CN115960109B - Preparation and application of condensed ring SHP2 phosphatase inhibitor - Google Patents

The invention discloses a preparation method and application of a condensed ring SHP2 phosphatase inhibitor. In particular, the invention relates to a compound shown in a general formula (I), a preparation method thereof, and a medicinal salt, a polymorph or an isomer containing the compound, and a pharmaceutical composition, in particular to a protein tyrosine phosphatase SHP-2 inhibitor. The invention relates to the use of said compounds and pharmaceutically acceptable salts, polymorphs or isomers thereof, wherein the substituents in the general formula (I) are as defined in the description, in the manufacture of a medicament for the treatment of leukemia, neuroblastoma, melanoma, acute bone leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, pancreatic cancer, head and neck squamous cell carcinoma, stomach cancer, liver cancer, anaplastic large cell lymphoma and glioblastoma.

Preparation and application of condensed ring SHP2 phosphatase inhibitor

Technical Field

The invention belongs to the field of medicine synthesis, and in particular relates to a novel condensed ring SHP2 phosphatase inhibitor, and a preparation method and application thereof.

Background

The present invention relates generally to novel fused ring compounds, methods of making the same, and uses as SHP2 phosphatase inhibitors (e.g., for the treatment of cancer).

SHP2 is a non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene, containing two N-terminal Src homology 2 (SH 2) domains, a Protein Tyrosine Phosphatase (PTP) domain, and a poorly sequenced C-terminal end. X-ray crystallography studies indicate that SHP2 inhibits its own phosphatase activity by blocking access to the catalytic site on the PTP domain using the N-terminal SH2 domain. Casein or peptide bisphosphate (e.g., IRS-1) has been demonstrated to bind to the SH2 domain of SHP2, disrupting the N-terminal SH2-PTP domain interaction. This binding allows the substrate to enter the catalytic site and activate the phosphatase.

SHP2 is recruited by RTKs to induce cellular signaling and is involved in multiple intracellular oncogenic signaling cascades, such as Jak/STAT, PI3K/AKT, RAS/Raf/MAPK, PD-1/PD-L1, and the mTOR pathway. The key gtpase RAS, in which extracellular signals are transmitted into the nucleus, plays a oncogenic role in its GTP binding mode regulated (tyrosine dephosphorylation in adaptor/scaffold proteins) by SHP2 into an activated state; on the other hand, SHP2 activation of RAS signaling in acquired resistance promotes compensatory activation of signaling pathways (e.g., negative feedback regulation of MEK activates RTKs, activating SHP2 to activate downstream pathways), in which case inhibition of SHP2 may eliminate reactivation of the RAS/Raf/ERK pathway and represent a potential therapeutic strategy as a new strategy to address RTK resistance issues.

Moreover, germ line or somatic mutations in PTPN11 that lead to overactivation of SHP2 have been identified in a variety of pathophysiological states: the dysplastic Noonan syndrome, hematological malignancies include juvenile myelomonocytic leukemia, myelodysplastic syndrome, B-cell acute lymphoblastic leukemia and acute myelogenous leukemia and low frequency solid tumors. Thus, SHP2 is one of the most attractive targets for the development of new therapies for the treatment of various diseases.

Patent application ;WO2015107494A1、WO2015107495A1、WO2017211303A1、WO2018057884A1、WO2018136265A1、WO2019167000A1、WO2020033828A1、WO2020063760A1、WO2020081848A1、WO2020247643A1 et al, related to published SHP2 targets. Several SHP-2 inhibitors have been introduced into the clinical study, such as RMC-4630 developed by TNO-155,Revolution Medicine, inc. of Novartis, and JAB-3068, of Beijing Gakesi, all of which have been introduced into the clinical phase I study. However, none of the marketed SHP-2 inhibitors have been developed for the treatment of noonan's syndrome, leopard skin syndrome, leukemia, neuroblastoma, melanoma, breast cancer, gastric cancer, lung cancer and colon cancer. Therefore, development of SHP-2 inhibitor drugs with good drug-forming property is urgently needed.

Disclosure of Invention

A compound having the general formula (I), a stereoisomer, a pharmaceutically acceptable salt, a polymorph or an isomer thereof, wherein the compound of the general formula (I) has the structure:

Wherein,

Each L ₁ is independently selected at each occurrence from a bond, O, CH ₂, NH, CO, or S;

Each L ₂ is independently selected at each occurrence from a bond, O, CH ₂、NH、CONH₂, CO, or S;

Each X ₁、X₂、X₃、X₅、X₆、X₇ is independently selected from N, CR ₉ at each occurrence;

Each R ₉ is independently at each occurrence selected from deuterium, halogen, oxo, -C _1-6 alkyl, -C _1-6 alkylene- (halogen) _1-3、C_1-6 heteroalkyl, -CN, -OC _1-6、-SC_1-6、-NHC_1-6、-N(C_1-6 alkyl) (C _1-6 alkyl), CONH ₂, COOH;

Each X ₄ is independently selected from N, C at each occurrence;

Each Ar ₁ is independently selected at each occurrence from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, 3-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, each heteroaryl, heterocycloalkyl independently containing at each occurrence 1,2, 3, or 4 heteroatoms selected from N, O, or S; each Ar ₁ is independently at each occurrence optionally substituted or unsubstituted with 1,2, 3,4, 5, or 6R ₁₉;

Each Ar ₂ is independently selected at each occurrence from H, phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, 3-10-membered cycloalkyl, 5-10-membered heterocycloalkyl, each heteroaryl, heterocycloalkyl independently containing at each occurrence 1,2, 3, or 4 heteroatoms selected from N, O, or S; each Ar ₂ is independently at each occurrence optionally substituted or unsubstituted with 1,2, 3,4, 5, or 6R ₁₉;

Each R ₁₉ is independently at each occurrence selected from deuterium, halogen, oxo, -C _1-6 alkyl, -C _1-6 alkylene- (halogen) _1-3、C_1-6 heteroalkyl, -CN, -OR ₁₀、-C_1-6 alkylene- (OR ₁₀)_1-3、-O-C_1-6 alkylene- (halogen) _1-3、-SR₁₀、-S-C_1-6 alkylene- (halogen) _1-3、-NR₁₀R₁₁, -C1-6 alkylene -NR₁₀R₁₁、-C(＝O)R₁₀、-C(＝O)OR₁₀、-OC(＝O)R₁₀、-C(＝O)NR₁₀R₁₁、-NR₁₀C(＝O)R₁₁、-S(O)₂NR₁₀R₁₁, OR-C _3-6 carbocyclyl, each R ₁₉ is independently optionally substituted with 1, 2, 3, 4, 5, OR 6 substituents selected from deuterium, halogen, -C _1-6 alkyl, -C _1-6 alkoxy, oxo 、-OR₁₀、-NR₁₀R₁₁、-CN、-C(＝O)R₁₀、-C(＝O)OR₁₀、-OC(＝O)R₁₀、-C(＝O)NR₁₀R₁₁、-NR₁₀C(＝O)R₁₁, OR-S (O) ₂NR₆R₁₁;

Each R ₁₀ and R ₁₁ is independently selected at each occurrence from hydrogen, deuterium, or-C _1-6 alkyl, each R ₁₀ and R ₁₁ being independently optionally substituted or unsubstituted with 1,2,3, 4,5, or 6R ₁₉; or R ₁₀ and R ₁₁ together with the N atom to which they are attached form a 3-10 membered heterocyclic ring, said 3-10 membered heterocyclic ring may further comprise 1,2,3 or 4 heteroatoms selected from N, O, S, S (=o) or S (=o) ₂, and said 3-10 membered heterocyclic ring is independently optionally substituted or unsubstituted with 1,2,3, 4,5 or 6R ₂₀;

Each R ₂₀ at each occurrence is independently selected from deuterium, halogen, oxo, -C _1-6 alkyl, -C _1-6 alkylene- (halogen) _1-3、C_1-6 heteroalkyl, -CN, -OC _1-6、-C_1-6 alkylene- (OC _1-6)_1-3、-O-C_1-6 alkylene- (halogen) _1-3、-SC_1-6、-S-C_1-6 alkylene- (halogen) _1-3, or-C _3-6 carbocyclyl;

Each X ₈ is independently selected at each occurrence from CR ₄R₅、SiR₄R₅, NH, O;

Each X ₉ is independently selected at each occurrence from CR ₆, NH, wherein X ₇ and X ₈ must be carbon if one;

Each R ₁ is independently at each occurrence selected from H, deuterium, -C _1-6 alkyl;

Each R ₂ is independently at each occurrence selected from H, deuterium, OH, CH ₂NH₂;

each R ₃、R₇、R₈ is independently selected at each occurrence from H, deuterium;

Each R ₄ is independently at each occurrence selected from H, deuterium, OH, C _0-3NR₁₂R₁₃;

each R ₅ is independently selected at each occurrence from H, deuterium, OH, C _1-6 alkyl, C _1-6 alkyl substituted with 1, 2,3, 4, 5 or 6 deuterium, OH, methyl, OCH ₃, 5-10 membered heteroaryl;

Each R ₆ is independently selected at each occurrence from H, deuterium, NH ₂;

Two of R ₁、R₂、R₃、R₄、R₅、R₆、R₇、R₈ may be connected as follows:

r ₁ and R ₂ may be linked to form a fused bicyclic ring using CH ₂NHCH₂,

R ₁ and R ₆ may be linked using an alkylene group to form a bridged bicyclic ring,

R ₂ and R ₃ may be linked to form a spiro ring using an alkylene substituted with NH ₂,

R ₄ and R ₅ can be linked to form C _3-12 cycloalkyl, C _3-12 heterocycloalkyl, C _3-12 bicycloalkyl, C _3-12 heterobicycloalkyl, wherein C _3-12 heterocycloalkyl, C _3-12 heterobicycloalkyl independently at each occurrence contains 1,2,3 or 4 heteroatoms selected from N, O, or S, each C _3-12 cycloalkyl, C _3-12 heterocycloalkyl, C _3-12 bicycloalkyl, C _3-12 heterobicycloalkyl independently at each occurrence is optionally substituted with deuterium, halogen, OH, CH ₃、OCH₃、NH₂ to form a spiro ring,

R ₁ and R ₇ can be connected to form a bridged bicyclic ring by alkylene, O, NH,

R ₂ and R ₆ may be linked through an alkylene group to form a bridged bicyclic ring,

R ₂ and R ₇ can be connected by alkylene, O to form a bridged bicyclic ring,

R ₄ and R ₆ can be linked to form a fused bicyclic ring by NHCH ₂, cycloalkyl substituted by NH ₂ for C _3-12,

Each a, b, c, d is independently selected at each occurrence from 0, 1;

in some embodiments, a compound of (I) above, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein each Independently at each occurrence selected from

And each is provided withIndependently at each occurrence selected from C optionally substituted or unsubstituted with 1,2, 3, 4, 5, or 6R ₉;

