TYK2 inhibitors

Abstract

The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof: # imgabs0 # wherein all the variables are as defined in the application. The compounds of the present disclosure are capable of inhibiting the activity of tyrosine kinase 2 (TYK2). The disclosure further provides methods of making the compounds of the disclosure and methods for their therapeutic use.

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Application No. 63 / 424,583, filed November 11, 2022, and U.S. Provisional Application No. 63 / 340,142, filed May 10, 2022. The entire contents of each of the foregoing applications are expressly incorporated herein by reference. Technical Field

[0003] Certain reagents for targeting the degradation of tyrosine kinase 2 (TYK2) are provided, as well as methods for preparing and using these reagents. Background Technology

[0004] Cytokines are small, secreted proteins released by cells that have specific effects on cell-cell interactions and communication. The cytokine pathway mediates a wide range of biological functions, including many aspects of inflammation and immunity, primarily through extracellular signaling.

[0005] Tyrosine kinase 2 (TYK2) is a member of the Janus kinase (JAK) family, a cytokine receptor-associated cytoplasmic protein kinase, and plays a central role in mediating cytokine signaling (Kisseleva et al., Gene, 2002, 285, 1; and Yamaoka et al., Genome Biology 2004, 5, 253). The JAK family also includes JAK1, JAK2, and JAK3. More specifically, cytokine binding to its homologous receptor triggers activation of JAK-associated receptors, leading to tyrosine phosphorylation of JAK-mediated signal transducers and activators of transcription (STAT) proteins, ultimately resulting in transcriptional activation of specific gene sets (Schindler et al., 2007, J. Biol. Chem. 282: 20059-63). Many cytokines known to activate the JAK family include the interferon (IFN) family (IFN-α, IFN-β, IFN-ω, Limitin, IFN-γ, IL-10, IL-19, IL-20, IL-22), the glycoprotein (gp)130 family (IL-6, IL-11, OSM, LIF, CNTF, NNT-1 / BSF-3, G-CSF, CT-1, leptin, IL-12, IL-23), the γC family (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), the IL-3 family (IL-3, IL-5, GM-CSF), single-chain families (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF), and G protein-coupled receptors (AT1).

[0006] TYK2 is important in the signaling of type I interferons (e.g., IFN-α), IL-6, IL-10, IL-12, and IL-23 (Liang, Y. et al., Expert Opinion on Therapeutic Targets, 2014, 18, 5, 571-580; Kisseleva et al., 2002, Gene 285: 1-24; and Watford, WT & O'Shea, JJ, 2006, Immunity 25: 695-697). Consistent with this, primary cells derived from TYK2-deficient humans are defective in the signaling of type I interferons, IL-6, IL-10, IL-12, and IL-23. TYK2 signals in combination with other members of the JAK family in the following combinations: TYK2 / JAK1, TYK2 / JAK2, and TYK2 / JAK1 / JAK2.

[0007] Studies show that inappropriate JAK activity can be caused by mutations, overexpression, inappropriate regulation, abnormal or dysregulated regulation, and excessive or insufficient production of growth factors or cytokines, thereby triggering a variety of biological cellular responses related to cell growth, cell differentiation, cell function, survival, apoptosis, and cell motility. Inappropriate JAK activity is involved in many diseases, including but not limited to cancer, cardiovascular disease, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative diseases such as Alzheimer's disease.

[0008] Small molecule JAK inhibitors have emerged as a significant therapeutic advance for autoimmune diseases. To date, all known small molecule JAK inhibitors in development are active site-directed inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain of the JAK protein (also known as the JH1 or “Janus homology 1” domain). This blocks the catalytic activity of the kinase by inhibiting ATP, downstream phosphorylation, and the resulting pathway signal transduction (Bryan et al., J. Med. Chem. 2018, 61, 9030-9058).

[0009] Because the ATP active site is highly homologous across the entire kinaseome, particularly within the JAK family, achieving high selectivity for specific JAK family members while maintaining selectivity across the kinaseome is a significant challenge. Therefore, many developed JAK inhibitors are pan-JAK inhibitors or exhibit moderate selectivity for one or more JAK family members. While these inhibitors have shown encouraging results in treating autoimmune diseases, adverse side effects leading to a narrow therapeutic index have been observed, indicating a need for improved treatments.

[0010] TYK2 has been shown to be important in the differentiation and function of various cell types that are important in inflammatory and autoimmune diseases, including natural killer cells, B cells, and T helper cells. Aberrant TYK2 expression is associated with a variety of autoimmune or inflammatory conditions.

[0011] We still need potent compounds that exhibit high selectivity for TYK2 relative to other members of the JAK family. Summary of the Invention

[0012] One aspect of this disclosure is the compound of formula (I):

[0013]

[0014] Or its pharmaceutically acceptable salt, wherein:

[0015] Ring A is an aromatic ring or heteroaromatic ring fused with ring B, which is a 5-membered heteroaromatic ring;

[0016] X 1 It is N or CH;

[0017] X 2 Is it N or CR? 2 ;

[0018] X 3 Is it N or CR? 3 ;

[0019] X 4 Is it N or CR? 4 ;

[0020] The ring C is a phenyl, a 5- or 6-membered monocyclic heterocyclic group, or a 5- to 6-membered heteroaryl group, each of which is optionally separated by one or more R groups. C replace;

[0021] Each R C Independently, they are halogenated, –CN, –NR N1 R N2 –NR N3 –C(O)–R 7 –NR N4 –SO2–R 7 –C(O)–R 7 –SO2–R 7 –OR O1 C 1-6 Alkyl, alkenyl, 3- to 7-membered monocyclic carbocyclic, phenyl, 5- to 12-membered monocyclic or bicyclic heteroaryl, or 4- to 9-membered monocyclic or bicyclic heterocyclic, wherein R C C represents 1-6Alkyl, 3 to 7-membered monocyclic carbocyclic, phenyl, 5 to 12-membered monocyclic or bicyclic heteroaryl, and 4 to 9-membered monocyclic or bicyclic heterocyclic groups are each optionally surrounded by one or more R C1 Replace, or two Rs C Together with the intermediate atom, it forms a 3- to 7-membered monocyclic carbocyclic group that may be optionally substituted with one or more halogens;

[0022] Each R C1 Independently, they are halogenated, oxidized, –CN, –OR O1 –NR N1 R N2 –C(O)-R 7 –C(O)-OR O3 –SO2-R 7 C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 5- to 12-membered monocyclic or bicyclic heteroaryl or 4- to 7-membered monocyclic heterocyclic, wherein R C1 The C mentioned 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered monocyclic heterocyclic groups are each optionally substituted by one or more substituents independently selected from the following: halogenated, oxo-substituted, –CN, –OR. O1 –NR N1 R N2 C 1-6 Alkyl, C 1-4 Haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 8-membered monocyclic heterocyclic;

[0023] R 1 It is H, C 1-6 Alkyl, -OR 1A –NR N1 R N2 C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic or 4- to 7-membered monocyclic heterocyclic, wherein R 1 The C mentioned 1-6 Alkyl, phenyl, C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 7-membered monocyclic heterocyclic groups are each optionally bounded by one or more R 8 replace;

[0024] R 1A Is it H or C? 1-3 alkyl;

[0025] Or R 1 and R 1A Together with the atoms to which they are attached, they form 5- or 6-membered monocyclic heterocycles;

[0026] R2 It is H or halogenated;

[0027] R 3 It is H, –NR N1 R N2 –CN, halogenated, –C(O)–R 7 –C(O)–OR O3 –SO2–R 7 –OR O4 C 1-6 Alkyl, alkenyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic or 4- to 9-membered monocyclic or bicyclic heterocyclic, wherein R 3 C represents 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 9-membered monocyclic or bicyclic heterocyclic groups are each optionally bound by one or more R 9 replace;

[0028] R 4 It is H or halogenated;

[0029] Each R 7 C is independent 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic or 4- to 7-membered monocyclic heterocyclic; wherein R 7 The C mentioned 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 7-membered monocyclic heterocyclic groups are each optionally substituted by one or more substituents independently selected from the following: halogenated, oxo-substituted, –CN, –OR. O1 –NR 1a R 1b C 1-6 Alkyl, C 1-4 Haloalkyl, 3- to 7-membered monocyclic carbocyclic and 4- to 7-membered monocyclic heterocyclic;

[0030] Each R 8 Independently, they are halogenated, oxidized, –CN, –OR O1 C 1-6 Alkyl, C 1-4 Haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic or 4- to 7-membered monocyclic heterocyclic;

[0031] Each R 9 Independently, it is halogenated, oxidized, or –OR O1 –NR N1 R N2 –CN, –C(O) –OR O3 –SO2-R 10 C 1-6Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic or 4- to 10-membered monocyclic or bicyclic heterocyclic, wherein R 9 The C mentioned 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic, and 4- to 10-membered monocyclic or bicyclic heterocyclic groups are each optionally substituted by one or more substituents independently selected from the following: halogenated, oxo-substituted, –CN, –OR. O1 –NR N1 R N2 C 1-6 Alkyl, C 1-4 Haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 7-membered monocyclic heterocyclic;

[0032] Each R O1 H and C independently 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic or bicyclic carbocyclic or 4- to 7-membered monocyclic or bicyclic heterocyclic, wherein R O1 The C mentioned 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic or bicyclic carbocyclic and 4- to 7-membered monocyclic or bicyclic heterocyclic groups are each optionally bound by one or more R O2 replace;

[0033] Each R O2 Independently, it is halogenated, OH, -CN, C 1-4 Alkoxy, C 1-4 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic or 4- to 7-membered monocyclic or bicyclic heterocyclic, wherein the C 1-4 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 7-membered monocyclic or bicyclic heterocyclic groups are each optionally halogenated, C 1-6 Alkyl or –OC 1-6 Alkyl substitution;

[0034] Each R O3 H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic or 4- to 7-membered monocyclic heterocyclic, wherein R O3 The C mentioned 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 7-membered monocyclic heterocyclic groups are each optionally bound by one or more R O2 replace;

[0035] R O4 It is H, C 1-6Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic or 4- to 7-membered monocyclic heterocyclic, wherein R O4 The C mentioned 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 7-membered monocyclic heterocyclic groups are each optionally substituted by one or more substituents independently selected from the following: halogenated, oxo-substituted, –CN, –OR. O1 –NR N1 R N2 C 1-6 Alkyl, C 1-4 Haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 7-membered monocyclic heterocyclic;

[0036] R N1 and R N2 H and C are independent of each other. 1-6 Alkyl, 4- to 7-membered monocyclic heterocyclic, 5- or 6-membered heteroaryl, or C 3-6 cycloalkyl, wherein R N1 and R N2 The C mentioned 1-6 Alkyl groups are each optionally C 1-4 Alkoxy or phenyl substitution, and wherein R is present. N1 and R N2 The C mentioned 3-6 Cycloalkyl, 4- to 7-membered monocyclic heterocyclic, and 5- or 6-membered heteroaryl groups are each optionally C 1-4 Alkyl substitution;

[0037] Each R N3 Independently, it is H or C 1-6 Alkyl; and

[0038] Each R N4 Independently, it is H or C 1-6 alkyl.

[0039] In one aspect, this disclosure is a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0040] Another aspect of this disclosure is a method for inhibiting TYK2 activity in a subject in need, comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0041] In some aspects, this disclosure is a method of treating a subject for a disease or condition that is responsive to inhibition of TYK2, comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein.

[0042] This disclosure also includes the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the manufacture of a medicament for inhibiting TYK2 activity. It also includes the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the manufacture of a medicament for treating a disease or condition that responds to inhibition of TYK2.

[0043] This disclosure also provides compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described herein, for inhibiting TYK2 activity. It also provides compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described herein, for treating diseases or conditions that respond to inhibition of TYK2.

[0044] Other features or advantages will become apparent from the following detailed description of several embodiments and from the appended claims. Detailed Implementation

[0045] The compounds described herein, or pharmaceutically acceptable salts thereof, exhibit high potency against TYK2. Furthermore, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, exhibit high selectivity for inhibiting TYK2 relative to other members of the JAK family, such as JAK1 and JAK2.

[0046] I. Definition

[0047] Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0048] The terms “a” and “an” do not imply a quantity limitation, but rather indicate the presence of at least one of the referenced items. Unless otherwise specified herein, references to value ranges are intended only to serve as a shorthand for individually referring to each individual value falling within the range, and each individual value is incorporated into this specification as individually referenced herein. The endpoints of all ranges are included within the range and can be combined independently. All methods described herein may be performed in a suitable order unless otherwise indicated herein or clearly contradicted by the context. Unless otherwise required, the use of examples or exemplary language (e.g., “such as”) is intended only to better illustrate the invention and not to limit the scope of the invention.

[0049] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. In some embodiments, the alkyl group comprises 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In some embodiments, the alkyl group comprises 6 to 20 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl. When indicated as "optionally substituted," the alkane group or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally one to three substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl).

[0050] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety attached by an oxygen bridge (i.e., --O--C). 1-4 Alkyl, wherein C 1-4 Alkyl groups are defined herein. Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, etc. Preferably, the alkoxy group has about 1-4 carbons, more preferably about 1-2 carbons.

[0051] As used in this article, the number of carbon atoms in a group is indicated by the prefix "C". x-xx "Specifies that x and xx are integers. For example, "C 1-4 "Alkyl" is an alkyl group having 1 to 4 carbon atoms.

[0052] As used herein, the term "aryl" refers to a carbocyclic (all-carbon) aromatic monocyclic or bicyclic ring system containing 6-10 carbon atoms. Examples of 6-10 membered aryl groups include phenyl and naphthyl. In some embodiments, the aryl group is phenyl.

[0053] The term "cycloalkyl" refers to a fully saturated monocyclic, bicyclic, or spiroalkyl group with 3-7, 3-6, or 5-7 carbon atoms. In some embodiments, the cycloalkyl group is a 3- to 6-membered monocyclic cycloalkyl group.

[0054] As used herein, the terms “carbocyclic,” “carbocyclic group,” and “ring of carbocyclic” refer to, for example, a monocyclic or bicyclic hydrocarbon group having 3-10, 3-8, 3-7, 3-5, 3-6, 4-6, 5-7, or 7-10 carbon atoms that are saturated or partially unsaturated (i.e., non-aromatic).

[0055] "Halogen" or "halogenated" can be fluorine, chlorine, bromine or iodine.

[0056] As used herein, the term "haloalkyl" or "halogenated alkyl" refers to an alkyl group as defined herein, wherein at least one hydrogen atom is replaced by a halogen atom. A haloalkyl group can be a monohalogenated, dihalogenated, or polyhalogenated alkyl group, including perhalogenated alkyl groups. A monohalogenated alkyl group may contain one iodine, bromine, chlorine, or fluorine atom within the alkyl group. Dihalogenated and polyhalogenated alkyl groups may contain two or more identical halogen atoms or combinations of different halogens within the alkyl group. Typically, polyhalogenated alkyl groups contain up to 9, or 8, or 7, or 6, or 5, or 4, or 3, or 2 halogens. Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. A perhalogenated alkyl group is an alkyl group in which all hydrogen atoms are replaced by halogen atoms.

[0057] As used herein, the term "heteroaryl" refers to an aromatic 5- to 6-membered monocyclic ring system or an 8- to 10-membered bicyclic ring system having 1 to 4 heteroatoms independently selected from O, N, and S, wherein N can be oxidized (e.g., N(O)) or quaternized, and S can optionally be oxidized to sulfoxides and sulfones. Examples of 5- to 6-membered monocyclic heteroaryl groups include, but are not limited to, pyrroleyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetraazinyl, etc. Examples of 8- to 10-membered bicyclic heteroaryl groups include, but are not limited to, imidazolthiazolyl, imidazolpyridyl, imidazol[1,2-a]pyridyl, imidazol[2,1-b]thiazolyl, indazole, 2H-indazole, indole, isoindole, and 2λ. 2 -Isoindolinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, purinyl, thienopyridyl and thieno[3,2-b]pyridyl.

[0058] As used herein, the term "heterocyclic group" refers to a saturated or unsaturated monocyclic or bicyclic ring system (e.g., fused ring system, bridged ring system, or spirocyclic system) having 3 to 14 ring members, or particularly 3 to 8, 3 to 7, 3 to 6, or 5 to 7, 4 to 7, or 4 to 6 ring members, wherein at least one of the ring members is a heteroatom and up to four (e.g., 1, 2, 3, or 4) of the ring members may be heteroatoms, wherein the heteroatoms are independently selected from O, S, and N, and wherein C may be oxidized (e.g., C(O)), N may be oxidized (e.g., N(O)) or quaternized, and S may optionally be oxidized to sulfoxides and sulfones. Heterocyclic groups may be attached to the remaining portion of the compounds of the invention on a heteroatom or carbon atom. The term nitrogen heterocycle refers to a non-aromatic heterocyclic group having at least one nitrogen ring atom. Examples of nitrogen heterocycles include, but are not limited to, nitrogen-containing butanes, pyrrolidines, piperidines, piperazines, and morpholines. Fully saturated heterocyclic groups include heterocyclic alkyl groups. Examples of 3- to 7-membered monocyclic heterocyclic groups include, but are not limited to, aziridinyl, ethylene oxide, thirranyl, oxaziridinyl, oxazirheptanyl, azirheptanyl, oxazirheptanyl, thiolanyl, pyrrolyl, tetrahydrofuranyl, thiolanyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, dioxolanyl, dithiopentanyl, oxthioalkyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxyl, dithiopentanyl, trioxyl, trithiopentanyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl. In one embodiment, the heterocyclic group is a 5- to 7-membered monocyclic heterocyclic group (saturated or partially unsaturated). Examples include pyrrolidinyl, tetrahydrofuranyl, thiopentanyl, imidazoalkyl, pyrazolyl, oxazolyl, oxazolyl, oxazolyl, isoxazolyl, thiazoalkyl, isothiazolyl, dioxazolyl, dithiopentanyl, oxazolyl, piperidinyl, tetrahydropyranyl, sulfidecyclopentanyl, piperazine, morpholinyl, thiomorpholinyl, dioxyl, disulfidecyclopentanyl, trioxyl, trisulfidecyclopentanyl, azirheptanyl, oxazolyl, thioheptanyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl.

[0059] The term "bicyclic heterocycle" refers to a bicyclic ring that is partially or fully saturated and contains one or two heteroatoms independently selected from sulfur, oxygen and / or nitrogen.

[0060] The term "partially or fully saturated heterocycle" refers to a non-aromatic ring that is partially or fully saturated and can exist as a monocyclic, bicyclic (including fused heterocycles), or spirocyclic ring. Unless otherwise specified, a heterocycle is typically a 3- to 7-membered ring containing 1 to 3 heteroatoms (preferably 1, 2, or 3 heteroatoms) independently selected from sulfur, oxygen, and / or nitrogen.

[0061] As used in this article, "hydroxyl" or "hydroxyl" refers to the -OH group.

[0062] As used herein, the term "fused ring system" is a ring system having two ring structures that share two adjacent ring atoms. In one embodiment, a fused ring system has 8 to 12 ring members.

[0063] As used herein, the term "bridged ring system" refers to a ring system having a carboxycyclic or heterocyclic ring, wherein two non-adjacent atoms of the ring are connected (bridged) by one or more (preferably one to three) atoms selected from C, N, O, and S. In one embodiment, the bridged ring system has 6 to 8 ring members.

[0064] As used herein, the term "spiro-ring system" is a ring system having two ring structures that share a common ring atom. In one embodiment, the spiro-ring system has 5 to 8 ring members.

[0065] As used herein, the terms “optionally substituted” and “substituted or unsubstituted” are used interchangeably. Generally, the term “optionally substituted” means that a hydrogen group in a given structure is replaced by a group of a specified substituent. Specific substituents are described in the definition and in the description of the compounds and examples thereof. Unless otherwise specified, an optionally substituted group may have a substituent at each substituted position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from the specified group, the substituents at each position may be the same or different.

[0066] The term "oxo" (=O) refers to an oxygen atom bonded to a carbon or sulfur atom via a double bond. Examples include carbonyl, sulfinyl, or sulfonyl groups (--C(O)--, --S(O)--, or --S(O)2--), such as ketones, aldehydes, or portions of acids, esters, amides, lactones, or lactam groups.

[0067] Unless otherwise stated, the term "compound of this disclosure" refers to compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VII'), (VIIA), (VIIA'), (VIIB), (VIII) or (VIII'), and all stereoisomers (including diastereomers and enantiomers), rotational isomers, tautomers, and isotopically labeled compounds (including deuterium-substituted compounds). Salts (particularly pharmaceutically acceptable salts) are also included where a salt-forming moiety is present.

[0068] The disclosed compounds can be synthesized via synthetic routes that include methods similar to those well known in the field of chemistry, particularly according to the description contained herein. Starting materials are generally available from commercial sources such as Sigma-Aldrich, or readily prepared using methods well known to those skilled in the art (e.g., by methods generally described in the following literature: Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, Vols. 1–19, Wiley, New York (1967–1999) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)). The protection of functional groups by protecting groups, the protecting groups themselves, and their cleavage reactions are described in, for example, standard reference works such as J.F.W. McOmie, “Protective Groups in Organic Chemistry,” Plenum Press, London and New York 1973; T.W. Greene and P.G. W. M. Uts, “Protective Groups in Organic Synthesis,” 3rd edition, Wiley, New York 1999; “The Peptides,” Volume 3 (edited by E. Gross and J. Meienhofer), Academic Press, London and New York 1981; “Methods of Organic Chemistry,” Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974; and H.-D. Jakubke and H. Jeschkeit, “Aminosauren, Peptide, Protein” Acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982. Protecting groups are characterized by their ability to be readily removed, for example by solvent decomposition, reduction, photolysis, or alternatively under physiological conditions (e.g., by enzymatic cleavage) (i.e., removal without undesirable secondary reactions).

[0069] The compounds and intermediates described herein can be isolated and used as the compounds themselves. Alternatively, when a salt-forming moiety is present, the compound or intermediate can be isolated and used as its corresponding salt. As used herein, the term "salt" refers to an acid addition salt or a base addition salt of the compounds disclosed herein. "Salt" particularly includes "pharmaceutically acceptable salts".

[0070] The term "pharmaceutically acceptable salt" refers to a salt that retains the biological efficacy and properties of the compounds disclosed herein and is generally not biologically or otherwise undesirable. In many cases, the compounds of this disclosure are capable of forming acidic and / or basic salts in the presence of amino and / or carboxyl groups or similar groups.

[0071] Salts of the compounds of this disclosure having at least one salifying group can be prepared in a manner known to those skilled in the art. For example, acid addition salts of the compounds of this disclosure can be obtained in a conventional manner, such as by treating the compounds of this disclosure with an acid or a suitable anion exchange reagent. The salts can be converted into free compounds according to methods known to those skilled in the art. Acid addition salts can be converted, for example, by treatment with a suitable basic agent.

[0072] Pharmaceutically acceptable acid addition salts can form with inorganic and organic acids, such as acetates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromoates, bicarbonates / carbonates, hydrogen sulfates / sulfates, camphor sulfonates, chlorides / hydrochlorides, alginates, citrates, ethanedisulfonates, fumarates, gluconate, glucuronide, gluconate, glucuronide, hippurate, hydroiodide / iodide, hydroxyethyl sulfonate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methyl sulfate, naphthate, naphthalenesulfonate, nicotinate, nitrates, octadecanoates, oleates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonic acids, propionates, stearates, succinates, sulfates, sulfosalicylates, tartrates, toluenesulfonates, and trifluoroacetates.

[0073] Inorganic acids that can derive salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0074] Organic acids that can form salts include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid. Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases.

[0075] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In some embodiments, the salt is derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0076] Organic bases that can derive salts include, for example, primary, secondary, and tertiary amines; substituted amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Some organic amines include isopropylamine, benzathine penicillin, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0077] The salts can be synthesized by conventional chemical methods from compounds containing basic or acidic moieties. Generally, such salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or an organic solvent or a mixture of both. Generally, where feasible, the use of non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred. Other suitable salt lists can be found, for example, in Remington's Pharmaceutical Sciences, 20th edition, Mack Publishing Company, Easton, Pa., (1985); and Stahl and Wermuth's Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, Weinheim, Germany, 2002).

[0078] In some embodiments, this disclosure provides deuterated compounds wherein any or more sites occupied by hydrogen may include enrichment of deuterium at a higher natural abundance than deuterium. For example, one or more hydrogen atoms are replaced by deuterium, the abundance of which is at least 3340 times greater than the natural abundance of deuterium, and the natural abundance of deuterium is 0.015% (i.e., at least 50.1% deuterium incorporated), at least 3500 times (52.5% deuterium incorporated at each specified deuterium atom), at least 4000 times (60% deuterium incorporated), at least 4500 times (67.5% deuterium incorporated), at least 5000 times (75% deuterium), at least 5500 times (82.5% deuterium incorporated), at least 6000 times (90% deuterium incorporated), at least 6333.3 times (95% deuterium incorporated), at least 6466.7 times (97% deuterium incorporated), at least 6600 times (99% deuterium incorporated), or at least 6633.3 times (99.5% deuterium incorporated). In one implementation, hydrogen exists in all locations in its natural abundance.

[0079] Isotope-labeled compounds of formula (I) can generally be prepared by conventional methods known to those skilled in the art or by methods similar to those described in the appended examples and preparations, using an appropriate isotope-labeling reagent instead of the previously used unlabeled reagent.

[0080] Pharmaceutically acceptable solvates according to this disclosure include those in which the crystallization solvent can be substituted with an isotope, such as D2O, d6-acetone, and d6-DMSO.

[0081] Those skilled in the art will recognize that the compounds of this disclosure may contain a chiral center and therefore may exist in different stereoisomeric forms. As used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric configurations that may exist for a given compound of this disclosure. It should be understood that substituents may be attached to the chiral center of a carbon atom. Therefore, this disclosure includes enantiomers, diastereomers, or racemates of compounds.

[0082] Based on the physicochemical differences of the components, such as by chromatography and / or fractional crystallization, any mixture of the resulting isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, and racemates.

[0083] For compounds containing asymmetric carbon atoms, the compound exists either as a single optically active isomer or as a mixture thereof, for example, as a racemic or diastereomeric mixture. Mixtures of diastereomeric compounds can be separated into their individual diastereomeric forms based on their physicochemical differences using methods well known to those skilled in the art (e.g., by chromatography and / or fractional crystallization). Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary agent, such as a chiral alcohol or moselyl chloride), separating the diastereomeric forms, and converting (e.g., hydrolyzing) the individual diastereomeric forms into their respective pure enantiomers. Enantiomers can also be separated using commercially available chiral HPLC columns.

[0084] Some of the compounds described herein contain one or more asymmetric centers or axes, and thus can produce enantiomers, diastereomers, and other stereoisomers that can be defined according to absolute stereochemistry as (R)- or (S)-. According to this disclosure, any structure without a specified stereochemistry should be understood to include all the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure forms, as well as mixtures thereof (such as racemic mixtures or mixtures enriched with enantiomers). How such optically active forms are prepared is well known in the art (e.g., by recrystallization to resolve racemic forms, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase). In some embodiments, the compounds described herein are isolated stereoisomers, wherein each of the compounds has a stereocenter and the stereoisomer is in the R configuration. In other embodiments, the compounds described herein are isolated stereoisomers, wherein each of the compounds has a stereocenter and the stereoisomer is in the S configuration. In one embodiment, the compounds described herein are isolated stereoisomers, each having two stereocenters and exhibiting an RR configuration. In one embodiment, the compounds described herein are isolated stereoisomers, each having two stereocenters and exhibiting an RS configuration. In one embodiment, the compounds described herein are isolated stereoisomers, each having two stereocenters and exhibiting an SR configuration. In one embodiment, the compounds described herein are isolated stereoisomers, each having two stereocenters and exhibiting an SS configuration. In one embodiment, the compounds described herein each have one or two stereocenters and are racemic mixtures.

[0085] When a specific stereoisomer of a compound is described by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. "Stereochemical purity" means the weight percentage of the desired stereoisomer relative to the combined weight of all stereoisomers.

[0086] When a disclosed compound is named or described by means of its structure without specifying its stereochemistry, and the compound has a chiral center, it is to be understood that the name or structure covers an enantiomer of the compound in a pure or substantially pure form, as well as mixtures thereof (such as racemic mixtures of compounds, and mixtures of enantiomers enriched relative to their corresponding optical isomers).

[0087] Those skilled in the art will recognize that the compounds of this disclosure may contain a chiral center and therefore may exist in different stereoisomeric forms. As used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric configurations that may exist for a given compound of this disclosure. It should be understood that substituents may be attached to the chiral center of a carbon atom. Therefore, this disclosure includes enantiomers, diastereomers, or racemates of compounds.

[0088] "Enantiomers" are a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. Where appropriate, the term is used to designate racemic mixtures. When specifying the stereochemistry of the compounds of this disclosure, a single stereoisomer with known relative and absolute configurations of the two chiral centers is designated using the conventional RS system (e.g., (1S,2S)); a single stereoisomer with a known relative configuration but an unknown absolute configuration is designated by an asterisk (e.g., (1R*,2R*)); and a racemic mixture with two letters (e.g., (1RS,2RS) is designated as a racemic mixture of (1R,2R) and (1S,2S); (1RS,2SR) is designated as a racemic mixture of (1R,2S) and (1S,2R)).

[0089] A “diastereomer” is a stereoisomer having at least two asymmetric atoms that are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon can be specified by R or S. Resolved compounds with unknown absolute configurations can be specified as (+) or (-) based on the direction (dextrorotatory or levorotatory) of their rotational plane-polarized light at the sodium D line wavelength. Alternatively, resolved compounds can be defined by the retention times of the corresponding enantiomers / diastereomers via chiral HPLC.

[0090] Some of the compounds described herein contain one or more asymmetric centers or axes, and thus can produce enantiomers, diastereomers, and other stereoisomers that can be defined by absolute stereochemistry as (R)- or (S)-.

[0091] Unless otherwise stated, the compounds disclosed herein are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)-stereoisomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (e.g., on chiral SFC or HPLC columns such as the CHIRALPAK column available from DAICEL Corp.). RTM and CHIRALCEL RTM (Separation is performed using a suitable solvent or solvent mixture to achieve good separation). If the compound contains a double bond, the substituent can be E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent can have a cis or trans configuration. All tautomers are also intended to be included.

[0092] The disclosed compounds may exist in tautomer forms and mixtures, and individual tautomers are contemplated. All such forms are included within the scope of this disclosure. Furthermore, some compounds may exhibit polymorphism. The terms "tautomer" or "tautomer form" refer to structural isomers of different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton shift tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is an imidazole moiety in which a proton can migrate between two ring nitrogens. Valence tautomers include interconversions via some bonding electron rearrangement.

[0093] II. Compounds disclosed herein

[0094] In a first aspect, the compounds of this disclosure are represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the variables are as described above.

[0095]

[0096] In a first embodiment, the compounds of this disclosure are represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0097] Ring A is an aromatic ring or heteroaromatic ring fused with ring B, which is a 5-membered heteroaromatic ring;

[0098] X 1 It is N or CH;

[0099] X 2 Is it N or CR? 2 ;

[0100] X 3 Is it N or CR? 3 ;

[0101] X 4 Is it N or CR? 4 ;

[0102] The ring C is a phenyl or a 5- to 6-membered heteroaryl group, each of which is optionally separated by one or more R groups. C replace;

[0103] Each R C Independently, they are halogenated, –CN, –NR N1 R N2 –NR N3 –C(O)–R 7 –NR N4 –SO2–R 7 –C(O)–R 7 –SO2–R 7 –OR O1 C 1-6 Alkyl, 3- to 7-membered monocyclic carbocyclic or 4- to 9-membered monocyclic or bicyclic heterocyclic groups, wherein R C The C mentioned 1-6 Alkyl groups, 3- to 7-membered monocyclic carbocyclic groups, and 4- to 9-membered monocyclic or bicyclic heterocyclic groups are each optionally surrounded by one or more R groups. C1 Replace, or two Rs C Together with the intermediate atom, it forms a 3- to 7-membered monocyclic carbocyclic group that may be optionally substituted with one or more halogens;

[0104] Each R C1 Independently, they are halogenated, oxidized, –CN, –OR O1 –NR N1 R N2 –C(O)-R 7 –C(O)-OR O3 –SO2-R 7 C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl or 4- to 7-membered monocyclic heterocyclic group, wherein R C1 The C mentioned 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered monocyclic heterocyclic groups are each optionally substituted by one or more substituents independently selected from the following: halogenated, oxo-substituted, –CN, –OR. O1 –NR N1 R N2 C 1-6 Alkyl, C 1-4Haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 8-membered monocyclic heterocyclic;

[0105] R 1 It is C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic or 4- to 7-membered monocyclic heterocyclic, wherein R 1 The C mentioned 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 7-membered monocyclic heterocyclic groups are each optionally bound by one or more R 8 replace;

[0106] R 1A Is it H or C? 1-3 alkyl;

[0107] Or R 1 and R 1A Together with the atoms to which they are attached, they form 5- or 6-membered monocyclic heterocycles;

[0108] R 2 It is H or halogenated;

[0109] R 3 It is H, –NR N1 R N2 –CN, halogenated, –C(O)–R 7 –C(O)–OR O3 –SO2–R 7 –OR O4 C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic or 4- to 9-membered monocyclic or bicyclic heterocyclic, wherein R 3 The C mentioned 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 9-membered monocyclic or bicyclic heterocyclic groups are each optionally bound by one or more R 9 replace;

[0110] R 4 It is H or halogenated;

[0111] Each R 7 C is independent 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic or 4- to 7-membered monocyclic heterocyclic; wherein R 7 The C mentioned 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 7-membered monocyclic heterocyclic groups are each optionally substituted by one or more substituents independently selected from the following: halogenated, oxo-substituted, –CN, –OR. O1 –NR 1a R1b C 1-6 Alkyl, C 1-4 Haloalkyl, 3- to 7-membered monocyclic carbocyclic and 4- to 7-membered monocyclic heterocyclic;

[0112] Each R 8 Independently, they are halogenated, oxidized, –CN, –OR O1 C 1-6 Alkyl, C 1-4 Haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic or 4- to 7-membered monocyclic heterocyclic;

[0113] Each R 9 Independently, it is halogenated, oxidized, or –OR O1 –NR N1 R N2 –CN, –C(O) –OR O3 –SO2-R 10 C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic or 4- to 7-membered monocyclic heterocyclic, wherein R 9 The C mentioned 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 7-membered monocyclic heterocyclic groups are each optionally substituted by one or more substituents independently selected from the following: halogenated, oxo-substituted, –CN, –OR. O1 –NR N1 R N2 C 1-6 Alkyl, C 1-4 Haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 7-membered monocyclic heterocyclic;

[0114] Each R O1 H and C independently 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic or bicyclic carbocyclic or 4- to 7-membered monocyclic or bicyclic heterocyclic, wherein R O1 The C mentioned 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic or bicyclic carbocyclic and 4- to 7-membered monocyclic or bicyclic heterocyclic groups are each optionally bound by one or more R O2 replace;

[0115] Each R O2 Independently, it is halogenated, OH, -CN, C 1-4 Alkoxy, C 1-4 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic or 4- to 7-membered monocyclic or bicyclic heterocyclic, wherein the C 1-4Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 7-membered monocyclic or bicyclic heterocyclic groups are each optionally halogenated, C 1-6 Alkyl or –OC 1-6 Alkyl substitution;

[0116] Each R O3 H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic or 4- to 7-membered monocyclic heterocyclic, wherein R O3 The C mentioned 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 7-membered monocyclic heterocyclic groups are each optionally bound by one or more R O2 replace;

[0117] R O4 It is H, C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic or 4- to 7-membered monocyclic heterocyclic, wherein R O4 The C mentioned 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 7-membered monocyclic heterocyclic groups are each optionally substituted by one or more substituents independently selected from the following: halogenated, oxo-substituted, –CN, –OR. O1 –NR N1 R N2 C 1-6 Alkyl, C 1-4 Haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic and 4- to 7-membered monocyclic heterocyclic;

[0118] R N1 and R N2 H and C are independent of each other. 1-6 Alkyl or C 3-6 cycloalkyl, wherein R N1 and R N2 The C mentioned 1-6 Alkyl groups are each optionally C 1-4 Alkyl substitution;

[0119] Each R N3 Independently, it is H or C 1-6 Alkyl; and

[0120] Each R N4 Independently, it is H or C 1-6 alkyl.

[0121] In the second embodiment, for compounds of formula (I) or pharmaceutically acceptable salts thereof, R 1AIt is H or –CH3; and the remaining variables are as described in the first aspect or the first embodiment.

[0122] In the third embodiment, the compound is of formula (II), (III), (IV), (V), or (VI):

[0123]

[0124] Or a pharmaceutically acceptable salt thereof; and the variables are as described in the first aspect or the first embodiment.

[0125] In the fourth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 2 It is H or F; and the remaining variables are as described in the first aspect or the first, second or third implementation scheme.

[0126] In the fifth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 2 It is H; and the remaining variables are as described in the first aspect or the first, second or third implementation scheme.

[0127] In the sixth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, the ring C is phenyl or a 5- to 6-membered heteroaryl group, each of which is optionally surrounded by one to three R groups. C Substitution; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, or fifth embodiments. In some embodiments, ring C is not a pyridyl group. In some embodiments, ring C is not a phenyl group. In the alternative sixth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, ring C is phenyl, a 5- or 6-membered monocyclic heterocyclic group, or a 5- to 6-membered heteroaryl group, each of which is optionally surrounded by one to three R... C Replace; and the remaining variables are as described in the first aspect or in the first, second, third, fourth or fifth embodiments.

[0128] In the seventh embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, the ring C is selected from imidazolyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyridyl, pyrimidinyl, thiadiazolyl, thiazolyl, and triazinyl, each of which is optionally surrounded by one or three R groups. CReplacement; and the remaining variables are as described in the first aspect or the first, second, third, fourth, or fifth embodiments. In some embodiments, the ring C is selected from imidazole, oxadiazol, oxazol, pyrazinyl, pyrimidinyl, thiadiazolyl, thiazolyl, and triazineyl, each of which is optionally replaced by one or three R... C Replacement. In some embodiments, the ring C is selected from pyrazinyl, pyrimidinyl, and thiazolyl, each of which is optionally replaced by one or three R groups. C Substitution. In the seventh alternative embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, the ring C is selected from pyridinone, pyridazinone, imidazolyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyridinyl, pyrimidinyl, thiadiazolyl, thiazolyl, and triazinyl, each of which is optionally surrounded by one or three R... C Replace; and the remaining variables are as described in the first aspect or in the first, second, third, fourth or fifth embodiments.

[0129] In the eighth embodiment, for compounds of formula (I), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salts thereof, ring C is selected from:

[0130]

[0131] in This represents the bond with ring B, and n is 0, 1, 2, or 3; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, or fifth embodiments. In some embodiments, ring C is selected from:

[0132]

[0133] In the alternative eighth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, ring C is selected from:

[0134]

[0135]

[0136] And among them The variable represents the bond to ring B, and n is 0, 1, 2, or 3; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, or fifth embodiments.

[0137] In the ninth embodiment, for compounds of formula (I), (II), (III), (IV), (V) or (VI) or pharmaceutically acceptable salts thereof, ring C is selected from:

[0138]

[0139]

[0140] in This indicates a bond with ring B, and two Rs in ring C. C The functional groups may be the same or different; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, or fifth embodiments. In some embodiments, the ring C is selected from:

[0141] In some implementations, ring C is Where R C It is C 1-3 The alkyl halogroup, more specifically C2-alkyl halogroup, and even more specifically -CF2CH3. In the alternative ninth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, the ring C is selected from:

[0142]

[0143]

[0144] And among them This indicates a bond with ring B, and two Rs in ring C. C The functional groups may be the same or different; and the remaining variables are as described in the first aspect or in the first, second, third, fourth or fifth embodiments.

[0145] In the tenth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, each R C Independently, it is halogenated, –NR N1 R N2 –NR N3 –C(O)–R 7 –NR N4 –SO2–R 7 –C(O)–R 7 –OR O1 C 1-6 Alkyl, C 3-6 Cycloalkyl or 4- to 8-membered monocyclic or bicyclic heterocyclic groups, wherein R C The C mentioned 1-6 Alkyl, C 3-6 The cycloalkyl group and the 4- to 8-membered monocyclic or bicyclic heterocyclic group are each optionally surrounded by one to three R groups. C1Replace; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiments, or any alternative embodiments described therein. In some embodiments, at least one R C It is C 1-3 Halogenated alkyl group. In some embodiments, at least one R C It is a C2 haloalkyl group. In some embodiments, at least one R C It is -CF2CH3. In the alternative tenth embodiment, for compounds of formula (I), (II), (III), (IV), (V) or (VI) or their pharmaceutically acceptable salts, each R C Independently, it is halogenated, –NR N1 R N2 –NR N3 –C(O)–R 7 –NR N4 –SO2–R 7 –C(O)–R 7 –OR O1 C 1-6 Alkyl, alkenyl, C 3-6 Cycloalkyl, phenyl, 5- to 12-membered monocyclic or bicyclic heteroaryl or 4- to 8-membered monocyclic or bicyclic heterocyclic, or two R groups C Together with the intermediate atom, it forms a 3- to 7-membered monocyclic carbocyclic group optionally substituted by one or two halogenations; wherein R C The C mentioned 1-6 Alkyl, C 3-6 Cycloalkyl, 5 to 12-membered monocyclic or bicyclic heteroaryl, and 4 to 8-membered monocyclic or bicyclic heterocyclic groups are each optionally surrounded by one to three R groups. C1 Replace; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiments or any alternative embodiments described therein.

