CN113717161B - Nitrogen-containing saturated heterocyclic compound, preparation method thereof, pharmaceutical composition and application - Google Patents

Nitrogen-containing saturated heterocyclic compound, preparation method thereof, pharmaceutical composition and application Download PDF

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CN113717161B
CN113717161B CN202110556657.6A CN202110556657A CN113717161B CN 113717161 B CN113717161 B CN 113717161B CN 202110556657 A CN202110556657 A CN 202110556657A CN 113717161 B CN113717161 B CN 113717161B
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CN113717161A (en
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邱关鹏
王永钢
邓代国
雷曾荣
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Guangzhou Fermizi Technology Co ltd
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    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
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Abstract

The invention relates to a nitrogen-containing saturated heterocyclic compound with a structure shown in a formula (I), a preparation method, a pharmaceutical composition and application thereof. The nitrogenous saturated heterocyclic compound is a somatostatin receptor subtype 4 (SSTR 4) agonist compound with novel structure, better drug effect, high bioavailability and better solubility.

Description

Nitrogen-containing saturated heterocyclic compound, preparation method thereof, pharmaceutical composition and application
Technical Field
The invention relates to an organic compound, in particular to a nitrogenous saturated heterocyclic compound, a preparation method, a pharmaceutical composition and application thereof.
Background
The somatostatin receptor family (somatostatin receptors, SSTRs) is a family of G protein-coupled receptors that mediate somatostatin and its analogs, with a variety of biological effects, the physiological functions and mechanisms of action of which have long been of interest. Studies have shown that the specific membrane receptors present on these cell membranes, including SSTR1, SSTR2, SSTR3, SSTR4 and SSTR5, can play an important role in regulating Growth Hormone (GH) secretion, inducing apoptosis, inhibiting tumor cell proliferation, inhibiting insulin action and inhibiting cell growth, and at the same time exhibit similar kinetic characteristics to other G-protein coupled receptor properties, through the cAMP, PTP and MAPK signaling pathways.
Somatostatin (SST) is a cyclic polypeptide that is widely distributed in the central nervous system and surrounding tissues and exists in vivo in both 14 peptide (SST-14) and 28 peptide (SST-28). The results of previous studies have shown that SST is mediated as a signaling molecule by a family of SST receptors on the cell membrane, with SST being only 2 forms. The complexity of SST physiological functions is manifested by the complexity of the receptor. Thus, the biological significance of SSTR is somewhat more important than SST. SSTRs have a 7 Transmembrane (TM) alpha helix structure similar to other G protein-coupled receptor structures, with N-glycosylation sites and palmitoylation sites in the N-terminal region (except SSTR 3). In addition, there is a highly conserved amino acid sequence unique to SSTR in TM 7.
SSTRs are coupled to a variety of cellular effector systems via G proteins, and are primarily involved in 4 important signaling pathways: first, cyclic adenosine monophosphate (cAMP) pathway; second, voltage-dependent Ca 2+ A pathway; thirdly, mitogen activated protein kinase (mitogen-activated protein kinases, MAPK) pathway; fourth is the protein tyrosine phosphatase (protein tyrosine phosphatase, PTP) pathway.
SSTR1 is associated with inhibition of cell growth; SSTR3 is involved in inhibiting GH, insulin release, and processing and regulating sensory signals and sensory and visceral functions, olfactory and other sensory functions in addition to inducing apoptosis; SSTR4 also inhibits release of GH and insulin and coordinates extrapyramidal motor and sensory functions; SSTR2 and SSTR5 play a major role in regulating and controlling the growth process of animals, mainly inhibit GH and insulin release, participate in central integration, also participate in mediating anti-proliferation effect of tumors and inducing apoptosis, are dominant subtypes mediating anti-tumor effect, and the results reveal that a close relationship exists between endocrine and immunity.
Among these five receptors, SSTR4 has reached the forefront as a potential mediator of central nervous system pathology, inflammation and even pain mechanisms. Targeting SSTR4 has the additional advantage that it limits secretion of the pituitary but does not inhibit secretion of glucagon, growth hormone or insulin. In the central nervous system, SSTR4 is expressed at relatively high levels in the hippocampus and neocortex, memory and learning areas, and in alzheimer's disease. Recent studies do indicate that SSTR4 agonists improve learning and memory in rodent models of alzheimer's disease, which corresponds to reduced β -amyloid levels. Furthermore, studies have also found that SSTR4 receptor stimulation may enhance clue memory in a dose-dependent manner, potentially with direct cognitive enhancing activity. Other studies have shown that SSTR4 and K + Ion channel binding can modulate hippocampal excitability, which is of instructive interest for SSTR4 agonists to treat certain forms of epilepsy. In addition, SSTR4 agonists act against acute and chronic related peripheral injuriesThe adverse and anti-inflammatory activities are effective in pain models in rodents. Recent research data show that nociceptors expressed by the capsaicin-sensitive receptor TRPV1 release SRIF acts on SSTR4 and SSTR2, producing an antinociceptive effect.
Pain is the most common and most disturbing symptom clinically in patients and is one of the main causes of patient visits. Pain can be classified into acute pain and chronic pain according to the duration of pain. Acute pain includes pain caused by tissue injury and pain caused by post-operative inflammation; chronic pain then includes nociceptive pain, neuropathic pain, visceral pain, and mixed pain. Analgesics, including narcotic analgesics (lidocaine, etc.), opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), which are currently being charged with pain treatment, are well known. Drugs with new mechanisms of action are also added to the analgesic lines, such as antidepressants, anticonvulsants. Although many patients may benefit from existing analgesics, these medications may only provide adequate relief from 1/4 of the patient's symptoms. In addition, the existing medicines generally have the problems of low tolerance, large toxic and side effects, poor long-term safety, potential medicine abuse, inconvenient use and the like, so that patients are in urgent need of safer and more effective analgesic medicines. While SSTR4 agonists are of increasing interest for use in the field of analgesia, the development of novel SSTR4 agonists has broad application prospects and is also urgently needed.
CN105473574a discloses the following compounds of formula (I), which are agonists of SSTR4, useful for the prevention or treatment of medical conditions associated with SSTR 4. However, there remains a broad need in the art for SSTR4 agonists that have good potency, high bioavailability and good solubility.
Figure BDA0003077502510000031
Disclosure of Invention
Based on this, it is necessary to provide a nitrogenous saturated heterocyclic compound, which is a somatostatin receptor subtype 4 (SSTR 4) agonist compound with novel structure, better drug effect, high bioavailability and better solubility.
The specific technical scheme is as follows:
a compound having the structure of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:
Figure BDA0003077502510000032
wherein A is selected from C 6-14 Aryl, 5-to 14-membered heteroaryl, 5-to 14-membered heterocyclyl and 5-to 14-membered cycloalkyl, and the aryl, heteroaryl, heterocyclyl and cycloalkyl groups in a are optionally further substituted with 0 to 5R 3 Substitution; wherein the heteroaryl and heterocyclyl each comprise 1 to 4 heteroatoms selected from N, O and S;
R 3 each independently selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, - (CH) 2 ) m -alkenyl, - (CH) 2 ) m -alkynyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, - (CH) 2 ) m - (3-to 10-membered heterocyclic group), -O- (CH) 2 ) m -C 3-10 Carbocyclyl and-O- (CH) 2 ) m - (3-to 10-membered heterocyclic group) containing 1 to 4 heteroatoms selected from N, O and S, and R 3 The alkyl, alkoxy, carbocycle or heterocycle of said (E) are each independently optionally further substituted with 0 to 4 groups selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 Substituted with alkoxy;
L 1 selected from single bonds or- (CR) a R b ) m-, wherein Ra and Rb Each independently selected from-H and C 1-6 An alkyl group;
L 2 selected from-NH-and-O-;
R 1 and R2 Each independently selected from-H, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein R is 1 and R2 Not simultaneously-H;
or R is 1 and R2 Together form a composition comprising 0 to 1 member selected from the group consisting of-O-, -NR 16 -, -SO-and-SO 2 -a 3 to 6 membered saturated cyclic group of groups;
R 16 selected from-H, C 1-6 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, halogen, hydroxy, cyano and C 3-6 Cycloalkyl;
m is selected from single bond, - (CR) c R d ) m- and -(CRc R d ) mO-, wherein Rc and Rd Each independently selected from-H and C 1-6 An alkyl group;
q is selected from one of the following structures:
Figure BDA0003077502510000041
wherein ,X1 ，X 2 ，X 3 Each independently selected from a single bond and- (CR) e R f ) n -；
X 4 Selected from-CH 2 -、-CH 2 CH 2- and -CH2 CH 2 CH 2 -；
R 4 、R 5 、R 6 、R 7 、R 9 、R 10 、R e 、R f Each independently selected from-H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, - (CH) 2 ) m - (3-to 10-membered heterocyclic group), - (CH) 2 ) m -O-C 3-10 Carbocyclyl, - (CH) 2 ) m -O- (3-to 10-membered heterocyclyl), phenyl and 5-to 6-membered heteroaryl, each containing 1 to 4 heteroatoms selected from N, O and S, and R 4 、R 5 、R 6 、R 7 、R 9 、R 10 、R e 、R f Each of the alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl and heterocycle groups described in (2)From 0 to 4 are optionally further selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 Substituted with alkoxy;
R 8 、R 11 、R 12 、R 13 、R 14 、R 15 each independently selected from-H, C 1-6 Alkyl and C 3-6 Cycloalkyl;
m, n, p, q is independently selected from 0, 1, 2 or 3 for each occurrence;
when X is 1 and X2 When the two are single bonds, R 4 、R 5 、R 6 、R 7 And not simultaneously-H.
The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound as described above or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.
The invention also provides the use of a compound as described above or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition that is affected by SSTR4 activation.
The invention also provides the use of a compound as described above or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment and/or prophylaxis of pain.
Compared with the prior art, the invention has one or more of the following beneficial effects:
the compound provided by the invention has excellent SSTR4 agonism through introducing specific substituent groups into specific sites of a mother nucleus structure or adopting a mother nucleus structure containing specific parallel rings, spiro rings or bridged rings, can be used as an SSTR4 agonist for preventing and/or treating diseases or symptoms influenced by SSTR4 activation, such as Alzheimer's disease and other CNS diseases, such as epilepsy and depression, and can be used for treating pain and/or inflammation from various sources. In addition, experimental study shows that the compound has high metabolic stability and excellent pharmacokinetic property.
Detailed Description
The compounds of the present invention and methods for their preparation, pharmaceutical compositions and uses are described in further detail below in conjunction with the specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art. The terminology used herein in the description is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and/or" as used herein means any and all combinations of one or more of the associated listed items.
The term "alkyl" refers to a saturated straight or branched chain aliphatic hydrocarbon group, specifically a saturated hydrocarbon containing primary (normal) carbon atoms, secondary carbon atoms, tertiary carbon atoms, quaternary carbon atoms, or combinations thereof. Phrases containing this term, e.g., "C 1-6 Alkyl "means an alkyl group containing 1 to 6 carbon atoms, which at each occurrence may be, independently of one another, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 An alkyl group. In one embodiment, an alkyl group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 10 carbon atoms, more preferably a lower alkyl group containing 1 to 4 carbon atoms, may be included. Non-limiting examples include: methyl, ethyl, 1-propyl, 2-propyl (i-Pr, i-propyl, -CH (CH) 3 ) 2 ) 1-butyl (n-Bu, n-butyl, -CH) 2 CH 2 CH 2 CH 3 ) 2-methyl-propan-1-yl (i-Bu, isobutyl, -CH) 2 CH(CH 3 ) 2 ) 2-DingRadicals (s-Bu, sec-butyl, -CH (CH) 3 )CH 2 CH 3 ) 2-methyl-propan-2-yl (t-Bu, t-butyl, -C (CH) 3 ) 3 ) 1-pentyl (n-pentyl, -CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH 3) CH2CH2CH 3), 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-butan-2-yl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-butan-2-yl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-butan-1-yl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-butan-1-yl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) Hex-1-yl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) Hexan-2-yl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) Hexan-3-yl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-pent-2-yl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-pent-2-yl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-pent-2-yl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-pent-3-yl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-pent-3-yl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-butan-2-yl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-butan-2-yl (-CH (CH) 3 )C(CH 3 ) 3 Octyl (- (CH) 2 ) 7 CH 3 ) And n-nonyl, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, cl, br, I, =o, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.
"alkoxy" refers to an-O-alkyl group, wherein alkyl is as defined herein above and is preferably an alkyl group having 1 to 12 carbon atoms. Phrases containing this term, e.g., "C 1-4 Alkoxy "refers to an-O-alkyl group in which the alkyl moiety contains 1 to 4 carbon atoms. At each occurrence, C 1-4 Alkoxy groups may be, independently of one another, C 1 Alkoxy, C 2 Alkoxy, C 3 Alkoxy, C 4 An alkoxy group. Alkoxy groups may be substituted or unsubstituted, non-limiting examples of which include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, or hexoxy. When substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, cl, br, I, =o, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.
"alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group as described above. Examples include "C 1-4 Alkoxy C 1-4 Alkyl "or" C 1-6 Alkoxy C 1-6 An alkyl group. For example, "C 1-4 Alkoxy C 1-4 Alkyl "means C 1-4 Alkoxy substituted C 1-4 Alkyl groups, each occurrence of which may be, independently of one another, C 1 Alkoxy C 1-4 Alkyl, C 2 Alkoxy C 1-4 Alkyl, C 3 Alkoxy C 1-4 Alkyl, C 4 Alkoxy C 1-4 An alkyl group. Alkoxyalkyl groups may be substituted or unsubstituted. Non-limiting examples of alkoxyalkyl groups include methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxymethyl, propoxyethyl, isopropoxymethyl, butoxypropyl, tert-butoxyethyl, pentoxyethyl, hexoxyethyl, cyclopropoxymethyl, cyclopropoxyethyl, cyclopropoxypropyl, or cyclohexyloxymethyl; when substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, cl, br, I, =o, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.
"alkenyl" is an alkyl group as defined herein that contains at least one carbon-carbon double bond. In one embodiment, the alkenyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, and even more preferably 2 to 6 carbon atoms. Non-limiting examples of alkenyl groups include substituted or unsubstituted vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, and the like, when substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, cl, br, I, =o, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, nitro, cyano, and amino.
"alkynyl" is an alkyl group as defined herein that contains at least one carbon-carbon triple bond. In one embodiment, the alkynyl group contains 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, and even more preferably 2-6 carbon atoms. Non-limiting examples of alkynyl groups include substituted or unsubstituted ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-butynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl and the like, and when substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, cl, br, I, =o, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, nitro, cyano and amino groups.
"carbocyclyl" or "cycloalkyl" refers to a saturated or partially unsaturated cyclic carbon-containing group. In one embodiment, carbocyclyl is a 3 to 6 membered monocyclic ring, a 3 to 8 membered monocyclic ring, a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring, or a 10 to 15 membered tricyclic ring system. Carbocycles include bridged or spiro rings. Non-limiting examples of carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentenyl, cyclohexadienyl, cycloheptatrienyl, benzocyclopentyl, bicyclo [3.2.1] octanyl, bicyclo [5.2.0] nonanyl, tricyclo [5.3.1.1] dodecyl, adamantyl, or spiro [3.3] heptanyl, and the like. Carbocyclyl groups may be optionally substituted. When substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, cl, br, I, =o, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.
"heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or partially unsaturated heteroatom-containing cyclic group, the heteroatoms selected from N, O and S. In one embodiment, the heterocyclyl may be a 3 to 8 membered monocyclic, 4 to 12 membered bicyclic or 10 to 15 membered tricyclic ring system, preferably a 3 to 10 membered heterocyclyl, and comprises at least one, preferably 1 to 4 heteroatoms selected from N, O or S. The heteroatom N or S in the heterocycle may be oxidized to various oxidation states to form, for example, an N-oxide. The heterocyclic ring may be attached to other parts of the molecule via a heteroatom or carbon atom. Heterocycles include bridged or spiro rings. Non-limiting examples of heterocycles include oxirane, aziridinyl, oxetanyl, azetidinyl, 1, 3-dioxolane, 1, 4-dioxa-bicyclo, 1, 3-dioxane, azepanyl, pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithiane, dihydrofuran, dihydropyran, dithiolane, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzodihydrofuran, dihydropyridinyl, tetrahydrothienyl, thioxotetrahydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, and the like; when substituted, the substituents are preferably 1 to 5 and are independently selected from F, cl, br, I, =o, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano and amino.
"aryl" refers to a substituted or unsubstituted all-carbon monocyclic or fused polycyclic unsaturated group having a conjugated pi-electron system. In one embodiment, the aryl group is a 6 to 14 membered aromatic ring, preferably a 6 to 10 membered aromatic ring. Non-limiting examples thereof include phenyl or naphthyl; the aryl group may be heteroaryl, heterocyclyl or cycloalkyl fused and the site of attachment to the molecule to which it is attached is on the aryl group. Non-limiting examples of aryl groups include benzofurans, benzocyclopentylalkyl groups, benzothiazoles, and the like. When the aryl group is substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, cl, br, I, =o, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.
"heteroaryl" means a monocyclic or fused polycyclic unsaturated group which is substituted or unsubstituted and contains at least one, preferably 1 to 4 heteroatoms selected from N, O and S. In one embodiment, the heteroaryl is a 5 to 15 membered heteroaryl ring, a 5 to 14 membered heteroaryl ring, or preferably a 5 to 10 membered heteroaryl ring, or more preferably a 5 to 6 membered heteroaryl ring, wherein the number of heteroatoms is 1 to 4, preferably 1 to 3, more preferably 1 to 2. Non-limiting examples of heteroaryl groups include pyridyl, furyl, thienyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzofuran, benzimidazole, benzopyridine, pyrrolopyridine, and the like. When heteroaryl is substituted, the substituents are preferably 1 to 5, and the substituents are independently selected from F, cl, br, I, =o, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, nitro, cyano, and amino.
"Heteroalkyl" refers to a radical produced by substitution of at least one carbon atom on an alkyl basis with a non-carbon atom, which may be an N atom, an O atom, and/or an S atom, etc. For example, if the carbon atom in the alkyl group attached to the parent core structure is replaced by a non-carbon atom, the resulting heteroalkyl groups are each alkoxy groups (e.g., -OCH 3 Etc.), alkylamino (e.g., -NHCH 3 、-N(CH 3 ) 2 Etc.) or alkylthio (e.g., -SCH) 3 ). If the carbon atom of the alkyl group attached to the parent core structure is not replaced by a non-carbon atom and the heteroatom is internal to the group, the resulting heteroalkyl groups are each an alkyloxyalkyl group (e.g., -CH 2 CH 2 -O-CH 3 Etc.), alkylaminoalkyl (e.g., -CH 2 NHCH 3 、-CH 2 N(CH 3 ) 2 Etc.) or alkylthio alkyl (e.g., -CH) 2 -S-CH 3 ). If the terminal carbon atom of the alkyl group is replaced by a non-carbon atom, the resulting heteroalkyl groups are each hydroxyalkyl groups (e.g., -CH 2 CH 2 -OH), aminoalkyl groups (e.g., -CH 2 NH 2 ) Or mercaptoalkyl (e.g., -CH) 2 CH 2 -SH)。
"amino" refers to a derivative of ammonia having the formula-N (X) 2 Or structural features of the formula-NR 'R' wherein each "X", R 'and R' is independently H, substituted or unsubstituted alkyl, substituted or unsubstitutedA substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl. Non-limiting types of amino groups include-NH 2 -N (alkyl) 2 -NH (alkyl), -N (cycloalkyl) 2 -NH (cycloalkyl), -N (heterocyclyl) 2 -NH (heterocyclyl), -N (aryl) 2 -NH (aryl), -N (alkyl) (heterocyclyl), -N (cycloalkyl) (heterocyclyl), -N (aryl) (heteroaryl), -N (alkyl) (heteroaryl), and the like.