Each R ₉ is independently at each occurrence selected from deuterium, halogen, oxo, -C _1-6 alkyl, -C _1-6 alkylene- (halogen) _1-3、C_1-6 heteroalkyl, -CN, -OC _1-6 alkyl, -SC _1-6 alkyl, -NHC _1-6 alkyl, -N (C _1-6 alkyl) (C _1-6 alkyl), CONH ₂, COOH;

In some embodiments, a compound of (I) described above, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein, Selected from the following structures:

In some embodiments, wherein Ar ₁ is independently selected at each occurrence from phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, 3-10-membered cycloalkyl, 5-10-membered heterocycloalkyl, each heteroaryl, heterocycloalkyl independently containing at each occurrence 1, 2, 3, or 4 heteroatoms selected from N, O, or S; each Ar ₁ is independently at each occurrence optionally substituted or unsubstituted with 1, 2, 3, 4, 5, or 6R ₁₉;

Each Ar ₂ is independently selected at each occurrence from H, phenyl, naphthyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl or 10-membered heteroaryl, 3-10-membered cycloalkyl, 5-10-membered heterocycloalkyl, each heteroaryl, heterocycloalkyl independently containing at each occurrence 1,2, 3, or 4 heteroatoms selected from N, O, or S; each Ar ₂ is independently at each occurrence optionally substituted or unsubstituted with 1,2, 3,4, 5, or 6R ₁₉;

Each R ₁₉ is independently at each occurrence selected from deuterium, halogen, oxo, -C _1-6 alkyl, -C _1-6 alkylene- (halogen) _1-3、C_1-6 heteroalkyl, -CN, -OR ₁₀、-C_1-6 alkylene- (OR ₁₀)_1-3、-O-C_1-6 alkylene- (halogen) _1-3、-SR₁₀、-S-C_1-6 alkylene- (halogen) _1-3、-NR₁₀R₁₁, -C1-6 alkylene -NR₁₀R₁₁、-C(＝O)R₁₀、-C(＝O)OR₁₀、-OC(＝O)R₁₀、-C(＝O)NR₁₀R₁₁、-NR₁₀C(＝O)R₁₁、-S(O)₂NR₁₀R₁₁, OR-C _3-6 carbocyclyl, each R ₁₉ is independently optionally substituted with 1, 2, 3, 4, 5, OR 6 substituents selected from deuterium, halogen, -C _1-6 alkyl, -C _1-6 alkoxy, oxo 、-OR₁₀、-NR₁₀R₁₁、-CN、-C(＝O)R₁₀、-C(＝O)OR₁₀、-OC(＝O)R₁₀、-C(＝O)NR₁₀R₁₁、-NR₁₀C(＝O)R₁₁, OR-S (O) ₂NR₆R₁₁;

Each R ₁₀ and R ₁₁ is independently selected at each occurrence from hydrogen, deuterium, or-C _1-6 alkyl, each R ₁₀ and R ₁₁ being independently optionally substituted or unsubstituted with 1,2,3, 4,5, or 6R ₁₉; or R ₁₀ and R ₁₁ together with the N atom to which they are attached form a 3-10 membered heterocyclic ring, said 3-10 membered heterocyclic ring may further comprise 1,2,3 or 4 heteroatoms selected from N, O, S, S (=o) or S (=o) ₂, and said 3-10 membered heterocyclic ring is independently optionally substituted or unsubstituted with 1,2,3, 4,5 or 6R ₂₀;

Each R ₂₀ at each occurrence is independently selected from deuterium, halogen, oxo, -C _1-6 alkyl, -C _1-6 alkylene- (halogen) _1-3、C_1-6 heteroalkyl, -CN, -OC _1-6、-C_1-6 alkylene- (OC _1-6)_1-3、-O-C_1-6 alkylene- (halogen) ₁-3、-SC_1-6、-S-C_1-6 alkylene- (halogen) _1-3, or-C _3-6 carbocyclyl;

Further preferably, each Ar ₂-L₂-Ar₁-L₁ -is selected from the following structures:

In some embodiments, the compound of formula (I) or an isomer, solvate or precursor thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds, isomers, solvates or precursors thereof, or pharmaceutically acceptable salts thereof:

another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (ii) or a tautomer, mesomer, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients, wherein the therapeutically effective amount of the present disclosure is optionally 0.1 to 2000mg.

The present disclosure also relates to a method of preparing the pharmaceutical composition comprising mixing a compound of formula (ii) or a tautomer, meso, racemate, enantiomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a compound of formula (ii) or a tautomer, meso, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier, diluent or excipient.

The disclosure further relates to the use of a compound of formula (ii) or a tautomer, meso, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of an SHP2 inhibitor.

The present disclosure further relates to the use of a compound of formula (II), or a tautomer, meso, racemate, enantiomer, diastereomer, atropisomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a disease or disorder mediated by SHP2 activity.

The disclosure further relates to the use of a compound of formula (I), or a tautomer, meso, racemate, enantiomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, as an SHP2 inhibitor in the manufacture of a medicament for the prevention and/or treatment of tumors or cancers.

The present disclosure further relates to the use of a compound of formula (I), or a tautomer, meso, racemate, enantiomer, diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the prevention or treatment of noonan syndrome, leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute bone leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, pancreatic cancer, head and neck squamous cell carcinoma, stomach cancer, liver cancer, anaplastic large cell lymphoma, and glioblastoma.

The present disclosure further relates to a compound represented by general formula (), or a tautomer, meso, racemate, enantiomer, diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The present disclosure also relates to compounds represented by general formula (), or tautomers, meso, racemic enantiomers, diastereomers, atropisomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, as SHP2 inhibitors.

The present disclosure also relates to a compound represented by the general formula (), or a tautomer, meso racemate, enantiomer, diastereomer, atropisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is useful as an SHP2 inhibitor for preventing and/or treating tumor or cancer.

The present disclosure also relates to a method of treatment for prophylaxis and/or treatment of tumors or cancers comprising administering to a patient in need thereof a therapeutically effective dose of a compound of the general formula as an inhibitor of SHP2, or a tautomer meso, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as a tablet dragee, lozenge, aqueous or oil suspension, dispersible powder or granule, emulsion, hard or soft capsule, or syrup or agent, the oral composition may be prepared according to any method known in the art for preparing pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants and preservatives to provide a pleasant and palatable pharmaceutical formulation, the tablet containing the active ingredient and nontoxic pharmaceutically acceptable excipients for the mixed preparation of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents, and lubricating agents. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or oil vehicle.

The aqueous suspension contains the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending agents, dispersing agents or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.

The oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of anti-hydrogenation.

The pharmaceutical compositions of the present disclosure may also be in the form of an oil-in-water emulsion, the oil phase may be a vegetable oil, or a mineral oil or a mixture thereof, the suitable emulsifier may be a naturally occurring phospholipid, and the emulsion may also contain a sweetener, a flavoring agent, a preservative and an antioxidant. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant the pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Acceptable vehicles or solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, which is prepared by injecting the injectable solution or microemulsion in a topically high amount into the bloodstream of a patient, or which is preferably administered in a manner which will maintain a constant circulating concentration of the compound of the present disclosure. To maintain such constant concentrations, an example of such a device that may be used with a continuous intravenous delivery device is a DELTEC CADD-plus. TM.5400 type intravenous pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The mixture may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as described above, and the sterile injectable preparation may be a sterile injectable solution or suspension in a parenterally-acceptable non-toxic diluent or solvent, which may be in the form of a sterile fixed oil as a solvent or suspending medium thereof, for which purpose any tempering fixed oil may be employed in addition to fatty acids.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of compound (II) of formula (I) or the type of pharmaceutically acceptable salt can be verified according to conventional treatment protocols.

Certain chemical terms

Unless stated to the contrary, the following terms used in the specification and claims.

The expression "C _x-y" as used herein with the following meaning represents a range of carbon atom numbers, where x and y are both integers, e.g. C _3-8 cycloalkyl represents cycloalkyl having 3-8 carbon atoms, i.e. cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms. It is also to be understood that "C _3-8" also includes any subrange therein, such as C _3-7、C_3-6、C_4-7、C_4-6、C_5-6, and the like.

"Alkyl" refers to a straight or branched hydrocarbon group containing 1 to 20 carbon atoms, for example 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, and 2-ethylbutyl. The alkyl group may be substituted or unsubstituted.

"Alkenyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon double bond and typically 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1, 4-pentadienyl and 1, 4-butadienyl. The alkenyl group may be substituted or unsubstituted.

"Alkynyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond and typically from 2 to 20 carbon atoms, for example from 2 to 8 carbon atoms, from 2 to 6 carbon atoms, or from 2 to 4 carbon atoms. Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl. The alkynyl group may be substituted or unsubstituted.

"Cycloalkyl" refers to a saturated cyclic hydrocarbyl substituent containing 3 to 14 carbon ring atoms. Cycloalkyl groups may be monocyclic, typically containing 3 to 7 carbon ring atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups may alternatively be bi-or tricyclic fused together, such as decalin, which cycloalkyl groups may be substituted or unsubstituted.

"Heterocyclyl", "heterocycloalkyl", "heterocycle" refers to a stable 3-18 membered monovalent non-aromatic ring comprising 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise indicated, a heterocyclyl group may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused, spiro or bridged ring systems, a nitrogen, carbon or sulfur atom on a heterocyclyl group may be optionally oxidized, a nitrogen atom may be optionally quaternized, and a heterocyclyl group may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule by a single bond through a carbon atom or heteroatom in the ring. The heterocyclic group containing a condensed ring may contain one or more aromatic or heteroaromatic rings as long as the atom attached to the remainder of the molecule is a non-aromatic ring. For the purposes of the present application, heterocyclyl is preferably a stable 4-11 membered monovalent non-aromatic mono-or bi-ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably a stable 4-8 membered monovalent non-aromatic mono-ring comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolyl, dihydrofuranyl, indolinyl, dioxolanyl, 1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.

"Spiroheterocyclyl" refers to a5 to 20 membered, monocyclic, polycyclic heterocyclic group sharing one atom (referred to as the spiro atom) between the monocyclic rings, wherein one or more of the ring atoms is selected from nitrogen, oxygen or a heteroatom of S (O) _m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. These may contain one or more double bonds, but the electronic system in which none of the rings has complete conjugation is preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, with single spirocycloalkyl groups and double spirocycloalkyl groups being preferred. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro-cyclic group. Non-limiting examples of spiroheterocyclyl groups include:

"fused heterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen or a heteroatom of S (O) _m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

"aryl" or "aryl" refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 membered, such as phenyl and naphthyl, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring.

"Heteroaryl" or "heteroaryl" refers to a 5-16 membered ring system containing 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. Unless otherwise indicated, heteroaryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused or bridged ring systems, so long as the point of attachment to the rest of the molecule is an aromatic ring atom, the nitrogen, carbon, and sulfur atoms of the heteroaromatic ring may be selectively oxidized, and the nitrogen atom may be selectively quaternized. For the purposes of the present application, heteroaryl groups are preferably stable 4-11 membered monoaromatic rings which contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably stable 5-8 membered monoaromatic rings which contain 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl groups include acridinyl, azepinyl, benzimidazolyl, benzindolyl, benzodioxinyl, benzodioxanyl, benzofuranonyl, benzofuranyl, benzonaphtofuranyl, benzopyronyl, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazole, furyl, imidazolyl, indazolyl, indolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quininyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, and the like. In the present application, the heteroaryl group is preferably a 5-8 membered heteroaryl group comprising 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridyl, pyrimidinyl, thiazolyl. The heteroaryl group may be substituted or unsubstituted.

