CN113717161A

CN113717161A - Nitrogen-containing saturated heterocyclic compound and preparation method, pharmaceutical composition and application thereof

Info

Publication number: CN113717161A
Application number: CN202110556657.6A
Authority: CN
Inventors: 邱关鹏; 王永钢; 邓代国; 雷曾荣
Original assignee: Guangzhou Fermizi Technology Co ltd
Current assignee: Guangzhou Fermizi Technology Co ltd
Priority date: 2020-05-21
Filing date: 2021-05-21
Publication date: 2021-11-30
Anticipated expiration: 2041-05-21
Also published as: WO2021233428A1; CN113717161B; TW202146403A

Abstract

The invention relates to a nitrogen-containing saturated heterocyclic compound with a structure shown in a formula (I), and a preparation method, a pharmaceutical composition and application thereof. The nitrogen-containing saturated heterocyclic compound is a somatostatin receptor subtype 4(SSTR4) agonist compound which has novel structure, better drug effect, high bioavailability and better solubility.

Description

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

Technical Field

The invention relates to an organic compound, in particular to a nitrogen-containing saturated heterocyclic compound, a preparation method, a pharmaceutical composition and application thereof.

Background

Somatostatin receptors (SSTRs) are a family of G-protein coupled receptors that mediate somatostatin and its analogs, and have a variety of biological effects, and their physiological functions and mechanisms of action have long been of interest. Studies have shown that specific membrane receptors present on these cell membranes include SSTR1, SSTR2, SSTR3, SSTR4 and SSTR5, which can play important roles in regulating Growth Hormone (GH) secretion, inducing apoptosis, inhibiting tumor cell proliferation, inhibiting insulin action and inhibiting cell growth through cAMP, PTP and MAPK signaling pathways, and exhibit kinetic characteristics similar to those of other G protein-coupled receptors.

Somatostatin (SST) is a cyclic polypeptide widely distributed in the central nervous system and in peripheral tissues and exists in vivo in both 14 peptide (SST-14) and 28 peptide (SST-28). It has been shown that SST is mediated as a signaling molecule by a family of SST receptors on the cell membrane, with SST having only 2 forms. The complexity of SST physiological function is manifested by the complexity of the receptors. Therefore, the biological significance of SSTR is somewhat more important than SST. SSTRs are structurally similar to other G protein-coupled receptors, with 7 Transmembrane (TM) alpha helical structures, with N-glycosylation 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: one is the cyclic adenosine monophosphate (cAMP) pathway; second, voltage dependent Ca²⁺(ii) a pathway; the mitogen-activated protein kinase (MAPK) pathway; and the fourth is the Protein Tyrosine Phosphatase (PTP) pathway.

SSTR1 is associated with inhibition of cell growth; SSTR3, in addition to inducing apoptosis, is involved in inhibiting GH, insulin release, and in processing and regulating sensory signals and the integration of sensory functions with visceral, olfactory and other sensory functions; SSTR4 also inhibits GH and insulin release and coordinates extrapyramidal motor and sensory functions; SSTR2 and SSTR5 play a main role in regulating the growth process of animals, mainly inhibit GH and insulin release, participate in central integration, participate in mediating the anti-proliferation effect of tumors and induce apoptosis, are the leading subtypes of mediating the anti-tumor effect, and the results all reveal that a close relationship exists between endocrine and immunity.

Among the five receptors, SSTR4 has gone to the forefront as a potential mediator of central nervous system pathology, inflammation, and even pain mechanisms. TargetingSSTR4 has the additional advantage that it limits pituitary secretion but does not inhibit glucagon, growth hormone or insulin secretion. In the central nervous system, the expression level of SSTR4 is relatively high in hippocampus and neocortex, memory and learning domains, and in alzheimer's disease pathology. Recent studies do indicate that SSTR4 agonists improve learning and memory in rodent models of alzheimer's disease, which corresponds to decreased levels of β -amyloid. Furthermore, SSTR4 receptor stimulation has also been found to enhance clue memory dose-dependently, and thus may have direct cognitive enhancing activity. Other studies have shown that SSTR4 is associated with K⁺Ion channel binding can modulate hippocampus excitability, which has been implicated in the treatment of certain forms of epilepsy with SSTR4 agonists. In addition, the effects of SSTR4 agonists are effective in rodent pain models associated with acute and chronic associated anti-peripheral injury and anti-inflammatory activity. Recent research data show that SRIF released from nociceptors expressed by the capsaicin-sensitive receptor TRPV1 acts on SSTR4 and SSTR2 to produce antinociceptive effects.

Pain is the most common and most disturbing symptom clinically, and is one of the main reasons for the patients to see a doctor. 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 includes nociceptive pain, neuropathic pain, visceral pain and mixed pain. Analgesics which are still well known to be responsible for the burden of pain management include narcotic analgesics (lidocaine and the like), opioids, non-steroidal anti-inflammatory drugs (NSAIDs). Drugs with new mechanisms of action have also been added to the array of analgesics, such as antidepressants, anticonvulsants. Although many patients can benefit from existing analgesics, these drugs also provide adequate relief from the symptoms of 1/4 patients. In addition, the existing drugs generally have the problems of low tolerance, large toxic and side effects, poor long-term safety, potential drug abuse, inconvenient use and the like, so that patients urgently need safer and more effective analgesic drugs. While the use of SSTR4 agonists in the field of analgesia is receiving increasing attention, the development of novel SSTR4 agonists has broad application prospects and is also urgently needed.

CN105473574A discloses compounds of formula (I) below, which are agonists of SSTR4 and are useful for the prevention or treatment of medical conditions associated with SSTR 4. However, there remains a wide need in the art for SSTR4 agonists that are potent, highly bioavailable, and well soluble.

Disclosure of Invention

Based on the above, there is a need for a nitrogen-containing saturated heterocyclic compound, which is a somatostatin receptor subtype 4(SSTR4) 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:

wherein A is selected from C_6-14Aryl, 5-to 14-membered heteroaryl, 5-to 14-membered heterocyclyl and 5-to 14-membered cycloalkyl, and said aryl, heteroaryl, heterocyclyl and cycloalkyl in A are optionally further substituted with 0 to 5R₃Substitution; wherein said heteroaryl and heterocyclyl each contain 1 to 4 heteroatoms selected from N, O and S;

R₃each independently selected from-H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkoxy radical C_1-4Alkyl, - (CH)₂)_m-alkenyl, - (CH)₂)_m-alkynyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3-to 10-membered heterocyclic group), -O- (CH)₂)_m-C_3-10Carbocyclyl and-O- (CH)₂)_m- (3-to 10-membered heterocyclic group) containing 1 to 4 heteroatoms selected from N, O and S, and R₃Each of said alkyl, alkoxy, carbocyclic or heterocyclic ring independently optionally further substituted by 0 to 4 substituents selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy;

L₁selected from single bond or- (CR)_aR_b)_m-, wherein R_a and R_bEach independently selected from-H and C_1-6An alkyl group;

L₂selected from-NH-and-O-;

R₁ and R₂Each independently selected from-H, C_1-6Alkyl and C_3-6Cycloalkyl, wherein R₁ and R₂Is not H at the same time;

or R₁ and R₂Together form a mixture containing 0 to 1 substituents selected from-O-, -NR₁₆-, -SO-and-SO₂-a 3 to 6 membered saturated cyclic group of the group of;

R₁₆is selected from-H, C_1-6Alkyl radical, C_1-4Alkoxy radical C_1-4Alkyl, halogen, hydroxy, cyano and C_3-6A cycloalkyl group;

m is selected from the group consisting of single bond, - (CR)_cR_d)_m- and -(CR_cR_d)_mO-, wherein R_c and R_dEach independently selected from-H and C_1-6An alkyl group;

q is selected from one of the following structures:

wherein ,X₁，X₂，X₃Each independently selected from the group consisting of a single bond and- (CR)_eR_f)_n-；

X₄Is selected from-CH₂-、-CH₂CH₂- and -CH₂CH₂CH₂-；

R₄、R₅、R₆、R₇、R₉、R₁₀、R_e、R_fEach independently selected from-H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3-to 10-membered heterocyclic group), - (CH)₂)_m-O-C_3-10Carbocyclyl, - (CH)₂)_m-O- (3 to 10 membered heterocyclyl), phenyl and 5 to 6 membered heteroaryl, said heterocyclyl and heteroaryl each containing 1 to 4 heteroatoms selected from N, O and S, and R₄、R₅、R₆、R₇、R₉、R₁₀、R_e、R_fThe alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl and heterocycle in (1) are each independently optionally further substituted with 0 to 4 substituents selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy;

R₈、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅each independently selected from-H, C_1-6Alkyl and C_3-6A cycloalkyl group;

m, n, p, q are each independently at each occurrence selected from 0, 1,2 or 3;

when X is present₁ and X₂When simultaneously a single bond, R₄、R₅、R₆、R₇Not being 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 prevention of a disease or condition which is affected by the activation of SSTR 4.

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 prevention of pain.

Compared with the prior art, the invention has one or more of the following beneficial effects:

the novel compounds provided by the present invention, which have excellent SSTR4 agonistic effect by introducing specific substituents at specific sites of the parent nuclear structure or by using a parent nuclear structure containing specific fused, spiro or bridged rings, can be used as SSTR4 agonists for preventing and/or treating diseases or conditions affected by SSTR4 activation, such as alzheimer's disease and other CNS disorders, such as epilepsy and depression, and can be used for treating pain and/or inflammation of various origins. In addition, experimental studies show that the compound of the present invention has high metabolic stability and excellent pharmacokinetic properties.

Detailed Description

The compounds of the present invention, methods for their preparation, pharmaceutical compositions and uses thereof are described in further detail in the following 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 same meaning as commonly understood by one of ordinary skill in the art. The terminology used in the description herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" means any and all combinations of one or more of the associated listed items.

The term "alkyl" refers to a saturated straight or branched aliphatic hydrocarbon group, specifically containing a primary (normal) carbon atom, a secondary carbon atom, a tertiary carbon atomSaturated hydrocarbons of carbon atoms, quaternary carbon atoms, or combinations thereof. Phrases containing the term, e.g., "C_1-6Alkyl "refers to an alkyl group containing 1 to 6 carbon atoms, which may be independently at each occurrence C₁Alkyl radical, C₂Alkyl radical, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl radical, C₆An alkyl group. In one embodiment, an alkyl group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 10 carbon atoms, and 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)₂CH₂CH₂CH₃) 2-methyl-propan-1-yl (i-Bu, isobutyl, -CH)₂CH(CH₃)₂) 2-butyl (s-Bu, sec-butyl, -CH (CH)₃)CH₂CH₃) 2-methyl-propan-2-yl (t-Bu, t-butyl, -C (CH)₃)₃) 1-pentyl (n-pentyl, -CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH3) CH2CH2CH3), 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-but-2-yl (-C (CH)₃)₂CH₂CH₃) 3-methyl-but-2-yl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-but-1-yl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-but-1-yl (-CH)₂CH(CH₃)CH₂CH₃) Hex-1-yl (-CH)₂CH₂CH₂CH₂CH₂CH₃) Hex-2-yl (-CH (CH)₃)CH₂CH₂CH₂CH₃) Hex-3-yl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-pent-2-yl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-pent-2-yl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-pent-2-yl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-pent-3-yl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-pent-3-yl (-CH (CH)₂CH₃)CH(CH₃)₂)2, 3-dimethyl-but-2-yl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-but-2-yl (-CH (CH)₃)C(CH₃)₃Octyl (- (CH)₂)₇CH₃) And n-nonyl, and various branched chain isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably 1 to 5, and are independently selected from F, Cl, Br, I, ═ O, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, nitro, cyano, and amino.

"alkoxy" means an-O-alkyl group, wherein alkyl is as defined herein above and is preferably an alkyl group having from 1 to 12 carbon atoms. Phrases containing the term, e.g., "C_1-4Alkoxy "refers to an-O-alkyl group having 1 to 4 carbon atoms in the alkyl moiety. At each occurrence, C_1-4Alkoxy groups may independently of one another be C₁Alkoxy radical, C₂Alkoxy radical, C₃Alkoxy radical, C₄An alkoxy group. Alkoxy groups may be substituted or unsubstituted, non-limiting examples of which include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, or hexyloxy. 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.

"alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group as described above. Examples include "C_1-4Alkoxy radical C_1-4Alkyl "or" C_1-6Alkoxy radical C_1-6Alkyl groups ". For example, "C_1-4Alkoxy radical C_1-4Alkyl is defined as being surrounded by C_1-4Alkoxy-substituted C_1-4Alkyl, which at each occurrence may be independently of one another C₁Alkoxy radical C_1-4Alkyl radical, C₂Alkoxy radical C_1-4Alkyl radical, C₃Alkoxy radical C_1-4Alkyl radical, C₄Alkoxy radical C_1-4An alkyl group. Alkoxyalkyl groups may be substituted or unsubstituted. Of alkoxyalkyl groupsNon-limiting examples include methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxymethyl, propoxyethyl, isopropoxymethyl, butoxypropyl, tert-butoxyethyl, pentoxyethyl, hexyloxyethyl, cyclopropyloxymethyl, cyclopropyloxyethyl, cyclopropyloxypropyl or cyclohexyloxymethyl; 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.

"alkenyl" is an alkyl group as defined herein, which 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 still 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, or 4-decenyl, and the like, and when substituted, the substituents are preferably 1 to 5, and 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, containing 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, further preferably 2 to 8 carbon atoms, and still further preferably 2 to 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 or 4-decynyl groups 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.

"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, 3-to 8-membered monocyclic, 3-to 10-membered monocyclic, 4-to 12-membered bicyclic, or 10-to 15-membered tricyclic ring system. Carbocycles include bridged or spiro rings. Non-limiting examples of carbocyclyl 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. The carbocyclyl group may be optionally substituted. 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.

"Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or partially unsaturated heteroatom-containing cyclic group, said heteroatom being 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, N-oxides. The heterocyclic ring may be attached to the rest of the molecule through a heteroatom or carbon atom. Heterocycles include bridged or spiro rings. Non-limiting examples of heterocycles include ethylene oxide, aziridine, oxetane, azetidine, 1, 3-dioxolane, 1, 4-dioxanone, 1, 3-dioxane, azepin, pyranyl, piperidinyl, morpholinyl, thiomorpholinyl, 1, 3-dithiane, dihydrofuran, dihydropyran, dithianyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, chromanyl, chroman, dihydropyridinyl, tetrahydrothienyl, thiooxidized tetrahydrothienyl, 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 fused to a heteroaryl, heterocyclyl or cycloalkyl group and is on the aryl group at the site of the molecule to which it is attached. Non-limiting examples of aryl groups include benzofuran, benzocyclopentyl, or benzothiazole, 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, hydroxyl, 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 group, 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 or pyrrolopyridine, and the like. When heteroaryl is 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.

