CN118369323A - Heterocyclic compounds as SHP2 inhibitors, compositions comprising the same, and methods of use thereof - Google Patents

Abstract

Disclosed herein are compounds of formula I, and/or stereoisomers, stable isotopes, or pharmaceutically acceptable salts or solvates of compounds of formula I; pharmaceutical compositions comprising these compounds, and the therapeutic use of these compounds, which are inhibitors of SHP2 potentially useful in the treatment of SHP 2-associated diseases, such as SHP 2-associated cancers.

Description

Heterocyclic compounds as SHP2 inhibitors, compositions comprising the same, and methods of use thereof

This application claims the following priority:

CN202210240216.X, application date: March 10, 2022

Technical Field

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

technical background

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

SHP2 is a ubiquitous non-receptor protein tyrosine phosphatase encoded by the human PTPN11 gene, with a 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. After 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, leading to SHP2 activation (Qu CK, el al. Cell Res 2000, 10, 279-88). SHP2 acts downstream of receptor tyrosine kinases 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).

The dysregulation of SHP2 is associated with a range of human diseases including cancer. SHP2 regulates the survival and proliferation of cancer cells mainly by activating the RAS-ERK signaling pathway (Matozaki T, el al. Cancer Sci 2009, 100, 1786-93). SHP2 mutations lead to Noonan and Leopard syndrome, while 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 in the absence of mutations in the enzyme itself, SHP2 activity is closely associated with tumorigenesis (Marsh-Armstrong B, et al. ACS Omega 2018, 3, 15763-15770). Recent studies have shown that SHP2 is essential for the growth and survival of 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). 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 become an attractive target in the treatment of various diseases mediated by SHP2.

Summary 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 diseases and disorders mediated by SHP2 (e.g., cancer).

Disclosed herein are compounds of formula I:

and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate 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 ^R3 is independently selected from H and optionally substituted C1-C3 alkyl;

^R4 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;

^R6 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 the two carbon atoms located between said R ⁴ and R ⁷ can together optionally form a cyclic group selected from C3-C6 cycloalkyl, a saturated or unsaturated 4-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S as ring members, C6-C10 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S as ring members; and

^X2 is selected from -C( ^R8 )-, or ^-X2 = ^X3- is selected from -[C( ^R8 )=C( ^R9 )]-, -[C( ^R8 )=N]-, -[N=C( ^R9 )]-; wherein ^R8 and ^R9 are independently selected from H, optionally substituted C1-C3 alkyl and -COOH.

The present invention further discloses a pharmaceutical composition, which comprises a compound of Formula I disclosed herein and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate of a compound of Formula I, and a pharmaceutically acceptable carrier.

Further disclosed herein is a method of inhibiting SHP2 activity, comprising contacting protein SHP2 with an effective amount of a compound of Formula I 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 for treating a treatable disease by inhibiting SHP2 in a patient, the method comprising administering to a patient identified as needing such treatment an effective amount of a compound of Formula I and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of a compound of Formula I disclosed herein.

Further disclosed herein is a method for treating a treatable disease by inhibiting SHP2 in a patient, the method comprising administering to a patient identified as needing such treatment an effective amount of a pharmaceutical composition comprising a compound of Formula I disclosed herein and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of a compound of Formula I, and a pharmaceutically acceptable carrier.

Further disclosed herein is a method of treating cancer in a patient, comprising administering to a patient identified as needing such treatment an effective amount of a pharmaceutical composition comprising a compound of Formula I disclosed herein and/or a stereoisomer, a stable isotope, or a 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 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.

Further disclosed herein is the use of 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 in the preparation of a medicament for treating a disease (such as cancer) that responds to SHP2 inhibition. In some embodiments, the cancer is selected from 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.

Further disclosed herein are compounds of Formula I and subclasses of Formula I disclosed herein, as well as pharmaceutically acceptable salts or solvates of these compounds, and all stereoisomers (including diastereoisomers and enantiomers, and isotopically enriched variants (including deuterium substitution)). The compounds can be used to treat conditions 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 can also be used or formulated with co-therapeutic agents; for example, compounds of Formula I and subclasses thereof can be used or formulated with one or more agents selected from SHP2 kinase inhibitors and non-SHP2 kinases and other 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 set forth below, unless the context in which they are used indicates otherwise. The following abbreviations and terms have the indicated meanings throughout this document.

Detailed ways

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

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

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

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

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 term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, "alkyl optionally substituted with X" includes both "alkyl not substituted with X" and "alkyl substituted with X". It will be understood by those skilled in the art that for any group containing one or more substituents, such a group is not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically unfeasible, and/or inherently instable in water at room temperature for a long enough time to be administered as a pharmaceutical formulation. When multiple substituents are present, unless otherwise stated, the substituents are independently selected, so where there are 2 or 3 substituents, for example, those substituents may be the same or different.

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

The term "alkyl" herein refers to a hydrocarbon group selected from straight and branched saturated hydrocarbon groups having up to 18 carbon atoms, such as from 1 to 12 carbon atoms, further such as from 1 to 8 carbon atoms, and even further such as from 1 to 6 carbon atoms. 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, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

Unless explicitly stated, an alkyl group may be optionally substituted by replacing the hydrogen atoms of the unsubstituted alkyl group with one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present on the unsubstituted alkyl group). If not otherwise specified, suitable substituents for the alkyl group may be selected from halogen elements, D, CN, oxo, hydroxy, substituted or unsubstituted C ₁ -C ₄ alkoxy, 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 _{-C 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) -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); wherein the substituents for the substituted C ₁ -C ₄ alkoxy, substituted C ₃ -C ₆ cycloalkyl, substituted 3-7 membered heterocycloalkyl, substituted aryl and substituted heteroaryl are up to three groups independently selected from the group consisting of halogen elements, D, -CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, oxo, hydroxy, C ₁ -C ₄ alkoxy, amino, -NH(C ₁ -C ₄ alkyl), -N(C ₁ -C ₄ alkyl) ₂ . In some embodiments, unless otherwise specified, the substituents of the alkyl group are selected from, for example, halogen elements, CN, oxo, hydroxy, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, 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" herein refers to a straight or branched chain alkyl group comprising 1 to 18 carbon atoms connected by an oxygen bridge (e.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy, etc.). Typically, the alkoxy group comprises 1 to 6 carbon atoms (e.g., 1 to 4 carbon atoms) connected by an oxygen bridge.

Unless explicitly stated, alkoxy groups may be optionally substituted by replacing the hydrogen atoms of the unsubstituted alkyl portion of the alkoxy group with one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present on the unsubstituted alkoxy group). Unless otherwise specified, suitable substituents are selected from, for example, the substituents listed above for alkyl groups, except that hydroxyl and amino groups are usually not present on the carbon directly connected to the oxygen of the substituted alkyl-O group.

The term "alkenyl" herein refers to a hydrocarbon group selected from straight and branched hydrocarbon groups, the hydrocarbon group comprising at least one C=C double bond and 2 to 18 (e.g., 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 groups. The point of attachment may be on an unsaturated carbon or a saturated carbon.

Unless clearly stated, alkenyl groups may be substituted with one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present on the unsubstituted alkenyl groups) to replace the unsubstituted hydrogen atoms of alkenyl groups. Unless otherwise specified, suitable substituents are selected from, for example, the substituents for alkyl groups listed above.

The term "alkynyl" herein refers to a hydrocarbon group selected from straight and branched hydrocarbon groups, the hydrocarbon group comprising at least one -C≡C- triple bond and 2 to 18 (e.g., 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-butynyl, 2-butynyl and 3-butynyl groups. The point of attachment can be on an unsaturated carbon or a saturated carbon.

Unless explicitly stated, an alkynyl group may be optionally substituted by replacing the unsubstituted hydrogen atoms of the alkynyl group with one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present on the unsubstituted alkynyl group). Unless otherwise specified, suitable substituents are selected from, for example, the substituents listed above for alkyl groups.

The term "alkylene" refers to a divalent alkyl group including 1 to 10 carbon atoms and two expanded valence bonds connected to other molecular parts. The two molecular parts connected to the alkylene can be on the same carbon atom or on different carbon atoms. Therefore, for example, propylene is a 3-carbon alkylene that can be 1,1-disubstituted, 1,2-disubstituted or 1,3-disubstituted. Unless otherwise specified, alkylene refers to a part including 1 to 6 carbon atoms (such as 1 to 4 carbon atoms). Representative examples of alkylene include, but are not limited to, methylene, ethylene, n-propylene, isopropylene, n-butylene, secondary butylene, isobutylene, tert-butylene, n-pentylene, isopentylene, neopentylene, n-hexylene, 3-methylhexylene, 2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene, n-nonylene, n-decylene, etc. Substituted alkylene is an alkylene group containing one or more (such as one, two or three) substituents; unless otherwise specified, suitable substituents are selected, for example, from the substituents listed above for alkyl groups.

Unless explicitly stated, an alkylene group may be optionally substituted by replacing the unsubstituted hydrogen atoms of an alkylene group with one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present in the unsubstituted alkylene group). Unless otherwise specified, suitable substituents are selected from, for example, the substituents for an alkyl group as listed above.

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

The term "haloalkyl" refers to that the alkyl defined herein is replaced by one or more halogen groups defined herein. Unless otherwise specified, the alkyl portion of the haloalkyl includes 1-4 carbon atoms. Halogenated alkyl can be monohalogenated alkyl, dihalogenated alkyl, trihalogenated alkyl or polyhalogenated alkyl (including perhalogenated alkyl). Monohalogenated alkyl can have an iodine, bromine, chlorine or fluorine in the alkyl group. Dihalogenated alkyl groups and polyhalogenated alkyl groups can have two or more identical halogen atoms or a combination of different halogen groups in the alkyl. Polyhalogenated alkyl includes, for example, up to 6, or 4, or 3, or 2 halogen groups. The example of haloalkyl includes, but is 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 (e.g., trifluoromethyl ₎ . In some embodiments, unless otherwise specified, haloalkyl groups include monofluoro-, difluoro-, and trifluoro-substituted methyl and ethyl groups (e.g., _-CF3 , _-CF2H , _-CFH2 , and _-CH2CF3 ).

Unless explicitly stated, haloalkyl groups may be optionally substituted by one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present in the unsubstituted haloalkyl groups) replacing the unsubstituted hydrogen atoms of haloalkyl. Unless otherwise specified, suitable substituents are selected from, for example, the substituents for alkyl groups as listed above.

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-trifluoroethoxy, 1,1,1,3,3,3-hexafluoro-2-propoxy, and the like. In some embodiments, the haloalkoxy group includes 1-4 carbon atoms and up to three halogen elements, for example, monofluoro, difluoro and trifluoro substituted methoxy and ethoxy groups.

Unless explicitly stated, haloalkoxy groups may be optionally substituted by one or more substituents (such as one, two or three substituents, or 1-4 substituents, or as many as the number of hydrogens present in the unsubstituted haloalkoxy groups) replacing the hydrogen atom of the unsubstituted alkyl part of haloalkoxy. Unless otherwise specified, suitable substituents are selected from, for example, the substituents for alkyl groups listed above, except that hydroxyl and amino groups are usually not present on the carbon directly connected to the oxygen of substituted haloalkyl-O groups.