[0146] In the eleventh embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, by R C C represents 3-6 The cycloalkyl group is selected from cyclobutane, cyclopentane, cyclopropane, and cyclohexane, and is derived from R. C The 4- to 8-membered monocyclic or bicyclic heterocyclic groups are selected from aziridine, 2,6-diazaspiro[3.3]heptyl, isothiazolyl, isothiazolidine dioxide, morpholinyl, oxabicycloheptyl, oxabicyclo[2.2.1]heptyl, piperidinyl, piperazinyl, pyrrolyl, pyrrolidone, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 2-oxa-6-azaspiro[3.4]octyl, and 7-oxabicyclo[2.2.1]heptyl, wherein C3-6 Each of the cycloalkyl group and the 4- to 8-membered monocyclic or bicyclic heterocyclic groups is optionally surrounded by one to three R groups. C1 Replacement; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiments, or any alternative embodiments described therein. In the eleventh alternative embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, wherein R C C represents 3-6 The cycloalkyl group is selected from cyclobutyl, cyclopentyl, cyclopropyl, and cyclohexyl, and is derived from R. C The 5 to 12 membered monocyclic or bicyclic heteroaryl groups represented are furanyl, pyrazolyl, imidazolyl, triazolyl, isoxazole, pyridyl, pyrimidinyl, isoydinolyl, 3H-imidazo[4,5-b]pyridyl, 1H-benzo[d][1,2,3]triazolyl, and are derived from R C The 4- to 8-membered monocyclic or bicyclic heterocyclic groups are selected from aziridine, 2,6-diazaspiro[3.3]heptyl, isothiazolyl, isothiazolidine dioxide, morpholinyl, oxabicycloheptyl, oxabicyclobutyl, piperidinyl, piperazinyl, pyrrolyl, pyrrolidone, tetrahydrofuranyl, pyridine-2(1H)-acyl, tetrahydro-2H-pyranyl, 2-oxabicyclo[2.1.1]hexyl, 2-oxa-6-azaspiro[3.4]octyl, and 7-oxabicyclo[2.2.1]heptyl, wherein C 3-6 Each of the following groups is optionally surrounded by one to three R groups: cycloalkyl, 5- to 12-membered monocyclic or bicyclic heteroaryl, and 4- to 8-membered monocyclic or bicyclic heterocyclic. C1 Replace, or two Rs C Together with the intermediate atom, a cyclopentyl group is formed that is substituted with one or two halogens; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiments or any alternative embodiments described therein.

[0147] In the twelfth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, by R C C represents 3-6 Cycloalkyl groups and 4- to 8-membered monocyclic or bicyclic heterocyclic groups are represented by the following formula:

[0148]

[0149]

[0150] in The symbol represents the bond with ring C, and n is 0, 1, 2, or 3; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiments, or any alternative embodiments described therein. In the alternative twelfth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R C C represents 3-6 Cycloalkyl groups and 4- to 8-membered monocyclic or bicyclic heterocyclic groups are represented by the following formula:

[0151]

[0152]

[0153]

[0154] in The variable represents the bond with ring C, and n is 0, 1, 2, or 3; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiments or any alternative embodiments described therein.

[0155] In the thirteenth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, by R C C represents 3-6 The cycloalkyl group and the 4- to 8-membered monocyclic or bicyclic heterocyclic group are independently selected from:

[0156]

[0157]

[0158] in The bond represents the ring C, and the two Rs C1 The functional groups may be the same or different; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiments or any alternative embodiments described therein. In the alternative thirteenth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, by R C C represents 3-6 The cycloalkyl group and the 4- to 8-membered monocyclic or bicyclic heterocyclic group are independently selected from:

[0159]

[0160]

[0161]

[0162] in The bond represents the ring C, and the two Rs C1 The functional groups may be the same or different; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiments or any alternative embodiments described therein.

[0163] In the fourteenth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, each R C1 Independently, halogenated, –CN, –OR O1 –NR N1 R N2 –C(O)-R 7 –C(O)-OR O3 –SO2-R 7 C 1-6 Alkyl or 4- to 6-membered monocyclic heterocyclic groups, wherein R C1 The C mentioned 1-6 The alkyl group is optionally substituted by one to three independent substituents selected from the following: halogenated and –OR a1 And R a1 It is H, C 1-4 Alkyl or 4- to 6-membered heterocyclic groups; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiments or any alternative embodiments described therein. In the alternative fourteenth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, each R C1 Independently, halogenated, –CN, –OR O1 –NR N1 R N2 –C(O)-R 7 –C(O)-OR O3 –SO2-R 7 C 1-6 Alkyl, C 3-6 Cycloalkyl or 4- to 6-membered monocyclic heterocyclic groups, wherein R C1 The C mentioned 1-6 The alkyl group is optionally substituted by one to three independent substituents selected from the following: halogenated and –OR a1 And R a1 It is H, C 1-4Alkyl or 4- to 6-membered heterocyclic groups; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiments or any alternative embodiments described therein.

[0164] In the fifteenth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, each R C1 Independently selected from F, –CN, OH, -OCH3, -OCHF2, -NH2, -N(CH3)2, -CH3, -CH2F, -CHF2, -CF3, -CH2-OH, -CH2-CH3, -CH(CH3)2, –C(O)-CH3, –C(O)-OC(CH3)3, –SO2-CH3,

[0165]

[0166] in Indicates with R C The bonds; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiments. In the alternative fifteenth embodiment, for compounds of formula (I), (II), (III), (IV), (V) or (VI) or their pharmaceutically acceptable salts, each R C1 Independently selected from F, Cl, –CN, OH, -OCH3, -OCHF2, -NH2, -N(CH3)2, -CH3, -CH2F, -CHF2, -CF3, -CH2-OH, -CH2-CH3, -CH(CH3)2, -CH2-O-CH3, -CH2-CH2-OCH3, –C(O)-CH3, –C(O)-OC(CH3)3, –SO2-CH3, cyclopropyl,

[0167]

[0168] in Indicates with R C The key; and the remaining variables as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth or thirteenth embodiments or any alternative embodiments described therein.

[0169] In the sixteenth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, each R CIndependently selected from Cl, -CH3, -CH2F, -CHF2, -CF3, -CH2-CH3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CHF-CH2F, -CH2-CHF2, -CH2-CF3, -C(CH3)3, -CF2CH3, -CHF-CH3, -CH(CH3)2, -CF(CH3)2, -(CH3)2-CH2F, -CF(C H3)2, -CH(CH3)-CHF2, -CH(CH3)-CF3, -(CH3)2-CF3, -CH2-CH2-CN, -CH2-C(CH3)2-CN, -C(CH3)2- OH, -CH(CH3)-OCH3, -C(CH3)2-OCH3, -CH(OH)-CH3, -OCH3, -O-CHF2, -C(CH3)(OCH3)-CH2-OCH3, - O-CF3, -CH(OCH3)-cyclopropyl, -O-CH2CH3, -O-CH2CHF2, -O-CH(CH3)2, -O-CH(CF3)2, -O-CH2-OCH3, -O- CH(CH3)-OCH3, -O-CH(CH3)-CH2-OCH3, -O(CH3)2-OCH3, -O-CH2-CH2-O-CH3, -O-CH2-CH(CH3)-OC H3, -CF(CH3)-CH2-OCH3, -CH(CF3)-NH2, -CH(OCH3)-C(CH3)3, -NH-C(O)-CH3, -NH-SO2-CH3, -N(CH3)2, -NHCH(CH3)2, -CHF-cyclopropyl, -CF(CH3)-cyclopropyl, -NH-cyclohexyl, -N(CH3)-CH2-CH2-OCH3, -CH(NH2)-CF3

[0170]

[0171]

[0172]

[0173]

[0174] in Represents the bond with ring C; and the remaining variables are as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiments, or any alternative embodiments described therein. In one embodiment, R CIt is –CF2CH3. In the alternative sixteenth embodiment, for compounds of formula (I), (II), (III), (IV), (V) or (VI) or their pharmaceutically acceptable salts, each R C Independently selected from -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -CH2-CH3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CHF-CH2F, -CH2-CHF2, -CH2-CH2-CH2F, -CH2-CF3, -C(CH3)3, -CF2CH3, -CHF-CH3, -CH(CH3)2, -CF(CH3)2, -C(CH3)2-CH2F, -CH(CH3)-CHF2, -CH(CH3)-CF3, -C(CH3) 2-CF3, -CH2-CH2-CN, -CH2OCH3, -CH2-C(CH3)2-CN, -C(CH3)2-OH, -CH(CH3)-OCH3, -C(CH3)2-OCH3, -C(CH3)2-CH2-OCH3, -CH( OH)-CH3, -C(CH3)(OH)-CF3, -CH=CH2, -OCH3, -O-CHF2, -C(CH3)(OCH3)-CH2-OCH3, -O-CF3, -CH(OCH3)-cyclopropyl, -OH, -O-CH2CH3, - O-CH2CHF2, -O-CH(CH3)2, -O-CH(CF3)2, -O-CH2-OCH3, -O-CH(CH3)-OCH3, -O-CH(CH3)-CH2-OCH3, -O-CH2-CH2-O-CH3, -O-CH 2-CH(CH3)-OCH3, -CF(CH3)-CH2-OCH3, -CH(CF3)-NH2, -CH(OCH3)-C(CH3)3, -NH-C(O)-CH3, -NH-SO2-CH3, -NH2, -NHCH3, -N(C H3)2, -NHCH(CH3)2, -NHCH2CH2CH3, -NHCH2C(CH3)2OCH3, cyclopropyl, -CHF-cyclopropyl, -CF(CH3)-cyclopropyl, -CH(OCH3)-cyclopropyl, -C(CH3)(OCH3)-cyclopropyl, -CF(OCH3)-cyclopropyl, -NH-cyclohexyl, -NH-cyclopropyl, -NH-N-methylpiperidine, -NH-CH2-cyclopropyl, -NH-CH2-CH2-OCH3, -N(CH3)-CH2-CH2-OCH3, -CH(NH2)-CF3

[0175]

[0176]

[0177]

[0178]

[0179] in The term represents the bond with ring C; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth or ninth embodiments or any alternative embodiments described therein.

[0180] In the seventeenth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 1 It is C 1-4 Alkyl or C 3-6 cycloalkyl, wherein R 1 The C mentioned 1-4 Alkyl and C 3-6 Each cycloalkyl group is optionally surrounded by one to three independently selected from the following R 8 Replacement: Halogenated, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Halogenated alkyl; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth or sixteenth embodiments or any alternative embodiments described therein. In the alternative seventeenth embodiment, for compounds of formula (I), (II), (III), (IV), (V) or (VI) or their pharmaceutically acceptable salts, R 1 It is H, C 1-4 Alkyl, -OR 1A –NR N1 R N2 Or C 3-6 cycloalkyl, wherein R 1 The C mentioned 1-4 Alkyl and C 3-6 Each cycloalkyl group is optionally surrounded by one to three independently selected from the following R 8 Replacement: Halogenated, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Halogenated alkyl; R 1A It is C 1-4 Alkyl; R N1 and R N2 Each is independently H or C 1-4Alkyl; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth or sixteenth embodiments or any alternative embodiments described therein.

[0181] In the eighteenth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 1 It is optionally selected by one to three independently chosen from the following R 8 Replacement C 1-4 Alkyl groups: halogenated, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Halogenated alkyl; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth or sixteenth embodiments or any alternative embodiments described therein.

[0182] In the nineteenth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 8 For each occurrence independently of halogen, -CN, C 1-3 Alkoxy groups; and the remaining variables are as described in the first aspect or the seventeenth or eighteenth embodiment or any alternative embodiments described therein.

[0183] In the twentieth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, each R 8 The variables are independently selected from F, -CN, and -OCH3; and the remaining variables are as described in the first aspect or the seventeenth or eighteenth embodiment or any alternative embodiments described therein.

[0184] In the twenty-first embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 1 Selected from -CH3, -CH2-CH3, -CH2-CHF2, -CH2-CH2-CN, -CH2-CH2-OCH3, cyclopropyl, And the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth or sixteenth embodiments or any alternative embodiments described therein. In the alternative twenty-first embodiment, for compounds of formula (I), (II), (III), (IV), (V) or (VI) or their pharmaceutically acceptable salts, R 1 Selected from –H, -CH3, -CD3, -CH2-CH3, -CH2-CHF2, -CH2-CH2-CN, -CH2-CH2-OCH3, -OCH3, -NH2, -NHCH3, -N(CH3)2, cyclopropyl, And the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth or sixteenth embodiments or any alternative embodiments described therein.

[0185] In the twenty-second embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 3 It is H, –NR N1 R N2 Halogenated, –C(O)–R 7 –C(O)–OR O3 –SO2–R 7 –OR O4 C 1-6 Alkyl, C 3-6 Cycloalkyl, 4- to 9-membered monocyclic or bicyclic heterocyclic groups, wherein R 3 The C mentioned 1-6 Alkyl, C 3-6 The cycloalkyl group and the 4- to 9-membered monocyclic or bicyclic heterocyclic group are each optionally surrounded by one to three R groups. 9 Replacement; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiments or any alternative embodiments described therein. In the twenty-second alternative embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 3 It is H, –NR N1 R N2 Halogenated, –C(O)–R 7 –C(O)–OR O3 –SO2–R 7 –ORO4 C 1-6 Alkyl, alkenyl C 3-6 Cycloalkyl, 5- or 6-membered heteroaryl, 4- to 10-membered monocyclic or bicyclic heterocyclic groups, wherein R 3 The C mentioned 1-6 Alkyl, C 3-6 The cycloalkyl group and the 4- to 9-membered monocyclic or bicyclic heterocyclic group are each optionally surrounded by one to three R groups. 9 Replace; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth or twenty-first embodiments or any alternative embodiments described therein.

[0186] In the twenty-third embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 3 It is C 3-6 Cycloalkyl or 4 to 9-membered monocyclic or bicyclic heterocyclic groups, each optionally surrounded by one or three R groups. 9 Replacement; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiments or any alternative embodiments described therein. In the twenty-third alternative embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 3 It is C 3-6 Cycloalkyl or 4 to 10-membered monocyclic or bicyclic heterocyclic groups, each optionally surrounded by one or three R groups. 9 Replace; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth or twenty-first embodiments or any alternative embodiments described therein.

[0187] In the twenty-fourth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 3Selected from aziridine, cyclobutyl, cyclopentyl, cyclopropyl, 2,5-diazabicyclo[2.2.1]heptyl, 3,6-diazabicyclo[3.1.1]heptyl, 3,6-diazabicyclo[3.2.0]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, morpholinyl, octahydropyrrolo[3,4-c]pyrroleyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 2λ 2 ,6-diazaspiro[3.3]heptyl, 1λ 2 ,7λ 2 -diazaspiro[4.4]nonyl, oxetyl, piperidinyl, piperazinyl, piperazin-2-one-yl, pyrrolidinyl, pyrrolidin-2-one-yl and tetrahydropyranyl, each of which is optionally divided by one to three R 9 Replace; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiments or any alternative embodiments described therein. In some embodiments, R 3 The formulation is selected from pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl and 3,6-diazabicyclo[3.1.1]heptyl, each of which is optionally surrounded by one to three R... 9 Replacement. In some implementations, R 3 It is a pyrroleyl group, optionally surrounded by one to three R... 9 Substitution. In the twenty-fourth embodiment of the substitution, for compounds of formula (I), (II), (III), (IV), (V) or (VI) or their pharmaceutically acceptable salts, R 3Selected from pyrazolyl, pyridinyl, azacyclobutyl, cyclobutyl, cyclopentyl, cyclopropyl, 2-oxazolo[3.3]heptyl, 1,7-diazaspiro[4.4]nonyl, 2,7-diazaspiro[3.5]nonyl, 7-oxa-2-azaspiro[3.5]nonyl, 1-oxa-7-azaspiro[4.4]nonyl, 2,6-diazaspiro[3.4]octyl, 2-oxa-6-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 2,7-diazaspiro[4.4]nonyl, 1,6- Diazaspiro[3.3]heptyl, 1-oxa-6-azaspiro[3.3]heptyl, 3,6-diazabicyclo[3.2.0]heptyl, 3,9-diazabicyclo[3.3.1]nonyl, 6-oxa-2,9-diazaspiro[4.5]decyl, 1,6-diazaspiro[3.4]octyl, 5-azaspiro[2.4]heptyl, 1,6-diazaspiro[3.4]octyl, 1,7-diazaspiro[4.4]nonyl, 2-oxa-7-azaspiro[4.4]nonyl, octahydropyrano[2,3-c]pyrrole , octahydro-1H-pyrrolo[3,4-b]pyridyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydropyrrolo[3,4-b]pyrryl, 3-oxa-6-azabicyclo[3.1.1]heptyl, hexahydro-1H-furano[3,4-c]pyrryl, 1,4-oxaazabicycloheptyl, 6-oxa-2-azaspiro[3.5]nonyl, 5-oxa-2-azaspiro[3.4]octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3-oxa-7-azabicyclo[3.3.1] Nonyl, 2,5-diazabicyclo[2.2.1]heptyl, 3,6-diazabicyclo[3.1.1]heptyl, 3,6-diazabicyclo[3.2.0]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, morpholinyl, octahydropyrrolo[3,4-c]pyrroleyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 2λ 2 ,6-diazaspiro[3.3]heptyl, 1λ 2 ,7λ 2 -diazaspiro[4.4]nonyl, oxetyl, piperidinyl, piperazinyl, piperazin-2-one-yl, pyrrolidinyl, pyrrolidin-2-one-yl and tetrahydropyranyl, each of which is optionally divided by one to three R 9Replace; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth or twenty-first embodiments or any alternative embodiments described therein.

[0188] In the twenty-fifth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 3 Selected from:

[0189]

[0190]

[0191] in Represents the bond with ring B, and m is 0, 1, 2, or 3; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiments or any alternative embodiments described therein. In some embodiments, R 3 Selected from:

[0192]

[0193] In the alternative twenty-fifth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 3 Selected from:

[0194]

[0195]

[0196]

[0197] in The variable represents the bond with ring B, and m is 0, 1, 2, 3, or 4; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment or any alternative embodiment described therein.

[0198] In the twenty-sixth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R3 Selected from:

[0199]

[0200]

[0201]

[0202] in Represents the bond with ring B; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiments or any alternative embodiments described therein. In some embodiments, R 3 Selected from:

[0203] In the alternative twenty-sixth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 3 Selected from:

[0204]

[0205]

[0206]

[0207] in The term represents the bond with ring B; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiments.

[0208] In the twenty-seventh embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 3 It is H, –NR N1 R N2 Halogenated, –C(O)–R 7 –C(O)–OR O3 –SO2–R 7 –OR O4 Or optionally by one to three R 9 Replacement C 1-6Alkyl; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth or twenty-first embodiments or any alternative embodiments described therein.

[0209] In the twenty-eighth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, each R 9 Independently, it is halogenated, OH, or -OC. 1-4 Alkyl, –NR a2 R a3 –CN, –C(O) –OR a1 –SO2-R a1 C 1-4 Alkyl or C 3-6 cycloalkyl, wherein R 9 The C mentioned 1-4 Alkyl and C 3-6 Each cycloalkyl group is optionally substituted by one to three independent substituents selected from the following: halogenated and C-substituted. 1-3 alkoxy groups; and R a1 R a2 and R a3 Each is C independently 1-3 Alkyl; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, or twenty-seventh embodiments or any alternative embodiments described therein. In some embodiments, each R 9 Independently, it is halogenated, -OR a1 –NR a2 R a3 –CN, –C(O) –OR a1 –SO2-R a1 C 1-4 Alkyl, C 3-6 Cycloalkyl or 4- to 7-membered monocyclic heterocyclic groups, wherein R 9 The C mentioned 1-4 Alkyl and C 3-6 Each cycloalkyl group is optionally substituted by one to three independent substituents selected from the following: halogenated and C-substituted. 1-3 alkoxy groups; and R a1 R a2 and R a3 Each is independently H or C1-3 Alkyl. In the alternative twenty-eighth embodiment, for compounds of formula (I), (II), (III), (IV), (V) or (VI) or their pharmaceutically acceptable salts, R 9 Independently, it is halogenated, -OR a1 –NR a2 R a3 –CN, –C(O) –OR a1 –SO2-R a1 C 1-4 Alkyl, C 3-6 Cycloalkyl or 4 to 10-membered monocyclic or bicyclic heterocyclic groups, wherein R is a cycloalkyl group or a 4 to 10-membered monocyclic or bicyclic heterocyclic group. 9 The C mentioned 1-4 Alkyl groups, 4- to 10-membered monocyclic or bicyclic heterocyclic groups, and C 3-6 Each cycloalkyl group is optionally substituted by one to three independent substituents selected from the following: halogenated, OH, -CN, C. 1-4 Alkyl and C 1-3 alkoxy groups; and R a1 R a2 and R a3 H and C are independent of each other. 3-4 cycloalkyl or C 1-3 Alkyl, wherein R a1 R a2 and R a3 The C mentioned 3-4 cycloalkyl groups are optionally C 1-4 Alkyl substitution, and wherein R is present. a1 R a2 and R a3 The C mentioned 1-3 Alkyl groups are optionally substituted with phenyl groups; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth or twenty-seventh embodiments or any alternative embodiments described therein.

[0210] In the twenty-ninth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, each R 9Independently selected from F, OH, -OCH3, -OCHF2, -OCF3, -N(CH3)2, –CN, -CH3, -CF3, -C(O)-OCH2CH3, –SO2-CH3, -CH2-OCH3, -CH2-CH2-OCH3, -CH2-CH3, cyclopropyl, -CHF2, and -CH2-CF3; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, or twenty-seventh embodiments or any alternative embodiments described therein. In some embodiments, each R 9 Independently selected from F, OH, -OCH3, -OCHF2, -OCF3, -NHCH3, -NH2, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -NHCH(CH3)2, –CN, -CH3, -CF3, -C(O)-OCH2CH3, –SO2-CH3, -CH2-OCH3, -CH2-CH2-OCH3, -CH2-CH3, pyrrolyl, morpholinyl, cyclopropyl, -CHF2, and -CH2-CF3. In the alternative twenty-ninth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, each R 9 Independently selected from F, OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCD3, -O-cyclopropyl, -NHCH3, -NH2, -N(CH3)2, -N(CD3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -NHCH(CH3)2, -NHCH2CH3, –CN, -CH3, -CH2F, -CF3, -C(O)-OCH2CH3, –SO2-CH3, -CH2-OCH3, -CH2-CH2-OCH3, -CH2-CH3, -CH2-CN, pyrrolyl, morpholinyl, azircyclic butyl, cyclopropyl, -CHF2, -CH2-CF3. And the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth or twenty-seventh embodiments or any alternative embodiments described therein.

[0211] In the thirtieth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, the two R... 9 Together with their intermediate atoms, they form 4- to 6-membered monocyclic heterocyclic groups, which are optionally substituted by one or two independent substituents selected from: halogenated, C-substituted ... 1-4 Alkyl and C 1-4 Halogenated alkyl; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth or twenty-seventh embodiments or any alternative embodiments described therein.

[0212] In the thirty-first embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 3 Selected from H, Cl, -CH3, -CH2F, -CHF2, -CF3, -CH2-CH3, -CHF-CH3, -CH(CH3)2, -CHF-CH2F, -CH2-CH2-CN, -CH2-CH2-CH3, -CH2-CH(CH3)2, -CH2-cyclopropyl, -CH2-OCH3, - CH(CH3)-CH2-CH3, -CH(CH3)-CF3, -CH(CH3)-OCH3, –N(CH3)2, -OCH3, -N(CH3)-CH2-CH2-OCH3, -C(O)-OCH3, –SO2–CH3, -O-CH(CH3)2, -O-CH2-CH2-OCH3, in The term indicates a bond with ring B; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment or any alternative embodiment described therein. In the alternative thirty-first embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 3Selected from H, Cl, -CN, -CH3, -CH2F, -CHF2, -CF3, -CH2-CH3, -CH2CF3, -CHF-CH3, -CH(CH3)2, -CH(CF3)2, -CHF-CH2F, -CH2-CH2-CN, -CH2-CH2-CH3, -CH(CH3)-CH2-CH3, -CH2-CH(CH3)2, -CH2-cyclopropyl, -CH2-morpholinyl, -CH2OH, -CH2-OCH3, -C(CH3)-CH2- CH3, -CH(CH3)-CF3, -CH(CH3)-OCH3, -CH2N(CH3)2, -CH=CH2, -NH2, -NHCH3, -NHCH2CH3, –N(CH3)2, -OCH3, -N(CH3)- CH2-CH2-OCH3, -N(CH3)CH2C(CH3)2OCH3, -C(O)-OCH3, -C(O)-OCH2CH3, –SO2–CH3, -O-CH(CH3)2, -O-CH2-CH2-OCH3,

[0213] in The term represents the bond with ring B; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth or twenty-first embodiments or any alternative embodiments described therein.

[0214] In the thirty-second embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, each R 7 C is independent 1-6 Alkyl, C 3-6 Cycloalkyl or 4- to 6-membered monocyclic heterocyclic groups, wherein R 7 The C mentioned 1-6 Alkyl, C 3-6 The cycloalkyl group and the 4- to 6-membered monocyclic heterocyclic group are each optionally substituted by one to three independent substituents selected from the following: halogenated, C-shaped, etc. 1-3 Alkyl and C 1-3Halogenated alkyl; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth or thirty-first embodiments or any alternative embodiments described therein.

[0215] In the thirty-third embodiment, for compounds of formula (I), (II), (III), (IV), (V) or (VI) or their pharmaceutically acceptable salts, each R 7 Independently selected from -CH3, And the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth or thirty-first implementation scheme or any alternative implementation scheme described therein.

[0216] In the thirty-fourth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, each R O1 H and C independently 1-6 Alkyl, 3- to 6-membered monocyclic or bicyclic carbocyclic, 4- to 6-membered monocyclic heterocyclic or 6-membered heteroaryl, wherein R O1 The C mentioned 1-6 Alkyl, 3- to 6-membered monocyclic or bicyclic carbocyclic, 4- to 6-membered monocyclic heterocyclic, and 6-membered heteroaryl are each optionally surrounded by one to three R O2 Replace; and each R O2 Independently, it is halogenated, OH, -CN, C 1-4 Alkoxy, C 1-4 Alkyl, 3- to 5-membered monocyclic carbocyclic, 4- to 7-membered monocyclic or bicyclic heterocyclic or phenyl, wherein the C 1-4 Alkyl, 3- to 5-membered monocyclic carbocyclic, 4- to 7-membered monocyclic or bicyclic heterocyclic and phenyl groups are each optionally C 1-3 Alkoxy, C 1-3The alkyl halogen or one to three halogenated substitutions; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second or thirty-third embodiments or any alternative embodiments described therein.

[0217] In the thirty-fifth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, by R O1 or R O2 The 4- to 7-membered monocyclic or bicyclic heterocyclic groups or 6-membered heteroaryl groups are each independently selected from morpholino, oxetane, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholino, azirne, oxaspiro[2.4]heptane, pyrrolidinyl, and piperidinyl; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, or thirty-third embodiments or any alternative embodiments described therein.

[0218] In the thirty-sixth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, each R O2 Independently selected from F, -CN, OH, -OCH3, -CH3, -CHF2, -CF3, in Indicates with R O1 The key; and the remaining variables as described in the first aspect or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth or thirty-fifth embodiments or any alternative embodiments described therein.

[0219] In the thirty-seventh embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, each R O1 Independently selected from H, -CH3, -CHF2, -CF3, -CH2-CH3, -CH2-CHF2, -CH2-CF3, -CH2-CH2-CH3, -CH(CH3)2, -CH(CF3)2, -CH2-CH2-OCH3, -CH(CH3)-CH2-OCH3, -CH2-CH(CH3)-OCH3,

[0220] And the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second or thirty-third implementation scheme or any alternative implementation scheme described therein.

[0221] In the thirty-eighth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, each R O3 C is independently, optionally substituted by one to three substituents independently selected from the following 1-6 Alkyl groups: Halogenated and C 1-4 Halogenated alkyl; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth or thirty-seventh embodiments or any alternative embodiments described therein.

[0222] In the thirty-ninth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, each R O3Independently, it is -CH3, -CH2CH3, or -C(CH3)3; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, or thirty-seventh embodiments or any alternative embodiments described therein.

[0223] In the fortieth embodiment, for compounds of formula (I), (II), (III), (IV), (V) or (VI) or their pharmaceutically acceptable salts, R O4 It is C 1-4 Alkyl or C 3-6 Cycloalkyl groups, each optionally substituted by one to three independent substituents selected from the following: halogenated and C-shaped. 1-3 Alkoxy; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiments or any alternative embodiments described therein.

[0224] In the forty-first embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R O4 Selected from -CH3, -CH2-CH3, -CH(CH3)2, -CH2-CH2-OCH3 and And the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth implementation schemes or any alternative implementation schemes described therein.

[0225] In the forty-second embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R N1 and R N2 H and C are independent of each other. 3-6 cycloalkyl or optionally C 1-3 alkoxy-substituted C 1-4 Alkyl; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, or forty-first embodiments or any alternative embodiments described therein.

[0226] In the forty-third embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R N1 and R N2 Each of these variables independently represents H, -CH3, -CH(CH3)2, -CH2-CH2-OCH3, or cyclohexyl; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, or forty-first embodiments or any alternative embodiments described therein.

[0227] In the forty-fourth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R N3It is H; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, or forty-third embodiments or any alternative embodiments described therein.

[0228] In the forty-fifth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R N4 It is H; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, or forty-fourth embodiments or any alternative embodiments described therein.

[0229] In the forty-sixth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 4 It is H; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty, forty-first, forty-second, forty-third, forty-fourth, forty-fourth, or forty-fifth embodiments or any alternative embodiments described therein. In the alternative forty-sixth embodiment, for compounds of formula (I), (II), (III), (IV), (V), or (VI) or their pharmaceutically acceptable salts, R 4It is H or –CH3; and the remaining variables are as described in the first aspect or in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, thirty-ninth, fortieth, forty-first, forty-second, forty-third, forty-fourth or forty-fifth embodiments or any alternative embodiments described therein.

[0230] In the forty-seventh embodiment, the compound is of formula (VII) or (VIII):

[0231]

[0232] Or a pharmaceutically acceptable salt thereof, wherein the ring C is optionally surrounded by one to three R C Substituted 6-membered heteroaryl; each R C Independently is –OR O1 C 1-4 Alkyl or 5-membered heterocyclic group, wherein R C The C mentioned 1-4 The alkyl group and the 5-membered heterocyclic group are each optionally surrounded by one to three R groups. C1 Replace; each R C1 Independently halogenated or –OR O1 ;R 3 It is H, C 1-4 Alkyl, C 3-5 Cycloalkyl or 5- to 7-membered monocyclic or bicyclic heterocyclic groups, wherein R 3 The C mentioned 1-4 Alkyl, C 3-5 The cycloalkyl group and the 5- to 7-membered monocyclic or bicyclic heterocyclic group are each optionally surrounded by one to three R groups. 9 Replace; each R 9 Independently is –OR O1 –NR N1 R N2 5 to 7-membered monocyclic heterocyclic groups or C 1-4 Alkyl; each R O1 H and C independently 1-4 Alkyl or C 3-5 cycloalkyl, wherein the C 1-4 Alkyl and C 3-5 Each cycloalkyl group is optionally R O2 Replace; each R O2 Independently –CN or C 1-4 alkoxy groups; and RN1 and R N2 Each is independently H or C 1-3 Alkyl group. In some embodiments, R 3 It is a 5- to 7-membered monocyclic or bicyclic heterocyclic group connected to a ring N atom and a ring B atom. In some embodiments, each R 9 Independently is –OR O1 –NR N1 R N2 Or C 1-4 Alkyl group. In an alternative forty-seventh embodiment, the compound is of formula (VII') or (VIII'):

[0233]

[0234] Or a pharmaceutically acceptable salt thereof, wherein the ring C is optionally surrounded by one to three R C Substituted 6-membered heteroaryl; each R C Independently is –OR O1 C 1-4 Alkyl or 5-membered heterocyclic group, wherein R C The C mentioned 1-4 The alkyl group and the 5-membered heterocyclic group are each optionally surrounded by one to three R groups. C1 Replace; each R C1 Independently halogenated or –OR O1 ;R 1 It is H or –CH3; R 3 It is H, C 1-4 Alkyl, C 3-5 Cycloalkyl or 5- to 7-membered monocyclic or bicyclic heterocyclic groups, wherein R 3 The C mentioned 1-4 Alkyl, C 3-5 The cycloalkyl group and the 5- to 7-membered monocyclic or bicyclic heterocyclic group are each optionally surrounded by one to three R groups. 9 Replace; each R 9 Independently is –OR O1 –NR N1 R N2 5 to 7-membered monocyclic heterocyclic groups or C 1-4 Alkyl; each R O1 H and C independently 1-4 Alkyl or C 3-5 cycloalkyl, wherein the C 1-4 Alkyl and C 3-5 Each cycloalkyl group is optionally R O2 Replace; each R O2 Independently –CN or C 1-4 alkoxy groups; and R N1 and R N2 Each is independently H or C1-3 Alkyl group. In some embodiments, R 3 It is a 5- to 7-membered monocyclic or bicyclic heterocyclic group connected to a ring N atom and a ring B atom. In some embodiments, each R 9 Independently is –OR O1 –NR N1 R N2 Or C 1-4 alkyl.

[0235] In the forty-eighth embodiment, for compounds of formula (VII), (VII'), (VIII) or (VIII') or their pharmaceutically acceptable salts, the ring C is pyridyl, pyrazinyl, or pyrimidinyl, each of which is optionally surrounded by one or two R... C Replace; and the remaining variables are as described in the first aspect or the forty-seventh embodiment or any alternative embodiment described therein.

[0236] In the forty-ninth embodiment, for compounds of formula (VII), (VII'), (VIII) or (VIII') or their pharmaceutically acceptable salts, the ring C is pyrimidinyl, pyrazinyl, or thiazolyl, each of which is optionally surrounded by one or two R groups. C Replace; and the remaining variables are as described in the first aspect or the forty-seventh embodiment or any alternative embodiment described therein.

[0237] In the fiftieth embodiment, for compounds of formula (VII), (VII'), (VIII) or (VIII') or their pharmaceutically acceptable salts, ring C is selected from:

[0238]

[0239] And among them The variable represents the bond to ring B, and n is 0, 1, or 2; and the remaining variables are as described in the first aspect or the forty-seventh embodiment or any alternative embodiment described therein.

[0240] In the fifty-first embodiment, for compounds of formula (VII), (VII'), (VIII) or (VIII') or their pharmaceutically acceptable salts, ring C is selected from:

[0241]

[0242] And among them The variable represents the bond to ring B, and n is 0, 1, or 2; and the remaining variables are as described in the first aspect or the forty-seventh embodiment or any alternative embodiment described therein.

[0243] In the fifty-second embodiment, for compounds of formula (VII), (VII'), (VIII) or (VIII') or their pharmaceutically acceptable salts, ring C is selected from:

[0244]

[0245] And among them This indicates a bond with ring B, and two Rs in ring C. C The functional groups may be the same or different; and the remaining variables are as described in the first aspect or the forty-seventh embodiment or any alternative embodiments described therein.

[0246] In the fifty-third embodiment, for compounds of formula (VII) or (VIII) or their pharmaceutically acceptable salts, ring C is selected from:

[0247]

[0248] And among them This indicates a bond with ring B, and two Rs in ring C. C The functional groups may be the same or different; and the remaining variables are as described in the first aspect or the forty-seventh embodiment.

[0249] In the fifty-fourth embodiment, for compounds of formula (VII) or (VIII) or their pharmaceutically acceptable salts, each RC is independently –ORO1, a C1-2 alkyl, a C1-2 haloalkyl, or a 5-membered oxygen-containing heterocyclic group optionally substituted with an RC1; and the remaining variables are as described in the first aspect or in embodiments forty-seven, forty-eight, forty-nine, fifty, fifty-one, fifty-two, or fifty-three. In some embodiments, R C At least one of them is C 1-2 Halogenated alkyl, more specifically –CF2CH3.

[0250] In the fifty-fifth embodiment, for compounds of formula (VII), (VII'), (VIII) or (VIII') or their pharmaceutically acceptable salts, R C It is arbitrarily assigned to an R C1 The substituted tetrahydrofuranyl group; and the remaining variables are as described in the first aspect or in embodiments forty-seven, forty-eight, forty-nine, fifty, fifty-one, fifty-two or fifty-three, or any alternative embodiments described therein.

[0251] In the fifty-sixth embodiment, for compounds of formula (VII), (VII'), (VIII) or (VIII') or their pharmaceutically acceptable salts, R C yes in The term represents the bond with ring C; and the remaining variables are as described in the first aspect or in embodiments forty-seven, forty-eight, forty-nine, fifty, fifty-one, fifty-two or fifty-three, or any alternative embodiments described therein.

[0252] In the fifty-seventh embodiment, for compounds of formula (VII), (VII'), (VIII) or (VIII') or their pharmaceutically acceptable salts, each R C1 Independently, it is F or -OCH3; and the remaining variables are as described in the first aspect or in the forty-seventh, forty-eighth, forty-ninth, fiftieth, fifty-first, fifty-second, fifty-third, fifty-fourth, fifty-fifth or fifty-sixth embodiments or any alternative embodiments described therein.

[0253] In the fifty-eighth embodiment, for compounds of formula (VII), (VII'), (VIII) or (VIII') or their pharmaceutically acceptable salts, each R C Independently selected from -CH3, -CF2CH3, -OCH3, -O-CH2-CH2-O-CH3, in Represents the bond with ring C; and the remaining variables are as described in the first aspect or embodiments forty-seven, forty-eight, forty-nine, fiftie, or fifty-one, fifty-two, fifty-three, fifty-four, fifty-five, or fifty-six, or any alternative embodiments described therein. In some embodiments, each R C Independently selected from -CH3, -CH2CH3, -CF2CH3, –CF(CH3)2

[0254] -OCH3, -O-CH2-CH2-O-CH3 in Indicates a bond with ring C. In the alternative fifty-eighth embodiment, for compounds of formula (VII), (VII'), (VIII) or (VIII') or their pharmaceutically acceptable salts, each R C Independently selected from -CH3, -CH2CH3, -CF2CH3, -CF(CH3)2, -OCH3, -O-CH2-CH2-O-CH3, in The key to ring C is indicated; and the remaining variables are as described in the first aspect or in embodiments forty-seven, forty-eight, forty-nine, fifty or fifty-one, fifty-two, fifty-three, fifty-four, fifty-five or fifty-six, or any alternative embodiments described therein.

[0255] In the fifty-ninth embodiment, for compounds of formula (VII), (VII'), (VIII) or (VIII') or their pharmaceutically acceptable salts, by R 3 The 5- to 7-membered monocyclic or bicyclic heterocyclic groups represented are selected from 3,6-diazabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, piperazine, and pyrrolidinyl, each of which is optionally represented by one or two R groups. 9 Replace; and the remaining variables are as described in the first aspect or in the forty-seventh, forty-eighth, forty-ninth, fiftieth, fifty-first, fifty-second, fifty-third, fifty-fourth, fifty-fifth, fifty-sixth, fifty-seventh or fifty-eighth embodiments or any alternative embodiments described therein.

[0256] In the sixtieth embodiment, for compounds of formula (VII), (VII'), (VIII) or (VIII') or their pharmaceutically acceptable salts, R 3 Selected from H, -CH2CH3,

[0257]

[0258] in The variable represents the bond with ring B, and m is 0, 1, or 2; and the remaining variables are as described in the first aspect or in the forty-seventh, forty-eighth, forty-ninth, fiftieth, fifty-first, fifty-second, fifty-third, fifty-fourth, fifty-fifth, fifty-sixth, fifty-seventh, or fifty-eighth embodiments or any alternative embodiments described therein.

[0259] In the sixty-first embodiment, for compounds of formula (VII), (VII'), (VIII) or (VIII') or their pharmaceutically acceptable salts, R 3 Selected from H, -CH2CH3,

[0260]

[0261] in The key to ring B is indicated; and the remaining variables are as described in the first aspect or in embodiments forty-seven, forty-eight, forty-nine, fifty, fifty, fifty-one, fifty-two, fifty-three, fifty-four or fifty-five, fifty-six, fifty-seven or fifty-eight, or any alternative embodiments described therein.