"Heteroalkyl" means a group resulting from the replacement of at least one carbon atom on the alkyl group by a non-carbon atom, which may be a N atom, an O atom, and/or an S atom, among others. For example, if the carbon atom of the alkyl group attached to the parent nuclear structure is replaced with a non-carbon atom, the resulting heteroalkyl group is individually an alkoxy group (e.g., -OCH)₃Etc.), alkylamino (e.g., -NHCH₃、-N(CH₃)₂Etc.) or alkylthio (e.g., -SCH)₃). If the carbon atom of the alkyl group bound to the parent nucleus structure is not replaced by a non-carbon atom and the hetero atom is embedded within the groupThen the resulting heteroalkyl groups are each independently alkyloxyalkyl (e.g., -CH)₂CH₂-O-CH₃Etc.), alkylaminoalkyl (e.g., -CH)₂NHCH₃、-CH₂N(CH₃)₂Etc.) or alkylsulfanyl (e.g., -CH₂-S-CH₃). If the terminal carbon atom of the alkyl group is replaced by a non-carbon atom, the resulting heteroalkyl group is each hydroxyalkyl (e.g., -CH)₂CH₂OH), aminoalkyl (e.g., -CH)₂NH₂) Or mercaptoalkyl (e.g., -CH)₂CH₂-SH)。

"amino" refers to a derivative of ammonia having the formula-N (X)₂Or a structural feature of the formula-NR 'R ", wherein each" X ", R' and R" is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Non-limiting types of amino groups include-NH₂-N (alkyl)₂NH (alkyl), -N (cycloalkyl)₂NH (cycloalkyl), -N (heterocyclyl)₂NH (heterocyclyl), -N (aryl)₂NH (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 salt" 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 formed 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 amines include naturally occurring substituted or unsubstituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, phentermine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine 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, or trifluoromethanesulfonic acid, and the like.

"stereoisomers" refers to isomers resulting from the different arrangement of atoms in a molecule, including 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 an organism.

"prodrug" refers to a substance that can be converted under physiological conditions or by degradation to a biologically active compound of the present invention. Prodrugs of the invention are prepared by modifying functional groups in the compound, which modifications may be removed by routine manipulation or in vivo, to yield the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is attached to any group in the compound. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group, a free amino group, or a free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, compounds of the present invention wherein a hydroxy or amino functional group is bonded to formic, acetic or benzoic acid.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, including instances where the event or circumstance occurs or does not. For example, "aryl is optionally substituted with alkyl" means that alkyl may, but need not, be present, and the term includes both the case where aryl is substituted with alkyl and the case 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, sterile water for injection, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious 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 gum 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 combined with 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, ether, and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric 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 a solution state and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

The term "metabolite" refers to a substance including products produced by the metabolism of the compounds of the present invention in vivo, including intermediate metabolites and final metabolites.

The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) in a particular crystal packing 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 shape, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause a crystalline form to dominate. Various polymorphs of a compound may be prepared by crystallization under different conditions.

The dosage form and mode of administration of the compound of the present invention or its pharmaceutical composition 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 mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, for example, glycerol; (d) disintegrating agents, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, complex silicates, and sodium carbonate; (e) solvents, such as paraffin; (f) absorption accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glycerol monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols 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 compounds, the liquid dosage forms may contain inert diluents (such as water or other solvents), solubilizing agents and emulsifiers as are 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 contain 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, aluminium 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 non-aqueous carriers, diluents, solvents or vehicles are selected from 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 sterile conditions with a pharmaceutically acceptable carrier, together with preservatives, buffers and/or propellants which may be required.

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:

specifically, in the formula (I), A is selected from C_6-14Aryl, 5-to 14-membered heteroaryl, 5-to 14-membered heterocyclyl and 5-to 14-membered cycloalkyl, and said aryl, heteroaryl, heterocyclyl and cycloalkyl in A are optionally further substituted with 0 to 5R₃Substitution; wherein said heteroaryl and heterocyclyl each contain 1 to 4 heteroatoms selected from N, O and S;

wherein ,R₃Each independently selected from-H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkoxy radical C_1-4Alkyl, - (CH)₂)_m-alkenyl, - (CH)₂)_m-alkynyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3-to 10-membered heterocyclic group), -O- (CH)₂)_m-C_3-10Carbocyclyl and-O- (CH)₂)_m- (3-to 10-membered heterocyclic group) containing 1 to 4 heteroatoms selected from N, O and S, and R₃Each of said alkyl, alkoxy, carbocyclic or heterocyclic ring independently optionally further substituted by 0 to 4 substituents selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy; m is independently selected for each occurrence from 0, 1,2 and 3.

In the formula (I), L₁Selected from the group consisting of single bonds and- (CR)_aR_b)_m-, wherein R_a and R_bEach independently selected from-H and C_1-6An alkyl group; m is independently selected for each occurrence from 0, 1,2 or 3.

In the formula (I), L₂Is selected from-NH-and-O-.

In the formula (I), R₁ and R₂Each independently selected from-H, C_1-6Alkyl and C_3-6Cycloalkyl, wherein R₁ and R₂Is not H at the same time; or R₁Can be mixed with R₂Together form a mixture containing 0 to 1 substituents selected from-O-, -NR₁₆-, -SO-and-SO₂-a 3 to 6 membered saturated cyclic group of the group of;

wherein ,R₁₆Is selected from-H, C_1-6Alkyl radical, C_1-4Alkoxy radical C_1-4Alkyl, halogen, hydroxy, cyano and C_3-6A cycloalkyl group.

In another specific embodiment, R₁ and R₂And may also be each independently selected from other cycloalkyl, alkyl, amino, alkoxy, aryl, heteroaryl, heteroalkyl, and heterocyclyl groups.

In the formula (I), M is selected from the group consisting of a single bond, - (CR)_cR_d)_m- and -(CR_cR_d)_mO-, wherein R_c and R_dIndependently selected from-H and C_1-6An alkyl group; m is independently selected for each occurrence from 0, 1,2 and 3.

Specifically, in formula (I), Q is selected from one of the following structures:

X₄Is selected from-CH₂-、-CH₂CH₂- and -CH₂CH₂CH₂-；

R₄、R₅、R₆、R₇、R₉、R₁₀、R_e、R_fEach independentlyIs selected from-H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3-to 10-membered heterocyclic group), - (CH)₂)_m-O-C_3-10Carbocyclyl, - (CH)₂)_m-O- (3 to 10 membered heterocyclyl), phenyl and 5 to 6 membered heteroaryl, said heterocyclyl and heteroaryl each containing 1 to 4 heteroatoms selected from N, O and S, and R₄、R₅、R₆、R₇、R₉、R₁₀、R_e、R_fThe alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl and heterocycle in (1) are each independently optionally further substituted with 0 to 4 substituents selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl radical, C_1-4Substituted by a substituent of alkoxy;

m, n, p, q are each independently at each occurrence selected from 0, 1,2 and 3.

In another specific embodiment, R₄、R₅、R₆、R₇、R₉、R₁₀、R_e、R_f、R₈、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅And may also each be independently selected from other cycloalkyl, alkyl, heterocyclyl, heteroaryl, alkoxy, or amino, aryl, and heteroalkyl groups.

In particular, in the formula (I), when X is₁ and X₂When simultaneously a single bond, R₄、R₅、R₆、R₇Not being simultaneously-H.

In one particular embodiment, A is selected from C_6-10Aryl and 5 to 10 membered heteroaryl, and said aryl or heteroaryl in A is optionally further substituted with 0 to 5R₃And (4) substitution. Preferably, A is 5 to 10 membered heteroaryl and optionally further substituted with 0 to 5R₃Substitution。

In one specific 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 by 1 to 5R₃And (4) substitution. Optionally, A is selected from naphthyl, indolyl, indazolyl and imidazo [1,2-a ]]Pyridyl group, and said naphthyl, indolyl, indazolyl or imidazo [1,2-a ]]Pyridyl is unsubstituted or optionally further substituted by 1 to 5R₃And (4) substitution.

In one particular embodiment, a is selected from one of the following structures:

preferably:

a is optionally further substituted by 0 to 5R₃And (4) substitution. Preferably, A is unsubstituted or optionally further substituted by 1 to 3R₃And (4) substitution.

In one particular embodiment, a is:

in one particular embodiment, a is:

in one particular embodiment, a is:

in one particular embodiment, a is:

in one particular implementation thereofIn the scheme, A is:

in one particular embodiment, a is:

in one particular embodiment, a is:

in one particular embodiment, a is:

in one particular embodiment, a is:

in another specific embodiment, a is optionally selected from other aryl, heteroaryl, or amino, alkoxy, cycloalkyl, alkyl, heteroalkyl, and heterocyclyl groups.

In one particular embodiment, R₃Each independently selected from-H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkoxy radical C_1-4Alkyl, - (CH)₂)_m-C_3-10Carbocyclyl, -O- (CH)₂)_m-C_3-10Carbocyclyl and-O- (CH)₂)_m- (3-to 10-membered heterocyclic group) containing 1 to 4 heteroatoms selected from N, O and S, and R₃The alkyl, alkoxy, carbocycle or heterocycle in (1) is further optionally substituted by 0 to 4 groups selected from H, F, Cl, Br, I, hydroxyl, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy. Preferably, R₃Each independently selected from-H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkoxy radical C_1-4Alkyl, cyclopropyl, cyclobutyl and cyclopropylmethyl. In thatIn one particular embodiment, R₃Is methyl. In one particular embodiment, R₃is-Cl. In one particular embodiment, R₃Is methoxy. In one particular embodiment, R₃Is CF₃。

In another specific embodiment, R₃And may also be selected from other alkyl, alkoxy, heterocyclyl, cycloalkyl, heteroalkyl, or amino, aryl, and heteroaryl groups.

In one particular embodiment, R₁ and R₂Each independently selected from C_1-6Alkyl and C_3-6A cycloalkyl group; or R₁Can be mixed with R₂Together form a mixture containing 0 to 1 atoms selected from-O-, -SO-and-SO₂-3 to 6 membered saturated cyclic group. Preferably, R₁ and R₂Each independently selected from methyl, ethyl, propyl, cyclopropyl and cyclobutyl; or R₁Can be mixed with R₂Together form a 3-membered saturated carbocyclic group.

In another specific embodiment, R₁ and R₂And may also each be independently selected from other alkyl, cycloalkyl, or amino, alkoxy, aryl, heteroaryl, heteroalkyl, and heterocyclyl groups.

In one particular embodiment, Q is selected from one of the following structures:

in another specific embodiment, Q may also be each independently selected from other heterocyclyl groups, cycloalkyl groups, amino groups, alkoxy groups, aryl groups, heteroaryl groups, heteroalkyl groups, and alkyl groups.

In one specific embodiment, X₄Is selected from-CH₂-、-CH₂CH₂- and -CH₂CH₂CH₂-。

In one particular embodiment, R₁₂、R₁₃、R₁₄、R₁₅Is selected from-H。

Specifically, the compound has a structure of formula (II):

in one particular embodiment, in formula (II), L₂is-NH-.

In one particular embodiment, in formula (II), L₁Selected from the group consisting of single bonds and- (CR)_aR_b)_m-, wherein R_a and R_bEach independently selected from-H and C_1-6An alkyl group. Preferably, L₁Selected from single bonds, -CH₂- and -CH₂CH₂-. More preferably, L₁Selected from the group consisting of single bonds and-CH₂-. Most preferably, L₁Is a single bond.

In one particular embodiment, in formula (II), X₁ and X₂Each independently selected from the group consisting of a single bond and- (CR)_eR_f)_n-. Preferably, X₁ and X₂Each independently selected from a single bond, -CH₂- and -CH₂CH₂-. More preferably, X₁ and X₂Each independently selected from the group consisting of a single bond and-CH₂-。

wherein ,R_e and R_fEach independently selected from-H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3-to 10-membered heterocyclic group), - (CH)₂)_m-O-C_3-10Carbocyclyl, - (CH)₂)_m-O- (3 to 10 membered heterocyclyl), phenyl and 5 to 6 membered heteroaryl, said heterocyclyl, heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, and R_e and R_fThe alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle in (1) is independently optionally further substituted by 0 to 4 groups selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy. Preferably, R_e、R_fEach independently selected from-H, methyl, ethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl. More preferably, R_e and R_fEach independently selected from-H and methyl. Most preferably, R_e and R_fEach is-H.

In one particular embodiment, in formula (II), R₄、R₅、R₆、R₇Each independently selected from-H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3-to 10-membered heterocyclic group), - (CH)₂)_m-O-C_3-10Carbocyclyl, - (CH)₂)_m-O- (3 to 10 membered heterocyclyl), phenyl and 5 to 6 membered heteroaryl, said heterocyclyl, heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, R₄、R₅、R₆、R₇The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle in (1) is independently optionally further substituted by 0 to 4 groups selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy. Preferably, R₄、R₅、R₆、R₇Each independently selected from-H, methyl, ethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl. More preferably, R₄、R₅、R₆、R₇Each independently selected from-H and methyl. In one particular embodiment, R₄、R₅、R₆、R₇Each independently is-H.

In one particular embodiment, in formula (II), R₈Is selected from-H, C_1-6Alkyl and C_3-6A cycloalkyl group. Preferably, R₈Selected from-H, methyl, ethyl and cyclopropyl. More preferably, R₈is-H.

In one particular embodiment, in formula (II), M is chosen from single bonds, - (CR)_cR_d)_m- and -(CR_cR_d)_mO-, wherein R_c and R_dEach independently selected from-H and C_1-6An alkyl group. Preferably, M is selected from the group consisting of a single bond, -CH₂-、-CH₂CH₂-、-CH₂O- and CH₂CH₂O-is formed. More preferably, M is selected from the group consisting of a single bond and-CH₂O-is formed. In one particular embodiment, M is a single bond. In one specific embodiment, M is-CH₂O-。

In one particular embodiment, in formula (II), R₁ and R₂Each independently selected from-H, C_1-6Alkyl radical, C_3-6Cycloalkyl, wherein R₁ and R₂Is not H at the same time; or, R₁Can be mixed with R₂Together form a mixture containing 0 to 1 substituents selected from-O-, -NR₁₆-, -SO-and SO₂-a 3 to 6 membered saturated cyclic group; r₁₆Is selected from-H, C_1-6Alkyl radical, C_1-4Alkoxy radical C_1-4Alkyl, halogen, hydroxy, cyano and C_3-6A cycloalkyl group.

Preferably, R₁、R₂Each independently selected from methyl, ethyl, isopropyl and cyclopropyl. More preferably, R₁、R₂Each independently is methyl.

Preferably, R₁Can be mixed with R₂Together form a mixture containing 0 to 1 atoms selected from-O-, -SO-and SO₂-3 to 6 membered saturated cyclic group. More preferably, R₁Can be mixed with R₂Together forming a cyclopropyl group.

Preferably, the compound has the structure of formula (III):

in one particular embodiment, in formula (III), X₁Selected from the group consisting of single bonds and-CH₂-。

In one particular embodiment, in formula (III), L₁Selected from the group consisting of single bonds and- (CR)_aR_b)_m-, wherein R_a，R_bIndependently selected from-H and C_1-6An alkyl group. Preferably, L₁Selected from single bonds, -CH₂- and -CH₂CH₂-. More preferably, L₁Selected from the group consisting of single bonds and-CH₂-. Most preferably, L₁Is a single bond.

In one particular embodiment, in formula (III), R₆、R₇Each independently selected from-H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3-to 10-membered heterocyclic group), - (CH)₂)_m-O-C_3-10Carbocyclyl, - (CH)₂)_m-O- (3 to 10 membered heterocyclyl), phenyl and 5 to 6 membered heteroaryl, said heterocyclyl and heteroaryl each containing 1 to 4 heteroatoms selected from N, O and S, R₄、R₅、R₆、R₇The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle in (1) is independently optionally further substituted by 0 to 4 groups selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy. Preferably, R₆、R₇Each independently selected from-H, methyl, ethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl. More preferably, R₆、R₇Each independently selected from-H and methyl. Most preferably, R₆、R₇Each independently is-H.