The term "cycloalkyl" as used herein refers to a hydrocarbon group selected from saturated and partially unsaturated cycloalkyl groups, such as monocyclic and polycyclic (e.g., bicyclic and tricyclic, adamantyl and spirocycloalkyl) groups, comprising from 3 to 20 carbon atoms. A monocyclic alkyl group is a cycloalkyl group comprising 3 to 20 carbon atoms, such as 3 to 8 carbon atoms. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl and cyclohexenyl. Bicyclic alkyl groups include bridged bicyclic alkyls, fused bicyclic alkyls and spirocycloalkyls. Bridged bicyclic alkyls contain a monocyclic cycloalkyl ring in which two non-adjacent carbon atoms of the monocyclic ring are connected by an alkylene bridge of one to three additional carbon atoms (i.e., a bridging group of the form -( _CH2 )n-, wherein n is 1, 2 or 3). Examples of bridged bicycloalkyls 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, and bicyclo[4.2.1]nonane, etc. Fused bicycloalkyls contain a monocyclic cycloalkyl ring fused to one of a phenyl, a monocyclic cycloalkyl, and a monocyclic heteroaryl. Examples of fused bicycloalkyls include, but are not limited to, bicyclo[4.2.0]octa-1,3,5-triene, 2,3-dihydro-1H-indene, 6,7-dihydro-5H-cyclopenta[b]pyridine, 5,6-dihydro-4H-cyclopenta[b]thiophene, and decalin, etc. Spirocycloalkyls contain two monocyclic ring systems that share a carbon atom forming a bicyclic ring system. Examples of spirocycloalkyl include but are not limited to Bicyclic cycloalkyl groups include, for example, 7 to 12 carbon atoms. Monocyclic or bicyclic alkyl groups are attached to the parent molecular moiety via any carbon atom contained within the cycloalkyl ring. Tricyclic alkyl groups include bridged tricyclic alkyl groups as used herein, wherein the bridged tricyclic alkyl groups refer to: 1) a bridged bicyclic alkyl ring, wherein two non-adjacent carbon atoms of the bridged bicyclic alkyl ring are connected via an alkylene bridge of one to three additional carbon atoms (i.e., a bridging group of the form of -(CH ₂ ) n-, wherein n is 1, 2 or 3); or 2) a fused bicyclic alkyl ring, wherein two non-shared ring atoms on each ring are connected via an alkylene bridge of one to three additional carbon atoms (i.e., a bridging group of the form of -(CH ₂ ) n-, wherein n is 1, 2 or 3), wherein "fused bicyclic alkyl ring" refers to a monocyclic alkyl ring fused to a monocyclic alkyl ring. Examples of bridged tricyclic alkyl groups include, but are not limited to, adamantyl. As used herein, bridged tricycloalkyl is attached to the parent molecular moiety through any ring atom. Ring atoms disclosed herein refer to carbon atoms on the ring skeleton. Cycloalkyl can be saturated or include at least one double bond (i.e., partially unsaturated), but not completely conjugated, and is not aromatic (as defined herein) cycloalkyl. Cycloalkyl can be substituted with at least one heteroatom selected from, for example, O, S and N.

Unless explicitly stated, cycloalkyl groups may be substituted with one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present in the unsubstituted cycloalkyl groups) to replace the hydrogen atoms of the unsubstituted cycloalkyl groups. In some embodiments, the substituted cycloalkyl groups include 1-4, such as 1-2 substituents. Unless otherwise specified, suitable substituents are selected from, for example, the substituents for alkyl groups as listed above.

The term "cycloalkylene" or "cycloalkylene ring" disclosed herein refers to a divalent cycloalkane ring connected via the same carbon atom 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 in an illustrative manner by the following structure, wherein n is 1, 2, 3, 4, or 5.

The terms "heterocycloalkyl", "heterocyclyl" or "heterocycle" disclosed herein refer to a "cycloalkyl" as defined above in which at least one of the ring carbon atoms is replaced by a heteroatom independently selected from O, N, S. The heterocyclyl includes, for example, 1, 2, 3 or 4 heteroatoms, and each of N, C and S can be independently oxidized in the cyclic ring system. The N atom can also be substituted to form a tertiary amine or an ammonium salt. The point of attachment of the heterocyclyl can be on a heteroatom or 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 is fused to a 5-, 6- and/or 7-membered cycloalkyl, heterocycle or carbocyclic aromatic ring, provided that when the heterocycle is fused to the carbocyclic aromatic ring, the point of attachment is at the heterocycle, and when the heterocycle is fused to the cycloalkyl, the point of attachment can be at the cycloalkyl or heterocycle. "Heterocyclyl" 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 (i.e., partially unsaturated). The heterocyclyl may be substituted, for example, by an oxo group. The point of attachment may be carbon or a heteroatom. Heterocyclyl is not a heteroaryl as defined herein.

Examples of heterocycles include, but are not limited to, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, oxiranyl, aziridinyl, thiirane, azetidinyl, oxetanyl, thietanyl, dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxetanyl, thietanyl, oxathianyl, dioxetanyl, oxathian ... Base, diazepine Base, thiazolyl 1-oxo-1-thiomorpholinyl, 1,1-dioxo-1-thiomorpholinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, 1,1-dioxo-1-thiomorpholinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, 1,1-dioxo-1-thiomorpholinyl,

Unless explicitly stated, the heterocyclic radical group may be optionally substituted by one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present in the unsubstituted heterocyclic radical group) replacing the hydrogen atom of the unsubstituted heterocyclic radical. In some embodiments, the substituted heterocyclic radical comprises 1-4, such as 1-2 or 1-3 substituents. Unless otherwise specified, otherwise suitable substituents are selected from, for example, the substituents for alkyl groups as listed above.

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

In some embodiments, the aryl group is selected from 5- and 6-membered carbocyclic aromatic rings fused to 5- to 7-membered cycloalkyl or optionally including at least one heterocycle (as defined in "heterocyclyl" or "heterocycle" below) of a heteroatom selected from, for example, N, O, and S, provided that when the carbocyclic aromatic ring is fused to the heterocycle, the point of attachment is at the carbocyclic aromatic ring, and when the carbocyclic aromatic ring is fused to the cycloalkyl group, the point of attachment can be at the carbocyclic aromatic ring or at the cycloalkyl group. The divalent groups formed by substituted benzene derivatives and having free valences at the ring atoms are named as substituted phenylene groups. The naming of the divalent groups obtained by removing a hydrogen atom from the carbon atom with free valences of the monovalent polycyclic hydrocarbon radical ending with "-base" is carried out by adding "subunit" to its corresponding monovalent group, for example, the naphthyl group with two attachment points is called naphthylene. However, aryl does not include heteroaryl or does not overlap with heteroaryl in any way, which is defined separately below. Thus, if one or more carbocyclic aromatic rings are fused to a heterocyclic aromatic ring (eg, heteroaryl as defined below), the resulting ring system is heteroaryl as defined herein, rather than aryl.

Unless explicitly stated, aryl groups may be substituted by one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present in the unsubstituted aryl groups) replacing the hydrogen atoms of unsubstituted aryl. In some embodiments, the substituted aryl comprises 1-5 substituents. Unless otherwise specified, otherwise suitable substituents are selected from, for example, the substituents for alkyl groups as listed above.

The term "heteroaryl" as used herein refers to a radical selected from a 5- to 7-membered aromatic monocyclic ring comprising at least one (e.g., 1 to 4 heteroatoms, or in some embodiments, 1 to 3 heteroatoms) heteroatom selected from, for example, N, O, and S, wherein the remaining ring atoms are carbon; an 8- to 12-membered bicyclic ring comprising 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) heteroatom selected from, for example, N, O, and S, 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 on a carbon or heteroatom; and an 11- to 14-membered tricyclic ring comprising 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) heteroatom selected from, for example, N, O, and S, Where the remaining ring atoms are carbon, and wherein at least one ring is aromatic, and at least one heteroatom is present in an aromatic ring, and wherein the point of attachment is on any ring.

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

In some embodiments, the heteroaryl group comprises 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 may be at the heteroaryl ring or at the aryl ring. Non-limiting examples include quinolyl and quinazolinyl.

In some embodiments, the heteroaryl group comprises 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]pyridinyl and 1H-pyrrolo[2,3-b]pyridinyl.

When the total number of S atoms and O atoms in the 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 heteroaromatic ring does not exceed 1.

Examples of heteroaryl groups include, but are not limited to, pyridyl, oxazolyl, pyrazinyl, pyrimidinyl, imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furanyl, benzofuranyl, benzimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, triazolyl, quinolyl, isoquinolyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-3-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4-b]pyridin-3-yl), benzoxazolyl (e.g., benzo[d ]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-oxadiazolyl, 1-oxa-2,4-oxadiazolyl, 1-oxa-2,5-oxadiazolyl, 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, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinoline.

Unless explicitly stated, heteroaryl groups may be optionally substituted by one or more substituents (such as one, two or three substituents, or 1-4 substituents, or up to the number of hydrogens present in the unsubstituted heteroaryl groups) replacing the hydrogen atoms of the unsubstituted heteroaryl groups. In some embodiments, the substituted heteroaryl groups include 1, 2 or 3 substituents. Unless otherwise specified, suitable substituents are selected from, for example, the substituents for alkyl groups as listed above.

Compounds disclosed herein may contain asymmetric centers, and therefore may exist as enantiomers. In the case 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 forms such as by resolving materials or by asymmetric synthesis. All such possible stereoisomers (such as substantially pure resolved enantiomers, their racemic mixtures, and mixtures of diastereomers) are intended to be included. All stereoisomers of compounds disclosed herein and/or their pharmaceutically acceptable salts are intended to be included. Unless otherwise explicitly mentioned, reference to an isomer is applicable to any one of the possible isomers. When the isomeric composition is not specified, all possible isomers are included.

When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are intended to include both E and Z geometric isomers.

As used herein, "pharmaceutically acceptable salts" include, but are not limited to, salts formed with inorganic acids selected from, for example, hydrochlorides, phosphates, hydrogen phosphates, hydrobromides, sulfates, sulfinates, and nitrates; and salts formed with organic acids selected from, for example, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate, alkanoate (e.g., acetate), and salts formed with HOOC-(CH2) _n -COOH, wherein 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.

In addition, if the compound disclosed herein is obtained in the form of acid addition salt, free base can be obtained by alkalizing the solution of acid salt. On the contrary, if the product is free base, according to the conventional procedure for preparing acid addition salt by basic compound, addition salt (such as pharmaceutically acceptable addition salt) can be produced by dissolving free base in suitable organic solvent and treating the solution with acid. Those skilled in the art will recognize that various synthetic methods can be used to prepare non-toxic pharmaceutically acceptable addition salt without excessive experimentation. "Treatment (treating)", "treatment (treat)", "treatment (treatment)" or "relief" refers to confirming that there is a need for a subject suffering from, for example, cancer to administer at least one compound disclosed herein and/or at least one of its stereoisomers (if any), at least one of its stable isotopes or at least one of its pharmaceutically acceptable salts.