[0262] In the sixty-second embodiment, for compounds of formula (VII), (VII'), (VIII) or (VIII') or their pharmaceutically acceptable salts, each R 9Independently selected from -OH, -OCH3, -N(CH3)2, and -CH3; and the remaining variables are as described in the first aspect or in embodiments forty-seven, forty-eight, forty-nine, fifty, fifty-one, fifty-two, fifty-three, fifty-four, fifty-five, fifty-six, fifty-seven, or fifty-eight, or any alternative embodiments described therein. In some embodiments, each R 9 It is independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2, pyrrolyl, morpholinyl, -CH2CH3 and -CH3.

[0263] In the sixty-third embodiment, for compounds of formula (VII), (VII'), (VIII) or (VIII') or their pharmaceutically acceptable salts, R O1 Each is independently selected from H, –CH3, -CH2CH2OCH3, cyclopropyl, And the remaining variables are as described in the first aspect or in the forty-seventh, forty-eighth, forty-ninth, fiftieth, fifty-first, fifty-second, fifty-third, fifty-fourth, fifty-fifth, fifty-sixth, fifty-seventh, fifty-eighth, fifty-ninth, sixtieth, sixty-first, or sixty-second embodiments or any alternative embodiments described therein.

[0264] In the sixty-fourth embodiment, for compounds of formula (VII), (VII'), (VIII) or (VIII') or their pharmaceutically acceptable salts, ring C is selected from the following:

[0265]

[0266] Where R C It is C 1-3 Alkyl or C 1-3 Alkoxy; and the remaining variables are as defined in embodiments 59, 60, 61, or 62, or any alternative embodiments described therein. In some embodiments, R C It is C 1-2 Alkyl or C 1-2 Alkyl group.

[0267] In the sixty-fifth embodiment, for compounds of formula (VII), (VII'), (VIII) or (VIII') or their pharmaceutically acceptable salts, ring C is selected from:

[0268]

[0269] Where R C For each occurrence of C independently 1-3 Alkyl, C1-3 Halogenated alkyl or C 1-3 Alkoxy; and the remaining variables are as defined in embodiments 59, 60, 61, or 62, or any alternative embodiments described therein. In some embodiments, for formula (C3), R C It is C 1-3 Haloalkyl; for formula (C4), one R C It is C 1-3 Alkyl group, and another one is C. 1-3 Alkyl or C 1-3 Alkyl group. In some embodiments, for formula (C3), R C It is –CF2CH3; for equation (C4), an R C It is –CF2CH3, and the other is C. 1-3 Alkyl or C 1-3 Alkyl group.

[0270] In the sixty-sixth embodiment, for the compound or a pharmaceutically acceptable salt thereof of the sixty-fourth or sixty-fifth embodiment, R 3 Selected from pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl and 3,6-diazabicyclo[3.1.1]heptyl, each of which is optionally separated by one or two R 9 Replace; R 9 Independently, it is halogenated, C 1-4 Alkyl, OH, -OC 1-4 Alkyl or –NR a2 R a3 And R a2 and R a3 Each is independently H or C 1-3 Alkyl group. In some embodiments, R 3 Selected from:

[0271]

[0272] Where R 9 It is C 1-3 Alkyl, -OC 1-3 Alkyl or –NR a2 R a3 And m is 0, 1, or 2.

[0273] In the sixty-seventh embodiment, for the compounds of the sixty-fourth, sixty-fifth, or sixty-sixth embodiments or their pharmaceutically acceptable salts, when only one R is present... C At that time, R C It is –CF2CH3, or when there are two Rs. C At that time, an R C It is –CF2CH3 and another RC It is C 1-3 Alkyl or C 1-3 alkoxy group; m is 1 or 2; and R 9 For each occurrence of C independently 1-3 Alkyl, -OC 1-3 Alkyl or –NR a2 R a3 And the remaining variables are as defined in embodiments sixty-four, sixty-five or sixty-six.

[0274] In the sixty-eighth embodiment, for the compound of the sixty-fourth or sixty-fifth embodiment or its pharmaceutically acceptable salt, the ring C is R C It is C 1-2 Alkyl or C 1-2 Alkoxy; R 3 yes m is 1 or 2; R 9 For each occurrence of C independently 1-2 Alkyl and –NR a2 R a3 And R a2 and R a3 It is C 1-2 Alkyl group. In some embodiments, R C It is –CH3, -CH2CH3, or –OCH3; and R 9 Each occurrence is independently –CH3 or –N(CH3)2.

[0275] In the sixty-ninth embodiment, for the compound of the sixty-fourth or sixty-fifth embodiment or its pharmaceutically acceptable salt, when only one R is present... C At that time, R C It is –CF2CH3, when there are two R C At that time, an R C It is –CF2CH3 and another R C It is –CH3, -CH2CH3, or –OCH3; and R 9 Each occurrence is independently –CH3 or –N(CH3)2.

[0276] In the seventieth embodiment, the compound is of formula (VIIA):

[0277]

[0278] Or a pharmaceutically acceptable salt thereof, wherein R C1a C is replaced by 1 to 3 halogens. 1-3 Alkyl; R C1b It is C 1-3 Alkyl; R 3Selected from Each R 9 Independently is –NR N1 R N2 C 1-4 Alkyl, morpholino, or pyrrolidinyl; and R N1 and R N2 Each is independently H or C 1-3 Alkyl group. In an alternative seventieth embodiment, the compound is of formula (VIIA'):

[0279]

[0280] Or a pharmaceutically acceptable salt thereof, wherein R1 is H or CH3; R C1a C is replaced by 1 to 3 halogens. 1-3 Alkyl; R C1b It is C 1-3 Alkyl; R 3 Selected from Each R 9 Independently is –NR N1 R N2 C 1-4 Alkyl, morpholino, or pyrrolidinyl; and R N1 and R N2 Each is independently H or C 1-3 alkyl.

[0281] In the seventy-first embodiment, for the compound of the seventieth embodiment or a pharmaceutically acceptable salt thereof, R C1a It is –CF2CH3; R C1b It is –CH3 or CH2CH3; and the remaining variables are as described in the first aspect or the seventieth embodiment.

[0282] In the seventy-second embodiment, for the compound of the seventy or seventy-first embodiment or its pharmaceutically acceptable salt, each R 9 Independently, they are -NH2, -NHCH3, -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2, -CH3 or -CH2CH3; and the remaining variables are as described in the first aspect or the seventieth or seventy-first embodiment.

[0283] In the seventy-third embodiment, the compound is of formula (VIIB):

[0284]

[0285] Or a pharmaceutically acceptable salt thereof, wherein: R C1aC is replaced by 1 to 3 halogens. 1-3 Alkyl; R C1b It is C 1-3 alkoxy group; n1 is 0 or 1; R 3 yes R 9 Yes – NR N1 R N2 And R N1 and R N2 Each is independently H or C 1-3 alkyl.

[0286] In the seventy-fourth embodiment, for the compound of the seventy-third embodiment or its pharmaceutically acceptable salt, R C1a It is –CF2CH3 or –CF(CH3)2; and the remaining variables are as described in the first aspect or the seventy-third embodiment.

[0287] In the seventy-fifth embodiment, for the compound of the seventy-third or seventy-fourth embodiment or its pharmaceutically acceptable salt, n1 is 0 or n1 is 1 and R C1b It is –OCH3; and the remaining variables are as described in the first aspect or in the seventy-third or seventy-fourth embodiment.

[0288] In the seventy-sixth embodiment, for the compounds or pharmaceutically acceptable salts of the embodiments seventy, seventy-first, seventy-second, seventy-third, seventy-fourth, or seventy-fifth, R 9 It is –NHCH(CH3)2; and the remaining variables are as described in the first aspect or in the seventieth, seventy-first, seventy-second, seventy-third, seventy-fourth or seventy-fifth embodiments.

[0289] In some embodiments, for the compounds of any of the embodiments 47 to 69, the compounds are represented by formula (VII) or a pharmaceutically acceptable salt thereof, and the variables described therein are defined as defined in any of the embodiments 47 to 69. In some embodiments, for the compounds of any of the embodiments 64 to 69, the compounds are represented by formula (VIII) or a pharmaceutically acceptable salt thereof, and the variables described therein are defined as defined in any of the embodiments 47 to 69.

[0290] In one embodiment, the compound disclosed herein is any of the compounds of Examples 1-958 or a pharmaceutically acceptable salt thereof.

[0291] This disclosure also includes the neutral forms of the compounds shown in the examples and pharmaceutically acceptable salts.

[0292] III. Pharmaceutical Composition

[0293] In one aspect, this disclosure is a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0294] The phrase “pharmaceutically acceptable” means that a substance, composition, or dosage form must be chemically and / or toxicologically compatible with the other components constituting the preparation and / or the mammals to be treated with it.

[0295] As used herein, the term "pharmaceuticalally acceptable carrier" includes solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, salts, preservatives, drug stabilizers, buffers (e.g., maleic acid, tartaric acid, lactic acid, citric acid, acetic acid, sodium bicarbonate, sodium phosphate, etc.), and combinations thereof, as known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990, pp. 1289-1329). Its use in therapeutic or pharmaceutical compositions should be considered except in cases where any conventional carrier is incompatible with the active ingredient.

[0296] The formulation can be prepared using conventional dissolution and mixing procedures. For example, the active pharmaceutical ingredient (i.e., the compound of this disclosure or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complex)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compounds of this disclosure are typically formulated into pharmaceutical dosage forms to provide easily controllable drug dosing and to offer patients a refined and easy-to-use product.

[0297] Pharmaceutical compositions (or formulations) for administration can be packaged in various ways depending on the method of administration. Generally, articles for dispensing include containers containing pharmaceutical formulations in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal tubes, etc. Containers may also include tamper-proof components to prevent accidental contact with the contents of the package. Furthermore, a label describing the contents of the container is affixed to the container. The label may also include appropriate warnings.

[0298] Pharmaceutical compositions comprising compounds disclosed herein are typically formulated for parenteral or oral administration.

[0299] For example, the oral pharmaceutical compositions disclosed herein may be formulated in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including but not limited to solutions, suspensions, or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical processes, such as sterilization, and / or may contain conventional inert diluents, lubricants, or buffers, as well as adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0300] Typically, pharmaceutical compositions are tablets or gelatin capsules containing an active ingredient and a) a diluent, such as lactose, glucose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) a lubricant, such as silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; for tablets, c) a binder, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone; d) a disintegrant, such as starch, agar, alginic acid, or its sodium salt, or an effervescent mixture, if desired; and / or e) an absorbent, colorant, flavoring agent, and sweetener.

[0301] Tablets can be film-coated or enteric-coated according to methods known in the art.

[0302] Suitable compositions for oral administration include the compounds of this disclosure in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically appealing and palatable preparation. Tablets may contain the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for manufacturing tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, delaying agents such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0303] Parenteral compositions (e.g., intravenous (IV) preparations) are aqueous isotonic solutions or suspensions. Parenteral compositions may be sterile and / or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts and / or buffers for adjusting osmotic pressure. Furthermore, they may contain other substances of therapeutic value. The compositions are typically prepared according to conventional mixing, granulation, or coating methods and contain about 0.1-75% or about 1-50% of the active ingredient.

[0304] An effective dose of the compound provided herein or a pharmaceutically acceptable salt thereof administered to a subject may be 10 μg to 500 mg.

[0305] Administration of the compounds described herein or their pharmaceutically acceptable salts to mammals includes any suitable method of delivery. Administration of the compounds described herein or their pharmaceutically acceptable salts to mammals includes external, enteral, parenteral, transdermal, mucosal, inhalation, intracerebrospinal, epidural, vaginal, intravenous, intramuscular, subcutaneous, intradermal, or intravitreal administration of the compounds described herein or their pharmaceutically acceptable salts to the mammal. Administration of the compounds described herein or their pharmaceutically acceptable salts to mammals also includes administration of compounds that metabolize the compounds described herein or their pharmaceutically acceptable salts to the mammal's body or body surface through external, enteral, parenteral, transdermal, mucosal, inhalation, intracerebrospinal, epidural, vaginal, intravenous, intramuscular, subcutaneous, intradermal, or intravitreal administration.

[0306] Therefore, compounds as described herein, or pharmaceutically acceptable salts thereof, can be administered systemically, for example or orally, in combination with pharmaceutically acceptable media such as inert diluents or assimilated food carriers. They can be encapsulated in hard or soft-shell gelatin capsules, compressed into tablets, or mixed directly with the patient's diet. For oral therapeutic administration, compounds as described herein, or pharmaceutically acceptable salts thereof, can be combined with one or more excipients and can be used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, or rice paper wafers. Such compositions and preparations should contain at least about 0.1% of the active compound. The percentage of the composition and preparation can, of course, vary and can conveniently be between about 2% and about 60% by weight of a given unit dosage form. The amount of the active compound in such therapeutically useful compositions is such that an effective dose level will be obtained.

[0307] Tablets, lozenges, pills, capsules, etc. may include the following: binders, such as astragalus gum, gum arabic, corn starch or gelatin; excipients, such as dicalcium phosphate; disintegrants, such as corn starch, potato starch, alginic acid, etc.; lubricants, such as magnesium stearate; or sweeteners, such as sucrose, fructose, lactose or aspartame or flavoring agents.

[0308] The active compound can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a non-toxic surfactant.

[0309] Exemplary drug dosage forms for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders containing an active ingredient, suitable for provisional preparation of sterile injectable or infusionable solutions or dispersions. In all cases, the final dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage.

[0310] Sterile injectable solutions can be prepared by blending the desired amount of the active compound with various other ingredients listed above (as needed) in a suitable solvent, followed by filtration and sterilization. In the case of sterile powders used to prepare sterile injectable solutions, preferred preparation methods include vacuum drying and freeze-drying techniques, which can produce powders containing the active ingredient plus any other desired components present in the previously sterile filtered solution.

[0311] Exemplary solid carriers may include finely crushed solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends thereof, in which compounds as described herein or their pharmaceutically acceptable salts may optionally be dissolved or dispersed at effective levels by means of a nontoxic surfactant.

[0312] Useful doses of the compounds described herein or their pharmaceutically acceptable salts can be determined by comparing their in vitro and in vivo activities in animal models. Methods for extrapolating effective doses from mice and other animals to humans are known in the art; see, for example, U.S. Patent No. 4,938,949, which is incorporated herein by reference in its entirety.

[0313] The amount of the compound or its pharmaceutically acceptable salt described herein required for treatment can vary not only with the specific salt chosen, but also with the route of administration, the nature of the disease being treated, and the patient's age and condition, and is ultimately determined by the attending physician or clinician. However, generally speaking, the dosage can range from about 0.1 to about 10 mg / kg body weight per day.

[0314] The compounds described herein or their pharmaceutically acceptable salts can be conveniently administered in unit dosage forms; for example, each unit dosage form contains 0.01 to 10 mg or 0.05 to 1 mg of the active ingredient. In some embodiments, a dose of 5 mg / kg or less may be suitable.

[0315] The desired dose can be conveniently provided as a single dose or in divided doses administered at appropriate intervals.

[0316] IV. Use of the compounds and compositions disclosed herein

[0317] The compounds described herein, or their pharmaceutically acceptable salts, may be used to reduce or inhibit the activity of TYK2 or otherwise affect the properties and / or behavior of TYK2, such as stability, phosphorylation, kinase activity, and interactions with other proteins.

[0318] Another aspect of this disclosure is a method for inhibiting TYK2 activity in a subject in need, comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0319] In some aspects, this disclosure is a method of treating a subject for a disease or condition that is responsive to inhibition of TYK2, comprising administering to the subject an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described herein.

[0320] This disclosure also includes the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the manufacture of a medicament for inhibiting TYK2 activity. It also includes the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the manufacture of a medicament for treating a disease or condition that responds to inhibition of TYK2.

[0321] This disclosure also provides compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described herein, for inhibiting TYK2 activity. It also provides compounds described herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described herein, for treating diseases or conditions that respond to inhibition of TYK2.

[0322] As used herein, the terms “inhibit,” “inhibition,” or “inhibiting” refer to a reduction or suppression of a given disease, symptom, condition, or illness, or a significant decrease in the baseline activity of a biological activity or process.

[0323] As used herein, the terms “subject” and “patient” are used interchangeably and refer to mammals in need of treatment, such as humans, companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cattle, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, a subject is a person in need of treatment.

[0324] As used herein, a subject “needs” treatment if the subject (preferably a person) would benefit biologically, medically, or in terms of quality of life from such treatment.

[0325] As used herein, the term "treatment" ("treat", "treating", or "treatment") refers to achieving a desired pharmacological and / or physiological effect. Such effect may be therapeutic and includes partially or substantially achieving one or more of the following results: partially or completely reducing the severity of a disease, symptom, or syndrome; alleviating or improving clinical symptoms or indicators associated with the symptom; or delaying, inhibiting, or reducing the likelihood of progression of the disease, symptom, or syndrome.

[0326] As used herein, the term "co-administration" refers to the presence of two active agents in an individual's blood. Co-administered active agents can be delivered simultaneously or sequentially.

[0327] The terms "combination therapy," "in combination with," or "drug combination" refer to the administration of two or more therapeutic agents to treat the therapeutic ailment or condition described herein. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses the co-administration of each active ingredient in multiple or separate containers (e.g., capsules, powders, and liquids). Powders and / or liquids may be reconstituted or diluted to the desired dose prior to administration. Furthermore, such administration also encompasses the administration of each type of therapeutic agent before, simultaneously with, or sequentially with each other, without specific time limitations. In each case, the treatment regimen will provide the beneficial effect of the drug combination in treating the ailment or condition described herein.

[0328] In some implementations, the methods described herein treat diseases or conditions that respond to inhibition of TYK2, including inflammation, autoimmune diseases, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoma, silicosis, cardiovascular diseases, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, traumatic brain injury, neurodegeneration, liver diseases, inflammatory bowel disease, Crohn's disease. Diseases, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxic shock, toxic shock syndrome, autoimmune diseases, osteoporosis, multiple sclerosis, endometriosis, menstrual pain, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, hair loss, Alzheimer's disease, flushing, eczema, psoriasis, atopic dermatitis, and sunburn.

[0329] The term "autoimmune disease" includes diseases or conditions involving inappropriate immune responses to natural antigens, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid antibody syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), celiac disease, dermatomyositis, type 1 diabetes, Goodpasseur syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, Sjögren's syndrome, temporal arteritis, and Wegener's granulomatosis.

[0330] The term "inflammatory condition" includes diseases or conditions involving acute or chronic inflammation, such as allergies, asthma, atopic dermatitis, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, such as Crohn's disease and ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis.

[0331] The term "cancer" includes diseases or conditions involving abnormal cell growth and / or proliferation, such as glioma, thyroid cancer, breast cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), gastric cancer, gastrointestinal stromal tumors, pancreatic cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (e.g., anaplastic large cell lymphoma), leukemia (e.g., acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g., colorectal cancer with high microsatellite instability).

[0332] The disclosed methods may include kits comprising a compound as described herein or a pharmaceutically acceptable salt thereof, and illustrative substances that describe administration of the compound as described herein or a pharmaceutically acceptable salt thereof, or a composition comprising the compound as described herein or a pharmaceutically acceptable salt thereof, to cells or a subject. This should be construed as including other embodiments of kits known to those skilled in the art, such as kits comprising a (e.g., sterile) solvent for dissolving or suspending the compound as described herein or a pharmaceutically acceptable salt thereof or a composition thereof prior to administration to cells or a subject. In some embodiments, the subject may be a human being.

[0333] example

[0334] For illustrative purposes, the following synthesis provides pathways for synthesizing the compounds disclosed herein, as well as key intermediates. Although specific starting materials and reagents are described in the synthetic schemes below, other starting materials and reagents may be used instead to provide various derivatives and / or reaction conditions. Furthermore, many compounds prepared by the procedures described below can be further modified according to this disclosure using conventional chemistry well known to those skilled in the art.

[0335] abbreviation:

[0336] Aq. refers to something that is water-related;

[0337] Bn stands for benzyl;

[0338] Boc stands for tert-butoxycarbonyl;

[0339] Boc2O refers to di-tert-butyl dicarbonate.

[0340] br means broad peak;

[0341] t-BuOH refers to tert-butanol

[0342] n-BuLi refers to n-butyllithium;

[0343] d means double peak;

[0344] dd means double double peak;

[0345] DCM stands for dichloromethane;

[0346] DEA refers to diethylamine.

[0347] DIPEA refers to N-ethyl diisopropylamine or N,N-diisopropylethylamine.

[0348] DMA stands for N,N-dimethylacetamide;

[0349] DMF stands for N,N-dimethylformamide;

[0350] DMSO stands for dimethyl sulfoxide;

[0351] DMSO-d6 refers to hexadeuterium dimethyl sulfoxide;

[0352] Et stands for ethyl;

[0353] EtOH refers to ethanol;

[0354] EtOAc refers to ethyl acetate;

[0355] Eq. refers to equivalent quantity;

[0356] HPLC stands for High Performance Liquid Chromatography.

[0357] IPA stands for 2-propanol.

[0358] LCMS stands for Liquid Chromatography-Mass Spectrometry.

[0359] LDA stands for lithium diisopropylamide;

[0360] m indicates multiple peaks;

[0361] Me refers to methyl;

[0362] MeCN stands for acetonitrile;

[0363] MeI refers to methyl iodide.

[0364] MeOH refers to methanol;

[0365] MeOH-d4 refers to deuterium-methanol;

[0366] MS m / z refers to the peak in the mass spectrum;

[0367] MsCl is intended to be sulfonyl chloride;

[0368] NBS stands for N-bromosuccinimide;

[0369] NOE stands for Nuclear-Ouhaus Effect Spectrophotometry;

[0370] PE stands for petroleum ether;

[0371] Pd(amphos)Cl2 refers to bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II).

[0372] Pd2(dba)3 refers to tris(dibenzylacetone)dipalladium(0);

[0373] Pd(dppf)Cl2 refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride;

[0374] PdCl2(PPh3)2 refers to bis(triphenylphosphine)palladium(II) chloride;

[0375] Pd / C refers to palladium supported on carbon;

[0376] q means four peaks;

[0377] rt refers to room temperature;

[0378] 's' indicates a single peak;

[0379] sat. means saturated;

[0380] SFC stands for Supercritical Fluid Chromatography.

[0381] soln. refers to a solution;

[0382] 't' signifies a triple peak;

[0383] TBME stands for tert-butyl methyl ether;

[0384] TEA stands for triethylamine;

[0385] TFA stands for trifluoroacetic acid;

[0386] THF stands for tetrahydrofuran;

[0387] TLC stands for Thin-Layer Chromatography.

[0388] TsCl refers to p-toluenesulfonyl chloride;

[0389] TsOH refers to p-toluenesulfonic acid; and

[0390] RuPhos Pd G3 refers to (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-diphenyl)[2-(2′-amino-1,1′-diphenyl)]palladium(II)methanesulfonate.

[0391] According to the first method, the compound of formula (I) can be prepared from the compounds of formulas (II) and (III), as shown in Scheme 1.

[0392]

[0393] Z is Cl or OC(O)R 1 .

[0394] The compound of formula (I) can be prepared from an amine of formula (II) and a compound of formula (III) by an amidation reaction according to step (a) of method, in the presence of a suitable organic base, optionally in a suitable polar aprotic solvent, at elevated temperatures. Preferred conditions include the reaction of the compound of formula (II) with the compound of formula (III) in the presence of TEA or DIPEA, optionally in DMF, between 25°C and 70°C.

[0395] According to the second method, the compound of formula (I) can be prepared from the compounds of formulas (IV) and (V), as shown in Scheme 2.

[0396]

[0397] Compound of formula (I) can be prepared from compounds of formulas (IV) and (V) according to method step (b) Buchwald-Hartwig cross-coupling reaction. Typical conditions include the reaction of the amide of formula (V) with the chloride of formula (IV) in the presence of a suitable inorganic base, a suitable palladium catalyst, a suitable phosphine ligand, a suitable solvent, at elevated temperatures, and optionally under microwave irradiation. Preferred conditions include the reaction of compounds of formulas (IV) and (V) in the presence of Brettphos Pd G3, tBuBrettphos Pd G3, tBuXPhos, Xantphos Pd G3, RuPhos Pd G3, Xantphos or BINAP, optionally in combination with Pd(OAc)2 or Pd2(dba)3, in the presence of a suitable base such as Zn(OAc)2, Cs2CO3, K3PO4 or t-BuONa, in a suitable solvent such as dioxane, THF or toluene, at a temperature between 70°C and 120°C, optionally under microwave irradiation.

[0398] According to the third method, the compound of formula (I) can be prepared from the compounds of formulas (VI) and (VII), as shown in Scheme 3.

[0399]

[0400] Hal is a halogen, usually F, Cl or Br.

[0401] The compound of formula (I) can be prepared from the compound of formula (VI) and the halide of formula (VII) by the Buchwald-Hartwig reaction as described in the previous scheme 2, step (b).

[0402] Alternatively, the compound of formula (I) can be prepared from the compound of formula (VI) and the halide of formula (VII) by an alkylation reaction in the presence of a suitable inorganic or organic base and a suitable aprotic polar solvent, at a temperature between room temperature and an elevated temperature. Preferred conditions include reacting the compound of formula (VI) with the compound of formula (VII) in the presence of DBU or NaH, t-BuOK, Cs2CO3 or K2CO3, in DMSO, DMF or THF, at a temperature between 50°C and 100°C.

[0403] Alternatively, the compound of formula (I) can be prepared from the compound of formula (VI) and the halide of formula (VII) via a Ullmann-type copper-mediated coupling reaction in step (d). Typical conditions include the reaction of the compound of formula (VI) with the compound of formula (VII), a copper catalyst, optionally with a suitable ligand, optionally in the presence of a suitable inorganic or organic base, in a suitable solvent, at elevated temperatures. Preferred conditions include the reaction in the presence of CuI, optionally with a suitable ligand such as N... 1 N 2 The compound of formula (VI) reacts with the compound of formula (VII) in the presence of dimethylethane-1,2-diamine, trans-N,N'-dimethylcyclohexane-1,2-diamine, proline, 2,6-DFPAO, or 2-(dimethylamino)acetic acid, optionally in the presence of a suitable inorganic base such as K2CO3 or K3PO4, in dioxane or DMSO, at a temperature between 90°C and 120°C, optionally under microwave irradiation.

[0404] According to the fourth method, when X 3 It is CR 3 Compounds of formula (I)(A) can be prepared from compounds of formulas (VII), (VIII) and (IX), as shown in scheme 4.

[0405]

[0406] Hal 2 It is a halogen, preferably Cl, Br or I.

[0407] The compound of formula (IX) can be prepared from the compounds of formulas (VII) and (VIII) according to steps (b), (c) and (d) of the method as described in the previous scheme 3.

[0408] When R 3 When the N atom is attached to ring B, the compound of formula (I) can be reacted with R via step (b) or (d) of the method as described in previous schemes 2 and 3, or via photocatalytic nickel cross-coupling reaction of method step (e) or nickel-catalyzed cross-coupling reaction of method step (j) through the compound of formula (IX).3 The compound is prepared by reacting H with R. Preferred conditions include, for step (e), reacting the compound of formula (IX) with R under blue light at elevated temperatures (typically 80 °C) in the presence of a suitable nickel catalyst such as (1,2-dimethoxyethane) nickel dibromide, Ru(bpy)3(PF6)2 or Ir[dF(CF3)ppy]2(dtbpy)PF6, a suitable base such as DABCO or 2,6-rutidine. 3 H reacts.

[0409] Preferred conditions include, for step (j), reacting the compound of formula (IX) with R in a suitable aprotic solvent such as DMPU at about 55°C in the presence of a suitable nickel catalyst such as nickel dibromide (1,2-dimethoxyethane), Zn, a suitable organic base such as DABCO and DBU or MTBD. 3 H reacts.

[0410] When R 3 When the C atom is attached to the ring B, the photocatalytic nickel cross-coupling reaction can proceed according to step (e) of the previously described method via the compound of formula (IX) and R. 3 Hal 2 The reaction is carried out to prepare the compound of formula (I).

[0411] When R 3 When the C atom is attached to the ring B, the palladium-catalyzed cross-coupling reaction (such as the Suzuki reaction) can be performed according to method step (f) by the compound of formula (IX) and R. 3 BPin is used to prepare compounds of formula (I). Typical cross-coupling reaction conditions include a palladium catalyst containing a suitable phosphine ligand, in the presence of an inorganic base, in a suitable aqueous solvent, between room temperature and the reflux temperature of the reaction, optionally in the presence of microwave radiation. Preferred conditions include, in the presence of Pd(dppf)Cl2, Pd(dtbpf)Cl2, Catacxium A-Pd G2, bis(tricyclohexylphosphine)palladium(O) and a suitable base such as Cs2CO3, Na2CO3 or K2CO3, in a suitable solvent such as dioxane or toluene aqueous solution, between 70°C and 100°C, reacting the compound of formula (IX) with R. 3 BPin reacts.

[0412] Alternatively, when R 3 When the C atom is attached to the ring B, the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction can be performed according to method step (k) using the compound of formula (IX) and KR. 3BF3 is used to prepare compounds of formula (I). Preferred conditions include the use of Pd(dppf)Cl2 and a suitable base such as Na2CO3, in a suitable solvent such as an aqueous solution of dioxane or toluene, between 70°C and 100°C, for the preparation of compounds of formula (IX) and KR. 3 BF3 reacts.

[0413] Alternatively, when R 3 When the C atom is attached to the ring B, the palladium-catalyzed Negishi cross-coupling reaction can be performed according to method step (l) using the compound of formula (IX) and R. 3 ZnHal is used to prepare compounds of formula (I). Preferred conditions include the preparation of compounds of formula (IX) and R in the presence of Pd(OAc)2 and SPhos, in a suitable solvent such as MeTHF, at room temperature. 3 ZnHal 2 A reaction occurs.

[0414] According to the fifth method, compounds of formula (II) can be prepared from compounds of formulas (VII), (X), (XI), (XII) and (XIII), as shown in Scheme 5.

[0415]

[0416] PG is an N-protecting group, typically a carbamate, and preferably a Boc.

[0417] The compound of formula (XI) can be prepared from the compound of formula (X) and the compound of formula (VII) according to steps b), c), or d) of the method described in previous schemes 2 and 3.

[0418] The compound of formula (XIII) can be prepared from the compound of formula (XI) and the protected amine of formula (XII) according to step (b) of the method described in previous scheme 2.

[0419] Compounds of formula (II) can be prepared from compounds of formula (XIII) by a deprotection reaction carried out in step (g) under standard conditions (such as treatment of compounds of formula (XIII) with HCl in dioxane at room temperature).

[0420] In some cases, since the protecting group PG is removed in situ under the conditions described in step (b) of the method, compounds of formula (II) can be prepared directly from compounds of formula (XI).

[0421] According to the sixth method, when X 3 It is CR 3Compounds of formula (IV)(A) can be prepared from compounds of formulas (VII), (XIV), (XV), (XVI) and (XVII), as shown in Scheme 6.

[0422]

[0423] Hal 2 It is a halogen, preferably I or Br. PG 2 It is a suitable aromatic amine protecting group, such as SEM, THP, toluenesulfonyl, or triphenylmethyl or Boc.

[0424] According to method step (h), under standard conditions, protecting the aromatic amine group allows obtaining a compound of formula (XV) from a compound of formula (XIV). For example, when PG 2 When using SEM, the compound of formula (XV) can be prepared by reacting the compound of formula (XIV) with SEMCl in the presence of NaH in THF at approximately room temperature. When PG 2 When it is THP, the compound of formula (XV) can be prepared by reacting the compound of formula (XIV) with 3,4-dihydro-2H-pyran in the presence of a catalyst such as MsOH, in a suitable solvent such as DCM, and at an elevated temperature such as 60°C. When PG 2 When the group is toluenesulfonyl, the compound of formula (XV) can be prepared by reacting the compound of formula (XIV) with toluenesulfonyl chloride in a suitable solvent such as DMF in the presence of a strong base such as NaH. When PG 2 When the methyl group is triphenylmethyl, the compound of formula (XV) can be prepared by reacting the compound of formula (XIV) with triphenylmethyl chloride in a suitable solvent such as DMF in the presence of a base such as Cs₂CO₃ at about 100°C. When PG 2 When it is Boc, the compound of formula (XV) can be prepared by reacting the compound of formula (XIV) with tert-butoxycarbonyl tert-butyl carbonate in a suitable solvent such as DCM at room temperature in the presence of a catalyst such as DMAP.

[0425] When R 3 When the N atom C is attached to the ring B, the compound of formula (XV) and R can be obtained according to step (b) or (d) of the method described in previous schemes 2 and 3. 3 Hal yields compounds of formula (XVI). Alternatively, when R 3 When C is attached to ring B, it can be produced from the compound of formula (XV) and R according to step (f) of the method described in previous scheme 4. 3 BPin yields compounds of formula (XVI). Alternatively, when R... 3When N is attached to ring B, it can be produced from the compound of formula (XV) and R according to step (d) of the method described in previous scheme 3. 3 H is a compound with formula (XVI).

[0426] Compounds of formula (XVII) can be obtained from compounds of formula (XVI) by standard deprotection reactions according to method step (g). For example, when PG 2 When the substance is THP, Boc, or SEM, deprotection can be achieved by reacting the compound of formula (XV) under acidic conditions (typically TFA or HCl in DCM, dioxane, or HFIP) at approximately room temperature. When PG 2 When it is triphenylmethyl, deprotection can be achieved by reacting the compound of formula (XV) with Et3SiH and TFA in DCM at approximately room temperature. When PG 2 When the group is toluenesulfonyl, deprotection can be achieved by reacting the compound of formula (XV) with NaOH in MeOH at about 50°C.

[0427] The compound of formula (IV)(A) can be obtained from the compounds of formulas (III) and (XVII) according to steps (b), (c) or (d) of the method described in previous schemes 2 and 3.

[0428] According to the seventh method, where X 3 It is CR 3 Compounds of formula (VI)(A) can be prepared from compounds of formula (VIII), (XVIII), (XIX) and (XX), as shown in Scheme 7.

[0429]

[0430] Hal 2 It is a halogen, preferably I or Br.

[0431] Compounds of formula (VIII) can be prepared from compounds of formula (XVIII) by method step i) halogenation reaction (such as bromination or iodination). Typical conditions include reacting the compound of formula (XVIII) with N-bromine or N-iodosuccinimide in a suitable solvent such as DMF at elevated temperatures such as 60 °C, or with I2 and a base such as KOH in DMF at room temperature.

[0432] The compound of formula (XIX) can be prepared from the compound of formula (VIII) according to step (h) of the method described in the previous scheme 6.

[0433] When R 3 When N is attached to ring B, it can be produced from the compound of formula (XIX) and R according to step (d) of the method described in previous scheme 6.3 H yields compounds of formula (XX). Alternatively, when R 3 When C is attached to ring B, the compound of formula (XX) can be obtained from the compound of formula (XIX) and R according to method step (f). 3 BPin is obtained, or from the compound of formula (XIX) and KR according to step (k) of the method as described in the previous scheme 4. 3 BF3 obtained.

[0434] The compound of formula (VI)(A) can be obtained from the compound of formula (XX) by step g) of the method described in the previous scheme 6.

[0435] According to the eighth method, where X 3 It is CR 3 The compounds of formula (VIII) can be prepared from the compounds of formulas (XXI) and (XXII), as shown in Scheme 8.

[0436]

[0437] Hal 3 It is a halogen, preferably Br or Cl.

[0438] The compound of formula (XXII) can be obtained from the compound of formula (XXI) and the compound of formula (V) according to step b) of the method described in the previous scheme 2.

[0439] Compound of formula (VIII) can be prepared from compound of formula (XXII) by method step (g) as described in previous scheme 6.

[0440] According to the ninth method, when X 3 It is CR 3 When, compounds of formula (IV)(A) can be prepared from compounds of formula (VII), (XIV), (XV) and (XXIII), as shown in Scheme 9.

[0441]

[0442] The compound of formula (XXIII) can be prepared from the compounds of formulas (XIV) and (VII) according to step (c) of the method described in the previous scheme 3.

[0443] The compound of formula (XXIII) and R can be used according to step (b) or (d) of the method described in previous schemes 2 and 3. 3 H prepares compounds of formula (IV)(A).

[0444] According to the tenth method, when X 3 It is CR 3In this case, the compound of formula (XX) can be prepared from the compounds of formulas (XVI) and (V), as shown in Scheme 10.

[0445]

[0446] The compound of formula (XX) can be prepared from the compounds of formulas (XVI) and (V) according to step (b) of the method described in the previous scheme 2.

[0447] According to the eleventh method, where X 3 It is NR 3 Compounds of formula (I)(B) can be prepared from compounds of formulas (V), (VI)(B), (VII), (XVI)(B), and (XX)(B), as shown in Scheme 11.

[0448]

[0449] The compound of formula (XVI)(B) can be prepared from the compound of formula (XI) by step (h) as described in the previous scheme 6.

[0450] The compound of formula (XX)(B) can be prepared from the compounds of formula (XVI)(B) and (V) according to step (b) of the method described in the previous scheme 2.

[0451] The compound of formula (VI) (B) can be prepared from the compound of formula (XX) (B) according to step (g) of the method described in the previous scheme 6.

[0452] Compounds of formula (I) (B) can be prepared from compounds of formulas (VI)(B) and (VII) according to steps (b), (c) or (d) of the method described in the previous scheme 3.

[0453] Compounds of formulas (III), (V), (VII), (X), (XI), (XII), (XIV), (XVIII), (XXI), and R 3 Hal 2 and R 3 H, R 3 BPin, KR 3 BF 3、 R 3 ZnHal 2 It is commercially available, or can be prepared by methods similar to those known in the literature or those described in the experimental section below.

[0454] Compounds of formulas (I), (II), (IV), (VI), (IX), (X), (XI), (XVI), (XX), and (XXIII) can be converted into alternative compounds of formulas (I), (II), (IV), (VI), (IX), (X), (XI), (XVI), (XX), and (XXIII) using standard chemical transformations known to those skilled in the art.

[0455] • To perform the Grignard reaction of the ester to provide a tertiary alcohol;

[0456] • Secondary amines are reduced with aldehydes to provide tertiary amines;

[0457] • Reduce the amined aldehyde with a secondary amine to provide a tertiary amine;

[0458] • In the presence of organic or inorganic bases, heteroatoms such as N or O are alkylated by reaction with alkylating agents such as alkyl halides or alkyl trifluoromethanesulfonates;

[0459] • Reduction of unsaturated bonds through hydrogenation;

[0460] • Reaction of aryl or heteroaryl halides with suitable borate esters under typical Suzuki reaction conditions;

[0461] • In the presence of an inorganic base, aryl or heteroaryl halides react with alkali metal alkoxides or aryl / heteroaryl alcohols to provide ethers;

[0462] • Fluorinate alcohols, aldehydes, or ketones with a suitable fluorinating agent to provide alkyl fluorides;

[0463] • Use a suitable reducing agent to reduce the ester to provide the alcohol;

[0464] • Sulfonation of the nitrogen atom to provide a sulfonamide; and

[0465] • Acetylation of the N atom is performed to provide an amide.

[0466] Those skilled in the art will understand that suitable protecting group strategies may be required to prepare compounds of formula (I). Typical protecting groups may include p-methoxybenzyl, benzyl, or carbamate, and preferably Boc or CBz for protecting primary or secondary amines, triphenylmethyl, SEM, or THP for protecting aromatic amines, and TBS or benzyl groups for protecting primary alcohols.

[0467] It should also be understood that conversions may need to be performed in a different order than those described in the scheme, or one or more conversions may need to be modified, in order to provide the desired compounds of the present invention.

[0468] HPLC code

[0469]

[0470]

[0471] General synthesis methods

[0472] Preparation 1 N-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

[0473]

[0474] A mixture of 6-chloro-1-tetrahydropyran-2-yl-pyrazolo[4,3-c]pyridine (1.00 g, 4.21 mmol), acetamide (497 mg, 8.42 mmol), Cs₂CO₃ (2.74 g, 8.42 mmol), and Brettphos Pd G₃ (114.5 mg, 0.126 mmol) in dioxane (15 mL) was degassed with N₂ and then heated at 100 °C for 1 hour in a sealed tube. The cooled mixture was filtered, the filtrate was concentrated under vacuum, and the crude product was purified by silica gel chromatography (0-70% EtOAc-EtOH 3:1, containing 2% NH₄OH in heptane) to give N-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (1.02 g, 93% yield) as a white powder. LCMS m / z = 261.1 [M+H] + .

[0475] Preparation 2 N-(1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

[0476]

[0477] TFA (8.76 g, 76.8 mmol) was added to a solution of N-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (Preparation 1, 1.00 g, 3.84 mmol) in DCM (15 mL), and the reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated under vacuum, and the residue was diluted with EtOAc and washed with aqueous NaHCO3 solution. The organic layer was dried, filtered, and concentrated under vacuum. The resulting solid was filtered off and washed with heptane / EtOAc (95 / 5) to give N-(1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (421 mg, 62% yield) as a grayish-white solid. 1H NMR (400MHz, MeOH-d4) δ: 8.83 (s, 1H), 8.23 ​​(s, 1H), 8.16 (s, 1H), 2.21 (s, 3H).

