TW202344251A - Atr inhibitors and uses thereof - Google Patents

Abstract

The present disclosure relates to novel compounds useful as inhibitors of ATR kinase，as well as pharmaceutical compositions comprising these compounds and methods of treatment by administration of these compounds or the pharmaceutical compositions.

Description

ATR inhibitors and their uses

The present invention generally relates to novel compounds useful as ATR inhibitors as well as pharmaceutical compositions containing such compounds and methods of treatment by administering such compounds or such pharmaceutical compositions.

ATR (also known as FRAP-related protein 1; FRP1, MEC1, SCKL, SECKL1) protein kinase is a member of the PI3-kinase-like kinase (PIKK) protein family involved in the repair and maintenance of the genome and its stability. It is essential for the viability of replicating cells and is activated during S phase to regulate initiation of replication origins and repair damaged replication forks. Therefore, ATR inhibitors have the potential to become an effective method for cancer treatment.

Although progress has been made with ATR inhibitors, there remains a strong need in this technology to develop improved drugs with inhibitory activity against ATR.

The present invention provides compounds capable of inhibiting ATR protein kinase, including stereoisomers, pharmaceutically acceptable salts, tautomers and prodrugs thereof. Methods of using such compounds to treat various diseases or conditions, such as cancer, are also provided.

In one aspect, the invention provides a compound having formula (I): Or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are each independently alkyl, alkenyl, alkynyl, heteroaryl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aromatic radical or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more R ^a ; or R ¹ and R ² together with the sulfur atoms to which they are connected form a visual Heterocyclyl substituted by one or more R ^b ; R ^a is independently selected from the group consisting of: hydroxyl, halogen, cyano, amine, alkyl, alkoxy and haloalkyl; R ^b is independently selected Free group consisting of: alkyl, alkenyl, alkynyl, alkoxy, cyano, halogen, hydroxyl, amine and nitro, wherein the alkyl, alkenyl and alkynyl groups are optionally modified by one or more independently Substituted with a group selected from the following: hydroxyl, halogen, cyano, amine and alkoxy; R ³ is ; Ring A is a 5- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl; R ⁴ is halogen, alkyl, haloalkyl or cycloalkyl in each occurrence; and m is 0, 1, 2 or 3.

In some embodiments, the invention provides a compound having formula (Ia): or its pharmaceutically acceptable salt.

In some embodiments, the invention provides a compound having a formula selected from the group consisting of: or its pharmaceutically acceptable salt.

In another aspect, the invention provides a compound selected from the group consisting of: , or its pharmaceutically acceptable salt.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In another aspect, the invention provides a method for treating cancer, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof or a medicament of the invention composition.

In another aspect, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating cancer.

In another aspect, the invention provides a compound of the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the invention for use in the treatment of cancer.

In another aspect, the invention provides a method for inhibiting ATR kinase in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof Or the pharmaceutical composition of the present invention.

Reference will now be made in detail to certain embodiments of the invention, examples of which are set forth in the accompanying structures and formulas. While the present invention will be described in conjunction with enumerated embodiments, it should be understood that these embodiments are not intended to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the invention as defined by the claimed claims. Those skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. To the extent that one or more of the incorporated references and similar materials (including but not limited to defined terms, term usage, described techniques, etc.) differs from or conflicts with this application, the present invention shall prevail. Accurate. All references, patents, and patent applications cited in this application are hereby incorporated by reference in their entirety.

It is to be understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. It must be noted that, as used in the specification and the appended claims, the singular forms "a or an" and "the" include their plural forms unless the context clearly indicates otherwise. Thus, for example, a reference to "a compound" includes plural compounds. definition

Definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this invention, chemical elements are identified according to the inside cover of the Periodic Table of the Elements, CAS Edition, Handbook of Chemistry and Physics, 75th Edition, and the specific functional groups are generally as described herein. described and defined. In addition, general principles of organic chemistry as well as specific functional moieties and reactivities are described in: Organic Chemistry, Thomas Sorrell, 2nd ed., University Science Books, Sausalito) 2006; Smith and March, March's Advanced Organic Chemistry), vol. 6th edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis), 4th edition , Cambridge University Press, Cambridge, 2004; the entire contents of each of the above references are incorporated herein by reference.

In general, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those that are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

It should be noted that if there is a discrepancy between the structure depicted and the name given to the structure, greater consideration will be given to the structure depicted. Additionally, if the stereochemistry of a structure or part of a structure is not indicated by, for example, a bold or dashed line, then the structure or part of the structure should be interpreted to encompass all stereoisomers thereof.

Throughout this invention, linking substituents are described. Where the structure clearly requires a linking group, the Markush variable listed for that group should be understood to mean the linking group. For example, if a structure requires a linking group and the Markush group definition for that variable lists "alkyl," then "alkyl" will be understood to mean the attached alkylene group.

Where the bond to a substituent is shown to cross a bond connecting two atoms in the ring, such substituent may be bonded to any atom in the ring. When a substituent is listed without specifying the atom through which such substituent is bonded to the remainder of a compound of a given formula, the substituent may be bonded through any atom in the formula. Combinations of substituents and/or variables are allowed, but only if such combinations result in stable compounds.

When any variable (eg, R ⁱ ) occurs more than once in any component or formula of a compound, its definition on each occurrence is independent of its definition on each other occurrence. Thus, for example, if a group is shown to be substituted with from 0 to 2 R ⁱ moieties, then the group may optionally be substituted with up to two R ⁱ moieties, and each occurrence of R ⁱ is independently selected from the group consisting of R ⁱ definition. Furthermore, combinations of substituents and/or variables are allowed, but only if such combinations result in stable compounds.

As used herein, the term " _Cij " refers to a range of numbers of carbon atoms, where i and j are integers, and the range of numbers of carbon atoms includes the endpoints (i.e., i and j) and every integer point therebetween, and where j is greater than i. For example, C _1-6 indicates a range of one to six carbon atoms, including one carbon atom, two carbon atoms, three carbon atoms, four carbon atoms, five carbon atoms, and six carbon atoms. In some embodiments, the term "C _1-12 " indicates 1 to 12 carbon atoms, especially 1 to 10 carbon atoms, especially 1 to 8 carbon atoms, especially 1 to 6 carbon atoms, especially 1 to 5 carbon atoms, especially 1 to 4 carbon atoms, especially 1 to 3 carbon atoms or especially 1 to 2 carbon atoms.

As used herein, the term "alkyl", whether used as part of another term or independently, refers to a saturated straight or branched chain hydrocarbon radical that may be independently substituted with one or more substituents as described below. . The term "C _ij alkyl" refers to an alkyl group having i to j carbon atoms. In some embodiments, alkyl groups contain 1 to 10 carbon atoms. In some embodiments, alkyl groups contain 1 to 9 carbon atoms. In some embodiments, the alkyl group contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms Or 1 to 2 carbon atoms. Examples of "C _1-10 alkyl" include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl. Examples of "C _1-6 alkyl" are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, 2-pentyl , 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2- Methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl and similar groups.

As used herein, the term "alkoxy", whether used as part of another term or independently, refers to an alkyl group, as previously defined, attached to the parent molecule through an oxygen atom. The term "C _ij alkoxy" means that the alkyl portion of the alkoxy group has i to j carbon atoms. In some embodiments, alkoxy groups contain 1 to 10 carbon atoms. In some embodiments, alkoxy groups contain 1 to 9 carbon atoms. In some embodiments, alkoxy contains 1 to 8 carbon atoms, 1 to 7 carbon atoms, 1 to 6 carbon atoms, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms or 1 to 2 carbon atoms. Examples of "C _1-6 alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy (for example, n-propoxy and isopropoxy), tertiary butoxy, neopentyloxy , n-hexyloxy and similar groups.

As used herein, the term "amine" refers to _-NH2 . Amino groups may also be substituted with one or more groups such as alkyl, aryl, carbonyl or other amine groups.

As used herein, the term "aryl," whether used as part of another term or independently, refers to monocyclic and polycyclic ring systems having a total of 5 to 20 ring members, wherein at least one ring in the system is an aromatic ring, and wherein each ring in the system contains 3 to 12 ring members. Examples of "aryl" include, but are not limited to, phenyl, biphenyl, azyl, anthracenyl and the like, which may have one or more substituents. As used herein, the scope of the term "aryl" also includes groups in which an aromatic ring is fused to one or more additional rings. In the case of polycyclic ring systems, only one ring needs to be aromatic (eg, 2,3-indoline), but all rings can be aromatic (eg, quinoline). The second ring can also be fused or bridged. Examples of polycyclic aromatic groups include, but are not limited to, benzofuranyl, indanyl, phthalimide, dimethylimide, phenanthridinyl or tetrahydrofuranyl, and the like. Aryl groups may be substituted at one or more ring positions with substituents as described above.

As used herein, the term "cycloalkyl", whether used as part of another term or independently, refers to monovalent non-aromatic saturated or partially unsaturated monocyclic and polycyclic ring systems in which all ring atoms are carbon , and the system contains at least three ring-forming carbon atoms. In some embodiments, the cycloalkyl group can contain 3 to 12 ring carbon atoms, 3 to 10 ring carbon atoms, 3 to 9 ring carbon atoms, 3 to 8 ring carbon atoms, 3 to 7 ring carbon atoms, 3 to 6 ring carbon atoms, 3 to 5 ring carbon atoms, 4 to 12 ring carbon atoms, 4 to 10 ring carbon atoms, 4 to 9 ring carbon atoms , 4 to 8 ring carbon atoms, 4 to 7 ring carbon atoms, 4 to 6 ring carbon atoms, 4 to 5 ring carbon atoms. Cycloalkyl groups may be saturated or partially unsaturated. Cycloalkyl groups may be substituted. In some embodiments, the cycloalkyl group can be a saturated cyclic alkyl group. In some embodiments, a cycloalkyl group can be a partially unsaturated cyclic alkyl group containing at least one double or triple bond in its ring system. In some embodiments, cycloalkyl groups can be monocyclic or polycyclic. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3- Alkenyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, Cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Examples of polycyclic cycloalkyl groups include, but are not limited to, adamantyl, norbornyl, fenyl, spiro-pentadienyl, spiro[3.6]-decyl, bicyclo[1,1,1]pentenyl , Bicyclo[2,2,1]heptenyl, etc.

As used herein, the term "cyano" refers to -CN.

As used herein, the term "halogen" refers to an atom selected from the group consisting of fluorine or fluoro, chlorine or chloro, bromine or bromo, and iodine or iodo.

As used herein, the term "haloalkyl" refers to an alkyl group, as defined above, substituted with one or more halogens, as defined above. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoro Propyl, 1,2-dibromoethyl, etc.

As used herein, the term "heteroatom" refers to nitrogen, oxygen, sulfur, or phosphorus, and includes any oxidized form of nitrogen or sulfur as well as any quaternary ammonium form of basic nitrogen (including N-oxides).

As used herein, the term "heteroalkyl" refers to an alkyl group in which at least one of its carbon atoms is replaced with a heteroatom selected from N, O, or S. Heteroalkyl groups may be carbon radicals or heteroatom radicals (i.e., heteroatoms may be present in the middle or at the terminal ends of the radical), and may be independently substituted with one or more substituents described herein, as appropriate . The term "heteroalkyl" encompasses alkoxy and heteroalkoxy groups.

As used herein, the term "heteroalkenyl" refers to an alkenyl group in which at least one of its carbon atoms is replaced with a heteroatom selected from N, O, or S. A heteroalkenyl group may be a carbon radical or a heteroatom radical (i.e., a heteroatom may be present in the middle or at a terminal end of the radical), and may be independently substituted with one or more substituents described herein, as appropriate .

As used herein, the term "heteroalkynyl" refers to an alkynyl group in which at least one of its carbon atoms is replaced by a heteroatom selected from N, O, or S. Heteroalkynyl groups may be carbon radicals or heteroatom radicals (i.e., heteroatoms may be present in the middle or at the terminal ends of the radical), and may be independently substituted, as appropriate, with one or more substituents described herein .

As used herein, the term "heteroaryl", whether used as part of another term or independently, refers to an aryl group having one or more heteroatoms in addition to carbon atoms. Heteroaryl groups can be monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, ethazolyl, isothiazolyl, thiadiazolyl, thiazolyl base, isothiazolyl, thiadiazolyl, pyridyl, pyridinyl, pyrimidinyl, pyridinyl, indolyl, purinyl, pyridinyl, benzofuranyl and pyridinyl. Heteroaryl also includes polycyclic groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the linking group or point of attachment is located on the heteroaromatic ring. Examples of polycyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, benzothienyl, benzofuryl, benzo[1,3]dioxolyl, dibenzofuranyl , indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, dihydroquinolyl, dihydroisoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl,㖕linyl, quinazolinyl, quinazolinyl, 4H-quinolinyl, carbazolyl, acridinyl, phenylinyl, thiophenyl, tetrahydroquinoline base, tetrahydroisoquinolyl, etc.

As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen, phosphorus and the like, and the remainder The ring atoms are carbon, one or more of which may be independently substituted with one or more substituents, as appropriate. In some embodiments, heterocyclyl is saturated heterocyclyl. In some embodiments, heterocyclyl is a partially unsaturated heterocyclyl group having one or more double bonds in its ring system. In some embodiments, the heterocyclyl group may contain any oxidized form of carbon, nitrogen, or sulfur and any quaternary ammonium form of the basic nitrogen. "Heterocyclyl" also includes groups in which the heterocyclyl is fused to a saturated, partially unsaturated, or fully unsaturated (ie, aromatic) carbocyclic or heterocyclic ring. Where possible, heterocyclyl groups may be carbon-linked or nitrogen-linked. In some embodiments, the heterocycle is carbon-linked. In some embodiments, the heterocycle is nitrogen-linked. For example, a group derived from pyrrole may be pyrrol-1-yl (nitrogen-linked) or pyrrol-3-yl (carbon-linked). Furthermore, the group derived from imidazole may be imidazol-1-yl (nitrogen-linked) or imidazol-3-yl (carbon-linked).

In some embodiments, the term "3- to 12-membered heterocyclyl" refers to a 3- to 12-membered saturated or partially unsaturated monocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Polycyclic heterocyclic systems. Fused, spiral and bridged chain systems are also included within the scope of this definition. Examples of monocyclic heterocyclyl groups include, but are not limited to, oxetanyl, 1,1-dilateral oxythietanylpyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolyl, furyl, Thienyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, thiazolyl, piperidinyl, piperazolyl, piperidinyl, pyridinyl, pyridinyl, pyridinyl, pyrimidinyl, pyrimidinyl , tri-𠯤 base, pyridinone base, pyrimidinone base, pyridinone base, pyrimidinone base, pyridinone base, pyrrolidinyl base, tri- base base, etc. Examples of fused heterocyclyl groups include, but are not limited to, phenyl fused rings or pyridyl fused rings, such as quinolyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinolinyl, quinolyl 𠯤yl, quinazolinyl, azaindolyl𠯤yl, pyridinyl, 𠳭alkenyl, isoethylalkenyl, indolyl, isoindolyl, indole𠯤yl, indazolyl, purinyl, benzene Furanyl, isobenzofuranyl, benzimidazolyl, benzothienyl, benzothiazolyl, carbazolyl, phenyl, thiopheneyl, phenanthridinyl, imidazo[1,2-a ]pyridyl, [1,2,4]triazolo[4,3-a]pyridyl, [1,2,3]triazolo[4,3-a]pyridyl and similar groups. Examples of spiroheterocyclyl include, but are not limited to, spiropyranyl, spiroheterocyclyl, and the like. Examples of bridged heterocyclyl groups include, but are not limited to, morphanyl, hexamethylenetetramine, 3-aza-bicyclo[3.1.0]hexane, 8-aza-bicyclo[3.2.1 ]octane, 1-aza-bicyclo[2.2.2]octane, 1,4-diazabicyclo[2.2.2]octane (DABCO) and similar groups.

As used herein, the term "hydroxy" refers to -OH.

As used herein, the term "partially unsaturated" refers to a group that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic (ie, fully unsaturated) moieties.

As used herein, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogens of the specified moiety have been replaced by a suitable substituent. It will be understood that "substituted" or "substituted" includes the implicit proviso that such substitution is consistent with the permissible valency of the atom being substituted and that the substitution results in a stable or chemically feasible compound, e.g., not Compounds that spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. Unless otherwise stated, an "optionally substituted" group may have appropriate substituents at each substitutable position of the group, and more than one position in any given structure may be substituted by more than one selected from the specified group. When substituents are substituted, the substituents may be the same or different at each position. It will be understood by those skilled in the art that, under appropriate circumstances, the substituents themselves may be substituted. Unless specifically stated to be "unsubstituted," references to the chemistry sections herein should be understood to include substituted variants. For example, reference to an "aryl" group or moiety implicitly includes both substituted and unsubstituted variants. compound

The present invention provides novel compounds of formula (I) and pharmaceutically acceptable salts thereof, synthetic methods for preparing these compounds, pharmaceutical compositions containing them and various uses of the disclosed compounds.

In one aspect, the invention provides a compound having formula (I): Or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are each independently alkyl, alkenyl, alkynyl, heteroaryl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocyclyl, aromatic radical or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted by one or more R ^a ; or R ¹ and R ² together with the sulfur atom to which they are connected form a visual Heterocyclyl substituted by one or more R ^b ; R ^a is independently selected from the group consisting of: hydroxyl, halogen, cyano, amine, alkyl, alkoxy and haloalkyl; R ^b is independently selected Free group consisting of: alkyl, alkenyl, alkynyl, alkoxy, cyano, halogen, hydroxyl, amine and nitro, wherein the alkyl, alkenyl and alkynyl groups are optionally modified by one or more independently Substituted with a group selected from the following: hydroxyl, halogen, cyano, amine and alkoxy; R ³ is ; Ring A is a 5- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl; R ⁴ is halogen, alkyl, haloalkyl or cycloalkyl in each occurrence; and m is 0, 1, 2 or 3.

In some embodiments, R ¹ and R ² are each independently C _1-3 alkyl, C _3-6 cycloalkyl or C _5-12 aryl.

In some embodiments, R ¹ and R ² are independently C _1-3 alkyl. In certain embodiments, R ¹ and R ² are the same. In certain embodiments, both R ¹ and R ² are methyl. In certain embodiments, R ¹ and R ² are different. In certain embodiments, one of ^R1 and ^R2 is methyl and the other is ethyl.

In some embodiments, R ¹ and R ² are independently C _3-6 cycloalkyl. In certain embodiments, both R ¹ and R ² are cyclopropyl.

In some embodiments, one of R ¹ and R ² is C _1-3 alkyl, and the other is C _3-6 cycloalkyl or C _5-12 aryl.

In some embodiments, Select from the group consisting of: .

In some embodiments, R ¹ and R ² together with the sulfur atom to which they are attached form a heterocyclyl group optionally substituted with one or more R ^b .

In some embodiments, R ¹ and R ² together with the sulfur atom to which they are attached form a 3- to 6-membered heterocyclyl group optionally substituted with one or more R ^b .

In some embodiments, Selected from , each of which is optionally replaced by one or more R ^b .

In some embodiments, Ring A is 5- to 6-membered heteroaryl. In certain embodiments, Ring A is pyrazolyl, pyrrolyl, or pyridinyl.

In some embodiments, ^R4 is halogen.

In some embodiments, R ⁴ is alkyl. In certain embodiments, R ⁴ is C _1-3 alkyl.

In some embodiments, R ⁴ is haloalkyl. In certain embodiments, R ⁴ is C _1-3 haloalkyl.

In some embodiments, R ⁴ is cycloalkyl. In certain embodiments, R ⁴ is C _3-6 cycloalkyl.

In some embodiments, m is 0, 1, or 2.

In some embodiments, Select from the group consisting of: .

In some embodiments, ^R3 is .

In some embodiments, ^R3 is .

In some embodiments, the invention provides a compound having formula (Ia): , or its pharmaceutically acceptable salt.

In some embodiments, the invention provides a compound selected from the group consisting of: , or its pharmaceutically acceptable salt.

In another aspect, the invention provides a compound selected from the group consisting of: , or its pharmaceutically acceptable salt.

Table 1 below shows exemplary compounds of the present invention. Table 1

Compounds provided herein are described with reference to both general formulas and specific compounds. In addition, the compounds of the present invention may exist in a variety of different forms or derivatives, including but not limited to prodrugs, soft drugs, active metabolic derivatives (active metabolites) and pharmaceutically acceptable salts thereof, all of which are within the scope of the present invention.

As used herein, the term "prodrug" refers to a compound that when metabolized under physiological conditions or transformed by solvolysis yields the desired active compound, or a pharmaceutically acceptable salt thereof. Prodrugs include, but are not limited to, esters, amides, carbamates, carbonates, ureas, solvates or hydrates of the active compound. Typically, prodrugs are inactive or less active than the active compound, but may provide one or more advantageous disposition, administration and/or metabolic properties. For example, some prodrugs are esters of the active compound; during metabolism, the ester group is cleaved to yield the active drug. In addition, some prodrugs are enzymatically activated to produce the active compound or compounds that upon further chemical reaction produce the active compound. A prodrug may be developed from the prodrug form to the active form in a single step, or may have one or more intermediate forms which may or may not themselves be active. The preparation and use of prodrugs are discussed in the following references: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Volume 14 of the A.C.S. Symposium Series, Bioreversible Carriers in Drug Design, Edward B. Roche, editor, American Pharmaceutical Association (Pergamon Press, 1987); Prodrugs: Challenges and Rewards, editors V. Stella, R. Borchardt, M. Hageman, R. Oliyai, H. Maag, J. Tilley , Springer Verlag New York, 2007, which references are hereby incorporated by reference in their entirety.

As used herein, the term "soft drug" refers to a compound that exerts a pharmacological effect but breaks down into inactive metabolite degradation products such that the active time is limited. See, for example, Soft drugs: Principles and methods for the design of safe drugs, Nicholas Bodor, Medicinal Research Reviews, Volume 4, Issue 4, 449-469, 1984, which reference is hereby incorporated by reference in its entirety.

As used herein, the term "metabolite," eg, an active metabolite, overlaps with prodrugs as described above. Thus, such metabolites are pharmacologically active compounds or compounds that are further metabolized into pharmacologically active compounds that are derivatives produced by metabolic processes in an individual's body. For example, such metabolites may result from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of an administered compound or salt or prodrug. Among them, active metabolites are such pharmacologically active derivative compounds. In the case of prodrugs, the prodrug compound is usually inactive or less active than the metabolite. For active metabolites, the parent compound may be the active compound or may be an inactive prodrug.

Prodrugs and active metabolites can be identified using conventional techniques known in the art. See, eg, Bertolini et al., 1997, J Med Chem 40:2011-2016; Shan et al., J Pharm Sci 86:756-757; Bagshawe, 1995, DrugDev Res 34:220-230; Wermuth, supra.

As used herein, the term "pharmaceutically acceptable" indicates that a substance or composition is chemically and/or toxicologically compatible with the other ingredients constituting the formulation and/or the subject being treated.

As used herein, unless otherwise indicated, the term "pharmaceutically acceptable salts" includes salts that retain the biological availability of the free acids and bases of the specified compound and are not biologically or otherwise undesirable. Considered pharmaceutically acceptable salt forms include, but are not limited to, single salts, double salts, triple salts, tetra salts, and the like. Pharmaceutically acceptable salts are nontoxic in the amounts and concentrations in which they are administered. The preparation of such salts can facilitate pharmacological use by modifying the physical properties of the compounds without preventing them from exerting their physiological effects. Useful modifications of physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of the drug.

Pharmaceutically acceptable salts include acid addition salts, such as those containing the following: sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, amine Sulfonate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylamine sulfonate and quinic acid salt. Pharmaceutically acceptable salts can be obtained from acids such as: hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethyl Sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylamine sulfonic acid, fumaric acid and quinic acid.

When acidic functional groups such as carboxylic acid or phenol are present, pharmaceutically acceptable salts also include base addition salts, such as those containing: benzathine, chloroprocaine ), choline, diethanolamine, ethanolamine, tertiary butylamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine and zinc . See, for example, Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl and Wermuth, Wiley-VCH, Weinheim , Germany, 2002. Such salts can be prepared using the appropriate corresponding base.

Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free base form of the compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcoholic solution containing the appropriate acid, and then isolated by evaporation of the solution. Thus, if a particular compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid such as hydrochloric acid, hydrogen Bromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid , salicylic acid; piperanosyl acids, such as glucuronic acid or galacturonic acid; alpha-hydroxy acids, such as citric acid or tartaric acid; amino acids, such as aspartic acid or glutamic acid; aromatic acids , such as benzoic acid or cinnamic acid; sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid or the like.

Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, using an inorganic or organic base such as an amine (primary, secondary or tertiary), a base Treat free acids with metal hydroxides or alkaline earth metal hydroxides. Illustrative examples of suitable salts include those derived from amino acids such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines ( Organic salts such as hydroxyethylpyrrolidine, piperidine, pyridine or piperidine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

It is also to be understood that the compounds of the present invention may exist in unsolvated, solvated (eg, hydrated) forms, and solid forms (eg, crystalline or polymorphic forms), and the invention is intended to encompass all such forms.

As used herein, the term "solvate" or "solvated form" refers to a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate, and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by combining one or more water molecules with a molecule of a substance in which water maintains its molecular state as _H2O . Examples of solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

As used herein, the terms "crystalline form", "crystalline form", "polymorph" and "polymorph" are used interchangeably and refer to the different crystal packing arrangements in which a compound (or a salt or solvate thereof) may As for the crystal structure of crystals, all these crystal structures have the same elemental composition. Different crystal forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystal form to dominate. Polymorphs of a compound can be prepared by crystallization under different conditions.

Depending on the choice of substituents, the compounds of the invention may comprise one or more asymmetric centers and may therefore exist in various stereoisomeric forms, for example, enantiomers and/or diastereomers. For example, the compounds provided herein may have an asymmetric carbon center, and thus the compounds provided herein may have the (R) or (S) stereoconfiguration at the carbon asymmetric center. Thus, the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers, or they may be in the form of mixtures of stereoisomers.

As used herein, the term "enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. The term "diastereomers" refers to a pair of optical isomers that are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity.

When a particular enantiomer is preferred, in some embodiments it may be provided substantially free of the relative enantiomer, and may also be referred to as "optically enriched." As used herein, "optically enriched" means that a compound consists of a significantly greater proportion of one enantiomer. In certain embodiments, the compound consists of at least about 90% by weight of the preferred enantiomer. In other embodiments, the compound consists of at least about 95%, 98%, or 99% by weight of the preferred enantiomer. Preferred enantiomers may be synthesized by any method known to those skilled in the art, for example by chromatography or crystallization, by using stereochemically homogeneous starting materials or by stereoselective synthesis from racemization. separated from the mixture. Optionally, derivatization can be performed prior to separation of the stereoisomers. Separation of mixtures of stereoisomers can be performed at intermediate steps during the synthesis of the compounds provided herein or it can be performed on the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of crystallized products or crystallized intermediates which, if necessary, are derivatized with reagents containing stereocenters of known configuration. Alternatively, the absolute stereochemistry can be determined by vibrational circular dichroism (VCD) spectroscopic analysis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H. et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962) ); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions, page 268 (edited by E.L. Eliel, Univ. of Notre Dame Press, Notre Dame, IN 1972).

In some embodiments, a mixture of diastereomers is provided, such as a mixture of diastereomers enriched in 51% or more of one of the diastereomers, including, for example, 60% or more, 70% or more, 80% or more, or 90% or more diastereomers.

In some embodiments, unless otherwise indicated, compounds provided herein may have one or more double bonds present as the Z or E isomer. Additionally, the present invention encompasses compounds in the form of individual isomers that are substantially free of other isomers and, alternatively, in the form of mixtures of multiple isomers (eg, racemic mixtures of enantiomers).

The compounds of the present invention may also exist in different tautomeric forms, and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted through low-energy barriers. For example, proton tautomers (also known as proton tautomers) include interconversions by proton migration, such as keto-enol, amide-imidic acid, lactam-lactam imine , imine-enamine isomerization, and cyclic forms in which protons may occupy two or more positions in the heterocyclic system (e.g., 1H- and 3H-imidazole, 1H-, 2H-, and 4H-1,2 , 4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole). Valence tautomers include interconversions through the reorganization of some of the bonding electrons. Tautomers can be in equilibrium or sterically locked into one form by appropriate substitutions. Unless otherwise stated, compounds of the invention identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms.

The present invention is also intended to include all isotopes of atoms in the compounds. Isotopes of atoms include atoms with the same atomic number but different mass numbers. For example, unless otherwise stated, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine or iodine in the compounds of the present invention are meant to also include their isotopes, such as but not limited to ¹ H, ² H, ³ H, ¹¹ C, ¹² C, ¹³ C, ¹⁴ C, ¹⁴ N, ¹⁵ N, ¹⁶ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³² S, ³³ S, ³⁴ S, ³⁶ S, ¹⁷ F, ¹⁸ F, ¹⁹ F, ³⁵ Cl, ³⁷ Cl, ⁷⁹ Br, ⁸¹ Br, ¹²⁴ I, ¹²⁷ I and ¹³¹ I. In some embodiments, hydrogen includes protium, deuterium, and tritium. In some embodiments, carbon includes ¹² C and ¹³ C. Synthesis of compounds

The synthesis of the compounds provided herein (including pharmaceutically acceptable salts thereof) is illustrated in the synthetic schemes in the Examples. The compounds provided herein may be prepared using any known organic synthesis technique and may be synthesized according to any of a variety of possible synthetic pathways, and thus such schemes are illustrative only and are not intended to limit what may be used to prepare the compounds herein. Other possible methods for the provided compounds. In addition, the steps in these processes are for better explanation and may be changed as needed. Examples of compounds in the Examples were synthesized for the purpose of research and possible submission to regulatory agencies.

The reactions for preparing the compounds of the present invention can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), intermediates or products at the temperatures at which the reaction is conducted (eg, a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction step, the appropriate solvent for the specific reaction step can be selected by one skilled in the art.

The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The requirements for protection and deprotection and the selection of appropriate protecting groups can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in the following references: T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd ed., Wiley & Sons, Inc., New York (1999); P. Kocienski, (Protecting Groups) , Georg Thieme Verlag, 2003; and Peter G.M. Wuts, Greene's Protective Groups in Organic Synthesis, 5th edition, Wiley, 2014, all of which are incorporated herein by reference in their entirety.

The reaction can be monitored according to any suitable method known in the art. For example, by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., ¹ H or ¹³ C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry or by means such as high performance liquid chromatography Product formation can be monitored using chromatographic methods such as HPLC, liquid chromatography-mass spectrometry (LCMS), or thin layer chromatography (TLC). Those skilled in the art can purify compounds through various methods, including high performance liquid chromatography (HPLC) ("Preparative LC-MS Purification: Improved Compound Specific Method Optimization" Karl F. Blom, Brian Glass, Richard Sparks, Andrew P. Combs J. Combi. Chem. 2004, 6(6), 874-883, this reference is incorporated by reference in its entirety) and normal phase silica gel chromatography.

The known starting materials of the present invention can be synthesized using or according to methods known in the art, or can be purchased from commercial suppliers. Unless otherwise stated, analytical grade solvents and commercially available reagents were used without further purification.

Unless otherwise stated, the reactions of the present invention are carried out under positive pressure of nitrogen or argon or in anhydrous solvents using drying tubes, and the reaction flasks are usually equipped with rubber septa for introducing substrates and reagents through syringes. . Glassware is oven dried and/or heat dried.