"Halogen" means fluorine, chlorine, bromine or iodine.

"Hydroxy" means-OH, "amino" means-NH ₂, "amido" means-NHCO-, -cyano "means-CN," nitro "means-CN," isocyano "means-NC, and" trifluoromethyl "means-CF ₃.

The term "heteroatom" or "hetero" as used herein alone or as part of other ingredients refers to an atom other than carbon and hydrogen, the heteroatom being independently selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but is not limited to these atoms, in embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as one another, or some or all of the two or more heteroatoms may be different.

The term "fused" or "fused ring" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.

The term "spiro" or "spiro" as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.

"Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur, e.g., an "optionally alkyl-substituted heterocyclic group" means that alkyl may but need not be present, and that the description includes instances where the heterocyclic group is substituted with alkyl and instances where the heterocyclic group is not substituted with alkyl.

"Substituted" means that one or more atoms, preferably 5, more preferably 1 to 3, in the group are independently substituted with a corresponding number of substituents. It goes without saying that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort, the substituents being in their possible chemical positions. For example, a carbon atom having a free amine or hydroxyl group bonded to an unsaturated (e.g., olefinic) bond may be unstable. Such substituents include, but are not limited to, hydroxy, amino, halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, and the like.

"Pharmaceutical composition" refers to a composition comprising one or more of the compounds described herein or a pharmaceutically acceptable salt or prodrug thereof, and other components such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and further exert biological activity.

"Isomer" refers to a compound having the same molecular formula but differing in the nature or sequence of their atoms bonded or the spatial arrangement of their atoms, and is referred to as an "isomer" and an isomer differing in the spatial arrangement of its atoms is referred to as a "stereoisomer". Stereoisomers include optical isomers, geometric isomers and conformational isomers. The compounds of the present invention may exist in the form of optical isomers. Depending on the configuration of the substituents around the chiral carbon atom, these optical isomers are in the "R" or "S" configuration. Optical isomers include enantiomers and diastereomers, and methods for preparing and separating optical isomers are known in the art.

The compounds of the invention may also exist as geometric isomers. The present invention contemplates various geometric isomers and mixtures thereof resulting from the distribution of substituents around carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl or heterocyclic groups. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as Z or E configuration, and substituents around cycloalkyl or heterocycle are designated as cis or trans configuration.

The compounds of the invention may also exhibit tautomerism, such as keto-enol tautomerism.

It is to be understood that the present invention includes any tautomeric or stereoisomeric form and mixtures thereof, and is not limited to any one tautomeric or stereoisomeric form used in the naming or chemical formulae of the compounds.

"Isotopes" are all isotopes of atoms that are present in compounds of the invention. Isotopes include those atoms having the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to ²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、³¹P、³²P、³⁵S、¹⁸F and ³⁶ Cl, respectively. Isotopically-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples using an appropriate isotopically-labeled reagent in place of a non-isotopically-labeled reagent. Such compounds have a variety of potential uses, for example as standards and reagents in assaying biological activity. In the case of stable isotopes, such compounds have the potential to advantageously alter biological, pharmacological or pharmacokinetic properties.

By "prodrug" is meant that the compounds of the invention may be administered in the form of a prodrug. Prodrugs refer to derivatives of the biologically active compounds of the present invention which are converted under physiological conditions in vivo, e.g., by oxidation, reduction, hydrolysis, etc. (each of which is performed with or without the aid of an enzyme). Examples of prodrugs are the following compounds: wherein the amine groups in the compounds of the invention are acylated, alkylated or phosphorylated, such as eicosanoylamino, propylamino, pivaloyloxymethylamino, or wherein the hydroxyl groups are acylated, alkylated, phosphorylated or converted to borates, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, propylaminooxy, or wherein the carboxyl groups are esterified or amidated, or wherein the sulfhydryl groups form disulfide bridges with carrier molecules, such as peptides, that selectively deliver the drug to the target and/or cytosol of the cell, these compounds may be prepared from the compounds of the invention according to well known methods.

"Pharmaceutically acceptable salts" or "pharmaceutically acceptable" refer to those prepared from pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. Where the compounds of the invention contain one or more acidic or basic groups, the invention also encompasses their corresponding pharmaceutically acceptable salts. Thus, the compounds according to the invention containing acidic groups may be present in salt form and may be used according to the invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium salts or salts with amines or organic amines, such as primary, secondary, tertiary, cyclic amines, etc., for example, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purine, piperazine, piperidine, choline, and caffeine, and particularly preferred organic bases are salts of isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The compounds of the invention containing basic groups may be present in salt form and may be used according to the invention in the form of their addition to inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds of the invention contain both acidic and basic groups in the molecule, the invention includes, in addition to the salt forms mentioned, also internal salts or betaines. The individual salts are obtained by conventional methods known to the person skilled in the art, for example by contacting these with organic or inorganic acids or bases in solvents or dispersants or by anion exchange or cation exchange with other salts.

Thus, in the present application, when referring to "a compound", "a compound of the application" or "a compound of the application" all such compound forms, e.g. prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers, meso, racemates, enantiomers, diastereomers and mixtures thereof are included.

Herein, the term "tumor" includes benign tumors and malignant tumors (e.g., cancers).

As used herein, the term "cancer" includes various malignant tumors that Bruton's tyrosine kinase participates in, including but not limited to, non-small cell lung cancer, esophageal cancer, melanoma, rhabdomyodur, cellular cancer, multiple myeloma, breast cancer ovarian cancer, endometrial cancer, cervical cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer, lung cancer, breast cancer, prostate cancer and liver cancer (e.g., hepatocellular cancer), more particularly liver cancer, gastric cancer and bladder cancer.

The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount" as used herein refers to an amount of at least one agent or compound that is sufficient to alleviate one or more symptoms of the disease or disorder being treated to some extent after administration. The result may be a reduction and/or alleviation of signs, symptoms, or causes of a disease or any other desired alteration of a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide clinically significant relief from a disorder. Effective amounts suitable in any individual case can be determined using techniques such as a dose escalation test.

The term "polymorph" or "polymorphic form" as used herein means that a compound of the present invention has a plurality of crystalline forms, some compounds of the present invention may have more than one crystalline form, and the present invention encompasses all polymorphic forms or mixtures thereof.

Intermediate compounds of the invention and polymorphs thereof are also within the scope of the present invention.

Crystallization often yields solvates of the compounds of the present invention, and the term "solvate" as used herein refers to a complex composed of one or more molecules of the compounds of the present invention and one or more molecules of a solvent.

The solvent may be water, in which case the solvate is a hydrate. In addition, an organic solvent is also possible. Thus, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like, as well as the corresponding solvated forms. The compounds of the invention may be true solvates, but in other cases the compounds of the invention may simply accidentally retain water or a mixture of water with some other solvent, the compounds of the invention may be reacted in one solvent or precipitated or crystallized in one solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.

The term "acceptable" in relation to a formulation, composition or ingredient as used herein means that there is no sustained detrimental effect on the overall health of the subject being treated.

The term "pharmaceutically acceptable" as used herein refers to a material (e.g., carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, i.e., the material can be administered to an individual without causing an adverse biological reaction or interacting in an adverse manner with any of the components contained in the composition.

"Pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, adjuvants, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersing agents, suspending agents, stabilizer isotonic agents, solvents, or emulsifiers that have been approved by the relevant government administration for use in humans and domestic animals.

The terms "subject," "patient," "subject," or "individual" as used herein refer to an individual having a disease, disorder, or condition, and the like, including mammals and non-mammals, examples of which include, but are not limited to, any member of the class mammalia: human, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal is a human.

The term "treatment" as used herein refers to the treatment of a disease condition associated with a mammal, particularly a human, including

(I) Preventing the occurrence of a disease or condition in a mammal, particularly a mammal that has been previously exposed to a disease or condition but has not been diagnosed with the disease or condition;

(ii) Inhibiting the disease or disorder, i.e., controlling its progression;

(iii) Alleviating the disease or condition, i.e., slowing the regression of the disease or condition;

(iv) Relieving symptoms caused by diseases or symptoms.

The terms "disease" and "disorder" as used herein may be used interchangeably or differently and, because some specific diseases or disorders have not yet been known to cause a disease (and therefore the cause of the disease is not yet known), they cannot be considered as a disease but rather can be considered as an unwanted condition or syndrome, more or less specific symptoms of which have been confirmed by clinical researchers.

The terms "administering," "administering," and the like as used herein refer to methods that enable delivery of a compound or composition to a desired site for biological action. Including, but not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In preferred embodiments, the compounds and compositions discussed herein are administered orally.

Detailed description of the preferred embodiments

The invention also provides a method for preparing the compound. The preparation of the compounds of the general formula (I) according to the invention can be carried out by the following exemplary methods and examples, which, however, should not be regarded as limiting the scope of the invention in any way. The compounds of the present invention may also be synthesized by synthetic techniques known to those skilled in the art, or by a combination of methods known in the art and methods described herein. The product obtained in each step is obtained using separation techniques known in the art including, but not limited to, extraction, filtration, distillation, crystallization, chromatographic separation, and the like. The starting materials and chemical reagents required for the synthesis may be conventionally synthesized or purchased according to literature (reaxys).

Unless otherwise indicated, temperatures are degrees celsius. Reagents were purchased from commercial suppliers such as Chemblocks Inc, ASTATECH INC or mikrin and these reagents were used directly without further purification unless otherwise indicated.

Unless otherwise indicated, the following reactions were carried out at room temperature, in anhydrous solvents, under positive pressure of nitrogen or gas, or using dry tubes; glassware drying and/or heat drying.

Column chromatography purification uses 200-300 mesh silica gel from the Qingdao marine chemical plant unless otherwise indicated; preparation of thin layer chromatography A thin layer chromatography silica gel prefabricated plate (HSGF 254) manufactured by Kagaku chemical industry research institute of tobacco, inc.; MS was determined using a Therno LCD Fleet model (ESI) liquid chromatograph-mass spectrometer.

Nuclear magnetic data (1H NMR) using BrukerAvance-400MHz or Varian Oxford-400Hz nuclear magnetic instruments, the solvents used for nuclear magnetic data were CDCl ₃、CD₃OD、D₂O、DMSO-d₆, etc., and when peak shape diversity was indicated on the basis of tetramethylsilane (0.000 ppm) or on the basis of residual solvent (CDCl _3:7.26ppm;CD₃OD:3.31ppm;D₂O:4.79ppm;DMSO-d₆: 2.50 ppm), the following abbreviations represent the different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet), dt (doublet). If the coupling constant is given, it is in Hertz (Hz).

