Pyrimidin-4(3H)-one heterocyclic compounds, their preparation process and pharmaceutical uses

Abstract

The present invention relates to pyrimidin-4(3H)-one heterocyclic compounds for inhibiting or modulating SHP2, methods for preparing them, and pharmaceutical uses thereof. Specifically, the present invention relates to a compound represented by general formula (I) and its pharmaceutically acceptable salts, pharmaceutical compositions containing the compound or its pharmaceutically acceptable salts, methods for using the compound or its pharmaceutically acceptable salts in the treatment and / or prevention of SHP2-mediated diseases, particularly cancer, and methods for preparing the compound or its pharmaceutically acceptable salts. The present invention further relates to the use of the compound or its pharmaceutically acceptable salts, or pharmaceutical compositions containing the compound or its pharmaceutically acceptable salts, in the preparation of medicaments for treating and / or preventing SHP2-mediated diseases, wherein all substituents of general formula (I) are as defined in the specification.

Description

Technical Field

[0001] The present invention relates to novel pyrimidin-4(3H)-one heterocyclic compounds or pharmaceutically acceptable salts thereof for inhibiting or modulating SHP2, pharmaceutical compositions containing the compounds or pharmaceutically acceptable salts thereof, methods for preparing the compounds or pharmaceutically acceptable salts thereof, the use of the compounds or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating and / or preventing SHP2-mediated diseases, particularly cancer, and pharmaceutical compositions containing the compounds or pharmaceutically acceptable salts thereof, and methods of administration thereof.

Background Art

[0002] Src homology 2 domain-containing phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase encoded by the protein tyrosine phosphatase non-receptor type 11 (PTPN11) gene. SHP2 contains two Src homology (SH2) domains, one of which is a protein tyrosine phosphatase (PTP) domain and the other is a C-terminal tail. In the normal state, SHP2 adapts to a self-inhibitory structure, and its N-SH2 binds to the PTP to block the substrate channel of the PTP catalytic site, thereby inhibiting PTP activity. When the SH2 binds to a diphosphotyrosine peptide (such as IRS-1), the self-inhibitory interaction of SH2-PTP is abandoned, the PTP catalytic site is exposed, and SHP2 can be in an active state capable of catalyzing the dephosphorylation of tyrosine.

[0003] SHP2 is widely expressed. As an oncogene, it mediates the activation of various oncogenic cell signaling pathways such as the RAS-ERK pathway, PI3K-ACT pathway, and JAK-STAT pathway, and promotes the survival and proliferation of cancer cells. SHP2 can bind to and dephosphorylate RAS, increase the association of RAS-RAF, and activate downstream cell proliferation signals. SHP2 also mediates a compensatory activation pathway after kinases such as MEK are inhibited, thereby leading to drug resistance in tumor therapy (Ruess DA, et al., Nat. Med. 2018, 24, 954-960). Therefore, the activation of SHP2 is closely related to the etiology of various diseases such as leukemia, melanoma, breast cancer, lung cancer, colon cancer, neuroblastoma, and hepatocellular carcinoma.

[0004] Furthermore, SHP2 also plays an important role in the immune checkpoint pathways of PD-1 and B and T lymphocyte attenuator (BTLA), not only inhibiting T cell activation but also promoting T cell immune non-responsiveness (Li J, et al., Cancer Res. 2015, 75, 508-518).

[0005] From the above, SHP2 has attracted attention as an anti-tumor target. However, due to the high homology of the catalytic site of PTP in the protein sequence and the high hydrophilicity of the catalytic pocket of PTP, the catalytic site of SHP2 has low selectivity, low cell permeability, and low bioavailability. The discovery of Novartis' allosteric inhibitor SHP099 (Chen Y, et al., Nature 2016, 535, 148-52) has provided a new channel for developing highly specific oral SHP2 inhibitors. Currently, as patent applications for SHP2 inhibitors, WO2015107495, WO2016203405, WO2018057884, WO2018013597, WO2017211303, etc. have been disclosed by multiple companies. In the present invention, a compound having a structure represented by general formula (I) was designed, and it was found that a compound having such a structure exhibits an excellent SHP2 activity inhibitory effect. Summary of the Invention

[0006] The present invention relates to General formula (I): [Chemical formula] [In the formula, Ring A is selected from the group consisting of phenyl and 6-membered heteroaryl, and ring B is selected from the group consisting of 5-membered heteroaryl rings fused to ring A, where phenyl and heteroaryl may optionally be D, halogen, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 6-membered heteroaryl, -OR a , -NR a R b , -C(O)R a , -C(O)NR a R b , -S(O)2R a , -S(O)2NR a R b , -NR a S(O)2R b , and -P(O)(CH3)2, and may be substituted by one or more substituents selected from the group consisting of, where alkyl, cycloalkyl, heterocyclyl, and heteroaryl may optionally be D, halogen, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocyclyl, -OR a , -NR a R b , -C(O)R a , and -C(O)NR a R b and may be substituted by one or more substituents selected from the group consisting of; R 1 is H, D, cyano, C 1-2 alkyl, cyclopropyl, -OR a , -NR a R b , and -C(O)NR a R bselected from the group consisting of, wherein one or more hydrogen atoms of alkyl and cyclopropyl may optionally be substituted by one or more substituents selected from the group consisting of D and fluoro; R 2 is H, C 1-2 alkyl, and cyclopropyl, wherein one or more hydrogen atoms of alkyl and cyclopropyl may optionally be substituted by one or more substituents selected from the group consisting of D, fluoro, and hydroxyl; R 4a and R 4b are each independently H, D, halogen, cyano, -OR a -, -NR a R b -, -C(O)R a -, -C(O)NR a R b C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, provided that R 4a and R 4b are not simultaneously selected from the group consisting of cyano, -OR a -, and -NR a R b wherein alkyl, cycloalkyl, heterocyclyl, and heteroaryl may optionally be substituted by one or more substituents selected from the group consisting of D, halogen, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 6-membered heteroaryl, -OR a -, -NR a R b -, -C(O)R a -, and -C(O)NR a R b ; R 4a and R 4b may optionally, together with the carbon atom to which they are attached, form a C 3-7 carbocyclic ring or a 4- to 8-membered heterocyclic ring; R 5a , R 5b , R 6a , and R 6b are each independently selected from the group consisting of H, D, fluoro, and methyl; R a and R b are independently H, C 1-6 Alkyl, C 3-6 cycloalkyl, and 4- to 7-membered heterocyclyl, wherein the alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one or more substituents selected from the group consisting of D, fluoro, cyano, oxo, hydroxyl, -OCH3, and -NH2. The present invention provides a compound as an SHP2 inhibitor, which is represented by the formula: or a prodrug, stable isotope derivative, pharmaceutically acceptable salt, isomer, and mixtures thereof.

[0007] One embodiment of the present invention relates to a compound represented by general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, and isomer thereof, and mixtures thereof, wherein the compound represented by general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, and isomer thereof, and mixtures thereof, is a compound represented by general formula (II): [ka] [In the formula, Ring A is selected from the group consisting of phenyl and 6-membered heteroaryl, and ring B is selected from the group consisting of 5-membered heteroaryl rings fused to ring A, wherein phenyl and heteroaryl are optionally selected from D, halogen, cyano, oxo, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 6-membered heteroaryl, -OR a , -NR a R b , -C(O)R a , -C(O)NR a R b, -S(O)2R a , -S(O)NR a R b , and -NR a S(O)2R b wherein alkyl, cycloalkyl, heterocyclyl, and heteroaryl are optionally substituted by one or more substituents selected from the group consisting of D, halogen, cyano, oxo, C 1-6 Alkyl, C 3-6 Cycloalkyl, 4- to 7-membered heterocyclyl, -OR a , -NR a R b , -C(O)R a , and -C(O)NR a R b may be substituted by one or more substituents selected from the group consisting of: R 1 H, D, cyano, C 1-2 Alkyl, -OR a , and -NR a R b wherein one or more hydrogen atoms of the alkyl may optionally be replaced by one or more substituents selected from the group consisting of D and fluoro; R 2 is H and C 1-2 alkyl, wherein one or more hydrogen atoms of the alkyl may optionally be replaced by one or more substituents selected from the group consisting of D and fluoro; R 4a and R 4b are each independently H, D, halogen, cyano, or -OR a , -NR a R b , -C(O)NR a R b , C 1-6 Alkyl, C 3-6 is selected from the group consisting of cycloalkyl, 4- to 7-membered heterocyclyl, and 5- to 6-membered heteroaryl, with the proviso that R 4a and R 4bis simultaneously cyano, -OR a , and -NR a R b and is not selected from the group consisting of, wherein alkyl, cycloalkyl, heterocyclyl, and heteroaryl are optionally D, halogen, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 6-membered heteroaryl, -OR a , -NR a R b , -C(O)R a , and -C(O)NR a R b and may be substituted by one or more substituents selected from the group consisting of; R 4a and R 4b may optionally together with the carbon atom to which they are attached form a C 3-7 carbocyclic ring or a 4- to 7-membered heterocyclic ring; R a and R b are each independently selected from the group consisting of H, C 1-6 alkyl, C 3-6 cycloalkyl, and 4- to 7-membered heterocyclyl, wherein alkyl, cycloalkyl, and heterocyclyl are optionally substituted by one or more substituents selected from the group consisting of D, fluoro, cyano, oxo, hydroxyl, -OCH3, and -NH2] represents a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, and isomer thereof, and mixtures thereof.

[0008] Another embodiment of the present invention relates to a compound of general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, and isomer thereof, and mixtures thereof, wherein the compound of general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, and isomer thereof, and mixtures thereof is of general formula (III):

Chemical formula

[0009] Another embodiment of the present invention relates to a compound represented by the general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, and isomer thereof, and mixtures thereof, wherein the compound represented by the general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, and isomer thereof, and mixtures thereof is represented by the general formula (IV): [Chemical formula] [wherein, ring A is selected from the group consisting of phenyl and 6-membered heteroaryl, ring B is selected from the group consisting of 5-membered heteroaryl rings fused to ring A, wherein phenyl and heteroaryl may optionally be substituted by one or more substituents selected from the group consisting of D, halogen, cyano, oxo, C 1-2 alkyl, -OR a , and -NR a R b and may be substituted by one or more substituents selected from the group consisting of D and fluoro, where one or more hydrogen atoms of the alkyl may optionally be substituted by one or more substituents selected from the group consisting of D and fluoro; X is selected from the group consisting of -O- and -CH2-; R 1 is independently selected from the group consisting of H, D, C 1-2 alkyl, and -NR a R b and may be substituted by one or more substituents selected from the group consisting of D and fluoro, where one or more hydrogen atoms of the alkyl may optionally be substituted by one or more substituents selected from the group consisting of D and fluoro; R 2 is selected from the group consisting of H and C 1-2 alkyl, and one or more hydrogen atoms of the alkyl may optionally be substituted by one or more substituents selected from the group consisting of D and fluoro; R 7 is selected from the group consisting of H, D, and C 1-2 alkyl, and one or more hydrogen atoms of the alkyl may optionally be substituted by one or more substituents selected from the group consisting of D and fluoro; R a and R b are each independently selected from the group consisting of H and C 1-2Selected from the group consisting of alkyl, wherein one or more hydrogen atoms of the alkyl may optionally be substituted by one or more substituents selected from the group consisting of D and fluoro represents a compound represented by or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, and isomer thereof, and a mixture thereof.

[0010] The present invention further relates to a compound represented by the general formula (I) as described above,

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

[0011] The compounds of the present invention can effectively inhibit the activity of SHP2, preferably with an IC 50 of less than 50 nM. The compounds of the present invention have a significant inhibitory effect on the growth of NCI-H358 cells, preferably with an IC 50 of less than 1,000 nM.

[0012] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound represented by the general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, and isomer thereof, and a mixture thereof, as well as a pharmaceutically acceptable carrier and excipient.

[0013] The present invention further relates to a pharmaceutical composition comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt, prodrug, stable isotope derivative, and isomers thereof, and mixtures thereof, and at least one additional drug, wherein the at least one additional drug includes, but is not limited to, chemotherapeutic drugs, target drugs, DNA synthesis inhibitors, antibody drugs, antibody-drug conjugates, anti-tumor drugs, and immunosuppressive drugs.

[0014] The present invention further provides the use of a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, its prodrug, stable isotope derivative, and isomers thereof, and mixtures thereof, or a pharmaceutical composition, in the preparation of a medicament for treating or preventing SHP2-mediated diseases (including but not limited to leukemia, Noonan syndrome, Leopard syndrome, neuroblastoma, lung cancer, breast cancer, colon cancer, esophageal cancer, gastric cancer, and head and neck cancer).

[0015] According to the present invention, the medicament can be in dosage forms including but not limited to tablets, capsules, solutions, lyophilized preparations, and injections.

[0016] The pharmaceutical preparation of the present invention can be administered in the form of dosage units containing a predetermined dose of the pharmaceutically active ingredient. This unit can contain the compound of the present invention in an amount of 0.5 mg to 1 g, preferably 1 mg to 700 mg, preferably 5 mg to 500 mg, depending on the disease to be treated, the administration method, and the age, weight, and condition of the patient. Furthermore, the pharmaceutical preparation can be prepared by methods known in the pharmaceutical art, for example, by mixing the pharmaceutically active ingredient with one or more excipients and / or adjuvants.

[0017] The pharmaceutical preparation of the present invention is suitable for administration by any appropriate approach including oral (oral or sublingual), rectal, nasal, topical (oral, sublingual, or transdermal), vaginal, or parenteral (subcutaneous, intramuscular, intravenous, or intradermal) approaches.

[0018] (Detailed Description of the Invention) The following terms in this specification and the claims have the following meanings unless otherwise specified.

[0019] "C x-y " means a range of the number of carbon atoms, where both x and y are integers. For example, C 3-8 Cycloalkyl means cycloalkyl having 3 to 8 carbon atoms, that is, cycloalkyl having 3, 4, 5, 6, 7, or 8 carbon atoms. "C 3-8 " includes, for example, C 3-7 C 3-6 C 4-7 C 4-6 and further includes any sub-range of C 5-6 ".

[0020] "Alkyl" means a saturated straight-chain or branched-chain hydrocarbyl group having 1 to 20 carbon atoms, for example, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Non-limiting examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-amyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, and 2-ethylbutyl, but are not limited thereto.

[0021] "Cycloalkyl or carbocycle" refers to a saturated cyclic hydrocarbyl substituent having 3 to 14 carbon ring atoms. Cycloalkyls can be monocyclic carbocycles, typically containing 3 to 8, 3 to 7, or 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyls can also be fused bicyclic or tricyclic carbocyclic rings, such as decahydronaphthyl, bicyclo[2.2.2]octane, and spiro[3.3]heptane.