For illustrative purposes, the following Examples section shows synthetic pathways for preparing the compounds of the invention as well as key intermediates. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds of the present invention. Although specific starting materials and reagents are depicted, other starting materials and reagents can be readily substituted to provide a variety of derivatives and/or reaction conditions. In addition, according to the present invention, many of the compounds prepared by the methods described below can be further modified using conventional chemical methods well known to those skilled in the art. Pharmaceutical composition

In another aspect, pharmaceutical compositions are provided that comprise one or more molecules or compounds of the invention or a pharmaceutically acceptable salt thereof.

In another aspect, there is provided a pharmaceutical composition comprising one or more molecules or compounds of the invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

As used herein, the term "pharmaceutical composition" refers to a preparation containing a molecule or compound of the present invention in a form suitable for administration to an individual.

As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is useful in the preparation of pharmaceutical compositions that are generally safe, nontoxic, and biologically and otherwise desirable, and includes those useful for veterinary medicine. It is an acceptable excipient for its intended use and human pharmaceutical use. As used herein, "pharmaceutically acceptable excipient" includes both one and more than one such excipient. The term "pharmaceutically acceptable excipient" also encompasses "pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent".

The particular excipients used will depend on the means and purposes in which the compounds of the invention are used. Solvents are generally selected on the basis that they will be considered safe by those skilled in the art when administered to mammals, including humans. Generally, safe solvents are nontoxic aqueous solvents, such as water and other nontoxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (eg, PEG 400, PEG 300), and the like, and mixtures thereof.

In some embodiments, suitable excipients may include buffers, such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives, such as octadecyldichloride. Methylbenzylammonium; hexamethylammonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butanol or benzyl alcohol; alkyl parabens, such as methyl or propyl paraben; o-phenyls diphenols; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic Polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates Compounds, including glucose, mannose, or dextran; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., Zn protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG).

In some embodiments, suitable excipients may include one or more stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing agents, etc. Auxiliaries, colorants, sweeteners, aromatics, flavorings and other additives known to provide the best presentation of the drug (i.e., the compound of the invention or a pharmaceutical composition thereof) or to assist in the manufacture of the pharmaceutical product (i.e. , drugs). Active pharmaceutical ingredients can also be embedded in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, such as in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, etc.). rice particles and nanocapsules) or hydroxymethylcellulose or gelatin microcapsules and poly-(methyl methacrylate) microcapsules in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences, 16th Edition, edited by Osol, A. (1980). "Liposomes" are small cells containing various types of lipids, phospholipids, and/or surfactants that can be used to deliver drugs, such as the compounds disclosed herein and, optionally, chemotherapeutic agents, to mammals, including humans. Vesicles. The components of liposomes are usually arranged in a bilayer, similar to the arrangement of lipids in biological membranes.

The pharmaceutical compositions provided herein may be in any form that permits administration of the composition to an individual, including but not limited to humans, and that allows the composition to be formulated to be compatible with the intended route of administration.

Various routes are contemplated for the pharmaceutical compositions provided herein, and thus the pharmaceutical compositions provided herein may be supplied in bulk or unit dosage form depending on the intended route of administration. For example, for oral, buccal and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, softgels and caplets may be acceptable as solid dosage forms, and emulsions, syrups, elixirs, suspensions Liquids and solutions may be acceptable as liquid dosage forms. For injection administration, emulsions and suspensions may be acceptable as liquid dosage forms, and powders suitable for reconstitution with suitable solutions may be acceptable as solid dosage forms. For inhalation administration, solutions, sprays, dry powders and aerosols may be acceptable dosage forms. For topical (including buccal and sublingual) or transdermal administration, powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches may be acceptable dosage forms. For vaginal administration, pessaries, tampons, creams, gels, pastes, foams and sprays may be acceptable dosage forms.

The amount of active ingredient in a unit dosage form of the composition is a therapeutically effective amount and will vary depending on the particular treatment involved. As used herein, the term "therapeutically effective amount" refers to a molecule, compound, or composition containing a molecule or compound that treats, ameliorates, or prevents an identified disease or condition or exhibits a detectable therapeutic or inhibitory effect. quantity. Effects can be detected by any assay known in the art. The precise effective amount for an individual will depend on the individual's weight, size and medical condition; the nature and extent of the condition; the rate of administration; the treatment or combination of treatments selected for administration; and the judgment of the prescribing physician. The therapeutically effective amount for a given condition can be determined by routine experimentation within the skill and judgment of the clinician.

In some embodiments, pharmaceutical compositions of the invention may be in the form of formulations for oral administration.

In certain embodiments, the pharmaceutical compositions of the present invention may be in the form of a tablet formulation. Pharmaceutically acceptable excipients suitable for tablet preparations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or alginic acid; binders , such as starch; lubricants, such as magnesium stearate, stearic acid or talc; preservatives, such as ethyl paraben or propyl paraben; and antioxidants, such as ascorbic acid. Tablet preparations may be uncoated or coated, in either case to modulate their disintegration and subsequent absorption of the active ingredients in the gastrointestinal tract, or to modify their stability and/or appearance, in either case using this technology Conventional coating agents and procedures are well known.

In certain embodiments, the pharmaceutical compositions of the present invention can be in the form of hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin; or in the form of soft gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin. Mix with water or oil such as peanut oil, liquid paraffin or olive oil.

In certain embodiments, pharmaceutical compositions of the present invention may be in the form of aqueous suspensions, which typically contain the active ingredient in fine powder form and one or more suspending agents, such as sodium carboxymethylcellulose, Cellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and gum arabic; dispersants or wetting agents, such as lecithin or condensation products of alkylene oxides and fatty acids (e.g. , polyoxyethylene stearate); or the condensation products of ethylene oxide and long-chain fatty alcohols, such as heptadecanthyloxycetyl alcohol; or ethylene oxide and alcohols derived from fatty acids and hexitols. Condensation products of partial esters, such as polyoxyethylene sorbitan monooleate; or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives (such as ethyl paraben or propyl paraben), antioxidants (such as ascorbic acid), coloring agents, flavorings and/or sweeteners (such as sucrose, saccharin or aspartame).

In certain embodiments, pharmaceutical compositions of the present invention may be in the form of oily suspensions, typically contained in vegetable oils (such as peanut oil, castor oil, olive oil, sesame oil, or coconut oil) or mineral oils (such as Active ingredients suspended in liquid paraffin). Oily suspensions may also contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions can be preserved by adding antioxidants such as ascorbic acid.

In certain embodiments, pharmaceutical compositions of the invention may be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, such as olive oil or peanut oil; or a mineral oil, such as liquid paraffin; or a mixture of any such oils. Suitable emulsifiers may be, for example, naturally occurring gums, such as acacia or tragacanth; naturally occurring phospholipids, such as soy, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate) and the condensation products of these partial esters and ethylene oxide, such as polyoxyethylene sorbitan monooleate. Lotions may also contain sweeteners, flavorings and preservatives.

In certain embodiments, the pharmaceutical compositions provided herein may be in the form of syrups and elixirs, which may contain sweeteners such as glycerin, propylene glycol, sorbitol, aspartame, or sucrose; agents; preservatives; flavorings and/or coloring agents.

In some embodiments, pharmaceutical compositions of the present invention may be in the form of formulations for injectable administration.

In certain embodiments, pharmaceutical compositions of the invention may be in the form of sterile injectable preparations, such as sterile injectable aqueous or oily suspensions. This suspension may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Alternatively, sterile fixed oils may customarily be used as solvents or suspending media. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

In some embodiments, pharmaceutical compositions of the invention may be in the form of formulations for inhaled administration.

In certain embodiments, pharmaceutical compositions of the present invention may be in the form of aqueous and non-aqueous (e.g., in fluorocarbon propellants) aerosols containing any suitable solvent and optionally Other compounds are present such as, but not limited to, stabilizers, antimicrobials, antioxidants, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof. Carriers and stabilizers vary with the requirements of the specific compound, but generally include nonionic surfactants (Tween, Pluronic, or polyethylene glycol), harmless proteins (such as serum albumin), sorbitan esters, oleic acid, Lecithin, amino acids (such as glycine), buffers, salts, sugars or sugar alcohols.

In some embodiments, pharmaceutical compositions of the invention may be in the form of formulations for topical or transdermal administration.

In certain embodiments, the pharmaceutical compositions provided herein may be in the form of creams, ointments, gels, and aqueous or oily solutions or suspensions, such creams, ointments, gels, and aqueous or oily solutions or suspensions. Usually, the active ingredients can be prepared by combining the active ingredients with commonly known topically acceptable excipients (such as animal fats and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, Bentonite, silicic acid, talc and zinc oxide or mixtures thereof) are prepared together.

In certain embodiments, pharmaceutical compositions provided herein may be formulated in the form of transdermal skin patches known to those of ordinary skill in the art.

In addition to the representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in the present invention. Such excipients and carriers are described, for example, in: "Remingtons Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991); "Remington: The Science and Practice of Pharmacy," edited by the University of the Sciences, Philadelphia of the Sciences in Philadelphia), 21st ed., LWW (2005), which reference is incorporated herein by reference.

In some embodiments, the pharmaceutical compositions of the present invention can be formulated into a single dosage form. The amount of a compound provided herein in a single dosage form will vary depending on the individual treated and the particular mode of administration.

In some embodiments, the pharmaceutical compositions of the present invention can be formulated such that 0.001 mg/kg body weight/day to 1000 mg/kg body weight/day can be administered, for example, 0.01 mg/kg body weight/day to 800 mg/kg body weight /day, 0.01 mg/kg body weight/day to 700 mg/kg body weight/day, 0.01 mg/kg body weight/day to 600 mg/kg body weight/day, 0.01 mg/kg body weight/day to 500 mg/kg body weight/day , 0.01 mg/kg body weight/day to 400 mg/kg body weight/day, 0.01 mg/kg body weight/day to 300 mg/kg body weight/day, 0.1 mg/kg body weight/day to 200 mg/kg body weight/day, 0.1 mg/kg body weight/day to 150 mg/kg body weight/day, 0.1 mg/kg body weight/day to 100 mg/kg body weight/day, 0.5 mg/kg body weight/day to 100 mg/kg body weight/day, 0.5 mg/ kg body weight/day to 80 mg/kg body weight/day, 0.5 mg/kg body weight/day to 60 mg/kg body weight/day, 0.5 mg/kg body weight/day to 50 mg/kg body weight/day, 1 mg/kg body weight /day to 50 mg/kg body weight/day, 1 mg/kg body weight/day to 45 mg/kg body weight/day, 1 mg/kg body weight/day to 40 mg/kg body weight/day, 1 mg/kg body weight/day A compound provided herein or a compound thereof at a dose of 35 mg/kg body weight/day, 1 mg/kg body weight/day to 30 mg/kg body weight/day, or 1 mg/kg body weight/day to 25 mg/kg body weight/day. Pharmaceutically acceptable salt. In some cases, dose levels below the lower end of the foregoing range may be more than adequate, while in other cases larger doses may be used without causing any deleterious side effects, provided that such larger doses are first divided into smaller doses. Commit throughout the day. For more information on routes of administration and dosing schedules, see Comprehensive Medicinal Chemistry, Volume 5, Chapter 25.3 (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press 1990, which reference is expressly incorporated herein by reference.

In some embodiments, the pharmaceutical compositions of the present invention can be formulated into short-acting, rapid-release, long-acting and sustained-release forms. Accordingly, the pharmaceutical formulations of the present invention may also be formulated for controlled release or slow release.

In another aspect, veterinary compositions are also provided, which veterinary compositions comprise one or more molecules or compounds of the invention or pharmaceutically acceptable salts thereof and a veterinary carrier. A veterinary carrier is a material useful for the purpose of administering the composition, and may be a solid, liquid or gaseous material that is otherwise inert or acceptable in the field of veterinary medicine and is compatible with the active ingredient. Such veterinary compositions may be administered parenterally, orally, or by any other desired route.

Pharmaceutical or veterinary compositions may be packaged in various ways depending on the method used to administer the drug. For example, an article for dispensing may include a container holding the composition in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. Containers may also include tamper-evident assemblies to prevent easy access to the contents of the package. In addition, the container has a label placed thereon describing the contents of the container. Labels may also include appropriate warnings. The compositions may also be packaged in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored by freeze-drying (lyophilization) requiring only the addition of a sterile liquid carrier, such as water for injection, immediately before use. conditions. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind previously described.

In another aspect, a pharmaceutical composition is also provided, which includes as a first active ingredient one or more compounds of the present invention or a pharmaceutically acceptable salt thereof and a second active ingredient.

In some embodiments, the second active ingredient has activities that are complementary to the compounds provided herein such that they do not adversely affect each other. Such ingredients are suitably present in combination and in amounts effective for the intended purpose.

In some embodiments, the second active ingredient may include: (i) anti-proliferative/anti-neoplastic drugs as used in medical oncology, and combinations thereof, such as alkylating agents (e.g., cis-platin ), carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (e.g. , antifolate agents, such as fluoropyrimidines (such as 5-fluorouracil and tegafur), raltitrexed (raltitrexed), methotrexate, cytarabine, hydroxyurea and gemcitabine); antifolates Oncology antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, ida idarubicin, mitomycin-C, dactinomycin, and mithramycin); antimitotic agents (e.g., vinca alkaloids such as vincristine) vincristine, vinblastine, vindesine and vinorelbine) and taxanes (such as paclitaxel and taxotere); and topoisomerase inhibition Agents (for example, epipodophyllotoxins such as etoposide and teniposide), amsacrine, topotecan and camptothecins); ( ii) Cytostatic agents such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene, and indoxifene) iodoxyfene), estrogen receptor down-modulators (e.g., fulvestrant), antiandrogens (e.g., bicalutamide, flutamide, nilutamide (nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestins ( For example, megestrol acetate), aromatase inhibitors (eg, anastrozole, letrozole, vorazole, and exemestane), and 5a-reducing Enzyme inhibitors (such as finasteride); (iii) Anti-invasive agents (such as c-Src kinase family inhibitors, such as 4-(6-chloro-2,3-methylenedioxyaniline) base)-7-[2-(4-methylpiperan-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530) and N-(2-chloro -6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperidine-1-yl]-2-methylpyrimidin-4-ylamine}thiazole-5-carboxylic acid amines (dasatinib, BMS-354825)) and metalloproteinase inhibitors, such as marimastat and urokinase plasminogen activator receptor function inhibitor); (iv) Growth Inhibitors of factor function: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (eg, the anti-erbB2 antibody trastuzumab [Herceptin™] and the anti-erbB1 antibody cetuximab ( cetuximab) [C225]); such inhibitors also include, for example, tyrosine kinase inhibitors, such as epidermal growth factor family inhibitors (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-fluoro-4- Fluorophenyl)-7-methoxy-6-(3-𠰌linepropoxy)quinazolin-4-amine (gefitinib, ZD 1839), N-(3-ethynylbenzene) base)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamide-N-(3 -Fluoro-4-fluorophenyl)-7-(3-𠰌linepropoxy)quinazolin-4-amine (CI 1033) and erbB2 tyrosine kinase inhibitors such as lapatinib) , hepatocyte growth factor family inhibitors, platelet-derived growth factor family inhibitors such as imatinib, serine/threonine kinase inhibitors (e.g., Ras/Raf signaling inhibitors such as farnesin Transferase inhibitors, such as sorafenib (BAY 43-9006)) and inhibitors of cell signaling through MEK and/or Akt kinase; (v) Anti-angiogenic agents, such as inhibition of vascular endothelial growth factor Anti-angiogenic agents, such as the anti-VEGF antibody bevacizumab (Avastin™) and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo-2-fluoro Anilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (ZD6474; Example 2 in WO 01/32651), 4-(4-fluoro- 2-Methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 in WO 00/47212 ), vatalanib (PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), as well as compounds that act by other mechanisms (e.g., linoramide linomide), integrin ανβ3 function inhibitor and angiostatin)]; (vi) vascular damaging agents, such as combretastatin A4 and international patent applications WO 99/02166, WO 00/40529, WO 00 /41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) antisense therapies, such as ISIS 2503, an anti-ras antisense agent; (viii) gene therapy methods, including for example replacement Abnormal genetic approaches, such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) approaches, such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase, and increased sensitivity to chemical methods of patient tolerance of therapy or radiation therapy (such as multi-drug resistance gene therapy); and (ix) immunotherapy methods, including ex vivo and in vivo methods of increasing the immunogenicity of patient tumor cells (such as using interleukins) (such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor), methods to reduce T-cell anergy, use of transfected immune cells (such as interleukin transfection dendritic cells), a method of using interleukin-transfected tumor cell lines, and a method of using anti-idiotypic antibodies. Methods of treating diseases

In one aspect, the invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof capable of inhibiting ATR kinase. The inhibitory properties of compounds of formula (I) can be demonstrated using the testing procedures described herein.

Accordingly, compounds of formula (I) may be used to treat (therapeutic or prophylactic) conditions or diseases in an individual that are mediated by ATR kinase.

As used herein, "individual" refers to humans and non-human animals. Examples of non-human animals include all vertebrates, e.g., mammals, such as non-human primates (especially higher primates), dogs, rodents (e.g., mice or rats), guinea pigs, cats; and non-mammals such as birds, amphibians, reptiles, etc. In preferred embodiments, the individual is a human. In another embodiment, the subject is an experimental animal or an animal suitable as a disease model.

In some embodiments, compounds of Formula (I) can be used as anti-tumor agents. In some embodiments, compounds of Formula (I) can be used as anti-proliferative agents, anti-apoptotic agents and/or anti-invasive agents in the inhibition and/or treatment of solid and/or liquid tumor diseases. In certain embodiments, compounds of Formula (I) can be used to prevent or treat tumors that are sensitive to inhibition of ATR. In certain embodiments, compounds of Formula (I) may be used to prevent or treat tumors that are mediated solely or in part by ATR.

In some embodiments, compounds of Formula (I) are useful in the treatment of proliferative diseases, including malignant diseases, such as cancer, as well as non-malignant diseases, such as inflammatory diseases, obstructive airway diseases, immune diseases, or cardiovascular diseases.

In some embodiments, compounds of Formula (I) may be used to treat cancers such as, but not limited to, hematological malignancies (such as leukemia, multiple myeloma), lymphomas (such as Hodgkin's disease, non-Hodgkin's disease), Non-Hodgkin's lymphomas (including mantle cell lymphoma) and myelodysplastic syndromes, as well as solid tumors and their metastases (such as breast cancer, lung cancer (NSCL), small cell lung cancer Lung cancer (SCLC), squamous cell carcinoma), endometrial cancer), central nervous system tumors (such as glioma, dysembryoplastic neuroepithelial tumor, glioblastoma multiforme, mixed glioma, neuro Tuboblastoma, retinoblastoma, neuroblastoma, germinomas and teratomas), gastrointestinal cancers (such as stomach cancer, esophageal cancer, hepatocellular (liver) cancer, bile duct cancer, colorectal and rectal cancer, small bowel cancer, pancreatic cancer), skin cancer (such as melanoma (especially metastatic melanoma)), thyroid cancer, head and neck cancer and salivary gland cancer, prostate cancer, testicular cancer, ovarian cancer, cervical cancer, uterine cancer, vaginal cancer , bladder cancer, renal cancer (including renal cell carcinoma, clear cell and renal oncocytoma), squamous cell carcinoma, sarcoma (such as osteosarcoma, chondrosarcoma, leiomyosarcoma, soft tissue sarcoma, Ewing's sarcoma) , gastrointestinal stromal tumor (GIST), Kaposi's sarcoma) and pediatric cancers (such as rhabdomyosarcoma and neuroblastoma).

In some embodiments, compounds of formula (I) can be used to treat autoimmune diseases and/or inflammatory diseases, such as but not limited to allergies, Alzheimer's disease, acute disseminated encephalomyelitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune hemolytic and thrombocytopenic states, autoimmune hepatitis, autoimmunity Sexual inner ear disease, bullous pemphigoid, celiac disease, chagas disease, chronic obstructive pulmonary disease, chronic idiopathic thrombocytopenic purpura (ITP), churg -strauss syndrome), Crohn's disease, dermatomyositis, type 1 diabetes, endometriosis, Goodpasture's syndrome (and related glomerulonephritis and Pulmonary hemorrhage), Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, Hidradenitis Suppurativa, Idiopathic Thrombocytopenic Purpura, Interstitial Cystitis, irritable bowel syndrome, lupus erythematosus, morphea, multiple sclerosis, myasthenia gravis, narcolepsy, neuromyotonia, Parkinson's disease, pemphigus vulgaris, pernicious anemia, multiple Myositis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, schizophrenia, septic shock, scleroderma, Sjogren's disease, systemic erythema Lupus (and related glomerulonephritis), temporal arteritis, tissue graft rejection and hyperacute rejection of transplanted organs, vasculitis (ANCA-associated vasculitis and other vasculitis), vitiligo and Wegener's granulomatosis ).

As used herein, the term "therapy" is intended to have its normal meaning, that is, to treat a disease in order to alleviate, completely or partially, one, some or all of its symptoms, or to correct or compensate for the underlying pathology, thereby achieving beneficial or Desired Clinical Outcomes. For purposes of the present invention, beneficial or desired clinical results include, but are not limited to, relief of symptoms, reduction in disease severity, stabilization of disease state (i.e., non-exacerbation), delay or slowing of disease progression, improvement of disease state. or mitigation and alleviation (whether partial or total), whether detectable or undetectable. "Treatment" may also mean prolongation of survival compared to expected survival in the absence of therapy. Conditions requiring therapy include conditions where a condition or disorder is already present, conditions where a condition or disorder is predisposed to the condition or condition, or conditions where a condition or disorder is to be prevented. Unless there is specific indication to the contrary, the term "therapy" also encompasses prevention. The terms "therapeutic" and "therapeutically" should be construed accordingly.

As used herein, the term "prophylaxis" or "prophylactic" is intended to have its normal meaning and includes primary prevention to prevent the progression of a disease as well as to protect the patient, temporarily or permanently, from the progression of the disease or Secondary prevention of worsening or developing new disease-related symptoms.

The terms "treatment" and "therapy" are used synonymously. Similarly, the term "treatment" may be considered "applied therapy," where "therapy" is as defined herein.

In another aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the invention, for therapy, for example in therapy associated with ATR kinase.

In another aspect, the present invention provides a use of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention in the preparation of a medicament for treating cancer.

In another aspect, the present invention provides a use of a compound of the present invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present invention in the preparation of a medicament for treating cancer.

In another aspect, the invention provides a compound of the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the invention for use in the treatment of cancer.

In some embodiments, compounds of Formula (I) may be further combined with other biologically active ingredients (such as, but not limited to, second and different anti-neoplastic agents) and non-pharmacological therapies (such as, but not limited to, surgery or radiation therapy). . For example, compounds of formula (I) may be used in combination with other pharmaceutically active compounds or non-pharmacological therapies, preferably compounds capable of enhancing the effects of compounds of formula (I). Compounds of formula (I) may be administered simultaneously with other therapies (as a single preparation or separate preparations) or sequentially. Typically, combination therapy contemplates the administration of two or more drugs/treatments during a single cycle or course of treatment.

In some embodiments, compounds of Formula (I) are used in combination with one or more traditional chemotherapeutic agents, which cover a broad range of therapeutic treatments in the field of oncology. These agents are administered at various stages of the disease to shrink tumors, destroy remaining cancer cells left after surgery, induce remission, maintain remission, and/or reduce symptoms associated with cancer or its treatment.

In some embodiments, compounds of Formula (I) are used in combination with one or more targeted anti-cancer agents that modulate protein kinases involved in various disease states.

In some embodiments, compounds of Formula (I) are used in combination with one or more targeted anti-cancer agents that modulate non-kinase biological targets, pathways or processes.

In some embodiments, compounds of Formula (I) are used in combination with one or more other anti-cancer agents, including but not limited to gene therapy, RNAi cancer therapy, chemoprotective agents (e.g., amfostine ), mesna, dexrazoxane), antibody conjugates (e.g., brentuximab vedotin, ibritumomab tioxetan), cancer immunotherapies (such as Leucin-2), cancer vaccines (e.g., sipuleucel-T), or monoclonal antibodies (e.g., bevacizumab, alemtuzumab, rituximab ( Rituximab), trastuzumab, etc.).

In some embodiments, compounds of formula (I) are used in combination with one or more anti-inflammatory agents, including but not limited to NSAIDs, non-specific and COX-2 specific cyclooxygenase inhibitors, gold compounds, Corticosteroids, methotrexate, tumor necrosis factor receptor (TNF) receptor antagonists, immunosuppressants, and methotrexate.

In some embodiments, compounds of Formula (I) are used in combination with radiation therapy or surgery. Radiation is usually delivered from inside a machine (implanting radioactive material near the cancer site) or externally using photon (x-ray or gamma ray) or particle radiation. When the combination therapy further includes radiation therapy, the radiation therapy may be administered at any suitable time so long as a beneficial effect is achieved from the combined effects of the therapeutic agent and the radiation therapy.

Accordingly, in another aspect, the invention provides a method for treating an ATR kinase-related disease in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound of the invention or a pharmaceutical thereof. The above acceptable salt or the pharmaceutical composition of the present invention. Example

For illustrative purposes, the following examples are included. However, it should be understood that these examples do not limit the invention and are merely intended to illustrate methods of practicing the invention. Those skilled in the art will recognize that the chemical reactions described can be readily adapted to prepare a variety of other compounds of the invention, and alternative methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, by modifications that are obvious to those skilled in the art, such as by appropriately protecting interfering groups, by using other suitable reagents and building blocks known in the art other than the described reagents and building blocks. Non-exemplary compounds according to the present invention can be successfully synthesized by routine modification of reagents and building blocks and/or reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for preparing other compounds of the invention. Example 1 (R)-4-(7-(3,5- dimethyl -1H-1,2,4- triazol -1- yl )-3-(3- methyl -1H- pyrazole -5) Synthesis of -yl ) isothiazolo [ 4,5-b] pyridin -5- yl )-3- methyl 𠰌 line Step 1. (3R)-4-(7-(3,5- dimethyl -1H-1,2,4- triazol -1- yl )-3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl ) isothiazolo [4,5-b] pyridin -5- yl )-3- methyl 𠰌 line

To a solution of 3,5-dimethyl-4H-1,2,4-triazole (45 mg, 0.461 mmol) in dioxane (30 mL) was added (3R)-4-{7-chloro- 3-[3-Methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl }-3-Methylpyroline (100 mg, 0.230 mmol), Ruphos (12 mg, 0.046 mmol), RuPhos-Pd-G3 (20 mg, 0.046 mmol) and Cs ₂ CO ₃ (224 mg, 0.690 mmol). The reaction mixture was degassed and injected with _N2 several times, and then stirred at 100 °C for 16 h under _N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0~100%, ethyl acetate/petroleum ether) to obtain (3R)-4-(7-(3,5-dimethyl- 1H-1,2,4-triazol-1-yl)-3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)iso Thiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line (52 mg, 0.095 mmol, 41.06%). LCMS: m/z 495.7 (M+H) ⁺ . Step 2. (R)-4-(7-(3,5- dimethyl -1H-1,2,4- triazol -1- yl )-3-(3- methyl -1H - pyrazole- 5- yl ) isothiazolo [4,5-b] pyridin -5- yl )-3- methyl 𠰌 line

To (3R)-4-(7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(3-methyl-1-(tetrahydro-2H) -pyran-2-yl)-1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)-3-methylpyrazoline (52 mg, 0.105 mmol) in DCM (1.5 mL) was added HCl (4 M in dihexane, 3 mL). The mixture was stirred at room temperature for 0.5 h. LC-MS showed the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeCN/H ₂ O containing 0.1% HCOOH) to give (R)-4-(7-(3,5-dimethyl-1H -1,2,4-triazol-1-yl)-3-(3-methyl-1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)-3 -Methyl phenanthroline (15 mg, 0.037 mmol, 34.76%). LCMS: m/z 411.6 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO) δ 13.19 (s, 1H), 7.28 (s, 1H), 7.12 (s, 1H), 4.53 (d, J = 5.1 Hz, 1H), 4.15 (d, J = 12.7 Hz, 1H), 4.07 (d, J = 8.5 Hz, 1H), 3.84 (d, J = 11.3 Hz, 1H), 3.75 (d, J = 11.4 Hz, 1H), 3.60 (t, J = 10.4 Hz, 1H), 2.80 (s, 3H), 2.40 (s, 3H), 2.32 (s, 3H), 1.28 (d, J = 6.6 Hz, 3H) Example 2 (R)-3- methyl -4-(7 -(5- Methyl -1H-1,2,4- triazol -1- yl )-3-(3- methyl -1H- pyrazol -5- yl ) isothiazolo [4,5-b] Synthesis of pyridin -5- yl ) 𠰌 line (R)-3- methyl -4-(7-(3- methyl -1H-1,2,4- triazol -1- yl )-3-(3 -Methyl - 1H- pyrazol -5- yl ) isothiazolo [4,5-b] pyridin -5- yl ) 𠰌 line Step 1. (3R)-3- methyl- 4-(3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-7 - (5- Methyl -1H-1,2,4- triazol -1- yl ) isothiazolo [4,5-b] pyridin -5- yl ) 𠰌 line and (3R)-3- methyl- 4-(3-(3- methyl -1-( tetrahydro -2H- piran -2- yl )-1H- pyrazol -5- yl )-7-(3- methyl -1H-1,2 ,4- triazol -1- yl ) isothiazolo [4,5-b] pyridin -5- yl ) mixture of 𠰌 line

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo [4,5-b]pyridin-5-yl}-3-methyl𠰌line (150 mg, 0.346 mmol), 5-methyl-1H-1,2,4-triazole (57 mg, 0.691 mmol) To a mixture of , RuPhos (32 mg, 0.069 mmol) and Cs ₂ CO ₃ (225 mg, 0.691 mmol) in DMF (8 mL) was added RuPhos-Pd-G3 (27 mg, 0.035 mmol). The mixture was degassed and injected with _N2 several times and stirred at 80 °C for 16 h. LC-MS showed the reaction was complete. The mixture was filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel (12 g), 0-100%, EA/PE) to obtain (3R)-3-methyl-4-(3-(3- Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-7-(5-methyl-1H-1,2,4-triazole-1- yl)isothiazolo[4,5-b]pyridin-5-yl)𠰌line and (3R)-3-methyl-4-(3-(3-methyl-1-(tetrahydro-2H-piper) Pyran-2-yl)-1H-pyrazol-5-yl)-7-(3-methyl-1H-1,2,4-triazol-1-yl)isothiazolo[4,5-b] A mixture of pyridin-5-yl)pyridinolines (120 mg, 72%). LC/MS (ESI): m/z 481.6 [M+1] ⁺ . Step 2. (R)-3- methyl -4-(7-(5- methyl -1H-1,2,4- triazol -1- yl )-3-(3- methyl- 1H- pyra) Azol -5- yl ) isothiazolo [4,5-b] pyridin -5- yl ) 𠰌 line (R)-3- methyl -4- (7-(3- methyl- 1H-1,2, 4- Triazol -1- yl )-3-(3- methyl -1H- pyrazol -5- yl ) isothiazolo [4,5-b] pyridin -5- yl ) 𠰌 line