[0478] Preparation 3 N-(3-iodo-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

[0479]

[0480] A mixture of N-(1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (Preparation 2, 1.5 g, 8.51 mmol) and NIS (2.87 g, 12.8 mmol) in DMF (20 mL) was stirred at 60 °C for 6 hours. The mixture was diluted with water and extracted with DCM (50 mL x 3). The combined organic matter was washed with brine (100 mL), dried (Na₂SO₄), and evaporated to dryness under vacuum to provide N-(3-iodo-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (2 g, 77%) as a yellow solid, which was ready for use without further purification. LCMS m / z = 302.9 [M+H] + .

[0481] Preparation 4 N-(3-iodo-1-triphenylmethyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

[0482]

[0483] Cs₂CO₃ (10.8 g, 33.10 mmol) and triphenylmethyl chloride (9.2 g, 33.1 mmol) were added to a solution of N-(3-iodo-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (Preparation 3, 5.0 g, 16.55 mmol) in DMF (50 mL), and the mixture was stirred at 100 °C for 16 hours. The reaction mixture was filtered, concentrated, and poured into EtOAc (80 mL). The precipitated solid was collected by filtration and washed with H₂O to give N-(3-iodo-1-triphenylmethyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (6.0 g, 66.6%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ: 10.48 (s, 1H), 8.48 (s, 1H), 7.34-7.29 (m, 11H), 7.28-7.15 (m, 5H), 1.94 (s, 3H).

[0484] Preparation 5 N-(3-methyl-1-triphenylmethyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

[0485]

[0486] A mixture of N-(3-iodo-1-triphenylmethyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (preparation 4, 250 mg, 0.459 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborane (576.5 mg, 4.59 mmol), K2CO3 (127 mg, 0.918 mmol), and Pd(dppf)Cl2.DCM (37.5 mg, 0.046 mmol) in dioxane (5 mL) and H2O (1 mL) was stirred at 120 °C under N2 for 12 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE / EtOAc = 1 / 1) to give N-(3-methyl-1-triphenylmethyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (120 mg, 60%) as a yellow solid. 1 H NMR(400MHz, CDCl3)δ:8.58-8.55(m,2H),7.30-7.26(m,15H),2.53(s,3H),2.05(s,3H).

[0487] Preparation 6 N-(3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

[0488]

[0489] TFA (8.9 g, 6.0 mL) was added to a solution of N-(3-methyl-1-triphenylmethyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (preparation 5, 2.8 g, 6.47 mmol) in DCM (30 mL), and the resulting mixture was stirred at 30 °C for 6 hours. The mixture was concentrated and purified by preparative HPLC-G (gradient: 0 to 30%) to give N-(3-methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (1.1 g, 89.3% yield) as a white solid. 1 HNMR(500MHz, CDCl3)δ:9.99(br s,1H),8.68(s,1H),8.28(s,1H),8.20(s,1H),2.61(s,3H),2.25(s,3H).

[0490] Preparation 7 6-Chloro-3-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-

[0491] c) Pyridine

[0492]

[0493] To a solution of 6-chloro-3-ethyl-1H-pyrazolo[4,3-c]pyridine (500 mg, 2.75 mmol) in DCM (5 mL), 4-methylbenzenesulfonic acid; hydrate (52.4 mg, 0.275 mmol) and 3,4-dihydro-2H-pyran (694.71 mg, 8.26 mmol) were added, and the mixture was stirred overnight at 40 °C. The reaction mixture was diluted with DCM and water, the organic layer was separated, dried, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (0-70% EtOAc in heptane) to give 6-chloro-3-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (686 mg, 93% yield) as a colorless oil. 1H NMR (400MHz, CDCl3) δ8.79(s,1H),7.48(s,1H),5.59(dd,J=2.64,9.66Hz,1H),4.12-4.02(m,1H),3.74(dt,J=2.89,1 1.11Hz, 1H), 3.02 (q, J = 7.61Hz, 2H), 2.54-2.39 (m, 1H), 2.19-2.02 (m, 2H), 1.83-1.71 (m, 3H), 1.42 (t, J = 7.53Hz, 3H). LCMS m / z=266.1[M+H] + .

[0494] Preparation 8: N-(3-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

[0495]

[0496] Following the procedure described in Preparation 1, N-(3-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (508 mg, 68% yield) was obtained as a white powder from 6-chloro-3-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide. LCMS m / z = 289.1 [M+H] + .

[0497] Preparation 9: N-(3-ethyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

[0498]

[0499] TFA (2.98 g, 26.12 mmol) was added to a solution of N-(3-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (preparation 8, 500 mg, 1.73 mmol) in DCM (5 mL), and the reaction mixture was stirred overnight at room temperature. The mixture was concentrated under vacuum, diluted with EtOAc, neutralized with 2 M NaHCO3, and then washed with brine. The organic layer was dried and concentrated under vacuum. The crude product was crystallized from MeCN to give N-(3-ethyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (305 mg, 1.49 mmol, 86% yield) as a white solid. 1H NMR (400MHz, MeOH-d4) δ 8.80 (d, J = 0.75Hz, 1H), 8.14 (s, 1H), 3.02 (q, J = 7.53Hz, 2H), 2.20 (s, 3H), 1.40 (t, J = 7.65Hz, 3H).

[0500] Preparation 10 N-(3-cyclopropyl-1-triphenylmethyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

[0501]

[0502] To a solution of N-(3-iodo-1-triphenylmethyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (Preparation 4, 4.0 g, 7.35 mmol) in dioxane (40 mL) and H₂O (8 mL), potassium cyclopropyltrifluoroborate (2.2 g, 14.7 mmol), Na₂CO₃ (1.6 g, 14.7 mmol), and Pd(dppf)Cl₂.DCM (600 mg, 0.735 mmol) were added, and the resulting mixture was stirred at 100 °C under N₂ for 16 hours. The mixture was poured into H₂O (80 mL) and extracted with EtOAc (3 x 100 mL x 3). The combined organic matter was dried (Na₂SO₄) and evaporated to dryness under vacuum. The residue was purified by chromatography (SiO2, 5-50% EtOAc / PE) to obtain N-(3-cyclopropyl-1-triphenylmethyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (2.5 g, 74%) as a yellow solid. 1 H NMR(400MHz, DMSO-d6)δ:10.31(s,1H),8.75(s,1H),7.31-7.26(m,11H),7.24-7. 15(m,5H),2.29-2.25(m,1H),1.92(s,3H),1.00-0.97(m,2H),0.90-0.88(m,2H).

[0503] Preparation 11 N-(3-Cyclopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

[0504]

[0505] TFA (11.9 g, 104 mmol) and triethylsilane (964 mg, 8.29 mmol) were added to a solution of the resulting N-(3-cyclopropyl-1-triphenylmethyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (preparation 10, 3.8 g, 8.29 mmol) in DCM (40 mL), and the resulting mixture was stirred at 25 °C for 3 hours. The reaction mixture was evaporated to dryness and the residue was purified by chromatography (SiO2, EtOAc) to give N-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (1.6 g, 89%) as a yellow solid. 1 H NMR(500MHz, DMSO-d6)δ:12.79(s,1H),10.61(s,1H),8.85(s,1H),8.04(s,1H),2.50-2.34(m,1H),2.11(s,3H),1.04-0.98(m,4H).

[0506] Preparation 12 N-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

[0507]

[0508] MsOH (1.91 g, 19.86 mmol) and DHP (1.67 g, 19.86 mmol) were added to a solution of N-(3-iodo-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (preparation 3, 2 g, 6.62 mmol) in THF (5 mL) and DCM (15 mL), and the mixture was stirred at 60 °C for 5 hours. The residue was poured into 10% NaOH (50 mL) and the aqueous phase was extracted with DCM (50 mL x 5). The combined organic matter was washed with brine (2 x 20 mL), dried (Na2SO4), and concentrated under vacuum. The residue was purified by chromatography (SiO2, 33% EtOAc / PE) to give N-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (1.5 g, 58%) as a yellow solid. 1 H NMR(500MHz,DMSO-d6)δ:10.73(s,1H),8.54(d,1H),8.29(s,1H),5.77-5.75(m,1H),3.88-3.85(m,1H),3. 74-3.67(m,1H),2.37-2.26(m,1H),2.13(s,3H),2.02-1.93(m,2H),1.81-1.71(m,1H),1.61-1.51(m,2H).

[0509] Preparation 13 6-Chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine

[0510]

[0511] NIS (3.7 g, 16.28 mmol) was added to a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine (2.5 g, 16.28 mmol) in DMF (30 mL), and the resulting mixture was stirred at 70 °C for 3 hours. The reaction mixture was evaporated to dryness to give 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (3.5 g, 77%) as a brown solid, which was used directly in the next step. LCMSm / z = 279.9 [M+H] + .

[0512] Preparation 146-Chloro-3-iodo-1-triphenylmethyl-1H-pyrazolo[4,3-c]pyridine

[0513]

[0514] Cs₂CO₃ (8.2 g, 25.05 mmol) and TrtCl (6.9 g, 25.05 mmol) were added to a solution of 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (Preparation 13, 3.5 g, 12.52 mmol) in DMF (40 mL), and the resulting mixture was stirred at 110 °C for 16 hours. The reaction mixture was filtered, concentrated, and poured into EtOAc (80 mL), and the resulting solid was collected by filtration to give 6-chloro-3-iodo-1-triphenylmethyl-1H-pyrazolo[4,3-c]pyridine (5.15 g, 79%) as a yellow solid. 1 HNMR (500MHz, CDCl3) δ: 8.51 (s, 1H), 7.23-7.29 (m, 15H), 5.99 (s, 1H).

[0515] Preparation 15 6-Chloro-3-cyclopropyl-1-triphenylmethyl-1H-pyrazolo[4,3-c]pyridine

[0516]

[0517] To a solution of 6-chloro-3-iodo-1-triphenylmethyl-1H-pyrazolo[4,3-c]pyridine (preparation 14, 4 g, 7.7 mmol) in dioxane (30 mL) and H₂O (6 mL), potassium cyclopropyltrifluoroborate (3.4 g, 23 mmol), Na₂CO₃ (1.63 g, 15.33 mmol), and Pd(dp pf)Cl₂.DCM (626 mg, 0.767 mmol) were added, and the reaction mixture was stirred at 100 °C under N₂ for 16 hours. The cooled reaction mixture was concentrated under vacuum, diluted with H₂O (50 mL), and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (30 mL x 2), dried over Na₂SO₄, and filtered. The mixture was concentrated and the residue was purified by silica gel chromatography (PE / EtOAc = 1 / 1) to give 6-chloro-3-cyclopropyl-1-triphenylmethyl-1H-pyrazolo[4,3-c]pyridine as a yellow solid (2.2 g, 65.8% yield). LCMS m / z = 436.1 [M+H] + .

[0518] Preparation 16 6-Chloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine

[0519]

[0520] TFA (4.5 g, 39.49 mmol) and Et3SiH (960.2 mg, 8.26 mmol) were added to a solution of 6-chloro-3-cyclopropyl-1-triphenylmethyl-1H-pyrazolo[4,3-c]pyridine (preparation 15, 900 mg, 2.06 mmol) in DCM (10 mL), and the reaction mixture was stirred at 25 °C for 5 h. The reaction mixture was concentrated under vacuum and the residue was purified by passing it through a silica column (PE / EtOAc = 1 / 1) to give 6-chloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine (230 mg, 57.5% yield) as a yellow solid. 1 H NMR: (400MHz, CDCl3) δppm: 8.87 (s, 1H), 7.35 (s, 1H), 2.28-2.24 (m, 1H), 1.14-1.11 (m, 4H).

[0521] Preparation 17 4-(6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine

[0522]

[0523] A mixture of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (2 g, 5.50 mmol), morpholine (958.5 mg, 11.0 mmol), L-proline (126.7 mg, 1.10 mmol), K₂CO₃ (1.5 g, 11.0 mmol), and CuI (314.3 mg, 1.65 mmol) in DMSO (20 mL) was stirred at 100 °C for 2 hours under N₂. The mixture was diluted with H₂O (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (30 mL x 2), dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE / EtOAc = 4 / 1) to give 4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine (700 mg, 39.4% yield), which was a yellow oil. 1 H NMR: (500MHz, CDCl3) δ: ppm 8.75(s,1H),7.36(s,1H),5.47-5.44(m,1H),3.91-3.89(m,4H),3.79- 3.71(m,2H),3.49-3.46(m,4H),2.12-1.99(m,2H),1.74-1.64(m,4H).

[0524] A mixture of 700 mg (2.17 mmol) of 4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine in HCl / EtOAc (4 M, 10 mL) was stirred at 20 °C for 12 hours. The mixture was concentrated under reduced pressure to give 520 mg (4-(6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine hydrochloride as a yellow solid. LCMS m / z = 239.2 [M+H] +

[0525] Preparation 18 6-Chloro-3-iodo-1-toluenesulfonyl-1H-pyrrolo[3,2-c]pyridine

[0526]

[0527] To a solution of 6-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (580 mg, 2.08 mmol) in DMF (5 mL) at 0 °C, NaH (99.9 mg, 2.50 mmol, 60% purity) was added and the mixture was stirred for 10 min. Toluenesulfonyl chloride (596 mg, 3.12 mmol) was added to the solution, and the mixture was stirred at 25 °C for 30 min. The mixture was treated with H2O (20 mL) and extracted with EtOAc (25 mL x 3). The combined organic matter was washed with brine (20 mL), dried (Na2SO4), and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 6-100% EtOAc / PE) to give 6-chloro-3-iodo-1-toluenesulfonyl-1H-pyrrolo[3,2-c]pyridine (680 mg, 75%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ: 8.43 (s, 1H), 7.89 (s, 1H), 7.81 (d, 2H), 7.66 (s, 1H), 7.33 (d, 2H), 2.41 (s, 3H).

[0528] Preparation 19 6-Chloro-3-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo[3,2-c]pyridine

[0529]

[0530] Cyclopropyl zinc bromide(II) (0.5 M, 3.37 mL) and Pd(PPh3)4 (293 mg, 0.253 mmol) were added to a solution of 6-chloro-3-iodo-1-toluenesulfonyl-1H-pyrrolo[3,2-c]pyridine (preparation 18, 730 mg, 1.69 mmol) in DMF (8 mL) under N2 conditions, and the mixture was stirred at 70 °C for 2 hours. The reaction mixture was concentrated, diluted with H2O (20 mL), and extracted with DCM (20 mL x 2). The combined organic matter was washed with brine (20 mL x 2) and evaporated to dryness under vacuum. The residue was purified by column chromatography (25% EtOAc / PE) to give 6-chloro-3-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo[3,2-c]pyridine (280 mg, 48%) as a white solid. 1 H NMR(500MHz, CDCl3)δ:8.66(s,1H),7.88(s,1H),7.76(d,2H),7.31-7.28(m,2H),7 .18(d,1H),2.39(s,3H),1.87-1.84(m,1H),0.99-0.95(m,2H),0.69-0.66(m,2H).

[0531] Preparation 20 N-(3-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide

[0532]

[0533] Acetamide (40.9 mg, 0.692 mmol), Cs₂CO₃ (376 mg, 1.15 mmol), and Brettphos Pd G₃ (52.3 mg, 0.058 mmol) were added to a solution of 6-chloro-3-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo[3,2-c]pyridin-6-yl)pyramide (190 mg, 89%) in dioxane (2 mL). The mixture was stirred at 100 °C for 1 hour under N₂. The mixture was concentrated under reduced pressure and purified by column chromatography (PE / EtOAc = 10 / 1 to 1 / 1) to give N-(3-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide as a white solid. 1H NMR(400MHz, CDCl3)δ:8.70(s,1H),8.49(s,1H),8.32(s,1H),7.85(d,2H),7.24(d,2H),7.1 6(s,1H),2.33(s,3H),2.21(s,3H),1.83-1.80(m,1H),0.94-0.91(m,2H),0.66-0.63(m,2H).

[0534] Preparation 21 N-(3-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide

[0535]

[0536] To a solution of N-(3-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide (preparation 20, 180 mg, 0.487 mmol) in MeOH (2 mL), NaOH (39 mg, 0.974 mmol) was added, and the mixture was stirred at 50 °C for 3 hours. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE / EtOAc = 1 / 1 to 0 / 1) to give N-(3-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide (80 mg, 76%) as a white solid. 1 HNMR(400MHz, CDCl3)δ:8.86(s,1H),8.75(s,1H),8.63(s,1H),8.27(s,1H),6.8 7(s,1H),2.24(s,3H),2.21-1.91(m,1H),0.93-0.89(m,2H),0.68-0.65(m,2H).

[0537] Preparation 22 6-Chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridine

[0538]

[0539] K₂CO₃ (566.1 g, 4.10 mol) was added to a solution of 6-chloro-1H-pyrrolo[3,2-c]pyridine (250 g, 1.64 mol) in MeCN (500 mL), followed by dropwise addition of PhSO₂Cl (318.33 g, 1.802 mol), and the reaction mixture was stirred at 25 °C for 4 hours. The reaction mixture was poured into ice water (3.0 L). The precipitate was collected by filtration and dried to provide 6-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (450 g, 93.8%) as a yellow solid. LCMS m / z = 293.1 [M+H] +

[0540] Preparation 23 N-(1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide

[0541]

[0542] Dioxane (2000 mL), 6-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 200 g, 683.2 mmol), AcNH2 (161.42 g, 2.73 mol), K2CO3 (141.6 g, 1.025 mol), XantPhos (23.72 g, 41.0 mmol), and Pd(OAc)2 (4.60 g, 20.5 mmol) were added sequentially to the reactor. The mixture was heated to 110 °C and stirred for 16 hours under a nitrogen atmosphere. The mixture was cooled to room temperature, and a solution of NaOH (109.30 g, 2.73 mol) in H2O (400 mL) was added. The resulting mixture was heated to 80 °C and stirred for 1 hour. The cooled reaction mixture was diluted with EtOAc (3000 mL) and H2O (400 mL). The insoluble substances were filtered off, and the filtrate was separated. The aqueous phase was extracted with EtOAc (1000 mL x 2). The combined organic extracts were dried over MgSO4, filtered, and concentrated. The precipitate was collected by filtration, and the filter cake was dried to give N-(1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide (90.0 g, 75.2%) as a grayish-white solid. LCMS m / z = 176.2 [M+H] +

[0543] Preparation 24 N-(3-bromo-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide

[0544]

[0545] NBS (81.28 g, 456.7 mmol) was added in portions to a stirred solution of N-(1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide (80.0 g, 456.7 mmol) in DMF (500 mL) at 0 °C, and the reaction mixture was stirred for 1 hour after each addition. The mixture was poured into a pre-cooled saturated aqueous solution of Na₂SO₃ (2 L) and then filtered. The filter cake was suspended in a saturated aqueous solution of Na₂CO₃ (2 L) and stirred for 1 hour at room temperature. The mixture was then filtered and dried to provide N-(3-bromo-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide (103.5 g, 89.2%) as a grayish-white solid. LCMS m / z = 254.1 [M+H] +

[0546] Preparation 25: 6-Chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester

[0547]

[0548] A solution of tert-butoxycarbonyl tert-butyl carbonate (7.84 g, 35.9 mmol) and DMAP (219 mg, 1.80 mmol) in DCM (50 mL) was slowly added over 10 minutes to a stirred solution of 6-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (5 g, 17.95 mmol) in DCM (100 mL), and the reaction mixture was then stirred at room temperature for 3 hours. The reaction mixture was washed with 0.1 N HCl, followed by brine. The organic layer was separated, dried, and concentrated under vacuum. The crude product was purified by silica gel chromatography (0-60% EtOAc in heptane) to give tert-butyl 6-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (6.51 g, 95% yield) as a white powder. LCMS m / z = 379.0 [M+H] + 1H NMR (400MHZ, CDCl3) δ8.46 (s, 1H), 8.04 (s, 1H), 7.71 (s, 1H), 1.69 (s, 9H).

[0549] Preparation 26: 6-Chloro-3-cyclopropyl-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester

[0550]

[0551] A mixture of tert-butyl 6-chloro-3-iodo-pyrrolo[3,2-c]pyridine-1-carboxylate (preparation 25, 2.5 g, 6.60 mmol) and dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(II) (47.3 mg, 0.066 mmol) in THF (50 mL) was purged with N2, and then zinc bromo(cyclopropyl)zinc (0.5 M, 15.85 mL) was slowly added and the reaction mixture was stirred overnight at room temperature. The mixture was quenched with water, concentrated under vacuum, and the residue was diluted with EtOAc, washed with water, and then the organic layer was separated, dried, and concentrated. The crude product was purified by silica gel chromatography (0-40% EtOAc in heptane) to give tert-butyl 6-chloro-3-cyclopropyl-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (1.32 g, 68% yield) as a white solid. LCMS m / z = 293.0 [M+H] + 1H NMR (400MHz, CDCl3) δ 8.69 (d, 1H, J = 0.8Hz), 8.00 (br s, 1H), 7.21 (s, 1H), 2.00-1.80 (m, 1H), 1.67 (s, 9H), 1.00-0.90 (m, 2H), 0.7-0.7 (m, 2H).

[0552] Preparation 27: 6-Chloro-3-cyclopropyl-1H-pyrrolo[3,2-c]pyridine

[0553]

[0554] TFA (3.72 g, 2.5 mL) was added to a solution of tert-butyl 6-chloro-3-cyclopropyl-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (preparation 26, 1.3 g, 4.44 mmol) in DCM (25 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under vacuum, and the residue was diluted with EtOAc and washed with aqueous NaHCO3 solution. The organic layer was separated, dried, and evaporated under reduced pressure to give 6-chloro-3-cyclopropyl-1H-pyrrolo[3,2-c]pyridine (910 mg, crude), which was used for the next step without purification. LCMS m / z = 193.0 [M+H]+

[0555] Preparation 28 6-Chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine

[0556]

[0557] NaH (478.3 mg, 11.96 mmol, 60% purity) was added to a solution of 6-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (2.2 g, 7.97 mmol) in THF (25 mL) at 25 °C, and the solution was stirred for 30 min. SEMCl (1.6 g, 9.57 mmol) was added, and the reaction mixture was stirred at 25 °C for 2 h. The mixture was quenched with H₂O (20 mL), extracted with EtOAc (20 mL x 2), and the combined organic phases were washed with brine (20 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine (3.2 g, 98.2% yield) as a yellow solid. 1 H NMR: (400MHz, CDCl3) δppm: 8.47 (s, 1H), 7.39 (s, 1H), 7.28 (s, 1H), 5.41 (s, 2H), 3.49-3.45 (m, 2H), 0.92-0.87 (m, 2H), -0.04 (s, 9H).

[0558] Preparation 29 2,6-Dibromo-4-isopropoxypyridine

[0559]

[0560] NaH (329.3 mg, 8.23 ​​mmol, 60% purity) was added to a solution of 2,4,6-tribromopyridine (247.4 mg, 4.12 mmol) in DMF (10 mL) at 0 °C, and the mixture was stirred for 30 min. Isopropanol (1.3 g, 4.12 mmol) was added, and the reaction mixture was stirred at 25 °C for 10 h. The mixture was diluted with H2O (30 mL), extracted with DCM (15 mL x 3), and the combined organic extracts were concentrated under vacuum. The crude product was purified by silica gel chromatography to give 2,6-dibromo-4-isopropoxypyridine (400 mg, 32.9% yield) as a colorless oil. 1 HNMR: (400MHz, CDCl3) δ: ppm 6.93 (s, 2H), 4.63-4.54 (m, 1H), 1.36 (d, J = 6.4Hz, 6H).

[0561] Preparation 30 2,6-Dibromo-4-(2-methoxyethoxy)pyridine

[0562]

[0563] To a solution of 2,6-dibromopyridin-4-ol (1.0 g, 3.95 mmol) in DMF (15.0 mL), 1-bromo-2-methoxyethane (549.6 mg, 3.95 mmol) and Cs₂CO₃ (2.6 g, 7.91 mmol) were added, and the reaction mixture was stirred at 90 °C for 12 hours. The mixture was poured into H₂O (50 mL), extracted with EtOAc (3 x 50 mL), and the combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 1) to give 2,6-dibromo-4-(2-methoxyethoxy)pyridine (1.2 g, 98.4% yield) as a colorless oil. 1 H NMR: (500MHz, CDCl3) δppm: 7.01 (s, 2H), 4.16-4.14 (m, 2H), 3.74-3.73 (m, 2H), 3.43 (s, 3H).

[0564] Preparation 31 3-(2-Fluoropyridin-4-yl)tetrahydrofuran-3-ol

[0565]

[0566] n-BuLi (2.5 M, 2.5 mL) was added dropwise to a solution of 4-bromo-2-fluoropyridine (1.0 g, 5.68 mmol) in THF (6.0 mL) for 30 minutes at -78 °C, followed by slow addition of a solution of dihydrofuran-3(2H)-one (489 mg, 5.68 mmol) in THF (4.0 mL). The resulting mixture was heated to 10 °C and stirred for 1.5 hours. The reaction mixture was quenched with NH4Cl (3 mL), concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1 to 1 / 1) to give 3-(2-fluoropyridin-4-yl)tetrahydrofuran-3-ol (480 mg, 46.1% yield) as a colorless oil. LCMS m / z = 184.3 [M+H]+;

[0567] Preparation 32 3-(4-chloropyridin-2-yl)tetrahydrofuran-3-ol

[0568]

[0569] Following a similar procedure to that described in Preparation 31, 3-(4-chloropyridin-2-yl)tetrahydrofuran-3-ol (560 mg, 54% yield) was obtained as a brown oil from 2-bromo-4-chloropyridine and dihydrofuran-3(2H)-one. ¹H NMR: (500 MHz, CDCl₃) δppm: 8.43 (d, J = 5.5 Hz, 1H), 7.52 (d, J = 1.5 Hz, 1H), 7.26–7.25 (m, 1H), 4.81–4.76 (m, 1H), 4.20–4.17 (m, 2H), 4.16–4.01 (m, 1H), 3.93–3.91 (m, 1H), 2.42–2.36 (m, 1H), 2.29–2.25 (m, 1H).

[0570] Preparation 33 1-(6-bromopyridin-2-yl)-2,2-dimethylprop-1-ol

[0571]

[0572] Following the procedure described in Preparation 31, 1-(6-bromopyridin-2-yl)-2,2-dimethylprop-1-ol (754 mg, 73.2% yield) was obtained as a yellow oil from 2,6-dibromopyridine and neopentanal. LCMS m / z = 244.2 [M+H] +

[0573] Preparation 34 3-(6-bromo-4-methoxypyridin-2-yl)tetrahydrofuran-3-ol

[0574]

[0575] n-BuLi (2.5 M, 4.95 mL) was slowly added to a solution of 2,6-dibromo-4-methoxypyridine (3.0 g, 11.24 mmol) in DCM (40 mL) at -70 °C under N2 for 30 minutes. Then, dihydrofuran-3(2H)-one (967.6 mg, 11.24 mmol) was slowly added to a solution of 2,6-dibromo-4-methoxypyridine (3.0 g, 11.24 mmol) at -70 °C under N2 for 1 hour. The mixture was quenched with NH4Cl (saturated, 30 mL), poured into H2O (50 mL), and extracted with EtOAc (3 x 80 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3 / 1) to give 3-(6-bromo-4-methoxypyridine-2-yl)tetrahydrofuran-3-ol (2.6 g, 84.4% yield) as a yellow oil. 1H NMR: (400MHz, CDCl3) δppm: 6.97-6.93(m,2H),4.32(s,1H),4.16-4.13(m,2H),4.00 -3.97(m,1H),3.90-3.89(m,1H),3.87(s,3H),2.44-2.36(m,1H),2.43-2.22(m,1H).

[0576] Preparations 35 to 44

[0577] Following a similar procedure to that described in Preparation 34, the compounds in the table below were prepared from suitable halopyridines and ketones.

[0578]

[0579]

[0580]

[0581]

[0582] Preparation 45 3-(5-bromopyridin-3-yl)tetrahydrofuran-3-ol

[0583]

[0584] iPrMgCl (2M, 2.5mL) was added dropwise to a solution of 3,5-dibromopyridine (1.0 g, 4.22 mmol) in THF (15.0 mL) at 0 °C, and the solution was stirred at 0 °C under N2 for 2 h. Dihydrofuran-3(2H)-one (363.4 mg, 4.22 mmol) was added, and the reaction mixture was stirred at 25 °C for 20 h. The mixture was quenched with NH4Cl (saturated, 10 mL), poured into H2O (20 mL), and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 1) to give 3-(5-bromopyridin-3-yl)tetrahydrofuran-3-ol (413.2 mg, 40.1% yield) as a yellow oil. 1 H NMR: (400MHz, CDCl3) δppm: 8.62-8.60 (m, 2H), 8.04-8.02 (m, 1H), 4.24-4.14 (m, 2H), 3.98-3.96 (m, 1H), 3.88-3.86 (m, 1H), 2.43-2.32 (m, 2H).

[0585] Preparation 462-Bromo-6-(prop-1-en-2-yl)pyridine

[0586]

[0587] To a solution of 2-(6-bromopyridin-2-yl)prop-2-ol (0.4 g, 1.85 mmol) in DCM (6.0 mL), methanesulfonic anhydride (967.4 mg, 5.55 mmol) and TEA (1.03 mL, 7.40 mmol) were added, and the reaction mixture was stirred at 18 °C for 2 h. The pH of the reaction mixture was adjusted to 8 using a saturated aqueous solution of NaHCO3. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1 to 5 / 1) to give 2-bromo-6-(prop-1-en-2-yl)pyridine (158 mg, 43.1% yield) as a colorless gel. LCMS m / z = 198.2 [M+H] + .1H NMR (400MHz, CDCl3) δppm: 7.51-7.47(m,1H),7.40-7.39(m,1H),7.38-7.34(m,1H),5.92(s,1H),5.32-5.31(m,1H),2.16(s,3H).

[0588] Preparation 47 2-(6-bromopyridin-2-yl)propane-1,2-diol

[0589]

[0590] To a solution of 2-bromo-6-(prop-1-en-2-yl)pyridine (preparation 46, 340 mg, 1.72 mmol) in acetone (2 mL) and water (4 mL), 4-methyl-4-oxomorpholino-4-onium hydrate (243.6 mg, 1.80 mmol) and OsO4 (2.2 mg, 8.58 μmol) were added, and the mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into water (20 mL), and the mixture was extracted with EtOAc (30 mL x 3). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE / EtOAc = 15 / 1 to 3 / 1) to give 2-(6-bromopyridin-2-yl)propane-1,2-diol (386 mg, 97% yield) as a colorless gel. 1H NMR: (400MHz, DMSO-d6) δppm:7.74-7.70(m,1H),7.66-7.64(m,1H),7.47-7.4 6(m,1H),5.17(s,1H),4.65(t,J=5.6Hz,1H),3.56-3.48(m,2H),1.34(s,3H).

[0591] Preparation 48 2-Fluoro-4-(3-methoxytetrahydrofuran-3-yl)pyridine

[0592]

[0593] To a solution of 3-(2-fluoropyridin-4-yl)tetrahydrofuran-3-ol (430 mg, 2.35 mmol) in THF (5.0 mL), NaH (103.4 mg, 2.59 mmol, 60% purity) was added, followed by CH3I (333.6 mg, 2.35 mmol), and the reaction mixture was stirred at 30 °C for 2 h. The reaction mixture was quenched with an aqueous solution of NH4Cl (3 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc = 3 / 1) to give 2-fluoro-4-(3-methoxytetrahydrofuran-3-yl)pyridine (324 mg, 69.9% yield) as a colorless oil. LCMS m / z = 198.3 [M+H] +

[0594] Preparation 49 2-Bromo-6-(1-Methoxy-2,2-dimethylpropyl)pyridine

[0595]

[0596] Following a similar procedure to that described in preparation 48, 2-bromo-6-(1-methoxy-2,2-dimethylpropyl)pyridine (735 mg, 98.7% yield) was obtained from 1-(6-bromopyridin-2-yl)-2,2-dimethylprop-1-ol as a colorless oil.

[0597] Preparation 50 3-Bromo-5-(3-methoxytetrahydrofuran-3-yl)pyridine

[0598]

[0599] Following a similar reaction as described in Preparation 48, 3-bromo-5-(3-methoxytetrahydrofuran-3-yl)pyridine (244.6 mg, 56.0%) was obtained as a yellow oil from 3-(5-bromopyridin-3-yl)tetrahydrofuran-3-ol. ¹H NMR: (400 MHz, CDCl₃) δppm: 8.63 (d, J = 2.0 Hz, 1H), 8.56 (d, J = 1.6 Hz, 1H), 7.86 (t, J = 2.5 Hz, 1H, 1H), 4.18–4.06 (m, 3H), 3.87–3.84 (m, 1H), 3.23 (s, 3H), 2.51–2.47 (m, 1H), 2.29–2.23 (m, 1H).

[0600] Preparation 51 2-Bromo-6-(1-Methoxycyclopentyl)pyridine

[0601]

[0602] Following the procedure described in Preparation 48, 2-bromo-6-(1-methoxycyclopentyl)pyridine (1.1 g, 86.65% yield) was obtained as a colorless oil from 1-(6-bromopyridin-2-yl)cyclopentan-1-ol (Preparation 35) and iodomethane. ¹H NMR: (400 MHz, CDCl₃) δppm: 7.55–7.47 (m, 2H), 7.33 (d, J = 8.0 Hz, 1H), 3.09 (s, 3H), 2.11–2.03 (m, 4H), 1.81–1.78 (m, 4H).

[0603] Preparation 52 2-Bromo-6-(1-Methoxycyclobutyl)pyridine

[0604]

[0605] Following the procedure described in Preparation 48, 2-bromo-6-(1-methoxycyclobutyl)pyridine, as a colorless oil, was obtained from 1-(6-bromopyridin-2-yl)cyclobut-1-ol (Preparation 40) and MeI. ¹H NMR: (400 MHz, CDCl₃) δppm: 7.54 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 3.04 (s, 3H), 2.56–2.52 (m, 2H), 2.34–2.31 (m, 2H), 1.89–1.82 (m, 2H).

[0606] Preparation 53 2-Bromo-6-(1,2-Dimethoxypropyl-2-yl)pyridine

[0607]

[0608] Following a similar procedure to that described in Preparation 48, 2-bromo-6-(1,2-dimethoxypropyl-2-yl)pyridine (326 mg, 80.8% yield) was obtained as a colorless gel from 2-(6-bromopyridin-2-yl)propane-1,2-diol (Preparation 47). ¹H NMR (400 MHz, CDCl₃) δppm: 7.56–7.51 (m, 2H), 7.36–7.35 (m, 1H), 3.64 (s, 2H), 3.33 (s, 3H), 3.25 (s, 3H), 1.54 (s, 3H).

[0609] Preparation 54 4-Chloro-2-(3-methoxytetrahydrofuran-3-yl)pyridine

[0610]

[0611] NaH (144.3 mg, 3.61 mmol, 60% purity) was added to a solution of 3-(4-chloropyridin-2-yl)tetrahydrofuran-3-ol (preparation 32, 360 mg, 1.8 mmol) in THF (10 mL) at 0 °C, and the solution was stirred at 20 °C for 10 min. CH3I (383.9 mg, 2.7 mmol) was added, and the reaction mixture was stirred at 20 °C for 2 h. The mixture was quenched with water (10 mL), extracted with EtOAc (10 mL x 3), and the organic layer was washed with brine (20 mL), filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc = 15 / 1 to 3 / 1) to give 4-chloro-2-(3-methoxytetrahydrofuran-3-yl)pyridine (300 mg, 77.9% yield) as a brown oil. 1H NMR: (400MHz, CDCl3) δppm: 8.47 (d, J = 5.6 Hz, 1H), 7.55 (d, J = 1.2 Hz, 1H), 7.23-7. 22(m,1H),4.17-3.99(m,4H),3.21(s,3H),2.64-2.56(m,1H),2.39-2.33(m,1H).

[0612] Preparations 55 to 61

[0613] Following a similar procedure to that described in Preparation 54, the compounds in the table below were prepared from suitable alcohols and iodomethane.

[0614]

[0615]

[0616] Preparation 62 2-Bromo-6-(3-(difluoromethoxy)tetrahydrofuran-3-yl)pyridine

[0617]

[0618] NaH (98.3 mg, 2.46 mmol, 60% purity) was added to a solution of 3-(6-bromopyridin-2-yl)tetrahydrofuran-3-ol (preparation 36,400 mg, 1.64 mmol) in THF (10 mL) at -60 °C, followed by the addition of CHF₂Cl (708.5 mg, 8.19 mmol). The resulting mixture was stirred at 25 °C for 12 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1 to 5 / 1) to give 2-bromo-6-(3-(difluoromethoxy)tetrahydrofuran-3-yl)pyridine (75 mg, 15.6% yield) as a white solid. 1H NMR (500MHz, CDCl3) δppm: 7.63-7.56 (m, 2H), 7.45 (d, J = 7.5Hz, 1H), 6.37 (t, J = 73.5Hz, 1H), 4 .26-4.20(m,2H),4.16-4.14(m,1H),4.07-4.05(m,1H),2.90-2.83(m,1H),2.51-2.47(m,1H).

[0619] Preparation 63 2-Bromo-6-(3-fluorotetrahydrofuran-3-yl)pyridine

[0620]

[0621] DAST (1.3 g, 8.19 mmol) was added to a solution of 3-(6-bromopyridin-2-yl)tetrahydrofuran-3-ol (preparation 36, 2 g, 8.19 mmol) in DCM (20 mL) at 0 °C, and the reaction mixture was stirred at 25 °C for 12 h. The mixture was quenched with Na₂CO₃ (20 mL), extracted with DCM (2 x 30 mL), and the combined organic phases were washed with brine (2 x 15 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1) to give 2-bromo-6-(3-fluorotetrahydrofuran-3-yl)pyridine (1.4 g, 67% yield) as a yellow oil. 1H NMR: (400MHz, CDCl3) δ: ppm 7.61-7.56(m,2H), 7.44-7.39(m,1H), 4.21-4.18(m,3H), 4.12-4.11(m,1H), 2.78-2.66(m,1H), 2.44-2.38(m,1H).

[0622] Preparation 64 2-Bromo-6-(3-fluorotetrahydrofuran-3-yl)-4-methylpyridine

[0623]

[0624] Following the procedure described in Preparation 63, 2-bromo-6-(3-fluorotetrahydrofuran-3-yl)-4-methylpyridine (1.4 g, 66.2% yield) was obtained as a yellow oil from 3-(6-bromo-4-methylpyridin-2-yl)tetrahydrofuran-3-ol (Preparation 123). ¹H NMR: (400 MHz, CDCl₃) δ: ppm 7.40 (s, ¹H), 7.26–7.24 (m, ¹H), 4.20–4.17 (m, ³H), 4.10–4.08 (m, ¹H), 2.78–2.63 (m, ¹H), 2.36–2.30 (m, ⁴H).

[0625] Preparation 65 2-Bromo-6-(3-fluorotetrahydrofuran-3-yl)-4-methoxypyridine

[0626]

[0627] Following a similar procedure to that described in Preparation 63, 2-bromo-6-(3-fluorotetrahydrofuran-3-yl)-4-methoxypyridine (1.7 g, 63.8% yield) was obtained as a yellow solid from 3-(6-bromo-4-methoxypyridin-2-yl)tetrahydrofuran-3-ol (Preparation 34). 1 H NMR: (400MHz, CDCl3) δppm: 7.11 (d, J = 2.0Hz, 1H), 6.91 (d, J = 2.0Hz, 1H), 4.20-4. 16(m,3H),4.13-4.09(m,1H),3.87(s,3H),2.78-2.65(m,1H),2.40-2.31(m,1H).

[0628] Preparation 66 2-Bromo-6-(3-fluorotetrahydrofuran-3-yl)-4-isopropoxypyridine

[0629]

[0630] DAST (224.1 mg, 1.39 mmol) was added to a solution of 3-(6-bromo-4-isopropoxypyridin-2-yl)tetrahydrofuran-3-ol (preparation 37, 210 mg, 0.695 mmol) in DCM (10 mL), and the reaction mixture was stirred at 25 °C for 10 h. The mixture was added to an aqueous solution of NaHCO3 (20 mL) and extracted with DCM (10 mL x 3). The combined organic phases were concentrated under vacuum, and the crude product was purified by silica gel chromatography (PE / EtOAc = 20 / 1) to give 2-bromo-6-(3-fluorotetrahydrofuran-3-yl)-4-isopropoxypyridine (185 mg, 87.5% yield) as a yellow oil. 1 H NMR: (500MHz, CDCl3) δ: ppm 7.07-7.06(m,1H),6.87(d,J=2.0Hz,1H),4.19-4.16(m,2H),4.15-4.11(m,2H), 4.10-4.08(m,1H),2.76-2.67(m,1H),2.38-2.29(m,2H),1.37(d,J=6.0Hz,6H).

