:183-187). Animal studies have also found that CGRP released by trigeminal activation can cause brain and meningeal vasodilation, mast cell release inflammatory mediators, and nociceptive biological information of intracranial vascular release to the center (Williamson D et al, microsc Res Tech 2001, 53:167-178). Various studies have shown that migraine is closely related to abnormal release and elevated levels of CGRP.
The molecular weight of CGRP is about 3800Da, and consists of 2800 base pairs, in 37 amino acid sequences of the CGRP, the 2 nd and 7 th positions of the N end are connected by disulfide bonds, the C end is phenylalanine residue, and the two structures are necessary groups for the biological activity of the CGRP. Human CGRP is currently known in both the α -CGRP and the β -CGRP types, where α -CGRP is mainly expressed in the nervous system, such as in the hypothalamus, cerebellum, brainstem and trigeminal system, and β -CGRP is mainly expressed in the intestinal sensory system. alpha-CGRP is formed by splicing of the Calcitonin (CT) gene, whereas beta-CGRP is encoded by an isolated gene, which has similar biological effects in the circulatory system despite the three amino acids difference between the two forms of CGRP (Edvinsson L Expert Opinion on Therapeutic Targets 2007, 11:1179-1188).
CGRP receptors belong to the G protein-coupled receptor and consist of 7 transmembrane protein complexes (calcitonin receptor-like receptor calcitonin receptor like receptor, CLR), 1 transmembrane protein receptor activity modifying protein (receptor activity modifying protein, RAMP 1) and 1 intracellular protein (receptor component protein receptor component protein, RCP) (Evans BN et al, J Biology Chem 2000, 275:38-43). RAMP1 is a class of small molecule transmembrane proteins that mediate membrane translocation of CLR in the form of chaperones, and RCP is a class of small molecule polypeptides that mediate downstream signaling of CLR. At present, the mechanism of the CGRP involved in migraine is not clear, and most students consider that the CGRP is involved in the processes of neurogenic inflammation, peripheral and central sensitization and cortical spreading inhibition as multifunctional neuropeptides, thereby inducing the migraine.
As CGRP and its receptors have been increasingly studied, our knowledge has increased, and CGR was first isolated from 1983 to 2018, three CGRP monoclonal drugs were approved for the us market for 35 years. At present, four CGRP monoclonal antibodies are marketed, besides CGRP monoclonal antibodies, research and development of CGRP receptor antagonists are also of great concern, after all, small molecular compounds have obvious advantages in terms of the friendliness of the administration mode, and three small molecular CGRP receptor antagonists are marketed up to the present.
In the development of CGRP receptor antagonists, there has been surprise and frustration, taking Olcegepant, telcagepant, MK-3207 as an example, although several clinical trials have proven the effectiveness of these drugs, these compounds can only be paused due to serious adverse reactions such as hepatotoxicity, etc. in a plurality of patients in clinical applications. Fortunately, the FDA approved Ubrogepant for the treatment of acute migraine in 2019 by constantly optimizing the screen for more suitable compounds, which was developed by Abbvie company. Rimegepant developed by Biohaven was also successfully approved for the treatment of acute migraine and for 5 months 2021 for the extension of indications for prophylactic treatment of episodic migraine. Atogepant developed by Abbvie corporation was approved by the FDA for prophylactic treatment of episodic migraine at month 9 of 2021. The successful marketing of the three small molecule drugs brings hopes for migraine patients worldwide, but has side effects such as constipation, nausea, somnolence and the like, so the search for safer and more effective CGRP small molecule drugs is very necessary.
Disclosure of Invention
In view of the above technical problems, the present application provides a substituted pyridocycloheptane derivative represented by general formula (I):
Wherein:
l is selected from-O-or-O (CO) -;
ring a is selected from a 5 membered heterocyclyl, a 5 membered heteroaryl ring, or a 7 membered heterocyclyl;
R 1 selected from halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl or cyano;
R 2 selected from halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl or cyano;
R 3 selected from heteroaryl or a fused ring, said heteroaryl or fused ring being optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, =o;
alternatively, two R 3 Together with the atoms to which they are attached form a 5-to 7-membered cycloalkyl or fused ring, said 5-to 7-membered cycloalkyl or fused ring being further substituted with one or more R a Is substituted by a substituent of (2);
each R a The same or different, each independently selected from = O, heteroaryl or fused ring, wherein the heteroaryl or fused ring is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, = O;
alternatively, two R a Together with the atoms to which they are attached, form a fused ring, said fused ring being optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, =o;
n is 0,1,2 or 3;
m is 0,1 or 2;
p is 1,2 or 3.
In a specific embodiment, ring A is pyrrolidine, the remainder L, R 1 、R 2 、R 3 The definitions of n, m and p are as described above for formula (I).
In a specific embodiment, ring a is isoxazole, the remainder L, R 1 、R 2 、R 3 N, m and pThe definition is as defined above for formula (I).
In a specific embodiment, ring A is azepane, the remainder L, R 1 、R 2 、R 3 The definitions of n, m and p are as described above for formula (I).
In one particular embodiment, L is-O-, the remaining ring A, R 1 、R 2 、R 3 The definitions of n, m and p are as described above for formula (I).
In a specific embodiment, L is-O (CO) -, the remaining rings A, R 1 、R 2 、R 3 The definitions of n, m and p are as described above for formula (I).
In a specific embodiment, R 1 Fluorine, the remaining ring A, L, R 2 、R 3 The definitions of n, m and p are as described above for formula (I).
In a specific embodiment, R 3 Is quinolin-2 (1H) -one, the remainder being L, ring A, R 1 、R 2 The definitions of n, m and p are as described above for formula (I).
In a specific embodiment, R 3 Is 1, 3-dihydro-2H-imidazo [4,5-b]Pyridin-2-one, the remainder L, ring A, R 1 、R 2 The definitions of n, m and p are as described above for formula (I).
In one particular embodiment, n is 2, the remainder of L, ring A, R 1 、R 2 、R 3 The definition of m and p is as defined above for formula (I).
In one particular embodiment, m is 0, the remaining L, rings A, R 1 、R 2 、R 3 The definition of n and p is as defined above for formula (I).
In one particular embodiment, p is 1 or 2, the remainder L, ring A, R 1 、R 2 、R 3 The definition of n and m is as defined above for formula (I).
In a specific embodiment, rings a and (R 3 ) p Is that The rest L, R 1 、R 2 、R a The definitions of n and m are as described above for formula (I), and B is as defined for formulas (VI) and (VII).
In a specific embodiment, L is selected from the group consisting of-O-or-O (CO) -, and ring A is selected from the group consisting ofR 3 Selected from->Or rings A and (R) 3 ) p Is->Or (b)The rest R 1 、R 2 、R a The definitions of n and m are as described above for formula (I), and B is as defined for formulas (VI) and (VII).
In a specific embodiment, L is selected from the group consisting of-O-or-O (CO) -, and ring A is selected from the group consisting ofR 3 Selected from->Or rings A and (R) 3 ) p Is-> R 1 Halogen, preferably fluorine, the remainder R 2 、R a The definitions of n and m are as described above for formula (I), and B is as defined for formulas (VI) and (VII).
In a specific embodiment, L is selected from the group consisting of-O-or-O (CO) -, and ring A is selected from the group consisting of R 3 Selected from->Or rings A and (R) 3 ) p Is-> R 1 Halogen, preferably fluorine, R 2 Selected from halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl or cyano, R a The definitions of n and m are as described above for formula (I), and B is as defined for formulas (VI) and (VII).
In a specific embodiment, L is selected from the group consisting of-O-or-O (CO) -, and ring A is selected from the group consisting ofR 3 Selected from->Or rings A and (R) 3 ) p Is-> R 1 Is halogen, R 2 Selected from halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl or cyano, R a Is =o, heteroaryl or fused ring, preferably +.>n and m are as defined above for formula (I), and B is as defined for formulas (VI) and (VII).
In a specific embodiment, L is selected from the group consisting of-O-or-O (CO) -, and ring A is selected from the group consisting ofR 3 Selected from->Or rings A and (R) 3 ) p Is-> R 1 Is halogen, R 2 Selected from halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl or cyano, R a Is =o, heteroaryl or fused ring, preferably +.>n is 2, m is as defined above for formula (I), and B is as defined for formulas (VI) and (VII).
In a specific embodiment, L is selected from the group consisting of-O-or-O (CO) -, and ring A is selected from the group consisting of R 3 Selected from->Or rings A and (R) 3 ) p Is-> R 1 Is halogen, R 2 Selected from halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl or cyano, R a Is =o, heteroaryl or fused ring, preferably +.>n is 2, m is 0, and B is as defined for formula (VI) and (VII).
In a specific embodiment, L is selected from the group consisting of-O (CO) -, and ring A is selected from the group consisting ofR 3 Selected from the group consisting of
Or rings A and (R) 3 ) p Is->R 1 Halogen, preferably fluorine, the remainder R 2 The definitions of n and m are as described above for formula (I), and B is as defined for formulas (VI) and (VII).
In a specific embodiment, L is selected from the group consisting of-O (CO) -, and ring A is selected from the group consisting ofR 3 Selected from the group consisting ofOr rings A and (R) 3 ) p Is->R 1 Halogen, preferably fluorine, R 2 Selected from halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl or cyano, n and m are as defined above for formula (I), and B is as defined for formulas (VI) and (VII).
In a specific embodiment, L is selected from the group consisting of-O (CO) -, and ring A is selected from the group consisting ofR 3 Selected from the group consisting ofOr rings A and (R) 3 ) p Is->R 1 Halogen, preferably fluorine, R 2 Selected from halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl or cyano, n is 2, m is as defined above for formula (I), and B is as defined for formulas (VI) and (VII).
In a specific embodiment, L is selected from the group consisting of-O (CO) -, and ring A is selected from the group consisting ofR 3 Selected from the group consisting ofOr rings A and (R) 3 ) p Is->R 1 Halogen, preferably fluorine, R 2 Selected from halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl or cyano, n is 2, m is 0, and B is as defined for formula (VI) and (VII).
In a specific embodiment, L is selected from the group consisting of-O-, ring A and (R 3 ) p Is thatThe rest R 1 、R 2 、R a The definition of n and m is as defined above for formula (I).
In a specific embodiment, L is selected from the group consisting of-O-, ring A and (R 3 ) p Is thatR 1 Halogen, preferably F, the remainder R 2 、R a The definition of n and m is as defined above for formula (I).
In a specific embodiment, L is selected from the group consisting of-O-, ring A and (R 3 ) p Is thatR 1 Halogen, preferably F, R 2 Selected from halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl or cyano, R a The definition of n and m is as defined above for formula (I).
In a specific embodiment, L is selected from the group consisting of-O-, ring A and (R 3 ) p Is thatR 1 Halogen, preferably F, R 2 Selected from halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl or cyano, n is 2, R a And m is as defined above for formula (I).
In a specific embodiment, L is selected from the group consisting of-O-, ring A and (R 3 ) p Is thatR 1 Halogen, preferably F, R 2 Selected from halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl or cyano, n is 2, m is 0, R a Is as defined above for formula (I).
In a specific embodiment, L is selected from the group consisting of-O-, ring A and (R 3 ) p Is thatR 1 Halogen, preferably F, R 2 Selected from halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl or cyano, n is 2, m is 0, R a Selected from =o, heteroaryl or fused ring, preferably +.>
In a preferred embodiment of the present application, there is provided a compound of formula (I) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, which is a compound of formula (II) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof:
wherein: ring A, L, R 3 And p is as defined in claim 1.
In a preferred embodiment of the present application, there is provided a compound of formula (II) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, which is a compound of formula (III) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof:
Wherein: ring A, R 3 And p is as defined in claim 1.
In a preferred embodiment of the present application, there is provided a compound of formula (II) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, which is a compound of formula (IV) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof:
wherein: ring A, R 3 And p is as defined in claim 1.
In a preferred embodiment of the present application, there is provided a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein ring a is selected from:
preferred embodiments of the present application provide a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from:
in a preferred embodiment of the present application, there is provided a compound of formula (III) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, which is a compound of formula (V) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof:
Wherein: r is R a Is defined as in claim 1.
In a preferred embodiment of the present application, there is provided a compound of formula (IV) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, which is a compound of formula (VI) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof:
wherein: ring B is selected from a 5-to 7-membered heterocyclyl group, said heterocyclyl group being optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, =o.
In a preferred embodiment of the present application, there is provided a compound of formula (IV) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, which is a compound of formula (VII):
wherein: ring B is selected from a 5-to 7-membered heterocyclyl group, said heterocyclyl group being optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, =o.
In a preferred embodiment of the present application, the compound of formula (I) is selected from:
/>
/>
Or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Note that: if there is a difference between the drawn structure and the name given to the structure, the drawn structure will be given greater weight.
Still further, the present application provides a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII), or a stereoisomer, tautomer, deuterated derivative, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or combination thereof.
The application provides the use of a compound shown in general formula (I), (II), (III), (IV), (V), (VI) or (VII) or a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for preparing a CGRP receptor antagonist.