To (3R)-3-methyl-4-(3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-7-( 5-Methyl-1H-1,2,4-triazol-1-yl)isothiazolo[4,5-b]pyridin-5-yl)𠰌line and (3R)-3-methyl-4- (3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-7-(3-methyl-1H-1,2,4 To a mixture of -triazol-1-yl)isothiazolo[4,5-b]pyridin-5-yl)triazolin (120 mg, 0.250 mmol) in DCM (1 mL) was added HCl (4 M in di in hexane, 3 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The mixture was concentrated to dryness. The crude product was purified by preparative-HPLC (C ₁₈ , 10-95%, MeCN/H ₂ O containing 0.1% HCOOH) to give (R)-3-methyl-4-(7-(5-methyl -1H-1,2,4-triazol-1-yl)-3-(3-methyl-1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl) 𠰌line (5 mg, 0.013 mmol, 20.20%) and (R)-3-methyl-4-(7-(3-methyl-1H-1,2,4-triazol-1-yl)-3 -(3-Methyl-1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)oxoline (20 mg, 0.050 mmol, 80.81%). LC/MS (ESI) m/z: 397.5 [M+1] ⁺ . P1: ¹ H NMR (400 MHz, DMSO) δ 8.34 (s, 1H), 7.37 (s, 1H), 7.13 (s, 1H) , 4.54 (d, J = 4.6 Hz, 1H), 4.16 (d, J = 13.1 Hz, 1H), 4.07 (d, J = 8.0 Hz, 1H), 3.83 (s, 1H), 3.74 (s, 1H) , 3.60 (s, 1H), 3.31 (d, J = 3.4 Hz, 1H), 2.86 (s, 3H), 2.32 (s, 3H), 1.29 (d, J = 6.6 Hz, 3H). P2: ¹ H NMR (400 MHz, DMSO) δ 9.74 (d, J = 1.7 Hz, 1H), 7.72 (d, J = 4.6 Hz, 1H), 7.12 (s, 1H), 4.63 – 4.54 (m, 1H ), 4.17 (d, J = 13.3 Hz, 1H), 4.09 – 4.03 (m, 1H), 3.84 (s, 1H), 3.74 (d, J = 9.0 Hz, 1H), 3.59 (d, J = 2.3 Hz , 1H), 3.30 (t, J = 11.3 Hz, 1H), 2.47 (s, 3H), 2.32 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H). Example 3 (R)-2-(3-(3- methyl - 1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridine- Synthesis of 7- yl ) propan -2- amine Step 1. 3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R)-3- methyl 𠰌 line yl ) isothiazolo [4,5-b] pyridine -7- carbonitrile

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (300 mg, 0.691 mmol) in DMF (2 mL) was added Zn(CN) ₂ (162 mg, 1.38 mmol) , DPPF (77 mg, 0.138 mmol) and Pd ₂ (dba) ₃ (63 mg, 0.069 mmol). The reaction was stirred at 120°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. Dilute the reaction with EA (10 mL) and water (10 mL). The organic layer was separated, washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by silica column chromatography (PE:EA = 1:1) to obtain the desired product (200 mg, 0.471 mmol, 68.2%) as a yellow solid. LC/MS (ESI) m/z: 425 (M+H) ⁺ . Step 2. 2-(3-(3- methyl- 1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R)-3- methyl yl 𠰌 linyl ) isothiazolo [4,5-b] pyridin -7- yl ) propan -2- amine

To 3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌line-4 at 0°C To a solution of -[1,2]thiazolo[4,5-b]pyridine-7-carbonitrile (100 mg, 0.236 mmol) in THF (2 mL) was added dropwise (in diethyl ether) Methyl magnesium bromide (0.71 mL, 2.12 mmol). The mixture was stirred at 0 °C for 30 min. Tetraisopropyl titanate (0.21 mL, 0.707 mmol) was added dropwise to the mixture. The mixture was then stirred at 50°C overnight. Dilute the reaction with EA (20 mL) and water (20 mL). The organic layer was separated, washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by preparative-TLC (DCM:MeOH = 20:1, V/V) to give the desired product (30 mg, 27.9%) as a yellow solid. LC/MS (ESI) m/z: 589 (M+H) ⁺ . Step 3. (R)-2-(3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridine -7- yl ) propan -2- amine

To 2-{3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌line-4 -[1,2]thiazolo[4,5-b]pyridin-7-yl}propan-2-amine (30 mg, 0.066 mmol) in DCM (1 mL) and HCl/dioxane (4 M) (1 mL) solution. The mixture was stirred at room temperature for 30 min. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give the desired product (3 mg, 12.3%). LC/MS (ESI) m/z: 372 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.07 (s, 1H), 6.99 (s, 1H), 4.53 (d, J = 5.4 Hz, 1H), 4.11 – 4.00 (m , 2H), 3.81 (d, J = 11.3 Hz, 1H), 3.72 (d, J = 10.8 Hz, 1H), 3.57 (t, J = 10.2 Hz, 1H), 3.22 (m, 1H), 2.29(s , 3H), 1.49 (d, J = 3.1 Hz, 6H), 1.20 (d, J = 6.6 Hz, 3H). Example 4 (3R)-4-[7-(1- cyclopropyl -1H-1,2,3- triazol -5- yl )-3-(3- methyl -1H- pyrazol -5- yl) Synthesis of )-[1,2] thiazolo [4,5-b] pyridin -5- yl ]-3- methyl 𠰌 line Step 1. N'-[(2Z)-1,1- dimethoxyprop -2- ylidene ]-4- toluene -1 -sulfonylhydrazine

To a mixture of 2,2-dimethoxyacetaldehyde (1.7 mL, 11.3 mmol) in MeOH (10 mL) was added 4-toluene-1-sulfonylhydrazine (2.0 mg, 10.7 mmol) under _N2 . The mixture was stirred at room temperature for 5 min. LC-MS showed the reaction was complete. The mixture was concentrated in vacuo to give the crude product N-{2-[2-Pendantoxy-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2- Dihydropyridin-1-yl]ethyl}methylsulfonamide (3.0 g, 10.5 mmol), the crude product was used in the next step without further purification. Step 2. 1- Cyclopropyl -1H-1,2,3- triazole

A mixture of N'-[( _2Z )-1,1-dimethoxyprop-2-ylidene]-4-toluene-1-sulfonylhydrazine in MeOH (30 mL) (3.0 g , 10.5 mmol), add cyclopropylamine (0.8 mL, 11.5 mmol) and TEA (1.60 mL, 11.5 mmol). The mixture was stirred at 75 °C for 15 h. LC-MS showed the reaction was complete. _H2O (10 mL) was added to the reaction mixture. The reaction mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried _{over Na2SO4} , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain 1-cyclopropyl-1H-1,2,3-triazole (400 mg, 3.66 mmol, 35%). LC/MS (ESI): m/z 110 [M+H] ⁺ . Step 3. (3R)-4-[7-(1- cyclopropyl -1H-1,2,3- triazol -5- yl )-3-[3- methyl -1-( tetrahydropyran) -2- yl )-1H- pyrazol -5- yl ]-[1,2] thiazolo [4,5-b] pyridin -5- yl ]-3- methyl 𠰌 line

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (50 mg, 0.115 mmol) in DMA (3 mL) was added 1-cyclopropyl-1H-1,2, 3-Triazole (76 mg, 0.691 mmol), tetramethylammonium acetate (32 mg, 0.230 mmol), and bis(triphenylphosphine)palladium(II) chloride (13 mg, 0.016 mmol). The reaction was stirred at 140 °C for 6 h under _N2 . LC-MS showed the reaction was complete. The mixture was poured into _H2O (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine and dried _{over Na2SO4} , filtered and concentrated in vacuo. The reactant was purified by preparative-TLC (PE:EA=1:1) to obtain (3R)-4-[3-chloro-7-(1-cyclopropyl-1H-1, 2,3-Triazol-5-yl)-[1,2]thiazolo[4,5-b]pyridin-5-yl]-3-methyl𠰌line (15 mg, 0.040 mmol, 49%). LC/MS (ESI): m/z 506.8 [M+H] ⁺ . Step 4. (3R)-4-[7-(1- cyclopropyl -1H-1,2,3- triazol -5- yl )-3-(3- methyl -1H- pyrazole -5- base )-[1,2] thiazolo [4,5-b] pyridin -5- yl ]-3- methyl 𠰌 line

To (3R)-4-[7-(1-cyclopropyl-1H-1,2,3-triazol-5-yl)-3-[3-methyl-1-(tetrahydropyran-2 -yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl]-3-methylpyrazoline (15 mg, 0.040 mmol) in DCM To the solution in (1 mL) was added HCl-dioxane (2 mL). The reaction was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative-HPLC (C18, 10-95%, MeOH/H ₂ O containing 0.1% HCOOH) to give (3R)-4-(7-(1-cyclopropyl-1H-1, 2,3-triazol-5-yl)-3-(3-methyl-1H-pyrazol-5-yl)-[1,2]thiazolo[4,5-b]pyridin-5-yl) -3-Methylpyroline (5 mg, 0.012 mmol, 9.99%). LC/MS (ESI): m/z 422.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 13.12 (d, J = 121.5 Hz, 1H), 8.25 (s, 1H), 7.62 (s, 1H), 7.15 (s, 1H), 4.72 – 4.40 (m, 1H ), 4.24 – 4.00 (m, 3H), 3.84 – 3.68 (m, 2H), 3.66 – 3.54 (m, 1H), 3.29 – 3.24 (m, 1H), 2.33 (s, 3H), 1.27 (d, J = 6.5 Hz, 3H), 1.21 – 1.09 (m, 4H). Example 5 (R)-4-(7-(1- cyclopropyl- 1H- pyrazol -5- yl )-3-(3- methyl - 1H- pyrazol -5- yl ) isothiazolo [4 , Synthesis of 5-b] pyridin -5- yl )-3- methyl 𠰌 line Step 1. (3R)-4-(7-(1- cyclopropyl -1H- pyrazol -5- yl )-3-(3- methyl -1-( tetrahydro -2H- pyran -2- base )-1H- pyrazol -5- yl ) isothiazolo [4,5-b] pyridin -5- yl )-3- methyl 𠰌 line

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (100 mg, 0.230 mmol) in dioxane (2.0 mL) and H ₂ O (0.4 mL) was added Pd ( PPh ₃ ) ₄ (53 mg, 0.046 mmol), 1-cyclopropyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (162 mg, 0.691 mmol) and K ₂ CO ₃ (159 mg, 1.15 mmol). The mixture was degassed and injected with _N2 several times, and then stirred at 80 °C for 16 h under _N2 . LC-MS showed the reaction was complete. The reaction mixture was poured into H ₂ O (20 mL) and extracted with EA (20 mL*3). The combined organic phases were washed with brine (20 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0~100%, ethyl acetate/petroleum ether) to obtain (3R)-4-(7-(1-cyclopropyl-1H-) as a colorless oil Pyrazol-5-yl)-3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)isothiazolo[4,5-b ]pyridin-5-yl)-3-methylpyridine (50 mg, 0.099 mmol, 42.91%). LC/MS (ESI): m/z 506.7 [M+H] ⁺ . Step 2. (R)-4-(7-(1- cyclopropyl -1H- pyrazol -5- yl )-3-(3- methyl - 1H- pyrazol -5- yl ) isothiazolo [ 4,5-b] pyridin -5- yl )-3- methyl 𠰌 line

To (3R)-4-(7-(1-cyclopropyl-1H-pyrazol-5-yl)-3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl) -1H-Pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line (50 mg, 0.099 mmol) in DCM (1.5 mL) Add HCl (4 M in dihexane, 3 mL). The mixture was stirred at room temperature for 0.5 h. LC-MS showed the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give (R)-4-(7-(1-cyclopropyl) as a white solid -1H-pyrazol-5-yl)-3-(3-methyl-1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌 Phenoline (10 mg, 0.024 mmol, 23.99%). LCMS: m/z 422.5 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO) δ 13.11 (d, J = 121.4 Hz, 1H), 7.64 (d, J = 1.7 Hz, 1H), 7.57 (s, 1H), 7.15 (s, 1H), 6.79 ( s, 1H), 4.55 (s, 1H), 4.17 (d, J = 12.8 Hz, 1H), 4.06 (d, J = 10.0 Hz, 1H), 3.96 (d, J = 5.0 Hz, 1H), 3.82 ( d, J = 11.4 Hz, 1H), 3.74 (d, J = 10.5 Hz, 1H), 3.59 (t, J = 10.4 Hz, 1H), 3.27 – 3.16 (m, 1H), 2.32 (s, 3H), 1.27 (d, J = 6.6 Hz, 3H), 1.08 – 0.92 (m, 4H). Example 6 (R)-4-(7-(1- cyclopropyl -1H-1,2,3- triazol -5- yl )-3-(1H- pyrazol -5- yl ) isothiazolo [ Synthesis of 4,5-b] pyridin -5- yl )-3- methyl 𠰌 line Step 1. (3R)-4-(7-(1- cyclopropyl -1H-1,2,3- triazol -5- yl )-3-(1-( tetrahydro -2H- piran -2) -yl ) -1H- pyrazol -5- yl ) isothiazolo [4,5-b] pyridin -5- yl )-3- methyl 𠰌 line

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (100 mg, 0.239 mmol) in DMA (3 mL) was added 4-(difluoromethyl)-4H-1 , 2,4-triazole (156 mg, 1.43 mmol), bis(triphenylphosphine)palladium(II) chloride (33 mg, 0.048 mmol) and tetramethylammonium acetate (318 mg, 2.39 mmol). The mixture was degassed and injected with _N2 several times, and then stirred at 140 °C for 6 h under _N2 . LC-MS showed the reaction was complete. The reaction mixture was poured into water (20 mL) and extracted with EA (20 mL * 3). The combined organic layers were washed with brine (20 mL), dried _{over Na2SO4} , filtered and concentrated. The residue was purified by preparative-TLC (PE:EA=1:1) to obtain (3R)-4-(7-(1-cyclopropyl-1H-1,2,3-triazole) as a yellow solid -5-yl)-3-(1-(tetrahydro-2H-piran-2-yl)-1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl) -3-Methylpyroline (25 mg, 0.051 mmol, 21.1%). LC/MS (ESI): m/z 493.1 [M+H] ⁺ . Step 2. (R)-4-(7-(1- cyclopropyl -1H-1,2,3- triazol -5- yl )-3-(1H- pyrazol -5- yl ) isothiazolo [4,5-b] pyridin -5- yl )-3- methyl 𠰌 line

To (3R)-4-(7-(1-cyclopropyl-1H-1,2,3-triazol-5-yl)-3-(1-(tetrahydro-2H-piran-2-yl) )-1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line (25 mg, 0.051 mmol) in DCM (1 mL) Add HCl (4 M in dihexane, 2 mL) dropwise. The reaction was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O containing 0.1% HCOOH) to give (R)-4-(7-(1-cyclopropyl-1H-1 ,2,3-triazol-5-yl)-3-(1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line(4 mg, 0.010 mmol, 19.29%). LC/MS (ESI): m/z 408.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 13.54 (d, J = 174.5 Hz, 1H), 8.26 (s, 1H), 7.68 (d, J = 29.0 Hz, 2H), 7.43 (s, 1H), 4.56 ( s, 1H), 4.23 – 4.04 (m, 3H), 3.83 – 3.72 (m, 2H), 3.57 (s, 1H), 3.13 – 2.98 (m, 1H), 1.32 – 1.24 (m, 4H), 1.15 ( dd, J = 8.5, 5.6 Hz, 3H). Example 7 (R)-2-(3-(3- methyl - 1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridine- Synthesis of 7- yl ) propan -1,1,1,3,3,3-d6-2- ol Step 1. 2-(3-(3- methyl- 1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R)-3- methyl 1,1,1,3,3,3 - d6-2 - ol ) isothiazolo [4,5-b] pyridin - 7 - yl )

To 3-[3-methyl-1-(tetrahydropyran- ₂ -yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl To a solution of methyl pyridine-7-carboxylate (100 mg, 0.219 mmol) in THF (5 mL) was added CD ₃ MgI (111 mg, 0.657 mmol). The reaction was stirred at 0 °C for 1 h. LC-MS showed the reaction was complete. The mixture was poured into saturated NH ₄ Cl and extracted with EA (20 mL * 3). The combined organic layers were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~50%, ethyl acetate/petroleum ether) to obtain 2-(3-(3-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl )Propan-1,1,1,3,3,3-d6-2-ol (85 mg, 0.183 mmol, 83.89%). LC/MS (ESI): m/z 380(M+H) ⁺ . Step 2. (R)-2-(3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridine -7- yl ) propan -1,1,1,3,3,3-d6-2- ol

To 2-(3-(3-methyl-1-(tetrahydro-2H-piran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌 Phinyl)isothiazolo[4,5-b]pyridin-7-yl)propan-1,1,1,3,3,3-d6-2-ol (50 mg, 0.099 mmol) in DCM (3 mL ) was added HCl (4 M in dioxane, 3 mL). The mixture was stirred at room temperature for 0.5 h. LC-MS showed the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give (R)-2-(3-(3-methyl-1H-pyrazole) -5-yl)-5-(3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)propan-1,1,1,3,3,3-d6-2 -Alcohol (10 mg, 24.43%). LCMS (ESI): m/z 380.2 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.09 (s, 1H), 6.56 (s, 1H), 4.36 (d, J = 4.8 Hz, 1H), 4.17 (dd, J = 12.6, 2.6 Hz, 2H ), 4.11-3.95 (m, 2H), 3.83-3.62 (m, 6H), 3.55 (td, J = 11.8, 2.8 Hz, 3H), 3.27 – 3.00 (m, 2H), 1.21 (d, J = 6.7 Hz, 3H). Example 8 2-(^2H ₃ ) methyl -2-[3-(3- methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl Synthesis of ]-[1,2] thiazolo [4,5-b] pyridin -7- yl ](^2H ₃ ) propionitrile Step 1. 2-{3- Chloro -5-[(3R)-3- methyl 𠰌 lin -4- yl ]-[1,2] thiazolo [4,5-b] pyridin -7- yl }- 2-(^2H ₃ ) methyl (^2H ₃ ) propionitrile

To 2-{3-chloro-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl} at 0°C To a solution of acetonitrile (120 mg, 0.389 mmol) and sodium (tertiary butoxy) (75 mg, 0.777 mmol) in anhydrous THF (3 mL) was added dropwise CD ₃ I (0.05 mL, 0.777 mmol) in anhydrous Solution in THF (2 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (40 mL), then washed with water and _brine , dried over anhydrous _Na2SO4 , filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 2:1, V/V) to obtain 2-{3-chloro-5-[(3R)-3-methyl𠰌line as a yellow solid -4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl}2-(^2H ₃ )methyl(^2H ₃ ) propionitrile (100 mg, 0.292 mmol, 75.05 %). LC/MS (ESI): m/z 343.1 [M+H] ⁺ . Step 2. 2-( methyl -d3)-2-(3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5 -((R)-3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridin -7- yl ) propionitrile -3,3,3-d3

To (R)-2-(3-chloro-5-(3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)-2-(methyl-d3)propionitrile -3,3,3-d3 (55 mg, 0.160 mmol), [3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]boronic acid (67 mg, 0.321 mmol) and K ₂ CO ₃ (66.51 mg, 0.481 mmol) in dioxane (4 mL) and H ₂ O (0.8 mL) was added Pd(PPh ₃ ) ₄ (37 mg, 0.032 mmol). The mixture was stirred at 100 °C for 16 h under _N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with _H2O (20 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain 2-(methyl-d3)-2-(3-(3-methyl-1-) as a brown oily substance. (Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridine -7-yl)propionitrile-3,3,3-d3 (30 mg, 39.6%). LC/MS (ESI): m/z 473.1 [M+H] ⁺ . Step 3. (R)-2-( methyl -d3)-2-(3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazole And [4,5-b] pyridin -7- yl ) propionitrile -3,3,3-d3

To 22-(methyl-d3)-2-(3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-( (R)-3-Methylpyridin-7-yl)isothiazolo[4,5-b]pyridin-7-yl)propionitrile-3,3,3-d3 (20 mg, 0.042 mmol) in DCM (1 mL ) was added dropwise to the solution in HCl-dioxane (4 M, 2 mL). The reaction was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O containing 0.1% HCOOH) to give (R)-2-(methyl-d3)-2-(3-( 3-Methyl-1H-pyrazol-5-yl)-5-(3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)propionitrile-3,3,3 -d3 (4 mg, 24.33%). LC/MS (ESI): m/z 390.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.13 (d, J = 8.0 Hz, 2H), 4.55 (s, 1H), 4.08 (dd, J = 27.8, 11.7 Hz, 2H), 3.83 (d, J = 11.1 Hz, 1H), 3.71 (d, J = 11.1 Hz, 1H), 3.54 (dd, J = 27.1, 16.0 Hz, 2H), 2.31 (s, 3H), 1.25 (d, J = 6.4 Hz, 3H ). Example 9 (R)-3- methyl -4-(3-(3- methyl -1H- pyrazol -5- yl )-7-(2H-1,2,3- triazol -2- yl ) Isothiazolo [4,5-b] pyridin -5- yl ) 𠰌 line and (R)-3- methyl -4-(3-(3- methyl -1H- pyrazol -5- yl )-7 Synthesis of -(1H-1,2,3- triazol -1- yl ) isothiazolo [4,5-b] pyridin -5- yl ) 𠰌 line

Step 1. (3R)-3- methyl- 4-(3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-7 -(2H-1,2,3- triazol -2- yl ) isothiazolo [4,5-b] pyridin -5- yl ) 𠰌 line and (3R)-3- methyl -4-(3- (3- methyl -1-( tetrahydro -2H- piran -2- yl )-1H- pyrazol -5- yl )-7-(1H-1,2,3- triazol -1- yl ) Isothiazolo [4,5-b] pyridin -5- yl ) 𠰌 line

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (120 mg, 0.277 mmol) in DMA (3 mL) was added 1H-1,2,3-triazole (0.05 mL, 0.830 mmol), CS ₂ CO ₃ (360 mg, 1.106 mmol), Ruphos (26 mg, 0.055 mmol), and Ruphos Pd G ₃ (46 mg, 0.055 mmol). After the reaction was stirred at 100°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. Dilute the reaction with EA (20 mL) and water (20 mL). The organic layer was separated, washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by preparative-TLC (DMC:MeOH = 40:1, V/V) to obtain 9-4 (40 mg, 0.086 mmol, 31.0%) as a yellow solid and 9-3 as a yellow solid. (60 mg, 0.129 mmol, 46.5%). LC/MS (ESI) m/z: 467 (M+H) ⁺ . Step 2. (R)-3- methyl -4-(3-(3- methyl -1H- pyrazol -5- yl )-7-(2H-1,2,3- triazol -2- yl) ) isothiazolo [4,5-b] pyridin -5- yl ) 𠰌 line

To (3R)-3-methyl-4-(3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-7-( 2H-1,2,3-triazol-2-yl)isothiazolo[4,5-b]pyridin-5-yl)oxoline (40 mg, 0.086 mmol) in DCM (1 mL) and HCl/di Solution in hexane (4 M) (1 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give the desired product (20 mg, 0.052 mmol, 61.0%). LC/MS (ESI) m/z: 383 [M+H] ⁺ .

¹ HNMR (400 MHz, DMSO) δ 13.10 (d,J = 114.2 Hz, 1H), 8.43 (s, 2H), 7.70 (s, 1H), 7.13 (s, 1H), 4.56 (d,J = 5.1 Hz , 1H), 4.16 (d,J = 12.7 Hz, 1H), 4.06 (d,J = 8.6 Hz, 1H), 3.83 (d,J = 11.3 Hz, 1H), 3.75 (d,J =9.0 Hz, 1H ), 3.60 (t,J = 10.4 Hz, 1H), 3.29 (m, 1H), 2.32 (s, 3H), 1.27 (d,J = 6.6 Hz, 3H). Step 3. (R)-3- methyl -4-(3-(3- methyl -1H- pyrazol -5- yl )-7-(1H-1,2,3- triazol -1- yl) ) isothiazolo [4,5-b] pyridin -5- yl ) 𠰌 line

To (3R)-3-methyl-4-(3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-7-( 1H-1,2,3-triazol-1-yl)isothiazolo[4,5-b]pyridin-5-yl)𠰌line (60 mg, 0.129 mmol) in DCM (1 mL) and HCl/di Solution in hexane (4 M) (1 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O containing 0.1% HCOOH) to give the desired product (30 mg, 0.078 mmol, 61.0%). LC/MS (ESI) m/z: 383 [M+H] ⁺ .

¹ HNMR (400 MHz, DMSO) δ 13.22 (s, 1H), 9.48 (s, 1H), 8.19 (s, 1H), 7.78 (s, 1H), 7.14 (s, 1H), 4.63 (d,J = 7.3 Hz, 1H), 4.21 (d,J = 12.7 Hz, 1H), 4.08 (d,J = 10.8 Hz, 1H), 3.87 (d,J = 11.2 Hz, 1H), 3.76 (d,J =11.2 Hz , 1H), 3.59 (d,J = 11.8 Hz, 1H), 3.30 (s, 1H), 2.32 (s, 3H), 1.29 (d,J = 6.5 Hz, 3H). Example 10 (R)-1-(3-(3- methyl - 1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridine- Synthesis of 7- yl ) cyclopropan -1- ol Step 1. 1-(3-(3- methyl- 1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R)-3- methyl yl (𠰌 linyl ) isothiazolo [4,5-b] pyridin -7- yl ) cyclopropan -1- ol

To 3-(3-methyl-1-(tetrahydro-2H-piran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌 at 0°C To a solution of ethylmagnesium bromide (0.940 mL, 0.940 mmol) in THF (2 mL) was added dropwise ). The mixture was stirred at 0 °C for 30 min. Tetraisopropyl titanate (0.059 mL, 0.564 mmol) was added dropwise to the mixture. The mixture was then stirred at 50°C overnight. Dilute the reaction with EA (20 mL) and water (20 mL). The organic layer was separated, washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by preparative-TLC (DCM:MeOH = 20:1, V/V) to give the desired product (20 mg, 0.044 mmol, 23.4%). LC/MS (ESI) m/z: 456 (M+H) ⁺ . Step 2. (R)-1-(3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridine -7- yl ) cyclopropan -1- ol

To 1-(3-(3-methyl-1-(tetrahydro-2H-piran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌 Phylino)isothiazolo[4,5-b]pyridin-7-yl)cyclopropan-1-ol (20 mg, 0.044 mmol) in DCM (1 mL) and HCl/dioxane (4 M) (1 mL) solution. The mixture was stirred at room temperature for 30 min. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O containing 0.1% HCOOH) to give the desired product (5 mg, 0.013 mmol, 30.7%). LC/MS (ESI) m/z: 372 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 13.07 (NH, 1H), 7.87 (s, 1H), 7.11 (s, 1H), 4.66 (s, 1H), 4.21 (d, J = 13.5 Hz, 1H), 4.07 (d, J = 9.3 Hz, 1H), 3.85 (d, J = 11.6 Hz, 1H), 3.75 (d, J = 9.7 Hz, 1H), 3.60 (t, J =10.9 Hz, 1H), 3.29 ( m, 1H), 2.31 (s, 3H), 1.27 (d, J = 6.5 Hz, 3H), 1.18 (t, J = 7.0 Hz, 4H). Example 11 (R)-4-(7-(4-( difluoromethyl )-4H-1,2,4- triazol -3- yl )-3-(3- methyl -1H - pyrazole- Synthesis of 5- yl ) isothiazolo [4,5-b] pyridin -5- yl )-3- methyl 𠰌 line Step 1. 4-( difluoromethyl )-4H-1,2,4- triazole

To a solution of 4H-1,2,4-triazole (13.0 mL, 217 mmol) in THF (250 mL) was added NaH (17.4 g, 434 mmol) and (bromodifluoromethyl)phosphonic acid at 0°C Diethyl ester (116 g, 434 mmol). The mixture was stirred at 0 °C for 3 h. TLC showed the reaction was complete. The mixture was quenched with _H2O (10 mL), then diluted with _H2O (250 mL) and extracted with EtOAc (250 mL*3). The combined organic layers were washed with brine (250 mL), dried _{over Na2SO4} , filtered and concentrated. The residue was purified by flash chromatography (silica gel (120 g), 0-10%, MeOH/DCM) to obtain 4-(difluoromethyl)-4H-1,2,4- as a colorless oil. Triazole (400 mg, 3.19 mmol, 1.47%). LC/MS (ESI): m/z 120.1 [M+H] ⁺ . Step 2. (3R)-4-(7-(4-( difluoromethyl )-4H-1,2,4- triazol -3- yl )-3-(3- methyl -1-( tetrazol ) Hydrogen -2H- pyran -2- yl )-1H- pyrazol -5- yl ) isothiazolo [4,5-b] pyridin -5- yl )-3- methyl 𠰌 line

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (200 mg, 0.461 mmol) in DMA (3 mL) was added 4-(difluoromethyl)-4H-1 , 2,4-triazole (329 mg, 2.76 mmol), tetramethylammonium acetate (184 mg, 1.38 mmol) and bis(triphenylphosphine)palladium(II) chloride (72 mg, 0.092 mmol). The reaction was degassed and injected with _N2 several times, and then stirred at 140 °C for 6 h under _N2 . LC-MS showed the reaction was complete. The reaction was poured into water (20 mL) and extracted with EA (20 mL * 3). The combined organic layers were washed with brine (20 mL), dried _{over Na2SO4} , filtered and concentrated. The residue was purified by preparative-TLC (PE:EA=1:2) to obtain (3R)-4-(7-(4-(difluoromethyl)-4H-1,2) as a yellow oil. ,4-triazol-3-yl)-3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)isothiazolo[4, 5-b]pyridin-5-yl)-3-methylpyridine (50 mg, 0.097 mmol, 21.0%). LC/MS (ESI): m/z 516.9 [M+H] ⁺ . Step 3. (R)-4-(7-(4-( difluoromethyl )-4H-1,2,4- triazol -3- yl )-3-(3- methyl -1H- pyrazole) -5- yl ) isothiazolo [4,5-b] pyridin -5- yl )-3- methyl 𠰌 line

To (3R)-4-(7-(4-(difluoromethyl)-4H-1,2,4-triazol-3-yl)-3-(3-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line (50 mg, 0.097 mmol) in To a solution in DCM (1 mL) was added HCl (4 M in dioxane, 2 mL). The reaction was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give (R)-4-(7-(4-(difluoromethyl)- 4H-1,2,4-triazol-3-yl)-3-(3-methyl-1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)- 3-Methylpyroline (10 mg, 0.023 mmol, 23.89%). LC/MS (ESI): m/z 432.8 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.36 (s, 1H), 8.28 (t, J = 58.7 Hz, 1H), 7.37 (s, 1H), 7.13 (s, 1H), 4.49 (d, J = 4.8 Hz, 1H), 4.17 – 4.06 (m, 2H), 3.86 (d, J = 11.4 Hz, 1H), 3.75 (d, J = 2.9 Hz, 1H), 3.65 – 3.59 (m, 2H), 3.22 – 3.19 (m, 1H), 2.32 (s, 3H), 1.27 (d, J = 6.7 Hz, 3H). Example 12 (3R)-3- methyl -4-[3-(3- methyl -1H- pyrazol -5- yl )-7-[5-( trifluoromethyl )-1H-1,2, Synthesis of 3- triazol -1- yl ]-[1,2] thiazolo [4,5-b] pyridin -5- yl ] 𠰌 line Step 1. (3R)-3- methyl -4-{3-[3- methyl -1-( tetrahydropyran -2- yl )-1H- pyrazol -5- yl ]-7-[5 -( Trifluoromethyl )-1H-1,2,3- triazol -1- yl ]-[1,2] thiazolo [4,5-b] pyridin -5- yl } 𠰌 line

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (100 mg, 0.230 mmol) in DMA (1.5 mL) was added 5-(trifluoromethyl)-1H-1 , 2,3-triazole (32 mg, 0.230 mmol) and Cs ₂ CO ₃ (75 mg, 0.230 mmol). The reaction was stirred at 160°C for 5 hours. LC-MS showed the reaction was complete. The mixture was poured into _H2O (10 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine, dried _{over Na2SO4} , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain (3R)-3-methyl-4-{3-[3-methyl as a white solid -1-(Tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-7-[5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl ]-[1,2]thiazolo[4,5-b]pyridin-5-yl}𠰌line (20 mg, 0.037 mmol, 16.2%). LC/MS (ESI) m/z: 535(M+H) ⁺ . Step 2. (3R)-3- Methyl -4-[3-(3- methyl -1H- pyrazol -5- yl )-7-[5-( trifluoromethyl )-1H-1,2 ,3- triazol -1- yl ]-[1,2] thiazolo [4,5-b] pyridin -5- yl ] 𠰌 line