Preparation of intermediate (S) -1, 3-dihydro-spiro [ indene-2, 4' -piperidine ] -1-amine

The compound 1-indanone (2.64 g,20 mmol) was dissolved in 30mL of N, N-dimethylformamide, naH (2.40 g,60mmol, 60%) was added at room temperature and the reaction stirred for 30 minutes. N-BOC-N, N-bis (2-bromomethyl) amine (7.28 g,22 mmol) was added thereto, and the temperature was raised to 50℃and the reaction was stirred for 12 hours. Cooled to room temperature, the reaction was quenched with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography to give tert-butyl 1-oxo-1, 3-dihydro-spiro [ indene-2, 4 '-piperidine ] -1' -carboxylate (2.11 g, yield 35%). LC/MS (ESI) m/z=202.1 [ M+H ] ⁺.

The compound tert-butyl 1-oxo-1, 3-dihydro-spiro [ indene-2, 4 '-piperidine ] -1' -carboxylate (1.0 g,3.32 mmol) and (R) -tert-butylsulfinamide (1.21 g,10.0 mmol) were dissolved in 10mL of tetrahydrofuran, ethyl titanate (4.87 mL,23.23 mmol) was added, and the mixture was heated to 65℃and stirred for 48 hours. Cooled to room temperature, ethyl acetate and water were added, stirred for 15 minutes, and the resulting solid was removed by filtration. The solution was separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure to give the crude product (R, E) -1- (tert-butylsulfimide) -1, 3-dihydro spiro [ indene-2, 4 '-piperidine ] -1' -carboxylic acid tert-butyl ester, which was used directly in the next step.

The compound (R, E) -1- (tert-butylsulfimide) -1, 3-dihydro-spiro [ indene-2, 4 '-piperidine ] -1' -carboxylic acid tert-butyl ester (1.21 g,3 mmol) was dissolved in 15mL of tetrahydrofuran and cooled to-45 ℃. Sodium borohydride (0.17 g,4.5 mmol) was added and the reaction was stirred for 18 hours at room temperature. Quenching with ice water, extracting with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography to give tert-butyl (S, R) -1- (tert-butylsulfinamide) -1, 3-dihydro-spiro [ indene-2, 4 '-piperidine ] -1' -carboxylate (485 mg, 40% yield).

The compound (S, R) -1- (tert-butylsulfinamide) -1, 3-dihydro-spiro [ indene-2, 4 '-piperidine ] -1' -carboxylic acid tert-butyl ester (481mg, 1.19 mmol) was dissolved in 1mL of dichloromethane, 1mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by reverse phase preparation of the column to give the compound (S) -1, 3-dihydro-spiro [ indene-2, 4' -piperidin ] -1-amine (229 mg, yield 95%). LC/MS (ESI) m/z=203.1 [ M+H ] ⁺.

Preparation of intermediate (S) -5, 7-dihydro-spiro [ cyclopenta [ b ] pyridin-6, 4' -piperidin ] -5-amine

The compound (S) -5, 7-dihydro-spiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -5-amine was obtained in a similar manner to the preparation of intermediate (S) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine starting from 6, 7-dihydro-5H-cyclopenta [ b ] pyridin-5-one. LC/MS (ESI) m/z=204.1 [ M+H ] ⁺.

Preparation of intermediate (S) -5, 7-dihydro-spiro [ cyclopenta [ c ] pyridin-6, 4' -piperidin ] -5-amine

The compound (S) -5, 7-dihydro-spiro [ cyclopenta [ c ] pyridin-6, 4 '-piperidin ] -5-amine was obtained in a similar manner to the preparation of intermediate (S) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine starting from 6, 7-dihydro-5H-cyclopenta [ c ] pyridin-5-one. LC/MS (ESI) m/z=204.1 [ M+H ] ⁺.

Preparation of intermediate (S) -5, 7-dihydro-spiro [ cyclopenta [ c ] pyridin-6, 4' -piperidin ] -7-amine

The compound (S) -5, 7-dihydro-spiro [ cyclopenta [ c ] pyridin-6, 4 '-piperidin ] -7-amine was obtained by a similar procedure as the intermediate (S) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine (starting with 5H-cyclopenta [ c ] pyridin-7 (6H) -one). LC/MS (ESI) m/z=204.1 [ M+H ] ⁺.

Preparation of intermediate (S) -5, 7-dihydro-spiro [ cyclopenta [ b ] pyridin-6, 4' -piperidin ] -7-amine

The compound (S) -5, 7-dihydro-spiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -7-amine was obtained by a similar procedure as the intermediate (S) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine (starting with 5H-cyclopenta [ b ] pyridin-7 (6H) -one). LC/MS (ESI) m/z=204.1 [ M+H ] ⁺.

Preparation of intermediate (R) -1- (4-methylpiperidin-4-yl) ethylamine

The compound (S) -5, 7-dihydro-spiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -7-amine was obtained in a similar manner to the preparation of intermediate (S) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine (starting from 4-acetyl-4-methylpiperidine-1-carboxylic acid tert-butyl ester). LC/MS (ESI) m/z=143.1 [ M+H ] ⁺.

Preparation of intermediate (4-methylpiperidin-4-yl) methylamine

The compound 1-BOC-4-formyl-4-methylpiperidine (0.68 g,3 mmol) and ammonium acetate (1.21 g,30.0 mmol) were dissolved in 10mL of methanol, and sodium cyanoborohydride (0.25 g,4 mmol) was added thereto and the reaction was stirred at room temperature for 1 hour. Chloroform was added to dilute the mixture, the mixture was washed with 3N sodium hydroxide solution and saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure to give tert-butyl 4- (aminomethyl) -4-methylpiperidine-1-carboxylate (513 mg, 75% yield). LC/MS (ESI) m/z=129.1 [ M+H ] ⁺.

The compound tert-butyl 4- (aminomethyl) -4-methylpiperidine-1-carboxylate (458 mg,2 mmol) was dissolved in 1mL of methanol, and a solution of HCl in 1, 4-dioxane (1 mL, 4M) was added thereto, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was purified by reverse direction preparation of a column to give the compound (4-methylpiperidin-4-yl) methylamine (240 mg, yield 93%). LC/MS (ESI) m/z=129.1 [ M+H ] ⁺.

Preparation of intermediate (S) -4, 6-dihydro-spiro [ cyclopenta [ b ] thiazol-5, 4' -piperidin ] -6-amine

To a 100mL suspension of phosphorus pentoxide (25.4 g,179.0 mmol) in methanesulfonic acid was added 3- (1, 3-thiazol-4-yl) propionic acid (5.0 g,32.0 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography to give the compound 4H-cyclopenta [ b ] thiazol-6 (5H) -one (1.2 g, yield 27%). LC/MS (ESI) m/z=140.0 [ M+H ] ⁺.

Subsequent steps compound (S) -4, 6-dihydro-spiro [ cyclopenta [ b ] thiazol-5, 4 '-piperidin ] -6-amine was obtained in a similar manner to the preparation of intermediate (S) -1, 3-dihydro-spiro [ inden-2, 4' -piperidin ] -1-amine (starting from 4H-cyclopenta [ b ] thiazol-6 (5H) -one). LC/MS (ESI) m/z=210.1 [ M+H ] ⁺.

Preparation of intermediate 7-bromo-3- (2, 3-dichlorophenyl) quinazoline-2, 4 (1H, 3H) -dione

The compound methyl 2-amino-4-bromobenzoate (1.15 g,5 mmol) was dissolved in 25mL of anhydrous 1, 4-dioxane, and 2, 3-dichlorophenyl isocyanate (1.13 g,6 mmol) and triethylamine (101 mg,1 mmol) were added. The reaction was carried out at 90℃for 48 hours with stirring. Cooled to room temperature, the reaction mixture was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography to give intermediate 7-bromo-3- (2, 3-dichlorophenyl) quinazoline-2, 4 (1 h,3 h) -dione (1.5 g, yield 78%). LC/MS (ESI) m/z=384.9 [ M+H ] ⁺.

Preparation of intermediate 7-chloro-3- (2, 3-dichlorophenyl) pteridine-2, 4 (1H, 3H) -dione

The compound 7-chloro-3- (2, 3-dichlorophenyl) pteridine-2, 4 (1H, 3H) -dione was obtained by a similar procedure to that used for the intermediate 7-bromo-3- (2, 3-dichlorophenyl) quinazoline-2, 4 (1H, 3H) -dione (starting material was replaced with methyl 3-amino-5-chloropyrazine-2-carboxylate). LC/MS (ESI) m/z=342.9 [ M+H ] ⁺.

Preparation of intermediate 7-chloro-3- (2, 3-dichlorophenyl) pyridine [2,3-d ] pyrimidine-2, 4 (1H, 3H) -dione

The compound 7-chloro-3- (2, 3-dichlorophenyl) pyridine [2,3-d ] pyrimidine-2, 4 (1H, 3H) -dione was obtained by a similar preparation method (starting material was changed to methyl 2-amino-6-chloronicotinate) as intermediate 7-bromo-3- (2, 3-dichlorophenyl) quinazoline-2, 4 (1H, 3H) -dione. LC/MS (ESI) m/z=342.0 [ M+H ] ⁺.

Preparation of intermediate 7-chloro-3- (7-chlorobenzo [ d ] thiazol-6-yl) pteridine-2, 4 (1H, 3H) -dione

The compound 7-chloro-3- (7-chlorobenzo [ d ] thiazol-6-yl) pteridine-2, 4 (1H, 3H) -dione was obtained by a similar preparation method as intermediate 7-bromo-3- (2, 3-dichlorophenyl) quinazoline-2, 4 (1H, 3H) -dione (starting from 3-amino-5-chloropyrazine-2-carboxylic acid methyl ester and 7-chlorobenzo [ d ] thiazol-6-amine). LC/MS (ESI) m/z=366.0 [ M+H ] ⁺.

Preparation of 7-bromo-3- (2-amino-3-chloropyridin-4-yl) quinazoline-2, 4 (1H, 3H) -dione

The compound 2-nitro-3-chloro-4-aminopyridine (0.87 g,5 mmol) was dissolved in dry dichloromethane 25mL and triethylamine (1.52 g,15 mmol) was added. Triphosgene (1.48 g,5 mmol) was added in portions under an ice-water bath, and the mixture was naturally returned to room temperature to react for 2 hours, quenched with water, and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. Crude 2-nitro-3-chloro-4-isocyanate pyridine is obtained and is directly used in the next step.

The compound 7-bromo-3- (2-nitro-3-chloropyridin-4-yl) quinazoline-2, 4 (1 h,3 h) -dione was obtained in a similar manner to the intermediate 7-bromo-3- (2, 3-dichlorophenyl) quinazoline-2, 4 (1 h,3 h) -dione (starting material was replaced with 2-nitro-3-chloro-4-isocyanatopyridine). LC/MS (ESI) m/z=396.9 [ M+H ] ⁺.