The application also provides the application of the compound shown in the general formula (I), (II), (III), (IV), (V), (VI) or (VII) or a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicines for preventing and/or treating diseases mediated by CGRP, wherein the diseases mediated by CGRP are preferably cerebrovascular diseases or vascular disorders; wherein the CGRP-mediated cerebrovascular or vascular disorders are selected from the group consisting of episodic migraine, non-premonitory migraine, chronic migraine, pure menstrual migraine, menstrual-related migraine, premonitory migraine, childhood/adolescent migraine, hemiplegic migraine, sporadic hemiplegic migraine, basal migraine, periodic vomiting, abdominal migraine, childhood benign paroxysmal vertigo, retinal migraine, cluster headache, dialysis headache, chronic headache of unknown cause, tension/pressure-induced headache, allergy-induced headache, osteoarthritis and associated osteoporotic fracture pain, hot flashes associated with menopause or with medical induced menopause caused by surgery or drug therapy, periodic vomiting syndrome, opioid withdrawal, psoriasis, asthma, obesity morphine tolerance, neurodegenerative diseases, epilepsy, allergic rhinitis, rosacea, toothache, ear pain, otitis media, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, gout, trigeminal neuralgia, nasal polyp, chronic sinusitis, temporomandibular syndrome, back pain, lower back pain, cough, dystonia pain, inflammatory pain, post-operative incision pain, sciatica, complex regional pain syndrome, behcet's disease, endometriosis, phantom limb syndrome, dysmenorrhea, pain associated with labor, pain caused by skin burns, or inflammatory bowel disease (including crohn's disease, ileitis and ulcerative colitis), gastroesophageal reflux disease, dyspepsia, irritable bowel syndrome, renal colic, cystitis, pain in the postoperative incision, sciatica, complex regional pain syndrome, behcet's disease, endometriosis, phantom limb syndrome, dysmenorrhea, pain associated with labor, pain caused by skin burns, or inflammatory bowel disease (including crohn's disease, ileitis and ulcerative colitis), chronic secondary visceral pain such as pancreatitis and prostatitis. The application further provides application of the compound shown in the general formula (I), (II), (III), (IV), (V), (VI) or (VII) or stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof or pharmaceutical composition thereof in preparing medicaments for preventing and/or treating cerebrovascular or vascular disorder diseases.
The present application provides a compound of formula (I), (II), (III), (IV), (V), (VI) or (VII) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, or pharmaceutical compositions thereof for the preparation of a medicament for the prophylaxis and/or treatment of narcolepsy, migraine without aura, chronic migraine, pure menstrual migraine, menstrual-related migraine, migraine with aura, childhood/adolescent migraine, hemiplegic migraine, sporadic hemiplegic migraine, basal migraine, periodic vomiting, abdominal migraine, benign paroxysmal vertigo in childhood, retinal migraine, cluster headache, dialysis headache, chronic headache of unknown origin, tension/pressure-induced headache, allergy-induced headache, osteoarthritis and related osteoporotic fracture pain, hectic fever associated with menopause or medical induced menopause caused by surgery or drug therapy periodic vomiting syndrome, opioid withdrawal, psoriasis, asthma, obesity, morphine tolerance, neurodegenerative diseases, epilepsy, allergic rhinitis, rosacea, dental pain, ear pain, otitis media, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, gout, trigeminal neuralgia, nasal polyp, chronic sinusitis, temporomandibular syndrome, back pain, lower back pain, cough, dystonia pain, inflammatory pain, post-operative incision pain, sciatica, complex regional pain syndrome, behcet's disease, endometriosis, phantom limb syndrome, dysmenorrhea, chronic sinusitis, temporomandibular syndrome, back pain, lower back pain, cough, dystonia pain, inflammatory pain, post-operative incision pain, sciatica, complex regional pain syndrome, behcet's disease, endometriosis, phantom limb syndrome, dysmenorrhoea, use of a medicament for treating chronic secondary visceral pain associated with labor, pain caused by skin burns, or inflammatory bowel disease (including crohn's disease, ileitis and ulcerative colitis), gastro-esophageal reflux disease, dyspepsia, irritable bowel syndrome, renal colic, cystitis, pancreatitis and prostatitis.
The compounds of the present application are optionally in the form of individual optical isomers, individual enantiomers or mixtures of racemates, in the form of tautomers and in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids.
The compounds of the present application may exist as tautomers. All tautomeric forms of the compounds of the present application are contemplated to be within the scope of the present application.
Detailed description of the invention
Unless stated to the contrary, some of the terms used in the specification and claims of this application are defined as follows:
"alkyl" when taken as a group or part of a group is meant to include C 1 -C 20 Straight chain or branched aliphatic hydrocarbon groups. Preferably C 1 -C 10 Alkyl, more preferably C 1 -C 6 An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.
"cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocycles. Preferably C 3 -C 12 Cycloalkyl, more preferably C 3 -C 8 Cycloalkyl, most preferably C 5 -C 7 Cycloalkyl groups. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred. Cycloalkyl groups may be optionally substituted or unsubstituted.
"heterocyclyl", "heterocycloalkyl", "heterocycle" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more of the ring-forming atoms are heteroatoms, such as oxygen, nitrogen, sulfur atoms, and the like, and include monocyclic, polycyclic, fused, bridged and spiro rings. Preferably having a 5 to 7 membered single ring or a 7 to 10 membered double or triple ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulphur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl, piperazinyl, hexahydropyrimidine, 1, 3-oxazin-2-one. The heterocyclic group may be substituted or unsubstituted.
"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 8-to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "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, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl. Heteroaryl groups may be substituted or unsubstituted.
"fused ring" refers to a polycyclic group wherein two or more cyclic structures share a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but at least one of the rings does not have a fully conjugated pi-electron aromatic system, while at least one of the rings has a fully conjugated pi-electron aromatic system, wherein 0, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, or S, and the remaining ring atoms are carbon. The fused ring preferably includes a double-or triple-ring fused ring, wherein the double-ring fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably 7 to 14 membered, more preferably 8 to 10 membered. Examples of "fused rings" include, but are not limited to:
"alkoxy" refers to a group of (alkyl-O-). Wherein alkyl is as defined herein. C (C) 1 -C 6 Is preferably selected. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
"hydroxy" refers to an-OH group.
"halogen" refers to fluorine, chlorine, bromine and iodine.
"amino" means-NH 2 。
"cyano" refers to-CN.
"nitro" means-NO 2 。
"carboxy" means-C (O) OH.
"DMSO" refers to dimethyl sulfoxide.
"BOC" refers to t-butoxycarbonyl.
"TFA" refers to trifluoroacetic acid.
"PMB" refers to p-methoxybenzyl.
"SEM" refers to (trimethylsilyl) ethoxymethyl.
"hydroxyalkyl" refers to hydroxy-substituted alkyl.
"haloalkyl" refers to a halogen substituted alkyl.
"aminoalkyl" refers to an amino-substituted alkyl group.
The term "leaving group", or "leaving group", is used in the term nucleophilic substitution reaction and elimination reaction as an atom or functional group that is released from a larger molecule in a chemical reaction. In nucleophilic substitution reactions, the reactant that is attacked by a nucleophile is referred to as a substrate (substrate), and the atom or group of atoms that breaks away from a pair of electrons in the substrate molecule is referred to as a leaving group. Groups that accept electrons easily and bear a strong negative charge are good leaving groups. The smaller the pKa of the leaving group conjugate acid, the easier the leaving group will be to disengage from the other molecule. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to be bound to other atoms, and the tendency to exist in anionic (or charge neutral leaving group) form is enhanced. Common leaving groups include, but are not limited to, halogen, methanesulfonyl, -OTs, -OTf, or-OH.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"substituted" or "substituted" as used herein, unless otherwise indicated, means that the group may be substituted with one or more groups selected from the group consisting of: alkyl, alkoxy, alkylthio, alkylamino, halogen, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl;
"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain the original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds represented by the general formula (I) may be metal salts, amine salts with suitable acids.
It will be appreciated by those skilled in the art that salts of the compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), including pharmaceutically acceptable salts, may be prepared. These salts can be prepared in situ during the final isolation and purification of the compound or by separately reacting the purified compound in its free acid or free base form with a suitable base or acid, respectively.
Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids, for example, acetates, aspartates, benzoates, benzenesulfonates, bromides/hydrobromides, bicarbonates, bisulphates/sulphates, camphorsulfonates, chlorides/hydrochlorides, citrates, ethanedisulfonates, fumarates, glucoheptonates, gluconates, glucuronates, hippurates, hydroiodides, isethionates, lactates, lactobionates, lauryl sulfates, malates, maleates, malonates, mandelates, methanesulfonates, methylsulfates, naphthoates, naphthalenesulfonates, nicotinates, nitrates, stearates, oleates, oxalates, palmitoates, pamonates, phosphates/hydrogen phosphates/dihydrogen phosphates, polygalacturonates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.
Inorganic acids that can form salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Organic acids from which salts may be formed 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, and the like. Pharmaceutically acceptable base addition salts may be formed with inorganic or organic bases.
Inorganic bases that may form salts include, for example, ammonium salts and metals of groups I to XII of the periodic Table of the elements. In certain embodiments, the salt is 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, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include isopropylamine, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
Pharmaceutically acceptable salts of the present application can be synthesized from basic or acidic moieties by conventional chemical methods. In general, these salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (Na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. These reactions are generally carried out in water or in an organic solvent, or in a mixture of both. Typically, a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile is required where appropriate. Other suitable salts are listed in "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and Stahl and weruth, "Handbook of Pharmaceutical Salts: properties, selection, and Use "(Wiley-VCH, weinheim, germany, 2002).
"deuterated derivative" refers to a compound that contains deuterium bound to carbon in at least one position and has a deuterium content attached to carbon that exceeds its natural content.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
The pharmaceutical compositions according to the present application can be formulated for specific routes of administration, such as oral administration, parenteral administration, rectal administration, and the like. Furthermore, the pharmaceutical compositions of the present application can be made in solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories) or in liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical procedures (e.g., sterilization) and/or can contain conventional inert diluents, lubricants or buffers and adjuvants such as preserving agents, stabilizing agents, wetting agents, emulsifying agents, buffering agents and the like.
Typically, the pharmaceutical composition is a tablet or capsule comprising the active ingredient and
a) Diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine and the like;
b) Lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; for tablets also contain
c) Binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired, and also
d) Disintegrants, for example starch, agar, alginic acid or a sodium salt thereof, or effervescent mixtures; and/or
e) Absorbents, colorants, flavors, and sweeteners.
The tablets may be film coated or enteric coated according to methods known in the art.
Suitable compositions for oral administration include an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the form of a tablet, lozenge, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule, or syrup or elixir. Compositions for oral use are prepared according to any method known in the art for preparing pharmaceutical compositions and can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide a finished and palatable preparation. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate); granulating and disintegrating agents (e.g., corn starch, or alginic acid); binding agents (e.g. starch, gelatin or acacia); and a lubricant (e.g., magnesium stearate, stearic acid, or talc). The tablets are uncoated or they are coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented in hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or in soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Some injectable compositions are isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants such as preserving, stabilizing, wetting or emulsifying agents, dissolution enhancing agents, salts for regulating the osmotic pressure and/or buffers. In addition, it may 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 contain about 1-50% of the active ingredient.
Since water may promote degradation of certain compounds, the present application also provides anhydrous pharmaceutical compositions and dosage forms comprising 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 in order to maintain their anhydrous nature. Thus, anhydrous compositions are packaged using materials known to prevent contact with water so that they can be contained in a suitable formulation kit. Examples of suitable packages include, without limitation, airtight foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.
The present application further provides pharmaceutical compositions and dosage forms comprising 1 or more agents that reduce the rate of decomposition of the compounds of the present application as active ingredients. The agent (which is referred to herein as a "stabilizer") includes, without limitation, an antioxidant (e.g., ascorbic acid), a pH buffer, or a salt buffer, and the like.
For an individual of about 50-70kg, the pharmaceutical composition or combination product of the present application can be a unit dose of about 1-1000mg of the active ingredient, or about 1-500mg or about 1-250mg or about 1-150mg or about 0.5-100mg, or about 1-50mg of the active ingredient. The therapeutically effective dose of a compound, pharmaceutical composition or combination thereof will depend on the species, weight, age and condition of the individual, the condition or disease it is being treated for, or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients required to prevent, treat or inhibit the development of the condition or disorder.
"stereoisomers" of a compound having a given stereochemical configuration refers to the opposite enantiomer of the compound and to any diastereomer that includes the geometric isomer (Z/E) of the compound. For example, if a compound has an S, R, Z stereochemical configuration, then its stereoisomers would include its opposite enantiomer having an R, S, Z configuration, as well as its diastereomers having an S, Z configuration, R, Z configuration, S, R, E configuration, R, S, E configuration, S, E configuration, and R, E configuration. If the stereochemical configuration of a compound is not specified, "stereoisomer" refers to any of the possible stereochemical configurations of the compound.
The compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII), stereoisomers thereof, or tautomers of the compounds of formula (I), (II), (III), (IV), (V), (VI) or (VII) or complexes of stereoisomers thereof, may be administered alone or in combination with one or more pharmaceutically active compounds. Generally, one or more of these compounds is administered in the form of a pharmaceutical composition (formulation) in combination with one or more pharmaceutically acceptable excipients. The choice of excipient will depend on the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form, among other things. Useful pharmaceutical compositions and methods for their preparation can be found, for example, in a.r.gennaro (editions), ramington: pharmaceutical science and practice (20 th edition, 2000)
The compounds of the present application may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present application, including but not limited to diastereomers, enantiomers and atropisomers (attopiomers) and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present application.
Unless otherwise indicated, structures described herein also include all stereoisomers (e.g., diastereomers, enantiomers and atropisomers and geometric (conformational) isomeric forms of such structures, e.g., R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.
The term "stereoisomer" refers to an isomer produced by the spatial arrangement of atoms in a molecule, and can be classified into cis-trans isomers, enantiomers, and enantiomers. Stereoisomers belong to one of the isomers. Isomers that occur as a result of the same order of connection of atoms or groups of atoms in a molecule, but different spatial arrangements are called stereoisomers.
The term "substantially enantiomerically pure" refers to an enantiomeric purity of greater than 90% for a given stereocenter. Thus, the term "substantially enantiomerically pure" means greater than 80% ee (enantiomeric excess). For compounds that exist as stereoisomers, such stereoisomers may be substantially enantiomerically pure at the stereocenter, or preferably may have an enantiomeric purity of greater than 97%, or more preferably have an enantiomeric purity of greater than 99%.