The term "effective amount" refers to an amount 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, that is effective for "treating" (as defined above) a disease or disorder in a subject.

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

Embodiment 1. A compound of formula I:

and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate 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 ^R3 is independently selected from H and optionally substituted C1-C3 alkyl;

^R4 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;

^R6 is selected from H and optionally substituted C1-C3 alkyl;

^X1 is selected from -O- and -C( ^R7 ) _2- , wherein ^R7 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 ^R4 , ^R7 and the two carbon atoms located between said ^R4 and ^R7 can together optionally form a cyclic group selected from C3-C6 cycloalkyl, a saturated or unsaturated 4-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S as ring members, C6-C10 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S as ring members; and

^X2 is selected from -C( ^R8 )-, or ^-X2 = ^X3- is selected from -[C( ^R8 )=C( ^R9 )]-, -[C( ^R8 )=N]-, -[N=C( ^R9 )]-;

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

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

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

Embodiment 4. The compound according to any one of Embodiments 1-3 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.

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

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

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

Embodiment 8. The compound according to any one of Embodiments 1-7 and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate thereof, wherein R ⁴ is CH ₃ .

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

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

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

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

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

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

Embodiment 15. The compound according to any one of Embodiments 1-13 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein X ¹ is -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 the two carbon atoms located between R ⁴ and R ⁷ can together optionally form a cyclic group selected from C3-C6 cycloalkyl, a saturated or unsaturated 4-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S as ring members, C6-C10 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S as ring members.

Embodiment 16. A compound according to any one of Embodiments 1-15, wherein ^-X2 = ^X3- is selected from -[C( ^R8 )=C( ^R9 )]-, -[C( ^R8 )=N]-, -[N=C( ^R9 )]-; wherein ^R8 and ^R9 are independently selected from H, optionally substituted C1-C3 alkyl and -COOH.

Embodiment 17. The compound according to any one of Embodiments 1-16 and/or a stereoisomer, a stable isotope, or a 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.

Embodiment 18. The compound and/or stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of any one of Embodiments 1-17, 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.

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

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

Embodiment 21. The compound according to any one of Embodiments 1-20 and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate thereof, wherein X ² is selected from -CH-, -CH(CH ₃ )-, -CH(CF ₃ )- and -CH(COOH)-.

Embodiment 22. The compound according to any one of Embodiments 1-21, and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate of the compound, wherein ^-X2 = ^X3- is selected from -[CH=CH]-, -[C( _CH3 )=CH]-, -[CH=C( _CH3 )]-, -[C( _CF3 )=CH]-, -[CH=C( _CF3 )]-, -[CH=C(COOH)]- and -[C(COOH)=CH]-.

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

Embodiment 27. A compound according to any one of Embodiments 1-26 and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate of the compound, wherein R ¹ is an optionally substituted C1-C3 alkyl, wherein the optionally substituted C1-C3 alkyl is substituted with 1-3 groups selected from =O, -NH ₂ and -OH.

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

Embodiment 29. The compound according to Embodiment 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:

Embodiment 30. A pharmaceutical composition comprising a compound as described in any one of Embodiments 1-29, and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, in admixture with at least one pharmaceutically acceptable carrier.

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

Embodiment 32. A method as described in 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 inhibitory amount of a compound as described in any one of embodiments 1-29, and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, or a pharmaceutical composition as described in embodiment 30.

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

Embodiment 34. A method as described in Embodiment 33, wherein the disease or disorder associated with SHP2 is selected from Noonan syndrome, Leopard 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 a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, or the pharmaceutical composition of embodiment 30 is administered orally.

Embodiment 36. Use of 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 a pharmaceutical composition as described in Embodiment 30 in the manufacture of a medicament for treating a disease or disorder associated with SHP2.

Embodiment 37. The use according to embodiment 36, wherein the disease or disorder associated with SHP2 is mediated by the activity of SHP2.

Embodiment 38. The use as described in Embodiment 37, wherein the disease or disorder associated with SHP2 is selected from Noonan syndrome, Leopard 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 according to any one of embodiments 36-38, wherein the medicament is formulated for oral administration.

Embodiment 40. 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 a pharmaceutical composition according to Embodiment 30 for use in the treatment of a SHP2-related disease or disorder.

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

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

Embodiment 43. The drug or pharmaceutical composition of any one of Embodiments 40-42, wherein the SHP2-related cancer is selected from 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 44. A method for inhibiting SHP2 activity in vitro or in vivo in cancer cells associated with SHP2 using 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.

In some embodiments, the compound of Formula I (such as Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF) has a chiral configuration that exhibits excess over its enantiomer, and thus the compound is optically active. For example, such compounds disclosed herein are substantially free of the opposite enantiomer (i.e., at least 95% of the compound has the chirality shown above).

Also disclosed herein are pharmaceutical compositions comprising a compound of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and 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.

Further disclosed herein is a method for inhibiting the activity of SHP2, comprising contacting 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 is a method for treating a treatable disease by inhibiting SHP2 in a patient, the method comprising administering to a patient identified as needing such treatment 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 is a method for treating a treatable disease by inhibiting SHP2 in a patient, the method comprising administering to a patient identified as needing such treatment an effective amount of a pharmaceutical composition comprising 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, and a pharmaceutically acceptable carrier.

Further disclosed herein is a method for treating cancer in a patient, the method comprising administering to a patient confirmed to need such treatment 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, a stable isotope, or a 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 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.

Further disclosed herein is the use of a compound of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, or Formula IF) and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate of a compound of Formula I in the preparation of a medicament for treating a disease (e.g., cancer) that responds to SHP2 inhibition. In some embodiments, the cancer is selected from 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.

Although the most appropriate route in any given case will depend on the specific host to which the active ingredient is being administered, and the nature and severity of the condition, pharmaceutical compositions comprising 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 solvates of compounds of Formula I, and pharmaceutically acceptable carriers, can be administered in various known ways, such as orally, topically, rectally, parenterally, by inhalation sprays, or via implantable kits. As used herein, the term "parenteral" includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The compositions disclosed herein can be conveniently present in unit dosage form and prepared by any method known in the art.

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 solvates of compounds of Formula I can be orally administered in solid dosage forms (such as capsules, tablets, lozenges, dragees, granules and powders) or in liquid dosage forms (such as elixirs, syrups, emulsions, dispersions and suspensions). 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 solvates of compounds of Formula I can also be administered parenterally in sterile liquid dosage forms (such as dispersions, suspensions or solutions). Other dosage forms that may be used to administer a compound of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of a compound of Formula I include ointments, creams, drops, skin patches or powders for topical administration, ophthalmic solutions or suspensions (i.e., eye drops) for ocular administration, aerosol sprays or powder compositions for inhalation or intranasal administration, or creams, ointments, sprays or suppositories for rectal or vaginal administration.

A gelatin capsule containing a compound of formula I (e.g., formula IA, formula IB, formula IC, formula ID, formula IE and formula IF) and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate of a compound of formula I and at least one powdered carrier (selected from, for example, lactose, starch, a cellulose derivative, magnesium stearate, stearic acid, etc.) can also be used. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be made into sustained release products to provide continuous release of the drug over a period of time. Compressed tablets can be sugar-coated or film-coated to cover any unpleasant taste and protect the tablet from environmental influences, or enteric-coated to selectively decompose in the gastrointestinal tract.

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

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

Pharmaceutically acceptable carriers are selected, for example, from carriers that are compatible with the active ingredients of the pharmaceutical composition (and in some embodiments, capable of stabilizing the active ingredients) and are harmless to the subject to be treated. For example, solubilizers such as cyclodextrins (which can form specific more soluble complexes with at least one compound disclosed herein and/or at least one pharmaceutically acceptable salt) can be used as pharmaceutical excipients for delivering the active ingredient. Examples of other carriers include colloidal silica, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments (such as D&C yellow #10). Suitable pharmaceutically acceptable carriers are disclosed in Remington's Pharmaceutical Sciences, A. Osol (a standard reference text in the art).

The efficacy of 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 or solvate of a compound of Formula I in treating cancer can be examined by in vivo assay. For example, 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 or solvate of a compound of Formula I can be administered to an animal (e.g., a mouse model) suffering from cancer, and its therapeutic effect can be obtained. One or more of the positive results shown in such tests are sufficient to increase the scientific knowledge base, and therefore sufficient to demonstrate the practicality of the tested compound and/or salt. Based on the results, the appropriate dosage range and route of administration for animals (such as humans) can also be determined.

For administration by inhalation, 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 salts or solvates of compounds of Formula I, can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer. 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 salts or solvates of compounds of Formula I can also be delivered in the form of a powder (which can be formulated), and the powder composition can be inhaled with the aid of an inhalation powder inhalation device. An exemplary delivery system for inhalation can be a metered dose inhalation (MDI) aerosol, which can be formulated as a suspension or solution of 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 or solvate of a compound of Formula I in at least one suitable propellant (selected from, for example, fluorocarbons and hydrocarbons).

For ocular administration, ophthalmic preparations can be formulated with a solution or suspension of a compound of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or a stereoisomer, stable isotope, or a pharmaceutically acceptable salt or solvate of a compound of Formula I at an appropriate weight percentage in an appropriate ophthalmic vehicle such that the compound of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or a stereoisomer, stable isotope, or a pharmaceutically acceptable salt or solvate of a compound of Formula I remains in contact with the eye surface for a sufficient period of time to allow the compound to penetrate into the cornea and internal areas of the eye.

Useful pharmaceutical dosage forms for administering 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 salts or solvates of compounds of Formula I include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injections, and oral suspensions.

The dosage 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 the active ingredient may be, for example, from 0.1 mg/day to 2000 mg/day. For example, 10-500 mg once a day or multiple times a day may be effective to obtain the desired result.

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 a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of a compound of Formula I can be present in a capsule in an amount of 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.

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

In some embodiments, a mixture of a compound of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of a compound of Formula I and a digestible oil (e.g., soybean oil, cottonseed oil, or olive oil) can be prepared and injected into gelatin with the aid of a positive displacement pump to form a soft gelatin capsule containing 75 mg or 100 mg of the active ingredient. The capsules are washed and dried.

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 a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of a compound of Formula I can be present in a tablet in an amount of 1 mg-500 mg, for example, 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.

In some embodiments, a large number of tablets can be prepared by conventional procedures so that the dosage unit includes, for example, 100 mg of a compound of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate of a compound of Formula I, 0.2 mg of colloidal silica, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose. Appropriate coatings may be applied, for example, to increase palatability or delay absorption.

In some embodiments, a parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of a compound of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of a compound of Formula I in 10% by volume propylene glycol. The solution is made up to the desired volume with water for injection and sterilized.

In some embodiments, an aqueous suspension can be prepared for oral administration. For example, an aqueous suspension comprising 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 stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate of a compound of Formula I, 100 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution (U.S.P.) and 0.025 ml of vanillin per 5 ml can be used.