In one particular embodiment, in formula (III), R₈Is selected from-H, C_1-6Alkyl and C_3-6A cycloalkyl group. Preferably, R₈Selected from-H, methyl, ethyl and cyclopropyl. More preferably, R₈is-H.

Preferably, the compound has the formula (IV):

in one particular embodiment, in formula (IV), R₄、R₅、R₆、R₇Each independently selected from-H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3-to 10-membered heterocyclic group), - (CH)₂)_m-O-C_3-10Carbocyclyl, - (CH)₂)_m-O- (3 to 10 membered heterocyclyl), phenyl and 5 to 6 membered heteroaryl, each of said heterocyclyl, heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, and R₄、R₅、R₆、R₇The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle in (1) is independently optionally further substituted by 0 to 4 groups selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy; r₄、R₅、R₆、R₇Not being simultaneously-H.

In one particular embodiment, in formula (IV), R₄、R₅、R₆is-H; r₇Is selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3-to 10-membered heterocyclic group), - (CH)₂)_m-O-C_3-10Carbocyclyl, - (CH)₂)_m-O- (3 to 10 membered heterocyclyl), phenyl and 5 to 6 membered heteroaryl, each of said heterocyclyl, heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, and R₇The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle in (1) is independently optionally further substituted by 0 to 4 groups selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy. More specifically, R₇Or R-containing groups substituted by said substituents₇The radicals being selected from C_1-6Alkyl radical, C_1-6Alkoxy, methoxymethyl, hydroxyMethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, phenyl, pyridyl, furanyl, imidazolyl, and thiazolyl; and R is₇Independently optionally further substituted by 0 to 4 substituents selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl radical, C_1-4Substituted by a substituent of alkoxy.

In one particular embodiment, in formula (IV), R₅、R₆、R₇is-H; r₄Is selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3-to 10-membered heterocyclic group), - (CH)₂)_m-O-C_3-10Carbocyclyl, - (CH)₂)_m-O- (3 to 10 membered heterocyclyl), phenyl and 5 to 6 membered heteroaryl, each of said heterocyclyl, heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, and R₄The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle in (1) is independently optionally further substituted by 0 to 4 groups selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy. More specifically, R₄Or R-containing groups substituted by said substituents₄The radicals being selected from C_1-6Alkyl, methoxymethyl, hydroxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclobutoxy, cyclopentyl, tetrahydrofuranyl, phenyl, pyridyl, furanyl, imidazolyl and thiazolyl, each of said phenyl, pyridyl, furanyl, imidazolyl, thiazolyl independently optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxy, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy.

In one particular embodiment, in formula (IV), L₁Selected from the group consisting of single bonds and- (CR)_aR_b)_m-, wherein R_a，R_bEach independently selected from-H and C_1-6An alkyl group. Preferably, L₁Selected from single bonds, -CH₂- and -CH₂CH₂-. More preferably, L₁Selected from the group consisting of single bonds and-CH₂-. Most preferably, L₁Is a single bond.

In one particular embodiment, in formula (IV), M is chosen from single bonds, - (CR)_cR_d)_m- and -(CR_cR_d)_mO-, wherein R_c、R_dEach independently selected from-H and C_1-6An alkyl group. Preferably, M is selected from the group consisting of a single bond, -CH₂-、-CH₂CH₂-、-CH₂O- and CH₂CH₂O-is formed. More preferably, M is selected from the group consisting of a single bond and-CH₂O-is formed. Most preferably M is a single bond.

In one particular embodiment, in formula (IV), R₁、R₂Each independently selected from-H, C_1-6Alkyl and C_3-6Cycloalkyl, wherein R₁ and R₂Is not H at the same time; or, R₁Can be mixed with R₂Together form a mixture containing 0 to 1 substituents selected from-O-, -NR₁₆-, -SO-and SO₂-a 3 to 6 membered saturated cyclic group of the group of; r₁₆Is selected from-H, C_1-6Alkyl radical, C_1-4Alkoxy radical C_1-4Alkyl, halogen, hydroxy, cyano and C_3-6A cycloalkyl group.

Preferably, R₁、R₂Each independently selected from methyl, ethyl, isopropyl and cyclopropyl. More preferably, R₁、R₂Each independently selected from methyl.

Preferably, R₁Can be mixed with R₂Together form a mixture containing 0 to 1-O-, -SO-and SO₂-3 to 6 membered saturated cyclic group. More preferably, R₁Can be mixed with R₂Together forming a cyclopropyl group.

In one particular embodiment, in formula (IV), R₈Is selected from-H, C_1-6Alkyl and C_3-6A cycloalkyl group. Preferably, R₈Selected from-H, methyl, ethyl and cyclopropyl. More preferably, R₈is-H.

Specifically, the compound has a structure of formula (V):

in one particular embodiment, in formula (V), X₃Selected from single bonds, -CH₂-、-CH₂CH₂- and -CH₂CH₂CH₂-。

In one particular embodiment, in formula (V), p, q are each independently selected at each occurrence from 0, 1,2 and 3.

In one particular embodiment, in formula (V), R₉、R₁₀Each independently selected from-H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3-to 10-membered heterocyclic group), - (CH)₂)_m-O-C_3-10Carbocyclyl, - (CH)₂)_m-O- (3 to 10 membered heterocyclyl), phenyl and 5 to 6 membered heteroaryl, each of said heterocyclyl, heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, R₉、R₁₀The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle in (1) is independently optionally further substituted by 0 to 4 groups selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy. Preferably, R₉、R₁₀Each independently selected from-H, methyl, ethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl. More preferably, R₉、R₁₀Each independently selected from-H and methyl. In one particular embodiment, R₉、R₁₀Each independently is-H.

In one particular embodiment, in formula (V), R₈Is selected from-H, C_1-6Alkyl and C_3-6A cycloalkyl group. Preferably, R₈Selected from-H, methyl, ethyl and cyclopropyl. More preferably, R₈is-H.

In one particular embodiment, in formula (V), p, q are each independently selected at each occurrence from 0, 1,2 and 3. Preferably, each occurrence of p, q is independently selected from 0, 1 and 2.

In one particular embodiment, in formula (V), L₂is-NH-.

In one particular embodiment, in formula (V), L₁Selected from the group consisting of single bonds and- (CR)_aR_b)_m-, wherein R_a，R_bIndependently selected from-H and C_1-6An alkyl group. Preferably, L₁Selected from single bonds, -CH₂- and -CH₂CH₂-. More preferably, L₁Selected from the group consisting of single bonds and-CH₂-. Most preferably, L₁Is a single bond.

In one particular embodiment, in formula (V), M is chosen from single bonds, - (CR)_cR_d)_m- and -(CR_cR_d)_mO-, wherein R_c、R_dIndependently selected from-H and C_1-6An alkyl group. Preferably, M is selected from the group consisting of a single bond, -CH₂-、-CH₂CH₂-、-CH₂O- and CH₂CH₂O-is formed. More preferably, M is selected from the group consisting of a single bond and-CH₂O-is formed. Most preferably M is a single bond.

In one particular embodiment, in formula (V), R₁、R₂Each independently selected from-H, C_1-6Alkyl and C_3-6Cycloalkyl, wherein R₁ and R₂Is not H at the same time; or, R₁Can be mixed with R₂Together form a mixture containing 0 to 1 substituents selected from-O-, -NR₁₆-, -SO-and SO₂-a 3 to 6 membered saturated cyclic group of the group of; r₁₆Is selected from-H, C_1-6Alkyl radical, C_1-4Alkoxy radical C_1-4Alkyl, halogen, hydroxy, cyano and C_3-6A cycloalkyl group.

In one embodiment, in formula (V), p, q are each 1; x₃is-CH₂-；R₉、R₁₀、R₁₁Each is-H; l is₁Is a single bond; l is₂is-NH-; m is a single bond.

Preferably, the compound has the formula (VI):

in one embodiment, in formula (VI), L₂is-NH-.

In one particular embodiment, in formula (VI), R₉、R₁₀Each independently selected from-H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3-to 10-membered heterocyclic group), - (CH)₂)_m-O-C_3-10Carbocyclyl, - (CH)₂)_m-O- (3 to 10 membered heterocyclyl), phenyl and 5 to 6 membered heteroaryl, each of said heterocyclyl, heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, R₉、R₁₀The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle in (1) is independently optionally further substituted by 0 to 4 groups selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy. Preferably, R₉、R₁₀Each independently selected from-H, methyl, ethyl, methoxy, ethoxy, cyclopropyl and cyclobutyl. More preferably, R₉、R₁₀Each independently selected from-H and methyl. In one particular embodiment, R₉、R₁₀Each independently is-H.

In one particular embodiment, in formula (VI), R₈Is selected from-H, C_1-6Alkyl and C_3-6A cycloalkyl group. Preferably, R₈Selected from-H, methyl, ethyl and cyclopropyl. More preferably, R₈is-H.

In one particular embodiment, in formula (VI), L₁Selected from the group consisting of single bonds and- (CR)_aR_b)_m-, wherein R_a，R_bEach independently selected from-H and C_1-6An alkyl group. Preferably, L₁Selected from single bonds, -CH₂- and -CH₂CH₂-. More preferably, L₁Selected from the group consisting of single bonds and-CH₂-. Most preferably, L₁Is a single bond.

In one particular embodiment, in formula (VI), M is chosen from single bonds, - (CR)_cR_d)_m- and -(CR_cR_d)_mO-, wherein R_c、R_dIndependently selected from-H and C_1-6An alkyl group. Preferably, M is selected from the group consisting of a single bond, -CH₂-、-CH₂CH₂-、-CH₂O- and CH₂CH₂O-is formed. More preferably, M is selected from the group consisting of a single bond and-CH₂O-is formed. Most preferably M is a single bond.

In one particular embodiment, in formula (VI), R₁、R₂Each independently selected from-H, C_1-6Alkyl and C_3-6Cycloalkyl, wherein R₁ and R₂Is not H at the same time; or, R₁Can be mixed with R₂Together form a complex containing 0 to 1-O-, -NR₁₆-, -SO-and SO₂-a 3 to 6 membered saturated cyclic group of the group of; r₁₆Is selected from-H, C_1-6Alkyl radical, C_1-4Alkoxy radical C_1-4Alkyl, halogen, hydroxy, cyano and C_3-6A cycloalkyl group.

Preferably, R₁Can be mixed with R₂Together form a mixture containing 0 to 1 atoms selected from-O-, -SO-and SO₂A 3 to 6 membered saturated cyclic group of the group of (a). More preferably, R₁Can be mixed with R₂Together forming a cyclopropyl group.

In one particular embodiment, in formula (VI), R₉、R₁₀、R₁₁Each is-H; l is₁Is a single bond; m is a single bond.

Further, the present invention relates to the following embodiments.

In one embodiment, the present invention is directed to a compound having the structure of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

wherein A is selected from C_6-14Aryl, 5-to 14-membered heteroaryl, 5-to 14-membered heterocyclyl and 5-to 14-membered cycloalkyl, and said aryl, heteroaryl, heterocyclyl and cycloalkyl in A are optionally further substituted with 0 to 5R₃Substitution; wherein said heteroaryl and heterocyclyl contain 1 to 4 heteroatoms selected from N, O and S;

R₃each independently selected from-H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkoxy radical C_1-4Alkyl, - (CH)₂)_m-alkenyl, - (CH)₂)_m-alkynyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3-to 10-membered heterocyclic group), -O- (CH)₂)_m-C_3-10Carbocyclyl and-O- (CH)₂)_m- (3-to 10-membered heterocyclic group) containing 1 to 4 hetero atoms selected from N, O and S, and R₃Wherein each of said alkyl, alkoxy, carbocyclyl or heterocyclyl is independently optionally further substituted with 0 to 4 substituents selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy;

L₁selected from the group consisting of single bonds and- (CR)_aR_b)_m-, wherein R_a and R_bEach independently selected from-H and C_1-6An alkyl group;

L₂selected from-NH-and-O-;

q is selected from one of the following structures:

wherein ,X₁、X₂ and X₃Each independently selected from the group consisting of a single bond and- (CR)_eR_f)_n-；

X₄Is selected from-CH₂-、-CH₂CH₂- and -CH₂CH₂CH₂-；

R₄、R₅、R₆、R₇、R₉、R₁₀、R_e and R_fEach independently selected from-H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3-to 10-membered heterocyclic group), - (CH)₂)_m-O-C_3-10Carbocyclyl, - (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 R₄、R₅、R₆、R₇、R₉、R₁₀、R_e、R_fThe alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle in (1) is independently optionally further substituted by 0 to 4 groups selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy;

m, n, p, q are each independently at each occurrence selected from 0, 1,2 and 3;

In one embodiment, the present invention relates to a compound having the structure of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, having the structure of formula (II):

wherein ,L₂is-NH-.

In one embodiment, the present invention relates to a compound having the structure 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):

wherein ,X₁Selected from single bond or-CH₂-。

In one embodiment, the present invention relates to a compound having the structure of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein the compound has the structure of formula (IV):

wherein ,R₄、R₅、R₆、R₇Each independently selected from-H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3-to 10-membered heterocyclic group), - (CH)₂)_m-O-C_3-10Carbocyclyl, - (CH)₂)_m-O- (3 to 10 membered heterocyclyl), phenyl and 5 to 6 membered heteroaryl, said heterocyclyl and heteroaryl each containing 1 to 4 heteroatoms selected from N, O and S, and R₄、R₅、R₆、R₇The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle in (1) is independently optionally further substituted by 0 to 4 groups selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy;

R₄、R₅、R₆ and R₇Not being 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,

R₄、R₅ and R₆Each is-H;

R₇is selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3-to 10-membered heterocyclic group), - (CH)₂)_m-O-C_3-10Carbocyclyl, - (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 R₇The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle in (1) is independently optionally further substituted by 0 to 4 groups selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy.

In one embodiment, the present invention relates to a compound of formula (IV) as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

R₅、R₆ and R₇Each is-H;

R₄is selected from C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3-to 10-membered heterocyclic group), - (CH)₂)_m-O-C_3-10Carbocyclyl, - (CH)₂)_m-O- (3 to 10 membered heterocyclyl), phenyl and 5 to 6 membered heteroaryl, said heterocyclyl and heteroaryl each containing 1 to 4 heteroatoms selected from N, O and S, and R₄The alkyl, alkoxy, carbocyclyl, phenyl, heteroaryl or heterocycle in (1) is independently optionally further substituted by 0 to 4 groups selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy.

R₇is selected from C_1-6Alkyl radical, C_1-6Alkoxy, methoxymethyl, hydroxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, phenyl, pyridyl, furyl, imidazolyl and thiazolyl; and R is₇Each independently optionally further substituted by 0 to 4 substituents selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy;

L₁is a single bond;

m is a single bond.

R₄is selected from C_1-6Alkyl, methoxymethyl, hydroxymethyl, monofluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclobutoxy, cyclopentyl, tetrahydrofuranyl, phenyl, pyridyl, furanyl, imidazolyl and thiazolyl, each of which is independently optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, hydroxy, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy;

L₁is 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,

R₆、R₇ and R₈Each is-H;

L₁is a single bond.

In one embodiment, the present invention relates to a compound having the structure of formula (I) above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, characterized by having the structure of formula (V):

X₃is a single bond, -CH₂-、-CH₂CH₂- and -CH₂CH₂CH₂-；

p, q are each independently at each occurrence selected from 0, 1,2 and 3.

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,

p and q are each 1;

X₃is-CH₂-；

R₉、R₁₀ and R₁₁Each is-H;

L₁is a single bond;

L₂is-NH-;

m is a single bond.

