TYK2 inhibitor

Abstract

The present disclosure relates to a compound of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, which is the compound of TIFF2025516586001342.tif4773, wherein all variable moieties are as defined herein, relates to said compound or a pharmaceutically acceptable salt thereof. The compounds of the present disclosure are capable of inhibiting the activity of tyrosine kinase 2 (TYK2). The present disclosure further provides methods for preparing the compounds of the present disclosure and methods of their therapeutic use.

Description

Technical Field

[0001] Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 424,583, filed Nov. 11, 2022, and U.S. Provisional Application No. 63 / 340,142, filed May 10, 2022. The entire contents of each of the above applications are hereby expressly incorporated by reference herein.

[0002] Certain agents that target the degradation of tyrosine kinase 2 (TYK2), as well as methods of making and using such agents, are provided.

Background Art

[0003] Cytokines are small secreted proteins secreted by cells and 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, mainly by extracellular signaling.

[0004] Tyrosine kinase 2 (TYK2) is a cytoplasmic protein kinase that associates with cytokine receptors and is a member of the Janus kinase (JAK) family, which 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, binding of a cytokine to its cognate receptor induces activation of the receptor that associates with JAK, which in turn causes JAK-mediated tyrosine phosphorylation of signal transducer and activator of transcription (STAT) proteins and ultimately activation of the transcriptional activity of a specific set of genes (Schindler et al., 2007, J. Biol. Chem. 282:20059-63). Numerous 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, LlF, 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), the single-chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF), and G protein-coupled receptors (AT1).

[0005] 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, W.T. & O’Shea, J.J., 2006, Immunity 25:695-697). Consistent with this, primary cells derived from TYK2-deficient humans are deficient in type I interferon, IL-6, IL-10, IL-12, and IL-23 signaling. TYK2 signals with other members of the JAK family in combinations of TYK2 / JAK1, TYK2 / JAK2, TYK2 / JAK1 / JAK2.

[0006] Studies have shown that inappropriate JAK activity can occur due to mutations, overexpression, or inappropriate regulation, dysregulation, or deregulation, and overproduction or underproduction of growth factors or cytokines, and thus can cause various biological cell responses related to cell proliferation, cell differentiation, cell function, survival, apoptosis, and cell motility. Inappropriate JAK activity has been associated with a number of 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 disorders such as Alzheimer's disease.

[0007] Small molecule JAK inhibitors have emerged as a major therapeutic advance in the treatment of autoimmune diseases. To date, all known small molecule JAK inhibitors that have advanced to development are active site-specific inhibitors that bind to the adenosine triphosphate (ATP) site of the catalytic domain of the JAK protein (also referred to as the JH1 or “Janus Homology 1” domain), preventing the catalytic activity of the kinase by blocking ATP, downstream phosphorylation, and the resulting pathway signaling (Bryan et al., J. Med. Chem. 2018, 61, 9030-9058).

[0008] Due to the high homology of the ATP active site across the entire kinome, particularly within the JAK family, it is a great challenge to achieve high selectivity for a specific JAK family member while maintaining selectivity across the kinome. As a result, many of the JAK inhibitors that have been developed are either pan-JAK inhibitors or moderately selective for one or more JAK family members. These inhibitors have shown promising results in the treatment of autoimmune diseases, but undesirable side effects resulting in a narrow therapeutic index have been observed, suggesting the need for improved therapies.

[0009] TYK2 has been shown to be important in the differentiation and function of multiple cell types important in inflammatory and autoimmune diseases, including natural killer cells, B cells, and helper T cell subsets. Aberrant TYK2 expression is associated with multiple autoimmune or inflammatory conditions.

[0010] There remains a need for potent compounds that show high selectivity for TYK2 compared to other members of the JAK family. SUMMARY OF THE INVENTION

[0011] One aspect of the present disclosure is a compound of formula (I): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein Ring A is an aromatic ring or an aromatic heterocyclic ring fused to ring B, which is a 5-membered aromatic heterocyclic ring, X 1 is N or CH, X 2 is N or CR 2 wherein X 3 is N or CR 3 wherein X 4 is N or CR 4 wherein Ring C is phenyl, 5- or 6-membered monocyclic heterocyclyl, or 5-6-membered heteroaryl, each of which is optionally substituted by one or more R C and each R is independently halo, -CN, -NR C R N1 R N2 , -NR N3 -C(O)-R 7 , -NR N4 -SO 2 -R 7 , -C(O)-R 7 , -SO 2 -R 7 , -OR O1 , C 1~6 alkyl, alkenyl, 3-7-membered monocyclic carbocyclyl, phenyl, 5-12-membered monocyclic or bicyclic heteroaryl, or 4-9-membered monocyclic or bicyclic heterocyclyl, where the C C represented by R 1~6 alkyl, 3-7-membered monocyclic carbocyclyl, phenyl, 5-12-membered monocyclic or bicyclic heteroaryl, and 4-9-membered monocyclic or bicyclic heterocyclyl are each optionally substituted by one or more R C1 or two R C are grouped together with the intervening atoms to form a 3-7-membered monocyclic carbocyclyl optionally substituted by one or more halo, each R C1 is independently halo, oxo, -CN, -OR O1 , -NR N1 R N2 , -C(O)-R 7 , -C(O)-OR O3 , -SO 2 -R 7 , C 1~6 alkyl, C 3~6 cycloalkyl, phenyl, 5-12-membered monocyclic or bicyclic heteroaryl, or 4-7-membered monocyclic heterocyclyl, where the C C1 represented by R 1~6 alkyl, phenyl, 5-6-membered heteroaryl, and 4-7-membered monocyclic heterocyclyl are each halo, oxo, -CN, -ORO1 、 -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, each optionally substituted by one or more substituents independently selected therefrom, R 1 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, where the C 1 alkyl, phenyl, C 1~6 cycloalkyl, 5 - to 6 - membered heteroaryl, 3 - to 7 - membered monocyclic carbocyclic, and 4 - to 7 - membered monocyclic heterocyclic represented by R 3~6 are each optionally substituted by one or more R 8 s, R 1A is H or C 1~3 alkyl, or or R 1 and R 1A together with the atom to which they are attached form a 5 - or 6 - membered monocyclic heterocycle, R 2 is H or halo, R 3 is H, -NR N1 R N2 、 -CN, halo, -C(O)-R 7 、 -C(O)-OR O3 、 -SO 2 -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, where the C 3 represented by R 1~6Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic, and 4- to 9-membered monocyclic or bicyclic heterocyclic are each optionally substituted with one or more R 9 wherein R 4 is H or halo, each R 7 is independently C 1~6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic, or 4- to 7-membered monocyclic heterocyclic, where the C 7 represented by R 1~6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic, and 4- to 7-membered monocyclic heterocyclic are each optionally substituted with one or more substituents independently selected from halo, oxo, -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, each R 8 is 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 carbocyclic, or 4- to 7-membered monocyclic heterocyclic, each R 9 is independently halo, oxo, -OR O1 , -NR N1 R N2 , -CN, -C(O)-OR O3 , -SO 2 -R 10 , C 1~6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic, or 4- to 10-membered monocyclic or bicyclic heterocyclic, where the C 9 represented by R 1~6Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic, and 4- to 10-membered monocyclic or bicyclic heterocyclic are each optionally substituted with one or more substituents independently selected from 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 carbocyclic, and 4- to 7-membered monocyclic heterocyclic, each R O1 is independently H, C 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, where the C O1 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic or bicyclic carbocyclic, and 4- to 7-membered monocyclic or bicyclic heterocyclic are each optionally substituted with one or more R 1~6 s, O2 each R O2 is independently halo, 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, where 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 are each optionally substituted with one or more halo, C 1~6 alkyl, or -O-C 1~6 alkyl, each R O3 is independently H, 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, where the C O3 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic, and 4- to 7-membered monocyclic or bicyclic heterocyclic are each optionally substituted with one or more halo, C 1~6 ​Alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic, and 4- to 7-membered monocyclic heterocyclic are each optionally substituted with one or more R O2 and R O4 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, where the C O4 represented by R 1~6 alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclic, and 4- to 7-membered monocyclic heterocyclic are each optionally substituted with one or more substituents independently selected from 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 carbocyclic, and 4- to 7-membered monocyclic heterocyclic, R N1 and R N2 are each independently H, C 1~6 alkyl, 4- to 7-membered monocyclic heterocyclic, 5- or 6-membered heteroaryl, or C 3~6 cycloalkyl, where the C N1 alkyl represented by R N2 and R 1~6 is each optionally substituted with C 1~4 alkoxy or phenyl, and the C N1 cycloalkyl, 4- to 7-membered monocyclic heterocyclic, 5- or 6-membered heteroaryl represented by R N2 and R 3~6 is each optionally substituted with C 1~4 alkyl, each R N3 is independently H or C 1~6 alkyl, each R N4 is independently H or C 1~6 alkyl, and the compound or a pharmaceutically acceptable salt thereof.

[0012] In one aspect, the present 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.

[0013] Another aspect of the present disclosure is a method of inhibiting TYK2 activity in a subject in need thereof, the method 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.

[0014] In some aspects, the present disclosure is a method of treating a disease or disorder that is responsive to inhibition of TYK2 in a subject, the method 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.

[0015] The present disclosure also includes the use of at least one compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for the manufacture of a medicament for inhibiting TYK2 activity. The present disclosure also includes the use of at least one compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for the manufacture of a medicament for treating a disease or disorder that is responsive to inhibition of TYK2.

[0016] The present disclosure also provides a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in inhibiting TYK2 activity. The present disclosure also provides a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in treating a disease or disorder that is responsive to inhibition of TYK2.

[0017] Other features or advantages will be apparent from the following detailed description of some embodiments and from the appended claims.

Best Mode for Carrying Out the Invention

[0018] The compounds or pharmaceutically acceptable salts described herein exhibit high potency against TYK2. In addition, the compounds of the present disclosure or pharmaceutically acceptable salts thereof have high selectivity for TYK2 inhibition compared to other members of the JAK family such as JAK1 and JAK2.

[0019] I. Definitions 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 relevant technical field.

[0020] The terms “a” and “an” do not mean a limitation of quantity, but rather mean the presence of at least one reference. Unless otherwise specified herein, descriptions of ranges of values are intended only as a shorthand method of referring individually to each separate value falling within the range, and each separate value is incorporated herein as if it were individually recited herein. All endpoints of all ranges are included within the range and can be combined independently. All methods described herein can be performed in a suitable order unless otherwise specified herein or clearly inconsistent with the context. Unless specifically required, the use of examples or illustrative language (e.g., “such as”) is intended only to better explain the invention and does not result in a limitation of the scope of the present disclosure.

[0021] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. In some embodiments, the alkyl contains 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 contains 6 to 20 carbon atoms. Representative examples of alkyl 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 radical or alkyl moiety may be unsubstituted or substituted with one or more substituents (generally 1 to 3 substituents, except in the case of halogen substituents such as perchloro or perfluoroalkyl).

[0022] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety bonded through an oxygen bridge (i.e., -O-C 1~4 alkyl group, where C1-4 alkyl is as defined herein, the -O-C 1~4 alkyl group). Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, etc. Preferably, the alkoxy group has about 1 to 4 carbons, more preferably 1 to 2 carbons.

[0023] As used herein, the number of carbon atoms in a group is specified herein by the prefix "C x~xx ", where x and xx are integers. For example, "C 1~4 alkyl" is an alkyl group having 1 to 4 carbon atoms.

[0024] As used herein, the term "aryl" refers to a monocyclic or bicyclic aromatic ring system of carbocyclic (all carbon) containing 6 to 10 carbon atoms. Examples of 6- to 10-membered aryl groups include phenyl and naphthyl. In some embodiments, aryl is phenyl.

[0025] The term "cycloalkyl" refers to a monocyclic or bicyclic or spiro hydrocarbon group that is completely saturated with 3 to 7 carbon atoms, 3 to 6 carbon atoms, or 5 to 7 carbon atoms. In some embodiments, cycloalkyl is a 3- to 6-membered monocyclic cycloalkyl.

[0026] As used herein, the terms "carbocycle", "carboscyclic", and "carbocyclic" refer to, for example, a saturated or partially unsaturated (i.e., non-aromatic) monocyclic or bicyclic hydrocarbon group of 3 to 10, 3 to 8, 3 to 7, 3 to 5, 3 to 6, 4 to 6, 5 to 7, or 7 to 10 carbon atoms.

[0027] "Halogen" or "halo" can be fluoro, chloro, bromo, or iodo.

[0028] As used herein, the term "haloalkyl" or "halo-substituted alkyl" refers to an alkyl group as defined herein in which at least one of the hydrogen atoms is replaced by a halo atom. A haloalkyl group can be a polyhaloalkyl including monohaloalkyl, dihaloalkyl, or perhaloalkyl. A monohaloalkyl can have one iodine, bromo, chloro, or fluoro in the alkyl group. Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups in the alkyl group. Typically, a polyhaloalkyl group contains up to 9 or 8 or 7 or 6 or 5 or 4 or 3 or 2 halo groups. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. A perhaloalkyl group refers to an alkyl group in which all hydrogen atoms are replaced by halo atoms.

[0029] As used herein, the term "heteroaryl" refers to a 5- to 6-membered aromatic monocyclic or 8- to 10-membered aromatic bicyclic system having 1 to 4 heteroatoms independently selected from O, N, and S, where N may be oxidized (e.g., N(O)) or quaternized, and S may optionally be oxidized to sulfoxide and sulfone. Examples of 5- to 6-membered monocyclic heteroaryl include, but are not limited to, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, etc. Examples of 8- to 10-membered bicyclic heteroaryl include, but are not limited to, imidazolothiazolyl, imidazopyridinyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, indazolyl, 2H-indazolyl, indolyl, isoindolyl, 2λ 2 -isoindolinyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, purinyl, thienopyridinyl, and thieno[3,2-b]pyridinyl.

[0030] As used herein, the term "heterocyclyl" refers to a saturated or unsaturated monocyclic or bicyclic ring system (e.g., fused, bridged, spiro ring systems) having 3 to 14 ring members, or particularly 3 to 8 ring members, 3 to 7 ring members, 3 to 6 ring members, or 5 to 7 ring members, 4 to 7 ring members, or 4 to 6 ring members, wherein at least 1 of the ring members is a heteroatom and up to 4 (e.g., 1, 2, 3, or 4) of the ring members may be heteroatoms, where the heteroatom is independently selected from O, S, and N, 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 sulfoxide and sulfone. The heterocyclyl group may be attached to the remainder of the compounds of the invention by a heteroatom or a carbon atom. The term azacyclic refers to a non-aromatic heterocyclyl having at least 1 nitrogen ring atom. Examples of azacyclic include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, and morpholine. Examples of fully saturated heterocyclyl groups include heterocycloalkyl groups. Examples of 3- to 7-membered monocyclic heterocyclyls include, but are not limited to, aziridinyl, oxiranyl, thiiranyl, oxaziridinyl, oxazepanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl. In one embodiment, the heterocyclyl is a 5- to 7-membered monocyclic heterocyclyl (saturated or partially unsaturated).Examples include pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, oxazepanyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl.

[0031] The term "bicyclic heterocycle" refers to a bicyclic ring that is partially saturated or fully saturated and contains 1 to 2 heteroatoms independently selected from sulfur, oxygen, and / or nitrogen.

[0032] The term "partially saturated or fully saturated heterocycle" refers to a non-aromatic ring that is either partially saturated or fully saturated and can exist as a monocyclic, bicyclic ring (including fused heterocycles), or a spiro ring. Unless otherwise specified, generally a heterocycle is 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.

[0033] As used herein, "hydroxyl" or "hydroxy" refers to the -OH group.

[0034] As used herein, the term "fused ring system" is a ring system having two cyclic structures that share two adjacent ring atoms. In one embodiment, the fused ring system has 8 to 12 ring members.

[0035] As used herein, the term "bridged ring system" is a ring system having a carbocyclic or heterocyclic ring, wherein two non-adjacent atoms of the ring are linked (bridged) by one or more (preferably 1 to 3) atoms selected from C, N, O, and S. In one embodiment, the bridged ring system has 6 to 8 ring members.

[0036] As used herein, the term "spirocyclic system" refers to a ring system having two cyclic structures sharing one ring atom. In one embodiment, the spirocyclic system has 5 to 8 ring members.

[0037] As used herein, the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted". Generally, the term "optionally substituted" refers to the replacement of a hydrogen radical in a given structure with a radical of a specified substituent. Specific substituents are described in the definitions as well as in the description of the compounds and their examples. Unless otherwise specified, an optionally substituted group may have substituents at each substitutable position of the group, and if two or more positions in any given structure may be substituted with two or more substituents selected from the specified groups, the substituents may be the same or different at all positions.

[0038] The term "oxo" (=O) refers to an oxygen atom bonded to a carbon or sulfur atom by a double bond. Examples include carbonyl, sulfinyl, or sulfonyl groups (-C(O)-, -S(O)-, or -S(O) 2 -), such as part of a ketone, aldehyde, or acid, ester, amide, lactone, or lactam group.

[0039] Unless otherwise specified, the term "compounds of the present 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), rotamers, tautomers, isotopically labeled compounds (including deuterium substitution). When there are moieties capable of forming salts, salts, particularly pharmaceutically acceptable salts, are similarly included.

[0040] The compounds of the present disclosure can be synthesized by synthetic routes that include processes similar to those well-known in the chemical arts, particularly in view of the descriptions contained herein. The starting materials are generally available from commercial sources such as Sigma-Aldrich or can be readily prepared using methods known to those of skill in the art (e.g., generally prepared by the methods described in Louis F. Fieser and Mary F. Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin (also available by Beilstein online database) including the appendices).The protection of functional groups by protecting groups, the protecting groups themselves, and their cleavage reactions are described in standard reference books such as J.F.W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press, London and New York 1973, T.W. Greene and P.G.M. Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley, New York 1999, “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, “Methoden der organischen Chemie” (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, Proteine” (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982. The characteristics of protecting groups are, for example, that they can be easily removed by solvolysis, reduction, photolysis, or alternatively under physiological conditions (e.g., enzymatic cleavage) (i.e., no unwanted secondary reactions occur).

[0041] The compounds and intermediates described herein can themselves be isolated and used as compounds. Alternatively, if there are moieties capable of forming salts, the compounds or intermediates can be isolated and used as their corresponding salts. As used herein, the term “salt” or “salts” refers to acid addition salts or base addition salts of the compounds of the present disclosure. “Salts” include, in particular, “pharmaceutically acceptable salts”.

[0042] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effects and properties of the compounds of the present disclosure and that are usually not biologically or otherwise undesirable. In many cases, the compounds of the present disclosure can form acidic salts and / or basic salts due to the presence of amino and / or carboxyl groups or similar groups.

[0043] Salts of the compounds of the present disclosure having at least one salt-forming base can be prepared by methods known to those skilled in the art. For example, acid addition salts of the compounds of the present disclosure are obtained according to custom, for example, by treating the compound with an acid or a suitable anion exchange reagent. The salt can be converted to the free compound 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.

[0044] Pharmaceutically acceptable acid addition salts, such as acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate can be formed by inorganic and organic acids.

[0045] Examples of inorganic acids from which the salt can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0046] Examples of organic acids from which salts can be derived include 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, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0047] Examples of inorganic bases from which salts can be derived include ammonium salts and metals in columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, and particularly preferred salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0048] Examples of organic bases from which salts can be derived include primary, secondary, and tertiary amines, substituted amines containing naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Specific organic amines include isopropylamine, benzathine, cholineate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0049] Salts can be synthesized from compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in the free acid form with a stoichiometric amount of an appropriate base (e.g., hydroxides, carbonates, bicarbonates of Na, Ca, Mg, or K), or by reacting these compounds in the free base form with a stoichiometric amount of an appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, when practicable, the use of a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable. A list of additional suitable salts can be found, for example, in “Remington’s Pharmaceutical Sciences”, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0050] In some embodiments, the present disclosure provides deuterated compounds in which any position or more positions occupied by hydrogen may include deuterium enrichment that exceeds the natural abundance of deuterium. For example, one or more hydrogen atoms are replaced with deuterium at an abundance at least 3340 times higher compared to the natural abundance of deuterium, such as 0.015% (i.e., at least 50.1% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each specified deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). In one embodiment, hydrogen is present at all positions at its natural abundance.

[0051] Isotopically labeled compounds of formula (I) can generally be prepared by using appropriate isotopically labeled reagents in place of the conventionally used unlabeled reagents by conventional techniques known to those skilled in the art or by processes similar to those described in the appended examples and preparations.

[0052] Pharmaceutically acceptable solvates according to the present disclosure include those in which the crystallization solvent may be isotopically substituted, such as D 2 O, d 6 -acetone, d 6 -DMSO.