To (3R)-3-methyl-4-{3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-7-[5-( Trifluoromethyl)-1H-1,2,3-triazol-1-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl}𠰌line (20 mg, 0.037 mmol ) to a solution of DCM (2 mL) was added HCl (4 M in dihexane, 2 mL). The reaction was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give (3R)-3-methyl-4-[3-(3-methyl -1H-pyrazol-5-yl)-7-[5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]-[1,2]thiazolo[4,5 -b]pyridin-5-yl]𠰌line (2 mg, 0.004 mmol, 11.9%). LC/MS (ESI) m/z:451(M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 6.95 (s, 2H), 4.33 (d, J = 5.4 Hz, 1H), 4.10 – 4.00 (m, 1H), 3.95 (d, J = 12.2 Hz, 1H ), 3.83 (d, J = 11.3 Hz, 1H), 3.79 – 3.72 (m, 1H), 3.62 (t, J = 10.3 Hz, 2H), 2.32 (s, 3H), 1.29 (d, J = 6.6 Hz ,3H). Example 13 (R)-3- methyl -4-(3-(3- methyl -1H- pyrazol -5- yl )-7-(3-( trifluoromethyl )-1H-1,2, Synthesis of 4- triazol -1- yl ) isothiazolo [4,5-b] pyridin -5- yl ) 𠰌 line Step 1. (3R)-3- methyl- 4-(3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-7 -(3-( Trifluoromethyl )-1H-1,2,4- triazol -1- yl ) isothiazolo [4,5-b] pyridin -5- yl ) 𠰌 line

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (200 mg, 0.461 mmol) in DMA (3 mL) was added 3-(trifluoromethyl)-4H-1 , 2,4-triazole (126 mg, 0.922 mmol) and Cs ₂ CO ₃ (300 mg, 2.30 mmol). The mixture was stirred at 140 °C for 12 h. LC-MS showed the reaction was complete. The reaction mixture was poured into _H2O (20 mL) and extracted with EA (20 mL*3). The combined organic phases were washed with brine (20 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0~100%, ethyl acetate/petroleum ether) to obtain (3R)-3-methyl-4-(3-(3-methyl- 1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-7-(3-(trifluoromethyl)-1H-1,2,4-triazole-1 -yl)isothiazolo[4,5-b]pyridin-5-yl)𠰌line (230 mg, 0.430 mmol, 93.36%). LC/MS (ESI): m/z 535.6 [M+H] ⁺ . Step 2. (R)-3- methyl- 4-(3-(3- methyl -1H- pyrazol -5- yl )-7-(3-( trifluoromethyl )-1H-1,2 ,4- triazol -1- yl ) isothiazolo [4,5-b] pyridin -5- yl ) 𠰌 line

To (3R)-3-methyl-4-(3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-7-( 3-(Trifluoromethyl)-1H-1,2,4-triazol-1-yl)isothiazolo[4,5-b]pyridin-5-yl)𠰌line (230 mg, 0.430 mmol) in To a solution in DCM (3 mL) was added HCl (4 M in dioxane, 3 mL). The mixture was stirred at room temperature for 0.5 h. LC-MS showed the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O containing 0.1% HCOOH) to give (R)-3-methyl-4-(3-(3-methyl -1H-pyrazol-5-yl)-7-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)isothiazolo[4,5-b]pyridine- 5-yl)𠰌line (10 mg, 0.022 mmol). LC/MS (ESI): m/z 451.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 13.11 (d, J = 124.8 Hz, 1H), 10.15 (s, 1H), 7.90 (s, 1H), 7.13 (s, 1H), 4.60 (s, 1H), 4.20 (d, J = 12.0 Hz, 1H), 4.09 (d, J = 8.8 Hz, 1H), 3.88 (d, J = 11.2 Hz, 1H), 3.75 (d, J = 11.7 Hz, 3H), 2.32 ( s, 3H), 1.29 (d, J = 6.6 Hz, 3H). Example 14 (R)-4-((3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridine Synthesis of -7- yl ) imino )-1,4l6- oxathiane 4- oxide Step 1. 4-((3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R)-3- Methyl ( pyridin -7-yl ) isothiazolo [4,5-b] pyridin -7- yl ) imino )-1,4l6- oxathiane 4- oxide

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (100 mg, 0.230 mmol) in dioxane (3 mL) was added (dicyclopropylimino-λ ^6-Sulfanyl)one (47 mg, 0.325 mmol), Pb ₂ (dba) ₃ (21 mg, 0.023 mmol), Xantphos (27 mg, 0.046 mmol), and Cs ₂ CO ₃ (250 mg, 0.767 mmol) . The reaction was stirred at 100°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction solution was filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100%, EA/PE) to obtain 4-((3-(3-methyl-1-(tetrahydro-2H-piper)) as a yellow solid. Pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)imine (85 mg, 0.160 mmol, 69.38%). LC/MS (ESI): m/z 533.2 (M+H) ⁺ . Step 2. (R)-4-((3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] Pyridin -7- yl ) imino )-1,4l6- oxathiane 4- oxide

To 4-((3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl 𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)imino)-1,4l6-oxathiane 4-oxide (50 mg, 0.094 mmol) in DCM (3 To the solution in mL) was added HCl (4 M in dihexane, 3 mL). The mixture was stirred at room temperature for 0.5 h. LC-MS showed the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give 4-{[3-(3-methyl-1H-pyrazole-5- base)-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl]imino}-1,4λ ^6-Oxathiane-4-one (15 mg, 0.033 mmol, 22.27%). LCMS (ESI): m/z 448.8 (M+H) +. ¹ H NMR (400 MHz, DMSO-d6) δ 7.09 (s, 1H), 6.56 (s, 1H), 4.36 (d, J = 4.8 Hz, 1H), 4.17 (dd, J = 12.6, 2.6 Hz, 2H ), 4.11-3.95 (m, 2H), 3.83-3.62 (m, 6H), 3.55 (td, J = 11.8, 2.8 Hz, 3H), 3.27-3.00 (m, 2H), 1.21 (d, J = 6.7 Hz, 3H). Example 15 (R) -Dimethyl ((3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] Synthesis of pyridin -7- yl ) imino )-l6- sulfanone Step 1. Dimethyl ((3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R)-3 -Methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridin -7- yl ) imino ) -l6- sulfanone

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (2 g, 4.61 mmol) in dioxane (25 mL) was added iminodimethyl-λ^6 - Thianone (0.52 g, 5.53 mmol), CS ₂ CO ₃ (4.50 g, 13.8 mmol), Pd ₂ (dba) ₃ (0.42 g, 0.461 mmol) and Xantphos (0.53 g, 0.922 mmol). The reaction was stirred at 100 °C for 16 h under nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction was poured into _H2O and extracted with EA (3*50 mL). The organic phase was washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain dimethyl ((3-(3-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl )imino)-16-sulfanone (1.9 g, 3.87 mmol, 84%). LC/MS (ESI): m/z 491(M+H) ⁺ . Step 2. (R) -Dimethyl ((3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b ] Pyridin -7- yl ) imino )-l6- sulfanone

To dimethyl((3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl To a solution of isothiazolo[4,5-b]pyridin-7-yl)imino)-16-sulfanone (1.9 g, 3.87 mmol) in DCM (20 mL) was added HCl (4 M in dihexane, 20 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction was concentrated in vacuo to give the crude product, which was purified by preparative-HPLC (C ₁₈ , 10-95%, MeCN/H ₂ O with 0.1% CHOOH) to give (R)-dimethyl (( 3-(3-methyl-1H-pyrazol-5-yl)-5-(3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)imino)- l6-Sulfanone (1.07 g, 2.63 mmol, 68%). LC/MS (ESI): m/z 407 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.06 (s, 1H), 6.54 (s, 1H), 4.36 (d, J = 4.7 Hz, 1H), 4.02 (d, J = 8.1 Hz, 1H), 3.95 (d, J = 11.3 Hz, 1H), 3.80 (d, J = 11.3 Hz, 1H), 3.75 – 3.68 (m, 1H), 3.56 (dd, J = 13.0, 10.4 Hz, 1H), 3.49 (d , J = 1.9 Hz, 6H), 3.22 (dd, J = 12.5, 8.8 Hz, 1H), 2.30 (s, 3H), 1.22 (d, J = 6.6 Hz, 3H). Example 16 (4-[3-(3- methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl ]-[1,2] thiazolo Synthesis of [4,5-b] pyridin -7- yl ] tetrahydropyran -4- ol Step 1. (3R)-4-[7-(3,6- dihydro -2H- pyran -4- yl )-3-[3- methyl -1-( tetrahydropyran -2- yl ) -1H- pyrazol -5- yl ]-[1,2] thiazolo [4,5-b] pyridin -5- yl ]-3- methyl 𠰌 line

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (100 mg, 0.230 mmol) in dioxane (5 mL) and H ₂ O (1 mL) was added 2- (3,6-Dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (73 mg, 0.346 mmol) , K ₂ CO ₃ (96 mg, 0.691 mmol) and Pd(PPh ₃ ) ₄ (53 mg, 0.046 mmol). The reaction was stirred at 100 °C for 16 h under _N2 . LC-MS showed the reaction was complete. _H2O (10 mL) was added to the mixture, and the reaction was extracted with EtOAc (3*20 mL). _The combined organic phases were washed with brine, dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain (3R)-4-[7-(3,6-dihydro- 2H-pyran-4-yl)-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4 ,5-b]pyridin-5-yl]-3-methyl𠰌line (80 mg, 0.166 mmol, 72.1%). LC/MS (ESI): m/z 483.2 [M+H] ⁺ . Step 2. 4-{3-[3- methyl -1-( tetrahydropyran -2- yl )-1H- pyrazol -5- yl ]-5 -[(3R)-3- methyl 𠰌 line -4- yl ]-[1,2] thiazolo [4,5-b] pyridin - 7- yl } tetrahydropyran -4- ol

To (3R)-4-[7-(3,6-dihydro-2H-piran-4-yl)-3-[3-methyl-1-(tetrahydropyran-2-yl) at 0°C )-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl]-3-methyl𠰌line (100 mg, 0.208 mmol) in IPA (5 mL) and DCM (1 mL) were added phenylsilane (0.052 mL, 0.415 mmol) and Mn(TMHD) ₃ (13 mg, 0.021 mmol). The mixture was stirred under _O2 at room temperature for 3 h. LC-MS showed the reaction was complete. The mixture was poured into _H2O and extracted with EtOAc (3*20 mL), washed with brine, dried over _Na2SO4 , filtered and concentrated in vacuo _. The residue was purified by preparative-TLC (PE:EA=1:1) to obtain 4-{3-[3-methyl-1-(tetrahydropyran-2-yl)-1H- as a white solid Pyrazol-5-yl]-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl}tetrahydropipaniline Pran-4-ol (30 mg, 0.060 mmol, 28.8%). LC/MS (ESI): m/z 500.1 [M+H] ⁺ . Step 3. 4-[3-(3- Methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl ]-[1,2] thiazolo [4,5-b] pyridin -7- yl ] tetrahydropyran -4- ol

To 4-{3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌line-4 To a solution of -[1,2]thiazolo[4,5-b]pyridin-7-yl}tetrahydropyran-4-ol (30 mg, 0.060 mmol) in DCM (3 mL) was added HCl (4 M in dihexane, 1 mL). The mixture was stirred at room temperature for 1 hour. LC-MS showed the reaction was complete. The reaction mixture was concentrated. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give 4-[3-(3-methyl-1H-pyrazol-5-yl) )-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl]tetrahydropyran-4-ol ( 5.8 mg, 0.013 mmol, 22.1%). LC/MS (ESI): m/z 416.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.10 (s, 2H), 6.18 (s, 1H), 4.58 (d, J = 5.2 Hz, 1H), 4.14 (d, J = 11.9 Hz, 1H), 4.07 – 3.94 (m, 1H), 3.88 – 3.76 (m, 5H), 3.71 (dd, J = 11.2, 2.7 Hz, 1H), 3.62 – 3.51 (m, 1H), 3.24 – 3.02 (m, 2H), 2.29 (s, 3H), 2.21 – 2.07 (m, 2H), 1.66 (d, J = 13.2 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H). Example 17 (R) -dicyclopropyl ((3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b ] Synthesis of pyridin -7- yl ) imino )-l6- sulfanone Step 1. Sulfenyldicyclopropane

To a solution of thionite chloride (0.511 mL, 7.044 mmol) in THF was added _C3H5MgBr (0.5 M in THF, _42.3 mL, 21.1 mmol) at 0°C. The reaction was stirred at 0°C for 1 hour. LC-MS showed the reaction was complete. The reaction mixture was diluted with EA (20 mL*3), washed with saturated NH ₄ Cl and brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, MeOH/DCM) to obtain sulfenyldicyclopropane (400 mg, 43.61%) as a brown liquid. LC/MS (ESI): m/z 130 (M+H) ⁺ . Step 2. N-( dicyclopropyl ( side oxy )-16- sulfanylidene )-2,2,2- trifluoroacetamide

To a solution of sulfenyldicyclopropane (350 mg, 2.69 mmol) in DCM (20 mL) was added Rh(OAc) ₂ (24 mg, 0.054 mmol), MgO (542 mg, 13.4 mmol), trifluoro Acetamide (608 mg, 5.38 mmol) and PhI(OAc) ₂ (1.3 g, 4.032 mmol). The reaction was stirred at room temperature under nitrogen atmosphere for 15 h. LC-MS showed the reaction was complete. The reaction mixture was filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~10%, MeOH/DCM) to obtain N-(dicyclopropyl(side oxy)-16-sulfanylidene)- as a yellow solid 2,2,2-Trifluoroacetamide (179 mg, 0.742 mmol, 27.61%). LC/MS (ESI): m/z 241 (M+H) ⁺ . Step 3. Dicyclopropyl ( imino )-16- sulfanone

To a solution of N-(dicyclopropyl(side oxy)-16-sulfanylidene)-2,2,2-trifluoroacetamide (174 mg, 0.721 mmol) in MeOH (2 mL) K ₂ CO ₃ (179 mg, 1.29 mmol) was added. The mixture was stirred at room temperature for 2 h. LC-MS showed the reaction was complete. The reaction mixture was filtered and concentrated. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give dicyclopropyl(imino)-16-sulfanone as a yellow liquid (47 mg, 0.324 mmol, 44.87%). LC/MS (ESI): m/z 145 [M+H] ⁺ . Step 4. Dicyclopropyl ((3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R)- 3- Methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridin -7- yl ) imino )-l6- sulfanone

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (94 mg, 0.217 mmol) in dioxane (3 mL) was added dicyclopropyl(imino)- l6-Thionone (47 mg, 0.325 mmol), Pb ₂ (dba) ₃ (21 mg, 0.023 mmol), Xantphos (26 mg, 0.046 mmol), and Cs ₂ CO ₃ (250 mg, 0.767 mmol). The reaction was stirred at 100°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100%, EA/PE) to obtain dicyclopropyl ((3-(3-methyl-1-(tetrahydro-2H)) as a yellow solid -pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl) Imino)-16-sulfanone (84 mg, 0.155 mmol, 71.45%). LC/MS (ESI): m/z 542 (M+H) ⁺ . Step 5. (R) -Dicyclopropyl ((3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5- b] Pyridin -7- yl ) imino )-l6- thionone

To dicyclopropyl((3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3- To a solution of methyl(trifluoroyl)isothiazolo[4,5-b]pyridin-7-yl)imino)-16-sulfanone (84 mg, 0.155 mmol) in DCM (1 mL) was added HCl (4 M in dihexane, 2 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give (R)-dicyclopropyl ((3-(3-methyl-1H -pyrazol-5-yl)-5-(3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)imino)-l6-sulfanone (30 mg, 42.3%). LC/MS (ESI): m/z 458 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ: 13.11 (s, 1H), 7.09 (s, 1H), 6.55 (s, 1H), 4.28 (s, 1H), 4.02 (d, J = 8.4 Hz, 1H), 3.92 (s, 1H), 3.79 (d, J = 11.1 Hz, 1H), 3.70 (d, J = 8.7 Hz, 1H), 3.55 (t, J = 10.3 Hz, 1H), 3.17 (t, J = 11.0 Hz, 1H), 3.06 – 2.94 (m, 2H), 2.31 (d, J = 17.9 Hz, 3H), 1.39 – 1.21 (m, 5H), 1.19 (d, J = 6.5 Hz, 3H), 1.18 – 1.10 (m, 3H). Example 18 (3R)-4-[7-(1- cyclopropyl -1H-1,2,3- triazol -5- yl )-3-(3- methyl -1H- pyrazol -5- yl) Synthesis of )-[1,2] thiazolo [4,5-b] pyridin -5- yl ]-3- methyl 𠰌 line Step 1. (3R)-3- methyl -4-{3-[3- methyl -1-( tetrahydropyran -2- yl )-1H- pyrazol -5- yl ]-7-[2 -( Tetrahydropyran -2- yl )-2H-1,2,3- triazol -4- yl ]-[1,2] thiazolo [4,5-b] pyridin -5- yl } 𠰌 line

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a mixture of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (100 mg, 0.230 mmol) in dioxane (5 mL) and H ₂ O (1 mL) was added 2- (Tetrahydropyran-2-yl)-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-1,2,3-triazole (77 mg , 0.277 mmol), K ₂ CO ₃ (95 mg, 0.691 mmol) and tetrakis(triphenylphosphine)palladium (27 mg, 0.023 mmol). The reaction was stirred at 100 °C for 15 h under _N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with EtOAc (100 mL), then washed with water and brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 1:1) to obtain (3R)-3-methyl-4-{3-[3-methyl-1-(tetrahydrofuran) as a yellow solid. Hydropyran-2-yl)-1H-pyrazol-5-yl]-7-[2-(tetrahydropyran-2-yl)-2H-1,2,3-triazol-4-yl] -[1,2]thiazolo[4,5-b]pyridin-5-yl}𠰌line (40 mg, 29.95%). LC/MS (ESI): m/z 552.0 [M+H] ⁺ . Step 2. (3R)-3- methyl -4-[3-(3- methyl -1H- pyrazol -5- yl )-7-(2H-1,2,3- triazol -4- yl )-[1,2] thiazolo [4,5-b] pyridin -5- yl ] 𠰌 line

To (3R)-3-methyl-4-{3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-7- at room temperature [2-(tetrahydropyran-2-yl)-2H-1,2,3-triazol-4-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl} To a solution of oxoline (50 mg, 0.091 mmol) in DCM (3 mL) was added HCl (4 M in dioxane, 1 mL). The mixture was stirred at room temperature for 1 hour. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give (3R)-3-methyl-4-[3-(3-methyl -1H-pyrazol-5-yl)-7-(2H-1,2,3-triazol-4-yl)[1,2]thiazolo[4,5-b]pyridin-5-yl]𠰌 Phenoline (10 mg, 0.026 mmol, 28.8%). LC/MS (ESI): m/z 383.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 7.77 (d, J = 15.6 Hz, 1H), 7.17 (d, J = 13.4 Hz, 1H), 4.62 (d, J = 5.8 Hz, 1H), 4.19 (d, J = 10.9 Hz, 1H), 4.10 – 4.05 (m, 1H), 3.85 (s, 1H), 3.75 (s, 1H), 3.71 (s, 1H), 3.30 (d , J = 3.6 Hz, 1H), 2.32 (s, 3H), 1.28 (t, J = 9.2 Hz, 3H). Example 19 (R)-(1-(3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridine Synthesis of -7- yl )-1H-1,2,4- triazol -3- yl ) methanol Step 1. 1-(3-(3- methyl- 1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R)-3- methyl 1H - 1,2,4 - Triazole - 3 - carboxylic acid _ _ _

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a mixture of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (100 mg, 0.230 mmol) and Cs ₂ CO ₃ (224 mg, 0.690 mmol) in DMA (1 mL) was added 1H-1,2,4-Triazole-5-carboxylic acid methyl ester (59 mg, 0.461 mmol). The reaction was stirred at 140 °C for 2 h. LC-MS showed the reaction was complete. The reaction mixture was adjusted to pH=7 with HCl (1 M) and extracted with EA (20 mL*5). The combined organic phases were washed with brine (20 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated to dryness. The residue was purified by preparative-TLC (DCM:MeOH = 10:1, V/V) to obtain 1-(3-(3-methyl-1-(tetrahydro-2H-piran-) as a yellow solid 2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)-1H-1 ,2,4-triazole-3-carboxylic acid (70 mg, 0.137 mmol, 59.50%). LC/MS (ESI): m/z 511.6 (M+H) ⁺ . Step 2. (1-(3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R)-3- Methyl (triazolinyl)isothiazolo [ 4,5 - b] pyridin -7- yl )-1H-1,2,4- triazol -3- yl ) methanol

To 1-(3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3 at -78°C -Methyl(triazole)isothiazolo[4,5-b]pyridin-7-yl)-1H-1,2,4-triazole-3-carboxylic acid (60 mg, 0.118 mmol) in THF (2 mL ) was added LiAlH ₄ (10 mg, 0.264 mmol). The mixture was stirred at -78 °C for 1 h. LC-MS showed the reaction was complete. _The reaction ^mixture was quenched with _Na2SO4.10H2O , _filtered and concentrated. The residue was purified by preparative-TLC (DCM:MeOH = 10:1, V/V) to obtain (1-(3-(3-methyl-1-(tetrahydro-2H-pyran)) as a yellow solid -2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)-1H- 1,2,4-triazol-3-yl)methanol (18 mg, 0.036 mmol, 30.84%). LC/MS (ESI): m/z 497.6 [M+H] ⁺ . Step 3. (R)-(1-(3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] Pyridin -7- yl )-1H-1,2,4- triazol -3- yl ) methanol

To (1-(3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl 𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)-1H-1,2,4-triazol-3-yl)methanol (16 mg, 0.032 mmol) in DCM (1 mL) To the solution was added HCl (4 M in dioxane, 1.5 mL). The mixture was stirred at room temperature for 0.5 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give (R)-(1-(3-(3-methyl-1H-pyra) Azol-5-yl)-5-(3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)-1H-1,2,4-triazol-3-yl) Methanol (5 mg, 0.012 mmol, 37.62%). LC/MS (ESI): m/z: 413 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 13.19 (s, 1H), 9.81 (s, 1H), 7.77 (s, 1H), 7.12 (s, 1H), 5.57 (s, 1H), 4.61 (d, J = 12.4 Hz, 3H), 4.19 (d, J = 12.7 Hz, 1H), 4.08 (d, J = 8.5 Hz, 1H), 3.86 (d, J = 11.2 Hz, 1H), 3.75 (d, J = 8.9 Hz, 1H), 3.60 (t, J = 10.5 Hz, 1H), 3.29 – 3.26 (m, 1H), 2.31 (s, 3H), 1.28 (d, J = 6.6 Hz, 3H). Example 20 1-{[3-(3- methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl ]-[1,2] thiazolo Synthesis of [4,5-b] pyridin -7- yl ] imino }-1λ^6- thiolan -1- one Step 1. 1-({3-[3- methyl -1-( tetrahydropyran -2- yl )-1H- pyrazol -5- yl ]-5-[(3R)-3- methyl 𠰌 Phin -4- yl ]-[1,2] thiazolo [4,5-b] pyridin -7- yl } imino )-1λ^6- thiolan -1- one

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (50 mg, 0.115 mmol) in dioxane (5 mL) was added 1-imino-1λ^6- Thiolan-1-one (17 mg, 0.138 mmol), Xantphos (27 mg, 0.046 mmol), Cs ₂ CO ₃ (113 mg, 0.346 mmol) and Pd ₂ (dba) ₃ (21 mg, 0.023 mmol) ). The reaction was stirred at 100 °C for 15 h under _N2 atmosphere. TLC showed the reaction was complete. _H2O (10 mL) was added to the mixture and extracted with EtOAc (3*20 mL). The organic layer was washed with brine, dried _{over Na2SO4} , filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0-100%, EA/Pe) to obtain 1-({3-[3-methyl-1-(tetrahydropyran-) as a yellow oil) 2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridine- 7-yl}imino)-1λ^6-thiolan-1-one (40 mg, 64%). LC/MS (ESI): m/z 517.2 [M+H] ⁺ . Step 2. 1-{[3-(3- methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl ]-[1,2] thiazole And [4,5-b] pyridin -7- yl ] imino }-1λ^6- thiolan -1- one

To 1-({3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌line- 4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl}imino)-1λ^6-thiolan-1-one (40 mg, 0.077 mmol) To a solution in DCM (4 mL) was added HCl (4 M in dioxane, 1 mL). The mixture was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give 1-{[3-(3-methyl-1H-pyrazole-5- base)-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl]imino}-1λ^6 -Thiolan-1-one (10 mg, 29.86%). LC/MS (ESI): m/z 433.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 12.98 (NH, 1H), 7.10 (s, 1H), 6.44 (s, 1H), 4.37 (d, J = 5.2 Hz, 1H), 4.00 (dd, J = 20.5, 8.8 Hz, 2H), 3.84 – 3.68 (m, 2H), 3.64 – 3.50 (m, 5H), 3.19 (td, J = 12.4, 3.2 Hz, 1H), 2.58 – 2.43 (m, 2H), 2.20 – 2.10 (m, 2H), 1.21 (d, J = 6.6 Hz, 3H), 1.21 (d, J = 6.6 Hz, 3H). Example 21 (R)-1-((3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridine Synthesis of -7- yl ) imino ) hexahydro -1l6- thiopyran 1- oxide Step 1. 1-((3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R)-3- Methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridin -7- yl ) imino ) hexahydro -1l6- thiopyran 1- oxide

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (100 mg, 0.230 mmol) in dioxane (3 mL) was added (dicyclopropylimino-λ ^6-Sulfanyl)one (47 mg, 0.325 mmol), Pd ₂₍ dba) ₃ (21 mg, 0.023 mmol), Xantphos (27 mg, 0.046 mmol), and Cs ₂ CO ₃ (250 mg, 0.767 mmol) . The reaction was stirred at 100°C overnight under nitrogen atmosphere. TLC showed the reaction was complete. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain 1-((3-(3-methyl-1-(tetrahydro-2H)) as a yellow solid -pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl) Imino)hexahydro-1l6-thiopyran 1-oxide (80 mg, 65.41%). LC/MS (ESI): m/z 531.2 [M+H] ⁺ . Step 2. (R)-1-((3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] Pyridin -7- yl ) imino ) hexahydro -1l6- thiopyran 1- oxide

To 1-((3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl 𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)imino)hexahydro-1l6-thiopyran 1-oxide (80 mg, 0.151 mmol) in DCM (1 mL) Add HCl/dioxane (2 mL) to the solution. The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give 1-{[3-(3-methyl-1H-pyrazole-5- base)-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl]imino}-1λ^6 -Thietan-1-one (30 mg, 44.56%). LC/MS (ESI): m/z 447 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.14 (s, 1H), 6.60 (s, 1H), 4.42 (s, 1H), 4.07 (d, J = 8.3 Hz, 1H), 4.01 (d, J = 11.8 Hz, 1H), 3.86 (d, J = 11.0 Hz, 1H), 3.71 (dd, J = 38.8, 16.0 Hz, 5H), 3.25 (s, 2H), 2.36 (s, 3H), 2.01 (d , J = 38.4 Hz, 4H), 1.72-1.68 (m, 2H), 1.28 (m, 3H). Example 22 (R)-4-(7-(1-( difluoromethyl ) cyclopropyl )-3-(3- methyl -1H- pyrazol -5- yl ) isothiazolo [4,5- b] Synthesis of pyridin -5- yl )-3- methyl 𠰌 line Step 1. (3R)-4-(7-(1-( difluoromethyl ) cyclopropyl )-3-(3- methyl- 1-( tetrahydro -2H- piran -2- yl )- 1H- Pyrazol -5- yl ) isothiazolo [4,5-b] pyridin -5- yl )-3- methyl 𠰌 line

To (R)-4-(3-chloro-7-(1-(difluoromethyl)cyclopropyl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line (50 mg, 0.139 mmol), (3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)boronic acid (58 mg, 0.278 mmol) and K ₂ To a mixture of CO ₃ (96 mg, 0.695 mmol) in dihexane (5 mL) and water (1 mL) was added Pd(PPh ₃ ) ₄ (16 mg, 0.014 mmol). The mixture was degassed and injected with _N2 several times, and then stirred at 80 °C for 16 h under _N2 . LC-MS showed the reaction was complete. The reaction mixture was poured into _H2O (30 mL) and extracted with EA (30 mL*3). The combined organic phases were washed with brine (30 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel, 0-100%, EA/PE) to obtain (3R)-4-(7-(1-(difluoromethyl)cyclopropyl)- as a yellow solid 3-(3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)- 3-Methylpyroline (40 mg, 0.082 mmol, 58.80%). LC/MS (ESI): m/z 490 [M+H] ⁺ . Step 2. (R)-4-(7-(1-( difluoromethyl ) cyclopropyl )-3-(3- methyl -1H- pyrazol -5- yl ) isothiazolo [4,5 -b] pyridin -5- yl )-3- methyl 𠰌 line

To (3R)-4-(7-(1-(difluoromethyl)cyclopropyl)-3-(3-methyl-1-(tetrahydro-2H-piran-2-yl)-1H- To a solution of pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line (40 mg, 0.082 mmol) in MeOH (2 mL) was added TsOH ( 14 mg, 0.082 mmol). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was poured into saturated NaHCO ₃ and extracted with EA (30 mL * 3). The combined organic phases were washed with brine, dried _over anhydrous _Na2SO4 , filtered and concentrated to dryness. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give (R)-4-(7-(1-(difluoromethyl)) ring Propyl)-3-(3-methyl-1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line (12 mg, 0.029 mmol ,72.07%). LC/MS (ESI): m/z: 406 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 7.23 (s, 1H), 7.11 (s, 1H), 5.98 (s, 1H), 4.51 (s, 1H), 4.17 – 3.96 (m, 2H), 3.81 (d , J = 11.6 Hz, 1H), 3.71 (d, J = 8.9 Hz, 1H), 3.56 (s, 1H), 3.17 (d, J = 5.3 Hz, 1H), 2.31 (d, J = 18.4 Hz, 3H ), 1.31 (s, 2H), 1.23 (d, J = 6.9 Hz, 5H). Example 23 (R)-1-((3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridine Synthesis of -7- yl ) imino )-1l6- thietane 1- oxide Step 1. 1-((3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R)-3- Methyl ( pyridin -7-yl ) isothiazolo [4,5-b] pyridin -7- yl ) imino )-1l6- thietane 1- oxide

To (3R)-4-{7-chloro-3-[1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5- b] To a solution of pyridin-5-yl}-3-methyl𠰌line (100 mg, 0.238 mmol) in dioxane (4 mL) was added 1-imino-1λ^6-thietane -1-one (30 mg, 0.286 mmol), Pd ₂₍ dba) ₃ (22 mg, 0.024 mmol), Xantphos (28 mg, 0.048 mmol) and _CS2 CO ₃ (233 mg, 0.714 mmol). The reaction was stirred at 100°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction was filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain 1-((3-(3-methyl-1-(tetrahydro-2H)) as a yellow solid -pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl) Imino)-1l6-thietane 1-oxide (80 mg, 0.160 mmol, 67.13%). LC/MS (ESI): m/z 501 (M+H) ⁺ . Step 2. (R)-1-((3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] Pyridin -7- yl ) imino )-1l6- thietane 1- oxide

To 1-({3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌line- 4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl}imino)-1λ^6-thietane-1-one (20 mg, 0.040 mmol) To a solution in MeOH (2 mL) was added TsOH (2 mg, 0.040 mmol). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give (R)-1-((3-(3-methyl-1H-pyra) Azol-5-yl)-5-(3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)imino)-1l6-thietane 1-oxide (12 mg, 0.029 mmol, 72.07%). LC/MS (ESI): m/z 418 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.10 (s, 1H), 6.38 (s, 1H), 4.50 (dd, J = 15.3, 6.9 Hz, 2H), 4.41 (dd, J = 9.8, 4.4 Hz , 2H), 4.36 (s, 1H), 3.82 – 3.67 (m, 2H), 3.55 (dd, J = 11.7, 8.8 Hz, 2H), 3.24 – 3.15 (m, 2H), 2.40 (dd, J = 10.6 , 4.9 Hz, 2H), 2.29 (s, 3H), 1.20 (d, J = 6.7 Hz, 3H). Example 24 ( Ethyl ( methyl )((3-(3- methyl -1H- pyrazol -5- yl )-5-((R)-3- methyl 𠰌 linyl ) isothiazolo [4, Synthesis of 5-b] pyridin -7- yl ) imino )-l6- sulfanone Step 1. Ethyl ( methyl )((3-(3- methyl- 1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R )-3- Methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridin -7- yl ) imino )-l6- sulfanone

To (3R)-4-{7-chloro-3-[1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5- b] To a solution of pyridin-5-yl}-3-methyl𠰌line (150 mg, 0.357 mmol) in dioxane (4 mL) was added ethyl(imino)methyl-λ^6-sulfide alkanone (57 mg, 0.536 mmol), Pd ₂ (dba) ₃ (33 mg, 0.036 mmol), Xantphos (41 mg, 0.071 mmol) and Cs ₂ CO ₃ (349 mg, 1.07 mmol). The reaction was stirred at 100°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction was filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain ethyl(methyl)((3-(3-methyl-1-()) as a yellow solid Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridine- 7-(yl)imino)-l6-thionone (120 mg, 66.83%). LC/MS (ESI) m/z: 503(M+H) ⁺ . Step 2. Ethyl ( methyl )((3-(3- methyl -1H- pyrazol -5- yl )-5-((R)-3- methyl 𠰌 linyl ) isothiazolo [4, 5-b] pyridin -7- yl ) imino )-l6- sulfanone

To ethyl(methyl)((3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)- A solution of 3-methyl(trimethyl)isothiazolo[4,5-b]pyridin-7-yl)imino)-16-sulfanone (100 mg, 0.198 mmol) in DCM (1 mL) Add HCl/dioxane (2 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by SFC to obtain 24a (16 mg, 19.16%) and 24b (12 mg, 14.37%). LC/MS (ESI) m/z: 420 [M+H] ⁺ .