[0631] Preparation 67 2-Bromo-6-(3-Fluoroxyheptan-3-yl)-4-methylpyridine

[0632]

[0633] DAST (898.1 mg, 5.57 mmol) was added to a solution of 3-(6-bromo-4-methylpyridin-2-yl)oxetane-3-ol (preparation 39,680 mg, 2.79 mmol) in DCM (10 mL) at 0 °C, and the reaction mixture was stirred at 20 °C for 12 h. The mixture was quenched with Na₂CO₃ (10 mL) and extracted with DCM (2 x 10 mL). The combined organic phases were washed with brine (2 x 10 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1) to give 2-bromo-6-(3-fluorooxetane-3-yl)-4-methylpyridine (280 mg, 40.8% yield) as a yellow oil. 1 H NMR: (500MHz, CDCl3) δ: ppm 7.31 (s, 1H), 7.27 (s, 1H), 5.16 (d, J = 8.0Hz, 1H), 5.11 (d, J = 9.0Hz, 1H), 4.97 (d, J = 8.5Hz, 1H), 4.92 (d, J = 8.5Hz, 1H), 2.36 (s, 3H).

[0634] Preparations 68 to 72

[0635] Following a similar procedure to that described in Preparation 67, the compounds in the table below were prepared from suitable alcohols and DAST.

[0636]

[0637]

[0638]

[0639] Preparation 73 3-(6-bromopyridin-2-yl)-3-methyldihydrofuran-2(3H)-one

[0640]

[0641] To a solution of 2-bromo-6-fluoropyridine (1.5 g, 8.52 mmol) and 3-methyldihydrofuran-2(3H)-one (1.7 g, 17.05 mmol) in toluene (15 mL), LiHMDS (1 M, 25.6 mL) was added, and the reaction mixture was stirred at 120 °C for 1.5 h under microwave irradiation. The reaction mixture was quenched with water (10 mL), extracted with DCM (15 mL x 3), and the combined organic phases were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1 to 5 / 1) to give 3-(6-bromopyridin-2-yl)-3-methyldihydrofuran-2(3H)-one (1.0 g, 45.8% yield) as a colorless oil. 1H NMR: (500MHz, CDCl3) δppm: 7.56-7.51 (m, 2H), 7.41-7.40 (m, 1H), 4.38-4.34 (m, 2H), 3.20-3.16 (m, 1H), 2.45-2.43 (m, 1H), 1.65 (s, 3H).

[0642] Preparation 74 2-(6-bromopyridin-2-yl)-2-methylbutane-1,4-diol

[0643]

[0644] NaBH4 (443.2 mg, 11.7 mmol) was slowly added to a solution of 3-(6-bromopyridin-2-yl)-3-methyldihydrofuran-2(3H)-one (preparation 73, 1.0 g, 3.90 mmol) in MeOH (10 mL) at 0 °C over 30 minutes, and the reaction mixture was then stirred at 30 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with brine (10 mL), and extracted with DCM (15 mL x 3). The combined organic phases were concentrated under vacuum, and the residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 1 to 0 / 1) to give 2-(6-bromopyridin-2-yl)-2-methylbutane-1,4-diol (305 mg, 30% yield) as a colorless oil. 1HNMR (400MHz, CDCl3) δppm: 7.55 (t, J = 8.0Hz, 1H), 7.36 (d, J = 8.0Hz, 1H), 7.28-7.26 (m, 1H), 4.55 (br s,1H),4.05-4.02(m,1H),3.70-3.62(m,2H),3.50-3.47(m,1H),2.13-2.08(m,1H),2.02-1.96(m,1H),1.25(s,3H).

[0645] Preparation 75 2-Bromo-6-(3-methyltetrahydrofuran-3-yl)pyridine

[0646]

[0647] NaH (93.8 mg, 2.35 mmol, 60% purity) was added to a solution of 2-(6-bromopyridin-2-yl)-2-methylbutane-1,4-diol (preparation 74, 305 mg, 1.17 mmol) in THF (5.0 mL) at -30 °C. The solution was stirred for 15 min, and then TsCl (245.9 mg, 1.29 mmol) was added. The resulting mixture was stirred at 70 °C for 2 h, then quenched with water (1 mL) and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give 2-bromo-6-(3-methyltetrahydrofuran-3-yl)pyridine (20.0 mg, 7.0% yield) as a colorless oil. LCMS m / z = 244.1 [M+H] +

[0648] Preparation 76 2-(3,6-dihydro-2H-pyran-4-yl)-6-fluoropyridine

[0649]

[0650] To a solution of 2-bromo-6-fluoropyridine (3.0 g, 17.05 mmol) in dioxane (40 mL) and H₂O (10 mL), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (2.9 g, 14.21 mmol), Pd(dppf)Cl₂ (1.1 g, 1.42 mmol) and K₂CO₃ (3.9 g, 28.41 mmol) were added, and the reaction mixture was stirred at 80 °C for 1 hour under N₂. The mixture was poured into H₂O (40 mL), extracted with EtOAc (30 mL x 3), and the combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1 to 5 / 1) to give 2-(3,6-dihydro-2H-pyran-4-yl)-6-fluoropyridine (1.6 g, 60.9% yield) as a colorless oil. 1 HNMR (500MHz, CDCl3) δppm: 7.73-7.72(m,1H),7.23-7.21(m,1H),6.80-6.78(m,2H),4.38-4.36(m,2H),3.94-3.92(m,2H),2.60-2.58(m,2H).

[0651] Preparation 77 2-(3,7-dioxabicyclo[4.1.0]hept-6-yl)-6-fluoropyridine

[0652]

[0653] 3-chloroperoxybenzoic acid (1.7 g, 10.05 mmol) was added to a solution of 2-(3,6-dihydro-2H-pyran-4-yl)-6-fluoropyridine (preparation 76, 1.6 g, 8.37 mmol) in DCM (20 mL) at 0 °C, and the resulting mixture was stirred at 25 °C for 12 hours. The reaction mixture was poured into saturated Na2CO3 (30 mL), extracted with EtOAc (20 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1 to 5 / 1) to give 2-(3,7-dioxabicyclo[4.1.0]hept-6-yl)-6-fluoropyridine (2.4 g, crude) as a white solid. 1HNMR (500MHz, CDCl3) δppm:7.81-7.77(m,1H),7.29-7.27(m,1H),6.87-6.85(m,1H),4.07 -3.74(m,2H),3.73-3.72(m,1H),3.65-3.62(m,1H),2.91-2.87(m,1H),2.12-2.08(m,1H).

[0654] Preparation 78 3-(6-Fluoropyridin-2-yl)tetrahydrofuran-3-carboxaldehyde

[0655]

[0656] BF3·Et2O (2.2 g, 15.37 mmol) was slowly added to a solution of 2-(3,7-dioxabicyclo[4.1.0]hept-6-yl)-6-fluoropyridine (preparation 77, 1.0 g, 5.12 mmol) in DCM (15 mL) at 0 °C, and the reaction mixture was stirred at 20 °C for 12 h. The mixture was poured into saturated Na2CO3 (20 mL), extracted with EtOAc (20 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give 3-(6-fluoropyridin-2-yl)tetrahydrofuran-3-carboxaldehyde (621.9 mg, 62.2% yield) as a white solid. 1 HNMR: (400MHz, CDCl3) δppm: 9.75 (s, 1H), 7.84-7.78 (m, 1H), 7.13-7.10 (m, 1H), 6.90-6.88 (m, 1H) ),4.55-4.53(m,1H),4.09-4.06(m,1H),3.99-3.97(m,2H),2.77-2.72(m,1H),2.48-2.43(m,1H).

[0657] Preparation 79 (3-(6-Fluoropyridin-2-yl)tetrahydrofuran-3-yl)methanol

[0658]

[0659] NaBH4 (116.3 mg, 3.07 mmol) was added to a mixture of 3-(6-fluoropyridin-2-yl)tetrahydrofuran-3-carboxaldehyde (preparation 78, 400 mg, 2.05 mmol) in MeOH (3 mL) at 0 °C, and the reaction mixture was then stirred at 25 °C for 1 hour. The mixture was quenched with NH4Cl aqueous solution (10 mL), poured into H2O (10 mL), extracted with EtOAc (10 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give (3-(6-fluoropyridin-2-yl)tetrahydrofuran-3-yl)methanol (310.3 mg, 76.8% yield) as a colorless oil. 1 HNMR: (500MHz, CDCl3) δppm: 7.81-7.76(m,1H),7.24-7.22(m,1H),6.83.-6.81(m,1H),4.05-3.86(m,6H),3.15(br s,1H),2.27-2.19(m,2H).

[0660] Preparation 80 2-Fluoro-6-(3-(fluoromethyl)tetrahydrofuran-3-yl)pyridine

[0661]

[0662] Deoxofluor (365.5 mg, 1.65 mmol) was slowly added to a solution of (3-(6-fluoropyridin-2-yl)tetrahydrofuran-3-yl)methanol (preparation 79, 310 mg, 1.57 mmol) in DCM (5.0 mL) at 0 °C, and the reaction mixture was stirred at 20 °C under N2 for 4 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give 2-fluoro-6-(3-(fluoromethyl)tetrahydrofuran-3-yl)pyridine (72.9 mg, 23.3% yield) as a white solid. 1H NMR (500MHz, CDCl3) δppm:7.79-7.74(m,1H),7.21-7.18(m,1H),6.84-6.81(m,1H) ,4.62(d,J=47.5Hz,2H),4.12-3.96(m,4H),2.40-2.37(m,1H),2.23-2.20(m,1H).

[0663] Preparation 81 2-Chloro-6-(3,6-dihydro-2H-pyran-4-yl)pyridine

[0664]

[0665] Following a similar procedure to that described in preparation 76, 2-chloro-6-(3,6-dihydro-2H-pyran-4-yl)pyridine (373 g, 62% yield) was obtained from 2-bromo-6-chloropyridine as a yellow oil. LCMS m / z = 196 [M+H] +

[0666] Preparation 82 2-(3,7-dioxabicyclo[4.1.0]hept-6-yl)-6-chloropyridine

[0667]

[0668] Following a similar procedure to that described in Preparation 77, 2-(3,7-dioxabicyclo[4.1.0]hept-6-yl)-6-chloropyridine (6.6 g, 61% yield) was obtained as a clear oil from 2-chloro-6-(3,6-dihydro-2H-pyran-4-yl)pyridine (Preparation 81). LCMS m / z = 212 [M+H] +

[0669] Preparation 83 3-(6-chloropyridin-2-yl)tetrahydrofuran-3-carboxaldehyde

[0670]

[0671] Sc(OTf)3 (0.46 g, 0.94 mmol) was added to a solution of 2-(3,7-dioxabicyclo[4.1.0]hept-6-yl)-6-chloropyridine (preparation 82, 6.60 g, 31.3 mmol) in anhydrous dioxane (100 mL), and the reaction mixture was stirred at 95 °C for 30 min under N2. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography (10-30% EtOAc in hexane) to give 3-(6-chloropyridin-2-yl)tetrahydrofuran-3-carboxaldehyde (5.40 g, 82% yield) as a clear oil. LCMS m / z = 212 [M+H] +

[0672] Preparation 84 2-Chloro-6-(3-vinyltetrahydrofuran-3-yl)pyridine

[0673]

[0674] Under N2 atmosphere, Ph3PCH3Br (9.68 g, 28.0 mmol) was added in portions to a solution of t-BuOK (3.13 g, 27.97 mmol) in anhydrous THF (80 mL) at 5–10 °C, and the resulting yellow suspension was stirred at room temperature for 1 hour, then cooled to 0 °C. 3-(6-chloropyridin-2-yl)tetrahydrofuran-3-carboxaldehyde (preparation 83, 4.40 g, 20.85 mmol) was added dropwise to THF (20 mL) at 0 °C, and the reaction mixture was stirred at 0–10 °C for 1 hour. The mixture was quenched with an aqueous solution of NH4Cl (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water and then with brine, dried over Na2SO4, and concentrated. The crude product was purified by silica gel chromatography, eluting with 10-20% EtOAc in hexane to give 2-chloro-6-(3-vinyltetrahydrofuran-3-yl)pyridine (3.90 g, 89% yield). LCMS m / z = 210 [M+H] +

[0675] Preparation 85 2-Chloro-6-(3-ethyltetrahydrofuran-3-yl)pyridine

[0676]

[0677] A mixture of 2-chloro-6-(3-vinyltetrahydrofuran-3-yl)pyridine (Preparation 84, 3.90 g, 18.66 mmol) and 10% Pd / C (0.50 g) in EtOAc was stirred for 1 hour under H2 (at saturation). The Pd / C was then passed through… Filter off. Concentrate the filtrate under vacuum and purify the residue by silica gel chromatography, eluting with 10-20% EtOAc in hexane to give 2-chloro-6-(3-ethyltetrahydrofuran-3-yl)pyridine (3.50 g, 89% yield). LCMS m / z = 212 [M+H] +

[0678] Preparation 86 2-(3-(difluoromethyl)tetrahydrofuran-3-yl)-6-fluoropyridine

[0679]

[0680] Deoxofluor (566.7 mg, 2.56 mmol) was slowly added to a solution of 3-(6-fluoropyridin-2-yl)tetrahydrofuran-3-carboxaldehyde (preparation 78, 200 mg, 1.02 mmol) in DCM (5 mL) at 0 °C, and the reaction mixture was stirred at 20 °C under N2 for 12 h. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EtOAc = 10 / 1 to 5 / 1) to give 2-(3-(difluoromethyl)tetrahydrofuran-3-yl)-6-fluoropyridine (56.1 mg, 25.2% yield) as a colorless oil. 1 HNMR (500MHz, CDCl3) δppm:7.82-7.78(m,1H),7.26-7.24(m,1H),6.89-6.86(m,1H),6.16(t ,J=56.0Hz,1H),4.31-4.29(m,1H),4.18-4.16(m,1H),4.04-3.92(m,2H),2.53-2.45(m,2H).

[0681] Preparation 87 3-(6-bromopyridin-2-yl)tetrahydrofuran-3-carboxynitrile

[0682]

[0683] 2-(6-bromopyridin-2-yl)acetonitrile (400 mg, 2.03 mmol) and 1-chloro-2-(chloromethoxy)ethane (261.9 mg, 2.03 mmol) in 10 mL of DMF were added to NaH (81.2 mg, 2.03 mmol) in 40 mL of DMF, and the reaction mixture was stirred at -10 °C for 30 min. The mixture was quenched with 10 mL of saturated NH4Cl, poured into 20 mL of H2O, and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc = 15 / 1 to 3 / 1) to give 3-(6-bromopyridin-2-yl)tetrahydrofuran-3-carboxynitrile (212.7 mg, 41.4% yield) as a yellow oil. 1 H NMR: (400MHz, CDCl3) δppm:7.66-7.60(m,2H),7.49-7.45(m,1H),4.41-4.38(m, 1H),4.21-4.18(m,2H),4.15-4.12(m,1H),2.86-2.80(m,1H),2.70-2.64(m,1H).

[0684] Preparation 881-(6-chloropyridin-2-yl)pyrrolidine-2-one

[0685]

[0686] Under N2, a suspension of 2-bromo-6-chloropyridine (2.0 g, 10.39 mmol), pyrrolidone-2-one (884.4 mg, 10.39 mmol), Pd2(dba)3 (475.9 mg, 0.52 mmol), Xantphos (601.4 mg, 1.04 mmol), and K2CO3 (2.87 g, 20.8 mmol) in dioxane (20 mL) was stirred at 100 °C for 16 hours. The reaction mixture was concentrated under vacuum, and the residue was diluted with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (EtOAc = 100%) to provide 1-(6-chloropyridin-2-yl)pyrrolidine-2-one as a white solid (1.10 g, 53.8% yield). LCMS m / z = 197.1 [M+H] +

[0687] Preparation 89 2-Chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridine

[0688]

[0689] 2-Chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Preparation 61, 11.9 g, 55.8 mmol) was dissolved in hexane (170 mL), degassed with N2, and then 4,4'-di-tert-butyl-2,2'-dipyridine (298 mg, 1.12 mmol), bis(1,5-cyclooctadiene)iridium(I) chloride dimer (381 mg, 0.56 mmol), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxacyclopentaborane) (16.7 g, 65.6 mmol) were added. The reaction mixture was heated at 75 °C for 1 hour under N2, and then cooled to room temperature. The solid formed was collected by filtration, washed with cold hexane and dried to give 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridine (6.0 g, 32% yield).

[0690] Preparation 902-Chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol

[0691]

[0692] Ozone (9.56 g, 15.6 mmol) in water (50 mL) was added dropwise to a mixture of 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridine (preparation 89, 4.4 g, 13.0 mmol) in THF (50 mL) at 0 °C, and the reaction mixture was stirred at this temperature for 1 hour. The mixture was quenched with Na₂SO₃ (saturated solution), extracted with EtOAc (100 mL x 2), and the combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to give 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridine-4-ol (3.3 g, crude) as a brown oil. LCMS m / z = 229.9 [M+H] +

[0693] Preparation 91 2-Chloro-4-methoxy-6-(3-methoxytetrahydrofuran-3-yl)pyridine

[0694]

[0695] MeI (166.8 mg, 1.18 mmol) was added under N2 to a mixture of 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (preparation 90, 180 mg, 0.784 mmol) and Cs2CO3 (383 mg, 1.18 mmol) in DMF (10 mL), and the reaction mixture was stirred at 40 °C for 0.5 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with H2O (10 mL x 3) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 2-chloro-4-methoxy-6-(3-methoxytetrahydrofuran-3-yl)pyridine (160 mg, 84% yield) as a yellow oil, which was used for the next step without further purification. 1H NMR (400MHz, CDCl3) δppm 7.00(d,J=2.0Hz,1H),6.76(d,J=2.0Hz,1H),4.17-4.02(m,3H),3.98-3.9 5(m,1H),3.88(s,3H),3.23(s,3H),2.68-2.60(m,1H),2.35-2.30(m,1H).

[0696] Preparation 922-Chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetane-3-yloxy)pyridine

[0697]

[0698] Following a similar procedure to that described in Preparation 91, 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Preparation 90) and 3-iodooxetane were used to obtain 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetane-3-yloxy)pyridine (120 mg, crude). LCMS m / z = 286.1 [M+H] +

[0699] Preparation 93 2-Chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(oxecyclobutane-2-ylmethoxy)pyridine

[0700]

[0701] A solution of oxetane-2-ylmethyl 4-methylbenzenesulfonate (500 mg, 2.18 mmol), 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (preparation 90, 633.0 mg, 2.61 mmol), and Cs₂CO₃ (1.8 g, 5.44 mmol) in DMF (5 mL) was stirred at 70 °C for 18 hours. The mixture was diluted with water (10 mL) and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (20 mL), filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE / EtOAc = 15 / 1 to 1 / 1) to give 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetane-2-ylmethoxy)pyridine (290 mg, 44.4% yield) as a colorless oil. 1 H NMR: (400MHz, CDCl3) δppm: 7.07 (d, J=1.6Hz, 1H), 6.83-6.82 (m, 1H), 5.16-5.13 (m, 1H), 4.75-4.65(m,2H),4.20-3.94(m,6H),3.21(s,3H),2.81-2.59(m,3H),2.32-2.30(m,1H).

[0702] Preparation 94 2-Chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(oxecyclobutane-3-ylmethoxy)pyridine

[0703]

[0704] Following the procedure described in Preparation 93, 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetane-3-ylmethoxy)pyridine (310 mg, 79.2%) was obtained as a colorless oil from 4-methylbenzenesulfonate oxetane-3-ylmethyl ester and 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridine-4-ol (Preparation 90). 1H NMR: (400MHz, CDCl3) δppm: 7.02-7.00 (m, 1H), 6.78 (d, J = 2.0Hz, 1H), 4.92-4.88 (m, 2H), 4.57-4.53 (m, 2H), 4.28-4.2 6(m,2H),4.11-4.09(m,3H),4.08-3.94(m,1H),3.47-3.43(m,1H),3.23(s,3H),2.66-2.60(m,1H),2.34-2.32(m,1H).

[0705] Preparation 95 2-Chloro-4-(3-(difluoromethyl)cyclobutoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine

[0706]

[0707] Following a similar procedure to that described in Preparation 93, 2-chloro-4-(3-(difluoromethyl)cyclobutyl 4-methylbenzenesulfonate and 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Preparation 90) were reacted to obtain 2-chloro-4-(3-(difluoromethyl)cyclobutoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine as a colorless oil (305 mg, 43.1% yield). LCMS m / z = 334.3 [M+H] +

[0708] Preparation 96 3-(benzyloxy)cyclobutyl 4-methylbenzenesulfonic acid

[0709]

[0710] TsCl (1.3 g, 6.73 mmol), DMAP (137.1 mg, 1.12 mmol), and TEA (1.1 g, 11.22 mmol) were added to a solution of 3-(benzyloxy)cyclobut-1-ol (1.0 g, 5.61 mmol) in DCM (15.0 mL), and the reaction mixture was stirred at 20 °C for 3 hours. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (PE / EtOAc = 5 / 1) to give 3-(benzyloxy)cyclobutyl 4-methylbenzenesulfonic acid (1.6 g, 84.7% yield) as a colorless oil. 1H NMR: (400MHz, CDCl3) δppm:7.78-7.75(m,2H),7.34-7.27(m,7H),4.49-4.41(m,1H) ,4.36(s,2H),3.66-3.58(m,1H),2.62-2.58(m,2H),2.44(s,3H),2.18-2.14(m,2H).

[0711] Preparation 97 4-(3-(benzyloxy)cyclobutoxy)-2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridine

[0712]

[0713] Following a similar procedure to that described in Preparation 93, 4-(3-(benzyloxy)cyclobutyl 4-methylbenzenesulfonate (Preparation 96) and 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Preparation 90) were prepared as a colorless oil to obtain 4-(3-(benzyloxy)cyclobutoxy)-2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridine (807 mg, 95%). 1H NMR (400MHz, CDCl3) δppm: 7.37-7.27 (m, 5H), 6.88 (d, J = 2.0Hz, 1H), 6.61 (d, J = 1.6Hz, 1H), 4.92-4.89 (m, 1H), 4.34 (s, 2H), 4. 12-4.10(m,1H),4.09-4.06(m,3H),3.96-3.93(m,1H),3.20(s,3H),2.64-2.58(m,3H),2.56-2.45(m,2H),2.44-2.29(m,1H).

[0714] Preparation 98 2-Chloro-4-(3,3-difluorocyclobutoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine

[0715]

[0716] 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Preparation 90) (114.2 mg, 0.435 mmol) and Cs₂CO₃ (283.7 mg, 0.871 mmol) were added to a solution of 3,3-difluorocyclobutyl 4-methylbenzenesulfonic acid (100 mg, 0.435 mmol) in DMF (3 mL), and the reaction mixture was stirred at 80 °C for 40 h. The mixture was purified by preparative HPLC-K (gradient: 40-70% MeCN) to give 2-chloro-4-(3,3-difluorocyclobutoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (50 mg, 35.9% yield) as a yellow gel. 1H NMR: (500MHz, MeOH-d4) δppm: 7.03 (d, J=2.5Hz, 1H), 6.90 (d, J=2.5Hz, 1H), 5.11-4.92(m,5H),3.23-3.19(m,5H),2.83-2.80(m,1H),2.80-2.75(m,3H).

[0717] Preparation 99 2-Chloro-4-ethoxy-6-(3-methoxytetrahydrofuran-3-yl)pyridine

[0718]

[0719] To a solution of 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (preparation 90, 100 mg, 0.435 mmol) in DMF (3 mL), K₂CO₃ (120.4 mg, 0.871 mmol) and iodoethane (101.9 mg, 0.653 mmol) were added, and the reaction mixture was stirred at 50 °C for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc = 1 / 1) to give 2-chloro-4-ethoxy-6-(3-methoxytetrahydrofuran-3-yl)pyridine (105 mg, 93.6% yield) as a colorless oil. LCMS m / z = 258.1 [M+H] +

[0720] Preparation 100 2-Chloro-4-isopropoxy-6-(3-methoxytetrahydrofuran-3-yl)pyridine

[0721]

[0722] Following the procedure described in Preparation 99, 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Preparation 90) and isopropanol were used to obtain 2-chloro-4-isopropoxy-6-(3-methoxytetrahydrofuran-3-yl)pyridine (95 mg, 80% yield) as a colorless oil.1 H NMR: (500MHz, CDCl3) δ: ppm 6.97-6.92(m,1H),6.71-6.68(m,1H),4.65-4.62(m,1H),4.13-4.05(m,3H),3.96-3. 93(m,1H),3.21(s,3H),2.66-2.59(m,1H),2.33-2.30(m,1H),1.37(d,J=6.0Hz,6H).

[0723] Preparation 101 2-Chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(2,2,2-trifluoroethoxy)pyridine

[0724]

[0725] K₂CO₃ (361.0 mg, 2.61 mmol) was added to a solution of 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (preparation 90, 200 mg, 0.871 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (202.1 mg, 0.871 mmol) in DMF (10.0 mL), and the reaction mixture was stirred at 70 °C for 8 hours. The mixture was diluted with H₂O (10 mL), extracted with EtOAc (10 mL x 3), and the combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc = 15 / 1 to 3 / 1) to give 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(2,2,2-trifluoroethoxy)pyridine (130 mg, 47.9% yield) and another 130 mg of impure product. LCMS m / z = 312.1 [M+H] +

[0726] Preparation 102 3-((2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-yl)oxy)cyclobut-1-ol

[0727]

[0728] A solution of 4-(3-(benzyloxy)cyclobutoxy)-2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridine (preparation 97, 200 mg, 0.513 mmol) in TFA (2.9 g, 26.1 mmol) was stirred at 100 °C for 4 hours. The mixture was purified by preparative HPLC-K (gradient: 24-54% MeCN) to give 3-((2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-yl)oxy)cyclobut-1-ol (105 mg, 68.3% yield) as a white solid. 1 H NMR: (400MHz, CDCl3) δppm: 6.89 (d, J = 2.0Hz, 1H), 6.61 (d, J = 2.0Hz, 1H), 4.96-4.92 (m, 1H), 4.66-4. 65(m,1H),4.12-4.06(m,3H),3.96-3.93(m,1H),3.21(s,3H),2.63-2.47(m,5H),2.46-2.30(m,1H).

[0729] Preparation 103 2-Chloro-4-(3-methoxycyclobutoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine

[0730]

[0731] Following a similar procedure to that described in Preparation 54, 2-chloro-4-(3-methoxycyclobutoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-yl)oxy)cyclobut-1-ol (Preparation 102) and CH3I were used to obtain 2-chloro-4-(3-methoxycyclobutoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (85.2 mg, 81.4% yield) as a colorless oil. 1 H NMR: (400MHz, CDCl3) δppm: 6.89 (d, J = 2.0Hz, 1H), 6.61 (d, J = 2.0Hz, 1H), 4.90-4.88 (m, 1H), 4.14-4.05 (m, 4H),3.96-3.93(m,1H),3.28(s,3H),3.21(s,3H),2.61-2.49(m,1H),2.48-2.42(m,4H),2.32-2.27(m,1H).

[0732] Preparation 104 4-(3-(benzyloxy)cyclobutoxy)-2,6-dichloropyridine

[0733]

[0734] 2,6-Dichloropyridin-4-ol (2.0 g, 12.0 mmol) and K₂CO₃ (3.33 g, 24.1 mmol) were added to a solution of 3-(benzyloxy)cyclobutoxy)4-methylbenzenesulfonic acid (preparation 96, 4 g, 12.03 mmol) in DMF (40 mL), and the reaction mixture was stirred at 70 °C for 16 h. The mixture was concentrated and the residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give 4-(3-(benzyloxy)cyclobutoxy)-2,6-dichloropyridine (3.4 g, 85.9% yield) as a yellow oil. 1HNMR: (400MHz, CDCl3) δppm: 7.39-7.29 (m, 5H), 6.68-6.66 (m, 2H), 4.89-4.86 (m,1H),4.45(s,2H),4.34-4.31(m,1H),2.60-2.52(m,2H),2.47-2.43(m,2H).

[0735] Preparation 105 4-(3-(benzyloxy)cyclobutoxy)-2-chloro-6-(furan-3-yl)pyridine

[0736]

[0737] Furan-3-ylboronic acid, K2CO3 (2.9 g, 20.67 mmol), and Pd(dppf)Cl2 (756.1 mg, 1.03 mmol) were added to a solution of 4-(3-(benzyloxy)cyclobutoxy)-2,6-dichloropyridine (preparation 104, 3.4 g, 10.33 mmol) in dioxane (30 mL) and H2O (6 mL), and the reaction mixture was stirred at 100 °C under N2 for 16 hours. The mixture was concentrated and purified by preparative HPLC-B (gradient = 62-92% MeCN) to give 4-(3-(benzyloxy)cyclobutoxy)-2-chloro-6-(furan-3-yl)pyridine (1.6 g, 43.0% yield) as a white oil. 1 H NMR: (400MHz, CDCl3) δppm: 8.03(s,1H),7.47(s,1H),7.39-7.31(m,5H),6.80-6.77(m,1H),6.66(s,1H),6.57( d,J=2.0Hz,1H),4.95-4.91(m,1H),4.46-4.45(m,2H),4.36-4.33(m,1H),2.57-2.54(m,2H),2.48-2.41(m,2H).

[0738] Preparation 1063-((2-chloro-6-(furan-3-yl)pyridin-4-yl)oxy)cyclobut-1-ol

[0739]

[0740] A solution of 4-(3-(benzyloxy)cyclobutoxy)-2-chloro-6-(furan-3-yl)pyridine (preparation 105, 1.5 g, 4.30 mmol) in TFA (20 mL) was stirred at 100 °C for 5 hours. The mixture was concentrated and the residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1) to give 3-((2-chloro-6-(furan-3-yl)pyridin-4-yl)oxy)cyclobut-1-ol (580 mg, 50.8% yield) as a yellow oil. 1 H NMR: (400MHz, CDCl3) δppm: 8.06 (s, 1H), 7.47 (d, J = 2.0Hz, 1H), 6.81-6.79 (m, 1H), 6.68(s,1H),6.55(d,J=1.6Hz,1H),5.50-5.44(m,1H),5.04-4.97(m,1H),1.85(br s,1H),1.30-1.24(m,2H),0.90-0.85(m,2H).

[0741] Preparation 107 2-Chloro-6-(furan-3-yl)-4-(3-methoxycyclobutoxy)pyridine

[0742]

[0743] NaH (159.6 mg, 3.99 mmol, 60% purity) was added to a mixture of 3-((2-chloro-6-(furan-3-yl)pyridin-4-yl)oxy)cyclobut-1-ol (preparation 106, 530 mg, 1.99 mmol) in THF (6.0 mL), and the solution was stirred at 25 °C for 30 min. MeI (566.3 mg, 3.99 mmol) was added, and the reaction mixture was stirred at 25 °C for 18 h. The reaction mixture was concentrated under vacuum, diluted with H₂O (20 mL), and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over Na₂SO₄, and filtered. The mixture was concentrated and the residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give 2-chloro-6-(furan-3-yl)-4-(3-methoxycyclobutoxy)pyridine (325 mg, 58.5% yield) as a yellow oil.

[0744] Preparation 108 4-(3-(benzyloxy)cyclobutoxy)-2-chloropyridine

[0745]

[0746] Cs₂CO₃ (37.7 g, 115.8 mmol) was added to a solution of 2-chloropyridin-4-ol (5.0 g, 38.6 mmol) and 3-(benzyloxy)cyclobutyl 4-methylbenzenesulfonic acid (preparation 96 g, 12.8 g, 38.60 mmol) in DMF (70 mL), and the reaction mixture was stirred at 100 °C for 6 h. The cooled mixture was concentrated under reduced pressure, and the residue was treated with H₂O (50 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (50 mL), dried over Na₂SO₄, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE / EtOAc = 3 / 1 to 1 / 1) to give 4-(3-(benzyloxy)cyclobutoxy)-2-chloropyridine (9.8 g, 87.6% yield) as a yellow oil. LCMS m / z = 290.7 [M+H] +

[0747] Preparation 109 1-(4-(3-(benzyloxy)cyclobutoxy)-6-chloropyridin-2-yl)ethyl-1-one

[0748]

[0749] Acetaldehyde (16.4 g, 372.7 mmol), TBHP (6.7 g, 74.55 mmol), TFA (4.7 g, 41 mmol), and FeSO4 (10.4 g, 37.27 mmol) were added to a solution of 4-(3-(benzyloxy)cyclobutoxy)-2-chloropyridine (preparation 108, 10.8 g, 37.27 mmol) in MeCN (120 mL), and the reaction mixture was stirred at 80 °C under N2 for 16 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was treated with H2O (150 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give 1-(4-(3-(benzyloxy)cyclobutoxy)-6-chloropyridin-2-yl)ethyl-1-one (640 mg, 5.18% yield) as a yellow oil and 4-(3-(benzyloxy)cyclobutoxy)-2-chloropyridine (8.6 g, 79.6% yield) as a pale yellow oil. LCMS m / z = 331.7 [M+H] +

[0750] Preparation 1104-(3-(benzyloxy)cyclobutoxy)-2-chloro-6-(1,1-difluoroethyl)pyridine

[0751]

[0752] DAST (7.3 g, 45.41 mmol) was added to a solution of 1-(4-(3-(benzyloxy)cyclobutoxy)-6-chloropyridin-2-yl)ethyl-1-one (preparation 109, 600 mg, 1.81 mmol) in DCM (10 mL), and the reaction mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with H₂O (10 mL) and extracted with DCM (20 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE / EtOAc = 5 / 1 to 1 / 1) to give 4-(3-(benzyloxy)cyclobutoxy)-2-chloro-6-(1,1-difluoroethyl)pyridine (300 mg, 46.9% yield) as a yellow gel. LCMS m / z = 353.9 [M+H] +

[0753] Preparation 111 3-((2-chloro-6-(1,1-difluoroethyl)pyridin-4-yl)oxy)cyclobut-1-ol

[0754]

[0755] A solution of 4-(3-(benzyloxy)cyclobutoxy)-2-chloro-6-(1,1-difluoroethyl)pyridine (preparation 110, 220.0 mg, 0.622 mmol) in TFA (10 mL) was stirred at 100 °C for 16 h. The cooled reaction mixture was treated with H₂O (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give 3-((2-chloro-6-(1,1-difluoroethyl)pyridin-4-yl)oxy)cyclobut-1-ol (80.0 mg, 48.8% yield) as a yellow solid. LCMS m / z = 359.6 [M+H] +

[0756] Preparation 112 2-Chloro-6-(1,1-difluoroethyl)-4-(3-methoxycyclobutoxy)pyridine

[0757]

[0758] Following a similar procedure to that described in Preparation 107, 2-chloro-6-(1,1-difluoroethyl)pyridin-4-yl)oxy)cyclobut-1-ol (Preparation 111) and CH3I were reacted to obtain 2-chloro-6-(1,1-difluoroethyl)-4-(3-methoxycyclobutoxy)pyridine (20 mg, 27.1% yield) as a colorless oil. LCMS m / z = 277.6 [M+H] +

[0759] Preparation 113 2-Chloro-4-((1-methoxypropyl-2-yl)oxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine

[0760]

[0761] DIAD (880.5 mg, 4.35 mmol) was added to a solution of 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (preparation 90, 500 mg, 2.18 mmol), 1-methoxyprop-2-ol (392.4 mg, 4.35 mmol), and PPh3 (1.1 g, 4.35 mmol) in THF (10 mL) at 0 °C under N2 conditions, and the reaction mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc = 3 / 1) to give 2-chloro-4-((1-methoxyprop-2-yl)oxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (485 mg, 73.8% yield) as a colorless oil. 1H NMR(500MHz, CDCl3)δppm:7.01(s,1H),6.76(s,1H),4.66-4.63(m,1H),4.12-4.06(m,3H),3.95-3.93(m,1H),3.95-3 .93(m,1H),3.56-3.51(m,1H),3.39(s,3H),3.20(s,3H),2.63-2.60(m,1H),2.31-2.28(m,1H),1.33(d,J=6.0Hz,3H).

[0762] Preparation 114 2-Chloro-4-(2-methoxypropoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine

[0763]

[0764] Following the method described in Preparation 113, 2-chloro-4-(2-methoxypropoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Preparation 90) and 2-methoxyprop-1-ol were used to obtain 2-chloro-4-(2-methoxypropoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (520 mg, 79%) as a colorless oil. 1H NMR (400MHz, CDCl3) δppm: 7.01 (s, 1H), 6.76 (s, 1H), 4.98-4.95 (m, 2H), 4.11-4.00 (m, 4H), 3. 73-3.72(m,1H),3.43(s,3H),3.20(s,3H),2.64-2.60(m,1H),2.32-2.31(m,1H),1.23(s,3H).

[0765] Preparation 115 2-Chloro-4-(2-methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine

[0766]

[0767] Following a similar procedure to that described in preparation 113, 2-chloro-4-(2-methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (preparation 90) and 2-methoxyeth-1-ol were used to obtain 2-chloro-4-(2-methoxyethoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine (175 mg, 46.6% yield) as a white solid. 1 H NMR: (400MHz, CDCl3) δ: ppm 7.06-7.03(m,1H),6.80-6.77(m,1H),4.19-4.06(m,5H),3.96-3.95(m,1H),3.7 8-3.75(m,2H),3.45(s,3H),3.20(s,3H),2.64-2.60(m,1H),2.32-2.29(m,1H).

[0768] Preparation 116 1-(6-chloro-4-(2-methoxyethoxy)pyridin-2-yl)ethyl-1-one

[0769]

[0770] To a solution of 2-chloro-4-(2-methoxyethoxy)pyridine (2.6 g, 13.9 mmol) in MeCN (30 mL), 2-hydroperoxy-2-methylpropane, acetaldehyde (5 M, 27.7 mL), TFA (1.7 g, 15.24 mmol), and FeSO4 (3.9 g, 13.9 mmol) were added, and the reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was concentrated under vacuum and poured into H2O (60 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) and the product was further purified by preparative HPLC-K (gradient: 33-63% MeCN) to give 1-(6-chloro-4-(2-methoxyethoxy)pyridin-2-yl)ethyl-1-one (42 mg, 1.3% yield) as a yellow solid. 1 H NMR: (500MHz, CDCl3) δppm: 7.50 (d, J = 2.0 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 4.23-4.21 (m, 2H), 3.77-3.75 (m, 2H), 3.44 (s, 3H), 2.68 (s, 3H).

[0771] Preparation 117 2-Chloro-6-(1,1-difluoroethyl)-4-(2-methoxyethoxy)pyridine

[0772]

[0773] DAST (58.9 mg, 0.366 mmol) was added to a solution of 1-(6-chloro-4-(2-methoxyethoxy)pyridin-2-yl)ethyl-1-one (preparation 116, 42.0 mg, 0.183 mmol) in DCM (2 mL) at 0 °C, and the resulting mixture was stirred at 50 °C for 24 h. The mixture was quenched with Na2CO3 (5 mL aqueous solution), poured into H2O (10 mL), and extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with brine (2 x 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc = 3 / 1) to give 2-chloro-6-(1,1-difluoroethyl)-4-(2-methoxyethoxy)pyridine (20 mg, 43.5% yield) as a yellow oil. 1H NMR (500MHz, CDCl3) δppm: 7.13 (d, J = 1.5Hz, 1H), 6.90 (s, 1H), 4.21-4.19 (m, 2H), 3.77-3.75 (m, 2H), 3.44 (s, 3H), 1.97 (t, J = 18.0Hz, 3H).

[0774] Preparation 118 2-Fluoro-6-(furan-3-yl)pyridine

[0775]

[0776] Furan-3-ylboronic acid (209.8 mg, 1.88 mmol), Pd(dppf)Cl2 (124.7 mg, 0.170 mmol), and Cs2CO3 (1.1 g, 3.41 mmol) were added to a solution of 2-bromo-6-fluoropyridine (300 mg, 1.70 mmol) in dioxane (4 mL) and H2O (0.5 mL), and the reaction mixture was stirred at 90 °C under N2 for 3 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1) to give 2-fluoro-6-(furan-3-yl)pyridine (215.9 mg, 77.6% yield) as a colorless oil. 1 H NMR: (500MHz, CDCl3) δppm: 8.04 (s, 1H), 7.77-7.74 (m, 1H), 7.49-7.48 (m, 1H), 7.33-7.31 (m, 1H), 6.86 (s, 1H), 6.78-6.77 (m, 1H).

[0777] Preparation 119 2-Fluoro-6-(tetrahydrofuran-3-yl)pyridine

[0778]

[0779] Pd / C (254.4 mg, 0.239 mmol, 10% purity) was added to a solution of 2-fluoro-6-(furan-3-yl)pyridine (preparation 118, 195 mg, 1.20 mmol) in MeOH (5.0 mL), and the mixture was stirred at 25 °C for 4 hours under 15 psi H2. The reaction mixture was filtered and concentrated under vacuum to give 2-fluoro-6-(tetrahydrofuran-3-yl)pyridine (171.3 mg, 85.7% yield) as a colorless oil. 1 H NMR: (400MHz, CDCl3) δppm: 7.74-7.67(m,1H),7.10-7.07(m,1H),6.78-6.75(m,1H),4.17 -4.04(m,2H),3.94-3.86(m,2H),3.55-3.51(m,1H),2.34-2.32(m,1H),2.24-2.21(m,1H).