[0053] It will be understood by those skilled in the art that the compounds of the present disclosure may have chiral centers and thus may exist in different stereoisomeric forms. As used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric structures that may exist for a given compound of the present disclosure. It is understood that substituents may be attached at chiral centers of carbon atoms. Accordingly, the present disclosure encompasses enantiomers, diastereomers, or racemates of the compounds.

[0054] Any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemic compounds, etc. based on the physicochemical differences of the components, for example, by chromatography and / or fractional recrystallization.

[0055] In compounds containing an asymmetric carbon atom, the compound exists in individual optically active isomeric forms or as mixtures thereof, for example, as a racemic mixture or a mixture of diastereomers. A mixture of diastereomers can be separated into their individual diastereomers based on their physicochemical differences by methods known to those skilled in the art, for example, by chromatography and / or fractional recrystallization. Enantiomers can be separated by converting a mixture of enantiomers into a mixture of diastereomers by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using commercially available chiral HPLC columns.

[0056] Some of the compounds described herein contain one or more chiral centers or axes and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- from the perspective of absolute stereochemistry. According to the present disclosure, any structure that does not specify stereochemistry is understood to encompass all various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, and mixtures thereof (e.g., racemic mixtures or mixtures enriched in enantiomers). Methods for preparing such optically active forms (e.g., resolution of racemates by recrystallization techniques, synthesis from optically active starting materials by chiral synthesis, or chromatographic separation using a chiral stationary phase) are well known in the art. In some embodiments, the compounds described herein are isolated stereoisomers, where each compound has one chiral center and the stereoisomer is in the R configuration. In other embodiments, the compounds described herein are isolated stereoisomers, where each compound has one chiral center and the stereoisomer is in the S configuration. In one embodiment, the compounds described herein are isolated stereoisomers, where each compound has two chiral centers and the stereoisomer is in the RR configuration. In one embodiment, the compounds described herein are isolated stereoisomers, where each compound has two chiral centers and the stereoisomer is in the RS configuration. In one embodiment, the compounds described herein are isolated stereoisomers, where each compound has two chiral centers and the stereoisomer is in the SR configuration. In one embodiment, the compounds described herein are isolated stereoisomers, where each compound has two chiral centers and the stereoisomer is in the SS configuration. In one embodiment, the compounds described herein are racemic mixtures, each having one or two chiral centers.

[0057] When a particular stereoisomer of a compound is indicated 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 total weight of all stereoisomers.

[0058] When the disclosed compound is named or indicated by a structure that does not show stereochemistry and the compound has one chiral center, the name or structure is understood to include one enantiomer of the compound in pure or substantially pure form, and mixtures thereof (e.g., the racemic mixture of the compound and mixtures in which one enantiomer is enriched compared to its corresponding optical isomer).

[0059] It will be understood by those skilled in the art that the compounds of the present disclosure may have chiral centers and thus may exist in different stereoisomeric forms. As used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric structures that may exist for a given compound of the present disclosure. It is understood that substituents may be attached at chiral centers of carbon atoms. Accordingly, the present disclosure includes enantiomers, diastereomers, or racemates of the compounds.

[0060] "Enantiomers" are a pair of stereoisomers that are mirror images that cannot be superimposed on each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term is used to refer to a racemic mixture, if necessary. When indicating the stereochemistry of the compounds of the present disclosure, a single stereoisomer having a known relative configuration and absolute configuration at two chiral centers is indicated using the conventional RS system (e.g., (1S,2S)), and a single stereoisomer having a known relative configuration but an unknown absolute configuration is indicated using a star (e.g., (1R*,2R*)), and a racemic compound is indicated using two letters (e.g., (1RS,2RS) as a racemic mixture of (1R,2R) and (1S,2S); (1RS,2SR) as a racemic mixture of (1R,2S) and (1S,2R)).

[0061] "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. If a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified as either R or S. An optically resolved compound with an unknown absolute configuration can be indicated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) in which it rotates plane-polarized light at the wavelength of the sodium D line. Alternatively, an optically resolved compound can be defined by the respective retention times of the corresponding enantiomers / diastereomers by chiral HPLC.

[0062] Some of the compounds described herein contain one or more asymmetric centers or axes and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- from the perspective of absolute stereochemistry.

[0063] Unless otherwise specified, the compounds of the present disclosure are intended to encompass all such possible stereoisomers, including racemic mixtures, optically pure forms, and intermediate mixtures. The optically active (R)- and (S)-stereoisomers can be prepared using chiral synthons or chiral reagents, or can be resolved using conventional techniques (e.g., chiral SFC or separated using an appropriate solvent or solvent mixture to achieve good separation on HPLC chromatography columns such as CHIRALPAK RTM and CHIRALCEL RTM ). When the compound contains a double bond, the substituents can be in the E configuration or the Z configuration. When the compound contains a disubstituted cycloalkyl, the cycloalkyl substituents can have the cis configuration or the trans configuration. All tautomeric forms are also intended to be included.

[0064] The disclosed compounds may exist in tautomeric forms, and mixtures and separated individual tautomers are intended. All such forms are included within the scope of the present disclosure. In addition, some compounds may exhibit polymorphism. The terms “tautomer” or “tautomeric form” refer to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversion by the movement of a proton, e.g., keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is an imidazole moiety where the proton can move between two ring nitrogens. Valence tautomers include interconversion by some rearrangement of the bonding electrons.

[0065] II. Compounds of the Present Disclosure In a first aspect, the compounds of the present disclosure are represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the variable moieties are as described above.

Chemical formula

[0066] In a second embodiment, for the compound of formula (I) or a pharmaceutically acceptable salt thereof, R 1A is H or -CH 3 and the remaining variable moieties are as described in the first aspect or the first embodiment.

[0067] In a third embodiment, the compound is of formula (II), (III), (IV), (V), or (VI):

Chemical formula

[0068] In a fourth embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 2 is H or F, and the remaining variable parts are as described in the first aspect, or the first, second, or third embodiment.

[0069] In a fifth embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 2 is H, and the remaining variable parts are as described in the first aspect, or the first, second, or third embodiment.

[0070] In a sixth embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, ring C is phenyl or a 5- to 6-membered heteroaryl, each of which is optionally substituted by 1 to 3 RCs, and the remaining variable parts are as described in the first aspect, or the first, second, third, fourth, or fifth embodiment. In some embodiments, ring C is not a pyridinyl group. In some embodiments, ring C is not a phenyl group. In an alternative sixth embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, ring C is phenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- to 6-membered heteroaryl, each of which is optionally substituted by 1 to 3 R C and the remaining variable parts are as described in the first aspect, or the first, second, third, fourth, or fifth embodiment.

[0071] In the seventh embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, 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 and the remaining variable moieties are as described in the first aspect or the first, second, third, fourth, or fifth embodiment. In some embodiments, ring C is selected from imidazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrimidinyl, thiadiazolyl, thiazolyl, and triazinyl, each of which is optionally substituted by one or three RC. In some embodiments, ring C is selected from pyrazinyl, pyrimidinyl, and thiazolyl, each of which is optionally substituted by one or three RC. In an alternative seventh embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, ring C is selected from pyridinonyl, 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 and the remaining variable moieties are as described in the first aspect or the first, second, third, fourth, or fifth embodiment.

[0072] In the eighth embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, ring C is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0073] In a ninth embodiment, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, ring C is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0074] In a tenth embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, each R C is independently halo, -NR N1 R N2 , -NR N3 -C(O)-R 7 , -NR N4 -SO 2 -R 7 , -C(O)-R 7 , -OR O1 C 1~6 alkyl, C 3~6 cycloalkyl, or a 4- to 8-membered monocyclic or bicyclic heterocyclyl, wherein the C C represented by R 1~6 alkyl, C3~6 Cycloalkyl, and monocyclic or bicyclic heterocyclyl of 4 to 8 members, each is optionally substituted with 1 to 3 R C1 and the remaining variable moieties 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 is C 1~3 haloalkyl. In some embodiments, at least one R C is C 2 haloalkyl. In some embodiments, at least one R C is -CF 2 CH 3 . In an alternative tenth embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salts thereof, each R C is independently halo, -NR N1 R N2 , -NR N3 -C(O)-R 7 , -NR N4 -SO 2 -R 7 , -C(O)-R 7 , -OR O1 , C 1~6 alkyl, alkenyl, C 3~6 cycloalkyl, phenyl, monocyclic or bicyclic heteroaryl of 5 to 12 members, or monocyclic or bicyclic heterocyclyl of 4 to 8 members, or two R C are grouped together with the intervening atoms to form a monocyclic carbocyclic ring of 3 to 7 members optionally substituted with 1 or 2 halo, wherein the C C represented by R 1~6 alkyl, C 3~6 cycloalkyl, monocyclic or bicyclic heteroaryl of 5 to 12 members, and monocyclic or bicyclic heterocyclyl of 4 to 8 members, each is optionally substituted with 1 to 3 R C1is arbitrarily substituted, and the remaining variable parts are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment, or any alternative embodiment described therein.

[0075] In the eleventh embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R C C represented by 3~6 The cycloalkyl is selected from cyclobutane, cyclopentane, cyclopropane, and cyclohexane, and R C The 4- to 8-membered monocyclic or bicyclic heterocyclyl represented by is selected from azetidinyl, 2,6-diazaspiro[3.3]heptanyl, isothiazolidinyl, isothiazolidinedioxide, morpholinyl, oxabicycloheptanyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 2-oxa-6-azaspiro[3.4]octanyl, and 7-oxabicyclo[2.2.1]heptanyl, where C 3~6 Each of the cycloalkyl and the 4- to 8-membered monocyclic or bicyclic heterocyclyl is optionally substituted with 1 to 3 R C1 and the remaining variable parts are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment, or any alternative embodiment described therein, or any alternative embodiment described therein. In an alternative eleventh embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, wherein R C C represented by 3~6 The cycloalkyl is selected from cyclobutyl, cyclopentyl, cyclopropyl, and cyclohexyl, and R CThe 5- to 12-membered monocyclic or bicyclic heteroaryl represented by is furanyl, pyrazolyl, imidazolyl, triazolyl, isoxazole, pyridinyl, pyrimidinyl, isoindolinyl, 3H-imidazo[4,5-b]pyridinyl, 1H-benzo[d][1,2,3]triazolyl, and R C The 4- to 8-membered monocyclic or bicyclic heterocyclyl represented by is selected from azetidinyl, 2,6-diazaspiro[3.3]heptanyl, isothiazolidinyl, isothiazolidinedioxide, morpholinyl, oxabicycloheptanyl, oxetanyl, piperidinyl, piperizinyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, pyridin-2(1H)-oyl, tetrahydro-2H-pyranyl, 2-oxabicyclo[2.1.1]hexanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 7-oxabicyclo[2.2.1]heptanyl, where 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 with 1 to 3 R C1 or two R C are combined with the intervening atoms to form a cyclopentyl substituted with one or two halos, and the remaining variable moieties 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.

[0076] In the twelfth embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or their pharmaceutically acceptable salts, R C The C 3~6 cycloalkyl and 4- to 8-membered monocyclic or bicyclic heterocyclyl are represented by the following formula: [Chemical formula] represented by, wherein [Chemical formula] represents a bond to ring C, n is 0, 1, 2, or 3, and the remaining variable parts are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, or ninth embodiment, or any alternative embodiment described therein. In an alternative twelfth embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R C C represented by 3~6 Cycloalkyl and 4- to 8-membered monocyclic or bicyclic heterocyclyl are of the following formula:

Chemical formula

Chemical formula

Chemical formula

[0077] In a thirteenth embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R C C represented by 3~6 Cycloalkyl and 4- to 8-membered monocyclic or bicyclic heterocyclyl are

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0078] In a fourteenth embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, each R C1 is independently halo, -CN, -OR O1 , -NR N1 R N2 , -C(O)-R 7 , -C(O)-OR O3 , -SO 2 -R 7 , C 1~6 alkyl, or 4- to 6-membered monocyclic heterocyclyl, wherein the C C1 alkyl represented by 1~6 is optionally substituted with 1 to 3 substituents independently selected from halo and -OR a1 , and Ra1 is H, C 1~4 alkyl, or 4- to 6-membered heterocyclyl, and the remaining variable moieties 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 in any alternative embodiments described therein. In an alternative fourteenth embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salts thereof, each R C1 is independently halo, -CN, -OR O1 , -NR N1 R N2 , -C(O)-R 7 , -C(O)-OR O3 , -SO 2 -R 7 , C 1~6 alkyl, C 3~6 cycloalkyl, or 4- to 6-membered monocyclic heterocyclyl, wherein the C C1 alkyl represented by R 1~6 is optionally substituted with 1 to 3 substituents independently selected from halo and -OR a1 , and R a1 is H, C 1~4 alkyl, or 4- to 6-membered heterocyclyl, and the remaining variable moieties 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 in any alternative embodiments described therein.

[0079] In a fifteenth embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salts thereof, each R C1 is F, -CN, OH, -OCH 3 , -OCHF 2 , -NH 2 , -N(CH 3 ) 2 , -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH2 -OH, -CH 2 -CH 3 , -CH(CH 3 ) 2 , -C(O)-CH 3 , -C(O)-OC(CH 3 ) 3 , -SO 2 -CH 3 ,

Chem.

Chem.

Chem.

Chemical formula

[0080] In the sixteenth embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, each R C is Cl, -CH 3 -, -CH 2 F, -CHF 2 -, -CF 3 -, -CH 2 -CH 3 -, -CH 2 -CH 2 F, -CH 2 -CHF 2 -, -CH 2 -CF 3 -, -CHF-CH 2 F, -CH 2 -CHF 2 -, -CH 2 -CF 3 -, -C(CH 3 ) 3 -, -CF 2 CH 3 -, -CHF-CH 3 -, -CH(CH 3 ) 2 -, -CF(CH 3 ) 2 -, -(CH 3 ) 2 -CH 2 F, -CF(CH 3 ) 2 -, -CH(CH 3 )-CHF 2 -, -CH(CH 3 )-CF 3 -, -(CH 3 )2 -CF 3 、-CH 2 -CH 2 -CN、-CH 2 -C(CH 3 ) 2 -CN、-C(CH 3 ) 2 -OH、-CH(CH 3 )-OCH 3 、-C(CH 3 ) 2 -OCH 3 、-CH(OH)-CH 3 、-OCH 3 、-O-CHF 2 、-C(CH 3 )(OCH 3 )-CH 2 -OCH 3 、-O-CF 3 、-CH(OCH 3 )-cyclopropyl、-O-CH 2 CH 3 、-O-CH 2 CHF 2 、-O-CH(CH 3 ) 2 、-O-CH(CF 3 ) 2 、-O-CH 2 -OCH 3 、-O-CH(CH 3 )-OCH 3 、-O-CH(CH 3 )-CH 2 -OCH 3 、-O(CH 3 ) 2 -OCH 3 、-O-CH 2 -CH 2 -O-CH 3 、-O-CH 2 -CH(CH 3 )-OCH 3 、-CF(CH 3 )-CH 2 -OCH 3 、-CH(CF 3 )-NH 2 、-CH(OCH 3 )-C(CH 3 ) 3 It should be noted that "シクロプロピル" is translated as "cyclopropyl" which means cyclopropyl in chemical terms. Also, some of the hyphens in the original text seem to be used in a way that might be specific to a certain chemical or technical context and their exact meaning and correct formatting might need further clarification based on more background knowledge., -NHC(O)-CH 3 , -NH-SO 2 -CH 3 , -N(CH 3 ) 2 , -NHCH(CH 3 ) 2 , -CHF-cyclopropyl, -CF(CH 3 )-cyclopropyl, -NH-cyclohexyl, -N(CH 3 )-CH 2 -CH 2 -OCH 3 , -CH(NH 2 )-CF 3 ,

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0081] In the seventeenth embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 1 is C 1~4 alkyl or C 3~6 cycloalkyl, wherein the C 1 alkyl and C 1~4 cycloalkyl represented by R 3~6 are each independently selected from halo, -CN, C 1~3 alkoxy, C 1~3 alkyl, and C 1~3 haloalkyl for 1 to 3 R 8is optionally replaced by, and the remaining variable parts are as described in the first aspect, or the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment, or any alternative embodiment described therein. In an alternative seventeenth embodiment, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 1 is H, C 1~4 alkyl, -OR 1A -NR N1 R N2 or C 3~6 cycloalkyl, where the C 1 alkyl and C 1~4 cycloalkyl represented by are each optionally substituted by 1 to 3 R 3~6 independently selected from halo, -CN, C 1~3 alkoxy, C 1~3 alkyl, and C 1~3 haloalkyl, and R 8 is C 1A alkyl, R 1~4 is C N1 alkyl, and R N2 and R 1~4 are each independently H or C

[0082] In an eighteenth embodiment, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 1 is halo, -CN, C 1~3 alkoxy, C 1~3 alkyl, and C 1~3 haloalkyl, and C 8 alkyl optionally substituted by 1 to 3 R 1~4is alkyl, and the remaining variable moieties are as described in the first aspect, or in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, or 16th embodiment, or in any alternative embodiment described therein.

[0083] In the 19th embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 8 is, in each occurrence, independently halo, -CN, C 1~3 is alkoxy, and the remaining variable moieties are as described in the first aspect, or in the 17th or 18th embodiment, or in any alternative embodiment described therein.

[0084] In the 20th embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, each R 8 is independently selected from F, -CN, and -OCH 3 and the remaining variable moieties are as described in the first aspect, or in the 17th or 18th embodiment, or in any alternative embodiment described therein.

[0085] In the 21st embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 1 is -CH 3 is -CH 2 -CH 3 is -CH 2 -CHF 2 is -CH 2 -CH 2 -CN, -CH 2 -CH 2 -OCH 3 is cyclopropyl,

Chemical formula

Chemical formula

[0086] In a twenty-second embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 3 is H, -NR N1 R N2 , halo, -C(O)-R 7 , -C(O)-OR O3 , -SO 2 -R 7 , -OR O4 , C 1~6 alkyl, C 3~6Cycloalkyl, a monocyclic or bicyclic heterocyclyl of 4 to 9 members, where R 3 The C represented by 1~6 alkyl, C 3~6 cycloalkyl, and the monocyclic or bicyclic heterocyclyl of 4 to 9 members are each optionally substituted by 1 to 3 R 9 , and the remaining variable moieties 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 an alternative twenty-second embodiment, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 3 is H, -NR N1 R N2 , halo, -C(O)-R 7 , -C(O)-OR O3 , -SO 2 -R 7 , -OR O 4, C 1~6 alkyl, alkenyl C 3~6 cycloalkyl, 5- or 6-membered heteroaryl, a monocyclic or bicyclic heterocyclyl of 4 to 10 members, where R 3 The C represented by 1~6 alkyl, C 3~6 cycloalkyl, and the monocyclic or bicyclic heterocyclyl of 4 to 9 members are each optionally substituted by 1 to 3 R 9 , and the remaining variable moieties 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.

[0087] In a twenty-third embodiment, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 3is C cycloalkyl or 4- to 9-membered monocyclic or bicyclic heterocyclyl, each optionally substituted by one or three Rs 9 and the remaining variable moieties are as described in the first aspect, or in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, or 21st embodiment, or any alternative embodiments described therein. In an alternative 23rd embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 3~6 is C cycloalkyl or 4- to 9-membered monocyclic or bicyclic heterocyclyl, each optionally substituted by one or three Rs 3 and the remaining variable moieties are as described in the first aspect, or in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, or 21st embodiment, or any alternative embodiments described therein. 9 is C cycloalkyl or 4- to 10-membered monocyclic or bicyclic heterocyclyl, each optionally substituted by one or three Rs 3~6 and the remaining variable moieties are as described in the first aspect, or in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, or 21st embodiment, or any alternative embodiments described therein.