24a :

¹ H NMR (400 MHz, DMSO-d6) δ 7.08 (s, 1H), 6.56 (s, 1H), 4.36 (d, J = 6.8 Hz, 1H), 4.07 – 3.90 (m, 2H), 3.80 (d , J = 11.3 Hz, 1H), 3.71 (dd, J = 11.3, 2.7 Hz, 1H), 3.62 (d, J = 7.3 Hz, 2H), 3.39 (s, 3H), 3.19 (td, J = 12.5, 3.6 Hz, 2H), 2.29 (s, 3H), 1.35 (t, J = 7.3 Hz, 3H), 1.20 (d, J = 6.7 Hz, 3H).

24b :

¹ H NMR (400 MHz, DMSO-d6) δ 7.08 (s, 1H), 6.56 (s, 1H), 4.35 (d, J = 6.5 Hz, 1H), 4.08 – 3.91 (m, 2H), 3.80 (d , J = 11.3 Hz, 1H), 3.71 (dd, J = 11.3, 2.7 Hz, 1H), 3.62 (d, J = 7.4 Hz, 2H), 3.40 (s, 3H), 3.19 (td, J = 12.6, 3.6 Hz, 2H), 2.29 (s, 3H), 1.35 (t, J = 7.3 Hz, 3H), 1.20 (d, J = 6.6 Hz, 3H). Example 25 (R)-4-(7-(1-( fluoromethyl ) cyclopropyl )-3-(3- methyl -1H- pyrazol -5- yl ) isothiazolo [4,5-b ] Synthesis of pyridin -5- yl )-3- methyl 𠰌 line Step 1. (3R)-4-(7-(1-( fluoromethyl ) cyclopropyl )-3-(3- methyl- 1-( tetrahydro -2H- piran -2- yl )-1H -Pyrazol -5- yl ) isothiazolo [4,5-b] pyridin -5- yl ) -3- methyl 𠰌 line

To (R)-4-(3-chloro-7-(1-(fluoromethyl)cyclopropyl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line( 30 mg, 0.088 mmol), (3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)boronic acid (37 mg, 0.176 mmol), and K ₂ CO To a mixture of ₃ (61 mg, 0.439 mmol) in dihexane (5 mL) and water (1 mL) was added Pd(PPh ₃ ) ₄ (10 mg, 0.009 mmol). The mixture was degassed and injected with _N2 several times, and then stirred at 80 °C for 16 h under _N2 . LC-MS showed the reaction was complete. The reaction mixture was poured into _H2O (30 mL) and extracted with EA (30 mL*3). The combined organic phases were washed with brine (30 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated to dryness. The residue was purified by preparative-TLC (PE:EA=1:1) to obtain (3R)-4-(7-(1-(fluoromethyl)cyclopropyl)-3-(3) as a yellow solid -Methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl 𠰌line (20 mg, 0.042 mmol, 48.32%). LC/MS (ESI): m/z 472 [M+H] ⁺ . Step 2. (R)-4-(7-(1-( fluoromethyl ) cyclopropyl )-3-(3- methyl -1H- pyrazol -5- yl ) isothiazolo [4,5- b] Pyridin -5- yl )-3- methyl 𠰌 line

To (3R)-4-(7-(1-(fluoromethyl)cyclopropyl)-3-(3-methyl-1-(tetrahydro-2H-piran-2-yl)-1H-pyra To a solution of oxazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyloxoline (20 mg, 0.042 mmol) in MeOH (2 mL) was added TsOH (7 mg, 0.042 mmol). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was poured into saturated NaHCO ₃ and extracted with EA (30 mL * 3). The combined organic phases were washed with brine (30 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated to dryness. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give (R)-4-(7-(1-(fluoromethyl)cyclopropane) yl)-3-(3-methyl-1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line (2 mg, 0.005 mmol, 12.17%). LC/MS (ESI): m/z 387 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 13.91 – 12.11 (m, 1H), 7.23 (s, 1H), 7.12 (s, 1H), 4.63 (s, 1H), 4.17 (d, J = 13.0 Hz, 1H ), 4.04 (d, J = 10.2 Hz, 1H), 3.81 (s, 1H), 3.73 (d, J = 10.1 Hz, 1H), 3.58 (s, 1H), 3.24 (s, 1H), 2.78 – 2.63 (m, 4H), 2.31 (s, 3H), 2.12 (s, 1H), 1.88 (d, J = 9.0 Hz, 1H), 1.24 (d, J = 6.1 Hz, 3H). Example 26 Cyclopropyl ( methyl )((3-(3- methyl -1H- pyrazol -5- yl )-5-((R)-3- methyl 𠰌 linyl ) isothiazolo [4, Synthesis of 5-b] pyridin -7- yl ) imino )-l6- sulfanone Step 1. ( Methylsulfenyl ) cyclopropane

To a solution of 1-bromo-4-methanesulfenylbenzene (1.8 mL, 13.7 mmol) in THF (30 mL) was slowly added C ₃ H ₅ MgBr (0.5 M in THF, 41 mL, 20.5 mmol). The mixture was stirred at 0 °C for 1.5 h. LC-MS showed the reaction was complete. The mixture was poured into saturated NH ₄ Cl and extracted with EA (20 mL × 3). The combined organic layers were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~50%, ethyl acetate/petroleum ether) to obtain (methylsulfinyl)cyclopropane (900 mg, 8.64 mmol, 63.10) as a yellow oil. %). LC/MS (ESI): m/z 105 [M+H] ⁺ . Step 2. Cyclopropyl ( imino ) methyl -λ^6- sulfanone

To (methylsulfinyl)cyclopropane (1 g, 9.600 mmol), MgO (1.55 g, 38.4 mmol), PhI(OAc) ₂ (4.64 g, 14.4 mmol) and Rh(OAc) ₂ (4.23 g, To a solution of 9.60 mmol) in DCM (30 mL) was added NH ₂ COONH ₄ (1.12 g, 14.4 mmol). The reaction mixture was stirred at 25 °C for 16 h. LC-MS showed the reaction was complete. The mixture was filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0~10%, MeOH/DCM) to obtain cyclopropyl(imino)methyl-λ^6-sulfanone (300 mg) as a colorless oil. , 2.52 mmol, 26.22%). LC/MS (ESI): m/z 120 [M+H] ⁺ . Step 3. Cyclopropyl ( methyl )((3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-(( R)-3- Methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridin -7- yl ) imino )-l6- sulfanone

To (3R)-4-{7-chloro-3-[1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5- b] To a solution of pyridin-5-yl}-3-methyl𠰌line (150 mg, 0.357 mmol) in dioxane (4 mL) was added cyclopropyl(imino)methyl-λ^6- Thianone (64 mg, 0.535 mmol), Pd ₂ (dba) ₃ (33 mg, 0.036 mmol), Xantphos (41 mg, 0.071 mmol), and _CS2 CO ₃ (349 mg, 1.07 mmol). The reaction was stirred at 100°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction was filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0~100%, ethyl acetate/petroleum ether) to obtain cyclopropyl(methyl)((3-(3-methyl-1-()) as a yellow solid Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridine- 7-(yl)imino)-16-thianone (60 mg, 0.117 mmol, 32.65%). LC/MS (ESI): m/z 515(M+H) ⁺ . Step 4. Cyclopropyl ( methyl )((3-(3- methyl -1H- pyrazol -5- yl )-5-((R)-3- methyl 𠰌 linyl ) isothiazolo [4 ,5-b] pyridin -7- yl ) imino )-l6- sulfanone

To cyclopropyl(methyl)((3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-((R) -3-Methylpyridin-7-yl)isothiazolo[4,5-b]pyridin-7-yl)imino)-16-sulfanone (80 mg, 0.155 mmol) in DCM (1 mL) HCl/dioxane (2 mL) was added to the solution. The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by SFC to obtain 26a (10 mg, 0.023 mmol, 14.93%) and 26b (5 mg, 0.012 mmol, 7.47%). LC/MS (ESI): m/z 420 [M+H] ⁺ .

26a :

¹ HNMR (400 MHz, DMSO-d6) δ 13.10 (s, 1H), 7.09 (s, 1H), 6.55 (s, 1H), 4.34 (d, J = 5.4 Hz, 1H), 4.01 (d, J = 8.3 Hz, 1H), 3.91 (s, 1H), 3.80 (d, J = 11.2 Hz, 1H), 3.70 (dd, J = 11.3, 2.7 Hz, 1H), 3.55 (d, J = 2.8 Hz, 1H) , 3.45 (s, 3H), 3.18 (dd, J = 12.5, 9.4 Hz, 1H), 3.08 – 3.00 (m, 1H), 2.29 (s, 3H), 1.40 – 1.31 (m, 1H), 1.24 (s , 2H), 1.21 – 1.08 (m, 5H).

26b :

¹ H NMR (400 MHz, DMSO-6d) δ 13.08 (s, 1H), 7.08 (s, 1H), 6.55 (s, 1H), 4.28 (d, J = 6.5 Hz, 1H), 4.00 (t, J = 13.1 Hz, 2H), 3.79 (d, J = 11.4 Hz, 1H), 3.75 – 3.54 (m, 2H), 3.55 (t, J = 10.3 Hz, 1H), 3.46 (s, 3H), 3.18 (dd , J = 12.6, 9.1 Hz, 1H), 3.02 (s, 1H), 2.29 (s, 3H), 1.42 – 1.33 (m, 1H), 1.24 (s, 2H), 1.20 (d, J = 6.7 Hz, 3H), 1.15 (s, 1H). Example 27 (R)-4-(7-(1-( difluoromethyl ) cyclopropyl )-3-(1H- pyrazol -5- yl ) isothiazolo [4,5-b] pyridine -5 -Synthesis of -3 - methyl 𠰌 line Step 1. (R)-4-(3- chloro -7-(1-( difluoromethyl ) cyclopropyl ) isothiazolo [4,5-b] pyridin -5- yl )-3- methyl 𠰌 line

To (R)-1-(3-chloro-5-(3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)cyclopropane-1-carbaldehyde (100 To a solution of mg, 0.296 mmol) in DCM (5 mL) was added DAST (143 mg, 0.888 mmol). The mixture was stirred at 0 °C for 1 h. LC-MS showed the reaction was complete. The mixture was poured into saturated NaHCO ₃ (30 mL) and extracted with DCM (30 mL*3). The combined organic phases were washed with brine (30 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-100%, EA/PE) to obtain (R)-4-(3-chloro-7-(1-(difluoromethyl)) ring as a white solid Propyl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line (50 mg, 0.139 mmol, 46.94%). LC/MS (ESI): m/z 360.8 [M+H] ⁺ . Step 2. (3R)-4-(7-(1-( difluoromethyl ) cyclopropyl )-3-(1-( tetrahydro -2H- pyran -2- yl )-1H - pyrazole- 5- yl ) isothiazolo [4,5-b] pyridin -5- yl )-3- methyl 𠰌 line

To (R)-4-(3-chloro-7-(1-(difluoromethyl)cyclopropyl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line (50 mg, 0.139 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxola Pd was added to a mixture of borane-2-yl)-1H-pyrazole (58 mg, 0.208 mmol) and dipotassium carbonate (58 mg, 0.417 mmol) in dihexane (5 mL) and water (1 mL). (PPh ₃ ) ₄ (35 mg, 0.030 mmol). The mixture was degassed and injected with _N2 several times, and then stirred at 80 °C for 16 h under _N2 . The mixture was poured into _H2O (20 mL) and extracted with EA (20 mL * 3). The combined organic phases were washed with brine, dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo. The residue was purified by preparative-TLC (PE:EA=1:1) to obtain (3R)-4-(7-(1-(difluoromethyl)cyclopropyl)-3-( 1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line(15 mg, 0.032 mmol, 56.75%). LC/MS (ESI): m/z 476.6 [M+H] ⁺ . Step 3. (R)-4-(7-(1-( difluoromethyl ) cyclopropyl ) -3-(1H- pyrazol -5- yl ) isothiazolo [4,5-b] pyridine- 5- yl )-3- methyl 𠰌 line

To (3R)-4-(7-(1-(difluoromethyl)cyclopropyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5- To a solution of isothiazo[4,5-b]pyridin-5-yl)-3-methyl𠰌line (15 mg, 0.032 mmol) in MeOH (1 mL) was added TsOH (5.5 mg, 0.032 mmol) ). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The mixture was poured into saturated NaHCO ₃ and extracted with EA (20 mL * 3). The combined organic phases were washed with brine (20 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give (R)-4-(7-(1-(difluoromethyl)) ring Propyl)-3-(1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)-3-methylpyrazoline (2 mg, 0.005 mmol, 12.17%). LC/MS (ESI): m/z 392 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 13.65 (s, 1H), 7.74 (s, 1H), 7.38 (d, J = 1.9 Hz, 1H), 7.23 (s, 1H), 5.99 (t, J = 55.6 Hz, 1H), 4.53 (d, J = 4.7 Hz, 1H), 4.22 – 3.99 (m, 2H), 3.81 (d, J = 11.3 Hz, 1H), 3.71 (dd, J = 11.4, 2.8 Hz, 1H ), 3.59 – 3.50 (m, 1H), 3.23 (dd, J = 12.6, 3.7 Hz, 1H), 1.31 (s, 2H), 1.23 (d, J = 6.7 Hz, 5H). Example 28 Dimethyl ({5-[(3R)-3- methyl 𠰌 lin -4- yl ]-3-(1H- pyrazol -5- yl )-[1,2] thiazolo [4,5 -Synthesis of -b] pyridin -7- yl } imino ) -λ ^6- sulfanone Step 1. Dimethyl ({5-[(3R)-3- methyl 𠰌 lin -4- yl ]-3-[1-( tetrahydropyran -2- yl )-1H- pyrazole -5- base ]-[1,2] thiazolo [4,5-b] pyridin -7- yl } imino ) -λ ^6- sulfanone

To (3R)-4-{7-chloro-3-[1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5- b] To a solution of pyridin-5-yl}-3-methyl𠰌line (100 mg, 0.238 mmol) in dioxane (4 mL) was added iminodimethyl-λ^6-sulfanone ( 27 mg, 0.286 mmol), Pd ₂ (dba) ₃ (22 mg, 0.024 mmol) and Xantphos (28 mg, 0.048 mmol), Cs ₂ CO ₃ (233 mg, 0.714 mmol). The reaction was stirred at 100°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. Dilute the reaction with EA (20 mL) and water (20 mL). The organic layer was separated, washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE:EA = 2:1, V/V) to obtain dimethyl ({5-[(3R)-3-methyl𠰌line-4) as a yellow solid -yl]-3-[1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl} Imino)-λ^6-sulfanone (72 mg, 63.4%). LC/MS (ESI) m/z: 478 (M+H) ⁺ . Step 2. Dimethyl ({5-[(3R)-3- methyl 𠰌 lin -4- yl ]-3-(1H- pyrazol -5- yl )-[1,2] thiazolo [4, 5-b] pyridin -7- yl } imino ) -λ ^6- sulfanone

To dimethyl({5-[(3R)-3-methyl𠰌lin-4-yl]-3-[1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl] -[1,2]thiazolo[4,5-b]pyridin-7-yl}imino)-λ^6-sulfanone (72 mg, 0.151 mmol) in DCM (1 mL) Add HCl (4 M in dihexane, 2 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give dimethyl ({5-[(3R)-3-methyl𠰌line- 4-yl]-3-(1H-pyrazol-5-yl)-[1,2]thiazolo[4,5-b]pyridin-7-yl}imino)-λ^6-sulfanone (40 mg, 67.5%). LC/MS (ESI) m/z: 393.1 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 7.71 (s, 1H), 7.37 (d, J = 1.8 Hz, 1H), 6.55 (s, 1H), 4.39 (d, J = 6.7 Hz, 1H), 4.03 – 3.94 (m, 2H), 3.80 (d, J = 11.2 Hz, 1H), 3.70 (dd, J = 11.4, 2.8 Hz, 1H), 3.55 (dd, J = 11.7, 8.9 Hz, 1H), 3.48 (d, J = 1.2 Hz, 6H), 3.23 – 3.16 (m, 1H), 1.21 (d, J = 6.6 Hz, 3H). Example 29 2-{5-[(3R)-3- methyl 𠰌 lin -4- yl ]-3-(1H- pyrazol -5- yl )-[1,2] thiazolo [4,5-b Synthesis of ] pyridin -7- yl } propan -2- ol Step 1. 5-[(3R)-3- methyl 𠰌 lin -4- yl ]-3-[1-( tetrahydropyran -2- yl )-1H- pyrazol -5- yl ]-[1 ,2] thiazolo [4,5-b] pyridine -7- carboxylic acid methyl ester

To (3R)-4-{7-chloro-3-[1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5- b]pyridin-5-yl}-3-methyl𠰌line (200 mg, 0.476 mmol) in MeOH (3 mL) was added Pd(dppf)Cl ₂ (70 mg, 0.095 mmol), TEA (0.33 mL, 2.38 mmol). The reaction was stirred at 65°C overnight under CO atmosphere. LC-MS showed the reaction was complete. The reaction mixture was filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain 5-[(3R)-3-methyl𠰌lin-4-yl]- as a yellow solid. 3-[1-(Tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridine-7-carboxylic acid methyl ester (75 mg ,35.51%). LC/MS (ESI): m/z 443(M+H) ⁺ . Step 2. 2-{5-[(3R)-3- methyl 𠰌 lin -4- yl ]-3-[1-( tetrahydropyran -2- yl )-1H- pyrazol -5- yl ] -[1,2] thiazolo [4,5-b] pyridin -7- yl } propan -2- ol

To 5-[(3R)-3-methyl𠰌lin-4-yl]-3-[1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2 To a mixture of methylthiazolo[4,5-b]pyridine-7-carboxylate (75 mg, 0.169 mmol) in THF (2 mL) was added methylmagnesium bromide (0.34 mL, 0.845 mmol). The reaction was stirred at 0 °C for 2 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with DCM (20 mL), washed with water and brine, dried over anhydrous _Na2SO4 , filtered and _concentrated . The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain 2-{5-[(3R)-3-methyl𠰌line-4- as a white solid base]-3-[1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl}propanol -2-ol (75 mg, 0.169 mmol, 99.9%). LC/MS (ESI): m/z 444 [M+H] ⁺ . Step 3. 2-{5-[(3R)-3- methyl 𠰌 lin -4- yl ]-3-(1H- pyrazol -5- yl )-[1,2] thiazolo [4,5- b] pyridin -7- yl } propan -2- ol

To 2-{5-[(3R)-3-methyl𠰌lin-4-yl]-3-[1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[ To a solution of 1,2]thiazolo[4,5-b]pyridin-7-yl}propan-2-ol (75 mg, 0.169 mmol) in DCM (2 mL) was added HCl/dioxane (2 mL ). The mixture was stirred at room temperature for 1 hour. LC-MS showed the reaction was complete. The reaction was concentrated in vacuo to give a crude product, which was purified by preparative-HPLC (C ₁₈ , 10-95%, MeCN/H ₂ O with 0.1% CHOOH) to give 2-{5-[(3R )-3-methyl𠰌lin-4-yl]-3-(1H-pyrazol-5-yl)-[1,2]thiazolo[4,5-b]pyridin-7-yl}propan-2 -Alcohol (14 mg, 0.039 mmol, 23.0%). LC/MS (ESI): m/z 361 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7.36 (s, 1H), 7.02 (s, 1H), 6.10 (s, 1H), 4.55 (s, 1H), 4.07-4.03 (m, 2H), 3.78-3.74 (m, 2H), 3.48 (s, 1H), 3.24 (d, J = 13.1 Hz, 1H), 1.56 (s, 6H), 1.20 (d, J = 6.0 Hz, 3H). Example 30 4-{5-[(3R)-3- methyl 𠰌 lin -4- yl ]-3-[1-( tetrahydropyran -2- yl )-1H- pyrazol -5- yl ]- Synthesis of [1,2] thiazolo [4,5-b] pyridin -7- yl } tetrahydropyran -4- ol Step 1. 4-[7-(3,6- dihydro -2H- pyran -4- yl )-3-[1-( tetrahydropyran- 2- yl )-1H- pyrazol -5- yl ]-[1,2] thiazolo [4,5-b] pyridin -5- yl ]-3- methyl 𠰌 line

To 4-{7-chloro-3-[1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridine- 5-yl}-3-methyl𠰌line (100 mg, 0.238 mmol), 2-(3,6-dihydro-2H-piran-4-yl)-4,4,5,5-tetramethyl -1,3,2-dioxaborane (75 mg, 0.357 mmol) and K ₂ CO ₃ (99 mg, 0.714 mmol) in dioxane (2 mL) and H ₂ O (0.2 mL) Pd(PPh ₃ ) ₄ (28 mg, 0.024 mmol) was added to the mixture. The mixture was stirred at 100 °C for 16 h under _N2 atmosphere. LC-MS showed the reaction was complete. The reaction mixture was diluted with _H2O (20 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by silica column chromatography (DCM:MeOH = 20:1) to obtain the desired product 4-[7-(3,6-dihydro-2H-piran-4-yl) as a brown solid. -3-[1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl]-3- Methylpyridine (65 mg, 58.4%). LC/MS (ESI): m/z 468.1 [M+H] ⁺ . Step 2. 4-{5-[(3R)-3- methyl 𠰌 lin -4- yl ]-3-(1H- pyrazol -5- yl )-[1,2] thiazolo [4,5- b] pyridin -7- yl } tetrahydropyran -4- ol

4-[7-(3,6-Dihydro-2H-pyran-4-yl)-3-[1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]- [1,2]thiazolo[4,5-b]pyridin-5-yl]𠰌line (60 mg, 0.132 mmol), (4Z)-5-{[bis({[(3Z)-2,2, 6,6-Tetramethyl-5-oxohept-3-en-3-yl]oxy})ruthenium]oxy}-2,6,6-trimethylhept-4-en-3-one( A mixture of 8.4 mg, 0.013 mmol) and phenylsilane (0.033 mL, 0.265 mmol) in IPA (1 mL) and H ₂ O (0.1 mL) was stirred at room temperature under an O ₂ atmosphere for 2 h. LC-MS showed the reaction was complete. The reaction mixture was diluted with _H2O (20 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with brine, dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to obtain 4-[5-(𠰌lin-4-yl)-3-[1-(tetrahydropyran) as a brown solid -2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl]tetrahydropyran-4-ol (20 mg, 0.042 mmol , 32.1%). LC/MS (ESI): m/z 472.1 [M+H] ⁺ . Step 3. 4-{5-[(3R)-3- methyl 𠰌 lin -4- yl ]-3-(1H- pyrazol -5- yl )-[1,2] thiazolo [4,5- b] pyridin -7- yl } tetrahydropyran -4- ol

To 4-{5-[(3R)-3-methyl𠰌lin-4-yl]-3-[1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[ To a solution of 1,2]thiazolo[4,5-b]pyridin-7-yl}tetrahydropyran-4-ol (20 mg, 0.04 mmol) in DCM (4 mL) was added HCl/dioxane (4 M, 1 mL). The mixture was stirred at room temperature for 1 hour. TLC showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O containing 0.1% HCOOH) to give 4-{5-[(3R)-3-methyl𠰌line-4- base]-3-(1H-pyrazol-5-yl)-[1,2]thiazolo[4,5-b]pyridin-7-yl}tetrahydropyran-4-ol (10 mg, 0.025 mmol ,20.16%). LC/MS (ESI): m/z 402.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H), 7.68 (s, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.11 (s, 1H), 6.22 (s, 1H ), 4.59 (d, J = 6.0 Hz, 1H), 4.23 – 4.04 (m, 1H), 4.00-3.96 (m, 1H), 3.90 – 3.76 (m, 5H), 3.71 (dd, J = 11.4, 2.7 Hz, 1H), 3.54 (dt, J = 22.6, 14.5 Hz, 2H), 3.27 – 3.11 (m, 2H), 2.29 – 2.08 (m, 2H), 1.66 (d, J = 13.4 Hz, 2H), 1.35 – 1.08 (m, 4H). Example 31 (R)-4-(7-(1-( fluoromethyl ) cyclopropyl )-3-(1H- pyrazol -5- yl ) isothiazolo [4,5-b] pyridine -5- Synthesis of methyl )-3- methyl 𠰌 line Step 1. (R)-1-(3- chloro -5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridin -7- yl ) cyclopropane -1- carbaldehyde

To (R)-1-(3-chloro-5-(3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)cyclopropane-1-carbonitrile at -78°C To a solution of DIBAL-H (1.0 M in toluene, 7.2 mL, 7.17 mmol) (800 mg, 2.39 mmol) in toluene (15 mL) was added. The mixture was stirred at -78 °C for 1 h. LC-MS showed the reaction was complete. The mixture was warmed to room temperature, poured into _H2SO4 (1 M in _water , 30 mL) and extracted with EA (50 mL * 3). The combined organic phases were washed with brine (30 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-100%, EA/PE) to obtain (R)-1-(3-chloro-5-(3-methyl𠰌linyl) as a yellow oily substance )isothiazolo[4,5-b]pyridin-7-yl)cyclopropane-1-carbaldehyde (400 mg, 1.18 mmol, 49.56%). LC/MS (ESI): m/z 338.8 [M+H] ⁺ . Step 2. (R)-(1-(3- chloro -5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridin -7- yl ) cyclopropyl ) methanol

To (R)-1-(3-chloro-5-(3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)cyclopropane-1-carbaldehyde (240 mg, 0.859 To a solution of NaBH ₄ (90 mg, 2.37 mmol) in MeOH (5 mL) was added. The mixture was stirred at 25 °C for 1 h. LC-MS showed the reaction was complete. The mixture was poured into _H2O and extracted with DCM (30 mL*3). The combined organic phases were washed with brine, dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo. The residue was purified by column chromatography (silica gel, 0-100%, EA/PE) to obtain (R)-(1-(3-chloro-5-(3-methyl𠰌linyl)) as a white solid Isothiazolo[4,5-b]pyridin-7-yl)cyclopropyl)methanol (200 mg, 0.592 mmol, 50.00%). LC/MS (ESI): m/z 340.8 [M+H] ⁺ . Step 3. (R)-4-(3- chloro -7-(1-( fluoromethyl ) cyclopropyl ) isothiazolo [4,5-b] pyridin -5- yl )-3- methyl 𠰌 phyline

To (R)-(1-(3-chloro-5-(3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)cyclopropyl)methanol (100 To a solution of mg, 0.294 mmol) in DCM (5 mL) was added DAST (285 mg, 1.77 mmol). The mixture was stirred at 0 °C for 1 h. LC-MS showed the reaction was complete. The mixture was poured into saturated NaHCO ₃ and extracted with DCM (30 mL * 3). The combined organic phases were washed with brine (30 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0-100%, EA/PE) to obtain (R)-4-(3-chloro-7-(1-(fluoromethyl)cyclopropane) as a white solid yl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line (50 mg, 0.146 mmol, 49.71%). LC/MS (ESI): m/z 342 [M+H] ⁺ . Step 4. (3R)-4-(7-(1-( fluoromethyl ) cyclopropyl )-3-(1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazole -5 -yl ) isothiazolo [4,5-b] pyridin -5- yl )-3 - methyl 𠰌 line

To (R)-4-(3-chloro-7-(1-(fluoromethyl)cyclopropyl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line( 20 mg, 0.059 mmol), 3-methyl-1-(tetrahydropyran-2-yl)-5-(tetramethyl-1,3,2-dioxaborolan-2-yl) _Pd (PPh ₃ ) _{4 (} 6.76 mg, 0.006 mmol). The mixture was stirred at 80 °C for 16 h. The mixture was poured into _H2O (20 mL) and extracted with EA (20 mL * 3). The combined organic phases were washed with brine (20 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by preparative-TLC (PE:EA=1:1) to obtain (3R)-4-(7-(1-(fluoromethyl)cyclopropyl)-3-(1) as a yellow solid -(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line (20 mg ,0.044 mmol, 74.71%). LC/MS (ESI): m/z 458 [M+H] ⁺ . Step 4. (R)-4-(7-(1-( fluoromethyl ) cyclopropyl )-3-(1H- pyrazol -5- yl ) isothiazolo [4,5-b] pyridine -5 -yl )-3 - methyl 𠰌 line

To (3R)-4-(7-(1-(fluoromethyl)cyclopropyl)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl )To a solution of isothiazo[4,5-b]pyridin-5-yl)-3-methyl𠰌line (50 mg, 0.109 mmol) in MeOH (5 mL) was added TsOH (19 mg, 0.109 mmol) . The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The mixture was poured into saturated NaHCO ₃ (20 mL) and extracted with EA (20 mL * 3). The combined organic phases were washed with brine (20 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give (R)-4-(7-(1-(fluoromethyl)cyclopropane) yl)-3-(1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line (10 mg, 0.027 mmol, 24.50%). LC/MS (ESI): m/z 374 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 13.46 (d, J = 169.5 Hz, 1H), 7.78 (d, J = 88.4 Hz, 1H), 7.39 (d, J = 1.9 Hz, 1H), 7.24 (s, 1H), 4.63 (s, 1H), 4.18 (d, J = 13.5 Hz, 1H), 4.04 (d, J = 11.0 Hz, 1H), 3.82 (d, J = 11.3 Hz, 1H), 3.72 (dd, J = 11.4, 2.8 Hz, 1H), 3.57 (td, J = 11.7, 2.8 Hz, 1H), 3.26 (d, J = 12.1 Hz, 1H), 2.85 – 2.58 (m, 4H), 2.12 (dd , J = 8.5, 2.9 Hz, 1H), 1.88 (d , J = 9.8 Hz, 1H), 1.24 (d , J = 6.6 Hz, 3H). Example 32 (3R)-4-[7-(1- ethyl- 1H-1,2,3- triazol -5- yl )-3-(1H- pyrazol -5- yl )-[1,2 Synthesis of ] thiazolo [4,5-b] pyridin -5- yl ]-3- methyl 𠰌 line Step 1. (3R)-4-[3- chloro -7-(1- ethyl -1H-1,2,3- triazol -5- yl )-[1,2] thiazolo [4,5- b] pyridin -5- yl ]-3- methyl 𠰌 line

(3R)-4-{3,7-Dichloro-[1,2]thiazolo[4,5-b]pyridin-5-yl}-3-methyl𠰌line (200 mg, 0.657 mmol), 1-ethyl-1H-1,2,3-triazole (383.12 mg, 3.945 mmol), tetramethylammonium acetate (262.70 mg, 1.972 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (92.29 mg, 0.131 mmol) ) in DMA (3 mL) was stirred at 140 °C for 8 h under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried _{over Na2SO4} , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain the title product (3R)-4-[3-chloro-7-(1-) as a yellow semi-solid Ethyl-1H-1,2,3-triazol-5-yl)-[1,2]thiazolo[4,5-b]pyridin-5-yl]-3-methyl𠰌line (118 mg, 0.323 mmol, 49.19%). LC-MS(ESI+): m/z (M+H) = 364.8, 366.8 Step 2. (3R)-4-[7-(1- ethyl -1H-1,2,3- triazole -5- base )-3-[1-( tetrahydropyran -2- yl )-1H- pyrazol -5- yl ]-[1,2] thiazolo [4,5-b] pyridin -5- yl ]- 3- Methyl 𠰌 line

(3R)-4-[3-Chloro-7-(1-ethyl-1H-1,2,3-triazol-5-yl)-[1,2]thiazolo[4,5-b] Pyridin-5-yl]-3-methyl𠰌line (118 mg, 0.323 mmol), 1-(tetrahydropyran-2-yl)-5-(tetramethyl-1,3,2-dioxa Cyclopentaborane-2-yl)-1H-pyrazole (179.92 mg, 0.647 mmol), Pd(PPh ₃ ) ₄ (74.74 mg, 0.065 mmol) and K ₂ CO ₃ (3 mL, 6.000 mmol) in dichloromethane A mixture of alkane (15 mL) and water (3 mL) was stirred at 100 °C overnight under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried _{over Na2SO4} , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain the title product (3R)-4-[7-(1-ethyl-) as a yellow oil. 1H-1,2,3-triazol-5-yl)-3-[1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[ 4,5-b]pyridin-5-yl]-3-methylpyridine (49 mg, 0.102 mmol, 31.53%). LC-MS(ESI+): m/z (M+H) = 480.8Step 3. (3R)-4-[7-(1- ethyl- 1H-1,2,3- triazol -5- yl ) -3-(1H- pyrazol -5- yl )-[1,2] thiazolo [4,5-b] pyridin -5- yl ]-3- methyl 𠰌 line

To (3R)-4-[7-(1-ethyl-1H-1,2,3-triazol-5-yl)-3-[1-(tetrahydropyran-2-yl)-1H- Pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl]-3-methyl𠰌line (49 mg, 0.102 mmol) in DCM (2 mL) TFA (2 mL) was added to the solution, and the resulting mixture was stirred at ambient temperature for 1 h. The mixture was concentrated and basified with saturated ammonium. The mixture was concentrated and the residue was purified by flash column chromatography (silica, 0-10% MeOH/DCM) and preparative-HPLC (C18, 10-95%, acetonitrile/water with 0.1% formic acid), The title product (3R)-4-[7-(1-ethyl-1H-1,2,3-triazol-5-yl)-3-(1H-pyrazol-5-yl)-[1, 2] Thiazolo[4,5-b]pyridin-5-yl]-3-methyl𠰌line (6.5 mg, 0.016 mmol, 16.08%). LC-MS(ESI+): m/z (M+H) = 396.8.