"halogen" means F, cl, br or I. "halo" refers to the replacement of one or more hydrogen atoms in a molecule or group with a halogen selected from F, cl, br or I.
"pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts with inorganic acids or bases or salts with organic acids and bases. Salts derived from inorganic bases include, but are not limited to, metal salts with Al, ca, li, mg, K, na and Zn; salts derived from organic bases include, but are not limited to, salts with primary, secondary or tertiary amines. The primary, secondary or tertiary amine includes naturally occurring substituted or unsubstituted amines, cyclic amines and basic ion exchange resins such as ammonia, isopropyl amine, trimethyl amine, diethyl amine, triethyl amine, tripropyl amine, diethanol amine, ethanol amine, dimethyl ethanol amine, 2-dimethyl amino ethanol, 2-diethyl amino ethanol, dicyclohexyl amine, caffeine, procaine, choline, betaine, benzathine, ethylenediamine, glucosamine, methyl glucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethyl piperidine or polyamine resins; salts derived from inorganic and organic acids include, but are not limited to, salts formed with: sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinylsulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, lysine, arginine, aspartic acid, cinnamic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethanesulfonic acid, and the like.
"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
"pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with other chemical components. Other components such as physiologically/pharmaceutically acceptable carriers or excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
"prodrug" refers to a substance that can be converted to a biologically active compound of the invention under physiological conditions or by degradation. Prodrugs of the invention are prepared by modifying functional groups in the compounds, which modifications may be removed by conventional procedures or in vivo, to give the parent compound. Prodrugs include compounds of the invention wherein a hydroxy, amino, or sulfhydryl group of a compound is attached to any group. When a prodrug of a compound of the invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group, a free amino group, or a free hydrophobic group, respectively. Examples of prodrugs include, but are not limited to, compounds formed from hydroxyl or amino functional groups in the compounds of the invention with formic acid, acetic acid or benzoic acid.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the event or circumstance occurs or is not. For example, "aryl optionally substituted with alkyl" means that alkyl groups may be, but need not be, present, and the term includes both cases where aryl is substituted with alkyl and cases where aryl is not substituted with alkyl.
"pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. As used herein, the term "pharmaceutically acceptable carrier" includes buffers compatible with pharmaceutical administration, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the patient. Suitable examples include, but are not limited to: (1) sugars such as lactose, glucose and sucrose; (2) Starches, such as corn starch, potato starch, and substituted or unsubstituted beta-cyclodextrin; (3) Cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) Oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) Polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) phosphate buffer; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.
The term "solvate" refers to a form of a compound or salt thereof that is bound to a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "solvate" includes solvates in solution and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.
The term "metabolite" refers to a substance comprising the products produced by the compounds of the invention in the metabolism in vivo, including intermediate metabolites and final metabolites.
The term "polymorph" refers to a crystalline form (or salt, hydrate or solvate thereof) of a compound of a particular crystal stacking arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can lead to a crystalline form predominating. Various polymorphs of a compound can be prepared by crystallization under different conditions.
The dosage form and the mode of administration of the compound of the present invention or the pharmaceutical composition thereof are not particularly limited.
Representative modes of administration include, but are not limited to: oral, intratumoral, rectal, parenteral (intravenous, intraperitoneal, intramuscular or subcutaneous) injection and/or topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, complex silicates, and sodium carbonate; (e) solvents, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, and sodium lauryl sulfate, or mixtures thereof.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents (such as water or other solvents), solubilizing agents and emulsifiers conventionally employed in the art. Specific examples are, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butanediol, dimethylformamide and oils, in particular cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. In addition to inert diluents, the compositions can also include adjuvants such as wetting agents, suspending agents, sweetening, flavoring, and perfuming agents. For example, the suspension may comprise a suspending agent. Specific examples are, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures thereof.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous or nonaqueous carriers, diluents, solvents or excipients are selected from the group consisting of water, ethanol and polyols, or suitable mixtures thereof.
Dosage forms for topical administration include ointments, powders, patches, sprays and inhalants. Is prepared by mixing the active ingredient under aseptic condition with pharmaceutically acceptable carrier, preservative, buffer and/or propellant if necessary.
The following are embodiments of the present invention.
Embodiments of the present invention provide a compound having the structure of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:
Figure BDA0003077502510000121
specifically, in formula (I), A is selected from C 6-14 Aryl, 5-to 14-membered heteroaryl, 5-to 14-membered heterocyclyl and 5-to 14-membered cycloalkyl, and the aryl, heteroaryl groups described in AThe radicals, heterocyclyl and cycloalkyl are optionally further substituted with 0 to 5R 3 Substitution; wherein the heteroaryl and heterocyclyl each comprise 1 to 4 heteroatoms selected from N, O and S;
wherein ,R3 Each independently selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, - (CH) 2 ) m -alkenyl, - (CH) 2 ) m -alkynyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, - (CH) 2 ) m - (3-to 10-membered heterocyclic group), -O- (CH) 2 ) m -C 3-10 Carbocyclyl and-O- (CH) 2 ) m - (3-to 10-membered heterocyclic group) containing 1 to 4 heteroatoms selected from N, O and S, and R 3 The alkyl, alkoxy, carbocycle or heterocycle of said (E) are each independently optionally further substituted with 0 to 4 groups selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 Substituted with alkoxy; m is independently selected from 0, 1, 2 and 3 for each occurrence.
Specifically, in formula (I), L 1 Selected from single bonds and- (CR) a R b ) m-, wherein Ra and Rb Each independently selected from-H and C 1-6 An alkyl group; m is independently selected from 0, 1, 2 or 3 for each occurrence.
Specifically, in formula (I), L 2 Selected from the group consisting of-NH-and-O-.
Specifically, in formula (I), R 1 and R2 Each independently selected from-H, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein R is 1 and R2 Not simultaneously-H; or R is 1 Can be combined with R 2 Together form a composition comprising 0 to 1 member selected from the group consisting of-O-, -NR 16 -, -SO-and-SO 2 -a 3 to 6 membered saturated cyclic group of groups;
wherein ,R16 Selected from-H, C 1-6 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, halogen, hydroxy, cyano and C 3-6 Cycloalkyl groups.
In another specific embodimentIn embodiments, R 1 and R2 And may each be independently selected from other cycloalkyl, alkyl, amino, alkoxy, aryl, heteroaryl, heteroalkyl, and heterocyclyl groups.
In particular, in formula (I), M is selected from single bond, - (CR) c R d ) m- and -(CRc R d ) mO-, wherein Rc and Rd Independently selected from-H and C 1-6 An alkyl group; m is independently selected from 0, 1, 2 and 3 for each occurrence.
Specifically, in formula (I), Q is selected from one of the following structures:
Figure BDA0003077502510000131
wherein ,X1 ，X 2 ，X 3 Each independently selected from a single bond and- (CR) e R f ) n -；
X 4 Selected from-CH 2 -、-CH 2 CH 2- and -CH2 CH 2 CH 2 -；
R 4 、R 5 、R 6 、R 7 、R 9 、R 10 、R e 、R f Each independently selected from-H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, - (CH) 2 ) m - (3-to 10-membered heterocyclic group), - (CH) 2 ) m -O-C 3-10 Carbocyclyl, - (CH) 2 ) m -O- (3-to 10-membered heterocyclyl), phenyl and 5-to 6-membered heteroaryl, each containing 1 to 4 heteroatoms selected from N, O and S, and R 4 、R 5 、R 6 、R 7 、R 9 、R 10 、R e 、R f The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl and heterocycle of said (I), independently of one another, are optionally further substituted with 0 to 4 groups selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl, C 1-4 Taking alkoxy groupsSubstituted by substituents;
R 8 、R 11 、R 12 、R 13 、R 14 、R 15 each independently selected from-H, C 1-6 Alkyl and C 3-6 Cycloalkyl;
m, n, p, q are each independently at each occurrence selected from 0, 1, 2 and 3.
In another specific embodiment, R 4 、R 5 、R 6 、R 7 、R 9 、R 10 、R e 、R f 、R 8 、R 11 、R 12 、R 13 、R 14 、R 15 And may each be independently selected from other cycloalkyl, alkyl, heterocyclyl, heteroaryl, alkoxy, or amino, aryl, and heteroalkyl groups.
Specifically, in formula (I), when X 1 and X2 When the two are single bonds, R 4 、R 5 、R 6 、R 7 And not simultaneously-H.
In one particular embodiment, A is selected from C 6-10 Aryl and 5 to 10 membered heteroaryl, and the aryl or heteroaryl in a is optionally further substituted with 0 to 5R 3 And (3) substitution. Preferably, a is a 5 to 10 membered heteroaryl and optionally further substituted with 0 to 5R 3 And (3) substitution.
In one particular embodiment, A is selected from phenyl, naphthyl, pyridyl, furyl, thienyl, pyrrolyl, indolyl, indazolyl, imidazo [1,2-a ]]Pyridyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl and imidazolyl, and a is unsubstituted or optionally further substituted with 1 to 5R 3 And (3) substitution. Alternatively, A is selected from the group consisting of naphthyl, indolyl, indazolyl and imidazo [1,2-a ]]Pyridyl, and said naphthyl, indolyl, indazolyl or imidazo [1,2-a ]]Pyridyl is unsubstituted or optionally further substituted with 1 to 5R 3 And (3) substitution.
In one particular embodiment, a is selected from one of the following structures:
Figure BDA0003077502510000141
preferably, it is:
Figure BDA0003077502510000142
a is optionally further substituted with 0 to 5R 3 And (3) substitution. Preferably A is unsubstituted or optionally further substituted with 1 to 3R 3 And (3) substitution.
In one particular embodiment, a is:
Figure BDA0003077502510000143
in one particular embodiment, a is: / >
Figure BDA0003077502510000144
In one particular embodiment, a is: />
Figure BDA0003077502510000145
In one particular embodiment, a is: />
Figure BDA0003077502510000146
In one particular embodiment, a is: />
Figure BDA0003077502510000151
In one particular embodiment, a is: />
Figure BDA0003077502510000152
In one particular embodiment, a is: />
Figure BDA0003077502510000153
In one particular embodiment, a is: />
Figure BDA0003077502510000154
In one particular embodiment, a is: />
Figure BDA0003077502510000155
In another specific embodiment, a is optionally selected from other aryl, heteroaryl, or amino, alkoxy, cycloalkyl, alkyl, heteroalkyl, and heterocyclyl.
In one particular embodiment, R 3 Each independently selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, -O- (CH) 2 ) m -C 3-10 Carbocyclyl and-O- (CH) 2 ) m - (3-to 10-membered heterocyclic group) containing 1 to 4 heteroatoms selected from N, O and S, and R 3 The alkyl, alkoxy, carbocycle or heterocycle of said (i) are each independently optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 The substituent of the alkoxy group is substituted. Preferably, R 3 Each independently selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, cyclopropyl, cyclobutyl, and cyclopropylmethyl. In one particular embodiment, R 3 Is methyl. In one particular embodiment, R 3 is-Cl. In one particular embodiment, R 3 Is methoxy. In one particular embodiment, R 3 Is CF (CF) 3 。
In another specific embodiment, R 3 But may also be selected from other alkyl, alkoxy, heterocyclyl, cycloalkyl, heteroalkyl, or amino, aryl, and heteroaryl groups.
In one particular embodiment, R 1 and R2 Each independently selected from C 1-6 Alkyl and C 3-6 Cycloalkyl; or R is 1 Can be combined with R 2 Together form a composition comprising 0 to 1 member selected from the group consisting of-O-, -SO-and-SO 2 3 to 3A 6-membered saturated cyclic group. Preferably, R 1 and R2 Each independently selected from methyl, ethyl, propyl, cyclopropyl and cyclobutyl; or R is 1 Can be combined with R 2 Together form a 3-membered saturated carbocyclyl.
In another specific embodiment, R 1 and R2 And may each be independently selected from other alkyl groups, cycloalkyl groups, or amino groups, alkoxy groups, aryl groups, heteroaryl groups, heteroalkyl groups, and heterocyclic groups.
In one particular embodiment, Q is selected from one of the following structures:
Figure BDA0003077502510000161
In another particular embodiment, Q may also be each independently selected from other heterocyclyl, cycloalkyl, amino, alkoxy, aryl, heteroaryl, heteroalkyl, and alkyl.
In one particular embodiment, X 4 Selected from-CH 2 -、-CH 2 CH 2- and -CH2 CH 2 CH 2 -。
In one particular embodiment, R 12 、R 13 、R 14 、R 15 Selected from-H.
Specifically, the compound has the structure of formula (II):
Figure BDA0003077502510000162
in one particular embodiment, in formula (II), L 2 is-NH-.
In one particular embodiment, in formula (II), L 1 Selected from single bonds and- (CR) a R b ) m-, wherein Ra and Rb Each independently selected from-H and C 1-6 An alkyl group. Preferably L 1 Selected from single bond, -CH 2- and -CH2 CH 2 -. More preferablyGround, L 1 Selected from single bonds and-CH 2 -. Most preferably L 1 Is a single bond.
In one particular embodiment, in formula (II), X 1 and X2 Each independently selected from a single bond and- (CR) e R f ) n -. Preferably X 1 and X2 Each independently selected from single bond, -CH 2- and -CH2 CH 2 -. More preferably, X 1 and X2 Each independently selected from a single bond and-CH 2 -。
wherein ,Re and Rf Each independently selected from-H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, - (CH) 2 ) m - (3-to 10-membered heterocyclic group), - (CH) 2 ) m -O-C 3-10 Carbocyclyl, - (CH) 2 ) m -O- (3-to 10-membered heterocyclyl), phenyl and 5-to 6-membered heteroaryl, said heterocycle, heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, and R e and Rf The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle of said (I), each independently optionally further being substituted with 0 to 4 groups selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 The substituent of the alkoxy group is substituted. Preferably, R e 、R f Each independently selected from-H, methyl, ethyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl. More preferably, R e and Rf Each independently selected from-H and methyl. Most preferably, R e and Rf Each is-H.
In one particular embodiment, in formula (II), R 4 、R 5 、R 6 、R 7 Each independently selected from-H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, - (CH) 2 ) m - (3-to 10-membered heterocyclic group), - (CH) 2 ) m -O-C 3-10 Carbocyclyl group、-(CH 2 ) m -O- (3-to 10-membered heterocyclyl), phenyl and 5-to 6-membered heteroaryl, said heterocycle, heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, R 4 、R 5 、R 6 、R 7 The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle of said (I), each independently optionally further being substituted with 0 to 4 groups selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 The substituent of the alkoxy group is substituted. Preferably, R 4 、R 5 、R 6 、R 7 Each independently selected from-H, methyl, ethyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl. More preferably, R 4 、R 5 、R 6 、R 7 Each independently selected from-H and methyl. In one particular embodiment, R 4 、R 5 、R 6 、R 7 Each independently is-H.
In one particular embodiment, in formula (II), R 8 Selected from-H, C 1-6 Alkyl and C 3-6 Cycloalkyl groups. Preferably, R 8 Selected from-H, methyl, ethyl and cyclopropyl. More preferably, R 8 is-H.
In one particular embodiment, in formula (II), M is selected from the group consisting of a single bond, - (CR) c R d ) m- and -(CRc R d ) mO-, wherein Rc and Rd Each independently selected from-H and C 1-6 An alkyl group. Preferably, M is selected from single bond, -CH 2 -、-CH 2 CH 2 -、-CH 2O- and CH2 CH 2 O-. More preferably, M is selected from the group consisting of a single bond and-CH 2 O-. In one particular embodiment, M is a single bond. In one particular embodiment, M is-CH 2 O-。
In one particular embodiment, in formula (II), R 1 and R2 Each independently selected from-H, C 1-6 Alkyl, C 3-6 Cycloalkyl, wherein R is 1 and R2 Not simultaneously-H; or, R 1 Can be combined with R 2 Together form a composition comprising 0 to 1 member selected from the group consisting of-O-, -NR 16 -, -SO-and SO 2 -a 3 to 6 membered saturated cyclic group; r is R 16 Selected from-H, C 1-6 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, halogen, hydroxy, cyano and C 3-6 Cycloalkyl groups.
Preferably, R 1 、R 2 Each independently selected from methyl, ethyl, isopropyl and cyclopropyl. More preferably, R 1 、R 2 Each independently is methyl.
Preferably, R 1 Can be combined with R 2 Together form a composition comprising 0 to 1 member selected from the group consisting of-O-, -SO-and SO 2 -a 3 to 6 membered saturated cyclic group. More preferably, R 1 Can be combined with R 2 Together forming a cyclopropyl group.
Preferably, the compound has the structure of formula (III):
Figure BDA0003077502510000181
in one particular embodiment, in formula (III), X 1 Selected from single bonds and-CH 2 -。
In one particular embodiment, in formula (III), L 1 Selected from single bonds and- (CR) a R b ) m-, wherein Ra ，R b Independently selected from-H and C 1-6 An alkyl group. Preferably L 1 Selected from single bond, -CH 2- and -CH2 CH 2 -. More preferably L 1 Selected from single bonds and-CH 2 -. Most preferably L 1 Is a single bond.
In one particular embodiment, in formula (III), R 6 、R 7 Each independently selected from-H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, - (CH) 2 ) m - (3-to 10-membered heterocyclic group), - (CH) 2 ) m -O-C 3-10 Carbocyclyl, - (CH) 2 ) m -O- (3-to 10-membered heterocyclyl), phenyl and 5-to 6-membered heteroaryl, each containing 1 to 4 heteroatoms selected from N, O and S, R 4 、R 5 、R 6 、R 7 The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle of said (I), each independently optionally further being substituted with 0 to 4 groups selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 The substituent of the alkoxy group is substituted. Preferably, R 6 、R 7 Each independently selected from-H, methyl, ethyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl. More preferably, R 6 、R 7 Each independently selected from-H and methyl. Most preferably, R 6 、R 7 Each independently is-H.
In one particular embodiment, in formula (III), R 8 Selected from-H, C 1-6 Alkyl and C 3-6 Cycloalkyl groups. Preferably, R 8 Selected from-H, methyl, ethyl and cyclopropyl. More preferably, R 8 is-H.
Preferably, the compound has the structure of formula (IV):
Figure BDA0003077502510000182
in one particular embodiment, in formula (IV), R 4 、R 5 、R 6 、R 7 Each independently selected from-H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, - (CH) 2 ) m - (3-to 10-membered heterocyclic group), - (CH) 2 ) m -O-C 3-10 Carbocyclyl, - (CH) 2 ) m -O- (3-to 10-membered heterocyclyl), phenyl and 5-to 6-membered heteroaryl, each containing 1 to 4 heteroatoms selected from N, O and S, and R 4 、R 5 、R 6 、R 7 The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle being independently of one another Optionally further comprises 0 to 4 groups selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino and C 1-4 Alkyl and C 1-4 Substituted with alkoxy; r is R 4 、R 5 、R 6 、R 7 And not simultaneously-H.
In one particular embodiment, in formula (IV), R 4 、R 5 、R 6 is-H; r is R 7 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, - (CH) 2 ) m - (3-to 10-membered heterocyclic group), - (CH) 2 ) m -O-C 3-10 Carbocyclyl, - (CH) 2 ) m -O- (3-to 10-membered heterocyclyl), phenyl and 5-to 6-membered heteroaryl, each containing 1 to 4 heteroatoms selected from N, O and S, and R 7 The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle of said (I), each independently optionally further being substituted with 0 to 4 groups selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 The substituent of the alkoxy group is substituted. More specifically, R 7 Or R-containing after substitution by the substituents 7 The radicals being selected from C 1-6 Alkyl, C 1-6 Alkoxy, methoxymethyl, hydroxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, phenyl, pyridinyl, furanyl, imidazolyl and thiazolyl; and R is 7 Independently optionally further substituted with 0 to 4 groups selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl, C 1-4 The substituent of the alkoxy group is substituted.