When a compound of Formula I (e.g., Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, and Formula IF), and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of a compound of Formula I is administered stepwise or co-administered with at least one other therapeutic agent, the same dosage form can generally be used. When the drugs are administered in physical combination, the dosage form and route of administration should be selected based on the compatibility of the combined drugs. Therefore, the term "co-administration" is understood to include at least two agents being administered 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 solvates of compounds of Formula I can be administered as the sole active ingredient or in combination with at least one second active ingredient, wherein the at least one second active ingredient is selected from, for example, other active ingredients known to be useful for treating a target disease in a patient (such as cancer, including, for example, colon cancer, gastric cancer, leukemia, lymphoma, melanoma and pancreatic cancer).

As used herein, the term "optical isomer" or "stereoisomer" refers to any of the various stereoisomer configurations that may exist for a given compound of the present disclosure, and includes geometric isomers. It should be understood that substituents can be attached to the chiral center of a carbon atom. The term "chirality" refers to molecules with non-overlapping properties on their mirror image partners, while the term "achirality" refers to molecules that overlap on their mirror image partners. The present disclosure includes enantiomers, diastereomers, or racemates of 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, the term is used to specify a racemic mixture. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is indicated according to the Cahn-lngold-Prelog IR-SJ system. When a compound is enantiomerically pure, the stereochemistry of each chiral carbon can be designated by R or S. Resolved compounds whose absolute configuration is unknown can be designated as (+) or (-), depending on the direction (right- or left-handed) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- in terms of absolute stereochemistry.

Depending on the choice of starting materials and synthetic procedures, the compounds may exist in the form of one of the possible isomers or as a mixture thereof (e.g., as a pure optical isomer, or as a mixture of isomers (depending on the number of asymmetric carbon atoms, such as a racemate and a diastereomeric mixture)). The present disclosure encompasses all such possible isomers (including racemic mixtures, diastereomeric mixtures and optically pure forms). Optically active (R)- and (S)-isomers may 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 configuration or the Z configuration unless otherwise specified. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis configuration or a trans configuration unless otherwise specified.

In many cases, the compounds of the present disclosure are capable of forming acid salts and/or basic 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" particularly includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the compounds of the present disclosure and are generally not biologically or otherwise undesirable.

Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, for example, acetate, adipate, aluminum, ascorbate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, hexanoate, chloride/hydrochloride, chloroprocaine, chlortheophyllonate, citrate, edetate, calcium edetate, ethandisulfonate, ethylsulfonate, ethylenediamine, fumarate, galactarate (mucate), glucoheptonate, gluconate, glucuronate, glutamate, glycolate, hexylresorcinate, resorcinate), hippurate, hydroiodide/iodide, hydroxynapthoate (xinapoate), isethionate, lactate, lactobionate, lauryl sulfate, lithium, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthoate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate/hydrogenphosphate/dihydrogenphosphate, polygalacturonate, procaine, propionate, salicylate, sebacate, stearate, subacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, bitartrate, toluenesulfonate, triphenylacetate, and trifluoroacetate. Additional lists of suitable salts 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). Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. 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, ethanesulfonic 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 of 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 include ammonium, potassium, sodium, calcium, and magnesium salts.

Organic bases from which salts can 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 disclosed herein can be synthesized from the basic or acidic moieties by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg or K), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or in an organic solvent or in a mixture of water and an organic solvent. Typically, the use of a non-aqueous medium (such as ether, ethyl acetate, tetrahydrofuran, toluene, chloroform, dichloromethane, methanol, ethanol, isopropanol or acetonitrile) is desirable where feasible.

Any formula given herein is intended to represent an unlabeled form of a compound (i.e., a compound in which all atoms exist in natural isotopic abundance and are not isotopically enriched) as well as an isotopically enriched or labeled form. 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 replaced by an atom of an atomic mass or mass number of the same element but having an atomic mass or atomic mass distribution different from that of the naturally occurring compound. Examples of isotopes that may be incorporated into the 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, 14 C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, and ¹²⁵ I, respectively ^. The present disclosure encompasses various isotopically labeled compounds as defined herein, for example, those compounds in which radioactive isotopes (such as 3H and 14C) are present at levels significantly above the natural abundance of these isotopes or those compounds in which non-radioactive isotopes (such as ^2H and ^13C ) are present. These isotopically labeled compounds are useful in metabolic studies (using ^14C ), reaction kinetic studies (using, for example, ^2H or ^3H ), detection techniques or imaging techniques (such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution determinations), or radiotherapy of patients. In particular, ^18F or F-labeled compounds may be particularly desirable for PET studies or SPECT studies. Isotopically labeled compounds of Formula I 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.

In addition, substitution with heavier isotopes, particularly deuterium (i.e., ^2H or D), can provide certain therapeutic advantages derived from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements or improvement in therapeutic index). It should be understood that deuterium herein is considered a substituent of a compound of Formula I if incorporated at a level substantially above the natural isotopic abundance. The present disclosure encompasses isotopically enriched variations of the compounds (e.g., deuterated variations as well as non-deuterated variations). Deuterated variations may be deuterated at a single site or at multiple sites.

The degree of incorporation of such isotopes, particularly deuterium, in an isotopically enriched compound can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" 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 designated as deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), 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 of crystallization may be isotopically substituted (eg, D ₂ O, d 6 -acetone, d ₆ -DMSO), as well as solvates with non-enriched solvents.

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, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavor enhancers, dyes, etc. and combinations thereof, as known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except in the case where any conventional carrier is incompatible with the active ingredient, its use in a therapeutic composition or pharmaceutical composition is contemplated.

The term "therapeutically effective amount" of a compound of the present disclosure refers to an amount of a compound of the present disclosure that will elicit a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity), or improve symptoms, alleviate a condition, slow or delay disease progression, or prevent a disease, 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, prevent and/or improve a condition or disorder or disease that (i) is mediated by a kinase (e.g., SHP2) or (ii) is associated with the activity of a kinase (e.g., SHP2) or (iii) is characterized by the activity (normal or abnormal) of SHP2; or (2) reduces or inhibits the activity of SHP2 or (3) reduces or inhibits the expression of SHP2.

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

As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. A subject also refers to, for example, a primate (e.g., a human, male animal, or female animal), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, a fish, a bird, etc. In certain embodiments, the subject is a primate. In specific embodiments, the subject is a 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 reducing the development of at least one of the disease or its clinical symptoms). In other embodiments, "treat," "treating," or "treatment" refer to alleviating or improving at least one physical parameter (including those that cannot be discerned by the patient). In other embodiments, "treat," "treating," or "treatment" refer to regulating a disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of a physical parameter), or both physically and physiologically. In other embodiments, "treat," "treating," or "treatment" refer to delaying the development or progression of a disease or disorder.

As used herein, a subject has a recognized "need for" a treatment if the subject would be expected to benefit biologically, medically, or in quality of life from such treatment.

As used herein, the terms “a,” “an,” “the” and similar terms used in the context of the disclosure (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

All methods described herein can be performed in any suitable order, unless otherwise specified herein or clearly contradictory in context. The use of any and all embodiments or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the present disclosure, and is not intended to limit the scope of the present disclosure claimed in any other way.

Any asymmetric atom (e.g., carbon, etc.) of one or more compounds of the present disclosure may exist in a racemic or enantiomerically enriched configuration (e.g., (R)-, (S)-, or (R,S)-configuration). In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess of (R)- or (S)-configuration; that is, for optically active compounds, for example, one enantiomer is typically used to substantially exclude the other enantiomer. Where possible, substituents at atoms having carbon-carbon double bonds may exist in cis-(Z)- or trans-(E)-form, and unless otherwise indicated, both are included in the present disclosure.

Thus, as used herein, the compounds 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 or trans) isomer, diastereomer, optical isomer (enantiomer), racemate, or mixture 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) of other isomers, calculated by weight relative to the amount of the preferred isomer.

Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.

Any resulting final product or racemate of intermediate product can be split into optical antipodes by known methods (e.g., by separating diastereomeric salts to obtain optically active acid or optically active base, and releasing the optically active acidic compound or optically active basic compound). In particular, the basic part can be thus adopted to split the compound of the present disclosure into its optically active antipodes, for example, by fractional crystallization with an optically active acid (e.g., tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, two-O, O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid) salt formed. The racemic product can also be split by chiral chromatography (e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent).

In addition, the compounds of the present disclosure (including its salt) can also be obtained in the form of its hydrate, or include other solvents for its crystallization. The compounds of the present disclosure can form solvates with pharmaceutically acceptable solvents (including water) inherently or by design; Therefore, the present disclosure is intended to include both solvated forms and non-solvated forms. The term "solvate" refers to a molecular complex of a compound of the present disclosure (including its pharmaceutically acceptable salt) and one or more solvent molecules. Such solvent molecules are those solvent molecules (e.g., water, ethanol, etc.) commonly used in the field of medicine that are known to be harmless to recipients. The term "hydrate" refers to a complex in which the solvent molecule is water.

Schemes 1-2 illustrate general methods for preparing compounds of the present disclosure and intermediates. Detailed descriptions and synthetic methods are disclosed in the following examples. Those skilled in the art will be able to find other synthetic methods or modify the following methods using conventional chemistry to prepare suitable compounds encompassed by Formula I. Therefore, 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 easily replaced to provide various compounds and/or reaction conditions.

Compounds of Formula I can be prepared by the general synthetic method illustrated in Scheme 1. Heteroarylthiol of Formula 3 can be prepared by a two-step process: first reacting a compound of Formula 1 (Z ₁ is Cl, Br or -OTf) with 2-ethylhexyl 3-mercaptopropionate of Formula 2 under Pd catalytic conditions (e.g., tris(dibenzylideneacetone)palladium (Pd ₂ (dba) ₃ ), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos) and diisopropylethylamine in tetrahydrofuran or dioxane solution), followed by treatment with potassium tert-butoxide in tetrahydrofuran. Heteroarylthiol 3 can be reacted with a compound of formula 4 (Z 2 and Z 3 are independently Cl, Br or _-OTf ) under Pd catalytic conditions (e.g., tris(dibenzylideneacetone)palladium (Pd ₂ (dba) ₃ ), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos) and diisopropylethylamine in tetrahydrofuran in dioxane solution) to provide a compound of formula 5. Compounds of formula 5 and amines of formula 6 _are coupled by nucleophilic substitution reaction or by Buchwald-Hartwig reaction to give compounds 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 with the compound of Formula 4 via a nucleophilic substitution reaction or a Buchwald-Hartwig reaction. The compound of Formula 7 and the heteroarylthiol of Formula 3 are coupled under Pd catalytic conditions (e.g., tris(dibenzylideneacetone)palladium ( _Pd2 (dba) ₃ ), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos) and diisopropylethylamine in tetrahydrofuran or dioxane solution) to give the compound of Formula I.