¹ H NMR (400 MHz, DMSO) δ 13.53 (d, J = 177.6 Hz, 1H), 8.22 (s, 1H), 7.82 (d, J = 89.9 Hz, 1H), 7.45 (d, J = 16.2 Hz, 2H), 4.62 – 4.47 (m, 3H), 4.19 (d, J = 12.2 Hz, 1H), 4.05 (d, J = 10.3 Hz, 1H), 3.83 (d, J = 11.2 Hz, 1H), 3.73 ( d, J = 11.1 Hz, 1H), 3.59 (t, J = 10.7 Hz, 1H), 3.30 – 3.23 (m, 1H), 1.38 (t, J = 7.2 Hz, 3H), 1.26 (d, J = 6.4 Hz, 3H). Example 33 (3R)-3- methyl -4-[7-(4- methyl -1H-1,2,3- triazol -1- yl )-3-(3- methyl -1H- pyrazole) Synthesis of -5- yl )-[1,2] thiazolo [4,5-b] pyridin -5- yl ] 𠰌 line Step 1. (3R)-4-{7- azido -3-[(4- methoxyphenyl ) methoxy ]-[1,2] thiazolo [4,5-b] pyridine -5- Base }-3- methyl 𠰌 line

To (3R)-4-{7-chloro-3-[(4-methoxyphenyl)methoxy]-[1,2]thiazolo[4,5-b]pyridin-5-yl}- To a suspension of 3-methylphenoline (300 mg, 0.739 mmol) in DMSO (5 mL) was added N ₃ Na (157 mg, 1.478 mmol) and Na ₂ CO ₃ (157 mg, 1.48 mmol). After the addition was complete, the mixture was heated at 80°C for 3 days. LC-MS showed the reaction was complete. Dilute the reaction with EA and water. Separate the two phases. The organic phase was washed with brine, dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to give crude product. The residue was purified by flash column chromatography (silica gel, 0~100%, ethyl acetate/petroleum ether) to obtain (3R)-4-{7-azide-3-[(4- Methoxyphenyl)methoxy]-[1,2]thiazolo[4,5-b]pyridin-5-yl}-3-methyl𠰌line (120 mg, 0.291 mmol, 39.36%). LC/MS (ESI): m/z 413 (M+H) ⁺ step 2. (3R)-4-{3-[(4- methoxyphenyl ) methoxy ]-7-(4- methyl Base -1H-1,2,3- triazol -1- yl )-[1,2] thiazolo [4,5-b] pyridin -5- yl }-3- methyl 𠰌 line

To (3R)-4-{7-azido-3-[(4-methoxyphenyl)methoxy]-[1,2]thiazolo[4,5-b]pyridin-5-yl} To a suspension of -3-methyl𠰌line (120 mg, 0.291 mmol) in MeOH (5 mL) and H ₂ O (1 mL) was added trimethyl(prop-1-yn-1-yl)silane ( 0.087 mL, 0.582 mmol), copper(II) sulfate pentahydrate (0.064 mL, 0.582 mmol), and sodium ascorbate (115 mg, 0.582 mmol). After the addition was complete, the mixture was stirred at room temperature overnight. LC-MS showed the reaction was complete. Dilute the reaction with EA and water. Separate the two phases. The organic phase was washed with brine, dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to give crude product. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain (3R)-4-{3-[(4-methoxyphenyl) as a yellow solid Methoxy]-7-(4-methyl-1H-1,2,3-triazol-1-yl)-[1,2]thiazolo[4,5-b]pyridin-5-yl}- 3-Methylpyroline (90 mg, 0.199 mmol, 68.36%). LC/MS (ESI): m/z 453(M+H) ⁺ . Step 3. 7-(4- Methyl -1H-1,2,3- triazol -1- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl ]-[1,2 ] thiazolo [4,5-b] pyridin -3- ol

(3R)-4-{3-[(4-methoxyphenyl)methoxy]-7-(4-methyl-1H-1,2,3-triazol-1-yl)-[ A solution of 1,2]thiazolo[4,5-b]pyridin-5-yl}-3-methyl𠰌line (90 mg, 0.199 mmol) in TFA (3 mL) was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction was concentrated in vacuo to obtain a crude product, which was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain 7-(4-methyl- 1H-1,2,3-triazol-1-yl)-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridine -3-ol (38 mg, 0.114 mmol, 57.48%). LC/MS (ESI): m/z 333(M+H) ⁺ . Step 4. Triflate 7-(4- methyl -1H-1,2,3- triazol -1- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl ] -[1,2] thiazolo [4,5-b] pyridin -3- yl ester

To 7-(4-methyl-1H-1,2,3-triazol-1-yl)-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazole To a mixture of [4,5-b]pyridin-3-ol (30 mg, 0.090 mmol) and DIPEA (34.93 mg, 0.271 mmol) in THF (5 mL) was added PhNTf ₂ (64.44 mg, 0.181 mmol). After stirring at room temperature for 16 hours, the mixture was concentrated to dryness. The residue was purified by flash chromatography (silica gel (12 g), 0-100%, EA/PE) to obtain 7-(4-methyl-1H-1,2, triflate) as a yellow solid. 3-Triazol-1-yl)-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-3-yl ester ( 35 mg, 0.075 mmol, 83.49%). LC/MS (ESI) m/z: 465.5 (M+1) ⁺ . Step 5. (3R)-3- methyl -4-{3-[3- methyl -1-( tetrahydropyran -2- yl )-1H- pyrazol -5- yl ]-7-(4 -Methyl - 1H-1,2,3- triazol -1- yl )-[1,2] thiazolo [4,5-b] pyridin -5- yl } 𠰌 line

To trifluoromethanesulfonic acid 7-(4-methyl-1H-1,2,3-triazol-1-yl)-5-[(3R)-3-methyl𠰌lin-4-yl]-[ 1,2]thiazolo[4,5-b]pyridin-3-yl ester (35 mg, 0.075 mmol), (3-methyl-1-(tetrahydro-2H-piran-2-yl)-1H To a mixture of -pyrazol-5-yl)boronic acid (37.35 mg, 0.226 mmol) and K ₂ CO ₃ (2 M in H2O, 0.188 mL, 0.377 mmol) in dihexane (1.5 mL) was added Pd(dppf )Cl ₂ (11.03 mg, 0.015 mmol). The mixture was stirred at 100°C for 16 hours. The mixture was filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel (12 g), 0-100%, EA/PE) to obtain (3R)-3-methyl-4-{3-[3- Methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-7-(4-methyl-1H-1,2,3-triazol-1-yl)- [1,2]thiazolo[4,5-b]pyridin-5-yl}𠰌line (32 mg, 0.067 mmol, 88.36%). LC/MS (ESI) m/z: 481.6 (M+1) ⁺ . Step 6. (3R)-3- methyl -4-[7-(4- methyl -1H-1,2,3- triazol -1- yl )-3-(3- methyl- 1H- pyra Azol -5- yl )-[1,2] thiazolo [4,5-b] pyridin -5- yl ] 𠰌 line

To (3R)-3-methyl-4-{3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-7-(4-methyl 1H-1,2,3-triazol-1-yl)-[1,2]thiazolo[4,5-b]pyridin-5-yl}𠰌line (32 mg, 0.067 mmol) in DCM ( To the mixture in 0.5 mL) was added HCl (4 M in dihexane, 1 mL). After stirring at room temperature for 1 hour, the mixture was concentrated to dryness. The crude product was then purified by preparative-HPLC (C18, 10-95%, MeCN/H ₂ O containing 0.1% HCOOH) to give (3R)-3-methyl-4-[7-(4-methyl -1H-1,2,3-triazol-1-yl)-3-(3-methyl-1H-pyrazol-5-yl)-[1,2]thiazolo[4,5-b]pyridine -5-yl]𠰌line (6 mg, 0.015 mmol, 22.73%). LC/MS (ESI) m/z: 397.5 (M+1) ⁺ .

¹ HNMR (400 MHz, DMSO) δ 13.10 (d, J = 117.1 Hz, 1H), 9.19 (s, 1H), 7.70 (s, 1H), 7.13 (s, 1H), 4.61 (dd, J = 13.1, 6.9 Hz, 1H), 4.27 – 4.15 (m, 1H), 4.07 (dd, J = 9.1, 3.7 Hz, 1H), 3.86 (dd, J = 14.2, 3.0 Hz, 1H), 3.75 (dd, J = 11.7 , 1.3 Hz, 1H), 3.60 (td, J = 11.8, 2.4 Hz, 1H), 3.28 (s, 1H), 2.42 (s, 3H), 2.31 (s, 3H), 1.28 (d, J = 6.3 Hz ,3H). Example 35 Methyl ({[3-(3- methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl ]-[1,2] thiazole Synthesis of [4,5-b] pyridin -7- yl ] imino }) phenyl - λ ^6- sulfanone Step 1. Imino ( methyl ) phenyl -λ^6- sulfanone

To a solution of (methylsulfanyl)benzene (1 mL, 8.05 mmol) in MeOH (80 mL) was added (acetyloxy)(phenyl)-λ^3-iodoacetate (3.5 mL, 18.52 mmol), diammonium carbonate (1 g, 12.08 mmol). The reaction was stirred at room temperature under an _O2 atmosphere for 5 minutes. LC-MS showed the reaction was complete. The reaction mixture was poured into _H2O (20 mL) and extracted with EA (20 mL×3). The combined organic phases were washed with brine (20 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel (10 g), 0-100%, EA/PE) to obtain the desired product imino(methyl)phenyl-λ^6-sulfane as a light yellow solid. Ketone (1.1 g, yield: 88%). LC/MS (ESI): m/z 156.1 [M+H] ⁺ . Step 2. (3S)-1-[3-(3- methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl ]-[1, 2] thiazolo [4,5-b] pyridin -7- yl ] pyrrolidin -3- ol

To a solution of imino(methyl)phenyl-λ^6-sulfanone (150 mg, 0.97 mmol) in dioxane (10 mL) was added (3R)-4-{7-chloro-3 -[3-Methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl} -3-Methylpyroline (419 mg, 0.97 mmol), Xantphos (112 mg, 0.19 mmol), Pd ₂ (dba) ₃ (89 mg, 0.10 mmol), CS ₂ CO ₃ (945 mg, 2.90 mmol). The reaction was stirred at 100 °C overnight under _N2 . The mixture was added _H2O (10 mL) and extracted with EtOAc (6 mL × 3). The combined organic phases were washed with brine (20 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated to dryness. The residue was purified by flash chromatography to obtain methyl ({3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[( 3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl}imino)phenyl-λ^6-sulfanone ( 120 mg, yield: 22%). LC-MS (ESI): m/z 534.6 [M+H] ⁺ . Step 3. Methyl ({[3-(3- methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl ]-[1,2] Thiazolo [4,5-b] pyridin -7- yl ] imino }) phenyl - λ ^6- sulfanone

To methyl({3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌line- 4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl}imino)phenyl-λ^6-sulfanone (60 mg, 0.109 mmol) in DCM (1 mL) was added HCl/dioxane (2 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by SFC to obtain 35a (14.4 mg, 0.031 mmol, 28.31%) and 35b (4 mg, yield: 7%). LC/MS (ESI) m/z: 468.8 [M+H] ⁺ .

35a :

¹ H NMR (400 MHz, DMSO-d6) δ 8.08 (t, J = 28.4 Hz, 2H), 7.71 (dt, J = 15.0, 7.3 Hz, 3H), 7.03 (s, 1H), 6.26 (s, 1H ), 4.13 – 3.86 (m, 2H), 3.84 – 3.61 (m, 5H), 3.55 (dd, J = 13.1, 10.8 Hz, 1H), 3.51 – 3.41 (m, 1H), 2.99 (td, J = 12.6 , 3.5 Hz, 1H), 2.27 (s, 3H), 1.11 (d, J = 6.6 Hz, 3H).

35b :

¹ H NMR (400 MHz, DMSO-d6) δ 8.06 – 7.97 (m, 2H), 7.76 – 7.60 (m, 3H), 7.02 (s, 1H), 6.16 (s, 1H), 3.97 – 3.82 (m, 3H), 3.69 (s, 3H), 3.67 – 3.56 (m, 2H), 3.45 – 3.42 (m, 1H), 2.99 (td, J = 12.8, 3.7 Hz, 1H), 2.27 (s, 3H), 0.73 (d, J = 6.6 Hz, 3H). Example 36 (R)-3- methyl -4-(3-(3- methyl -1H- pyrazol -5- yl )-7- 𠰌 linisothiazolo [4,5-b] pyridine -5- Synthesis of base ) 𠰌 line Step 1. (3R)-3- methyl- 4-(3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-7 - 𠰌 lineisothiazolo [4,5-b] pyridin -5- yl ) 𠰌 line

To (3R)-4-(7-chloro-3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)isothiazolo[4 ,5-b]pyridin-5-yl)-3-methyl𠰌line (60 mg, 0.14 mmol) in cyclotenine (2 mL) was added with 𠰌line (0.02 mL, 0.28 mmol), DIPEA ( 0.12 mL, 0.69 mmol) and KF (8 mg, 0.14 mmol). The reaction was stirred at 120°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was poured into water and extracted with EA (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by preparative-TLC (PE:EA = 1:1, V/V) to obtain (3R)-3-methyl-4-(3-(3-methyl-1- (Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-7-𠰌linylisothiazo[4,5-b]pyridin-5-yl)𠰌line (50 mg , yield: 75%). LC/MS (ESI): m/z 485.6 (M+H) ⁺ . Step 2. (R)-3- Methyl -4-(3-(3- methyl - 1H- pyrazol -5- yl )-7- 𠰌 linylisothiazo [4,5-b] pyridine- 5- yl ) 𠰌 line

To (3R)-3-methyl-4-(3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-7-𠰌 To a solution of lynoisothiazolo[4,5-b]pyridin-5-yl)oxoline (35 mg, 0.07 mmol) in DCM (1 mL) was added HCl (4 M in dimethane, 2 mL ). The mixture was stirred at room temperature for 0.5 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O with 0.1% HCOOH) to give (R)-3-methyl-4-(3-(3-methyl -1H-pyrazol-5-yl)-7-𠰌linyisothiazolo[4,5-b]pyridin-5-yl)𠰌line (5 mg, yield: 18%). LC/MS (ESI): m/z 401 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 7.11 (s, 1H), 6.36 (s, 1H), 4.49 (d, J = 6.3 Hz, 1H), 4.01 (dd, J = 16.5, 8.1 Hz, 2H), 3.80 (dd, J = 10.7, 6.3 Hz, 5H), 3.69 (dd, J = 11.3, 2.7 Hz, 1H), 3.57 – 3.51 (m, 1H), 3.41 (d, J = 2.4 Hz, 4H), 3.20 (td, J = 12.8, 3.7 Hz, 1H), 2.29 (s, 3H), 1.20 (d, J = 6.6 Hz, 3H). Example 37 (3R,3'R)-4,4'-(3-(3- methyl -1H- pyrazol -5- yl ) isothiazolo [4,5-b] pyridine -5,7- di Synthesis of bis (3 - methyl 𠰌 line ) Step 1. (3R,3'R)-4,4'-(3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl ) Isothiazolo [4,5-b] pyridine -5,7- diyl ) bis (3- methyl 𠰌 line )

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo [4,5-b]pyridin-5-yl}-3-methyl𠰌line (80 mg, 0.18 mmol), (3R)-3-methyl𠰌line (37 mg, 0.37 mmol) and CS ₂ CO ₃ (120 mg, 0.37 mmol) in N,N-dimethylformamide (2 mL) was added RuPhos Pd G3 (15 mg, 0.02 mmol), RuPhos (17 mg, 0.04 mmol). The mixture was stirred at 80 °C for 16 h under _N2 . LC-MS showed the reaction was complete. The mixture was poured into _H2O (50 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by flash chromatography (silica gel (12 g), 0-100%, EA/PE) to obtain (3R)-3-methyl-4-{3-[3- Methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-7-[(3R)-3-methyl𠰌lin-4-yl]-[1,2] Thiazolo[4,5-b]pyridin-5-yl}noline (70 mg, yield: 76%). LC/MS (ESI): m/z 498.65 [M+H] ⁺ . Step 2. (3R,3'R)-4,4'-(3-(3- methyl -1H- pyrazol -5- yl ) isothiazolo [4,5-b] pyridine -5,7- Diyl ) bis (3- methyl 𠰌 line )

To (3R)-3-methyl-4-{3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-7-[(3R) -3-Methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl}𠰌line (70 mg, 0.14 mmol) in DCM (1 mL) HCl/dioxane (1 mL) was added to the mixture. The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The mixture was concentrated to dryness. The crude product was then purified by preparative-HPLC (C ₁₈ , 10-95%, MeCN/H ₂ O with 0.1% HCOOH) to give (3R)-3-methyl-4-[3-(3-methyl base-1H-pyrazol-5-yl)-7-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl ]𠰌line (23 mg, yield: 39%). LC/MS (ESI): m/z 414.5 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 7.10 (s, 1H), 6.29 (s, 1H), 4.48 (d, J = 5.4 Hz, 1H), 4.11 – 3.94 (m , 4H), 3.78 (d, J = 10.0 Hz, 3H), 3.72 – 3.50 (m, 3H), 3.42 – 3.38 (m, 2H), 3.19 (td, J = 12.8, 3.7 Hz, 1H), 2.29 ( s, 3H), 1.21 (d, J = 6.6 Hz, 3H), 1.13 (d, J = 6.6 Hz, 3H). Example 38 (S)-1-(3-(3- methyl -1H- pyrazol -5- yl )-5-((R)-3- methyl 𠰌 linyl ) isothiazolo [4,5- b] Synthesis of pyridin -7- yl ) pyrrolidin -3- ol Step 1. (3S)-1-(3-(3- methyl- 1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R) -3- Methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridin -7- yl ) pyrrolidin- 3- ol

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a mixture of [4,5-b]pyridin-5-yl}-3-methylpyridin-3-ol (80 mg, 0.18 mmol) in cycloterine (2 mL) was added (3S)-pyrrolidin-3-ol (19 mg, 0.22 mmol) and DIEA (0.2 mL, 0.92 mmol) and KF (11 mg, 0.18 mmol). The mixture was stirred at 120 °C for 15 h. LC-MS showed the reaction was complete. The mixture was poured into water (30 mL) and extracted with EA (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by preparative-TLC (PE:EA = 1:1, V/V) to obtain (3S)-1-(3-(3-methyl-1-(tetrahydro-2H) as a yellow solid -pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl) Pyrrolidin-3-ol (30 mg, yield: 34%). LC/MS (ESI): m/z 485.8 [M+H] ⁺ . Step 2. (S)-1-(3-(3- methyl -1H- pyrazol -5- yl )-5-((R)-3- methyl 𠰌 linyl ) isothiazolo [4,5 -b] pyridin -7- yl ) pyrrolidin -3- ol

To (3S)-1-(3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3 To a solution of -methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)pyrrolidin-3-ol (30 mg, 0.06 mmol) in DCM (1 mL) was added HCl (4 M in dihexane, 1 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O containing 0.1% HCOOH) to give (S)-1-(3-(3-methyl-1H-pyrazole) -5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)pyrrolidin-3-ol (10 mg, yield: 20%). LC/MS (ESI): m/z 401.3 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 7.08 (s, 1H), 5.80 (s, 1H), 5.13 (d, J = 2.6 Hz, 1H), 4.45 (s, 2H), 4.05 – 3.86 (m , 2H), 3.82 – 3.65 (m, 5H), 3.57 – 3.42 (m, 2H), 3.15 (td, J = 12.6, 3.8 Hz, 1H), 2.30 (d, J = 19.1 Hz, 3H), 2.09 ( ddd, J = 12.9, 8.6, 4.5 Hz, 1H), 1.98 (d, J = 3.0 Hz, 1H), 1.17 (d, J = 6.6 Hz, 3H). Example 39 (R)-1-(3-(3- methyl -1H- pyrazol -5- yl )-5-((R)-3- methyl 𠰌 linyl ) isothiazolo [4,5- b] Synthesis of pyridin -7- yl ) pyrrolidin -3- ol Step 1. (3R)-1-(3-(3- methyl- 1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R) -3- Methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridin -7- yl ) pyrrolidin- 3- ol (ZYM-N191165-196)

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a mixture of [4,5-b]pyridin-5-yl}-3-methylpyroline (80 mg, 0.18 mmol) in cycloterine (2 mL) was added (R)-pyrrolidin-3-ol (19 mg, 0.22 mmol) and DIEA (0.2 mL, 0.92 mmol) and KF (11 mg, 0.18 mmol). The mixture was stirred at 120 °C for 15 h. LC-MS showed the reaction was complete. The mixture was poured into water (50 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by preparative-TLC (PE:EA = 1:1, V/V) to obtain (3R)-1-(3-(3-methyl-1-(tetrahydro-2H) as a yellow solid -pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl) Pyrrolidin-3-ol (30 mg, yield: 34%). LC/MS (ESI): m/z 485.8 [M+H] ⁺ . Step 2. (R)-1-(3-(3- methyl -1H- pyrazol -5- yl )-5-((R)-3- methyl 𠰌 linyl ) isothiazolo [4,5 -b] pyridin -7- yl ) pyrrolidin -3- ol (KYH-N211770-025-1)

To (3R)-1-(3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3 To a solution of -methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)pyrrolidin-3-ol (30 mg, 0.06 mmol) in DCM (1 mL) was added HCl (4 M in dihexane, 1 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O containing 0.1% HCOOH) to give (R)-1-(3-(3-methyl-1H-pyrazole) -5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)pyrrolidin-3-ol (10 mg, yield: 20%). LC/MS (ESI): m/z 401.3 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 7.08 (s, 1H), 5.80 (s, 1H), 5.14 (d, J = 3.3 Hz, 1H), 4.45 (s, 2H ), 3.97 (t, J = 10.9 Hz, 2H), 3.80 – 3.75 (m, 2H), 3.70 (dd, J = 11.4, 8.8 Hz, 3H), 3.57 – 3.50 (m, 2H), 3.20 – 3.12 ( m, 1H), 2.28 (s, 3H), 2.09 (td, J = 8.6, 4.3 Hz, 1H), 1.99 (s, 1H), 1.18 (d , J = 6.6 Hz, 3H). Example 40 (R)-4-(7-(3,3- difluoroazetidin -1- yl )-3-(3- methyl -1H- pyrazol -5- yl ) isothiazolo [ Synthesis of 4,5-b] pyridin -5- yl )-3- methyl 𠰌 line Step 1. (3R)-4-(7-(3,3- difluoroazetidin -1- yl )-3-(3- methyl -1-( tetrahydro -2H- piran -2) -yl ) -1H- pyrazol -5- yl ) isothiazolo [4,5-b] pyridin -5- yl )-3- methyl 𠰌 line

To 3,3-difluoroazetidine (21 mg, 0.23 mmol), (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran- 2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl}-3-methyl𠰌line (100 mg, 0.23 mmol) and To a solution of Ruphos (12 mg, 0.05 mmol) in DMF (1.5 mL) was added RuPhos-Pd-G ₃ (20 mg, 0.05 mmol). The reaction mixture was stirred at 80 °C for 16 h under _N2 atmosphere. LC-MS showed the reaction was complete. The reaction solution was diluted with H ₂ O (20 mL), and extracted with EA (20 mL×3). The combined organic layers were washed with water and brine (20 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0~100%, ethyl acetate/petroleum ether) to obtain (3R)-4-[7-(3,3-difluoro nitrogen) as a colorless viscous oil. Heterocyclobutan-1-yl)-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4 ,5-b]pyridin-5-yl]-3-methyl𠰌line (45 mg, yield: 40%). LC/MS (ESI): m/z 491 [M+1] ⁺ . Step 2. (R)-4-(7-(3,3- difluoroazetidin -1- yl )-3-(3- methyl -1H- pyrazol -5- yl ) isothiazolo [4,5-b] pyridin -5- yl )-3- methyl 𠰌 line

To (R)-4-(7-(3,3-difluoroazetidin-1-yl)-3-(3-methyl-1H-pyrazol-5-yl)isothiazolo[4 To a mixture of ,5-b]pyridin-5-yl)-3-methylpyroline (50 mg, 0.10 mmol) in DCM (1 mL) was added HCl (4 M in dioxane, 3 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The mixture was concentrated to dryness. The crude product was purified by preparative-HPLC (C ₁₈ , 10-95%, MeCN/H ₂ O containing 0.1% HCOOH) to give (R)-4-(7-(3,3-bis) as a yellow solid Fluorazetidin-1-yl)-3-(3-methyl-1H-pyrazol-5-yl)isothiazolo[4,5-b]pyridin-5-yl)-3-methyl 𠰌line (9 mg, yield: 22%). LC/MS (ESI) m/z: 407 [M+1] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 7.11 (s, 1H), 6.04 (s, 1H), 4.66 (t, J = 12.2 Hz, 4H), 4.47 (d, J = 4.6 Hz, 1H), 4.01 (d, J = 11.0 Hz, 2H), 3.79 (d, J = 11.2 Hz, 1H), 3.68 (dd, J = 11.3, 2.8 Hz, 1H), 3.52 (dt, J = 11.6, 6.0 Hz, 1H ), 3.18 (dd, J = 12.5, 9.0 Hz, 1H), 2.29 (s, 3H), 1.20 (d, J = 6.6 Hz, 3H). Example 41 Ethyl ((3-(3- methyl -1H- pyrazol -5- yl )-5-((R)-3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridine Synthesis of -7- yl ) imino )( phenyl ) -λ ^6- sulfanone Step 1. Ethyl ((3-(3- methyl -1( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R)-3- methyl yl( pyridin -7- yl ) isothiazolo [4,5-b] pyridin -7- yl ) imino )( phenyl ) -λ ^6- sulfanone

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (150 mg, 0.35 mmol) in dioxane (3 mL) was added ethyl(imino)phenyl- λ^6-Thionone (70 mg, 0.42 mmol), Cs ₂ CO ₃ (338 mg, 1.0 mmol), Pd ₂ (dba) ₃ (32 mg, 0.035 mmol), and Xantphos (40 mg, 0.07 mmol). The reaction was stirred at 100°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction was filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain ethyl ((3-(3-methyl-1-(tetrahydro-2H)) as a yellow solid -pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl) Imino)(phenyl)-λ^6-sulfanone (190 mg, yield: 97%). LC/MS (ESI): m/z 567.7 (M+H) ⁺ . Step 2. Ethyl ((3-(3- methyl -1H- pyrazol -5- yl )-5-((R)-3- methyl 𠰌 linyl ) isothiazolo [4,5-b] Pyridin -7- yl ) imino )( phenyl ) -λ ^6- sulfanone

To ethyl((3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl 𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)imino)(phenyl)-λ^6-sulfanone (190 mg, 0.34 mmol) in DCM (4 mL) To the solution was added HCl (4 M in dioxane, 4 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by SFC to obtain 41a (22 mg, yield: 13%) and 41b (15 mg, yield: 9%). LC/MS (ESI): m/z 483.6 (M+H) ⁺ .