[0780] Preparation 120 2-Fluoro-6-(furan-3-yl)-4-methylpyridine

[0781]

[0782] Following the procedure described in preparation 118, 2-fluoro-6-(furan-3-yl)-4-methylpyridine (226 mg, 80.8% yield) was obtained as a colorless oil from 2-bromo-6-fluoro-4-methylpyridine and furan-3-ylboronic acid. 1 H NMR: (400MHz, CDCl3) δppm: 8.02 (s, 1H), 7.48-7.46 (m, 1H), 7.14 (s, 1H), 6.84 (d, J = 1.2Hz, 1H), 6.59 (s, 1H), 2.40 (s, 3H).

[0783] Preparation 121 2-Fluoro-4-methyl-6-(tetrahydrofuran-3-yl)pyridine

[0784]

[0785] Following a similar procedure to that described in preparation 119, 2-fluoro-6-(furan-3-yl)-4-methylpyridine (preparation 120) was used to obtain 2-fluoro-4-methyl-6-(tetrahydrofuran-3-yl)pyridine as a colorless oil (197 mg, 85.4% yield). 1 H NMR: (400MHz, CDCl3) δppm: 6.90 (s, 1H), 6.58 (s, 1H), 4.16-4.11 (m, 1H), 4.06-4.04 (m, 1H) ,3.94-3.82(m,2H),3.49-3.47(m,1H),2.36(s,3H),2.33-2.30(m,1H),2.23-2.19(m,1H).

[0786] Preparation 122 2-Bromo-6-(furan-3-yl)-4-methoxypyridine

[0787]

[0788] Following the procedure described in Preparation 118, 2-bromo-6-(furan-3-yl)-4-methoxypyridine (300 mg, 63% yield) was obtained as a white solid from 2,6-dibromo-4-methoxypyridine and furan-3-ylboronic acid. LCMS m / z = 254.1 [M+H] +

[0789] Preparation 123 3-(6-bromo-4-methylpyridin-2-yl)tetrahydrofuran-3-ol

[0790]

[0791] n-BuLi (2.5 M, 1.59 mL) was added dropwise to a solution of 2,6-dibromo-4-methylpyridine (1.0 g, 3.99 mmol) in DCM (10 mL) at -78 °C over 30 minutes. Then, a solution of dihydrofuran-3(2H)-one (343.1 mg, 3.99 mmol) in DCM (5 mL) was slowly added to the mixture at -78 °C. The reaction mixture was heated to 15 °C under N2 for 2 hours. The mixture was concentrated under vacuum, and the crude product was purified by silica gel column chromatography (PE / EtOAc = 10 / 1 to 5 / 1) to give 3-(6-bromo-4-methylpyridin-2-yl)tetrahydrofuran-3-ol (570 mg, 55.4% yield) as a yellow solid. LCMS m / z = 258.0 [M+H] +

[0792] Preparation 124 2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine

[0793]

[0794] Following a similar procedure to that described in Preparation 54, 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine (500 mg, 94.9% yield) was obtained as a brown oil from 3-(6-bromo-4-methylpyridin-2-yl)tetrahydrofuran-3-ol (Preparation 123) and CH3I. LCMS m / z = 272.1 [M+H] +

[0795] Preparation 125 2,6-Dichloro-4-(2-methoxypropoxy)pyridine

[0796]

[0797] Following a similar procedure to that described in preparation 113, 2,6-dichloro-4-(2-methoxypropoxy)pyridine (690 mg, 95.9% yield) was obtained as a yellow oil from 2,6-dichloropyridin-4-ol and 2-methoxyprop-1-ol. 1 H NMR: (500MHz, CDCl3) δppm: 6.81 (s, 2H), 4.00-3.94 (m, 2H), 3.72-3.70 (m, 1H), 3.42 (s, 3H), 1.25 (d, J = 6.5Hz, 3H).

[0798] Preparation 126 2-Chloro-6-(furan-3-yl)-4-(2-methoxypropoxy)pyridine

[0799]

[0800] To a solution of 2,6-dichloro-4-(2-methoxypropoxy)pyridine (preparation 125, 680 mg, 2.88 mmol) in dioxane (10 mL) and H₂O (1 mL), furan-3-ylboronic acid (257.8 mg, 2.30 mmol), K₂CO₃ (796.1 mg, 5.76 mmol), and Pd(dppf)Cl₂ (210.8 mg, 0.288 mmol) were added, and the reaction mixture was stirred at 100 °C for 3 hours under N₂. The mixture was concentrated under vacuum, and the crude product was purified by silica gel column chromatography (PE / EtOAc = 1 / 0 to 20 / 1) to give 2-chloro-6-(furan-3-yl)-4-(2-methoxypropoxy)pyridine (410 mg, 53.2% yield) as a yellow oil. LCMS m / z = 268.1 [M+H] +

[0801] Preparation 127 2,4-Dichloro-6-(1,1-difluoroethyl)pyridine

[0802]

[0803] Following a similar procedure to that described in preparation 117, 2,4-dichloro-6-(1,1-difluoroethyl)pyridine (2.0 g, 75.8% yield) was obtained from 1-(4,6-dichloropyridin-2-yl)acetone and DAST. ¹H NMR: (400 MHz, CDCl₃) δppm: 7.59 (s, ¹H), 7.43 (s, ¹H), 2.00 (t, J = 18.8 Hz, ³H).

[0804] Preparation 128 2-Chloro-4-(2-fluoroprop-2-yl)pyridine

[0805]

[0806] DAST (14.9 g, 92.56 mmol) was added to a solution of 1-(2-chloropyridin-4-yl)ethyl-1-one (4.8 g, 30.85 mmol) in DCM (50 mL), and the resulting mixture was stirred at 25 °C for 16 h. The mixture was quenched with H2O (30 mL) and extracted with DCM (30 mL x 2). The combined organic phases were washed with brine (30 mL x 2), dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1) to give 2-chloro-4-(2-fluoroprop-2-yl)pyridine (4.8 g, 87.6% yield) as a yellow oil. 1 H NMR: (500MHz, CDCl3) δppm: 8.51-8.49 (m, 1H), 7.45 (s, 1H), 7.34-7.32 (m, 1H), 1.96-1.87 (m, 3H).

[0807] Preparation 129 2-Chloro-6-(1,1-difluoroethyl)-4-isopropoxypyridine

[0808]

[0809] A solution of Na (21.7 mg, 0.943 mmol) in i-PrOH (5 mL) was stirred at 50 °C for 2 h, followed by the addition of 2,4-dichloro-6-(1,1-difluoroethyl)pyridine (preparation 127, 200 mg, 0.943 mmol). The mixture was stirred at 60 °C for 18 h, followed by vacuum concentration. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1) to give 2-chloro-6-(1,1-difluoroethyl)-4-isopropoxypyridine (62 mg, 27.9% yield) as a yellow oil. ¹H NMR: (500 MHz, CDCl₃) δppm: 7.05 (s, 1H), 6.82 (s, 1H), 4.68–4.63 (m, 1H), 2.01–1.94 (m, 3H), 1.38 (d, J = 6.0 Hz, 6H).

[0810] Preparation 130 2-(6-bromopyridin-2-yl)prop-2-ol

[0811]

[0812] CH3MgBr (3M, 2.50 mL) was slowly added to a solution of 1-(6-bromopyridin-2-yl)ethyl-1-one (1 g, 5.0 mmol) in THF (10 mL) at 0 °C, and the reaction mixture was stirred under N2 for 12 h. The reaction mixture was concentrated, diluted with H2O (50 mL), and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried over Na2SO4, and filtered. The mixture was concentrated, and the residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give 2-(6-bromopyridin-2-yl)prop-2-ol (910 mg, 84.% yield) as a white oil. 1 H NMR: (400MHz, CDCl3) δppm: 7.57-7.53 (m, 1H), 7.39-7.26 (m, 2H), 4.06 (br s, 1H), 1.54 (s, 6H).

[0813] Preparation 131 2-Bromo-6-(2-Methoxypropyl-2-yl)pyridine

[0814]

[0815] Following the procedure described in Preparation 54, 2-bromo-6-(2-methoxypropyl-2-yl)pyridine (432 mg, 81.1% yield) was obtained as a yellow gel from 2-(6-bromopyridin-2-yl)prop-2-ol (Preparation 130) and CH3I. ¹H NMR: (400 MHz, CDCl3) δppm: 7.55–7.49 (m, 2H), 7.35–7.33 (m, 1H), 3.18 (s, 3H), 1.53 (s, 6H).

[0816] Preparation 132 2-Bromo-6-(2-fluoroprop-2-yl)pyridine

[0817]

[0818] DAST (298.4 mg, 1.85 mmol) was added to a solution of 2-(6-bromopyridin-2-yl)prop-2-ol (preparation 130, 200 mg, 0.926 mmol) in DCM (3.0 mL), and the reaction mixture was stirred at 20 °C for 12 h. The mixture was quenched with an aqueous solution of Na₂CO₃ (20 mL) and extracted with DCM (20 mL x 2). The combined organic phases were washed with brine (20 mL x 2), dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give 2-bromo-6-(2-fluoroprop-2-yl)pyridine (190 mg, 94.1% yield) as a yellow oil. 1 H NMR: (400MHz, CDCl3) δppm: 7.58-7.49 (m, 2H), 7.38 (d, J = 7.6Hz, 1H), 1.73 (s, 3H), 1.67 (s, 3H).

[0819] Preparation 133 2-Chloro-6-(1,1-difluoroethyl)-4-methoxypyridine

[0820]

[0821] MeONa (47.1 mg, 0.871 mmol) was added to a solution of 2,4-dichloro-6-(1,1-difluoroethyl)pyridine (preparation 127, 151 mg, 0.726 mmol) in MeOH (6 mL), and the reaction mixture was stirred at 30 °C for 36 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1) to give 2-chloro-6-(1,1-difluoroethyl)-4-methoxypyridine (40 mg, 27.1% yield) as a yellow oil. ¹H NMR: (400 MHz, CDCl₃) δppm: 7.01 (s, 1H), 6.72 (d, J = 1.6 Hz, 1H), 3.87 (s, 3H), 1.70 (s, 3H), 1.65 (s, 3H).

[0822] Alternative synthesis: DAST (3.7 g, 3.0 mL) was added to a solution of 1-(6-chloro-4-methoxypyridin-2-yl)ethyl-1-one (preparation 134, 328 mg, 1.77 mmol) in DCM (5 mL), and the reaction mixture was stirred at 25 °C for 48 hours. The mixture was concentrated to dryness under vacuum, and the crude product was purified by column chromatography (PE) to give 2-chloro-6-(1,1-difluoroethyl)-4-methoxypyridine (87.0 mg, 23.7% yield) as a colorless oil. 1H NMR: (500MHz, CDCl3) δppm: 7.11 (d, J = 2.0 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 3.91 (s, 3H), 2.03-1.95 (m, 3H).

[0823] Preparation 134 1-(6-chloro-4-methoxypyridin-2-yl)ethyl-1-one

[0824]

[0825] K₂S₂O₈ (3.8 g, 13.9 mmol) was added to a solution of 2-chloro-4-methoxypyridine (1.0 g, 6.97 mmol), 2-oxopropionic acid (613.4 mg, 6.97 mmol), and AgNO₃ (236.6 mg, 1.39 mmol) in DCM (5 mL) and H₂O (5 mL), and the reaction mixture was stirred at 25 °C for 16 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (60 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by column chromatography (PE / EtOAc = 1 / 0 to 8 / 1) to give 1-(6-chloro-4-methoxypyridin-2-yl)ethyl-1-one (86.0 mg, 6.7% yield) as a white solid. LCMS m / z = 186.1 [M+H] +

[0826] Preparation 135 2-Bromo-6-(oxetane-3-yl)pyridine

[0827]

[0828] To a solution of 2,6-dibromopyridine (1 g, 4.22 mmol) and 3-bromooxetane (1.3 g, 8.44 mmol) in DME (20 mL), dtbbpy (113.1 mg, 0.422 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (47.4 mg, 0.042 mmol), LiOH (202.2 mg, 8.44 mmol), NiCl2·glycol dimethyl ether (92.5 mg, 0.422 mmol), and TTMSS (1.1 g, 4.22 mmol) were added, and the mixture was stirred and irradiated with a blue LED at 20 °C under N2 for 12 h. The reaction mixture was concentrated under vacuum, diluted with H2O (20 mL), and extracted with EtOAc (3 x 20 mL). The combined organic phases were washed with brine (2 x 20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give 2-bromo-6-(oxetane-3-yl)pyridine (400 mg, 44.3% yield) as a yellow oil. 1 H NMR: (500MHz, CDCl3) δppm: 7.54 (t, J=8.0Hz, 1H), 7.38 (d, J=8.0Hz, 1H), 7.2 9(d,J=7.5Hz,1H),5.05-5.02(m,2H),4.91-4.89(m,2H),4.38-4.35(m,1H).

[0829] Preparation 136 2-Chloro-6-(furan-3-yl)-4-(2-methoxyethoxy)pyridine

[0830]

[0831] Following the procedure described in preparation 126, 2-chloro-6-(furan-3-yl)-4-(2-methoxyethoxy)pyridine (183 mg, 80.1% yield) was obtained from 2,6-dichloro-4-(2-methoxyethoxy)pyridine as a colorless oil. 1 H NMR: (400MHz, CDCl3) δ: ppm 8.04(d,J=8.0Hz,1H),7.48-7.46(m,1H),6.93-6.88(m,1H),6.81(d,J=6.0Hz, 1H), 6.72 (d, J = 2.0Hz, 1H), 4.24-4.15 (m, 2H), 3.78-3.74 (m, 2H), 3.45 (s, 3H).

[0832] Preparation 137:(1-(6-bromopyridin-2-yl)-2,2,2-trifluoroethyl)tert-butyl carbamate

[0833]

[0834] To a solution of 1-(6-bromopyridin-2-yl)-2,2,2-trifluoroethyl-1-amine (200 mg, 0.784 mmol) in DCM (5 mL), (Boc)₂O (179.7 mg, 0.823 mmol) and TEA (238.1 mg, 2.35 mmol) were added, and the reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (PE / EtOAc = 10 / 1 to 5 / 1) to give tert-butyl 1-(1-(6-bromopyridin-2-yl)-2,2,2-trifluoroethyl)carbamate (80.2 mg, 28.8% yield) as a colorless oil. 1 H NMR: (400MHz, CDCl3) δppm: 7.61-7.57 (m, 1H), 7.52 (d, J = 7.6Hz, 1H), 7.33 (d, J = 7.6Hz, 1H), 6.12-6.10 (m, 1H), 5.42-5.35 (m, 1H), 1.48 (s, 9H).

[0835] Preparation 138 :(1-(6-(6-acetamido-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-2,2,2-trifluoroethyl)tert-butyl carbamate

[0836]

[0837] To a mixture of tert-butyl carbamate (1-(6-bromopyridin-2-yl)-2,2,2-trifluoroethyl)carbamate (preparation 137, 80 mg, 0.225 mmol) and N-(1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (59.5 mg, 0.338 mmol) in dioxane (3 mL), K₂CO₃ (93.4 mg, 0.676 mmol), CuI (8.6 mg, 0.045 mmol), and N,N'-dimethylethane-1,2-diamine (7.9 mg, 0.090 mmol) were added, and the reaction mixture was stirred at 100 °C under N₂ for 12 hours. The mixture was poured into H₂O (15 mL), extracted with EtOAc (10 mL x 3), and the combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give a colorless oily substance (1-(6-(6-acetamido-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-2,2,2-trifluoroethyl) tert-butyl carbamate (66.9 mg, 65.9% yield). 1H NMR: (500MHz, CDCl3) δppm: 9.66 (s, 1H), 8.79 (s, 1H), 8.23 ​​(s, 1H), 8.13 (s, 1H), 8.05 (d, J = 9.0 Hz, 1H), 7.90-7.87 (m, 1H), 6.84 (d, J = 9.5Hz, 1H), 5.60-5.57 (m, 1H), 2.28 (s, 3H), 1.43 (s, 9H).

[0838] Preparation 139 6-Chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine

[0839]

[0840] To a solution of 2-bromo-6-(3-methoxytetrahydrofuran-3-yl)pyridine (preparation 55, 1.0 g, 6.51 mmol) and 6-chloro-1H-pyrazolo[4,3-c]pyridine (1.7 g, 6.51 mmol) in dioxane (40 mL), K₂CO₃ (2.7 g, 19.5 mmol), CuI (248.0 mg, 1.30 mmol), and N,N'-dimethylethane-1,2-diamine (229.6 mg, 2.60 mmol) were added, and the reaction mixture was stirred at 100 °C for 6 hours. The cooled mixture was treated with H₂O (50 mL), extracted with EtOAc (30 mL x 3), and the combined organic phases were washed with brine (80 mL), dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE / EtOAc = 15 / 1 to 3 / 1) to give 6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine as a white solid (1.5 g, 69.6% yield). LCMS m / z = 331.1 [M+H] +

[0841] Preparation 140 2-Chloro-7-(5-(3-methoxytetrahydrofuran-3-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine

[0842]

[0843] N was added to a solution of 3-bromo-5-(3-methoxytetrahydrofuran-3-yl)pyridine (preparation 50, 400 mg, 1.55 mmol) and 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (238.0 mg, 1.55 mmol) in dioxane (5 mL). 1 N 2 Dimethylethane-1,2-diamine (27.3 mg, 0.310 mmol), CuI (118.1 mg, 0.620 mmol), and K2CO3 (428.4 mg, 3.10 mmol) were reacted and stirred at 90 °C under N2 for 2 hours. The cooled mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1 to 1 / 1) to give 2-chloro-7-(5-(3-methoxytetrahydrofuran-3-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (260 mg, 50.7% yield) as a yellow oil. 1H NMR: (400MHz, CDCl3) δppm: 8.94-8.90 (m, 2H), 8.71-8.68 (m, 1H), 8.25-8.22 (m, 1H), 7.57 (d, J = 3.6Hz, 1H), 6. 82(d,J=3.6Hz,1H),4.11-4.19(m,3H),3.98-3.95(m,1H),3.26(s,3H),2.60-2.56(m,1H),2.40-2.35(m,1H).

[0844] Preparation 141 :4-(6-chloro-1-(6-(1,1-difluoroethyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine

[0845]

[0846] Following the procedure described in Preparation 140, 4-(6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine (Preparation 17) and 2-bromo-6-(1,1-difluoroethyl)pyridine were used to obtain 4-(6-chloro-1-(6-(1,1-difluoroethyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine (60 mg, 37.7%) as a white solid. 1 H NMR: (400MHz, CDCl3) δ: ppm 8.86(s,1H),8.65(s,1H),7.96-7.90(m,2H),7.47(d,J=6.8Hz,1H),3.97-3.94(m,4H),3.62-3.59(m,4H),2.12(t,J=18.4Hz,3H).

[0847] Preparation 142 6-Chloro-3-cyclopropyl-1-(6-(1,1-difluoroethyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine

[0848]

[0849] Following the procedure described in preparation 140, 6-chloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine (preparation 16) and 2-bromo-6-(1,1-difluoroethyl)pyridine were used to obtain 6-chloro-3-cyclopropyl-1-(6-(1,1-difluoroethyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine (170 mg, 49.2%) as a white solid. 1H NMR: (400MHz, CDCl3) δppm: 8.88 (s, 1H), 8.58 (s, 1H), 8.02 (d, J = 8.4Hz, 1H), 7.94 (t, J = 7.6H) z, 1H), 7.51 (d, J = 7.6Hz, 1H), 2.33-2.29 (m, 1H), 2.12 (t, J = 18.4Hz, 3H), 1.24-1.19 (m, 4H).

[0850] Preparation 143 :(3S)-1-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidine-3-amine

[0851]

[0852] To a solution of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (500 mg, 1.38 mmol) in DMSO (10 mL), (S)-N,N-dimethylpyrrolidine-3-amine (471.1 mg, 4.13 mmol), K₂CO₃ (570.2 mg, 4.13 mmol), CuI (26.2 mg, 0.138 mmol), and L-proline (15.8 mg, 0.138 mmol) were added, and the reaction mixture was stirred at 100 °C for 20 h. The mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (60 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH = 0 / 1 to 10 / 1) to give (3S)-1-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidine-3-amine (261.0 mg, 54.3% yield) as a yellow solid. LCMS m / z = 350.1 [M+H] +

[0853] Preparation 144 :(3R)-1-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidine-3-amine

[0854]

[0855] To a solution of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (500 mg, 1.38 mmol) in DMSO (10 mL), (R)-N,N-dimethylpyrrolidine-3-amine (314.1 mg, 2.75 mmol), K₂CO₃ (380.1 mg, 2.75 mmol), L-proline (31.7 mg, 0.275 mmol), and CuI (78.6 mg, 0.413 mmol) were added, and the reaction mixture was stirred at 100 °C under N₂ for 16 h. The cooled mixture was quenched with H₂O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (10 mL x 2), dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc = 0 / 1) to give (3R)-1-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidine-3-amine (300 mg, 62.4% yield) as a yellow solid. LCMS m / z = 350.1 [M+H] +

[0856] Preparation 145 (S)-1-(6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidine-3-amine

[0857]

[0858] TFA (1.3 mL) was added to a solution of (3S)-1-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidine-3-amine (preparation 143, 304 mg, 0.869 mmol) in DCM (5 mL), and the mixture was stirred at 25 °C for 5 hours. The mixture was adjusted to pH 7 with NaHCO3 solution and then extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC-L (gradient: 17-47% MeCN) to give (S)-1-(6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidine-3-amine as a white solid (106.2 mg, 46.0% yield). LCMS m / z = 266.1 [M+H] +

[0859] Preparation 146(R)-1-(6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidine-3-amine

[0860]

[0861] A solution of (3R)-1-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidine-3-amine (preparation 144, 260 mg, 0.743 mmol) in HCl / dioxane (4 M, 5 mL) was stirred at 25 °C for 6 hours. The reaction mixture was concentrated to give (R)-1-(6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidine-3-amine (210 mg, crude, HCl salt) as a yellow solid. LCMS m / z = 266.1 [M+H] +

[0862] Preparation 147 (S)-1-(6-chloro-1-(6-(1,1-difluoroethyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidine-3-amine

[0863]

[0864] To a solution of (S)-1-(6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidine-3-amine (preparation 145, 100 mg, 0.376 mmol) in dioxane (5 mL), 2-bromo-6-(1,1-difluoroethyl)pyridine (100.3 mg, 0.452 mmol), Cs₂CO₃ (245.2 mg, 0.753 mmol), and BrettPhos Pd G₃ (34.1 mg, 0.038 mmol) were added, and the reaction mixture was stirred at 100 °C for 1 hour under N₂. The cooled mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL x 3). The combined organic phases were washed with brine (30 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography (PE / EtOAc = 1 / 1) to give (S)-1-(6-chloro-1-(6-(1,1-difluoroethyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidine-3-amine (55.3 mg, 36.1% yield) as a yellow solid. LCMS m / z = 408.7 [M+H] +

[0865] Preparation 148:(R)-1-(6-chloro-1-(6-(1,1-difluoroethyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidine-3-amine

[0866]

[0867] To a solution of (R)-1-(6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidine-3-amine (preparation 146, 190 mg, 0.715 mmol) in dioxane (5 mL), 2-bromo-6-(1,1-difluoroethyl)pyridine (158.8 mg, 0.715 mmol), K3PO4 (303.5 mg, 1.43 mmol), and BrettPhos Pd G3 (64.8 mg, 0.0715 mmol) were added, and the reaction mixture was stirred at 100 °C under N2 for 16 hours. The mixture was concentrated and purified by preparative HPLC-P (gradient: 63 to 92% MeCN) to give (R)-1-(6-chloro-1-(6-(1,1-difluoroethyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidine-3-amine (40 mg, 13.8% yield) as a yellow solid. 1 H NMR: (400MHz, CDCl3) δ: ppm 8.83(s,1H),8.58(s,1H),7.96-7.87(m,2H),7.42(d,J=7.2Hz,1H),3.97-3.93(m,2H),3.77-3.75 (m,1H),3.56-3.51(m,1H),2.95-2.93(m,1H),2.37(s,6H),2.31-2.29(m,1H),2.16-2.04(m,4H).

[0868] Preparation 149 4-(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)morpholine

[0869]

[0870] To a solution of 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine (preparation 28, 300 mg, 0.734 mmol) in DMSO (10 mL), K₂CO₃ (304.3 mg, 2.20 mmol), CuI (28.0 mg, 0.147 mmol), L-proline (33.8 mg, 0.294 mmol), and morpholine (383.7 mg, 4.40 mmol) were added, and the reaction mixture was stirred at 100 °C for 1 hour under microwave irradiation. The cooled reaction mixture was treated with H₂O (30 mL) and extracted with EtOAc (20 mL x 3). The organic phase was washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE / EtOAc = 5 / 1 to 1 / 1) to give 4-(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)morpholine (110 mg, 40.7% yield) as a yellow solid. 1 H NMR: (400MHz, CDCl3) δppm: 8.67(s,1H),7.34(s,1H),6.67(s,1H),5.34(s,2H),3.94 -3.91(m,4H),3.48-3.43(m,2H),3.10-3.07(m,4H),0.91-0.87(m,2H),-0.04(s,9H).

[0871] Preparation 150 4-(6-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl)morpholine

[0872]

[0873] TFA (1 M, 1.0 mL) was added to a solution of 4-(6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)morpholine (preparation 149, 110 mg, 0.299 mmol) in DCM (5 mL), and the reaction mixture was stirred at 25 °C for 16 h. NH3·H2O (10.48 mg, 0.299 mmol) was slowly added, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was treated with H2O (10 mL), extracted with DCM (15 mL x 3), the combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE / EtOAc = 3 / 1 to 0 / 1) to give 4-(6-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl)morpholine (60.0 mg, 84.4% yield) as a yellow solid. LCMS m / z = 238.1 [M+H] +

[0874] Preparation 151 :4-(6-chloro-1-(4-(1,1-difluoroethyl)pyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)morpholine

[0875]

[0876] Cs₂CO₃ (185.1 mg, 0.568 mmol) and BrettPhos Pd G₃ (17.2 mg, 0.019 mmol) were added to a solution of 4-(6-chloro-1H-pyrrolo[3,2-c]pyridin-3-yl)morpholine (preparation 150, 45.0 mg, 0.189 mmol) and 2-chloro-4-(1,1-difluoroethyl)pyridine (33.6 mg, 0.189 mmol) in toluene (5.0 mL), and the reaction mixture was stirred at 100 °C under N₂ for 1 hour. The cooled mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc = 15 / 1 to 5 / 1) to give 4-(6-chloro-1-(4-(1,1-difluoroethyl)pyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)morpholine (32.0 mg, 44.6% yield) as a pale yellow solid. LCMS m / z = 379.1 [M+H] +

[0877] Preparation 152 1-(6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine

[0878]

[0879] BINAP (47.1 mg, 0.076 mmol), Pd(OAc)2 (13.6 mg, 0.060 mmol), and Cs2CO3 (689.5 mg, 2.12 mmol) were added to a solution of 6-chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine (preparation 139, 500 mg, 1.51 mmol) and NH2Boc (159.4 mg, 1.36 mmol) in dioxane (10 mL), and the reaction mixture was stirred at 100 °C for 16 h. The cooled mixture was treated with H2O (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (20 mL), dried over Na₂SO₄, filtered, concentrated, and then purified by silica gel column chromatography (PE / EtOAc = 15 / 1 to 5 / 1) to give 1-(6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine (180 mg, 38.3% yield) as a yellow solid. LCMS m / z = 312.2 [M+H] +

[0880] Preparation 153 :(7-(5-(3-methoxytetrahydrofuran-3-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)tert-butyl carbamate

[0881]

[0882] A mixture of 2-chloro-7-(5-(3-methoxytetrahydrofuran-3-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (preparation 140, 250 mg, 0.756 mmol), NH2Boc (88.5 mg, 0.755 mmol), BINAP (94.1 mg, 0.151 mmol), Pd(OAc)2 (17.0 mg, 0.076 mmol) and Cs2CO3 (492.5 mg, 1.51 mmol) in dioxane (5 mL) was stirred at 110 °C for 2 hours under N2. The cooled reactants were concentrated under reduced pressure and the residue was purified by silica gel chromatography (PE / EtOAc = 1 / 1 to 1 / 2) to give tert-butyl (7-(5-(3-methoxytetrahydrofuran-3-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)carbamate (205 mg, 65.9% yield) as a yellow solid. 1H NMR: (400MHz, CDCl3) δppm: 8.93 (d, J = 2.4Hz, 1H), 8.87-8.85 (m, 2H), 8.68 (s, 1H), 7.55 (d, J = 4.0Hz, 1H), 6.77(d,J=3.6Hz,1H),4.19-4.11(m,3H),4.04-4.02(m,1H),3.24(s,3H),2.62-2.52(m,2H),1.54(s,9H).

[0883] Preparation 154 7-(5-(3-methoxytetrahydrofuran-3-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine

[0884]

[0885] A mixture of (7-(5-(3-methoxytetrahydrofuran-3-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)carbamate tert-butyl (preparation product 153, 205 mg, 0.498 mmol) in HCl / dioxane (4 M, 5 mL) was stirred at 25 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give 7-(5-(3-methoxytetrahydrofuran-3-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine hydrochloride (162 mg, 93.5% yield) as a white solid. LCMS m / z = 312.2 [M+H] +

[0886] Preparation 155 N-(3-(4-methylpiperazin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

[0887]

[0888] A mixture of N-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (preparation 12, 2 g, 5.18 mmol), 1-methylpiperazine (1.6 g, 15.54 mmol), L-proline (119.3 mg, 1.04 mmol), K2CO3 (1.4 g, 10.4 mmol) and CuI (296 mg, 1.55 mmol) in DMSO (20 mL) was stirred at 100 °C under N2 for 16 hours. The mixture was evaporated to dryness and the residue was purified by preparative HPLC-A (gradient = 13-43% MeCN) to give N-(3-(4-methylpiperazin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (1.2 g, 65%) as a yellow solid. LCMS m / z = 359.2 [M+H] + .

[0889] Preparations 156 to 158

[0890] The title compound was prepared from N-(3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (Preparation 12) and a suitable amine using a similar method to that described for Preparation 155.

[0891]

[0892]

[0893] Preparation 159 N-(3-(4-methylpiperazin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

[0894]

[0895] A mixture of N-(3-(4-methylpiperazin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (preparation 155, 1.2 g, 3.35 mmol) in HCl / dioxane (4 M, 10 mL) was stirred at 10 °C for 12 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC-B (gradient = 0-15% MeCN) to give N-(3-(4-methylpiperazin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (400 mg, 43%) as a yellow solid. 1H NMR(500MHz,MeOH-d4)δ:7.98(s,1H),7.60(s,1H),4.18-4.16(m,2H),3.61-3.41(m,6H),2.86(s,3H),2.26(s,3H).

[0896] Preparation 160 N-(3-(pyrrolidone-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

[0897]

[0898] Using a similar method to that described for preparation 159, N-(3-(pyrrolidone-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (157) was prepared as a yellow oil (110 mg, crude product). + .

[0899] Preparation 161 N-(3-(3-cyanozazine-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

[0900]

[0901] TFA (595 mg, 5.22 mmol) was added to a solution of N-(3-(3-cyanozylidene-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (preparation 156, 120 mg, 0.353 mmol) in DCM (2 mL), and the mixture was stirred at 20 °C for 12 hours. The reaction mixture was evaporated to dryness to give N-(3-(3-cyanozylidene-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (150 mg, crude) as a brown oil, which was ready for use without further purification. LCMS m / z = 256.9 [M+H] + .

[0902] Preparation 162 N-(3-(4-methoxypiperidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide trifluoroacetate

[0903]

[0904] Using a similar method to that described for preparation 161, N-(3-(4-methoxypiperidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide trifluoroacetate (318 mg, crude) was prepared as a yellow oil from N-(3-(4-methoxypiperidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (preparation 158). LCMS m / z = 290.2 [M+H] + .

[0905] Preparation 163 3-(2-Chloroprene-4-yl)tetrahydrofuran-3-ol

[0906]

[0907] n-BuLi (2.5 M, 20.9 mL) was added dropwise to a solution of 2,2,6,6-tetramethylpiperidine (7.4 g, 52.39 mmol) in THF (20 mL) at -70 °C. The mixture was stirred at -70 °C for 30 min, and 2-chloropyrimidine (2.0 g, 17.46 mmol) was added dropwise to THF (20.0 mL), and the mixture was stirred at -70 °C for 1 h. Dihydrofuran-3(2H)-one (6.1 g, 69.85 mmol) was slowly added to the mixture, and stirring was continued for 10 min. The temperature was then raised to 0 °C, and the mixture was stirred for 1 h. The mixture was quenched with NH4Cl (saturated, 20 mL) and poured into H2O (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic matter was dried (Na2SO4) and evaporated to dryness under vacuum. The residue was purified by chromatography (SiO2, 25-50% EtOAc / PE) to obtain 3-(2-chloropyrimidin-4-yl)tetrahydrofuran-3-ol (904.6 mg), which was a yellow oil. 1 H NMR(500MHz, CDCl3)δ:7.93(d,1H),7.55(d,1H),4.20-4.16(m,2H),4.03-4.01(m,1H),3.94-3.93(m,1H),2.53-2.49(m,1H),2.28-2.25(m,1H).

[0908] Preparation 164 3-(2-chloropyrimidin-4-yl)oxetane-3-ol

[0909]

[0910] Using a similar method as described for preparation 163, 3-(2-chloropyrimidin-4-yl)oxetane-3-ol (preparation 164) and oxetane-3-one were used to prepare 3-(2-chloropyrimidin-4-yl)oxetane-3-ol (790 mg, 24%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ: 8.73 (d, 1H), 7.87 (d, 1H), 5.02-5.00 (m, 2H), 4.76-4.74 (m, 2H).

[0911] Preparation 165 3-(6-bromopyrimidin-4-yl)tetrahydrofuran-3-ol

[0912]

[0913] n-BuLi (2.5 M, 1.7 mL) was added to a solution of 4,6-dibromopyrimidine (1.0 g, 4.20 mmol) in DCM (10 mL) at -70 °C under N2, and the mixture was stirred for 30 min. Dihydrofuran-3(2H)-one (362 mg, 4.20 mmol) was added to the solution, and the mixture was stirred at -70 °C for 2 h. The mixture was quenched with saturated NH4Cl aqueous solution (3 mL), diluted with water (10 mL), and extracted with DCM (15 mL x 3). The combined organic matter was washed with brine (20 mL) and evaporated to dryness. The residue was purified by silica gel column chromatography (PE / EtOAc = 15 / 1 to 3 / 1) to provide 3-(6-bromopyrimidine-4-yl)tetrahydrofuran-3-ol (305 mg, 30%) as a colorless oil. 1 H NMR(400MHz,MeOH-d4)δ:8.87(s,1H),8.03(s,1H),4.17-4.11(m,2H),4.07-4.04(m,1H),3.88-3.86(m,1H),2.63-2.55(m,1H),2.17-2.12(m,1H).

[0914] Preparation 166 2-Chloro-4-(3-methoxytetrahydrofuran-3-yl)pyrimidine

[0915]

[0916] NaH (360.7 mg, 9.02 mmol, 60% purity) was added to a solution of 3-(2-chloropyrimidin-4-yl)tetrahydrofuran-3-ol (preparation 163, 904.6 mg, 4.51 mmol) in THF (10 mL) at 0 °C and stirred for 10 min. CH3I (960 mg, 6.76 mmol) was added to the mixture and stirring was continued at 25 °C for 12 h. The mixture was quenched with NH4Cl (saturated, 10 mL), poured into H2O (20 mL), and extracted with EtOAc (3 x 20 mL). The combined organic matter was dried (Na2SO4) and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO2, 20-50% EtOAc / PE) to give 2-chloro-4-(3-methoxytetrahydrofuran-3-yl)pyrimidine (356 mg, 37%) as a yellow oil. 1 H NMR(500MHz, CDCl3)δ:8.63(d,1H),7.52(d,1H),4.16-4.10(m,3H),3.98-3.96(m,1H),3.27(s,3H),2.64-2.58(m,1H),2.58-2.35(m,1H).

[0917] Preparation 167 4-Bromo-6-(3-Methoxytetrahydrofuran-3-yl)pyrimidine

[0918]

[0919] Using a similar method as described for preparation 166, 4-bromo-6-(3-methoxytetrahydrofuran-3-yl)pyrimidine (190 mg, 90%) was prepared as a colorless oil from 3-(6-bromopyrimidin-4-yl)tetrahydrofuran-3-ol (preparation 165). 1 HNMR (400MHz, MeOH-d4) δ: 8.90 (s, 1H), 7.90 (d, 1H), 4.13-4.04 (m, 4H), 3.28 (s, 3H), 3.59-3.52 (m, 1H), 2.44-2.41 (m, 1H).

[0920] Preparation 168 2-Chloro-4-(3-fluorotetrahydrofuran-3-yl)pyrimidine

[0921]

[0922] DAST (161 mg, 0.997 mmol) was added to a solution of 3-(2-chloropyrimidin-4-yl)tetrahydrofuran-3-ol (preparation 163, 100 mg, 0.498 mmol) in DCM (5 mL), and the mixture was stirred at 25 °C for 10 hours. The mixture was quenched with NH4Cl aqueous solution (30 mL) and extracted with DCM (3 x 10 mL). The combined organic matter was evaporated to dryness and the residue was purified by column chromatography (SiO2, 20% EtOAc / PE) to give 2-chloro-4-(3-fluorotetrahydrofuran-3-yl)pyrimidine (47.3 mg, 47%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ: 8.71-8.67(m,1H), 7.61-7.59(m,1H), 4.24-4.19(m,3H), 4.18-4.09(m,1H), 2.75-2.63(m,1H), 2.48-2.38(m,1H).

[0923] Preparation 169 2-Chloro-4-(3-Fluoroxyheptan-3-yl)pyrimidine

[0924]

[0925] Using a similar method as described for preparation 168, 2-chloro-4-(3-fluorooxocyclobutane-3-yl)pyrimidine (390 mg, 52%) was prepared as a yellow oil from 3-(2-chloropyrimidin-4-yl)oxetane-3-ol (preparation 164). 1 HNMR (400MHz, CDCl3) δ: 8.70 (d, 1H), 7.48 (d, 1H), 5.15-5.07 (m, 2H), 5.03-4.95 (m, 2H).

[0926] Preparation 170 2-Chloro-4-(furan-3-yl)pyrimidine

[0927]

[0928] A mixture of 2,4-dichloropyrimidine (2.0 g, 13.42 mmol), furan-3-ylboronic acid (1.5 g, 13.42 mmol), Pd(dppf)Cl2 (982.3 mg, 1.34 mmol), and K2CO3 (3.7 g, 26.85 mmol) in dioxane (25 mL) and H2O (5 mL) was stirred at 100 °C for 2 hours under N2. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give 2-chloro-4-(furan-3-yl)pyrimidine (700 mg, 29%) as a yellow oil.1 H NMR (400MHz, CDCl3) δ: 8.55 (d, 1H), 8.22 (s, 1H), 7.55-7.52 (m, 1H), 7.31 (d, 1H), 6.90 (s, 1H).

[0929] Preparation 171 N-(3-cyclopropyl-1-(4-(furan-3-yl)pyrimidin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

[0930]

[0931] A mixture of 2-chloro-4-(furan-3-yl)pyrimidine (preparation 170, 100 mg, 0.554 mmol), N-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (preparation 11, 120 mg, 0.554 mmol), and Cs₂CO₃ (360.8 mg, 1.11 mmol) in DMF (5 mL) was stirred at 60 °C for 2 hours. The mixture was concentrated and the residue was purified by silica gel chromatography (PE / EtOAc = 1 / 1) to give N-(3-cyclopropyl-1-(4-(furan-3-yl)pyrimidine-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (70 mg, 35%) as a yellow solid. 1 HNMR(400MHz,CDCl3)δ:9.65(s,1H),8.87(br s,1H),8.80-8.77(m,2H),8.72(s,1H),7.62(s,1H),7.28(s,1H),7.18(s, 1H),2.41-2.36(m,1H),2.33(s,3H),1.33-1.31(m,2H),1.22-1.19(m,2H).

[0932] Preparation 172 1-(3-chloropyrazin-2-yl)ethyl-1-one

[0933]

[0934] K₂S₂O₈ (11.8 g, 43.66 mmol) and AgNO₃ (860.2 mg, 5.06 mmol) were added to a solution of 2-chloropyrazine (1.0 g, 8.73 mmol) and 2-oxopropionic acid (768.9 mg, 8.73 mmol) in DCM (10 mL) and H₂O (10 mL) at 25 °C, and the mixture was stirred at 25 °C for 16 hours. The mixture was filtered, and the filtrate was treated with H₂O (20 mL) and extracted with DCM (3 x 15 mL). The combined organic matter was washed with brine (20 mL), dried (Na₂SO₄), and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO₂, 6-50% EtOAc / PE) to give 1-(3-chloropyrazin-2-yl)ethyl-1-one (150 mg, 11%) as a pale yellow solid. 1 H NMR (500MHz, CDCl3) δ: 8.56 (d, 1H), 8.51 (d, 1H), 2.71 (s, 3H).