In one particular embodiment, in formula (IV), R 5 、R 6 、R 7 is-H; r is R 4 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, - (CH) 2 ) m - (3-to 10-membered heterocyclic group), - (CH) 2 ) m -O-C 3-10 Carbocyclyl, - (CH) 2 ) m -O- (3-to 10-membered heterocyclyl), phenyl and 5-to 6-membered heteroaryl, each containing 1 to 4 heteroatoms selected from N, O and S, and R 4 The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle of said (I), each independently optionally further being substituted with 0 to 4 groups selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 The substituent of the alkoxy group is substituted. More specifically, R 4 Or R-containing after substitution by the substituents 4 The radicals being selected from C 1-6 Alkyl, methoxymethyl, hydroxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclobutoxy, cyclopentyl, tetrahydrofuranyl, phenyl, pyridinyl, furanyl, imidazolyl and thiazolyl, each of said phenyl, pyridinyl, furanyl, imidazolyl, thiazolyl being independently optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, hydroxy, cyano, amino, C 1-4 Alkyl and C 1-4 The substituent of the alkoxy group is substituted.
In one particular embodiment, in formula (IV), L 1 Selected from single bonds and- (CR) a R b ) m-, wherein Ra ，R b Each independently selected from-H and C 1-6 An alkyl group. Preferably L 1 Selected from single bond, -CH 2- and -CH2 CH 2 -. More preferably L 1 Selected from single bonds and-CH 2 -. Most preferably L 1 Is a single bond.
In one particular embodiment, in formula (IV), M is selected from the group consisting of a single bond, - (CR) c R d ) m- and -(CRc R d ) mO-, wherein Rc 、R d Each independently selected from-H and C 1-6 An alkyl group. Preferably, M is selected from single bond, -CH 2 -、-CH 2 CH 2 -、-CH 2O- and CH2 CH 2 O-. More preferably, M is selected from the group consisting of a single bond and-CH 2 O-. Most preferably M is a single bond.
In one particular embodiment, in formula (IV), R 1 、R 2 Each independently selected from-H, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein R is 1 and R2 Not simultaneously-H; or, R 1 Can be combined with R 2 Together form a composition comprising 0 to 1 member selected from the group consisting of-O-, -NR 16 -, -SO-and SO 2 -a 3 to 6 membered saturated cyclic group of groups; r is R 16 Selected from-H, C 1-6 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, halogen, hydroxy, cyano and C 3-6 Cycloalkyl groups.
Preferably, R 1 、R 2 Each independently selected from methyl, ethyl, isopropyl and cyclopropyl. More preferably, R 1 、R 2 Each independently selected from methyl.
Preferably, R 1 Can be combined with R 2 Together form a catalyst comprising 0 to 1-O-, -SO-and SO 2 -a 3 to 6 membered saturated cyclic group. More preferably, R 1 Can be combined with R 2 Together forming a cyclopropyl group.
In one particular embodiment, in formula (IV), R 8 Selected from-H, C 1-6 Alkyl and C 3-6 Cycloalkyl groups. Preferably, R 8 Selected from-H, methyl, ethyl and cyclopropyl. More preferably, R 8 is-H.
Specifically, the compound has the structure of formula (V):
Figure BDA0003077502510000201
in one particular embodiment, in formula (V), X 3 Selected from single bond, -CH 2 -、-CH 2 CH 2- and -CH2 CH 2 CH 2 -。
In one particular embodiment, in formula (V), p, q are each independently selected from 0, 1, 2 and 3 for each occurrence.
In one particular embodiment, in formula (V), R 9 、R 10 Each independently selected from-H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, - (CH) 2 ) m - (3-to 10-membered heterocyclic group), - (CH) 2 ) m -O-C 3-10 Carbocyclyl, - (CH) 2 ) m -O- (3-to 10-membered heterocyclyl), phenyl and 5-to 6-membered heteroaryl, each containing 1 to 4 heteroatoms selected from N, O and S, R 9 、R 10 The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle of said (I), each independently optionally further being substituted with 0 to 4 groups selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 The substituent of the alkoxy group is substituted. Preferably, R 9 、R 10 Each independently selected from-H, methyl, ethyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl. More preferably, R 9 、R 10 Each independently selected from-H and methyl. In one particular embodiment, R 9 、R 10 Each independently is-H.
In one particular embodiment, in formula (V), R 8 Selected from-H, C 1-6 Alkyl and C 3-6 Cycloalkyl groups. Preferably, R 8 Selected from-H, methyl, ethyl and cyclopropyl. More preferably, R 8 is-H.
In one particular embodiment, in formula (V), p, q are each independently selected from 0, 1, 2 and 3 for each occurrence. Preferably, p, q are each independently selected from 0, 1 and 2 for each occurrence.
In one particular embodiment, in formula (V), L 2 is-NH-.
In one particular embodiment, in formula (V), L 1 Selected from single bonds and- (CR) a R b ) m-, wherein Ra ，R b Independently selected from-H and C 1-6 An alkyl group. Preferably L 1 Selected from single bond, -CH 2- and -CH2 CH 2 -. More preferably L 1 Selected from single bonds and-CH 2 -. Most preferably L 1 Is a single bond.
In one particular embodiment, in formula (V), M is selected from the group consisting of a single bond, - (CR) c R d ) m- and -(CRc R d ) mO-, wherein Rc 、R d Independently selected from-H and C 1-6 An alkyl group. Preferably, M is selected from single bond, -CH 2 -、-CH 2 CH 2 -、-CH 2O- and CH2 CH 2 O-. More preferably, M is selected from the group consisting of a single bond and-CH 2 O-. Most preferably M is a single bond.
In one particular embodiment, in formula (V), R 1 、R 2 Each independently selected from-H, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein R is 1 and R2 Not simultaneously-H; or, R 1 Can be combined with R 2 Together form a composition comprising 0 to 1 member selected from the group consisting of-O-, -NR 16 -, -SO-and SO 2 -a 3 to 6 membered saturated cyclic group of groups; r is R 16 Selected from-H, C 1-6 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, halogen, hydroxy, cyano and C 3-6 Cycloalkyl groups.
Preferably, R 1 、R 2 Each independently selected from methyl, ethyl, isopropyl and cyclopropyl. More preferably, R 1 、R 2 Each independently is methyl.
Preferably, R 1 Can be combined with R 2 Together form a composition comprising 0 to 1 member selected from the group consisting of-O-, -SO-and SO 2 -a 3 to 6 membered saturated cyclic group. More preferably, R 1 Can be combined with R 2 Together forming a cyclopropyl group.
In one embodiment, in formula (V), p, q are each 1; x is X 3 is-CH 2 -；R 9 、R 10 、R 11 Each is-H; l (L) 1 Is a single bond; l (L) 2 is-NH-; m is a single bond.
Preferably, the compound has the structure of formula (VI):
Figure BDA0003077502510000221
in one embodiment, in formula (VI), L 2 is-NH-.
In one particular embodiment, in formula (VI), R 9 、R 10 Each independently selected from-H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, - (CH) 2 ) m - (3-to 10-membered heterocyclic group), - (CH) 2 ) m -O-C 3-10 Carbocyclyl, - (CH) 2 ) m -O- (3-to 10-membered heterocyclyl), phenyl and 5-to 6-membered heteroaryl, each containing 1 to 4 heteroatoms selected from N, O and S, R 9 、R 10 The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle of said (I), each independently optionally further being substituted with 0 to 4 groups selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 The substituent of the alkoxy group is substituted. Preferably, R 9 、R 10 Each independently selected from-H, methyl, ethyl, methoxy, ethoxy, cyclopropyl, and cyclobutyl. More preferably, R 9 、R 10 Each independently selected from-H and methyl. In one particular embodiment, R 9 、R 10 Each independently is-H.
In one particular embodiment, in formula (VI), R 8 Selected from-H, C 1-6 Alkyl and C 3-6 Cycloalkyl groups. Preferably, R 8 Selected from-H, methyl, ethyl and cyclopropyl. More preferably, R 8 is-H.
In one particular embodiment, in formula (VI), L 1 Selected from single bonds and- (CR) a R b ) m-, wherein Ra ，R b Each independently selected from-H and C 1-6 An alkyl group. Preferably L 1 Selected from single bond, -CH 2- and -CH2 CH 2 -. More preferably L 1 Selected from single bonds and-CH 2 -. Most preferably L 1 Is a single bond.
In one particular embodiment, in formula (VI), M is selected from the group consisting of a single bond, - (CR) c R d ) m- and -(CRc R d ) mO-, wherein Rc 、R d Independently selected from-H and C 1-6 An alkyl group. Preferably, M is selected from single bond, -CH 2 -、-CH 2 CH 2 -、-CH 2O- and CH2 CH 2 O-. More preferably, M is selected from the group consisting of a single bond and-CH 2 O-. Most preferably M is a single bond.
In one particular embodiment, in formula (VI), R 1 、R 2 Each independently selected from-H, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein R is 1 and R2 Not simultaneously-H; or, R 1 Can be combined with R 2 Together form a compound comprising 0 to 1-O-, -NR 16 -, -SO-and SO 2 -a 3 to 6 membered saturated cyclic group of groups; r is R 16 Selected from-H, C 1-6 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, halogen, hydroxy, cyano and C 3-6 Cycloalkyl groups.
Preferably, R 1 、R 2 Each independently selected from methyl, ethyl, isopropyl and cyclopropyl. More preferably, R 1 、R 2 Each independently is methyl.
Preferably, R 1 Can be combined with R 2 Together form a composition comprising 0 to 1 member selected from the group consisting of-O-, -SO-and SO 2 -3 to 6 membered saturated cyclic groups of the group. More preferably, R 1 Can be combined with R 2 Together forming a cyclopropyl group.
In one particular embodiment, in formula (VI), R 9 、R 10 、R 11 Each is-H; l (L) 1 Is a single bond; m is a single bond.
Further, the present invention relates to the following embodiments.
In one embodiment, the invention relates to a compound of the structure of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:
Figure BDA0003077502510000231
wherein A is selected from C 6-14 Aryl, 5-to 14-membered heteroaryl, 5-to 14-membered heterocyclyl and 5-to 14-membered cycloalkyl, and the aryl, heteroaryl, heterocyclyl and cycloalkyl groups in a are optionally further substituted with 0 to 5R 3 Substitution; wherein the heteroaryl and heterocyclyl contain 1 to 4 heteroatoms selected from N, O and S;
R 3 each independently selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, - (CH) 2 ) m -alkenyl, - (CH) 2 ) m -alkynyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, - (CH) 2 ) m - (3-to 10-membered heterocyclic group), -O- (CH) 2 ) m -C 3-10 Carbocyclyl and-O- (CH) 2 ) m - (3-to 10-membered heterocyclic group) containing 1 to 4 hetero atoms selected from N, O and S, and R 3 The alkyl, alkoxy, carbocyclyl or heterocyclyl radicals described in (a) are each independently optionally further substituted with 0 to 4 groups selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 Substituted with alkoxy;
L 1 selected from single bonds and- (CR) a R b ) m-, wherein Ra and Rb Each independently selected from-H and C 1-6 An alkyl group;
L 2 selected from-NH-and-O-;
R 1 and R2 Each independently selected from-H, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein R is 1 and R2 Not simultaneously-H;
or R is 1 and R2 Together form a composition comprising 0 to 1 member selected from the group consisting of-O-, -NR 16 -, -SO-and-SO 2 -a 3 to 6 membered saturated cyclic group of groups;
R 16 selected from-H,C 1-6 Alkyl, C 1-4 Alkoxy C 1-4 Alkyl, halo, hydroxy, cyano and C 3-6 Cycloalkyl;
m is selected from single bond, - (CR) c R d ) m- and -(CRc R d ) mO-, wherein Rc and Rd Each independently selected from-H and C 1-6 An alkyl group;
q is selected from one of the following structures:
Figure BDA0003077502510000241
/>
wherein ,X1 、X 2 and X3 Each independently selected from a single bond and- (CR) e R f ) n -；
X 4 Selected from-CH 2 -、-CH 2 CH 2- and -CH2 CH 2 CH 2 -；
R 4 、R 5 、R 6 、R 7 、R 9 、R 10 、R e and Rf Each independently selected from-H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, - (CH) 2 ) m - (3-to 10-membered heterocyclic group), - (CH) 2 ) m -O-C 3-10 Carbocyclyl, - (CH) 2 ) m -O- (3-to 10-membered heterocyclyl), phenyl and 5-to 6-membered heteroaryl, said heterocyclyl or heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, and R 4 、R 5 、R 6 、R 7 、R 9 、R 10 、R e 、R f The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle of said (I), each independently optionally further being substituted with 0 to 4 groups selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 Substituted with alkoxy;
R 8 、R 11 、R 12 、R 13 、R 14 、R 15 each independently selected from-H, C 1-6 Alkyl and C 3-6 Cycloalkyl;
m, n, p, q is independently at each occurrence selected from 0, 1, 2 and 3;
when X is 1 and X2 When the two are single bonds, R 4 、R 5 、R 6 、R 7 And not simultaneously-H.
In one embodiment, the present invention relates to a compound of the structure of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, said compound having the structure of formula (II):
Figure BDA0003077502510000242
wherein ,L2 is-NH-.
In one embodiment, the present invention relates to a compound of formula (II) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that it has the structure of formula (III):
Figure BDA0003077502510000251
wherein ,X1 Selected from single bonds or-CH 2 -。
In one embodiment, the present invention relates to a compound of the above structure of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that the compound has the structure of formula (IV):
Figure BDA0003077502510000252
wherein ,R4 、R 5 、R 6 、R 7 Each independently selected from-H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, - (CH) 2 ) m - (3-to 10-membered heterocyclic group), - (CH) 2 ) m -O-C 3-10 Carbocyclyl, - (CH) 2 ) m -O- (3-to 10-membered heterocyclyl), phenyl and 5-to 6-membered heteroaryl, each containing 1 to 4 heteroatoms selected from N, O and S, and R 4 、R 5 、R 6 、R 7 The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle of said (I), each independently optionally further being substituted with 0 to 4 groups selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 Substituted with alkoxy;
R 4 、R 5 、R 6 and R7 And not simultaneously-H.
In one embodiment, the present invention relates to a compound of the structure of formula (IV) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
R 4 、R 5 and R6 Each is-H;
R 7 selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, - (CH) 2 ) m - (3-to 10-membered heterocyclic group), - (CH) 2 ) m -O-C 3-10 Carbocyclyl, - (CH) 2 ) m -O- (3-to 10-membered heterocyclyl), phenyl and 5-to 6-membered heteroaryl, said heterocycle or heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, and R 7 The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle of said (I), each independently optionally further being substituted with 0 to 4 groups selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 The substituent of the alkoxy group is substituted.
In one embodiment, the present invention relates to a compound of formula (IV) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
R 5 、R 6 and R7 Each is-H;
R 4 selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, - (CH) 2 ) m - (3-to 10-membered heterocyclic group), - (CH) 2 ) m -O-C 3-10 Carbocyclyl, - (CH) 2 ) m -O- (3-to 10-membered heterocyclyl), phenyl and 5-to 6-membered heteroaryl, each containing 1 to 4 heteroatoms selected from N, O and S, and R 4 The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle of said (I), each independently optionally further being substituted with 0 to 4 groups selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 The substituent of the alkoxy group is substituted.
In one embodiment, the present invention relates to a compound of the structure of formula (IV) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
R 7 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, methoxymethyl, hydroxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, phenyl, pyridinyl, furanyl, imidazolyl and thiazolyl; and R is 7 Each independently optionally further substituted with 0 to 4 groups selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 Substituted with alkoxy;
L 1 is a single bond;
m is a single bond.
In one embodiment, the present invention relates to a compound of the structure of formula (IV) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
R 4 selected from C 1-6 Alkyl, methoxymethyl, hydroxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclobutoxy, cyclopentyl, tetrahydrofuranyl, phenyl, pyridinyl, furanyl, imidazolyl and thiazolyl, each of said phenyl, pyridinyl, furanyl, imidazolyl and thiazolyl being independently optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, hydroxy, cyano, amino, C 1-4 Alkyl and C 1-4 Substituted with alkoxy;
L 1 is a single bond;
M is a single bond.
In one embodiment, the present invention relates to a compound of the structure of formula (III) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
R 6 、R 7 and R8 Each is-H;
L 1 is a single bond.
In one embodiment, the present invention relates to a compound of the above structure of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized by having the structure of formula (V):
Figure BDA0003077502510000271
X 3 is a single bond, -CH 2 -、-CH 2 CH 2- and -CH2 CH 2 CH 2 -；
p, q are each independently selected from 0, 1, 2 and 3 for each occurrence.
In one embodiment, the present invention relates to a compound of the structure of formula (V) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
p and q are each 1;
X 3 is-CH 2 -；
R 9 、R 10 and R11 Each is-H;
L 1 is a single bond;
L 2 is-NH-;
m is a single bond.
In one embodiment, the present invention relates to a compound of the structure of formula (V) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized by having the structure of formula (VI):
Figure BDA0003077502510000272
wherein ,L2 is-NH-.
In one embodiment, the present invention relates to a compound of the structure of formula (V) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
R 9 、R 10 、R 11 is-H;
L 1 is a single bond;
m is a single bond.
In one embodiment, the present invention relates to a compound of the structure of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
X 4 selected from-CH 2 -、-CH 2 CH 2- and -CH2 CH 2 CH 2 -；
R 12 、R 13 、R 14 、R 15 Each is-H.
In one embodiment, the present invention relates to a compound of the structure of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
a is selected from one of the following structures:
Figure BDA0003077502510000281
in one embodiment, the present invention relates to a compound of the structure of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
a is selected from one of the following structures:
Figure BDA0003077502510000282
In one embodiment, the present invention relates to a compound of the structure of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
a is selected from one of the following structures:
Figure BDA0003077502510000291
in one embodiment, the present invention relates to a compound of the structure of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
a is selected from one of the following structures:
Figure BDA0003077502510000292
in one embodiment, the present invention relates to a compound of the structure of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
a is selected from one of the following structures:
Figure BDA0003077502510000293
in one embodiment, the present invention relates to a compound of the structure of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
R 3 each independently selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, - (CH) 2 ) m -C 3-10 Carbocyclyl, -O- (CH) 2 ) m -C 3-10 Carbocyclyl and-O- (CH) 2 ) m - (3-to 10-membered heterocyclic group) containing 1 to 4 heteroatoms selected from N, O and S, and R 3 The alkyl, alkoxy, carbocycle or heterocycle of said (i) are each independently optionally further substituted with 0 to 4 groups selected from H, F, cl, br, I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 An alkoxy substituent.
In one embodiment, the present invention relates to a compound of the structure of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
R 3 each independently selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxy C 1-4 Alkyl, cyclopropyl, cyclobutyl, and cyclopropylmethyl.
In one embodiment, the present invention relates to a compound of the structure of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
R 1 、R 2 each independently selected from C 1-6 Alkyl and C 3-6 Cycloalkyl;
Or R is 1 and R2 Together form a composition comprising 0 to 1 member selected from the group consisting of-O-, -SO-and-SO 2 -3 to 6 membered saturated cyclic groups of the group.
In one embodiment, the present invention relates to a compound of the structure of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
R 1 、R 2 each independently selected from methyl, ethyl, propyl, cyclopropyl and cyclobutyl;
or R is 1 and R2 Together form a 3-membered saturated carbocyclyl.
In one embodiment, the present invention relates to a compound of the structure of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized in that,
q is selected from one of the following structures:
Figure BDA0003077502510000301
R 4 、R 5 、R 6 、R 7 and not simultaneously-H.