41a :

¹ H NMR (400 MHz, DMSO-d6) δ 8.00 – 7.87 (m,2H), 7.75 (t, J = 7.4 Hz, 1H), 7.67 (t, J = 7.5 Hz, 2H), 7.02 (s, 1H ), 6.16 (s, 1H), 3.94 (d, J = 7.8 Hz, 1H), 3.85 (d, J = 12.0 Hz, 2H), 3.81 – 3.73 (m, 2H), 3.63 (dt, J = 11.4, 7.1 Hz, 2H), 3.44 (dd, J = 11.8, 9.0 Hz, 1H), 3.07 – 2.89 (m, 1H), 2.27 (s, 3H), 1.25 (t, J = 7.3 Hz, 3H), 0.71 ( d, J = 6.6 Hz, 3H).

41b :

¹ H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.04 – 7.90 (m, 2H), 7.75 (d, J = 7.3 Hz, 1H), 7.68 (t, J = 7.6 Hz, 2H ), 7.04 (s, 1H), 6.27 (s, 1H), 4.02 (d, J = 5.2 Hz, 1H), 3.93 (dd, J = 11.3, 3.3 Hz, 1H), 3.81 – 3.74 (m, 3H) , 3.71 (d, J = 11.2 Hz, 1H), 3.56 (dd, J = 11.4, 2.8 Hz, 1H), 3.46 (td, J = 11.7, 2.8 Hz, 1H), 2.98 (td, J = 12.6, 3.7 Hz, 1H), 2.27 (s, 3H), 1.23 (t, J = 7.3 Hz, 3H), 1.10 (d, J = 6.6 Hz, 3H). Example 42 Methyl ((3-(3- methyl -1H- pyrazol -5- yl )-5-((R)-3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridine Synthesis of -7- yl ) imino )( pyridin -2- yl ) -λ ^6- sulfanone Step 1. Imino ( methyl )( pyridin -2- yl )-λ^6- sulfanone

To a suspension of 2-(methylsulfanyl)pyridine (1 g, 8.0 mmol) in MeOH (10 mL) was added (diethyloxyiodide)benzene (6 g, 18.40 mmol) and ammonium carbonate ( 1 g, 12.00 mmol). The mixture was stirred at room temperature for 10 minutes under air. LC-MS showed the reaction was complete. The reaction was poured into water and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100%, ethyl acetate/petroleum ether) to obtain imino(methyl)(pyridin-2-yl)-λ^6 as a yellow solid - Thianone (520 mg, yield: 42%). LC/MS (ESI): m/z 157.2 (M+H) ⁺ . Step 2. Methyl ((3-(3- methyl -1( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R)-3- methyl yl( pyridin -2-yl ) isothiazolo [4,5-b] pyridin -7- yl ) imino )( pyridin - 2- yl ) -λ ^6- sulfanone

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methylpyridine (200 mg, 0.46 mmol) in dimethane (5 mL) was added imino(methyl)(pyridine- 2-yl)-λ^6-thianone (86 mg, 0.55 mmol), Cs ₂ CO ₃ (450 mg, 1.4 mmol), Pd ₂ (dba) ₃ (42 mg, 0.05 mmol), and Xantphos (53 mg ,0.09 mmol). The reaction was stirred at 100°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The reaction was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100%, ethyl acetate/petroleum ether) to obtain methyl ((3-(3-methyl-1(tetrahydro-2H)) as a yellow solid -pyran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl) Imino)(pyridin-2-yl)-λ^6-sulfanone (200 mg, yield: 78%). LC/MS (ESI): m/z 554.2 (M+H) ⁺ . Step 3. Methyl ((3-(3- methyl -1H- pyrazol -5- yl )-5-((R)-3- methyl 𠰌 linyl ) isothiazolo [4,5-b] Pyridin -7- yl ) imino )( pyridin -2- yl ) -λ ^6- sulfanone

To methyl((3-(3-methyl-1(tetrahydro-2H-piran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌 Phylyl)isothiazolo[4,5-b]pyridin-7-yl)imino)(pyridin-2-yl)-λ^6-sulfanone (200 mg, 0.36 mmol) in DCM (3 mL ), add HCl/dioxane (3 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeOH/H ₂ O containing 0.1% HCOOH) to give the crude product. The crude product was purified by SFC to obtain 42a (18 mg, yield: 11%) and 42b (26 mg, yield: 16%) as white solids. LC/MS (ESI): m/z 470.3 (M+H) ⁺ .

42a :

¹ H NMR (400 MHz, DMSO-d6) δ 12.95 (d, J = 101.2 Hz, 1H), 8.80 (d, J = 4.1 Hz, 1H), 8.30 (t, J = 26.0 Hz, 1H), 8.20 ( t, J = 7.7 Hz, 1H), 7.76 (dd, J = 7.4, 4.8 Hz, 1H), 7.03 (s, 1H), 6.33 (s, 1H), 4.14 (s, 1H), 3.96 (d, J = 9.0 Hz, 1H), 3.82 (d, J = 11.9 Hz, 1H), 3.74 (d, J = 11.5 Hz, 1H), 3.71 (s, 3H), 3.60 (d, J = 10.8 Hz, 1H), 3.49 (t, J = 10.6 Hz, 1H), 3.02 (t, J = 11.1 Hz, 1H), 2.26 (s, 3H), 1.12 (d, J = 6.6 Hz, 3H).

42b :

¹ H NMR (400 MHz, DMSO-d6) δ 12.94 (d, J = 100.0 Hz, 1H), 8.78 (d, J = 3.8 Hz, 1H), 8.40 (d, J = 7.9 Hz, 1H), 8.21 ( td, J = 7.8, 1.7 Hz, 1H), 7.94 – 7.58 (m, 1H), 7.01 (s, 1H), 6.26 (s, 1H), 4.07 – 3.92 (m, 2H), 3.88 (d, J = 12.5 Hz, 1H), 3.78 – 3.61 (m, 5H), 3.47 (td, J = 11.6, 2.6 Hz, 1H), 3.10 – 2.92 (m, 1H), 2.26 (s, 3H), 0.80 (dd, J = 19.5, 6.9 Hz, 3H). Example 43 (S)-3- methyl- 4-(3-(3- methyl -1H- pyrazol -5- yl )-5-((R)-3- methyl 𠰌 linyl ) isothiazolo Synthesis of [4,5-b] pyridin -7- yl ) 𠰌 line Step 1. (3S)-3- methyl- 4-(3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5 -((R)-3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridin -7- yl ) 𠰌 line

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (100 mg, 0.23 mmol) in DMF (5 mL) was added (3S)-3-methyl𠰌line (47 mg, 0.46 mmol), Cs ₂ CO ₃ (150 mg, 0.46 mmol), RuPhos (22 mg, 0.05 mmol), and RuPhos-Pd-G ₃ (19 mg, 0.02 mmol). The reaction was stirred at 80°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. The mixture was poured into water (30 mL) and extracted with EA (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100%, ethyl acetate/petroleum ether) to obtain (3S)-3-methyl-4-(3-(3-methyl) as a yellow solid. Base-1-(tetrahydro-2H-piran-2-yl)-1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5 -b]pyridin-7-yl)𠰌line (70 mg, yield: 61%). LC/MS (ESI): m/z 499.7 (M+H) ⁺ . Step 2. (S)-3- methyl -4-(3-(3- methyl -1H- pyrazol -5- yl )-5-((R)-3- methyl 𠰌 linyl ) isothiazole And [4,5-b] pyridin -7- yl ) 𠰌 line

To (3S)-3-methyl-4-(3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-5-( To a solution of (R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)𠰌line (80 mg, 0.16 mmol) in DCM (2 mL) was added HCl ( 4 M in dihexane, 2 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The reaction was concentrated in vacuo. The residue was purified by preparative-HPLC (C ₁₈ , 10-95%, MeCN/H ₂ O containing 0.1% CHOOH) to give (S)-3-methyl-4-(3-(3-methyl -1H-pyrazol-5-yl)-5-((R)-3-methyl𠰌linyl)isothiazolo[4,5-b]pyridin-7-yl)𠰌line (22 mg, yield :33%). LC/MS (ESI): m/z 415.6 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 7.10 (s, 1H), 6.30 (s, 1H), 4.47 (d, J = 5.4 Hz, 1H), 4.01 (dd, J = 13.0, 5.6 Hz, 4H), 3.79 (d, J = 10.7 Hz, 3H), 3.70 (dd, J = 11.3, 2.6 Hz, 1H), 3.63 (dt, J = 11.4, 7.8 Hz, 1H), 3.59 – 3.49 (m, 1H), 3.40 (d, J = 5.5 Hz, 2H), 3.19 (td, J = 12.7, 3.6 Hz, 1H), 2.29 (s, 3H), 1.15 (dd, J = 24.0, 6.6 Hz, 6H). Example 44 (R) -diethyl ((3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] Synthesis of pyridin -7- yl ) imino )-l6- sulfanone Step 1. Diethyl ( imino )-16- sulfanone

To a mixture of (ethylsulfanyl)ethane (1 g, 11.09 mmol) and ammonium carbamate (1.7 g, 12.81 mmol) in MeOH (10 mL) was added PhI(OAc) ₂ (8.9 g, 27.63 mmol). The mixture was stirred at 25°C for 3 hours. LC-MS showed the reaction was complete. The mixture was filtered and concentrated. The residue was then purified by flash chromatography (silica gel (12 g), 0-50%, EA/PE) to obtain diethyl(imino)-λ^6-thianone (512 mg, yield: 38%). LC/MS (ESI): m/z 121.2 [M+1] ⁺ . Step 2. Diethyl ((3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R)-3 -Methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridin -7- yl ) imino ) -l6- sulfanone

To diethyl(imino)-λ^6-sulfanone (27 mg, 0.223 mmol), (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropentane) Pyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl}-3-methyl𠰌line (80 mg, 0.18 mmol ), CS ₂ CO ₃ (180 mg, 0.55 mmol) and XantPhos (21 mg, 0.04 mmol) in dihexane (1 mL) was added Pd ₂ (dba) ₃ (17 mg, 0.02 mmol). The mixture was stirred at 80 °C for 16 h under _N2 . LC-MS showed the reaction was complete. The mixture was poured into _H2O (50 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel (4 g), 0-10%, MeOH/DCM) to afford diethyl ({3-[3-methyl-1-(tetrahydropipaniline)) as a yellow solid. Pyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b] Pyridin-7-yl}imino)-λ^6-sulfanone (30 mg, yield: 26%). LC/MS (ESI): m/z 518.7 [M+H] ⁺ . Step 3. (R) -diethyl ((3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b ] Pyridin -7- yl ) imino )-l6- sulfanone

To diethyl({3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌line -4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl}imino)-λ^6-sulfanone (50 mg, 0.10 mmol) in DCM (1 mL ), add HCl/dioxane (1 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The mixture was concentrated to dryness. The crude product was then purified by preparative-HPLC (C ₁₈ , 10-95%, MeCN/H ₂ O with 0.1% HCOOH) to give diethyl ({[3-(3-methyl-1H-pyrazole -5-yl)-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl]imino}) -λ^6-thianone (27.9 mg, 0.06 mmol, 67%). LC/MS (ESI): m/z 434.59 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 7.08 (s, 1H), 6.58 (s, 1H), 4.32 (d, J = 5.6 Hz, 1H), 3.97 (dd, J = 27.2, 10.1 Hz, 2H ), 3.79 (d, J = 11.3 Hz, 1H), 3.70 (dd, J = 11.3, 2.6 Hz, 1H), 3.55 (q, J = 7.4 Hz, 5H), 3.22 – 3.11 (m, 1H), 2.29 (s, 3H), 1.31 (t, J = 7.3 Hz, 6H), 1.19 (d, J = 6.6 Hz, 3H). Example 45 Methyl [ methyl ({1-[3-(3- methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin- 4 - yl ]-[ Synthesis of 1,2] thiazolo [4,5-b] pyridin -7- yl ] cyclopropyl }) pendant oxy -λ^6- sulfanylidene ] amine Step 1. Methyl [ methyl (1-{3-[3- methyl -1-( tetrahydropyran -2- yl )-1H- pyrazol -5- yl ]-5-[(3R)- 3- Methyl 𠰌 lin -4- yl ]-[1,2] thiazolo [4,5-b] pyridin -7- yl } cyclopropyl ) pendant oxy -λ^6- sulfanylidene ] amine

To imido(methyl)(1-{3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)- 3-Methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl}cyclopropyl)-λ^6-sulfanone (30 mg, 0.06 mmol ) To a suspension in THF (3 mL) was added CH ₃ I (0.007 mL, 0.12 mmol) and t-BuOK (26 mg, 0.23 mmol). After the addition was complete, the mixture was stirred at room temperature for 3 hours. LC-MS showed the reaction was complete. Dilute the reaction with EA (50 mL) and water (50 mL). The organic phase was washed with brine (50 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to give crude product. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain methyl [methyl (1-{3-[3-methyl-1- (Tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4, 5-b]pyridin-7-yl}cyclopropyl) pendant oxy-λ^6-sulfanylidene]amine (30 mg, yield: 97%). LC/MS (ESI): m/z 531(M+H) ⁺ . Step 2. Methyl [ methyl ({1-[3-(3- methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl ]- [1,2] thiazolo [4,5-b] pyridin -7- yl ] cyclopropyl }) pendant oxy -λ^6- sulfanylidene ] amine

To methyl[methyl(1-{3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3- Methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl}cyclopropyl) pendant oxy-λ^6-sulfanylidene]amine (30 To a solution of mg, 0.06 mmol) in DCM (2 mL) was added HCl/dioxane (2 mL). The mixture was stirred at room temperature for 1 hour. LC-MS showed the reaction was complete. The reaction was concentrated in vacuo to give a crude product, which was purified by preparative-HPLC (C18, 10-95%, MeCN/H ₂ O with 0.1% CHOOH) to give methyl [methyl ({1- [3-(3-Methyl-1H-pyrazol-5-yl)-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5- b]Pyridin-7-yl]cyclopropyl}) pendant oxy-λ^6-sulfanylidene]amine (6 mg, yield: 23%). LC/MS (ESI): m/z 447(M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 12.98 (s, 1H), 7.43 (d, J = 5.0 Hz, 1H), 7.09 (s, 1H), 4.50 (s, 1H), 4.13 (d, J = 12.6 Hz, 1H), 4.03 (d, J = 10.9 Hz, 1H), 3.82 (d, J = 11.4 Hz, 1H), 3.71 (d, J = 9.2 Hz, 1H), 3.57 (t, J = 10.4 Hz, 1H), 3.26 – 3.16 (m, 1H), 2.96 (d, J = 9.5 Hz, 3H), 2.69 (d, J = 6.1 Hz, 3H), 2.30 (s, 3H), 1.76 (d, J = 10.2 Hz, 1H), 1.72 – 1.59 (m, 1H), 1.45 (q, J = 9.7 Hz, 2H), 1.30 – 1.13 (m, 3H). Example 46 (R)-1-(3-(3- methyl - 1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridine- Synthesis of 7- yl ) azetidin -3- ol Step 1. 1-(3-(3- methyl- 1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R)-3- methyl yl( 𠰌 linyl ) isothiazolo [4,5-b] pyridin -7- yl ) azetidin- 3- ol

To azetidin-3-ol (45 mg, 0.616 mmol), (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)- 1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl}-3-methyl𠰌line (90 mg, 0.21 mmol) and CS ₂ CO ₃ ( To a mixture of 315 mg, 0.97 mmol) in DMF (1 mL) was added RuPhos (18 mg, 0.04 mmol) and RuPhos-Pd-G3 (18 mg, 0.02 mmol). The mixture was stirred at 80 °C for 16 h under _N2 . LC-MS showed the reaction was complete. The mixture was poured into _H2O (30 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (30 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by flash chromatography (silica gel (12 g), 0-100%, EA/PE) to obtain 1-{3-[3-methyl-1-(tetrahydropyran-) as a yellow liquid 2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridine- 7-yl}azetidin-3-ol (51 mg, yield: 18%). LC/MS (ESI): m/z 471.2 [M+H] ⁺ . Step 2. (R)-1-(3-(3- methyl -1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridine -7- yl ) azetidin -3- ol

To 1-{3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌line-4 -[1,2]thiazolo[4,5-b]pyridin-7-yl}azetidin-3-ol (51 mg, 0.11 mmol) in DCM (1 mL) Add HCl/dioxane (1 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The mixture was concentrated to dryness. The crude product was then purified by preparative-HPLC (C18, 10-95%, MeCN/H ₂ O containing 0.1% HCOOH) to give 1-[3-(3-methyl-1H-pyrazol-5-yl) )-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl]azetidin-3-ol (9.3 mg, yield: 22%). LC/MS (ESI): m/z 387.4 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 7.05 (s, 1H), 5.80 (s, 1H), 4.67 (s, 1H), 4.42 (t, J = 7.3 Hz, 3H), 4.04 – 3.91 (m , 4H), 3.78 (d, J = 11.3 Hz, 1H), 3.69 (dd, J = 11.4, 2.7 Hz, 1H), 3.58 – 3.45 (m, 2H), 2.29 (s, 3H), 1.19 (d, J = 6.6 Hz, 3H). Example 47 Methyl (1- methyl -1H- pyrazol -4- yl )((3-(3- methyl -1H- pyrazol -5- yl )-5-((R)-3- methyl Synthesis of 𠰌 linyl ) isothiazolo [4,5-b] pyridin -7- yl ) imino )-l6- thianone Step 1. 1- Methyl -4-( methylthio )-1H- pyrazole

To 4-iodo-1-methyl-1H-pyrazole (1.5 g, 7.21 mmol), CH ₃ SNa (750 mg, 7.21 mmol) and Xantphos (0.5 g, 0.86 mmol) in dihexane (15 mL) Pd ₂ (dba) ₃ (0.4 g, 0.44 mmol) was added to the mixture. The mixture was stirred at 80 °C for 16 h under _N2 . LC-MS showed the reaction was complete. The mixture was poured into _H2O (50 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by flash chromatography (silica gel (40 g), 0-60%, EA/PE) to obtain 1-methyl-4-(methylsulfanyl)-1H-pyrazole as a yellow solid (160 mg, yield: 17%). LC/MS (ESI): m/z 129.2 [M+H] ⁺ . Step 2. Imino ( methyl )(1- methyl -1H- pyrazol -4- yl )-16- sulfanone

To a mixture of 1-methyl-4-(methylsulfanyl)-1H-pyrazole (100 mg, 0.78 mmol) and PhI(OAc) ₂ (643 mg, 0.78 mmol) in MeOH (1 mL) _NH2COONH4 ( ₁₅₅ mg, 0.78 mmol) was added. The mixture was stirred at 25°C for 3 hours. LC-MS showed the reaction was complete. The mixture was poured into _H2O (50 mL) and extracted with DCM (50 mL x 3). The mixture was filtered and concentrated to dryness to give imino(methyl)(1-methyl-1H-pyrazol-4-yl)-λ^6-sulfanone (115 mg, yield: 93%). LC/MS (ESI): m/z 160.2 [M+1] ⁺ . Step 3. Methyl ((3-(3- methyl -1( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-5-((R)-3- methyl ( 1 - Methyl-1H- pyrazol-4 - yl ) isothiazolo [4,5-b] pyridin -7 - yl ) imino ) -16 - sulfanone

To imino(methyl)(1-methyl-1H-pyrazol-4-yl)-λ^6-sulfanone (110 mg, 0.69 mmol), (3R)-4-{7-chloro- 3-[3-Methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl }-3-Methylpyroline (100 mg, 0.23 mmol), xantphos (26 mg, 0.05 mmol) and Pd ₂ (dba) ₃ (21 mg, 0.02 mmol) in a mixture of dioxane (1 mL) _CS2CO3 (230 mg _, 0.71 mmol) was added. The mixture was stirred at 100 °C for 16 h under _N2 . LC-MS showed the reaction was complete. The mixture was filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel (4 g), 0-100%, EA/PE) to obtain methyl ({3-[3-methyl-1-(tetrahydropyran)) as a yellow solid -2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridine -7-yl}imino)(1-methyl-1H-pyrazol-4-yl)-λ^6-sulfanone (131 mg, yield: 34%). LC/MS (ESI): m/z 556.8 [M+H] ⁺ . Step 4. Methyl (1- methyl -1H- pyrazol -4- yl )((3-(3- methyl -1H- pyrazol -5- yl )-5-((R)-3- methyl yl (𠰌 linyl ) isothiazolo [4,5-b] pyridin -7- yl ) imino )-l6- sulfanone

To methyl({3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌line- 4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl}imino)(1-methyl-1H-pyrazol-4-yl)-λ^6-sulfide To a mixture of alkanone (131 mg, 0.235 mmol) in DCM (2 mL) was added HCl (2 mL). The mixture was stirred at room temperature for 1 h. LC-MS showed the reaction was complete. The mixture was concentrated to dryness. The crude product was then purified by preparative-HPLC (C ₁₈ , 10-95%, MeCN/H ₂ O containing 0.1% HCOOH) to afford 47a (18 mg, yield: 17%) and 47b (12 mg, yield: rate: 11%). LC/MS (ESI): m/z 472.8 [M+H] ⁺ .

47a :

¹ H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.96 (s, 1H), 7.05 (s, 1H), 6.40 (s, 1H), 4.14 (d, J = 6.0 Hz, 1H ), 3.97 (d, J = 8.5 Hz, 1H), 3.86 (d, J = 15.4 Hz, 4H), 3.76 (d, J = 11.2 Hz, 1H), 3.64 (d, J = 6.5 Hz, 4H), 3.51 (t, J = 11.0 Hz, 1H), 3.08 (t, J = 10.7 Hz, 1H), 2.28 (s, 3H), 1.15 (d, J = 6.6 Hz, 3H).

47b :

¹ H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.93 (s, 1H), 7.04 (s, 1H), 6.31 (s, 1H), 3.98 (d, J = 8.3 Hz, 2H ), 3.93 – 3.85 (m, 4H), 3.73 (d, J = 11.1 Hz, 1H), 3.66 (d, J = 11.8 Hz, 4H), 3.50 (t, J = 10.4 Hz, 1H), 3.05 (dd , J = 12.8, 9.1 Hz, 1H), 2.27 (s, 3H), 0.91 (d, J = 6.6 Hz, 3H). Example 48 4,4 - Difluoro -1-[3-(3- methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl ]-[ Synthesis of 1,2] thiazolo [4,5-b] pyridin -7- yl ] cyclohexan -1 -ol Step 1. (3R)-4-[7-(4,4- difluorocyclohex -1- en -1- yl )-3-[3- methyl -1-( tetrahydropyran -2- yl) )-1H- pyrazol -5- yl ]-[1,2] thiazolo [4,5-b] pyridin -5- yl ]-3- methyl 𠰌 line

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (150 mg, 0.35 mmol) in dioxane (3 mL) was added 2-(4,4-difluorocyclic Hex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (169 mg, 0.69 mmol), Pd(PPh ₃ ) ₄ (40 mg, 0.04 mmol) and K ₂ CO ₃ (48 mg, 0.35 mmol). The reaction was stirred at 100°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. Dilute the reaction with EA (50 mL) and water (50 mL). The organic phase was washed with brine (50 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain (3R)-4-[7-(4,4-difluorocyclohexane-) as a yellow solid 1-en-1-yl)-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4, 5-b]pyridin-5-yl]-3-methyl𠰌line (150 mg, yield: 84%). LC/MS (ESI): m/z 516(M+H) ⁺ . Step 2. 4,4- Difluoro -1-{3-[3- methyl -1-( tetrahydropyran -2- yl )-1H- pyrazol -5- yl ]-5-[(3R) -3- Methyl 𠰌 lin -4- yl ]-[1,2] thiazolo [4,5-b] pyridin- 7- yl } cyclohexan -1- ol

To (3R)-4-[7-(4,4-difluorocyclohex-1-en-1-yl)-3-[3-methyl-1-(tetrahydropyran-2-yl)- 1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl]-3-methyl𠰌line (150 mg, 0.29 mmol) in isopropyl alcohol (1 mL) and a suspension in DCM (5 mL) were added phenylsilane (0.07 mL, 0.58 mmol) and Mn(TMHD) ₃ (18 mg, 0.03 mmol). After the addition was complete, the mixture was stirred at room temperature overnight. LC-MS showed the reaction was complete. The organic phase was washed with brine (50 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain 4,4-difluoro-1-{3-[3-methyl-1 as a yellow solid -(Tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4 ,5-b]pyridin-7-yl}cyclohexan-1-ol (70 mg, yield: 45%). LC/MS (ESI): m/z 534(M+H) ⁺ . Step 3. 4,4- Difluoro -1-[3-(3- methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl ]- [1,2] thiazolo [4,5-b] pyridin -7- yl ] cyclohexan -1- ol

To 4,4-difluoro-1-{3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3 -Methylpyridin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl}cyclohexan-1-ol (70 mg, 0.13 mmol) in DCM (3 mL) Add HCl/dioxane (3 mL) to the solution. The mixture was stirred at room temperature for 1 hour. LC-MS showed the reaction was complete. The reaction was concentrated in vacuo to give a crude product, which was purified by preparative-HPLC (C18, 10-95%, MeCN/H ₂ O with 0.1% CHOOH) to give 4,4-difluoro-1- [3-(3-Methyl-1H-pyrazol-5-yl)-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5- b]pyridin-7-yl]cyclohexan-1-ol (12 mg, yield: 20%). LC/MS (ESI): m/z 450(M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 7.08 (d, J = 12.5 Hz, 2H), 6.30 (s, 1H), 4.58 (d, J = 6.4 Hz, 1H), 4.12 (d, J = 12.0 Hz, 1H), 4.01 (d, J = 8.1 Hz, 1H), 3.79 (d, J = 11.4 Hz, 1H), 3.70 (d, J = 8.6 Hz, 1H), 3.55 ( t, J = 10.4 Hz, 1H), 3.26 – 3.13 (m, 1H), 2.39 – 2.09 (m, 7H), 1.98 (dd, J = 55.2, 16.6 Hz, 4H), 1.20 (d, J = 6.6 Hz ,3H). Example 49 1- Cyclopropyl -4-[3-(3- methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl ]-[1 ,Synthesis of 2] thiazolo [4,5-b] pyridin -7- yl ] piperidin- 4- ol Step 1. (3R)-3- methyl- 4-(3-(3- methyl -1-( tetrahydro -2H- pyran -2- yl )-1H- pyrazol -5- yl )-7 -(1,2,3,6- tetrahydropyridin -4- yl ) isothiazolo [4,5-b] pyridin -5- yl ) 𠰌 line

To ( _3R )-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]- [1,2]thiazolo[4,5-b]pyridin-5-yl}-3-methyl𠰌line (250 mg, 0.58 mmol) and 4-(tetramethyl-1,3,2-dioxo To a solution of cyclopentane-2-yl)-1,2,3,6-tetrahydropyridine (144 mg, 0.69 mmol) in dimethane (2 mL) and H ₂ O (0.5 mL) was added Pd(PPh ₃ ) ₄ (67 mg, 0.06 mmol), followed by dipotassium carbonate (398 mg, 2.88 mmol). The mixture was refluxed and stirred for 16 hours until the starting material was completely consumed. The reaction mixture was cooled to room temperature and concentrated in vacuo to remove most of the solvent. The residue was poured into water (20 mL) and extracted with EA (20 mL). The organic layer was dried over _Na2SO4 , filtered _and concentrated. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain (3R)-3-methyl-4-{3-[3-methyl as a yellow solid -1-(Tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-7-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2]thiazole And[4,5-b]pyridin-5-yl}𠰌line (150 mg, yield: 54%). Step 2. (3R)-4-(7-(1- cyclopropyl -1,2,3,6- tetrahydropyridin -4- yl )-3-(3- methyl -1-( tetrahydropyridin- 4-yl ) 2H- pyran -2- yl )-1H- pyrazol -5- yl ) isothiazolo [4,5-b] pyridin -5- yl )-3- methyl 𠰌 line

To (3R)-3-methyl-4-{3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl] with stirring under _N -7-(1,2,3,6-tetrahydropyridin-4-yl)-[1,2]thiazolo[4,5-b]pyridin-5-yl}𠰌line (150 mg, 0.31 mmol) To a solution of cyclopropylboronic acid (80 mg, 0.94 mmol) in DCE (3 mL), disodium carbonate (165 mg, 1.56 mmol) was added, followed by Py (71 mg, 0.62 mmol) and Cu(OAc) ₂ (6 mg, 0.03 mmol). The mixture was refluxed and stirred at 70°C for 16 hours until the starting material was completely consumed. The reaction mixture was cooled to room temperature and concentrated in vacuo to remove most of the solvent. The residue was poured into water (20 mL) and extracted with EA (20 mL). The organic layer was dried over _Na2SO4 , filtered _and concentrated. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain (3R)-4-(7-(1-cyclopropyl-1) as a yellow oil ,2,3,6-tetrahydropyridin-4-yl)-3-(3-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)iso Thiazolo[4,5-b]pyridin-5-yl)-3-methyl𠰌line (90 mg, yield: 56%). Step 3. 1- Cyclopropyl -4-{3-[3- methyl -1-( tetrahydropyran -2- yl )-1H- pyrazol -5- yl ]-5-[(3R)- 3- Methyl 𠰌 lin -4- yl ]-[1,2] thiazolo [4,5-b] pyridin -7- yl } piperidin -4- ol

To (3R)-4-[7-(1-cyclopropyl-1,2,3,6-tetrahydropyridin-4-yl)-3-[3-methyl-1-(tetrahydropyran- 2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl]-3-methylpyrazoline (90 mg, 0.17 mmol) in To a suspension in isopropanol (0.5 mL) and DCM (2.5 mL) was added phenylsilane (0.02 mL, 0.17 mmol) and Mn(TMHD) ₃ (104 mg, 0.17 mmol). After the addition was complete, the mixture was stirred at room temperature overnight. LC-MS showed the reaction was complete. Dilute the reaction with EA (30 mL) and water (30 mL). The organic phase was washed with brine (30 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to give crude product. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain 1-cyclopropyl-4-{3-[3-methyl-1- as a yellow solid (Tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4, 5-b]pyridin-7-yl}piperidin-4-ol (50 mg, 54%). LC/MS (ESI): m/z 539(M+H) ⁺ . Step 4. 1- Cyclopropyl -4-[3-(3- methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl ]-[ 1,2] thiazolo [4,5-b] pyridin -7- yl ] piperidin -4- ol

To 1-cyclopropyl-4-{3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3- Methylpyridin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl}piperidin-4-ol (50 mg, 0.09 mmol) in DCM (2 mL) Add HCl/dioxane (2 mL) to the solution. The mixture was stirred at room temperature for 1 hour. LC-MS showed the reaction was complete. The reaction was concentrated in vacuo to give a crude product, which was purified by preparative-HPLC (C18, 10-95%, MeCN/ _H2O with 0.1% HCOOH) to give 1-cyclopropyl-4-[ 3-(3-Methyl-1H-pyrazol-5-yl)-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b ]pyridin-7-yl]piperidin-4-ol (6 mg, yield: 14%). LC/MS (ESI): m/z 455(M+H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.07 (s, 1H), 7.00 (s, 1H), 5.94 (s, 1H), 4.53 (s, 1H), 4.11 (d, J = 12.6 Hz, 1H) , 3.99 (d, J = 8.5 Hz, 1H), 3.77 (d, J = 11.3 Hz, 1H), 3.68 (d, J = 9.0 Hz, 1H), 3.53 (t, J = 10.2 Hz, 1H), 3.18 (t, J = 11.0 Hz, 1H), 2.73 (d, J = 57.7 Hz, 4H), 2.28 (s, 4H), 2.02 (s, 2H), 1.71 (s, 3H), 1.18 (d, J = 6.6 Hz, 3H), 0.38 (d, J = 57.6 Hz, 4H). Example 50 1- Methyl -4-[3-(3- methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl ]-[1, 2] Synthesis of thiazolo [4,5-b] pyridin -7- yl ] piperidin -4- ol Step 1. (3R)-3- methyl -4-[7-(1- methyl -1,2,3,6- tetrahydropyridin -4- yl )-3-[3- methyl -1- ( Tetrahydropyran -2- yl )-1H- pyrazol -5- yl ]-[1,2] thiazolo [4,5-b] pyridin -5- yl ] 𠰌 line