In one embodiment, the present invention relates to a compound having 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):

wherein ,L₂is-NH-.

R₉、R₁₀、R₁₁is-H;

L₁is 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,

X₄is selected from-CH₂-、-CH₂CH₂- and -CH₂CH₂CH₂-；

R₁₂、R₁₃、R₁₄、R₁₅Each is-H.

a is selected from one of the following structures:

a is selected from one of the following structures:

a is selected from one of the following structures:

a is selected from one of the following structures:

a is selected from one of the following structures:

R₃each independently selected from-H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkoxy radical C_1-4Alkyl, - (CH)₂)_m-C_3-10Carbocyclyl, -O- (CH)₂)_m-C_3-10Carbocyclyl and-O- (CH)₂)_m- (3-to 10-membered heterocyclic group) containing 1 to 4 heteroatoms selected from N, O and S, and R₃Each of said alkyl, alkoxy, carbocycle or heterocycle is independently optionally further substituted by 0 to 4 substituentsFrom H, F, Cl, Br, I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Alkoxy substituents.

R₃each independently selected from-H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkoxy radical C_1-4Alkyl, cyclopropyl, cyclobutyl and cyclopropylmethyl.

R₁、R₂each independently selected from C_1-6Alkyl and C_3-6A cycloalkyl group;

or R₁ and R₂Together form a mixture containing 0 to 1 atoms selected from-O-, -SO-and-SO₂A 3 to 6 membered saturated cyclic group of the group of (a).

R₁、R₂each independently selected from methyl, ethyl, propyl, cyclopropyl and cyclobutyl;

or R₁ and R₂Together form a 3-membered saturated carbocyclic group.

q is selected from one of the following structures:

R₄、R₅、R₆、R₇not being simultaneously-H.

wherein A is selected from C_6-14Aryl, 5-to 14-membered heteroaryl, 5-to 14-membered heterocyclyl and 5-to 14-membered cycloalkyl, and said aryl, heteroaryl, heterocyclyl or cycloalkyl in A is optionally further substituted with 0 to 5R₃Substitution; wherein the heteroaryl or heterocyclyl group contains 1 to 4 heteroatoms selected from N, O and S;

R₃each independently selected from-H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C_1-4Alkyl radical, C_1-4Alkoxy and C_1-4Alkoxy radical C_1-4Alkyl, and R₃Each of said alkyl or alkoxy groups in (1) is independently optionally further substituted by 0 to 4 groups selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy;

R₁、R₂each independently selected from-H, C_1-6Alkyl and C_3-6Cycloalkyl, wherein R₁ and R₂Is not H at the same time;

or R₁ and R₂Together form a 3-to 6-membered saturated cyclic group;

m is selected from the group consisting of single bond, - (CR)_cR_d)_m- and -(CR_cR_d)_mO-, wherein R_cOr R_dIndependently selected from-H and C_1-6An alkyl group;

q is selected from one of the following structures:

X₄Is selected from-CH₂-、-CH₂CH₂- and -CH₂CH₂CH₂-；

R₄、R₅、R₆、R₇、R₉、R₁₀、R_e、R_fEach independently selected from-H, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkoxy radical C_1-6Alkyl and phenyl, and R₄、R₅、R₆、R₇、R₉、R₁₀、R_e、R_fThe alkyl, alkoxy and phenyl groups in (1) are each independently optionally further substituted by 0 to 4 groups selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy;

when X is present₁，X₂When simultaneously a single bond, R₄、R₅、R₆、R₇Not being 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,

wherein ,

represents a single or double bond, provided that two

Wherein and only one represents a double bond;

X₁is CR_3’Or NR₃；

X₂Is CR_3’Or NR₃；

or ,X₁And substituents thereof and adjacent carbon atoms and substituents R thereof_3’Together form a phenyl ring or a 5-to 6-membered heteroaromatic ring optionally substituted with 1-4R_3’Substitution;

R₃is selected from-H, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6An alkynyl group;

R_3’selected from-H, halogen, cyano, -OR, -NR' R ", C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, - (CH)₂)_n-C_3-10Carbocyclyl, - (CH)₂)_n- (3-to 10-membered heterocyclic group), - (CH)₂)_n-C_6-10Aryl, - (CH)₂)_n- (5-to 6-membered heteroaryl) and-SR_x；

R₄Is selected from-H, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, - (CH)₂)_n-C_3-10Carbocyclyl, - (CH)₂)_n- (3-to 10-membered heterocyclic group), - (CH)₂)_n-C_6-10Aryl and- (CH)₂)_n- (5 to 6 membered heteroaryl); wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with halogen, cyano, -OR, -NR' R ", C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl substitution;

R₅is selected from-H, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, - (CH)₂)_n-C_3-10Carbocyclyl, - (CH)₂)_n- (3-to 10-membered heterocyclic group), - (CH)₂)_n-C_6-10Aryl and- (CH)₂)_n- (5 to 6 membered heteroaryl);

R₁ and R₂Each independently selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

r is selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

r 'and R' are each selected from-H, C_1-6Alkyl and halo C_1-6Alkyl, or R' and R "together with the nitrogen atom to which they are attached form a 3-to 10-membered heterocyclyl;

R_xis selected from-H, C_1-6Alkyl, halo C_1-6Alkyl, - (CH)₂)_n-C_2-6Alkenyl, - (CH)₂)_n-C_2-6Alkynyl, - (CH)₂)_n-C_3-10Carbocyclyl, - (CH)₂)_n- (3-to 10-membered heterocyclic group), - (CH)₂)_n-C_6-10Aryl 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) as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

represents a single or double bond, provided that two

Wherein and only one represents a double bond;

X₁is CR_3’Or NR₃；

X₂Is CR_3’；

X₁And substituents thereof and adjacent carbon atoms and substituents R thereof_3’Together form a phenyl ring or a 5-to 6-membered heteroaromatic ring which is substituted with 1-4R_3’Substitution;

R₄Is selected from-H, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, - (CH)₂)_n-C_3-10Carbocyclyl, - (CH)₂)_n- (3-to 10-membered heterocyclic group), - (CH)₂)_n-C_6-10Aryl and- (CH)₂)_n- (5 to 6 membered heteroaryl); said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl being optionally substituted with halogen, cyano, -OR, -NR' R ", C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl substitution;

r is selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

n is 0, 1,2 or 3;

s is 0 or 1;

r is 0 or 1.

represents a single or double bond, provided that two

Wherein and only one represents a double bond;

X₁is CR_3’Or NR₃；

X₂Is NR₃；

X₁And substituents thereof and adjacent carbon atoms and substituents R thereof_3’Together form a phenyl ring or a 5-to 6-membered heteroaromatic ring, which phenyl ring or 5-to 6-membered heteroaromatic ringThe aromatic ring being substituted by 1-4R_3’Substitution;

r is selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

r 'and R' are each selected from-H, C_1-6Alkyl and halo C_1-6Alkyl, or R 'and R' together with the nitrogen atom to which they are attachedTo a 3 to 10 membered heterocyclyl group;

n is 0, 1,2 or 3;

s is 0 or 1;

r is 0 or 1.

represents a single or double bond, provided that two

Wherein and only one represents a double bond;

X₁is CR_3’；

X₂Is NR₃；

X₁And substituents thereof and adjacent carbon atoms and substituents R thereof_3’Together form a phenyl ring, said phenyl ring being substituted by 1-4R_3’Substitution;

R₃is selected from-H and C_1-6An alkyl group;

R_3’is C_1-6An alkyl group;

R₄is selected from-H and C_1-6An alkyl group;

R₅is selected from-H and C_1-6An alkyl group;

R₁ and R₂Each 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,

wherein ,

represents a single or double bond, provided that two

Wherein and only one represents a double bond;

X₁is CR_3’Or NR₃；

X₂Is CR_3’Or NR₃；

R₃is selected from C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6An alkynyl group;

R₄Is selected from C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, - (CH)₂)_n-C_3-10Carbocyclyl, - (CH)₂)_n- (3-to 10-membered heterocyclic group), - (CH)₂)_n-C_6-10Aryl and- (CH)₂)_n- (5 to 6 membered heteroaryl); wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with halogen, cyano, -OR, -NR' R ", C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl substitution;

r is selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

n is 0, 1,2 or 3.

In one embodiment, the present invention relates to a compound of formula (b) as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

wherein ,

represents a single or double bond, provided that two

Wherein and only one represents a double bond;

X₁is CR_3’Or NR₃；

X₂Is CR_3’；

R₄Is selected from C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, - (CH)₂)_n-C_3-10Carbocyclyl, - (CH)₂)_n- (3-to 10-membered heterocyclic group), - (CH)₂)_n-C_6-10Aryl and- (CH)₂)_n- (5 to 6 membered heteroaryl); said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl being optionally substituted with halogen, cyano, -OR, -NR' R ", C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl substitution;

r is selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

n is 0, 1,2 or 3.

In one embodiment, the present invention relates to a compound of formula (b) as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

represents a single or double bond, provided that two

Wherein and only one represents a double bond;

X₁is CR_3’Or NR₃；

X₂Is NR₃；

X₁And substituents thereof and adjacent carbon atoms and substituents R thereof_3’Together form a phenyl ring or a 5-to 6-membered heteroaromatic ring, which phenyl ring or 5-to 6-membered heteroaromatic ringThe heteroaromatic ring being substituted by 1-4R_3’Substitution;

r is selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

r 'and R' are each selected from-H, C_1-6Alkyl and halo C_1-6Alkyl, or R 'and R' together with the nitrogen atom to which they are attached form 3 toA 10-membered heterocyclic group;

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,

wherein ,

r is selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

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) as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

R_3’selected from halogen, cyano, C_1-6Alkyl, halo C_1-6Alkyl and-SR_x；

R₄Is selected from C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6An alkynyl group;

R₅is selected from-H, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6An alkynyl group;

R_xis selected from C_1-6Alkyl, halo C_1-6Alkyl and- (CH)₂)_n-C_3-6A carbocyclic group;

n is 0, 1,2 or 3;

t is 0, 1 or 2.

R_3’is selected from C_1-4Alkyl and-SR_x；

R₄Is C_1-4An alkyl group;

R₅is selected from-H and C_1-4An alkyl group;

R₁ and R₂Each independently selected from-H and C_1-4An alkyl group;

R_xis selected from C_1-4Alkyl and halo C_1-4An alkyl group;

t is 1 or 2.

In one embodiment, the present invention relates to a compound of formula (c) as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

wherein ,

R_3’is C_1-4An alkyl group;

R₄is C_1-4An alkyl group;

R₅is-H;

R₁ and R₂Each 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,

wherein ,

R_3’selected from-H, halogen, cyano, -OR, -NR' R ", C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl and-SR_x；

r is selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

n is 0, 1,2 or 3.

In one embodiment, the present invention relates to a compound of formula (c-1) as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

R_3’selected from halogen, C_1-4Alkyl, halo C_1-4Alkyl and-SR_x；

R₄Is selected from C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,Halogen substituted C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6An alkynyl group;

n is 0, 1,2 or 3.

In one embodiment, the present invention relates to a compound of formula (c-1) as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

wherein ,

R_3’is selected from C_1-4Alkyl and-SR_x；

R₄Is C_1-4Alkyl and halo C_1-4An alkyl group;

R₅is selected from-H and C_1-4An alkyl group;

R_xis selected from C_1-4Alkyl and halo C_1-4An alkyl group.

wherein ,

R_3’is C_1-4An alkyl group;

R₄is C_1-4An alkyl group;

R₅is-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,

wherein ,

r is selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

r 'and R' are each selected from-H, C_1-6Alkyl and halo C_1-6Alkyl, or R 'and R' together with the nitrogen atom to which they are attachedForming a 3-to 10-membered heterocyclic group;

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) as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

R₃is selected from C_1-6Alkyl and halo C_1-6An alkyl group;

R_3’selected from-H, halogen, cyano, C_1-6Alkyl, halo C_1-6Alkyl and-SR_x；

n is 0, 1,2 or 3;

t is 0, 1 or 2.

R₃is C_1-4An alkyl group;

R_3’is selected from-H, C_1-4Alkyl and-SR_x；

R₄Is C_1-4An alkyl group;

R₅is selected from-H and C_1-4An alkyl group;

R₁ and R₂Each independently selected from-H and C_1-4An alkyl group;

R_xis selected from C_1-4Alkyl and halo C_1-4An alkyl group;

t is 0 or 1.

In one embodiment, the present invention relates to a compound of formula (d) as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

wherein ,

R₃is C_1-4An alkyl group;

R_3’is selected from-H and C_1-4An alkyl group;

R₄is C_1-4An alkyl group;

R₅is-H;

R₁ and R₂Each 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,

wherein ,

R_3’selected from-H, halogen, cyano, andOR、-NR’R”、C_1-6alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl and-SR_x；

r is selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

n is 0, 1,2 or 3.

In one embodiment, the present invention relates to a compound of formula (d-1) as described above, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein,

R₃is selected from C_1-6Alkyl and halo C_1-6An alkyl group;

R_3’selected from-H, halogen, cyano, C_1-6Alkyl and halo C_1-Alkyl and-SR_x；

R₄Is selected from C_1-6Alkyl and halo C_1-6An alkyl group;

R₅is selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

n is 0, 1,2 or 3.

R₃is C_1-4An alkyl group;

R_3’is selected from-H, C_1-4Alkyl and-SR_x；

R₄Is C_1-4An alkyl group;

R₅is selected from-H and C_1-4An alkyl group;

R_xis selected from C_1-4Alkyl and halo C_1-4An alkyl group.

R₃is C_1-4An alkyl group;

R_3’is selected from-H and C_1-4An alkyl group;

R₄is C_1-4An alkyl group;

R₅is-H.

In one particular embodiment, the compound is selected from one of the following structures:

in a specific 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.

Embodiments of the present invention also provide a method for preparing the compound, comprising the steps of:

carrying out a condensation reaction with a compound 1 and a compound 2, wherein G represents a nitrogen protecting group;

and removing the nitrogen protecting group in the product of the condensation reaction. 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 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, for use in the manufacture of a medicament for the treatment and/or prevention of a disease or condition affected by the activation of SSTR 4.

In one specific embodiment, the disease or condition affected by the activation of SSTR4 is pain.

Embodiments of the present invention also provide 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, for use in the treatment and/or prevention of pain.

In one embodiment, the present invention provides a compound of the present invention, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a pharmaceutical composition of the present invention for use in the treatment and/or prevention of a disease or condition that is affected by the activation of SSTR 4. In one embodiment, the compound or composition is for use in the treatment and/or prevention of pain.

In one embodiment, the present invention provides a method of treating a disease or condition affected by the 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 described herein.

In a specific embodiment, the pain is neuropathic pain.

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 is provided for the purpose of illustrating the embodiments and the advantageous effects thereof, and is not intended to limit the scope of the present disclosure.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (and) Mass Spectrometry (MS). NMR shift (. delta.) of 10^-6The units in (ppm) are given. NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometers in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform(CDCl₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS).

MS was measured by Agilent 6120B (ESI) and Agilent 6120B (APCI).

HPLC was carried out using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18100X 4.6 mm).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by 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.

The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

Known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Tatan technology, Annaiji chemistry, Shanghai Demer, Chengdong chemical, Shaoshan far chemical technology, and Bailingwei technology.

The nitrogen atmosphere means that the reaction flask is connected with a nitrogen balloon with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is room temperature, unless otherwise specified.