[0022] "Heterocyclyl or heterocyclic ring" refers to a heterocyclic ring having 3 to 20 ring atoms, e.g., 3 to 14, 3 to 12, 3 to 10, 3 to 8, 3 to 6, or 5 to 6 ring atoms (nitrogen, oxygen, or S(O) excluding -OO-, -OS-, and -SS- in the ring structure). m(where m is an integer from 0 to 2), and the remainder are carbon atoms. Preferably, there are 3 to 12, more preferably 3 to 10, even more preferably 4 to 7, even more preferably 4 to 6, and most preferably 5 or 6 ring atoms (wherein 1 to 4, more preferably 1 to 3, and most preferably 1 to 2 heteroatoms). Non-limiting examples of monoheterocyclic groups include, but are not limited to, pyrrolidinyl, oxetanyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and azetidinyl. Polyheterocyclic groups include fused, bridged, or spiropolyheterocycles, such as octahydrocyclopentadieno[c]pyrrole, octahydropyrrolo[1,2-a]pyrazine, 3,8-diazabicyclo[3.2.1]octane, 5-azaspiro[2.4]heptane, and 2-oxa-7-azaspiro[3.5]nonane.

[0023] "Aryl or aryl ring" means a monocyclic or fused polycyclic aromatic group having 6 to 14 carbon atoms, preferably 6 to 10 members, such as phenyl and naphthyl, most preferably phenyl. The aromatic ring may be fused to a heteroaryl ring, heterocyclic ring, or cycloalkyl ring, where the ring attached to the parent structure is an aryl ring. Non-limiting examples include: [ka] These include, but are not limited to:

[0024] "Heteroaryl or heteroaryl ring" means a heteroaromatic system having 5 to 14 ring atoms (1 to 4 of which are selected from heteroatoms of oxygen, sulfur, and nitrogen). Heteroaryl preferably has 5 to 10 members, more preferably 5 to 6 members, for example, furyl, thienyl, pyridyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, and isoindolyl. The heteroaryl ring may be fused to an aryl ring, a heterocyclic ring or a cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring. Non-limiting examples include [Chemical formula] but are not limited thereto.

[0025] "Halogen" means F, Cl, Br, or I.

[0026] "Cyano" means -CN.

[0027] "Oxo" means =O.

[0028] "Optionally" means that the events or circumstances described below may occur but do not have to occur, and includes the cases where the events or circumstances occur or do not occur. For example, "a heterocyclic group optionally substituted by alkyl" means that alkyl may or may not be present, and this description includes the cases where the heterocyclic group is substituted by alkyl and the cases where the heterocyclic group is not substituted by alkyl.

[0029] "Substitution" means that one or more, preferably 5, more preferably 1 to 3 hydrogen atoms in the base are independently substituted by the corresponding number of substituents. Naturally, the substituents are arranged only at possible chemical positions, and those skilled in the art can determine possible or impossible substitutions without much effort (theoretical or experimental). For example, an amino or hydroxyl group with free hydrogen may become unstable when bonded to a carbon atom having an unsaturated bond (e.g., olefinic). Substituents include, but are not limited to, halogen, cyano, nitro, oxo, -SF5, C 1-4 alkyl, C 3-7 cycloalkyl, 4- to 7-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl are included.

[0030] "Isomer" means a compound having the same molecular formula but different bonding characteristics or orders, or a compound having a different spatial arrangement of its atoms. Isomers having different spatial arrangements of atoms are called "stereoisomers". Stereoisomers include optical isomers, geometric isomers, and conformational isomers.

[0031] The compounds of the present invention can exist in the form of optical isomers. Optical isomers include enantiomers and diastereomers. Enantiomers are two stereoisomers that are mirror images of each other but cannot be superimposed. A racemic mixture or racemate is one in which the left- and right-handed enantiomers of a chiral molecule are present in equal amounts. Diastereomers are stereoisomers that are not mirror images of each other and cannot be superimposed on the other. When a compound is a single isomer and its absolute configuration is determined, it is called an "R" or "S" isomer according to the arrangement of the substituents on the chiral carbon atom; when its absolute configuration is not determined, it is called a (+) or (-) isomer according to the measured optical rotation value. Methods for preparing and separating optical isomers are known in the art.

[0032] The compounds of the present invention may further exist in the form of geometric isomers resulting from the distribution of substituents around a carbon-carbon double bond, a carbon-nitrogen double bond, a cycloalkyl group, or a heterocyclic group. Substituents around a carbon-carbon double bond or a carbon-nitrogen double bond may be designated as Z- or E-configuration, and substituents around a cycloalkyl or heterocyclic ring may be designated as cis- or trans-configuration.

[0033] The compounds of the present invention may further exhibit tautomerism, eg, keto-enol tautomerism.

[0034] It should be understood that the present invention includes any tautomeric or stereoisomeric forms and mixtures thereof and is not limited solely to any tautomeric or stereoisomeric form used in the compound naming or chemical structure.

[0035] "Isotopes" include all isotopes of atoms present in the compounds of the present invention. Isotopes include atoms with the same atomic number but different masses. Examples of isotopes suitable for inclusion in the compounds of the present invention may be hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, 2 H(D), 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, and 36Although Cl is present, it is not limited thereto. The isotope-labeled compounds in the present invention can generally be prepared by the prior art known to those skilled in the art or by a method similar to the method described in the embodiments using appropriate isotope-labeled reagents instead of non-isotope-labeled reagents. Such compounds have various potential uses, for example, as standards and reagents for determining biological activity. In the case of stable isotopes, such compounds have the potential to beneficially alter biological, pharmacological, or pharmacokinetic properties. In the present invention, deuterium (D) can be mentioned as a preferred isotope. For example, the hydrogen of methyl, methylene, or methine may be substituted with deuterium.

[0036] The compounds of the present invention can be administered in the form of prodrugs. A "prodrug" means a derivative that can be converted into a biologically active compound under in vivo physiological conditions such as oxidation, reduction, and hydrolysis (which can occur in the absence or presence of enzymes). Examples of prodrugs in the present invention include compounds in which amino is acylated, alkylated, or phosphorylated, such as eicosanoylamino, alanyl amino, and pivaloyloxymethyl amino; or compounds in which hydroxyl is acylated, alkylated, phosphorylated, or converted to a boronate, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, and alanyloxy; compounds in which carboxyl is esterified or amidated; compounds in which thiol forms a disulfide bridge with a carrier molecule (such as a peptide) to selectively deliver the drug to the cell target and / or cytosol, and the like. Prodrugs can be prepared from the compounds of the present invention by known methods.

[0037] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salts" means salts prepared from pharmaceutically acceptable bases or acids including inorganic bases or inorganic acids and organic bases or organic acids. The present invention further includes pharmaceutically acceptable salts of the compounds of the present invention containing one or more acidic or basic groups. Thus, the compounds of the present invention having acidic groups can exist in the form of salts and function and are used, according to the present invention, for example, as alkali metal salts, alkaline earth metal salts, or ammonium salts. More specific examples of these salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts formed with ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or amino acids. The compounds of the present invention having basic groups can exist in the form of salts and are used as salts made with inorganic or organic acids according to the present invention. Examples of suitable acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, trimethylacetic acid, propanedioic 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. On the condition that the compounds of the present invention contain both acidic and basic groups in the molecule, the present invention further includes inner salts or betaine salts in addition to the salt forms mentioned. Each salt can be obtained by conventional methods known to those skilled in the art, for example, by mixing the compound with an organic or inorganic acid or base in a solvent or dispersant, or by anion or cation exchange with another salt.

[0038] "Pharmaceutical composition" refers to a composition containing one or more compounds described herein, or pharmaceutically acceptable salts, prodrugs, stable isotope derivatives, and isomers thereof, and mixtures thereof, as well as other components, such as pharmaceutically acceptable carriers and excipients. Pharmaceutical compositions are intended for ease of administration to the body and for better absorption of the pharmaceutical components effective to exert biological activity.

[0039] Thus, when reference is made herein to "compound(s)," "compound(s) of the invention," or "compound(s) described in the present invention," it is intended to include all compound forms, such as pharmaceutically acceptable salts, prodrugs, stable isotopic derivatives and isomers, and mixtures thereof.

[0040] As used herein, "therapeutically effective dose" means the dose of a compound of the present invention that can effectively inhibit the function of SHP2 and / or treat or prevent a disease.

[0041] As used herein, the term "patient" means a mammal, particularly a human.

[0042] Synthesis method The present invention further provides methods for preparing the above-mentioned compounds. The compounds of the present invention represented by general formula (I) can be prepared by the following exemplary methods and examples, but these methods and examples should not be construed as limiting the scope of the present invention in any way. The compounds of the present invention can also be synthesized by synthetic techniques known to those skilled in the art or by combining methods known in the art with the methods of the present invention. The products obtained from each step of the reaction can be obtained by separation techniques known in the art, including, but not limited to, extraction, filtration, distillation, crystallization, and chromatographic separation. The starting materials and chemical reagents used in the synthesis can be synthesized according to the literature (which can be queried through SciFinder) or purchased.

[0043] The heterocyclic compounds of the present invention represented by general formula (I) can be synthesized according to the route shown in Method A: 1) A1 is subjected to a base-catalyzed substitution reaction or a condensation reaction in the presence of a condensing agent between NH from a piperidine compound A2 to give intermediate A3; 2) A3 is subjected to a Buchwald-Hartwig Ross coupling reaction with a sulfhydryl from a 5,6-fused heteroaryl to give product A4.

[0044] Method A: [ka]

[0045] The heterocyclic compound of the present invention represented by general formula (I) can also be synthesized according to the route shown in Method B: 1) A1 and A2a are subjected to a base-catalyzed substitution reaction or a condensation reaction in the presence of a condensing agent to give intermediate A3a; 2) A3a keto is subjected to a reductive amination reaction with (R)-2-methylpropane-2-sulfinamide to give A5a; 3) A5a is subjected to a Buchwald-Hartwig cross-coupling reaction with a sulfhydryl from a 5,6-fused heteroaryl to give A6a; 4) A6a is deprotected under acidic conditions to give product A4a.

[0046] Method B [ka] [Example]

[0047] The starting materials of the present invention were synthesized by methods known in the art or purchased from chemical companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc. and Beijing Ouhe Technology Co., Ltd.

[0048] The structure of the compound was measured by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The measurement by NMR was performed using a Bruker Ascend 400 MHz NMR spectrometer, with solvents such as deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), or deuterated methanol (CD3OD), an internal standard of tetramethylsilane (TMS), and chemical shifts in units of 10 -6 (ppm). For MS measurement, an Agilent SQD (ESI) mass spectrometer (Agilent 6120) was used.

[0049] For high-performance liquid chromatography (HPLC), an Agilent 1260 DAD high-performance liquid chromatograph (Poroshell120 EC-C18, 50×3.0 mm, 2.7 μm column) or a Waters Arc high-performance liquid chromatograph (Sunfire C18, 150×4.6 mm, 5 μm column) was used.

[0050] In an embodiment, unless otherwise specified, the reaction was carried out at room temperature (20 - 30 °C).

[0051] In an embodiment, unless otherwise specified, the reaction was carried out under an argon or nitrogen atmosphere. An argon or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.

[0052] A hydrogen atmosphere means evacuating the reaction bottle, filling it with hydrogen (repeating this 3 times), and then connecting it to a hydrogen balloon with a volume of about 1 L.

[0053] For microwave reactions, a CEM Discover-SP type microwave reactor was used.

[0054] The reaction process of the examples was monitored using an Agilent LC / MS system (1260 / 6120) or thin-layer chromatography (TLC) with a silica gel plate thickness of 0.15 - 0.2 mm (GF254, Qingdao Haiyang Chemical Co., Ltd.).

[0055] The purification of the compounds was carried out by column chromatography or TLC. For column chromatography, silica gel of 200 - 300 mesh (Qingdao Haiyang Chemical Co., Ltd.) was used, and for TLC, a silica gel GF254 plate with a thickness of 0.4 - 0.5 mm (GF254, Qingdao Haiyang Chemical Co., Ltd.) was used.

[0056] The eluent systems for column chromatography or TLC were usually a) dichloromethane - methanol system, b) petroleum ether - ethyl acetate system, or those shown in the examples. The volume ratio of the solvents was adjusted according to the difference in the polarity of the compounds and further adjusted by adding a small amount of triethylamine or other acidic or basic reagents.

[0057] Alternatively, the compounds were purified by a Waters MS - guided automatic preparation system (mass spectrometer detector: SQD2) that gradient - eluted a reverse - phase column (XBridge - C18, 19×150 mm, 5 μm) at a flow rate of 20 mL / min using an appropriate acetonitrile / water (containing 0.1% trifluoroacetic acid or formic acid, or 0.05% aqueous ammonia) according to the polarity of the compound. In some examples, 1N dilute hydrochloric acid was added after purification by the automatic preparation system, and then the solvent was removed under reduced pressure to obtain the hydrochloride salt.

[0058] The abbreviation DMF means N,N - dimethylformamide.

[0059] The abbreviation DIPEA means N,N - diisopropylethylamine.

[0060] The abbreviation DBU means 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0061] The abbreviation NBS means N-bromosuccinimide.

[0062] The abbreviation NIS means N-iodosuccinimide.

[0063] The abbreviation XantPhos means 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.

[0064] The abbreviation Pd2(dba)3 means tris(dibenzylideneacetone)dipalladium.

[0065] Castros reagent means benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate.

