WO2023169170A1

WO2023169170A1 - Heterocyclic compound as shp2 inhibitor, composition comprising heterocyclic compound, and method using same

Info

Publication number: WO2023169170A1
Application number: PCT/CN2023/076423
Authority: WO
Inventors: 利群; 张劲涛; 简善忠; 李傲; 袁霞; 徐汶
Original assignee: 捷思英达控股有限公司; 徐汶
Priority date: 2022-03-10
Filing date: 2023-02-16
Publication date: 2023-09-14

Abstract

Disclosed in the present invention are a compound of formula I, and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound of formula I, a pharmaceutical composition comprising the compound, and the therapeutic use of the compound, wherein the compound is a potentially useful inhibitor of SHP2 in the treatment of SHP2-related diseases (such as SHP2-related cancers).

Description

Heterocyclic compounds as SHP2 inhibitors, compositions including the heterocyclic compounds, and methods of using the same

This application claims the following priority rights:

CN202210240216.X, application date: March 10, 2022

Technical field

The present disclosure belongs to the field of medical technology, and particularly relates to a heterocyclic compound as a SHP2 inhibitor, a composition including the heterocyclic compound, and a method of using the same.

technical background

Disclosed herein are novel heterocyclic compounds that can act as inhibitors of SHP2 (Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2). Further provided herein are pharmaceutical compositions comprising at least one such compound, and methods of using at least one such compound in the treatment of SHP2-modulated diseases and disorders, such as cancer.

SHP2 is a ubiquitous non-receptor protein tyrosine phosphatase encoded by the human PTPN11 gene, with relatively conserved structure and function. It contains a protein tyrosine phosphatase catalytic domain (PTP domain), two SH2 domains, and a C-terminal tail with two tyrosine phosphorylation sites and a proline-rich motif . SHP2 catalyzes the dephosphorylation of phosphotyrosine, a key control element in mammalian signal transduction. Upon stimulation by growth factors or cytokines, the N-SH2 domain binds to specific phosphotyrosine residues on cell surface receptors to induce conformational changes, thereby exposing and catalytically activating the PTP domain, resulting in SHP2 activation (Qu CK,el al. Cell Res 2000,10,279-88). SHP2 acts downstream of receptor tyrosine kinase and upstream of RAS (Yuan XR et.al.J Med Chem 2020,10.1021/acs.jmedchem.0c00249). In addition, the immune checkpoint PD-1 signals through SHP2 to inhibit the activity of T cells in the tumor microenvironment (Marasco et al., Sci. Adv. 2020; 6:eaay4458).

Dysregulation of SHP2 is associated with a range of human diseases, including cancer. SHP2 mainly regulates the survival and proliferation of cancer cells by activating the RAS-ERK signaling pathway (Matozaki T, el al. Cancer Sci 2009, 100, 1786-93). SHP2 mutations cause Noonan and Leopardskin syndromes, and mutations that increase the basal activity of SHP2 are the most common cause of sporadic juvenile myelomonocytic leukemia (Tartaglia, M, et al. Nat. Genet. 2003, 34, 148-150) . These rare diseases predispose patients to cancer. Even when the enzyme itself does not carry mutations, SHP2 activity is closely related to tumorigenesis ((Marsh-Armstrong B, et al. ACS Omega 2018, 3, 15763-15770)). Recent studies have shown that SHP2 is important for RTK-driven (Chen YN, et al. Nature 2016, 535, 148-52) and mutant KRAS-driven cancers (Mainardi S, et al. Nat Med 2018, 24, 961-7; Ruess DA, et al. Nat Med 2018, 24, 954-60) is required for growth and survival. Recent studies have also shown that SHP2 inhibition triggers anti-tumor immunity and enhances PD-1 blockade (Zhao, MX, et al. Acta Pharmaceutica Sinica B, 2019, 9, 304-315). Therefore, SHP2 has emerged as an attractive target in the treatment of various diseases mediated by SHP2.

Contents of the invention

Disclosed herein are a series of novel heterocyclic compounds useful as SHP2 inhibitors. Further disclosed herein are pharmaceutical compositions comprising at least one such novel compound, methods of preparing the novel compounds, and methods of using at least one such compound to treat SHP2-mediated diseases and disorders (eg, cancer).

Disclosed herein are compounds of formula I:

and/or stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of the compound of formula I, wherein,

Y is selected from:

R ¹ is selected from H, NH ₂ and optionally substituted C1-C3 alkyl;

R ² is selected from H, halogen, -CN, -OH, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkenyl, optionally substituted C1-C3 alkynyl, optionally substituted C1-C3 alkoxy and optionally substituted C1-C3 haloalkyl;

Each R ³ is independently selected from H and optionally substituted C1-C3 alkyl;

R ⁴ is selected from H and optionally substituted C1-C6 alkyl;

R ⁵ is selected from H, halogen, NH ₂ , -CN, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkenyl, optionally substituted C1-C3 alkynyl, optionally substituted C1-C3 alkoxy and optionally substituted C1-C3 haloalkyl;

R ⁶ is selected from H and optionally substituted C1-C3 alkyl;

X ¹ is selected from -O- and -C(R ⁷ ) ₂ -, wherein R ⁷ is selected from H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, C6-C10 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S as ring members; or, wherein R ⁴ , R ⁷ and are located in the R ⁴ and R The two carbon atoms between ⁷ may together optionally form 4-7 selected from C3-C6 cycloalkyl, saturated or unsaturated containing 1-2 heteroatoms selected from N, O and S as ring members cyclic groups containing 1 to 4 heteroatoms selected from N, O and S as ring members; and

X ² is selected from -C(R ⁸ )-, or -X ² =X ³ - is selected from -[C(R ⁸ )=C(R ⁹ )]-, -[C(R ⁸ )=N]-, -[N=C(R ⁹ )]-; wherein, R ⁸ and R ⁹ are independently selected from H, optionally substituted C1-C3 alkyl and -COOH.

Further disclosed herein are pharmaceutical compositions comprising a compound of Formula I and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate of a compound of Formula I disclosed herein, and a pharmaceutically acceptable Acceptable carrier.

Further disclosed herein are methods of inhibiting the activity of SHP2, the methods comprising reacting protein SHP2 with an effective amount of a compound of Formula I disclosed herein and/or a stereoisomer, stable isotope, or pharmaceutically acceptable amount of a compound of Formula I disclosed herein. Salt or solvate contact.

Further disclosed herein are methods of treating a treatable disease by inhibiting SHP2 in a patient, said method comprising administering to a patient identified in need of such treatment an effective amount of a compound of Formula I and/or a steric form of a compound of Formula I disclosed herein. isomers, stable isotopes, or pharmaceutically acceptable salts or solvates.

Further disclosed herein are methods of treating a treatable disease by inhibiting SHP2 in a patient, comprising administering to a patient identified in need of such treatment an effective amount of a pharmaceutical composition comprising a compound of Formula I disclosed herein and/or stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of the compounds of formula I, and pharmaceutically acceptable carriers.

Further disclosed herein are methods of treating cancer in a patient, comprising administering to a patient identified in need of such treatment an effective amount of a compound of Formula I disclosed herein and/or a stereoisomer, stable isotope of a compound of Formula I , or a pharmaceutical composition of a pharmaceutically acceptable salt or solvate, and a pharmaceutically acceptable carrier. In some embodiments, the cancer is selected from juvenile myelomonocytic leukemia, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma cell carcinoma, gastric cancer, anaplastic large cell lymphoma, and glioblastoma.

Further disclosed herein are compounds of Formula I and/or stereoisomers, stable isotopes or pharmaceutically acceptable salts or solvates of compounds of Formula I in medicaments for the treatment of diseases responsive to SHP2 inhibition, such as cancer. application in preparation. In some embodiments, the cancer is selected from juvenile myelomonocytic leukemia, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma , gastric cancer, anaplastic large cell lymphoma and glioblastoma.

Further disclosed herein are compounds of Formula I and compounds of subclasses of Formula I disclosed herein, as well as pharmaceutically acceptable salts or solvates of these compounds, as well as all stereoisomers (including diastereoisomers) and enantiomers, as well as isotopically enriched variants (including deuterium substitutions). The compounds can be used to treat conditions that are responsive to SHP2 inhibition, such as those disclosed herein, and can be used to prepare medicaments for treating these disorders. The pharmaceutical compositions and methods disclosed herein may also be used or formulated with co-therapeutics; for example, compounds of Formula I and compounds of its subformulas may be used with one or more agents selected from the group consisting of SHP2 kinase inhibitors and non-SHP2 kinase inhibitors and other Used together or formulated with therapeutic agents.

Further disclosed herein are methods and key intermediate compounds useful for making the compounds of Formula I disclosed herein.

As used herein, the following words, phrases, and symbols are generally intended to have the meanings stated below, unless the context in which they are used indicates otherwise. The following abbreviations and terms have the meanings indicated throughout this document.

Detailed ways

Unless otherwise specified or obvious from the context, the following definitions apply:

A dash ("-") not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CONR _a R _b is connected through a carbon atom.

Unless expressly stated otherwise, use of the terms "a", "an", etc. refers to one or more.

The term "halogen" or "halogen" as used herein refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). Halogen-substituted groups and moieties, such as alkyl groups substituted with halogen elements (haloalkyl), may be monohalogenated, polyhalogenated, or perhalogenated. In some embodiments, unless otherwise specified, chlorine and fluorine are examples of halogen substituents on alkyl or cycloalkyl groups; unless otherwise specified, fluorine, chlorine, and bromine are, for example, on aryl groups. group or heteroaryl group used on.

Unless otherwise specified, the term "heteroatom" or "hetero atom" as used herein refers to a nitrogen (N) atom or an oxygen (O) atom or a sulfur (S) atom.

As used herein, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the stated event or circumstance occurs and where the described event or circumstance does not What happened. For example, "alkyl optionally substituted with X" includes both "alkyl not substituted with X" and "alkyl substituted with X." Those skilled in the art will understand that for any group containing one or more substituents, such groups are not intended to introduce sterically impractical, synthetically unfeasible and/or inherently insufficiently stable in water at room temperature. Any substitution or replacement mode of administration as a pharmaceutical preparation for an extended period of time. When multiple substituents are present, the substituents are independently selected unless otherwise stated, so that where 2 or 3 substituents are present, for example, those substituents may be the same or different.

In some embodiments, "substituted with at least one group" means that one hydrogen on the specified atom or group is replaced with one selected from the specified group of substituents. In some embodiments, "substituted with at least one group" means that two hydrogens on a specified atom or group are independently replaced with two selected from the specified group of substituents. In some embodiments, "substituted with at least one group" means that three hydrogens on a specified atom or group are independently replaced with three selected from the specified group of substituents. In some embodiments, "substituted with at least one group" means that four hydrogens on a specified atom or group are independently replaced with four selected from the specified group of substituents.

The term "alkyl" as used herein refers to a group selected from groups having up to 18 carbon atoms, such as from 1 to 12 carbon atoms, further such as from 1 to 8 carbon atoms, even further such as from 1 to 6 carbon atoms) straight-chain and branched-chain saturated hydrocarbon radicals. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neo Pentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, etc.

Unless expressly stated otherwise, an alkyl group may optionally be substituted by one or more substituents (eg, one, two, or three substituents, or 1 to 4 substituents, or up to number of hydrogens on the alkyl group) are substituted in place of the hydrogen atoms of the unsubstituted alkyl group. If not otherwise specified, suitable substituents for the alkyl group may be selected from the group consisting of halogen elements, D, CN, hydroxyl groups, hydroxyl groups, substituted or unsubstituted C ₁ -C ₄ alkoxy groups, substituted or Unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted 3-7 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O and S as ring members, Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring members, amino, -NH (C ₁ -C ₄ alkyl), -N(C ₁ -C ₄ alkyl) ₂ , -S(=O) _0-2 (C ₁ -C ₄ alkyl), -S(=NR)(=O)( C ₁ -C ₄ alkyl), -C (=O) (C ₁ -C ₄ alkyl), -C (=NOH) (C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ ( C ₁ -C ₄ alkyl), -S (=O) _1-2 NH ₂ , -S (=O) _1-2 NH (C ₁ -C ₄ alkyl), -S (=O) _1-2 N(C ₁ -C ₄ alkyl) ₂ , -CONH ₂ , -C(=O)NH(C ₁ -C ₄ ), -C(=O)N(C ₁ -C ₄ alkyl) ₂ , - C(=NOH)NH(C ₁ -C ₄ alkyl), -OC(=O)(C ₁ -C ₄ alkyl), -NHC(=O)(C ₁ -C ₄ alkyl), -NHC (=NOH)(C ₁ -C ₄ alkyl), -NH(C=O)NH ₂ , -NHC(=O)O(C ₁ -C ₄ alkyl), -NHC(=O)NH(C ₁ -C ₄ alkyl), NHC (=NOH)NH (C ₁ -C ₄ alkyl), -NHS (=O) _1-2 (C ₁ -C ₄ alkyl), -NHS (=O) _{1 -2} NH ₂ , and -NHS(=O) _1-2 NH(C ₁ -C ₄ alkyl); among them, for substituted C ₁ -C ₄ alkoxy, substituted C ₃ -C ₆ The substituents of cycloalkyl, substituted 3-7 membered heterocycloalkyl, substituted aryl and substituted heteroaryl are up to three independently selected from halogen elements, D, -CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, hydroxyl group, hydroxyl group, C ₁ -C ₄ alkoxy group, amino, -NH(C ₁ -C ₄ alkyl), -N(C ₁ - C ₄ alkyl) ₂ group. In some embodiments, unless otherwise specified, the substituents of the alkyl group are selected from, for example, halogen, CN, oxy, hydroxyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl base, phenyl, amino, -NH(C ₁ -C ₄ alkyl), -N(C ₁ -C ₄ alkyl) ₂ , C ₁ -C ₄ alkylthio, C ₁ -C ₄ alkylsulfonyl , -C(=O)(C ₁ -C ₄ alkyl), -CO ₂ H, -CO ₂ (C ₁ -C ₄ alkyl), -OC(=O)(C ₁ -C ₄ alkyl) , -NHC(=O)(C ₁ -C ₄ alkyl) and -NHC(=O)O(C ₁ -C ₄ alkyl).

The term "alkoxy" as used herein refers to a linear or branched alkyl group containing 1 to 18 carbon atoms (such as methoxy, ethoxy, propoxy, isopropoxy) connected through an oxygen bridge. , n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy base, 3-methylpentyloxy, etc.). Typically, an alkoxy group includes 1 to 6 carbon atoms (eg, 1 to 4 carbon atoms) connected through an oxygen bridge.

Unless expressly stated otherwise, an alkoxy group may optionally be present in the unsubstituted number of hydrogens on the alkoxy group) in place of the hydrogen atoms of the unsubstituted alkyl portion of the alkoxy group. Unless otherwise specified, suitable substituents are selected from, for example, those listed above for alkyl groups, except that hydroxyl and amino groups are generally not present in direct connection with the oxygen of the substituted alkyl-O group. on the carbon.

The term "alkenyl" as used herein refers to a hydrocarbon group selected from linear and branched chain hydrocarbon groups including at least one C=C double bond and 2 to 18 (eg, 2 to 6) carbon atoms. Examples of alkenyl groups may be selected from ethenyl or vinyl (-CH═CH ₂ ), prop-1-enyl (-CH═CHCH ₃ ), prop-2-enyl (- CH ₂ CH═CH ₂ ), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-Methylbut-1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hex-1,3-dienyl group. The point of attachment can be on an unsaturated carbon or a saturated carbon.

Unless expressly stated, an alkenyl group may optionally be substituted by one or more substituents (eg, one, two, or three substituents, or 1 to 4 substituents, or up to number of hydrogens on the alkenyl group) are substituted in place of the unsubstituted hydrogen atoms of the alkenyl group. Unless otherwise specified, suitable substituents are selected, for example, from those listed above for alkyl groups.

The term "alkynyl" as used herein refers to a hydrocarbon group selected from straight and branched chain hydrocarbon groups including at least one -C≡C- triple bond and 2 to 18 (eg, 2 to 6) carbon atoms. Examples of alkynyl groups include ethynyl (-C≡CH), 1-propynyl (-C≡CCH ₃ ), 2-propynyl (propargyl, -CH ₂ C≡CH), 1-butanyl Alkynyl, 2-butynyl and 3-butynyl groups. The point of attachment can be on an unsaturated carbon or a saturated carbon.

Unless expressly stated, an alkynyl group may optionally be substituted by one or more substituents (eg, one, two, or three substituents, or 1 to 4 substituents, or up to number of hydrogens on the alkynyl group) are substituted in place of the unsubstituted hydrogen atoms of the alkynyl group. Unless otherwise specified, suitable substituents are selected, for example, from those listed above for alkyl groups.

The term "alkylene" refers to a divalent alkyl group containing 1 to 10 carbon atoms and two expanded valence bonds to other molecular moieties. The two molecular moieties attached to the alkylene group may be on the same carbon atom or on different carbon atoms. Thus, for example, propylene is a 3-carbon alkylene group which may be 1,1-disubstituted, 1,2-disubstituted or 1,3-disubstituted. Unless otherwise specified, alkylene refers to a moiety including 1 to 6 carbon atoms (eg, 1 to 4 carbon atoms). Representative examples of alkylene include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, sec-butylene, isobutylene, tert-butylene, n-pentylene base, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-Octyl, n-nonyl, n-decyl, etc. A substituted alkylene group is an alkylene group containing one or more (such as one, two or three) substituents; unless otherwise specified, suitable substituents are selected from, for example, as listed above Substituents for alkyl groups.

Unless expressly stated, an alkylene group may optionally be present in the unsubstituted number of hydrogen atoms on the alkylene group) in place of the unsubstituted hydrogen atoms of the alkylene group. Unless otherwise specified, suitable substituents are selected, for example, from those listed above for alkyl groups.

Similarly, "alkenylene" and "alkynylene" respectively refer to alkylene groups including double or triple bonds; for example, they are 2-6 (eg, 2-4) carbon atoms in length and may Substituted as discussed above for alkylene groups.

The term "haloalkyl" refers to a hydrocarbyl group, as defined herein, substituted with one or more halogen groups, as defined herein. Unless otherwise specified, the hydrocarbyl portion of a haloalkyl group includes 1 to 4 carbon atoms. The haloalkyl group may be monohaloalkyl, dihaloalkyl, trihaloalkyl or polyhaloalkyl (including perhaloalkyl). A monohaloalkyl group may have one iodine, bromine, chlorine or fluorine within the hydrocarbyl group. Dihaloalkyl groups and polyhaloalkyl groups may have two or more of the same halogen atoms or a combination of different halogen groups within the hydrocarbyl group. Polyhaloalkyl groups include, for example, up to 6, or 4, or 3, or 2 halogen groups. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, Difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. Perhaloalkyl refers to a hydrocarbon group in which all hydrogen atoms are replaced by halogen atoms (for example, trifluoromethyl). In some embodiments, unless otherwise specified, haloalkyl groups include monofluoro-, difluoro-, and trifluoro-substituted methyl and ethyl groups (e.g., -CF ₃ , -CF ₂ H, - CFH ₂ and -CH ₂ CF ₃ ).

Unless expressly stated otherwise, a haloalkyl group may optionally be substituted by one or more substituents (eg, one, two, or three substituents, or 1 to 4 substituents, or up to number of hydrogen atoms on the haloalkyl group) are substituted in place of the unsubstituted hydrogen atoms of the haloalkyl group. Unless otherwise specified, suitable substituents are selected, for example, from those listed above for alkyl groups.

As used herein, the term "haloalkoxy" refers to haloalkyl-O-, wherein haloalkyl is as defined above. Examples of haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, 2-chloroethoxy, 2,2,2-trifluoro Ethoxy, 1,1,1,3,3,3-hexafluoro-2-propoxy, etc. In some embodiments, haloalkoxy groups include 1-4 carbon atoms and up to three halogen elements, for example, monofluoro, difluoro and trifluoro substituted methoxy groups and ethoxy groups .