Synthesis method of compound of the application
In order to complete the purpose of the application, the application adopts the following technical scheme:
the present application provides a process for the preparation of a compound of formula (I) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, said process comprising:
the method comprises the following steps:
nucleophilic substitution is carried out on the compound shown in the general formula (Ia) and the compound shown in the general formula (Ib) under alkaline conditions to obtain a compound shown in the general formula (Ic), and the compound shown in the general formula (Ic) is subjected to acidic conditions to obtain a compound shown in the general formula (I);
wherein:
x is halogen;
R 1 、R 2 、R 3 the definitions of m, n, p and ring A are as described in formula (I).
The second method is as follows:
nucleophilic substitution is carried out on the compound shown in the general formula (Ia) and the compound shown in the general formula (Ib) under alkaline conditions to obtain a compound shown in the general formula (Ic), and the compound shown in the general formula (Ic) is subjected to acidic conditions to obtain a compound shown in the general formula (I);
wherein:
R 1 、R 2 、R 3 the definitions of m, n, p and ring A are as described in formula (I).
Detailed Description
The following examples are used to further describe the present application, but they are not intended to limit the scope of the present application.
Examples
The preparation of representative compounds represented by formula (I) and related structural identification data are presented in the examples. It must be noted that the following examples are given by way of illustration and not by way of limitation. 1 The H NMR spectrum was determined with a Bruker instrument (400 MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation method: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm.
Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and, unless otherwise indicated, various starting materials and reagents are either commercially available or synthesized according to known methods, all of which are used without further purification and, unless otherwise indicated, commercially available manufacturers include, but are not limited to, aldrich Chemical Company, ABCR GmbH & co.kg, acros Organics, praise chemical technology limited, and vision chemical technology limited, etc.
CD 3 OD: deuterated methanol.
CDCl 3 : deuterated chloroform.
DMSO-d 6 : deuterated dimethyl sulfoxide.
D 2 O: heavy water.
The argon atmosphere means that the reaction flask is connected to an argon balloon of about 1L volume.
The examples are not particularly described, and the solution in the reaction is an aqueous solution.
Purifying the compound using a C18 reverse phase column or semi-preparative purification, a silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from the group consisting of: a: petroleum ether and tetrahydrofuran systems; b: acetonitrile and water systems; c: petroleum ether and ethyl acetate systems; d: methylene chloride and methanol systems; the volume ratio of the solvent is different according to the polarity of the compound, and can be adjusted by adding a small amount of acidic or alkaline reagent, such as trifluoroacetic acid, acetic acid or triethylamine.
Example 1-A (5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl- (3 aR,5R,6 aS) -2 '-oxo-1', 2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2 (3H) -carboxylic acid ester 1-A example 1-B (5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl- (3 aR,5R,6 aS) -2 '-oxo-1', 2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2 (3H) -carboxylic acid ester
Maleic acid 1a (4 g,34.46 mmol) and benzyl bromide (14.74 g,86.15 mmol) were dissolved in N, N-dimethylformamide (40 mL), potassium carbonate (19.02 g,137.85 mmol) was added, stirred at 25℃for 48 hours, water (40 mL) was added, extraction was performed with ethyl acetate (80 mL X3), the organic phases were combined, concentrated under reduced pressure to give a crude product, and the obtained residue was purified by column chromatography (eluent: C system) to give dibenzyl maleate 1b (2.43 g), yield: 22.61%.
1 H NMR(400 MHz,CDCl 3 )δ7.38-7.31(m,10H),6.29(s,2H),5.14(s,4H).
Second step
(3S, 4R) -pyrrolidine-1-carboxylic acid tert-butyl 3, 4-dicarboxylic acid dibenzyl ester
Dibenzyl maleate 1b (1.6 g,5.40 mmol), glycine (8.11 g,107.99 mmol) and paraformaldehyde (971.93 mg,32.40 mmol) were dissolved in toluene (100 mL), stirred for 4 hours at 130 ℃, after the reaction was completed, concentrated under reduced pressure, ethanol (30 mL) was added, di-tert-butyl dicarbonate (1.41 g,6.48 mmol) was added, stirred for 18 hours at 25 ℃, after the reaction was completed, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (eluent: A system) to give dibenzyl (3S, 4R) -pyrrolidine-1-carboxylate-3, 4-dicarboxylate 1c (1.40 g), yield: 47.19%.
MS m/z(ESI):462.4[M+23]
Third step
(3S, 4R) -3, 4-bis (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Dibenzyl (3 s,4 r) -pyrrolidine-1-carboxylate 1c (900 mg,2.05 mmol) was dissolved in tetrahydrofuran (30 mL), lithium aluminum hydride (466.89 mg,12.29 mmol) was added at zero degrees celsius and stirred for 30 minutes, 25% sodium hydroxide solution was added to quench the reaction, filtered and concentrated under reduced pressure to give tert-butyl (3 s,4 r) -3, 4-bis (hydroxymethyl) pyrrolidine-1-carboxylate 1d (473 mg), yield: 100% of the reaction mixture was directly subjected to the next reaction without purification. MS m/z (ESI) 254.0[ M+23]
Fourth step
(3S, 4R) -3, 4-bis (((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester
Tert-butyl (3 s,4 r) -3, 4-bis (hydroxymethyl) pyrrolidine-1-carboxylate 1d (473 mg,2.05 mmol) and triethylamine (2.07 g,20.45 mmol) were dissolved in dichloromethane (25 mL), methanesulfonyl chloride (1.41 g,12.27 mmol) was added at zero degrees celsius and stirred for 30 min, 1M diluted hydrochloric acid was added to adjust ph=5, extracted with dichloromethane (30 ml×3), the organic phases were combined, concentrated under reduced pressure and the resulting residue was purified by column chromatography (eluent: a system) to give tert-butyl (3 s,4 r) -3, 4-bis (((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylate 1e (790 mg), yield: 89.73%. 1 H NMR(400MHz,CDCl 3 )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).
Fifth step (3 aR,5S,6 aS) -2 '-oxo-1' - ((2- (trimethylsilyl) ethoxy) methyl) -1',2',3a,4,6 a-hexahydro-1H-spiro [ cyclopent ]
[c] Pyrrole-5, 3' -pyrrolo [2,3-b ] pyridine ] -2 (3H) -carboxylic acid tert-butyl ester 1g-A
(3 aR,5R,6 aS) -2 '-oxo-1' - ((2- (trimethylsilyl) ethoxy) methyl) -1',2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta ] e
[c] Pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2 (3H) -carboxylic acid tert-butyl ester 1g-B
1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one 1f (850 mg,3.21 mmol) and tert-butyl (3S, 4R) -3, 4-bis (((methylsulfonyl) oxy) methyl) pyrrolidine-1-carboxylate 1e (1.25 g,3.21 mmol) were dissolved in N, N-dimethylformamide (20 mL), cesium carbonate (3.67 g,11.25 mmol) was added, stirred at 80℃for 21 hours, water (20 mL) was added, extracted with ethyl acetate (40 mL. Times.3) and the organic phases were combined, the resulting residue was purified by column chromatography (eluent: A system) to give (3 aR,5S,6 aS) -2 '-oxo-1' - ((2- (trimethylsilyl) ethoxy) methyl) -1',2',3a,4,6 a-hexahydro-1H-spiro [ 3, 3-b ] pyrrole ] pyridine (38 mg,3 mg) and tert-butyl (3H-pyrrolo [ 3, 3mg, 3 ] pyrrole [ 62 mg, 3mg, respectively): 5.42% and (3 ar,5r,6 as) -2' -oxo-1 ' - ((2- (trimethylsilyl) ethoxy) methyl) -1',2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2 (3H) -carboxylic acid tert-butyl ester 1g-B (126 mg), yield: 7.67%.
MS m/z(ESI):460.6[M+1]
MS m/z(ESI):460.5[M+1]
1 H NMR(400MHz,CDCl 3 )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).
1 H NMR(400MHz,CDCl 3 )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).
Sixth step (3 aR,5S,6 aS) -2, 3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3 '-pyrrolo [2,3-B ] pyridine ] -2' (1 'H) -one 1H-A (3 aR,5R,6 aS) -2, 3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2 '(1' H) -one 1H-B
(3 aR,5S,6 aS) -2' -oxo-1 ' - ((2- (trimethylsilyl) ethoxy) methyl) -1',2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2 (3H) -carboxylic acid tert-butyl ester 1g-A (89 mg, 193.62. Mu. Mol) and (3 aR,5R,6 aS) -2' -oxo-1 ' - ((2- (trimethylsilyl) ethoxy) methyl) -1',2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2 (3H) -carboxylic acid tert-butyl ester 1g-B (90 mg, 195.80. Mu. Mol) was dissolved in trifluoroacetic acid (3 mL), stirred at 25℃for 3 hours, after completion of the reaction, concentrated under reduced pressure, tetrahydrofuran (2.00 mL) and aqueous ammonia (1 mL) were added, stirring was continued for 1 hour, and concentrated under reduced pressure to give (3 aR,5S,6 aS) -2, 3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2' (1 ' H) -one 1H-A (44 mg), yield: 98.8% and (3 aR,5R,6 aS) -2, 3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridin ] -2' (1 ' H) -one 1H-B (44 mg), yield: 97.7%, and the next reaction was directly carried out without purification.
MS m/z(ESI):230.2[M+1]
MS m/z(ESI):230.2[M+1]
Seventh step
((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-yl) carbamic acid tert-butyl ester
(5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-ol 1i (1 g,3.44 mmol) was dissolved in methylene chloride (20 mL), triethylamine (1.39 g,13.78 mmol) and di-tert-butyl dicarbonate (902.14 mg,4.13 mmol) were added respectively, stirring was carried out at 15℃for 24 hours, and after completion of the reaction, the reaction was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (eluent: C system) to give ((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-yl) carbamic acid tert-butyl ester 1j (850 mg), yield: 63.20%.
MS m/z(ESI):391.2[M+1]
Eighth step
(5S, 6S, 9R) -5- ((tert-Butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl- (3 aR,5S,6 aS) -2 '-oxo-1', 2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-b ] pyridine ] -2 (3H) room-for-a-round
Formic acid ester
(3 aR,5S,6 aS) -2, 3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3 '-pyrrolo [2,3-b ] pyridin ] -2' (1 'H) -one 1H-A (13 mg, 43.02. Mu. Mol) and triethylamine (13.06 mg, 129.05. Mu. Mol) were dissolved in N, N-dimethylformamide (0.5 mL), bis (1H-imidazol-1-yl) methanone 1k (10.46 mg, 64.53. Mu. Mol) was added, stirred at 25℃for 2 hours, after the reaction was completed, reduced to-15℃and ((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-yl) carbamic acid tert-butyl ester 1j (16.8 mg, 43.02. Mu. Mol), sodium bis (trimethylsilyl) was added dropwise to sodium bis (trimethylsilyl) amide (0.301. Mu. Mol), and saturated ammonium chloride was concentrated by a chromatography column chromatography (3X, 20 mL), and the saturated ammonium chloride solution was purified (20X) after the phase was separated by a saturated chromatography column (3X) chromatography column: D system), to give (5S, 6S, 9R) -5- ((tert-butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl- (3 aR,5S,6 aS) -2' -oxo-1 ',2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-b ] pyridine ] -2 (3H) -carboxylic acid ester 1l-a (10 mg), yield: 32.40%.
MS m/z(ESI):646.5[M+1]
Ninth step (5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl- (3 aR,5S,6 aS) -2' -oxo
-1',2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-b ] pyridine ] -2 (3H) -carboxylic acid ester
(5S, 6S, 9R) -5- ((tert-Butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl- (3 aR,5S,6 aS) -2 '-oxo-1', 2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ C ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2 (3H) -carboxylate 1l-A (10 mg, 15.49. Mu. Mol) was dissolved in a dioxane solution of hydrochloric acid (5 mL), stirred at 25℃for 3 hours, after the reaction was completed, ethyl acetate (30 mL) was added, pH=8 was adjusted with saturated sodium bicarbonate solution, the aqueous phase was extracted with ethyl acetate (30 mL. Times.3), the organic phases were combined, and the resulting residue was concentrated under reduced pressure through a C18 reverse phase column to prepare a separate (B system) to give (5S, 6S, 9R) -5-amino-6- (2, 3-difluoro [2,3-B ] pyridine ] -2 (3H) -carboxylate (5 mg, 15.49. Mu. Mol), and (3 mg, 3B) of pyrido [2,3-B ] pyridine ] -2- (3, 3-H) -carboxylate (3 mg, 9-tetrafluoro [2,3-B ] pyridine were prepared by reverse phase column chromatography: 22.49%.
MS m/z(ESI):546.5[M+1]
1 H NMR(400MHz,CDCl 3 )δ8.50-8.34(m,1H),8.04(s,1H),7.89-7.86(m,1H),7.74-7.61(m,1H),7.44-7.01(m,5H),6.11-6.05(m,1H),5.00-4.91(m,1H),4.03-3.46(m,4H),3.21-3.12(m,3H),2.39-1.81(m,8H).
Tenth step
(5S, 6S, 9R) -5- ((tert-Butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl- (3 aR,5R,6 aS) -2 '-oxo-1', 2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-b ] pyridine ] -2 (3H) room-for-a-round
Formic acid ester
(3 aR,5R,6 aS) -2, 3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ C ] pyrrole-5, 3 '-pyrrolo [2,3-B ] pyridin ] -2' (1 'H) -one 1H-B (36 mg, 119.13. Mu. Mol) and triethylamine (36.16 mg, 357.38. Mu. Mol) were dissolved in N, N-dimethylformamide (914.63. Mu. L), bis (1H-imidazol-1-yl) methanone 1k (23.18 mg, 143. Mu. Mol) was added, stirred for 2 hours at 25℃and after the reaction was completed, cooled to 15℃below zero, after adding ((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-5-yl) carbamic acid tert-butyl ester 1j (46.5 mg,119. Mu. Mol), a sodium bis (trimethylsilyl) amide solution (0.83 mL, 833. Mu. Mol) was added dropwise, stirred at 25℃for 18 hours, after completion of the reaction, quenched with saturated ammonium chloride solution (5 mL), extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, and the resulting residue was purified by column chromatography (eluent: C system), to give (5S, 6S, 9R) -5- ((tert-butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl- (3 aR,5R,6 aS) -2' -oxo-1 ',2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2 (3H) -carboxylic acid ester 1l-B (25 mg), yield: 29.25%.