[0066] Example 1 (R)-5-((1H-pyrrolo[2,3-b]pyridin-4-yl)thio)-2-(1-amino-8-azaspiro[4.5]decan-8-yl)-3-methylpyrimidin-4(3H)-one hydrochloride [ka] [ka]

[0067] Process 1 2-Chloro-5-iodopyrimidin-4(3H)-one (1b) 2,4-Dichloro-5-iodopyrimidine 1a (8.0 g, 29.1 mmol) was dissolved in tetrahydrofuran (THF) (100 mL) and sodium hydroxide solution (1 N, 45 mL) was added at 0 °C; the reaction mixture was warmed to room temperature and stirred for 16 h. The pH was adjusted to acidic with citric acid, and the reaction mixture was extracted with ethyl acetate (60 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and desolvated under reduced pressure to give the desired product 1b (6.7 g, solid) in 91% yield. MS m / z (ESI): 257 [M+1]

[0068] Process 2 2-Chloro-5-iodo-3-methylpyrimidin-4(3H)-one (1c) 1b (5.6 g, 21.7 mmol) was dissolved in THF (100 mL), iodomethane (3.7 g, 26 mmol) and DIPEA (8.4 g, 65.1 mmol) were added, and the mixture was heated to 60 °C and stirred for 16 h. The resulting mixture was poured into water (120 mL) and extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 3 / 7) to give the desired product 1c (2.2 g, solid) in 37% yield. MS m / z (ESI): 271 [M+1]

[0069] Process 3 8-(5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-8-azaspiro[4.5]decan-1-one (1d) To a solution of 1c (1.0 g, 3.65 mmol) in acetonitrile (25 mL), 8-azaspiro[4.5]decan-1-one (hydrochloride, 586 mg, 3.1 mmol) and potassium carbonate (1.51 g, 11 mmol) were added, and the reaction mixture was heated to 80 °C and stirred for 16 h. After cooling to room temperature, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 7 / 3) to give the desired product 1d (1.2 g, solid) in 85% yield. MS m / z (ESI): 388 [M+1]

[0070] Process 4 (R)-N-((R)-8-(5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (1e) To a solution of 1d (1.2 g, 3.1 mmol) in THF (30 mL) were added (R)-2-methylpropane-2-sulfinamide (750 mg, 6.2 mmol) and tetraethyl titanate (2.82 g, 12.4 mmol), and the reaction mixture was heated to 90 °C and stirred for 16 h. After cooling to 0 °C, methanol (10 mL) and lithium borohydride in THF (2.0 M, 1.5 mL, 3 mmol) were added and stirred for 1 h. The reaction was quenched with ammonium chloride solution, and the resulting mixture was filtered. The filtrate was extracted with ethyl acetate (25 mL × 3); the combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 2 / 1) to give the desired product 1e (1.4 g, solid) in 93% yield. MS m / z (ESI): 493 [M+1]

[0071] Process 5 Ethyl 3-((1H-pyrrolo[2,3-b]pyridin-4-yl)thio)propionate (1g) To a solution of 4-bromo-1H-pyrrolo[2,3-b]pyridine 1f (300 mg, 1.52 mmol) in dioxane (20 mL) was added ethyl 3-mercaptopropanoate (408 mg, 3.04 mmol), DIPEA (588 mg, 4.56 mmol), Pd2(dba)3 (140 mg, 0.152 mmol), and XantPhos (132 mg, 0.228 mmol). The reaction mixture was heated to 100 °C under a nitrogen atmosphere and reacted for 2 h. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 7 / 3) to give the desired product 1g (200 mg, oil) in 53% yield. MS m / z (ESI): 251 [M+1]

[0072] Process 6 Sodium 1H-pyrrolo[2,3-b]pyridine-4-thiolate(1h) To a solution of 1g (200 mg, 0.8 mmol) in methanol (20 mL) was added sodium methoxide (30%, 158 mg, 0.88 mmol) in methanol, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to give the desired product 1h (100 mg, solid) in 73% yield. This product was used directly in the next step without purification. MS m / z (ESI): 151 [M+1]

[0073] Process 7 (R)-N-((R)-8-(5-((1H-pyrrolo[2,3-b]pyridin-4-yl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (1i) 1h (55 mg, 0.32 mmol) was dissolved in dioxane (6 mL) and 1e (82 mg, 0.16 mmol), DIPEA (128 mg, 0.99 mmol), Pd(dba) (30 mg, 0.033 mmol), and XantPhos (29 mg, 0.049 mmol) were added. The reaction mixture was heated to 80 °C under nitrogen protection and reacted for 2 h. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 9) to give the desired product 1i (30 mg, solid) in 37% yield. MS m / z (ESI): 515 [M+1]

[0074] Process 8 (R)-5-((1H-pyrrolo[2,3-b]pyridin-4-yl)thio)-2-(1-amino-8-azaspiro[4.5]decan-8-yl)-3-methylpyrimidin-4(3H)-one hydrochloride (1) 1i (30 mg, 0.058 mmol) was dissolved in methanol (5 mL), HCl in dioxane (4.0 M, 5 mL) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative reverse-phase high-performance liquid chromatography (preparative RP-HPLC) to give the desired product 1 (7.1 mg, solid) in 31% yield. MS m / z (ESI): 411 [M+1] 1 H NMR (400 MHz, DMSO-d6) δ 12.68 (s, 1H), 8.24 - 8.14 (m, 5H), 7.68 (s, 1H), 6.91 - 6.87 (m, 1H), 6.74 (s, 1H), 3.75 - 3.64 (m, 2H), 3.43 (s, 3H), 3.19 - 3.08 (m, 3H), 2.08 - 2.05 (m, 1H), 1.92 - 1.64 (m, 7H), 1.54 - 1.51 (m, 1H), 1.44 - 1.41 (m, 1H).

[0075] Example 2 (R)-2-(1-Amino-8-azaspiro[4.5]decan-8-yl)-3-methyl-5-((1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thio)pyrimidin-4(3H)-one formate

Chem.

[0076] Step 1 Ethyl 3-((1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thio)propionate (2b) To a mixture of 4-bromo-1-methyl-1H-pyrrolo[2,3-b]pyridine 2a (200 mg, 0.95 mmol), ethyl 3-mercaptopropanoate (255 mg, 1.9 mmol), DIPEA (368 mg, 2.85 mmol), XantPhos (55 mg, 0.095 mmol), and dioxane (10 mL) was added Pd2(dba)3 (87 mg, 0.095 mmol). The reaction mixture was heated to 100 °C under nitrogen protection and reacted for 2 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, the filtrate was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 3 / 7) to obtain the target product 2b (240 mg, solid) in a yield of 96%. MS m / z (ESI): 265 [M+1]

[0077] Step 2 1-Methyl-1H-pyrrolo[2,3-b]pyridine-4-thiol (2c) To a solution of 2b (240 mg, 0.91 mmol) in THF (5 mL) was added potassium tert-butoxide (204 mg, 1.82 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified to pH = 4 with hydrochloric acid (6N) and extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was desolvated under reduced pressure to obtain the target product 2c (130 mg, solid) in a yield of 87%. MS m / z (ESI): 165 [M+1]

[0078] Process 3 (R)-2-Methyl-N-((R)-8-(1-methyl-5-((1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thio)-6-oxo-1,6-dihydropyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (2d) To a mixture of 2c (50 mg, 0.24 mmol), 1e (110 mg, 0.22 mmol), DIPEA (85 mg, 0.66 mmol), XantPhos (13 mg, 0.022 mmol), and dioxane (5 mL) was added Pd2(dba)3 (20 mg, 0.022 mmol). The reaction mixture was heated to 100 °C under nitrogen protection and reacted for 2 h. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 9) to give the desired product 2d (80 mg, solid) in 68% yield. MS m / z (ESI): 529 [M+1]

[0079] Process 4 (R)-2-(1-amino-8-azaspiro[4.5]decan-8-yl)-3-methyl-5-((1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thio)pyrimidin-4(3H)-one formate (2) 2d (80 mg, 0.14 mmol) was dissolved in methanol (8 mL), and a solution of HCl in dioxane (4.0 M, 2 mL) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to give the desired product 2 (21.7 mg, solid) in 34% yield. MS m / z (ESI): 425 [M+1] 1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.14 (s, 1H), 8.03 (d, J = 5.1 Hz, 1H), 7.51 (d, J = 3.5 Hz, 1H), 6.58 (d, J = 5.1 Hz, 1H), 6.44 (d, J = 3.5 Hz, 1H), 3.80 (s, 3H), 3.66 - 3.58 (m, 2H), 3.41 (s, 3H), 3.07 (t, J = 11.5 Hz, 2H), 2.99 - 2.96 (m, 1H), 2.0 - 1.92 (m, 1H), 1.80 - 1.68 (m, 4H), 1.60 - 1.53 (m, 3H), 1.40 (d, J = 12.9 Hz, 1H), 1.33 (d, J = 13.1 Hz, 1H).

[0080] Example 3 (R)-5-((1H-indazol-4-yl)thio)-2-(1-amino-8-azaspiro[4.5]decan-8-yl)-3-methylpyrimidin-4(3H)-one hydrochloride [ka]

[0081] Process 1 Ethyl 3-((1H-indazol-4-yl)thio)propionate (3b) To a solution of 4-bromo-1H-indazole 3a (500 mg, 2.53 mmol) in dioxane (20 mL) was added ethyl 3-mercaptopropanoate (680 mg, 5.06 mmol), DIPEA (979 mg, 7.59 mmol), Pd(dba) (231 mg, 0.253 mmol), and XantPhos (219 mg, 0.397 mmol). The reaction mixture was heated to 100 °C under a nitrogen atmosphere and reacted for 2 h. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 2.6 / 1) to give the desired product 3b (560 mg, solid) in 89% yield. MS m / z (ESI): 251 [M+1]

[0082] Process 2 Sodium 1H-indazole-4-thiolate (3c) To a solution of 3b (560 mg, 2.24 mmol) in methanol (20 mL) was added sodium methoxide in methanol (30%, 443.5 mg, 2.46 mmol), and the mixture was stirred at 30° C. for 1 h. The reaction mixture was desolvated under reduced pressure to give the desired product 3c (200 mg, solid) in 51% yield. This product was used directly in the next step without further purification. MS m / z (ESI): 151 [M+1]

[0083] Process 3 (R)-N-((R)-8-(5-((1H-indazol-4-yl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (3d) To a solution of 3c (70 mg, 0.41 mmol) in dioxane (6 mL), 1e (50 mg, 0.10 mmol), DIPEA (37.2 mg, 0.30 mmol), Pd(dba) (9.1 mg, 0.01 mmol), and XantPhos (8.7 mg, 0.015 mmol) were added. The reaction mixture was heated to 80 °C under nitrogen protection and reacted for 4 h. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 9) to give the desired product 3d (50 mg, solid) in 96% yield. MS m / z (ESI): 515 [M+1]

[0084] Process 4 (R)-5-((1H-indazol-4-yl)thio)-2-(1-amino-8-azaspiro[4.5]decan-8-yl)-3-methylpyrimidin-4(3H)-one hydrochloride (3) 3d (50 mg, 0.097 mmol) was dissolved in methanol (5 mL), and a solution of HCl in dioxane (4.0 M, 5 mL) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to give the desired product 3 (16 mg, solid) in 41% yield. MS m / z (ESI): 411 [M+1] 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (brs, 3H), 8.06 (s, 1H), 7.97 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 8.3, 7.2 Hz, 1H), 6.83 (d, J = 6.8 Hz, 1H), 3.60 (d, J = 13.5 Hz, 1H), 3.52 (d, J = 13.3 Hz, 1H), 3.40 (s, 3H), 3.17 - 3.12 (m, 1H), 3.05 - 2.98 (m, 2H), 2.07 - 2.04 (m, 1H), 1.77 - 1.62 (m, 7H), 1.49 (d, J = 12.8 Hz, 1H), 1.39 (d, J = 13.1 Hz, 1H).

[0085] Example 4 (R)-2-(1-amino-8-azaspiro[4.5]decan-8-yl)-3-methyl-5-(pyrazolo[1,5-a]pyridin-4-ylthio)pyrimidin-4(3H)-one formate [ka]

[0086] Process 1 Ethyl 4-bromopyrazolo[1,5-a]pyridine-3-carboxylate (4b) To a solution of 3-bromopyridine 4a (5.0 g, 32.0 mmol) in acetonitrile (25 mL) was added O-(2,4-dinitrophenyl)hydroxylamine (6.37 g, 32.0 mmol), and the mixture was heated to 40° C. and stirred for 16 h. The reaction mixture was desolvated under reduced pressure, and the residue was slurried in ether and dried to give a yellow solid (3.8 g).

[0087] The above product (2.0 g, 5.6 mmol) was dissolved in DMF (20 mL), potassium carbonate (12.1 g, 88.1 mmol) and ethyl propiolate (7.1 g, 52.8 mmol) were added, and the reaction mixture was stirred at room temperature for 20 h. The resulting mixture was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 3 / 7) to give the desired product 4b (350 mg, solid) in 8% yield. MS m / z (ESI): 269 [M+1]

[0088] Process 2 4-Bromopyrazolo[1,5-a]pyridine (4c) 4b (350 mg, 1.30 mmol) was dissolved in hydrobromic acid solution (12 mL), heated to 100 °C, and stirred for 6 h. The reaction mixture was cooled to room temperature, neutralized with sodium hydroxide solution (2 N), and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to give the desired product 4c (200 mg, solid) in 79% yield. MS m / z (ESI): 197 [M+1]

[0089] Process 3 Ethyl 3-(pyrazolo[1,5-a]pyridin-4-ylthio)propionate (4d) To a solution of 4c (200 mg, 1.02 mmol) in dioxane (20 mL) were added ethyl 3-mercaptopropanoate (680 mg, 5.06 mmol), DIPEA (394 mg, 3.06 mmol), Pd2(dba)3 (93.3 mg, 0.102 mmol), and XantPhos (88.4 mg, 0.153 mmol). The reaction mixture was heated to 100 °C under a nitrogen atmosphere and reacted for 2 hours. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 3 / 7) to obtain the desired product 4d (240 mg, solid) in 94% yield. MS m / z (ESI): 251 [M+1]

[0090] Step 4 Sodium pyrazolo[1,5-a]pyridine-4-thiolate (4e) To a solution of 4d (230 mg, 0.92 mmol) in methanol (20 mL) was added sodium methoxide (30% in methanol, 182 mg, 1.01 mmol), and the reaction mixture was stirred at 30 °C for 4 hours. The reaction mixture was desolvated under reduced pressure to obtain the desired product 4e (150 mg, solid) in 95% yield. This product was used directly in the next step without purification. MS m / z (ESI): 151 [M+1]

[0091] Step 5 (R)-2-Methyl-N-((R)-8-(1-methyl-6-oxo-5-(pyrazolo[1,5-a]pyridin-4-ylthio)-1,6-dihydropyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)propane-2-sulfinamide (4f) To 4e (85.3 mg, 0.495 mmol) in dioxane (6 mL) was added 1e (70 mg, 0.142 mmol), DIPEA (54.9 mg, 0.426 mmol), Pd(dba) (12.9 mg, 0.0142 mmol), and XantPhos (12.3 mg, 0.0213 mmol). The reaction mixture was heated to 80 °C under nitrogen protection and reacted for 4 h. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 13) to give the desired product 4f (40 mg, solid) in 55% yield. MS m / z (ESI): 515 [M+1]

[0092] Process 6 (R)-2-(1-amino-8-azaspiro[4.5]decan-8-yl)-3-methyl-5-(pyrazolo[1,5-a]pyridin-4-ylthio)pyrimidin-4(3H)-one formate (4) 4f (40 mg, 0.078 mmol) was dissolved in methanol (5 mL), and HCl in dioxane (4.0 M, 5 mL) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to give the desired product 4 (16 mg, solid) in 51% yield. MS m / z (ESI): 411 [M+1] 1H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 6.9 Hz, 1H), 8.39 (s, 1H), 8.09 (s, 1H), 8.03 (d, J = 2.2 Hz, 1H), 6.89 (d, J = 7.0 Hz, 1H), 6.80 (t, J = 7.0 Hz, 1H), 6.63 (d, J = 1.7 Hz, 1H), 3.64 - 3.53 (m, 2H), 3.39 (s, 3H), 3.05 - 2.97 (m, 3H), 1.98 - 1.95 (m, 1H), 1.80 - 1.67 (m, 4H), 1.64 - 1.53 (m, 3H), 1.40 (d, J = 13.0 Hz, 1H), 1.32 (d, J = 13.3 Hz, 1H).