Unless expressly stated otherwise, a haloalkoxy group may optionally be substituted by one or more substituents (eg, one, two, or three substituents, or 1 to 4 substituents, or up to The number of hydrogens on the haloalkoxy group) is substituted for the hydrogen atoms of the unsubstituted alkyl portion of the haloalkoxy group. Unless otherwise specified, suitable substituents are selected from, for example, those listed above for alkyl groups, except that hydroxyl and amino groups are generally not present in direct connection with the oxygen of the substituted haloalkyl-O group on the carbon.

The term "cycloalkyl" as used herein refers to saturated and partially unsaturated cyclic hydrocarbon radicals (such as monocyclic and polycyclic (e.g., bicyclic and tricyclic, adamantyl and Spirocycloalkyl) group) hydrocarbyl. Monocycloalkyl groups are cyclic hydrocarbyl groups containing from 3 to 20 carbon atoms (eg, from 3 to 8 carbon atoms). Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecanyl, cyclododecyl, and cyclohexenyl. Bicycloalkyl groups include bridged bicycloalkyl, fused bicycloalkyl and spirocycloalkyl. Bridged bicycloalkyl contains a monocyclic cycloalkyl ring in which two non-adjacent carbon atoms of the monocyclic ring are bridged by an alkylene group of one to three additional carbon atoms (i.e., -(CH ₂ )n-form A bridging group, where n is 1, 2 or 3) is connected. Examples of bridged bicycloalkyl groups include, but are not limited to, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2 .2]nonane, bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane, etc. Fused bicycloalkyl contains a monocyclic cycloalkyl ring fused to one of phenyl, monocyclic cycloalkyl, and monocyclic heteroaryl. Examples of fused bicycloalkyl groups include, but are not limited to, bicyclo[4.2.0]oct-1,3,5-triene, 2,3-dihydro-1H-indene, 6,7-dihydro-5H-cyclo Penta[b]pyridine, 5,6-dihydro-4H-cyclopenta[b]thiophene and decalin, etc. Spirocycloalkyl groups contain two monocyclic ring systems that share carbon atoms to form a bicyclic ring system. Examples of spirocycloalkyl include, but are not limited to Bicyclic cycloalkyl groups include, for example, 7 to 12 carbon atoms. Monocycloalkyl or bicycloalkyl groups are attached to the parent molecular moiety through any carbon atoms contained within the cycloalkyl ring. A tricycloalkyl group includes a bridged tricycloalkyl group as used herein, which bridged tricycloalkyl refers to: 1) a bridged bicycloalkyl ring, wherein the bridged bicycloalkyl ring The two are incompatible The adjacent carbon atoms are connected through an alkylene bridge of one to three additional carbon atoms (i.e., a bridging group of the form -(CH ₂ )n-, where n is 1, 2, or 3); or 2) fused Bicycloalkyl rings in which the two non-shared ring atoms on each ring are bridged by an alkylene group of one to three additional carbon atoms (i.e., a bridging group of the form -(CH ₂ )n-, where n is 1, 2 or 3) linkage, where "fused bicycloalkyl ring" refers to a monocycloalkyl ring fused to a monocycloalkyl ring. Examples of bridged tricycloalkyl groups include, but are not limited to, adamantyl As used herein, a bridged tricycloalkyl group is attached to the parent molecular moiety through any ring atom. Ring atoms disclosed herein refer to carbon atoms in the ring backbone. Cycloalkyl groups may be saturated or include at least one double bond (ie, partially unsaturated), but are not fully conjugated and are not aromatic (as defined herein) cycloalkyl groups. Cycloalkyl groups may be substituted by at least one heteroatom selected from, for example, O, S and N.

Unless expressly stated otherwise, a cycloalkyl group may optionally be present in the unsubstituted The number of hydrogen atoms on the cycloalkyl group) is substituted in place of the hydrogen atoms of the unsubstituted cycloalkyl group. In some embodiments, substituted cycloalkyl groups contain 1-4, such as 1-2 substituents. Unless otherwise specified, suitable substituents are selected, for example, from those listed above for alkyl groups.

The term "cycloalkylene" or "cycloalkylene ring" disclosed herein refers to a divalent cycloalkane ring connected via the same carbon atoms of the cycloalkane ring by removing two hydrogen atoms from the same carbon atom. Examples of cycloalkylene rings include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene. It can be represented illustratively by the following structure, where n is 1, 2, 3, 4 or 5.

The term "heterocycloalkyl", "heterocyclyl" or "heterocycle" disclosed herein refers to a "cycloalkyl" as defined above in which at least one ring carbon atom is replaced by a heteroatom independently selected from O, N, S. base". Heterocyclyl groups include, for example, 1, 2, 3, or 4 heteroatoms, and each of N, C, and S can be independently oxidized in the cyclic ring system. N atoms can also be substituted to form tertiary amines or ammonium salts. The point of attachment to a heterocyclyl group can be on a heteroatom or on a carbon. "Heterocyclyl" herein also refers to a 5- to 7-membered saturated or partially unsaturated carbocyclic ring (heterocycle) including at least one heteroatom selected from, for example, N, O, and S, which carbocyclic ring is identical to the 5-membered , 6-membered and/or 7-membered cycloalkyl, heterocyclic or carbocyclic aromatic rings are fused, provided that when the heterocyclic ring is fused with the carbocyclic aromatic ring, the connection point is at the heterocyclic ring, and when the heterocyclic ring is fused with the carbocyclic aromatic ring, When an alkyl group is fused, the point of attachment can be at the cycloalkyl group or the heterocycle. "Heterocyclyl" as used herein also refers to an aliphatic spirocycle including at least one heteroatom selected from, for example, N, O, and S. The ring may be saturated or have at least one double bond (ie, partially unsaturated). Heterocyclyl groups may be substituted, for example, by oxo groups. The point of attachment can be a carbon or a heteroatom. Heterocyclyl is not heteroaryl as defined herein.

Examples of heterocycles include, but are not limited to, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, oxiranyl, aziridinyl, thiazanyl Cyclopropanyl, azetidinyl, oxetanyl, thietanyl, dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thio Oxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxeptanyl, thieptanyl, oxithianyl, dioxanyl , oxazepanyl, oxazepanyl, dithiazepanyl, thiazepanyl and diazepanyl, dithiazepanyl , azathianeyl, oxaza base, diazepine base, thiaazepine base, dihydrothienyl, dihydropyranyl, dihydrofuryl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, indolyl, dioxanyl, pyridyl Zozolinyl, dithiocyclohexanyl, dithiocyclopentanyl, pyrazolidinyl, imidazolinyl, pyrimidinonyl, 1,1-dioxo-thiomorpholinyl, 3 -Azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl and azabis Cycl[2.2.2]hexyl. Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholine base, 1,1-dioxo-1-thiomorpholinyl,

Unless expressly stated otherwise, a heterocyclyl group may optionally be present in the unsubstituted The number of hydrogen atoms on the heterocyclyl group) is substituted in place of the hydrogen atoms of the unsubstituted heterocyclyl group. In some embodiments, substituted heterocyclyl contains 1-4, such as 1-2 or 1-3 substituents. Unless otherwise specified, suitable substituents are selected, for example, from those listed above for alkyl groups.

The term "aryl" refers to an aromatic hydrocarbon group containing 5 to 15 carbon atoms in the ring portion. In some embodiments, aryl refers to a group selected from the group consisting of 5- and 6-membered carbocyclic aromatic rings, e.g., phenyl; selected from, e.g., naphthalene, indane, and 1,2,3,4-tetrahydroquinoline Bicyclic ring systems (such as 7- to 12-membered bicyclic ring systems in which at least one ring is carbocyclic and aromatic); and tricyclic ring systems (such as 10- to 15-membered tricyclic ring systems in which at least one ring is carbocyclic and aromatic), for example, fluorene.

In some embodiments, the aryl group is selected from a heterocycle fused to a 5- to 7-membered cycloalkyl group or optionally including at least one heteroatom selected from, for example, N, O, and S (e.g., "heterocycle" below). "base" or "heterocycle") of 5- and 6-membered carbocyclic aromatic rings, provided that when the carbocyclic aromatic ring is fused to the heterocyclic ring, the point of attachment is at the carbocyclic aromatic ring, and when the carbocyclic aromatic ring is fused to the heterocyclic ring When an aromatic ring is fused to a cycloalkyl group, the point of attachment can be at the carbocyclic aromatic ring or at the cycloalkyl group. A divalent group formed from a substituted benzene derivative and having a free valence at a ring atom is named a substituted phenylene group. A divalent group obtained by removing a hydrogen atom from a carbon atom with a free valence of a monovalent polycyclic hydrocarbon group whose name ends with "-yl" is named by adding "sub-base" to its corresponding monovalent group. For example, a naphthyl group with two points of attachment is called a naphthylene group. However, aryl does not include or overlap in any way with heteroaryl, which is separately defined below. Therefore, if one or more carbocyclic aromatic rings are fused to a heterocyclic aromatic ring (e.g., heteroaryl, as defined below), the resulting ring system is a heteroaryl, as defined herein, and not an aryl .

Unless expressly stated otherwise, an aryl group may optionally be substituted by one or more substituents (eg, one, two, or three substituents, or 1 to 4 substituents, or as many as 1 to 4 substituents present in the unsubstituted number of hydrogens on the aryl group) are substituted in place of the hydrogen atoms of the unsubstituted aryl group. In some embodiments, substituted aryl groups contain 1-5 substituents. Unless otherwise specified, suitable substituents are selected, for example, from those listed above for alkyl groups.

The term "heteroaryl" as used herein refers to a group selected from a 5- to 7-membered aromatic monocyclic ring that includes at least one (e.g., 1 to 4) heteroatoms, or In some embodiments, 1 to 3 heteroatoms) are selected from heteroatoms such as N, O, and S, wherein the remaining ring atoms are carbon; 8 to 12 membered bicyclic rings, the 8 to 12 membered bicyclic rings include at least One (e.g., 1 to 4 heteroatoms, or in some embodiments, 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms) is selected from the group consisting of, for example, N, O, and S Atoms wherein the remaining ring atoms are carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring and wherein the point of attachment is on any ring and is on a carbon or heteroatom; and 11-membered to 14-membered tricyclic rings, the 11- to 14-membered tricyclic rings include at least one (e.g., 1 to 4 heteroatoms, or in some embodiments, 1 to 3 heteroatoms, or in other embodiments, 1 or 2 heteroatoms) selected from heteroatoms such as N, O and S, wherein the remaining ring atoms are carbon, and where at least one ring is aromatic, and where at least one heteroatom is present in the aromatic ring, and where the point of attachment is on any ring.

In some embodiments, a heteroaryl group contains a 5- to 7-membered heterocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl ring. For such fused bicyclic heteroaryl ring systems in which only one ring includes at least one heteroatom, the point of attachment can be at the heteroaromatic ring or at the cycloalkyl ring.

In some embodiments, a heteroaryl group contains a 5- to 7-membered heterocyclic aromatic ring fused to a 5- to 7-membered aryl ring. For such fused bicyclic heteroaryl ring systems in which only one of the rings includes at least one heteroatom, the point of attachment can be at the heteroaromatic ring or at the aryl ring. Non-limiting examples include quinolinyl and quinazolinyl.

In some embodiments, a heteroaryl group contains a 5- to 7-membered heterocyclic aromatic ring fused to an additional 5- to 7-membered heterocyclic aromatic ring. Non-limiting examples include 1H-pyrazolo[3,4-b]pyridyl and 1H-pyrrolo[2,3-b]pyridyl.

When the total number of S atoms and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S atoms and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S atoms and O atoms in the aromatic heterocycle does not exceed 1.

Examples of heteroaryl groups include, but are not limited to, pyridyl, zolinyl, pyrazinyl, pyrimidinyl, imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiazolyl Diazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furyl, benzofuranyl, benzimidazolyl, indolyl, isoindolyl, indolinyl, phthalazine base, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, triazolyl, quinolyl, isoquinolyl, pyrazolyl, pyrrolopyridyl (such as 1H-pyrrolo[2,3-b] Pyridin-3-yl), pyrazolopyridyl (such as 1H-pyrazolo[3,4-b]pyridin-3-yl), benzoxazolyl (such as benzo[d]oxazole-6- base), pteridyl, purinyl, 1-oxa-2,3-oxazolyl, 1-oxa-2,4-oxazolyl, 1-oxa-2,5-oxazolyl, 1 -Oxa-3,4-oxadiazolyl, 1-thia-2,3-oxadiazolyl, 1-thia-2,4-oxadiazolyl, 1-thia-2,5-oxadiazolyl , 1-Thia-3,4-oxadiazolyl, furazyl, benzofurazyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, Naphthodinyl, furopyridyl, benzothiazolyl (such as benzo[d]thiazol-6-yl), indazolyl (such as 1H-indazol-5-yl) and 5,6,7,8- Tetrahydroisoquinoline.

Unless explicitly stated, a heteroaryl group may optionally be substituted by one or more substituents (eg, one, two, or three substituents, or 1 to 4 substituents, or up to The number of hydrogen atoms on the heteroaryl group) is substituted in place of the hydrogen atoms of the unsubstituted heteroaryl group. In some embodiments, substituted heteroaryl groups contain 1, 2, or 3 substituents. Unless otherwise specified, suitable substituents are selected, for example, from those listed above for alkyl groups.

Compounds disclosed herein may contain asymmetric centers and, therefore, may exist as enantiomers. Where compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to the broader category of stereoisomers. It is well known in the art how to prepare optically active bodies, for example by resolving materials or by asymmetric synthesis. All such possible stereoisomers (eg, substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereoisomers) are intended to be included. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are intended to be included. Unless otherwise explicitly mentioned, reference to one isomer applies to any one of the possible isomers. When no isomeric composition is specified, all possible isomers are included.

When a compound disclosed herein contains an olefinic double bond, such double bond is intended to encompass both E and Z geometric isomers, unless otherwise specified.

As used herein, "pharmaceutically acceptable salts" include, but are not limited to, salts with inorganic acids selected from, for example, hydrochlorides, phosphates, hydrogen phosphates, hydrobromides, sulfuric acid salts Salts, sulfinates and nitrates; and salts with organic acids selected from, for example, malates, maleates, fumarates, tartrates, succinates, citric acid Salt, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, alkanoate (such as acetate), and with Salts formed by HOOC-(CH2) _n -COOH, where n is selected from 0 to 4. Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium.

Furthermore, if a compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, the addition salt can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for the preparation of acid addition salts from base compounds (e.g. Pharmaceutically acceptable addition salts). One skilled in the art will recognize a variety of synthetic methods that can be used to prepare nontoxic pharmaceutically acceptable addition salts without undue experimentation. "Treating", "treat", "treatment" or "mitigation" refers to the administration of at least one compound disclosed herein, and/or at least One stereoisomer thereof (if any), at least one stable isotope thereof, or at least one pharmaceutically acceptable salt thereof.

The term "effective amount" refers to at least one compound disclosed herein, and/or at least one stereoisomer thereof, if any, that is effective for "treating" (as defined above) a disease or disorder in a subject ), at least one stable isotope thereof, or at least one pharmaceutically acceptable salt thereof.

Various embodiments are disclosed herein. It will be appreciated that features specified in each embodiment may be combined with other specified features to provide further embodiments of the disclosure. The following non-limiting enumeration of embodiments is representative of the present disclosure.

Embodiment 1. A compound of formula I:

Y is selected from:

R ¹ is selected from H, NH ₂ and optionally substituted C1-C3 alkyl;

R ⁴ is selected from H and optionally substituted C1-C6 alkyl;

R ⁶ is selected from H and optionally substituted C1-C3 alkyl;

X ¹ is selected from -O- and -C(R ⁷ ) ₂ -, where R ⁷ is selected from H, optionally substituted C1-C3 alkyl, optionally Substituted C1-C3 alkoxy, C6-C10 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S as ring members; or, wherein, R ⁴ , R ⁷ and the two carbon atoms located between R ⁴ and R ⁷ may together optionally form a group selected from C3-C6 cycloalkyl, saturated or unsaturated containing 1-2 selected from N, O and S 4-7-membered heterocyclyl, C6-C10 aryl, and 5-10-membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S as ring members. group; and

X ² is selected from -C(R ⁸ )-, or -X ² =X ³ - is selected from -[C(R ⁸ )=C(R ⁹ )]-, -[C(R ⁸ )=N]-, -[N＝C(R ⁹ )]-;

Wherein, R ⁸ and R ⁹ are independently selected from H, optionally substituted C1-C3 alkyl and -COOH.

Embodiment 2. The compound of Embodiment 1 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein ^R is selected from H and optionally Substituted C1-C3 alkyl.

Embodiment 3. The compound according to Embodiment 1 or 2 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein R ¹ is H.

Embodiment 4. The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-3, wherein R ² Selected from H, C1-C3 hydroxyalkyl and halogen.

Embodiment 5. The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-4, wherein R ² It's H.

Embodiment 6. The compound according to any one of embodiments 1-5 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein -N The (R ³ ) ₂ group is -NH ₂ .

Embodiment 7. The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-6, wherein R ⁴ Selected from H and optionally substituted C1-C3 alkyl.

Embodiment 8. The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-7, wherein R ⁴ It's CH ₃ .

Embodiment 9. The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-8, wherein R ⁵ Selected from H and halogen.

Embodiment 10. The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-9, wherein R ⁵ It's halogen.

Embodiment 11. The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-10, wherein R ⁵ It's Cl.

Embodiment 12. The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-11, wherein R ⁶ Selected from H and halogen.

Embodiment 13. The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-12, wherein R ⁶ It's H.

Embodiment 14. The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-13, wherein, X ¹ It's -O-.

Embodiment 15. The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-13, wherein, X ¹ is -C(R ⁷ ) ₂ -, said R ⁷ is selected from H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, C6-C10 aryl and containing 5-10 membered heteroaryl with 1-4 heteroatoms selected from N, O and S as ring members; or, wherein R ⁴ , R ⁷ and two carbons located between R ⁴ and R ⁷ The atoms may together optionally form a group selected from C3-C6 cycloalkyl, saturated or unsaturated 4-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S as ring members, C6- C10 aryl groups and 5-10 membered heteroaryl cyclic groups containing 1-4 heteroatoms selected from N, O and S as ring members.

Embodiment 16. The compound according to any one of embodiments 1-15, wherein ^-X2 = ^X3- is selected from -[C(R ⁸ )=C(R ⁹ )]-, -[C(R ⁸ )=N]-, -[N=C(R ⁹ )]-; where R ⁸ and R ⁹ are independently selected From H, optionally substituted C1-C3 alkyl and -COOH.

Embodiment 17. The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-16, wherein X ² Selected from -C(R ⁸ )-; wherein, R ⁸ is selected from H, optionally substituted C1-C3 alkyl and -COOH.

Embodiment 18. The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-17, wherein -X ² = ^X3 -is -[C( ^R8 )=C( ^R9 )]-; wherein ^R8 and ^R9 are independently selected from H, optionally substituted C1-C3 alkyl and -COOH.

Embodiment 19. The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-18, wherein R ⁸ Selected from H, -CH ₃ , -CF ₃ and -COOH.

Embodiment 20. The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-19, wherein R ⁹ Selected from H, -CH ₃ , -CF ₃ and -COOH.

Embodiment 21. The compound and/or a stereoisomer, ^stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-20, wherein Selected from -CH-, -CH(CH ₃ )-, -CH(CF ₃ )- and -CH(COOH)-.

Embodiment 22. The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-21, wherein -X ² ⁼ _{_} _{_} _{_} , -[CH=C(CF ₃ )]-, -[CH=C(COOH)]- and -[C(COOH)=CH]-.

Embodiment 23. The compound according to Embodiment 1 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein the compound is selected from the group consisting of Formula IA A compound wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X ¹ , X ² and X ³ are as defined in Embodiment 1.

Embodiment 24. The compound according to Embodiment 1 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein the compound is selected from the group consisting of Formula IB and IC, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X ¹ and X ² are as defined in Embodiment 1.

Embodiment 25. The compound according to Embodiment 1 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein the compound is selected from the group consisting of the following formula ID and IE, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ , X ¹ and X ² are as defined in Embodiment 1.

Embodiment 26. The compound according to Embodiment 1 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein the compound is selected from the group consisting of the following formula IF A compound of which R ¹ , R ² , R ³ , R ⁴ , R ⁵ and X ¹ are as defined in Embodiment 1.