[0088] In a 24th embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 3 is azetidinyl, cyclobutyl, cyclopentyl, cyclopropyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3,6-diazabicyclo[3.2.0]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 2λ 2 ,6-diazaspiro[3.3]heptanyl, 1λ 2 ,7λ 2-diazaspiro[4.4]nonanyl, oxetanyl, piperidinyl, piperazinyl, piperazin-2-on-yl, pyrrolidinyl, pyrrolidin-2-on-yl, and tetrahydropyranyl, each of which is optionally substituted by 1 to 3 R 9 and the remaining variable moieties are 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, or twenty-first embodiment, or any alternative embodiment described therein. In some embodiments, R 3 is selected from pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, and 3,6-diazabicyclo[3.1.1]heptanyl, each of which is optionally substituted by 1 to 3 R 9 . In some embodiments, R 3 is pyrrolidinyl optionally substituted by 1 to 3 R 9 . In an alternative twenty-fourth embodiment, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 3is pyrazolyl, pyridinyl, azetidinyl, cyclobutyl, cyclopentyl, cyclopropyl, 2-oxaspiro[3.3]heptanyl, 1,7-diazaspiro[4.4]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 7-oxa-2-azaspiro[3.5]nonanyl, 1-oxa-7-azaspiro[4.4]nonanyl, 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]nonanyl, 1,6-diazaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, 3,6-diazabicyclo[3.2.0]heptanyl, 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]heptanyl, 1,6-diazaspiro[3.4]octanyl, 1,7-diazaspiro[4.4]nonanyl, 2-oxa-7-azaspiro[4.4]nonanyl, octahydropyrano[2,3-c]pyrrolyl, octahydro-1H-pyrrolo[3,4-b]pyridinyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydropyrrolo[3,4-b]pyrrolyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 1,4-oxazepanyl, 6-oxa-2-azaspiro[3.5]nonanyl, 5-oxa-2-azaspiro[3.4]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3,6-diazabicyclo[3.2.0]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 2λ 2 ,6-diazaspiro[3.3]heptanyl, 1λ 2 ,7λ2 -Diaza-spiro[4.4]nonanyl, oxetanyl, piperidinyl, piperazinyl, piperazin-2-one-yl, pyrrolidinyl, pyrrolidin-2-one-yl, and tetrahydropyranyl, each of which is optionally substituted by 1 to 3 R 9 and the remaining variable moieties are 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, or twenty-first embodiment, or any alternative embodiment described therein.

[0089] In the twenty-fifth embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 3 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

[0090] In the twenty - sixth embodiment, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 3 is

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0091] In a 27th embodiment, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 3 is H, -NR N1 R N2 , halo, -C(O)-R 7 , -C(O)-OR O3 , -SO 2 -R 7 , -OR O4 , or C 9 alkyl optionally substituted with 1 to 3 R 1~6 wherein the remaining variable moieties 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.

[0092] In the 28th embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salts thereof, each R 9 is independently halo, -OH, -OC 1~4 alkyl, -NR a2 R a3 , -CN, -C(O)-OR a1 , -SO 2 -R a1 , C 1~4 alkyl, or C 3~6 cycloalkyl, wherein the C 9 represented by R 1~4 alkyl and C 3~6 cycloalkyl are each optionally substituted with 1 to 3 substituents independently selected from halo and C 1~3 alkoxy, and R a1 , R a2 , and R a3 are each independently C 1~3 alkyl, and the remaining variable moieties are as described in the first aspect, or as in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, or 27th embodiment, or any alternative embodiments described therein. In some embodiments, each R 9 is independently halo, -OR a1 , -NR a2 R a3 , -CN, -C(O)-OR a1 , -SO 2 -R a1 , C 1~4 alkyl, C 3~6 cycloalkyl, or a 4- to 7-membered monocyclic heterocyclyl, wherein the C 9 represented by R 1~4 alkyl and C 3~6 cycloalkyl are each optionally substituted with 1 to 3 substituents independently selected from halo and C 1~3 alkoxy, and R a1 , Ra2 , and R a 3 is independently H or C 1~3 In an alternative twenty-eighth embodiment, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharma- ceutically acceptable salt thereof, R is alkyl. 9 are independently halo, -OR a1 , -NR a2 R a3 , -CN, -C(O)-OR a1 , -SO 2 -R a1 , C 1~4 Alkyl, C 3~6 cycloalkyl, or 4-10 membered monocyclic or bicyclic heterocyclyl, where R 9 The C represented by 1~4 Alkyl, 4-10 membered monocyclic or bicyclic heterocyclyl, and C 3~6 Cycloalkyl is halo, -OH, -CN, C 1~4 Alkyl, and C 1~3 is optionally substituted with 1 to 3 substituents independently selected from alkoxy; a1 , R a2 , and R a 3 is independently H, C 3~4 Cycloalkyl, or C 1~3 is alkyl, R a1 , R a2 , and R a3 The C represented by 3~4 Cycloalkyl is C 1~4 is optionally substituted with alkyl, R a1 , R a2 , and the C represented by Ra3 1~3 The alkyl is optionally substituted with phenyl, and the remaining variables are 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, or twenty-seventh embodiment, or any alternative embodiment described therein.

[0093] In the 29th embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or pharmaceutically acceptable salts thereof, each R 9 is independently selected from F, -OH, -OCH 3 , -OCHF 2 , -OCF 3 , -N(CH 3 ), -CN, -CH 2 , -CF 3 , -C(O)-OCH 3 CH 2 CH 3 , -SO 2 -CH 3 , -CH 2 -OCH 3 , -CH 2 -CH 2 -OCH 3 , -CH 2 -CH 3 , cyclopropyl, -CHF 2 , and -CH 2 -CF 3 , and the remaining variable moieties are as described in the first aspect, or as in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, or 27th embodiment, or any alternative embodiments described therein. In some embodiments, each R 9 is independently selected from F, OH, -OCH 3 , -OCHF 2 , -OCF 3 , -NHCH 3 , -NH 2 , -N(CH 3 ), -N(CH 2 CH 2 CH 3 ), -N(CH 2 )(CH 3 )(CH 2 CH 3 ), -NHCH(CH 3 ), -CN, -CH 2 , -CF 3 , -C(O)-OCH 3 CH 2CH 3 、 -SO 2 -CH 3 、 -CH 2 -OCH 3 、 -CH 2 -CH 2 -OCH 3 、 -CH 2 -CH 3 、 pyrrolidinyl, morpholinyl, cyclopropyl, -CHF 2 、 and -CH 2 -CF 3 is independently selected from. In an alternative 29th embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, each R 9 is F, OH, -OCH 3 、 -OCH 2 CH 3 、 -OCH(CH 3 ) 2 、 -OCHF 2 、 -OCF 3 、 -OCD 3 、 -O - cyclopropyl, -NHCH 3 、 -NH 2 、 -N(CH 3 ) 2 、 -N(CD 3 ) 2 、 -N(CH 2 CH 3 ) 2 、 -N(CH 3 )(CH 2 CH 3 )、 -NHCH(CH 3 ) 2 、 -NHCH 2 CH 3 、 -CN、 -CH 3 、 -CH 2 F、 -CF 3 、 -C(O)-OCH 2 CH 3 、 -SO 2 -CH 3 、 -CH 2 -OCH 3 、 -CH 2 -CH 2 -OCH 3 、 -CH 2 -CH3 、 -CH 2 -CN, pyrrolidinyl, morpholinyl, azetidinyl, cyclopropyl, -CHF 2 、 -CH 2 -CF 3 、

Chem.

[0094] In the 30th embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 9 two of which are grouped together with the atoms between them to form a 4- to 6-membered monocyclic heterocyclyl optionally substituted with one or two substituents independently selected from halo, C 1~4 alkyl, and C 1~4 haloalkyl, and the remaining variable moieties are as described in the first aspect, or in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, or 27th embodiment, or any alternative embodiments described therein.

[0095] In the 31st embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 3 is H, Cl, -CH 3 、 -CH 2 F, -CHF 2 、 -CF 3 、 -CH 2 -CH 3 、 -CHF-CH3 , -CH(CH 3 ) 2 , -CHF-CH 2 F, -CH 2 -CH 2 -CN, -CH 2 -CH 2 -CH 3 , -CH 2 -CH(CH 3 ) 2 , -CH 2 -cyclopropyl, -CH 2 -OCH 3 , -CH(CH 3 )-CH 2 -CH 3 , -CH(CH 3 )-CF 3 , -CH(CH 3 )-OCH 3 , -N(CH 3 ) 2 , -OCH 3 , -N(CH 3 )-CH 2 -CH 2 -OCH 3 , -C(O)-OCH 3 , -SO 2 -CH 3 , -O-CH(CH 3 ) 2 , -O-CH 2 -CH 2 -OCH 3 ,

Chem.

Chem.

Chem.

Chem.

[0096] In the thirty-second embodiment, for the compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, each R 7 is independently C 1~6 alkyl, C 3~6 cycloalkyl, or 4- to 6-membered monocyclic heterocyclyl, wherein the C 7 represented by R 1~6 alkyl, C 3~6Cycloalkyl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted with 1 to 3 substituents independently selected from halo, C 1~3 alkyl, and C 1~3 haloalkyl, and the remaining variable moieties 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 embodiment, or any alternative embodiment described therein.

[0097] In a thirty-third embodiment, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, each R 7 is -CH 3 ,

Chemical formula

[0098] In a thirty-fourth embodiment, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, each R O1 is independently H, C 1~6 alkyl, a 3- to 6-membered monocyclic or bicyclic carbocyclyl, a 4- to 6-membered monocyclic heterocyclyl, or a 6-membered heteroaryl, where the C O1 alkyl, 3- to 6-membered monocyclic or bicyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, and 6-membered heteroaryl represented by R 1~6 are each optionally substituted with 1 to 3 RO2 is optionally substituted by, each R O2 is independently halo, OH, -CN, C 1~4 alkoxy, C 1~4 alkyl, a 3- to 5-membered monocyclic carbocyclyl, a 4- to 7-membered monocyclic or bicyclic heterocyclyl, or phenyl, wherein said C 1~4 alkyl, a 3- to 5-membered monocyclic carbocyclyl, a 4- to 7-membered monocyclic or bicyclic heterocyclyl, and phenyl are each optionally substituted by C 1~3 alkoxy, C 1~3 haloalkoxy, or 1 to 3 halos, and the remaining variable moieties are as described in the first aspect, or in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, or 33rd embodiments, or any alternative embodiments described therein.

[0099] In a 35th embodiment, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R O1 or R O2 represents a 4- to 7-membered monocyclic or bicyclic heterocyclyl or 6-membered heteroaryl independently selected from morpholino, oxetanyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, azetidinyl, oxaspiro[2.4]heptane, pyrrolidinyl, and piperidinyl, and the remaining variable moieties are as described in the first aspect, or in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, or 33rd embodiments, or any alternative embodiments described therein.

[0100] In a thirty-sixth embodiment, for a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharma- ceutically acceptable salt thereof, each R O2 are F, -CN, OH, -OCH 3 , -CH 3 , -CHF 2 , -CF 3 , [ka] are independently selected from [ka] is R O1 and the remaining variables are 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 embodiment, or any alternative embodiments described therein.

[0101] In a thirty-seventh embodiment, for a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharma- ceutically acceptable salt thereof, each R O1 -H, -CH 3 , -CHF 2 , -CF 3 , -CH 2 -CH 3 , -CH 2 -CHF 2 , -CH 2 -CF 3 , -CH 2 -CH 2 -CH 3 , -CH(CH 3 ) 2 , -CH(CF 3 ) 2 , -CH 2 -CH 2 -OCH 3 , -CH(CH 3)-CH 2 -OCH 3 , -CH 2 -CH(CH 3 )-OCH 3 , [ka] and the remaining variables are 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, or thirty-third embodiment, or any alternative embodiments described therein.

[0102] In a thirty-eighth embodiment, for a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharma- ceutically acceptable salt thereof, each R O3 are independently halo and C 1~4 C optionally substituted with 1 to 3 substituents independently selected from haloalkyl 1~6 and the remaining variables are 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, thirty-fifth, thirty-sixth, or thirty-seventh embodiment, or any alternative embodiments described therein.

[0103] In a thirty-ninth embodiment, for a compound of Formula (I), (II), (III), (IV), (V), or (VI), or a pharma- ceutically acceptable salt thereof, each R O3 are independently -CH 3 , -CH 2 CH 3 , or -C(CH 3 ) 3and the remaining variable part is as described in the first embodiment, 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, thirty-fifth, thirty-sixth, or thirty-seventh embodiment, or any alternative embodiment described therein.

[0104] In the fortieth embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R O4 is each independently optionally substituted with 1 to 3 substituents selected from halo and C 1~3 alkoxy-substituted C 1~4 alkyl or C 3~6 cycloalkyl, and the remaining variable part is as described in the first embodiment, 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, thirty-fifth, thirty-sixth, thirty-seventh, thirty-eighth, or thirty-ninth embodiment, or any alternative embodiment described therein.

[0105] In the forty-first embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R O4 is -CH 3 , -CH 2 -CH 3 , -CH(CH 3 ) 2 , -CH 2 -CH 2 -OCH 3 , and

Chemical formula

[0106] In the 42nd embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R N1 and R N2 are each independently H, C 1~3 C optionally substituted with alkoxy 3~6 cycloalkyl or C 1~4 alkyl, and the remaining variable parts are as described in the first aspect, or in the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, 36th, 37th, 38th, 39th, 40th, or 41st embodiment, or any alternative embodiment described therein.

[0107] In the 43rd embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R N1 and R N2 are each independently H, -CH 3 , -CH(CH 3 ) 2 , -CH 2 -CH 2 -OCH 3represents cyclohexyl, and the remaining variable part is 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 embodiment, or any alternative embodiment described therein.

[0108] In the forty - fourth embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R N3 is H, and the remaining variable part is 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 embodiment, or any alternative embodiment described therein.

[0109] In the forty - fifth embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R N4 is H, and the remaining variable part is 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 embodiment, or any alternative embodiment described therein.

[0110] In the 46th embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 4 is H, and the remaining variable moieties are as described in the first aspect, or the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, 36th, 37th, 38th, 39th, 40th, 41st, 42nd, 43rd, 44th, or 45th embodiment, or any alternative embodiment described therein. In an alternative 46th embodiment, for the compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 4 is H or -CH 3 and the remaining variable moieties are as described in the first aspect, or the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th, 31st, 32nd, 33rd, 34th, 35th, 36th, 37th, 38th, 39th, 40th, 41st, 42nd, 43rd, 44th, or 45th embodiment, or any alternative embodiment described therein.

[0111] In the 47th embodiment, the compound is of formula (VII) or (VIII):

Chemical formula

Chemical formula

[0112] In the 48th embodiment, for a compound of formula (VII), (VII’), (VIII), or (VIII’), or a pharmaceutically acceptable salt thereof, ring C is pyridinyl, pyrazinyl, or pyrimidinyl, each of which is optionally substituted by one or two R C and the remaining variable moieties are as described in the first aspect or the 47th embodiment or any alternative embodiment described therein.

[0113] In the 49th embodiment, for a compound of formula (VII), (VII’), (VIII), or (VIII’), or a pharmaceutically acceptable salt thereof, ring C is pyrimidinyl, pyrazinyl, or thiazolyl, each of which is optionally substituted by one or two R C and the remaining variable moieties are as described in the first aspect or the 47th embodiment or any alternative embodiment described therein.

[0114] In the 50th embodiment, for a compound of formula (VII), (VII’), (VIII), or (VIII’), or a pharmaceutically acceptable salt thereof, ring C is

Chemical formula

Chemical formula

[0115] In the 51st embodiment, for the compound of formula (VII), (VII’), (VIII), or (VIII’), or a pharmaceutically acceptable salt thereof, ring C is

Chemical formula

Chemical formula

[0116] In the 52nd embodiment, for the compound of formula (VII), (VII’), (VIII), or (VIII’), or a pharmaceutically acceptable salt thereof, ring C is

Chemical formula

Chemical formula

[0117] In the 53rd embodiment, for the compound of formula (VII) or (VIII) or a pharmaceutically acceptable salt thereof, ring C is

Chemical formula

Chemical formula

[0118] In the 54th embodiment, for the compound of formula (VII) or (VIII) or a pharmaceutically acceptable salt thereof, each RC is independently -ORO1, C1-2 alkyl, C1-2 haloalkyl, or an oxygen-containing 5-membered heterocyclyl optionally substituted with one RC1, and the remaining variable parts are as described in the first aspect, or the 47th, 48th, 49th, 50th, 51st, 52nd, or 53rd embodiment. In some embodiments, at least one of R C is C 1~2 haloalkyl, more specifically, -CF 2 CH 3 is.

[0119] In the 55th embodiment, for the compound of formula (VII), (VII’), (VIII), or (VIII’) or a pharmaceutically acceptable salt thereof, R C is tetrahydrofuranyl optionally substituted with one R C1 and the remaining variable parts are as described in the first aspect, or the 47th, 48th, 49th, 50th, 51st, 52nd, or 53rd embodiment, or any alternative embodiment described therein.

[0120] In the 56th embodiment, for the compound of formula (VII), (VII’), (VIII), or (VIII’) or a pharmaceutically acceptable salt thereof, R C is

Chemical formula

Chemical formula

[0121] In the 57th embodiment, for a compound of formula (VII), (VII’), (VIII), or (VIII’), or a pharmaceutically acceptable salt thereof, each R C1 is independently F or -OCH 3 and the remaining variable moieties are as described in the first aspect, or in embodiments 47, 48, 49, 50, 51, 52, 53, 54, 55, or 56, or any alternative embodiments described therein, or any alternative embodiments described therein.

[0122] In the 58th embodiment, for a compound of formula (VII), (VII’), (VIII), or (VIII’), or a pharmaceutically acceptable salt thereof, each R C is -CH 3 -CF 2 CH 3 -OCH 3 -O-CH 2 -CH 2 -O-CH 3 ,

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

[0123] In a 59th embodiment, for the compounds of formula (VII), (VII’), (VIII), or (VIII’), or a pharmaceutically acceptable salt thereof, R 3The 5- to 7-membered monocyclic or bicyclic heterocyclyl represented by is selected from 3,6-diazabicyclo[3.1.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, piperazinyl, and pyrrolidinyl, each of which is optionally substituted by one or two R 9 and the remaining variable moieties are as described in the first aspect, or in embodiments 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, or 58, or in any alternative embodiments described therein.

[0124] In the 60th embodiment, for the compound of formula (VII), (VII’), (VIII), or (VIII’), or a pharmaceutically acceptable salt thereof, R 3 is H, -CH 2 CH 3 ,

Chemical formula

Chemical formula

[0125] In the 61st embodiment, for the compound of formula (VII), (VII’), (VIII), or (VIII’), or a pharmaceutically acceptable salt thereof, R 3 is H, -CH 2 CH 3 ,

Chemical formula

Chemical formula

[0126] In a 62nd embodiment, for a compound of formula (VII), (VII'), (VIII), or (VIII'), or a pharmaceutically acceptable salt thereof, each R 9 is independently selected from -OH, -OCH 3 , -N(CH 3 ) 2 , and -CH 3 , and the remaining variable moieties are as described in the first aspect, or in embodiments 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, or 58, or in any alternative embodiments described therein. In some embodiments, each R 9 is independently selected from -OH, -OCH 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), -N(CH 2 CH 3 ) 2 , pyrrolidinyl, morpholinyl, -CH 2 CH 3 , and -CH 3 .

[0127] In a 63rd embodiment, for a compound of formula (VII), (VII'), (VIII), or (VIII'), or a pharmaceutically acceptable salt thereof, R O1 is each independently H, -CH 3 , -CH 2 CH 2 OCH 3 , cyclopropyl,

Chemical Structure

[0128] In the 64th embodiment, for the compound of formula (VII), (VII’), (VIII), or (VIII’), or a pharmaceutically acceptable salt thereof, ring C is

Chemical formula

[0129] In the 65th embodiment, for the compound of formula (VII), (VII’), (VIII), or (VIII’), or a pharmaceutically acceptable salt thereof, ring C is

Chemical formula

[0130] In the 66th embodiment, for the compound of the 64th or 65th embodiment, or a pharmaceutically acceptable salt thereof, R 3 is selected from pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, and 3,6-diazabicyclo[3.1.1]heptanyl, each of which is optionally substituted by one or two R 9 where R 9 is independently halo, C 1~4 alkyl, OH, -OC 1~4 alkyl, or -NR a2 R a3 and R a2 and R a3 are each independently H or C 1~3 alkyl. In some embodiments, R 3 is

Chemical formula

[0131] In the 67th embodiment, for the compound of the 64th, 65th, or 66th embodiment, or a pharmaceutically acceptable salt thereof, when only one R C is present, RC is -CF 2 CH 3 or, when two Rs C are present, one of the Rs C is -CF 2 CH 3 and the other R C is C 1~3 alkyl or C 1~3 alkoxy, m is 1 or 2, and R 9 is, in each occurrence, independently C 1~3 alkyl, -OC 1~3 alkyl, or -NR a2 R a3 and the remaining variable moieties are as defined in Embodiment 64, 65, or 66.