[0093] Example 5 (R)-2-(1-amino-8-azaspiro[4.5]decan-8-yl)-3-methyl-5-(pyrazolo[1,5-a]pyridin-5-ylthio)pyrimidin-4(3H)-one hydrochloride [ka]

[0094] Process 1 Ethyl 3-(pyrazolo[1,5-a]pyridin-5-ylthio)propionate (5b) To a solution of 5-bromopyrazolo[1,5-a]pyridine 5a (320 mg, 1.62 mmol) in dioxane (20 mL) was added ethyl 3-mercaptopropanoate (326 mg, 2.43 mmol), DIPEA (627 mg, 4.86 mmol), Pd(dba) (148 mg, 0.162 mmol), and XantPhos (140 mg, 0.243 mmol). The reaction mixture was heated to 100 °C under a nitrogen atmosphere and reacted for 6 h. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 3 / 1) to give the desired product 5b (400 mg, oil) in 97% yield. MS m / z (ESI): 251 [M+1]

[0095] Process 2 Pyrazolo[1,5-a]pyridine-5-thiol (5c) To a solution of 5b (400 mg, 1.6 mmol) in methanol (20 mL) was added sodium methoxide (30%, 317 mg, 1.76 mmol) in methanol, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water (100 mL), the pH was adjusted to weakly acidic with citric acid, and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 2 / 3) to give the desired product 5c (100 mg, oil) in 42% yield. MS m / z (ESI): 151 [M+1]

[0096] Process 3 (R)-2-Methyl-N-((R)-8-(1-methyl-6-oxo-5(pyrazolo[1,5-a]pyridin-5-ylthio)-1,6-dihydropyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl)propane-2-sulfinamide (5d) 5c (30 mg, 0.20 mmol) was dissolved in dioxane (6 mL), and 1e (50 mg, 0.10 mmol), DIPEA (38.7 mg, 0.30 mmol), Pd2(dba)3 (9.0 mg, 0.010 mmol), and XantPhos (8.5 mg, 0.015 mmol) were added. The reaction mixture was heated to 80 °C under nitrogen protection and reacted for 2 h. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 9) to give the desired product 5d (60 mg, solid, crude product). MS m / z (ESI): 515 [M+1]

[0097] Process 4 (R)-2-(1-Amino-8-azaspiro[4.5]decane-8-yl)-3-methyl-5-(pyrazolo[1,5-a]pyridin-5-ylthio)pyrimidin-4(3H)-one hydrochloride (5) 5d (60 mg, crude product) was dissolved in methanol (5 mL), HCl (4.0 M, 5 mL) in dioxane was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to give the title product 5 (14.1 mg, solid) in 34% yield in two steps. MS m / z (ESI): 411 [M+1] 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J = 7.3 Hz, 1H), 8.13 (s, 1H), 8.06 (brs, 3H), 7.95 (s, 1H), 7.94 (d, J = 2.2 Hz, 2H), 7.33 (d, J = 1.4 Hz, 1H), 6.68 (dd, J = 7.3, 2.1 Hz, 1H), 6.44 (dd, J = 2.2, 0.7 Hz, 1H), 3.66 (d, J = 13.4 Hz, 1H), 3.58 (d, J = 13.3 Hz, 1H), 3.41 (s, 3H), 3.21 - 3.14 (m, 1H), 3.10 - 3.02 (m, 2H), 2.07 - 2.03 (m, 1H), 1.87 - 1.58 (m, 7H), 1.50 (d, J = 12.8 Hz, 1H), 1.41 (d, J = 12.9 Hz, 1H).

[0098] Example 6 (R)-5-((1H-Indazol-5-yl)thio)-2-(1-amino-8-azaspiro[4.5]decane-8-yl)-3-methylpyrimidin-4(3H)-one hydrochloride

Chemical Structure

[0099] Step 1 Ethyl 3-((1H-indazol-5-yl)thio)propionate (6b) To a mixture of 5-bromo-1H-indazole 6a (520 mg, 2.65 mmol), ethyl 3-mercaptopropanoate (533 mg, 3.98 mmol), DIPEA (1.02 g, 7.95 mmol), XantPhos (153 mg, 0.265 mmol), and dioxane (10 mL) was added Pd2(dba)3 (243 mg, 0.265 mmol). Then, the reaction mixture was heated to 100 °C under nitrogen protection and reacted for 2 hours. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain the target product 6b (630 mg, solid) in a 95% yield. MS m / z (ESI): 251 [M+1]

[0100] Step 2 1H-Indazole-5-thiol (6c) To a solution of 6b (500 mg, 2.0 mmol) in THF (10 mL) was added potassium tert-butoxide (672 mg, 6.0 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was acidified to pH = 4 with hydrochloric acid (6N) and extracted with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was desolvated under reduced pressure to obtain the target product 6c (300 mg, solid) in a 100% yield. MS m / z (ESI): 151 [M+1]

[0101] Step 3 (R)-N-((R)-8-(5-((1H-Indazol-5-yl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)-2-methylpropane-2-sulfinamide (6d) To a mixture of 6c (60 mg, 0.4 mmol), 1e (100 mg, 0.2 mmol), DIPEA (77 mg, 0.6 mmol), XantPhos (12 mg, 0.02 mmol), and dioxane (5 mL) was added Pd2(dba)3 (18 mg, 0.02 mmol). The reaction mixture was then heated to 100 °C under nitrogen protection and reacted for 2 h. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give the desired product 6d (70 mg, solid) in 67% yield. MS m / z (ESI): 515 [M+1]

[0102] Process 4 (R)-5-((1H-indazol-5-yl)thio)-2-(1-amino-8-azaspiro[4.5]decan-8-yl)-3-methylpyrimidin-4(3H)-one hydrochloride (6) 6d (70 mg, 0.14 mmol) was dissolved in methanol (5 mL), and HCl in dioxane (4.0 M, 5 mL) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to give the desired product 6 (30 mg, solid) in 54% yield. MS m / z (ESI): 411 [M+1] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 3H), 8.05 (s, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.34 (dd, J = 8.7, 1.6 Hz, 1H), 3.56 (d, J = 13.2 Hz, 1H), 3.49 (d, J = 13.5 Hz, 1H), 3.39 (s, 3H), 3.17 - 3.13 (m, 1H), 3.06 - 2.96 (m, 2H), 2.07 - 2.01 (m, 1H), 1.90 - 1.61 (m, 7H), 1.52 (d, J = 13.1 Hz, 1H), 1.39 (d, J = 13.0 Hz, 1H).

[0103] Example 7 (R)-2-(1-amino-8-azaspiro[4.5]decan-8-yl)-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-3-methylpyrimidin-4(3H)-one hydrochloride [ka]

[0104] Process 1 5-Bromo-4-chloro-2H-indazole (7b) To 4-bromo-3-chloro-2-methylaniline 7a (1.0 g, 4.58 mmol) in acetic acid (20 mL) was added an aqueous solution (4 mL) of sodium nitrite (396 mg, 5.73 mmol) under ice-bath cooling, and the mixture was stirred at room temperature for 1 h. Most of the solvent was removed by rotary evaporation, and the residue was suspended in water (30 mL) and filtered. The filter cake was washed with water (25 mL × 3) and air-dried to give the desired product 7b (780 mg, solid) in 74% yield. This product was used directly in the next step without purification. MS m / z (ESI): 231 [M+1]

[0105] Process 2 5-Bromo-4-chloro-2-methyl-2H-indazole (7c) To 7b (760 mg, 3.3 mmol) in ethyl acetate (15 mL) was added trimethyloxonium tetrafluoroborate (733 mg, 4.95 mmol) under ice-bath cooling, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with petroleum ether (30 mL), stirred for 10 minutes, and filtered. The filtrate was added to ethyl acetate (20 mL) and washed with sodium bicarbonate solution (30 mL × 3) and saturated brine (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1.4 / 1) to give the desired product 7c (460 mg, solid) in 57% yield. MS m / z (ESI): 245 [M+1]

[0106] Process 3 Ethyl 3-((4-chloro-2-methyl-2H-indazol-5-yl)thio)propionate (7d) To a solution of 7c (440 mg, 1.8 mmol) in dioxane (20 mL) was added ethyl 3-mercaptopropanoate (483 mg, 3.6 mmol), DIPEA (697 mg, 5.4 mmol), Pd(dba) (165 mg, 0.18 mmol), and XantPhos (156 mg, 0.27 mmol). The reaction mixture was heated to 100 °C under a nitrogen atmosphere and stirred for 16 h. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1.7 / 1) to give the desired product 7d (300 mg, solid) in 59% yield. MS m / z (ESI): 299 [M+1]

[0107] Process 4 Sodium 4-chloro-2-methyl-2H-indazole-5-thiolate (7e) To a solution of 7d (140 mg, 0.47 mmol) in methanol (20 mL) was added sodium methoxide in methanol (30%, 93 mg, 0.52 mmol) and stirred at 30° C. for 32 h. The reaction mixture was desolvated under reduced pressure to give the desired product 7e (100 mg, solid) in 96% yield. This product was used directly in the next step without purification. MS m / z (ESI): 199 [M+1]

[0108] Process 5 (R)-N-((R)-8-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (7f) 7e (80 mg, 0.36 mmol) was dissolved in dioxane (8 mL), and 1e (100 mg, 0.20 mmol), DIPEA (77 mg, 0.60 mmol), Pd2(dba)3 (18 mg, 0.020 mmol), and XantPhos (18 mg, 0.030 mmol) were added. The reaction mixture was heated to 90 °C under nitrogen protection and reacted for 2 h. After cooling to room temperature, the reaction mixture was poured into a mixture of ethyl acetate (15 mL) and petroleum ether (15 mL) and filtered. The filter cake was dried to give the desired product 7f (61 mg, solid) in 54% yield. MS m / z (ESI): 563 [M+1]

[0109] Process 6 (R)-2-(1-amino-8-azaspiro[4.5]decan-8-yl)-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-3-methylpyrimidin-4(3H)-one hydrochloride (7) 7f (61 mg, 0.11 mmol) was dissolved in methanol (5 mL), and HCl in dioxane (4.0 M, 5 mL) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to give the desired product 7 (16 mg, solid) in 31% yield. MS m / z (ESI): 459 [M+1] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.12 (brs, 3H), 7.90 (s, 1H), 7.51 (dd, J = 9.0, 0.7 Hz, 1H), 6.99 (d, J = 9.0 Hz, 1H), 4.17 (s, 3H), 3.60 (d, J = 13.3 Hz, 1H), 3.53 (d, J = 13.3 Hz, 1H), 3.40 (s, 3H), 3.16 - 3.13 (m, 1H), 3.06 - 2.98 (m, 2H), 2.07 - 2.04 (m, 1H), 1.87 - 1.60 (m, 7H), 1.49 (d, J = 13.0 Hz, 1H), 1.39 (d, J = 13.1 Hz, 1H).

[0110] Example 8 (R)-2-(1-Amino-8-azaspiro[4.5]decan-8-yl)-5-((4-chloropyrazolo[1,5-a]pyridin-5-yl)thio)-3-methylpyrimidin-4(3H)-one formate [Chemical formula]

[0111] Step 1 tert-Butyl [[(2,4,6-trimethylphenyl)sulfonyl]oxy]carbamate (8b) 2,4,6-Trimethylbenzenesulfonyl chloride 8a (2.0 g, 9.15 mmol) and tert-butyl hydroxycarbamate (1.22 g, 9.15 mmol) were dissolved in tert-butyl methyl ether (30 mL), cooled to 0 °C, and triethylamine (1.4 mL, 10.1 mmol) was added dropwise. The reaction mixture was heated to room temperature and stirred for 4 hours. The reaction mixture was washed with water, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to obtain the target product 8b (2.5 g, solid) in a yield of 87%. MS m / z (ESI): 338 [M+23], 216 [M+1-100]

[0112] Step 2 O-(Mesitylsulfonyl)hydroxylamine (8c) 8b (2.5 g, 7.93 mmol) was added portionwise to trifluoroacetic acid (20 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 2 hours. Ice water was slowly added, and the mixture was stirred for 15 minutes. After filtration, the filter cake was washed with water until the filtrate became neutral. The filter cake was dried to obtain the target product 8c (1.5 g, solid) in a yield of 88%. MS m / z (ESI): 216 [M+1]

[0113] Step 3 Ethyl 5-bromo-4-chloropyrazolo[1,5-a]pyridine-3-carboxylate (8e) 4-Bromo-3-chloropyridine 8d (1.4 g, 7.28 mmol) was dissolved in acetonitrile (25 mL), 8c (1.6 g, 7.28 mmol) was added, and the reaction mixture was reacted overnight at 40 °C with stirring. After filtration, the filter cake was dried to obtain a yellow solid product (1.7 g).

[0114] The above product (1.6 g, 3.92 mmol) and ethyl propiolate (0.42 g, 4.32 mmol) were dissolved in DMF (15 mL), potassium carbonate (1.1 g, 7.84 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was quenched with water, and the reaction mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 2) to obtain the target product 8e (120 mg, solid) in a yield of 5.8%. MS m / z (ESI): 303, 305 [M+1]

[0115] Step 4 5-Bromo-4-chloropyrazolo[1,5-a]pyridine (8f) 8e (110 mg, 0.36 mmol) was dissolved in hydrobromic acid solution (3 mL), heated to 100 °C, and stirred for 3 hours. The reaction mixture was cooled to room temperature, neutralized with sodium hydroxide solution (2 M), and extracted with dichloromethane (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 3 / 7) to obtain the target product 8f (65 mg, solid) in a yield of 77%. MS m / z (ESI): 231, 233 [M+1]

[0116] Step 5 Ethyl 3-((4-chloropyrazolo[1,5-a]pyridin-5-yl)thio)propionate (8g) To a solution of 8f (60 mg, 0.26 mmol) in dioxane (5 mL), ethyl 3-mercaptopropanoate (38 mg, 0.29 mmol), DIPEA (67 mg, 0.52 mmol), Pd2(dba)3 (24 mg, 0.026 mmol), and XantPhos (30 mg, 0.052 mmol) were added. The reaction mixture was heated to 100 °C under a nitrogen atmosphere and reacted for 3 h. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 28) to give the desired product 8g (60 mg, solid) in 81% yield. MS m / z (ESI): 285 [M+1]

[0117] Process 6 Sodium 4-chloropyrazolo[1,5-a]pyridine-5-thiolate(8h) To a solution of 8g (60 mg, 0.21 mmol) in methanol (3 mL) was added sodium methoxide in methanol (30%, 45.5 mg, 0.25 mmol), and the mixture was stirred at 30° C. for 4 h. The reaction mixture was desolvated under reduced pressure to give the desired product 8h (40 mg, solid) in 92% yield. This product was used directly in the next step without purification. MS m / z (ESI): 185 [M+1]

[0118] Process 7 (R)-N-((R)-8-(5-((4-chloropyrazolo[1,5-a]pyridin-5-yl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (8i) 8h (40 mg, 0.19 mmol) was dissolved in dioxane (5 mL) and 1e (95 mg, 0.19 mmol), DIPEA (49 mg, 0.38 mmol), Pd(dba) (17 mg, 0.02 mmol), and XantPhos (22 mg, 0.04 mmol) were added. The reaction mixture was heated to 100 °C under nitrogen protection and reacted for 4 h. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 28) to give the desired product 8i (32 mg, oil) in 30% yield. MS m / z (ESI): 549 [M+1]

[0119] Process 8 (R)-2-(1-amino-8-azaspiro[4.5]decan-8-yl)-5-((4-chloropyrazolo[1,5-a]pyridin-5-yl)thio)-3-methylpyrimidin-4(3H)-one formate (8) 8i (32 mg, 0.06 mmol) was dissolved in methanol (2 mL), and HCl in dioxane (4.0 M, 1 mL) was added and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to give the desired product 8 (13 mg, solid) in 47% yield. MS m / z (ESI): 445 [M+1] 1 H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 7.3 Hz, 1H), 8.35 (s, 1H), 8.19 (s, 1H), 8.06 (d, J = 2.2 Hz, 1H), 6.60 (d, J = 1.8 Hz, 1H), 6.48 (d, J = 7.3 Hz, 1H), 3.69 - 3.60 (m, 2H), 3.41 (s, 3H), 3.09 (t, J = 11.7 Hz, 2H), 3.02 - 2.99 (m, 1H), 2.00 - 1.91 (m, 1H), 1.76 - 1.50 (m, 7H), 1.42 (d, J = 13.2 Hz, 1H), 1.35 (d, J = 12.9 Hz, 1H).