MS m/z(ESI):645.9[M+1]
Eleventh step
(5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl- (3 aR,5R,6 aS) -2 '-oxo-1', 2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ c ] pyrrole-5, 3' -pyrrolo [2,3-b ] pyridine ] -2 (3H) -carboxylic acid ester
Dissolving (5S, 6S, 9R) -5- ((tert-butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl- (3 aR,5R,6 aS) -2 '-oxo-1', 2',3a,4,6 a-hexahydro-1H-spiro [ cyclopenta [ C ] pyrrole-5, 3' -pyrrolo [2,3-B ] pyridine ] -2 (3H) -carboxylate 1l-B (25 mg, 38.72. Mu. Mol) in dioxane hydrochloride solution (6 mL), stirring at 25 ℃ for 3 hours, concentrating under reduced pressure, adding ethyl acetate (30 mL), adjusting pH=8 with saturated sodium bicarbonate solution, extracting the aqueous phase with ethyl acetate (30 mL×3), combining the organic phases, concentrating under reduced pressure to obtain a residue, and preparing an eluent (B system) via a C18 reverse phase column to obtain (5S, 6S, 9R) -5-amino-6- (2, 3-difluoro [2,3-B ] pyridine ] -2 (3H) -carboxylate (25 mg, 38.72. Mu. Mol), stirring at 25 ℃ for 3 hours, concentrating under reduced pressure, adding ethyl acetate (30 mL), adjusting pH=8, and separating the aqueous phase with saturated sodium bicarbonate solution (30 mL×3) to obtain the residue: 26.98%.
MS m/z(ESI):546.4[M+1]
1 H NMR(400MHz,CDCl 3 )δ8.72-8.61(m,1H),8.14-8.08(m,1H),7.94-7.86(m,1H),7.57-7.55(m,1H),7.47-7.42(m,1H),7.22-7.00(m,4H),6.10-6.05(m,1H),5.05-4.99(m,1H),4.01-3.74(m,3H),3.40-3.37(m,2H),3.22-3.10(m,2H),2.33-1.93(m,8H).
Example 2
(5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl-3- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-1-yl) pyrrolidine-1-carboxylic acid ester
First step
3- ((2-aminopyridin-3-yl) amino) pyrrolidine-1-carboxylic acid tert-butyl ester
Pyridine-2, 3-diamine 2a (2 g,18.33 mmol) and 3-oxopyrrolidine-1-carboxylic acid tert-butyl ester 2b (4.07 g,21.99 mmol) were dissolved in ethyl acetate (20 mL), the temperature was reduced to 5℃and trifluoroacetic acid (4.81 g,42.16 mmol) was added, stirring was carried out at 5℃for 30 min, the temperature was reduced to zero℃and sodium triacetoxyborohydride (5.80 g,27.50 mmol) was added portionwise and stirring was carried out at 25℃for 30 min. After the reaction was completed, the reaction solution was placed in an ice-water bath, ph=8 was adjusted with sodium hydroxide solution, and stirred for half an hour. Extraction with ethyl acetate (100 mL. Times.2), washing with saturated brine (50 mL), drying over anhydrous sodium sulfate, and concentration under reduced pressure gave tert-butyl 3- ((2-aminopyridin-3-yl) amino) pyrrolidine-1-carboxylate 2c (5.10 g), yield: 99.3%, and the next reaction was directly carried out without purification.
MS m/z(ESI):279.2[M+1]
Second step
3- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-1-yl) pyrrolidine-1-carboxylic acid tert-butyl ester
3- ((2-aminopyridin-3-yl) amino) pyrrolidine-1-carboxylic acid tert-butyl ester 2c (4.41 g,15.75 mmol) was dissolved in acetonitrile (70 mL), N-diisopropylethylamine (4.50 g,34.85 mmol) and bis (1H-imidazol-1-yl) methanone 1k (3.85 g,23.76 mmol) were added and reacted at 25℃for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, 30mL of water was added, the mixture was extracted with methylene chloride (100 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by column chromatography (eluent: C system) to give tert-butyl 3- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-1-yl) pyrrolidine-1-carboxylate 2d (2.90 g), yield: 60.16%.
MS m/z(ESI):305.2[M+1]
1 H NMR(400MHz,DMSO-d 6 )δ11.62(s,1H),7.91(dd,J＝1.2,5.2Hz,1H),7.51-7.44(m,1H),7.01(dd,J＝5.2,8.0Hz,1H),5.03-4.92(m,1H),3.61(br d,J＝2.0Hz,2H),3.57-3.49(m,1H),3.33-3.27(m,1H),2.48-2.38(m,1H),2.20-2.08(m,1H),1.45-1.37(m,9H).
Third step
1- (pyrrolidin-3-yl) -1, 3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one
Tert-butyl 3- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-1-yl) 2d (0.2 g, 660. Mu. Mol) is dissolved in ethyl acetate solution of hydrochloric acid (6 mL), reacted at 15℃for 12 hours, and after completion of the reaction, concentrated under reduced pressure to give 1- (pyrrolidin-3-yl) -1, 3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one 2e (134 mg), yield: 99% of the reaction mixture was directly subjected to the next reaction without purification.
MS m/z(ESI):205.1[M+1]
Fourth step
1- (1- (1H-imidazole-1-carbonyl) pyrrolidin-3-yl) -1, 3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one
Di (1H-imidazol-1-yl) methanone 1k (160.53 mg, 990. Mu. Mol) and N, N-diisopropylethylamine (170.61 mg,1.32 mmol) were added to a 5mL tetrahydrofuran solution, and 1- (pyrrolidin-3-yl) -1, 3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one 2e (134 mg, 653. Mu. Mol) was added, reacted at 40℃for 3 hours, after the completion of the reaction, concentrated under reduced pressure to give 1- (1- (1H-imidazole-1-carbonyl) pyrrolidin-3-yl) -1, 3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one 2f (195 mg), yield: 65.7% and the next reaction was carried out without purification.
MS m/z(ESI):299.1[M+1]
Fifth step
(5S, 6S, 9R) -5- ((tert-Butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl
-3- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-1-yl) pyrrolidine-1-carboxylic acid ester
Tert-butyl ((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-yl) carbamate 1j (195.21 mg, 500. Mu. Mol) and 1- (1- (1H-imidazole-1-carbonyl) pyrrolidin-3-yl) -1, 3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one 2f (195 mg, 650. Mu. Mol) were dissolved in N, N-dimethylformamide (5 mL), and 1M sodium bis (trimethylsilyl) amide (311.84 mg,1.70 mmol) was added dropwise thereto at-15℃under nitrogen atmosphere, followed by stirring at 30℃for 3 hours. After the completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined and concentrated under reduced pressure, and the resulting residue was isolated by C18 reverse phase column preparation (eluent: B system) to give 2g (165 mg) of (5S, 6S, 9R) -5- ((tert-butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl-3- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-B ] pyridin-1-yl) pyrrolidine-1-carboxylic acid ester in a yield of 2g (165 mg): 53.17%.
MS m/z(ESI):621.3[M+1]
Sixth step (5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl-3- (2-oxo-2, 3-dihydro)
-1H-imidazo [4,5-b ] pyridin-1-yl) pyrrolidine-1-carboxylic acid ester
(5S, 6S, 9R) -5- ((tert-Butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl-3- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-1-yl) pyrrolidine-1-carboxylate 2g (146 mg, 230. Mu. Mol) was dissolved in dichloromethane (4 mL), 1mL trifluoroacetic acid was added and stirred at 15℃for 2 hours. After the reaction was completed, the resulting residue was concentrated under reduced pressure and separated by a C18 reverse phase column preparation (eluent: B system) to give (5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl-3- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-B ] pyridin-1-yl) pyrrolidine-1-carboxylate 2 (76.70 mg), yield: 55.43%.
MS m/z(ESI):521.2[M+1]
1 H NMR(400MHz,DMSO-d 6 )δ11.81-11.49(m,1H),8.48-8.38(m,1H),8.06-7.99(m,1H),7.97-7.90(m,1H),7.64-7.44(m,1H),7.41-7.17(m,4H),7.12-6.96(m,1H),6.06-5.96(m,1H),5.17-5.00(m,1H),4.47(br d,J＝9.2Hz,1H),4.07-3.37(m,4H),2.96-2.81(m,1H),2.44-2.02(m,4H),1.91-1.46(m,4H).
Example 3
(5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl-4- (2-oxo-2, 3-dihydro)
-1H-imidazo [4,5-b ] pyridin-1-yl) azepane-1-carboxylic acid ester
First step
4- ((2-aminopyridin-3-yl) amino) azepane-1-carboxylic acid tert-butyl ester
Pyridine-2, 3-diamine 2a (2 g,18.33 mmol), tert-butyl 4-oxo-azepane-1-carboxylate 3a (4.69 g,22.00 mmol) was dissolved in acetonitrile (20 mL), the temperature was lowered to 5℃and trifluoroacetic acid (2.09 g,18.33 mmol) was added dropwise, stirring was carried out at 5℃for 30 minutes, the temperature was lowered to zero℃and sodium triacetoxyborohydride (5.80 g,27.50 mmol) was added portionwise and reacted at 25℃for 30 minutes. After the reaction was completed, the reaction solution was placed in an ice-water bath, ph=8 was adjusted with sodium hydroxide solution, and stirred for half an hour. Extraction with ethyl acetate (100 mL. Times.2), washing with saturated brine (50 mL), drying over anhydrous sodium sulfate, and concentration under reduced pressure gave 4- ((2-aminopyridin-3-yl) amino) azepane-1-carboxylic acid tert-butyl ester 3b (6.77 g), yield: 100% of the reaction mixture was directly subjected to the next reaction without purification.
MS m/z(ESI):307.2[M+1]
Second step
4- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-1-yl) azepan-1-carboxylic acid tert-butyl ester
4- ((2-aminopyridin-3-yl) amino) azepane-1-carboxylic acid tert-butyl ester 3b (6.77 g,22.05 mmol) was dissolved in acetonitrile (70 mL), N-diisopropylethylamine (6.28 g,48.62 mmol) and bis (1H-imidazol-1-yl) methanone 1k (5.38 g,33.15 mmol) were added and reacted at 25℃for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, 30mL of water was added, the mixture was extracted with methylene chloride (100 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by column chromatography (eluent: C system) to give tert-butyl 4- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-1-yl) azepan-1-carboxylate 3C (2.78 g), yield: 37.84%.
MS m/z(ESI):333.2[M+1]
1 H NMR(400MHz,DMSO-d 6 )δ11.51(s,1H),7.89(d,J＝4.8Hz,1H),7.46(d,J＝8.0Hz,1H),6.98(t,J＝6.4Hz,1H),4.33-4.21(m,1H),3.57-3.44(m,2H),3.33-3.23(m,2H),2.30-2.13(m,2H),1.81(br s,3H),1.65(br s,1H),1.43(d,J＝4.8Hz,9H).
Third step
1- (azepan-4-yl) -1, 3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one
Tert-butyl 4- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-1-yl) azepan-1-carboxylate 3c (0.2 g, 600. Mu. Mol) is dissolved in ethyl acetate solution of hydrochloric acid (6 mL), reacted at 15℃for 12 hours, and after completion of the reaction concentrated under reduced pressure to give 1- (azepan-4-yl) -1, 3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one 3d (139 mg), yield: 99.4% and the next reaction was carried out without purification.
MS m/z(ESI):233.0[M+1]
Fourth step
1- (1- (1H-imidazole-1-carbonyl) azepan-4-yl) -1, 3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one
Di (1H-imidazol-1-yl) methanone 1k (145.94 mg, 900. Mu. Mol) and N, N-diisopropylethylamine (155.09 mg,1.20 mmol) were added to 5mL of tetrahydrofuran, 1- (azepan-4-yl) -1, 3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one 3d (139 mg, 596. Mu. Mol) was added, and after the completion of the reaction, the reaction was reacted for 3 hours at 40℃and concentrated under reduced pressure to give 1- (1- (1H-imidazole-1-carbonyl) azepan-4-yl) -1, 3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one 3e (195 mg), yield: 34%, without purification, the next reaction was directly carried out.
MS m/z(ESI):327.1[M+1]
Fifth step
(5S, 6S, 9R) -5- ((tert-Butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl
-4- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-1-yl) azepane-1-carboxylic acid ester
Tert-butyl ((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-yl) carbamate 1j (179.45 mg, 460. Mu. Mol) and 1- (1- (1H-imidazole-1-carbonyl) azepan-4-yl) -1, 3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one 3e (195 mg, 600. Mu. Mol) were dissolved in N, N-dimethylformamide (5 mL), and 1M sodium bis (trimethylsilyl) amide (311.84 mg,1.70 mmol) was added dropwise at-15℃and stirred at 30℃for 3 hours. After the completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution (20 mL), extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined and concentrated under reduced pressure, and the resulting residue was isolated by C18 reverse phase column preparation (eluent: B system) to give (5S, 6S, 9R) -5- ((tert-butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl-4- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-B ] pyridin-1-yl) azepan-1-carboxylate 3f (146 mg), yield: 48.76%.