[0132] In Embodiment 68, for the compound of Embodiment 64 or 65, or a pharmaceutically acceptable salt thereof, ring C is

Chemical formula

Chemical formula

[0133] In the 69th embodiment, for the compound of the 64th or 65th embodiment, or a pharmaceutically acceptable salt thereof, when only one R C is present, R C is -CF 2 CH 3 ; or when two Rs C are present, one of the Rs C is -CF 2 CH 3 , and the other R C is -CH 3 , -CH 2 CH 3 , or -OCH 3 ; and R 9 is, in each occurrence, independently, -CH 3 or -N(CH 3 ) 2 .

[0134] In the 70th embodiment, the compound is represented by formula (VIIA):

Chemical formula

Chemical formula

Chemical formula

[0135] In the 71st embodiment, for the compound of the 70th embodiment or a pharmaceutically acceptable salt thereof, R C1a is -CF 2 CH 3 and R C1b is -CH 3 or CH 2 CH 3 and the remaining variable moieties are as described in the first aspect or the 70th embodiment. In the 72nd embodiment, for the compound of the 70th or 71st embodiment, or a pharmaceutically acceptable salt thereof, each R 9 is independently -NH 2 -NHCH 3 -N(CH 3 ) 2 -N(CH 3 )(CH 2 CH 3 ) -N(CH 2 CH 3 ) 2 [Chemical formula] ​​-CH 3 、 or -CH 2 CH 3 and the remaining variable part is as described in the first aspect, or the 70th or 71st embodiment.

[0136] In the 73rd embodiment, the compound has the formula (VIIB):

Chemical formula

Chemical formula

[0137] In the 74th embodiment, for the compound of the 73rd embodiment or a pharmaceutically acceptable salt thereof, R C1a is -CF 2 CH 3 or -CF(CH 3 ) 2 and the remaining variable part is as described in the first aspect or the 73rd embodiment.

[0138] In the 75th embodiment, for the compound of the 73rd or 74th embodiment or a pharmaceutically acceptable salt thereof, n1 is 0, or n1 is 1 and R C1b is -OCH 3 and the remaining variable part is as described in the first aspect or the 73rd or 74th embodiment.

[0139] In the 76th embodiment, for the compound of the 70th, 71st, 72nd, 73rd, 74th, or 75th embodiment, or a pharmaceutically acceptable salt thereof, R 9 is, -NHCH(CH 3 ) 2 and the remaining variable parts are as described in the first aspect or the 70th, 71st, 72nd, 73rd, 74th, or 75th embodiment.

[0140] In some embodiments, for any compound of the 47th to 69th embodiments, the compound is represented by formula (VII) or a pharmaceutically acceptable salt thereof, and the definitions of the variable parts shown therein are as defined in any of the 47th to 69th embodiments. In some embodiments, for any compound of the 64th to 69th embodiments, the compound is represented by formula (VIII) or a pharmaceutically acceptable salt thereof, and the definitions of the variable parts shown therein are as defined in any of the 47th to 69th embodiments.

[0141] In one embodiment, the compound of the present disclosure is any of the compounds of Examples 1 to 958 or a pharmaceutically acceptable salt thereof.

[0142] The present disclosure also includes both the neutral form of the compounds shown in the examples and pharmaceutically acceptable salts.

[0143] III. Pharmaceutical Compositions In one aspect, the present 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.

[0144] The phrase "pharmaceutically acceptable" indicates that a substance, composition, or dosage form must be chemically and / or toxicologically compatible with the other ingredients that make up the formulation and / or the mammal being treated therewith.

[0145] As used herein, the term "pharmaceutically acceptable carrier" includes solvents, dispersion media, surfactants, antioxidants, preservatives (e.g., antibacterial, 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 the like, generally recognized as safe (GRAS) as known to those of ordinary skill in the art, and combinations thereof (see, e.g., Remington’s Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Its use is intended in therapeutic or pharmaceutical compositions, except where any conventional carrier is incompatible with the active ingredient.

[0146] Formulations can be prepared using conventional dissolution and mixing procedures. For example, a bulk drug substance (i.e., the compound of the present disclosure or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compounds of the present disclosure are typically formulated into pharmaceutical dosage forms in order to provide a drug with an easily adjustable dosage and to provide a simple and easy-to-handle product for the patient.

[0147] Pharmaceutical compositions (or formulations) for use can be packaged in a variety of ways depending on the method used to administer the drug. Generally, articles for distribution include a container in which a pharmaceutical formulation in a suitable form is disposed. Suitable containers are known to those of ordinary skill in the art and include, for example, bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container can also include an anti-tampering mechanism to prevent inadvertent access to the contents of the package. In addition, the container has a label thereon that describes the contents of the container. The label can also include appropriate warnings.

[0148] Pharmaceutical compositions containing the compounds of the present disclosure are generally formulated for use in parenteral or oral administration.

[0149] For example, the oral pharmaceutical composition of the present disclosure can be made 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 composition can be subjected to conventional pharmaceutical processes such as sterilization and / or can contain conventional inert diluents, lubricants, or buffering agents, in addition to adjuvants such as preservatives, stabilizers, wetting agents, emulsifying agents, and buffer solutions.

[0150] Typically, the pharmaceutical composition is a) a diluent such as lactose, dextrose, 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; and in the case of tablets, c) a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; optionally, d) a disintegrant such as starch, agar, alginic acid or its sodium salt, or a foaming mixture; and / or e) a tablet or gelatin capsule containing the active ingredient together with absorbents, colorants, flavorings, and sweeteners.

[0151] Tablets can be film-coated or enteric-coated by methods known in the art.

[0152] Suitable compositions for oral administration include tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or the compounds of the present disclosure in the form of syrups or elixirs. Compositions intended for oral use are prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets may contain the active ingredient mixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, time-delay substances such as glyceryl monostearate or glyceryl distearate may be used. Preparations for oral use may be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium such as peanut oil, liquid paraffin, or olive oil.

[0153] The parenteral composition (e.g., intravenous (IV) formulation) is an aqueous isotonic solution or suspension. The parenteral composition can be sterilized and / or can contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solubilizing agents, salts for adjusting osmotic pressure, and / or buffers. In addition, they can also contain other therapeutically valuable substances. The compositions are generally prepared by conventional mixing, granulating, or coating methods respectively and contain from about 0.1% to 75% or from about 1% to 50% of the active ingredient.

[0154] The effective dose of the compounds or pharmaceutically acceptable salts thereof provided herein to be administered to a subject can be from 10 μg to 500 mg.

[0155] The administration of the compounds or pharmaceutically acceptable salts thereof described herein to a mammal includes any suitable delivery method. The administration of the compounds or pharmaceutically acceptable salts thereof described herein to a mammal includes administering the compounds or pharmaceutically acceptable salts thereof described herein to the mammal locally, enterally, parenterally, transdermally, transmucosally, via inhalation, intracavity, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally. Also, the administration of the compounds or pharmaceutically acceptable salts thereof described herein to a mammal includes administering to the mammal a compound that is metabolized in the body or on the body surface of the mammal to the compounds or pharmaceutically acceptable salts thereof described herein locally, enterally, parenterally, transdermally, transmucosally, via inhalation, intracavity, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally.

[0156] Accordingly, the compounds described herein or pharmaceutically acceptable salts thereof can be administered systemically orally, for example, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an absorbable edible carrier. They can be encapsulated in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the food of the patient's diet. For oral therapeutic administration, the compounds described herein or pharmaceutically acceptable salts thereof can be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, or wafers. Such compositions and preparations should contain at least about 0.1% of the active compound. The percentages of the compositions and preparations can of course vary and can conveniently be about 2 to about 60% by weight of a given unit dosage form. The amount of the active compound in such therapeutically useful compositions can be such as to achieve an effective dosage level.

[0157] Tablets, troches, pills, capsules, etc. can contain the following: binders such as tragacanth, acacia, 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 sweetening agents such as sucrose, fructose, lactose, or aspartame, or flavoring agents.

[0158] The active compounds can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compounds or salts thereof can be prepared in water and optionally mixed with a non-toxic surfactant.

[0159] Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions containing the active ingredient, or sterile powders containing the active ingredient suitable for the extemporaneous preparation of injectable or infusible sterile solutions or dispersions. In all cases, the final dosage form must be sterile, liquid, and stable under the conditions of manufacture and storage.

[0160] Aseptic injection solutions can be prepared by incorporating the required amount of the active compound into a suitable solvent containing the various other ingredients listed above, followed by filter sterilization, if necessary. In the case of sterile powders for preparing aseptic injection solutions, preferred methods of preparation can be vacuum drying and lyophilization techniques that can yield powders of the active ingredient and any additional desired ingredients present in a previously sterile-filtered solution.

[0161] Exemplary solid carriers can include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like. Useful liquid carriers include water, alcohol, or glycol, or water-alcohol / glycol mixtures in which the compounds described herein or their pharmaceutically acceptable salts can be dissolved or dispersed at effective levels, optionally with the aid of a non-toxic surfactant.

[0162] Useful dosages of the compounds described herein or their pharmaceutically acceptable salts can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for extrapolation of effective dosages in mice and other animals to humans are known to those of skill in the art, see, for example, U.S. Patent No. 4,938,949, which is incorporated herein by reference in its entirety.

[0163] The amount of the compounds described herein or their pharmaceutically acceptable salts required for use in treatment can vary depending not only on the particular salt selected, but also on the route of administration, the nature of the condition being treated, and the age and condition of the patient, and can ultimately be at the discretion of the attending physician or clinician. However, generally, the dosage can be in the range of about 0.1 to about 10 mg / kg body weight per day.

[0164] The compounds described herein or their pharmaceutically acceptable salts can conveniently be administered in unit dosage forms containing from 0.01 to 10 mg or from 0.05 to 1 mg of the active ingredient per unit dosage form. In some embodiments, dosages of 5 mg / kg or less may be suitable.

[0165] The desired dosage may conveniently be provided as a single dosage or as divided dosages administered at appropriate intervals.

[0166] IV. Use of the Compounds and Compositions of the Present Disclosure The compounds or pharmaceutically acceptable salts described herein may be used to decrease or inhibit the activity of TYK2 or otherwise affect the properties and / or behavior of TYK2, such as stability, phosphorylation, kinase activity, interaction with other proteins, etc.

[0167] Another aspect of the present disclosure is a method of inhibiting TYK2 activity in a subject in need thereof, the method comprising administering to the subject an effective amount of at least one compound or a pharmaceutically acceptable salt thereof described herein, or a pharmaceutical composition described herein.

[0168] In some aspects, the present disclosure is a method of treating a disease or disorder that is responsive to inhibition of TYK2 in a subject, the method comprising administering to the subject an effective amount of at least one compound or a pharmaceutically acceptable salt thereof described herein, or a pharmaceutical composition described herein.

[0169] The present disclosure also includes the use of at least one compound or a pharmaceutically acceptable salt thereof described herein, or a pharmaceutical composition described herein, for the manufacture of a medicament for inhibiting TYK2 activity. The use of at least one compound or a pharmaceutically acceptable salt thereof described herein, or a pharmaceutical composition described herein, for the manufacture of a medicament for treating a disease or disorder that is responsive to inhibition of TYK2 is also included.

[0170] The present disclosure also provides a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, which is used to inhibit TYK2 activity. Also provided is a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, which is used to treat a disease or disorder that is affected by inhibition of TYK2.

[0171] As used herein, the terms "inhibit", "inhibition", or "inhibiting" refer to a reduction or suppression of a given condition, symptom, or disorder or disease, or a significant decrease in the baseline activity of a biological activity or biological process.

[0172] As used herein, the terms "subject" and "patient" may be used interchangeably and mean a mammal in need of treatment, such as a human, companion animal (e.g., dog, cat, etc.), livestock (e.g., cow, pig, horse, sheep, goat, etc.) and laboratory animal (e.g., rat, mouse, guinea pig, etc.). Typically, the subject is a human in need of treatment.

[0173] As used herein, a subject (preferably a human) is "in need of" such treatment if the subject would biologically, medically, or in terms of quality of life benefit from the treatment.

[0174] As used herein, the terms "treating" or "treatment" refer to obtaining a desired pharmacological and / or physiological effect. The effect can be therapeutic and include partial or substantial achievement of one or more of the following results: reducing the degree of a disease, disorder, or syndrome, partially or completely; alleviating or ameliorating clinical symptoms or signs associated with the disorder; or delaying, inhibiting, or reducing the likelihood of progression of a disease, disorder, or syndrome.

[0175] As used herein, the term "co-administer" refers to the presence of two active agents in an individual's blood. The co-administered active agents can be delivered simultaneously or sequentially.

[0176] The terms "combination therapy" or "in combination with" or "drug combination" refer to the administration of two or more therapeutic agents for treating a treatment condition or disorder described in the present disclosure. Such administration includes co-administration of these therapeutic agents in a substantially simultaneous manner, for example, in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration includes co-administration in multiple containers or separate containers (e.g., capsules, powders, and liquids) for each active ingredient. The powders and / or liquids can be reconstituted or diluted to a desired dosage prior to administration. In addition, such administration also includes the use of each type of therapeutic agent that is administered to each other before, simultaneously with each other, or sequentially with each other without a specific time limit. In any case, the treatment plan provides a beneficial effect of the drug combination in treating the condition or disorder described herein.

[0177] In some embodiments, the methods described herein treat a disease or disorder that is responsive to inhibition of TYK2, where such disease or disorder includes inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, head trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxin shock, toxic shock syndrome, autoimmune disease, osteoporosis, multiple sclerosis, endometriosis, dysmenorrhea, vaginitis, candidiasis, cancer, fibrosis, 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.

[0178] The term "autoimmune disorder" encompasses diseases or disorders associated with 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 in children, dermatomyositis, type 1 diabetes, Goodpasture 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.

[0179] The term "inflammatory disorder" encompasses diseases or disorders associated with acute or chronic inflammation, such as allergies, asthma, atopic dermatitis, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g., Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis.

[0180] The term "cancer" encompasses diseases or disorders associated with 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 tumor, pancreatic cancer, cholangiocarcinoma, 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 colorectal cancer (e.g., high-frequency microsatellite instability colorectal cancer).

[0181] The disclosed method may include a kit containing instructional materials that may describe the administration of a compound described herein or a pharmaceutically acceptable salt thereof, and a composition containing a compound described herein or a pharmaceutically acceptable salt thereof, or a compound described herein or a pharmaceutically acceptable salt thereof, to a cell or subject. This is to be construed as encompassing other embodiments of kits known to those skilled in the art, such as kits containing a solvent (e.g., a sterile solvent) for dissolving or suspending a compound described herein or a pharmaceutically acceptable salt thereof, or a composition, prior to administering the compound described herein or a pharmaceutically acceptable salt thereof, or the composition, to a cell or subject. In some embodiments, the subject can be a human.

Example

[0182] For illustrative purposes, the syntheses described below provide routes for synthesizing the compounds and important intermediates of the present disclosure. Specific starting materials and reagents are shown in the following synthetic procedures, but other starting materials and reagents may be substituted to obtain various derivatives and / or reaction conditions. In addition, many of the compounds prepared by the procedures described below can be further modified using conventional chemistry known to those skilled in the art in light of the present disclosure. Abbreviations: Aq. means aqueous, Bn means benzyl, Boc means tert-butoxycarbonyl, Boc 2 O means di-tert-butyl dicarbonate, br means broad line, t-BuOH means tert-butanol, n-BuLi means n-butyllithium, d means doublet, dd means double doublet, DCM means dichloromethane, DEA means diethylamine, DIPEA means N-ethyldiisopropylamine or N,N-diisopropylethylamine, DMA means N,N-dimethylacetamide, DMF means N,N-dimethylformamide, DMSO means dimethyl sulfoxide, DMSO-d 6 means hexadeuterodimethyl sulfoxide, Et means ethyl, EtOH means ethanol, EtOAc means ethyl acetate, Eq. means equivalent, HPLC means high performance liquid chromatography, IPA means 2-propanol, LCMS means liquid chromatography mass spectrometry, LDA means lithium diisopropylamide, m means multiplet, Me means methyl, MeCN means acetonitrile, MeI means iodomethane, MeOH means methanol, MeOH-d 4 means deuteromethanol, MS m / z means mass spectrum peak, MsCl means methanesulfonyl chloride, NBS means N-bromosuccinimide, NOE means nuclear Overhauser effect spectroscopy, PE means petroleum ether, Pd(amphos)Cl 2 means bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), Pd 2 (dba) 3 means tris(dibenzylideneacetone)dipalladium(0), Pd(dppf)Cl 2 means dichlorobis[1,1'-bis(diphenylphosphino)ferrocene]palladium(II), PdCl 2 (PPh 3 ) 2 means bis(triphenylphosphine)palladium(II) dichloride, Pd / C means palladium on carbon, q means quartet, rt means room temperature, s means singlet, sat. means saturated, SFC means supercritical fluid chromatography, soln. means solution, t means triplet, TBME means tert-butyl methyl ether, TEA means triethylamine, TFA means trifluoroacetic acid, THF means tetrahydrofuran, TLC means thin layer chromatography, TsCl means tosyl chloride, TsOH means para-toluenesulfonic acid, RuPhos Pd G3 means (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate.

[0183] According to the first process, the compound of formula (I) can be prepared from the compounds of formulas (II) and (III) as shown in Scheme 1.

Chemical formula

[0184] Z is Cl or OC(O)R 1 is.

[0185] The compound of formula (I) can be prepared from the amine of formula (II) and the compound of formula (III) by process step (a) (amidation reaction at high temperature in the presence of a suitable organic base, optionally in a suitable polar aprotic solvent). Preferred conditions include the reaction of the compound of formula (II) and the compound of formula (III) at 25 - 70 °C in the presence of TEA or DIPEA, optionally in DMF.

[0186] According to a second process, the compound of formula (I) can be prepared from the compounds of formula (IV) and (V) as shown in Scheme 2.

Chemical formula

[0187] The compound of formula (I) can be prepared from the compounds of formula (IV) and (V) by the backward Hartwig cross-coupling reaction of process step (b). Typical conditions include the reaction of the amide of formula (V) and the chloride of formula (IV) at high temperature in a suitable solvent, optionally under microwave irradiation, in the presence of a suitable palladium catalyst in the presence of a suitable inorganic base and a suitable phosphine ligand. Preferred conditions include the reaction of the compounds of formula (IV) and (V) at 70 °C - 120 °C in a suitable solvent such as dioxane, THF, or toluene, optionally under microwave irradiation, in the presence of, optionally, Pd(OAc) 2 or Pd 2 (dba) 3 in combination with BrettPhos Pd G3, tBuBrettphos Pd G3, tBuXPhos, Xantphos Pd G3, RuPhos Pd G3, Xantphos, or BINAP, in the presence of a suitable base such as Zn(OAc) 2 , Cs 2 CO 3 , K 3 PO 4 , or t-BuONa.

[0188] According to the third process, the compound of formula (I) can be prepared from the compounds of formulas (VI) and (VII) as shown in Scheme 3.

Chemical formula

[0189] Hal is halogen, usually F, Cl, or Br.

[0190] The compound of formula (I) can be prepared from the compound of formula (VI) and the halide of formula (VII) by the backward Hartwig reaction of process step (b) as described above in Scheme 2.

[0191] Alternatively, the compound of formula (I) can be prepared from the compound of formula (VI) and the halide of formula (VII) by process step (c) (alkylation reaction at room temperature to high temperature in the presence of a suitable inorganic or organic base and a suitable polar aprotic solvent). Preferred conditions include the reaction of the compound of formula (VI) and the compound of formula (VII) in DMSO, DMF, or THF at 50 - 100 °C in the presence of DBU or NaH, t-BuOK, Cs 2 CO 3 or K 2 CO 3 The reaction includes the reaction of the compound of formula (VI) and the compound of formula (VII) in DMSO, DMF, or THF at 50 - 100 °C in the presence of DBU or NaH, t-BuOK, Cs

[0192] Alternatively, the compound of formula (I) can be prepared from the compound of formula (VI) and the halide of formula (VII) by the Ullmann-type copper-mediated coupling reaction of process step (d). Typical conditions include the reaction of the compound of formula (VI) and the compound of formula (VII) at high temperature in a suitable solvent in the presence of a copper catalyst optionally combined with a suitable ligand and optionally in the presence of a suitable inorganic or organic base. Preferred conditions include the reaction in the presence of CuI and optionally a suitable ligand, such as N 1 ,N 2 -dimethylethane-1,2-diamine, trans-N,N’-dimethylcyclohexane-1,2-diamine, proline, 2,6-DFPAO, or 2-(dimethylamino)acetic acid, and optionally a suitable inorganic base, such as K2 CO 3 or K 3 PO 4 In the presence of CO or KPO, the reaction between the compound of formula (VI) and the compound of formula (VII) in dioxane or DMSO at 90 - 120 °C, optionally under microwave irradiation, is included.