[0120] Example 9 (R)-5-((2-(1-amino-8-azaspiro[4.5]decan-8-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)thio)-4-chloro-2-methyl-2H-indazole-3-carbonitrile [ka]

[0121] Process 1 5-Bromo-4-chloro-2-methyl-2H-indazole-3-carbaldehyde (9a) 7c (800 mg, 3.28 mmol) was dissolved in THF (20 mL) and cooled to -78 °C. Lithium diisopropylamide (2 M, 2.95 mL, 5.9 mmol) in THF was added and stirred for 90 min. The mixture was then warmed to 0 °C and stirred for 30 min. The reaction mixture was then cooled to -78 °C, DMF (0.76 mL) was added dropwise, stirred for 0.5 h, warmed to room temperature, and stirred for 2 h. The reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 3 / 7) to give the desired product 9a (520 mg, solid) in 60% yield. MS m / z (ESI): 273 [M+1]

[0122] Process 2 5-Bromo-4-chloro-2-methyl-2H-indazole-3-carboxaldoxime (9a) 9a (490 mg, 1.8 mmol) was dissolved in isopropanol (8 mL), methanol (8 mL), and water (8 mL), and hydroxylamine hydrochloride (497 mg, 7.2 mmol) and sodium carbonate (763 mg, 7.2 mmol) were added. The mixture was heated to 50 °C and stirred for 16 h. The resulting mixture was poured into water (60 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 3 / 7) to give the desired product 9b (470 mg, solid) in 92% yield. MS m / z (ESI): 288 [M+1]

[0123] Process 3 5-Bromo-4-chloro-2-methyl-2H-indazole-3-carbonitrile (9c) 9b (470 mg, 1.63 mmol) was dissolved in acetonitrile (30 mL), copper acetate (147 mg, 0.81 mmol) was added, and the mixture was heated to 85 °C and stirred overnight. The reaction mixture was desolvated under reduced pressure, and the residue was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (25 mL × 3), dried over anhydrous sodium sulfate, and desolvated under reduced pressure to give the desired product 9c (390 mg, solid) in 89% yield. MS m / z (ESI): 270 [M+1]

[0124] Process 4 Ethyl 3-((4-chloro-3-cyano-2-methyl-2H-indazol-5-yl)thio)propionate (9d) To a solution of 9c (380 mg, 1.4 mmol) in dioxane (5 mL) were added ethyl 3-mercaptopropanoate (385 mg, 2.8 mmol), DIPEA (542 mg, 4.2 mmol), Pd2(dba)3 (128 mg, 0.14 mmol), and XantPhos (121 mg, 0.21 mmol). The reaction mixture was heated to 100 °C under nitrogen protection and reacted for 16 h. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain the target product 9d (350 mg, solid) in 77% yield. MS m / z (ESI): 324 [M+1]

[0125] Step 5 Sodium 4-chloro-3-cyano-2-methyl-2H-indazole-5-thiolate (9e) To a solution of 9d (195 mg, 0.60 mmol) in methanol (20 mL) was added sodium methoxide (30%, 130 mg, 0.72 mmol) in methanol, and the mixture was stirred at 30 °C for 16 h. The reaction mixture was desolvated under reduced pressure to obtain the target product 9e (220 mg, solid, crude product). This product was used directly in the next step without purification. MS m / z (ESI): 224 [M+1]

[0126] Step 6 (R)-N-((R)-8-(5-((4-chloro-3-cyano-2-methyl-2H-indazol-5-yl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-8-azaspiro[4.5]dec-1-yl)-2-methylpropan-2-sulfinamide (9f) 9e (89.2 mg, 0.36 mmol) was dissolved in dioxane (6 mL) and 1e (120 mg, 0.24 mmol), DIPEA (92.8 mg, 0.72 mmol), Pd(dba) (21.9 mg, 0.024 mmol), and XantPhos (20.8 mg, 0.036 mmol) were added. The reaction mixture was heated to 80 °C under nitrogen protection and reacted for 16 h. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 12) to give the desired product 9f (90 mg, solid) in 63% yield over two steps. MS m / z (ESI): 588 [M+1]

[0127] Process 7 (R)-5-((2-(1-amino-8-azaspiro[4.5]decan-8-yl)-1-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)thio)-4-chloro-2-methyl-2H-indazole-3-carbonitrile formate (9) 9f (90 mg, 0.15 mmol) was dissolved in methanol (10 mL), and HCl in dioxane (4.0 M, 10 mL) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to give the desired product 9 (14 mg, solid) in 19% yield. MS m / z (ESI): 484 [M+1] 1 H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.79 (brs, 3H), 7.75 (d, J = 9.0 Hz, 1H), 7.05 (d, J = 9.1 Hz, 1H), 4.34 (s, 3H), 3.69 (d, J = 14.1 Hz, 1H), 3.61 (d, J = 14 Hz, 1H), 3.41 (s, 3H), 3.24 - 3.16 (m, 1H), 3.13 - 3.06 (m, 2H), 2.08 - 2.04 (m, 1H), 1.80 - 1.64 (m, 7H), 1.49 - 1.41 (m, 2H).

[0128] Example 10 (S)-2-(4-Amino-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-3-methylpyrimidin-4(3H)-one [Chemical formula]

[0129] Step 1 2-((tert-Butyldimethylsilyl)oxy)ethan-1-ol (10b) At 0 °C, tert-butyldimethylsilyl chloride (50 g, 334 mmol) was added dropwise to a mixture of ethylene glycol 10a (124 g, 2 mol), imidazole (34 g, 500 mmol), and dichloromethane (500 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (300 mL) and dichloromethane (600 mL) and separated. The aqueous phase was extracted with dichloromethane (300 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to obtain the target product 10b (35 g, oil) in a yield of 10%. MS m / z (ESI): 177 [M+1]

[0130] Step 2 2-((tert-Butyldimethylsilyl)oxy)acetaldehyde (10c) Oxalyl chloride (27.6 g, 218.9 mmol) was added dropwise to dichloromethane (500 mL) at -30 °C, and the mixture was cooled to -78 °C. Dimethyl sulfoxide (21.7 g, 278.6 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for 30 minutes, and 10b (35 g, 199 mmol) in dichloromethane (100 mL) was slowly added and stirred for 1 hour. Triethylamine (100.5 g, 995 mmol) was added dropwise, and the mixture was stirred at -78 °C for 30 minutes and then stirred at room temperature overnight. The reaction mixture was successively washed with water (300 mL), dilute hydrochloric acid (1 N, 400 mL × 2), saturated sodium bicarbonate solution (400 mL), and saturated brine (400 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product 10c (34 g, oil) in 98% yield. 1 H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 4.11 (s, 2H), 0.82 (s, 9H), 0.00 (s, 6H).

[0131] Step 3 1-tert-Butyl 4-ethyl 4-(2-((tert-butyldimethylsilyl)oxy)-1-hydroxyethyl)piperidine-1,4-dicarboxylate (10d) To a solution of lithium diisopropylamide (2 M, 148 mL, 296 mmol) in THF and THF (400 mL) at -10 °C, 1-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate (50 g, 197 mmol) in THF (100 mL) was added dropwise, and the reaction mixture was stirred at 0 °C for 30 minutes. 10c (34 g, 197 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 hour and at room temperature for 1 hour. A mixture of saturated sodium bicarbonate solution and water (400 mL, 1 / 4 v / v) was added, followed by ethyl acetate (200 mL), and the resulting mixture was separated. The aqueous phase was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 2 / 3) to obtain the target product 10d (75 g, oil) in 88% yield. MS m / z (ESI): 332 [M+1-100]

[0132] Step 4 tert-Butyl 4-(2-((tert-butyldimethylsilyl)oxy)-1-hydroxyethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (10e) To 10d (75 g, 174 mmol) in THF (600 mL), lithium borohydride (2 M, 130 mL, 261 mmol) in THF was added, and the mixture was stirred at room temperature for 2 hours. After cooling to 0 °C, the reaction was quenched with saturated sodium bicarbonate solution and water (150 mL, 1 / 2 v / v), and the reaction mixture was diluted with ethyl acetate (200 mL) and filtered. The filtrate was separated, and the aqueous phase was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the target product 10e (55 g, oil) in 81% yield. MS m / z (ESI): 290 [M+1-100]

[0133] Step 5 tert-Butyl 4-(1,2-dihydroxyethyl)-4-(hydroxymethyl)piperidine-1-carboxylate (10f) To 10e (55 g, 128.5 mmol) in THF (400 mL) was added tetrabutylammonium fluoride (1 M, 193 mL, 193 mmol) in THF, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with saturated sodium bicarbonate solution and water (100 mL, 1 / 2 v / v), ethyl acetate (200 mL) was added, and the two phases were separated. The aqueous phase was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4 - 1 / 0) to give the desired product 10f (23 g, oil) in 65% yield. MS m / z (ESI): 176 [M+1-100]

[0134] Step 6 tert-Butyl 4-hydroxy-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (10g) Sodium hydride (60%, 11.7 g, 292.6 mmol) was suspended in THF (100 mL), cooled to 0 °C, and 10f (23 g, 83.6 mmol) in THF (100 mL) and p-toluenesulfonyl chloride (16 g, 83.6 mmol) in THF (200 mL) were added dropwise. The reaction mixture was stirred at 0 °C for 2 h. Saturated ammonium chloride solution (50 mL) was added slowly, and the reaction mixture was stirred vigorously until gas evolution ceased. Saturated ammonium chloride solution (100 mL) and saturated brine (100 mL) were added, and the resulting mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 0 / 1 - 1 / 0) to give the desired product 10h (8.5 g, oil) in 39% yield. MS m / z (ESI): 158 [M+1-100]

[0135] Project 7 tert-Butyl 4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (10h) A reaction mixture of 10 g (8.5 g, 32.9 mmol), Dess-Martin periodinane (27.4 g, 64.56 mmol) and dichloromethane (200 mL) was stirred at 0 °C for 2 h. Saturated sodium bicarbonate solution and saturated sodium thiosulfate solution (100 mL, 1 / 1 v / v) were added and the resulting mixture was stirred vigorously. The two phases were separated and the aqueous phase was extracted with dichloromethane (200 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 2 / 3) to give the desired product 10h (6.2 g, oil) in 74% yield. MS m / z (ESI): 156 [M+1-100]

[0136] Project 8 2-Oxa-8-azaspiro[4.5]decan-4-one (10i) To 10h (500 mg, 1.96 mmol) in dichloromethane (8 mL) was added HCl in dioxane (4 M, 2 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was desolvated under reduced pressure to give the desired product 10i (hydrochloride, 370 mg, solid) in 99% yield. This product was used directly in the next step without purification. MS m / z (ESI): 156 [M+1]

[0137] Project 9 8-(5-Iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-oxa-8-azaspiro[4.5]decan-4-one (10j) A mixture of 10i (hydrochloride, 106 mg, 0.555 mmol), potassium carbonate (153 mg, 1.11 mmol), and acetonitrile (4 mL) was added to 1c (100 mg, 0.37 mmol). The mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was cooled to room temperature, mixed with water (5 mL) and ethyl acetate (20 mL), and phase separation was carried out. The aqueous phase was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 4) to obtain the target product 10j (70 mg, solid) in a 49% yield. MS m / z (ESI): 390 [M+1]

[0138] Step 10 (R)-N-((S)-8-(5-Iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-oxa-8-azaspiro[4.5]decane-4-yl)-2-methylpropan-2-sulfinamide (10k) A reaction mixture of 10j (60 mg, 0.15 mmol), (R)-2-methylpropan-2-sulfinamide (36.3 mg, 0.3 mmol), tetraethyl titanate (137 mg, 0.6 mmol), and THF (5 mL) was heated to 90 °C and stirred for 4 h. The mixture was cooled to 0 °C, methanol (2 mL) and lithium borohydride (2.0 M, 0.15 mL, 0.3 mmol) in THF were added, and the mixture was stirred for 1 h. The reaction mixture was mixed with water (5 mL) and dichloromethane (20 mL), and the two phases were separated. The aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 9) to obtain the target product 10k (70 mg, solid) in a 92% yield. MS m / z (ESI): 495 [M+1]

[0139] Step 11 (R)-N-((S)-8-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropan-2-sulfinamide (10l) To a mixture of 10k (70 mg, 0.14 mmol), 7e (37.4 mg, 0.17 mmol), DIPEA (54 mg, 0.42 mmol), XantPhos (8.1 mg, 0.014 mmol), and dioxane (4 mL) was added Pd2(dba)3 (12.8 mg, 0.014 mmol), and the reaction mixture was heated to 100 °C under nitrogen protection and reacted for 2 hours. The reaction mixture was cooled to room temperature, mixed with water (5 mL) and dichloromethane (20 mL), and the two phases were separated. The aqueous phase was extracted with dichloromethane (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 9) to obtain the target product 10l (50 mg, solid) in a yield of 63%. MS m / z (ESI): 565 [M+1]

[0140] Step 12 (S)-2-(4-Amino-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-3-methylpyrimidin-4(3H)-one (10) 10l (50 mg, 0.09 mmol) was dissolved in methanol (8 mL), HCl (4.0 M, 2 mL) in dioxane was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to obtain the target product 10 (5.8 mg, solid) in a yield of 14%. MS m / z (ESI): 461 [M+1] 11H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.91 (s, 1H), 7.51 (d, J = 9.0 Hz, 1H), 6.99 (d, J = 9.0 Hz, 1H), 4.18 (s, 3H), 4.02 - 3.95 (m, 1H), 3.69 (d, J = 8.5 Hz, 1H), 3.63 (d, J = 8.5 Hz, 1H), 3.39 (s, 3H), 3.15 - 3.13 (m, 1H), 3.08 - 3.00 (m, 2H), 1.84 - 1.76 (m, 1H), 1.72 - 1.65 (m, 1H), 1.54 - 1.43 (m, 2H).