In one embodiment, the present invention relates to a compound of the above structure of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized by having the structure of formula (V):
Figure BDA0003077502510000302
wherein A is selected from C 6-14 Aryl, 5-to 14-membered heteroaryl, 5-to 14-membered heterocyclyl and 5-to 14-membered cycloalkyl, and the aryl, heteroaryl, heterocyclyl or cycloalkyl in a is optionally further substituted with 0 to 5R 3 Substitution; wherein the heteroaryl or heterocyclyl contains 1 to 4 heteroatoms selected from N, O and S;
R 3 each independently selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C 1-4 Alkyl, C 1-4 Alkoxy and C 1-4 Alkoxy C 1-4 Alkyl, and R 3 The alkyl or alkoxy radicals mentioned in (a) are each independently optionally further substituted with 0 to 4 groups selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 Substituted with alkoxy;
R 1 、R 2 each independently selected from-H, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein R is 1 and R2 Not simultaneously-H;
or R is 1 and R2 Together forming a 3 to 6 membered saturated cyclic group;
m is selected from single bond, - (CR) c R d ) m- and -(CRc R d ) mO-, wherein Rc Or R is d Independently selected from-H and C 1-6 An alkyl group;
q is selected from one of the following structures:
Figure BDA0003077502510000311
wherein ,X1 ，X 2 ，X 3 Each independently selected from a single bond and- (CR) e R f ) n -；
X 4 Selected from-CH 2 -、-CH 2 CH 2- and -CH2 CH 2 CH 2 -；
R 4 、R 5 、R 6 、R 7 、R 9 、R 10 、R e 、R f Each independently of the otherIs selected from-H, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy C 1-6 Alkyl and phenyl, and R 4 、R 5 、R 6 、R 7 、R 9 、R 10 、R e 、R f The alkyl, alkoxy and phenyl radicals described in (a) are each independently optionally further substituted with 0 to 4 groups selected from the group consisting of-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C 1-4 Alkyl and C 1-4 Substituted with alkoxy;
R 8 、R 11 、R 12 、R 13 、R 14 、R 15 each independently selected from-H, C 1-6 Alkyl and C 3-6 Cycloalkyl;
m, n, p, q is independently at each occurrence selected from 0, 1, 2 and 3;
when X is 1 ，X 2 When the two are single bonds, R 4 、R 5 、R 6 、R 7 And not simultaneously-H.
In one embodiment, the present invention relates to a compound of formula (a), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,
Figure BDA0003077502510000321
wherein ,
Figure BDA0003077502510000322
represents a single bond or a double bond, provided that two +.>
Figure BDA0003077502510000323
Wherein only one represents a double bond; />
X 1 Is CR (CR) 3’ Or NR (NR) 3 ；
X 2 Is CR (CR) 3’ Or NR (NR) 3 ；
or ,X1 And substitution thereofRadicals and adjacent carbon atoms and substituents R thereof 3’ Together form a benzene ring or a 5-to 6-membered heteroaromatic ring, which is optionally substituted with 1 to 4R 3’ Substitution;
R 3 selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;
R 3’ selected from-H, halogen, cyano, -OR, -NR' R, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl, - (CH) 2 ) n - (5-to 6-membered heteroaryl) and-SR x ；
R 4 Selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl); wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with halogen, cyano, -OR, -NR' R ", C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl substitution;
R 5 selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
R 1 and R2 Each independently selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r is selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r 'and R' are each selected from-H, C 1-6 Alkyl and halogenated C 1-6 Alkyl, or R' and R "together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocyclyl;
R x selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, - (CH) 2 ) n -C 2-6 Alkenyl, - (CH) 2 ) n -C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
n is 0, 1, 2 or 3;
s is 0, 1 or 2;
r is 0, 1 or 2.
In one embodiment, the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,
Figure BDA0003077502510000331
represents a single bond or a double bond, provided that two +.>
Figure BDA0003077502510000332
Wherein only one represents a double bond;
X 1 is CR (CR) 3’ Or NR (NR) 3 ；
X 2 Is CR (CR) 3’ ；
X 1 And substituents and adjacent carbon atoms thereof and substituents R thereof 3’ Together form a benzene ring or a 5-to 6-membered heteroaromatic ring, which is substituted with 1 to 4R 3’ Substitution;
R 3 selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;
R 3’ selected from-H, halogen, cyano, -OR, -NR' R, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl, - (CH) 2 ) n - (5-to 6-membered heteroaryl) and-SR x ；
R 4 Selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl); the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with halogen, cyano, -OR, -NR' R ", C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl substitution;
R 5 selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
R 1 and R2 Each independently selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r is selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r 'and R' are each selected from-H, C 1-6 Alkyl and halogenated C 1-6 Alkyl, or R' and R "together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocyclyl;
R x selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, - (CH) 2 ) n -C 2-6 Alkenyl, - (CH) 2 ) n -C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl group,-(CH 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
n is 0, 1, 2 or 3;
s is 0 or 1;
r is 0 or 1.
In one embodiment, the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,
Figure BDA0003077502510000341
represents a single bond or a double bond, provided that two +.>
Figure BDA0003077502510000342
Wherein only one represents a double bond;
X 1 is CR (CR) 3’ Or NR (NR) 3 ；
X 2 Is NR (NR) 3 ；
X 1 And substituents and adjacent carbon atoms thereof and substituents R thereof 3’ Together form a benzene ring or a 5-to 6-membered heteroaromatic ring, which is substituted with 1 to 4R 3’ Substitution;
R 3 selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;
R 3’ selected from-H, halogen, cyano, -OR, -NR' R, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl, - (CH) 2 ) n - (5-to 6-membered heteroaryl) and-SR x ；
R 4 Selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl); the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with halogen, cyano, -OR, -NR' R ", C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl substitution;
R 5 selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
R 1 and R2 Each independently selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r is selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r 'and R' are each selected from-H, C 1-6 Alkyl and halogenated C 1-6 Alkyl, or R' and R "together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocyclyl;
R x selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, - (CH) 2 ) n -C 2-6 Alkenyl, - (CH) 2 ) n -C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
n is 0, 1, 2 or 3;
s is 0 or 1;
r is 0 or 1.
In one embodiment, the present invention relates to a compound of formula (a) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,
Figure BDA0003077502510000351
represents a single bond or a double bond, provided that two +.>
Figure BDA0003077502510000352
Wherein only one represents a double bond; />
X 1 Is CR (CR) 3’ ；
X 2 Is NR (NR) 3 ；
X 1 And substituents and adjacent carbon atoms thereof and substituents R thereof 3’ Together form a benzene ring, said benzene ring being substituted with 1 to 4R 3’ Substitution;
R 3 selected from-H and C 1-6 An alkyl group;
R 3’ is C 1-6 An alkyl group;
R 4 selected from-H and C 1-6 An alkyl group;
R 5 selected from-H and C 1-6 An alkyl group;
R 1 and R2 Each independently is methyl;
s is 1;
r is 1.
In one embodiment, the present invention relates to a compound of formula (b), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,
Figure BDA0003077502510000353
wherein ,
Figure BDA0003077502510000354
represents a single bond or a double bond, provided that two +.>
Figure BDA0003077502510000355
Wherein only one represents a double bond;
X 1 is CR (CR) 3’ Or NR (NR) 3 ；
X 2 Is CR (CR) 3’ Or NR (NR) 3 ；
or ,X1 And substituents and adjacent carbon atoms thereof and substituents R thereof 3’ Together form a benzene ring or a 5-to 6-membered heteroaromatic ring, which is optionally substituted with 1 to 4R 3’ Substitution;
R 3 selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;
R 3’ selected from-H, halogen, cyano, -OR, -NR' R, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl, - (CH) 2 ) n - (5-to 6-membered heteroaryl) and-SR x ；
R 4 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl); wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with halogen, cyano, -OR, -NR' R ", C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl substitution;
R 5 selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
R 1 and R2 Each independently selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r is selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r 'and R' are each selected from-H, C 1-6 Alkyl and halogenated C 1-6 Alkyl, or R' and R "together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocyclyl;
R x selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, - (CH) 2 ) n -C 2-6 Alkenyl, - (CH) 2 ) n -C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
n is 0, 1, 2 or 3.
In one embodiment, the present invention relates to a compound of formula (b) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,
wherein ,
Figure BDA0003077502510000361
represents a single bond or a double bond, provided that two +.>
Figure BDA0003077502510000362
Wherein only one represents a double bond;
X 1 is CR (CR) 3’ Or NR (NR) 3 ；
X 2 Is CR (CR) 3’ ；
X 1 And substituents and adjacent carbon atoms thereof and substituents R thereof 3’ Together form a benzene ring or a 5-to 6-membered heteroaromatic ring, which is substituted with 1 to 4R 3’ Substitution;
R 3’ selected from-H, halogen, cyano, -OR, -NR' R, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl, - (CH) 2 ) n - (5-to 6-membered heteroaryl) and-SR x ；
R 4 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl); the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with halogen, cyano, -OR, -NR' R ", C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl substitution;
R 5 selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
R 1 and R2 Each independently selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r is selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r 'and R' are each selected from-H, C 1-6 Alkyl and halogenated C 1-6 Alkyl, or R' and R "together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocyclyl;
R x selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, - (CH) 2 ) n -C 2-6 Alkenyl, - (CH) 2 ) n -C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
n is 0, 1, 2 or 3.
In one embodiment, the present invention relates to a compound of formula (b) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,
Figure BDA0003077502510000371
represents a single bond or a double bond, provided that two +.>
Figure BDA0003077502510000372
Wherein only one represents a double bond;
X 1 is CR (CR) 3’ Or NR (NR) 3 ；
X 2 Is NR (NR) 3 ；
X 1 And substituents and adjacent carbon atoms thereof and substituents R thereof 3’ Together form a benzene ring or a 5-to 6-membered heteroaromatic ring, which is substituted with 1 to 4R 3’ Substitution;
R 3 selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;
R 3’ selected from-H, halogen, cyano, -OR, -NR' R, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl, - (CH) 2 ) n - (5-to 6-membered heteroaryl) and-SR x ；
R 4 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl); the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with halogen, cyano, -OR, -NR' R ", C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl substitution;
R 5 selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
R 1 and R2 Each independently selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r is selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r 'and R' are each selected from-H, C 1-6 Alkyl and halogenated C 1-6 Alkyl, or R' and R "together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocyclyl;
R x selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, - (CH) 2 ) n -C 2-6 Alkenyl, - (CH) 2 ) n -C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
n is 0, 1, 2 or 3.
In one embodiment, the present invention relates to a compound of formula (c), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,
Figure BDA0003077502510000381
wherein ,
R 3’ selected from-H, halogen, cyano, -OR, -NR' R, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl, - (CH) 2 ) n - (5-to 6-membered heteroaryl) and-SR x ；
R 4 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl); wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with halogen, cyano, -OR, -NR' R ", C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl substitution;
R 5 selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
R 1 and R2 Each independently selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r is selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r 'and R' are each selected from-H, C 1-6 Alkyl and halogenated C 1-6 Alkyl, or R' and R"forms together with the nitrogen atom to which they are attached a 3 to 10 membered heterocyclyl;
R x selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, - (CH) 2 ) n -C 2-6 Alkenyl, - (CH) 2 ) n -C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
n is 0, 1, 2 or 3;
t is 0, 1, 2, 3, 4 or 5.
In one embodiment, the present invention relates to a compound of formula (c) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,
R 3’ Selected from halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl and-SR x ；
R 4 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;
R 5 selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;
R 1 and R2 Each independently selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
R x selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl and- (CH) 2 ) n -C 3-6 Carbocyclyl;
n is 0, 1, 2 or 3;
t is 0, 1 or 2.
In one embodiment, the present invention relates to a compound of formula (c) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,
R 3’ selected from C 1-4 Alkyl and-SR x ；
R 4 Is C 1-4 An alkyl group;
R 5 selected from-H and C 1-4 An alkyl group;
R 1 and R2 Each independently selected from-H and C 1-4 An alkyl group;
R x selected from C 1-4 Alkyl and halogenated C 1-4 An alkyl group;
t is 1 or 2.
In one embodiment, the present invention relates to a compound of formula (c) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,
wherein ,
R 3’ is C 1-4 An alkyl group;
R 4 is C 1-4 An alkyl group;
R 5 is-H;
R 1 and R2 Each independently is methyl;
t is 1.
In one embodiment, the present invention relates to a compound of formula (c-1), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,
Figure BDA0003077502510000401
/>
wherein ,
R 3’ selected from-H, halogen, cyano, -OR, -NR' R, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and-SR x ；
R 4 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;
R 5 selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;
r is selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r 'and R' are each selected from-H, C 1-6 Alkyl and halogenated C 1-6 Alkyl, or R' and R "together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocyclyl;
R x selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, - (CH) 2 ) n -C 2-6 Alkenyl, - (CH) 2 ) n -C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
n is 0, 1, 2 or 3.
In one embodiment, the present invention relates to a compound of formula (c-1) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,
R 3’ selected from halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl and-SR x ；
R 4 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;
R 5 selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;
R x selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl and- (CH) 2 ) n -C 3-6 Carbocyclyl;
n is 0, 1, 2 or 3.
In one embodiment, the present invention relates to a compound of formula (c-1) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,
wherein ,
R 3’ selected from C 1-4 Alkyl and-SR x ；
R 4 Is C 1-4 Alkyl and halogenated C 1-4 An alkyl group;
R 5 selected from-H and C 1-4 An alkyl group;
R x selected from C 1-4 Alkyl and halogenated C 1-4 An alkyl group.
In one embodiment, the present invention relates to a compound of formula (c-1) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,
wherein ,
R 3’ is C 1-4 An alkyl group;
R 4 is C 1-4 An alkyl group;
R 5 is-H.
In one embodiment, the present invention relates to a compound of formula (d), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,
Figure BDA0003077502510000411
wherein ,
R 3 selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;
R 3’ selected from-H, halogen, cyano, -OR, -NR' R, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl, - (CH) 2 ) n - (5-to 6-membered heteroaryl) and-SR x ；
R 4 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl); wherein the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups are optionally substituted with halogen, cyano, -OR, -NR' R ", C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl substitution;
R 5 selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
R 1 and R2 Each independently selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r is selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r 'and R' are each selected from-H, C 1-6 Alkyl and halogenated C 1-6 Alkyl, or R' and R "together with the nitrogen atom to which they are attached form a 3 to 10 membered heterocyclyl;
R x selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, - (CH) 2 ) n -C 2-6 Alkenyl, - (CH) 2 ) n -C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
n is 0, 1, 2 or 3;
t is 0, 1, 2, 3 or 4.
In one embodiment, the present invention relates to a compound of formula (d) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,
R 3 Selected from C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
R 3’ selected from-H, halogen, cyano, C 1-6 Alkyl, halogenated C 1-6 Alkyl and-SR x ；
R 4 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;
R 5 selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;
R 1 and R2 Each independently selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
R x selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl and- (CH) 2 ) n -C 3-6 Carbocyclyl;
n is 0, 1, 2 or 3;
t is 0, 1 or 2.
In one embodiment, the present invention relates to a compound of formula (d) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,
R 3 is C 1-4 An alkyl group;
R 3’ selected from-H, C 1-4 Alkyl and-SR x ；
R 4 Is C 1-4 An alkyl group;
R 5 selected from-H and C 1-4 An alkyl group;
R 1 and R2 Each independently selected from-H and C 1-4 An alkyl group;
R x selected from C 1-4 Alkyl and halogenated C 1-4 An alkyl group;
t is 0 or 1.
In one embodiment, the present invention relates to a compound of formula (d) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,
wherein ,
R 3 is C 1-4 An alkyl group;
R 3’ selected from-H and C 1-4 An alkyl group;
R 4 is C 1-4 An alkyl group;
R 5 is-H;
R 1 and R2 Each independently is methyl;
t is 0 or 1.
In one embodiment, the present invention relates to a compound of formula (d-1), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,
Figure BDA0003077502510000431
wherein ,
R 3 selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;
R 3’ selected from-H, halogen, cyano, -OR, -NR' R, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and-SR x ；
R 4 Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;
R 5 selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl;
r is selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
r 'and R' are each selected from-H, C 1-6 Alkyl and halogenated C 1-6 Alkyl, or R 'and R' together with the nitrogen atom to which they are attached form 3 toA 10 membered heterocyclyl group;
R x selected from-H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, - (CH) 2 ) n -C 2-6 Alkenyl, - (CH) 2 ) n -C 2-6 Alkynyl, - (CH) 2 ) n -C 3-10 Carbocyclyl, - (CH) 2 ) n - (3-to 10-membered heterocyclic group), - (CH) 2 ) n -C 6-10 Aryl and- (CH) 2 ) n - (5-to 6-membered heteroaryl);
n is 0, 1, 2 or 3.
In one embodiment, the present invention relates to a compound of formula (d-1) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,
R 3 Selected from C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
R 3’ selected from-H, halogen, cyano, C 1-6 Alkyl and halogenated C 1- Alkyl and-SR x ；
R 4 Selected from C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
R 5 selected from-H, C 1-6 Alkyl and halogenated C 1-6 An alkyl group;
R x selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl and- (CH) 2 ) n -C 3-6 Carbocyclyl;
n is 0, 1, 2 or 3.
In one embodiment, the present invention relates to a compound of formula (d-1) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,
R 3 is C 1-4 An alkyl group;
R 3’ selected from-H, C 1-4 Alkyl and-SR x ；
R 4 Is C 1-4 An alkyl group;
R 5 selected from-H and C 1-4 An alkyl group;
R x selected from C 1-4 Alkyl and halogenated C 1-4 An alkyl group.
In one embodiment, the present invention relates to a compound of formula (d-1) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,
R 3 is C 1-4 An alkyl group;
R 3’ selected from-H and C 1-4 An alkyl group;
R 4 is C 1-4 An alkyl group;
R 5 is-H.
In one particular embodiment, the compound is selected from one of the following structures:
Figure BDA0003077502510000451
in one particular embodiment, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, and trifluoromethanesulfonate, or a combination thereof.
Preferably, the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, phosphate, acetate, maleate, succinate, fumarate, malate, oxalate, tartrate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, and trifluoromethanesulfonate, or a combination thereof.
The embodiment of the invention also provides a preparation method of the compound, which comprises the following steps:
Figure BDA0003077502510000461
performing condensation reaction on a compound 1 and a compound 2, wherein G represents a nitrogen protecting group;
and removing the nitrogen protecting group in the condensation reaction product. Embodiments of the present invention also provide a pharmaceutical composition comprising a therapeutically effective amount of a compound as described above or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, and a pharmaceutically acceptable carrier or excipient.
Embodiments of the present invention also provide the use of a compound as described above or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition that is affected by SSTR4 activation.
In one particular embodiment, the disease or condition affected by SSTR4 activation is pain.
Embodiments of the present invention also provide the use of a compound as described above or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment and/or prophylaxis of pain.
In one embodiment, the invention provides a compound of the invention or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof or a pharmaceutical composition of the invention for use in the treatment and/or prevention of a disease or condition affected by SSTR4 activation. In one embodiment, the compound or composition is for use in the treatment and/or prevention of pain.
In one embodiment, the invention provides a method of treating a disease or condition affected by activation of SSTR4 comprising administering a compound described herein or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof or a pharmaceutical composition described herein. In one embodiment, the invention provides a method of treating pain comprising administering a compound or pharmaceutical composition of the invention.
In one specific embodiment, the pain is neuralgia.
In one specific embodiment, the pain is back pain, chronic back pain, trigeminal neuralgia, complex regional pain syndrome type I, complex regional pain syndrome type II, irritable bowel syndrome, diabetic neuropathy, pain caused by osteoarthritis, tumor pain, muscle fiber pain.
The following detailed description of the invention and the advantages achieved by the embodiments are intended to help the reader to better understand the nature and features of the invention, and are not intended to limit the scope of the invention.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was performed using a (Bruker Avance III and Bruker Avance 300) magnetonuclear apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard is Tetramethylsilane (TMS).
MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
HPLC was determined using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18X10.6mm).
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-0.20 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
The known starting materials of the present invention may be synthesized using or according to methods known in the art, or may be purchased from the companies of tetan technology, an Naiji chemistry, shanghai de mer, chengdu Kelong chemical, shaoshan chemical technology, carbofuran technology, etc.
The nitrogen atmosphere is defined as the reaction flask being connected to a nitrogen balloon of about 1L volume.
The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.
The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.
The reaction was carried out under nitrogen atmosphere without specific description in the examples.
The examples are not specifically described, and the solution refers to an aqueous solution.
The temperature of the reaction was room temperature, unless otherwise specified in the examples.
The room temperature is the most suitable reaction temperature and is 20-30 ℃.
Chemical synthesis related abbreviations:
ac: acetyl group
AcOH: acetic acid
Bn: benzyl group
Boc: boc-group
Bz: benzoyl group
DIPEA: diisopropylethylamine
DMF: n, N-dimethylformamide
DCM: dichloromethane (dichloromethane)
DIEA: n, N-diisopropylethylamine
EA: acetic acid ethyl ester
Et: ethyl group
EtOAc: acetic acid ethyl ester
Et 3 N triethylamine
HATU:2- (7-aza-1H-benzotriazol-1-yl) -1, 3-tetramethyluronium hexafluorophosphate
HPLC: high performance liquid chromatography
LiHMDS: lithium hexamethyldisilazide
Me: methyl group
MeLi: methyl lithium
NMP: n-methylpyrrolidone
Raney-Ni: raney nickel
NEt 3 : triethylamine
overlapping: overnight
Raney-Ni: raney nickel
SEM: (trimethylsilyl) ethoxymethyl
SEMCl:2- (trimethylsilyl) ethoxymethyl chloride
SFC: supercritical fluid chromatography
TBTU:2- (1H-benzotriazol-1-yl) -1, 3-tetramethyluronium tetrafluoroborate
TEA: triethylamine
TEMPO:2, 6-tetramethylpiperidine oxide
THF: tetrahydrofuran (THF)
TLC: thin layer chromatography
TFA: trifluoroacetic acid
TBAF: tetra-n-butyl ammonium fluoride
Burgess' reagent: the primary gics reagent, CAS No.:29684-56-8
And rt: room temperature
h: hours of
The synthetic content is as follows:
intermediate 1:
2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-amine hydrochloride (intermediate 1)
Figure BDA0003077502510000491
The first step: (3-methylpyridin-2-yl) methylamine (1 b)
Figure BDA0003077502510000492
Compound 1a (10.0 g,84.6mmol,1 eq) was added to a 500mL autoclave, etOH (200 mL) and Raney nickel (Raney Ni) (4.00 g) were added under argon and the autoclave was sealed. The gas in the high-pressure reaction kettle is replaced by hydrogen for 3 to 4 times, and the hydrogen is continuously introduced, so that the pressure in the reaction kettle is kept at about 50Psi, and the reaction is stirred for 32 hours at 35 ℃. The reaction was stopped, the mixture was filtered through celite, washed with 50mL of EtOH, the filtrate was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound 1b (6.85 g, yield: 66.2%) as a dark purple liquid, which was used in the next reaction without purification.
1 H NMR(400MHz,CDCl 3 )δ8.52-8.40(m,1H),7.50-7.39(m,1H),7.20-6.93(m,1H),3.96(s,2H),2.92(s,3H).
MS(ESI):m/z＝123.0[M+H] + .
And a second step of: (2-methyl-1- (((3-methylpyridin-2-yl) methyl) amino) -1-oxopropan-2-yl) carbamic acid tert-butyl ester (1 c)
Figure BDA0003077502510000501
Compound 1b (5.50 g,45.0mmol,1 eq), N-t-butoxycarbonyl-2-methylalanine (9.13 g,45.0mmol,1 eq), TBTU (14.4 g,45.0mmol,1 eq) and Et 3 N (13.7 g,135mmol,3 eq) was added separately to the flask and THF (400 mL) was added and stirred at 20deg.C for 12 hours. The solvent was evaporated and the residue was diluted with 300mL of dichloromethane, washed with 1M NaOH (150 ml×2) and brine (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give compound 1c (4.35 g, yield: 31.1%) as a pale yellow solid.
MS(ESI):m/z＝308.2[M+H] + .
And a third step of: (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamic acid tert-butyl ester (1 d)
Figure BDA0003077502510000502
Compound 1c (3.80 g,12.4mmol,1 eq) was dissolved in dichloromethane (30 mL), cooled to 0deg.C, and then added with Burger reagent (Burgess' reagent) (3.55 g,14.9mmol,1.2 eq). The mixture was stirred at 20℃for 4 days. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give 1d (1.76 g, yield: 47.5%) as a pale yellow solid.
MS(ESI):m/z＝290.2[M+H] + .
Fourth step: 2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-amine hydrochloride (intermediate 1)
Figure BDA0003077502510000503
A solution of compound 1d (900 mg,3.12mmol,1 eq) in methanol (4 mL) was cooled to 0deg.C and HCl/methanol (4M, 16 mL) was added and stirred at 0deg.C for 2h. The mixture was concentrated under reduced pressure to give intermediate 1 (850 mg, crude) as a white solid, which was used directly in the next reaction.
MS(ESI):m/z＝190.2[M+H] + .
Intermediate 2:
2- (1-methyl-1H-indazol-3-yl) propan-2-amine (intermediate 2)
Figure BDA0003077502510000511
The first step: 1-methyl-1H-indazole-3-carbonitrile (2 b)
Figure BDA0003077502510000512
1H-indazole-3-carbonitrile 2a (3 g,20.9 mmol) was dissolved in dry DMF (50 mL), cooled to 0deg.C, then sodium hydrogen 60% (1.2 g,30 mmol) was added slowly in portions and stirred for 30 min. Methyl iodide (4.26 g,30 mmol) was added thereto dropwise, and the mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (50 mL. Times.2). The organic phase was dried over anhydrous sodium sulfate and dried in vacuo to give crude oil. The crude product was purified by silica gel column (petroleum ether: ethyl acetate=5:1) to give 1-methyl-1H-indazole-3-carbonitrile 2b (2.5 g, yield: 75.7%).
MS(ESI):m/z＝158.1[M+H] + .
And a second step of: 2- (1-methyl-1H-indazol-3-yl) propan-2-amine (intermediate 2)
Figure BDA0003077502510000513
Cerium trichloride (3.13 g,12.7 mmol) was stirred in dry tetrahydrofuran (30 mL) for 1 hour. Cooled to-78 ℃, methyl lithium (9.8 mL,12.7mmol, 1.3M) was added dropwise thereto, and stirring was continued for 1 hour. A solution of 1-methyl-1H-indazole-3-carbonitrile 2b (500 mg,3.18 mmol) in tetrahydrofuran (5 mL) was added dropwise thereto, followed by slowly warming to room temperature and stirring for 16 hours. The reaction mixture was quenched with 6mL of 10% aqueous sodium hydroxide solution and filtered. The filtrate was dried over anhydrous sodium sulfate and dried in vacuo to give crude yellow oil. Purification of the crude product by silica gel column (petroleum ether: ethyl acetate=1:1) afforded 2- (1-methyl-1H-indazol-3-yl) propan-2-amine (intermediate 2) (250 mg, yield: 48%).
MS(ESI):m/z＝190.1[M+H] + .
Intermediate 3-P1 and intermediate 3-P2:
3- (Boc) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid (intermediate 3-P1 and intermediate 3-P2)
Figure BDA0003077502510000521
First step 1-benzyl-3-methyl-lH-pyrrole-2, 5-dione (3 b)
Figure BDA0003077502510000522
3-methylfuran-2, 5-dione (20 g, 0.178 mol) and benzylamine (19.1 g, 0.178 mol) were stirred in glacial acetic acid (80 mL) at 100deg.C for 4 hours and the solvent was removed in vacuo. The residue was purified by a silica gel column (petroleum ether: ethyl acetate=10:1) to give 1-benzyl-3-methyl-1H-pyrrole-2, 5-dione 3b (28 g, yield: 80%) as a white solid.
MS(ESI):m/z＝202.1[M+H] + .
And a second step of: (5-benzyl-6 a-methyl-4, 6-dioxo-1, 3a,4,5,6 a-hexahydropyrrolo [3,4-c ] pyrazole-3-carboxylic acid ethyl ester (3 c)
Figure BDA0003077502510000523
1-benzyl-3-methyl-1H-pyrrole-2, 5-dione 3b (28 g,0.139 mol) and ethyl diazoacetate (48 g,0.418 mol) were stirred in toluene (100 mL) at 50℃for 3 days. The solvent was removed in vacuo. The residue was purified by silica gel column (petroleum ether: ethyl acetate=8:1) to give ethyl 5-benzyl-6 a-methyl-4, 6-dioxo-1, 3a,4,5,6 a-hexahydropyrrolo [3,4-c ] pyrazole-3-carboxylate 3c (42 g, yield: 95%) as a white solid.
MS(ESI):m/z＝316.1[M+H] + .
Third step 3-benzyl-1-methyl-2, 4-dioxo-3-azabicyclo [3.1.0] hexane-6-carboxylic acid ethyl ester (3 d)
Figure BDA0003077502510000531
5-benzyl-6 a-methyl-4, 6-dioxo-1, 3a,4,5,6 a-hexahydropyrrolo [3,4-c ] pyrazole-3-carboxylic acid ethyl ester 3c (14 g,44.4 mmol) was suspended in toluene (50 mL), warmed to 200 ℃ (temperature of oil bath), and stirred for 1 hour. Thin layer chromatography monitoring showed complete conversion of the starting material. And 3-pot reaction is carried out in parallel. The resulting black viscous residues were combined and purified by silica gel column (petroleum ether: ethyl acetate=30:1) to give 3d (22 g, yield: 57.4%) of 3-benzyl-1-methyl-2, 4-dioxo-3-azabicyclo [3.1.0] hexane-6-carboxylic acid ethyl ester as a white solid.
MS(ESI):m/z＝288.1[M+H] + .
Fourth step: 3-benzyl-1-methyl-3-azabicyclo [3.1.0] hexane-6-carbaldehyde (3 e)
Figure BDA0003077502510000532
3d (22 g,76.6 mmol) of ethyl 3-benzyl-1-methyl-2, 4-dioxo-3-azabicyclo [3.1.0] hexane-6-carboxylate was divided into 2 batches (i.e. 11 g. Times.2) and dissolved in dry THF (190 mL. Times.2), lithium aluminum hydride (5.8 g. Times.2, 153.2 mmol) was added in portions under ice-water bath and stirred at room temperature for 18 hours. The reaction solution was quenched with sodium sulfate decahydrate (59.2 g×2,183.8 mmol) in an ice-water bath. The solid was filtered off, and the filtrate was dried in vacuo to give a crude product of 3-benzyl-1-methyl-3-azabicyclo [3.1.0] hexane-6-carbaldehyde 3e (15 g, yield: 91%) as a pale yellow oil in yield: . Without purification, the mixture was directly put into the next step.
MS(ESI):m/z＝216.1[M+H] + .
Fifth step: (3-benzyl-1-methyl-3-azabicyclo [3.1.0] hex-6-yl) methanol (3 f)
Figure BDA0003077502510000533
3-benzyl-1-methyl-3-azabicyclo [3.1.0] hexane-6-carbaldehyde (15 g,69.8 mmol) was dissolved in methanol (240 mL), and sodium borohydride (660 mg,17.4 mmol) was added in portions under an ice-water bath and stirred at room temperature for 2 hours. Acetone (30 mL) was slowly added dropwise under ice-water bath to quench the reaction, and stirred for 30 minutes. Spin-drying in vacuum to obtain crude oil. The crude product was purified by silica gel column (dichloromethane: methanol=60:1) to give racemate (3-benzyl-1-methyl-3-azabicyclo [3.1.0] hex-6-yl) methanol 3f (10.1 g, light yellow oil, yield: 66.7%).
MS(ESI):m/z＝218.1[M+H] + .
Chiral resolution of 10.1 g of the racemate 3f obtained above gave 4.5g of each of 3f-P1 (compound with a short retention time) and 3f-P2 (compound with a long retention time).
Specific conditions for chiral resolution are shown in the following table:
Figure BDA0003077502510000541
sixth step: 6- (hydroxymethyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (3 g)
Figure BDA0003077502510000542
3-benzyl-1-methyl-3-azabicyclo [3.1.0] hex-6-yl) methanol 3f-P1 (4.5, 20.7 mmol) was dissolved in methanol (60 mL) and palladium on charcoal (0.45 g), triethylamine (6.3 g,62.2 mmol) and di-tert-butyl dicarbonate (6.8 g,31.1 mmol) were added. A hydrogen balloon was inserted, replaced three times with hydrogen, and then stirred at room temperature overnight. After the reaction is finished, filtering off palladium carbon, and spin-drying filtrate to obtain a crude product. Purification of the crude product over a silica gel column (petroleum ether: ethyl acetate=6:1) afforded tert-butyl 6- (hydroxymethyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylate 3g-P1 (3.1 g, light yellow oil, yield: 65.9%).
MS(ESI):m/z＝228.1[M+H] + .
3-benzyl-1-methyl-3-azabicyclo [3.1.0] hex-6-yl) methanol 3f-P2 (4.5 g,20.7 mmol) was dissolved in methanol (60 mL) and palladium on charcoal (0.45 g), triethylamine (6.3 g,62.2 mmol) and di-tert-butyl dicarbonate (6.8 g,31.1 mmol) were added. A hydrogen balloon was inserted, replaced three times with hydrogen, and then stirred at room temperature overnight. After the reaction is finished, filtering off palladium carbon, and spin-drying filtrate to obtain a crude product. Purification of the crude product on a silica gel column (petroleum ether: ethyl acetate=6:1) afforded tert-butyl 6- (hydroxymethyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylate 3g-P2 (3.5 g, pale yellow oil, yield: 74.4%).
MS(ESI):m/z＝228.1[M+H] + .
Seventh step: 3- (Boc) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid (intermediate 3-P1 and intermediate 3-P2)
Figure BDA0003077502510000551
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3g-P1 (3.1 g,13.7 mmol) of tert-butyl 6- (hydroxymethyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylate was dissolved in acetonitrile (30 mL) and 2, 6-tetramethylpiperidine nitroxide (TEMPO) (0.13 g,0.819 mmol) and 18% aqueous sodium chlorite solution (18 mL) were added at room temperature. After stirring for 5 minutes, 10% aqueous sodium hypochlorite (2 mL in 20mL water, 12 mL) was added dropwise and stirred overnight at room temperature. Extraction with ethyl acetate (40 mL. Times.2), drying of the organic phase over anhydrous sodium sulfate, and spin-drying in vacuo gave an oil which was 3- (tert-butoxycarbonyl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid intermediate 3-P1 (3.0 g, yield: 90%): . The mixture was directly taken to the next step without purification.
MS(ESI):m/z＝242.1[M+H] + .
1 HNMR(400MHz,DMSO-d 6 )δ12.20(brs,1H),3.56-3.44(m,2H),3.38-3.12(m,2H),1.81(t,1H),1.37(s,9H),1.32-1.27(m,4H).
3g-P2 (3.5 g,15.4 mmol) of tert-butyl 6- (hydroxymethyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylate (35 mL) was dissolved in acetonitrile and 2, 6-tetramethylpiperidine nitroxide (0.144 g,0.925 mmol) and 18% aqueous sodium chlorite solution (21 mL) were added at room temperature. After stirring for 5 minutes, 10% aqueous sodium hypochlorite (2 mL in 20mL water, 14 mL) was added dropwise and stirred overnight at room temperature. Extraction with ethyl acetate (40 mL. Times.2), drying of the organic phase over anhydrous sodium sulfate, and spin-drying in vacuo gave an oil which was 3- (tert-butoxycarbonyl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid intermediate 3-P2 (3.3 g, yield: 81%) which was directly fed to the next step without purification.
MS(ESI):m/z＝242.1[M+H] + .
1 HNMR(400MHz,DMSO-d 6 )δ12.22(brs,1H),3.56-3.44(m,2H),3.38-3.12(m,2H),1.81(t,1H),1.37(s,9H),1.32-1.27(m,4H).
Intermediate 4:
7-methyl-1H-indazole-3-carbonitrile (intermediate 4)
Figure BDA0003077502510000561
7-methyl-1H-indazole-3-carbonitrile 4a (1.0 g,6.39 mmol) was dissolved in dry DMF (10 mL), cooled to 0deg.C, then sodium hydrogen 60% (0.40 g,10 mmol) was slowly added, stirred for 30min, methyl iodide (1.42 g,10 mmol) was added dropwise, and the mixture was slowly warmed to room temperature and stirred for 16H. 25mL of a 10% aqueous ammonium chloride solution was quenched, extracted with ethyl acetate (50 mL. Times.2), and the filtrate dried over anhydrous sodium sulfate, dried under vacuum to give a crude product, which was purified on a silica gel column (petroleum ether: ethyl acetate=5:1) to give 7-methyl-1H-indazole-3-carbonitrile intermediate 4 (1.0 g, yield: 91.8%).
MS(ESI):m/z＝172.1[M+1] + .
Example 1
N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) -5-azaspiro [2.4] heptane-1-carboxamide hydrochloride (Compound 1)
Figure BDA0003077502510000562
The first step: 1- ((2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) -5-azaspiro [2.4] heptane-5-carboxylic acid tert-butyl ester (1B)
Figure BDA0003077502510000571
Intermediate 1 (80 mg,0.354mmol,1 eq), 5-Boc-5-azaspiro [2.4] heptane-1-carboxylic acid 1A (94 mg,0.389mmol,1.1 eq), HATU (162 mg,0.424mmol,1.2 eq) and DIPEA (184 mg,1.42mmol,4 eq) were dissolved in DMF (1.5 mL) and stirred at 25 ℃ for 12 hours. The mixture was diluted with 10mL of water and extracted with ethyl acetate (8 ml×3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give 1B (110 mg, yield: 63.1%) as a pale yellow solid.
MS(ESI):m/z＝413.2[M+H] + .
And a second step of: n- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) -5-azaspiro [2.4] heptane-1-carboxamide hydrochloride (Compound 1)
Figure BDA0003077502510000572
Compound 1B (110 mg,0.36mmol,1 eq) was dissolved in ethyl acetate (2 mL), cooled to 0deg.C, HCl/ethyl acetate (4M, 6 mL) was added, and stirred at 0deg.C for 1 hour. The mixture was concentrated under reduced pressure to give a residue. To the residue were added 30mL of purified water and 1mL of MeCN, followed by lyophilization, to give compound 1 (70 mg, yield: 75.2%) as a gray solid.
1 H NMR(400MHz,CD 3 OD)δ8.53-8.43(dd,1H),8.08(s,1H),7.09-7.21(m,1H),7.05(d,1H),3.36-3.47(m,1H),3.27-3.30(m,1H),3.17-3.25(m,1H),3.06-3.14(m,1H),2.54(s,3H),2.09-2.18(m,1H),1.95(m,6H),1.77-1.90(m,2H),1.60-1.70(m,1H),1.03(m,1H).
MS(ESI):m/z＝313.1[M+H] + .
Example 2
(3 aR,5r,6 aS) -N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide hydrochloride (Compound 2)
Figure BDA0003077502510000581
The first step: (3 aR,5r,6 aS) -5- ((2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (2B)
Figure BDA0003077502510000582
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Intermediate 1 (40 mg,0.177mmol,1 eq), compound 2A (CAS No.: 442877-23-8) (45 mg,0.177mmol,1.1 eq), HATU (81 mg,0.212mmol,1.2 eq) and DIPEA (92 mg, 0.178 mmol,4 eq) were dissolved in DMF (1 mL) and the solution stirred at 25℃for 12 hours. The mixture was diluted with 10mL of water and extracted with ethyl acetate (8 ml×3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give 2B (60 mg, yield: 66.5%) as a pale yellow solid.