Compounds of Formula 7 can also be converted to heteroarylthiols of Formula 8 by the same two-step method as described above for compounds of Formula 3. Compounds of Formula 8 and compounds of Formula 1 are coupled under Pd catalytic conditions (e.g., tris(dibenzylideneacetone)palladium ( _Pd2 (dba) ₃ ), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos) and diisopropylethylamine in tetrahydrofuran or dioxane solution) to give compounds 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. Compounds of formula 4 are coupled with heteroarylthiols of formula 9 under Pd catalytic conditions (e.g., tris(dibenzylideneacetone)palladium (Pd ₂ (dba) ₃ ), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos) and diisopropylethylamine in tetrahydrofuran or dioxane solution) to give compounds of formula 10. Compounds of formula 10 and amines of formula 6 are reacted by nucleophilic substitution reaction or Buchwald-Hartwig reaction to give compounds of formula 11. Alternatively, the compound of formula 11 can be obtained by coupling the compound of formula 7 and the heteroarylthiol of formula 9 under Pd catalytic conditions (e.g., tris(dibenzylideneacetone)palladium ( _Pd2 (dba) ₃ ), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos) and diisopropylethylamine in tetrahydrofuran or dioxane solution). The compound of formula 11 can be converted into the compound of formula I by reacting with a suitable reagent in an alcohol solvent (e.g., ethanol and isopropanol) at elevated temperature. For example, the suitable reagent for the compound of formula I ( ^X1 = ^X2 = CH) can be 2-chloroacetaldehyde or for the compound of formula I ( ^X1 = _CCH3 , ^X2 = CH) can be 1-bromo-2,2-dimethoxypropane; or for the compound of formula I ( ^X1 = _CCF3 , ^X2 = CH) can be 3-bromo-1,1,1-trifluoropropyl-2-one.

Scenario 2

Example

The following examples illustrate certain embodiments of the present disclosure and how to make and use them. Therefore, the following examples are not intended to limit the scope of the present 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. According to one or more of the assays described herein, the following example compounds were found to be inhibitors of SHP2.

In the following examples, the following abbreviations are used: BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BOC tert-butyloxycarbonyl Boc ₂ O Di-tert-butyl dicarbonate B ₂ (Pin) _2- bis(pinacolato)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(diphenylphosphino)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 Isopropanol 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(diphenylphosphino)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)triethylenediamine bis(tetrafluoroborate) TBAF Tetrabutylammonium fluoride TBDMSCl tert-Butyldimethylchlorosilane 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 isocyanide Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

Example 1

Preparation of (3S,4S)-8-(5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-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 aqueous 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 and washed with water (100 mL x 2), dried over Na ₂ SO ₄ , 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)propanoate

To a solution of the product of step 1 above (24 g, 115.7 mmol), 2-ethylhexyl 3-mercaptopropionate (27.8 g, 127.3 mmol), Pd ₂ dba ₃ (2.65 g, 2.9 mmol), Xantphos (3.35 g, 5.79 mmol) and DIPEA (30 g, 231.4 mmol) in dioxane (240 mL) was charged with N ₂ 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×2) and brine (300 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=5/1-2/1) to give the title compound (43 g, yield: ～100%).

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

To a solution of the product of step 2 (5.0 g, 14.5 mmol) in THF (40 mL) was slowly added KOtBu/THF (4.9 g/44 mL) at -78 ° C and under N ₂ 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 give the title compound (1.7 g, yield: 74%).

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

A solution of the product of step 3 above (700 mg, 4.37 mmol), 2-bromo-5-chloropyrazine (931 mg, 4.8 mmol), Pd ₂ dba ₃ (200 mg, 0.218 mmol), Xantphos (253 mg, 0.437 mmol) and a solution of DIPEA (1.13 g, 8.75 mmol) in dioxane (7 mL) were filled 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 flash column chromatography on a C18 reverse phase column (MeOH/H ₂ O) to give 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-azaspiro [4.5]Decyl-4-amine

A solution of the product of step 4 above (214 mg, 0.783 mmol), (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (200 mg, 0.735 mmol) and DIPEA (304 mg, 2.35 mmol) in NMP (2 mL) was filled 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] tert-butyl decylcarbamate

To an ice-cooled solution of the product of step 5 above (396 mg, crude, -0.783 mmol) and TEA (238 mg, 2.35 mmol) in THF was added _Boc2O (205 mg, 0.94 mmol). The mixture was allowed to warm to room temperature, stirred for 0.5 hours, and then concentrated. The residue was purified by silica gel flash column chromatography to give 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- tert-Butyl azaspiro[4.5]decane-4-yl)carbamate

To a solution of the product of 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 NaHCO ₃ solution (50 mL), water (50 mL) and brine (50 mL), dried over Na ₂ SO ₄ , 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-nitropropene Heterospiro[4.5]decyl-4-amine hydrochloride

A solution of the product of step 7 above (crude, from the previous step) in 4N HCl/dioxane was stirred at room temperature overnight. The suspension was concentrated and the resulting 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

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

Step 1: ((3S,4S)-8-(5-((8-chloro-2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3-methyl-2-oxo tert-Butyl 8-azaspiro[4.5]decane-4-yl)carbamate

To a solution of the product of step 6 of Example 1 (50 mg, 0.099 mmol) in isopropanol (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/H ₂ O, 30 min). The fractions containing the product were freeze dried overnight to give the desired product (32 mg, yield: 59%).

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

To a solution of the product of 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 minutes). The fractions containing the product were freeze-dried overnight to give 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

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

2-Bromo-1,1-dimethoxypropane (108 mg, 0.592 mmol) and TsOH·H ₂ O (7 mg, 0.04 mmol) were added to a solution of the product of step 6 of Example 1 (100 mg, 0.197 mmol) in EtOH (1.5 mL). 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 give the title compound (11 mg, yield: 12%). MS (ESI) m/z: 445.2 [M+1] +; ¹ H NMR (400 MHz, CD ₃ OD)δ8.29(d,J＝3.2Hz,2H),8.03(d,J＝7.3Hz,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),3.7 3(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

Preparation of (3S,4S)-8-(5-((8-chloro-2-(trifluoromethyl)imidazo[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 of step 6 (75 mg, 0.148 mmol) of Example 1 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 give the free base. The free base was treated with 2N HCl/EtOAc and concentrated to give the hydrochloride (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), 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

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

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

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-oxopropanoate (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 NaHCO ₃ (10 mL) solution and brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE/EA=10/1 to 1/1) to give the title compound (320 mg, yield: 89%).

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

To a solution of the product of 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 1 N 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/H ₂ O) 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

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

Step 1: 7-((5-((3S,4S)-4-((tert-butyloxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrrolidone (2-oxazine-2-yl)thio)-8-chloroimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester

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

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

A mixture of the product of 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 Na ₂ SO ₄ and concentrated. The residue was purified by preparative TLC (DCM/MeOH=10/1) to give the title compound (81 mg, yield: 50%).

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

To the ice-water cooling solution of the product of step 2 (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 ground together with EtOAc (5 mL), filtered and dried to obtain 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

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

Step 1: tert-Butyl 5-bromo-4-chloro-1H-indazole-1-carboxylate

To a solution of 5-bromo-4-chloro-1H-indazole (1.0 g, 4.32 mmol) in THF (5 mL) were 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, then diluted with EA (100 mL). The mixture was washed with water (30 mL×2) and brine (30 mL), dried over Na ₂ SO ₄ , 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)propanoate

A mixture of the product of step 1 above (2.0 g, 6.04 mmol), 2-ethylheptyl 3-mercaptopropionate (1.7 g, 7.85 mmol), Pd ₂ dba ₃ (274 mg, 0.3 mmol), XantPhos (347 mg, 0.6 mmol) and DIPEA (1.5 g, 12.1 mmol) in dioxane (15 mL) was filled with N ₂ and stirred at 110° C. overnight. The mixture was cooled to room temperature, diluted with EA (100 mL), washed with water (30 mL×2) and brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (DCM/EtOAc=5/1 to 3/2) to give the title compound (1.6 g, yield: 57%).

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

A mixture of the product of 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, warmed to -10°C, treated with aqueous K ₂ CO ₃ solution (2M, 50 mL), and extracted with MTBE (50 mL×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 Na ₂ SO ₄ , filtered and concentrated to give the title compound (510 mg, yield: 51%).

Step 4: tert-((3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decyl-4-yl)carbamic acid Butyl Ester

To a solution of 2,5-dibromopyrazine (357 mg, 1.5 mmol) and dihydrochloridized (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]decyl-4-amine (1.95 mmol, 1.3 mmol) in NMP (10 mL) was added DIPEA (775 mg, 6.0 mmol). 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 Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=4/1 to 3/2) to give 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] tert-Butyl decane-4-yl)carbamate

A mixture of the product of step 3 above (200 mg, 0.70 mmol), the product of step 4 above (273 mg, 0.64 mmol), Pd ₂ dba ₃ (55 mg, 0.06 mmol), XantPhos (75 mg, 0.13 mmol) and DIPEA (165 mg, 1.28 mmol) in dioxane (5 mL) was charged 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×2) and brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash column chromatography (DCM/EtOAc=3/2) to give 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] Decane-4-yl)amine trifluoroacetate

To a solution of the product of step 5 (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/H ₂ O) 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＝6.5Hz,3H).

Example 8

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

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

A mixture of 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 filled 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×2) and brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (DCM/EtOAc=4/1-2/1) to give 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-nitropropane Heterospiro[4.5]decane-4-yl)carbamic acid tert-butyl ester

A mixture of the product of step 1 above (210 mg, 0.67 mmol), (3S, 4S)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine dihydrochloride (149 mg, 0.61 mmol), and 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×2) and brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative TLC (DCM/EtOAc=1/1) to give 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-nitropropane Heterospiro[4.5]decane-4-amine trifluoroacetate

To a solution of the product of step 2 (140 mg, 0.22 mmol) in DCM (5 mL) was slowly added TFA (2 mL) with ice-water bath 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 (MeOH/H ₂ O=10%-95%) to give 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).

Embodiment 9

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

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

To a solution of the product of step 2 in Example 7 (2.0 g, 5.43 mmol) in DMF (30 mL) were 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 hours. The reaction mixture was diluted with EtOAc (100 mL), and washed with Na ₂ S ₂ O ₃ (saturated aqueous solution, 30 mL), water (30 mL) and brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=3/1) to give 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)propanoate

To a solution of the product of step 1 above (2.0 g, 4.05 mmol) in DCM (30 mL) were 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 NaHCO ₃ (aqueous solution, 30 mL), water (30 mL) and brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=8/1) to give the title compound (1.7 g, yield: 73%).

Step 3: 2-Ethylhexyl 3-((4-chloro-3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)thio)propanoate

A mixture of the product of step 2 above (1.3 g, 2.25 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-triphenylboroxine (1.4 g, 11.2 mmol), 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 stirred at 105° C. overnight. The mixture was cooled to room temperature. The reaction mixture was diluted with EtOAc (100 mL), washed with water (30 mL×2) and brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash column chromatography (DCM/EtOAc=10/1 to 8/1) to give 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 of 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 a K ₂ CO ₃ solution (2N, 20 mL) was added thereto. The reaction mixture was extracted with MTBE (30 mL×2). The pH value of the aqueous phase was adjusted to 5-6 with 6N HCl in an ice-water bath, and the aqueous phase was extracted with DCM/IPA (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative TLC (PE/EtOAc=2/1) to give 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-yl tert-butyl (3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

A mixture of 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, 0.57 mmol) in dioxane (5 mL) was filled with N ₂ and stirred at 100° C. overnight. The mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with water (30 mL×2) and brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative TLC (PE/EtOAc=1/1) to give 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-nitropropene Heterospiro[4.5]decan-4-amine hydrochloride

To a solution of the product of step 5 above (80 mg, 0.13 mmol) in MeOH (3 mL) was slowly added HCl/dioxane (4N, 2 mL) under ice-water bath cooling. 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/ _H2O =10%-90%) to give 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 = 9.3 Hz,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

Preparation of (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

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

To LDA (50 mL, 50 mmol, 1 M) was added a solution of 1-bromo-2-chloro-3-fluorobenzene (10 g, 47.75 mmol) in anhydrous THF (45 mL) at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 1 hour, and then DMF (5.22 g, 71.53 mmol) was slowly added. The resulting mixture was warmed to -20 °C and quenched with saturated NH ₄ Cl solution (35 mL). The mixture was extracted with EtOAc (200 mL), washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel flash column chromatography (PE) to give the title compound (9.0 g, yield: 80%) as a white solid.