MS m/z(ESI):649.3[M+1]
Sixth step (5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl-4- (2-oxo-2, 3-dihydro)
-1H-imidazo [4,5-b ] pyridin-1-yl) azepane-1-carboxylic acid ester
(5S, 6S, 9R) -5- ((tert-Butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl-4- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-b ] pyridin-1-yl) azepane-1-carboxylate 3f (146 mg, 230. Mu. Mol) is dissolved in dioxane hydrochloride solution (8 mL) and stirred at 15℃for 12 hours. After the reaction was completed, the resulting residue was concentrated under reduced pressure and separated by a C18 reverse phase column preparation (eluent: B system) to give (5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl-4- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-B ] pyridin-1-yl) azepane-1-carboxylate 3 (69.40 mg), yield: 56.21%.
MS m/z(ESI):549.2[M+1]
1 H NMR(400MHz,DMSO-d 6 )δ11.72-11.28(m,1H),8.65-8.38(m,1H),8.10-8.01(m,1H),7.94-7.89(m,1H),7.71-7.48(m,1H),7.42-7.37(m,1H),7.37-7.29(m,2H),7.29-7.20(m,1H),7.06-6.80(m,1H),6.14-5.98(m,1H),4.66-4.33(m,2H),3.90-3.71(m,1H),3.65-3.42(m,2H),3.33-3.24(m,1H),2.93-2.80(m,1H),2.70-2.52(m,1H),2.42-2.11(m,4H),2.03-1.64(m,7H).
Example 4
(5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl-2 ' -oxo-1 ',2' -dihydrospiro
[ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid ester
First step
(3-bromopyridin-2-yl) carbamic acid tert-butyl ester
1M sodium bis (trimethylsilyl) amide (127.9 mL,127.90 mmol) was dissolved in tetrahydrofuran (80 mL), the temperature was reduced to zero degrees Celsius, 3-bromopyridine-2-amine 4a (10 g,58.13 mmol) was added, the reaction was maintained at zero degrees Celsius for 0.5 hours, then di-tert-butyl dicarbonate (16.4 g,75.58 mmol) was dissolved in tetrahydrofuran (20 mL), and the reaction was carried out at zero degrees Celsius for 1 hour. After completion of the reaction, the reaction mixture was poured into an ice saturated aqueous ammonium chloride solution (200 mL), extracted with methylene chloride (200 mL. Times.3), washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the obtained residue was purified by column chromatography (eluent: C system) to give tert-butyl (3-bromopyridin-2-yl) carbamate 4b (13.59 g), yield: 71.4%.
MS m/z(ESI):273.0[M+1]
Second step
4- (2- ((tert-Butoxycarbonyl) amino) pyridin-3-yl) -4-hydroxyazepan-1-carboxylic acid tert-butyl ester
Under the protection of nitrogen, tert-butyl (3-bromopyridin-2-yl) carbamate 4b (3 g,11.02 mmol) was dissolved in tetrahydrofuran (20 mL), the temperature was lowered to-78 ℃, 2.5M of n-butyllithium (13.2 mL,33.08 mmol) was slowly added dropwise, the reaction was carried out at-78 ℃ for 0.5 hour, and then a solution of tert-butyl 4-oxo-azepane-1-carboxylate 3a (7.05 g,33.08 mmol) in tetrahydrofuran (10 mL) was added dropwise, and the reaction was carried out at 20 ℃ for 2 hours. After the reaction was completed, the reaction mixture was quenched with 50mL of saturated aqueous ammonium chloride solution of ice, and concentrated under reduced pressure to give tert-butyl 4c (4.48 g) of 4- (2- ((tert-butoxycarbonyl) amino) pyridin-3-yl) -4-hydroxyazepan-1-carboxylate, yield: 99.6% and the next reaction was carried out without purification.
MS m/z(ESI):408.2[M+1]
Third step
To a solution of tert-butyl 4- (2- ((tert-butoxycarbonyl) amino) pyridin-3-yl) -4-hydroxyazepan-1-carboxylate 4c (4.48 g,10.99 mmol) in tetrahydrofuran (30 mL) was added 1M potassium tert-butoxide solution (16.5 mL,16.48 mmol) and the mixture was reacted at 20℃for 16 hours. After the completion of the reaction, 100mL of methylene chloride and 100mL of water were added, the mixture was washed with a saturated sodium chloride solution and concentrated under reduced pressure, and the obtained residue was purified by column chromatography (eluent: C system) to give tert-butyl 2 '-oxo-1', 2 '-dihydrospiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylate 4d (807.2 mg), yield: 21.9%.
MS m/z(ESI):334.1[M+1]
1 H NMR(400MHz,DMSO-d 6 )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)
Fourth step
Spiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazin ] -2' (1 ' H) -one
2' -oxo-1 ',2' -dihydrospiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid tert-butyl ester 4d (90.00 mg,0.27 mmol) was dissolved in methanol (1 mL), 4M dioxane hydrochloride solution (0.6 mL,2.70 mmol) was added, and the mixture was reacted at 25℃for 16 hours, after the completion of the reaction, the mixture was concentrated under reduced pressure to give spiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -2' (1 ' H) -one 4e (68 mg), yield: 100% of the reaction mixture was directly subjected to the next reaction without purification.
MS m/z(ESI):234.1[M+1]
Fifth step
1- (1H-imidazole-1-carbonyl) spiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazin ] -2' (1 ' H) -one
Spiro [ azepan-4, 4 '-pyrido [2,3-d ] [1,3] oxazine ] -2' (1 'H) -one 4e (68.00 mg,0.25 mmol) was dissolved in N, N-dimethylformamide (1 mL), N-diisopropylethylamine (68.19 mg,0.50 mmol) and bis (1H-imidazol-1-yl) methanone 1k (60.75 mg,0.37 mmol) were added and reacted at 40℃for 3 hours, after the reaction was completed, concentrated under reduced pressure to give 1- (1H-imidazole-1-carbonyl) spiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -2 '(1' H) -one 4f (82.65 mg), yield: 100% of the reaction mixture was directly subjected to the next reaction without purification.
MS m/z(ESI):328.1[M+1]
Sixth step (5S, 6S, 9R) -5- ((tert-Butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl-2 '-oxo-1', 2 '-dihydrospiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid ester
Under nitrogen protection, 1- (1H-imidazole-1-carbonyl) spiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazin ] -2' (1 ' H) -one 4f (82.65 mg,0.25 mmol) was dissolved in N, N-dimethylformamide (2 mL), 1M sodium bis (trimethylsilyl) amide (1.0 mL,1.01 mmol) was slowly added dropwise at-15℃under nitrogen, stirring was continued for 0.5H, a solution of ((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-5-yl) carbamic acid tert-butyl ester 1j (59.1 mg,0.15 mmol) was slowly added to the reaction solution, after the reaction was completed at 20℃for 16H, saturated ammonium chloride solution was added to quench dichloromethane (50X 3 mL), the phase was combined and the saturated aqueous solution was concentrated to give a saturated solution of C (18 mL), which was eluted by a phase (18 mL of the saturated aqueous phase) column was prepared; B system) to give 4g (53.8 mg) of (5S, 6S, 9R) -5- ((tert-butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl-2 ' -oxo-1 ',2' -dihydrospiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid ester, yield: 24.7%.
MS m/z(ESI):650.3[M+1]
Seventh step (5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl-2 ' -oxo-1 ',2' -dihydrospiro
[ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid ester
(5S, 6S, 9R) -5- ((tert-Butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl-2 '-oxo-1', 2 '-dihydrospiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylate 4g (53.8 mg,0.08 mmol) was dissolved in methanol (1 mL) and 4M dilute hydrochloric acid (22.3 mL,0.82 mmol) was added at zero℃and stirred at 20℃for 16H. After the reaction was completed, the resulting residue was concentrated under reduced pressure and separated by C18 reverse phase column preparation (eluent: B system) to give (5 s,6s,9 r) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl-2 '-oxo-1', 2 '-dihydrospiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylate 4 (31.34 mg), yield: 68.8%. MS m/z (ESI): 550.3[ M+1]
1 H NMR(400MHz,DMSO-d 6 )δ10.90-10.77(m,1H),8.49-8.17(m,2H),8.14-7.68(m,2H),7.54-7.02(m,5H),6.09-5.95(m,1H),4.52-4.50(m,1H),4.09-3.64(m,3H),3.29-2.86(m,3H),2.28-1.71(m,11H).
Example 4-A
(5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl- (R) -2 '-oxo-1', 2 '-dihydrospiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid ester 4-A
Example 4-B
(5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl- (S) -2 '-oxo-1', 2 '-dihydrospiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid ester 4-B
First step
(R) -2 '-oxo-1', 2 '-dihydro-spiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid tert-butyl ester 4d-A
(S) -2 '-oxo-1', 2 '-dihydro-spiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid tert-butyl ester 4d-B
Tert-butyl 2 '-oxo-1', 2 '-dihydrospiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylate 4d (0.918 mg,2.75 mmol) was purified by chiral resolution of SFC (column type: waters SFC-150, dnicel IG, 20X 250mm,10 μm; mobile phase: A for CO2 and B for Ethanol; detection wavelength: 214nm; column temperature: 40 ℃ C.) to give single configuration compounds (shorter retention time) and single configuration compounds (longer retention time).
Single configuration compounds (shorter retention time):
400mg, yield: 43.6%, retention time 1.612 min, chiral purity 100% ee.
MS m/z(ESI):334.2[M+1]
Single configuration compounds (longer retention time):
410mg, yield: 44.7%, retention time 2.030 minutes, chiral purity 99.1% ee.
MS m/z(ESI):334.2[M+1]
Second step
(R) -spiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazin ] -2' (1 ' H) -one
(S) -spiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazin ] -2' (1 ' H) -one
The chiral resolution of (R) -2' -oxo-1 ',2' -dihydrospiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid tert-butyl ester 4d-A (100 mg, 299.96. Mu. Mol) or (S) -2' -oxo-1 ',2' -dihydrospiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid tert-butyl ester 4d-B (100 mg, 299.96. Mu. Mol) was dissolved in 4M dioxane hydrochloride solution (2 mL), reacted at 30℃for 3 hours, after the reaction was completed, concentrated under reduced pressure to give (R) -spiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -2' (1 ' H) -ketone 4e-A (100 mg), yield: 100%, directly carrying out the next reaction without purification; (S) -spiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazin ] -2' (1 ' h) -one 4e-B (120 mg), yield: 100% of the reaction mixture was directly subjected to the next reaction without purification.
MS m/z(ESI):234.1[M+1]
MS m/z(ESI):234.1[M+1]
Third step
(5S, 6S, 9R) -5- ((tert-Butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl
- (R) -2 '-oxo-1', 2 '-dihydro-spiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid ester
(R) -spiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazin ] -2' (1 ' H) -one 4e-A (80 mg, 233.48. Mu. Mol) and N, N-diisopropylethylamine (63.37 mg, 490.30. Mu. Mol) were dissolved in N, N-dimethylformamide (2.6 mL), bis (1H-imidazol-1-yl) methanone 1k (56.79 mg, 350.21. Mu. Mol) was added and stirred at 25℃for 2 hours, after the end of the reaction, reduced to zero degrees Celsius, ((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-yl) carbamic acid tert-butyl ester 1j (72.92 mg, 186.78. Mu. Mol), potassium tert-butoxide solution (1M, 1.40 mL) was added dropwise, stirred at zero degrees Celsius for 30 minutes, stirred at 25℃for 3 hours, and the saturated aqueous solution was concentrated by chromatography (20X) and the extract was concentrated to give a saturated solution, which was eluted by a column chromatography (20X-extraction column chromatography, extraction phase) and concentrated to obtain the residual phase: a system) to give (5S, 6S, 9R) -5- ((tert-butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl- (R) -2' -oxo-1 ',2 '-dihydrospiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid ester 4g-a (110 mg), yield: 65.27%.
MS m/z(ESI):650.3[M+1]
Fourth step (5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl- (R) -2 '-oxo-1', 2 '-dihydrospiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid ester
(5S, 6S, 9R) -5- ((tert-Butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl- (R) -2 '-oxo-1', 2 '-dihydrospiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylate 4g-A (110.00 mg, 169.31. Mu. Mol) was dissolved in 4M dioxane solution (6 mL) of hydrochloric acid, reacted at 25℃for 1 hour, after which the reaction was completed, the pH was adjusted to weak base with a small amount of N, N-diisopropylethylamine and acetonitrile, and the resulting residue was isolated via a C18 reverse phase column (eluent: B system) to give (5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl- (R) -2 '-oxo-1, 3' -pyrido [2, 3-oxazine ] -1-carboxylate (25 mg, 3-d ] [1, 4-oxazine) and the resulting residue was isolated by reaction of C18 reverse phase column chromatography: 26.75%.
MS m/z(ESI):550.2[M+1]
1 H NMR(400MHz,DMSO-d 6 )δ10.83-10.80(m,1H),8.30-8.28(m,1H),8.22-8.18(m,1H),8.05-8.00(m,1H),7.78-7.48(m,1H),7.40-7.20(m,4H),7.11-7.06(m,1H),6.05-6.01(m,1H),4.49-4.45(m,1H),4.06-3.98(m,1H),3.70-3.62(m,1H),3.30-3.24(m,2H),2.88-2.82(m,1H)2.29-2.06(m,8H),1.77-1.64(m,3H).