The compound 7-bromo-3- (2-nitro-3-chloropyridin-4-yl) quinazoline-2, 4 (1H, 3H) -dione (1.19 g,3 mmol) was dissolved in 15mL of methanol, replaced with hydrogen 3 times, and Raney nickel (119 mg) was added. The reaction was stirred at room temperature under hydrogen for 12 hours. The reaction solution was filtered and evaporated to dryness under reduced pressure to give intermediate 7-bromo-3- (2-amino-3-chloropyridin-4-yl) quinazolin-2, 4 (1H, 3H) -dione (1.05 g, 95% yield). LC/MS (ESI) m/z=367.0 [ m+h ] ⁺.

Preparation of intermediate 3- (2-amino-3-chloropyridin-4-yl) -7-chloropteridine-2, 4 (1H, 3H) -dione

The compound 3- (2-amino-3-chloropyridin-4-yl) -7-chloropteridine-2, 4 (1H, 3H) -dione was obtained by a similar preparation method as intermediate 7-bromo-3- (2-amino-3-chloropyridin-4-yl) quinazoline-2, 4 (1H, 3H) -dione (intermediate 3-amino-5-chloropyrazine-2-carboxylic acid methyl ester). LC/MS (ESI) m/z=325.0 [ M+H ] ⁺.

Preparation of intermediate 3- (2-amino-3-chloropyridin-4-yl) -7-chloropyridine [2,3-d ] pyrimidine-2, 4 (1H, 3H) -dione

The compound 3- (2-amino-3-chloropyridin-4-yl) -7-chloropyridine [2,3-d ] pyrimidine-2, 4 (1H, 3H) -dione was obtained using a similar preparation method as intermediate 7-bromo-3- (2-amino-3-chloropyridin-4-yl) quinazoline-2, 4 (1H, 3H) -dione (intermediate 2-amino-6-chloronicotinic acid methyl ester). LC/MS (ESI) m/z=324.0 [ M+H ] ⁺.

Preparation of intermediate 7-chloro-3- (3-chloro-2- (cyclopropylamino) pyridin-4-yl) pteridine-2, 4 (1H, 3H) -dione

The compound 2, 3-dichloropyridin-4-amine (1.63 g,10 mmol) was dissolved in 20mL of cyclopropylamine and heated to 120deg.C under microwaves for 30 minutes. Cooled to room temperature, the reaction solution was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography to give intermediate 3-chloro-N ² -cyclopropylpyridine-2, 4-diamine (1.06 g, yield 65%). LC/MS (ESI) m/z=163.0 [ M+H ] ⁺.

The compound 3-chloro-N ² -cyclopropylpyridine-2, 4-diamine (0.82 g,5 mmol) was dissolved in 25mL of anhydrous dichloromethane and triethylamine (1.52 g,15 mmol) was added. Triphosgene (1.48 g,5 mmol) was added in portions under an ice-water bath, and the mixture was naturally returned to room temperature to react for 4 hours, quenched with water, and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. Crude 3-chloro-N-cyclopropyl-4-isocyanate pyridine-2-diamine is obtained and is directly used in the next step.

The compound methyl 3-amino-5-chloropyrazine-2-carboxylate (0.94 g,5 mmol) was dissolved in 20mL of anhydrous 1, 4-dioxane, and 3-chloro-N-cyclopropyl-4-isocyanatopyridine-2-diamine (0.84 g,4 mmol) and triethylamine (101 mg,1 mmol) were added. The reaction was carried out at 90℃for 72 hours with stirring. Cooled to room temperature, the reaction mixture was evaporated to dryness under reduced pressure, and the residue was purified by column chromatography to give intermediate 7-chloro-3- (3-chloro-2- (cyclopropylamino) pyridin-4-yl) pteridine-2, 4 (1 h,3 h) -dione (1.5 g, 69%). LC/MS (ESI) m/z=365.0 [ M+H ] ⁺.

Preparation of the intermediate 7-chloro-3- (3-chloro-2- (cyclopropylamino) pyridin-4-yl) pyridine [2,3-d ] pyrimidine-2, 4 (1H, 3H) -dione

The compound 7-chloro-3- (3-chloro-2- (cyclopropylamino) pyridin-4-yl) pyridine [2,3-d ] pyrimidine-2, 4 (1H, 3H) -dione was obtained in a similar preparation process (intermediate was exchanged for methyl 2-amino-6-chloronicotinate) as intermediate 7-chloro-3- (3-chloro-2- (cyclopropylamino) pyridin-4-yl) pteridine-2, 4 (1H, 3H) -dione. LC/MS (ESI) m/z=364.0 [ M+H ] ⁺.

Preparation of intermediate N- (3-amino-2-chlorobenzene) -2-hydroxy-4-oxa-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide

The compounds triethyl methanetricarboxylate (9.28 g,40 mmol) and 2-aminopyridine (1.88 g,20 mmol) were dissolved in 70mL xylene and heated to 120deg.C and reacted with stirring for 24 hours. Cooled to room temperature, filtered, and the filter cake was washed 3 times with methanol and dried to give the compound ethyl 2-hydroxy-4-oxo-pyridine [1,2-a ] pyrimidine-3-carboxylate (1.16 g, yield 25%). LC/MS (ESI) m/z=235.1 [ M+H ] ⁺.

The compound ethyl 2-hydroxy-4-oxo-pyrido [1,2-a ] pyrimidine-3-carboxylate (936 mg,4 mmol) was dissolved in 10mL of methanol under nitrogen, palladium on carbon (80 mg) was then added, hydrogen was replaced 3 times, and the reaction was stirred at room temperature for 2 hours. Filtration and concentration under reduced pressure gave the compound ethyl 2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyrido [1,2-a ] pyrimidine-3-carboxylate (904 mg, 95% yield). LC/MS (ESI) m/z=239.1 [ M+H ] ⁺.

The compound 2-chlorobenzene-1, 3-diamine (552 mg,3.8 mmol) and ethyl 2-hydroxy-4-oxo-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxylate (284 mg,3.8 mmol) were dissolved in chlorobenzene 20mL and heated to reflux and stirred for 3 hours. Cooled to room temperature, filtered and dried to give the compound N- (3-amino-2-chloro-benzene) -2-hydroxy-4-oxa-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide (661 mg, 52% yield). LC/MS (ESI) m/z=335.1 [ M+H ] ⁺.

Preparation of the intermediate N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) -2-hydroxy-4-oxa-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide

The compound N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) -2-hydroxy-4-oxa-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide was obtained in a similar manner to the previous two steps of preparation of the intermediate 7-bromo-3- (2-amino-3-chloropyridin-4-yl) quinazoline-2, 4 (1H, 3H) -dione. LC/MS (ESI) m/z=516.1 [ M+H ] ⁺.

Preparation of the intermediate N- (3- (7-bromo-2, 4-dioxa-1, 2-dihydropyridine [3,2-d ] pyrimidin-3 (4H) -yl) -2-chlorophenyl) -2-hydroxy-4-oxa-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide

The compound N- (3- (7-bromo-2, 4-dioxa-1, 2-dihydropyridin [3,2-d ] pyrimidin-3 (4H) -yl) -2-chlorophenyl) -2-hydroxy-4-oxa-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide was obtained in a similar manner to the previous two steps of preparation of the intermediate 7-bromo-3- (2-amino-3-chloropyridin-4-yl) quinazoline-2, 4 (1H, 3H) -dione. LC/MS (ESI) m/z=559.0 [ M+H ] ⁺.

Preparation of the intermediate N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropyridine [2,3-d ] pyrimidin-3 (4H) -yl) phenyl) -2-hydroxy-4-oxa-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide

The compound N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropyridin [2,3-d ] pyrimidin-3 (4H) -yl) phenyl) -2-hydroxy-4-oxa-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide was obtained in a similar manner to the previous two steps of preparation of the intermediate 7-bromo-3- (2-amino-3-chloropyridin-4-yl) quinazoline-2, 4 (1H, 3H) -dione. LC/MS (ESI) m/z=515.1 [ M+H ] ⁺.

Preparation of the intermediate N- (3- (7-bromo-2, 4-dioxa-1, 2-dihydroquinazolin-3 (4H) -yl) -2-chlorophenyl) -2-hydroxy-4-oxa-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide

The compound N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropyridin [2,3-d ] pyrimidin-3 (4H) -yl) phenyl) -2-hydroxy-4-oxa-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide was obtained in a similar manner to the previous two steps of preparation of the intermediate 7-bromo-3- (2-amino-3-chloropyridin-4-yl) quinazoline-2, 4 (1H, 3H) -dione. LC/MS (ESI) m/z=558.0 [ M+H ] ⁺.

Preparation of the intermediate N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) -1-methyl-1H-pyrazole-3-carboxamide

To 10mL of thionyl chloride was added 1-methylpyrazole-3-carboxylic acid (630 mg,5 mmol), stirred under reflux for 2 hours, concentrated under reduced pressure to give an acid chloride, 15mL of methylene chloride, pyridine (593 mg,7.5 mmol), 2-chlorobenzene-1, 3-diamine (317 mg,2.5 mmol), 4-dimethylaminopyridine (153 mg,1.25 mmol) were added to the acid chloride, and the reaction was stirred at room temperature for 2 hours. The mixture was quenched with water, extracted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography to give the compound N- (3-amino-2-chlorobenzene) -1-methyl-1H-pyrazole-3-carboxamide (520 mg, yield 83%). LC/MS (ESI) m/z=251.1 [ M+H ] ⁺.

The next two steps were carried out using a procedure similar to the previous two steps of the intermediate 7-bromo-3- (2-amino-3-chloropyridin-4-yl) quinazoline-2, 4 (1H, 3H) -dione (starting material was changed to N- (3-amino-2-chloro) -1-methyl-1H-pyrazole-3-carboxamide) to give the compound N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) -1-methyl-1H-pyrazole-3-carboxamide. LC/MS (ESI) m/z=432.0 [ M+H ] ⁺.

Preparation of the intermediate N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) -1-methyl-1H-pyrazole-4-carboxamide

The compound N- (2-chloro-3- (7-chloro-2, 4-dioxo-1, 2-dihydropteridin-3 (4H) -yl) phenyl) -1-methyl-1H-pyrazole-4-carboxamide was obtained using a similar preparation method (starting material was changed to 1-methylpyrazole-4-carboxylic acid) as intermediate N- (2-chloro-3- (7-chloro-2, 4-dioxo-1, 2-dihydropteridin-3 (4H) -yl) phenyl) -1-methyl-1H-pyrazole-4-carboxamide. LC/MS (ESI) m/z=432.0 [ M+H ] ⁺.

Preparation of intermediate N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) benzamide

The compound N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) benzamide was obtained by a similar preparation method (starting material was changed to benzoic acid) as intermediate N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl). LC/MS (ESI) m/z=428.0 [ M+H ] ⁺.

Preparation of the intermediate N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) pyrazine-2-carboxamide

The compound N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) pyrazine-2-carboxamide is obtained by a similar preparation method (starting material is replaced by 2-carboxylic acid pyrazine) as intermediate N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) pyrazine-2-carboxamide. LC/MS (ESI) m/z=430.0 [ M+H ] ⁺.