Embodiment 27. The compound and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to any one of embodiments 1-26, wherein R ¹ is an optionally substituted C1-C3 alkyl group, wherein the optionally substituted C1-C3 alkyl group is substituted by 1-3 groups selected from =O, _-NH2 and -OH.

Embodiment 28. The compound of any one of embodiments 1-27 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein R ² is an optionally substituted C1-C3 alkyl group, wherein the optionally substituted C1-C3 alkyl group is substituted by 1-3 groups selected from =O, _-NH2 and -OH.

Embodiment 29. The compound of Embodiment 1 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein the compound is selected from the following compounds:

Embodiment 30. A pharmaceutical composition comprising a compound of any one of embodiments 1-29 admixed with at least one pharmaceutically acceptable carrier, and/or the Stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of a compound.

Embodiment 31. A method of treating a disease or disorder associated with SHP2 in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of any one of embodiments 1-29 A compound, and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of said compound, or a pharmaceutical composition as described in Embodiment 30.

Embodiment 32. The method of embodiment 31, wherein the method comprises determining whether the disease in the subject is a SHP2-related disease or disorder, and administering to the subject in need thereof a therapeutically effective SHP2-inhibiting amount. A compound as described in any one of embodiments 1-29, and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of said compound, or as described in embodiment 30 pharmaceutical compositions.

Embodiment 33. The method of embodiment 31 or 32, wherein the SHP2-associated disease or disorder is mediated by the activity of SHP2.

Embodiment 34. The method of embodiment 33, wherein the disease or disorder associated with SHP2 is selected from Noonan syndrome, leopard skin syndrome, juvenile myelomonocytic leukemia, melanoma, acute myeloid leukemia , breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma and glioblastoma.

Embodiment 35. The method of any one of embodiments 31-34, wherein the compound of any one of embodiments 1-29, and/or the stereoisomer of the compound is administered orally. isotope, or a pharmaceutically acceptable salt or solvate, or a pharmaceutical composition as described in Embodiment 30.

Embodiment 36. The compound of any one of embodiments 1-29, and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, or as implemented Use of the pharmaceutical composition described in Scheme 30 in the manufacture of a medicament for treating SHP2-related diseases or disorders.

Embodiment 37. The use of embodiment 36, wherein the SHP2-related disease or disorder is mediated by the activity of SHP2.

Embodiment 38. The use of embodiment 37, wherein the disease or disorder associated with SHP2 is selected from Noonan syndrome, leopard skin syndrome, juvenile myelomonocytic leukemia, melanoma, acute myeloid leukemia , breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma and glioblastoma.

Embodiment 39. The use of any one of embodiments 36-38, wherein the medicament is formulated for oral administration.

Embodiment 40. The compound of any one of embodiments 1-29, and/or the stereoisomer, stable isotope, or pharmaceutical composition of the compound for use in the treatment of SHP2-related diseases or disorders. An acceptable salt or solvate, or a pharmaceutical composition according to embodiment 30.

Embodiment 41. The medicament or pharmaceutical composition of embodiment 40, wherein the SHP2-related disease or disorder is SHP2-related cancer.

Embodiment 42. The medicament or pharmaceutical composition of embodiment 40 or 41, wherein the SHP2-related disease or disorder is a SHP2-related cancer, and the use includes determining whether the cancer in the subject is a SHP2-related cancer. , and administering a therapeutically effective amount of said compound or said composition to a subject in need thereof.

Embodiment 43. The medicament or pharmaceutical composition of any one of embodiments 40-42, wherein the SHP2-related cancer is selected from the group consisting of juvenile myelomonocytic leukemia, melanoma, acute myelogenous leukemia, and breast cancer. , esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma and glioblastoma.

Embodiment 44. A method for inhibiting the interaction with SHP2 using the compound of any one of embodiments 1-29, and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate of the compound. Methods related to SHP2 activity in cancer cells in vitro or in vivo.

In some embodiments, a compound of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF) has a chiral configuration exhibiting more than its enantiomers, and thus the compound is optically active . For example, this article discloses Such compounds are essentially free of opposite enantiomers (i.e., at least 95% of the compounds have the chirality shown above).

Also disclosed herein are pharmaceutical compositions comprising compounds of Formula I (eg, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or stereoisomers of compounds of Formula I isotopes, or pharmaceutically acceptable salts or solvates, and pharmaceutically acceptable carriers.

Further disclosed herein are methods for inhibiting the activity of SHP2, the method comprising combining protein SHP2 with an effective amount of a compound of Formula I (such as Formula IA, Formula IB, Formula IC, Formula ID, Formula IE or Formula IF) disclosed herein, and/ or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of a compound of formula I.

Further disclosed herein are methods of treating a treatable disease by inhibiting SHP2 in a patient, comprising administering to a patient identified in need of such treatment an effective amount of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula IA, Formula IB, Formula IC, Stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of compounds of formula ID, formula IE, or formula IF) and/or compounds of formula I.

Further disclosed herein are methods of treating a treatable disease by inhibiting SHP2 in a patient, comprising administering to a patient identified in need of such treatment an effective amount of a pharmaceutical composition comprising Formula I disclosed herein (e.g. Stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of compounds of formula IA, formula IB, formula IC, formula ID, formula IE or formula IF) and/or compounds of formula I, and pharmaceutical acceptable carrier.

Further disclosed herein are methods of treating cancer in a patient, comprising administering to a patient identified in need of such treatment an effective amount of a compound of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, or Formula IE) disclosed herein. A pharmaceutical composition of a compound of formula IF) and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of a compound of formula I, and a pharmaceutically acceptable carrier. In some embodiments, the cancer is selected from juvenile myelomonocytic leukemia, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma cell carcinoma, gastric cancer, anaplastic large cell lymphoma, and glioblastoma.

Further disclosed herein are compounds of Formula I (such as Formula IA, Formula IB, Formula IC, Formula ID, Formula IE or Formula IF) and/or stereoisomers, stable isotopes or pharmaceutically acceptable salts of the compounds of Formula I Or the use of the solvate in the preparation of a medicament for the treatment of a disease responsive to SHP2 inhibition, such as cancer. In some embodiments, the cancer is selected from juvenile myelomonocytic leukemia, melanoma, acute myelogenous leukemia, breast cancer, esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma , gastric cancer, anaplastic large cell lymphoma and glioblastoma.

Although the most appropriate route in any given situation will depend on the specific host to which the active ingredient is being administered, and the nature and severity of the condition, formulas including Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, The pharmaceutical composition of the compound of formula IE and formula IF), and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound of formula I, and a pharmaceutically acceptable carrier can be It is administered in various known ways, such as orally, topically, rectally, parenterally, by inhalation spray, or via an implantable kit. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, Intralesional and intracranial injection techniques or infusion techniques. The compositions disclosed herein may conveniently be presented in unit dosage form and prepared by any method known in the art.

Formula I (e.g., e.g. Compounds of Formula IA, Formula IB, Formula IC, Formula ID, Formula IE and Formula IF), and/or stereoisomers, stable isotopes, or pharmaceuticals of compounds of Formula I Scientifically acceptable salts or solvates. Compounds of Formula I (eg, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and /or stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of compounds of formula I. Others may also be used to administer compounds of Formula I (such as Formula IA, Formula IB, Formula IC, Formula ID, Formula IE and Formula IF), and/or stereoisomers, stable isotopes, or pharmaceutically acceptable compounds of Formula I. Acceptable dosage forms of the salt or solvate include ointments, creams, drops, skin patches or powders for topical administration, ophthalmic solutions or suspension forms for ocular administration (i.e., eye drops formulations), aerosol sprays or powder compositions for inhalation or intranasal administration, or creams, ointments, sprays or suppositories for rectal or vaginal administration.

Compounds containing formula I (such as formula IA, formula IB, formula IC, formula ID, formula IE and formula IF), and/or stereoisomers, stable isotopes, or pharmaceutically acceptable compounds of formula I may also be used. Gelatin capsules of salts or solvates and at least one powdery carrier (selected from, for example, lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc.). Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be formulated as sustained-release products to provide continuous release of the drug over a period of time. Compressed tablets may be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the environment, or enteric-coated to selectively break down in the gastrointestinal tract.

Liquid dosage forms for oral administration may also include at least one agent selected from colorants and flavoring agents to increase patient acceptance.

In general, water, suitable oils, saline, aqueous dextrose (glucose) solutions and related sugar solutions and glycols (such as propylene glycol or polyethylene glycol) may be suitable carriers for injectable solutions Example. Solutions for parenteral administration may include a water-soluble salt of at least one compound disclosed herein, at least one suitable stabilizer, and at least one buffering substance, if desired. Antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid, alone or in combination, may be examples of suitable stabilizers. Citric acid and its salts and sodium ethylenediaminetetraacetate (EDTA) may also be used as examples of suitable stabilizers. In addition, the injection solution may also include at least one preservative selected from, for example, benzalkonium chloride, methyl and propylparabens, and chlorobutanol.

Pharmaceutically acceptable carriers are selected, for example, from carriers that are compatible with (and, in some embodiments, capable of stabilizing the active ingredients) of the pharmaceutical composition and not deleterious to the subject to be treated. For example, solubilizers such as cyclodextrins (which can form specific more soluble complexes with at least one compound and/or at least one pharmaceutically acceptable salt disclosed herein) may be used for delivery of the active ingredient of pharmaceutical excipients. Examples of other carriers include colloidal silica, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments (eg, D&C Yellow #10). Suitable pharmaceutically acceptable carriers are disclosed in Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in the art.

Compounds of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or stereoisomers, stable isotopes, or pharmaceutical compounds of Formula I can be examined by in vivo assays. Acceptable Salts or Solvates for their Efficacy in the Treatment of Cancer. For example, a compound of Formula I (eg, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or a compound of Formula I can be administered to an animal (eg, a mouse model) suffering from cancer. Stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates, and their therapeutic effects can be obtained. The display of positive results by one or more of such tests is sufficient to add to the scientific knowledge base and, therefore, to demonstrate the utility of the tested compounds and/or salts. Based on the results, appropriate dosage ranges and routes of administration for animals (eg, humans) can also be determined.

For administration by inhalation, compounds of Formula I (eg, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE and Formula IF) can be conveniently delivered in the form of an aerosol spray from a pressurized package or a nebulizer, and /or stereoisomerism of compounds of formula I conformation, stable isotope, or pharmaceutically acceptable salt or solvate. Compounds of Formula I (such as Formula IA, Formula IB, Formula IC, Formula ID, Formula IE and Formula IF), and/or stereoisomers, stable isotope, or a pharmaceutically acceptable salt or solvate, and the powder composition can be inhaled via an inhaled powder inhalation device. An exemplary delivery system for inhalation may be a metered dose inhalation (MDI) aerosol, which may be formulated as Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of compounds of formula I in at least one suitable propellant selected from, for example, fluorocarbons and hydrocarbons compound) in suspensions or solutions.

For ocular administration, an appropriate weight percent of a compound of Formula I (eg, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or a compound of Formula I may be used in a suitable ophthalmic vehicle. Formulate ophthalmic preparations using solutions or suspensions of stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates, such that Formula I (such as Formula IA, Formula IB, Formula IC, Formula ID, Formula Compounds of formula IE and formula IF), and/or stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of compounds of formula I remain in contact with the optic surface for a period of time sufficient to allow penetration of the compound into the eye cornea and internal areas.

For use in administering compounds of Formula I (such as Formula IA, Formula IB, Formula IC, Formula ID, Formula IE and Formula IF), and/or stereoisomers, stable isotopes, or pharmaceutically acceptable compounds of Formula I Useful pharmaceutical dosage forms of the salts or solvates include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral vascular injections, and oral suspensions.

The dose administered will depend on a variety of factors (such as the age, health and weight of the recipient, the extent of the disease, the type of concurrent treatment (if any), the frequency of treatment and the nature of the desired effect). Typically, the daily dose of active ingredient may, for example, range from 0.1 mg/day to 2000 mg/day. For example, 10-500 mg once a day or multiple times a day can be effective in obtaining desired results.

In some embodiments, compounds of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or stereoisomers, stable isotopes, or pharmaceutically acceptable compounds of Formula I Acceptable salts or solvates are available as 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, 400 mg, and 500 mg. The amount is present in the capsule.

In some embodiments, a compound of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or the stereoisomerism of a compound of Formula I can be prepared by administering, for example, 100 mg of a powder form. form, stable isotope, or pharmaceutically acceptable salt or solvate, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate. Fill each of standard two-piece hard gelatin capsules to prepare large quantities. Unit capsule.

In some embodiments, compounds of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or stereoisomers, stable isotopes, or pharmaceutically acceptable compounds of Formula I A mixture of an acceptable salt or solvate and a digestible oil (such as soybean oil, cottonseed oil, or olive oil) can be prepared and injected into the gelatin with the aid of a positive displacement pump to form gelatin containing 75 mg or 100 mg. Soft gelatin capsule with active ingredient. Wash and dry capsules.

In some embodiments, compounds of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or stereoisomers, stable isotopes, or pharmaceutically acceptable compounds of Formula I Acceptable salts or solvates may be in amounts from 1 mg to 500 mg, such as 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 200 mg, 250 mg , 300mg, 400mg and 500mg are present in tablets.

In some embodiments, large quantities of tablets may be prepared by conventional procedures such that a dosage unit includes, for example, 100 mg of a compound of Formula I (eg, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or Stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of a compound of formula I, 0.2 mg silica colloid, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch, and 98.8 mg lactose. Suitable coatings may be applied, for example, to increase palatability or to delay absorption.

In some embodiments, the compound of Formula I (eg, Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or Stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of the compounds are used to prepare parenteral compositions suitable for administration by injection. The solution was brought to the desired volume using water for injection and sterilized.

In some embodiments, aqueous suspensions can be prepared for oral administration. For example, stereoisomers including 100 mg of finely separated compounds of formula I (such as formula IA, formula IB, formula IC, formula ID, formula IE and formula IF) and/or a compound of formula I per 5 ml may be used. , stable isotope, or pharmaceutically acceptable salt or solvate, 100 mg sodium carboxymethylcellulose, 5 mg sodium benzoate, 1.0 g sorbitol solution (U.S.P.) and 0.025 ml vanillin in an aqueous suspension.

When a compound of Formula I (such as Formula IA, Formula IB, Formula IC, Formula ID, Formula IE and Formula IF), and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt of a compound of Formula I, or When the solvate is administered stepwise or co-administered with at least one other therapeutic agent, the same dosage form can generally be used. When drugs are administered in physical combinations, the dosage form and route of administration should be selected based on the compatibility of the combined drugs. The term "co-administration" is therefore understood to include the administration of at least two agents simultaneously or sequentially, or alternatively as a fixed dose combination of at least two active ingredients.

Compounds of Formula I (such as Formula IA, Formula IB, Formula IC, Formula ID, Formula IE and Formula IF), and/or stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvents of compounds of Formula I The compound may be administered as the sole active ingredient or in combination with at least one second active ingredient selected, for example, from the group known to be effective in treating the target disease in a patient, such as cancer, including, for example, colon cancer, Other active ingredients useful in gastric cancer, leukemia, lymphoma, melanoma and pancreatic cancer).

As used herein, the term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present disclosure, and includes geometric isomers . It will be understood that substituents may be attached at the chiral center of the carbon atom. The term "chiral" refers to molecules that have non-overlapping properties on their mirror image partners, whereas the term "achiral" refers to molecules that have overlapping properties on their mirror image partners. The present disclosure encompasses enantiomers, diastereomers, or racemates of the compounds. "Enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, this term is used to designate racemic mixtures. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog IR-SJ system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon can be specified by R or S. Resolved compounds whose absolute configuration is unknown can be assigned (+) or (-) depending on the direction in which they rotate plane-polarized light (dextrorotatory or levorotatory) at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and thereby can give rise to enantiomers, diastereoisomers and others that may be defined with respect to absolute stereochemistry as (R)- Or the stereoisomeric form of (S)-.

Depending on the choice of starting materials and synthetic procedure, compounds can be in the form of one of the possible isomers or as a mixture thereof (e.g., as pure optical isomers) or as a mixture of isomers (according to the asymmetric carbon number of atoms, such as racemates and diastereomeric mixtures)) present. This disclosure encompasses all such possibilities isomers (including racemic mixtures, diastereomeric mixtures and optically pure forms). Optical (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration unless otherwise specified. If a compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent may have a cis or trans configuration unless otherwise specified.

In many cases, the compounds of the present disclosure are capable of forming acid salts and/or base salts due to the presence of amino groups and/or carboxyl groups or groups similar thereto. As used herein, the term "salt" refers to an acid addition salt or a base addition salt of a compound of the present disclosure. "Salt" specifically includes "pharmaceutically acceptable salt". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present disclosure and generally are not biologically or otherwise undesirable.

Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, for example, acetates, adipates, aluminum salts, ascorbates, aspartates, benzoates, benzenesulfonates , bromide/hydrobromide, hydrocarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caproate, chloride/hydrochloride, chloroprocaine, chlorophylline Salt (chlortheophyllonate), citrate, ethylenediaminetetraacetate, calcium edetate, ethandisulfonate, ethyl sulfonate, ethylenediamine, fumarate, galactose galactarate (mucate), glucoheptonate, gluconate, glucuronate, glutamate, glycolate, hexyl resorcinate ), hippurate, hydroiodide/iodide, hydroxynapthoate (xinafoate), isethionate, lactate, lactosuronate, lauryl sulfate Salt, lithium salt, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, Octearate, Oleate, Oxalate, Palmitate, Pamoate, Pantothenate, Phosphate/Hydrogen Phosphate/Dihydrogen Phosphate, Polygalacturonate, Pluca Cain, propionate, salicylate, sebacate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, tannin, tartrate, tartaric acid Hydrogen salts, tosylate, triphenyl acetate and trifluoroacetate. Can be found in, for example, REMINGTON'S PHARMACEUTICAL SCIENCES, 20th ed., Mack Publishing Company, Easton, Pa., (1985) and HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION, AND USE, by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002 ) to find an additional list of suitable salts. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethylsulfonate acid, toluenesulfonic acid, trifluoroacetic acid, sulfosalicylic acid, etc.

Pharmaceutically acceptable base addition salts can be formed with inorganic or organic bases, and can have inorganic or organic counterions.

Inorganic counterions of such basic salts include, for example, ammonium salts and metals from Groups I to XII of the Periodic Table. In certain embodiments, the counterion is selected from sodium, potassium, ammonium, alkylammonium having one to four C1-C4 alkyl groups, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts Contains ammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like. Suitable organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present disclosure can be synthesized from the basic or acidic moieties by conventional chemical methods. Typically, the free acid forms of these compounds are reacted with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates of Na, Ca, Mg or K, etc.) or the free base forms of these compounds are Such salts can be prepared by reaction with stoichiometric amounts of the appropriate acid. Such reactions are usually carried out in water or in organic solvents or in water and a mixture of organic solvents. Generally, the use of non-aqueous media such as diethyl ether, ethyl acetate, tetrahydrofuran, toluene, chloroform, methylene chloride, methanol, ethanol, isopropanol or acetonitrile is desired where feasible.

Any formula given herein is intended to represent the unlabeled form of a compound (ie, a compound in which all atoms are present in natural isotopic abundance and are not isotopically enriched) as well as isotopically enriched or labeled forms. An isotopically enriched or labeled compound has a structure depicted by the formula given herein, except that at least one atom of the compound is substituted by an atomic mass or mass number of the same element but with an atomic mass or mass number that is different from the naturally occurring atomic mass or atomic mass distribution. Atomic substitution. Examples of isotopes that may be incorporated into enriched or labeled compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, respectively , ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I. The present disclosure encompasses various isotopically labeled compounds as defined herein, for example those in which radioactive isotopes (such as 3H and 14C) or non-radioactive isotopes (such as ² H and ¹³ C) those compounds. These isotopically labeled compounds are useful in metabolic studies (using ¹⁴ C), reaction kinetic studies (using, for example, ² H or ³ H), detection techniques, or imaging techniques such as positron emission tomography including drug or matrix tissue distribution determination. (PET) or single photon emission computed tomography (SPECT)), or radioactive therapy of patients. In particular, ^18F or labeled compounds may be particularly desirable for PET studies or SPECT studies. Isotopically labeled reagents may generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying Examples and Preparations, using appropriate isotopically labeled reagents in place of previously employed unlabeled reagents. Compounds of formula I.

Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., ^H or D), may provide certain therapeutic advantages derived from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements or therapeutic index improvement). It will be understood that deuterium is considered herein to be a substituent in the compounds of Formula I if incorporated at levels substantially above the natural isotope abundance. The present disclosure encompasses isotopically enriched variations of compounds (eg, deuterated as well as non-deuterated variations). Deuterated variations can be deuterated at a single site or at multiple sites.

The degree of incorporation of such isotopes (especially deuterium) in an isotopically enriched compound can be defined by the isotope enrichment coefficient. As used herein, the term "isotopic enrichment coefficient" means the ratio between the isotopic abundance of a particular isotope in a sample and the natural abundance of that isotope in a non-enriched sample. If a substituent in a compound of the present disclosure is labeled deuterium, such compound has for each designated deuterium atom at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation) , at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping) , an isotope enrichment factor of at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

Pharmaceutically acceptable solvates according to the present disclosure include those in which the solvent crystallization may be isotopically substituted (eg, _D2O , d6-acetone, _d6 -DMSO), as well as those with non-enriched solvents Solvates.

As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents Agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavor enhancers, dyes, etc. and combinations thereof, as those skilled in the art have Known (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except in the event that any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

The term "therapeutically effective amount" of a compound of the present disclosure means one that will cause a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity), or ameliorate symptoms, alleviate a condition, slow or delay disease progression, or prevention Amounts of compounds of the present disclosure for diseases, etc. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that, when administered to a subject, is effective to: (1) at least partially alleviate, inhibit, Preventing and/or ameliorating a condition or disorder or disease (i) mediated by a kinase (e.g., SHP2) or (ii) associated with the activity of a kinase (e.g., SHP2) or (iii) based on the activity of SHP2 (normal or abnormal); or (2) reduce or inhibit the activity of SHP2 or (3) reduce or inhibit the expression of SHP2.

In additional non-limiting embodiments, the term "therapeutically effective amount" refers to an amount of a compound of the present disclosure that is effective, at least in part, when administered to a cell or tissue or non-cellular biological material or medium. Reduce or inhibit the activity of SHP2 or at least partially reduce or inhibit the expression of SHP2.

As used herein, the term "subject" refers to an animal. Typically, animals are mammals. Subjects also refer to, for example, primates (eg, humans, male or female animals), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In certain embodiments, the subject is human.

As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, activity, effect, symptom, or disorder, or disease, or A significant decrease in the baseline activity of a biological activity or process.

As used herein, in one embodiment, the terms "treat," "treating," or "treatment" of any disease or disorder refer to ameliorating the disease or disorder (i.e., slowing or preventing or Reduce the development of the disease or at least one of its clinical symptoms). In additional embodiments, "treat," "treating," or "treatment" refers to alleviating or improving at least one physical parameter (including those physical parameters that are not discernible by the patient). In additional embodiments, "treat," "treating," or "treatment" refers to physical aspects (e.g., stabilization of discernible symptoms), physiological aspects (e.g., improvement of physical parameters). stabilizing), or regulating disease or disorder in the body and physiology. In additional embodiments, "treat," "treating," or "treatment" refers to delaying the development or progression of a disease or disorder.

As used herein, a subject has an affirmative "need" for such treatment if such subject is expected to benefit biologically, medically, or in terms of quality of life.

As used herein, the terms "a", "an", "the" and similar terms used in the context of this disclosure (especially in the context of the claims) will be understood to mean Covers both the singular and the plural unless otherwise indicated herein or otherwise clearly contradicted by context.

All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (eg, "such as") provided herein is intended merely to better illuminate the disclosure and does not otherwise limit the scope of the claimed disclosure.

Any asymmetric atom (e.g., carbon, etc.) of one or more compounds of the present disclosure may be in a racemic or enantiomerically enriched configuration (e.g., (R)-, (S)-, or (R)- ,S)-configuration) exists. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, (R)- or (S)-configuration Isomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess; i.e., for optical activity Compounds, for example, typically use one enantiomer to the substantial exclusion of the other. Where possible, substituents at atoms with carbon-carbon double bonds may be present in the cis-(Z)- or trans-(E)-form, and unless otherwise stated, both are included within this disclosure.

Thus, as used herein, a compound of the present disclosure may be in the form of one of the possible isomers, rotamers, atropisomers, or as a mixture thereof (e.g., as a substantially pure geometric (cis) (form or trans) isomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof). As used herein, "substantially pure" or "substantially free of other isomers" means that the product contains less than 5% by weight (e.g., less than 2% by weight) relative to the amount of the preferred isomer. % by weight) of other isomers.

Any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers on the basis of physicochemical differences in the components, for example by chromatography and/or fractional crystallization. body, racemate.

Any resulting racemate of the final product or intermediate product may be converted into a racemate by known methods (for example, by isolating a diastereomeric salt to obtain an optically active acid or base, and releasing the optically active acidic compound or optically basic compound). Split into optical antipodes. In particular, basic moieties may thereby be employed to resolve the compounds of the present disclosure into their optical antipodes, for example, by fractional crystallization with an optically active acid (e.g., tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, Salts formed from di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid). Racemic products can also be resolved by chiral chromatography (eg, high pressure liquid chromatography (HPLC) using chiral adsorbents).

In addition, the compounds of the present disclosure (including salts thereof) may also be obtained in the form of their hydrates or contain other solvents for their crystallization. The compounds of the present disclosure may form solvates, intrinsically or by design, with pharmaceutically acceptable solvents, including water; thus, the present disclosure is intended to encompass both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the present disclosure (including pharmaceutically acceptable salts thereof) and one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field and known to be harmless to the recipient (eg, water, ethanol, etc.). The term "hydrate" refers to a complex in which the solvent molecule is water.

Schemes 1-2 illustrate general methods for preparing compounds and intermediates of the present disclosure. Detailed descriptions and synthetic methods are disclosed in the examples below. One skilled in the art will be able to find other synthetic methods or modify the methods described below using conventional chemistry to prepare suitable compounds encompassed by Formula I. Accordingly, these methods are equally applicable to the preparation of compounds of other embodiments. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be readily substituted to provide a variety of compounds and/or reaction conditions.

Compounds of formula I can be prepared by the general synthetic methods illustrated in Scheme 1. The heteroaryl thiol of formula 3 can be prepared by a two-step method: first, the compound of formula 1 (Z ₁ is Cl, Br or -OTf) and 2-ethylhexyl 3-mercaptopropionate of formula 2 are prepared under Pd catalytic conditions. (such as tris(dibenzylideneacetone)palladium (Pd ₂ (dba) ₃ ), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos) and diisopropyl ethylamine in tetrahydrofuran or dioxane solution) and then treated with potassium tert-butoxide in tetrahydrofuran. Heteroarylthiols 3 can be synthesized under Pd catalyzed conditions (such as tris(dibenzylideneacetone)palladium (Pd ₂ (dba) ₃ ), 4,5-bis(diphenylphosphine)-9,9-dimethyl Xantphos and diisopropylethylamine in tetrahydrofuran in dioxane are reacted with a compound of Formula 4 ( _Z2 and _Z3 are independently Cl, Br or -OTf) to provide a compound of Formula 5. Coupling the compound of formula 5 and the amine of formula 6 by nucleophilic substitution reaction or by Buchwald-Hartwig reaction gives the compound of formula I.

Alternatively, the amine of Formula 6 can be converted to the compound of Formula 7 by coupling the amine of Formula 6 to the compound of Formula 4 via a nucleophilic substitution reaction or Buchwald-Hartwig reaction. Compounds of formula 7 and heteroaryl thiols of formula 3 under Pd catalytic conditions (such as tris(dibenzylideneacetone)palladium (Pd ₂ (dba) ₃ ), 4,5-bis(diphenylphosphine)-9, 9-Dimethylxanthene (Xantphos) and diisopropylethylamine are coupled in tetrahydrofuran or dioxane solution) to obtain the compound of formula I.

Compounds of Formula 7 can also be converted to heteroaryl thiols of Formula 8 by the same two-step process as described above for compounds of Formula 3. The compound of formula 8 and the compound of formula 1 are coupled under Pd catalytic conditions (for example, tris(dibenzylideneacetone)palladium (Pd ₂ (dba) ₃ ), 4,5-bis(diphenylphosphine)-9, 9-dimethylxanthene (Xantphos) and diisopropylethylamine in tetrahydrofuran or dioxane solution) to obtain the compound of formula I.

plan 1

Compounds of formula I (wherein X ¹ is selected from CH, N, CR ⁵ and X ² is CH) can be synthesized by the general synthesis method illustrated in Scheme 2 below. The compound of formula 4 and the heteroaryl thiol of formula 9 are synthesized under Pd catalyzed conditions (such as tris(dibenzylideneacetone)palladium (Pd ₂ (dba) ₃ ), 4,5-bis(diphenylphosphine)-9 , 9-dimethylxanthene (Xantphos) and diisopropylethylamine in tetrahydrofuran or dioxane solution) are coupled to obtain the compound of formula 10. The compound of formula 10 and the amine of formula 6 can obtain the compound of formula 11 through nucleophilic substitution reaction or Buchwald-Hartwig reaction. Alternatively, the compound of formula 7 and the heteroaryl thiol of formula 9 can be synthesized under Pd catalyzed conditions (for example, tris(dibenzylideneacetone)palladium (Pd ₂ (dba) ₃ ), 4,5-bis(diphenyl) (Xantphos)-9,9-dimethylxanthene (Xantphos) and diisopropylethylamine in tetrahydrofuran or dioxane solution) are coupled to obtain the compound of formula 11. Compounds of formula 11 can be converted to compounds of formula I by reaction with suitable reagents at elevated temperatures in alcoholic solvents such as ethanol and isopropyl alcohol. For example, a suitable reagent for compounds of formula I (X ¹ =X ² =CH) may be 2-chloroacetaldehyde or for compounds of formula I (X ¹ =CCH ₃ , X ² =CH) may be 1- Bromo-2,2-dimethoxypropane; or the compound of formula I (X ¹ =CCF ₃ , X ² =CH) may be 3-bromo-1,1,1-trifluoropropyl-2- ketone.

Scenario 2

Example

The following examples illustrate certain embodiments of the disclosure and how to make and use them. Therefore, the following examples are not intended to limit the scope of the invention. Those skilled in the art will readily recognize that various non-critical parameters and conditions can be changed or modified to produce substantially the same results. The following example compounds were found to be inhibitors of SHP2 according to one or more of the assays described herein.

In the following examples, the following abbreviations are used:
BINAP 2,2'-bis(diphenylphosphine)-1,1'-binaphthyl
BOC tert-butoxycarbonyl
Boc ₂ O di-tert-butyl dicarbonate
B ₂ (Pin) ₂ bis(pinacol)diboron
BTEAC Benzyltriethylammonium Chloride
CDI carbonyldiimidazole
dba dibenzylideneacetone
DCE 1,2-dichloroethylene
DCM dichloromethane
DHP Dihydropyran
DIAD diisopropyl azodicarboxylate
DIPEA Diisopropylethylamine
DMA dimethylacetamide
DMAP 4-dimethylaminopyridine
DMF dimethylformamide
DMSO dimethyl sulfoxide
Dppf 1,1'-Bis(diphenylphosphine)ferrocene
EDCI N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride
EDTA ethylenediaminetetraacetic acid
EtOAc Ethyl acetate
EtOH ethanol
Et ₃ BHLi Lithium triethylborohydride
HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
IPA isopropyl alcohol
KHMDS potassium hexamethyldisilazane
KO ^t Bu Potassium tert-butoxide
LiHMDS Lithium hexamethyldisilazane
LG leaving group
LDA lithium diisopropylamide
MeOH methanol
MsCl methanesulfonyl chloride
MTBE Methyl tert-butyl ether
NMM N-methylmorpholine
NMP N-methylpyrrolidone
NCS N-chlorosuccinimide
Pd ₂ dba ₃ tris(dibenzylideneacetone)palladium
Pd(dppf)Cl ₂ [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride
PE petroleum ether
PG protecting group
PPTS Pyridinium p-toluenesulfonate
Prep-TLC preparative thin layer chromatography
PTSA p-toluenesulfonic acid
N-Fluoro-N'-(chloromethyl)triethylenediaminebis(tetrafluoroborate)
TBAF Tetra-n-butylammonium fluoride
TBDMSCl tert-butyldimethylsilyl chloride
TEA triethylamine
TES triethylsilane
TFA trifluoroacetic acid
Tf trifluoromethanesulfonyl
Tf ₂ O trifluoromethanesulfonic anhydride
TLC thin layer chromatography
THF Tetrahydrofuran
THP tetrahydropyran
TMS trimethylsilyl
TsOH p-toluenesulfonic acid
TosMIC tosylmethyl isonitrile
Xantphos 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene
XPhos 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl

Example 1

(3S,4S)-8-(5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo Preparation of hetero-8-azaspiro[4.5] decane-4-amine hydrochloride

Step 1: 4-Bromo-3-chloropyridin-2-amine

A solution of 4-bromo-3-chloro-2-fluoropyridine (25 g, 118.8 mmol) in ammonia (28%, 200 mL) was stirred in an autoclave at 120°C for 2 hours. The mixture was cooled to room temperature and extracted with DCM (500 mL x 2). The _resulting organic layers were combined, washed with water (100 mL x 2), dried over _Na2SO4 , filtered and concentrated to give the product as a white solid (24 g, yield: 98%).

Step 2: 2-ethylhexyl 3-((2-amino-3-chloropyridin-4-yl)thio)propionate

To the product of the above step 1 (24g, 115.7mmol), 2-ethylhexyl 3-mercaptopropionate (27.8g, 127.3mmol), Pd ₂ dba ₃ (2.65g, 2.9mmol), Xantphos (3.35g, 5.79 mmol) and DIPEA in dioxane (240 mL) (30g, 231.4mmol) solution was charged with _N2 and stirred at 110°C for 4 hours. The mixture was cooled to room temperature and filtered. The filtrate was diluted with EtOAc (1000 mL), washed with water (300 mL x 2 ₎ and brine (300 mL), dried over _Na2SO4 , filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=5/1-2/1) to obtain the title compound (43 g, yield: ~100%).

Step 3: 2-Amino-3-chloropyridine-4-thiol

To a solution of the product of step 2 above (5.0 g, 14.5 mmol) in THF (40 mL) was slowly added KOtBu/THF (4.9 g/44 mL) at -78 °C under _N2 protection. After the addition was complete, the mixture was stirred at -78°C for 30 minutes. The mixture was allowed to warm to room temperature and concentrated. The residue was purified by silica gel flash column chromatography (DCM/MeOH=50/1 to 10/1) to obtain the title compound (1.7 g, yield: 74%).

Step 4: 3-chloro-4-((5-chloropyridin-2-yl)thio)pyridin-2-amine

The product of the above step 3 (700mg, 4.37mmol), 2-bromo-5-chloropyrazine (931mg, 4.8mmol), Pd ₂ dba ₃ (200mg, 0.218mmol), Xantphos (253mg, 0.437mmol) solution and A solution of DIPEA (1.13 g, 8.75 mmol) in dioxane (7 mL) was charged with N ₂ and stirred at 110° C. for 6 hours. The mixture was cooled to room temperature and concentrated. The residue was stirred with EtOAc (100 mL) and filtered. The filtrate was concentrated and purified by C18 reverse phase column flash column chromatography (MeOH/H ₂ O) to obtain the title compound (655 mg, yield: 55%).

Step 5: (3S,4S)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa- 8-Azaspiror [4.5]Decyl-4-amine

To the product of step 4 above (214 mg, 0.783 mmol), (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (200 mg, 0.735 mmol) and A solution of DIPEA (304 mg, 2.35 mmol) in NMP (2 mL) was charged with _N2 and stirred at 130 °C for 18 h. The mixture was purified by flash column chromatography (MeOH/ _H2O ) on a C18 reverse phase column to give the crude title compound (396 mg, crude yield: >100%).

Step 6: ((3S,4S)-8-(5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa -8-azaspiro [4.5]Decyl-4-yl)carbamic acid tert-butyl ester

To an ice-water cooled solution of the product from step 5 above (396 mg, crude, ~0.783 mmol) and TEA (238 mg, 2.35 mmol) in THF was added Boc ₂ O (205 mg, 0.94 mmol). The mixture was warmed to room temperature, stirred for 0.5 hours, and then concentrated. The residue was purified by silica gel flash column chromatography to obtain the title compound (205 mg, yield: 50%).

Step 7: ((3S,4S)-8-(5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3-methyl -2-oxa-8- Azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester

To a solution of the product from step 6 above (1.7 g, 3.35 mmol) in EtOH (25 mL) was added 2-chloroacetaldehyde (1.9 g, 10 mmol) at room temperature. The mixture was stirred at reflux overnight. The mixture was concentrated, diluted with water (10 mL) and extracted with DCM/MeOH (10/1, 150 mL). The organic layer was washed with saturated _NaHCO3 solution ₍ 50 mL), water (50 mL) and brine (50 mL), dried over _Na2SO4 , and concentrated to give the crude title compound. The crude title compound was used in the next step without further purification.

Step 8: (3S,4S)-8-(5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3-methyl- 2-oxa-8-nitrogen Heterospiro[4.5]decyl-4-amine hydrochloride

A solution of the product from step 7 above (crude, from the previous step) in 4N HCl/dioxane was stirred at room temperature overnight. The suspension was concentrated and the solid was triturated with MTBE (25 mL) and filtered. The filter cake was collected and dried under vacuum to give the title compound (1.6 g, yield: ~100%). MS (ESI) m/z: 431.2[M+1]+; ¹ H NMR (400MHz, DMSO-d6) δ8.67 (d, J = 7.2Hz, 1H), 8.53 (s, 1H), 8.36 (m ,5H),8.12(s,1H),6.91(d,J＝7.0Hz,1H),4.34-4.21(m,3H),3.95(d,J＝8.9Hz,2H),3.64(d,J＝ 8.9Hz,1H),3.36(s,1H),3.15(m,2H),1.87(s,2H),1.65(m,2H),1.23(d,J＝6.4Hz,3H).

Example 2

(3S,4S)-8-(5-((8-chloro-2-methylimidazol[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3-methyl -Preparation of 2-oxa-8- azaspiro[4.5]decane-4-amine hydrochloride

Step 1: ((3S,4S)-8-(5-((8-chloro-2-methylimidazol[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)- 3-Methyl-2-oxo Hetero-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester

To a solution of the product of step 6 of Example 1 (50 mg, 0.099 mmol) in isopropyl alcohol (1 mL) was added 1-bromo-2,2-dimethoxypropane (22 mg, 0.118 mmol). The mixture was stirred at 80°C overnight, cooled to room temperature and concentrated. The residue was purified by reverse phase preparative HPLC (5-95% MeOH/ _H2O , 30 min). The product-containing fractions were freeze-dried overnight to obtain the desired product (32 mg, yield: 59%).

Step 2: (3S,4S)-8-5-((8-chloro-3-methylimidazol[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3- Methyl-2-oxa- 8-Azaspiro[4.5]decane-4-amine hydrochloride

To a solution of the product from step 1 above (32 mg, 0.00587 mmol) in EA (5 mL) was added 2N HCl/EA (3 mL). The mixture was stirred at room temperature for 2 hours and concentrated. The residue was purified by reverse phase preparative HPLC (5-95% MeOH/ _H2O , 30 min). The product-containing fractions were freeze-dried overnight to obtain the desired product (7 mg, yield: 26%). MS(ESI)m/z:445.2[M+1]+; ¹ H NMR(400MHz, DMSO-d6)δ8.42(s,1H),8.30(d,J＝9.3Hz,2H),7.73(s ,1H),6.38(d,J＝7.1Hz,1H),4.08(s,1H),3.90(s,2H),3.69(d,J＝8.5Hz,1H),3.50(d,J＝8.2Hz ,1H),3.47–3.37(m,3H),2.94(d,J＝4.5Hz,1H),2.33(s,3H),1.76(m,1H),1.66(m,1H),1.54(m, 2H), 1.09 (d, J = 6.3Hz, 3H).