Fifth step
(5S, 6S, 9R) -5- ((tert-Butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl
- (S) -2 '-oxo-1', 2 '-dihydro-spiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid ester
Dissolving (S) -spiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazin ] -2' (1 ' H) -one 4e-B (80 mg, 233.48. Mu. Mol) and N, N-diisopropylethylamine (70.91 mg, 548.68. Mu. Mol) in N, N-dimethylformamide (4 mL), adding di (1H-imidazol-1-yl) methanone 1k (63.55 mg, 391.92. Mu. Mol), stirring at 25℃for 2 hours, cooling to zero degrees Celsius after completion of the reaction, adding ((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-5-yl) carbamic acid tert-butyl ester 1j (81.61 mg,209. Mu. Mol), dropping potassium tert-butoxide (1M, 1.6 mL), stirring at zero degrees Celsius for 30 minutes at 25℃for 3 hours, eluting with saturated ammonium chloride (20X, 9R) -6-hydroxy-6, 9-cyclohepta (5H) -7, 9-cyclohepta) carbamic acid tert-butyl carbamate, concentrating to obtain a solution, eluting with saturated ethyl acetate, and purifying the saturated solution (3, 7, 9-oxo-carbonyl) by a chromatography system, and eluting with saturated ethyl acetate (3S, 7-7H-cyclohepta) with saturated ethyl acetate (3-N-methyl acetate) in water, 2 '-dihydrospiro [ azepane-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid ester 4g-B (111 mg), yield: 55.58%.
MS m/z(ESI):650.3[M+1]
Sixth step (5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl- (S) -2 '-oxo-1', 2 '-dihydrospiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylic acid ester
(5S, 6S, 9R) -5- ((tert-Butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl- (S) -2 '-dihydro-spiro [ azepan-4, 4' -pyrido [2,3-d ] [1,3] oxazine ] -1-carboxylate 4g-B (110 mg, 169.31. Mu. Mol) was dissolved in 4M dioxane solution of hydrochloric acid (6 mL), reacted for 1 hour at 25 ℃, after completion of the reaction, the pH was adjusted to weakly alkaline with a small amount of N, N-diisopropylethylamine and acetonitrile, and the resulting residue was isolated via a C18 reverse phase column (eluent: B system) to give (5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl- (S) -2 '-oxo-2' -pyrido [2,3-d ] [1, 86 ] oxazine-4, 57 mg of 1-dihydro-spiro [ B ] [1, 3-oxazine ] (1 mg, 57): 60.09%.
MS m/z(ESI):550.2[M+1]
1 H NMR(400MHz,DMSO-d 6 )δ10.84-10.82(m,1H),8.31-8.29(m,1H),8.24-8.18(m,1H),8.05-8.00(m,1H),7.81-7.74(m,1H),7.41-7.07(m,5H),6.04-6.01(m,1H),4.52-4.47(m,1H),3.92-3.87(m,1H),3.77-3.64(m,2H),3.28-3.22(m,2H),3.03-2.82(m,2H)2.18-2.01(m,7H),1.80-1.66(m,3H).
Example 5
(5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl-4- (2-oxo-1, 2-dihydroquinolin-3-yl) azepane-1-carboxylic acid ester
First step
4- (2-methoxy-2-oxoethylene) azepane-1-carboxylic acid tert-butyl ester
Methyl 2- (dimethoxyphosphoryl) acetate 5a (1.87 g,10.32 mmol) was dissolved in tetrahydrofuran (15 mL), the temperature was reduced to zero degrees centigrade, sodium hydride (518.1 mg,12.95 mmol) was added in portions, the reaction was carried out at zero degrees centigrade for 0.5 hours, then a solution of t-butyl 4-oxo-azepane-1-carboxylate 3a (2.00 g,9.38 mmol) in tetrahydrofuran (5 mL) was added at zero degrees centigrade, the reaction was carried out at 25℃for 16 hours, after the completion of the reaction, the reaction solution was poured into an ice saturated aqueous ammonium chloride solution (100 mL), extracted with methylene chloride (100 mL. Times.3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and the resulting residue was purified by column chromatography (eluent: C system) to give t-butyl 4- (2-methoxy-2-oxoethylene) azepane-1-carboxylate 5b (1.81 g), yield: 71.4%.
MS m/z(ESI):292.1[M+23]
Second step
4- (2-methoxy-2-oxoethyl) azepane-1-carboxylic acid tert-butyl ester
4- (2-methoxy-2-oxoethylene) azepane-1-carboxylic acid tert-butyl ester 5b (1.89 g,7.02 mmol) was dissolved in methanol (20 mL), 10% palladium on carbon (189 mg) was added, the reaction was carried out at 25℃for 16 hours under nitrogen, after the completion of the reaction, filtration and three rinsing with methanol were carried out, and the filtrate was concentrated under reduced pressure to give 4- (2-methoxy-2-oxoethyl) azepane-1-carboxylic acid tert-butyl ester 5c (1.76 g), yield: 92.6% of the reaction mixture was directly subjected to the next reaction without purification.
MS m/z(ESI):294.1[M+23]
Third step
4- (1-hydroxy-3-methoxy-1- (2-nitrophenyl) -3-oxopropan-2-yl) azepan-1-carboxylic acid tert-butyl ester
Tert-butyl 4- (2-methoxy-2-oxoethyl) azepane-1-carboxylate 5c (1.76 g,6.49 mmol) was dissolved in tetrahydrofuran (17 mL), cooled to-78℃and 2M lithium diisopropylamide solution (4.2 mL,8.43 mmol) was added dropwise and reacted at-78℃for 0.5 h, and 2-nitrobenzaldehyde 5d (1.66 g,11.03 mmol) in tetrahydrofuran (5 mL) was added dropwise at-78 ℃. After the reaction was completed, the reaction mixture was quenched with ice saturated aqueous ammonium chloride (100 mL), extracted with methylene chloride (100 mL. Times.3), the combined organic phases were washed with saturated aqueous sodium chloride (100 mL), and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (eluent: C system) to give tert-butyl 4- (1-hydroxy-3-methoxy-1- (2-nitrophenyl) -3-oxopropan-2-yl) azepane-1-carboxylate 5e (2.38 g), yield: 85.0%.
MS m/z(ESI):445.3[M+23]
Fourth step
4- (4-hydroxy-2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) azepane-1-carboxylic acid tert-butyl ester
4- (1-hydroxy-3-methoxy-1- (2-nitrophenyl) -3-oxopropan-2-yl) azepan-1-carboxylic acid tert-butyl ester 5e (2.38 g,6.6 mmol) was dissolved in methanol (30 mL) under nitrogen protection, 10% palladium on carbon (189.5 mg) was added, the reaction was reacted at 25℃for 16 hours, after the completion of the reaction, the reaction solution was filtered, washed three times with methanol, concentrated under reduced pressure, acetic acid (25 mL) was added, reacted at 80℃for 2 hours, after the completion of the reaction, concentrated under reduced pressure to give 4- (4-hydroxy-2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) azepan-1-carboxylic acid tert-butyl ester 5f (3.22 g), yield: 100% of the reaction mixture was directly subjected to the next reaction without purification. MS m/z (ESI): 361.2[ M+1]
Fifth step
3- (azepan-4-yl) quinolin-2 (1H) -one
4- (4-hydroxy-2-oxo-1, 2,3, 4-tetrahydroquinolin-3-yl) azepan-1-carboxylic acid tert-butyl ester 5f (3.22 g,8.94 mmol) was dissolved in methanol (30 mL), 4M diluted hydrochloric acid (22.3 mL,89.44 mmol) was added at zero degrees Celsius, stirred at 25 degrees Celsius for 16 hours, after completion of the reaction acetonitrile was added to slurry (15 mL), and filtered to give 3- (azepan-4-yl) quinolin-2 (1H) -one 5g (1.42 g), yield: 88%.
MS m/z(ESI):243.1[M+1]
1 H NMR(400MHz,DMSO-d 6 )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).
Sixth step
3- (1- (1H-imidazole-1-carbonyl) azepan-4-yl) quinolin-2 (1H) -one
5g (90.3 mg,0.29 mmol) of 3- (azepan-4-yl) quinolin-2 (1H) -one was dissolved in N, N-dimethylformamide (1 mL), N-diisopropylethylamine (74.87 mg,0.58 mmol) and 1k (70.4 mg,0.43 mmol) of bis (1H-imidazol-1-yl) methanone were added and reacted at 40℃for 3 hours, after which the reaction was completed, concentrated under reduced pressure to give 3- (1- (1H-imidazole-1-carbonyl) azepan-4-yl) quinolin-2 (1H) -one 5H (109.2 mg), yield: 100% of the reaction mixture was directly subjected to the next reaction without purification.
MS m/z(ESI):337.2[M+1]
Seventh step
(5S, 6S, 9R) -5- ((tert-Butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl
-4- (2-oxo-1, 2-dihydroquinolin-3-yl) azepane-1-carboxylic acid ester
Tert-butyl ((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-5-yl) carbamate 1j (100 mg,0.25 mmol) is dissolved in N, N-dimethylformamide (1 mL), 1M sodium bis (trimethylsilyl) amide (1.0 mL,1.16 mmol) is added dropwise at-15℃under nitrogen, stirring is continued for 0.5H, 3- (1- (1H-imidazole-1-carbonyl) azepan-4-yl) quinolin-2 (1H) -one 5H (109.2 mg,1.02 mmol) is added, the reaction is quenched at 25℃for 16H by pouring the reaction solution into saturated aqueous ammonium chloride solution, the combined organic phases are extracted with dichloromethane (50 mL. Times.3), washed with saturated sodium chloride solution (50 mL) and concentrated under reduced pressure to give the eluent (18) as the reverse phase, the prepared column is eluted: B system) to give (5 s,6s,9 r) -5- ((tert-butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl-4- (2-oxo-1, 2-dihydroquinolin-3-yl) azepane-1-carboxylate 5i (134.1 mg), yield: 79.4%.
MS m/z(ESI):659.3[M+1]
Eighth step (5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl-4- (2-oxo-1, 2-dihydroquinolin-3-yl) azepane-1-carboxylic acid ester
(5S, 6S, 9R) -5- ((tert-Butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl-4- (2-oxo-1, 2-dihydroquinolin-3-yl) azepan-1-carboxylate 5i (3.22 g,8.94 mmol) was dissolved in methanol (30 mL) and 4M dilute hydrochloric acid (22.3 mL,89.44 mmol) was added at zero degrees Celsius and stirred at 25℃for 16 hours. After the reaction was completed, the resulting residue was concentrated under reduced pressure and separated by a C18 reverse phase column preparation (eluent: B system) to give (5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl-4- (2-oxo-1, 2-dihydroquinolin-3-yl) azepan-1-carboxylate 5 (58.9 mg), yield: 51.8%.
MS m/z(ESI):559.3[M+1]
1 H NMR(400MHz,DMSO-d 6 )δ11.79-11.78(m,1H),8.52-8.36(m,1H),8.08-7.96(m,1H),7.80-7.61(m,2H),7.44-7.13(m,7H),6.07-5.98(m,1H),4.48(m,1H),3.87-3.47(m,3H),3.19-2.80(m,3H),2.34-2.05(m,3H),1.97-1.62(m,9H).
Example 6
(5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl-2 ' -oxo-1 ',2' -dihydrospiro
[ azepane-4, 3' -pyrrolo [2,3-b ] pyridine ] -1-carboxylic acid ester
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First step
3- (benzyl (2-ethoxy-2-oxoethyl) amino) propionic acid methyl ester
Methyl 3- (benzylamino) propionate 6a (8 g,41.43 mmol) and sodium carbonate (6.88 g,41.43 mmol) were dissolved in tetrahydrofuran (90 mL), ethyl 2-bromoacetate 6b (6.88 g,41.43 mmol) was added, the reaction was carried out at 45℃for 14 hours, after the completion of the reaction, the residue was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (eluent: C system) to give methyl 3- (benzyl (2-ethoxy-2-oxoethyl) amino) propionate 6C (11.45 g), yield: 99%.
MS m/z(ESI):280.1[M+1]
Second step
3- (benzyl (2-hydroxyethyl) amino) propan-1-ol
Methyl 3- (benzyl (2-ethoxy-2-oxoethyl) amino) propionate 6c (5.0 g,17.91 mmol) was dissolved in tetrahydrofuran (90 mL), a 1M solution of lithium aluminum hydride in tetrahydrofuran (37.61 mL,37.61 mmol) was added dropwise at zero℃and reacted at 25℃for 12 hours, after the completion of the reaction, 1mL of water and 1mL of sodium hydroxide solution were added to the reaction solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3- (benzyl (2-hydroxyethyl) amino) propan-1-ol 6d (3.40 g), yield: 93.3%, and the next reaction was directly carried out without purification.
MS m/z(ESI):210.2[M+1]
Third step
N-benzyl-3-chloro-N- (2-chloroethyl) propan-1-amine
3- (benzyl (2-hydroxyethyl) amino) propan-1-ol 6d (3.0 g,14.34 mmol) was dissolved in chloroform (20 mL), 1M thionyl chloride (30 mL) was added, stirred at 80℃for 4 hours, and concentrated under reduced pressure to give N-benzyl-3-chloro-N- (2-chloroethyl) propan-1-amine 6e (3.20 g), yield: 94% of the reaction mixture was directly subjected to the next reaction without purification.
MS m/z(ESI):246.0[M+1]
Fourth step
1-benzyl-1 '- ((2- (trimethylsilyl) ethoxy) methyl) spiro [ azepane-4, 3' -pyrrolo [2,3-b ] pyridine ] -2 '(1' H) the process for preparing the same
Ketone compounds
1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 3-dihydro-2H-pyrrolo [2,3-b ] pyridin-2-one 1f (1.29 g,4.90 mmol), cesium carbonate (4.79 g,14.70 mmol) and sodium iodide (367.26 mg,2.45 mmol) were dissolved in N, N-dimethylformamide (18 mL), stirred for 15 min at 25℃N-benzyl-3-chloro-N- (2-chloroethyl) propan-1-amine 6e (1.8 g,7.34 mmol), stirred at 60℃for 6H, after completion of the reaction, extracted with saturated sodium chloride solution and ethyl acetate, the organic phases were combined, and the resulting residue was purified by column chromatography (eluent: C system) to give 1-benzyl-1 ' - ((2- (trimethylsilyl) ethoxy) methyl) spiro [ azepan-4, 3' -pyrrolo [2,3-b ] pyridin ] -2' H) -one (600 mg), yield: 28%.