[0935] Preparation 173 2-Chloro-3-(1,1-difluoroethyl)pyrazine

[0936]

[0937] DAST (154.4 mg, 0.958 mmol) was added to a solution of 1-(3-chloropyrazin-2-yl)ethyl-1-one (preparation 172, 150 mg, 0.958 mmol) in DCM (5 mL) at 25 °C, and the mixture was stirred at 25 °C for 24 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (25% EtOAc / PE) to give 2-chloro-3-(1,1-difluoroethyl)pyrazine (34 mg, 20%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ: 8.51 (d, 1H), 8.48 (d, 1H), 2.15-2.07 (m, 3H).

[0938] Preparation 174 6-Chloro-N-methoxy-N-methylpyrazine-2-carboxamide

[0939]

[0940] Add (COCl)₂ (4.8 g, 37.84 mmol, 3.20 mL) and DMF (0.2 mL) to a solution of 6-chloropyrazine-2-carboxylic acid (5.0 g, 31.5 mmol) in DCM (50 mL), and stir the mixture at 10 °C for 12 hours. Add N,O-dimethylhydroxylamine hydrochloride (4.0 g, 41 mmol) to the mixture, followed by dropwise addition of TEA (9.6 g, 94.6 mmol). Stir the resulting mixture at 10 °C for 2 hours, dilute with H₂O (20 mL), and extract with DCM (3 x 20 mL). Wash the combined organic matter with brine (2 x 20 mL), dry (Na₂SO₄), and evaporate to dryness under vacuum. The residue was purified by column chromatography (SiO2, 25% EtOAc / PE) to obtain 6-chloro-N-methoxy-N-methylpyrazine-2-carboxamide (3.2 g, 50%), which was a yellow oil. 1 HNMR (500MHz, CDCl3) δ: 8.78 (br s, 1H), 8.67 (s, 1H), 3.78 (s, 3H), 3.38 (s, 3H).

[0941] Preparation 175 1-(6-chloropyrazin-2-yl)ethyl-1-one

[0942]

[0943] MeMgBr (3M, 5.29 mL) was added dropwise to a solution of 6-chloro-N-methoxy-N-methylpyrazine-2-carboxamide (preparation 174, 3.2 g, 15.9 mmol) in THF (30 mL) at 0 °C under N2. The resulting mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was quenched with NH4Cl (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic matter was washed with brine (2 x 15 mL), dried (Na2SO4), and evaporated to dryness under vacuum. The residue was purified by chromatography (SiO2, 25% EtOAc / PE) to give 1-(6-chloropyrazine-2-yl)ethyl-1-one (1.2 g, 48%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ: 9.10 (s, 1H), 8.77 (s, 1H), 2.70 (s, 3H).

[0944] Preparation 176 2-Chloro-6-(1,1-difluoroethyl)pyrazine

[0945]

[0946] DAST (2.5 g, 15.33 mmol) was added to a solution of 1-(6-chloropyrazin-2-yl)ethyl-1-one (preparation 175, 1.2 g, 7.66 mmol) in DCM (10 mL), and the resulting mixture was stirred at 10 °C for 12 h. The mixture was quenched with H2O (10 mL) and extracted with DCM (2 x 15 mL). The combined organic matter was washed with brine (2 x 10 mL), dried (Na2SO4), and evaporated to dryness under vacuum. The residue was purified by chromatography (SiO2, 16% EtOAc / PE) to give 2-chloro-6-(1,1-difluoroethyl)pyrazine (420 mg, 31%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ: 8.84 (s, 1H), 8.70 (s, 1H), 2.04 (t, 3H).

[0947] Preparation 177 1-(2-Chloropremine-4-yl)ethyl-1-one

[0948]

[0949] K₂S₂O₈ (4.7 g, 17.46 mmol) was added to a solution of 2-chloropyrimidine (1 g, 8.73 mmol), 2-oxopropionic acid (769 mg, 8.73 mmol), and AgNO₃ (297 mg, 1.75 mmol) in DCM (5 mL) and H₂O (5 mL), and the resulting mixture was stirred at 30 °C for 16 h. The mixture was extracted with DCM (3 x 10 mL), and the combined organic matter was washed with brine (2 x 10 mL), dried (Na₂SO₄), and evaporated to dryness under vacuum. The residue was purified by column chromatography (SiO₂, 16-25% EtOAc / PE) to provide 1-(2-chloropyrimidin-4-yl)ethyl-1-one (70 mg, 5%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ: 8.86 (d, 1H), 7.84 (d, 1H), 2.72 (s, 3H).

[0950] Preparation 178 2-Chloro-4-(1,1-difluoroethyl)pyrimidine

[0951]

[0952] Using a similar method as described for preparation 176, 2-chloro-4-(1,1-difluoroethyl)pyrimidine (40 mg, 70%) was prepared as a yellow oil from 1-(2-chloropyrimidin-4-yl)ethyl-1-one (preparation 177). 1H NMR (500MHz, CDCl3) δ: 8.82-8.76 (m, 1H), 7.61-7.54 (m, 1H), 2.00 (t, J = 19.0Hz, 3H).

[0953] Preparation 179 1-(2-chloro-6-methylpyrimidin-4-yl)ethyl-1-one

[0954]

[0955] MeMgBr (3M, 1.76 mL) was added to a solution of methyl 2-chloro-6-methylpyrimidin-4-carboxylate (985 mg, 5.28 mmol) in THF (10 mL) under a nitrogen atmosphere at 0 °C and stirred for 5 hours. The reaction mixture was quenched with H2O (30 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic matter was dried (Na2SO4), evaporated to dryness, and the residue was purified by silica gel chromatography (16% EtOAc / PE) (PE / ethyl acetate = 5 / 1) to give 1-(2-chloro-6-methylpyrimidin-4-yl)ethyl-1-one (147 mg, 16%) as a white solid. 1 H NMR (400MHz, CDCl3) δ: 7.69 (s, 1H), 2.70 (s, 3H), 2.63 (s, 3H).

[0956] Preparation 180 2-Chloro-4-(1,1-difluoroethyl)-6-methylpyrimidine

[0957]

[0958] Using a similar method to that described for preparation 176, 2-chloro-4-(1,1-difluoroethyl)-6-methylpyrimidine, which is a yellow oil, was prepared from 1-(2-chloro-6-methylpyrimidin-4-yl)ethyl-1-one (preparation 179).

[0959] Preparation 181 1-(4-(benzyloxy)pyrimidin-2-yl)ethyl-1-one

[0960]

[0961] CH3MgBr (3M, 2.05 mL) was added dropwise to a solution of methyl 4-(benzyloxy)pyrimidin-2-carboxylate (1.5 g, 6.14 mmol) in THF (20 mL) at 0 °C. The mixture was stirred for 1 hour, and then stirred at 25 °C under N2 for 12 hours. The mixture was quenched with NH4Cl (20 mL saturated), poured into H2O (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic matter was dried (Na2SO4) and evaporated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give a colorless oily 1-(4-(benzyloxy)pyrimidin-2-yl)ethyl-1-one (288 mg, 21%). 1 HNMR (400MHz, CDCl3) δ: 8.61 (d, 1H), 7.49-7.35 (m, 5H), 6.90 (d, 1H), 5.52 (s, 2H), 2.75 (s, 3H).

[0962] Preparation 182 4-(benzyloxy)-2-(1,1-difluoroethyl)pyrimidine

[0963]

[0964] DAST (904 mg, 5.61 mmol) was added to a solution of 1-(4-(benzyloxy)pyrimidin-2-yl)ethyl-1-one (preparation 181, 640 mg, 2.80 mmol) in DCM (5 mL) at 0 °C, and the resulting mixture was stirred at 25 °C for 12 hours. The mixture was quenched with Na2CO3 (10 mL), poured into H2O (20 mL), and extracted with EtOAc (2 x 20 mL). The combined organic matter was washed with brine (2 x 15 mL), dried (Na2SO4), and evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give 4-(benzyloxy)-2-(1,1-difluoroethyl)pyrimidine (537 mg, 76%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ: 8.52 (d, 1H), 7.48-7.35 (m, 5H), 6.81 (d, 1H), 5.48 (s, 2H), 2.03 (t, 3H).

[0965] Preparation 183 2-(1,1-difluoroethyl)pyrimidin-4-ol

[0966]

[0967] A solution of 4-(benzyloxy)-2-(1,1-difluoroethyl)pyrimidine (preparation 182,537.1 mg, 2.15 mmol) in TFA (4.47 g, 39.2 mmol) was stirred at 100 °C for 12 hours. The mixture was purified by preparative HPLC-D (0-20% MeCN) to give 2-(1,1-difluoroethyl)pyrimidine-4-ol (230 mg, 67%) as a white solid. 1 H NMR (400MHz, CDCl3) δ: 7.99 (d, 1H), 6.55 (d, 1H), 2.03 (t, 3H).

[0968] Preparation 184 4-Chloro-2-(1,1-difluoroethyl)pyrimidine

[0969]

[0970] A solution of 2-(1,1-difluoroethyl)pyrimidin-4-ol (preparation 183, 100 mg, 0.625 mmol) in POCl3 (2 mL) was stirred at 100 °C for 2 hours. The reaction mixture was concentrated and added to H2O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic matter was dried (Na2SO4) and concentrated to give 4-chloro-2-(1,1-difluoroethyl)pyrimidin (85 mg, 76%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ: 8.74 (d, 1H), 7.44 (d, 1H), 2.07 (t, 3H).

[0971] Preparation 185 2-(4-(benzyloxy)pyrimidin-2-yl)prop-2-ol

[0972]

[0973] CH3MgBr (3M, 2.05 mL) was added dropwise to a solution of methyl 4-(benzyloxy)pyrimidin-2-carboxylate (1.5 g, 6.14 mmol) in THF (20 mL) at 0 °C. The mixture was stirred for 1 hour, then heated to 25 °C under N2 for 12 hours. The mixture was quenched with NH4Cl (20 mL saturated), poured into H2O (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic matter was dried (Na2SO4) and evaporated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give 2-(4-(benzyloxy)pyrimidin-2-yl)prop-2-ol (358 mg, 24%) as a white solid. 1H NMR (400MHz, CDCl3) δ: 8.40 (d, 1H), 7.46-7.34 (m, 5H), 6.65 (d, 1H), 5.44 (s, 2H), 4.68 (s, 1H), 1.56 (s, 6H).

[0974] Preparation 186 4-(benzyloxy)-2-(2-fluoroprop-2-yl)pyrimidine

[0975]

[0976] Following a similar procedure as described in preparation 182, 4-(benzyloxy)-2-(2-fluoroprop-2-yl)pyrimidine (556 mg, 79%) was obtained as a yellow oil from 2-(4-(benzyloxy)pyrimidin-2-yl)prop-2-ol (preparation 185). 1 HNMR (500MHz, CDCl3) δ: 8.48-8.46 (m, 1H), 7.46-7.33 (m, 5H), 6.67 (d, 1H), 5.45 (s, 2H), 1.79 (s, 3H), 1.74 (s, 3H).

[0977] Preparation 187 2-(2-fluoroprop-2-yl)pyrimidin-4-ol

[0978]

[0979] A solution of 4-(benzyloxy)-2-(2-fluoropropionic-2-yl)pyrimidine (preparation 186, 556 mg, 2.26 mmol) in TFA (4.47 g, 39.2 mmol) was stirred at 100 °C for 12 hours. The mixture was purified by preparative HPLC-E (0-30% MeCN) to give 2-(2-fluoropropionic-2-yl)pyrimidine-4-ol (258 mg, 73%) as a white solid. 1 H NMR (500MHz, CDCl3) δ: 7.91 (d, 1H), 6.36 (d, 1H), 1.76 (s, 3H), 1.71 (s, 3H).

[0980] Preparation 188 4-Chloro-2-(2-fluoroprop-2-yl)pyrimidine

[0981]

[0982] A solution of 2-(2-fluoroprop-2-yl)pyrimidin-4-ol (preparation 187, 100 mg, 0.64 mmol) in POCl3 (2 mL) was stirred at 100 °C for 2 hours. The mixture was concentrated and added to H2O (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic matter was dried over anhydrous Na2SO4, filtered, and concentrated to give 4-chloro-2-(2-fluoroprop-2-yl)pyrimidin (82 mg, 73%) as a colorless oil. 1 H NMR (500MHz, CDCl3) δ: 8.66 (d, 1H), 7.29 (d, 1H), 1.81 (s, 3H), 1.77 (s, 3H).

[0983] Preparation 189 4,6-Dichloro-2-(1,1-difluoroethyl)pyrimidine

[0984]

[0985] Part 1: Na (1.1 g, 48.27 mmol) in EtOH (20 mL) was stirred at 60 °C for 2 hours. Ethyl 2,2-difluoropropionate (5 g, 36.20 mmol) and malonamide (2.46 g, 24.13 mmol) were added to the solution, and the resulting mixture was stirred at 100 °C for 12 hours. The mixture was concentrated, and the residue was diluted with H₂O (10 mL) and extracted with EtOAc (20 mL x 2). The pH of the aqueous phase was adjusted to 1–3 with aqueous HCl solution, and the mixture was concentrated under reduced pressure to give 2-(1,1-difluoroethyl)pyrimidine-4,6-diol (3 g) as a yellow solid, which was ready for use without further purification. 1 ¹H NMR (500MHz, MeOH-d⁴) δ: 5.71 (s, 1H), 1.69 (t, 3H). Part 2: A mixture of 2-(1,1-difluoroethyl)pyrimidine-4,6-diol (Part 1, 3.0 g, 17.03 mmol) in POCl₃ (24.7 g, 161 mmol) was stirred at 80 °C for 3 h. The mixture was poured into H₂O (40 mL) and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (20 mL x 2), dried (Na₂SO₄), and evaporated to dryness. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1) to give 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine (1.0 g, 28%) as a colorless oil. 1 H NMR (500MHz, CDCl3) δ: 7.49 (s, 1H), 2.05 (t, 3H).

[0986] Preparation 1904-Chloro-2-(1,1-difluoroethyl)-6-methoxypyrimidine

[0987]

[0988] MeONa (101.5 mg, 1.88 mmol) was added to a solution of 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine (preparation 189, 400 mg, 1.88 mmol) in MeOH (5 mL), and the resulting mixture was stirred at 15 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1) to give 4-chloro-2-(1,1-difluoroethyl)-6-methoxypyrimidine (300 mg, 77%) as a colorless oil. 1 H NMR (500MHz, CDCl3) δ: 6.81 (s, 1H), 4.05 (s, 3H), 2.02 (t, 3H).

[0989] Preparation 191 3-(4-chloropyrimidin-2-yl)oxetane-3-ol

[0990]

[0991] n-BuLi (2.5 M, 2.17 mL) was added dropwise to a solution of 2-bromo-4-chloropyrimidine (1.0 g, 5.17 mmol) in toluene (10 mL) at -70 °C under N2 for 30 minutes. Oxycyclic butane-3-one (410 mg, 5.69 mmol) was slowly added to the mixture, and the resulting mixture was heated to room temperature and stirred for 3 hours. The mixture was quenched with H2O (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (10 mL x 2), dried (Na2SO4), and evaporated to dryness under vacuum. The residue was purified by silica gel chromatography (50–100% EtOAc / PE) to give 3-(4-chloropyrimidin-2-yl)oxycyclic butane-3-ol (320 mg, 33%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ: 8.71 (d, 1H), 7.36 (d, 1H), 5.04-5.02 (m, 2H), 4.99-4.97 (m, 1H).

[0992] Preparation 192 3-(4-chloropyrimidin-2-yl)tetrahydrofuran-3-ol

[0993]

[0994] Using a similar method to that described for preparation 191, 3-(4-chloropyrimidin-2-yl)tetrahydrofuran-3-ol (653 mg, 35%), a brown oily substance, was prepared from 2-bromo-4-chloropyrimidin and dihydrofuran-3(2H)-one. 1 H NMR (400MHz, CDCl3) δ: 8.63 (d, 1H), 7.30 (d, 1H), 4.61 (s, 1H), 4.22-4.16 (m, 3H), 3.98-3.96 (m, 1H), 2.67-2.59 (m, 1H), 2.26-2.22 (m, 1H).

[0995] Preparation 193 4-Chloro-2-(3-Fluoroxyheptan-3-yl)pyrimidine

[0996]

[0997] Following a similar procedure as described in preparation 176, 4-chloro-2-(3-fluorooxetane-3-yl)pyrimidine (60 mg, 19%) was obtained as a yellow oil from 3-(4-chloropyrimidin-2-yl)oxetane-3-ol (preparation 191). 1 HNMR (500MHz, CDCl3) δ: 8.73 (d, 1H), 7.39 (d, 1H), 5.21-5.19 (m, 1H), 5.16-5.15 (m, 1H), 5.14-5.11 (m, 1H), 5.10-5.07 (m, 1H).

[0998] Preparation 194 4-Chloro-2-(3-fluorotetrahydrofuran-3-yl)pyrimidine

[0999]

[1000] Using a similar method as described for preparation 176, 4-chloro-2-(3-fluorotetrahydrofuran-3-yl)pyrimidine (143 mg, 46%) was prepared as a yellow oil from 3-(4-chloropyrimidin-2-yl)tetrahydrofuran-3-ol (preparation 192). 1 H NMR (500MHz, CDCl3) δ: 8.67 (d, 1H), 7.33 (d, 1H), 4.35-4.18 (m, 4H), 2.77-2.72 (m, 1H), 2.71-2.57 (m, 1H).

[1001] Preparation 195 4-(benzyloxy)-2-(2-methoxypropyl-2-yl)pyrimidine

[1002]

[1003] A solution of 2-(4-(benzyloxy)pyrimidin-2-yl)prop-2-ol (preparation 185, 1.6 g, 6.43 mmol) and NaH (514 mg, 12.85 mmol, 60% purity) in THF (10 mL) was stirred at 25 °C for 30 min. Then, MeI (1.8 g, 12.85 mmol) was added and the mixture was stirred at 25 °C for 12 h. The mixture was quenched with H₂O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic matter was evaporated to dryness under vacuum, and the residue was purified by silica gel chromatography (PE / EtOAc = 2 / 1) to give 4-(benzyloxy)-2-(2-methoxyprop-2-yl)pyrimidine (1.4 g, 82%) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ: 8.48-8.44(m,1H),7.46(d,2H),7.39-7.33(m,3H),6.64(d,1H),5.45(s,2H),3.19(s,3H),1.61(s,3H).

[1004] Preparation 196 2-(2-Methoxypropyl-2-yl)pyrimidin-4-ol

[1005]

[1006] A solution of 4-(benzyloxy)-2-(2-methoxypropyl-2-yl)pyrimidine (preparation 195, 1.3 g, 4.92 mmol) in TFA (10 mL) was stirred at 100 °C for 10 hours. The mixture was concentrated under vacuum and purified by silica gel chromatography (PE / EtOAc = 1 / 2) to give 2-(2-methoxypropyl-2-yl)pyrimidine-4-ol (1.1 g, 138%) as a gray solid. 1 H NMR (400MHz, CDCl3) δ: 7.94 (d, 1H), 6.35 (d, 1H), 3.32 (s, 3H), 1.53 (s, 6H).

[1007] Preparation 197 4-Chloro-2-(2-Methoxypropyl-2-yl)pyrimidine

[1008]

[1009] A solution of 2-(2-methoxypropyl-2-yl)pyrimidin-4-ol (preparation 196, 0.2 g, 1.19 mmol) in POCl3 (4 mL) was stirred at 100 °C for 12 hours. The mixture was added to H2O (30 mL) and extracted with DCM (20 mL x 3). The combined organic matter was dried (Na2SO4) and evaporated to dryness under vacuum to give 4-chloro-2-(2-methoxypropyl-2-yl)pyrimidin (90 mg, 41%) as a yellow oil, which was ready for use without further purification.

[1010] Preparation 198 S-methyl dithiocarbonate O-(3-(4-chloropyrimidin-2-yl)tetrahydrofuran-3-yl) ester

[1011]

[1012] To a solution of 3-(4-chloropyrimidin-2-yl)tetrahydrofuran-3-ol (preparation 192, 600 mg, 2.99 mmol) in THF (8 mL), NaH (359 mg, 8.97 mmol, 60% purity) was added, and the mixture was stirred for 30 min. CS2 (227.7 mg, 2.99 mmol) was added and stirred for 30 min, followed by CH3I (424.5 mg, 2.99 mmol), and the resulting mixture was stirred at 50 °C for 2 h. The mixture was quenched with H2O (20 mL) and extracted with EtOAc (20 mL x 3). The organic phase was washed with brine (20 mL), dried (Na2SO4), and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 20 / 1 to 3 / 1) to give S-methyl dithiocarbonate O-(3-(4-chloropyrimidin-2-yl)tetrahydrofuran-3-yl) ester (120.7 mg, 14%) as a colorless oil. 1 H NMR(400MHz, CDCl3)δ:8.57(d,1H),7.20(d,1H),4.57-4.55(m,1H),4.48-4.45 (m,1H),4.14-4.10(m,2H),2.90-2.85(m,1H),2.82-2.77(m,1H),2.54(s,3H).

[1013] Preparation 199 S-methyl dithiocarbonate O-(3-(4-chloropyrimidin-2-yl)oxetane-3-yl) ester

[1014]

[1015] Using a similar method as described for preparation 198, S-methyl dithiocarbonate O-(3-(4-chloropyrimidin-2-yl)oxetane-3-ol (preparation 191) was prepared as a yellow oil (450 mg, 38%). 1 H NMR (400MHz, CDCl3) δ: 8.55 (d, 1H), 7.21 (d, 1H), 5.20-5.18 (m, 2H), 5.13-5.11 (m, 2H), 2.59 (s, 3H).

[1016] Preparation 200 4-Chloro-2-(tetrahydrofuran-3-yl)pyrimidine

[1017]

[1018] AIBN (6.8 mg, 0.041 mmol) and tributyltin (240.2 mg, 0.825 mmol) were added to a solution of S-methyl dithiocarbonate O-(3-(4-chloropyrimidin-2-yl)tetrahydrofuran-3-yl) ester (preparation 198, 120 mg, 0.413 mmol) in toluene (3 mL), and the resulting mixture was stirred at 125 °C for 1 hour under N2. The mixture was quenched with KF aqueous solution (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic matter was washed with brine (10 mL), dried (Na2SO4), and evaporated to dryness under vacuum. The residue was concentrated and purified by silica gel chromatography (PE / EtOAc = 20 / 1 to 3 / 1) to give 4-chloro-2-(tetrahydrofuran-3-yl)pyrimidine (52.5 mg, 69%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ: 8.56 (d, 1H), 7.21 (d, 1H), 4.24-4.19 (m, 1H), 4.07-4.03 (m, 2H), 3.96-3.94 (m, 1H), 3.76-3.74 (m, 1H), 2.41-2.35 (m, 2H).

[1019] Preparation 201 4-Chloro-2-(oxetane-3-yl)pyrimidine

[1020]

[1021] Using a similar method to that described for preparation 200, 4-chloro-2-(oxetane-3-yl)pyrimidine (105 mg, 38%) was prepared as a yellow oil from S-methyl dithiocarbonate O-(3-(4-chloropyrimidin-2-yl)oxetane-3-yl) ester (preparation 199). 1H NMR (400MHz, CDCl3) δ: 8.63 (d, 1H), 7.27-7.26 (m, 1H), 5.07-5.01 (m, 4H), 4.52-4.46 (m, 1H).

[1022] Preparation 202 2-(4,6-Dichloropyrimidin-2-yl)prop-2-ol

[1023]

[1024] n-BuLi (2.5 M, 1.46 mL) was added to a solution of 4,6-dichloro-2-iodopyrimidine (1 g, 3.64 mmol) in toluene (10 mL) at -78 °C under N2 for 30 minutes, followed by slow addition of acetone (211 mg, 3.64 mmol). The resulting mixture was heated to room temperature for 2 hours. The reaction mixture was quenched with NH4Cl (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic compounds were washed with brine (10 mL x 2), dried (Na2SO4), and evaporated to dryness under vacuum. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to give 2-(4,6-dichloropyrimidin-2-yl)prop-2-ol (500 mg, 66%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ: 7.30 (s, 1H), 3.92 (br s, 1H), 1.59 (s, 6H).

[1025] Preparation 203 3-(4,6-Dichloropyrimidin-2-yl)oxecyclobutane-3-ol

[1026]

[1027] Using a similar method to that described for preparation 202, 3-(4,6-dichloropyrimidin-2-yl)oxetane-3-ol (380 mg, 47%) was prepared as a yellow solid from 4,6-dichloro-2-iodopyrimidine and oxetane-3-one. 1 H NMR (500MHz, CDCl3) δ: 7.40 (s, 1H), 5.03 (d, 2H), 4.94 (d, 2H), 4.60 (br s, 1H).

[1028] Preparation 204 3-(4,6-Dichloropyrimidin-2-yl)tetrahydrofuran-3-ol

[1029]

[1030] Using a similar method to that described for preparation 202, 3-(4,6-dichloropyrimidin-2-yl)tetrahydrofuran-3-ol (1.72 g, 50%), which is a yellow oil, was prepared from 4,6-dichloro-2-iodopyrimidine and dihydrofuran-3(2H)-one. 1 HNMR (400MHz, CDCl3) δ: 7.34 (s, 1H), 4.24-4.15 (m, 4H), 3.98-3.96 (m, 1H), 2.64-2.59 (m, 1H), 2.26-2.22 (m, 1H).

[1031] Preparation 205 3-(4-chloro-6-methoxypyrimidin-2-yl)tetrahydrofuran-3-ol

[1032]

[1033] To a solution of 3-(4,6-dichloropyrimidin-2-yl)tetrahydrofuran-3-ol (preparation 204, 1.6 g, 6.81 mmol) in MeOH (20 mL), NaOMe (735 mg, 13.61 mmol) was added, and the resulting mixture was stirred at 20 °C for 3 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography (PE / EtOAc = 20 / 1 to 3 / 1) to give 3-(4-chloro-6-methoxypyrimidin-2-yl)tetrahydrofuran-3-ol (1.3 g, 82%) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ: 6.68 (s, 1H), 4.56 (s, 1H), 4.21-4.15 (m, 3H), 4.02 (s, 3H), 3.96-3.94 (m, 1H), 2.64-2.56 (m, 1H), 2.22-2.17 (m, 1H).

[1034] Preparation 206 4,6-Dichloro-2-(2-fluoroprop-2-yl)pyrimidine

[1035]

[1036] Following a similar procedure as described in preparation 176, 4,6-dichloro-2-(2-fluoroprop-2-yl)pyrimidine (350 mg, 69%) was obtained as a yellow oil from 2-(4,6-dichloropyrimidin-2-yl)prop-2-ol (preparation 202). 1 H NMR (500MHz, CDCl3) δ: 7.34 (s, 1H), 1.80 (s, 3H), 1.75 (s, 3H).

[1037] Preparation 2074,6-Dichloro-2-(3-fluorooxetane-3-yl)pyrimidine

[1038]

[1039] Following a similar procedure to that described in Preparation 176, 4,6-dichloro-2-(3-fluorooxocyclobutane-3-yl)pyrimidine (350 mg, 91%) was prepared as a yellow oil from 3-(4,6-dichloropyrimidin-2-yl)oxetane-3-ol (Preparation 203). 1 H NMR: (400MHz, CDCl3) δ: ppm 7.44 (s, 1H), 5.20-5.17 (m, 1H), 5.14-5.12 (m, 1H), 5.09-5.07 (m, 1H), 5.04-5.02 (m, 1H).

[1040] Preparation 208 4-Chloro-2-(2-fluoroprop-2-yl)-6-methoxypyrimidine

[1041]

[1042] To a solution of 4,6-dichloro-2-(2-fluoroprop-2-yl)pyrimidine (preparation 206, 350 mg, 1.67 mmol) in MeOH (5 mL), NaOMe (90.5 mg, 1.67 mmol) was added, and the resulting mixture was stirred at 10 °C for 12 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1) to give 4-chloro-2-(2-fluoroprop-2-yl)-6-methoxypyrimidine (280 mg, 82%) as a yellow oil. 1 H NMR (500MHz, CDCl3) δ: 6.59 (s, 1H), 3.93 (s, 3H), 1.69 (t, 6H).

[1043] Preparation 209 4-Chloro-2-(3-fluorooxetane-3-yl)-6-methoxypyrimidine

[1044]

[1045] Using a similar method as described for preparation 208, 4,6-dichloro-2-(3-fluorooxetane-3-yl)pyrimidine (preparation 207) was used to prepare 4-chloro-2-(3-fluorooxetane-3-yl)-6-methoxypyrimidine as a white solid (260 mg, 76%). 1H NMR (400MHz, CDCl3) δ: 6.75 (s, 1H), 5.20-5.13 (m, 2H), 5.07-4.99 (m, 2H), 4.04 (s, 3H).

[1046] Preparation 210 4-Chloro-2-(3-fluorotetrahydrofuran-3-yl)-6-methoxypyrimidine

[1047]

[1048] Using a similar method to that described for preparation 176, 4-chloro-2-(3-fluorotetrahydrofuran-3-yl)-6-methoxypyrimidine (141 mg, 70%) was prepared as a colorless oil from 3-(4-chloro-6-methoxypyrimidin-2-yl)tetrahydrofuran-3-ol (preparation 205). 1 H NMR (500MHz, CDCl3) δ: 6.71 (s, 1H), 4.32-4.15 (m, 4H), 4.02 (s, 3H), 2.74-2.69 (m, 1H), 2.67-2.53 (m, 1H).

[1049] Preparation 211 4-Chloro-6-(1-ethoxyvinyl)-2-methylpyrimidine

[1050]

[1051] Pd(PPh3)4 (1.77 g, 1.53 mmol) was added to a solution of 4,6-dichloro-2-methylpyrimidine (5 g, 30.67 mmol) and tributyl(1-ethoxyvinyl)stanane (11.08 g, 30.67 mmol) in DMF (40 mL) under N2 conditions, and the mixture was stirred at 120 °C for 12 h. The mixture was quenched with KF solution (20 mL) and extracted with DCM (40 mL x 3). The combined organic matter was washed (with brine), dried (with Na2SO4), and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 1 / 0 to 19 / 1) to give 4-chloro-6-(1-ethoxyvinyl)-2-methylpyrimidine (2.9 g, 48%) as a colorless oil. 1 H NMR (500MHz, CDCl3) δ: 7.47 (s, 1H), 5.69 (d, 1H), 4.53 (d, J = 2.5Hz, 1H), 3.96 (q, 2H), 2.70 (s, 3H), 1.44 (t, 3H).

[1052] Preparation 212 1-(6-chloro-2-methylpyrimidin-4-yl)ethyl-1-one

[1053]

[1054] HCl (3M, 14.60 mL) was added to a solution of 4-chloro-6-(1-ethoxyvinyl)-2-methylpyrimidine (preparation 211, 2.9 g, 14.6 mmol) in acetone (15 mL), and the mixture was stirred at 25 °C for 2 hours. The reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic matter was washed with brine (20 mL), dried (Na₂SO₄), and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc = 19 / 1) to give 1-(6-chloro-2-methylpyrimidin-4-yl)ethyl-1-one (712 mg, 28%) as a colorless oil. 1 H NMR (500MHz, CDCl3) δ: 7.71 (s, 1H), 2.79 (s, 3H), 2.69 (s, 3H).

[1055] Preparation 213 4-Chloro-6-(1,1-difluoroethyl)-2-methylpyrimidine

[1056]

[1057] Using a similar method to that described for preparation 176, 4-chloro-6-(1,1-difluoroethyl)-2-methylpyrimidine (186 mg, 24%) was prepared as a colorless oil from 1-(6-chloro-2-methylpyrimidin-4-yl)ethyl-1-one (preparation 212). 1 HNMR (500MHz, CDCl3) δ: 7.46 (s, 1H), 2.76 (s, 3H), 1.97 (t, 3H).

[1058] Preparation 214 4-(benzyloxy)-6-methylpyrimidine-2-carboxylic acid methyl ester

[1059]

[1060] Pd(dppf)Cl2 (1.40 g, 1.92 mmol) was added to a solution of 4-(benzyloxy)-2-chloro-6-methylpyrimidine (4.5 g, 19.17 mmol) and TEA (9.7 g, 95.87 mmol) in MeOH (50 mL), and the mixture was stirred at 80 °C for 16 hours under CO (50 psi). The mixture was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (PE / EtOAc = 9 / 1 to 5 / 1) to give methyl 4-(benzyloxy)-6-methylpyrimidine-2-carboxylate (2.8 g, 56%) as a green oil. 1H NMR(500MHz,MeOH-d4)δ:7.28-7.53(m,5H),6.94(s,1H),5.50(s,2H),4.00(s,3H),2.50(s,3H).

[1061] Preparation 215 1-(4-(benzyloxy)-6-methylpyrimidin-2-yl)ethyl-1-one

[1062]

[1063] Under N2, CH3MgBr (3M, 4.03mL) was added to a solution of methyl 4-(benzyloxy)-6-methylpyrimidin-2-carboxylate (preparation 214, 2.6g, 10.07mmol) in THF (40mL), and the mixture was stirred for 2 hours. The reaction mixture was quenched by adding water (20mL) and extracted with EtOAc (40mL x 3). The combined organic layers were washed with brine (40mL), dried (Na2SO4), and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (PE / EtOAc = 9 / 1 to 5 / 1) to give 1-(4-(benzyloxy)-6-methylpyrimidin-2-yl)ethyl-1-one (312mg, 13%) as a yellow oil. LCMS m / z = 243.0 [M+H] + .

[1064] Preparation 216 4-(benzyloxy)-2-(1,1-difluoroethyl)-6-methylpyrimidine

[1065]

[1066] Following a similar procedure to that described in Preparation 176, 4-(benzyloxy)-2-(1,1-difluoroethyl)-6-methylpyrimidine (208 mg, 61.1% yield) was obtained as a yellow oil from 1-(4-(benzyloxy)-6-methylpyrimidin-2-yl)ethyl-1-one (...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Ring A is an aromatic ring or a heteroaromatic ring fused to Ring B which is a 5-membered heteroaromatic ring; X 1 is N or CH; X 2 Is N or CR 2 ; X 3 Is N or CR 3 ; X 4 Is N or CR 4 ; Ring C is phenyl, 5- or 6-membered monocyclic heterocyclic group or 5- to 6-membered heteroaryl, each of which is optionally substituted by one or more R C replace; Each R C are independently halo, –CN, –NR N1 R N2 ,–NR N3 –C(O)–R 7 ,–NR N4 –SO2–R 7 ,–C(O)–R 7 , –SO2–R 7 ,–OR O1 , C 1-6 Alkyl, alkenyl, 3- to 7-membered monocyclic carbocyclic group, phenyl, 5- to 12-membered monocyclic or bicyclic heteroaryl, or 4- to 9-membered monocyclic or bicyclic heterocyclic group, wherein R C C 1-6 alkyl, 3 to 7 membered monocyclic carbocyclyl, phenyl, 5 to 12 membered monocyclic or bicyclic heteroaryl, and 4 to 9 membered monocyclic or bicyclic heterocyclyl are each optionally substituted by one or more R C1 Replace, or two R C Together with the middle atom, it forms a 3- to 7-membered monocyclic carbocyclic group optionally substituted by one or more halogen groups; Each R C1 are independently halo, oxo, –CN, –OR O1 ,–NR N1 R N2 , –C(O)-R 7 , –C(O)-OR O3 、–SO2-R 7 , C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 5- to 12-membered monocyclic or bicyclic heteroaryl, or 4- to 7-membered monocyclic heterocyclic group, wherein R C1 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N1 R N2 , C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 8-membered monocyclic heterocyclyl; R 1 It is H, C 1-6 Alkyl, -OR 1A ,–NR N1 R N2 , C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, wherein R 1 The C 1-6 Alkyl, phenyl, C 3-6 Cycloalkyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted by one or more R 8 replace; R 1A Is H or C 1-3 alkyl; or R 1 and R 1A together with the atoms to which they are attached, form a 5- or 6-membered monocyclic heterocyclic ring; R 2 is H or halogenated; R 3 is H, –NR N1 R N2 , –CN, halogenated, –C(O)–R 7 ,–C(O)–OR O3 , –SO2–R 7 ,–OR O4 , C 1-6 Alkyl, alkenyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 9-membered monocyclic or bicyclic heterocyclic group, wherein R 3 C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 9-membered monocyclic or bicyclic heterocyclyl are each optionally substituted by one or more R 9 replace; R 4 is H or halogenated; Each R 7 Independently C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group; wherein R 7 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR 1a R 1b , C 1-6 Alkyl, C 1-4 haloalkyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl; Each R 8 are independently halo, oxo, –CN, –OR O1 , C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, or 4- to 7-membered monocyclic heterocyclyl; Each R 9 are independently halo, oxo, –OR O1 ,–NR N1 R N2 , –CN, –C(O)–OR O3 、–SO2-R 10 , C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group, or 4- to 10-membered monocyclic or bicyclic heterocyclic group, wherein R 9 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 10-membered monocyclic or bicyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N1 R N2 , C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl; Each R O1 Independently H, C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic or bicyclic carbocyclic group, or 4- to 7-membered monocyclic or bicyclic heterocyclic group, wherein R O1 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic or bicyclic carbocyclyl, and 4- to 7-membered monocyclic or bicyclic heterocyclyl are each optionally substituted by one or more R O2 replace; Each R O2 are independently halo, OH, -CN, C 1-4 Alkoxy, C 1-4 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group, or 4- to 7-membered monocyclic or bicyclic heterocyclic group, wherein the C 1-4 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group and 4- to 7-membered monocyclic or bicyclic heterocyclic group are each optionally substituted with one or more halogenated, C 1-6 Alkyl or –OC 1-6 Alkyl substitution; Each R O3 Independently H, C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, wherein R O3 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted by one or more R O2 replace; R O4 It is H, C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, wherein R O4 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N1 R N2 , C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl; R N1 and R N2 Each independently is H, C 1-6 alkyl, 4- to 7-membered monocyclic heterocyclic group, 5- or 6-membered heteroaryl or C 3-6 Cycloalkyl, wherein R N1 and R N2 The C 1-6 The alkyl groups are each optionally replaced by C 1-4 substituted with alkoxy or phenyl, and wherein R N1 and R N2 The C 3-6 Cycloalkyl, 4 to 7 membered monocyclic heterocyclyl, 5 or 6 membered heteroaryl are each optionally substituted by C 1-4 Alkyl substitution; Each R N3 independently H or C 1-6 Alkyl; and Each R N4 independently H or C 1-6 alkyl.

2. The compound of claim 1, wherein: Ring A is an aromatic ring or a heteroaromatic ring fused to Ring B which is a 5-membered heteroaromatic ring; X 1 is N or CH; X 2 Is N or CR 2 ; X 3 Is N or CR 3 ; X 4 Is N or CR 4 ; Ring C is phenyl or 5- to 6-membered heteroaryl, each of which is optionally substituted by one or more R C replace; Each R C are independently halo, –CN, –NR N1 R N2 ,–NR N3 –C(O)–R 7 ,–NR N4 –SO2–R 7 ,–C(O)–R 7 , –SO2–R 7 ,–OR O1 , C 1-6 alkyl, 3 to 7 membered monocyclic carbocyclic group or 4 to 9 membered monocyclic or bicyclic heterocyclic group, wherein R C The C 1-6 The alkyl, 3- to 7-membered monocyclic carbocyclic group and 4- to 9-membered monocyclic or bicyclic heterocyclic group are each optionally substituted by one or more R C1 Replace, or two R C Together with the middle atom, it forms a 3- to 7-membered monocyclic carbocyclic group optionally substituted by one or more halogen groups; Each R C1 are independently halo, oxo, –CN, –OR O1 ,–NR N1 R N2 , –C(O)-R 7 , –C(O)-OR O3 、–SO2-R 7 , C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, or 4- to 7-membered monocyclic heterocyclic group, wherein R C1 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N1 R N2 , C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 8-membered monocyclic heterocyclyl; R 1 It is C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, wherein R 1 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted by one or more R 8 replace; R 1A Is H or C 1-3 alkyl; or R 1 and R 1A together with the atoms to which they are attached, form a 5- or 6-membered monocyclic heterocyclic ring; R 2 is H or halogenated; R 3 is H, –NR N1 R N2 , –CN, halogenated, –C(O)–R 7 ,–C(O)–OR O3 , –SO2–R 7 ,–OR O4 , C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group, or 4- to 9-membered monocyclic or bicyclic heterocyclic group, wherein R 3 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 9-membered monocyclic or bicyclic heterocyclyl are each optionally substituted by one or more R 9 replace; R 4 is H or halogenated; Each R 7 Independently C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group; wherein R 7 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR 1a R 1b , C 1-6 Alkyl, C 1-4 haloalkyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl; Each R 8 are independently halo, oxo, –CN, –OR O1 , C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, or 4- to 7-membered monocyclic heterocyclyl; Each R 9 are independently halo, oxo, –OR O1 ,–NR N1 R N2 , –CN, –C(O)–OR O3 、–SO2-R 10 , C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, wherein R 9 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N1 R N2 , C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl; Each R O1 Independently H, C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic or bicyclic carbocyclic group, or 4- to 7-membered monocyclic or bicyclic heterocyclic group, wherein R O1 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic or bicyclic carbocyclyl, and 4- to 7-membered monocyclic or bicyclic heterocyclyl are each optionally substituted by one or more R O2 replace; Each R O2 are independently halo, OH, -CN, C 1-4 Alkoxy, C 1-4 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group, or 4- to 7-membered monocyclic or bicyclic heterocyclic group, wherein the C 1-4 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group and 4- to 7-membered monocyclic or bicyclic heterocyclic group are each optionally substituted with one or more halogenated, C 1-6 Alkyl or –OC 1-6 Alkyl substitution; Each R O3 Independently H, C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, wherein R O3 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted by one or more R O2 replace; R O4 It is H, C 1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic group or 4- to 7-membered monocyclic heterocyclic group, wherein R O4 The C 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of halo, oxo, -CN, -OR O1 ,–NR N1 R N2 , C 1-6 Alkyl, C 1-4 haloalkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 7-membered monocyclic heterocyclyl; R N1 and R N2 Each independently is H, C 1-6 Alkyl or C 3-6 Cycloalkyl, wherein R N1 and R N2 The C 1-6 The alkyl groups are each optionally replaced by C 1-4 Alkoxy substitution; Each R N3 independently H or C 1-6 Alkyl; and Each R N4 independently H or C 1-6 alkyl.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1A It is H or –CH3.