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (100 mg, 0.23 mmol) in dioxane (2 mL) was added 1-methyl-4-(tetramethyl (1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (103 mg, 0.46 mmol), Pd(PPh ₃ ) ₄ (27 mg, 0.02 mmol) and K ₂ CO ₃ (95 mg, 0.69 mmol). The reaction was stirred at 100°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. Dilute the reaction with EA (50 mL) and water (50 mL). The organic phase was washed with brine (50 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain (3R)-3-methyl-4-[7-(1-methyl) as a yellow solid -1,2,3,6-tetrahydropyridin-4-yl)-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[ 1,2]thiazolo[4,5-b]pyridin-5-yl]𠰌line (110 mg, yield: 96%). LC/MS (ESI): m/z 495(M+H) ⁺ . Step 2. 1- Methyl -4-{3-[3- methyl -1-( tetrahydropyran -2- yl )-1H- pyrazol -5- yl ]-5-[(3R)-3 -Methyl 𠰌 lin -4- yl ]-[1,2] thiazolo [4,5-b] pyridin - 7-yl } piperidin - 4- ol

To (3R)-3-methyl-4-[7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-[3-methyl-1-(tetrahydropyridin-4-yl) Hydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl]𠰌line (110 mg, 0.22 mmol) in iso To a suspension in propanol (1 mL) and DCM (5 mL) was added phenylsilane (0.03 mL, 0.22 mmol) and Mn(TMHD) ₃ (134 mg, 0.22 mmol). After the addition was complete, the mixture was stirred at room temperature overnight. LC-MS showed the reaction was complete. Dilute the reaction with EA (50 mL) and water (50 mL). The organic phase was washed with brine (50 mL), dried over anhydrous _Na2SO4 , filtered and concentrated _in vacuo to give crude product. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain 1-methyl-4-{3-[3-methyl-1-( Tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5 -b]pyridin-7-yl}piperidin-4-ol (80 mg, yield: 70%). LC/MS (ESI): m/z 513(M+H) ⁺ . Step 3. 1- Methyl -4-[3-(3- methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl ]-[1 ,2] thiazolo [4,5-b] pyridin -7- yl ] piperidin -4- ol

To 1-methyl-4-{3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl [1,2]thiazolo[4,5-b]pyridin-7-yl}piperidin-4-ol (80 mg, 0.16 mmol) in DCM (4 mL) HCl/dioxane (4 mL) was added to the solution. The mixture was stirred at room temperature for 1 hour. LC-MS showed the reaction was complete. The reaction was concentrated in vacuo to give a crude product, which was purified by preparative-HPLC (C18, 10-95%, MeCN/H ₂ O with 0.1% CHOOH) to give 1-methyl-4-[3 -(3-Methyl-1H-pyrazol-5-yl)-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b] Pyridin-7-yl]piperidin-4-ol (22 mg, yield: 33%). LC/MS (ESI): m/z 429(M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 7.07 (d, J = 15.5 Hz, 2H), 5.97 (s, 1H), 4.54 (d, J = 6.5 Hz, 1H), 4.12 (d, J = 11.8 Hz, 1H), 4.01 (dd, J = 11.2, 3.0 Hz, 1H), 3.79 (d, J = 11.3 Hz, 1H), 3.70 (dd, J = 11.3, 2.6 Hz, 1H), 3.60 – 3.50 (m ,2H), 3.28 – 3.09 (m, 2H), 2.72 (d, J = 10.7 Hz, 1H), 2.46 (d, J = 11.1 Hz, 1H), 2.29 (d, J = 3.4 Hz, 6H), 2.16 (dt, J = 13.1, 9.1 Hz, 2H), 1.74 (d, J = 13.1 Hz, 2H), 1.20 (d, J = 6.6 Hz, 3H). Example 51 (3R)-4-[7-(4,4- difluoropiperidin -1- yl )-3-(3- methyl -1H- pyrazol -5- yl )-[1,2] thiazole Synthesis of [4,5-b] pyridin -5- yl ]-3- methyl 𠰌 line Step 1. (3R)-4-[7-(4,4- difluoropiperidin -1- yl )-3-[3- methyl -1-( tetrahydropyran -2- yl )-1H- Pyrazol -5- yl ]-[1,2] thiazolo [4,5-b] pyridin -5- yl ]-3- methyl 𠰌 line

To (3R)-4-{7-chloro-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo To a solution of [4,5-b]pyridin-5-yl}-3-methyl𠰌line (100 mg, 0.23 mmol) in DMF (2 mL) was added 4,4-difluoro-1-(tetramethyl (1,3,2-dioxaborolan-2-yl)piperidine (114 mg, 0.46 mmol), RuPhos (22 mg, 0.05 mmol), RuPhos Pd G3 (19 mg, 0.02 mmol) and Cs ₂ CO ₃ (150 mg, 0.46 mmol). The reaction was stirred at 100°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. Dilute the reaction with EA (50 mL) and water (50 mL). The organic phase was washed with brine (50 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain (3R)-4-[7-(4,4-difluoropiperidine-) as a yellow solid 1-yl)-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-[1,2]thiazolo[4,5-b] Pyridin-5-yl]-3-methylpyridine (100 mg, yield: 84%). LC/MS (ESI): m/z 519(M+H) ⁺ . Step 2. (3R)-4-[7-(4,4- difluoropiperidin -1- yl )-3-(3- methyl -1H- pyrazol -5- yl )-[1,2] Thiazolo [4,5-b] pyridin -5- yl ]-3- methyl 𠰌 line

To (3R)-4-[7-(4,4-difluoropiperidin-1-yl)-3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazole -5-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl]-3-methyl𠰌line (100 mg, 0.19 mmol) in DCM (3 mL) Add HCl/dioxane (3 mL) and stir at room temperature for 1 hour. LC-MS showed the reaction was complete. The reaction was concentrated in vacuo to give a crude product, which was purified by preparative-HPLC (C18, 10-95%, MeCN/H ₂ O with 0.1% CHOOH) to give (3R)-4-[7- (4,4-difluoropiperidin-1-yl)-3-(3-methyl-1H-pyrazol-5-yl)-[1,2]thiazolo[4,5-b]pyridine-5 -yl]-3-methyl𠰌line (56 mg, yield: 67%). LC/MS (ESI): m/z 435(M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 7.09 (s, 1H), 6.43 (s, 1H), 4.50 (d, J = 5.7 Hz, 1H), 4.03 (t, J = 12.6 Hz, 2H), 3.79 (d, J = 11.2 Hz, 1H), 3.70 (d, J = 10.9 Hz, 1H), 3.65 – 3.58 (m, 4H), 3.57 – 3.51 (m, 1H), 3.22 (dd, J = 17.5, 7.9 Hz, 1H), 2.30 (s, 3H), 2.23 – 2.09 (m, 4H), 1.21 (d, J = 6.6 Hz, 3H). Example 52 (R)-2-(3-(3- methyl - 1H- pyrazol -5- yl )-5-(3- methyl 𠰌 linyl ) isothiazolo [4,5-b] pyridine- Synthesis of 7- yl ) propan -2- ol Step 1. (3- Methyl -1H- pyrazol -5- yl ) boronic acid

To a solution of [3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]boronic acid (500 mg, 2.38 mmol) in DCM (5 mL) was added HCl/ Dihexane (7 mL) and stirred at 60°C overnight. LC-MS showed the reaction was complete. The reaction was concentrated in vacuo to obtain the crude product (3-methyl-1H-pyrazol-5-yl)boronic acid (290 mg, yield: 97%) as a white solid. LC/MS (ESI): m/z 127 (M+H) ⁺ . Step 2. (3R)-4-[7- chloro -3-(3- methyl -1H- pyrazol -5- yl )-[1,2] thiazolo [4,5-b] pyridine -5- base ]-3- methyl 𠰌 line

To 7-chloro-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-3-yl trifluoromethanesulfonate ( To a solution of 800 mg, 1.91 mmol) in dihexane (10 mL) were added (3-methyl-1H-pyrazol-5-yl)boronic acid (289 mg, 2.30 mmol), Pd(PPh ₃ ) ₄ ( 221 mg, 0.19 mmol) and K ₂ CO ₃ (794 mg, 5.74 mmol). The reaction was stirred at 100°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. Dilute the reaction with EA (50 mL) and water (50 mL). The organic phase was washed with brine (50 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain (3R)-4-[7-chloro-3-(3-methyl- 1H-pyrazol-5-yl)-[1,2]thiazolo[4,5-b]pyridin-5-yl]-3-methyl𠰌line (200 mg, yield: 30%). LC/MS (ESI): m/z 350(M+H) ⁺ . Step 3. (3R)-3- Methyl -4-[3-[3- methyl -1H- pyrazol -5- yl ]-7-[2-( tetrahydropyran -2- yl )-2H -1,2,3- triazol -4- yl ]-[1,2] thiazolo [4,5-b] pyridin -5- yl ] 𠰌 line

To (3R)-4-[7-chloro-3-(3-methyl-1H-pyrazol-5-yl)-[1,2]thiazolo[4,5-b]pyridin-5-yl] To a solution of -3-methylpyroline (200 mg, 0.57 mmol) in dimethane (3 mL) was added 2-(tetrahydropyran-2-yl)-4-(tetramethyl-1,3 ,2-dioxaborolan-2-yl)-2H-1,2,3-triazole (319 mg, 1.14 mmol), Pd(PPh ₃ ) ₄ (66 mg, 0.06 mmol) and K ₂ CO ₃ (237 mg, 1.71 mmol). The reaction was stirred at 100°C overnight under nitrogen atmosphere. LC-MS showed the reaction was complete. Dilute the reaction with EA (50 mL) and water (50 mL). The organic phase was washed with brine (50 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain (3R)-3-methyl-4-[3-[3-methyl as a yellow solid -1H-pyrazol-5-yl]-7-[2-(tetrahydropyran-2-yl)-2H-1,2,3-triazol-4-yl]-[1,2]thiazolo [4,5-b]pyridin-5-yl]𠰌line (100 mg, yield: 37%). LC/MS (ESI): m/z 467(M+H) ⁺ . Step 4. (3R)-3- Methyl -4-[3-(3- methyl - 1-{[2-( trimethylsilyl ) ethoxy] methyl } -1H - pyrazole- 5- yl )-7-[2-( tetrahydropyran -2- yl )-2H-1,2,3- triazol -4- yl ]-[1,2] thiazolo [4,5-b ] pyridin -5- yl ] 𠰌 line

To (3R)-3-methyl-4-[3-[3-methyl-1H-pyrazol-5-yl]-7-[2-(tetrahydropyran-2-yl)-2H-1 ,2,3-triazol-4-yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl]𠰌line (350 mg, 0.75 mmol) in THF (5 mL) NaH (45 mg, 1.50 mmol) and SEMCl (0.2 mL, 0.90 mmol) were added to the solution. The mixture was stirred from 0 °C to room temperature for 2 h. TLC showed the reaction was complete. _H2O (10 mL) was added to the mixture and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried _{over Na2SO4} and evaporated to dryness. The residue was purified by flash silica column chromatography to obtain (3R)-3-methyl-4-[3-(3-methyl-1-{[2-(trimethyl)) as a colorless oil Silyl)ethoxy]methyl}-1H-pyrazol-5-yl)-7-[2-(tetrahydropyran-2-yl)-2H-1,2,3-triazole-4 -yl]-[1,2]thiazolo[4,5-b]pyridin-5-yl]𠰌line (230 mg, yield: 51%). LC/MS (ESI): m/z 598.1 [M+H] ⁺ . Step 5. (3R)-3- Methyl -4-[3-(3- methyl - 1-{[2-( trimethylsilyl ) ethoxy] methyl } -1H - pyrazole- 5- yl )-7-(2H-1,2,3- triazol -4- yl )-[1,2] thiazolo [4,5-b] pyridin - 5- yl ] 𠰌 line

To (3R)-3-methyl-4-[3-(3-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-5- yl)-7-[2-(tetrahydropyran-2-yl)-2H-1,2,3-triazol-4-yl]-[1,2]thiazolo[4,5-b]pyridine To a solution of -5-yl]phosphonoline (350 mg, 0.59 mmol) in DCM (5 mL) was added TFA (3 mL). The reaction was stirred at room temperature for 2 h. TLC showed the reaction was complete. After removing the solvent, the reactant was purified by flash silica gel column chromatography to obtain (3R)-3-methyl-4-[3-(3-methyl-1-{[2 -(Trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-7-(2H-1,2,3-triazol-4-yl)-[1,2 ]thiazolo[4,5-b]pyridin-5-yl]𠰌line (220 mg, yield: 73%). LC/MS (ESI): m/z 513.1 [M+H] ⁺ . Step 6. (3R)-4-{7-[1-( difluoromethyl )-1H-1,2,3- triazol -4- yl ]-3-(3- methyl -1-{[ 2-( Trimethylsilyl ) ethoxy ] methyl }-1H- pyrazol -5- yl )-[1,2] thiazolo [4,5-b] pyridin -5- yl }-3 -Methyl 𠰌 line _

To (3R)-3-methyl-4-[3-(3-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole at 0°C -5-yl)-7-(2H-1,2,3-triazol-4-yl)-[1,2]thiazolo[4,5-b]pyridin-5-yl]𠰌line (230 mg To a solution of diethyl (bromodifluoromethyl)phosphonate (240 mg, 0.90 mmol) and NaH (36 mg, 0.90 mmol) in THF (5 mL) was added. The reaction was stirred at 0 °C for 2 h. TLC showed the reaction was complete. _H2O (10 mL) was added to the mixture and extracted with EA (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried _{over Na2SO4} and evaporated to dryness. The residue was purified by flash silica gel column chromatography to obtain (3R)-3-methyl-4-[3-(3-methyl-1H-pyrazol-5-yl)- as a colorless oil. 7-(2H-1,2,3-triazol-4-yl)-[1,2]thiazolo[4,5-b]pyridin-5-yl]𠰌line (50 mg, yield: 29% ). LC/MS (ESI): m/z 563.1 [M+H] ⁺ . Step 7. (3R)-4-{7-[1-( Difluoromethyl )-1H-1,2,3- triazol -4- yl ]-3-(3- methyl -1H- pyrazole -5- yl )-[1,2] thiazolo [4,5-b] pyridin -5- yl }-3- methyl 𠰌 line

To (3R)-4-{7-[1-(difluoromethyl)-1H-1,2,3-triazol-4-yl]-3-(3-methyl-1-{[2- (Trimethylsilyl)ethoxy]methyl}-1H-pyrazol-5-yl)-[1,2]thiazolo[4,5-b]pyridin-5-yl}-3-methyl To a solution of phospholine (50 mg, 0.09 mmol) in DCM (5 mL) was added TFA (2 mL), and stirred at room temperature for 2 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative-HPLC (C18, 10-95%, MeOH/HO with 0.1% HCOOH) to give (3R)-4-{7-[1-(difluoromethyl)-1H-1 ,2,3-triazol-4-yl]-3-(3-methyl-1H-pyrazol-5-yl)-[1,2]thiazolo[4,5-b]pyridin-5-yl }-3-Methyl𠰌line (5 mg, yield: 13%). LC/MS (ESI): m/z 433.1 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.39 (dd, J = 118.8, 60.5 Hz, 1H), 7.81 (s, 1H), 7.14 (s, 1H), 4.58 (d , J = 6.0 Hz, 1H), 4.18 (d, J = 12.9 Hz, 1H), 4.08 (d, J = 8.8 Hz, 1H), 3.86 (d, J = 11.5 Hz, 1H), 3.76 (d, J = 9.0 Hz, 1H), 3.60 (t, J = 10.9 Hz, 1H), 3.18 (s, 1H), 2.31 (s, 3H), 1.27 (d, J = 6.5 Hz, 3H). Example 53 Cyano [ methyl ({1-[3-(3- methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin - 4 - yl ]-[ Synthesis of 1,2] thiazolo [4,5-b] pyridin -7- yl ] cyclopropyl }) pendant oxy -λ^6- sulfanylidene ] amine Step 1. ( Cyanoimino )( methyl )({3-[3- methyl -1-( tetrahydropyran -2- yl )-1H- pyrazol -5- yl ]-5-[ (3R)-3- Methyl 𠰌 lin - 4- yl ]-[1,2] thiazolo [4,5-b] pyridin- 7- yl } methyl ) -λ ^6- sulfanone

To imino(methyl)({3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R) at -78°C )-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl}methyl)-λ^6-sulfanone (80 mg, 0.16 mmol) in DCM (5 mL) were added Py (0.03 mL, 0.33 mmol) and BrCN (0.024 mL, 0.33 mmol), and stirred from -78°C to room temperature for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain the desired product (cyanoimino) (methyl) ({3-[3 -Methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2 ]thiazolo[4,5-b]pyridin-7-yl}methyl)-λ^6-sulfanone (40 mg, yield: 48%). LC/MS (ESI): m/z 516.7 [M+H] ⁺ . Step 2. Cyano [ methyl (1-{3-[3- methyl -1-( tetrahydropyran -2- yl )-1H- pyrazol -5- yl ]-5-[(3R)- 3- methyl 𠰌 lin -4- yl ]-[1,2] thiazolo [4,5-b] pyridin -7- yl } cyclopropyl ) pendant oxy -λ^6- sulfanylidene ] amine

To (cyanoimino)(methyl)({3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R )-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl}methyl)-λ^6-sulfanone (40 mg, 0.08 To a solution of 1,2-dibromoethane (29 mg, 0.16 mmol), TBAB (13 mg, 0.04 mmol) and NaOH (31 mg, 0.78 mmol) was added. The reaction was stirred at 60°C for 2 hours. LC-MS showed the reaction was complete. Dilute the reaction with EA (50 mL) and water (50 mL). The organic phase was washed with brine (50 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 0~100% ethyl acetate/petroleum ether) to obtain cyano[methyl(1-{3-[3-methyl-1- (Tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4, 5-b]pyridin-7-yl}cyclopropyl) pendant oxy-λ^6-sulfanylidene]amine (15 mg, yield: 36%). LC/MS (ESI): m/z 542(M+H) ⁺ . Step 3. Cyano [ methyl ({1-[3-(3- methyl -1H- pyrazol -5- yl )-5-[(3R)-3- methyl 𠰌 lin -4- yl ]- [1,2] thiazolo [4,5-b] pyridin -7- yl ] cyclopropyl }) pendant oxy -λ^6- sulfanylidene ] amine

To cyano[methyl(1-{3-[3-methyl-1-(tetrahydropyran-2-yl)-1H-pyrazol-5-yl]-5-[(3R)-3- Methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b]pyridin-7-yl}cyclopropyl) pendant oxy-λ^6-sulfanylidene]amine (15 To a solution of mg, 0.03 mmol) in DCM (2 mL) was added HCl/dioxane (2 mL). The mixture was stirred at room temperature for 1 hour. LC-MS showed the reaction was complete. The reaction was concentrated in vacuo to give the crude product, which was purified by preparative-HPLC (C18, 10-95%, MeCN/H ₂ O with 0.1% CHOOH) to give cyano[methyl({1-[ 3-(3-Methyl-1H-pyrazol-5-yl)-5-[(3R)-3-methyl𠰌lin-4-yl]-[1,2]thiazolo[4,5-b ]pyridin-7-yl]cyclopropyl}) pendant oxy-λ^6-sulfanylidene]amine (2 mg, yield: 15%). LC/MS (ESI): m/z 458(M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J = 3.8 Hz, 1H), 7.11 (s, 1H), 4.50 (s, 1H), 4.15 (d, J = 13.9 Hz, 1H), 4.06 (d, J = 11.2 Hz, 1H), 3.83 (d, J = 11.5 Hz, 1H), 3.72 (dd, J = 11.4, 2.8 Hz, 1H), 3.58 (t, J = 9.6 Hz, 4H), 3.25 (dd, J = 12.7, 3.6 Hz, 1H), 2.31 (s, 3H), 2.05 – 1.91 (m, 2H), 1.79 (td, J = 11.9, 6.2 Hz, 2H), 1.26 (dd, J = 6.6, 3.0 Hz, 5H). Biochemical assays

assay 1 : ATR Inhibition assay

Detection of ATR kinase activity utilizes a mobility shift assay to measure phosphorylation of the substrate protein FAM-RAD17 (GL, catalog number: 514318, lot number: P19042-MJ524315). The assay was developed and implemented by Chempartner. All test compounds were dissolved in 100% DMSO at a concentration of 20 mM, and the compounds were prepared and assayed as follows: 1) Transfer 80 μl of 20 mM compound to 40 μl of 100% DMSO in a 96-well plate. 2) Serially dilute the compound by transferring 20 μl to 60 μl of 100% DMSO in the next well, and so on, for a total of 10 concentrations. 3) Add 100 μl 100% DMSO to two empty wells in the same 96-well plate for no compound control and no enzyme control. Mark the board as the source disk. 4) Transfer 40 μl of compound from the source plate to a new 384-well plate as an intermediate plate. 5) Transfer 60 nl of compound to the assay plate via Echo. 6) Add ATR kinase (Eurofins, catalog number: 14-953, lot number: D14JP007N) to kinase base buffer (50 mM HEPES, pH 7.5; 0.0015% Brij-35; 0.01% Triton) to prepare a 2× enzyme solution , then add 10 μl of 2× enzyme solution to each well of the 384-well plate, and incubate at room temperature for 10 min. 7) Add FAM-RAD17 and ATP (Sigma, catalog number: A7699-1G, CAS number: 987-65-5) to the kinase base buffer to prepare a 2× peptide solution, and then add 10 μl to the assay plate. 8) Incubate at 28°C for the specified period of time. Add 40 μl of stop buffer (100 mM HEPES, pH 7.5; 0.015% Brij-35; 0.2% Coating Reagent #3; 50 mM EDTA) to stop the reaction. 9) Collect the data on the caliper. Convert conversion value to suppression value. Inhibition % = (maximum conversion rate)/(max - min)*100 Among them, "max" represents the DMSO control; "min" represents the low control. Fit the data in XLFit excel plug-in version 5.4.0.8 to obtain the IC50 value. The formula used is: Y = Bottom + (Top - Bottom)/(1 + (IC50/X)^Hill Slope) where X refers to the concentration not converted into logarithmic form.

Table 2 below lists _IC50 values for exemplary compounds of formula (I). Table 2 Compound number ATR IC ₅₀ (nM) 1 6.7 2b 10.0 3 6.9 5 1.7 6 5.4 7 1.8 8 1.1 9a 4.2 11 1.9 14 6.1 15 11.0 16 1.7 17 5.6 18 4.2 19 21.0 20 6.5 twenty one 2.7 32 5.7

For other compounds provided herein for which results are not shown, the _IC50 against ATR kinase for all compounds did not exceed 1000 nM. Some of these compounds have an _IC50 against ATR kinase not exceeding 500 nM, some not exceeding 400 nM, some not exceeding 300 nM, some not exceeding 200 nM, or not exceeding 100 nM, or even not exceeding 50 nM.

Therefore, the compounds of the invention have good inhibitory effects on ATR kinase activity as determined by the ATR inhibition assay.

assay 2 : Tumor cell anti-proliferation assay (CTG Determination )

Human colorectal cancer cells HT-29 (HTB-38) and LoVo (CCL-229) were selected for CTG determination. These two cell lines were originally obtained from the American Type Culture Collection (ATCC). . Add FBS and appropriate additives to the basal medium to prepare complete medium, then rinse the cell layer briefly with 0.25% (w/v) trypsin-0.038% (w/v) EDTA solution to remove all trypsin inhibitors. of trace serum. Afterwards, add an appropriate volume of trypsin-EDTA solution to the flask and observe the cells under an inverted microscope until the cell layer is dispersed. Finally, add an appropriate volume of complete growth medium and aspirate cells by gentle pipetting. Numbers were collected and counted with Vi-cell XR and cell density adjusted, cells were seeded into 96-well opaque wall clear bottom tissue culture treated dishes in a _CO2 incubator for 20 to 24 hours. The concentration of all test compounds in DMSO was 10 mM. The compounds were then added to the cell culture medium in 3-fold serial dilutions to a final DMSO concentration of 0.5%. Incubate the plate at 37 °C for 96 h under 5% _CO2 . Prior to measurement, transfer an appropriate volume of CellTiter-Glo buffer to an amber bottle containing CellTiter-Glo substrate to reconstitute the lyophilized enzyme/substrate mixture and mix gently to form CellTiter-Glo Reagent (Promega catalog number: G7573). Equilibrate the plate and its contents to room temperature for approximately 30 minutes, then add 100 μL of CellTiter-Glo reagent to the assay plate, mix the contents on an orbital shaker for 2 minutes to induce cell lysis, and incubate at room temperature. Incubate for 10 minutes to stabilize the luminescence signal. Finally, the clear bottom was adhered with white backing sealant and the glow recorded with Enspire. The IC ₅₀ value and GI ₅₀ value were calculated using the XLFit curve fitting software using the 4-parameter logistic model Y = bottom + (top - bottom)/(1 + (IC50/X)^Hill slope).

Table 3 below provides _IC50 values for exemplary compounds of formula (I). table 3 Compound number LoVo IC ₅₀ (nM) 1 36 2a 16 2b 51 3 30 4 twenty one 5 9 6 17 7 20 8 6 9a 11 9b 62 10 93.5 11 4.8 13 143 14 15.7 15 35.7 16 7 17 10.7 18 9 19 69.1 20 18.4 twenty one 7.2 twenty two 16.9 twenty three 26.1 24a 16 24b 24.7 25 65.1 26a 15.6 26b 44.1 27 16.8 28 39.4 29 14.6 30 3 31 50 32 18 33 8 34 47 35a 299 35b 103 36 37 37 10 38 53 39 46 40 151 41a 621 41b 146 42a 64 42b 286 43 12 44 8 45 twenty one 46 34 47a 28 47b 162 48 8 49 5 50 5 51 55 52 twenty two 53 10 pharmacokinetic studies

The purpose of this study was to determine the pharmacokinetic parameters of the compound in the plasma of fasted male CD-1 mice in vivo following intravenous (IV) or oral (PO) administration.

Test product preparation

Formulations for intravenous and oral administration are:

For IV administration: Vehicle containing 0.20 mg/mL test compound (10% DMSO+10% Solutol+80% water)

For PO administration: vehicle containing 1 mg/mL test compound (10% DMSO+10% Solutol+80% water)

research design group Number of animals Nominal dose (mg/kg) Dose concentration (mg/mL) Route of administration Collect 1 3 1 0.2 intravenously plasma 2 3 10 1 oral* plasma *Animals were fasted prior to oral administration. Food supply was resumed 4 hours after dosing for animals dosed orally.

invest

The test article is administered as a single IV or PO dose.

Collection interval

Group IV: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h and 24 h after administration.

PO group: 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after administration.

analysis program

PK blood samples were centrifuged at approximately 6800 G for 6 minutes at 2-8°C, and the resulting plasma was transferred to appropriately labeled tubes within 2 hours of blood collection/centrifugation and stored frozen at approximately -70°C.

Method development and biological sample analysis of test article (heparin sodium anticoagulant) were performed by LC-MS/MS. Confirm analytical results using quality control samples to determine intra-assay variation. > The accuracy of 66.7% of the quality control samples was between 80-120% of the known value.

Pharmacokinetic analysis

Standard parameter sets, including area under the curve (AUC _(0-t) and AUC _(0-∞) ), elimination half-life (T _1/2 ), and maximum plasma concentration, were calculated by the study leader using Phoenix WinNonlin 7.0 (Pharsight, USA) (Cmax) and the time to reach maximum plasma concentration (Tmax) and other parameters.

Table 4 below provides results for exemplary compounds of formula (I). Route of administration 15 16 IV C ₀ (ng/mL) 1331 946 T _1/2 (h) 2.17 1.85 Cl (mL/min/kg) 8.08 13.1 AUC _0-last (ng.h/mL) 1940 1222 PO C _max (ng/mL) 2707 3670 T _1/2 (h) 3.35 3.18 T _max (h) 0.583 0.750 AUC _0-last (ng.h/mL) 19456 14650 bioavailability(%) 94.0 116

The foregoing description is considered to be illustrative only of the principles of the invention. Further, since many modifications and variations will be apparent to those skilled in the art, it is not intended to limit the invention to the exact construction and processes shown above. Accordingly, all suitable modifications and equivalents may be deemed to fall within the scope of the invention as defined by the appended claims.

Claims (29)

A compound having formula (I): or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are each independently an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, Heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R ^a ; or R ¹ and R ² together with the sulfur atoms to which they are connected form a heterocyclic ring optionally substituted with one or more R ^b group; R ^a is independently selected from the group consisting of: hydroxyl, halogen, cyano, amine, alkyl, alkoxy and haloalkyl; R ^b is independently selected from the group consisting of: alkyl, alkenyl, Alkynyl, alkoxy, cyano, halogen, hydroxyl, amine and nitro, wherein the alkyl, alkenyl and alkynyl are optionally substituted with one or more groups independently selected from: hydroxyl, halogen , cyano group, amine group and alkoxy group; R ³ is ; Ring A is a 5- to 6-membered heterocyclyl or a 5- to 6-membered heteroaryl; R ⁴ is halogen, alkyl, haloalkyl or cycloalkyl in each occurrence; and m is 0, 1, 2 or 3. For example, the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are each independently a C _1-3 alkyl group, a C _3-6 cycloalkyl group or a C _5-12 aryl group. For example, the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are independently C _1-3 alkyl. For example, the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are independently C _3-6 cycloalkyl. For example, the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein one of R ¹ and R ² is C _1-3 alkyl, and the other is C _3-6 cycloalkyl or C _{5- 12} Aryl. For example, the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Select from the group consisting of: . For example, the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² together with the sulfur atoms to which they are connected form a heterocyclyl group optionally substituted by one or more R ^b . For example, the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Selected from , each of which is optionally replaced by one or more R ^b . For example, the compound of claim 1 or its pharmaceutically acceptable salt, wherein ring A is a 5- to 6-membered heteroaryl group. For example, the compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein ring A is pyrazolyl, pyrrolyl or pyridyl. For example, the compound of claim 1 or its pharmaceutically acceptable salt, wherein R ⁴ is halogen. Such as the compound of claim 1 or its pharmaceutically acceptable salt, wherein R ⁴ is an alkyl group. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a C _1-3 alkyl group. Such as the compound of claim 1 or its pharmaceutically acceptable salt, wherein R ⁴ is a haloalkyl group. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a C _1-3 haloalkyl group. Such as the compound of claim 1 or its pharmaceutically acceptable salt, wherein R ⁴ is a cycloalkyl group. For example, the compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a C _3-6 cycloalkyl group. For example, the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2. For example, the compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Select from the group consisting of: . Such as the compound of claim 1 or its pharmaceutically acceptable salt, wherein R ³ is . Such as the compound of claim 1 or its pharmaceutically acceptable salt, wherein R ³ is . A compound according to any one of the preceding claims, having formula (Ia): , or its pharmaceutically acceptable salt. Such as the compound of claim 1, which is selected from the group consisting of: , or its pharmaceutically acceptable salt. A compound selected from the group consisting of: , or its pharmaceutically acceptable salt. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A method for treating cancer, the method comprising administering to an individual in need an effective amount of a compound as claimed in any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof or a pharmaceutical combination as claimed in claim 25 things. Use of a compound as claimed in any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as claimed in claim 23 in the preparation of a medicament for treating cancer. The compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 25, which is used to treat cancer. A method for inhibiting ATR kinase in an individual in need thereof, the method comprising administering to the individual an effective amount of a compound as claimed in any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof or as claimed The pharmaceutical composition of item 25.