MS m/z(ESI):438.2[M+1]
Fifth step
1-Benzylpro [ azepan-4, 3' -pyrrolo [2,3-b ] pyridin-2 ' (1 ' H) -one
1-benzyl-1 ' - ((2- (trimethylsilyl) ethoxy) methyl) spiro [ azepane-4, 3' -pyrrolo [2,3-B ] pyridin ] -2' (1 ' H) -one 6f (0.60 g,1.37 mmol) was dissolved in ethyl acetate hydrochloride (12 mL) and methanol (12 mL), reacted at 90℃for 12 hours, after the end of the reaction, the resulting residue was concentrated under reduced pressure and isolated by C18 reverse phase column preparation (eluent: B system) to give 1-benzyl spiro [ azepane-4, 3' -pyrrolo [2,3-B ] pyridin ] -2' (1 ' H) -one 6g (200 mg), yield: 47.4%. MS m/z (ESI): 308.1[ M+1]
Sixth step
Spiro [ azepan-4, 3' -pyrrolo [2,3-b ] pyridin ] -2' (1 ' H) -one
1-Benzylpro [ azepan-4, 3 '-pyrrolo [2,3-B ] pyridin ] -2' (1 'H) -one 6g (200 mg,0.65 mmol) was dissolved in dichloroethane (15 mL) under nitrogen protection, chloroethyl 1-chloroformate (1.86 g,13.03 mmol) was added, stirred at 70℃for 18 hours, concentrated under reduced pressure, methanol (15 mL) was added, stirred at 90℃for 2 hours, and after completion of the reaction the resulting residue was isolated by C18 reverse phase column preparation (eluent: B system) to give spiro [ azepan-4, 3' -pyrrolo [2,3-B ] pyridin ] -2 '(1' H) -one 6h (30 mg), yield: 21.28%.
MS m/z(ESI):218.0[M+1]
1 H NMR(400MHz,CDCl 3 )δ11.09(s,1H),9.5(s,1H),8.09(d,J＝5.2Hz,1H),7.85(d,J＝7.2Hz,1H),7.03(dd,J＝6.0,5.6Hz,1H),3.48(m,2H),3.20(s,2H),2.25-1.99(m,6H).
Seventh step
1- (1H-imidazole-1-carbonyl) spiro [ azepane-4, 3' -pyrrolo [2,3-b ] pyridin ] -2' (1 ' H) -one
Di (1H-imidazol-1-yl) methanone 1k (50.37 mg, 310.70. Mu. Mol) and N, N-diisopropylethylamine (26.77 mg, 207.10. Mu. Mol) were added to tetrahydrofuran (5 mL), stirred at 40℃for 10 minutes, spiro [ azepan-4, 3 '-pyrrolo [2,3-b ] pyridine ] -2' (1 'H) -one (45 mg, 206.42. Mu. Mol) was added thereto, reacted at 40℃for 3 hours, and after the completion of the reaction, concentrated under reduced pressure to give 1- (1H-imidazole-1-carbonyl) spiro [ azepan-4, 3' -pyrrolo [2,3-b ] pyridine ] -2 '(1' H) -one 6i, which was directly subjected to the next reaction without purification.
Eighth step (5S, 6S, 9R) -5- ((tert-Butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl-2' -)
Oxo-1 ',2' -dihydro-spiro [ azepane-4, 3' -pyrrolo [2,3-b ] pyridine ] -1-carboxylic acid ester
The above concentrate of 1- (1H-imidazole-1-carbonyl) spiro [ azepan-4, 3' -pyrrolo [2,3-B ] pyridin ] -2' (1 ' H) -one 6i was dissolved in N, N-dimethylformamide (5 mL), 1M sodium bis (trimethylsilyl) amide (140.52 mg, 766.30. Mu. Mol) was added at-15 ℃, stirred at 30℃for 3 hours, quenched with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, and the residue obtained was concentrated under reduced pressure, and isolated via a C18 reverse phase column (eluent: B) to give (5S, 6S, 9R) -5-tert-butoxycarbonyl) -6- (trimethylsilyl) amino sodium (140.52 mg, 766.30. Mu. Mol), and the resulting residue was isolated (5 mL) of 1M bis (trimethylsilyl) amino sodium (140.52 mg, 766.30. Mu. Mol), and the resulting residue was concentrated under reduced pressure to give (5S, 6S, 9R) -6- (2, 9R) -9-hydroxy-6- (2, 9-cycloheptyl) amino [ 5-yl ] pyridine-5-yl) carbamate (5 mL), and the following 3M sodium bis (trimethylsilyl) amide (140.52 mg, 766.30. Mu. Mol) was stirred at-3℃for 3 hours, and the reaction was completed: 49.53%.
MS m/z(ESI):634.4[M+1]
Ninth step (5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl-2 ' -oxo-1 ',2' -dihydro-spiro
[ azepane-4, 3' -pyrrolo [2,3-b ] pyridine ] -1-carboxylic acid ester
(5S, 6S, 9R) -5- ((tert-Butoxycarbonyl) amino) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl-2 '-oxo-1', 2 '-dihydrospiro [ azepan-4, 3' -pyrrolo [2,3-B ] pyridine ] -1-carboxylate 6j (65 mg, 102.60. Mu. Mol) was dissolved in dioxane hydrochloride solution (4 mL), stirred at 15℃for 12 hours, after the reaction was completed, the resulting residue was concentrated under reduced pressure and the resulting residue was subjected to C18 reverse phase column to prepare a separate (eluent: B system) to give (5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl-2 '-oxo-1', 2 '-dihydrospiro [ azepan-4, 3' -pyrrolo [2,3-B ] pyridine ] -1-carboxylate (9 mg) yield (9.22 mg): 16.84%.
MS m/z(ESI):534.3[M+1]
1 H NMR(400MHz,DMSO-d 6 )δ11.08-10.92(m,1H),8.56-8.36(m,1H),8.13-7.94(m,2H),7.85-7.69(m,1H),7.45-7.20(m,4H),7.06-6.82(m,1H),6.11-6.01(m,1H),4.61-4.49(m,1H),4.12-3.42(m,4H),2.96-2.83(m,1H),2.18-2.01(m,4H),1.85-1.64(m,4H).
Example 7-A
1- ((R) -3- (((5 s,6s, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl) oxy)
Phenyl) -5,6,7, 8-tetrahydro-4H-cyclohepta [ d ] isoxazol-6-yl) -1, 3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one 7-A
Example 7-B
1- ((S) -3- (((5S, 6S,9 r) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl) oxy)
Phenyl) -5,6,7, 8-tetrahydro-4H-cyclohepta [ d ] isoxazol-6-yl) -1, 3-dihydro-2H-imidazo [4,5-B ] pyridin-2-one 7-B
First step
9-oxo-1, 4-dioxaspiro [4.6] undecane-8-carboxylic acid ethyl ester
1, 4-Dioxaspiro [4.5] decan-8-one 7a (500 mg,3.20 mmol) was dissolved in tetrahydrofuran (5 mL) under nitrogen protection, the temperature was lowered to-20℃and boron trifluoride tetrahydrofuran solution (337.43 mg,4.96 mmol) was slowly added thereto, followed by reaction at-20℃for 1 hour, stirring at 20℃for 1 hour, adding potassium carbonate solution to adjust pH=6, extraction with ethyl acetate (100 mL. Times.3), merging the organic phases, and concentration under reduced pressure, and the resulting residue was purified by column chromatography (eluent: A system) to give ethyl 9-oxo-1, 4-dioxaspiro [4.6] undecane-8-carboxylate 7b (480 mg), yield: 58.79%.
MS m/z(ESI):243.1[M+1]
Second step
N-hydroxy-9-oxo-1, 4-dioxaspiro [4.6] undecane-8-carboxamide
Ethyl 9-oxo-1, 4-dioxaspiro [4.6] undecane-8-carboxylate 7b (380 mg,1.57 mmol) was dissolved in methanol (2 mL), the temperature was lowered to-70 ℃, a mixed solution of sodium hydroxide (65.88 mg,1.65 mmol) was slowly added dropwise (2.4 mL), a mixed solution of hydroxylamine hydrochloride (103.62 mg,3.14 mmol) and sodium hydroxide (131.76 mg,3.29 mmol) was added dropwise (4.8 mL), stirring was carried out at zero℃for 2 hours, pH=3 was adjusted with 1M dilute hydrochloric acid, extraction (100 mL. Times.3) was carried out with ethyl acetate, the organic phases were combined, and concentrated under reduced pressure to give N-hydroxy-9-oxo-1, 4-dioxaspiro [4.6] undecane-8-carboxamide 7c, which was directly subjected to the next reaction without purification.
Third step
3-hydroxy-4, 5,7, 8-tetrahydro-6H-cyclohepta [ d ] isoxazol-6-one
The above concentrated solution of N-hydroxy-9-oxo-1, 4-dioxaspiro [4.6] undecane-8-carboxamide 7c and 3mL of trifluoroacetic acid were added to methylene chloride (3 mL), stirred at 25℃for 18 hours, after completion of the reaction, concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (eluent: D system) to give 3-hydroxy-4, 5,7, 8-tetrahydro-6H-cyclohepta [ D ] isoxazol-6-one 7D (120 mg), yield: 42.25%.
MS m/z(ESI):168.1[M+1]
1 H NMR(400MHz,CDCl 3 )δ2.97-2.93(m,2H),2.82-2.75(m,4H),2.66-2.63(m,2H).
Fourth step
((5S, 6S, 9R) -9-chloro-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-yl) carbamic acid tert-butyl ester
Tert-butyl ((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9-hydroxy-6, 7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-yl) carbamate 1j (671.80 mg,2.56 mmol) was dissolved in dichloromethane (20 mL), N-chlorosuccinimide (342.02 mg,2.56 mmol) was added, stirring was carried out at 20℃for 2 hours, and the resulting residue was concentrated under reduced pressure and purified by column chromatography (eluent: A system) to give tert-butyl ((5S, 6S, 9R) -9-chloro-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-yl) carbamate 7e (350 mg), yield: 60.16%.
MS m/z(ESI):409.2[M+1]
Fifth step ((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9- ((6-oxo-5, 6,7, 8-tetrahydro-4H-cyclohepta [ d ] isoxazol-3-yl) oxy) -6,7,8,9 ]
tetrahydro-5H-cyclohepta [ b ] pyridin-5-yl) carbamic acid tert-butyl ester
3-hydroxy-4, 5,7, 8-tetrahydro-6H-cyclohepta [ d ] isoxazol-6-one 7d (100 mg, 598.22. Mu. Mol) and ((5S, 6S, 9R) -9-chloro-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-yl) carbamic acid tert-butyl ester 7e (293.51 mg, 717.87. Mu. Mol) were dissolved in N, N-dimethylformamide (7 mL), potassium carbonate (90.81 mg, 658.05. Mu. Mol) was added, stirred at 80℃for 6 hours, water (25 mL) and ethyl acetate (50 mL) were added, the organic phases were combined and concentrated under reduced pressure to give a residue which was purified by column chromatography (eluent: A system) to give ((5S, 6S, 9R) -6- ((2, 3-difluorophenyl) -9- ((6-oxo-5, 8, 7-tetrahydro-6-7H-cyclohepta [ 7, 8-7-H-oxazol-6-one [ b ] pyridin-5-yl), and (220 mg, 7-H-7-yl) carbamic acid tert-butyl ester: 61.34%.
MS m/z(ESI):540.4[M+1]
Sixth step
((5S, 6S, 9R) -9- (((R) -6- ((2-aminopyridin-3-yl) amino) -5,6,7, 8-tetrahydro-4H-cyclohepta [ d ] isoxazol-3-yl) oxy)
Tert-butyl-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-yl) carbamate 7g-A ((5S, 6S, 9R) -9- (((S) -6- ((2-aminopyridin-3-yl) amino) -5,6,7, 8-tetrahydro-4H-cyclohepta [ d ] isoxazol-3-yl) oxy
7g-B of tert-butyl-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-5-yl) carbamate
Under nitrogen protection, tert-butyl ((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9- ((6-oxo-5, 6,7, 8-tetrahydro-4H-cyclohepta [ d ] isoxazol-3-yl) oxy) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-yl) carbamate 7f (180 mg, 333.60. Mu. Mol) and pyridine-2, 3-diamine 2a (36.41 mg, 333.60. Mu. Mol) were dissolved in dichloroethane (4 mL), tetraisopropyl titanate (94.81 mg, 333.60. Mu. Mol) and trifluoroacetic acid (76.07 mg, 667.20. Mu. Mol) were added, respectively, sodium triacetoxyborohydride (106.08 mg, 500.40. Mu. Mol) was added at 40℃for 18 hours with stirring at 40℃for 5 hours, saturated solution quenching (30 mL), ethyl acetate extraction (50 mL. Times 3) and the combined organic phase was concentrated to give a chromatography column (eluent: a system) to give 7g-a (55 mg) of tert-butyl ((5 s,6s, 9R) -9- (((R) -6- ((2-aminopyridin-3-yl) amino) -5,6,7, 8-tetrahydro-4H-cycloheptyl [ d ] isoxazol-3-yl) oxy) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-yl) carbamate, yield: 23.45% and ((5S, 6S,9 r) -9- (((S) -6- ((2-aminopyridin-3-yl) amino) -5,6,7, 8-tetrahydro-4H-cycloheptyl [ d ] isoxazol-3-yl) oxy) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-5-yl) carbamic acid tert-butyl ester 7g-B (69 mg), yield: 29.42%.