Preparation of the intermediate N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) pyridine-2-carboxamide

The compound N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) pyridine-2-carboxamide is obtained by a similar preparation method (starting material is changed to pyridine-2-carboxylate) as intermediate N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) pyridine-2-carboxamide. LC/MS (ESI) m/z=429.0 [ M+H ] ⁺.

Preparation of the intermediate N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) pyrimidine-4-carboxamide

The compound N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) pyrimidine-4-carboxamide was obtained by a similar preparation method (starting material was changed to 4-pyrimidinecarboxylic acid) as intermediate N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) -1-methyl-1H-pyrazole-3-carboxamide. LC/MS (ESI) m/z=430.0 [ M+H ] ⁺.

Preparation of the intermediate N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) -1-methyl-1H-indole-7-carboxamide

The compound N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) -1-methyl-1H-indole-7-carboxamide was obtained in a similar manner to the intermediate N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) -1-methyl-1H-indole-3-carboxamide (starting material was 1-methyl-7-indolecarboxylic acid). LC/MS (ESI) m/z=481.1 [ M+H ] ⁺.

Preparation of the intermediate N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) -1-methyl-1H-indazole-7-carboxamide

The compound N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) -1-methyl-1H-indazole-7-carboxamide was obtained in a similar manner to the intermediate N- (2-chloro-3- (7-chloro-2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) phenyl) -1-methyl-1H-indazole-7-carboxamide (starting material was changed to 1-methyl-7-indazole-carboxylic acid). LC/MS (ESI) m/z=482.0 [ M+H ] ⁺.

Preparation of intermediate 7-chloro-3- (2-chloro-3- (pyrimidin-4-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione

The compound 4-bromopyrimidine (4.97 g,31.25 mmol) was dissolved in 80mL of toluene, hexa-n-butylditin (18.05 g,31.25 mmol) and tetraphenylphosphine palladium (1.79 g,1.56 mmol) was added thereto, and the mixture was heated to 120℃and reacted under stirring for 6 hours. Cooled to room temperature, and the reaction solution was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound 4- (tributylstannyl) pyrimidine (3.23 g, yield 28%).

The compound 4- (tributylstannyl) pyrimidine (1.85 g,5 mmol) was dissolved in 40mL of xylene, 2-chloro-3 iodoaniline (1.27 g,5 mmol) and tetrakis triphenylphosphine palladium (289 mg,0.25 mmol) were added, and the reaction was stirred at 120℃for 3 hours. Cooled to room temperature, and the reaction solution was evaporated to dryness under reduced pressure. The residue was purified by column chromatography to give the compound 2-chloro-3- (pyrimidin-4-yl) aniline (0.67 g, yield 65%). LC/MS (ESI) m/z=206.0 [ m+h ] ⁺.

The next two steps were performed in a similar manner to the previous two steps of the intermediate 7-bromo-3- (2-amino-3-chloropyridin-4-yl) quinazoline-2, 4 (1H, 3H) -dione to give the compound 7-chloro-3- (2-chloro-3- (pyrimidin-4-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione. LC/MS (ESI) m/z=387.0 [ M+H ] ⁺.

Preparation of intermediate 7-chloro-3- (2-chloro-3- (pyridin-3-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione

The compound 7-chloro-3- (2-chloro-3- (pyridin-3-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione was obtained by a similar preparation method (starting material was changed to 3-bromopyridine) as intermediate 7-chloro-3- (2-chloro-3- (pyrimidin-4-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione. LC/MS (ESI) m/z=386.0 [ M+H ] ⁺.

Preparation of intermediate 7-chloro-3- (2-chloro-3- (pyrazin-2-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione

The compound 7-chloro-3- (2-chloro-3- (pyrazin-2-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione was obtained by a similar preparation method (starting material was changed to 2-bromopyrazine) as intermediate 7-chloro-3- (2-chloro-3- (pyrimidin-4-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione. LC/MS (ESI) m/z=387.0 [ M+H ] ⁺.

Preparation of intermediate 7-chloro-3- (2-chloro-3- (pyrazin-2-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione

The compound 7-chloro-3- (2-chloro-3- (1-methyl-1H-pyrazol-3-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione was obtained by a similar preparation method (starting material was changed to 3-bromo-1-methylpyrrole) as intermediate 7-chloro-3- (2-chloro-3- (pyrimidin-4-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione. LC/MS (ESI) m/z=389.0 [ M+H ] ⁺.

Preparation of intermediate 7-chloro-3- (2-chloro-3- (pyrimidine-4-amino) phenyl) pteridine-2, 4 (1H, 3H) -dione

The compound 4-bromopyrimidine (1.59 g,10 mmol) was dissolved in 15mL of toluene, sodium t-butoxide (1.15 g,12 mmol), 4, 5-bisdiphenyllin-9, 9-dimethylxanthene (60 mg), nitrogen was substituted 3 times, tris (dibenzylideneacetone) dipalladium (85 mg) was added, and the reaction was refluxed with stirring for 3 hours. Cooled to room temperature, the reaction was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography to give the compound 2-chloro-N ¹ - (pyrimidin-4-yl) benzene-1, 3-diamine (1.52 g, yield 52%). LC/MS (ESI) m/z=221.1 [ M+H ] ⁺.

The next two steps were performed in a similar manner to the previous two steps of the intermediate 7-bromo-3- (2-amino-3-chloropyridin-4-yl) quinazoline-2, 4 (1H, 3H) -dione to give the compound 7-chloro-3- (2-chloro-3- (pyrimidin-4-amino) phenyl) pteridine-2, 4 (1H, 3H) -dione. LC/MS (ESI) m/z=402.0 [ m+h ] ⁺.

Preparation of intermediate 7-chloro-3- (2-chloro-3- (pyridin-2-amino) phenyl) pteridine-2, 4 (1H, 3H) -dione

The compound 7-chloro-3- (2-chloro-3- (pyridin-2-amino) phenyl) pteridine-2, 4 (1H, 3H) -dione was obtained by a similar preparation method (starting material was changed to 2-bromopyridine) as intermediate 7-chloro-3- (2-chloro-3- (pyrimidin-4-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione. LC/MS (ESI) m/z=401.0 [ M+H ] ⁺.

Preparation of intermediate 7-chloro-3- (2-chloro-3- (pyrazin-2-amino) phenyl) pteridine-2, 4 (1H, 3H) -dione

The compound 7-chloro-3- (2-chloro-3- (pyrazin-2-amino) phenyl) pteridine-2, 4 (1H, 3H) -dione was obtained by a similar preparation method (starting material was changed to 2-bromopyrazine) as intermediate 7-chloro-3- (2-chloro-3- (pyrimidin-4-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione. LC/MS (ESI) m/z=402.0 [ m+h ] ⁺.

Preparation of intermediate 7-chloro-3- (2-chloro-3- (pyrimidine-2-amino) phenyl) pteridine-2, 4 (1H, 3H) -dione

The compound 7-chloro-3- (2-chloro-3- (pyrimidin-2-amino) phenyl) pteridine-2, 4 (1H, 3H) -dione was obtained by a similar preparation method (starting material was changed to 2-bromopyrimidine) as intermediate 7-chloro-3- (2-chloro-3- (pyrimidin-4-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione. LC/MS (ESI) m/z=402.0 [ m+h ] ⁺.

Example 1

Preparation of 7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2, 3-dichlorophenyl) quinazoline-2, 4 (1H, 3H) -dione

The compound 7-bromo-3- (2, 3-dichlorophenyl) quinazoline-2, 4 (1H, 3H) -dione (772 mg,2 mmol) was dissolved in toluene 8mL and (3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decane dihydrochloride (284 mg,2.4 mmol), cesium carbonate (1.95 g,6.0 mmol), bis (dibenzylideneacetone) palladium (12 mg,0.02 mmol), 2-dicyclohexylphosphorus-2 ',6' -diisopropyloxy-1, 1' -biphenyl (19 mg,0.04 mmol) was added. The nitrogen was replaced 3 times and reacted at 90℃for 6 hours with stirring. Cooling to room temperature, allowing the reaction solution to pass through a short silica gel column, leaching with ethyl acetate, and evaporating to dryness under reduced pressure. The residue was purified by column chromatography to give the desired product 1 (494 mg, yield 52％).¹H NMR(400MHz,DMSO-d₆)δ:11.51(s,1H),7.83(d,1H),7.51-7.45(m,2H),7.31-7.26(m,2H),6.83(d,1H),4.10-4.07(m,1H),3.89-3.45(m,4H),3.32-3.25(m,2H),2.91(d,1H),1.77-1.32(m,6H),1.13(d,3H);LC/MS(ESI):m/z＝475.1[M+H]⁺.

Example 2

Preparation of (S) -7- (4-amino-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2, 3-dichlorophenyl) quinazoline-2, 4 (1H, 3H) -dione

Compound 2 (415 mg, 45% yield) was obtained by a method similar to example 1. LC/MS (ESI) m/z=461.1 [ M+H ] ⁺.

Example 3

Preparation of (S) -3- (2-amino-3-chloropyridin-4-yl) -7- (4-amino-2-oxa-8-azaspiro [4.5] decan-8-yl) quinazoline-2, 4 (1H, 3H) -dione

Compound 3 (222 mg, yield) was obtained in a similar manner to example 1 25％).¹H NMR(400MHz,DMSO-d₆)δ:11.23(s,1H),7.82(d,1H),7.51-7.45(m,1H),7.30-7.26(m,1H),6.85(d,1H),6.64(d,1H),5.87(s,2H),4.12-4.08(m,1H),3.89-3.45(m,5H),3.32-3.25(m,2H),2.82-2.74(m,1H),1.74-1.29(m,6H);LC/MS(ESI):m/z＝443.2[M+H]⁺.

Example 4

Preparation of (S) -7- (1-amino-1, 3-dihydro-spiro [ indene-2, 4' -piperidin ] -1-yl) -3- (2, 3-dichlorophenyl) quinazolin-2, 4 (1H, 3H) -dione

Compound 4 (548 mg, yield) was obtained in a similar manner to example 1 54％).¹H NMR(400MHz,DMSO-d₆)δ:11.28(s,1H),7.83(d,1H),7.51-7.45(m,2H),7.31-7.23(m,6H),6.83(d,1H),4.08-4.03(m,1H),3.53-3.45(m,2H),3.32-3.25(m,2H),2.91-2.79(m,2H),1.65-1.30(m,6H);LC/MS(ESI):m/z＝507.1[M+H]⁺.

Example 5

Preparation of (S) -7- (5-amino-5, 7-dihydro-spiro [ cyclopenta [ c ] pyridin-6, 4 '-piperidin ] -1' -yl) -3- (2, 3-dichlorophenyl) quinazoline-2, 4 (1H, 3H) -dione

Compound 5 (498 mg, yield) was obtained in a similar manner to example 1 49％).¹H NMR(400MHz,DMSO-d₆)δ:11.50(s,1H),8.28-8.23(m,2H),7.83(d,1H),7.51-7.45(m,2H),7.31-7.23(m,3H),6.83(d,1H),4.03-3.95(m,1H),3.52-3.45(m,2H),3.32-3.25(m,2H),2.71-2.63(m,2H),1.61-1.29(m,6H);LC/MS(ESI):m/z＝508.1[M+H]⁺.