[0193] According to the fourth process, when X 3 is C-R 3 the compound of formula (I)(A) can be prepared from the compounds of formula (VII), (VIII), and (IX) as shown in Scheme 4.

Chemical formula

[0194] Hal 2 is a halogen, preferably Cl, Br, or I.

[0195] The compound of formula (IX) can be prepared from the compounds of formula (VII) and (VIII) by process steps (b), (c), and (d) as described above in Scheme 3.

[0196] R 3 When R is bonded to ring B via an N atom, the compound of formula (I) can be prepared by the reaction of the compound of formula (IX) with R 3 H according to process step (b) or (d) as described above in Schemes 2 and 3, or by the photocatalytic nickel cross-coupling reaction of process step (e) or the nickel-catalyzed cross-coupling reaction of process step (j). The preferred conditions for step (e) are in the presence of a suitable nickel catalyst, such as (1,2-dimethoxyethane)nickel dibromide, Ru(bpy) 3 (PF6) 2 , or Ir[dF(CF 3 )ppy] 2 (dtbpy)PF 6 , a suitable base, such as DABCO or 2,6-lutidine, under blue light, at a high temperature, usually 80 °C, of the compound of formula (IX) and R3 It includes the reaction with H.

[0197] The preferred conditions for step (j) are in the presence of a suitable nickel catalyst, such as (1,2-dimethoxyethane)nickel dibromide, Zn, a suitable organic base, such as DABCO and DBU or MTBD, and a suitable aprotic solvent, such as DMPU, at about 55 °C, for the compound of formula (IX) and R 3 It includes the reaction with H.

[0198] R 3 When R is bonded to ring B via a C atom, the compound of formula (I) is, as described above, the compound of formula (IX) and R by the photocatalytic nickel cross-coupling reaction of process step (e) 3 Hal 2 can be prepared by reaction with.

[0199] R 3 When R is bonded to ring B via a C atom, the compound of formula (I) can be prepared from the compound of formula (IX) and R by the palladium-catalyzed cross-coupling reaction of process step (f), such as the Suzuki reaction 3 BPin. 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, at room temperature to the reflux temperature of the reactants, optionally in the presence of microwave irradiation. Preferred conditions are Pd(dppf)Cl 2 Pd(dtbpf)Cl 2 Catacxium A-Pd G2, bis(tricyclohexylphosphine)palladium(0) and a suitable base, such as Cs 2 CO 3 Na 2 CO 3 or K 2 CO 3 in the presence of, in a suitable solvent, such as aqueous dioxane or toluene, at 70 °C to 100 °C, for the reaction of the compound of formula (IX) and R 3 BPin.

[0200] Alternatively, R 3When it is bonded to ring B via a C atom, the compound of formula (I) can be prepared from the compound of formula (IX) and KR by the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction in process step (k). 3 BF 3 It can be prepared from. Preferred conditions are in the presence of Pd(dppf)Cl 2 and a suitable base, such as Na 2 CO 3 in a suitable solvent, such as aqueous dioxane or toluene, at 70 °C to 100 °C, the reaction of the compound of formula (IX) and KR 3 BF 3 .

[0201] Alternatively, when R 3 is bonded to ring B via a C atom, the compound of formula (I) can be prepared from the compound of formula (IX) and R 3 ZnHal by the palladium-catalyzed Negishi cross-coupling reaction in process step (l). Preferred conditions are in the presence of Pd(OAc) 2 and SPhos in a suitable solvent, such as MeTHF, at room temperature, the reaction of the compound of formula (IX) and R 3 ZnHal 2 .

[0202] According to a fifth process, the compound of formula (II) can be prepared from the compounds of formula (VII), (X), (XI), (XII), and (XIII) as shown in Scheme 5.

Chemical formula

[0203] PG is an N-protecting group, usually a carbamate, preferably Boc.

[0204] The compound of formula (XI) can be prepared from the compound of formula (X) and the compound of formula (VII) by process step b), c), or d) as described above in Schemes 2 and 3.

[0205] The compound of formula (XIII) can be prepared from the compound of formula (XI) and the protected amine of formula (XII) by process step (b) as described above in Scheme 2.

[0206] The compound of formula (II) can be prepared from the compound of formula (XIII) by a deprotection reaction in step (g) carried out under standard conditions, for example, treatment of the compound of formula (XIII) with HCl in dioxane at room temperature.

[0207] In some cases, it may be possible to directly prepare the compound of formula (II) from the compound of formula (XI) because the protecting group PG is removed in situ under the conditions described in process step (b).

[0208] According to the sixth process, when X 3 is C-R 3 the compound of formula (IV)(A) can be prepared from the compounds of formula (VII), (XIV), (XV), (XVI), and (XVII) as shown in Scheme 6.

Chemical formula

[0209] Hal 2 is a halogen, preferably I or Br. PG 2 is a suitable aromatic amine protecting group, for example, SEM, THP, tosyl or trityl, or Boc.

[0210] The compound of formula (XV) can be obtained from the compound of formula (XIV) by protection of the aromatic amine group under standard conditions in process step (h). For example, when PG 2 is SEM, the compound of formula (XV) can be prepared by reaction of the compound of formula (XIV) with SEMCl in the presence of NaH in THF at approximately room temperature. When PG 2When PG is THP, the compound of formula (XV) can be prepared by reacting the compound of formula (XIV) with 3,4-dihydro-2H-pyran in a suitable solvent, such as DCM, in the presence of a catalyst, such as MsOH, at a high temperature, such as 60 °C. 2 When PG is tosyl, the compound of formula (XV) can be prepared by reacting the compound of formula (XIV) with tosyl chloride in a suitable solvent, such as DMF, in the presence of a strong base, such as NaH. 2 When PG is trityl, the compound of formula (XV) is prepared by reacting the compound of formula (XIV) with trityl chloride in a suitable solvent, such as DMF, at about 100 °C in the presence of a base, such as Cs 2 CO 3 When PG is Boc, the compound of formula (XV) can be prepared by reacting the compound of formula (XIV) with tert-butyl tert-butoxycarbonyl in a suitable solvent, such as DCM, at room temperature in the presence of a catalyst, such as DMAP. 2 When PG is Boc, the compound of formula (XV) can be prepared by reacting the compound of formula (XIV) with tert-butyl tert-butoxycarbonyl in a suitable solvent, such as DCM, at room temperature in the presence of a catalyst, such as DMAP.

[0211] R 3 When R is C-bonded to ring B via an N atom, the compound of formula (XVI) can be obtained from the compound of formula (XV) and R 3 Hal by process step (b) or (d) as described above in Schemes 2 and 3. Alternatively, when R 3 is C-bonded to ring B, the compound of formula (XVI) can be obtained from the compound of formula (XV) and R 3 BPin by process step (f) as described above in Scheme 4. Alternatively, when R 3 is N-bonded to ring B, the compound of formula (XVI) can be obtained from the compound of formula (XV) and R 3 H by process step (d) as described above in Scheme 3.

[0212] The compound of formula (XVII) can be obtained from the compound of formula (XVI) by a standard deprotection reaction of process step (g). For example, PG 2When PG is THP, Boc, or SEM, deprotection can be achieved by reaction of the compound of formula (XV) under acidic conditions, typically in TFA or HCl in DCM, dioxane, or HFIP, at approximately room temperature. 2 When PG is trityl, deprotection can be achieved by reaction of the compound of formula (XV) with Et 3 SiH and TFA in DCM at approximately room temperature. 2 When PG is tosyl, deprotection can be achieved by reaction of the compound of formula (XV) with NaOH in MeOH at about 50 °C.

[0213] The compound of formula (IV)(A) can be obtained from the compounds of formula (III) and (XVII) by process step (b), (c), or (d) as described above in Schemes 2 and 3.

[0214] X 3 is C-R 3 According to a seventh process in which X is C-R, the compound of formula (VI)(A) can be prepared from the compounds of formula (VIII), (XVIII), (XIX), and (XX) as shown in Scheme 7.

Chemical formula

[0215] Hal 2 is a halogen, preferably I or Br.

[0216] The compound of formula (VIII) can be prepared from the compound of formula (XVIII) by the halogenation reaction of process step (i), for example bromination or iodination. Typical conditions include reaction of the compound of formula (XVIII) with N-bromo or N-iodosuccinimide in a suitable solvent, such as DMF, at an elevated temperature, such as 60 °C, or reaction of the compound of formula (XVIII) with I 2 and a base, such as KOH, in DMF at room temperature.

[0217] The compound of formula (XIX) can be prepared from the compound of formula (VIII) by process step (h) as described above in Scheme 6.

[0218] R 3 When R is N-bonded to ring B, the compound of formula (XX) can be obtained from the compound of formula (XIX) and R 3 H by process step (d) as described above in Scheme 6. Alternatively, when R 3 is C-bonded to ring B, the compound of formula (XX) can be obtained from the compound of formula (XIX) and R 3 BPin by process step (f) as described above in Scheme 4, or from the compound of formula (XIX) and KR 3 BF 3 by process step (k).

[0219] The compound of formula (VI)(A) can be obtained from the compound of formula (XX) by process step (g) as described above in Scheme 6.

[0220] X 3 is C-R 3 According to an eighth process in which X is C-R

Chemical formula

[0221] Hal 3 is a halogen, preferably Br or Cl.

[0222] The compound of formula (XXII) can be obtained from the compound of formula (XXI) and the compound of formula (V) by process step (b) as described above in Scheme 2.

[0223] The compound of formula (VIII) can be prepared from the compound of formula (XXII) by process step (g) as described above in Scheme 6.

[0224] According to the 9th process, X 3 is C-R 3 When this is the case, the compound of formula (IV)(A) can be prepared from the compounds of formulas (VII), (XIV), (XV), and (XXIII) as shown in Scheme 9.

Chem.

[0225] The compound of formula (XXIII) can be prepared from the compounds of formulas (XIV) and (VII) by process step (c) as described above in Scheme 3.

[0226] The compound of formula (IV)(A) can be prepared from the compound of formula (XXIII) and R 3 H by process step (b) or (d) as described above in Schemes 2 and 3.

[0227] According to the 10th process, X 3 is C-R 3 When this is the case, the compound of formula (XX) can be prepared from the compounds of formulas (XVI) and (V) as shown in Scheme 10.

Chem.

[0228] The compound of formula (XX) can be prepared from the compounds of formulas (XVI) and (V) by process step (b) as described above in Scheme 2.

[0229] X 3 is N-R 3 According to the 11th process where this is the case, the compound of formula (I)(B) can be prepared from the compounds of formulas (V), (VI)(B), (VII), (XVI)(B), and (XX)(B) as shown in Scheme 11.

Chem.

[0230] The compound of formula (XVI)(B) can be prepared from the compound of formula (XI) by process step (h) as described above in Scheme 6.

[0231] The compound of formula (XX)(B) can be prepared from the compounds of formula (XVI)(B) and (V) by process step (b) as described above in Scheme 2.

[0232] The compound of formula (VI)(B) can be prepared from the compound of formula (XX)(B) by process step (g) as described above in Scheme 6.

[0233] The compound of formula (I)(B) can be prepared from the compounds of formula (VI)(B) and (VII) by process step (b), (c) or (d) as described above in Scheme 3.

[0234] Compounds of formula (III), (V), (VII), (X), (XI), (XII), (XIV), (XVIII), (XXI), R 3 Hal 2 , and R 3 H, R 3 BPin, KR 3 BF 3 , R 3 ZnHal 2 can be commercially available or prepared in a manner similar to the methods known in the literature or by the methods described in the following Examples section.

[0235] Compounds of formula (I), (II), (IV), (VI), (IX), (X), (XI), (XVI), (XX), and (XXIII) can be converted to other compounds of formula (I), (II), (IV), (VI), (IX), (X), (XI), (XVI), (XX), and (XXIII) by standard chemical transformations known to those skilled in the art. Examples of these transformations include, but are not limited to, the following: · Grignard reaction of esters to obtain tertiary alcohols, · Reductive amination of secondary amines with aldehydes to obtain tertiary amines, ·Reductive amination of aldehydes with secondary amines to obtain tertiary amines ·Alkylation of heteroatoms, such as N or O, by reaction with an alkylating agent, such as alkyl halide or alkyl triflate, in the presence of an organic or inorganic base ·Reduction of unsaturated bonds by hydrogenation ·Reaction of an aryl halide or heteroaryl halide with a suitable boronic acid ester under typical Suzuki reaction conditions ·Reaction of an aryl halide or heteroaryl halide with an alkali metal alkoxide or aryl / heteroaryl alcohol in the presence of an inorganic base to obtain an ether ·Fluorination of alcohols, aldehydes, or ketones with a suitable fluorinating agent to obtain alkyl fluorides ·Reduction of esters using a suitable reducing agent to obtain alcohols ·Sulfonation of N atoms to obtain sulfonamides, and ·Acetylation of N atoms to obtain amides

[0236] Those skilled in the art will understand that it may be necessary to utilize an appropriate protecting group strategy for the preparation of the compounds of formula (I). Typical protecting groups may include p-methoxybenzyl, benzyl, or carbamates, preferably Boc or CBz for the protection of primary or secondary amines, trityl, SEM, or THP groups for the protection of aromatic amines, and TBS or benzyl groups for the protection of primary alcohols.

[0237] Furthermore, it will be understood that in order to obtain the compounds of the present invention, it may be necessary or desirable to perform the transformations in an order different from that described in the scheme, or to modify one or more of the transformations.

Table 1-1

Table 1-2

[0238] General synthesis method Preparation 1: N-(1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide [Chemical formula] 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), Cs 2 CO 3 (2.74 g, 8.42 mmol), and BrettPhos Pd G3 (114.5 mg, 0.126 mmol) in dioxane (15 mL) was degassed with N 2 and then heated at 100 °C for 1 hour in a sealed tube. The cooled mixture was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (0 - 70% EtOAc - EtOH 3:1 (containing 2% NH 4 OH) in heptane) to obtain 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] + .

[0239] Preparation 2: N-(1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide [Chemical formula] 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) was added TFA (8.76 g, 76.8 mmol), and the reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated under reduced pressure, the residue was diluted with EtOAc, and NaHCO 3It was washed with an aqueous solution. The organic layer was dried, filtered, and concentrated under reduced pressure. The obtained solid was filtered out and washed with heptane / EtOAc (95 / 5) to obtain N-(1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (421 mg, 62% yield) as an off-white solid. 1H NMR (400 MHz, MeOH-d 4 ) δ: 8.83 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 2.21 (s, 3H).

[0240] Preparation 3: N-(3-Iodo-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide [Chemical formula] 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 × 3). The combined organic components were washed with brine (100 mL), dried (Na 2 SO 4 ) and evaporated to dryness under reduced pressure to obtain N-(3-iodo-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide as a yellow solid (2 g, 77%), which was used without further purification. LCMS m / z = 302.9 [M+H] + .

[0241] Preparation 4: N-(3-Iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide [Chemical formula] 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) was added Cs 2 CO 3(10.8 g, 33.10 mmol) and trityl chloride (9.2 g, 33.1 mmol) were added, and the mixture was stirred at 100 °C for 16 h. The reaction mixture was filtered, concentrated, and poured into EtOAc (80 mL). The precipitated solid was collected by filtration and washed with H 2 O to give N-(3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide as a yellow solid (6.0 g, 66.6%). 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0242] Preparation 5: N-(3-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

Chemical Structure

[0243] Preparation 6: N-(3-Methyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

Chem.

[0244] Preparation 7: 6-Chloro-3-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

Chem.

[0245] Preparation 8: N-(3-Ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide [Chemical formula] N-(3-Ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide was obtained as a white powder (508 mg, 68% yield) from 6-chloro-3-ethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (Preparation 7) according to the procedure described in Preparation 1. LCMS m / z = 289.1 [M+H] + .

[0246] Preparation 9: N-(3-Ethyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide [Chemical formula] 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) was added TFA (2.98 g, 26.12 mmol), and the reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure, diluted with EtOAc, neutralized with 2M NaHCO 3 and then washed with brine. The organic layer was dried and concentrated under reduced pressure. 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 (400 MHz, MeOH-d 4 ) δ 8.80 (d, J = 0.75 Hz, 1H), 8.14 (s, 1H), 3.02 (q, J = 7.53 Hz, 2H), 2.20 (s, 3H), 1.40 (t, J = 7.65 Hz, 3H).

[0247] Preparation 10: N-(3-Cyclopropyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide [Chemical formula] To a solution of N-(3-Iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (Preparation 4, 4.0 g, 7.35 mmol) in dioxane (40 mL) and H 2 O (8 mL) were added potassium cyclopropyltrifluoroborate (2.2 g, 14.7 mmol), Na 2 CO 3 (1.6 g, 14.7 mmol), and Pd(dppf)Cl 2 ·DCM (600 mg, 0.735 mmol), and the resulting mixture was N 2Below, it was stirred at 100 °C for 16 hours. The mixture was poured into H 2 O (80 mL), and extracted with EtOAc (3 × 100 mL × 3). The combined organic components were dried (Na 2 SO 4 ), and evaporated to dryness under reduced pressure. The residue was purified by chromatography (SiO 2 , 5 - 50% EtOAc / PE) to obtain N-(3-cyclopropyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide as a yellow solid (2.5 g, 74%). 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0248] Preparation 11: N-(3-cyclopropyl-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

Chemical formula

[0249] Preparation 12: N-(3-Iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

Chemical Structure

[0250] Preparation 13: 6-Chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine [Chemical formula] To a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine (2.5 g, 16.28 mmol) in DMF (30 mL) was added NIS (3.7 g, 16.28 mmol), and the resulting mixture was stirred at 70 °C for 3 h. The reaction mixture was evaporated to dryness to give 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine as a brown solid (3.5 g, 77%), which was used directly in the next step. LCMS m / z = 279.9 [M+H] + .

[0251] Preparation 14: 6-Chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine [Chemical formula] 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) were added Cs 2 CO 3 (8.2 g, 25.05 mmol) and TrtCl (6.9 g, 25.05 mmol), and the resulting mixture was stirred at 110 °C for 16 h. The reaction mixture was filtered, concentrated, poured into EtOAc (80 mL), and the resulting solid was collected by filtration to give 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine as a yellow solid (5.15 g, 79%). 1 H NMR (500 MHz, CDCl 3 ) δ: 8.51 (s, 1H), 7.23 - 7.29 (m, 15H), 5.99 (s, 1H).

[0252] Preparation 15: 6-Chloro-3-cyclopropyl-1-trityl-1H-pyrazolo[4,3-c]pyridine [Chemical formula] Dioxane (30 mL) and H 2To a solution of 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (Preparation 14, 4 g, 7.7 mmol) in O(6 mL), potassium cyclopropyltrifluoroborate (3.4 g, 23 mmol), Na 2 CO 3 (1.63 g, 15.33 mmol), and Pd(dppf)Cl 2 ·DCM (626 mg, 0.767 mmol) were added, and the reaction was stirred at 100 °C for 16 h under N 2 . The cooled reaction was concentrated under reduced pressure, diluted with H 2 O (50 mL), and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (30 mL × 2), dried over Na 2 SO 4 , 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-trityl-1H-pyrazolo[4,3-c]pyridine (2.2 g, 65.8% yield) as a yellow solid. LCMS m / z = 436.1 [M+H] + .

[0253] Preparation 16: 6-Chloro-3-cyclopropyl-1H-pyrazolo[4,3-c]pyridine

Chemical Structure

[0254] Preparation 17: 4-(6-Chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine [Chemical Structure] 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), K 2 CO 3 (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 h under N 2 . The mixture was diluted with H 2 O (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic phases were washed with brine (30 mL × 2), dried over Na 2 SO 4 4-(6-Chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine (700 mg, 39.4% yield) was obtained as a yellow oil by purifying the residue by silica gel chromatography (PE / EtOAc = 4 / 1). 1 H NMR: (500 MHz, CDCl 3 ) 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).

[0255] A mixture of 4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine (700 mg, 2.17 mmol) in HCl / EtOAc (4 M, 10 mL) was stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure to afford 4-(6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine hydrochloride (520 mg) as a yellow solid. LCMS m / z = 239.2 [M+H] + .

[0256] Preparation 18: 6-Chloro-3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridine [Chemical formula] To a solution of 6-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine (580 mg, 2.08 mmol) in DMF (5 mL) was added NaH (99.9 mg, 2.50 mmol, 60% purity) at 0 °C and the mixture was stirred for 10 min. Tosyl chloride (596 mg, 3.12 mmol) was added thereto and the mixture was stirred at 25 °C for 30 min. The mixture was treated with H 2 O (20 mL) and extracted with EtOAc (25 mL × 3). The combined organic layers were washed with brine (20 mL), dried (Na 2 SO 4 ) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO 2 , 6 - 100% EtOAc / PE) to give 6-chloro-3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridine as a yellow solid (680 mg, 75%). 1 1H NMR (400 MHz, CDCl 3 ) 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).