MS m/z(ESI):632.9[M+1]
MS m/z(ESI):632.9[M+1]
Seventh step
((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9- (((R) -6- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-b ] pyridine-1 ]
Phenyl) -5,6,7, 8-tetrahydro-4H-cyclohepta [ d ] isoxazol-3-yl) oxy) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-yl) carbamic acid tert-butyl ester
7g of ((5S, 6S, 9R) -9- (((R) -6- ((2-aminopyridin-3-yl) amino) -5,6,7, 8-tetrahydro-4H-cycloheptyl [ d ] isoxazol-3-yl) oxy) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-yl) carbamic acid tert-butyl ester 7g-A (27 mg, 42.67. Mu. Mol) and N, N-diisopropylethylamine (16.55 mg, 128.02. Mu. Mol) were dissolved in tetrahydrofuran, bis (1H-imidazol-1-yl) methanone 1k (10.38 mg, 64.01. Mu. Mol) was added, and the resulting residue was stirred for 18 hours at 45℃and was purified by column chromatography to give ((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9- (((R) -6- (2-oxo-2, 3-dihydro-1-yl) methanone [ 1k (10.38 mg, 64.01. Mu. Mol) and N, N-diisopropylethylamine (16.55 mg, 128.02. Mu. Mol) were dissolved in tetrahydrofuran to give ((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9- (. 6- (2-difluoro-2-b-amino) pyridin-5-yl) amino) 1k (7. Mu. Mol) and the residue was obtained by stirring for 18 hours at 45 ℃. 60.48%.
MS m/z(ESI):659.4[M+1]
Eighth step
1- ((R) -3- (((5 s,6s, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl) oxy)
Phenyl) -5,6,7, 8-tetrahydro-4H-cyclohepta [ d ] isoxazol-6-yl) -1, 3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one
Tert-butyl ((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9- (((R) -6- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-B ] pyridin-1-yl) -5,6,7, 8-tetrahydro-4H-cyclohepta [ d ] isoxazol-3-yl) oxy) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-5-yl) carbamate 7H-A (40 mg, 60.73. Mu. Mol) is dissolved in dioxane hydrochloride solution (6 mL), stirred at 25℃for 3 hours, after the reaction is completed, concentrated under reduced pressure, and the resulting residue is subjected to C18 reverse phase column preparation isolation (eluent: B system) to give 1- ((R) -3- ((5S, 6S, 9R) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-pyridin-5-yl) 1- ([ 2, 3-diisopropylethylamine) pH=8, to give 1- ((R) -3- ([ 5S,6, 9-dihydro-5-B ] pyridin-yl) 1, 6, 9-dihydro-7H-imidazo [4,5-B ] pyridin-yl), and the resulting residue is isolated by C18 reverse phase column preparation (eluent: B system: 46.75%.
MS m/z(ESI):559.3[M+1]
1 H NMR(400MHz,CD 3 OD)δ8.39(dd,J＝4.8,1.6Hz,1H),8.01(d,J＝7.6Hz,1H),7.93(dd,J＝5.2,1.2Hz,1H),7.60(dd,J＝8.0,1.2Hz,1H),7.41(dd,J＝7.6,4.8Hz,1H),7.27-7.16(m,3H),7.05(dd,J＝8.0,5.2Hz,1H),6.07(dd,J＝9.6,4.0Hz,1H),4.68(d,J＝9.6Hz,1H),4.50(t,J＝11.2Hz,1H),3.13-2.98(m,2H),2.92-2.82(m,2H),2.61-2.32(m,4H),2.17-2.07(m,3H),1.96-1.84(m,2H).
Ninth step
((5S, 6S, 9R) -6- (2, 3-difluorophenyl) -9- (((S) -6- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-b ] pyridine-1 ]
Phenyl) -5,6,7, 8-tetrahydro-4H-cyclohepta [ d ] isoxazol-3-yl) oxy) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-5-yl) carbamic acid
Tert-butyl ester
7g of ((5S, 6S, 9R) -9- (((S) -6- ((2-aminopyridin-3-yl) amino) -5,6,7, 8-tetrahydro-4H-cycloheptyl [ d ] isoxazol-3-yl) oxy) -6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-5-yl) carbamic acid tert-butyl ester 7g-B (69.00 mg, 109.06. Mu. Mol) and N, N-diisopropylethylamine (42.28 mg, 327.17. Mu. Mol) were dissolved in tetrahydrofuran (2 mL), bis (1H-imidazol-1-yl) methanone 1k (26.53 mg, 163.58. Mu. Mol) was added, and the resulting residue was stirred at 45℃for 18 hours and concentrated under reduced pressure to give ((5S, 6S, 9R) -6- (((2-oxo-2-dihydro-3-imidazol-1-yl) methanone [ 26.53mg, 163.58. Mu. Mol) and N, N-diisopropylethylamine (42.28 mg, 327.17. Mu. Mol) were dissolved in tetrahydrofuran to give a white solid of ((5S, 6S, 9R) -6- (. 6- (2, 3-difluorophenyl) -6- (. 6-difluoro-B) pyridin-5-yl) amino) tert-butyl) which was purified by column chromatography (eluent: A system).
MS m/z(ESI):659.4[M+1]
Tenth step
1- ((S) -3- (((5S, 6S,9 r) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ b ] pyridin-9-yl) oxy)
Phenyl) -5,6,7, 8-tetrahydro-4H-cyclohepta [ d ] isoxazol-6-yl) -1, 3-dihydro-2H-imidazo [4,5-b ] pyridin-2-one
Tert-butyl ((5S, 6S,9 r) -6- (2, 3-difluorophenyl) -9- (((S) -6- (2-oxo-2, 3-dihydro-1H-imidazo [4,5-B ] pyridin-1-yl) -5,6,7, 8-tetrahydro-4H-cyclohepta [ d ] isoxazol-3-yl) oxy) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-5-yl) carbamate 7H-B (55 mg,83.50 μmol) is dissolved in dioxane hydrochloride solution (6 mL), stirred for 3 hours at 25 ℃, after the reaction is completed, concentrated under reduced pressure, ph=8 with N, N-diisopropylethylamine and the resulting residue is isolated by C18 reverse phase column preparation (eluent: B system) to give 1- ((S) -3- (((5S, 6S,9 r) -5-amino-6- (2, 3-difluorophenyl) -6,7,8, 9-tetrahydro-5H-cyclohepta [ B ] pyridin-9-yl) oxy) -5,6,7, 8-tetrahydro-4H-cyclohepta [ d ] isoxazol-6-yl) -1, 3-dihydro-2H-imidazo [4,5-B ] pyridin-2-one 7-B (16 mg), yield: 33.20%.
MS m/z(ESI):559.4[M+1]
1 H NMR(400MHz,CD 3 OD)δ8.40(dd,J＝4.8,1.6Hz,1H),8.05(d,J＝7.6Hz,1H),7.93(dd,J＝5.6,1.2Hz,1H),7.62(dd,J＝8.0,1.2Hz,1H),7.41(dd,J＝8.0,5.2Hz,1H),7.62-7.15(m,3H),7.05(dd,J＝8.0,5.6Hz,1H),6.07(dd,J＝9.6,4.0Hz,1H),4.63(d,J＝9.2Hz,1H),4.52(t,J＝10.4Hz,1H),3.05-2.82(m,4H),2.51-2.31(m,4H),2.18-2.07(m,3H),1.94-1.86(m,2H).
Biological evaluation
Test example 1 determination of the inhibitory Effect of Compounds of the present application on CGRP Signal pathway in SK-N-MC cells
The inhibition of CGRP signaling pathway in vitro is evaluated by measuring cAMP levels, the principle being that upon binding of CGRP to CGRP receptor, activation of CGRP signaling pathway induces an increase in cAMP levels, whereby a decrease in cAMP levels is indicative of inhibition of CGRP signaling pathway, as follows:
cAMP assay was performed using the CAMP-GSDYNAMIC KIT detection kit (Cisbio, 62AM4 PEB).
SK-N-MC (ATCC, HTB-10) cells endogenously expressing CGRP receptor were cultured in EMEM+10% FBSIn the basal phase, cells were collected in the logarithmic growth phase. Cells were resuspended in Stimulation Buffer containing 0.5mM IBMX and 5. Mu.L of cell suspension per well was added to a 96 well microplate (Cisbio, 66PL 96025) at a cell density of 15000 cells/well according to the instructions of the kit. 2.5. Mu.L of a gradient of diluted compound solution (highest concentration of 100nM, 3-fold dilution of compound solution, total 11 concentrations) was added to each well, and after incubation at 37℃for 30 minutes, 2.5. Mu.L of 40ng/mL human. Alpha. -CGRP (Bachem, H-1470.0500) diluted in Stimulation Buffer containing 0.5mM IBMX was added to each well, with a final concentration of 10ng/mL, and after incubation at 37℃for 30 minutes, 5. Mu.L of Anti-cAMP-Cryptate solution and 5. Mu.L of cAMP-d2 solution were added to each well. Incubation was performed at room temperature for 60 min, and HTRF signals were read using an enzyme label (Molecular Devices). IC of compounds for inhibition of cAMP level elevation was calculated using Graphpad Prism based on compound concentration and HTRF signal 50 Values.
The biological activity of the compounds of the present application was determined by the above assay, measured in [ alpha-CGRP]IC at 10ng/mL 50 The values are shown in Table 1 below.
TABLE 1 IC for the inhibition of CGRP Signal pathway by Compounds of the present application in SK-N-MC cells 50
Examples numbering IC 50 (μM)
Example 1-A 0.03651
Example 1-B 0.08375
Example 4 0.00751
Compounds of preferred activity in examples 7-A and 7-B 0.01922
Conclusion: the compound has obvious inhibition effect on CGRP signal paths in SK-N-MC cells.

Claims (14)

1. A compound of formula (I) or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof:
wherein:
l is selected from-O-or-O (CO) -;
ring a is selected from a 5 membered heterocyclyl, a 5 membered heteroaryl ring, or a 7 membered heterocyclyl;
R 1 selected from halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl or cyano;
R 2 selected from halogen, alkyl, deuterated alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl or cyano;
R 3 selected from heteroaryl or a fused ring, said heteroaryl or fused ring being optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, =o;
alternatively, two R 3 Together with the atoms to which they are attached form a 5-to 7-membered cycloalkyl or fused ring, said 5-to 7-membered cycloalkyl or fused ring being further substituted with one or more R a Is substituted by a substituent of (2);
each R a Identical or different, each independently selected from =o, heteroaryl or fused ring, wherein said heteroaryl or fused ring is optionally further substituted with one or more groups selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, =O is substituted with a substituent;
alternatively, two R a Together with the atoms to which they are attached, form a fused ring, said fused ring being optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, =o;
n is 0,1,2 or 3;
m is 0,1 or 2;
p is 1,2 or 3.
2. The compound of claim 1, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, which is a compound of formula (II):
wherein: ring A, L, R 3 And p is as defined in claim 1.
3. The compound of claim 2, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, which is a compound of formula (III):
Wherein: ring A, R 3 And p is as defined in claim 1.
4. The compound of claim 2, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, which is a compound of formula (IV):
wherein: ring A, R 3 And p is as defined in claim 1.
5. The compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein ring a is selected from:
6. the compound according to any one of claims 1 to 4, or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R 3 Selected from:
7. a compound according to claim 3, or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, which is a compound according to formula (V):
wherein: r is R a Is defined as in claim 1.
8. The compound of claim 4, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, which is a compound of formula (VI):
Wherein: ring B is selected from a 5-to 7-membered heterocyclyl group, said heterocyclyl group being optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, =o.
9. The compound of claim 4, or a stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, which is a compound of formula (VII):
wherein: ring B is selected from a 5-to 7-membered heterocyclyl group, said heterocyclyl group being optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, =o.
10. A compound according to any one of claims 1 to 9, or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, wherein said compound is:
11. a pharmaceutical composition comprising:
a compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.
12. Use of a compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the preparation of a CGRP receptor antagonist.
13. Use of a compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, deuterated derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the manufacture of a medicament for the prevention and/or treatment of a disease mediated by CGRP, wherein the disease mediated by CGRP is a cerebrovascular or vascular disorder.
14. The use according to claim 13, wherein the CGRP-mediated cerebrovascular or vascular disorders are selected from the group consisting of episodic migraine, non-premonitory migraine, chronic migraine, pure menstrual migraine, menstrual-related migraine, premonitory migraine, childhood/adolescent migraine, hemiplegic migraine, sporadic hemiplegic migraine, basal migraine, periodic vomiting, abdominal migraine, childhood benign paroxysmal vertigo, retinal migraine, cluster headache, dialysis headache, chronic headache of unknown cause, tension/pressure-induced headache, allergy-induced headache, osteoarthritis and associated osteoporotic fracture pain, hot flashes associated with menopause or with medical induced menopause caused by surgery or drug therapy, periodic vomiting syndrome, opioid withdrawal, psoriasis, asthma, obesity morphine tolerance, neurodegenerative diseases, epilepsy, allergic rhinitis, rosacea, toothache, ear pain, otitis media, sunburn, joint pain associated with osteoarthritis and rheumatoid arthritis, cancer pain, fibromyalgia, diabetic neuropathy, gout, trigeminal neuralgia, nasal polyp, chronic sinusitis, temporomandibular syndrome, back pain, lower back pain, cough, dystonia pain, inflammatory pain, post-operative incision pain, sciatica, complex regional pain syndrome, behcet's disease, endometriosis, phantom limb syndrome, dysmenorrhea, pain associated with labor, pain caused by skin burns, or inflammatory bowel disease (including Crohn's disease, ileitis and ulcerative colitis), gastroesophageal reflux disease, dyspepsia, irritable bowel syndrome, renal colic, cystitis, post-operative incision pain, sciatica, complex regional pain syndrome, behcet's disease, endometriosis, phantom limb syndrome, dysmenorrhea, pain associated with labor, pain caused by skin burns, or inflammatory bowel disease (including Crohn's disease, ileitis and ulcerative colitis), chronic secondary visceral pain such as pancreatitis and prostatitis.
CN202310935051.2A 2022-07-29 2023-07-27 Pyridocycloheptane derivative and preparation method and application thereof Pending CN117466893A (en)

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