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

To a solution of the product of 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 under vacuum. The residue was ground with water and the solid was collected by filtration. The solid was washed with water (2×50 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)propanoate

To a solution of the product of step 2 above (5.5 g, 23.76 mmol) in dioxane (60 mL) were added 2-methylhexyl 3-mercaptopropionate (5.19 g, 23.76 mmol), DIPEA (6.13 g, 47.52 mmol), Xantphos (1.38 g, 2.38 mmol) and Pd ₂ (dba) ₃ (435 mg, 0.48 mmol). The mixture was stirred at 110 ° C overnight under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered. The filtrate was concentrated and the filter residue was dissolved in EtOAc (200 mL), washed with water (50 mL) and brine (40 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=50/1 to 10/1) to give 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) was added dropwise t-BuOK (1.42 g, 12.7 mmol) at -78°C under 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 give the title compound (662 mg, yield: 100%)

Step 5: tert-Butyl 7-chloro-6-mercapto-1H-indazole-1-carboxylate

To a solution of the product of step 4 (500 mg, 2.71 mmol) in THF (10 mL) at 0°C, DMAP (33 mg, 0.271 mmol) and (Boc) ₂ O (885 mg, 4.06 mmol) were added. The reaction mixture was stirred for 1 hour while the temperature was raised 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 give the title compound (439 mg, yield: 57%).

Step 6: 6-((5-((3S,4S)-4-((tert-butyloxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrrolidone tert-butyl ((2-oxazine-2-yl)thio)-7-chloro-1H-indazole-1-carboxylate

To a solution of the product of step 5 above (180 mg, 0.631 mmol) in dioxane (4 mL) were added the product of step 4 of example 7 (179 mg, 0.421 mmol), DIPEA (109 mg, 0.842 mmol), Xantphos (24 mg, 0.0421 mmol) and Pd ₂ (dba) ₃ (19 mg, 0.0211 mmol). The mixture was stirred at 110° C. overnight under a 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 Na ₂ SO ₄ and concentrated. The residue was purified by flash column chromatography on silica gel (PE/EtOAc=1/1) to give 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 of step 6 (87 mg 0.138 mmol) in EtOAc (1 mL) was added HCl/EtOAc (4 mL, 2 M). The mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration, washed with EtOAc, and dried under vacuum to give 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).

Embodiment 11

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

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

To a solution of the product of step 3 in Example 10 (1.38 g, 3.89 mmol) in DMF (20 mL) were 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 a 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: Ethyl 7-chloro-6-((3-((2-methylhexyl)oxy)-3-oxopropyl)thio)-1H-indazole-3-carboxylate

To a solution of the product of 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 balloon filled with carbon monoxide. 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 Na ₂ SO ₄ and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=8/1 to 4/1) to give the title compound (1.1 g, yield: 60%).

Step 3: 1-tert-butyl 7-chloro-6-((3-((2-methylhexyl)oxy)-3-oxopropyl)thio)-1H-indazole-1,3-dicarboxylate 3-Ethyl ester

To a solution of the product of step 2 (1.1 g, 2.58 mmol) in THF (15 mL) at 0°C, DMAP (31 mg, 0.258 mmol) and (Boc) _2O (842 mg, 3.86 mmol) were added. The reaction mixture was stirred for 4 hours while gradually warming 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 give the title compound (625 mg, yield: 46%).

Step 4: 7-Chloro-6-mercapto-1H-indazole-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl ester

To a solution of the product of step 3 above (625 mg, 1.186 mmol) in THF (5 mL) was added dropwise a solution of t-BuOK (400 mg, 3.558 mmol) in THF (5 mL) at -78°C under 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 Na ₂ SO ₄ and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=4/1) to give the title compound (303 mg, yield: 72%).

Step 5: 6-((5-((3S,4S)-4-((tert-butyloxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrrolidone 3-tert-butyl 7-chloro-1H-indazole-1,3-dicarboxylic acid ester (2-oxazine-2-yl)thio)-1-tert-butyl 7-chloro-1H-indazole-1,3-dicarboxylate

To a solution of the product of step 4 above (240 mg, 0.673 mmol) in dioxane (4 mL) were added the product of step 4 in Example 7 (191 mg, 0.448 mmol), DIPEA (173 mg, 1.344 mmol), XantPhos (51 mg, 0.0896 mmol) and Pd ₂ (dba) ₃ (41 mg, 0.0448 mmol). The mixture was stirred at 110° C. overnight under a 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 Na ₂ SO ₄ and concentrated. The resulting residue was purified by Pre-TLC (PE/EtOAc=1/1) to give the title compound (24 mg, yield: 8%).

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

To a solution of the product of 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 (1 N) at 0° C. and extracted with EtOAc (60 mL). The organic layer was washed with water (10 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by preparative TLC (DCM/MeOH=10/1) to give the title compound (7 mg, yield: 30%).

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

To a solution of the product of step 6 above (7 mg, 0.0104 mmol) in EtOAc (1 mL) was added HCl/EtOAc (2 mL, 2 M). 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

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

Step 1: tert-Butyl 7-bromo-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

To a solution of 7-bromo-1H-pyrazolo[4,3-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. The reaction mixture was diluted with EtOAc (100 mL), washed with water (30 mL×2) and brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (1.14 g, yield: 75%).

Step 2: tert-butyl 7-((3-((2-ethylhexyl)oxy)-3-oxopropyl)thio)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate Base ester

A mixture of the product of step 1 above (1.14 g, 3.8 mmol), 2-ethylheptyl 3-mercaptopropionate (917 mg, 4.2 mmol), Pd ₂ dba ₃ (174 mg, 0.19 mmol), Xantphos (220 mg, 0.38 mmol) and ()DIPEA (982 mg, 7.6 mmol) in dioxane (10 mL) was filled 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×2) and brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=4/1-1/1) to give the title compound (700 mg, yield: 42%).

Step 3: tert-Butyl 7-mercapto-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

A mixture of the product of step 2 (700 mg, 1.6 mmol) in anhydrous THF (20 mL) solution was cooled to -78 °C and a THF (10 mL) solution of t-BuOK (541 mg, 4.8 mmol) was added thereto. 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). The pH value of the aqueous phase was adjusted to 5-6 with HCl (6N) under cooling in an ice-water bath, and extracted with DCM/IPA (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (270 mg, yield: 67%).

Step 4: 7-((5-((3S,4S)-4-((tert-butyloxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrrolidone tert-butyl (2-oxazine-2-yl)thio)-1H-pyrazolo[4,3-b]pyridine-1-carboxylate

A mixture of 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) solution was filled 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×2) and brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (DCM/EtOAc=3/2) to give 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 (260 mg, 0.435 mmol) in DCM (5 mL) was slowly added TFA (2 mL) under ice-water bath cooling. The mixture was stirred at room temperature for 2 hours and then diluted with DCM (2 mL). The mixture was concentrated to give the trifluoroacetate salt of the title compound (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).

Embodiment 13

Preparation of (3S,4S)-8-(5-((1H-pyrazolo[3,4-b]pyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-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 Na ₂ SO ₄ , filtered and concentrated to give the title compound (1.58 g, crude), which was used in the next step without any further purification.

Step 2: tert-butyl 4-((3-((2-ethylheptyl)oxy)-3-oxopropyl)thio)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate Base ester

A mixture of the product of step 1 above (1.5 g, 5.03 mmol), 2-ethylheptyl 3-mercaptopropionate (1.21 g, 5.54 mmol), Pd ₂ dba ₃ (116 mg, 0.12 mmol), XantPhos (146 mg, 0.25 mmol) and DIPEA (1.3 g, 10 mmol) in dioxane (15 mL) was filled 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×2) and brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=4/1-2/1) to give the title compound (2 g, yield: 88.5%).

Step 3: tert-Butyl 4-mercapto-1H-pyrazolo[3,4-b]pyridine-1-carboxylate

A mixture of the product of step 2 (500 mg, 1.14 mmol) in anhydrous THF (10 mL) solution was cooled to -78 °C and a solution of KO ^t Bu (541 mg, 4.8 mmol) in THF (10 mL) was slowly added thereto. The mixture was stirred at -78 °C for 1 hour, warmed to -10 °C, diluted with aqueous K ₂ CO ₃ 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 Na ₂ SO ₄ , 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-butyloxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrrolidone tert-butyl (2-oxazine-2-yl)thio)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate

A mixture of the product of step 3 above (1.14 mmol), the product of step 4 of example 7 (485 mg, 1.14 mmol), Pd ₂ dba ₃ (52 mg, 0.057 mmol), XantPhos (66 mg, 0.11 mmol) and DIPEA (295 mg, 2.28 mmol) in dioxane (5 mL) solution was filled with N ₂ and stirred at 110° C. overnight. The mixture was cooled to room temperature, diluted with EA (100 mL), washed with water (30 mL×2) and brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (DCM/EtOAc=3/2) to give 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]decan-4-amine

To the product of step 4 (100 mg) in DCM (2.5 mL) solution was slowly added TFA (1 mL) under ice-water bath cooling. The mixture was stirred at room temperature for 2 hours, diluted with DCM (2 mL) and concentrated. The residue was treated with saturated NaHCO ₃ solution (2 mL), extracted with DCM/IPA (3/1, 10 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH=10/1) to give 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),4.0 9–3.99(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＝6.4 Hz,3H).

Embodiment 14

Preparation of 5-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)pyrazin-2-yl)thio)-4-chloro-1H- benzo[d]imidazol-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 diluted with water (80 mL). The precipitate was filtered and collected, and the title compound (1.12 g, yield: 99%) was obtained after drying.

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

A mixture of the product of step 1 above (910 mg, 3.68 mmol), 2-ethylhexyl 3-mercaptopropionate (883 mg, 4.04 mmol), Pd ₂ dba ₃ (168 mg, 0.184 mmol), Xantphos (212 mg, 0.368 mmol) and DIPEA (1.43 g, 11.04 mmol) in dioxane (15 mL) solution was filled with N ₂ and stirred at 110° C. for 6 hours. 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 Na ₂ SO ₄ , and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=5/1-1/1) to give 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 of step 2 (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 N _2. 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 give 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)pyrazin-2-yl)-3-methyl tert-butyl 2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

A mixture of 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 (85 mg, 0.664 mmol) in dioxane (3 mL) was filled with N ₂ and stirred at 110° C. for 5 hours. 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 Na ₂ SO ₄ , and then concentrated. The residue was purified by preparative TLC (DCM/MeOH=10/1) to give the title compound (81 mg, yield: 45%).