[0257] Preparation 19: 6-Chloro-3-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-c]pyridine [Chemical formula] A solution of 6-chloro-3-iodo-1-tosyl-1H-pyrrolo[3,2-c]pyridine (Preparation 18, 730 mg, 1.69 mmol) in DMF (8 mL) was added with cyclopropylzinc(II) bromide (0.5 M, 3.37 mL) and Pd(PPh 3 ) 4 (293 mg, 0.253 mmol) under N 2 and the mixture was stirred at 70 °C for 2 h. The reaction was concentrated, diluted with H 2 O (20 mL), and extracted with DCM (20 mL × 2). The combined organic fractions were washed with brine (20 mL × 2) and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (25% EtOAc / PE) to give 6-chloro-3-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-c]pyridine as a white solid (280 mg, 48%). 1 H NMR (500 MHz, CDCl 3 ) 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).

[0258] Preparation 20: N-(3-Cyclopropyl-1-tosyl-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide [Chemical formula] To a solution of 6-chloro-3-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-c]pyridine (Preparation 19, 200 mg, 0.577 mmol) in dioxane (2 mL) were added acetamide (40.9 mg, 0.692 mmol), Cs 2 CO 3 (376 mg, 1.15 mmol), and BrettPhos Pd G3 (52.3 mg, 0.058 mmol), and the mixture was under N 2It was stirred at 100 °C for 1 hour. The mixture was concentrated under reduced pressure and purified by column chromatography (PE / EtOAc = 10 / 1 to 1 / 1) to obtain N-(3-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide (190 mg, 89%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.70 (s, 1H), 8.49 (s, 1H), 8.32 (s, 1H), 7.85 (d, 2H), 7.24 (d, 2H), 7.16 (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).

[0259] Preparation 21: N-(3-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide [Chemical formula] To a solution of N-(3-cyclopropyl-1-tosyl-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide (Preparation 20, 180 mg, 0.487 mmol) in MeOH (2 mL) was added NaOH (39 mg, 0.974 mmol), 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 obtain N-(3-cyclopropyl-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide (80 mg, 76%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.86 (s, 1H), 8.75 (s, 1H), 8.63 (s, 1H), 8.27 (s, 1H), 6.87 (s, 1H), 2.24 (s, 3H), 2.21 - 1.91 (m, 1H), 0.93 - 0.89 (m, 2H), 0.68 - 0.65 (m, 2H).

[0260] Preparation 22: 6-Chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridine [Chemical formula] To a solution of 6-chloro-1H-pyrrolo[3,2-c]pyridine (250 g, 1.64 mol) in MeCN (500 mL) was added K 2 CO 3 (566.1 g, 4.10 mol), followed by dropwise addition of PhSO 2 Cl (318.33 g, 1.802 mol). The reaction mixture was stirred at 25 °C for 4 h. The reaction mixture was poured into ice water (3.0 L). The precipitate was collected by filtration and dried to give 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] + .

[0261] Preparation 23: N-(1H-Pyrrolo[3,2-c]pyridin-6-yl)acetamide [Chemical formula] Into a reactor were sequentially charged dioxane (2000 mL), 6-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 200 g, 683.2 mmol), AcNH 2 (161.42 g, 2.73 mol), K 2 CO 3 (141.6 g, 1.025 mol), Xantphos (23.72 g, 41.0 mmol), and Pd(OAc) 2 (4.60 g, 20.5 mmol). The mixture was heated to 110 °C and stirred under N 2 atmosphere for 16 h. The mixture was cooled to room temperature, and a solution of NaOH (109.30 g, 2.73 mol) in H 2 O (400 mL) was added. The resulting mixture was heated to 80 °C and stirred for 1 h. The cooled reaction mixture was extracted with EtOAc (3000 mL) and H 2It was diluted with O (400 mL). The insoluble matter was removed by filtration, and the filtrate was separated. The aqueous phase was extracted with EtOAc (1000 mL × 2), and the combined organic extracts were dried over MgSO 4 and filtered and concentrated. The precipitate was collected by filtration, and the filter cake was dried to obtain N-(1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide (90.0 g, 75.2%) as an off-white solid. LCMS m / z = 176.2 [M+H] + .

[0262] Preparation 24: N-(3-Bromo-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide [Chemical formula] 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), NBS (81.28 g, 456.7 mmol) was added portionwise at 0 °C. Once the addition was complete, the reaction mixture was stirred for 1 hour. The mixture was poured into a pre-cooled saturated Na 2 SO 3 aqueous solution (2 L), and then filtered. The filter cake was suspended in a saturated Na 2 CO 3 aqueous solution (2 L), stirred at room temperature for 1 hour, then the mixture was filtered and dried to obtain N-(3-bromo-1H-pyrrolo[3,2-c]pyridin-6-yl)acetamide (103.5 g, 89.2%) as an off-white solid. LCMS m / z = 254.1 [M+H] + .

[0263] Preparation 25: tert-Butyl 6-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine-1-carboxylate [Chemical formula] A solution of tert-butyl 6-chloro-3-iodo-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (5 g, 17.95 mmol) in DCM (100 mL) was stirred and a solution of tert-butyl carbonate (7.84 g, 35.9 mmol) and DMAP (219 mg, 1.80 mmol) in DCM (50 mL) was slowly added thereto over 10 minutes. The reaction was then stirred at room temperature for 3 hours. The reaction mixture was washed with 0.1 N HCl and then with brine. The organic layer was separated, dried and concentrated under reduced pressure. 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 (400 MHZ, CDCl 3 ) δ 8.46 (s, 1H), 8.04 (s, 1H), 7.71 (s, 1H), 1.69 (s, 9H).

[0264] Preparation 26: tert-Butyl 6-chloro-3-cyclopropyl-1H-pyrrolo[3,2-c]pyridine-1-carboxylate [Chemical formula] A mixture of tert-butyl 6-chloro-3-iodopyrrolo[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 N 2It was purged, and then bromo(cyclopropyl)zinc (0.5 M, 15.85 mL) was slowly added, and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with water, concentrated under reduced pressure, the residue was diluted with EtOAc, washed with water, then the organic layer was separated, dried, and concentrated. The crude product was purified by silica gel chromatography (0 - 40% EtOAc in heptane) to obtain 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 (400 MHz, CDCl 3 ) δ 8.69 (d, 1H, J = 0.8 Hz), 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).

[0265] Preparation 27: 6-Chloro-3-cyclopropyl-1H-pyrrolo[3,2-c]pyridine

Chemical Structure

[0266] Preparation 28: 6-Chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine

Chem.

[0267] Preparation 29: 2,6-Dibromo-4-isopropoxypyridine

Chem.

[0268] Preparation 30: 2,6-Dibromo-4-(2-methoxyethoxy)pyridine

Chemical Structure

[0269] Preparation 31: 3-(2-Fluoropyridin-4-yl)tetrahydrofuran-3-ol

Chemical Structure

[0270] Preparation 32: 3-(4-chloropyridin-2-yl)tetrahydrofuran-3-ol

Chemical formula

[0271] Preparation 33: 1-(6-bromopyridin-2-yl)-2,2-dimethylpropan-1-ol

Chemical formula

[0272] Preparation 34: 3-(6-Bromo-4-methoxypyridin-2-yl)tetrahydrofuran-3-ol [Chemical formula] To a solution of 2,6-dibromo-4-methoxypyridine (3.0 g, 11.24 mmol) in DCM (40 mL) was slowly added n-BuLi (2.5 M, 4.95 mL) dropwise at -70 °C under N 2 . Then, dihydrofuran-3(2H)-one (967.6 mg, 11.24 mmol) was slowly added dropwise at -70 °C over 1 h under N 2 . The mixture was quenched with NH 4 Cl (saturated, 30 mL), poured into H 2 O (50 mL), extracted with EtOAc (3 × 80 mL), and the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, concentrated, and the residue was purified by silica gel chromatography (petroleum ether / EtOAc = 3 / 1) to give 3-(6-bromo-4-methoxypyridin-2-yl)tetrahydrofuran-3-ol (2.6 g, 84.4% yield) as a yellow oil. 1 H NMR: (400 MHz, CDCl 3 ) δ ppm: 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).

[0273] Preparations 35 - 44 The compounds in the following table were prepared from the appropriate halopyridine and ketone according to a procedure similar to that described in Preparation 34.

Table 2-1

Table 2-2

Table 2-3

Table 2-4

[0274] Preparation 45: 3-(5-Bromopyridin-3-yl)tetrahydrofuran-3-ol

Chem.

[0275] Preparation 46: 2 - Bromo - 6 - (prop - 1 - en - 2 - yl)pyridine [Chemical formula] To a solution of 2 - (6 - bromopyridin - 2 - yl)propan - 2 - ol (0.4 g, 1.85 mmol) in DCM (6.0 mL) were added methanesulfonic anhydride (967.4 mg, 5.55 mmol) and TEA (1.03 mL, 7.40 mmol), and the reaction mixture was stirred at 18 °C for 2 h. The pH of the reaction mixture was adjusted to 8 using saturated NaHCO 3 aqueous solution, and the mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (10 mL), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1 - 5 / 1) to give 2 - bromo - 6 - (prop - 1 - en - 2 - yl)pyridine (158 mg, 43.1% yield) as a colorless gum. LCMS m / z = 198.2 [M + H] + . 1H NMR (400 MHz, CDCl 3 ) δ ppm: 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).

[0276] Preparation 47: 2 - (6 - bromopyridin - 2 - yl)propane - 1,2 - diol [Chemical formula] 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) were added 4-methyl-4-oxide-morpholin-4-ium hydrate (243.6 mg, 1.80 mmol) and OsO 4 (2.2 mg, 8.58 μmol), and the mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into water (20 mL), and the mixture was extracted with EtOAc (30 mL × 3). The combined organic extracts were dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. 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 gum. 1 H NMR: (400 MHz, DMSO-d 6 ) δ ppm: 7.74 - 7.70 (m, 1H), 7.66 - 7.64 (m, 1H), 7.47 - 7.46 (m, 1H), 5.17 (s, 1H), 4.65 (t, J = 5.6 Hz, 1H), 3.56 - 3.48 (m, 2H), 1.34 (s, 3H).

[0277] Preparation 48: 2-Fluoro-4-(3-methoxytetrahydrofuran-3-yl)pyridine

Chemical formula

[0278] Preparation 49: 2-Bromo-6-(1-methoxy-2,2-dimethylpropyl)pyridine [Chemical formula] 2-Bromo-6-(1-methoxy-2,2-dimethylpropyl)pyridine was obtained as a colorless oil (735 mg, 98.7% yield) from 1-(6-bromopyridin-2-yl)-2,2-dimethylpropan-1-ol according to the same procedure as described in Preparation 48.

[0279] Preparation 50: 3-Bromo-5-(3-methoxytetrahydrofuran-3-yl)pyridine [Chemical formula] 3-Bromo-5-(3-methoxytetrahydrofuran-3-yl)pyridine was obtained as a yellow oil (244.6 mg, 56.0%) from 3-(5-bromopyridin-3-yl)tetrahydrofuran-3-ol according to the same reaction as described in Preparation 48. 1H NMR: (400 MHz, CDCl 3 ) δ ppm: 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).

[0280] Preparation 51: 2-Bromo-6-(1-methoxycyclopentyl)pyridine [Chemistry] 2-Bromo-6-(1-methoxycyclopentyl)pyridine was obtained as a colorless oil (1.1 g, 86.65% yield) from 1-(6-bromopyridin-2-yl)cyclopentan-1-ol (Preparation 35) and methyl iodide according to the procedure described in Preparation 48. 1H NMR: (400 MHz, CDCl 3 ) δ ppm: 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).

[0281] Preparation 52: 2-Bromo-6-(1-methoxycyclobutyl)pyridine [Chemistry] 2-Bromo-6-(1-methoxycyclobutyl)pyridine was obtained as a colorless oil from 1-(6-bromopyridin-2-yl)cyclobutan-1-ol (Preparation 40) and MeI according to the procedure described in Preparation 48. 1H NMR: (400 MHz, CDCl 3 ) δ ppm: 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).

[0282] Preparation 53: 2-Bromo-6-(1,2-dimethoxypropan-2-yl)pyridine [Chemistry] 2-Bromo-6-(1,2-dimethoxypropan-2-yl)pyridine was obtained as a colorless gum (326 mg, 80.8% yield) from 2-(6-bromopyridin-2-yl)propane-1,2-diol (Preparation 47) according to a procedure similar to that described in Preparation 48. 1H NMR (400 MHz, CDCl 3 ) δ ppm: 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).

[0283] Preparation 54: 4-Chloro-2-(3-methoxytetrahydrofuran-3-yl)pyridine

Chemical Structure

[0284] Preparations 55 - 61 The compounds in the following table were prepared from the appropriate alcohol and methyl iodide according to a procedure similar to that described in Preparation 54.

Table 3-1

Table 3-2

Table 3-3

[0285] Preparation 62: 2-Bromo-6-(3-(difluoromethoxy)tetrahydrofuran-3-yl)pyridine

Chem.

[0286] Preparation 63: 2-Bromo-6-(3-fluorotetrahydrofuran-3-yl)pyridine [Chemistry] To a solution of 3-(6-bromopyridin-2-yl)tetrahydrofuran-3-ol (Preparation 36, 2 g, 8.19 mmol) in DCM (20 mL) was added DAST (1.3 g, 8.19 mmol) at 0 °C, and the reaction mixture was stirred at 25 °C for 12 h. The mixture was quenched with Na 2 CO 3 (20 mL), extracted with DCM (2 × 30 mL), the combined organic phases were washed with brine (2 × 15 mL), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1) to afford 2-bromo-6-(3-fluorotetrahydrofuran-3-yl)pyridine (1.4 g, 67% yield) as a yellow oil. 1H NMR: (400 MHz, CDCl 3 ) 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).

[0287] Preparation 64: 2-Bromo-6-(3-fluorotetrahydrofuran-3-yl)-4-methylpyridine [Chemistry] 2-Bromo-6-(3-fluorotetrahydrofuran-3-yl)-4-methylpyridine was obtained as a yellow oil from 3-(6-bromo-4-methylpyridin-2-yl)tetrahydrofuran-3-ol (Preparation 123) according to the procedure described in Preparation 63 (1.4 g, 66.2% yield). 1H NMR: (400 MHz, CDCl 3 ) 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).

[0288] Preparation 65: 2-Bromo-6-(3-fluorotetrahydrofuran-3-yl)-4-methoxypyridine

Chem.

[0289] Preparation 66: 2-Bromo-6-(3-fluorotetrahydrofuran-3-yl)-4-isopropoxypyridine

Chem.

[0290] Preparation 67: 2 - Bromo - 6 - (3 - fluorooxetan - 3 - yl) - 4 - methylpyridine

Chemical Structure

[0291] Preparations 68 - 72 The following table compounds were prepared from the appropriate alcohols and DAST according to a procedure similar to that described in Preparation 67.

Table 4-1

Table 4-2

[0292] Preparation 73: 3-(6-Bromopyridin-2-yl)-3-methyldihydrofuran-2(3H)-one

Chem.

[0293] Preparation 74: 2-(6-Bromopyridin-2-yl)-2-methylbutane-1,4-diol

Chem.

[0294] Preparation 75: 2-Bromo-6-(3-methyltetrahydrofuran-3-yl)pyridine

Chemical Structure

[0295] Preparation 76: 2-(3,6-Dihydro-2H-pyran-4-yl)-6-fluoropyridine [Chemical formula] To a solution of 2-bromo-6-fluoropyridine (3.0 g, 17.05 mmol) in dioxane (40 mL) and H 2 O (10 mL) was added 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.9 g, 14.21 mmol), Pd(dppf)Cl 2 (1.1 g, 1.42 mmol), and K 2 CO 3 (3.9 g, 28.41 mmol). The reaction mixture was stirred at 80 °C for 1 h under N 2 . The mixture was poured into H 2 O (40 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over anhydrous Na 2 SO 4 and filtered, then concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1 - 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 H NMR (500 MHz, CDCl 3 ) δ ppm: 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).

[0296] Preparation 77: 2-(3,7-Dioxabicyclo[4.1.0]heptan-6-yl)-6-fluoropyridine [Chemical formula] 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) was added with 3-chlorobenzenepeloxoic acid (1.7 g, 10.05 mmol) at 0 °C, and the resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was poured into saturated Na 2 CO 3 (30 mL), extracted with EtOAc (20 mL × 3), and the combined organic layers were dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1 - 5 / 1) to obtain 2-(3,7-dioxabicyclo[4.1.0]heptan-6-yl)-6-fluoropyridine (2.4 g, crude product) as a white solid. 1 H NMR (500 MHz, CDCl 3 ) δ ppm: 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).

[0297] Preparation 78: 3-(6-Fluoropyridin-2-yl)tetrahydrofuran-3-carbaldehyde [Chemical Structure] To a solution of 2-(3,7-dioxabicyclo[4.1.0]heptan-6-yl)-6-fluoropyridine (Preparation 77, 1.0 g, 5.12 mmol) in DCM (15 mL) was slowly added BF 3 ·Et 2 O (2.2 g, 15.37 mmol) at 0 °C, and the reaction mixture was stirred at 20 °C for 12 h. The mixture was poured into saturated Na 2 CO 3 (20 mL), extracted with EtOAc (20 mL × 3), and the combined organic layers were dried over anhydrous Na 2 SO 4It was dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1 - 3 / 1) to obtain 3-(6-fluoropyridin-2-yl)tetrahydrofuran-3-carbaldehyde (621.9 mg, 62.2% yield) as a white solid. 1 H NMR: (400 MHz, CDCl 3 ) δ ppm: 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).

[0298] Preparation 79: (3-(6-Fluoropyridin-2-yl)tetrahydrofuran-3-yl)methanol

Chemical Structure

[0299] Preparation 80: 2-Fluoro-6-(3-(fluoromethyl)tetrahydrofuran-3-yl)pyridine

Chem.

[0300] Preparation 81: 2-Chloro-6-(3,6-dihydro-2H-pyran-4-yl)pyridine

Chem.

[0301] Preparation 82: 2-(3,7-dioxabicyclo[4.1.0]heptan-6-yl)-6-chloropyridine

Chem.

[0302] Preparation 83: 3-(6-Chloropyridin-2-yl)tetrahydrofuran-3-carbaldehyde

Chem.

[0303] Preparation 84: 2-Chloro-6-(3-vinyltetrahydrofuran-3-yl)pyridine

Chem.

[0304] Preparation 85: 2-Chloro-6-(3-ethyltetrahydrofuran-3-yl)pyridine [Chemical formula] 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 under H 2 2 (balloon) for 1 hour. The Pd / C was removed by filtration through Celite®. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with 10 - 20% EtOAc in hexanes to afford 2-chloro-6-(3-ethyltetrahydrofuran-3-yl)pyridine (3.50 g, 89% yield). LCMS m / z = 212 [M+H] + .

[0305] Preparation 86: 2-(3-(Difluoromethyl)tetrahydrofuran-3-yl)-6-fluoropyridine [Chem.] To a solution of 3-(6-fluoropyridin-2-yl)tetrahydrofuran-3-carbaldehyde (Preparation 78, 200 mg, 1.02 mmol) in DCM (5 mL) was slowly added DeoxoFluor (566.7 mg, 2.56 mmol) at 0 °C, and the reaction mixture was stirred at 20 °C for 12 h under N 2 atmosphere. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EtOAc = 10 / 1 - 5 / 1) to afford 2-(3-(difluoromethyl)tetrahydrofuran-3-yl)-6-fluoropyridine (56.1 mg, 25.2% yield) as a colorless oil. 1 H NMR (500 MHz, CDCl 3 3) δ ppm: 7.82 - 7.78 (m, 1H), 7.26 - 7.24 (m, 1H), 6.89 - 6.86 (m, 1H), 6.16 (t, J = 56.0 Hz, 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).

[0306] Preparation 87: 3-(6-Bromopyridin-2-yl)tetrahydrofuran-3-carbonitrile [Chem.] To NaH (81.2 mg, 2.03 mmol, 60% purity) in DMF (40 mL) were added 2-(6-bromopyridin-2-yl)acetonitrile (400 mg, 2.03 mmol) and 1-chloro-2-(chloromethoxy)ethane (261.9 mg, 2.03 mmol) in DMF (10 mL) at -10 °C, and the reaction mixture was stirred at -10 °C for 30 min. The mixture was quenched with NH 4 Cl (saturated, 10 mL), poured into H 2 2O (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over anhydrous Na 2 2SO 4It was dried, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc = 15 / 1 - 3 / 1) to obtain 3-(6-bromopyridin-2-yl)tetrahydrofuran-3-carbonitrile (212.7 mg, 41.4% yield) as a yellow oil. 1 H NMR: (400 MHz, CDCl 3 ) δ ppm: 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).