The room temperature is the most suitable reaction temperature and is 20-30 ℃.

Abbreviations related to chemical synthesis:

ac: acetyl group

AcOH: acetic acid

Bn: benzyl radical

Boc: tert-butyloxycarbonyl radical

Bz: benzoyl radical

DIPEA: diisopropylethylamine

DMF: n, N-dimethylformamide

DCM: methylene dichloride

DIEA: n, N-diisopropylethylamine

EA: ethyl acetate

Et: ethyl radical

EtOAc: ethyl acetate

Et₃N triethylamine

HATU: 2- (7-aza-1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate

HPLC: high performance liquid chromatography

LiHMDS: lithium hexamethyldisilazide

Me: methyl radical

MeLi: methyl lithium

NMP: n-methyl pyrrolidone

Raney-Ni: raney nickel

NEt₃: triethylamine

overnight: overnight

Raney-Ni: raney nickel

SEM: (trimethylsilyl) ethoxymethyl group

SEMCl: 2- (trimethylsilyl) ethoxymethyl chloride

SFC: supercritical fluid chromatography

TBTU: 2- (1H-benzotriazol-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate

TEA: triethylamine

TEMPO: 2,2,6, 6-tetramethylpiperidine oxide

THF: tetrahydrofuran (THF)

TLC: thin layer chromatography

TFA: trifluoroacetic acid

TBAF: tetra-n-butylammonium fluoride

Burgess' reagent: bergels reagent, CAS No.: 29684-56-8

rt: at room temperature

h: hour(s)

Synthesizing:

intermediate 1:

2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-amine hydrochloride (intermediate 1)

The first step is as follows: (3-methylpyridin-2-yl) methylamine (1b)

Compound 1a (10.0g, 84.6mmol, 1eq) was charged to a 500mL autoclave, EtOH (200mL) and Raney nickel (Raney Ni) (4.00g) were added under argon protection, and the autoclave was sealed. Replacing the gas in the high-pressure reaction kettle with hydrogen for 3 to 4 times, continuously introducing the hydrogen to keep the pressure in the reaction kettle at about 50Psi, and stirring and reacting 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 as a dark purple liquid (6.85g, yield: 66.2%), which was used in the next reaction without purification.

¹H NMR(400MHz,CDCl₃)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]⁺.

The second step is that: (2-methyl-1- (((3-methylpyridin-2-yl) methyl) amino) -1-oxopropan-2-yl) carbamic acid tert-butyl ester (1c)

The compound 1b (5.50g, 45.0mmol, 1eq), N-tert-butoxycarbonyl-2-methylalanine (9.13g, 45.0mmol, 1eq), TBTU (14.4g, 45.0mmol, 1eq) and Et₃N (13.7g, 135mmol, 3eq) was added separately to the flask and THF (400mL) was added and stirred at 20 ℃ for 12 h. The solvent was evaporated and the residue was diluted with 300mL of dichloromethane, washed with 1M NaOH (150 mL. times.2) and brine (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and reducedConcentrated 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 (4.35g, yield: 31.1%) as a pale yellow solid.

MS(ESI):m/z＝308.2[M+H]⁺.

The third step: (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamic acid tert-butyl ester (1d)

Compound 1c (3.80g, 12.4mmol, 1eq) was dissolved in dichloromethane (30mL), cooled to 0 ℃ and burges' reagent (3.55g, 14.9mmol, 1.2eq) was added. 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 (1.76g, yield: 47.5%) as a pale yellow solid.

MS(ESI):m/z＝290.2[M+H]⁺.

The fourth step: 2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-amine hydrochloride (intermediate 1)

A solution of compound 1d (900mg, 3.12mmol, 1eq) in methanol (4mL) was cooled to 0 ℃ and HCl/methanol (4M, 16mL) was added and stirred at 0 ℃ for 2 h. The mixture was concentrated under reduced pressure to give intermediate 1(850mg, 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)

The first step is as follows: 1-methyl-1H-indazole-3-carbonitrile (2b)

1H-indazole-3-carbonitrile 2a (3g, 20.9mmol) was dissolved in dry DMF (50mL), cooled to 0 deg.C, and then sodium hydride 60% (1.2g,30mmol) was added thereto slowly in portions and stirred for 30 min. Methyl iodide (4.26g,30mmol) was added dropwise thereto, and the mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction solution was quenched with saturated aqueous ammonium chloride (100mL) and extracted with ethyl acetate (50 mL. times.2). The organic phase was dried over anhydrous sodium sulfate and dried by rotary drying in vacuo to give a 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 (2.5g, yield: 75.7%).

MS(ESI):m/z＝158.1[M+H]⁺.

The second step is that: 2- (1-methyl-1H-indazol-3-yl) propan-2-amine (intermediate 2)

Cerium trichloride (3.13g, 12.7mmol) was stirred in dry tetrahydrofuran (30mL) for 1 hour. The temperature was reduced to-78 deg.C, methyllithium (9.8mL,12.7mmol,1.3M) was added dropwise thereto, and stirring was continued for 1 hour. Then, a solution of 1-methyl-1H-indazole-3-carbonitrile 2b (500mg,3.18mmol) in tetrahydrofuran (5mL) was added dropwise thereto, and the mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction solution was quenched with 6mL of 10% aqueous sodium hydroxide solution and filtered. The filtrate was dried over anhydrous sodium sulfate and rotary dried in vacuo to give a crude yellow oil. The crude product was purified by silica gel column (petroleum ether: ethyl acetate ═ 1: 1) to give 2- (1-methyl-1H-indazol-3-yl) propan-2-amine (intermediate 2) (250mg, yield: 48%).

MS(ESI):m/z＝190.1[M+H]⁺.

Intermediate 3-P1 and intermediate 3-P2:

3- (tert-Butoxycarbonyl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid (intermediate 3-P1 and intermediate 3-P2)

First step 1-benzyl-3-methyl-lH-pyrrole-2, 5-dione (3b)

3-Methylfuran-2, 5-dione (20g,0.179mol) and benzylamine (19.1g,0.179mol) were stirred in glacial acetic acid (80mL) at 100 ℃ for 4 h, and the solvent was removed in vacuo. The residue was purified by silica gel column (petroleum ether: ethyl acetate ═ 10: 1) to give 1-benzyl-3-methyl-1H-pyrrole-2, 5-dione 3b (28g, yield: 80%) as a white solid.

MS(ESI):m/z＝202.1[M+H]⁺.

The second step is that: (5-benzyl-6 a-methyl-4, 6-dioxo-1, 3a,4,5,6,6 a-hexahydropyrrolo [3,4-c ] pyrazole-3-carboxylic acid ethyl ester (3c)

1-benzyl-3-methyl-1H-pyrrole-2, 5-dione 3b (28g,0.139mol) and ethyl diazoacetate (48g,0.418mol) were stirred in toluene (100mL) 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 white solid (ethyl 5-benzyl-6 a-methyl-4, 6-dioxo-1, 3a,4,5,6,6 a-hexahydropyrrolo [3,4-c ] pyrazole-3-carboxylate 3c (42g, yield: 95%).

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 (3d)

Ethyl 5-benzyl-6 a-methyl-4, 6-dioxo-1, 3a,4,5,6,6 a-hexahydropyrrolo [3,4-c ] pyrazole-3-carboxylate 3c (14g,44.4mmol) was suspended in toluene (50mL), warmed to 200 deg.C (temperature of oil bath), and stirred for 1 hour. Thin layer chromatography monitoring indicated complete conversion of starting material. Putting the mixture into 3 pots in parallel for reaction. The resulting black viscous residues were combined and purified by silica gel column (petroleum ether: ethyl acetate: 30: 1) to give ethyl 3-benzyl-1-methyl-2, 4-dioxo-3-azabicyclo [3.1.0] hexane-6-carboxylate 3d (22g, yield: 57.4%) as a white solid product.

MS(ESI):m/z＝288.1[M+H]⁺.

The fourth step: 3-benzyl-1-methyl-3-azabicyclo [3.1.0] hexane-6-carbaldehyde (3e)

Ethyl 3-benzyl-1-methyl-2, 4-dioxo-3-azabicyclo [3.1.0] hexane-6-carboxylate 3d (22g, 76.6mmol) was dissolved in dry THF (190 mL. times.2) in 2 portions (i.e., 11 g. times.2), and lithium aluminum hydride (5.8 g. times. 2,153.2mmol) was added in portions in an ice-water bath and stirred at room temperature for 18 hours. The reaction was quenched with sodium sulfate decahydrate (59.2 g. times. 2,183.8mmol) in an ice-water bath. The solid was filtered off and the filtrate was spin-dried in vacuo to give the crude product as a pale yellow oil in 3-benzyl-1-methyl-3-azabicyclo [3.1.0] hexane-6-carbaldehyde 3e (15g, yield: 91%): . The next step was carried out without purification.

MS(ESI):m/z＝216.1[M+H]⁺.

The fifth step: (3-benzyl-1-methyl-3-azabicyclo [3.1.0] hex-6-yl) methanol (3f)

3-benzyl-1-methyl-3-azabicyclo [3.1.0] hexane-6-carbaldehyde (15g,69.8mmol) was dissolved in methanol (240mL), and sodium borohydride (660mg,17.4mmol) was added portionwise in an ice-water bath and stirred at room temperature for 2 hours. The reaction was quenched by slowly adding acetone (30mL) dropwise in an ice water bath and stirred for 30 min. Spin-dry in vacuo to give 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 (10.1g, light yellow oil, yield: 66.7%).

MS(ESI):m/z＝218.1[M+H]⁺.

10.1g of the racemic compound 3f obtained above was subjected to chiral resolution to obtain 4.5g of each of 3f-P1 (short-retention compound) and 3f-P2 (long-retention compound).

The specific conditions for chiral resolution are shown in the following table:

and a sixth step: 6- (hydroxymethyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (3g)

3-benzyl-1-methyl-3-azabicyclo [3.1.0] hex-6-yl) methanol 3f-P1(4.5, 20.7mmol) was dissolved in methanol (60mL) and palladium on charcoal (0.45g), triethylamine (6.3g,62.2mmol) and di-tert-butyl dicarbonate (6.8g,31.1mmol) were added. A hydrogen balloon was inserted, the hydrogen was replaced three times, and then stirred at room temperature overnight. After the reaction is finished, filtering the palladium-carbon, and spin-drying the filtrate to obtain a crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate ═ 6: 1) to give 3g-P1(3.1g, pale yellow oil, yield: 65.9%) of tert-butyl 6- (hydroxymethyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylate.

MS(ESI):m/z＝228.1[M+H]⁺.

3-benzyl-1-methyl-3-azabicyclo [3.1.0] hex-6-yl) methanol 3f-P2(4.5g, 20.7mmol) was dissolved in methanol (60mL), and palladium on charcoal (0.45g), triethylamine (6.3g,62.2mmol) and di-tert-butyl dicarbonate (6.8g,31.1mmol) were added. A hydrogen balloon was inserted, the hydrogen was replaced three times, and then stirred at room temperature overnight. After the reaction is finished, filtering the palladium-carbon, and spin-drying the filtrate to obtain a crude product. The crude product was purified by silica gel column (petroleum ether: ethyl acetate ═ 6: 1) to give 3g-P2(3.5g, pale yellow oil, yield: 74.4%) of tert-butyl 6- (hydroxymethyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylate.

MS(ESI):m/z＝228.1[M+H]⁺.

The seventh step: 3- (tert-Butoxycarbonyl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid (intermediate 3-P1 and intermediate 3-P2)

3g-P1(3.1g,13.7mmol) of tert-butyl 6- (hydroxymethyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylate was dissolved in acetonitrile (30mL), and 2,2,6, 6-tetramethylpiperidine nitroxide (TEMPO) (0.13g,0.819mmol) and 18% aqueous sodium chlorite (18mL) were added at room temperature. After stirring for 5 minutes, a 10% aqueous sodium hypochlorite solution (2mL in 20mL water, 12mL) was added dropwise and stirred at room temperature overnight. Extraction with ethyl acetate (40 mL. times.2), drying of the organic phase over anhydrous sodium sulfate, and spin-drying in vacuo afforded an oil which was 3- (tert-butoxycarbonyl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid intermediate 3-P1(3.0g, yield: 90%): . The reaction mixture was directly used in the next step without purification.

MS(ESI):m/z＝242.1[M+H]⁺.

¹HNMR(400MHz,DMSO-d₆)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(3.5g,15.4mmol) of tert-butyl 6- (hydroxymethyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylate was dissolved in acetonitrile (35mL), and 2,2,6, 6-tetramethylpiperidine nitroxide (0.144g,0.925mmol) and 18% aqueous sodium chlorite (21mL) were added at room temperature. After stirring for 5 minutes, a 10% aqueous sodium hypochlorite solution (2mL in 20mL water, 14mL) was added dropwise and stirred at room temperature overnight. Extraction with ethyl acetate (40 mL. times.2) and drying of the organic phase over anhydrous sodium sulfate followed by 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(3.3g, yield: 81%) which was directly used in the next step without purification.

MS(ESI):m/z＝242.1[M+H]⁺.

¹HNMR(400MHz,DMSO-d₆)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)

7-methyl-1H-indazole-3-carbonitrile 4a (1.0g, 6.39mmol) was dissolved in dry DMF (10mL), cooled to 0 deg.C, then sodium hydrogen 60% (0.40g,10 mmol) was added slowly, stirred for 30min, iodomethane (1.42g,10mmol) was added dropwise, warmed slowly 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), the filtrate was dried over anhydrous sodium sulfate and dried in vacuo to give a crude product, which was purified with silica gel column (petroleum ether: ethyl acetate 5: 1) to give 7-methyl-1H-indazole-3-carbonitrile intermediate 4(1.0g, 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)

The first step is as follows: 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)

Intermediate 1(80mg, 0.354mmol, 1eq), 5-Boc-5-azaspiro [2.4] heptane-1-carboxylic acid 1A (94mg, 0.389mmol, 1.1eq), HATU (162mg, 0.424mmol, 1.2eq), and DIPEA (184mg, 1.42mmol, 4eq) were dissolved in DMF (1.5mL) and stirred at 25 ℃ for 12 h. The mixture was diluted with 10mL of water and extracted with ethyl acetate (8 mL. times.3). The combined organic layers were washed with brine (15mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (petroleum ether: ethyl acetate ═ 1: 1) to give 1B (110mg, yield: 63.1%) as a pale yellow solid.

MS(ESI):m/z＝413.2[M+H]⁺.

The second step is that: n- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) -5-azaspiro [2.4] heptane-1-carboxamide hydrochloride (Compound 1)

Compound 1B (110mg, 0.36mmol, 1eq) was dissolved in ethyl acetate (2mL), cooled to 0 deg.C, HCl/ethyl acetate (4M, 6mL) was added, and stirred at 0 deg.C for 1 h. 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 as a gray solid (70mg, yield: 75.2%).

¹H NMR(400MHz,CD₃OD)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

(3aR,5r,6aS) -N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide hydrochloride (Compound 2)

The first step is as follows: (3aR,5r,6aS) -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)

Intermediate 1(40mg, 0.177mmol, 1eq), compound 2A (CAS No.:442877-23-8) (45mg, 0.177mmol, 1.1eq), HATU (81mg, 0.212mmol, 1.2eq) and DIPEA (92mg, 0.718mmol, 4eq) were dissolved in DMF (1mL) and the solution was stirred at 25 ℃ for 12 hours. The mixture was diluted with 10mL of water and extracted with ethyl acetate (8 mL. times.3). The combined organic layers were washed with brine (15mL), 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 (60mg, yield: 66.5%) as a pale yellow solid.