Example 3

(3S,4S)-8-(5-((8-chloro-3-methylimidazol[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3-methyl Preparation of -2-oxa-8-azaspiro [4.5]decane-4-amine

To a solution of the product of step 6 of Example 1 (100 mg, 0.197 mmol) in EtOH (1.5 mL) was added 2-bromo-1,1-dimethoxypropane (108 mg, 0.592 mmol) and TsOH·H ₂ O (7mg), 0.04mmol). The mixture was stirred at reflux for 12 hours. The reaction was cooled to room temperature, neutralized with saturated NaHCO ₃ solution, and extracted with DCM (20 mL × 2). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative TLC to obtain the title compound (11 mg, yield: 12%). MS (ESI) m/z: 445.2[M+1]+; ¹ H NMR (400MHz, CD ₃ OD) δ8.29 (d, J = 3.2 Hz, 2H), 8.03 (d, J = 7.3 Hz, 1H ),7.35(s,1H),6.54(d,J＝7.2Hz,1H),4.29–4.22(m,1H),4.14–4.04(m,2H),3.89(d,J＝8.7Hz,1H) ,3.73(d,J＝8.7Hz,1H),3.48–3.42(m,1H),3.41–3.35(m,1H),3.04(d,J＝4.9Hz,1H),2.48(s,3H), 1.90–1.81(m,1H),1.78(m,1H),1.76–1.64(m,2H),1.23(d,J＝6.5Hz,3H).

Example 4

(3S,4S)-8-(5-((8-chloro-2-(trifluoromethyl)imidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl) Preparation of -3-methyl-2-oxa -8-azaspiro[4.5]decane-4-amine hydrochloride

To a solution of the product of step 6 of Example 1 (75 mg, 0.148 mmol) in EtOH (1 mL) was added 3-bromo-1,1,1-trifluoropropyl-2-one (56.5 mg, 0.296 mmol). The mixture was stirred at reflux for 12 hours. The mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC (MeOH/H ₂ O = 10%-90%) to obtain the free base. The free base was treated with 2N HCl/EtOAc and concentrated to give the hydrochloride salt (30 mg, yield: 37%). MS (ESI) m/z: 499.2[M+1]+; ¹ H NMR (400MHz, DMSO-d6) δ8.60 (s, 1H), 8.48 (d, J = 0.7Hz, 1H), 8.44 (d ,J＝7.3Hz,1H),8.34(d,J＝1.0Hz,1H),6.58(d,J＝7.3Hz,1H),4.36–4.14(m,3H),3.94(d,J＝9.0Hz ,1H),3.65(d,J＝9.0Hz,1H),3.36(m,1H),3.20–3.06(m,2H),1.82(m,2H),1.76–1.55(m,2H),1.24( d,J＝6.5Hz,3H).

Example 5

7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio Preparation of 8-chloroimidazo [1,2-a]pyridine-3-carboxylic acid

Step 1: 7-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8 -base) Pyrazin-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester

To a solution of the product of step 6 of Example 1 (300 mg, 0.592 mmol) in EtOH (4 mL) was added ethyl 2-chloro-3-oxopropionate (185 mg, 1.184 mmol). The mixture was stirred at 60°C for 6 hours and then cooled to room temperature. The mixture was diluted with EA (50 mL), washed with saturated _NaHCO3 (10 mL) solution and brine (20 mL), dried over _Na2SO4 , filtered and concentrated _. The residue was purified by silica gel flash column chromatography (PE/EA=10/1 to 1/1) to obtain the title compound (320 mg, yield: 89%).

Step 2: 7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazine-2- base)thio)- 8-Chloroimidazo[1,2-a]pyridine-3-carboxylic acid

To a solution of the product from step 1 above (320 mg, 0.53 mmol) in THF (5 mL) was added aqueous NaOH (1 N, 3 mL) at room temperature. The mixture was stirred at room temperature for 4 hours and then concentrated to remove THF. The aqueous residue was adjusted to pH 4-5 with IN HCl and the mixture was stirred for 2 hours. The reaction mixture was extracted with DCM/MeOH (10/1, 20 mL×3). The combined organics were concentrated and purified by reverse phase flash column chromatography (5-95% MeOH/ _H2O ) to give the title compound (35 mg, yield: 18%). MS(ESI)m/z:475.2[M+1]+; ¹ H NMR(400MHz, DMSO-d6)δ9.28(d,J＝7.2Hz,1H),8.42(s,1H),8.28(s ,1H),7.89(s,1H),6.54(d,J＝7.2Hz,1H),4.13(m,3H),3.85(d,J＝8.7Hz,1H),3.62(d,J＝8.7Hz ,1H),3.32(m,1H),3.22(m,2H),1.82–1.51(m,4H),1.18(d,J＝6.3Hz,3H).

Example 6

7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio Preparation of 8-chloroimidazo [1,2-a]pyridine-2-carboxylic acid trifluoroacetic acid

Step 1: 7-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8 -base)pyridine Ethyl azin-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-2-carboxylate

To a mixture of the product of step 6 of Example 1 (280 mg, 0.55 mmol) in DME (5 mL) was added ethyl 3-bromo-2-oxopropionate (162 mg, 0.83 mmol) while cooling in an ice-water bath. The mixture was stirred at room temperature overnight and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=1/1 to DCM/MeOH=20/1) to obtain the title compound (170 mg, yield: 51%).

Step 2: 7-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane- 8-yl)pyridine Azin-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-2-carboxylic acid

A mixture of the product from step 1 above (170 mg, 0.29 mmol) and LiOH·H ₂ O (25 mg, 0.59 mmol) in THF/H ₂ O (6/2 mL) was stirred at 20°C for 2 hours. The reaction was adjusted to pH 5-6 by 6N HCl. The _mixture was extracted with DCM/MeOH (10/1, 50 mL), dried over _Na2SO4 and concentrated. The residue was purified by preparative TLC (DCM/MeOH=10/1) to obtain the title compound (81 mg, yield: 50%).

Step 3: 7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazine-2- base)thio)-8- Chloroimidazo[1,2-a]pyridine-2-carboxylic acid trifluoroacetic acid

To an ice-cold solution of the product from step 2 above (40 mg, 0.069 mmol) in DCM (2 mL) was slowly added TFA (1 mL). The mixture was stirred at room temperature for 2 hours, diluted with DCM (2 mL) and concentrated. The residue was triturated with EtOAc (5 mL), filtered and dried to give the title compound (35 mg, yield: 90%). MS(ESI)m/z:475.1[M+1]+; ¹ H NMR(400MHz, DMSO-d6)δ8.51(s,1H),8.47(s,1H),8.39(d,J＝7.3Hz ,1H),8.34(s,1H),7.95(s,3H),6.51(d,J＝7.3Hz,1H),4.29–4.14(m,3H),3.88(d,J＝9.1Hz,1H) ,3.69(d,J＝8.9Hz,1H),3.41(m,1H),3.16(m,2H),1.72(m,3H),1.58(m,1H),1.21(d,J＝6.6Hz, 3H).

Example 7

(3S,4S)-8-(5-((4-chloro-1H-indazol-5-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-nitrogen Preparation of heterospiro[4.5]decane-4- amine-trifluoroacetate

Step 1: 5-Bromo-4-chloro-1H-indazole-1-carboxylic acid tert-butyl ester

To a solution of 5-bromo-4-chloro-1H-indazole (1.0 g, 4.32 mmol) in THF (5 mL) was added Boc ₂ O (1.4 g, 6.48 mmol) and DMAP (52 mg, 0.43 mmol). The mixture was stirred at room temperature for 1 hour and then diluted with EA (100 mL). The mixture was washed with water (30 mL x 2) and brine (30 mL), dried over _Na2SO4 , filtered and concentrated to give the title compound (1.4 g, yield: 98% ₎ .

Step 2: 2-ethylheptyl 3-((4-chloro-1H-indazol-5-yl)thio)propionate

The product of the above step 1 (2.0g, 6.04mmol), 2-ethylheptyl 3-mercaptopropionate (1.7g, 7.85mmol), Pd ₂ dba ₃ (274mg, 0.3mmol), XantPhos (347mg, 0.6mmol) A mixture of DIPEA (1.5 g, 12.1 mmol) in dioxane (15 mL) was charged with _N2 and stirred at 110 °C overnight. The mixture was cooled to room temperature, diluted with EA (100 mL), washed with water ₍ 30 mL x 2) and brine (30 mL), dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash column chromatography (DCM/EtOAc=5/1 to 3/2) to obtain the title compound (1.6 g, yield: 57%).

Step 3: 4-Chloro-1H-indazole-5-thiol

A mixture of the product from step 2 above (1.6 g, 3.42 mmol) in anhydrous THF (20 mL) was cooled to -78°C and a solution of KOtBu (1.2 g, 10.2 mmol) in THF (6 mL) was added. The mixture was stirred at -78°C for 1 hour, heated to -10°C, treated with K ₂ CO ₃ aqueous solution (2M, 50mL), and extracted with MTBE (50mL×2). The aqueous phase was adjusted to pH=5-6 with HCl (6N) under ice-water cooling. The mixture was extracted with DCM/IPA (50 _mL ×2), washed with brine (50 mL), dried over _Na2SO4 , filtered and concentrated to give the title compound (510 mg, yield: 51%).

Step 4: ((3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decyl-4-yl)amino Tertiary formate Butyl ester

To 2,5-dibromopyrazine (357 mg, 1.5 mmol) and (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decyl-4-amine dihydrochloride ( 1.95mmol, 1.3mmol) DIPEA (775mg, 6.0mmol) was added to the solution of NMP (10mL). The mixture was stirred at 110°C overnight and then cooled to room temperature. Boc ₂ O (491 mg, 2.25 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 2 hours, diluted with EA (100 mL), washed with water ₍ 30 mL x 2) and brine (30 mL), dried over _Na2SO4 , filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=4/1 to 3/2) to obtain the title compound (540 mg, yield: 85%).

Step 5: ((3S,4S)-8-(5-((4-chloro-1H-indazol-5-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa -8-Azaspiro[4.5] Decan-4-yl)carbamic acid tert-butyl ester

To the product of step 3 above (200mg, 0.70mmol), the product of step 4 above (273mg, 0.64mmol), Pd ₂ dba ₃ (55mg, 0.06mmol), XantPhos (75mg, 0.13mmol) and DIPEA (165mg, 1.28mmol) ) in dioxane (5 mL) was purged with nitrogen and stirred at 110°C overnight. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with water (30 mL x 2) and brine (30 mL), dried over _Na2SO4 , _filtered and concentrated. The residue was purified by silica gel flash column chromatography (DCM/EtOAc=3/2) to obtain the title compound (200 mg, yield: 45%).

Step 6: (3S,4S)-8-(5-((4-chloro-1H-indazol-5-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa- 8-Azaspiro[4.5] Decan-4-yl)amine trifluoroacetate

To a solution of the product of step 5 above (200 mg, 0.32 mmol) in DCM (5 mL) was added TFA (2 mL) under ice-water cooling. The mixture was stirred at room temperature for 2 hours, diluted with DCM (2 mL) and concentrated. The residue was purified by reverse phase flash column chromatography (5-95% MeOH/ _H2O ) to give the title compound (125 mg, yield: 72%). MS(ESI)m/z:431.3[M+1]+; ¹ H NMR(400MHz, DMSO-d6)δ8.31(s,1H),8.12(s,1H),8.07(s,1H),7.93 (b,3H),7.51(d,J＝8.7Hz,1H),7.30(d,J＝8.6Hz,1H),4.22–4.03(m,3H),3.85(d,J＝9.0Hz,1H) ,3.66(d,J＝9.0Hz,1H),3.37(s,1H),3.13–2.98(m,1H),1.68(m,3H),1.53(m,1H),1.19(d,J＝6.5 Hz,3H).

Example 8

(3S,4S)-8-(6-amino-5-((4-chloro-1H-indazol-5-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa Preparation of -8-azaspiro[4.5] decane-4-amine trifluoroacetate

Step 1: 6-chloro-3-((4-chloro-1H-indazol-5-yl)thio)pyrazin-2-amine

To 3-bromo-6-chloropyrazin-2-amine (208 mg, 1.0 mmol), the product of step 3 of Example 7 (340 mg, 1.8 mmol), Pd ₂ dba ₃ (92 mg, 0.1 mmol), Xantphos (116 mg , 0.2 mmol), and DIPEA (260 mg, 2.0 mmol) in dioxane (5 mL) was charged with N ₂ and stirred at 110 °C overnight. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with water ₍ 30 mL x 2) and brine (30 mL), dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash column chromatography (DCM/EtOAc=4/1-2/1) to obtain the title compound (210 mg, yield: 68%).

Step 2: ((3S,4S)-8-(6-amino-5-((4-chloro-1H-indazol-5-yl)thio)pyrazin-2-yl)-3-methyl- 2-oxa-8-nitrogen Heterospiro[4.5]decan-4-yl)carbamic acid tert-butyl ester

The product of the above step 1 (210mg, 0.67mmol), (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine dihydrochloride (149mg, 0.61 mmol), DIPEA (330 mg, 2.55 mmol) in NMP (5 mL) was stirred at 100°C overnight. The mixture was cooled to room temperature and Boc ₂ O (167 mg, 0.77 mmol) was added. The mixture was stirred at room temperature for 2 hours, diluted with EtOAc (100 mL), washed with water ( ₃₀ mL x 2) and brine (30 mL), dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative TLC (DCM/EtOAc=1/1) to obtain the title compound (140 mg, yield: 38%).

Step 3: (3S,4S)-8-(6-amino-5-((4-chloro-1H-indazol-5-yl)thio)pyrazin-2-yl)-3-methyl-2 -oxa-8-nitrogen Heterospiro[4.5]decane-4-amine trifluoroacetate

To a solution of the product of step 2 above (140 mg, 0.22 mmol) in DCM (5 mL) was slowly added TFA (2 mL) while cooling with an ice-water bath. The mixture was stirred at room temperature for 2 hours, diluted with DCM (2 mL) and concentrated. The residue was purified by reverse-phase flash column chromatography (MeOH/H ₂ O = 10%-95%) to obtain the title compound (35 mg, yield: 25%). MS (ESI) m/z: 445.3[M+1]+; ¹ H NMR (400MHz, CD ₃ OD) δ8.07 (s, 1H), 7.54 (s, 1H), 7.39 (d, J = 8.8Hz ,1H),7.08(d,J＝8.8Hz,1H),4.43–4.11(m,3H),3.99(d,J＝9.2Hz,1H),3.88(d,J＝9.3Hz,1H),3.45 –3.39(m,1H),3.20–3.02(m,2H),1.88–1.64(m,4H),1.33(d,J＝6.5Hz,3H).

Example 9

(3S,4S)-8-(5-((4-chloro-3-methyl-1H-indazol-5-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo Preparation of hetero-8-azaspiro[4.5] decane-4-amine hydrochloride

Step 1: 2-ethylhexyl 3-((4-chloro-3-iodo-1H-indazol-5-yl)thio)propionate

To a solution of the product of step 2 in Example 7 (2.0 g, 5.43 mmol) in DMF (30 mL) was added KOH (0.9 g, 16.3 mmol) and I ₂ (2.8 g, 10.9 mmol). _The mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with _EtOAc (100 mL) and washed with _Na2S2O3 (aq. sat., 30 mL), water (30 mL) and brine (30 mL), dried _over _Na2SO4 , Filter and concentrate. The residue was purified by silica gel flash column chromatography (PE/EtOAc=3/1) to obtain the title compound (2.0 g, yield: 75%).

Step 2: 2-ethylhexyl 3-((4-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)thio)propionate ester

To a solution of the product from step 1 above (2.0 g, 4.05 mmol) in DCM (30 mL) was added TsOH·H ₂ O (78 mg, 0.41 mmol) and DHP (510 mg, 6.07 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (100 mL) and washed with _NaHCO3 (aq, 30 mL), water (30 mL) and brine (30 mL), dried over _Na2SO4 , filtered and concentrated _. The residue was purified by silica gel flash column chromatography (PE/EtOAc=8/1) to obtain the title compound (1.7 g, yield: 73%).

Step 3: 3-((4-chloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)thio)propionic acid 2-ethyl Hexyl ester

To the product of the above step 2 (1.3g, 2.25mmol), 2,4,6-trimethyl-1,3,5,2,4,6-triphenylboroxane (1.4g, 11.2mmol), A mixture of Pd(dppf)Cl ₂ ·DCM (180 mg, 0.22 mmol) and K ₂ CO _{3 (} 0.9 g, 6.75 mmol) in dioxane/H ₂ O (15/3 mL) was charged with N ₂ and incubated at 105 Stir overnight at ℃. The mixture was cooled to room temperature. The reaction mixture was diluted with EtOAc (100 mL), washed with water (30 mL x 2 ₎ and brine (30 mL), dried over _Na2SO4 , filtered and concentrated. The residue was purified by silica gel flash column chromatography (DCM/EtOAc=10/1~8/1) to obtain the title compound (490 mg, yield: 47%).

Step 4: 4-Chloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-thiol

A solution of the product from step 3 above (570 mg, 1.22 mmol) in anhydrous THF (10 mL) was cooled to -78°C and a solution of KOtBu (411 mg, 3.67 mmol) in THF (6 mL) was added. After the mixture was stirred at -78°C for 1 hour, it was warmed to -10°C, and K ₂ CO ₃ solution (2N, 20 mL) was added thereto. The reaction mixture was extracted with MTBE (30 mL×2). Use 6N HCl in an ice-water bath to adjust the pH value of the aqueous phase to 5-6, and extract the aqueous phase with DCM/IPA (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over _Na2SO4 , filtered and concentrated _. The residue was purified by preparative TLC (PE/EtOAc=2/1) to obtain the title compound (260 mg, yield: 76%).

Step 5: ((3S,4S)-8-(5-((4-chloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl) )Thio)pyrazine-2- tert-butyl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

To the product of step 4 above (105 mg, 0.37 mmol), the product of step 4 of Example 7 (122 mg, 0.29 mmol), Pd ₂ dba ₃ (27 mg, 0.03 mmol), Xantphos (33 mg, 0.06 mmol) and DIPEA (74 mg, A mixture of 0.57 mmol) in dioxane (5 mL) was charged with _N2 and stirred at 100 °C overnight. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with water ₍ 30 mL x 2) and brine (30 mL), dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative TLC (PE/EtOAc=1/1) to obtain the title compound (80 mg, yield: 45%).

Step 6: (3S,4S)-8-(5-((4-chloro-3-methyl-1H-indazol-5-yl)thio)pyrazin-2-yl)-3-methyl- 2-oxa-8-nitrogen Heterospiro[4.5]decane-4-amine hydrochloride

To a solution of the product from step 5 above (80 mg, 0.13 mmol) in MeOH (3 mL) was slowly added HCl/dioxane (4 N, 2 mL) while cooling in an ice-water bath. The mixture was stirred at 40°C for 1 hour, then diluted with DCM (2 mL) and concentrated. The residue was purified by reverse-phase flash column chromatography (MeOH/H ₂ O = 10%-90%) to obtain the title compound (66 mg, yield: 100%). MS(ESI)m/z:445.3[M+1]+; ¹ H NMR(400MHz, CD ₃ OD)δ8.45(s,1H),8.06(s,1H),7.48(s,2H),4.24 (d,J＝45.5Hz,3H),3.98(d,J＝9.0Hz,1H),3.85(d,J＝9.3Hz,1H),3.46(s,1H),3.30–3.20(m,2H) ,2.79(s,3H),1.91(s,3H),1.75(s,1H),1.30(d,J＝6.7Hz,3H).

Example 10

(3S,4S)-8-(5-((7-chloro-1H-indazol-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-nitrogen Preparation of heterospiro[4.5]decane-4- amine hydrochloride

Step 1: 4-Bromo-3-chloro-2-fluorobenzaldehyde

A solution of 1-bromo-2-chloro-3-fluorobenzene (10 g, 47.75 mmol) in anhydrous THF (45 mL) was added dropwise to LDA (50 mL, 50 mmol, 1 M) under a nitrogen atmosphere at -78°C. The mixture was stirred at -78°C for 1 hour, then DMF (5.22g, 71.53mmol) was slowly added. The resulting mixture was warmed to -20°C and quenched with saturated _NH4Cl solution (35 mL). The mixture was extracted with EtOAc ₍ 200 mL), washed with brine (30 mL), dried over _Na2SO4 and concentrated. The residue was purified by silica gel flash column chromatography (PE) to obtain the title compound as a white solid (9.0 g, yield: 80%).