[0141] Example 11 2-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-3-methylpyrimidin-4(3H)-one formate

Chemical Structure

[0142] Step 1 Methyl (S)-2-((tert-butyldimethylsilyl)oxy)propanoate (11b) To imidazole (68.5 g, 1008 mmol) in dichloromethane (800 mL) at 0 °C, methyl (S)-2-hydroxypropanoate 11a (70 g, 672 mmol) was added dropwise, and tert-butyldimethylsilyl chloride (120 g, 807 mmol) was added slowly. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (600 mL) and extracted with dichloromethane (500 mL × 2). The organic phases were combined, washed with dilute hydrochloric acid (1 N, 300 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the desired product 11b (150 g, oil) in 99% yield. 1H NMR (400 MHz, CDCl3) δ 4.32 (q, J = 6.7 Hz, 1H), 3.70 (s, 3H), 1.38 (d, J = 6.8 Hz, 3H), 0.88 (s, 9H), 0.08 (s, 3H), 0.05 (s, 3H).

[0143] Process 2 (S)-2-((tert-butyldimethylsilyl)oxy)propionaldehyde (11c) 11b (151.2 g, 693 mmol) in dichloromethane (1,200 mL) was cooled to -78 °C, and diisobutylaluminum hydride in n-hexane (1 M, 832 mL, 832 mmol) was added dropwise. The reaction mixture was warmed to -40 °C and stirred for 1 h. The reaction mixture was poured into saturated potassium sodium tartrate solution (140 mL), mixed with ether (100 mL), and stirred at room temperature for 2 h. The two phases were separated, and the aqueous phase was extracted with ether. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 4 / 1) to give the desired product 11c (62.3 g, oil) in 48% yield. 1 H NMR (400 MHz, CDCl3) δ 9.60 (s, 1H), 4.09 (q, J = 6.8 Hz, 1H), 1.27 (d, J = 6.9 Hz, 3H), 0.91 (s, 9H), 0.10 (s, 3H), 0.08 (s, 3H).

[0144] Process 3 1-tert-butyl 4-ethyl 4-(2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)piperidine-1,4-dicarboxylate (11d) To a solution of lithium diisopropylamide (1 M, 425 mL, 425 mmol) in THF and THF (800 mL) at −50° C., 1-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate (72.8 g, 283.5 mmol) in THF (50 mL) was added dropwise, and the reaction mixture was stirred at −10° C. for 1 h. 11c (53.3 g, 283.5 mmol) was added and stirred at −10° C. for 1 h. The reaction mixture was warmed to 0° C. and stirred for 1 h, followed by stirring at room temperature for 1 h. A mixture of saturated sodium bicarbonate solution and water (400 mL, 1 / 4 v / v) was added, and ethyl acetate (500 mL) was added. The resulting mixture was separated. The aqueous phase was extracted with ethyl acetate (500 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the desired product 11d (120 g, oil, crude product). This product was used directly in the next step without purification. MS m / z (ESI): 346 [M+1-100]

[0145] Process 4 tert-Butyl 4-(2S)-2-((tert-butyldimethylsilyl)oxy)-1-hydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylate (11e) To 11d (120 g, 269.6 mmol) in THF (1,200 mL) was added lithium borohydride in THF (2 M, 270 mL, 539.2 mmol), and the reaction mixture was stirred at room temperature for 16 h. After cooling to 0 °C, the reaction was quenched with saturated sodium bicarbonate solution and water (600 mL, 1 / 2 v / v), and the mixture was diluted with ethyl acetate (800 mL) and filtered. The two phases of the filtrate were separated, and the aqueous phase was extracted with ethyl acetate (500 mL × 3). The organic phases were combined, washed with saturated brine (300 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the desired product 11e (90 g, oil, crude product). This product was used directly in the next step without further purification. MS m / z (ESI): 404 [M+1]

[0146] Process 5 tert-Butyl 4-((2S)-1,2-dihydroxypropyl)-4-(hydroxymethyl)piperidine-1-carboxylate (11f) To 11e (90 g, 223 mmol) in THF (1300 mL) was added tetrabutylammonium fluoride in THF (1 M, 303 mL, 303 mmol), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated sodium bicarbonate solution and water (800 mL, 1 / 2 v / v), ethyl acetate (800 mL) was added, the two phases were separated, and the aqueous phase was extracted with ethyl acetate (500 mL × 3). The organic phases were combined, washed with saturated brine (300 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 49 / 1) to give the desired product 11f (24.5 g, oil) in 26% yield over three steps. MS m / z (ESI): 290 [M+1]

[0147] Process 6 tert-Butyl (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane e-8-carboxylate (11g) Sodium hydride (60%, 10.8 g, 270.0 mmol) was suspended in THF (600 mL) and cooled to 0 °C. 11f (22.3 g, 77.1 mmol) in THF (40 mL) was added dropwise, followed by p-toluenesulfonyl chloride (14.6 g, 77.1 mmol) in THF (50 mL). The reaction mixture was stirred at 0 °C for 6 h. After cooling to -20 °C, saturated ammonium chloride solution (10 mL) was slowly added to the reaction mixture and vigorously stirred until gas evolution ceased. The mixture was extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated brine (150 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give the desired product 11g (12.1 g, oil) in 58% yield. MS m / z (ESI): 172 [M+1-100]

[0148] Step 7 tert-Butyl (S)-3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate (11h) To 11 g (12.1 g, 44.6 mmol) in dichloromethane (140 mL) at 0 °C was slowly added Dess-Martin periodinane (37.8 g, 89.2 mmol), and the reaction mixture was stirred at room temperature for 16 h. Saturated sodium bicarbonate solution was added until the solution became neutral, and the solution was extracted with dichloromethane (150 mL × 3). The organic phases were combined, washed with saturated brine (80 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 3 / 7) to give the desired product 11h (8.36 g, oil) in 70% yield. MS m / z (ESI): 170 [M+1-100]

[0149] Step 8 (S)-3-Methyl-2-oxa-8-azaspiro[4.5]decan-4-one (11i) 11h (1.2 g, 4.46 mmol) was dissolved in HCl (4 M, 20 mL) in dioxane and stirred at room temperature for 2 h. The reaction mixture was desolvated under reduced pressure to give the desired product 11i (hydrochloride, 800 mg, solid) in 87% yield. MS m / z (ESI): 170 [M+1]

[0150] Step 9 (S)-8-(5-Iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-one (11j) To 2-chloro-5-iodo-3-methylpyrimidin-4(3H)-one 1c (130 mg, 0.481 mmol) in acetonitrile (20 mL) was added 11i (hydrochloride, 108 mg, 0.529 mmol) and potassium carbonate (199 mg, 1.44 mmol), and the reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was cooled to room temperature, mixed with water (50 mL), and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1.3 / 1) to give the desired product 11j (180 mg, solid) in 92% yield. MS m / z (ESI): 404 [M+1]

[0151] Step 10 (R)-N-((3S,4S)-8-(5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide (11k) To a solution of 11j (180 mg, 0.446 mmol) in THF (2 mL), (R)-2-methylpropane-2-sulfinamide (108 mg, 0.892 mmol) and tetraethyl titanate (813 mg, 3.59 mmol) were added, heated to 90 °C, and stirred for 16 h. After cooling to 0 °C, the mixture was added with methanol (5 mL) and lithium borohydride in THF (2.0 M, 0.23 mL, 0.46 mmol) and stirred for 1 h. The reaction was quenched with saturated ammonium chloride solution, and the resulting mixture was filtered. The filtrate was extracted with ethyl acetate (25 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane=1 / 16) to give the desired product 11k (90 mg, solid) in a 39% yield. MS m / z (ESI): 509 [M+1]

[0152] Step 11 (R)-N-((3S,4S)-8-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide (11l) To 11k (80 mg, 0.157 mmol) in dioxane (5 mL) were added 7e (60 mg, 0.27 mmol), DIPEA (60.7 mg, 0.471 mmol), XantPhos (14.2 mg, 0.023 mmol), and Pd2(dba)3 (14.4 mg, 0.0157 mmol). The reaction mixture was heated to 80 °C under nitrogen protection and reacted for 4 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 13) to give the desired product 11l (55 mg, solid) in 60% yield. MS m / z (ESI): 579 [M+1]

[0153] Step 12 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-3-methylpyrimidin-4(3H)-one formate (11) 11l (55 mg, 0.095 mmol) was dissolved in methanol (5 mL), and HCl in dioxane (4.0 M, 5 mL) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to give the desired product 11 (16.8 mg, solid) in 37% yield. MS m / z (ESI): 475 [M+1] 11H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.21 (s, 1H), 7.91 (s, 1H), 7.51 (d, J = 9.1 Hz, 1H), 6.99 (d, J = 9.0 Hz, 1H), 4.18 (s, 3H), 4.11 - 4.05 (m, 1H), 3.68 (d, J = 8.6 Hz, 1H), 3.51 (d, J = 8.6 Hz, 1H), 3.47 - 3.43 (m, 2H), 3.41 (s, 3H), 3.20 - 3.03 (m, 2H), 3.00 (d, J = 4.9 Hz, 1H), 1.89 - 1.82 (m, 1H), 1.77 - 1.72 (m, 1H), 1.62 - 1.53 (m, 2H), 1.11 (d, J = 6.4 Hz, 3H).

[0154] Example 12 2-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-((4-chloropyrazolo[1,5-a]pyridin-5-yl)thio)-3-methylpyrimidin-4(3H)-one formate [Chemical formula]

[0155] Step 1 (R)-N-((3S,4S)-8-(5-((4-chloropyrazolo[1,5-a]pyridin-5-yl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)-2-methylpropan-2-sulfinamide (12a) 11k (140 mg, 0.28 mmol) was dissolved in dioxane (16 mL) and 8h (60 mg, 0.29 mmol), DIPEA (71.5 mg, 0.56 mmol), Pd(dba) (25.3 mg, 0.03 mmol), and XantPhos (32 mg, 0.06 mmol) were added. The reaction mixture was heated to 100 °C under nitrogen protection and reacted for 16 h. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 25) to give the desired product 12a (100 mg, solid) in 64% yield. MS m / z (ESI): 565 [M+1]

[0156] Process 2 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-((4-chloropyrazolo[1,5-a]pyridin-5-yl)thio)-3-methylpyrimidin-4(3H)-one formate (12) 12a (86 mg, 0.166 mmol) was dissolved in methanol (5 mL) and mixed with HCl in dioxane (4.0 M, 1 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to give the desired product 12 (16.8 mg, solid) in 19% yield. MS m / z (ESI): 461 [M+1] 1H NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 7.3 Hz, 1H), 8.26 (s, 1H), 8.17 (s, 1H), 8.04 (d, J = 2.1 Hz, 1H), 6.59 (d, J = 1.5 Hz, 1H), 6.48 (d, J = 7.3 Hz, 1H), 4.14 - 4.07 (m, 1H), 3.72 (d, J = 8.7 Hz, 1H), 3.57 - 3.51 (m, 3H), 3.39 (s, 3H), 3.21 - 3.07 (m, 2H), 3.06 (d, J = 4.9Hz, 1H), 1.88 - 1.75 (m, 2H), 1.66 - 1.55 (m, 2H), 1.12 (d, J = 6.4 Hz, 3H).

[0157] Example 13 (R)-5-((1H-indazol-4-yl)thio)-6-amino-2-(1-amino-8-azaspiro[4.5]decan-8-yl)-3-methylpyrimidin-4(3H)-one formate [ka]

[0158] Process 1 6-Amino-5-bromo-3-methylpyrimidine-2,4(1H,3H)-dione (13b) 6-Amino-3-methylpyrimidine-2,4(1H,3H)-dione (1.0 g, 7.08 mmol) was dissolved in DMF (6 mL), NBS (1.38 g, 7.8 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (20 mL) and filtered. The filter cake was washed with water (5 mL × 2) and dried under vacuum to give the desired product 13b (1.0 g, solid) in 64% yield. MS m / z (ESI): 220 [M+1]

[0159] Process 2 8-(4-amino-5-bromo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-8-azaspiro[4.5]decan-1-one (13c) 13b (200 mg, 0.91 mmol) was dissolved in DMF (5 mL), 8-azaspiro[4.5]decan-1-one (167 mg, 1.1 mmol), Castros reagent (1.2 g, 2.73 mmol), and DBU (692 mg, 4.55 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (10 mL × 3) and saturated brine (10 mL). The organic phase was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 7 / 3) to give the desired product 13c (170 mg, oil) in 53% yield. MS m / z (ESI): 355 [M+1]

[0160] Process 3 (R)-N-((R)-8-(4-amino-5-bromo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (13d) To 13c (160 mg, 0.45 mmol) in THF (15 mL), (R)-2-methylpropane-2-sulfinamide (110 mg, 0.9 mmol) and tetraethyl titanate (411 mg, 1.8 mmol) were added, heated to 90 °C, and stirred overnight. After cooling to room temperature, the mixture was added with methanol (5 mL) and lithium borohydride in THF (2.0 M, 0.5 mL) and stirred for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 20) to give the desired product 13d (200 mg, oil) in 96% yield. MS m / z (ESI): 460 [M+1]

[0161] Process 4 (R)-N-((R)-8-(5-((1H-indazol-4-yl)thio)-4-amino-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-8-azaspiro[4.5]decan-1-yl)-2-methylpropane-2-sulfinamide (13e) 13d (100 mg, 0.22 mmol) was dissolved in dioxane (10 mL) and sodium 1H-indazole-4-thiolate 3c (75 mg, 0.44 mmol), DIPEA (84 mg, 0.66 mmol), Pd(dba) (40 mg, 0.044 mmol), and XantPhos (51 mg, 0.088 mmol) were added. The reaction mixture was heated to 100 °C under nitrogen protection and stirred overnight. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by preparative thin-layer chromatography to give the desired product 13e (30 mg, solid) in 26% yield. MS m / z (ESI): 530 [M+1]

[0162] Process 5 (R)-5-((1H-indazol-4-yl)thio)-6-amino-2-(1-amino-8-azaspiro[4.5]decan-8-yl)-3-methylpyrimidin-4(3H)-one formate (13) 13e (30 mg, 0.056 mmol) was dissolved in methanol (2 mL), and HCl in dioxane (4.0 M, 2 mL) was added and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to give the desired product 13 (5 mg, solid) in 21% yield. MS m / z (ESI): 426 [M+1] 1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 8.12 (s, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.20 (t, J = 7.7 Hz, 1H), 6.78 (d, J = 7.0 Hz, 1H), 3.65 - 3.57 (m, 2H), 3.42 (s, 3H), 3.27 - 3.25 (m, 1H), 3.09 (t, J = 12.3 Hz, 2H), 2.22 - 2.17 (m, 1H), 1.85 - 1.72 (m, 7H), 1.54 (t, J = 13.5 Hz, 2H).