¹H NMR(400MHz,CDCl₃)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]⁺.

The second step is that: (3aR,5r,6aS) -N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide hydrochloride (Compound 2)

A solution of compound 2B (60mg, 0.14mmol, 1eq) in ethyl acetate (2mL) was cooled to 0 deg.C, HCl/ethyl acetate (4M, 6mL) was added and stirred at 0 deg.C for 1 h. 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 as an orange oil (50mg, yield: 97.9%).

¹H NMR(400MHz,CD₃OD)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

(3aR,5s,6aS) -N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide hydrochloride (Compound 3)

The first step is as follows: (3aR,5s,6aS) -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)

Intermediate 1(40mg, 0.177mmol, 1eq), compound 3A (CAS:1401464-09-2) (45mg, 0.177mmol, 1.1eq), HATU (81mg, 0.212mmol, 1.2eq) and DIPEA (92mg, 1.42mmol, 4eq) were dissolved in DMF (1mL) 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. times.3). The combined organic layers were washed with brine (15mL), 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 (60mg, yield: 66.5%) as a pale yellow solid.

¹H NMR(400MHz,CDCl₃)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]⁺.

The second step is that: (3aR,5s,6aS) -N- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide hydrochloride (Compound 3)

Compound 3B (60mg, 0.14mmol, 1eq) was dissolved in ethyl acetate (2mL), cooled to 0 ℃, HCl/ethyl acetate (4M, 6mL) was added, and stirred at 0 ℃ for 2 h. The mixture was concentrated under reduced pressure to give a residue. To the residue were added 30mL of purified water, 1mL of MeCN, followed by lyophilization, to give Compound 3 as a pale yellow oil (33mg, yield: 64.7%).

¹H NMR(400MHz,CD₃OD)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

(3aR,5s,6aS) -N- (2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide hydrochloride (Compound 4)

The first step is as follows: 2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-amine (4B)

Cerium trichloride (1.15g, 4.67mmol) was stirred in dry tetrahydrofuran (10mL) for 1 hour, cooled to-78 deg.C, and methyllithium (2.35mL,4.67mmol,2M) was added dropwise and stirred for 1 hour. Then, a solution of 1, 7-dimethyl-1H-indazole-3-carbonitrile (intermediate 4) (200mg,1.17mmol) in tetrahydrofuran (5mL) was added dropwise thereto, and the mixture was gradually 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, and spin dry in vacuo to give 4B as a yellow oil (180mg, crude, unpurified).

The second step is that: (3aR,5s,6aS) -N- (2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide hydrochloride (Compound 4)

2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-amine 4B (60mg,0.3mmoL), compound 3A (75mg,0.3mmoL), HATU (170mg,0.45mmoL) and diisopropylethylamine (78mg,0.6mmoL) were dissolved in N, N-dimethylformamide (1mL), stirred at room temperature for 16 hours and the reaction was purified by preparative HPLC to give a white solid (75 mg). This product was added to a 3M ethyl acetate hydrochloride solution (4mL), stirred for 2 hours, and the solvent was removed in vacuo to give compound 4(45mg, yield: 36.8%) as a white solid.

¹H NMR(400MHz,CD₃OD)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)

Intermediate 1(50mg,0.26mmoL), compound 5A (CAS:1222996-05-5) (66mg,0.26mmoL), HATU (148mg,0.39mmoL), and diisopropylethylamine (101mg,0.78mmoL) were dissolved in N, N-dimethylformamide (2mL) and stirred at room temperature for 16 hours. Ethyl acetate (60mL) was added, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and rotary dried in vacuo to give a yellow crude product (75 mg). The crude product was added to a 4M solution of hydrochloric acid in dioxane (4mL), stirred at room temperature for 2 hours and the solvent removed in vacuo. The residue was purified by preparative HPLC to give (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 (34mg, yield: 39.3%) as a white solid.

¹H NMR(400MHz,CD₃OD)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)

The first step is as follows: 5- ((2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) tert-butyl-2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester (6B)

Intermediate 1(50mg g,0.26mmol) was dissolved in DMF (0.5mL), and 2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] heptane-5-carboxylic acid (127.51mg,0.53mmol), N-diisopropylethylamine (68.25mg,0.53mmol) and HATU (150.79mg,0.40mmol) were added at room temperature, and the reaction was stirred at room temperature for 8 hours. Ethyl acetate (3mL) 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 to 1:3) to obtain compound 6B (50mg, yield: 45.9%) as a white solid.

MS(ESI):m/z＝413.0[M+H]⁺

The second step is that: n- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) -2-azabicyclo [2.2.1] heptane-5-carboxamide hydrochloride (Compound 6)

6B (50mg,0.12mmol) was dissolved in dioxane hydrochloride solution (1mL) and reacted at room temperature for 1 hour. The reaction was concentrated, ethyl acetate (3mL) was added, slurried and filtered. Lyophilized to give a white solid compound 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(25mg, yield: 67.7%).

¹H NMR(400MHz,CD₃OD)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

(3aR,5s,6aS) -N- (2- (7-methyl-1H-indazol-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide (Compound 7)

The first step is as follows: 7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole-3-carbonitrile (7B)

7-methyl-1H-indazole-3-carbonitrile 7A (1g, 6.36mmol) was dissolved in dry DMF (5mL), cooled to 0 deg.C, then NaH (370mg, 9.54mmol) was added slowly and stirred for 30 min. Then, (2- (chloromethoxy) ethyl) trimethylsilane (1.60g,9.54mmol) was added dropwise thereto, and the mixture was gradually warmed to room temperature and stirred for 16 hours. Quenched with 5mL of 10% aqueous ammonium chloride solution and extracted with ethyl acetate (100mLX 2). The filtrate was dried over anhydrous sodium sulfate and dried by rotary drying in vacuo to give an oil. The oil was purified by silica gel column (petroleum ether: ethyl acetate ═ 5: 1) to give 7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazole-3-carbonitrile 7B (1.2g, yield: 65.9%).

The second step is that: 2- (7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) propan-2-amine (7C)

Cerium trichloride (320mg, 1.3mmol) was stirred in dry tetrahydrofuran (5mL) for 1 hour, cooled to-78 deg.C, and methyllithium (1mL,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 (100mg, 0.32mmol) in tetrahydrofuran (1mL) was added dropwise, and the mixture was allowed to warm to room temperature slowly and stirred for 16 hours. Quenched with 1mL of 10% aqueous sodium hydroxide, filtered, and the filtrate was dried over anhydrous sodium sulfate and dried by spin-drying in vacuo to give 2- (7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) propan-2-amine 7C as a yellow oil (80mg, crude, unpurified).

The third step: (3aR,5s,6aS) -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)

2- (7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) propan-2-amine 7C (60mg, 0.18mmoL), compound (3aR,5s,6aS) -2- (tert-butoxycarbonyl) octahydrocyclopenta [ C ] pyrrole-5-carboxylic acid (75mg,0.18mmoL), HATU (64mg,0.25mmoL) and diisopropylethylamine (78mg,0.6mmoL) were dissolved in N, N-dimethylformamide (1mL) and stirred at room temperature for 16 hours. The reaction solution was purified by preparative HPLC to give 7D as a white solid (75mg, yield: 75%).

MS(ESI):m/z＝501.0[M-55]⁺.

The fourth step: (3aR,5s,6aS) -N- (2- (7-methyl-1H-indazol-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide (Compound 7)

(3aR,5s,6aS) -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 (75mg,0.13mmol) was dissolved in dichloromethane (2mL), trifluoroacetic acid (0.5mL) was added and stirred at room temperature for 3 hours. The solvent was dried by rotation, and the obtained residue was purified by preparative HPLC to give a white solid, which was Compound 7(20mg, yield: 45%).

¹H NMR(400MHz,CDCl₃)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)

The first step is as follows: 1-benzyl-3-methyl-1H-pyrrole-2, 5-dione (8B)

3-Methylfuran-2, 5-dione 8A (5.0g,44.61mmol) and benzylamine (4.78g,44.61mmol) were stirred in glacial acetic acid (20mL) at 100 ℃ for 4 h. 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 (8.3g, yield: 92.4%) as a white solid.

The second step is that: 5-benzyl-6 a-methyl-4, 6-dioxo-1, 3a,4,5,6,6 a-hexahydropyrrolo [3,4-C ] pyrazole-3-carboxylic acid ethyl ester (8C)

1-benzyl-3-methyl-1H-pyrrole-2, 5-dione 8B (4.0g,19.88mmol) and ethyl diazoacetate (9.07g,79.51mmol) were stirred in toluene (30mL) at 50 ℃ for 4 days. The solvent was removed in vacuo and the residue was purified by silica gel column (petroleum ether: ethyl acetate ═ 2: 1) to give 8C (5.7g, 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)

8C (3.0g,9.96mmol) was stirred at 200 ℃ for 1 hour. The residue was purified by silica gel column (petroleum ether: ethyl acetate ═ 4: 1) to give 8D (1.9g, yield: 66.4%) as a white solid.

The fourth step: (3-benzyl-1-methyl-3-azabicyclo [3.1.0] hex-6-yl) methanol (8E)

8D (1.7g, 5.92mmol) was dissolved in dry THF (30mL), and lithium aluminum hydride (0.829g,29.60mmol) was added portionwise 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 by rotary drying in vacuo to give an oil. The oil was purified by silica gel column (dichloromethane: methanol ═ 20: 1) to give 8E (0.8g, yield: 62.5%) as a pale yellow oil.

MS(ESI):m/z＝218.1[M+H]⁺.

The fifth step: 6- (hydroxymethyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (8F)

8E (700mg, 3.22mmol) was dissolved in methanol (10mL), and palladium on charcoal (50mg), triethylamine (966mg,9.66mmol) and di-tert-butyl dicarbonate (1.05g,4.83mmol) were added. A hydrogen balloon was inserted, the hydrogen was replaced three times, and then stirred at room temperature overnight. After the reaction is finished, filtering the palladium-carbon, and spin-drying the filtrate to obtain a crude product. The crude product was purified by silica gel column (dichloromethane: methanol ═ 10: 1) to give 8F (350mg, yield: 47.8%) as a pale yellow oil.

MS(ESI):m/z＝172.1[M-55]⁺.

And a sixth step: 3- (tert-Butoxycarbonyl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid (8G)

8F (100mg,0.44mmol) was dissolved in acetonitrile (1mL), and 2,2,6, 6-tetramethylpiperidine nitroxide (3.4mg,0.022mmol) and 10% aqueous sodium chlorite (79.2mg,0.88mmol) were added at room temperature and stirred for 30 minutes. Then 10% aqueous sodium hypochlorite (65mg,0.88mmol) was added. Stir at rt overnight and extract with ethyl acetate (10mL × 2). The filtrate was dried over anhydrous sodium sulfate and dried by rotary drying in vacuo to give 8G as an oil, which was directly used in the next reaction without purification (80mg, yield: 75%).

MS(ESI):m/z＝186.1[M-55]⁺.

The 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)

8G (80mg,0.33mmoL), intermediate 1(62.7mg,0.33mmoL), HATU (190mg,0.5mmoL) and triethylamine (99mg,0.99mmoL) were dissolved in N, N-dimethylformamide (1mL) and stirred at room temperature for 16 hours. The reaction was extracted with ethyl acetate (10mL x2), the filtrate was dried over anhydrous sodium sulfate and dried by rotary drying in vacuo to give an oil. The oil was purified by column chromatography (petroleum ether: ethyl acetate ═ 2: 1) to give the product 8H (70mg, 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)

8H (70mg,0.169mmol) was dissolved in 4M hydrogen chloride in methanol (2mL, 8mmol) and stirred at room temperature for 18H. The solvent was dried by rotation, and the residue was purified by preparative HPLC to give Compound 8(20mg, yield: 37.7%) as a white solid.

¹H NMR(400MHz,CDCl₃)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 synthetic method of example 8, compound 8-P1 was synthesized using intermediate 3-P1 and intermediate 1. The intermediate 3-P2 and the intermediate 1 are used for synthesizing the compound 8-P2. The compound 8-P1 and the compound 8-P2 are optically pure isomers of the 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]⁺.

¹H 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]⁺.

¹H 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-methylimidazol [1,5-a ] pyridin-3-yl) propan-2-yl) -5-azaspiro [2.4] heptane-1-carboxamide (Compound 9)

The first step is as follows: benzyl 1- ((2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) -5-azaspiro [2.4] heptane-5-carboxylate (9B)

5- ((phenoxy) carbonyl) -5-azaspiro [2.4] heptane-1-carboxylic acid 9A (500mg,1.82mmol) and HATU (760mg,1.99mmol) were in dry N, N-dimethylformamide (10mL) and stirred at room temperature for half an hour. Then 2- (8-methylimidazol [1,5-a ] pyridin-3-yl) propan-2-amine intermediate 1(344mg,1.82mmol) and triethylamine (0.5mL) were added, and the reaction was 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 dried in vacuo and the crude product was purified by preparative HPLC to give 9B-P1(140mg) and 9B-P2(150 mg).

MS(ESI):m/z＝447.1[M+H]⁺.

The 9B-P1 was then resolved by hand to give 9B-P1-1(70mg, shorter retention compound) and 9B-P1-2(65mg, longer retention compound). The conditions for chiral resolution are shown in the table below:

the 9B-P2 was then resolved by hand to give 9B-P2-1(65mg, shorter retention compound) and 9B-P2-2(80mg, longer retention compound). The conditions for chiral resolution are shown in the table below:

the second step is that: n- (2- (8-methylimidazol [1,5-a ] pyridin-3-yl) propan-2-yl) -5-azaspiro [2.4] heptane-1-carboxamide (Compound 9)

Benzyl 1- ((2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) -5-azaspiro [2.4] heptane-5-carboxylate 9B-P1-1(70mg,0.157mmol) was dissolved in dichloromethane (3mL), then boron tribromide (197mg,0.786mmol) was added and the reaction stirred at room temperature for half an hour. The excess boron tribromide is removed by vacuum spin-drying at a bath temperature not exceeding 20 ℃. And adjusting the pH of the residue to 7-8 by using saturated sodium bicarbonate aqueous solution, and performing vacuum spin drying to obtain a crude product. The crude product was purified by preparative HPLC to give compound 9(14mg, yield: 28.6%) as a white solid.

MS(ESI):m/z＝313.0[M+H]⁺.

¹H 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-methylimidazol [1,5-a ] pyridin-3-yl) propan-2-yl) -5-azaspiro [2.4] heptane-1-carboxamide (Compound 10)

Benzyl 1- ((2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) -5-azaspiro [2.4] heptane-5-carboxylate 9B-P1-2(65mg,0.146mmol) was dissolved in dichloromethane (3mL), then boron tribromide (183mg,0.73mmol) was added and the reaction stirred at room temperature for half an hour. Excess boron tribromide was removed by vacuum spin-drying at a bath temperature not exceeding 20 ℃. And adjusting the pH of the residue to 7-8 by using saturated sodium bicarbonate aqueous solution, and performing vacuum spin drying to obtain a crude product. The crude product was purified by preparative HPLC to give compound 10(6mg, yield: 13.2%) as a white solid.

MS(ESI):M/Z＝313.0[M+H]⁺.