Step 2: 6-bromo-7-chloro-1H-indazole

To a solution of the product from step 1 above (9.0 g, 37.90 mmol) in THF (38 mL) was added hydrazine hydrate (38 mL, 85%) at room temperature. The mixture was stirred at 90°C overnight. The reaction mixture was concentrated in vacuo. The residue was triturated with water and the solid collected by filtration. The solid was washed with water (2 x 50 mL) and dried under vacuum to give the title compound as a white solid (8.77 g, yield: 100%).

Step 3: 2-methylhexyl 3-((7-chloro-1H-indazol-6-yl)thio)propionate

To the solution of the product of step 2 above (5.5g, 23.76mmol) in dioxane (60mL), 2-methylhexyl 3-mercaptopropionate (5.19g, 23.76mmol) and DIPEA (6.13g, 47.52mmol) were added ), Xantphos (1.38g, 2.38mmol) and Pd ₂ (dba) ₃ (435mg, 0.48mmol). The mixture was stirred at 110°C overnight under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated and the residue was dissolved in EtOAc (200 mL), washed with water ₍ 50 mL) and brine (40 mL), dried over _Na2SO4 and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=50/1 to 10/1) to obtain the title compound (3.08 g, yield: 37%).

Step 4: 7-Chloro-1H-indazole-6-thiol

To a solution of the product of step 3 above (1.5 g, 4.23 mmol) in THF (15 mL), t-BuOK (1.42 g, 12.7 mmol) was added dropwise at -78°C under a nitrogen atmosphere. The reaction was stirred at -78°C for 1 hour. The pH of the reaction mixture was adjusted to 5 with HCl (6N) at -15°C. The reaction mixture was concentrated, and the residue was extracted with DCM/IPA (3/1, 2 × 200 mL), dried over Na ₂ SO ₄ , and concentrated to obtain the title compound (662 mg, yield: 100%)

Step 5: 7-Chloro-6-mercapto-1H-indazole-1-carboxylic acid tert-butyl ester

To a solution of the product from step 4 above (500 mg, 2.71 mmol) in THF (10 mL) was added DMAP (33 mg, 0.271 mmol) and (Boc) ₂ O (885 mg, 4.06 mmol) at 0 °C. The reaction solution was stirred for 1 hour while raising the temperature to 0°C. The reaction mixture was concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=50/1 to 10/1) to obtain the title compound (439 mg, yield: 57%).

Step 6: 6-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8 -base)pyridine Azin-2-yl)thio)-7-chloro-1H-indazole-1-carboxylic acid tert-butyl ester

To a solution of the product of step 5 above (180 mg, 0.631 mmol) in dioxane (4 mL), the product of step 4 of Example 7 (179 mg, 0.421 mmol), DIPEA (109 mg, 0.842 mmol), and Xantphos (24 mg, 0.0421mmol) and Pd ₂ (dba) ₃ (19mg, 0.0211mmol). The mixture was stirred at 110°C overnight under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated. The residue was _dissolved in EtOAc (100 mL), washed with water (20 mL) and brine (20 mL), dried over _Na2SO4 and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=1/1) to obtain the title compound (87 mg, yield: 33%).

Step 7: (3S,4S)-8-(5-((7-chloro-1H-indazol-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa- 8-Azaspiro[4.5] Decane-4-amine hydrochloride

To a solution of the product from step 6 above (87 mg 0.138 mmol) in EtOAc (1 mL) was added HCl/EtOAc (4 mL, 2M). The mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration, washed with EtOAc, and dried under vacuum to obtain the title compound (56 mg, yield: 81%). MS(ESI)m/z:431.3[M+1]+; ¹ H NMR(400MHz, DMSO-d6)δ8.39(s,1H),8.29(s,3H),8.20(s,1H),8.14 (s,1H),7.63(d,J＝8.4Hz,1H),6.79(d,J＝8.4Hz,1H),4.18(m,3H),3.91(d,J＝9.0Hz,1H),3.63 (d,J＝9.0Hz,1H),3.34(m,1H),3.08(m,2H),1.78(m,2H),1.62(m,2H),1.22(d,J＝6.4Hz,3H) .

Example 11

6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio Generation)-7-chloro-1H- Preparation of indazole-3-carboxylic hydrochloride

Step 1: 2-methylhexyl 3-((7-chloro-3-iodo-1H-indazol-6-yl)thio)propionate

To a solution of the product of step 3 in Example 10 (1.38 g, 3.89 mmol) in DMF (20 mL) was added I ₂ (1.97 g, 7.78 mmol) and KOH (0.653 g, 11.67 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 6 hours. The resulting mixture was diluted with EtOAc (120 mL), washed with water (50 mL), Na ₂ SO _{3 (} 50 mL) and brine (30 mL), dried over Na ₂ SO ₄ and concentrated to give the title compound (2.07 g, yield: 100%) .

Step 2: 7-Chloro-6-((3-((2-methylhexyl)oxy)-3-oxopropyl)thio)-1H-indazole-3-carboxylic acid ethyl ester

To a solution of the product from step 1 above (1.87 g, 3.89 mmol) in EtOH (40 mL) was added TEA (1.41 g, 14.0 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (273 mg, 0.389 mmol). The mixture was stirred overnight at 80°C under a carbon monoxide filled balloon. Then, the mixture was filtered and the filtrate was concentrated. The residue was extracted with EtOAc (200 mL), washed with water ( ₄₀ mL) and brine (40 mL), dried over _Na2SO4 and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=8/1 to 4/1) to obtain the title compound (1.1 g, yield: 60%).

Step 3: 7-Chloro-6-((3-((2-methylhexyl)oxy)-3-oxopropyl)thio)-1H-indazole-1,3-dicarboxylic acid 1- tert-butyl 3-ethyl ester

To a solution of the product of step 2 above (1.1 g, 2.58 mmol) in THF (15 mL) was added DMAP (31 mg, 0.258 mmol) and (Boc) ₂ O (842 mg, 3.86 mmol) at 0 °C. The reaction mixture was stirred for 4 hours while gradually raising the temperature to room temperature. The reaction mixture was concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=15/1 to 8/1) to obtain the title compound (625 mg, yield: 46%).

Step 4: 1-tert-butyl 3-ethyl 7-chloro-6-mercapto-1H-indazole-1,3-dicarboxylate

To a solution of the product of step 3 above (625 mg, 1.186 mmol) in THF (5 mL), a solution of t-BuOK (400 mg, 3.558 mmol) in THF (5 mL) was added dropwise at -78°C and a nitrogen atmosphere. The reaction mixture was stirred at -78°C for 1 hour and the pH was adjusted to 5 with HCl (6N) at -15°C. The reaction mixture was concentrated. The residue was dissolved in EtOAc (100 mL), washed with water ₍ 30 mL) and brine (30 mL), dried over _Na2SO4 and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=4/1) to obtain the title compound (303 mg, yield: 72%).

Step 5: 6-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8 -base)pyridine Azin-2-yl)thio)-7-chloro-1H-indazole-1,3-dicarboxylate 1-tert-butyl 3-ethyl ester

To the solution of the product of step 4 above (240 mg, 0.673 mmol) in dioxane (4 mL), the product of step 4 in Example 7 (191 mg, 0.448 mmol), DIPEA (173 mg, 1.344 mmol), and XantPhos (51 mg, 0.0896mmol) and Pd ₂ (dba) ₃ (41 mg, 0.0448mmol). The mixture was stirred at 110°C overnight under nitrogen atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was _dissolved in EtOAc (100 mL), washed with water (20 mL) and brine (20 mL), dried over _Na2SO4 and concentrated. The obtained residue was purified by Pre-TLC (PE/EtOAc=1/1) to obtain the title compound (24 mg, yield: 8%).

Step 6: 1-(tert-butoxycarbonyl)-6-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-aza miscellaneous snail [4.5]Decan-8-yl)pyrazin-2-yl)thio)-7-chloro-1H-indazole-3-carboxylic acid

To a solution of the product from step 5 above (24 mg, 0.034 mmol) in THF/MeOH/water (1.5 mL/1.0 mL/0.5 mL) was added LiOH·H ₂ O (6 mg, 0.0.137 mmol). The mixture was stirred at 45°C for 6 hours. The reaction mixture was concentrated and diluted with water (2 mL). The resulting mixture was adjusted to pH 5 with HCl (1N) at 0°C and extracted with EtOAc (60 mL). The organic layer was _washed with water (10 mL), dried over _Na2SO4 and concentrated. The residue was purified by preparative TLC (DCM/MeOH=10/1) to obtain the title compound (7 mg, yield: 30%).

Step 7: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazine-2- base)thio)-7- Chloro-1H-indazole-3-carboxylic acid hydrochloride

To a solution of the product from step 6 above (7 mg, 0.0104 mmol) in EtOAc (1 mL) was added HCl/EtOAc (2 mL, 2M). The mixture was stirred at room temperature for 4 hours. The precipitate was collected and washed with EtOAc and dried in vacuo to give the title compound (3 mg, yield: 56%). MS(ESI)m/z:475.2[M+1]+.

Example 12

(3S,4S)-8-(5-((1H-pyrazolo[4,3-b]pyridin-7-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo Preparation of hetero-8-azaspiro[4.5] decane-4-amine trifluoroacetate

Step 1: 7-Bromo-1H-pyrazolo[4,3-b]pyridine-1-carboxylic acid tert-butyl ester

To a solution of 7-bromo-1H-pyrazolo[4,3-b]pyridine (1.0g, 5mmol) in THF (10mL) was added Boc ₂ O (1.65g, 7.5mmol) and DMAP (62mg, 0.5mmol) . The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc ₍ 100 mL), washed with water (30 mL x 2) and brine (30 mL), dried over _Na2SO4 , filtered and concentrated to give the title compound (1.14 g, yield: 75%).

Step 2: 7-((3-((2-ethylhexyl)oxy)-3-oxopropyl)thio)-1H-pyrazolo[4,3-b]pyridine-1-carboxylic acid Uncle Ding base ester

The product of the above step 1 (1.14g, 3.8mmol), 2-ethylheptyl 3-mercaptopropionate (917mg, 4.2mmol), Pd ₂ dba ₃ (174mg, 0.19mmol), Xantphos (220mg, 0.38mmol) and A mixture of () DIPEA (982 mg, 7.6 mmol) in dioxane (10 mL) was charged with _N2 and stirred at 110°C overnight. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with water ₍ 30 mL x 2) and brine (30 mL), dried over _Na2SO4 , filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=4/1-1/1) to obtain the title compound (700 mg, yield: 42%).

Step 3: 7-Mercapto-1H-pyrazolo[4,3-b]pyridine-1-carboxylic acid tert-butyl ester

A mixture of the product of step 2 above (700 mg, 1.6 mmol) in anhydrous THF (20 mL) was cooled to -78°C and a solution of t-BuOK (541 mg, 4.8 mmol) in THF (10 mL) was added. The mixture was stirred at -78°C for 1 hour, warmed to -10°C, diluted with K ₂ CO ₃ solution (2N, 50 mL), and extracted with MTBE (50 mL × 2). Adjust the pH value of the aqueous phase to 5-6 with HCl (6N) while cooling in an ice-water bath, and extract with DCM/IPA (50 mL×2). The combined organic layers were _washed with brine (50 mL), dried over _Na2SO4 , filtered and concentrated to give the title compound (270 mg, yield: 67%).

Step 4: 7-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8 -base)pyridine Azin-2-yl)thio)-1H-pyrazolo[4,3-b]pyridine-1-carboxylic acid tert-butyl ester

To the product of step 3 above (270 mg, 1.07 mmol), the product of step 4 of Example 7 (412 mg, 0.96 mmol), Pd ₂ dba ₃ (40 mg, 0.05 mmol), Xantphos (62 mg, 0.1 mmol) and () DIPEA (277.6 mg, 2.14 mmol) in dioxane (5 mL) was charged with _N2 and stirred at 110 °C overnight. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with water ₍ 30 mL x 2) and brine (30 mL), dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash column chromatography (DCM/EtOAc=3/2) to obtain the title compound (260 mg, yield: 45%).

Step 5: (3S,4S)-8-(5-((1H-pyrazolo[4,3-b]pyridin-7-yl)thio)pyrazin-2-yl)-3-methyl- 2-oxa-8-nitrogen Heterospiro[4.5]decane-4-amine trifluoroacetate

To a solution of the product of step 4 above (260 mg, 0.435 mmol) in DCM (5 mL) was slowly added TFA (2 mL) while cooling in an ice-water bath. The mixture was stirred at room temperature for 2 hours and then diluted with DCM (2 mL). The mixture was concentrated to give the title compound as the trifluoroacetate salt (175 mg, yield: 81.2%). MS(ESI)m/z:398.1[M+1]+; ¹ H NMR(400MHz,DMSO-d6)δ13.72(s,1H),8.47(s,1H),8.41–8.23(m,3H) ,8.07(s,3H),6.79(s,1H),4.33–4.11(m,3H),3.89(d,J＝8.6Hz,1H),3.68(d,J＝8.8Hz,1H),3.41( s, 1H), 3.14 (d, J = 11.5Hz, 2H), 1.67 (m, 4H), 1.21 (d, J = 5.3Hz, 3H).

Example 13

(3S,4S)-8-(5-((1H-pyrazolo[3,4-b]pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo Preparation of hetero-8-azaspiro[4.5] decyl-4-amine

Step 1: 4-Bromo-1H-pyrazolo[3,4-b]pyridine-1-carboxylic acid tert-butyl ester

To a solution of 4-bromo-1H-pyrazolo[3,4-b]pyridine (1.0 g, 5 mmol) in THF (10 mL) was added Boc ₂ O (1.65 g, 7.5 mmol) and DMAP (62 mg, 0.5 mmol) )). The mixture was stirred at room temperature for 1 hour, then diluted with EtOAc (100 mL), washed with water (30 mL × 2) and _brine (30 mL), dried over _Na2SO4 , filtered, and concentrated to give the title compound (1.58 g, crude product) , which was used in the next step without any further purification.

Step 2: 4-((3-((2-ethylheptyl)oxy)-3-oxopropyl)thio)-1H-pyrazolo[3,4-b]pyridine-1-carboxy Sour tert-butyrate base ester

The product of the above step 1 (1.5g, 5.03mmol), 2-ethylheptyl 3-mercaptopropionate (1.21g, 5.54mmol), Pd ₂ dba ₃ (116mg, 0.12mmol), XantPhos (146mg, 0.25mmol) A mixture of DIPEA (1.3 g, 10 mmol) in dioxane (15 mL) was charged with _N2 and stirred at 110 °C overnight. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with water ₍ 30 mL x 2) and brine (30 mL), dried over _Na2SO4 , filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=4/1-2/1) to obtain the title compound (2 g, yield: 88.5%).

Step 3: 4-Mercapto-1H-pyrazolo[3,4-b]pyridine-1-carboxylic acid tert-butyl ester

A mixture of the product of step 2 above (500 mg, 1.14 mmol) in anhydrous THF (10 mL) was cooled to -78°C and a solution of KO ^t Bu (541 mg, 4.8 mmol) in THF (10 mL) was slowly added. The mixture was stirred at -78°C for 1 hour, heated to -10°C, diluted with K ₂ CO ₃ aqueous solution (2N, 50 mL), and extracted with MTBE (50 mL×2). The pH value of the aqueous phase was adjusted to 5-6 with HCl (6N), and extracted with DCM/IPA (50 mL×2). The combined _organic layers were washed with brine (50 mL), dried over _Na2SO4 , and concentrated to give the crude title compound (300 mg), which was used in the next step without further purification.

Step 4: 4-((5-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-8 -base)pyridine Azin-2-yl)thio)-1H-pyrazolo[3,4-b]pyridine-1-carboxylic acid tert-butyl ester

To the product of step 3 above (1.14mmol), the product of step 4 of Example 7 (485mg, 1.14mmol), Pd ₂ dba ₃ (52mg, 0.057mmol), XantPhos (66mg, 0.11mmol) and DIPEA (295mg, 2.28 mmol) in dioxane (5 mL) was charged with _N2 and stirred at 110 °C overnight. The mixture was cooled to room temperature, diluted with EA (100 mL), washed with water ₍ 30 mL x 2) and brine (30 mL), dried over _Na2SO4 , filtered and concentrated. The residue was purified by flash column chromatography (DCM/EtOAc=3/2) to obtain the title compound (100 mg, yield: 14%).

Step 5: (3S,4S)-8-(5-((1H-pyrazolo[4,3-b]pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl- 2-oxa-8-nitrogen Heterospiro[4.5]decane-4-amine

To a solution of the product from step 4 above (100 mg) in DCM (2.5 mL) was slowly added TFA (1 mL) while cooling in an ice-water bath. The mixture was stirred at room temperature for 2 hours, diluted with DCM (2 mL) and concentrated. The residue was treated with saturated _NaHCO3 solution (2 mL), extracted with DCM/IPA (3/1, 10 mL), dried over _Na2SO4 , filtered and concentrated _. The residue was purified by preparative TLC (DCM/MeOH=10/1) to obtain the title compound (65 mg). MS(ESI)m/z:398.1[M+1]+; ¹ H NMR(400MHz,DMSO-d6)δ13.73(s,1H),8.44(s,1H),8.34(s,1H),8.24 (d,J＝4.9Hz,1H),7.87(s,1H),6.62(d,J＝4.9Hz,1H),4.09–3.99(m,1H),3.89(d,J＝5.7Hz,2H) ,3.66(d,J＝8.4Hz,1H),3.45(m,3H),2.90(d,J＝5.1Hz,1H),1.74(m,1H),1.63(m,2H),1.52(m, 3H), 1.06 (d, J = 6.4Hz, 3H).

Example 14

5-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio Preparation of 4-chloro-1H- benzo[d]imidazole-2(3H)-one hydrochloride

Step 1: 5-Bromo-4-chloro-1,3-dihydro-2H-benzo[d]imidazol-2-one

A solution of 4-bromo-3-chlorobenzene-1,2-diamine (800 mg, 3.61 mmol) and CDI (879 mg, 5.42 mmol) in THF (15 mL) was stirred at room temperature overnight. The mixture was adjusted to pH 4-5 with 1N HCl, and then diluted with water (80 mL). The precipitate was filtered and collected, and dried to obtain the title compound (1.12 g, yield: 99%).

Step 2: 2-ethylhexyl 4-((4-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)thio)butyrate

The product of the above step 1 (910mg, 3.68mmol), 2-ethylhexyl 3-mercaptopropionate (883mg, 4.04mmol), Pd ₂ dba ₃ (168mg, 0.184mmol), Xantphos (212mg, 0.368mmol) and DIPEA (1.43 g, 11.04 mmol) in dioxane (15 mL) was charged with _N2 and stirred at 110 °C for 6 h. The mixture was cooled to room temperature and filtered. The filtrate was diluted with EtOAc (150 mL), washed with water (50 mL) and brine ₍ 50 mL), dried over _Na2SO4 , and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=5/1-1/1) to obtain the title compound (1.33 g, yield: 77%).

Step 3: 4-Chloro-5-mercapto-1,3-dihydro-2H-benzo[d]imidazol-2-one

To a solution of the product from step 2 above (1.33 g, 3.46 mmol) in THF (8 mL) was slowly added KO ^t Bu/THF (1.94 g/20 mL) at -78 °C and _N2 . After the addition was complete, the mixture was stirred at -78°C for 30 minutes. The mixture was allowed to warm to room temperature and concentrated. The residue was purified by silica gel flash column chromatography (DCM/MeOH=50/1 to 10/1) to obtain the title compound (633 mg, yield: 91%).