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

2N HCl/EtOAc (2 ml) was added to the mixture of the product of step 4 (81 mg, 0.148 mmol) in EtOAc (2 mL) solution. 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).

Embodiment 15

Preparation of (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-amine

Step 1: 2-Ethylhexyl 3-((2-aminopyridin-4-yl)thio)propanoate

A solution of 4-bromopyridin-2-amine (1 g, 5.78 mmol), 2-ethylhexyl 3-mercaptopropionate (1.39 g, 6.36 mmol), Pd ₂ dba ₃ (130 mg, 0.14 mmol), Xantphos (165 mg, 0.289 mmol) and N,N-diisopropylethylamine (1.5 g, 11.56 mmol) in 1,4-dioxane (12 mL) was stirred overnight at 110° C. under nitrogen protection. The reaction solution was cooled to room temperature, the mixture was 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 give the title compound (1.44 g, yield: 80%).

Step 2: 2-Aminopyridine-4-thiol

2-Ethylhexyl 3-((2-aminopyridin-4-yl)thio)propanoate (1.44 g, 4.65 mmol) was dissolved in dry tetrahydrofuran (15 mL), the mixture was cooled to -78 ° C, and a solution of potassium tert-butoxide (1.56 g, 13.95 mmol) in tetrahydrofuran (15 mL) was added. The mixture was stirred at -78 ° C for 1 hour, warmed to -15 ° C, and acidified to pH = 3-4 with 6N hydrochloric acid in an ice-water bath. The mixture was concentrated, and 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 give the crude title compound (613 mg).

Step 3: ((3S,4S)-8-(5-((2-aminopyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5] tert-Butyl decane-4-yl)carbamate

A solution of 2-aminopyridine-4-thiol (550 mg, 4.36 mmol), tert-butyl ((3S, 4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate (1.3 g, 3.05 mmol), Pd ₂ dba ₃ (119.7 mg, 0.13 mmol), Xantphos (75.68 mg, 0.13 mmol) and N,N-diisopropylethylamine (1.127 g, 8.72 mmol) in N-methylpyrrolidone (10 mL) was stirred at 120° C. under nitrogen atmosphere for 2 h. The mixture was cooled and purified by reverse phase flash column chromatography (C18, methanol/10 mM aqueous ammonium bicarbonate solution, 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- tert-Butyl 8-azaspiro[4.5]decane-4-yl)carbamate

To a mixture of 1-bromo-2,2-dimethoxypropane (174 mg, 0.95 mmol) and tert-butyl ((3S,4S)-8-(5-((2-aminopyridin-4-yl)thio)pyrazin-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). The mixture was stirred at 80° C. overnight under nitrogen protection. The mixture was cooled to room temperature and concentrated to give the crude title compound, which was 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]decan-4-amine

To a solution of tert-butyl ((3S,4S)-3-methyl-8-(5-((2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate (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 give the title compound (10.3 mg, total yield for 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

Preparation of (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 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]decan-4-amine

To a solution of (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]decan-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-amine dihydrochloride (101 mg, 0.42 mmol) and N,N-diisopropylethylamine (206 mg, 1.6 mmol). The mixture was stirred at 100° C. overnight, 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)pyrazin-2-yl)-3-methyl 2-Oxa-8-azaspiro[4.5]decane-4-yl)carbamate

To a solution of (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]decan-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 give the title compound (115 mg, total yield for 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]decan-4-amine

Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl ((3S, 4S)-8-(6-amino-5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate (115 mg, 0.21 mmol) in dichloromethane (5 mL) under an ice-water bath. The mixture was stirred at room temperature for 3 hours and concentrated. The residue was purified by flash chromatography (methanol/water=10%-70%) to give the title compound (81 mg, yield: 69%). MS (ESI) m/z: 446.3; ¹ H NMR (400MHz, Methanol-d ₄ ) δ8.11 (d, J = 7.2Hz, 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).

Embodiment 17

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

In an ice-water bath, N,N-diisopropylethylamine (361 mg, 3.57 mmol) and di-tert-butyl dicarbonate (388 mg, 1.78 mmol) were added to a solution of (3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-amine (500 mg, 1.19 mmol) in N,N-dimethylformamide (50 mL) in sequence. 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 give 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)pyrazin-2-yl)-3- tert-Butyl methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

A solution of tert-butyl ((3S, 4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate (150 mg, 0.29 mmol) and 1-chloropropane-2-one (99 mg, 0.86 mmol) in isopropanol (3 mL) was irradiated at 130 ° C for 10 minutes in a microwave reactor 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)pyrazin-2-yl)-3- Methyl-2-oxa-8-azaspiro[4.5]decan-4-amine

In an ice-water bath, trifluoroacetic acid (1 mL) was added to a solution of tert-butyl ((3S,4S)-8-(6-amino-5-((8-chloro-2-methylimidazo[1,2-a]pyridin-7-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate (crude) in dichloromethane (3 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 give the title compound (27 mg, total yield for 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).

Embodiment 18

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

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

At 0 ° C, NaH (60% in mineral oil, 320 mg, 8 mmol) was added to a solution of 8-chloro-7-iodoimidazo[1,2-a]pyridine (1.5 g, 5.3 mmol) in anhydrous tetrahydrofuran (50 mL). The mixture was stirred for 10 minutes and selectfluor (1.9 g, 5.34 mmol) 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 give the title compound (500 mg, yield: 31%).

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

A mixture of 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 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) was irradiated in a microwave reactor for 15 minutes at 100 ° C. 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 give the title compound (450 mg, yield: 69%).

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

A solution of 2-ethylhexyl 3-((8-chloro-2-fluoroimidazo[1,2-a]pyridin-7-yl)thio)propanoate (450 mg, 1.16 mmol) in anhydrous tetrahydrofuran (10 mL) 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. After filtration , the filtrate was concentrated, and the residue was treated with dichloromethane/methanol (10/1, 50 mL), stirred for 30 minutes, and after filtration, the filtrate was concentrated to give 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 tert-Butyl 8-azaspiro[4.5]decane-4-yl)carbamate

8-Chloro-2-fluoroimidazo[1,2-a]pyridine-7-thiol (214 mg, 1.05 mmol), tert-butyl ((3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate (300 mg, 0.7 mmol), Pd ₂ dba ₃ (128 mg, 0.14 mmol 10 mL) were irradiated in a microwave reactor at 150° C. for 15 minutes. The mixture was purified by reverse phase flash column chromatography (C18, methanol/10 mM aqueous ammonium bicarbonate solution, 10%-90%) to give 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 tert-Butyl 8-azaspiro[4.5]decane-4-yl)carbamate

A solution of tert-butyl ((3S,4S)-8-(5-((8-chloro-2-fluoroimidazo[1,2-a]pyridin-7-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate (150 mg, 0.27 mmol) in dichloromethane (5 mL) was cooled to 0 ° C, and trifluoroacetic acid (2 mL) was slowly added. 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 sodium bicarbonate aqueous solution. Extracted with dichloromethane/methanol = 20/1 (15 mL × 2). The organic phase was discarded and the aqueous phase was concentrated. 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. Filter, concentrate the filtrate, and purify by reverse phase flash column chromatography (C18, methanol/10 mM aqueous ammonium bicarbonate solution, 10%-90%) to obtain the title compound (54 mg, yield: 44%). MS (ESI) m/z: 449.1; ¹ H NMR (400 MHz, dmso) δ8.42 (s, 1H), 8.31 (s, 1H), 8.17 (d, J = 7.2 Hz, 1H), 7.39 (d, J = 7.1 Hz, 1H), 6.49 (d, J = 7.3 Hz, 1H), 4.10-4.04 (m, 1H), 3.90 (s, 2H), 3.68 (d, J = 8.5 Hz ,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).

Embodiment 19

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

Step 1: 3-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-yl)-6-bromo-5-methylpyrazine-2-yl 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] decan-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-yl)- 5-Methylpyrazine-2-carboxylic acid ethyl ester

To the cooled reaction mixture of the previous step, di-tert-butyl dicarbonate (466 mg, 2.22 mmol) was added. 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, 2-step total yield: 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-carboxylic acid ethyl ester

A suspension of 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 (300 mg, 0.59 mmol), 8-chloroimidazo[1,2-a]pyridine-7-thiol (141 mg, 0.76 mmol), Xantphos (34 mg, 0.059 mmol) and N,N-diisopropylethylamine (151 mg, 1.172 mmol) in 1,4-dioxane (8 mL) was irradiated in a microwave reactor at 150° C. for 25 minutes under nitrogen atmosphere. 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 give 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-methylpyrazine-2-yl)- tert-Butyl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-yl)carbamate

A solution of ethyl 3-((3S,4S)-4-((tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]decane-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) was cooled to -20°C under a nitrogen atmosphere, and lithium triethylborohydride (1.0 M in tetrahydrofuran, 0.45 mL, 0.45 mmol) was added dropwise. After the addition, the mixture was stirred at -20°C for 30 minutes, allowed to warm to room temperature naturally, 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 give 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-chloroimidazo[1,2-a] pyridin-7-yl)thio)-5-methylpyrazin-2-yl)methanol

Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl ((3S,4S)-8-(5-((8-chloroimidazo[1,2-a]pyridin-7-yl)thio)-3-(hydroxymethyl)-6-methylpyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate (85 mg, 0.15 mmol) in dichloromethane (5 mL) in an ice-water bath. The ice bath was removed, the mixture was warmed 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 give the title compound (35 mg, yield: 50%). MS (ESI) m/z: 475.2; ¹ H NMR (400MHz, Methanol-d ₄ ) δ8.27 (d, J = 7.1Hz, 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).

Embodiment 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]decan-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 stirred in a microwave reactor at 100° C. for 15 minutes. The mixture was cooled to room temperature, diluted with water (5 mL), extracted with ethyl acetate (10 ml), and the organic phase was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (106 mg, 94% yield) as a light yellow solid.

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

A mixture of 3,8-dichloro-7-iodoimidazo[1,2-a]pyridine (1.0 g, 3.20 mmol), 2-ethylheptyl 3-mercaptopropionate (908 mg, 4.16 mmol), 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) was stirred at 120 ° C for 15 minutes in a microwave reactor under a 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 give the title compound (1.23 g, crude product).