[0163] Example 14 6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-3-methylpyrimidin-4(3H)-one formate [ka]

[0164] Process 1 (S)-8-(4-amino-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-one (14a) 6-Amino-3-methylpyrimidine-2,4(1H,3H)-dione 13a (400 mg, 2.8 mmol) was dissolved in DMF (25 mL), and 11i (576 mg, 2.8 mmol), Castro's reagent (6.18 g, 14 mmol), and DBU (1.29 g, 8.5 mmol) were added. The mixture was stirred at room temperature overnight. The reaction was quenched with water (60 mL), and the reaction mixture was extracted with a mixed solvent of dichloromethane and methanol (10 / 1 v / v, 50 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 9) to obtain the target product 14a (700 mg, oil) in 84% yield. MS m / z (ESI): 293 [M+1]

[0165] Step 2 (R)-N-((3S,4S)-8-(4-Amino-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)-2-methylpropan-2-sulfinamide (14b) To 14a (700 mg, 2.3 mmol) in THF (30 mL), (R)-2-methylpropan-2-sulfinamide (557 mg, 4.6 mmol) and tetraethyl titanate (2.06 g, 9.2 mmol) were added. The reaction mixture was heated to 90 °C and stirred for 16 h. After cooling to 0 °C, methanol (10 mL) and lithium borohydride in THF (2.0 M, 1.35 mL) were added to the mixture, and the mixture was stirred for 1 h. The reaction was quenched with ammonium chloride solution, the mixture was filtered, and the filtrate was extracted with ethyl acetate (25 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 10) to obtain the target product 14b (80 mg, solid) in 8.7% yield. MS m / z (ESI): 398 [M+1]

[0166] Step 3 (R)-N-((3S,4S)-8-(4-amino-5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide (14c) 14b (80 mg, 0.2 mmol) was dissolved in acetonitrile (10 mL), NIS (54.2 mg, 0.24 mmol) was added, and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 12) to give the desired product 14c (100 mg, solid) in 95% yield. MS m / z (ESI): 524 [M+1]

[0167] Process 4 (R)-N-((3S,4S)-8-(4-amino-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropane-2-sulfinamide (14d) 14c (50 mg, 0.095 mmol) was dissolved in dioxane (6 mL) and 7e (22.8 mg, 0.114 mmol), DIPEA (36.7 mg, 0.285 mmol), Pd2(dba)3 (8.6 mg, 0.0095 mmol), and XantPhos (8.2 mg, 0.014 mmol) were added. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 16 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 14) to give the desired product 14d (46 mg, solid) in 82% yield. MS m / z (ESI): 594 [M+1]

[0168] Process 5 6-Amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-3-methylpyrimidin-4(3H)-one formate (14) 14d (46 mg, 0.077 mmol) was dissolved in methanol (5 mL), and HCl in dioxane (4.0 M, 5 mL) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to give the desired product 14 (6.5 mg, solid) in 17% yield. MS m / z (ESI): 490 [M+1] 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.20 (s, 1H), 7.46 (d, J = 9.0 Hz, 1H), 6.76 (d, J = 9.0 Hz, 1H), 4.15 (s, 3H), 4.10 - 4.06 (m, 1H), 3.69 (d, J = 8.5 Hz, 1H), 3.52 (d, J = 8.5 Hz, 1H), 3.39 - 3.37 (m, 2H), 3.29 (s, 3H), 3.11 - 2.97 (m, 3H), 1.85 - 1.71 (m, 2H), 1.63 - 1.54 (m, 2H), 1.11 (d, J = 6.4 Hz, 3H).

[0169] Example 15 6-amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-((4-chloropyrazolo[1,5-a]pyridin-5-yl)thio)-3-methylpyrimidin-4(3H)-one formate [ka]

[0170] Process 1 (R)-N-((3S,4S)-8-(4-Amino-5-((4-chloropyrazolo[1,5-a]pyridin-5-yl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropan-2-sulfinamide (15a) 14c (40 mg, 0.076 mmol) was dissolved in dioxane (4 mL), and 8h (31.3 mg, 0.152 mmol), DIPEA (29.4 mg, 0.228 mmol), Pd2(dba)3 (6.9 mg, 0.0076 mmol), and XantPhos (6.5 mg, 0.0114 mmol) were added. The reaction mixture was heated to 80 °C under nitrogen protection and stirred for 16 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 17) to obtain the target product 15a (35 mg, solid) in a yield of 79%. MS m / z (ESI): 580 [M+1]

[0171] Step 2 6-Amino-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-((4-chloropyrazolo[1,5-a]pyridin-5-yl)thio)-3-methylpyrimidin-4(3H)-one formate (15) 15a (35 mg, 0.06 mmol) was dissolved in methanol (5 mL), HCl (4.0 M in dioxane, 5 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to obtain the target product 15 (4.2 mg, solid) in a yield of 15%. MS m / z (ESI): 476 [M+1] 11H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 2.3 Hz, 1H), 6.55 (d, J = 1.7 Hz, 1H), 6.45 (d, J = 7.3 Hz, 1H), 4.28 -- 4.23 (m, 1H), 3.89 (d, J = 8.9 Hz, 1H), 3.77 (d, J = 8.9 Hz, 1H), 3.63 - 3.56 (m, 2H), 3.43 (s, 3H), 3.24 - 3.02 (m, 3H), 1.97 - 1.90 (m, 2H), 1.79 - 1.69 (m, 2H), 1.26 (d, J = 6.5 Hz, 3H).

[0172] Example 16 2-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-3-methylpyrimidin-4(3H)-one formate

Chemical formula

[0173] Step 1 tert-Butyl ((1-benzyl-4-methylpiperidin-4-yl)methyl)carbamate (16b) A reaction mixture of 1-benzyl-4-methylpiperidine-4-carbonitrile 16a (2 g, 9.3 mmol), di-tert-butyl dicarbonate (6.1 g, 27.9 mmol), nickel chloride hexahydrate (2.2 g, 9.3 mmol), and methanol (50 mL) was stirred at room temperature for 15 minutes. After cooling to 0 °C, the reaction mixture was mixed with sodium borohydride (1.77 g, 46.5 mmol), warmed to room temperature, and stirred for 8 hours. The reaction mixture was desolvated under reduced pressure, the residue was suspended in dichloromethane, and filtered. The filtrate was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain the target product 16b (1.2 g, oil) in 40% yield. MS m / z (ESI): 319 [M+1]

[0174] Process 2 tert-Butyl ((4-methylpiperidin-4-yl)methyl)carbamate (16c) 16b (1.2 g, 3.77 mmol) was dissolved in methanol (20 mL), palladium on carbon (10%, water content 55%, 1.2 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 3 h. The reaction mixture was filtered, the filter cake was washed with methanol, and the filtrate was concentrated to give the desired product 16c (810 mg, oil) in 94% yield. MS m / z (ESI): 229 [M+1]

[0175] Process 3 tert-Butyl ((1-(5-iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (16d) To a mixture of 16c (150 mg, 0.66 mmol), potassium carbonate (228 mg, 1.65 mmol), and acetonitrile (10 mL), 1c (150 mg, 0.55 mmol) was added, heated to 90° C., and stirred for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 9) to give the desired product 16d (150 mg, solid) in 58% yield. MS m / z (ESI): 463 [M+1]

[0176] Process 4 tert-Butyl ((1-(5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (16e) A reaction mixture of 16d (150 mg, 0.32 mmol), 7e (86 mg, 0.39 mmol), DIPEA (124 mg, 0.96 mmol), Pd2(dba)3 (29 mg, 0.032 mmol), XantPhos (18.5 mg, 0.032 mmol), and dioxane (4 mL) was heated to 90 °C under nitrogen protection and stirred for 3 hours. The reaction mixture was desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 9) to obtain the target product 16e (130 mg, solid) in a yield of 75%. MS m / z (ESI): 533 [M+1]

[0177] Step 5 2-(4-(Aminomethyl)-4-methylpiperidin-1-yl)-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-3-methylpyrimidin-4(3H)-one formate (16) 16e (130 mg, 0.24 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to obtain the target product 16 (32.4 mg, solid) in a yield of 31%. MS m / z (ESI): 433 [M+1] 1 1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.37 (s, 1H), 7.91 (s, 1H), 7.51 (d, J = 9.0 Hz, 1H), 6.99 (d, J = 9.0 Hz, 1H), 4.18 (s, 3H), 3.40 - 3.36 (m, 5H), 3.17 (t, J = 10.2 Hz, 2H), 2.65 (s, 2H), 1.63 - 1.57 (m, 2H), 1.42 (d, J = 11.1 Hz, 2H), 1.01 (s, 3H).

[0178] Example 17 2-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-methyl-5-((1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thio)pyrimidin-4(3H)-one formate [Chemical Structure]

[0179] Step 1 (R)-2-Methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)propan-2-sulfinamide (17b) tert-Butyl (3S,4S)-4-(((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decanecarboxylate 17a (300 mg, 0.8 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the desired product 17b (350 mg, crude product). This product was used directly in the next step without purification. MS m / z (ESI): 275 [M+1]

[0180] Step 2 (R)-N-((3S,4S)-8-(5-Iodo-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropan-2-sulfinamide (17c) A reaction mixture of 1c (216 mg, 0.8 mmol), 17b (crude product, 350 mg, 0.8 mmol), potassium carbonate (562 mg, 4.05 mmol), and acetonitrile (10 mL) was heated to 80 °C and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 9) to obtain the desired product 17c (360 mg, solid) in 89% yield. MS m / z (ESI): 509 [M+1]

[0181] Process 3 (R)-2-Methyl-N-((3S,4S)-3-methyl-8-(1-methyl-5-((1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thio)-6-oxo-1,6-dihydropyrimidin-2-yl)-2-oxa-8-azaspiro[4.5]decan-4-yl)propane-2-sulfinamide (17d) A reaction mixture of 17c (180 mg, 0.35 mmol), 2c (70 mg, 0.42 mmol), DIPEA (135 mg, 1.05 mmol), Pd(dba) (32 mg, 0.035 mmol), XantPhos (20 mg, 0.035 mmol), and dioxane (5 mL) was heated to 90 °C under nitrogen protection and stirred for 2 h. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 9) to give the desired product 17d (160 mg, solid) in 83% yield. MS m / z (ESI): 545 [M+1]

[0182] Process 4 2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-methyl-5-((1-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)thio)pyrimidin-4(3H)-one formate (17) 17d (160 mg, 0.29 mmol) was dissolved in methanol (4 mL), and HCl in dioxane (4.0 M, 2 mL) was added and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to give the desired product 17 (36 mg, solid) in 28% yield. MS m / z (ESI): 441 [M+1] 11H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.14 (s, 1H), 8.03 (d, J = 5.1 Hz, 1H), 7.51 (d, J = 3.5 Hz, 1H), 6.58 (d, J = 5.1 Hz, 1H), 6.44 (d, J = 3.5 Hz, 1H), 4.12 - 4.04 (m, 1H), 3.80 (s, 3H), 3.70 (d, J = 8.6 Hz, 1H), 3.53 - 3.48 (m, 3H), 3.40 (s, 3H), 3.19 - 3.08 (m, 2H), 3.02 (d, J = 4.9 Hz, 1H), 1.88 - 1.84 (m, 2H), 1.64 - 1.54 (m, 2H), 1.11 (d, J = 6.4 Hz, 3H).

[0183] Example 18 5-((1H-Pyrrolo[2,3-b]pyridin-4-yl)thio)-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-methylpyrimidin-4(3H)-one formate

Chemical Structure

[0184] Step 1 1H-Pyrrolo[2,3-b]pyridine-4-thiol (18a) To 1 g (250 mg, 1 mmol) in THF (5 mL) was added potassium tert-butoxide (224 mg, 2 mmol), and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water, and the resulting mixture was washed with ethyl acetate. The aqueous phase was acidified to pH = 4 with hydrochloric acid (6N) and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the filtrate was desolvated under reduced pressure to obtain the target product 18a (100 mg, solid) in 67% yield. MS m / z (ESI): 151 [M+1]

[0185] Step 2 (R)-N-((3S,4S)-8-(5-((1H-Pyrrolo[2,3-b]pyridin-4-yl)thio)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)-2-methylpropan-2-sulfinamide (18b) A reaction mixture of 17c (180 mg, 0.35 mmol), 18a (63 mg, 0.42 mmol), DIPEA (135 mg, 1.05 mmol), Pd2(dba)3 (32 mg, 0.035 mmol), XantPhos (20 mg, 0.035 mmol), and dioxane (5 mL) was heated to 90 °C under nitrogen protection and stirred for 2 hours. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 9) to obtain the target product 18b (150 mg, solid) in 80% yield. MS m / z (ESI): 531 [M+1]

[0186] Step 3 5-((1H-Pyrrolo[2,3-b]pyridin-4-yl)thio)-2-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-methylpyrimidin-4(3H)-one formate (18) 18b (150 mg, 0.28 mmol) was dissolved in methanol (4 mL), HCl (4.0 M, 2 mL) in dioxane was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative RP-HPLC to obtain the target product 18 (37.9 mg, solid) in 31% yield. MS m / z (ESI): 427 [M+1] 11H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 8.25 (s, 1H), 8.14 (s, 1H), 7.99 (d, J = 5.1 Hz, 1H), 7.47 - 7.45 (m, 1H), 6.54 (d, J = 5.1 Hz, 1H), 6.42 (d, J = 2.3 Hz, 1H), 4.15 - 4.05 (m, 1H), 3.71 (d, J = 8.5 Hz, 1H), 3.52 - 3.48 (m, 3H), 3.41 (s, 3H), 3.24 - 3.05 (m, 3H), 1.89 - 1.75 (m, 2H), 1.65 - 1.55 (m, 2H), 1.12 (d, J = 6.2 Hz, 3H).

[0187] Example 19 2-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-3-(methyl-d3)pyrimidin-4(3H)-one

Chemical Structure

Chemical Structure

[0188] Step 1 (3S,4S)-3-Methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (19b) tert-Butyl (3S,4S)-4-(((R)-tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane e-8-carboxylate 19a (95.0 g, 254 mmol) and HCl in methanol (4 M, 1 L) were stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (500 mL), and a mixture of petroleum ether and ethyl acetate (1 / 1, 4 L) was slowly added. The resulting mixture was stirred at room temperature for 2 h. After filtration, the filter cake was dried to give the desired product 19b (64.1 g, solid, dihydrochloride) in >100% yield. MS m / z (ESI): 171 [M+1] 1 H NMR (400 MHz, DMSO-d6) δ 9.12 (brs, 2H), 8.33 (s, 3H), 4.25 - 4.19 (m, 1H), 3.82 (d, J = 9.1 Hz, 1H), 3.64 (d, J = 9.1 Hz, 1H), 3.47 (brs, 1H), 3.27 - 3.24 (m, 1H), 3.19 - 3.16 (m, 1H), 2.94 - 2.85 (m, 2H), 2.03 - 1.85 (m, 2H), 1.79 - 1.67 (m, 2H), 1.23 (d, J = 6.5 Hz, 3H).