¹H 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-methylimidazol [1,5-a ] pyridin-3-yl) propan-2-yl) -5-azaspiro [2.4] heptane-1-carboxamide (Compound 11)

Benzyl 1- ((2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) -5-azaspiro [2.4] heptane-5-carboxylate 9B-P2-1(65mg,0.146mmol) was dissolved in dichloromethane (3mL), then boron tribromide (183mg,0.73mmol) was added and the reaction stirred at room temperature for half an hour. And (3) carrying out vacuum spin-drying at the water bath temperature of not more than 20 ℃ to remove excessive boron tribromide, adjusting the pH of the residue to 7-8 by using a saturated sodium bicarbonate aqueous solution, and carrying out vacuum spin-drying to obtain a crude product. The crude product was purified by preparative HPLC to give compound 11(10mg, yield: 22.0%) as a white solid.

MS(ESI):M/Z＝313.0[M+H]⁺.

¹H NMR(400MHz,CD₃OD)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-methylimidazol [1,5-a ] pyridin-3-yl) propan-2-yl) -5-azaspiro [2.4] heptane-1-carboxamide (Compound 12)

Benzyl 1- ((2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) -5-azaspiro [2.4] heptane-5-carboxylate 9B-P2-2(80mg,0.179mmol) was dissolved in dichloromethane (3mL), then boron tribromide (224mg,0.894mmol) was added and the reaction stirred at room temperature for half an hour. And (3) carrying out vacuum spin-drying at the water bath temperature of not more than 20 ℃ to remove excessive boron tribromide, adjusting the pH of the residue to 7-8 by using a saturated sodium bicarbonate aqueous solution, and carrying out vacuum spin-drying to obtain a crude product. This crude product was purified by preparative HPLC to give compound 12(19mg, yield: 34.0%) as a white solid.

MS(ESI):M/Z＝313.0[M+H]⁺.

¹H NMR(400MHz,CD₃OD)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)

The first step is as follows: 2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-amine (13B)

Cerium trichloride (1.71g, 6.97mmol) was stirred in anhydrous tetrahydrofuran (20mL) for 1 hour. The temperature was reduced to-78 ℃ and methyllithium (5.4mL,6.97mmol, 1.3M) was added dropwise thereto, followed by stirring for 1 hour. Then, a solution of 7-methyl-1H-indazole-3-carbonitrile (intermediate 4) (300mg,1.74mmol) in anhydrous tetrahydrofuran (3mL) was added dropwise thereto, and the mixture was gradually warmed to room temperature and stirred for 16 hours. Quenched with 8mL of 10% aqueous sodium hydroxide, filtered, and the filtrate was dried over anhydrous sodium sulfate and dried by rotary evaporation in vacuo to give the crude yellow oil. The crude product was purified by silica gel column (petroleum ether: ethyl acetate 1: 1) to give 2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-amine 13B (180mg, yield: 50.5%).

MS(ESI):m/z＝204.1[M+H]⁺.

The second step is that: 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)

2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-amine 13B (180mg, 0.96mmoL), the compound 3- (tert-butoxycarbonyl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid (232mg,0.96mmoL), HATU (547mg,1.44mmoL) and triethylamine (303mg,3.0mmoL) were dissolved in N, N-dimethylformamide (3mL) and stirred at room temperature for 16 hours. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and dried by rotary drying in vacuo to give an oil. Purification on silica gel column (petroleum ether: ethyl acetate ═ 1: 1) gave 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 (200mg, yield: 48.6%).

Chiral resolution yielded 13C-P1(80mg, shorter retention compound) and 13C-P2(80mg, longer retention compound).

The conditions for chiral resolution are shown in the table below:

MS(ESI):m/z＝427.1[M+H]⁺.

the third step: 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)

Tert-butyl 6- ((2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylate 13C-P1(75mg,0.17mmol) was dissolved in 3N dioxane hydrochloride (2mL) and stirred at room temperature for 3 hours. And (4) carrying out rotary drying on the solvent in the reaction liquid to obtain a crude product. This 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 (compound 13) (13.6mg, yield: 23.8%).

MS(ESI):m/z＝327.1[M+H]⁺.

¹H NMR(400MHz,CD₃OD)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)

Tert-butyl 6- ((2- (1, 7-dimethyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) -1-methyl-3-azabicyclo [3.1.0] hexane-3-carboxylate 13C-P2(75mg,0.17mmol) was dissolved in dichloromethane (2mL), trifluoroacetic acid (0.5mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was spin-dried to remove the solvent and trifluoroacetic acid. Adjusting the pH of the residue to alkalescence by using ammonia water, and spin-drying 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) (19.8mg, yield: 34.7%).

MS(ESI):m/z＝327.2[M+H]⁺.

¹H NMR(400MHz,CD₃OD)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)

(7C Synthesis method reference example 7)

The first step is as follows: 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)

2- (7-methyl-1- ((2- (trimethylsilyl) ethoxy) methyl) -1H-indazol-3-yl) propan-2-amine 7C (140mg,0.43mmol), the compound 3- (tert-butoxycarbonyl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid 8G (106mg,0.43mmol), HATU (190mg,0.5mmol), and triethylamine (150mg,1.5mmol) were dissolved in N, N-dimethylformamide (2mL) and stirred at room temperature for 16 hours. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and dried by rotary drying in vacuo to give a crude oil. The crude product was purified by a silica gel column (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 (150mg, yield: 47.3%).

Chiral resolution gave 15A-P1(60mg, shorter retention compound) and 15A-P2(60mg, longer retention compound).

The conditions for chiral resolution are shown in the table below:

MS(ESI):m/z＝543.2[M+H]⁺.

the second step is that: 1-methyl-N- (2- (7-methyl-1H-indazol-3-yl) propan-2-yl) -3-azabicyclo [3.1.0] hexane-6-carboxamide (Compound 15)

(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(60mg,0.11mmol) was dissolved in dichloromethane (2mL), trifluoroacetic acid (0.5mL) was added, and the mixture was stirred at room temperature for 3 hours. And (3) carrying out spin-drying on the reaction solution to remove the solvent and trifluoroacetic acid, adjusting the pH of the residue to be alkalescent by using ammonia water, and carrying out spin-drying to obtain a crude product. The crude product was purified by preparative thin layer chromatography (prep-TLC) to give Compound 15(21.4mg, yield: 44.5%) as a product.

MS(ESI):m/z＝313.1[M+H]⁺.

¹H NMR(400MHz,CD₃OD)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)

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(60mg,0.11mmol) was dissolved in dichloromethane (2mL), trifluoroacetic acid (0.5mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was spin-dried to remove the solvent and trifluoroacetic acid. Adjusting the pH of the residue to alkalescence by using ammonia water, and spin-drying to obtain a crude product. The crude product was purified by preparative thin layer chromatography (prep-TLC) to give the product (Compound 16) (10.4mg, yield: 20.4%).

MS(ESI):m/z＝313.1[M+H]⁺.

¹H NMR(400MHz,CD₃OD)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

(3aR,5s,6aS) -N- (2- (1-methyl-1H-indazol-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide formate salt (Compound 17)

The first step is as follows: (3aR,5s,6aS) -5- ((2- (1-methyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester (17A)

2- (1-methyl-1H-indazol-3-yl) propan-2-amine (intermediate 2) (80mg,0.42mmol), the compound (3aR,5s,6aS) -2- (tert-butoxycarbonyl) octahydrocyclopenta [ c ] pyrrole-5-carboxylic acid 3A (108mg,0.42mmol), HATU (239mg,0.63mmol) and triethylamine (202mg,2.0mmol) were dissolved in N, N-dimethylformamide (2mL) and stirred at room temperature for 16 hours. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and dried by rotary drying in vacuo to give a crude oil. The crude product was purified by silica gel column (petroleum ether: ethyl acetate ═ 1: 1) to give (3aR,5s,6aS) -5- ((2- (1-methyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl ester 17A (50mg, yield: 27.7%).

MS(ESI):m/z＝427.2[M+H]⁺.

The second step is that: (3aR,5s,6aS) -N- (2- (1-methyl-1H-indazol-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide formate salt (Compound 17)

Tert-butyl (3aR,5s,6aS) -5- ((2- (1-methyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylate 17A (40mg,0.093mmol) was dissolved in dichloromethane (2mL), trifluoroacetic acid (0.5mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was spun to dryness and the residue was purified by preparative HPLC to give (3aR,5s,6aS) -N- (2- (1-methyl-1H-indazol-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide formate (compound 17) aS a white solid (4mg, yield: 13.3%).

MS(ESI):m/z＝327.2[M+H]⁺.

¹H NMR(400MHz,CD₃OD)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)

The first step is as follows: 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)

3- (tert-Butoxycarbonyl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid (intermediate 3-P2) (200mg,0.829mmol) and HATU (315mg,0.828mmol) were stirred in dry N, N-dimethylformamide (10mL) at room temperature for half an hour, then 2- (1-methyl-1H-indazol-3-yl) propan-2-amine (intermediate 2) (131mg,0.691mmol) and DIEA (0.5mL) were added and stirred at room temperature overnight. Pouring the reaction solution into water, extracting an organic phase by using ethyl acetate, washing the combined organic phase by using saturated saline solution, drying the combined organic phase by using anhydrous sodium sulfate, and performing vacuum spin drying to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (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 (122mg, yield: 42.8%, pale yellow oil).

MS(ESI):m/z＝413.2[M+H]⁺.

The second step is that: 1-methyl-N- (2- (1-methyl-1H-indazol-3-yl) propan-2-yl) -3-azabicyclo [3.1.0] hexane-6-carboxamide (Compound 18)

Tert-butyl 1-methyl-6- ((2- (1-methyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate 18A (122mg,0.296mmol) was dissolved in hydrochloric acid-dioxane solution (5mL) and reacted at room temperature overnight. And (4) removing the solvent in the reaction solution in a vacuum rotary manner to obtain a crude product. This crude product was purified by preparative HPLC to give pure compound 18(17mg, yield: 18.4%) as a white solid.

MS(ESI):m/z＝313.1[M+H]⁺.

¹H 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)

The first step is as follows: 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)

A solution of 3- (tert-butoxycarbonyl) -1-methyl-3-azabicyclo [3.1.0] hexane-6-carboxylic acid (intermediate 3-P1) (200mg,0.829mmol) and HATU (315mg,0.828mmol) in dry N, N-dimethylformamide (10mL) was stirred at room temperature for half an hour, then 2- (1-methyl-1H-indazol-3-yl) propan-2-amine (intermediate 2) (131mg,0.691mmol) and DIEA (0.5mL) were added and stirred at room temperature overnight. Pouring the reaction solution into water, extracting an organic phase by using ethyl acetate, washing the combined organic phase by using saturated saline solution, drying the combined organic phase by using anhydrous sodium sulfate, and performing vacuum spin drying to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (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 (110mg, yield: 38.6%, pale yellow oil).

MS(ESI):m/z＝413.2[M+H]⁺.

The second step is that: 1-methyl-N- (2- (1-methyl-1H-indazol-3-yl) propan-2-yl) -3-azabicyclo [3.1.0] hexane-6-carboxamide (Compound 19)

Tert-butyl 1-methyl-6- ((2- (1-methyl-1H-indazol-3-yl) propan-2-yl) carbamoyl) -3-azabicyclo [3.1.0] hexane-3-carboxylate 19A (110mg,0.267mmol) was dissolved in hydrochloric acid-dioxane solution (5mL) and reacted at room temperature overnight. And (4) removing the solvent in the reaction solution in a vacuum rotary manner to obtain a crude product. The crude product was purified by preparative HPLC to give pure compound (compound 19) as a white solid (22mg, yield: 26.4%).

MS(ESI):M/Z＝313.1[M+H]⁺.

¹H 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

(3aR,5s,6aS) -N- (2- (8-chloroimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide (Compound 20)

The first step is as follows: (1- (((3-Chloropyridin-2-yl) methyl) amino) -2-methyl-1-oxopropan-2-yl) carbamic acid tert-butyl ester (20B)

2- ((tert-Butoxycarbonyl) amino) -2-methylpropanoic acid (1.42g,6.99mmol) and HATU (2.93g,7.71mmol) were stirred in dry tetrahydrofuran (200mL) at room temperature for half an hour. (3-Chloropyridin-2-yl) methylamine 20A (1.0g,7.01mmol) and triethylamine (1.96mL) were then added and stirred at room temperature overnight. The reaction solution was poured into water, the organic phase was extracted with ethyl acetate, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and spin-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 obtain pure product 20B (2.0g, yield: 87.3%).

MS(ESI):M/Z＝328.1[M+H]⁺.

The second step is that: (tert-butyl 2- (8-chloroimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamate (20C)

Tert-butyl (1- (((3-chloropyridin-2-yl) methyl) amino) -2-methyl-1-oxopropan-2-yl) carbamate 20B (600mg,3.05mmol) was dissolved in dichloromethane (40mL) and Bougus's reagent (2.9g,12.2mmol) was added and the reaction stirred at 40 ℃ overnight. The reaction solution was poured into water, the organic phase was extracted with dichloromethane, the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was dried by rotary vacuum to give tert-butyl (2- (8-chloroimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamate 20C (100mg, crude).

MS(ESI):M/Z＝310.1[M+H]⁺

The third step: 2- (8-Chloroimidazo [1,5-a ] pyridin-3-yl) propan-2-amine hydrochloride (20D)

Tert-butyl (2- (8-chloroimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamate 20C (30mg,0.097mmol) was stirred in hydrochloric acid-ethyl acetate solution (20mL) at room temperature overnight. The solvent was dried by rotary evaporation in vacuo to give 2- (8-chloroimidazo [1,5-a ] pyridin-3-yl) propan-2-amine hydrochloride 20D (40mg, crude).

MS(ESI):M/Z＝210.1[M+H]⁺.

The fourth step: (3aR,5s,6aS) -N- (2- (8-chloroimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide (Compound 20)

(3aR,5s,6aS) -2- (tert-Butoxycarbonyl) octahydrocyclopenta [ c ] pyrrole-5-carboxylic acid 3A (37mg,0.145mmol) and HATU (60mg,0.158mmol) were stirred in N, N-dimethylformamide (15mL) at room temperature for half an hour. Then, 2- (8-chloroimidazo [1,5-a ] pyridin-3-yl) propan-2-amine hydrochloride 20D (30mg,0.143mmol) and triethylamine (0.1mL) were added, and the reaction was stirred at room temperature overnight. The reaction solution was vacuum-dried to give a crude product (100mg), which was added to a methanol solution (10mL), and a hydrochloric acid-dioxane solution (2mL) was added dropwise, stirred at room temperature overnight, and vacuum-dried to further give a crude product (compound 20). The crude product was purified by preparative HPLC to give a pale yellow oil (2.27mg, yield: 4.59%).

MS(ESI):m/z＝347.1[M+H]⁺

¹H NMR(400MHz,CDCl₃)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

(3aR,5s,6aS) -N- (2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide (Compound 21)

The first step is as follows: (3-methoxypyridin-2-yl) methylamine (21B)

2-cyano-3-methoxypyridine 21A (1.4g,10.45mmol) was dissolved in methanol (50mL), palladium on charcoal (200mg) was added, and the reaction was carried out overnight under hydrogen protection. After the reaction was completed, filtration was carried out to obtain a filtrate, and the organic phase was spin-dried to obtain a white solid which was (3-methoxypyridin-2-yl) methylamine 21B (0.95g, yield: 65.9%).

MS(ESI):m/z＝139.1[M+H]⁺.