1 H NMR(400MHz,CDCl 3 )δ7.94-7.92(m,1H),7.34(s,1H),6.91(s,1H),6.51-6.48(m,2H),3.48-3.43(m,2H),3.17-3.37(m,2H),2.71-2.85(m,1H),2.55-2.69(m,2H),2.41(s,3H),2.14(m,2H),1.91(s,6H),1.74-1.70(m,2H),1.44(s,9H).
MS(ESI):m/z＝427.2[M+H] + .
And a second step of: (3 aR,5r,6 aS) -N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide hydrochloride (Compound 2)
Figure BDA0003077502510000583
A solution of compound 2B (60 mg,0.14mmol,1 eq) in ethyl acetate (2 mL) was cooled to 0deg.C, HCl/ethyl acetate (4M, 6 mL) was added and stirred at 0deg.C for 1h. The mixture was concentrated under reduced pressure to give a residue. To the residue were added 30mL of water and 1mL of MeCN, followed by lyophilization to give compound 2 (50 mg, yield: 97.9%) as an orange oil.
1 H NMR(400MHz,CD 3 OD)δ8.37(d,1H),8.08(s,1H),7.13-7.05(m,1H),7.05-6.98(m,1H),3.28-3.23(m,2H),3.08(d,2H),2.81-2.97(m,3H),2.52(s,3H),2.16-2.28(m,2H),1.90(s,6H),1.39-1.50(m,2H).
MS(ESI):m/z＝327.1[M+H] + .
Example 3
(3 aR,5s,6 aS) -N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide hydrochloride (Compound 3)
Figure BDA0003077502510000591
The first step: (3 aR,5s,6 aS) -5- ((2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (3B)
Figure BDA0003077502510000592
Intermediate 1 (40 mg,0.177mmol,1 eq), compound 3A (CAS: 1401464-09-2) (45 mg,0.177mmol,1.1 eq), HATU (81 mg,0.212mmol,1.2 eq) and DIPEA (92 mg,1.42mmol,4 eq) were dissolved in DMF (1 mL) and the solution was stirred at 25℃for 1 hour. The mixture was diluted with 10mL of water and extracted with ethyl acetate (8 ml×3). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give 3B (60 mg, yield: 66.5%) as a pale yellow solid.
1 H NMR(400MHz,CDCl 3 )δ7.95(br s,1H),7.37(s,1H),6.86(s,1H),6.49(m,2H),3.54(m,2H),3.15(m,2H),2.84-2.91(m,1H),2.80(m,2H),2.43(s,3H),2.07-2.12(m,2H),1.92(s,6H),1.78(m,2H),1.48(s,9H).
MS(ESI):m/z＝427.2[M+H] + .
And a second step of: (3 aR,5s,6 aS) -N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide hydrochloride (Compound 3)
Figure BDA0003077502510000601
Compound 3B (60 mg,0.14mmol,1 eq) was dissolved in ethyl acetate (2 mL), cooled to 0deg.C, HCl/ethyl acetate (4M, 6 mL) was added, and stirred at 0deg.C for 2h. The mixture was concentrated under reduced pressure to give a residue. To the residue was added 30mL of purified water, 1mL of MeCN, and then lyophilized to give compound 3 (33 mg, yield: 64.7%) as a pale yellow oil.
1 H NMR(400MHz,CD 3 OD)δ8.40(d,1H),8.07(s,1H),7.12-7.05(m,1H),7.04-6.98(m,1H),3.44-3.55(m,2H),3.00-3.14(m,1H),2.80-2.96(m,4H),2.52(s,3H),1.90(s,6H),1.72-1.83(m,4H).
MS(ESI):m/z＝327.1[M+H] + .
Example 4
(3 aR,5s,6 aS) -N- (2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide hydrochloride (Compound 4)
Figure BDA0003077502510000602
The first step: 2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-amine (4B)
Figure BDA0003077502510000603
Cerium trichloride (1.15 g,4.67 mmol) was stirred in dry tetrahydrofuran (10 mL) for 1 hour, cooled to-78 ℃, and methyllithium (2.35 mL,4.67mmol, 2M) was added dropwise and stirred for 1 hour. A solution of 1, 7-dimethyl-1H-indazole-3-carbonitrile (intermediate 4) (200 mg,1.17 mmol) in tetrahydrofuran (5 mL) was added dropwise thereto, and the mixture was slowly warmed to room temperature and stirred for 16 hours. Quench with 1mL of 20% aqueous sodium hydroxide, filter, dry the filtrate over anhydrous sodium sulfate, spin-dry under vacuum to give 4B as a yellow oil (180 mg, crude, unpurified).
And a second step of: (3 aR,5s,6 aS) -N- (2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide hydrochloride (Compound 4)
Figure BDA0003077502510000611
2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-amine 4B (60 mg,0.3 mmol), compound 3A (75 mg,0.3 mmol), HATU (170 mg,0.45 mmoL) and diisopropylethylamine (78 mg,0.6 mmol) were dissolved in N, N-dimethylformamide (1 mL) and stirred at room temperature for 16H and the reaction was purified by preparative HPLC to give a white solid (75 mg). The product was added to a 3M ethyl acetate hydrochloride solution (4 mL), stirred for 2 hours, and the solvent was removed in vacuo to give compound 4 (45 mg, yield: 36.8%) as a white solid.
1 H NMR(400MHz,CD 3 OD)δ7.82(d,1H),7.28(d,1H),7.08(t,1H),4.35(s,3H),3.51-3.49(m,2H),3.11-3.01(m,1H),3.04-2.90(m,4H),2.78(s,3H),1.83-1.76(m,10H).
MS(ESI):m/z＝341.1[M+H] + .
Example 5
(1R, 3r, 5S) -N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) -8-azabicyclo [3.2.1] octane-3-carboxamide hydrochloride (Compound 5)
Figure BDA0003077502510000612
Intermediate 1 (50 mg,0.26 mmol), compound 5A (CAS: 1222996-05-5) (66 mg,0.26 mmol), HATU (148 mg,0.39 mmol) and diisopropylethylamine (101 mg,0.78 mmol) were dissolved in N, N-dimethylformamide (2 mL) and stirred at room temperature for 16 hours. Ethyl acetate (60 mL) was added, and the mixture was washed successively with water, saturated brine, dried over anhydrous sodium sulfate and spun-dried in vacuo to give a yellow crude product (75 mg). The crude product was added to a 4M solution of dioxane (dioxane) hydrochloric acid (4 mL), stirred at room temperature for 2 hours, and the solvent was removed in vacuo. Purification of the residue by preparative HPLC gave (1R, 3r, 5S) -N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) -8-azabicyclo [3.2.1] octane-3-carboxamide hydrochloride as a white solid (34 mg, yield: 39.3%).
1 H NMR(400MHz,CD 3 OD)δ8.78(s,1H),8.42(d,1H),8.10(s,1H),7.09-7.05(m,2H),3.94-3.75(m,2H),2.88-2.85(m,1H),2.54(s,3H),2.28-2.24(m,4H),1.94(s,6H),1.88-1.85(m,4H).
MS(ESI):m/z＝327.2[M+H] + .
Example 6
N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) -2-azabicyclo [2.2.1] heptane-5-carboxamide hydrochloride (Compound 6)
Figure BDA0003077502510000621
The first step: tert-butyl 5- ((2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) tert-butyl-2-azabicyclo [2.2.1] heptane-2-carboxylate (6B)
Figure BDA0003077502510000622
Intermediate 1 (50 mg, 0.26 mmol) was dissolved in DMF (0.5 mL), 2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] heptane-5-carboxylic acid (127.51 mg,0.53 mmol), N-diisopropylethylamine (68.25 mg,0.53 mmol) and HATU (150.79 mg,0.40 mmol) were added at room temperature and the reaction stirred at room temperature for 8 hours. Ethyl acetate (3 mL) was added to the reaction mixture, which was washed with saturated brine (10 mL. Times.3) and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1 to 1:3) to give compound 6B (50 mg, yield: 45.9%) as a white solid.
MS(ESI):m/z＝413.0[M+H] +
And a second step of: n- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) -2-azabicyclo [2.2.1] heptane-5-carboxamide hydrochloride (Compound 6)
Figure BDA0003077502510000631
6B (50 mg,0.12 mmol) was dissolved in dioxane hydrochloride solution (1 mL) and reacted at room temperature for 1 hour. The reaction was concentrated, ethyl acetate (3 mL) was added, slurried and filtered. Lyophilization afforded the compound as a white solid, which was N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) -2-azabicyclo [2.2.1] heptane-5-carboxamide hydrochloride compound 6 (25 mg, yield: 67.7%).
1 H NMR(400MHz,CD 3 OD)δ9.07(s,1H),8.39(d,1H),8.09(s,1H),7.17–6.95(m,2H),3.98(m,1H),3.11(m,1H),3.01(m,1H),2.89(m,1H),2.78(m,1H),2.52(s,3H),1.95–1.81(m,10H).
MS(ESI):m/z＝313.0[M+H] + .
Example 7
(3 aR,5s,6 aS) -N- (2- (7-methyl-1H-indazol-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide (Compound 7)
Figure BDA0003077502510000632
The first step: 7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole-3-carbonitrile (7B)
Figure BDA0003077502510000641
7-methyl-1H-indazole-3-carbonitrile 7A (1 g,6.36 mmol) was dissolved in dry DMF (5 mL), cooled to 0deg.C, then NaH (370 mg,9.54 mmol) was slowly added and stirred for 30 min. (2- (chloromethoxy) ethyl) trimethylsilane (1.60 g,9.54 mmol) was added dropwise thereto, and the mixture was slowly warmed to room temperature and stirred for 16 hours. Quench with 5mL of 10% aqueous ammonium chloride and extract with ethyl acetate (100 mLX 2). The filtrate was dried over anhydrous sodium sulfate and dried in vacuo to give an oil. The oil was purified by column on silica gel (petroleum ether: ethyl acetate=5:1) to give 7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole-3-carbonitrile 7B (1.2 g, yield: 65.9%).
And a second step of: 2- (7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) propan-2-amine (7C)
Figure BDA0003077502510000642
Cerium trichloride (320 mg,1.3 mmol) was stirred in dry tetrahydrofuran (5 mL) for 1 hour, cooled to-78deg.C, and methyllithium (1 mL,1.3mmol, 1.3M) was added dropwise and stirred for 1 hour. A solution of 7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole-3-carbonitrile 7B (100 mg,0.32 mmol) in tetrahydrofuran (1 mL) was added dropwise, slowly warmed to room temperature and stirred for 16 hours. Quench with 1mL of 10% aqueous sodium hydroxide, filter, dry the filtrate over anhydrous sodium sulfate, spin-dry in vacuo to give a yellow oil which is 2- (7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) propan-2-amine 7C (80 mg, crude, unpurified).
And a third step of: (3 aR,5s,6 aS) -5- ((2- (7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) propan-2-yl) carbamoyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (7D)
Figure BDA0003077502510000643
2- (7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) propan-2-amine 7C (60 mg,0.18 mmol), the compound (3 aR,5s,6 aS) -2- (tert-butoxycarbonyl) octahydrocyclopenta [ C ] pyrrole-5-carboxylic acid (75 mg,0.18 mmol), HATU (64 mg,0.25 mmoL) and diisopropylethylamine (78 mg,0.6 mmol) were dissolved in N, N-dimethylformamide (1 mL) and stirred at room temperature for 16H. The reaction solution was purified by preparative HPLC to give 7D (75 mg, yield: 75%) as a white solid.
MS(ESI):m/z＝501.0[M-55] + .
Fourth step: (3 aR,5s,6 aS) -N- (2- (7-methyl-1H-indazol-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide (Compound 7)
Figure BDA0003077502510000651
(3 aR,5s,6 aS) -5- ((2- (7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) propan-2-yl) carbamoyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester 7D (75 mg,0.13 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 3 hours. The solvent was dried by rotation and the resulting residue was purified by preparative HPLC to give a white solid which was compound 7 (20 mg, yield: 45%).
1 H NMR(400MHz,CDCl 3 )δ7.64(d,1H),7.14(m,2H),7.07(d,1H),3.19(m,1H),2.75(m,3H),2.57(m,1H),2.52(s,3H),2.00(m,4H),1.91(s,6H),1.75(m,2H).
MS(ESI):m/z＝327.2[M+H] + .
Example 8
1-methyl-N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) -3-azabicyclo [3.1.0] hexane-6-carboxamide (Compound 8)
Figure BDA0003077502510000661
The first step: 1-benzyl-3-methyl-1H-pyrrole-2, 5-dione (8B)
Figure BDA0003077502510000662
3-methylfuran-2, 5-dione 8A (5.0 g,44.61 mmol) and benzyl amine (4.78 g,44.61 mmol) were stirred in glacial acetic acid (20 mL) at 100deg.C for 4 hours. The solvent was removed in vacuo and the residue was purified by silica gel column (petroleum ether: ethyl acetate=3:1) to give 1-benzyl-3-methyl-1H-pyrrole-2, 5-dione 8B (8.3 g, yield: 92.4%) as a white solid.
And a second step of: 5-benzyl-6 a-methyl-4, 6-dioxo-1, 3a,4,5,6 a-hexahydropyrrolo [3,4-C ] pyrazole-3-carboxylic acid ethyl ester (8C)
Figure BDA0003077502510000663
1-benzyl-3-methyl-1H-pyrrole-2, 5-dione 8B (4.0 g,19.88 mmol) and ethyl diazoacetate (9.07 g,79.51 mmol) were stirred in toluene (30 mL) at 50℃for 4 days. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=2:1) to give 8C (5.7 g, yield: 95.1%) as a white solid.
Third step 3-benzyl-1-methyl-2, 4-dioxo-3-azabicyclo [3.1.0] hexane-6-carboxylic acid ethyl ester (8D)
Figure BDA0003077502510000671
8C (3.0 g,9.96 mmol) was stirred at 200deg.C for 1 hour. The residue was purified by a silica gel column (petroleum ether: ethyl acetate=4:1) to give 8D (1.9 g, yield: 66.4%) as a white solid.
Fourth step: (3-benzyl-1-methyl-3-azabicyclo [3.1.0] hex-6-yl) methanol (8E)
Figure BDA0003077502510000672
8D (1.7 g,5.92 mmol) was dissolved in dry THF (30 mL), lithium aluminum hydride (0.829 g,29.60 mmol) was added in portions under a water bath and stirred at room temperature for 18 hours. Quench with 30mL of 10% aqueous ammonium chloride and extract with ethyl acetate (100 mL. Times.3). The filtrate was dried over anhydrous sodium sulfate and dried in vacuo to give an oil. The oil was purified by silica gel column (dichloromethane: methanol=20:1) to give 8E (0.8 g, yield: 62.5%) as a pale yellow oil.
MS(ESI):m/z＝218.1[M+H] + .
Fifth step: 6- (hydroxymethyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (8F)
Figure BDA0003077502510000673
8E (700 mg,3.22 mmol) was dissolved in methanol (10 mL), palladium on charcoal (50 mg), triethylamine (966 mg,9.66 mmol) and di-tert-butyl dicarbonate (1.05 g,4.83 mmol) were added. A hydrogen balloon was inserted, replaced three times with hydrogen, and then stirred at room temperature overnight. After the reaction is finished, filtering off palladium carbon, and spin-drying filtrate to obtain a crude product. The crude product was purified by silica gel column (dichloromethane: methanol=10:1) to give 8F (350 mg, yield: 47.8%) as a pale yellow oil.
MS(ESI):m/z＝172.1[M-55] + .
Sixth step: 3- (Boc) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid (8G)
Figure BDA0003077502510000674
8F (100 mg,0.44 mmol) was dissolved in acetonitrile (1 mL), 2, 6-tetramethylpiperidine nitroxide (3.4 mg,0.022 mmol) and 10% aqueous sodium chlorite solution (79.2 mg,0.88 mmol) were added at room temperature and stirred for 30 min. Then 10% aqueous sodium hypochlorite (65 mg,0.88 mmol) was added. Stirred overnight at room temperature and extracted with ethyl acetate (10 ml x 2). The filtrate was dried over anhydrous sodium sulfate, and dried in vacuo to give 8G as an oil, which was directly fed to the next reaction without purification (80 mg, yield: 75%).
MS(ESI):m/z＝186.1[M-55] + .
Seventh step: 1-methyl-6- ((2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (8H)
Figure BDA0003077502510000681
8G (80 mg,0.33 mmol), intermediate 1 (62.7 mg,0.33 mmol), HATU (190 mg,0.5 mmol) and triethylamine (99 mg,0.99 mmol) were dissolved in N, N-dimethylformamide (1 mL) and stirred at room temperature for 16 h. The reaction was extracted with ethyl acetate (10 ml x 2), and the filtrate was dried over anhydrous sodium sulfate and dried under vacuum to give an oil. The oil was purified by column chromatography (petroleum ether: ethyl acetate=2:1) to give product 8H (70 mg, yield: 75%).
MS(ESI):m/z＝413.1[M+H] + .
Eighth step: 1-methyl-N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) -3-azabicyclo [3.1.0] hexane-6-carboxamide (Compound 8)
Figure BDA0003077502510000682
8H (70 mg,0.169 mmol) was dissolved in 4M hydrogen chloride in methanol (2 mL,8 mmol) and stirred at room temperature for 18 hours. The solvent was dried by rotation, and the residue was purified by preparative HPLC to give compound 8 (20 mg, yield: 37.7%) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ8.04-7.97(m,1H),7.34(s,1H),6.47(d,2H),3.07(m,3H),2.88(d,1H),2.40(s,3H),1.90(s,6H),1.87(m,1H),1.62(d,1H),1.22(s,3H).
MS(ESI):m/z＝313.1[M+H] + .
Referring to the synthesis method of example 8, compound 8-P1 was synthesized using intermediate 3-P1 and intermediate 1. The intermediate 3-P2 is used for synthesizing the compound 8-P2 from the intermediate 1. Compound 8-P1 and compound 8-P2 are optically pure isomers of compound 8.
1-methyl-N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) -3-azabicyclo [3.1.0] hexane-6-carboxamide (Compound 8-P1)
MS(ESI):m/z＝313.1[M+H] + .
1 H NMR(400MHz,DMSO-d6)：δ8.37(s,1H),8.12(d,1H),7.22(s,1H),6.53–6.47(m,2H),2.92-2.77(m,3H),2.67–2.61(m,1H),2.33(s,3H),2.03–1.91(m,2H),1.67(s,3H),1.63(s,3H),0.98(s,3H).
1-methyl-N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) -3-azabicyclo [3.1.0] hexane-6-carboxamide (Compound 8-P2)
MS(ESI):m/z＝313.1[M+H] + .
1 H NMR(400MHz,DMSO-d6)：δ8.45(s,1H),8.12(d,1H),7.22(s,1H),6.54–6.47(m,2H),3.02–2.90(m,3H),2.75(d,1H),2.33(s,3H),2.03–1.97(m,1H),1.72(d,1H),1.68(s,3H),1.63(s,3H),0.96(s,3H).
Example 9
N- (2- (8-methylimidazole [1,5-a ] pyridin-3-yl) propan-2-yl) -5-azaspiro [2.4] heptane-1-carboxamide (Compound 9)
Figure BDA0003077502510000691
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The first step: 1- ((2- (8-methylimidazole [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) -5-azaspiro [2.4] heptane-5-carboxylic acid benzyl ester (9B)
Figure BDA0003077502510000701
5- ((phenoxy) carbonyl) -5-azaspiro [2.4] heptane-1-carboxylic acid 9A (500 mg,1.82 mmol) and HATU (760 mg,1.99 mmol) were in dry N, N-dimethylformamide (10 mL) and stirred at room temperature for half an hour. 2- (8-methylimidazole [1,5-a ] pyridin-3-yl) propan-2-amine intermediate 1 (344 mg,1.82 mmol) and triethylamine (0.5 mL) were then added and the reaction stirred at room temperature overnight. The reaction mixture was poured into water, extracted with ethyl acetate, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was spun-dried in vacuo and the crude product purified by preparative HPLC to give 9B-P1 (140 mg) and 9B-P2 (150 mg).