[0307] Preparation 88: 1-(6-chloropyridin-2-yl)pyrrolidin-2-one

Chemical Structure

[0308] Preparation 89: 2-Chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [Chemical formula] 2-Chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridine (Preparation 61, 11.9 g, 55.8 mmol) was dissolved in hexane (170 mL), degassed with N 2 , then 4,4'-di-tert-butyl-2,2'-bipyridine (298 mg, 1.12 mmol), bis(1,5-cyclooctadiene)dirhodium(I) dichloride (381 mg, 0.56 mmol), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (16.7 g, 65.6 mmol) were added. The reaction was heated at 75 °C for 1 h under N 2 and the mixture was 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-dioxaborolan-2-yl)pyridine (6.0 g, 32% yield).

[0309] Preparation 90: 2-Chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol [Chemical formula] Oxone (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-dioxaborolan-2-yl)pyridine (Preparation 89, 4.4 g, 13.0 mmol) in THF (50 mL) at 0 °C, then the reaction was stirred at this temperature for 1 h. The mixture was quenched with Na 2 SO 3 (saturated solution), extracted with EtOAc (100 mL × 2), and the combined organic layers were dried over anhydrous Na 2 SO 4It was dried, filtered, and concentrated to obtain 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (3.3 g, crude product) as a brown oil. LCMS m / z = 229.9 [M+H] + .

[0310] Preparation 91: 2-Chloro-4-methoxy-6-(3-methoxytetrahydrofuran-3-yl)pyridine [Chemical formula] MeI (166.8 mg, 1.18 mmol) was added to a mixture of 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Preparation 90, 180 mg, 0.784 mmol) and Cs 2 CO 3 (383 mg, 1.18 mmol) in DMF (10 mL) under N 2 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 × 3). The combined organic layers were washed with H 2 O (10 mL × 3) and brine (20 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to obtain 2-chloro-4-methoxy-6-(3-methoxytetrahydrofuran-3-yl)pyridine (160 mg, 84% yield) as a yellow oil, which was used in the next step without further purification. 1H NMR (400 MHz, CDCl 3 ) δ ppm 7.00 (d, J = 2.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 4.17 - 4.02 (m, 3H), 3.98 - 3.95 (m, 1H), 3.88 (s, 3H), 3.23 (s, 3H), 2.68 - 2.60 (m, 1H), 2.35 - 2.30 (m, 1H).

[0311] Preparation 92: 2-Chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3-yloxy)pyridine [Chemical formula] 2-Chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3-yloxy)pyridine (120 mg, crude product) was obtained from 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-ol (Preparation 90) and 3-iodooxetane according to a procedure similar to that described in Preparation 91. LCMS m / z = 286.1 [M+H] + 。

[0312] Preparation 93: 2-Chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-2-ylmethoxy)pyridine

Chemical formula

[0313] Preparation 94: 2-Chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(oxetan-3-ylmethoxy)pyridine

Chem.

[0314] Preparation 95: 2-Chloro-4-(3-(difluoromethyl)cyclobutoxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine

Chem.

[0315] Preparation of 3-(benzyloxy)cyclobutyl 4-methylbenzenesulfonate

Chem.

[0316] Preparation of 4-(3-(benzyloxy)cyclobutoxy)-2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridine

Chem.

[0317] Preparation 98: 2 - chloro - 4-(3,3 - difluorocyclobutoxy) - 6-(3 - methoxytetrahydrofuran - 3 - yl)pyridine

Chemical Structure

[0318] Preparation 99: 2 - chloro - 4 - ethoxy - 6-(3 - methoxytetrahydrofuran - 3 - yl)pyridine

Chemical Structure

[0319] Preparation 100: 2-Chloro-4-isopropoxy-6-(3-methoxytetrahydrofuran-3-yl)pyridine

Chemical Structure

[0320] Preparation 101: 2-Chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(2,2,2-trifluoroethoxy)pyridine [Chemical formula] 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) was added with K 2 CO 3 (361.0 mg, 2.61 mmol), and the reaction mixture was stirred at 70 °C for 8 hours. The mixture was diluted with H 2 O (10 mL), extracted with EtOAc (10 mL × 3), and the combined organic layers were dried over anhydrous Na 2 SO 4 and filtered, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc = 15 / 1 - 3 / 1) to obtain 2-chloro-6-(3-methoxytetrahydrofuran-3-yl)-4-(2,2,2-trifluoroethoxy)pyridine (130 mg, 47.9% yield) and an additional 130 mg of impure product. LCMS m / z = 312.1 [M+H] + .

[0321] Preparation 102: 3-((2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-yl)oxy)cyclobutan-1-ol [Chemical formula] 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 obtain 3-((2-chloro-6-(3-methoxytetrahydrofuran-3-yl)pyridin-4-yl)oxy)cyclobutan-1-ol (105 mg, 68.3% yield) as a white solid. 1 H NMR: (400 MHz, CDCl 3) δ ppm: 6.89 (d, J = 2.0 Hz, 1H), 6.61 (d, J = 2.0 Hz, 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).

[0322] Preparation 103: 2 - Chloro - 4-(3 - methoxycyclobutoxy)-6-(3 - methoxytetrahydrofuran - 3 - yl)pyridine

Chemical Structure

[0323] Preparation 104: 4-(3 - (Benzyloxy)cyclobutoxy)-2,6 - dichloropyridine

Chemical Structure

[0324] Preparation 105: 4-(3-(Benzyloxy)cyclobutoxy)-2-chloro-6-(furan-3-yl)pyridine

Chemical Structure

[0325] Preparation 106: 3 - ((2 - chloro - 6 - (furan - 3 - yl) pyridin - 4 - yl) oxy) cyclobutan - 1 - ol

Chemical Structure

[0326] Preparation 107: 2 - chloro - 6 - (furan - 3 - yl) - 4 - (3 - methoxycyclobutoxy) pyridine

Chemical Structure

[0327] Preparation 108: 4-(3-(Benzyloxy)cyclobutoxy)-2-chloropyridine

Chemical formula

[0328] Preparation 109: 1-(4-(3-(Benzyloxy)cyclobutoxy)-6-chloropyridin-2-yl)ethan-1-one [Chemical Structure] To a solution of 4-(3-(benzyloxy)cyclobutoxy)-2-chloropyridine (Preparation 108, 10.8 g, 37.27 mmol) in MeCN (120 mL) were added acetaldehyde (16.4 g, 372.7 mmol), TBHP (6.7 g, 74.55 mmol), TFA (4.7 g, 41 mmol), and FeSO 4 (10.4 g, 37.27 mmol), and the reaction mixture was stirred at 80 °C for 16 h under N 2 atmosphere. The mixture was concentrated under reduced pressure to give a residue, which was treated with H 2 O (150 mL) and extracted with EtOAc (100 mL × 3). The combined organic phases were washed with brine (200 mL), dried over Na 2 SO 4 4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EtOAc = 5 / 1 - 3 / 1) to afford 1-(4-(3-(benzyloxy)cyclobutoxy)-6-chloropyridin-2-yl)ethan-1-one as a yellow oil (640 mg, 5.18% yield) and 4-(3-(benzyloxy)cyclobutoxy)-2-chloropyridine as a pale yellow oil (8.6 g, 79.6% yield). LCMS m / z = 331.7 [M+H] + .

[0329] Preparation 110: 4-(3-(Benzyloxy)cyclobutoxy)-2-chloro-6-(1,1-difluoroethyl)pyridine [Chemical Structure] A solution of 1-(4-(3-(benzyloxy)cyclobutoxy)-6-chloropyridin-2-yl)ethan-1-one (Preparation 109, 600 mg, 1.81 mmol) in DCM (10 mL) was added to DAST (7.3 g, 45.41 mmol), and the reaction mixture was stirred at 25 °C for 16 h. The reaction was quenched with H 2 O (10 mL) and extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (10 mL), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EtOAc = 5 / 1 to 1 / 1) to afford 4-(3-(benzyloxy)cyclobutoxy)-2-chloro-6-(1,1-difluoroethyl)pyridine (300 mg, 46.9% yield) as a yellow gum. LCMS m / z = 353.9 [M+H] + .

[0330] Preparation 111: 3-((2-chloro-6-(1,1-difluoroethyl)pyridin-4-yl)oxy)cyclobutan-1-ol [Chemical formula] 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 was treated with H 2 O (20 mL) and extracted with EtOAc (15 mL × 3). The combined organic phases were washed with brine (30 mL), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc = 5 / 1 to 3 / 1) to afford 3-((2-chloro-6-(1,1-difluoroethyl)pyridin-4-yl)oxy)cyclobutan-1-ol (80.0 mg, 48.8% yield) as a yellow solid. LCMS m / z = 359.6 [M+H] + .

[0331] Preparation 112: 2-Chloro-6-(1,1-difluoroethyl)-4-(3-methoxycyclobutoxy)pyridine

Chem.

[0332] Preparation 113: 2-Chloro-4-((1-methoxypropan-2-yl)oxy)-6-(3-methoxytetrahydrofuran-3-yl)pyridine

Chem.

[0333] Preparation 114: 2 - Chloro - 4-(2 - methoxypropoxy)-6-(3 - methoxytetrahydrofuran - 3 - yl)pyridine

Chemical Structure

[0334] Preparation 115: 2 - Chloro - 4-(2 - methoxyethoxy)-6-(3 - methoxytetrahydrofuran - 3 - yl)pyridine

Chemical Structure

[0335] Preparation 116: 1-(6-Chloro-4-(2-methoxyethoxy)pyridin-2-yl)ethan-1-one

Chemical Structure

[0336] Preparation 117: 2 - Chloro - 6 - (1,1 - difluoroethyl) - 4 - (2 - methoxyethoxy)pyridine [Chemical Structure] To a solution of 1 - (6 - chloro - 4 - (2 - methoxyethoxy)pyridin - 2 - yl)ethan - 1 - one (Preparation 116, 42.0 mg, 0.183 mmol) in DCM (2 mL) was added DAST (58.9 mg, 0.366 mmol) at 0 °C, and then the resulting mixture was stirred at 50 °C for 24 h. The mixture was quenched with Na 2 CO 3 (aqueous solution, 5 mL), poured into H 2 O (10 mL), and extracted with EtOAc (2 × 10 mL). The combined organic phases were washed with brine (2 × 10 mL), dried over Na 2 SO 4 , 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 (500 MHz, CDCl 3 ) δ ppm: 7.13 (d, J = 1.5 Hz, 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 = 18.0 Hz, 3H).

[0337] Preparation 118: 2 - Fluoro - 6 - (furan - 3 - yl)pyridine [Chemical Structure] Dioxane (4 mL) and H2 To a solution of 2-bromo-6-fluoropyridine (300 mg, 1.70 mmol) in O(0.5 mL), furan-3-ylboronic acid (209.8 mg, 1.88 mmol), Pd(dppf)Cl 2 (124.7 mg, 0.170 mmol), and Cs 2 CO 3 (1.1 g, 3.41 mmol) were added, and the reaction mixture was stirred at 90 °C for 3 h under N 2 . The mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc = 10 / 1) to afford 2-fluoro-6-(furan-3-yl)pyridine (215.9 mg, 77.6% yield) as a colorless oil. 1 H NMR: (500 MHz, CDCl 3 ) δ ppm: 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).

[0338] Preparation 119: 2-Fluoro-6-(tetrahydrofuran-3-yl)pyridine

Chemical Structure

[0339] Preparation 120: 2-Fluoro-6-(furan-3-yl)-4-methylpyridine

Chemical Structure

[0340] Preparation 121: 2-Fluoro-4-methyl-6-(tetrahydrofuran-3-yl)pyridine

Chemical Structure

[0341] Preparation 122: 2 - Bromo - 6 - (furan - 3 - yl) - 4 - methoxypyridine [Chemical formula] 2 - Bromo - 6 - (furan - 3 - yl) - 4 - methoxypyridine was obtained as a white solid (300 mg, 63% yield) from 2,6 - dibromo - 4 - methoxypyridine and furan - 3 - ylboronic acid according to the procedure described in Preparation 118. LCMS m / z = 254.1 [M + H] + .

[0342] Preparation 123: 3 - (6 - Bromo - 4 - methylpyridin - 2 - yl)tetrahydrofuran - 3 - ol [Chemical formula] To a solution of 2,6 - dibromo - 4 - methylpyridine (1.0 g, 3.99 mmol) in DCM (10 mL) was added dropwise n - BuLi (2.5 M, 1.59 mL) at - 78 °C over 30 minutes, and 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 was allowed to warm naturally to 15 °C over 2 hours under N 2 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EtOAc = 10 / 1 - 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] + .

[0343] Preparation 124: 2-Bromo-6-(3-methoxytetrahydrofuran-3-yl)-4-methylpyridine

Chemical Structure

[0344] Preparation 125: 2,6-Dichloro-4-(2-methoxypropoxy)pyridine

Chemical Structure

[0345] Preparation 126: 2-Chloro-6-(furan-3-yl)-4-(2-methoxypropoxy)pyridine

Chemical Structure

[0346] Preparation 127: 2,4-Dichloro-6-(1,1-difluoroethyl)pyridine

Chemical Structure

[0347] Preparation 128: 2-Chloro-4-(2-fluoropropan-2-yl)pyridine

Chemical Structure

[0348] Preparation 129: 2-Chloro-6-(1,1-difluoroethyl)-4-isopropoxypyridine

Chemical formula

[0349] Preparation 130: 2-(6-Bromopyridin-2-yl)propan-2-ol

Chemical formula

[0350] Preparation 131: 2-Bromo-6-(2-methoxypropan-2-yl)pyridine

Chemical Structure

[0351] Preparation 132: 2-Bromo-6-(2-fluoropropan-2-yl)pyridine

Chemical Structure

[0352] Preparation 133: 2-chloro-6-(1,1-difluoroethyl)-4-methoxypyridine [Chemical formula] To a solution of 2,4-dichloro-6-(1,1-difluoroethyl)pyridine (Preparation 127, 151 mg, 0.726 mmol) in MeOH (6 mL) was added MeONa (47.1 mg, 0.871 mmol), 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 afford 2-chloro-6-(1,1-difluoroethyl)-4-methoxypyridine (40 mg, 27.1% yield) as a yellow oil. 1H NMR: (400 MHz, CDCl 3 ) δ ppm: 7.01 (s, 1H), 6.72 (d, J = 1.6 Hz, 1H), 3.87 (s, 3H), 1.70 (s, 3H), 1.65 (s, 3H).

[0353] Alternative synthesis: To a solution of 1-(6-chloro-4-methoxypyridin-2-yl)ethan-1-one (Preparation 134, 328 mg, 1.77 mmol) in DCM (5 mL) was added DAST (3.7 g, 3.0 mL), and the reaction mixture was stirred at 25 °C for 48 h. The mixture was concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (PE) to afford 2-chloro-6-(1,1-difluoroethyl)-4-methoxypyridine (87.0 mg, 23.7% yield) as a colorless oil. 1 H NMR: (500 MHz, CDCl 3 ) δ ppm : 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).

[0354] Preparation 134: 1-(6-chloro-4-methoxypyridin-2-yl)ethan-1-one

Chemical formula

[0355] Preparation 135: 2-Bromo-6-(oxetan-3-yl)pyridine [Chemical formula] 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(CF 3 )ppy] 2 (dtbbpy)PF 6 (47.4 mg, 0.042 mmol), LiOH (202.2 mg, 8.44 mmol), NiCl 2 ·glyme (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 for 12 h under N 2 . The reaction was concentrated under reduced pressure, diluted with H 2 O (20 mL), and extracted with EtOAc (3 × 20 mL). The combined organic phases were washed with brine (2 × 20 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1) to give 2-bromo-6-(oxetan-3-yl)pyridine (400 mg, 44.3% yield) as a yellow oil. 1 1H NMR: (500 MHz, CDCl 3 ) δ ppm: 7.54 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 5.05 - 5.02 (m, 2H), 4.91 - 4.89 (m, 2H), 4.38 - 4.35 (m, 1H).

[0356] Preparation 136: 2-Chloro-6-(furan-3-yl)-4-(2-methoxyethoxy)pyridine [Chemical formula] 2-Chloro-6-(furan-3-yl)-4-(2-methoxyethoxy)pyridine was obtained as a colorless oil (183 mg, 80.1% yield) from 2,6-dichloro-4-(2-methoxyethoxy)pyridine according to the procedure described in Preparation 126. 1 H NMR: (400 MHz,CDCl 3 ) δ: ppm 8.04 (d, J=8.0 Hz, 1H), 7.48-7.46 (m, 1H), 6.93-6.88 (m, 1H), 6.81 (d, J=6.0 Hz, 1H), 6.72 (d, J=2.0 Hz, 1H), 4.24-4.15 (m, 2H), 3.78-3.74 (m, 2H), 3.45 (s, 3H).

[0357] Preparation 137: tert-Butyl (1-(6-bromopyridin-2-yl)-2,2,2-trifluoroethyl)carbamate

Chemical formula

[0358] Preparation 138: tert-Butyl (1-(6-(6-acetamido-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-2,2,2-trifluoroethyl)carbamate [Chemical formula] To a mixture of tert-butyl (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), K 2 CO 3 (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 for 12 h under N 2 . The mixture was poured into H 2 O (15 mL), extracted with EtOAc (10 mL × 3), and the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1 - 3 / 1) to give tert-butyl (1-(6-(6-acetamido-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-2,2,2-trifluoroethyl)carbamate (66.9 mg, 65.9% yield) as a colorless oil. 1H NMR: (500 MHz, CDCl 3 ) δ ppm: 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 = 9.5 Hz, 1H), 5.60 - 5.57 (m, 1H), 2.28 (s, 3H), 1.43 (s, 9H).

[0359] Preparation 139: 6-Chloro-1-(6-(3-methoxytetrahydrofuran-3-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine [Chemical Structure] 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) were added K 2 CO 3 (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), and the reaction mixture was stirred at 100 °C for 6 h. The cooled mixture was treated with H 2 O (50 mL), extracted with EtOAc (30 mL × 3), the combined organic phases were washed with brine (80 mL), dried over Na 2 SO 4 and filtered, 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 (1.5 g, 69.6% yield) as a white solid. LCMS m / z = 331.1 [M+H] + .

[0360] Preparation 140: 2-Chloro-7-(5-(3-methoxytetrahydrofuran-3-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine [Chemical Structure] 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) were added N 1 ,N 2-Dimethylethane-1,2-diamine (27.3 mg, 0.310 mmol), CuI (118.1 mg, 0.620 mmol), and K 2 CO 3 (428.4 mg, 3.10 mmol) were added, and the reaction mixture was stirred at 90 °C for 2 h under N2. The cooled mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (PE / EtOAc = 3 / 1 - 1 / 1) to afford 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. 1 1H NMR: (400 MHz, CDCl 3 ) δ ppm: 8.94 - 8.90 (m, 2H), 8.71 - 8.68 (m, 1H), 8.25 - 8.22 (m, 1H), 7.57 (d, J = 3.6 Hz, 1H), 6.82 (d, J = 3.6 Hz, 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).

[0361] Preparation 141: 4-(6-Chloro-1-(6-(1,1-difluoroethyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine

Chemical formula

[0362] Preparation 142: 6 - chloro - 3 - cyclopropyl - 1 - (6 - (1,1 - difluoroethyl)pyridin - 2 - yl)-1H - pyrazolo[4,3 - c]pyridine

Chemical Structure

[0363] Preparation 143: (3S)-1 - (6 - chloro - 1 - (tetrahydro - 2H - pyran - 2 - yl)-1H - pyrazolo[4,3 - c]pyridin - 3 - yl)-N,N - dimethylpyrrolidin - 3 - amine

Chemical Structure

[0364] Preparation 144: (3R)-1-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidin-3-amine

Chemical Structure

[0365] Preparation 145: (S)-1-(6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidin-3-amine

Chemical Structure

[0366] Preparation 146: (R)-1-(6-Chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidin-3-amine [Chemical formula] A solution of (3R)-1-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidin-3-amine (Preparation 144, 260 mg, 0.743 mmol) in HCl / dioxane (4M, 5 mL) was stirred at 25 °C for 6 h. The reaction mixture was concentrated to give (R)-1-(6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidin-3-amine (210 mg, crude product, HCl salt) as a yellow solid. LCMS m / z = 266.1 [M+H] + .