Example 6

Preparation of (S) -7- (7-amino-5, 7-dihydro-spiro [ cyclopenta [ c ] pyridin-6, 4 '-piperidin ] -1' -yl) -3- (2, 3-dichlorophenyl) quinazoline-2, 4 (1H, 3H) -dione

Compound 6 (437 mg, 43% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=508.1 [ M+H ] ⁺.

Example 7

Preparation of (S) -7- (5-amino-5, 7-dihydro-spiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) -3- (2, 3-dichlorophenyl) quinazoline-2, 4 (1H, 3H) -dione

Compound 7 (528 mg, 52% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=508.1 [ M+H ] ⁺.

Example 8

Preparation of (S) -7- (7-amino-5, 7-dihydro-spiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) -3- (2, 3-dichlorophenyl) quinazoline-2, 4 (1H, 3H) -dione

Compound 8 (416 mg, yield 41%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=508.1 [ M+H ] ⁺.

Example 9

Preparation of (R) -7- (4- (1-aminoethyl) -4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) quinazoline-2, 4 (1H, 3H) -dione

Compound 9 (394 mg, 44% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=449.1 [ M+H ] ⁺.

Example 10

Preparation of 7- (4- (aminoethyl) -4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) quinazoline-2, 4 (1H, 3H) -dione

Compound 10 (328 mg, yield) was obtained in a similar manner to example 1 38％).¹H NMR(400MHz,DMSO-d₆)δ:11.42(s,1H),7.93(s,1H),7.51-7.45(m,2H),7.26(d,1H),3.48-3.39(m,2H),3.34-3.26(m,2H),2.63(s,2H),1.72-1.45(m,4H),1.12(s,3H);LC/MS(ESI):m/z＝433.1[M+H]⁺.

Example 11

Preparation of 7- (4-amino-4-methylpiperidin-1-yl) -3- (2, 3-dichlorophenyl) quinazoline-2, 4 (1H, 3H) -dione

Compound 11 (361 mg, yield) was obtained in a similar manner to example 1 43％).¹H NMR(400MHz,DMSO-d₆)δ:11.42(s,1H),7.93(s,1H),7.51-7.45(m,2H),7.26(d,1H),3.45-3.37(m,2H),3.32-3.25(m,2H),1.82-1.65(m,4H),1.24(s,3H);LC/MS(ESI):m/z＝421.1[M+H]⁺.

Example 12

Preparation of 7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2, 3-dichlorophenyl) pteridine-2, 4 (1H, 3H) -dione

Compound 12 (485 mg, 51% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=477.1 [ M+H ] ⁺.

Example 13

Preparation of (S) -7- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -3- (2, 3-dichlorophenyl) pteridine-2, 4 (1H, 3H) -dione

Compound 13 (436 mg, yield) was obtained in a similar manner to example 1 43％).¹H NMR(400MHz,DMSO-d₆)δ:11.42(s,1H),7.95(s,1H),7.49-7.43(m,2H),7.25(d,1H),4.08-4.03(m,1H),3.57-3.48(m,2H),3.33-3.25(m,2H),2.91-2.77(m,2H),1.65-1.31(m,4H);LC/MS(ESI):m/z＝509.1[M+H]⁺.

Example 14

Preparation of (S) -7- (5-amino-5, 7-dihydro-spiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) -3- (2, 3-dichlorophenyl) pteridine-2, 4 (1H, 3H) -dione

Compound 14 (395 mg, 39% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=510.1 [ m+h ] ⁺.

Example 15

Preparation of (S) -7- (5-amino-5, 7-dihydro-spiro [ cyclopenta [ c ] pyridin-6, 4 '-piperidin ] -1' -yl) -3- (2, 3-dichlorophenyl) pteridine-2, 4 (1H, 3H) -dione

Compound 15 (506 mg, yield 50%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=510.1 [ m+h ] ⁺.

Example 16

Preparation of (S) -7- (7-amino-5, 7-dihydro-spiro [ cyclopenta [ c ] pyridin-6, 4 '-piperidin ] -1' -yl) -3- (2, 3-dichlorophenyl) pteridine-2, 4 (1H, 3H) -dione

Compound 16 (425 mg, 42% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=510.1 [ m+h ] ⁺.

Example 17

Preparation of 3- (2-amino-3-chloropyridin-4-yl) -7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pteridine-2, 4 (1H, 3H) -dione

Compound 17 (222 mg, yield) was obtained in a similar manner to example 1 29％).¹H NMR(400MHz,DMSO-d₆)δ:11.35(s,1H),7.95(s,1H),7.83(d,1H),7.30-7.26(m,1H),5.93(s,2H),4.10-4.07(m,1H),3.89-3.45(m,4H),3.32-3.24(m,2H),2.92(d,1H),1.77-1.32(m,6H),1.14(d,3H);LC/MS(ESI):m/z＝459.2[M+H]⁺.

Example 18

Preparation of (S) -7- (1-amino-1, 3-dihydro-spiro [ indene-2, 4 '-piperidin ] -1' -yl) -3- (2-amino-3-chloropyridin-4-yl) pteridine-2, 4 (1H, 3H) -dione

Compound 18 (222 mg, 21% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=491.2 [ M+H ] ⁺.

Example 19

Preparation of (S) -3- (2-amino-3-chloropyridin-4-yl) -7- (5-amino-5, 7-dihydro-spiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) pteridine-2, 4 (1H, 3H) -dione

Compound 19 (244 mg, 23% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=492.2 [ M+H ] ⁺.

Example 20

Preparation of (S) -3- (2-amino-3-chloropyridin-4-yl) -7- (5-amino-5, 7-dihydro-spiro [ cyclopenta [ c ] pyridin-6, 4 '-piperidin ] -1' -yl) pteridine-2, 4 (1H, 3H) -dione

Compound 20 (202 mg, yield) was obtained in a similar manner to example 1 19％).¹H NMR(400MHz,DMSO-d₆)δ:11.50(s,1H),7.95(s,1H),7.83(d,1H),7.30-7.26(m,1H),5.84(s,2H),4.03-3.96(m,1H),3.52-3.45(m,2H),3.32-3.25(m,2H),2.73-2.65(m,2H),1.61-1.30(m,6H);LC/MS(ESI):m/z＝492.2[M+H]⁺.

Example 21

Preparation of (S) -3- (2-amino-3-chloropyridin-4-yl) -7- (7-amino-5, 7-dihydro-spiro [ cyclopenta [ c ] pyridin-6, 4 '-piperidin ] -1' -yl) pteridine-2, 4 (1H, 3H) -dione

Compound 21 (266 mg, 25% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=492.2 [ M+H ] ⁺.

Example 22

Preparation of (S) -3- (2-amino-3-chloropyridin-4-yl) -7- (7-amino-5, 7-dihydro-spiro [ cyclopenta [ b ] pyridin-6, 4 '-piperidin ] -1' -yl) pteridine-2, 4 (1H, 3H) -dione

Compound 22 (223 mg, 21% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=492.2 [ M+H ] ⁺.

Example 23

Preparation of 3- (2-amino-3-chloropyridin-4-yl) -7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) pteridine-2, 4 (1H, 3H) -dione

Compound 23 (280 mg, yield) was obtained in a similar manner to example 1 26％).¹H NMR(400MHz,DMSO-d₆)δ:11.35(s,1H),7.95(s,1H),7.88(d,1H),7.30-7.26(m,1H),5.23(s,1H),4.10-4.07(m,1H),3.89-3.45(m,4H),3.32-3.24(m,2H),2.92(d,1H),2.53-2.46(m,1H),1.77-1.32(m,6H),1.14(d,3H),0.81-0.77(m,2H),0.57-0.52(m,2H);LC/MS(ESI):m/z＝499.2[M+H]⁺.

Example 24

Preparation of (S) -7- (5-amino-5, 7-dihydro-spiro [ cyclopenta [ c ] pyridin-6, 4 '-piperidin ] -1' -yl) -3- (3-chloro-2- (cyclopropylamino) pyridin-4-yl) -pteridine-2, 4 (1H, 3H) -dione

Compound 24 (356 mg, 31% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=532.2 [ M+H ] ⁺.

Example 25

Preparation of 7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2, 3-dichlorophenyl) pyridine [2,3-d ] pyrimidine-2, 4 (1H, 3H) -dione

Compound 25 (443 mg, 43% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=477.1 [ M+H ] ⁺.

Example 26

Preparation of (S) -7- (5-amino-5, 7-dihydro-spiro [ cyclopenta [ c ] pyridin-6, 4 '-piperidin ] -1' -yl) -3- (2, 3-dichlorophenyl) pyridine [2,3-d ] pyrimidine-2, 4 (1H, 3H) -dione

Compound 26 (560 mg, yield) was obtained in a similar manner to example 1 51％).¹H NMR(400MHz,DMSO-d₆)δ:11.35(s,1H),8.28-8.23(m,2H),7.56-7.45(m,3H),7.31-7.23(m,2H),6.55(d,1H),4.05-3.96(m,1H),3.52-3.45(m,2H),3.31-3.25(m,2H),2.72-2.63(m,2H),1.64-1.29(m,6H);LC/MS(ESI):m/z＝509.1[M+H]⁺.

Example 27

Preparation of (S) -3- (2-amino-3-chloropyridin-4-yl) -7- (5-amino-5, 7-dihydro-spiro [ cyclopenta [ c ] pyridin-6, 4 '-piperidin ] -1' -yl) pyridine [2,3-d ] pyrimidine-2, 4 (1H, 3H) -dione

Compound 27 (265 mg, yield 25%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=491.2 [ M+H ] ⁺.

Example 28

Preparation of (S) -7- (5-amino-5, 7-dihydro-spiro [ cyclopenta [ c ] pyridin-6, 4 '-piperidin ] -1' -yl) -3- (3-chloro-2- (cyclopropylamino) pyridin-4-yl) pyridin [2,3-d ] pyrimidine-2, 4 (1H, 3H) -dione

Compound 28 (344 mg, 30% yield) was obtained by a method similar to that of example 1. LC/MS (ESI) m/z=531.2 [ M+H ] ⁺.

Example 29

Preparation of (S) -7- (6-amino-4, 6-dihydro-spiro [ cyclopenta [ b ] thiazol-5, 4 '-piperidin ] -1' -yl) -3- (2, 3-dichlorophenyl) pteridine-2, 4 (1H, 3H) -dione

Compound 29 (457 mg, yield 41%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=516.1 [ M+H ] ⁺.

Example 30

Preparation of (S) -7- (5-amino-5, 7-dihydro-spiro [ cyclopenta [ c ] pyridin-6, 4 '-piperidin ] -1' -yl) -3- (7-chlorobenzo [ d ] thiazol-6-yl) pteridine-2, 4 (1H, 3H) -dione

Compound 30 (449 mg, 39% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=533.1 [ M+H ] ⁺.