Step 4: ((3S,4S)-8-(5-((4-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)thio)pyrazine -2-base)-3-methyl Tert-butyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

The product of step 3 above (100 mg, 0.498 mmol), the product of step 4 of Example 7 (142 mg, 0.332 mmol), Pd ₂ dba ₃ (15 mg, 0.017 mmol), Xantphos (19 mg, 0.033 mmol), and () DIPEA ( A mixture of 85 mg, 0.664 mmol) in dioxane (3 mL) was charged with _N2 and stirred at 110 °C for 5 h. The mixture was cooled to room temperature and concentrated. The residue was dissolved in EtOAc (60 mL), washed with water ₍ 30 mL) and brine (30 mL), dried over _Na2SO4 , and concentrated. The residue was purified by preparative TLC (DCM/MeOH=10/1) to obtain the title compound (81 mg, yield: 45%).

Step 5: 5-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazine-2- base)thio)-4- Chloro-1H-benzo[d]imidazol-2(3H)-one hydrochloride

To a mixture of the product from step 4 above (81 mg, 0.148 mmol) in EtOAc (2 mL) was added 2N HCl/EtOAc (2 ml). The suspension was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The residue was purified by C18 reverse phase flash column chromatography (MeOH/H2O) to give the hydrochloride salt of the title compound (16 mg, yield: 22%). MS(ESI)m/z:447.2[M+1]+; ¹ H NMR(400MHz, DMSO-d6)δ11.23(s,1H),11.04(s,1H),8.28(s,1H),8.07 (s,3H),7.95(s,1H),7.05(d,J＝8.1Hz,1H),6.89(d,J＝8.1Hz,1H),4.24–4.01(m,3H),3.87(d, J＝9.0Hz,1H),3.64(d,J＝9.1Hz,1H),3.34(s,1H),3.03(m,2H),1.77–1.62(m,3H),1.54(m,1H), 1.20(d,J=6.5Hz,3H).

Example 15

(3S,4S)-3-methyl-8-(5-((2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-2- Preparation of oxa-8-azaspiro [4.5]decane-4-amine

Step 1: 2-ethylhexyl 3-((2-aminopyridin-4-yl)thio)propionate

4-Bromopyridin-2-amine (1g, 5.78mmol), 2-ethylhexyl 3-mercaptopropionate (1.39g, 6.36mmol), Pd ₂ dba ₃ (130mg, 0.14mmol), Xantphos (165mg, 0.289mmol) and a solution of N,N-diisopropylethylamine (1.5g, 11.56mmol) in 1,4-dioxane (12mL) was stirred overnight at 110°C under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (30 mL × 2) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10/1-1/1) to obtain the title compound (1.44 g, yield: 80%).

Step 2: 2-Aminopyridine-4-thiol

Dissolve 2-ethylhexyl 3-((2-aminopyridin-4-yl)thio)propionate (1.44g, 4.65mmol) in dry tetrahydrofuran (15mL), cool the mixture to -78°C, and add A solution of potassium tert-butoxide (1.56 g, 13.95 mmol) in tetrahydrofuran (15 mL). The mixture was stirred at -78°C for 1 hour, allowed to warm to -15°C, and acidified with 6N hydrochloric acid in an ice-water bath to pH=3-4. The mixture was concentrated, the residue was slurried with methanol at room temperature for 30 minutes, filtered, and the filtrate was concentrated. The residue was slurried with dichloromethane/methanol = 10/1 (50 mL) for 30 minutes, filtered, and the filtrate was concentrated to obtain a crude title compound (613 mg).

Step 3: ((3S,4S)-8-(5-((2-aminopyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-nitrogen Miscellaneous snail[4.5] Decan-4-yl)carbamic acid tert-butyl ester

2-Aminopyridine-4-thiol (550 mg, 4.36 mmol), ((3S, 4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8- Azaspiro[4.5]dec-4-yl)carbamic acid tert-butyl ester (1.3g, 3.05mmol), Pd ₂ dba ₃ (119.7mg, 0.13mmol), Xantphos (75.68mg, 0.13mmol) and N,N- A solution of diisopropylethylamine (1.127g, 8.72mmol) in N-methylpyrrolidone (10mL) was stirred at 120°C in a nitrogen atmosphere for 2h. The mixture was cooled and purified by reverse phase flash column chromatography (C18, methanol/10mM aqueous ammonium bicarbonate, 10%-90%) to give the title compound (1 g, yield: 70%).

Step 4: ((3S, 4S)-3-methyl-8-(5-((2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl )-2-oxa- 8-Azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester

To 1-bromo-2,2-dimethoxypropane (174 mg, 0.95 mmol) and ((3S,4S)-8-(5-((2-aminopyridin-4-yl)thio)pyrazine- To a mixture of tert-butyl 2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate (300 mg, 0.63 mmol) in isopropanol (2 mL) was added TsOH ·H ₂ O (12 mg, 0.06 mmol). Under nitrogen protection, stir at 80°C overnight. Cool to room temperature and concentrate to give the crude title compound, which is used in the next step without further purification.

Step 5: (3S, 4S)-3-methyl-8-(5-((2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl) -2-oxa- 8-Azaspiro[4.5]decane-4-amine

To ((3S,4S)-3-methyl-8-(5-((2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)- To a solution of 2-oxa-8-azaspiro[4.5]dec-4-yl)carbamic acid tert-butyl ester (crude) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 2 h and concentrated. The residue was diluted with water, adjusted to pH=9-10 with 6N sodium hydroxide, extracted with dichloromethane/methanol (10/1, 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (dichloromethane/methanol=10/1) to obtain the title compound (10.3 mg, total yield in 2 steps: 3.9%). MS (ESI) m/z: 411.2; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.38 (s, 1H), 8.36 (d, J = 7.1Hz, 1H), 8.24 (s, 1H), 7.62 (s,1H),7.14(s,1H),6.66(d,J＝7.1Hz,1H),4.11–4.00(m,1H),3.88(s,2H),3.67(d,J＝8.4Hz, 1H),3.48(d,J＝8.5Hz,1H),2.91(d,J＝5.1Hz,1H),2.28(s,3H),1.70–1.58(m,2H),1.53(m,2H), 1.08(d,J=6.4Hz,3H).

Example 16

(3S,4S)-8-(6-amino-5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3-methyl Preparation of -2-oxa-8- azaspiro [4.5]decane-4-amine trifluoroacetate

Step 1: (3S,4S)-8-(6-amino-5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3 -Methyl-2- Oxa-8-azaspiro[4.5]decane-4-amine

To (3S,4S)-8-(6-amino-5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3-methyl To a solution of methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (100 mg, 0.32 mmol) in N-methylpyrrolidone (5 mL) was added (3S, 4S)-3-methyl 2 -Oxa-8-azaspiro[4.5]decane-4-aminodihydrochloride (101 mg, 0.42 mmol) and N,N-diisopropylethylamine (206 mg, 1.6 mmol). The mixture was stirred at 100°C overnight, the mixture was cooled to room temperature and used directly in the next reaction.

Step 2: tert-Butyl((3S,4S)-8-(6-amino-5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazine-2- base)-3-methyl Base-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

To (3S,4S)-8-(6-amino-5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3-methyl To a solution of methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (0.32 mmol) in N-methylpyrrolidone (5 mL) was added Boc ₂ O (139 mg, 0.64 mmol). The mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate (100 mL), washed with water (30 mL×2) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative TLC (dichloromethane/methanol=20/1) to obtain the title compound (115 mg, total yield in 2 steps: 33%).

Step 3: (3S,4S)-8-(6-amino-5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3 -Methyl-2- Oxa-8-azaspiro[4.5]decane-4-amine

To ((3S,4S)-8-(6-amino-5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl) in an ice water bath )-3-Methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester (115 mg, 0.21 mmol) in dichloromethane (5 mL) was added trifluoro Acetic acid (3 mL). The mixture was stirred at room temperature for 3 hours and concentrated. The residue was purified by flash chromatography (methanol/water=10%-70%) to obtain the title compound (81 mg, yield: 69%). MS (ESI) m/z: 446.3; ¹ H NMR (400MHz, Methanol-d ₄ ) δ8.11 (d, J = 7.2 Hz, 1H), 7.59 (s, 1H), 7.55 (s, 1H), 6.26 (d,J＝7.1Hz,1H),4.29–4.18(m,1H),4.12–3.98(m,2H),3.89(d,J＝8.7Hz,1H),3.73(d,J＝8.7Hz, 1H),3.34(d,J＝11.1Hz,1H),3.28(s,1H),3.05(d,J＝4.9Hz,1H),2.40(s,3H),1.87–1.59(m,4H), 1.24(d,J=6.4Hz,3H).

Example 17

(3S,4S)-8-(6-amino-5-((8-chloro-2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl) Preparation of -3-methyl-2-oxa -8-azaspiro[4.5]decane-4-amine

Step 1: ((3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl- 2-oxa-8- Azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester

In an ice water bath, add (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl To a solution of methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (500 mg, 1.19 mmol) in N,N-dimethylformamide (50 mL), N,N-diiso Propylethylamine (361 mg, 3.57 mmol) and di-tert-butyl dicarbonate (388 mg, 1.78 mmol). The mixture was stirred at room temperature for 3 hours, diluted with ethyl acetate (100 mL), washed with water (30 mL×2) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether/ethyl acetate=2/1-dichloromethane/methanol=20/1) to obtain the title compound (530 mg, yield: 85%).

Step 2: ((3S,4S)-8-(6-amino-5-((8-chloro-2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazine- 2-base)-3- Methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester

((3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2- Oxa-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester (150 mg, 0.29 mmol) and 1-chloropropan-2-one (99 mg, 0.86 mmol) in isopropanol (3 mL ) solution was irradiated in a microwave reactor at 130°C for 10 minutes under nitrogen protection. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (30 mL × 2) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was used in the next step without further purification.

Step 3: (3S,4S)-8-(6-amino-5-((8-chloro-2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazine-2 -base)-3- Methyl-2-oxa-8-azaspiro[4.5]decane-4-amine

In an ice water bath, add ((3S,4S)-8-(6-amino-5-((8-chloro-2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyridine To a solution of tert-butylazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (crude product) in dichloromethane (3 mL) was added Trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 2 h and concentrated. The residue was purified by reverse-phase flash column chromatography (methanol/[ammonium bicarbonate (10 mmol/L)]=10%-70%) to obtain the title compound (27 mg, total yield in 2 steps: 20%). MS (ESI) m/z: 460.2; ¹ H NMR (400MHz, Methanol-d ₄ ) δ8.11 (d, J = 7.2Hz, 1H), 7.59 (s, 1H), 7.55 (s, 1H), 6.26 (d,J＝7.1Hz,1H),4.29–4.18(m,1H),4.12–3.98(m,2H),3.89(d,J＝8.7Hz,1H),3.73(d,J＝8.7Hz, 1H),3.34(d,J＝11.1Hz,1H),3.28(s,1H),3.05(d,J＝4.9Hz,1H),2.40(s,3H),1.87–1.59(m,4H), 1.24(d,J=6.4Hz,3H).

Example 18

(3S,4S)-8-(5-((8-chloro-2-fluoroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3-methyl Preparation of -2-oxa-8-azaspiro [4.5]decane-4-amine

Step 1: 8-Chloro-2-fluoro-7-iodoimidazo[1,2-a]pyridine

To a solution of 8-chloro-7-iodoimidazo[1,2-a]pyridine (1.5 g, 5.3 mmol) in anhydrous tetrahydrofuran (50 mL) at 0 °C was added NaH (60% in mineral oil, 320 mg , 8mmol). The mixture was stirred for 10 minutes and selectfluor (1.9g, 5.34mmol) was added. The resulting mixture was stirred at 60°C overnight, cooled to room temperature, diluted with ethyl acetate (30 mL) and filtered. The filtrate was washed with water (20 mL) and brine (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 20/1-8/1) to obtain the title compound (500 mg, yield: 31%).

Step 2: 2-ethylhexyl 3-((8-chloro-2-fluoroimidazo[1,2-a]pyridin-7-yl)thio)propionate

8-Chloro-2-fluoro-7-iodoimidazo[1,2-a]pyridine (500 mg, 1.68 mmol), 2-ethylhexyl 3-mercaptopropionate (403 mg, 1.84 mmol), Pd ₂ dba A mixture of ₃ (77 mg, 0.08 mmol), Xantphos (92.5 mg, 0.16 mmol) and N,N-diisopropylethylamine (433 mg, 3.36 mmol) in 1,4-dioxane (10 mL), 100 °C, irradiate in a microwave reactor for 15 minutes. The mixture was cooled, diluted with ethyl acetate (100 mL), washed with water (30 mL×2) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 20/1-5/1) to obtain the title compound (450 mg, yield: 69%).

Step 3: 8-Chloro-2-fluoroimidazo[1,2-a]pyridine-7-thiol

2-ethylhexyl 3-((8-chloro-2-fluoroimidazo[1,2-a]pyridin-7-yl)thio)propionate (450 mg, 1.16 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL ) solution was cooled to -78°C, and a solution of potassium tert-butoxide (391 mg, 3.49 mmol) in tetrahydrofuran (5 ml) was slowly added. The mixture was stirred at -78°C for 1 hour, allowed to warm to -15°C, acidified to pH≈3-4 with 6N hydrochloric acid in an ice-water bath, and then concentrated. The residue was treated with methanol (50 ml) and stirred for 30 minutes. filter Afterwards, the filtrate was concentrated, and the residue was treated with dichloromethane/methanol (10/1, 50 mL) and stirred for 30 minutes. After filtration, the filtrate was concentrated to obtain the crude title compound (250 mg), which was used in the next step without any further purification.

Step 4: ((3S,4S)-8-(5-((8-chloro-2-fluoroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)- 3-Methyl-2-oxo Hetero-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester

8-Chloro-2-fluoroimidazo[1,2-a]pyridine-7-thiol (214 mg, 1.05 mmol), ((3S,4S)-8-(5-bromopyrazin-2-yl) -3-Methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester (300 mg, 0.7 mmol), Pd ₂ dba ₃ (128 mg, 0.14 mmol 10 mL) in Irradiate in a microwave reactor at 150°C for 15 minutes. The mixture was purified by reverse phase flash column chromatography (C18, methanol/10mM aqueous ammonium bicarbonate, 10%-90%) to afford the title compound (150 mg, yield: 39%).

Step 5: ((3S,4S)-8-(5-((8-chloro-2-fluoroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)- 3-Methyl-2-oxo Hetero-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester

((3S,4S)-8-(5-((8-chloro-2-fluoroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3- A solution of methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamic acid tert-butyl ester (150 mg, 0.27 mmol) in dichloromethane (5 mL) was cooled to 0°C, and then slowly added Fluoroacetic acid (2 mL). The mixture was stirred at room temperature for 30 minutes and concentrated. The residue was dissolved in water (15 mL) and the pH was adjusted to 9-10 with saturated aqueous sodium bicarbonate solution. Extract with dichloromethane/methanol=20/1 (15mL×2). Discard the organic phase and concentrate the aqueous phase. The residue was treated with methanol (50 ml) and stirred for 30 minutes. After filtration, the filtrate was concentrated, and the residue was treated with dichloromethane/methanol = 10/1 (50 ml) and stirred for 30 minutes. Filtration, concentration of the filtrate, and purification by reverse-phase flash column chromatography (C18, methanol/10mM aqueous ammonium bicarbonate solution, 10%-90%) gave the title compound (54 mg, yield: 44%). MS (ESI) m/z: 449.1; ¹ H NMR (400MHz, dmso) δ8.42 (s, 1H), 8.31 (s, 1H), 8.17 (d, J = 7.2Hz, 1H), 7.39 (d, J＝7.1Hz,1H),6.49(d,J＝7.3Hz,1H),4.10–4.04(m,1H),3.90(s,2H),3.68(d,J＝8.5Hz,1H),3.49( d,J＝8.5Hz,2H),3.39(s,1H),2.94(d,J＝5.5Hz,1H),1.79–1.72(m,1H),1.68–1.61(m,1H),1.59–1.53 (m,1H),1.52–1.45(m,1H),1.08(d,J＝6.3Hz,3H).

Example 19

(3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-((8-chloroimidazo[ Preparation of 1,2-a]pyridin- 7-yl)thio)-5-methylpyrazin-2-yl)methanol

Step 1: 3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-bromo-5-methyl pyrazine-2- Ethyl carboxylate

To a solution of ethyl 6-bromo-3-chloro-5-methylpyrazine-2-carboxylate (400 mg, 1.44 mmol) in N-methylpyrrolidone (10 mL) was added (3S,4S)-3-methyl -2-oxa-8-azaspiro[4.5]decane-4-amine dihydrochloride (384 mg, 1.58 mmol) and N,N-diisopropylethylamine (900 mg, 7.2 mmol). The mixture was stirred at 100 °C overnight, cooled to room temperature, and used in the next step without any treatment.

Step 2: 6-bromo-3-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane- 8- (ethyl)-5-methylpyrazine-2-carboxylate

To the cooled reaction mixture of the previous step was added di-tert-butyl dicarbonate (466 mg, 2.22 mmol). The mixture was stirred at room temperature for 2 h, diluted with ethyl acetate (100 mL), washed with water (30 mL × 2) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Prep-TLC (petroleum ether/ethyl acetate = 3/1) to obtain the title compound (460 mg, total yield in 2 steps: 62%).

Step 3: 3-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl) -6- ((8-Chloroimidazo[1,2-a]pyridin-7-yl)thio)-5-methylpyrazine-2-carboxylate ethyl ester

6-Bromo-3-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl )-5-methylpyrazine-2-carboxylic acid ethyl ester (300mg, 0.59mmol), 8-chloroimidazo[1,2-a]pyridine-7-thiol (141mg, 0.76mmol), Xantphos (34mg , 0.059mmol) and N,N-diisopropylethylamine (151mg, 1.172mmol) in 1,4-dioxane (8mL) were irradiated in a microwave reactor at 150°C for 25 seconds in a nitrogen atmosphere. minute. The mixture was cooled, diluted with ethyl acetate (100 mL), washed with water (30 mL × 2) and brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Prep-TLC (dichloromethane/methanol=20/1) to obtain the title compound (180 mg, yield: 50%).

Step 4: ((3S,4S)-8-(5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)-3-(hydroxymethyl)-6-methyl pyrazine-2- tert-butyl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

3-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6 -((8-Chloroimidazo[1,2-a]pyridin-7-yl)thio)-5-methylpyrazine-2-carboxylate (140 mg, 0.23 mmol) in anhydrous tetrahydrofuran (3 mL ) solution was cooled to -20°C under a nitrogen atmosphere, and lithium triethylborohydride (1.0M in tetrahydrofuran, 0.45mL, 0.45mmol) was added dropwise. After the dropwise addition, the mixture was stirred at -20°C for 30 minutes, allowed to naturally rise to room temperature, diluted with ethyl acetate (100mL), washed with water (30mL×2) and brine (30mL), dried over anhydrous sodium sulfate, and filtered and concentrated. The residue was purified by Prep-TLC (dichloromethane/methanol=20/1) to obtain the title compound (85 mg, yield: 65%).

Step 5: (3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-6-((8-chloroimidazole) and[1,2-a] Pyridin-7-yl)thio)-5-methylpyrazin-2-yl)methanol

To ((3S,4S)-8-(5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)-3-(hydroxymethyl)-6-methylpyridine tert-butylazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (85 mg, 0.15 mmol) in dichloromethane (5 mL) Trifluoroacetic acid (1 mL) was added to the ice-water bath solution. The ice bath was removed, the mixture was raised to room temperature, stirred for 3 h, and concentrated. The residue was purified by reverse-phase flash column chromatography (methanol/[ammonium bicarbonate (10 mmol/L)]=10%-70%) to obtain the title compound (35 mg, yield: 50%). MS (ESI) m/z: 475.2; ¹ H NMR (400MHz, Methanol-d ₄ ) δ8.27 (d, J = 7.1 Hz, 1H), 7.87 (s, 1H), 7.59 (s, 1H), 6.54 (d,J＝7.0Hz,1H),4.60(s,2H),4.32–4.18(m,1H),3.86(d,J＝8.7Hz,1H),3.72(d,J＝8.9Hz,1H) ,3.67(d,J＝5.6Hz,2H),3.26 –3.18(m,1H),3.14(d,J＝10.7Hz,1H),3.04(d,J＝4.7Hz,1H),2.51(s,3H),1.99–1.82(m,2H),1.74( m, 2H), 1.23 (d, J = 6.4Hz, 3H).