The second step is that: (1- (((3-methoxypyridin-2-yl) methyl) amino) -2-methyl-1-oxopropan-2-yl) carbamic acid tert-butyl ester (21C)

2- ((tert-butoxycarbonyl) amino) -2-methylpropanoic acid (1.68g,8.26mmol), HATU (3.14g,8.26mmol) were dissolved in DMF (20mL) and (3-methoxypyridin-2-yl) methylamine 21B (0.95g,6.88mmol) and DIEA (2.66g, 20.64mmol) were added and reacted for 1 h. After the reaction was completed, water (50mL) was added and quenched, followed by extraction with ethyl acetate (30 mL. times.3), the organic phase was washed once with 50mL of a saturated aqueous NaCl solution, the organic phase was dried over anhydrous sodium sulfate, filtered with suction, and the organic phase was spin-dried to obtain a residue. The residue was purified by silica gel column (petroleum ether: ethyl acetate ═ 2: 1) to give a white solid as tert-butyl (1- (((3-methoxypyridin-2-yl) methyl) amino) -2-methyl-1-oxopropan-2-yl) carbamate 21C (1.4g, yield: 62.9%).

MS(ESI):m/z＝324.1[M+H]⁺.

The third step (tert-butyl 2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamate (21D)

Tert-butyl (1- (((3-methoxypyridin-2-yl) methyl) amino) -2-methyl-1-oxopropan-2-yl) carbamate 21C (0.6g,1.86mmol) was dissolved in dry DCM (10mL), Bougus reagent (0.89g,3.72mmol) was added and stirred overnight. After completion of the reaction, the reaction mixture was quenched with water (40mL) and extracted with ethyl acetate (20 mL. times.3). The organic phase is washed once with 50mL of saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The organic phase was suction filtered and spin dried to give 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 (0.175g, yield: 30.9%) as a white solid.

MS(ESI):m/z＝306.1[M+H]⁺.

The fourth step: 2- (8-Methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-amine hydrochloride (21E)

Tert-butyl (2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamate 21D (0.05g,0.164mmol) was added to a 4M solution of hydrochloric acid in 1, 4-dioxane (3mL) and stirred for 30 min. After the reaction was complete, it was spin-dried in vacuo to give a crude oil, 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]⁺.

The fifth step: (3aR,5s,6aS) -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)

(3aR,5s,6aS) -2- (tert-Butoxycarbonyl) octahydrocyclopenta [ c ] pyrrole-5-carboxylic acid (74.6mg, 0.29mmol) and HATU (111mg,0.29mmol) were dissolved in DMF (2mL) and the crude oil of 2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-amine 21E (0.057g) and DIEA (94mg, 0.73mmol) were added and reacted for 1 h. After the reaction was completed, water (10mL) was added and the mixture was quenched and then extracted with ethyl acetate (5 mL. times.3), and the organic phase was washed once with 20mL of a saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The organic phase was suction filtered and spin dried to give a residue. The residue was purified by preparative thin layer chromatography (petroleum ether: ethyl acetate ═ 2: 1) to give a white solid which was (3aR,5s,6aS) -5- ((2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) carbamoyl) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -carboxylic acid tert-butyl 21F (50mg, yield: 69.4%).

MS(ESI):m/z＝443.1[M+H]⁺.

And a sixth step: (3aR,5s,6aS) -N- (2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide (Compound 21)

To (3aR,5s,6aS) -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 (50mg,0.069mmol) was added a 4M solution of hydrochloric acid in 1, 4-dioxane (3mL) and stirred for 30 min. After the completion of the reaction, it was spin-dried in vacuo and purified by Pre-HPLC to give (3aR,5s,6aS) -N- (2- (8-methoxyimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) octahydrocyclopenta [ c ] pyrrole-5-carboxamide (compound 21) (25mg, yield: 64.66%).

MS(ESI):m/z＝343.1[M+H]⁺.

¹H 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)

The first step is as follows: 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)

2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-amine intermediate 1(120mg, 0.53mmol), 1-tert-butoxycarbonyl-piperidine-4-acetic acid (141mg, 0.58mmol), HATU (242mg, 0.64mmol) and DIPEA (274mg, 2.12mmol) were dissolved in DMF (2 mL). The solution was stirred at 25 ℃ for 12 hours. The mixture was diluted with water (10mL) and extracted with ethyl acetate (8 mL. times.3). The combined organic phases were washed with brine (15mL), 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 (170mg, yield: 64.6%) as a pale yellow solid.

MS(ESI):M/Z＝415.2[M+H]⁺.

¹H NMR(400MHz,CDCl₃):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).

The second step is that: n- (2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) -2- (piperidin-4-yl) acetamide hydrochloride (Compound 22)

Tert-butyl 4- (2- ((2- (8-methylimidazo [1,5-a ] pyridin-3-yl) propan-2-yl) amino) -2-oxoethyl) piperidine-1-carboxylate 22A (150mg, 0.36mmol) was dissolved in ethyl acetate (2mL), cooled to 0 ℃, and then hydrochloric acid/ethyl acetate (4M, 6mL) was added and stirred at 0 ℃ for 0.5 hour. The mixture was dried under vacuum, diluted with water (30mL) and acetonitrile (1mL), and lyophilized to give compound 22 as a pale yellow solid (110mg, yield: 86.6%).

MS(ESI):M/Z＝315.2[M+H]⁺.

¹HNMR(400MHz，CD₃OD)：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 analogous to example 8:

test example:

test example 1 determination of the Activity of human somatostatin type-IV receptor SSTR4 agonists

The purpose of the test is as follows: the Cell-based human SSTR4 cAMP assay was used to determine the agonistic effect of test compounds on SSTR4 receptors.

Cell culture and reagent preparation: cell lines: Flp-In-CHO-SSTR4 stable transformant (stable pool); ham's F-12K + 10% FBS +1 Xpenicillin-streptomycin (PS) + 600. mu.g/ml hygromycin B; the cell inoculation culture medium comprises Ham's F-12K + 10% FBS; experimental buffer 1X HBSS +20mM HEPES + 0.1% BSA +500uM IBMX.

And (3) test operation:

Flp-In-CHO-SSTR4 stable pool cell line was cultured In complete medium at 37 ℃ with 5% CO₂To 70 to 90 percent fusion degree.

After TrypLE digestion, cells were resuspended in inoculation medium and plated in 384-well cell culture plates (384PE plates) with 7,000 cells per well at 37 ℃ in 5% CO₂The culture was carried out overnight.

1. Working solutions (8X) of a positive control compound and a test compound are prepared.

2. The cell culture plates were removed and centrifuged 5s upside down at 200g to remove the medium, then 15. mu.l of assay buffer was added quickly to each assay well and centrifuged 5s at 200 g.

3. Add 2.5. mu.l of 8 XCompound working solution diluted in step 3 to the corresponding assay wells, centrifuge at 200g for 5s at room temperature, and incubate at 37 ℃ for 10 min.

4. Prepare 4uM Forskolin working solution (8X).

5. The cell plate was taken out and equilibrated to room temperature, then 2.5. mu.l of the 8X Forskolin working solution prepared in step 6 was added to the corresponding test well, 200g, RT,5s, and left to stand at 37 ℃ for 30 min.

6. The Eu-cAMP tracer and the Uliaght-anti-cAMP are frozen and thawed, the Eu-cAMP tracer is diluted by 50 times by using a detection buffer solution, and the Uliaght-anti-cAMP is diluted by 150 times.

7. Add 10. mu.l Eu-cAMP tracer to all experimental wells, then add 10. mu.l detection buffer to NC wells, and add 10. mu.l Uliaght-anti-cAMP to the remaining experimental wells.

8. The reaction plate was centrifuged at 200g for 30s at room temperature, and after standing at 25 ℃ for 1h, data were collected by Envision

Data analysis

1) Factor Z' 1-3 (SD)_Max+SD_Min) /(average)_Max-average_Min)

2)CV_Max＝(SD_MaxAverage_Max)*100％

3)CV_Min＝(SD_MinAverage_Min)*100％

4) Signal/background

5) Vehicle control (Min): assay buffer

6) Positive control (Max) 1,000nM somatotatin 14

7) Compound EC was calculated using GraphPad non-linear fitting equation₅₀:

Y ═ bottom + (Top-bottom)/(1 +10^ ((LogEC)₅₀-X)*HillSlope))

X is the log value of the concentration of the compound; ratio of Y to HTRF

TABLE 1 assay results for human somatostatin type IV receptor SSTR4 agonist activity

And (4) conclusion: the compound has obvious human growth hormone type IV receptor SSTR4 agonistic activity.

Test example 2 metabolic stability of liver microsome

The metabolic degradation of the test compounds was analyzed at 37 ℃ with 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 (0.5mg/mL, 238.5. mu.L). After a pre-incubation at 37 ℃ for 5min, NADPH (5mM, 60. mu.L) was added to start the reaction. A fixed volume of the reaction mixture (30 μ L) was sampled into solution at fixed time points (0,5,15,30,60min) to quench the reaction. After centrifugation (4000rpm,15min), the supernatant (100 μ L) was mixed with distilled water (100 μ L), and then subjected to LC-MS/MS analysis to test the amount of the compound. By the first order reaction kinetics equation (C)_t＝C₀×e^-ket，T_1/2Ln2/ke) to calculate the half-life.

TABLE 2 analysis of human and rat liver microsomes

And (4) conclusion: the compound of the invention has better metabolic stability in liver microsomes.

Test example 3 pharmacokinetic evaluation

The drug concentrations in the plasma of rats at different times after oral and intravenous administration of the test compounds were determined by LC/MS/MS method using rats as test animals. The pharmacokinetic behavior of the compounds of the invention in rats was studied and their pharmacokinetic profile was evaluated.

Test animals:

for each compound, 6 healthy adult SD (Sprague-Dawley) rats, males, divided into oral and intravenous administration groups of 3 per group, purchased from shanghai siple-bikeka experimental animals ltd, animal production license number: SCXK (Shanghai) 2008-0016.

Preparing the medicine:

a certain amount of the medicine is weighed and dissolved in 5 percent of Dimethylacetamide (DMA), 5 percent of polyethylene glycol-15 hydroxystearate (solutol) and 90 percent of saline solution to prepare 0.2mg/mL solution.

Administration:

SD rats were given oral and intravenous injections after overnight fasting.

And (3) test operation:

the test compounds were administered to rats orally and intravenously. Blood was collected 0.2mL from the submaxillary vein or other suitable vessel at 0.083,0.25,0.5,1,2,4,8 and 24 hours post-dose, placed in K2-EDTA tubes, and then stored on ice. Plasma was separated by centrifugation at 6800g for 6 min at 2-8 ℃ over one hour, stored at-80 ℃ and analyzed by LC/MS/MS, rats fed 4 hours after dosing.

TABLE 3 pharmacokinetic parameters in rats

And (4) conclusion: the compound of the invention has good drug absorption.

The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. A compound having the structure of formula (I), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof:

R₃each independently selected from-H, -F, -Cl, -Br, -I, hydroxy, cyano, amino, C_1-4Alkyl radical, C_1-4Alkoxy radical, C_1-4Alkoxy radical C_1-4Alkyl, - (CH)₂)_m-alkenyl, - (CH)₂)_m-alkynyl, - (CH)₂)_m-C_3-10Carbocyclyl, - (CH)₂)_m- (3 to 10 membered)Heterocyclyl), -O- (CH)₂)_m-C_3-10Carbocyclyl and-O- (CH)₂)_m- (3-to 10-membered heterocyclic group) containing 1 to 4 hetero atoms selected from N, O and S, and R₃Wherein each of said alkyl, alkoxy, carbocyclyl or heterocyclyl is independently optionally further substituted with 0 to 4 substituents selected from-H, -F, -Cl, -Br, -I, hydroxy, mercapto, cyano, amino, C_1-4Alkyl and C_1-4Substituted by a substituent of alkoxy;

L₂selected from-NH-and-O-;

q is selected from one of the following structures:

X₄Is selected from-CH₂-、-CH₂CH₂- and -CH₂CH₂CH₂-；

2. A compound of formula (a), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

wherein ,

represents a single or double bond, provided that two

Wherein and only one represents a double bond;

X₁is CR₃' or NR₃；

X₂Is CR₃' or NR₃；

or ,X₁And substituents thereof and adjacent carbon atoms and substituents R thereof₃' together form a phenyl ring or a 5-to 6-membered heteroaromatic ring, optionally substituted with 1-4R₃' substitution;

R₃' is selected from-H, halogen, cyano, -OR, -NR ' R ', C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, - (CH)₂)_n-C_3-10Carbocyclyl, - (CH)₂)_n- (3-to 10-membered heterocyclic group), - (CH)₂)_n-C_6-10Aryl, - (CH)₂)_n- (5-to 6-membered heteroaryl) and-SR_x；

R₅is selected from-H, C_1-6Alkyl radicalHalogen substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, - (CH)₂)_n-C_3-10Carbocyclyl, - (CH)₂)_n- (3-to 10-membered heterocyclic group), - (CH)₂)_n-C_6-10Aryl and- (CH)₂)_n- (5 to 6 membered heteroaryl);

r is selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

n is 0, 1,2 or 3;

s is 0, 1 or 2;

r is 0, 1 or 2.

3. A compound of formula (b), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

wherein ,

represents a single or double bond, provided that two

Wherein and only one represents a double bond;

X₁is CR₃' or NR₃；

X₂Is CR₃' or NR₃；

R₅is selected from-H, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, - (CH)₂)_n-C_3-10Carbocyclyl, - (CH)₂)_n- (3 to 10 membered)Heterocyclyl), - (CH)₂)_n-C_6-10Aryl and- (CH)₂)_n- (5 to 6 membered heteroaryl);

r is selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

n is 0, 1,2 or 3.

4. A compound of formula (c), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

wherein ,

R₄Is selected from C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,Halogen substituted C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, - (CH)₂)_n-C_3-10Carbocyclyl, - (CH)₂)_n- (3-to 10-membered heterocyclic group), - (CH)₂)_n-C_6-10Aryl and- (CH)₂)_n- (5 to 6 membered heteroaryl); wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with halogen, cyano, -OR, -NR' R ", C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl and C_2-6Alkynyl substitution;

r is selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

n is 0, 1,2 or 3;

t is 0, 1,2, 3,4 or 5.

5. A compound of formula (c-1), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

wherein ,

R₃' is selected from-H, halogen, cyano, -OR, -NR ' R ', C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl and-SR_x；

r is selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

n is 0, 1,2 or 3.

6. A compound of formula (d), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

wherein ,

r is selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

r 'and R' are each selected from-H, C_1-6Alkyl and halo C_1-6Alkyl, or R'And R' together with the nitrogen atom to which they are attached form a 3-to 10-membered heterocyclyl;

n is 0, 1,2 or 3;

t is 0, 1,2, 3 or 4.

7. A compound of formula (d-1), or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof,

wherein ,

r is selected from-H, C_1-6Alkyl and halo C_1-6An alkyl group;

r 'and R' are each selected from-H, C_1-6Alkyl and halo C_1-6Alkyl, or R 'and R' with the nitrogen to which they are attachedThe atoms taken together form a 3-to 10-membered heterocyclyl;

n is 0, 1,2 or 3.

8. The compound of claim 1, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, wherein the compound is selected from the group consisting of:

9. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-8, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, in combination with a pharmaceutically acceptable carrier or excipient.

10. Use of a compound according to any one of claims 1-8, or a stereoisomer, N-oxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt, polymorph or prodrug thereof, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the treatment and/or prevention of a disease or condition which is affected by the activation of SSTR 4.