Example 30

Preparation of 7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (7-chlorobenzo [ d ] thiazol-6-yl) pteridine-2, 4 (1H, 3H) -dione

Compound 31 (367 mg, yield) was obtained in a similar manner to example 1 34％).¹H NMR(400MHz,DMSO-d₆)δ:11.35(s,1H),8.92(s,1H),7.95(s,1H),7.85(d,1H),7.53(d,1H),4.12-4.09(m,1H),3.85-3.47(m,4H),3.32-3.24(m,2H),2.92(d,1H),1.75-1.30(m,6H),1.14(d,3H);LC/MS(ESI):m/z＝500.1[M+H]⁺.

Example 32

Preparation of (S) -3- (2-amino-3-chloropyridin-4-yl) -7- (6-amino-4, 6-dihydro-spiro [ cyclopenta [ b ] thiazol-5, 4 '-piperidin ] -1' -yl) pteridine-2, 4 (1H, 3H) -dione

Compound 32 (247 mg, 23% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=498.1 [ M+H ] ⁺.

Example 33

Preparation of N- (3- (7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) -2-chlorophenyl) -2-hydroxy-4-oxa-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide

Compound 33 (448 mg, yield) was obtained in a similar manner to example 1 32％).¹H NMR(400MHz,DMSO-d₆)δ:12.31(br s,1H),11.42(s,1H),7.97(s,1H),7.63-7.52(m,2H),7.28-7.25(m,1H),5.51(br s,3H),4.13-4.10(m,1H),3.93-3.45(m,8H),2.95(d,1H),2.74(s,2H),1.85-1.41(m,8H),1.14(d,3H);LC/MS(ESI):m/z＝650.2[M+H]⁺.

Example 34

Preparation of N- (3- (7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -2, 4-dioxa-1, 2-dihydropyridin [3,2-d ] pyrimidin-3 (4H) -yl) -2-chlorophenyl) -2-hydroxy-4-oxa-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide

Compound 34 (406 mg, 29% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=649.2 [ m+h ] ⁺.

Example 35

Preparation of N- (3- (7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -2, 4-dioxa-1, 2-dihydropyridin [2,3-d ] pyrimidin-3 (4H) -yl) -2-chlorophenyl) -2-hydroxy-4-oxa-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide

Compound 35 (574 mg, 41% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=649.2 [ m+h ] ⁺.

Example 36

Preparation of N- (3- (7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -2, 4-dioxa-1, 2-dihydroquinazolin-3 (4H) -yl) -2-chlorophenyl) -2-hydroxy-4-oxa-6, 7,8, 9-tetrahydro-4H-pyridine [1,2-a ] pyrimidine-3-carboxamide

Compound 36 (531 mg, 38% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=648.2 [ M+H ] ⁺.

Example 37

Preparation of N- (3- (7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) -2-chlorophenyl) -1-methyl-1H-pyrazole-3-carboxamide

Compound 37 (586 mg, yield) was obtained in a similar manner to example 1 48％).¹H NMR(400MHz,DMSO-d₆)δ:11.50(s,1H),8.45(d,1H),7.95(s,1H),7.63-7.52(m,3H),7.33-7.28(m,1H),6.65(d,1H),4.18(s,1H),4.12-4.09(m,1H),3.85-3.47(m,4H),3.32-3.24(m,2H),2.92(d,1H),1.75-1.30(m,6H),1.14(d,3H);LC/MS(ESI):m/z＝566.2[M+H]⁺.

Example 38

Preparation of N- (3- (7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) -2-chlorophenyl) -1-methyl-1H-pyrazole-4-carboxamide

Compound 38 (525 mg, 43% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=566.2 [ m+h ] ⁺.

Example 39

Preparation of N- (3- (7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) -2-chlorophenyl) benzamide

Compound 39 (448 mg, 37% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=562.2 [ M+H ] ⁺.

Example 40

Preparation of N- (3- (7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) -2-chlorophenyl) pyrazine-2-carboxamide

Compound 40 (499 mg, yield) was obtained in a similar manner to example 1 41％).¹H NMR(400MHz,DMSO-d₆)δ:11.43(s,1H),9.26(s,1H),8.75(d,1H),8.56(s,1H),8.34(d,1H),7.95(s,1H),7.63-7.52(m,2H),7.33-7.28(m,1H),4.12-4.09(m,1H),3.83-3.47(m,4H),3.32-3.24(m,2H),2.92(d,1H),1.75-1.30(m,6H),1.14(d,3H);LC/MS(ESI):m/z＝564.2[M+H]⁺.

Example 41

Preparation of N- (3- (7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) -2-chlorophenyl) pyridine-2-carboxamide

Compound 41 (558 mg, 46% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=563.2 [ m+h ] ⁺.

Example 42

Preparation of N- (3- (7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) -2-chlorophenyl) pyrimidine-4-carboxamide

Compound 42 (389 mg, 32% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=564.2 [ M+H ] ⁺.

Example 43

Preparation of N- (3- (7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) -2-chlorophenyl) -1-methyl-1H-indole-7-carboxamide

Compound 43 (477 mg, 36% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=615.2 [ M+H ] ⁺.

Example 44

Preparation of N- (3- (7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -2, 4-dioxa-1, 2-dihydropteridin-3 (4H) -yl) -2-chlorophenyl) -1-methyl-1H-indazole-7-carboxamide

Compound 44 (545 mg, yield 41%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=616.2 [ M+H ] ⁺.

Example 45

Preparation of 7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2-chloro-3- (pyrimidin-4-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione

Compound 45 (371 mg, yield) was obtained in a similar manner to example 1 33％).¹H NMR(400MHz,DMSO-d₆)δ:11.43(s,1H),9.26(s,1H),8.75(d,1H),8.56(s,1H),8.34(d,1H),7.95(s,1H),7.63-7.52(m,2H),7.33-7.28(m,1H),4.12-4.09(m,1H),3.83-3.47(m,4H),3.32-3.24(m,2H),2.92(d,1H),1.75-1.30(m,6H),1.14(d,3H);LC/MS(ESI):m/z＝521.2[M+H]⁺.

Example 46

Preparation of 7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2-chloro-3- (pyridin-3-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione

Compound 46 (460 mg, 41% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=520.2 [ M+H ] ⁺.

Example 47

Preparation of 7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2-chloro-3- (pyrazin-2-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione

Compound 47 (483 mg, 43% yield) was obtained by a method similar to that of example 1. LC/MS (ESI) m/z=521.2 [ M+H ] ⁺.

Example 48

Preparation of 7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2-chloro-3- (1-methyl-1H-pyrazol-3-yl) phenyl) pteridine-2, 4 (1H, 3H) -dione

Compound 48 (327 mg, 29% yield) was obtained in a similar manner to example 1. LC/MS (ESI) m/z=523.2 [ M+H ] ⁺.

Example 49

Preparation of 7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2-chloro-3- (pyrimidin-4-amino) phenyl) pteridine-2, 4 (1H, 3H) -dione

Compound 49 (347 mg, yield) was obtained in a similar manner to example 1 30％).¹H NMR(400MHz,DMSO-d₆)δ:11.36(s,1H),8.95(s,1H),8.35(d,1H),7.97-7.95(m,2H),7.43-7.32(m,2H),7.13-7.08(m,1H),5.93(s,1H),4.12-4.09(m,1H),3.81-3.45(m,4H),3.30-3.22(m,2H),2.89(d,1H),1.73-1.29(m,6H),1.14(d,3H);LC/MS(ESI):m/z＝536.2[M+H]⁺.

Example 50

Preparation of 7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2-chloro-3- (pyridin-2-amino) phenyl) pteridine-2, 4 (1H, 3H) -dione

Compound 50 (311 mg, yield 27%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=535.2 [ m+h ] ⁺.

Example 51

Preparation of 7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2-chloro-3- (pyrazin-2-amino) phenyl) pteridine-2, 4 (1H, 3H) -dione

Compound 51 (405 mg, 35% yield) was obtained by a method similar to example 1. LC/MS (ESI) m/z=536.2 [ M+H ] ⁺.

Example 52

Preparation of 7- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [4.5] decan-8-yl) -3- (2-chloro-3- (pyrimidin-2-amino) phenyl) pteridine-2, 4 (1H, 3H) -dione

Compound 52 (474 mg, yield 41%) was obtained by a method similar to example 1. LC/MS (ESI) m/z=536.2 [ M+H ] ⁺.

Example 53 biological Activity test

The invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.

SHP2 allosteric inhibition assay

Determination of the inhibitory Effect of Compounds on SHP-2 kinase Activity

The purpose of this test is to measure the ability of a compound to inhibit the allosteric activity of the SHP-2 full-length protein. Experimental instrument: centrifuge (5810R) was purchased from Eppendorf corporation, pipettor from Rainin corporation of Eppendorf domain, and microplate reader was purchased from BioTek corporation of America, model SYNERGYHL full function microplate reader.

The experimental method comprises the following steps: in vitro SHP-2 activity assays were performed using Homogeneous Full LENGTH SHP-2Assay Kit (BPS Bioscience, # 79330). First, 18. Mu.L of Master Mix was added to a 96-well low adsorption microplate (NUNC, # 267342), i.e., a reaction buffer containing 0.5 mM DTT and 1X of SHP-2activating Peptide, and 5mM of DTT was added to the reaction buffer, after centrifugation, 5 dishes of test compound/DMSO (1% final DMSO content, V/V) was added to each well, the test compound was dissolved in DMSO to ImM, three-fold serial dilutions were performed, 10 concentrations were performed, the final concentration of the reaction system ranged from 1. Mu.M to 0.05 nM), SHP-2 was diluted to a final concentration of 0.06nM in the reaction buffer of 1X, 2. Mu.L of SHP-2 was added to the reaction microplate, and after centrifugation, the reaction mixture was incubated at room temperature for 60 minutes with full activity control (compound only DMSO) and full inhibition control were set on the reaction plate.

After the incubation, 25. Mu.L Substrate solution per well, containing 10. Mu.M final Substrate and 5mM DTT, was added and incubation was continued for 30 minutes at room temperature after centrifugation. After the reaction, the excitation wavelength was set to 340nM, the emission wavelength was 455nM, and the gain value was 75 on SYNERGY HL full-function microplate reader (Biotek).

The experimental data processing method comprises the following steps:

The percent inhibition ratio data {% inhibition = 100- [ (test compound-Min mean)/(Max mean-Min mean) ] X100} for wells treated with compound were calculated from positive control wells (DMSO control wells) and negative control wells (no kinase added) on the reaction plate based on the values of total active control and total inhibitory control as Max and Min. IC50 values for test compounds were calculated using GRAPHPAD PRISM fit percent inhibition and ten point concentration data to a 4 parameter nonlinear logic formula.

Conclusion of experiment:

From the above schemes, it was found that the example compounds of the present invention showed the biological activities in SHP-2 kinase activity assay as shown in Table 1 below. Wherein "A" represents IC ₅₀.ltoreq.10 nM; "B" means 10< IC ₅₀.ltoreq.100 nM; "C" means 100< IC ₅₀ < 1000nM; "D" means 1000< IC ₅₀ nM.

IC ₅₀ value of Compound of Table 1 for inhibiting SHP2