Example 20

(3S,4S)-8-(5-[(3,8-dichloroimidazo[1,2-a]pyridin-7-yl)thio]pyrazin-2-yl)-3-methyl- 2-oxa-8- azaspiro[4.5]decane-4-amine

Step 1: 3,8-Dichloro-7-iodoimidazo[1,2-a]pyridine

A solution of 8-chloro-7-iodoimidazo[1,2-a]pyridine (100 mg, 0.36 mmol) and NCS (52.74 mg, 0.39 mmol) in N,N-dimethylformamide (2 mL) was reacted in a microwave Stir at 100°C for 15 minutes. The mixture was cooled to room temperature, diluted with water (5 mL), extracted with ethyl acetate (10 ml), washed the organic phase with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound as a light yellow solid (106 mg , yield 94%).

Step 2: 2-ethylhexyl 3-[(3,8-dichloroimidazo[1,2-a]pyridin-7-yl)sulfinyl]propionate

3,8-Dichloro-7-iodoimidazo[1,2-a]pyridine (1.0g, 3.20mmol), 2-ethylheptyl 3-mercaptopropionate (908mg, 4.16mmol), Pd ₂ dba ₃ (0.15 mg, 0.16 mmol), XantPhos (0.19 g, 0.32 mmol) and N,N-diisopropylethylamine (0.83 g, 6.4 mmol) in 1,4-dioxane (2 mL) The mixture was stirred in a microwave reactor at 120°C for 15 minutes under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water (10 ml) and extracted with ethyl acetate (50 ml). The organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate = 10/1 to 6/1) to obtain the title compound (1.23 g, crude product).

Step 3: 3,8-Dichloroimidazo[1,2-a]pyridine-7-thiol

Dissolve 2-ethylhexyl 3-((3,8-dichloroimidazo[1,2-a]pyridin-7-yl)thio)propionate (1.23 g, 3.05 mmol) in dry tetrahydrofuran (10 mL) The solution was cooled to -78°C, and a solution of potassium tert-butoxide (1.03 g, 9.15 mmol) in tetrahydrofuran (6 mL) was added dropwise. The mixture was stirred at -78°C for 1 h, heated to -10°C and treated with aqueous solution. K2CO3 solution (2M, 20mL) and extracted with MTBE (20mL×2). The aqueous phase was adjusted to pH=3-4 with HCl (6N) in an ice-water bath, and extracted with dichloromethane/methanol (50 mL×2). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (0.372 mg, yield: 55.68%).

Step 4: tert-Butyl N-[(3S,4S)-8-(5-[(3,8-dichloroimidazo[1,2-a]pyridin-7-yl)sulfinyl]pyrazine- 2- methyl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl]carbamate

3,8-Dichloroimidazo[1,2-a]pyridine-7-thiol (120mg, 0.55mmol), N-[(3S,4S)-8-(5-bromopyrazin-2-yl) -3-Methyl-2-oxa-8-azaspiro[4.5]dec-4-yl]carbamic acid tert-butyl ester (282.2mg, 0.66mmol), Pd2(dba)3 (15.11mg, 0.017mmol) and XantPhos (9.55mg, 0.016mmol (142.16mg, 1.1 mmol) in 1,4-dioxane (3 mL) was stirred in a microwave reactor at 120 °C for 15 min under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with ethyl acetate (50 mL), washed with water (20 mL×2) and brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash column chromatography (dichloromethane/methanol=10/1) to obtain the title compound (41 mg, yield: 13%).

Step 5: (3S,4S)-8-(5-[(3,8-dichloroimidazo[1,2-a]pyridin-7-yl)sulfinyl]pyrazin-2-yl)-3 -Methyl-2- Oxa-8-azaspiro[4.5]decane-4-amine

To ((3S,4S)-8-(5-((3,8-dichloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3-methyl To a solution of tert-butyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate (40 mg, 0.071 mmol) in dichloromethane (3 mL) in an ice-water bath, trifluoroacetic acid (1 mL ). The mixture was stirred at room temperature for 3 h, diluted with dichloromethane/methanol (10/1, 10 mL), and concentrated. The residue was purified by reverse phase flash column chromatography (5-95%, methanol/water) to give the title compound (8 mg, yield: 24%). MS (ESI) m/z: 465.2; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.42 (s, 1H), 8.31 (s, 1H), 8.20 (s, 1H), 7.71 (d, J＝ 7.2Hz,1H),6.56(s,1H),4.07(s,1H),3.92(s,3H),3.69(s,3H),2.97(s,2H),1.60(m,4H),1.21( s,3H).

Example 21

(S)-1'-(5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene Preparation of -2,4'-piperidine]-1- amine

2-Chloro-5-[(8-chloroimidazo[1,2-a]pyridin-7-yl]thio]pyrazine (90 mg, 0.30 mmol), (1S)-1,3-dihydrospiro [Inden-2,4'-piperidine]-1-amine dihydrochloride (90.81 mg, 0.33 mmol) and N,N-diisopropylethylamine (193.5 mg, 1.50 mmol) in N-methylpyrrolidone (2 mL) solution was stirred in a microwave reactor at 160 °C for 20 min under nitrogen atmosphere. Cooled to room temperature and purified by reversed phase flash column chromatography (C18, methanol/10 mM aqueous ammonium bicarbonate, 10%-90%) , the title compound (40 mg, yield: 28%) was obtained. MS (ESI) m/z: 464.1; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.44–8.35 (m, 2H), 8.29 (s, 1H),7.98(d,J＝4.6Hz,1H),7.56(s,1H),7.31(d,J＝6.1Hz,1H),7.16(dd,J＝6.9,4.3Hz,3H),6.43( d,J＝7.1Hz,1H),4.32–4.19(m,2H),3.86(s,1H),3.28–3.19(m,2H),3.19–3.14(m,2H),3.07(d,1H) ,2.64(d,J＝15.6Hz,1H),1.83–1.74(m,1H),1.71–1.61(m,1H),1.57–1.48(m,1H),1.19–1.10(m,1H).

Example 22

(S)-1'-(5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[ring Preparation of pentane[b] pyridin -6,4'-piperidin]-5-amine

2-Chloro-5-[(8-chloroimidazo[1,2-a]pyridin-7-yl]thio]pyrazine (90 mg, 0.30 mmol), (5S)-5,7-dihydrospiro N of [cyclopentane[b]pyridine-6,4'-piperidine]-5-amine trihydrochloride (112.55 mg, 0.36 mmol) and N,N-diisopropylethylamine (387 mg, 3 mmol) - A solution of methylpyrrolidone (1.5 mL) was stirred at 180°C for 30 min in a microwave reactor under nitrogen atmosphere. Cooled to room temperature and purified by reversed phase flash column chromatography (C18, methanol/10mM aqueous ammonium bicarbonate solution, 10% -90%) purification to obtain the title compound (33 mg, yield: 21%). MS (ESI) m/z: 463.1; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.43 (s, 1H), 8.40 (d,J＝7.2Hz,1H),8.31(d,J＝6.4Hz,2H),7.98(s,1H),7.65(d,J＝7.5Hz,1H),7.56(s,1H),7.22 –7.12(m,1H),6.43(d,J＝7.1Hz,1H),4.33–4.20(m,2H),3.91(s,1H),3.28–3.24(m,2H),3.22–3.18(m ,2H),3.11(d,J＝16.3Hz,1H),2.76(d,J＝16.3Hz,1H),1.84–1.65(m,2H),1.60–1.51(m,1H),1.20–1.11( m,1H).

Bioactivity testing

SHP2 is allosterically activated through the binding of a dityrosyl phosphorylated peptide to its Src homology 2 (SH2) domain. The activation step results in the release of the autoinhibitory interface of SHP2, which further renders SHP2PTP active for substrate recognition and reaction catalysis. The catalytic activity of SHP2 was monitored by prompt fluorescence assay using the surrogate substrate DiFMUP. Specifically, the phosphatase reaction was performed in an OptiPlate™-384F black assay plate (Perkin Elmer, Cat#6007279) at room temperature using a final reaction volume of 20uL and the following assay buffer conditions: 25mM HEPES, pH 7.2, 25mM KCl, 1mM EDTA, 0.01% Brij-35, 5mM DTT, and 1% DMSO (final). Test samples were prepared by incubating 0.2 nM SHP2 (PTPN11/SHP2-FL, BPS, cat#79018) with 0.5 μM SHP2 activating polypeptide (BPS, cat#79310-2), and the prepared test samples were used to monitor the test Inhibition of SHP2 by compounds (final concentrations 0.051-1000 nM). After incubation for 20 minutes at room temperature, the surrogate substrate DiFMUP (6,8-difluoro-7-hydroxy-4-methylcoumarin, Invitrogen, cat#D6567, 20 μM final concentration) was added to the reaction. The plates were read dynamically on Paradigm for 60 minutes (with excitation wavelength 360 nm and emission wavelength 460 nm). Inhibitor dose response curves were analyzed using normalized _IC50 regression curves using a control-based normalization method for curve fitting.

_IC50 values for compounds of the present disclosure are listed in Table 1.

Cell viability test

Proliferation assay of MiaPaCa-2 cells (human pancreatic cancer cells) in 3D culture. To evaluate the inhibitory effect of compounds on cell proliferation, MiaPaCa-2 cells in logarithmic growth phase were seeded at optimal density and grown as spheroids. Cells were cultured for 24 hours before adding different concentrations of compounds. Cells were then cultured with compounds for 5 days, and cell viability was assessed using CCK8. Briefly, 2500 cells were seeded in round-bottom ultra-low adsorption 96-well plates (from Corning), incubated at 37°C, and compounds were dissolved in DMSO (from Sigma) after 24 h to obtain 10 mM stocks. . Then, the 10 mM stock solution was serially diluted with DMSO at a dilution ratio from 3 to 10 times to obtain a series of concentration compound stock solutions. Transfer 5 μL of the above compound stock solution to to 95 μL culture medium to obtain a 50× compound stock solution; then transfer 4 μL of the above 50× compound stock solution to the wells of cells containing 196 μL culture medium, and the final concentration of the compound in the cell culture plate reaches 1× (compound stock solution dilution 1000 times). The final concentration of DMSO is 0.1%. Spheroid cells were incubated with the compound for 5 days. Then 20 μL of WST-8 solution (DOJINDO, Cell Counting KIT-8) was added to each well. The cell culture plate was further incubated at 37°C for 1.5 hours, and then the absorbance at 450 nm was measured using a microplate reader. Compounds were tested in triplicate at each concentration, and IC ₅₀ values were calculated using GraphPad Prism. In addition, compounds TNO155 and Deamino-TNO155 (Novartis compounds) were used as a control experimental group. The chemical structures of compounds TNO155 and Deamino-TNO155 are as follows:

The _IC50 values of the compounds of the present disclosure and the compounds of the control experimental group are listed in Table 1.

Table 1

*The IC ₅₀ value: nM.
"/" means: not tested.

hERG safety test

In this assay, CHO-hERG cells are used to specifically evaluate the effect of test compounds on hERG channels. The anterior compound current and the posterior compound current were measured by patch clamp and used to calculate hERG suppression. Dissolve the compound to be tested in DMSO and dilute it with extracellular fluid to obtain a working solution. For each concentration, two replicate cells were tested. During testing, hERG currents were recorded at room temperature using conventional whole-cell patch-clamp current techniques. Cells were seeded in a recording chamber on an inverted microscope and individual cells in the recording chamber were randomly selected for recording. Cells will be continuously perfused by the perfusion system. For each cell, the percent inhibition by the test compound was calculated from the recorded current using the following formula: (peak tail current recorded after test compound perfusion/peak tail current recorded by solvent control perfusion) × 100%. For each concentration, the percent inhibition was calculated from the average data of all recorded cells, and the _IC50 value was derived from the concentration effect curve by the Hill equation in Origin software.

The _IC50 values for hERG activity of selected compounds are listed in Table 3.

CYP isoenzyme inhibition test

Determine CYP activity using the marker substrates in Table 2. Enzyme activity was measured in the presence and absence of test compound at 8 concentrations (n=1). Known inhibitors were tested at a single concentration (3.00 μM, n=2) as positive controls. The incubation mixture containing microsomes, substrate and standard inhibitors or test compounds was heated at 37°C for 10.0 minutes. Start the reaction by adding NADPH and incubate for 10.0 minutes. After incubation, ice-cold acetonitrile was added to terminate the reaction. Metabolites produced by the substrate reaction were determined by LC-MS/MS to determine percent inhibition, and _IC50 values were calculated from the concentration effect curve.

Table 2

_IC50 values for Cyp 3A4 activity of selected compounds are listed in Table 3.

Table 3. Activity against hERG and Cyp3A4 enzymes

Rat pharmacokinetic assay

Test compounds were administered to Sprauge-Dawley rats at 1 mg/kg intravenously and 5 mg/kg orally. Test compounds were dissolved in 10% DMSO+10% Solutol+80% _H2O . Blood samples were collected into test tubes containing sodium heparin at 5 minutes, 0.25, 0.50, 1, 2, 4, 6, 8 and 24 hours after dosing and centrifuged at 8000 rpm for 6 minutes to separate plasma. The concentration of test compound in plasma was determined by LC/MS/MS) method. use Professional 5.2's non-partitioned module calculates parameter values.

The PK parameters (pharmacokinetic parameters) of the selected compounds are listed in Table 4.

Table 4

Claims

A compound of formula I:

and/or stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of the compound of formula I, wherein,

Y is selected from

R 1 is selected from H, NH 2 and optionally substituted C1-C3 alkyl;

R 2 is selected from H, halogen, -CN, -OH, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkenyl, optionally substituted C1-C3 alkynyl, optionally substituted C1-C3 alkoxy and optionally substituted C1-C3 haloalkyl;

Each R 3 is independently selected from H and optionally substituted C1-C3 alkyl;

R 4 is selected from H and optionally substituted C1-C6 alkyl;

R 5 is selected from H, halogen, NH 2 , -CN, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkenyl, optionally substituted C1-C3 alkynyl, optionally substituted C1-C3 alkoxy and optionally substituted C1-C3 haloalkyl;

R 6 is selected from H and optionally substituted C1-C3 alkyl;

X 1 is selected from -O- and -C(R 7 ) 2 -, wherein R 7 is selected from H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, C6-C10 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S as ring members; or, wherein R 4 , R 7 and are located in the R 4 and R The two carbon atoms between 7 may together optionally form 4-7 selected from C3-C6 cycloalkyl, saturated or unsaturated containing 1-2 heteroatoms selected from N, O and S as ring members cyclic groups containing 1 to 4 heteroatoms selected from N, O and S as ring members; and

X 2 is selected from -C(R 8 )-, or -X 2 =X 3 - is selected from -[C(R 8 )=C(R 9 )]-, -[C(R 8 )=N]-, -[N=C(R 9 )]-; wherein, R 8 and R 9 are independently selected from H, optionally substituted C1-C3 alkyl and -COOH.
The compound of claim 1 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein R1 is selected from H and optionally substituted C1 -C3 alkyl.
The compound of claim 1 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein R 2 is selected from H, C1-C3 hydroxyalkyl and halogen.
The compound of claim 1 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein the -N(R 3 ) 2 group is -NH 2 .
The compound of claim 1 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein R 4 is selected from H and optionally substituted C1 -C3 alkyl; or.
The compound of claim 1 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein R 5 is selected from H and halogen.
The compound of claim 1 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein R 6 is selected from H and halogen.
The compound of claim 1 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein X 1 is -O-.
The compound of claim 1 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein X 1 is -C(R 7 ) 2 -, so Said R 7 is selected from H, optionally substituted C1-C3 alkyl, optionally substituted C1-C3 alkoxy, C6-C10 aryl and contains 1-4 selected from N, O and S A 5-10 membered heteroaryl group with a heteroatom as a ring member; or, wherein R 4 , R 7 and the two carbon atoms located between R 4 and R 7 can together form a cycloalkane selected from C3-C6 base, saturated or unsaturated 4-7 membered heterocyclyl groups containing 1-2 heteroatoms selected from N, O and S as ring members, C6-C10 aryl groups and 1-4 heteroatoms selected from N, O A 5-10 membered heteroaryl cyclic group with a heteroatom of S as a ring member.
The compound of claim 1 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein -X 2 =X 3 - is selected from -[C( R 8 )=C(R 9 )]-, -[C(R 8 )=N]-, -[N=C(R 9 )]-; wherein, R 8 and R 9 are independently selected from H, Optionally substituted C1-C3 alkyl and -COOH.
The compound of claim 1 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein X 2 is selected from -C(R 8 )-; wherein , R 8 is selected from H, optionally substituted C1-C3 alkyl and -COOH.
The compound of claim 1 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein -X 2 =X 3 - is -[C(R 8 )=C(R 9 )]-; wherein, R 8 and R 9 are independently selected from H, optionally substituted C1-C3 alkyl and -COOH.
The compound of claim 1 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein R 8 and R 9 are independently selected from H, -CH 3 , -CF 3 and -COOH.
The compound of claim 1 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein X 2 is selected from -CH-, -CH(CH 3 )-, -CH(CF 3 )- and -CH(COOH)-.
The compound of claim 1 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein -X 2 =X 3 - is selected from -[CH= CH]-, -[C(CH3)＝CH]-, -[CH＝C(CH3)]-, -[C(CF3)＝CH]-, -[CH＝C(CF3)]-, -[ CH=C(COOH)]- and -[C(COOH)=CH]-.
The compound of claim 1 and/or the stereoisomer, stable isotope, or drug of the compound A scientifically acceptable salt or solvate, wherein the compound is selected from the following compounds of Formula IA, Formula IB, Formula IC, Formula ID, Formula IE or Formula IF, wherein the R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 and X 3 are as defined in claim 1 .
The compound of claim 16 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein R 1 is an optionally substituted C1-C3 alkane group, wherein the optionally substituted C1-C3 alkyl group is substituted by 1-3 groups selected from =O, -NH2 and -OH.
The compound of claim 16 and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein R 2 is an optionally substituted C1-C3 alkane group, wherein the optionally substituted C1-C3 alkyl group is substituted by 1-3 groups selected from =O, -NH2 and -OH.
The compound of claim 1 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein the compound is selected from the following compounds:
A pharmaceutical composition comprising a compound according to any one of claims 1-19 and/or a stereoisomer of the compound mixed with at least one pharmaceutically acceptable carrier. conformation, stable isotope, or pharmaceutically acceptable salt or solvate.
A method of treating a disease or disorder associated with SHP2 in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-19, and /or stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of the compound, or A pharmaceutical composition as claimed in claim 20.
The method of claim 21 , wherein the method includes determining whether the disease in the subject is a SHP2-related disease or disorder, and administering to the subject in need thereof a therapeutically effective SHP2-inhibiting amount of claim 1 The compound described in any one of -19, and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, or the pharmaceutical composition described in claim 20 .
The method of claim 21, wherein the SHP2-related disease or disorder is mediated by the activity of SHP2.
The method of claim 23, wherein the SHP2-related disease or disorder is selected from the group consisting of Noonan syndrome, leopard skin syndrome, juvenile myelomonocytic leukemia, melanoma, acute myeloid leukemia, breast cancer, Esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma, and glioblastoma.
The method of claim 21, wherein the compound of any one of claims 1-19, and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable compound of the compound is administered orally. salt or solvate, or a pharmaceutical composition according to claim 20.
The compound according to any one of claims 1-19, and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, or according to claim 20 Use of the pharmaceutical composition in the manufacture of a medicament for the treatment of a disease or disorder associated with SHP2.
The use of claim 26, wherein the SHP2-related disease or disorder is mediated by the activity of SHP2.
The use of claim 27, wherein the SHP2-related disease or disorder is selected from Noonan syndrome, leopard skin syndrome, juvenile myelomonocytic leukemia, melanoma, acute myeloid leukemia, breast cancer, Esophageal cancer, lung cancer, colon cancer, head cancer, neuroblastoma, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma, and glioblastoma.
The use of claim 26, wherein the medicament is formulated for oral administration.