4. The compound of claim 1 or 2, wherein the compound is represented by formula (II), (III), (IV), (V) or (VI): or a pharmaceutically acceptable salt thereof.

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 2 It is H or F.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 2 It's H.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring C is phenyl, a 5- or 6-membered monocyclic heterocyclic group, or a 5- to 6-membered heteroaryl group, each of which is optionally substituted by one to three R C replace.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring C is phenyl or a 5- to 6-membered heteroaryl, each of which is optionally substituted by one to three R C replace.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring C is selected from pyridonyl, pyridazinonyl, pyrazinonyl, imidazolyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyridinyl, pyrimidinyl, thiadiazolyl, thiazolyl and triazinyl, each of which is optionally substituted by one or three R C replace.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring C is selected from imidazolyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyridinyl, pyrimidinyl, thiadiazolyl, thiazolyl and triazinyl, each of which is optionally substituted by one or three R C replace.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring C is selected from imidazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrimidinyl, thiadiazolyl, thiazolyl and triazinyl, each of which is optionally substituted by one or three R C replace.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring C is selected from pyrazinyl, pyrimidinyl and thiazolyl, each of which is optionally substituted by one or three R C replace.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring C is selected from: And among them represents a bond to ring B, and n is 0, 1, 2 or 3.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring C is selected from: And among them represents a bond to ring B, and n is 0, 1, 2 or 3.

15. The compound according to claim 13 or 14, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from:

16. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring C is selected from: And among them represents a bond to ring B, and the two R C The groups may be the same or different.

17. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring C is selected from: And among them represents a bond to ring B, and the two R C The groups may be the same or different.

18. The compound according to claim 16 or 17, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from:

19. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein each R C are independently halogenated, –NR N1 R N2 ,–NR N3 –C(O)–R 7 ,–NR N4 –SO2–R 7 ,–C(O)–R 7 ,–OR O1 , C 1-6 Alkyl, alkenyl, C 3-6 Cycloalkyl, phenyl, 5- to 12-membered monocyclic or bicyclic heteroaryl, or 4- to 8-membered monocyclic or bicyclic heterocyclic group, or two R C Together with the middle atom, it forms a 3- to 7-membered monocyclic carbocyclic group optionally substituted by one or two halogen groups; wherein R C The C 1-6 Alkyl, C 3-6 The cycloalkyl, 5- to 12-membered monocyclic or bicyclic heteroaryl and 4- to 8-membered monocyclic or bicyclic heterocyclyl are each optionally substituted by one to three R C1 replace.

20. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, wherein each R C are independently halogenated, –NR N1 R N2 ,–NR N3 –C(O)–R 7 ,–NR N4 –SO2–R 7 ,–C(O)–R 7 ,–OR O1 , C 1-6 Alkyl, C 3-6 Cycloalkyl, or 4 to 8 membered monocyclic or bicyclic heterocyclic group, wherein R C The C 1-6 Alkyl, C 3-6 The cycloalkyl group and the 4- to 8-membered monocyclic or bicyclic heterocyclic group are each optionally substituted by one to three R C1 replace.

21. The compound of claim 19 or 20, or a pharmaceutically acceptable salt thereof, wherein at least one R C It is C 1-3 Halogenated alkyl.

22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein at least one R C It is –CF2CH3.

23. The compound according to claim 19 or a pharmaceutically acceptable salt thereof, wherein R C The C 3-6 The cycloalkyl group is selected from the group consisting of cyclobutyl, cyclopentyl, cyclopropyl and cyclohexyl, and R C The 5- to 12-membered monocyclic or bicyclic heteroaryl represented by is furanyl, pyrazolyl, imidazolyl, triazolyl, isoxazole, pyridyl, pyrimidyl, isoindolyl, 3H-imidazo[4,5-b]pyridyl, 1H-benzo[d][1,2,3]triazolyl, and R C The 4- to 8-membered monocyclic or bicyclic heterocyclic group represented by is selected from azetidinyl, 2,6-diazaspiro[3.3]heptyl, isothiazolidinyl, isothiazolidine dioxide, morpholinyl, oxabicycloheptyl, oxetanyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidonyl, tetrahydrofuranyl, pyridin-2(1H)-acyl, tetrahydro-2H-pyranyl, 2-oxabicyclo[2.1.1]hexanyl, 2-oxa-6-azaspiro[3.4]octanyl and 7-oxabicyclo[2.2.1]heptyl, wherein the C 3-6 Each of the cycloalkyl, 5- to 12-membered monocyclic or bicyclic heteroaryl, and 4- to 8-membered monocyclic or bicyclic heterocyclyl is optionally substituted by one to three R C1 Replace, or two R C Together with the middle atom, it forms a cyclopentyl group substituted by one or two halogen groups.

24. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein R C The C 3-6 The cycloalkyl group and the 4- to 8-membered monocyclic or bicyclic heterocyclic group are represented by the following formula: in represents a bond to ring C, and n is 0, 1, 2 or 3.

25. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R C The C 3-6 The cycloalkyl group and the 4- to 8-membered monocyclic or bicyclic heterocyclic group are represented by the following formula: in represents a bond to ring C, and n is 0, 1, 2 or 3.

26. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein R C C 3-6 The cycloalkyl and 4 to 8 membered monocyclic or bicyclic heterocyclic groups are independently selected from: in represents a bond to ring C, and two R C1 The groups may be the same or different.

27. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R C C 3-6 The cycloalkyl and 4 to 8 membered monocyclic or bicyclic heterocyclic groups are independently selected from: in represents a bond to ring C, and two R C1 The groups may be the same or different.

28. A compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, wherein Each R C1 are independently halo, –CN, –OR O1 ,–NR N1 R N2 , –C(O)-R 7 , –C(O)-OR O3 、–SO2-R 7 , C 1-6 Alkyl, C 3-6 Cycloalkyl, or a 4- to 6-membered monocyclic heterocyclic group, wherein R C1 The C 1-6 Alkyl is optionally substituted by one to three independently selected from halo and -OR a1 substituted with a substituent; and R a1 It is H, C 1-4 Alkyl or 4 to 6-membered heterocyclic group.

29. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 27, wherein Each R C1 are independently halo, –CN, –OR O1 ,–NR N1 R N2 , –C(O)-R 7 , –C(O)-OR O3 、–SO2-R 7 , C 1-6 alkyl or a 4- to 6-membered monocyclic heterocyclic group, wherein R C1 The C 1-6 Alkyl is optionally substituted by one to three independently selected from halo and -OR a1 substituted with a substituent; and R a1 It is H, C 1-4 Alkyl or 4 to 6-membered heterocyclic group.

30. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein each R C1 independently selected from F, Cl, –CN, OH, –OCH3, –OCHF2, –NH2, –N(CH3)2, –CH3, –CH2F, –CHF2, –CF3, –CH2-OH, –CH2-CH3, –CH(CH3)2, –CH2-O-CH3, –CH2-CH2-OCH3, –C(O)-CH3, –C(O)-OC(CH3)3, –SO2-CH3, cyclopropyl, in Represents R C key.

31. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein each R C1 independently selected from F, -CN, OH, -OCH3, -OCHF2, -NH2, -N(CH3)2, -CH3, -CH2F, -CHF2, -CF3, -CH2-OH, -CH2-CH3, -CH(CH3)2, -C(O)-CH3, -C(O)-OC(CH3)3, -SO2-CH3, in Represents R C key.

32. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein each R C independently selected from -F, -Cl, -CH3, -CH2F, -CHF2, -CF3, -CH2-CH3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CHF-CH2F, -CH2-CHF2, -CH2-CH2-CH2F, -CH2-CF3, -C(CH3)3, -CF2CH3, -CHF-CH3, -CH(CH3)2, -CF(CH3)2, -C(CH3)2-CH2F, -CH(CH3)-CHF2, -CH(CH3)-CF3, -C(CH3)3, -CF2CH3, -CHF-CH3, -CH(CH3)2, -CF(CH3)2, -C(CH3)2-CH2F, -CH(CH3)-CHF2, -CH(CH3)-CF3, -C(CH3) )2-CF3, -CH2-CH2-CN, -CH2OCH3, -CH2-C(CH3)2-CN, -C(CH3)2-OH, -CH(CH3)-OCH3, -C(CH3)2-OCH3, -C(CH3)2-CH2-OCH3, -CH (OH)-CH3, -C(CH3)(OH)-CF3, -CH=CH2, -OCH3, -O-CHF2, -C(CH3)(OCH3)-CH2-OCH3, -O-CF3, -CH(OCH3)-cyclopropyl, -OH, -O-CH2CH3, -O-CH2CHF2, -O-CH(CH3)2, -O-CH(CF3)2, -O-CH2-OCH3, -O-CH(CH3)-OCH3, -O-CH(CH3)-CH2-OCH3, -O-CH2-CH2-O-CH3, -O-CH 2-CH(CH3)-OCH3, -CF(CH3)-CH2-OCH3, -CH(CF3)-NH2, -CH(OCH3)-C(CH3)3, -NH-C(O)-CH3, -NH-SO2-CH3,-NH2, -NHCH3, -N(C H3)2, -NHCH(CH3)2, -NHCH2CH2CH3, -NHCH2C(CH3)2OCH3, cyclopropyl, -CHF-cyclopropyl, -CF(CH3)-cyclopropyl, -CH(OCH3)-cyclopropyl, -C(CH3)(OCH3)-cyclopropyl, -CF(OCH3)-cyclopropyl, -NH-cyclohexyl, -NH-cyclopropyl, -NH-N-methylpiperidine, -NH-CH2-cyclopropyl, -NH-CH2-CH2-OCH3, -N(CH3)-CH2-CH2-OCH3, -CH(NH2)-CF3, in represents the bond to ring C.

33. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein each R C independently selected from Cl, -CH3, -CH2F, -CHF2, -CF3, -CH2-CH3, -CH2-CH2F, -CH2-CHF2, -CH2-CF3, -CHF-CH2F, -CH2-CHF2, -CH2-CF3, -C(CH3)3, -CF2CH3, -CHF-CH3, -CH(CH3)2, -CF(CH3)2, -C(CH3)2-CH2F, - CF(CH3)2, -CH(CH3)-CHF2, -CH(CH3)-CF3, -C(CH3)2-CF3, -CH2-CH2-CN, -CH2-C(CH3)2-CN, -C (CH3)2-OH, -CH(CH3)-OCH3, -C(CH3)2-OCH3, -CH(OH)-CH3, -OCH3, -O-CHF2, -C(CH3)(OCH3)-CH 2-OCH3, -O-CF3, -CH(OCH3)-cyclopropyl, -O-CH2CH3, -O-CH2CHF2, -O-CH(CH3)2, -O-CH(CF3)2, -O-CH2 -OCH3, -O-CH(CH3)-OCH3, -O-CH(CH3)-CH2-OCH3, -O-CH2-CH2-O-CH3, -O-CH2-CH(CH3)-OCH3, -CF(CH3)-CH2-OCH3, -CH(CF3)-NH2, -CH(OCH3)-C(CH3)3, -NH-C(O)-CH3, -NH-SO2-CH3, -N(CH3)2, -NHCH(CH3)2, -CHF-cyclopropyl, -CF(CH3)-cyclopropyl, -NH-cyclohexyl, -N(CH3)-CH2-CH2-OCH3, -CH(NH2)-CF3, in represents the bond to ring C.

34. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 33, wherein: R 1 It is H, C 1-4 Alkyl, -OR 1A ,–NR N1 R N2 , or C 3-6 Cycloalkyl, wherein R 1 The C 1-4 Alkyl and C 3-6 The cycloalkyl groups are each optionally substituted by one to three independently selected R 8 Substitution: halogen, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Haloalkyl; R 1A It is C 1-4 alkyl; R N1 and R N2 Each independently is H or C 1-4 alkyl.

35. A compound as described in any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R 1 It is C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein R 1 The C 1-4 Alkyl and C 3-6 The cycloalkyl groups are each optionally substituted by one to three independently selected R 8 Substitution: halogen, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

36. A compound as described in any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally one to three independently selected from the following R 8 Substituted C 1-4 Alkyl: halo, -CN, C 1-3 Alkoxy, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

37. A compound as described in any one of claims 34 to 36, or a pharmaceutically acceptable salt thereof, wherein R 8 For each occurrence is independently halo, -CN, C 1-3 Alkoxy.

38. The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein each R 8 Independently selected from F, -CN and -OCH3.

39. The compound of claim 34 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from -H, -CH3, -CD3, -CH2-CH3, -CH2-CHF2, -CH2-CH2-CN, -CH2-CH2-OCH3, -OCH3, -NH2, -NHCH3, -N(CH3)2, cyclopropyl, 40. The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from -CH3, -CH2-CH3, -CH2-CHF2, -CH2-CH2-CN, -CH2-CH2-OCH3, cyclopropyl, 41. A compound as described in any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R 3 is H, –NR N1 R N2 , halogenated, –C(O)–R 7 ,–C(O)–OR O3 , –SO2–R 7 ,–OR O4 , C 1-6 Alkyl, alkenyl C 3-6 Cycloalkyl, 5- or 6-membered heteroaryl, 4- to 10-membered monocyclic or bicyclic heterocyclic group, wherein R 3 The C 1-6 Alkyl, C 3-6 The cycloalkyl group and the 4- to 9-membered monocyclic or bicyclic heterocyclic group are each optionally substituted by one to three R 9 replace.

42. A compound as described in any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R 3 is H, –NR N1 R N2 , halogenated, –C(O)–R 7 ,–C(O)–OR O3 , –SO2–R 7 ,–OR O4 , C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 9 membered monocyclic or bicyclic heterocyclic group, wherein R 3 The C 1-6 Alkyl, C 3-6 The cycloalkyl group and the 4- to 9-membered monocyclic or bicyclic heterocyclic group are each optionally substituted by one to three R 9 replace.

43. The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein R 3 It is C 3-6 Cycloalkyl or 4 to 10 membered monocyclic or bicyclic heterocyclic group, each optionally substituted by one or three R 9 replace.

44. The compound of claim 42 or a pharmaceutically acceptable salt thereof, wherein R 3 It is C 3-6 Cycloalkyl or 4 to 9 membered monocyclic or bicyclic heterocyclic group, each optionally substituted by one or three R 9 replace.

45. The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of pyrazolyl, pyridinyl, azetidinyl, cyclobutyl, cyclopentyl, cyclopropyl, 2-oxaspiro[3.3]heptyl, 1,7-diazaspiro[4.4]nonyl, 2,7-diazaspiro[3.5]nonyl, 7-oxa-2-azaspiro[3.5]nonyl, 1-oxa-7-azaspiro[4.4]nonyl, 2,6-diazaspiro[3.4]octanyl, 2-oxa-6-azaspiro[3.4]octanyl, 6-oxa-2-azaspiro[3.4]octanyl, 2,7-diazaspiro[4.4]nonyl, 1,6- Diazaspiro[3.3]heptyl, 1-oxa-6-azaspiro[3.3]heptyl, 3,6-diazabicyclo[3.2.0]heptyl, 3,9-diazabicyclo[3.3.1]nonanyl, 6-oxa-2,9-diazaspiro[4.5]decanyl, 1,6-diazaspiro[3.4]octanyl, 5-azaspiro[2.4]heptyl, 1,6-diazaspiro[3.4]octanyl, 1,7-diazaspiro[4.4]nonanyl, 2-oxa-7-azaspiro[4.4]nonanyl, octahydropyrano[2,3-c]pyrrole 1,4-oxa-1H-pyrrolo[3,4-b]pyridinyl, ...c]pyrrolyl, 1,4-oxa-1H-pyrrolo[3,4-c]pyrrolyl, 1,4-oxa-1H-pyrrolo[3,4-b]pyrrolyl, 1,4-oxa-1H-pyrrolo[3,4-b]pyrrolyl, 1,4-oxa-1H-pyrrolo[3,4-b]pyrrolyl, 1,4-oxa-1H-pyrrolo[3, nonyl, 2,5-diazabicyclo[2.2.1]heptyl, 3,6-diazabicyclo[3.1.1]heptyl, 3,6-diazabicyclo[3.2.0]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 2λ 2 ,6-diazaspiro[3.3]heptyl, 1λ 2 ,7λ 2 -diazaspiro[4.4]nonyl, oxetanyl, piperidinyl, piperazinyl, piperazin-2-one-yl, pyrrolidinyl, pyrrolidin-2-one-yl and tetrahydropyranyl, each of which is optionally substituted by one to three R 9 replace.

46. ​​The compound of claim 42 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of azetidinyl, cyclobutyl, cyclopentyl, cyclopropyl, 2,5-diazabicyclo[2.2.1]heptyl, 3,6-diazabicyclo[3.1.1]heptyl, 3,6-diazabicyclo[3.2.0]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 2λ 2 ,6-diazaspiro[3.3]heptyl, 1λ 2 ,7λ 2 -diazaspiro[4.4]nonyl, oxetanyl, piperidinyl, piperazinyl, piperazin-2-one-yl, pyrrolidinyl, pyrrolidin-2-one-yl and tetrahydropyranyl, each of which is optionally substituted by one to three R 9 replace.

47. The compound of claim 41 or 42, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl and 3,6-diazabicyclo[3.1.1]heptyl, each of which is optionally substituted by one to three R 9 replace.

48. The compound of claim 41 or 42, or a pharmaceutically acceptable salt thereof, wherein R 3 is optionally replaced by one to three R 9 Substituted pyrrolidinyl.

49. A compound as described in any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from: in represents a bond to ring B, and m is 0, 1, 2, 3 or 4.

50. The compound of claim 49 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from:

51. A compound as described in any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from: in represents a bond to ring B.

52. A compound as described in any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from: in represents a bond to ring B.

53. A compound as described in any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R 3 is H, –NR N1 R N2 , halogenated, –C(O)–R 7 ,–C(O)–OR O3 , –SO2–R 7 ,–OR O4 or optionally one to three R 9 Substituted C 1-6 alkyl.

54. A compound as described in any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, wherein each R 9 are independently halogenated, OH, -OC 1-4 Alkyl, –NR a2 R a3 , –CN, –C(O)–OR a1 、–SO2-R a1 , C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein R 9 The C 1-4 Alkyl and C 3-6 The cycloalkyl groups are each optionally substituted with one to three substituents independently selected from the group consisting of halo and C 1-3 Alkoxy; and R a1 , R a2 and R a3 Each independently is C 1-3 alkyl.

55. A compound as described in any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, wherein each R 9 are independently halo, -OR a1 ,–NR a2 R a3 , –CN, –C(O)–OR a1 、–SO2-R a1 , C 1-4 Alkyl, C 3-6 Cycloalkyl, or a 4- to 10-membered monocyclic or bicyclic heterocyclic group, wherein R 9 The C 1-4 alkyl, 4 to 10 membered monocyclic or bicyclic heterocyclic group and C 3-6 The cycloalkyl groups are each optionally substituted with one to three substituents independently selected from the group consisting of halo, OH, -CN, C 1-4 Alkyl and C 1-3 Alkoxy; and R a1 , R a2 and R a3 Each independently is H, C 3-4 Cycloalkyl or C 1-3 Alkyl, wherein R a1 , R a2 and R a3 The C 3-4 The cycloalkyl group is optionally substituted with C 1-4 alkyl substituted, and wherein R a1 , R a2 and R a3 The C 1-3 The alkyl group is optionally substituted with a phenyl group.

56. A compound as described in any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, wherein each R 9 are independently halo, -OR a1 ,–NR a2 R a3 , –CN, –C(O)–OR a1 、–SO2-R a1 , C 1-4 Alkyl, C 3-6 Cycloalkyl or 4 to 7 membered monocyclic heterocyclic group, wherein R 9 The C 1-4 Alkyl and C 3-6 The cycloalkyl groups are each optionally substituted with one to three substituents independently selected from the group consisting of halo and C 1-3 Alkoxy; and R a1 , R a2 and R a3 Each independently is H or C 1-3 alkyl.

57. The compound of claim 55 or a pharmaceutically acceptable salt thereof, wherein each R 9 independently selected from F, OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCHF2, -OCF3, -OCD3, -O-cyclopropyl, -NHCH3, -NH2, -N(CH3)2, -N(CD3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -NHCH(CH3)2, -NHCH2CH3, -CN, -CH3, -CH2F, -CF3, -C(O)-OCH2CH3, -SO2-CH3, -CH2-OCH3, -CH2-CH2-OCH3, -CH2-CH3, -CH2-CN, pyrrolidinyl, morpholinyl, azetidinyl, cyclopropyl, -CHF2, -CH2-CF3, 58. The compound of claim 54 or a pharmaceutically acceptable salt thereof, wherein each R 9 Independently selected from F, OH, -OCH3, -OCHF2, -OCF3, -N(CH3)2, -CN, -CH3, -CF3, -C(O)-OCH2CH3, -SO2-CH3, -CH2-OCH3, -CH2-CH2-OCH3, -CH2-CH3, cyclopropyl, -CHF2 and -CH2-CF3.

59. The compound of claim 56 or a pharmaceutically acceptable salt thereof, wherein each R 9 Independently selected from F, OH, -OCH3, -OCHF2, -OCF3, -NHCH3, -NH2, -N(CH3)2, -N(CH2CH3)2, -N(CH3)(CH2CH3), -NHCH(CH3)2, -CN, -CH3, -CF3, -C(O)-OCH2CH3, -SO2-CH3, -CH2-OCH3, -CH2-CH2-OCH3, -CH2-CH3, pyrrolidinyl, morpholinyl, cyclopropyl, -CHF2 and -CH2-CF3.

60. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 53, wherein two R 9 Together with their middle atoms, they form a 4- to 6-membered monocyclic heterocyclic group, which is optionally substituted by one to two substituents independently selected from the following: halo, C 1-4 Alkyl and C 1-4 Halogenated alkyl.

61. A compound as described in any one of claims 1-40 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from H, Cl, -CN, -CH3, -CH2F, -CHF2, -CF3, -CH2-CH3, -CH2CF3, -CHF-CH3, -CH(CH3)2, -CH(CF3)2, -CHF-CH2F, -CH2-CH2-CN, -CH2-CH2-CH3, -CH(CH3)-CH2-CH3, -CH2-CH(CH3)2, -CH2-cyclopropyl, -CH2-morpholinyl, -CH2OH, -CH2-OCH3, -C(CH3)-CH2- CH3, -CH(CH3)-CF3, -CH(CH3)-OCH3, -CH2N(CH3)2, -CH=CH2, -NH2, -NHCH3, -NHCH2CH3, –N(CH3)2, -OCH3, -N(CH3)- CH2-CH2-OCH3, -N(CH3)CH2C(CH3)2OCH3, -C(O)-OCH3, -C(O)-OCH2CH3, –SO2–CH3, -O-CH(CH3)2, -O-CH2-CH2-OCH3, in represents a bond to ring B.

62. A compound as described in any one of claims 1-40 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from H, Cl, -CH3, -CH2F, -CHF2, -CF3, -CH2-CH3, -CHF-CH3, -CH(CH3)2, -CHF-CH2F, -CH2-CH2-CN, -CH2-CH2-CH3, -CH2-CH(CH3)2, -CH2-cyclopropyl, -CH2-OCH3, - CH(CH3)-CH2-CH3, -CH(CH3)-CF3, -CH(CH3)-OCH3, –N(CH3)2, -OCH3, -N(CH3)-CH2-CH2-OCH3, -C(O)-OCH3, –SO2–CH3, -O-CH(CH3)2, -O-CH2-CH2-OCH3, in represents a bond to ring B.

63. A compound as described in any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, wherein each R 7 Independently C 1-6 Alkyl, C 3-6 Cycloalkyl or 4 to 6-membered monocyclic heterocyclic group, wherein R 7 The C 1-6 Alkyl, C 3-6 The cycloalkyl and 4 to 6 membered monocyclic heterocyclyl are each optionally substituted with one to three substituents independently selected from the group consisting of halo, C 1-3 Alkyl and C 1-3 Halogenated alkyl.

64. The compound of claim 63 or a pharmaceutically acceptable salt thereof, wherein each R 7 Independently selected from:

65. The compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, wherein: Each R O1 Independently H, C 1-6 alkyl, 3- to 6-membered monocyclic or bicyclic carbocyclic group, 4- to 6-membered monocyclic heterocyclic group or 6-membered heteroaryl, wherein R O1 The C 1-6 The alkyl group, the 3- to 6-membered monocyclic or bicyclic carbocyclyl group, the 4- to 6-membered monocyclic heterocyclyl group and the 6-membered heteroaryl group are each optionally substituted by one to three R O2 Replacement; and Each R O2 are independently halo, OH, -CN, C 1-4 Alkoxy, C 1-4 alkyl, 3 to 5 membered monocyclic carbocyclic group, 4 to 7 membered monocyclic or bicyclic heterocyclic group or phenyl, wherein the C 1-4 The alkyl group, the 3- to 5-membered monocyclic carbocyclic group, the 4- to 7-membered monocyclic or bicyclic heterocyclic group and the phenyl group are each optionally substituted by C 1-3 Alkoxy, C 1-3 Haloalkoxy or one to three halosubstituted.

66. The compound of claim 65 or a pharmaceutically acceptable salt thereof, wherein R O1 or R O2 The 4- to 7-membered monocyclic or bicyclic heterocyclic group or 6-membered heteroaryl represented by is each independently selected from morpholino, oxetanyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, azetidinyl, oxaspiro[2.4]heptane, pyrrolidinyl and piperidinyl.

67. A compound as described in any one of claims 1 to 66, or a pharmaceutically acceptable salt thereof, wherein each R O2 independently selected from F, -CN, OH, -OCH3, -CH3, -CHF2, -CF3, in Represents R O1 key.

68. A compound as described in any one of claims 1-66 or a pharmaceutically acceptable salt thereof, wherein each R O1 independently selected from H, -CH3, -CHF2, -CF3, -CH2-CH3, -CH2-CHF2, -CH2-CF3, -CH2-CH2-CH3, -CH(CH3)2, -CH(CF3)2, -CH2-CH2-OCH3, -CH(CH3)-CH2-OCH3, -CH2-CH(CH3)-OCH3, 69. A compound as described in any one of claims 1 to 68, or a pharmaceutically acceptable salt thereof, wherein each R O3 is independently C optionally substituted by one to three substituents independently selected from 1-6 Alkyl: halo and C 1-4 Halogenated alkyl.

70. A compound as described in any one of claims 1-68, or a pharmaceutically acceptable salt thereof, wherein each R O3 are independently -CH3, -CH2CH3 or -C(CH3)3.

71. A compound as described in any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, wherein R O4 It is C 1-4 Alkyl or C 3-6 cycloalkyl, each optionally substituted with one to three substituents independently selected from the group consisting of halo and C 1-3 Alkoxy.

72. A compound as described in any one of claims 1-70 or a pharmaceutically acceptable salt thereof, wherein R O4 Selected from -CH3, -CH2-CH3, -CH(CH3)2, -CH2-CH2-OCH3 and 73. Compound 1-72 or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 72, wherein R N1 and R N2 Each independently is H, C 3-6 Cycloalkyl or optionally C 1-3 Alkoxy substituted C 1-4 alkyl.

74. A compound as described in any one of claims 1 to 72, or a pharmaceutically acceptable salt thereof, wherein R N1 and R N2 Each independently represents H, -CH3, -CH(CH3)2, -CH2-CH2-OCH3 or cyclohexyl.

75. A compound as described in any one of claims 1 to 74, or a pharmaceutically acceptable salt thereof, wherein R N3 It's H.

76. A compound as described in any one of claims 1 to 75, or a pharmaceutically acceptable salt thereof, wherein R N4 It's H.

77. A compound as described in any one of claims 1 to 76, or a pharmaceutically acceptable salt thereof, wherein R 4 It is H or –CH3.

78. The compound of claim 77 or a pharmaceutically acceptable salt thereof, wherein R 4 It's H.

79. The compound of claim 1, wherein the compound is represented by formula (VII') or (VIII'): or a pharmaceutically acceptable salt thereof, wherein: Ring C is optionally substituted by one to three R C Substituted 6-membered heteroaryl; Each R C Independently is –OR O1 , C 1-4 Alkyl or 5-membered heterocyclic group, wherein R C The C 1-4 The alkyl group and the 5-membered heterocyclic group are each optionally substituted by one to three R C1 replace; Each R C1 are independently halogenated or –OR O1 ; R 1 is H or –CH3; R 3 It is H, C 1-4 Alkyl, C 3-5 Cycloalkyl or 5 to 7 membered monocyclic or bicyclic heterocyclic group, wherein R 3 The C 1-4 Alkyl, C 3-5 The cycloalkyl group and the 5- to 7-membered monocyclic or bicyclic heterocyclic group are each optionally substituted by one to three R 9 replace; Each R 9 Independently is –OR O1 ,–NR N1 R N2 , a 5- to 7-membered monocyclic heterocyclic group or C 1-4 alkyl; Each R O1 Independently H, C 1-4 Alkyl or C 3-5 Cycloalkyl, wherein the C 1-4 Alkyl and C 3-5 The cycloalkyl groups are each optionally substituted by R O2 replace; Each R O2 Independently –CN or C 1-4 Alkoxy; R N1 and R N2 Each independently is H or C 1-3 alkyl.

80. The compound of claim 1, wherein the compound is represented by formula (VII) or (VIII): or a pharmaceutically acceptable salt thereof, wherein: Ring C is optionally substituted by one to three R C Substituted 6-membered heteroaryl; Each R C Independently is –OR O1 , C 1-4 Alkyl or 5-membered heterocyclic group, wherein R C The C 1-4 The alkyl group and the 5-membered heterocyclic group are each optionally substituted by one to three R C1 replace; Each R C1 are independently halogenated or –OR O1 ; R 3 It is H, C 1-4 Alkyl, C 3-5 Cycloalkyl or 5 to 7 membered monocyclic or bicyclic heterocyclic group, wherein R 3 The C 1-4 Alkyl, C 3-5 The cycloalkyl group and the 5- to 7-membered monocyclic or bicyclic heterocyclic group are each optionally substituted by one to three R 9 replace; Each R 9 Independently is –OR O1 ,–NR N1 R N2 , a 5- to 7-membered monocyclic heterocyclic group or C 1-4 alkyl; Each R O1 Independently H, C 1-4 Alkyl or C 3-5 Cycloalkyl, wherein the C 1-4 Alkyl and C 3-5 The cycloalkyl groups are each optionally substituted by R O2 replace; Each R O2 Independently –CN or C 1-4 Alkoxy; R N1 and R N2 Each independently is H or C 1-3 alkyl.

81. The compound of claim 79 or 80, wherein each R 9 Independently is –OR O1 ,–NR N1 R N2 or C 1-4 alkyl.

82. The compound of claim 79 or 80, or a pharmaceutically acceptable salt thereof, wherein Ring C is pyridyl, pyrazinyl or pyrimidinyl, each of which is optionally substituted by one or two R C replace.

83. The compound of claim 79 or 80, or a pharmaceutically acceptable salt thereof, wherein Ring C is pyrimidinyl, pyrazinyl or thiazolyl, each of which is optionally substituted by one or two R C replace.

84. The compound of claim 79 or 80, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from: And among them represents a bond to ring B, and n is 0, 1 or 2.

85. The compound of claim 79 or 80, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from: And among them represents a bond to ring B, and n is 0, 1 or 2.

86. The compound of claim 79 or 80, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from: And among them represents a bond to ring B, and the two R C The groups may be the same or different.

87. The compound of claim 79 or 80, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from: And among them represents a bond to ring B, and the two R C The groups may be the same or different.

88. A compound as described in any one of claims 79-87 or a pharmaceutically acceptable salt thereof, wherein each R C Independently is –OR O1 , C 1-2 Alkyl, C 1-2 haloalkyl or optionally with one R C1 A substituted 5-membered oxygen-containing heterocyclic group.

89. A compound as described in any one of claims 79-88 or a pharmaceutically acceptable salt thereof, wherein R C is optionally replaced by an R C1 Substituted tetrahydrofuranyl.

90. A compound as described in any one of claims 79-89 or a pharmaceutically acceptable salt thereof, wherein R C yes in represents the bond to ring C.

91. A compound as described in any one of claims 79-90, or a pharmaceutically acceptable salt thereof, wherein each R C1 is independently F or -OCH3.

92. A compound as described in any one of claims 79-88 or a pharmaceutically acceptable salt thereof, wherein each R C Independently selected from -CH3, -CH2CH3, -CF2CH3, -CF(CH3)2, -OCH3, -O-CH2-CH2-O-CH3, in represents the bond to ring C.

93. A compound as described in any one of claims 79-88, or a pharmaceutically acceptable salt thereof, wherein each R C Independently selected from -CH3, -CF2CH3, -OCH3, -O-CH2-CH2-O-CH3, in represents the bond to ring C.

94. A compound as described in any one of claims 79-88 or a pharmaceutically acceptable salt thereof, wherein each R C Independently selected from -CH3, -CH2CH3, -CF2CH3, -CF(CH3)2-OCH3, -O-CH2-CH2-O-CH3, in represents the bond to ring C.

95. A compound as described in any one of claims 79-94 or a pharmaceutically acceptable salt thereof, wherein R 3 The 5- to 7-membered monocyclic or bicyclic heterocyclic group represented by is selected from 3,6-diazabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, piperazinyl and pyrrolidinyl, each of which is optionally substituted by one or two R 9 replace.

96. A compound as described in any one of claims 79-94, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from H, -CH2CH3, in represents a bond to ring B, and m is 0, 1 or 2.

97. A compound as described in any one of claims 79-94, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from H, -CH2CH3, in represents a bond to ring B.

98. A compound as described in any one of claims 79-97 or a pharmaceutically acceptable salt thereof, wherein each R 9 Independently selected from -OH, -OCH3, -N(CH3)2 and -CH3.

99. A compound as described in any one of claims 79-97 or a pharmaceutically acceptable salt thereof, wherein each R 9 Independently selected from -OH, -OCH3, -NH2, -NHCH3, -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2, pyrrolidinyl, morpholinyl, -CH2CH3 and -CH3.

100. A compound as described in any one of claims 79-99 or a pharmaceutically acceptable salt thereof, wherein R O1 Each is independently selected from H, -CH3, -CH2CH2OCH3, cyclopropyl, 101. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 58 and 95-99, wherein: Ring C is selected from the following: R C It is C 1-3 Alkyl or C 1-3 Alkoxy; R 3 is selected from pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl and 3,6-diazabicyclo[3.1.1]heptyl, each of which is optionally substituted by one to two R 9 replace; R 9 are independently halogenated, C 1-4 Alkyl, OH, -OC 1-4 Alkyl or –NR a2 R a3 ;and R a2 and R a3 Each independently is H or C 1-3 alkyl.

102. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 79, 80, and 95-99, wherein: Ring C is selected from the following: R C For each occurrence independently C 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 Alkoxy; R 3 is selected from pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl and 3,6-diazabicyclo[3.1.1]heptyl, each of which is optionally substituted by one to two R 9 replace; R 9 are independently halogenated, C 1-4 Alkyl, OH, -OC 1-4 Alkyl or –NR a2 R a3 ;and R a2 and R a3 Each independently is H or C 1-3 alkyl.

103. The compound of claim 101 or 102, or a pharmaceutically acceptable salt thereof, wherein: R in formula (C2) C It is C 1-2 Alkyl or C 1-2 Alkoxy; R in formula (C3) C It is C 1-2 haloalkyl; and For formula (C4), an R C It is C 1-2 haloalkyl, and the other is C 1-3 Alkyl or C 1-3 Alkoxy.

104. A compound as described in any one of claims 101-103 or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from: And R 9 It is C 1-3 Alkyl, -OC 1-3 Alkyl or –NR a2 R a3 ; and m is 0, 1 or 2.

105. The compound of any one of claims 101-104 or a pharmaceutically acceptable salt thereof, wherein: R in formula (C3) C is –CF2CH3, and for formula (C4), one R C is –CF2CH3 and the other R C It is C 1-3 Alkyl or C 1-3 Alkoxy; m is 1 or 2; and R 9 For each occurrence independently C 1-3 Alkyl, -OC 1-3 Alkyl or –NR a2 R a3 .

106. The compound of any one of claims 101-104 or a pharmaceutically acceptable salt thereof, wherein: Ring C is R C It is C 1-2 Alkyl or C 1-2 Alkoxy; R 3 yes R 9 For each occurrence independently C 1-2 Alkyl or –NR a2 R a3 ;and R a2 and R a3 It is C 1-2 alkyl.

107. The compound of claim 106 or a pharmaceutically acceptable salt thereof, wherein R C yes –CH3, -CH2CH3, or –OCH3.

108. A compound as described in any one of claims 101-107 or a pharmaceutically acceptable salt thereof, wherein R 9 It is –CH3 or –N(CH3)2.

109. The compound of claim 1, wherein the compound is represented by formula (VIIA'): or a pharmaceutically acceptable salt thereof, wherein: R 1 is H or CH3; R C1a is C substituted with 1 to 3 halogen groups 1-3 alkyl; R C1b It is C 1-3 alkyl; R 3 Selected from Each R 9 Independently is –NR N1 R N2 , C 1-4 alkyl, morpholinyl or pyrrolidinyl; and R N1 and R N2 Each independently is H or C 1-3 alkyl.

110. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound is represented by formula (VIIA): or a pharmaceutically acceptable salt thereof, wherein: R C1a is C substituted with 1 to 3 halogen groups 1-3 alkyl; R C1b It is C 1-3 alkyl; R 3 Selected from Each R 9 Independently is –NR N1 R N2 , C 1-4 alkyl, morpholinyl or pyrrolidinyl; and R N1 and R N2 Each independently is H or C 1-3 alkyl.

111. The compound of claim 109 or 110, or a pharmaceutically acceptable salt thereof, wherein R C1a is –CF2CH3 and R C1b It is –CH3 or CH2CH3.

112. A compound as described in any one of claims 109-111 or a pharmaceutically acceptable salt thereof, wherein each R 9 are independently -NH2, -NHCH3, -N(CH3)2, -N(CH3)(CH2CH3), -N(CH2CH3)2, -CH3 or -CH2CH3.

113. The compound of claim 1, wherein the compound is represented by the formula: or a pharmaceutically acceptable salt thereof, wherein: R C1a is C substituted with 1 to 3 halogen groups 1-3 alkyl; R C1b It is C 1-3 Alkoxy; n1 is 0 or 1 R 3 yes R 9 Yes – NR N1 R N2 ; R N1 and R N2 Each independently is H or C 1-3 alkyl.

114. The compound of claim 113 or a pharmaceutically acceptable salt thereof, wherein R C1a It is –CF2CH3 or –CF(CH3)2.

115. The compound of claim 113 or a pharmaceutically acceptable salt thereof, wherein n1 is 0 or n1 is 1 and R C1b It is –OCH3.

116. A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 113-115, wherein R 9 It is –NHCH(CH3)2.

117. A pharmaceutical composition comprising a compound according to any one of claims 1 to 116 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

118. A method of inhibiting tyrosine kinase 2 (TYK2) activity in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1-116 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 117.

119. A method of treating a disease or condition responsive to inhibition of tyrosine kinase 2 (TYK2) in a subject, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1-116 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 117.

120. The method of claim 119, wherein the disease or condition is inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoma, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, brain trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, Colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxic shock, toxic shock syndrome, osteoporosis, multiple sclerosis, endometriosis, menstrual pain, vaginitis, candidiasis, cancer, fibrosis, systemic sclerosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, alopecia, Alzheimer's disease, skin flushing, eczema, psoriasis, atopic dermatitis, and sunburn.

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