MS(ESI):m/z＝447.1[M+H] + .
Chiral resolution of 9B-P1 gave 9B-P1-1 (70 mg, compound with shorter retention time) and 9B-P1-2 (65 mg, compound with longer retention time). The conditions for chiral resolution are shown in the following table:
Figure BDA0003077502510000702
Figure BDA0003077502510000711
Chiral resolution of 9B-P2 gave 9B-P2-1 (65 mg, compound with shorter retention time) and 9B-P2-2 (80 mg, compound with longer retention time). The conditions for chiral resolution are shown in the following table:
Figure BDA0003077502510000712
and a second step of: n- (2- (8-methylimidazole [1,5-a ] pyridin-3-yl) propan-2-yl) -5-azaspiro [2.4] heptane-1-carboxamide (Compound 9)
Figure BDA0003077502510000713
Benzyl 1- ((2- (8-methylimidazol [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) -5-azaspiro [2.4] heptane-5-carboxylate 9B-P1-1 (70 mg,0.157 mmol) was dissolved in dichloromethane (3 mL), then boron tribromide (197mg, 0.786 mmol) was added and the reaction stirred at room temperature for half an hour. Spin-drying in vacuo at a water bath temperature of no more than 20 ℃ to remove excess boron tribromide. The residue is then adjusted to pH 7-8 with saturated aqueous sodium bicarbonate solution and then dried in vacuo to give the crude product. The crude product was purified by preparative HPLC to give compound 9 (14 mg, yield: 28.6%) as a white solid.
MS(ESI):m/z＝313.0[M+H] + .
1 H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.15–8.07(m,1H),7.22(s,1H),6.57–6.42(m,2H),2.87–2.75(m,2H),2.44–2.27(m,5H),1.89–1.78(m,1H),1.75–1.54(m,8H),0.90–0.79(m,2H).
Example 10
N- (2- (8-methylimidazole [1,5-a ] pyridin-3-yl) propan-2-yl) -5-azaspiro [2.4] heptane-1-carboxamide (Compound 10)
Figure BDA0003077502510000721
Benzyl 1- ((2- (8-methylimidazol [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) -5-azaspiro [2.4] heptane-5-carboxylate 9B-P1-2 (65 mg,0.146 mmol) was dissolved in dichloromethane (3 mL), then boron tribromide (183mg, 0.73 mmol) was added and the reaction stirred at room temperature for half an hour. Excess boron tribromide was removed by vacuum spin-drying at a water bath temperature of no more than 20 ℃. The residue is then adjusted to pH 7-8 with saturated aqueous sodium bicarbonate solution and then dried in vacuo to give the crude product. The crude product was purified by preparative HPLC to give compound 10 (6 mg, yield: 13.2%) as a white solid.
MS(ESI):M/Z＝313.0[M+H] + .
1 H NMR(400MHz,DMSO-d6)δ8.52(s,1H),8.15–8.07(m,1H),7.22(s,1H),6.57–6.42(m,2H),3.02–2.80(m,3H),2.33(m,1H),1.91–1.70(m,3H),1.68(s,3H),1.62(s,3H)0.92–0.79(m,2H).
Example 11
N- (2- (8-methylimidazole [1,5-a ] pyridin-3-yl) propan-2-yl) -5-azaspiro [2.4] heptane-1-carboxamide (Compound 11)
Figure BDA0003077502510000731
Benzyl 1- ((2- (8-methylimidazol [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) -5-azaspiro [2.4] heptane-5-carboxylate 9B-P2-1 (65 mg,0.146 mmol) was dissolved in dichloromethane (3 mL), then boron tribromide (183mg, 0.73 mmol) was added and the reaction stirred at room temperature for half an hour. And (3) removing excessive boron tribromide by vacuum spin-drying at the water bath temperature of not more than 20 ℃, regulating the pH value of the residue to 7-8 by using saturated sodium bicarbonate aqueous solution, and then obtaining a crude product by vacuum spin-drying. The crude product was purified by preparative HPLC to give compound 11 (10 mg, yield: 22.0%) as a white solid.
MS(ESI):M/Z＝313.0[M+H] + .
1 H NMR(400MHz,CD 3 OD)δ8.14(d,1H),7.30(s,1H),6.62–6.51(m,2H),3.02–2.77(m,4H),2.39(s,3H),1.87–1.72(m,7H),1.62–1.45(m,2H),1.07–0.93(m,2H).
Example 12
N- (2- (8-methylimidazole [1,5-a ] pyridin-3-yl) propan-2-yl) -5-azaspiro [2.4] heptane-1-carboxamide (Compound 12)
Figure BDA0003077502510000741
Benzyl 1- ((2- (8-methylimidazol [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) -5-azaspiro [2.4] heptane-5-carboxylate 9B-P2-2 (80 mg, 0.178 mmol) was dissolved in dichloromethane (3 mL), followed by the addition of boron tribromide (224 mg,0.894 mmol) and the reaction stirred at room temperature for half an hour. And (3) removing excessive boron tribromide by vacuum spin-drying at the water bath temperature of not more than 20 ℃, regulating the pH value of the residue to 7-8 by using saturated sodium bicarbonate aqueous solution, and then obtaining a crude product by vacuum spin-drying. The crude product was purified by preparative HPLC to give compound 12 (19 mg, yield: 34.0%) as a white solid.
MS(ESI):M/Z＝313.0[M+H] + .
1 H NMR(400MHz,CD 3 OD)δ8.14(d,1H),7.30(s,1H),6.62–6.51(m,2H),3.07–2.84(m,4H),2.39(s,3H),1.89–1.72(m,7H),1.66–1.52(m,2H),1.09–0.96(m,2H).
Example 13
N- (2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-yl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxamide formate salt (Compound 13)
Figure BDA0003077502510000751
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The first step: 2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-amine (13B)
Figure BDA0003077502510000752
Cerium trichloride (1.71 g,6.97 mmol) was stirred in anhydrous tetrahydrofuran (20 mL) for 1 hour. Cooled to-78 ℃, methyl lithium (5.4 mL,6.97mmol, 1.3M) was added dropwise thereto, and stirred for 1 hour. A solution of 7-methyl-1H-indazole-3-carbonitrile (intermediate 4) (300 mg,1.74 mmol) in anhydrous tetrahydrofuran (3 mL) was then added dropwise thereto, slowly warmed to room temperature and stirred for 16 hours. Quenched with 8mL of 10% aqueous sodium hydroxide, filtered, and the filtrate dried over anhydrous sodium sulfate, and spun-dried in vacuo to give a crude yellow oil. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give 2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-amine 13B (180 mg, yield: 50.5%).
MS(ESI):m/z＝204.1[M+H] + .
And a second step of: 6- ((2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (13C)
Figure BDA0003077502510000753
2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-amine 13B (180 mg,0.96 mmol), the compound 3- (tert-butoxycarbonyl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid (232 mg,0.96 mmol), HATU (547 mg,1.44 mmoL) and triethylamine (303 mg,3.0 mmol) were dissolved in N, N-dimethylformamide (3 mL) and stirred at room temperature for 16H. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and dried in vacuo to give an oil. Purification on a silica gel column (petroleum ether: ethyl acetate=1:1) afforded 6- ((2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester 13C (200 mg, yield: 48.6%).
Chiral resolution yielded 13C-P1 (80 mg, compound with shorter retention time) and 13C-P2 (80 mg, compound with longer retention time).
The conditions for chiral resolution are shown in the following table:
Figure BDA0003077502510000761
MS(ESI):m/z＝427.1[M+H] + .
and a third step of: n- (2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-yl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxamide formate salt (Compound 13)
Figure BDA0003077502510000771
6- ((2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester 13C-P1 (75 mg,0.17 mmol) was dissolved in 3N dioxane hydrochloride (2 mL) and stirred at room temperature for 3 hours. The reaction solution is dried by spin to obtain crude product. The crude product was purified by preparative HPLC to give N- (2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-yl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxamide formate salt (compound 13) (13.6 mg, yield: 23.8%).
MS(ESI):m/z＝327.1[M+H] + .
1 H NMR(400MHz,CD 3 OD)δ8.49(s,1H),7.65(d,1H),7.05(d,1H),6.96–6.85(m,1H),4.24(s,3H),3.45-3.33(m,3H),3.23(d,1H),2.74(s,3H),1.94(t,1H),1.85-1.72(m,7H),1.12(s,3H).
Example 14
N- (2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-yl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxamide (Compound 14)
Figure BDA0003077502510000772
6- ((2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester 13C-P2 (75 mg,0.17 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and stirred at room temperature for 3 hours. The reaction solution was spin-dried to remove the solvent and trifluoroacetic acid. The pH of the residue is regulated to be alkalescent by ammonia water, and the residue is dried by spin to obtain a crude product. The crude product was purified by preparative thin layer chromatography (prep-TLC) to give N- (2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-yl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxamide (compound 14) (19.8 mg, yield: 34.7%).
MS(ESI):m/z＝327.2[M+H] + .
1 H NMR(400MHz,CD 3 OD)δ7.66(d,1H),7.05(d,1H),6.91(t,1H),4.24(s,3H),3.04–2.90(m,3H),2.73–2.71(m,4H),1.77(s,3H),1.75(s,3H),1.64(m,1H),1.57(d,1H),1.06(s,3H).
Example 15
1-methyl-N- (2- (7-methyl-1H-indazol-3-yl) propan-2-yl) -3-azabicyclo [3.1.0] hexane-6-carboxamide (Compound 15)
Figure BDA0003077502510000781
(7C Synthesis method reference example 7)
The first step: 1-methyl-6- ((2- (7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) propan-2-yl) carbamoyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (15A)
Figure BDA0003077502510000782
2- (7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) propan-2-amine 7C (140 mg,0.43 mmol), the compound 3- (tert-butoxycarbonyl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid 8G (106 mg,0.43 mmol), HATU (190 mg,0.5 mmol) and triethylamine (150 mg,1.5 mmol) were dissolved in N, N-dimethylformamide (2 mL) and stirred at room temperature for 16H. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and dried in vacuo to give crude oil. The crude product was purified by column on silica gel (petroleum ether: ethyl acetate=1:1) to give 1-methyl-6- ((2- (7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) propan-2-yl) carbamoyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester compound 15A (150 mg, yield: 47.3%).
After chiral resolution 15A-P1 (60 mg, compound with shorter retention time) and 15A-P2 (60 mg, compound with longer retention time) were obtained.
The conditions for chiral resolution are shown in the following table:
Figure BDA0003077502510000791
MS(ESI):m/z＝543.2[M+H] + .
and a second step of: 1-methyl-N- (2- (7-methyl-1H-indazol-3-yl) propan-2-yl) -3-azabicyclo [3.1.0] hexane-6-carboxamide (Compound 15)
Figure BDA0003077502510000792
(1R, 5R, 6R) -1-methyl-6- ((2- (7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) propan-2-yl) carbamoyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester 15A-P1 (60 mg,0.11 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 3 hours. The reaction solution is dried by spin to remove the solvent and trifluoroacetic acid, the residue is adjusted to be alkalescent by ammonia water, and the crude product is obtained by spin drying. The crude product was purified by preparative thin layer chromatography (prep-TLC) to give compound 15 (21.4 mg, yield: 44.5%).
MS(ESI):m/z＝313.1[M+H] + .
1 H NMR(400MHz,CD 3 OD)δ7.67(d,1H),7.08(s,1H),6.97(t,1H),3.42-3.33(m,2H),3.17(s,2H),2.51(s,3H),1.91(s,1H),1.81(d,6H),1.71(d,1H),1.13(s,3H).
Example 16
1-methyl-N- (2- (7-methyl-1H-indazol-3-yl) propan-2-yl) -3-azabicyclo [3.1.0] hexane-6-carboxamide (Compound 16)
Figure BDA0003077502510000801
1-methyl-6- ((2- (7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) propan-2-yl) carbamoyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester 15A-P2 (60 mg,0.11 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added and stirred at room temperature for 3 hours. The reaction solution was dried by spin-drying to remove the solvent and trifluoroacetic acid. The pH of the residue is regulated to be alkalescent by ammonia water, and the residue is dried by spin to obtain a crude product. The crude product was purified by preparative thin layer chromatography (prep-TLC) to give the product (compound 16) (10.4 mg, yield: 20.4%).
MS(ESI):m/z＝313.1[M+H] + .
1 H NMR(400MHz,CD 3 OD)δ7.67(d,1H),7.09(d,1H),6.97(t,1H),3.45-3.33(m,3H),3.18(d,1H),2.51(s,3H),1.91(s,1H),1.81(d,6H),1.74(s,1H),1.13(s,3H).
Example 17
(3 aR,5s,6 aS) -N- (2- (1-methyl-1H-indazol-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide formate salt (Compound 17)
Figure BDA0003077502510000811
The first step: (3 aR,5s,6 aS) -5- ((2- (1-methyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (17A)
Figure BDA0003077502510000812
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2- (1-methyl-1H-indazol-3-yl) propan-2-amine (intermediate 2) (80 mg,0.42 mmol), the compound (3 aR,5s,6 aS) -2- (tert-butoxycarbonyl) octahydrocyclopenta [ c ] pyrrole-5-carboxylic acid 3A (108 mg,0.42 mmol), HATU (239 mg,0.63 mmol) and triethylamine (202 mg,2.0 mmol) were dissolved in N, N-dimethylformamide (2 mL) and stirred at room temperature for 16H. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and dried in vacuo to give crude oil. The crude product was purified by column on silica gel (petroleum ether: ethyl acetate=1:1) to give (3 ar,5s,6 as) -5- ((2- (1-methyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester 17A (50 mg, yield: 27.7%).
MS(ESI):m/z＝427.2[M+H] + .
And a second step of: (3 aR,5s,6 aS) -N- (2- (1-methyl-1H-indazol-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide formate salt (Compound 17)
Figure BDA0003077502510000821
(3 aR,5s,6 aS) -5- ((2- (1-methyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester 17A (40 mg,0.093 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.5 mL) was added, and stirred at room temperature for 3 hours. The reaction solution was dried by spin-drying, and the residue was purified by preparative HPLC to give (3 aR,5s,6 aS) -N- (2- (1-methyl-1H-indazol-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide formate salt (compound 17) as a white solid (4 mg, yield: 13.3%).
MS(ESI):m/z＝327.2[M+H] + .
1 H NMR(400MHz,CD 3 OD)δ8.56(s,1H),7.82(d,1H),7.45(d,1H),7.35(t,1H),7.07(t,1H),3.99(s,3H),3.50-3.40(m,2H),3.02-2.90(m,1H),2.89–2.72(m,4H),1.95-1.82(m,2H),1.78(s,6H),1.75-1.63(m,2H).
Example 18
1-methyl-N- (2- (1-methyl-1H-indazol-3-yl) propan-2-yl) -3-azabicyclo [3.1.0] hexane-6-carboxamide (Compound 18)
Figure BDA0003077502510000822
The first step: 1-methyl-6- ((2- (1-methyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (18A)
Figure BDA0003077502510000831
3- (tert-Butoxycarbonyl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid (intermediate 3-P2) (200 mg,0.829 mmol) and HATU (315 mg, 0.8238 mmol) were stirred in dry N, N-dimethylformamide (10 mL) at room temperature for half an hour, then 2- (1-methyl-1H-indazol-3-yl) propan-2-amine (intermediate 2) (131 mg,0.691 mmol) and DIEA (0.5 mL) were added and stirred overnight at room temperature. The reaction solution was poured into water, the organic phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and dried under vacuum to give a crude product. The crude product was isolated and purified by column chromatography on silica gel (petroleum ether: ethyl acetate=3:1) to give 1-methyl-6- ((2- (1-methyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester 18A (122 mg, yield: 42.8%, light yellow oil).
MS(ESI):m/z＝413.2[M+H] + .
And a second step of: 1-methyl-N- (2- (1-methyl-1H-indazol-3-yl) propan-2-yl) -3-azabicyclo [3.1.0] hexane-6-carboxamide (Compound 18)
Figure BDA0003077502510000832
1-methyl-6- ((2- (1-methyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester 18A (122 mg, 0.298 mmol) was dissolved in a solution of hydrochloric acid in dioxane (5 mL) and reacted overnight at room temperature. The solvent is removed by vacuum spin of the reaction solution to obtain crude product. The crude product was purified by preparative HPLC to give pure compound 18 as a white solid (17 mg, yield: 18.4%).
MS(ESI):m/z＝313.1[M+H] + .
1 H NMR(400MHz,DMSO-d6)δ8.28(s,1H),7.85(d,1H),7.51(d,1H),7.32(t,1H),7.03(t,1H),3.95(s,3H),2.90-2.70(m,3H),2.60-2.52(m,1H),1.66(d,7H),1.39(t,1H),1.24(s,1H),0.97(s,3H).
Example 19
1-methyl-N- (2- (1-methyl-1H-indazol-3-yl) propan-2-yl) -3-azabicyclo [3.1.0] hexane-6-carboxamide (Compound 19)
Figure BDA0003077502510000841
The first step: 1-methyl-6- ((2- (1-methyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (19A)
Figure BDA0003077502510000842
A solution of 3- (tert-butoxycarbonyl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid (intermediate 3-P1) (200 mg,0.829 mmol) and HATU (315 mg, 0.8238 mmol) in dry N, N-dimethylformamide (10 mL) was stirred at room temperature for half an hour, then 2- (1-methyl-1H-indazol-3-yl) propan-2-amine (intermediate 2) (131 mg,0.691 mmol) and DIEA (0.5 mL) were added and stirred at room temperature overnight. The reaction solution was poured into water, the organic phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and dried under vacuum to give a crude product. The crude product was isolated and purified by column chromatography on silica gel (petroleum ether: ethyl acetate=3:1) to give 1-methyl-6- ((2- (1-methyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester 19A (110 mg, yield: 38.6%, light yellow oil).
MS(ESI):m/z＝413.2[M+H] + .
And a second step of: 1-methyl-N- (2- (1-methyl-1H-indazol-3-yl) propan-2-yl) -3-azabicyclo [3.1.0] hexane-6-carboxamide (Compound 19)
Figure BDA0003077502510000843
1-methyl-6- ((2- (1-methyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester 19A (110 mg,0.267 mmol) was dissolved in a solution of hydrochloric acid in dioxane (5 mL) and reacted overnight at room temperature. The solvent is removed by vacuum spin of the reaction solution to obtain crude product. The crude product was purified by preparative HPLC to give pure white solid (compound 19) (22 mg, yield: 26.4%).
MS(ESI):M/Z＝313.1[M+H] + .
1 H NMR(400MHz,DMSO-d6)δ8.30(s,1H),7.85(d,1H),7.51(d,1H),7.32(t,1H),7.03(t,1H),3.95(s,3H),2.90-2.70(m,3H),2.60-2.52(m,1H),1.66(d,7H),1.39(t,1H),1.24(s,1H),0.97(s,3H).
Example 20
(3 aR,5s,6 aS) -N- (2- (8-chloroimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide (Compound 20)
Figure BDA0003077502510000851
The first step: (1- (((3-chloropyridin-2-yl) methyl) amino) -2-methyl-1-oxopropan-2-yl) carbamic acid tert-butyl ester (20B)
Figure BDA0003077502510000852
2- ((tert-Butoxycarbonyl) amino) -2-methylpropanoic acid (1.42 g,6.99 mmol) and HATU (2.93 g,7.71 mmol) were stirred in dry tetrahydrofuran (200 mL) at room temperature for half an hour. (3-chloropyridin-2-yl) methylamine 20A (1.0 g,7.01 mmol) and triethylamine (1.96 mL) were then added and stirred overnight at room temperature. The reaction solution was poured into water, the organic phase was extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and dried in vacuo to give a crude yellow oil. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate=3:1) to give pure 20B (2.0 g, yield: 87.3%).