[0189] Process 2 2-Chloro-5-iodo-3-(methyl-d3)pyrimidin-4(3H)-one (19c) To 2-chloro-5-iodopyrimidin-4(3H)-one 1b (5.0 g, 19.5 mmol) in THF (100 mL) was added DBU (3.85 g, 25.3 mmol), and the resulting mixture was cooled to 0 °C. Iodomethane-d3 (3.39 g, 23.4 mmol) was added. The reaction mixture was heated to 50 °C and stirred for 6 h. The reaction mixture was desolvated under reduced pressure. The residue was mixed with ethyl acetate (3.5 L) and washed with dilute hydrochloric acid (0.5 N, 1 L×) and brine (800 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 19 - 1 / 4) to give the desired product 19c (3.3 g, solid) in 62% yield. MS m / z (ESI): 274[M+1]

[0190] Step 3 2-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-iodo-3-(methyl-d3)pyrimidin-4(3H)-one (19d) A reaction mixture of 19c (1.8 g, 6.5 mmol), 19b (1.67 g, 6.9 mmol, dihydrochloride), cesium carbonate (9.5 g, 29.3 mmol), and acetonitrile (60 mL) was stirred at room temperature for 3 h under nitrogen protection. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 9 / 1) to give the desired product 19d (2.4 g, solid) in 91% yield. MS m / z (ESI): 408[M+1]

[0191] Step 4 2-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-5-((4-chloro-2-methyl-2H-indazol-5-yl)thio)-3-(methyl-d3)pyrimidin-4(3H)-one (19) A reaction mixture of 7e (1.9 g, 9.0 mmol), 19d (2.3 g, 5.65 mmol), copper iodide (430 mg, 2.26 mmol), 1,10-phenanthroline (814 mg, 4.52 mmol), potassium phosphate (2.3 g, 11.3 mmol), and dioxane (50 mL) was heated to 100 °C under nitrogen protection and stirred overnight. The reaction mixture was cooled to room temperature and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 9). The resulting crude product (2.5 g) was mixed with acetonitrile (25 mL) and stirred at 90 °C for 3 hours and then at room temperature for 16 hours. After filtration, the filter cake was dried under vacuum at 40 °C for 4 hours to give the desired product 19 (1.47 g, solid) in 54% yield. MS m / z (ESI): 478[M+1] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.91 (s, 1H), 7.50 (dd, J = 9.0, 0.9 Hz, 1H), 6.98 (d, J = 9.0 Hz, 1H), 4.17 (s, 3H), 4.05 - 4.02 (m, 1H), 3.64 (d, J = 8.5 Hz, 1H), 3.47 (d, J = 8.5 Hz, 1H), 3.48 - 3.37 (m, 2H), 3.15 - 3.05 (m, 2H), 2.90 (d, J = 5.1 Hz, 1H), 1.86 - 1.80 (m, 1H), 1.74 - 1.68 (m, 1H), 1.59 - 1.50 (m, 2H), 1.38 (brs, 2H), 1.07 (d, J = 6.4 Hz, 3H).

[0192] Biological experiments Measurement of SHP2 activity inhibition The effect of the compounds of the invention on SHP2 activity is assessed by a rapid fluorescent detection method using the surrogate substrate DiFMUP.

[0193] The experimental method is outlined below: The recombinant human SHP2 full-length protein was expressed and purified by the protein purification and identification platform of Tsinghua University; the diphosphopeptide (H2N-LN(pY)IDLDLV-(dPEG8)LST(pY)ASINFQK-amide) was synthesized by Nanjing GenScript Biotechnology Co., Ltd.; the surrogate substrate DiFMUP was purchased from Thermo Fisher Scientific (Cat. No. D6567); the reaction buffer contained the following components: 60 mM HEPES (pH 7.2), 75 mM NaCl, 75 mM KCl, 1 mM EDTA, 0.05% Tween 20, and 5 mM DTT.

[0194] This compound was dissolved in DMSO (Sigma, Cat. No. D5879) and diluted to 100 μM. The resulting solution was serially diluted 4-fold with DMSO to a minimum concentration of 6.1 nM, and each concentration point was diluted 25-fold with the reaction buffer.

[0195] 10 μL of the compound solution and 10 μL of the 0.25 nM SHP2 protein solution were added to a 384-well microplate (Corning, Cat. No. 3575), mixed well, and incubated at room temperature for 30 minutes. 10 μL of 0.5 μM diphosphopeptide (dissolved in the reaction buffer) was added, mixed well, and incubated at room temperature for 30 - 60 minutes. Subsequently, 10 μL of 60 μM DiFMUP solution (dissolved in the reaction buffer) was added, mixed well, and left standing at room temperature. After 30 minutes, the fluorescence signal was measured at 340 nm (excitation wavelength) / 450 nm (emission wavelength) using a microplate reader (EnSpire, Perkin Elmer). The fluorescence intensity value was positively correlated with the degree of dephosphorylation of the substrate, thereby reflecting the catalytic activity of SHP2. In the experiment, the protein-free group was set as the 100% inhibition group, and the protein-added and compound-free group was set as the 0% inhibition group. The inhibition curve of the compound was plotted using XLfit software, and the inhibition IC50 was calculated. The experimental results are shown in the table below.

Table 2

[0196] The compounds in the embodiments of the present invention have an inhibitory effect on SHP2 activity, and the preferred IC 50 is less than 50 nM.

[0197] Measurement of NCI-H358 cell growth inhibition The effect of the compounds of the present invention on the growth of the human non-small cell lung cancer cell line NCI-H358 is evaluated by a luminescence cell viability assay.

[0198] The outline of the experimental method is as follows: The compound was dissolved in DMSO (Sigma, Cat. No. D5879) and diluted to 5 mM. The resulting solution was serially diluted 4-fold with DMSO to a minimum concentration of 0.31 μM, and each concentration point was diluted 50-fold with RPMI 1640 medium (Thermo Fisher Scientific, Cat. No. 11995073). When the IC 50 value of the compound was low, the initial concentration of the compound was further decreased.

[0199] NCI-H358 cells (ATCC, Cat. No. CRL-5807) were cultured in RPMI 1640 complete medium (RPMI 1640 medium containing 10% FBS (GBICO, Cat. No. 10099-141) and 100 units / mL penicillin-streptomycin (Thermo Fisher Scientific, Cat. No. 15140122)). Cells (15,000 cells / mL) were seeded into 96-well plates in 90 μL of complete medium. After overnight culture, 10 μL of compound solution was added to each well and the plates were cultured at 37°C in a 5% CO2 incubator for 5 days. Following the instructions in the CellTilter-Glo (CTG) kit (Promega, Cat. No. G7572), the cell culture plates were removed from the incubator and allowed to equilibrate to room temperature. The cells were thoroughly lysed with 50 μL of CTG reagent and allowed to stand at room temperature for 10 minutes. Luminescence signals were read using a microplate reader (EnVision, Perkin Elmer). In the experiment, a group containing 10 μM positive control RMC-4550 served as a negative control (100% inhibition), and a group containing 0.2% DMSO served as a positive control (0% inhibition). Compound inhibition curves were plotted using XLfit software, and the inhibitory IC values were calculated. 50 The experimental results are shown in the table below. [Table 3]

[0200] The compounds in accordance with the present invention have an inhibitory effect on cell proliferation and are preferred IC 50 is less than 1,000 nM.

[0201] Measurement of hERG potassium channel blockade The effect of the compounds of the invention on arrhythmia potential is assessed by measuring blockade of the hERG potassium channel.

[0202] The experimental method is outlined below: Extracellular fluid: 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2, 2 mM CaCl2, 10 mM D-glucose, 10 mM HEPES, 1.25 mM NaH2PO4, pH = 7.4.

[0203] Electrode solution: 20 mM KCl, 115 mM K-aspartate, 1 mM MgCl2, 5 mM EGTA, 10 mM HEPES, and 2 mM Na2-ATP, pH = 7.2.

[0204] Compound solution: The test compound was dissolved in DMSO to form a 10 mM stock solution, which was diluted to 3 mM with DMSO and then further diluted to 3 μM with the extracellular solution for subsequent use.

[0205] Cell culture: HEK293 cell line (Creacell, Cat. No. A-0320) stably expressing the hERG potassium channel was cultured in Dulbecco's modified Eagle's medium (DMEM, Gibco, Cat. No. 11995-065) containing 10% fetal bovine serum (Gibco, Cat. No. 1428478) and 0.8 mg / mL G418 (Amresco, Cat. No. E859-5G), where the culture temperature was 37°C and the carbon dioxide concentration was 5%. The used medium was removed, and the cell line was washed once with PBS (Gibco, Cat. No. 1009-141). TrypLE TM Express (Gibco, Cat. No. 12604021) was added at 1 mL and incubated at 37°C for 30 seconds. When the cells detached from the bottom of the cell culture dish, 5 mL of pre-warmed complete medium was added, and the cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000 rpm for 5 minutes to collect the cells. 2.5 * 10 5 cells were seeded in a 6 cm cell culture dish (final volume: 5 mL). Before the patch clamp experiment, 3 * 10 3 cells were spread on a coverslip and cultured on a 24-well plate (final volume: 500 μL), and detected after 18 hours.

[0206] The voltage stimulation method for recording whole-cell hERG potassium current by whole-cell patch clamp is as follows: After forming a whole-cell seal, the cell membrane was clamped at a voltage of -80 mV. The clamping voltage was depolarized from -80 mV to -50 mV and held for 0.5 seconds (leak current detection), stepped to 30 mV and held for 2.5 seconds, rapidly returned to -50 mV and held for 4 seconds to excite the peak-tail current of the hERG channel, and the hERG potassium current was recorded every 10 seconds. Experimental data were collected with an EPC-10USB patch clamp amplifier (HEKA) and stored in PatchMaster (HEKA v2x73) software.

[0207] Measurement: A glass capillary tube (Sutter Instruments) was used as the recording electrode with a microelectrode puller (Sutter Instruments). A coverslip containing cells collected from a 24-well plate placed in an incubator was placed under an inverted microscope. The electrode solution was poured into the recording electrode, and the microelectrode puller (Sutter Instruments) was operated to bring the recording electrode into contact with the cell surface, providing negative pressure suction to form a GΩ seal. Rapid electrostatic capacitance compensation was applied, and continuous negative pressure suction was applied until the cell membrane was ruptured to form the whole-cell recording mode. In the whole-cell recording mode, low-speed capacitance compensation was performed, and the membrane capacitance and series resistance were recorded, and during this time, no leak current compensation was given. When the hERG peak-tail current in the whole-cell recording was stable for 3 - 5 minutes, 8 mL of extracellular fluid without compound (blank control) and 3 μM test substance solution were perfused under gravity and sequentially flowed through the recording chamber to act on the cells for 5 minutes (or until the current was stable). The current of each cell measured with extracellular fluid without compound was used as the respective control group. Independently, 2 - 3 cells were repeatedly measured. All electrophysiological experiments were performed at room temperature.

[0208] Data analysis: First, the current after the action of the test compound and the current of the blank control were normalized.

Number

Number

Table 4

Chemical formula

change

Chem.

Chem.

Chem.

Claims

1. General formula (II): 【Chemical 1】 [wherein, Ring A is selected from the group consisting of a phenyl ring and a 6-membered heteroaryl ring containing one heteroatom selected from N; Ring B is a 5-membered heteroaryl ring fused to Ring A, where the 5-membered heteroaryl ring contains one or two heteroatoms selected from N; Here, the phenyl ring defined in ring A and the heteroaryl rings defined in rings A and B may optionally be substituted by one or more substituents selected from the group consisting of D, halogen, cyano, C 1-6 alkyl, -OH and -NH 2 and may be substituted by one or more substituents selected from the group consisting of; R 1 is selected from the group consisting of H, D, cyano, C 1-2 alkyl and -NH 2 ; and R 2 is selected from the group consisting of H and C 1-2 alkyl, wherein one or more hydrogen atoms of the alkyl may optionally be substituted by one or more substituents selected from the group consisting of D and fluoro; R 4a and R 4b are each independently selected from C 1-6 alkyl, where the alkyl may optionally be substituted by one or more substituents selected from the group consisting of D and -NH 2 ; R 4a and R 4b may optionally, together with the carbon atom to which they are attached, form a C 3-7 carbocyclic ring, or a 4- to 7-membered heterocyclic ring containing one oxygen] A compound represented by, or a pharmaceutically acceptable salt or stable isotope derivative thereof, or a mixture thereof.

2. General formula (IV): 【Chemical 2】 [wherein, Ring A is selected from the group consisting of a phenyl ring and a 6-membered heteroaryl ring, Ring B is a 5-membered heteroaryl ring fused to Ring A, Here, the phenyl ring defined in ring A and the heteroaryl ring defined in rings A and B may optionally be substituted by one or more substituents selected from the group consisting of D, halogen, cyano, C 1-2 alkyl, -OH and -NH 2 and may be substituted by one or more substituents selected from the group consisting of; X is selected from the group consisting of -O- and -CH 2 -; R 1 is selected from the group consisting of H, D, C 1-2 alkyl and -NH 2 ; and R 2 is selected from the group consisting of H and C 1-2 alkyl, wherein one or more hydrogen atoms of the alkyl may optionally be substituted by one or more substituents selected from the group consisting of D and fluoro; R 7 is selected from the group consisting of H, D and C 1-2 alkyl, wherein one or more hydrogen atoms of the alkyl may optionally be substituted by one or more substituents selected from the group consisting of D and fluoro] A compound represented by, or a pharmaceutically acceptable salt or stable isotope derivative thereof, or a mixture thereof.

3. 【Fig. 3】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt or stable isotope derivative thereof, or a mixture thereof.

4. A pharmaceutical composition comprising the compound according to any one of Claims 1 to 3 or a pharmaceutically acceptable salt or stable isotope derivative thereof, or a mixture thereof, and one or more pharmaceutically acceptable carriers and excipients.

5. A pharmaceutical composition comprising the compound according to any one of Claims 1 to 3 or a pharmaceutically acceptable salt or stable isotope derivative thereof, or a mixture thereof and at least one additional drug, wherein the additional drug is selected from the group consisting of chemotherapeutic drugs, targeted drugs, DNA synthesis inhibitors, antibody drugs, antibody-drug conjugates, antitumor drugs and immunosuppressive drugs.

6. The pharmaceutical composition according to Claim 4 or 5 for treating and / or preventing a disease associated with abnormal SHP2 activity, wherein the disease is selected from the group consisting of leukemia, Noonan syndrome, Leopard syndrome, neuroblastoma, melanoma, lung cancer, breast cancer, esophageal cancer, colon cancer, head and neck cancer and gastric cancer.

Images