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

A solution of 2-ethylhexyl 3-((3,8-dichloroimidazo[1,2-a]pyridin-7-yl)thio)propanoate (1.23 g, 3.05 mmol) in dry tetrahydrofuran (10 mL) 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, 20 mL), and extracted with MTBE (20 mL×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-yl 2-oxa-8-azaspiro[4.5]decane-4-yl]carbamate

3,8-Dichloroimidazo[1,2-a]pyridine-7-thiol (120 mg, 0.55 mmol), tert-butyl N-[(3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl]carbamate (282.2 mg, 0.66 mmol), Pd2(dba)3 (15.11 mg, 0.017 mmol) and XantPhos (9.55 mg, 0.016 mmol (142.16 mg, 1.1 A suspension of 1,4-dioxane (3 mL) in 1,4-dioxane (600 mmol) was stirred in a microwave reactor at 120°C for 15 minutes under a 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 give 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]decan-4-amine

Trifluoroacetic acid (1 mL) was added to an ice-water bath solution of tert-butyl ((3S, 4S)-8-(5-((3,8-dichloroimidazo[1,2-a]pyridin-7-yl)thio)pyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decane-4-yl)carbamate (40 mg, 0.071 mmol) in dichloromethane (3 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), 3.6 9(s,3H),2.97(s,2H),1.60(m,4H),1.21(s,3H).

Embodiment 21

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

A solution of 2-chloro-5-[(8-chloroimidazo[1,2-a]pyridin-7-yl]thio]pyrazine (90 mg, 0.30 mmol), (1S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine dihydrochloride (90.81 mg, 0.33 mmol) and N,N-diisopropylethylamine (193.5 mg, 1.50 mmol) in N-methylpyrrolidone (2 mL) was stirred at 160° C. for 20 minutes in a microwave reactor under nitrogen atmosphere. The mixture was cooled to room temperature and purified by reverse phase flash column chromatography (C18, methanol/10 mM aqueous ammonium bicarbonate solution, 10%-90%) to give the title compound (40 mg, yield: 28%). MS (ESI) m/z: 464.1; ¹ H NMR (400 MHz, 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

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

A solution of 2-chloro-5-[(8-chloroimidazo[1,2-a]pyridin-7-yl]thio]pyrazine (90 mg, 0.30 mmol), (5S)-5,7-dihydrospiro[cyclopentane[b]pyridine-6,4'-piperidin]-5-amine trihydrochloride (112.55 mg, 0.36 mmol) and N,N-diisopropylethylamine (387 mg, 3 mmol) in N-methylpyrrolidone (1.5 mL) was stirred at 180° C. for 30 minutes in a microwave reactor under nitrogen atmosphere. The mixture was cooled to room temperature and purified by reverse phase flash column chromatography (C18, methanol/10 mM aqueous ammonium bicarbonate solution, 10%-90%) to give the title compound (33 mg, yield: 21%). MS (ESI) m/z: 463.1; ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.43(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),1.2 0–1.11(m,1H).

Biological activity test

SHP2 is allosterically activated by binding of a doubly tyrosylphosphopeptide to its Src homology 2 (SH2) domain. The activation step results in the release of the autoinhibitory interface of SHP2, which further renders the SHP2PTP active for substrate recognition and reaction catalysis. The catalytic activity of SHP2 was monitored using a prompt fluorescence assay using the surrogate substrate DiFMUP. Specifically, phosphatase reactions were performed at room temperature in an OptiPlate TM-384F black assay plate (Perkin Elmer, Cat# 6007279) using a final reaction volume of 20 uL and the following assay buffer conditions: 25 mM HEPES, pH 7.2, 25 mM KCl, 1 mM EDTA, 0.01% Brij-35, 5 mM DTT, and 1% DMSO (final). The test samples were prepared by incubating 0.2 nM SHP2 (PTPN11/SHP2-FL, BPS, cat#79018) with 0.5 μM SHP2 activating peptide (BPS, cat#79310-2), and the prepared test samples were used to monitor the inhibitory effect of the test compound (final concentration of 0.051-1000 nM) on SHP2. After incubation at room temperature for 20 minutes, the alternative substrate DiFMUP (6,8-difluoro-7-hydroxy-4-methylcoumarin, Invitrogen, cat#D6567, 20 μM final concentration) was added to the reaction. The plate was dynamically read on Paradigm for 60 minutes (wherein the excitation wavelength was 360 nm and the emission wavelength was 460 nm). The inhibitor dose response curve was analyzed using a normalized IC ₅₀ regression curve fitted using a control-based normalization method.

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

Cell viability test

MiaPaCa-2 cell (human pancreatic cancer cell) proliferation assay in 3D culture. To evaluate the inhibitory effect of the compounds on cell proliferation, MiaPaCa-2 cells in the logarithmic growth phase were seeded at an optimal density and grown in the form of spheroids. The cells were cultured for 24 hours before adding different concentrations of the compounds. The cells were then cultured with the compounds for 5 days, and cell viability was assessed using CCK8. In brief, 2500 cells were seeded in a round-bottom ultra-low adsorption 96-well plate (from Corning), incubated at 37°C, and after 24 hours the compounds were dissolved in DMSO (from Sigma) to obtain a 10mM stock solution. The 10mM stock solution was then serially diluted with DMSO at a dilution ratio of 3 to 10 times to obtain a series of concentrations of compound stock solutions. 5 μL of the above compound stock solution was transferred to 95 μL of culture medium to obtain 50× compound stock solution; then 4 μL of the above 50× compound stock solution was transferred to the well of cells containing 196 μL of culture medium, and the final concentration of the compound in the cell culture plate reached 1× (the compound stock solution was diluted 1000 times). The final concentration of DMSO was 0.1%. The spheroid cells were incubated under the action of 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 an ELISA reader. Three replicate wells were tested for each concentration of the compound, and the IC ₅₀ value was calculated using GraphPad Prism. In addition, compounds TNO155 and Deamino-TNO155 (Novartis compounds) were used as control experimental groups, and 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 testing

In this assay, CHO-hERG cells are used to specifically evaluate the effects of test compounds on hERG channels. The pre-compound current and post-compound current are measured by patch clamp, and the current is applied to calculate hERG inhibition. The compound to be tested is dissolved in DMSO and diluted with extracellular fluid to obtain a working solution. For each concentration, two replicate cells are tested. During the test, the hERG current is recorded at room temperature using a conventional whole-cell patch clamp current technique. The cells are seeded in a recording chamber on an inverted microscope, and a single cell in the recording chamber is randomly selected for recording. The cells will be continuously perfused by the perfusion system. For each cell, the inhibition percentage of the test compound is calculated by the following formula using the recorded current: (peak-tail current recorded after perfusion of the test compound/peak-tail current recorded by perfusion of the solvent control) × 100%. For each concentration, the inhibition percentage is calculated by the average data of all recorded cells, and the IC ₅₀ value is derived from the concentration-effect curve by the Hill equation in the Origin software.

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

CYP isoenzyme inhibition test

Use the marker substrates in Table 2 to determine the activity of CYP. At 8 concentrations, measure the activity of the enzyme in the presence and absence of the test compound (n=1). Test known inhibitors at a single concentration (3.00 μM, n=2) as positive controls. The incubation mixture containing microsomes, substrates and standard inhibitors or test compounds was heated at 37°C for 10.0 minutes. The reaction was started by adding NADPH and incubated for 10.0 minutes. After incubation, ice-cold acetonitrile was added to terminate the reaction. The metabolites produced by the substrate reaction were determined by LC-MS/MS to determine the inhibition percentage, and the IC ₅₀ value was calculated from the concentration effect curve.

Table 2

The _IC50 values of Cyp3A4 activity of selected compounds are listed in Table 3.

Table 3. Activity against hERG and Cyp3A4 enzymes

Pharmacokinetics in rats

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

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

Table 4

Claims (29)

A compound of formula I: and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate 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 ^R3 is independently selected from H and optionally substituted C1-C3 alkyl; ^R4 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; ^R6 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 the two carbon atoms located between said R ⁴ and R ⁷ can together optionally form a cyclic group selected from C3-C6 cycloalkyl, a saturated or unsaturated 4-7 membered heterocyclyl containing 1-2 heteroatoms selected from N, O and S as ring members, C6-C10 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S as ring members; and ^X2 is selected from -C( ^R8 )-, or ^-X2 = ^X3- is selected from -[C( ^R8 )=C( ^R9 )]-, -[C( ^R8 )=N]-, -[N=C( ^R9 )]-; wherein ^R8 and ^R9 are independently selected from H, optionally substituted C1-C3 alkyl and -COOH. The compound according to claim 1 and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate of the compound, wherein R ¹ is selected from H and an optionally substituted C1-C3 alkyl group. The compound according to claim 1 and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate of the compound, wherein R ² is selected from H, C1-C3 hydroxyalkyl and halogen. The compound and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to claim 1, wherein the -N(R ³ ) ₂ group is -NH ₂ . The compound according to claim 1 and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate of the compound, wherein R ⁴ is selected from H and an optionally substituted C1-C3 alkyl; or The compound according to 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 according to 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 according to claim 1 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, wherein X ¹ is -O-. The compound according to 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 -, and the R ⁷ is selected from H, an optionally substituted C1-C3 alkyl, an optionally substituted C1-C3 alkoxy, a C6-C10 aryl, and a 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 the R ⁴ and R ⁷ can together form a cyclic group selected from C3-C6 cycloalkyl, a saturated or unsaturated 4-7 membered heterocyclic group containing 1-2 heteroatoms selected from N, O and S as ring members, a C6-C10 aryl, and a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O and S as ring members. The compound and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to claim 1, 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 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound as claimed in claim 1, 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 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to claim 1, 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 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to claim 1, wherein R ⁸ and R ⁹ are independently selected from H, -CH ₃ , -CF ₃ and -COOH. The compound and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound according to claim 1, wherein X ² is selected from -CH-, -CH(CH ₃ )-, -CH(CF ₃ )- and -CH(COOH)-. The compound according to 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 according to claim 1 and/or its stereoisomer, stable isotope, or pharmaceutically 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 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 and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of claim 16, 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, -NH ₂ and -OH. The compound and/or the stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of claim 16, wherein R ² is an optionally substituted C1-C3 alkyl group, wherein the optionally substituted C1-C3 alkyl group is substituted with 1-3 groups selected from =O, -NH ₂ and -OH. The compound according to 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 to 19, and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, in admixture with at least one pharmaceutically acceptable carrier. A method for 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 as described in any one of claims 1 to 19, and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, or a pharmaceutical composition as described in claim 20. The method of claim 21, 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 inhibitory amount of a compound as described in any one of claims 1 to 19, and/or a stereoisomer, stable isotope, or pharmaceutically acceptable salt or solvate of the compound, or a pharmaceutical composition as described in claim 20. The method of claim 21, wherein the disease or disorder associated with SHP2 is mediated by the activity of SHP2. The method of claim 23, wherein the disease or disorder associated with SHP2 is selected from Noonan syndrome, Leopard 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 according to any one of claims 1 to 19, and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate of the compound, or the pharmaceutical composition according to claim 20 is administered orally. Use of a compound according to any one of claims 1 to 19, and/or a stereoisomer, a stable isotope, or a pharmaceutically acceptable salt or solvate of said compound, or a pharmaceutical composition according to claim 20 in the manufacture of a medicament for treating a disease or disorder associated with SHP2. The use according to claim 26, wherein the disease or disorder associated with SHP2 is mediated by the activity of SHP2. The use of claim 27, wherein the disease or disorder associated with SHP2 is selected from Noonan syndrome, Leopard 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 according to claim 26, wherein the medicament is formulated for oral administration.