MS(ESI):M/Z＝328.1[M+H] + .
And a second step of: (2- (8-chloroimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamic acid tert-butyl ester (20C)
Figure BDA0003077502510000861
Tert-butyl (1- (((3-chloropyridin-2-yl) methyl) -2-methyl-1-oxopropan-2-yl) carbamate 20B (600 mg,3.05 mmol) was dissolved in dichloromethane (40 mL) and then the bergs reagent (2.9 g,12.2 mmol) was added and the reaction stirred at 40 ℃ overnight. The reaction solution was poured into water, the organic phase was extracted with methylene chloride, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was dried by vacuum spin-drying to give tert-butyl (2- (8-chloroimidazo [1,5-a ] pyridin-3-yl) prop-2-yl) carbamate 20C (100 mg, crude product).
MS(ESI):M/Z＝310.1[M+H] +
And a third step of: 2- (8-chloroimidazo [1,5-a ] pyridin-3-yl) propan-2-amine hydrochloride (20D)
Figure BDA0003077502510000862
Tert-butyl (2- (8-chloroimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamate 20C (30 mg,0.097 mmol) is stirred in hydrochloric acid-ethyl acetate solution (20 mL) overnight at room temperature. The solvent was dried under vacuum to give 2- (8-chloroimidazo [1,5-a ] pyridin-3-yl) propan-2-amine hydrochloride 20D (40 mg, crude).
MS(ESI):M/Z＝210.1[M+H] + .
Fourth step: (3 aR,5s,6 aS) -N- (2- (8-chloroimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide (Compound 20)
Figure BDA0003077502510000863
(3 aR,5s,6 aS) -2- (tert-Butoxycarbonyl) octahydrocyclopenta [ c ] pyrrole-5-carboxylic acid 3A (37 mg,0.145 mmol) and HATU (60 mg,0.158 mmol) were stirred in N, N-dimethylformamide (15 mL) for half an hour at room temperature. 2- (8-Chloroimidazole [1,5-a ] pyridin-3-yl) propan-2-amine hydrochloride 20D (30 mg,0.143 mmol) and triethylamine (0.1 mL) were then added and the reaction stirred at room temperature overnight. The reaction solution was dried in vacuo to give a crude product (100 mg), which was added to a methanol solution (10 mL), hydrochloric acid-dioxane solution (2 mL) was added dropwise, and stirred overnight at room temperature, and dried in vacuo to give a further crude product (compound 20). The crude product was purified by preparative HPLC to give a pale yellow oil (2.27 mg, yield: 4.59%).
MS(ESI):m/z＝347.1[M+H] +
1 H NMR(400MHz,CDCl 3 )δ8.10(d,1H),7.61(s,1H),7.49(m,1H),6.70(d,1H),6.44(t,1H),3.40-3.30(m,2H),3.10-2.90(m,5H),2.00-1.90(m,2H),1.85(s,6H),1.80-1.70(m,2H).
Example 21
(3 aR,5s,6 aS) -N- (2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide (Compound 21)
Figure BDA0003077502510000871
The first step: (3-methoxypyridin-2-yl) methylamine (21B)
Figure BDA0003077502510000872
2-cyano-3-methoxypyridine 21A (1.4 g,10.45 mmol) was dissolved in methanol (50 mL), palladium on charcoal (200 mg), hydrogen protected, and reacted overnight. After the completion of the reaction, the filtrate was filtered, and the organic phase was dried by rotation to give a white solid which was (3-methoxypyridin-2-yl) methylamine 21B (0.95 g, yield: 65.9%).
MS(ESI):m/z＝139.1[M+H] + .
And a second step of: (1- (((3-methoxypyridin-2-yl) methyl) amino) -2-methyl-1-oxopropan-2-yl) carbamic acid tert-butyl ester (21C)
Figure BDA0003077502510000881
2- ((tert-Butoxycarbonyl) amino) -2-methylpropanoic acid (1.68 g,8.26 mmol), HATU (3.14 g,8.26 mmol) were dissolved in DMF (20 mL) and then (3-methoxypyridin-2-yl) methylamine 21B (0.95 g,6.88 mmol) and DIEA (2.66 g,20.64 mmol) were added and reacted for 1h. After the completion of the reaction, water (50 mL) was added to quench, followed by extraction with ethyl acetate (30 mL. Times.3), and the organic phase was washed once with 50mL of saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, suction filtered, and the organic phase was dried to give a residue. The residue was purified by a silica gel column (petroleum ether: ethyl acetate=2:1) to give a white solid which was tert-butyl (1- (((3-methoxypyridin-2-yl) methyl) amino) -2-methyl-1-oxopropan-2-yl) carbamate 21C (1.4 g, yield: 62.9%).
MS(ESI):m/z＝324.1[M+H] + .
Third step (tert-butyl 2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamate (21D)
Figure BDA0003077502510000882
Tert-butyl (1- (((3-methoxypyridin-2-yl) methyl) amino) -2-methyl-1-oxopropan-2-yl) carbamate 21C (0.6 g,1.86 mmol) was dissolved in dry DCM (10 mL), and the Bobber reagent (0.89 g,3.72 mmol) was added and stirred overnight. After completion of the reaction, the mixture was quenched with water (40 mL) and extracted with ethyl acetate (20 mL. Times.3). The organic phase was washed once with 50mL of saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. Suction filtration and spin drying of the organic phase gave a residue. The residue was purified by a silica gel column (petroleum ether: ethyl acetate=1:1) to give tert-butyl 2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamate 21D (0.175 g, yield: 30.9%) as a white solid.
MS(ESI):m/z＝306.1[M+H] + .
Fourth step: 2- (8-Methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-amine hydrochloride (21E)
Figure BDA0003077502510000891
Tert-butyl (2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamate 21D (0.05 g,0.164 mmol) is added to a solution of 4M hydrochloric acid in 1, 4-dioxane (3 mL) and stirred for 30min. After the reaction was completed, the crude oil was obtained by vacuum spin-drying as 2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-amine hydrochloride 21E (0.057 g).
MS(ESI):m/z＝206.1[M+H] + .
Fifth step: (3 aR,5s,6 aS) -5- ((2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (21F)
Figure BDA0003077502510000892
(3 aR,5s,6 aS) -2- (tert-Butoxycarbonyl) octahydrocyclopenta [ c ] pyrrole-5-carboxylic acid (74.6 mg,0.29 mmol) and HATU (111 mg,0.29 mmol) were dissolved in DMF (2 mL) and then crude oil of 2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-amine 21E (0.057 g) and DIEA (94 mg,0.73 mmol) were added and reacted for 1h. After completion of the reaction, quenched with water (10 mL) and extracted with ethyl acetate (5 mL. Times.3), the organic phase was washed once with 20mL of saturated aqueous NaCl and dried over anhydrous sodium sulfate. Suction filtration and spin drying of the organic phase gave a residue. The residue was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate=2:1) to give (3 ar,5s,6 as) -5- ((2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl 21F (50 mg, yield: 69.4%).
MS(ESI):m/z＝443.1[M+H] + .
Sixth step: (3 aR,5s,6 aS) -N- (2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide (Compound 21)
Figure BDA0003077502510000901
To (3 ar,5s,6 as) -5- ((2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester 21F (50 mg,0.069 mmol) was added a solution of 4M hydrochloric acid in 1, 4-dioxane (3 mL) and stirred for 30min. After the reaction was completed, it was dried in vacuo and purified by Pre-HPLC to give (3 aR,5s,6 aS) -N- (2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide (compound 21) (25 mg, yield: 64.66%).
MS(ESI):m/z＝343.1[M+H] + .
1 H NMR(400MHz,DMSO-d6)δ8.21(s,1H),7.87(d,1H),7.22(s,1H),6.52(t,1H),6.09(d,1H),3.88(s,3H),3.02-2.90(m,2H),2.75(s,1H),2.42(s,2H),2.32-2.20(m,2H),1.63(s,6H),1.60-1.42(m,4H),1.23(s,1H).
Example 22
N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) -2- (piperidin-4-yl) acetamide hydrochloride (Compound 22)
Figure BDA0003077502510000902
/>
The first step: 4- (2- ((2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) amino) -2-oxoethyl) piperidine-1-carboxylic acid tert-butyl ester (22A)
Figure BDA0003077502510000903
2- (8-methylimidazole [1,5-a ] pyridin-3-yl) propan-2-amine intermediate 1 (120 mg,0.53 mmol), 1-tert-butoxycarbonyl-piperidine-4-acetic acid (141 mg,0.58 mmol), HATU (242 mg,0.64 mmol) and DIPEA (274 mg,2.12 mmol) were dissolved in DMF (2 mL). The solution was stirred at 25℃for 12 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (8 mL. Times.3). The combined organic phases were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and the solvent was dried under vacuum. The crude product was purified by flash chromatography on silica gel (petroleum ether: ethyl acetate=1:1) to give 22A (170 mg, yield: 64.6%) as a pale yellow solid.
MS(ESI):M/Z＝415.2[M+H] + .
1 H NMR(400MHz,CDCl 3 ):δ7.99-7.90(m,1H),7.35(s,1H),6.93(s,1H),6.54-6.45(m,2H),2.75-2.65(m,2H),2.42(s,3H),2.16(d,2H),1.98-1.96(m,1H),1.92(s,6H),1.69(s,1H)1.66(s,2H),1.47-1.53(m,1H),1.46(s,9H),1.08-1.21(m,2H).
And a second step of: n- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) -2- (piperidin-4-yl) acetamide hydrochloride (Compound 22)
Figure BDA0003077502510000911
Tert-butyl 4- (2- ((2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) amino) -2-oxoethyl) piperidine-1-carboxylate 22A (150 mg,0.36 mmol) was dissolved in ethyl acetate (2 mL), cooled to 0℃and hydrochloric acid/ethyl acetate (4M, 6 mL) was added and stirred at 0℃for 0.5 h. The mixture was dried under vacuum, diluted with water (30 mL) and acetonitrile (1 mL), and lyophilized to give compound 22 (110 mg, yield: 86.6%) as a pale yellow solid.
MS(ESI):M/Z＝315.2[M+H] + .
1 HNMR(400MHz，CD 3 OD)：δ8.39(d,1H),8.08(s,1H),7.06-7.15(m,1H),7.03(d,1H),3.29(s,2H),2.82-2.97(m,2H),2.52(s,3H),2.27(d,2H),1.92-2.00(m,1H),1.90(s,6H),1.75-1.72(m,2H),1.36-1.48(m,2H).
The following compounds were synthesized using a preparation method similar to example 8:
Figure BDA0003077502510000912
/>
Figure BDA0003077502510000921
/>
Figure BDA0003077502510000931
test example:
test example 1, determination of human somatostatin type IV receptor SSTR4 agonist activity
Test purpose: the agonism of the test compounds to the SSTR4 receptor was determined using the Cell-based human SSTR4 cAMP assay.
Cell culture and reagent preparation: cell lines: flp-In-CHO-SSTR4 stable pool (stable pool); complete medium Ham's F-12K+10% FBS+1x penicillin-streptomycin (PS) +600 μg/ml hygromycin B; cell inoculation culture medium is Ham's F-12K+10% FBS; experiment buffer 1X HBSS+20mM HEPES+0.1%BSA+500uM IBMX.
Test procedure:
Flp-In-CHO-SSTR4 stable pool cell line was cultured In complete medium at 37℃in 5% CO 2 To 70 to 90 percent of fusion degree.
After the TrypLE digestion treatment, the cells were resuspended in an inoculation medium, inoculated into 384-well cell culture plates (384 PE plates), 7,000 cells were inoculated per well, and incubated at 37℃with 5% CO 2 Culturing overnight.
1. Positive control compound and test compound working solution (8X) were prepared.
2. The cell culture plates were removed, centrifuged at 200g for 5s at room temperature and the medium was removed, then 15. Mu.l of assay buffer was rapidly added to each well and centrifuged at 200g for 5s at room temperature.
3. 2.5 μl of the 8X compound working solution diluted in step 3 was added to the corresponding test wells, centrifuged at 200g for 5s at room temperature and incubated at 37℃for 10min.
4. 4uM Forskolin working solution (8X) was prepared.
5. The cell plates were taken out and equilibrated to room temperature, then 2.5. Mu.l of the 8 XForskolin working solution prepared in step 6 was added to the corresponding test wells, 200g, RT,5s, and allowed to stand at 37℃for 30min.
6. Freezing and thawing Eu-cAMP tracer and Uliacht-anti-cAMP, diluting Eu-cAMP tracer 50 times with detection buffer, and diluting Uliacht-anti-cAMP 150 times.
7. Mu.l Eu-cAMP tracer was added to all wells, then 10. Mu.l detection buffer was added to NC wells, and 10. Mu.l Uliacht-anti-cAMP was added to the remaining wells.
8. The reaction plate was centrifuged at 200g at room temperature for 30s and allowed to stand at 25℃for 1 hour, after which data were collected by Envision
Data analysis
1) Z' factor = 1-3 (SD Max +SD Min ) (average) Max -average Min )
2)CV Max ＝(SD Max Average/average Max )*100％
3)CV Min ＝(SD Min Average/average Min )*100％
4) S/B = signal/background
5) Vehicle control (Min): assay buffer
6) Positive control (Max) 1,000nM Somatostatin 14
7) Calculation of Compound EC using GraphPad nonlinear fitting equation 50 :
Y=bottom+ (top-bottom)/(1+10 ++logec 50 -X)*HillSlope))
X is the log value of the compound concentration; HTRF ratio Y
TABLE 1 determination of human somatostatin IV receptor SSTR4 agonist activity
Figure BDA0003077502510000941
Figure BDA0003077502510000951
Conclusion: the compound has obvious human growth hormone IV type receptor SSTR4 agonistic activity.
Test example 2, liver microsome Metabolic stability
The test compounds were assayed for metabolic degradation at 37 ℃ using pooled human and male rat liver microsomes, respectively.
The final incubation reaction solution contained phosphate buffer (pH 7.4), positive control compound (dextromethorphan) or test compound (200. Mu.M, 1.5. Mu.L) and liver microsomes (0.5 mg/mL, 238.5. Mu.L). After 5 minutes of pre-incubation at 37℃NADPH (5 mM, 60. Mu.L) was added to start the reaction. A fixed volume of the reaction mixture (30. Mu.L) was sampled into the solution at fixed time points (0, 5,15,30,60 min) to quench the reaction. After centrifugation (4000 rpm,15 min), the supernatant (100. Mu.L) was taken and mixed with distilled water (100. Mu.L) and then LC-MS/MS analysis was performed to test the amount of the compound. By first order reaction kinetics equation (C t ＝C 0 ×e -ket ，T 1/2 =ln2/ke) to calculate half-life.
TABLE 2 human liver microsome and Male rat liver microsome analysis test results
Figure BDA0003077502510000952
Conclusion: the compound has better metabolic stability in liver microsomes.
Test example 3, pharmacokinetic evaluation
The concentration of the drug in plasma was determined at various times after oral and intravenous administration of the test compound to rats using LC/MS method. The pharmacokinetic behavior of the compound of the invention in rats was studied and its pharmacokinetic profile was evaluated.
Test animals:
6 healthy adult SD (Sprague-Dawley) rats, males, were used for each compound, and the animals were divided into oral and intravenous administration groups of 3, purchased from Shanghai Sipule-BiKai laboratory animals Co., ltd., animal production license number: SCXK 2008-0016 (Shanghai).
Preparing the medicine:
a certain amount of the drug was weighed and dissolved in 5% Dimethylacetamide (DMA) +5% polyethylene glycol-15 hydroxystearate (solutol) +90% saline solution to prepare a 0.2mg/mL solution.
Administration:
SD rats were orally and intravenously administered after overnight fast.
Test procedure:
the test compounds were administered orally and intravenously to rats. Blood was collected from the submaxillary vein or other suitable vessel 0.2mL at 0.083,0.25,0.5,1,2,4,8 and 24 hours post-administration, placed in a K2-EDTA tube, and then stored on ice. Plasma was isolated within one hour by centrifugation at 6800g for 6 minutes at 2-8deg.C and stored at-80deg.C for LC/MS/MS analysis, and rats fed 4 hours after dosing.
TABLE 3 pharmacokinetic parameters for rats
Figure BDA0003077502510000961
Conclusion: the drug substitution absorption of the compound of the invention is good.
The technical features of the above-described embodiments may be arbitrarily combined, and all possible combinations of the technical features in the above-described embodiments are not described for brevity of description, however, as long as there is no contradiction between the combinations of the technical features, they should be considered as the scope of the description.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.

Claims (12)

1. A compound of formula (a) or a pharmaceutically acceptable salt thereof,
Figure FDA0004203684210000011
wherein ,
Figure FDA0004203684210000013
represents a single bond or a double bond, provided that two +.>
Figure FDA0004203684210000014
Wherein only one represents a double bond;
X 1 is NR (NR) 3 ；
X 2 Is CR (CR) 3’ ；
X 1 And substituents and adjacent carbon atoms thereof and substituents R thereof 3’ Together form a 5-to 6-membered heteroaromatic ring, said 5-to 6-membered heteroaromatic ring being substituted with 1-2R 3’ Substitution;
R 3’ selected from-H, halogen, -OR and C 1-6 An alkyl group;
R 4 is-H;
R 5 is-H;
R 1 and R2 Each independently is C 1-6 An alkyl group;
r is C 1-6 An alkyl group;
s is 1;
r is 1.
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
R 1 and R2 Each independently is methyl;
R 3’ is C 1-4 An alkyl group.
3. A compound of formula (a) or a pharmaceutically acceptable salt thereof,
Figure FDA0004203684210000012
wherein ,
Figure FDA0004203684210000022
represents a single bond or a double bond, provided that two +.>
Figure FDA0004203684210000023
Wherein only one represents a double bond;
X 1 is CR (CR) 3’ ；
X 2 Is NR (NR) 3 ；
X 1 And substituents and adjacent carbon atoms thereof and substituents R thereof 3’ Together form a benzene ring, said benzene ring being substituted with 1-2R 3’ Substitution;
R 3 selected from-H and C 1-6 An alkyl group;
R 3’ selected from-H and C 1-6 An alkyl group;
R 4 is-H;
R 5 is-H;
R 1 and R2 Each independently is C 1-6 An alkyl group;
s is 1;
r is 1.
4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein,
R 3’ is C 1-4 An alkyl group;
R 3 selected from H or C 1-4 An alkyl group; r is R 1 and R2 Each independently is methyl.
5. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
Figure FDA0004203684210000021
6. the compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, maleate, succinate, mandelate, fumarate, malonate, malate, 2-hydroxypropionate, oxalate, glycolate, salicylate, glucuronate, galacturonate, citrate, tartrate, aspartate, glutamate, benzoate, cinnamate, p-toluenesulfonate, benzenesulfonate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, and combinations thereof.
7. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 7 for the manufacture of a medicament for the treatment and/or prophylaxis of diseases or conditions which are affected by SSTR4 activation.
9. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 7 in the manufacture of a medicament for the treatment and/or prophylaxis of pain.
10. The use according to claim 9, wherein the pain is neuralgia.
11. The use according to claim 9, wherein the pain is back pain, trigeminal neuralgia, complex regional pain syndrome type I, complex regional pain syndrome type II, irritable bowel syndrome, diabetic neuropathy, pain caused by osteoarthritis, tumor pain or muscle fiber pain.
12. The use of claim 9, wherein the pain is chronic back pain.
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