[0367] Preparation 147: (S)-1-(6-Chloro-1-(6-(1,1-difluoroethyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidin-3-amine [Chemical formula] To a solution of (S)-1-(6-chloro-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidin-3-amine (Preparation 145, 100 mg, 0.376 mmol) in dioxane (5 mL) were added 2-bromo-6-(1,1-difluoroethyl)pyridine (100.3 mg, 0.452 mmol), Cs 2 CO 3 (245.2 mg, 0.753 mmol), and BrettPhos Pd G3 (34.1 mg, 0.038 mmol). The reaction mixture was stirred at 100 °C for 1 h under N 2 . The cooled mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL × 3). The combined organic phases were washed with brine (30 mL × 3) and dried over anhydrous Na 2 SO 4It was dried, filtered, and concentrated above. The crude product was purified by silica gel column (PE / EtOAc = 1 / 1) to obtain (S)-1-(6-chloro-1-(6-(1,1-difluoroethyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidin-3-amine (55.3 mg, 36.1% yield) as a yellow solid. LCMS m / z = 408.7 [M+H] + 。

[0368] Preparation 148: (R)-1-(6-chloro-1-(6-(1,1-difluoroethyl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-3-yl)-N,N-dimethylpyrrolidin-3-amine

Chemical formula

[0369] Preparation 149: 4-(6-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridin-3-yl)morpholine

Chemical Structure

[0370] Preparation 150: 4-(6-Chloro-1H-pyrrolo[3,2-c]pyridin-3-yl)morpholine [Chemical formula] 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) was added TFA (1 M, 1.0 mL), and the reaction mixture was stirred at 25 °C for 16 h. NH 3 ·H 2 O (10.48 mg, 0.299 mmol) was added slowly, and the mixture was stirred at 25 °C for 16 h. The reaction mixture was treated with H 2 O (10 mL), extracted with DCM (15 mL × 3), the combined organic phases were washed with brine (20 mL), dried over Na 2 SO 4 and filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE / EtOAc = 3 / 1~0 / 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] + .

[0371] Preparation 151: 4-(6-Chloro-1-(4-(1,1-difluoroethyl)pyridin-2-yl)-1H-pyrrolo[3,2-c]pyridin-3-yl)morpholine [Chemical formula] 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) was added with Cs 2 CO 3 (185.1 mg, 0.568 mmol) and BrettPhos Pd G3 (17.2 mg, 0.019 mmol), and the reaction was stirred at 100 °C for 1 h under N 2 . The cooled mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc = 15 / 1 - 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] + .

[0372] Preparation 152: 1-(6-(3-Methoxytetrahydrofuran-3-yl)pyridin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-amine [Chemical formula] 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 NH 2 Boc (159.4 mg, 1.36 mmol) in dioxane (10 mL) was added BINAP (47.1 mg, 0.076 mmol), Pd(OAc) 2 (13.6 mg, 0.060 mmol), and Cs 2 CO 3 (689.5 mg, 2.12 mmol), and the reaction was stirred at 100 °C for 16 h. The cooled mixture was treated with H 2 O (15 mL), and extracted with EtOAc (20 mL × 3). The combined organic phases were washed with brine (20 mL), and Na 2 SO 4It was dried, filtered, concentrated, and then purified by silica gel column chromatography (PE / EtOAc = 15 / 1 - 5 / 1) to obtain 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] + 。

[0373] Preparation 153: tert-Butyl (7-(5-(3-methoxytetrahydrofuran-3-yl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)carbamate

Chem.

[0374] Preparation 154: 7-(5-(3 - Methoxytetrahydrofuran - 3 - yl)pyridin - 3 - yl)-7H - pyrrolo[2,3 - d]pyrimidin - 2 - amine

Chemical Structure

[0375] Preparation 155: N-(3-(4 - Methylpiperazin - 1 - yl)-1-(tetrahydro - 2H - pyran - 2 - yl)-1H - pyrazolo[4,3 - c]pyridin - 6 - yl)acetamide

Chemical Structure

[0376] Preparation 156 - 158 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 the appropriate amine using a method similar to that described in Preparation 155.

Table 5-1

Table 5-2

[0377] Preparation 159: N-(3-(4-methylpiperazin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

Chemical Structure

[0378] Preparation 160: N-(3-(Pyrrolidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

Chem.

[0379] Preparation 161: N-(3-(3-Cyanoazetidin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

Chem.

[0380] Preparation 162: N-(3-(4-Methoxypyridin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide trifluoroacetate [Chemical Structure] N-(3-(4-Methoxypyridin-1-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide trifluoroacetate was prepared as a yellow oil (318 mg, crude product) from N-(3-(4-Methoxypyridin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide (Preparation 158) using a method similar to the method described in Preparation 161. LCMS m / z = 290.2 [M+H] + .

[0381] Preparation 163: 3-(2-Chloropyrimidin-4-yl)tetrahydrofuran-3-ol [Chemical Structure] 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 minutes, 2-chloropyrimidine (2.0 g, 17.46 mmol) in THF (20.0 mL) was added dropwise, and the mixture was stirred at -70 °C for 1 hour. To this, dihydrofuran-3(2H)-one (6.1 g, 69.85 mmol) was slowly added, stirring was continued for 10 minutes, then the temperature was warmed to 0 °C and the mixture was stirred for 1 hour. The mixture was quenched with NH 4 Cl (saturated, 20 mL), poured into H 2 O (30 mL), and extracted with EtOAc (3 × 30 mL). The combined organic components were dried (Na 2 SO 4 ), and evaporated to dryness under reduced pressure. The residue was chromatographed (SiO 2, purified by 25 - 50% EtOAc / PE, to give 3-(2-chloropyrimidin-4-yl)tetrahydrofuran-3-ol as a yellow oil (904.6 mg). 1 H NMR (500 MHz, CDCl 3 ) 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).

[0382] Preparation 164: 3-(2-Chloropyrimidin-4-yl)oxetan-3-ol

Chem.

[0383] Preparation 165: 3-(6-Bromopyrimidin-4-yl)tetrahydrofuran-3-ol

Chem.

[0384] Preparation 166: 2-Chloro-4-(3-methoxytetrahydrofuran-3-yl)pyrimidine

Chemical Structure

[0385] Preparation 167: 4 - Bromo - 6 - (3 - methoxytetrahydrofuran - 3 - yl)pyrimidine

Chem.

[0386] Preparation 168: 2 - Chloro - 4 - (3 - fluorotetrahydrofuran - 3 - yl)pyrimidine

Chem.

[0387] Preparation 169: 2-Chloro-4-(3-fluorooxetan-3-yl)pyrimidine

Chemical Structure

[0388] Preparation 170: 2-Chloro-4-(furan-3-yl)pyrimidine

Chemical Structure

[0389] Preparation 171: N-(3-Cyclopropyl-1-(4-(furan-3-yl)pyrimidin-2-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)acetamide

Chem.

[0390] Preparation 172: 1-(3-Chloropyrazin-2-yl)ethan-1-one

Chem.

[0391] Preparation 173: 2-Chloro-3-(1,1-difluoroethyl)pyrazine

Chemical Structure

[0392] Preparation 174: 6-Chloro-N-methoxy-N-methylpyrazine-2-carboxamide [Chemical formula] To a solution of 6-chloropyrazine-2-carboxylic acid (5.0 g, 31.5 mmol) in DCM (50 mL) was added (COCl) 2 (4.8 g, 37.84 mmol, 3.20 mL) and DMF (0.2 mL), and the mixture was stirred at 10 °C for 12 h. To this was added N,O-dimethylhydroxylamine hydrochloride (4.0 g, 41 mmol), and then TEA (9.6 g, 94.6 mmol) was added dropwise. The resulting mixture was stirred at 10 °C for 2 h, diluted with H 2 O (20 mL), and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried (Na 2 SO 4 ), and evaporated to dryness under reduced pressure. The residue was purified by column chromatography (SiO 2 , 25% EtOAc / PE) to give 6-chloro-N-methoxy-N-methylpyrazine-2-carboxamide as a yellow oil (3.2 g, 50%). 1 1H NMR (500 MHz, CDCl 3 ) δ: 8.78 (br s, 1H), 8.67 (s, 1H), 3.78 (s, 3H), 3.38 (s, 3H).

[0393] Preparation 175: 1-(6-Chloropyrazin-2-yl)ethan-1-one [Chemical formula] To a solution of 6-chloro-N-methoxy-N-methylpyrazine-2-carboxamide (Preparation 174, 3.2 g, 15.9 mmol) in THF (30 mL) was added MeMgBr (3 M, 5.29 mL) dropwise at N 2 under 0 °C. The resulting mixture was allowed to warm to room temperature naturally and stirred for 2 h. The reaction mixture was quenched with NH 4It was quenched with Cl (10 mL) and extracted with EtOAc (2 × 20 mL). The combined organic components were washed with brine (2 × 15 mL) and dried (Na 2 SO 4 ), and evaporated to dryness under reduced pressure. The residue was purified by chromatography (SiO 2 , 25% EtOAc / PE) to obtain 1-(6-chloropyrazin-2-yl)ethan-1-one as a yellow oil (1.2 g, 48%). 1 1H NMR (400 MHz, CDCl 3 ) δ: 9.10 (s, 1H), 8.77 (s, 1H), 2.70 (s, 3H).

[0394] Preparation 176: 2-Chloro-6-(1,1-difluoroethyl)pyrazine

Chemical Structure

[0395] Preparation 177: 1-(2-Chloropyrimidin-4-yl)ethan-1-one

Chemical Structure

[0396] Preparation 178: 2-Chloro-4-(1,1-difluoroethyl)pyrimidine

Chemical Structure

[0397] Preparation 179: 1-(2-Chloro-6-methylpyrimidin-4-yl)ethan-1-one

Chemical Structure

[0398] Preparation 180: 2-Chloro-4-(1,1-difluoroethyl)-6-methylpyrimidine

Chemical formula

[0399] Preparation 181: 1-(4-(Benzyloxy)pyrimidin-2-yl)ethan-1-one

Chemical formula

[0400] Preparation 182: 4-(Benzyloxy)-2-(1,1-difluoroethyl)pyrimidine

Chemical formula

[0401] Preparation 183: 2-(1,1-Difluoroethyl)pyrimidin-4-ol

Chem.

[0402] Preparation 184: 4-Chloro-2-(1,1-difluoroethyl)pyrimidine

Chem.

[0403] Preparation 185: 2-(4-(Benzyloxy)pyrimidin-2-yl)propan-2-ol

Chem.

[0404] Preparation 186: 4-(Benzyloxy)-2-(2-fluoropropan-2-yl)pyrimidine

Chemical Structure

[0405] Preparation 187: 2-(2-Fluoropropan-2-yl)pyrimidin-4-ol [Chemical formula] A solution of 4-(benzyloxy)-2-(2-fluoropropan-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 h. The mixture was purified by preparative HPLC-E (0 - 30% MeCN) to give 2-(2-fluoropropan-2-yl)pyrimidin-4-ol (258 mg, 73%) as a white solid. 1 1H NMR (500 MHz, CDCl 3 ) δ: 7.91 (d, 1H), 6.36 (d, 1H), 1.76 (s, 3H), 1.71 (s, 3H).

[0406] Preparation 188: 4-Chloro-2-(2-fluoropropan-2-yl)pyrimidine [Chemical formula] A solution of 2-(2-fluoropropan-2-yl)pyrimidin-4-ol (Preparation 187, 100 mg, 0.64 mmol) in POCl 3 (2 mL) was stirred at 100 °C for 2 h. The mixture was concentrated, added to H 2 2O (10 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous Na 2 2SO 4 4, filtered, and concentrated to give 4-chloro-2-(2-fluoropropan-2-yl)pyrimidine (82 mg, 73%) as a colorless oil. 1 1H NMR (500 MHz, CDCl 3 ) δ: 8.66 (d, 1H), 7.29 (d, 1H), 1.81 (s, 3H), 1.77 (s, 3H).

[0407] Preparation 189: 4,6-Dichloro-2-(1,1-difluoroethyl)pyrimidine [Chemical formula] Part 1: Na (1.1 g, 48.27 mmol) in EtOH (20 mL) was stirred at 60 °C for 2 h. To this solution, ethyl 2,2-difluoropropanoate (5 g, 36.20 mmol) and malonamide (2.46 g, 24.13 mmol) were added, and the resulting mixture was stirred at 100 °C for 12 h. The mixture was concentrated, and the residue was diluted with H 2 O (10 mL) and extracted with EtOAc (20 mL × 2). The aqueous phase was adjusted to pH 1 - 3 with aqueous HCl solution, and the mixture was concentrated under reduced pressure to obtain 2-(1,1-difluoroethyl)pyrimidine-4,6-diol as a yellow solid (3 g), which was used without further purification. 1 H NMR (500 MHz, MeOH-d 4 ) 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 POCl 3 (24.7 g, 161 mmol) was stirred at 80 °C for 3 h. The mixture was poured into H 2 O (40 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were washed with brine (20 mL × 2), dried (Na 2 SO 4 ) and evaporated to dryness. The residue was purified by silica gel chromatography (PE / EtOAc = 5 / 1) to obtain 4,6-dichloro-2-(1,1-difluoroethyl)pyrimidine as a colorless oil (1.0 g, 28%). 1 H NMR (500 MHz, CDCl 3 ) δ: 7.49 (s, 1H), 2.05 (t, 3H).

[0408] Preparation 190: 4-Chloro-2-(1,1-difluoroethyl)-6-methoxypyrimidine

Chemical Structure

[0409] Preparation 191: 3-(4-Chloropyrimidin-2-yl)oxetan-3-ol

Chemical Structure

[0410] Preparation 192: 3-(4-Chloropyrimidin-2-yl)tetrahydrofuran-3-ol

Chem.

[0411] Preparation 193: 4-Chloro-2-(3-fluorooxetan-3-yl)pyrimidine

Chem.

[0412] Preparation 194: 4-Chloro-2-(3-fluorotetrahydrofuran-3-yl)pyrimidine

Chem.

[0413] Preparation 195: 4-(Benzyloxy)-2-(2-methoxypropan-2-yl)pyrimidine

Chemical Structure

[0414] Preparation 196: 2-(2-Methoxypropan-2-yl)pyrimidin-4-ol

Chemical Structure

[0415] Preparation 197: 4-Chloro-2-(2-methoxypropan-2-yl)pyrimidine

Chemical formula

[0416] Preparation 198: O-(3-(4-Chloropyrimidin-2-yl)tetrahydrofuran-3-yl) S-methyl dithiocarbonate

Chemical formula

[0417] Preparation 199: O-(3-(4-chloropyrimidin-2-yl)oxetan-3-yl) S-methyl dithiocarbonate

Chemical Structure

[0418] Preparation 200: 4 - Chloro - 2 - (tetrahydrofuran - 3 - yl) pyrimidine

Chem.

[0419] Preparation 201: 4 - Chloro - 2 - (oxetan - 3 - yl) pyrimidine

Chem.

[0420] Preparation 202: 2-(4,6-Dichloropyrimidin-2-yl)propan-2-ol

Chemical Structure

[0421] Preparation 203: 3-(4,6-Dichloropyrimidin-2-yl)oxetan-3-ol

Chemical Structure

[0422] Preparation 204: 3-(4,6-Dichloropyrimidin-2-yl)tetrahydrofuran-3-ol

Chemical formula

[0423] Preparation 205: 3-(4-Chloro-6-methoxypyrimidin-2-yl)tetrahydrofuran-3-ol

Chemical formula

[0424] Preparation 206: 4,6-Dichloro-2-(2-fluoropropan-2-yl)pyrimidine

Chemical formula

[0425] Preparation 207: 4,6-Dichloro-2-(3-fluorooxetan-3-yl)pyrimidine

Chemical formula

[0426] Preparation 208: 4-Chloro-2-(2-fluoropropan-2-yl)-6-methoxypyrimidine

Chemical formula

[0427] Preparation 209: 4-Chloro-2-(3-fluorooxetan-3-yl)-6-methoxypyrimidine

Chemical formula

[0428] Preparation 210: 4-Chloro-2-(3-fluorotetrahydrofuran-3-yl)-6-methoxypyrimidine

Chem.

[0429] Preparation 211: 4-Chloro-6-(1-ethoxyvinyl)-2-methylpyrimidine

Chem.

Claims

1. Equation (I): 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt thereof, wherein the formula is Ring A is an aromatic ring or aromatic heterocycle formed by condensation with ring B, which is a five-membered aromatic heterocycle. X １ is N or CH, X ２ is N or CR ２ And, X ３ is N or CR ３ And, X ４ is N or CR ４ And, Ring C is a phenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- to 6-membered heteroaryl, each of which contains one or more R Ｃ It is arbitrarily replaced by, Each R Ｃ is independently halo, -CN, -NR Ｎ１ R Ｎ２ , -NR Ｎ３ -C(O)-R ７ , -NR Ｎ４ -SO ２ -R ７ , -C(O)-R ７ , -SO ２ -R ７ , -OR Ｏ１ , C １～６ alkyl, alkenyl, 3- to 7-membered monocyclic carbocyclyl, phenyl, 5- to 12-membered monocyclic or bicyclic heteroaryl, or 4- to 9-membered monocyclic or bicyclic heterocyclyl, wherein the C Ｃ represented by R[[ID=二十九]] 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 with one or more R Ｃ１ or two R Ｃ are grouped together with the intervening atoms to form a 3- to 7-membered monocyclic carbocyclyl optionally substituted with one or more halo, Each R Ｃ１ These are independently: halo, oxo, -CN, -OR Ｏ１ , -NR Ｎ１ R Ｎ２ , -C(O)-R ７ , -C(O)-OR Ｏ３ , -SO ２ -R ７ , C １～６ Alkyl, C ３～６ A cycloalkyl, phenyl, a 5-12 member monocyclic or bicyclic heteroaryl, or a 4-7 member monocyclic heterocyclil, where R Ｃ１ The C represented by １～６ Alkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered monocyclic heterocyclyl are classified as halo, oxo, -CN, and -OR, respectively. Ｏ１ , -NR Ｎ１ R Ｎ２ , C １～６ Alkyl, C １～４ They are optionally substituted with one or more substituents independently selected from haloalkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyrill, and 4-8 membered monocyclic heterocyclyl. R １ H, C １～６ Alkyl, -OR １Ａ , -NR Ｎ１ R Ｎ２ , C ３～６ The cycloalkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyrill, or 4-7 membered monocyclic heterocycline, where R １ The C represented by １～６ Alkyl, phenyl, C ３～６ Cycloalkyls, 5-6 membered heteroaryls, 3-7 membered monocyclic carbocyclyls, and 4-7 membered monocyclic heterocyclyls each contain one or more R ８ It is arbitrarily replaced by, R １Ａ is H or C １～３ Is it alkyl? or R １ and R １Ａ These, together with the atoms to which they are bonded, form a monocyclic heterocycle of 5 or 6 members. R ２ H or halo, R ３ H, -NR Ｎ１ R Ｎ２ -CN, Halo, -C(O)-R ７ , -C(O)-OR Ｏ３ , -SO ２ -R ７ , -OR Ｏ４ , C １～６ Alkyl, alkenyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyclyl, or 4-9 member monocyclic or bicyclic heterocyclyl, where R ３ The C represented by １～６ Alkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyclyl, and 4-9 membered monocyclic or bicyclic heterocyclyl each contain one or more R ９ It is arbitrarily replaced with, R ４ H or halo, Each R ７ Independently, C １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyrill, or 4-7 member monocyclic heterocycline, where R ７ The C represented by １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyclyl, and 4-7 member monocyclic heterocyclyl are classified as halo, oxo, -CN, and -OR, respectively. Ｏ１ , -NR １ａ R １ｂ , C １～６ Alkyl, C １～４ It is optionally substituted with one or more substituents independently selected from haloalkyl groups, 3- to 7-membered monocyclic carbocyclines, and 4- to 7-membered monocyclic heterocyclines. Each R ８ These are independently: halo, oxo, -CN, -OR Ｏ１ , C １～６ Alkyl, C １～４ They are haloalkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyclyl, or 4-7 member monocyclic heterocyclyl. Each R ９ is, independently, halo, oxo, -OR Ｏ１ , -NR Ｎ１ R Ｎ２ , -CN, -C(O)-OR Ｏ３ , -SO ２ -R １０ , C １～６ alkyl, phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered monocyclic carbocyclyl, or 4- to 10-membered monocyclic or bicyclic heterocyclyl, where the C ９ represented by R 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 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 H and C are independent of each other. １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic or bicyclic carbocyclyl, or 4-7 member monocyclic or bicyclic heterocyclyl, where R Ｏ１ The C represented by １～６ Alkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic or bicyclic carbocyclyl, and 4-7 membered monocyclic or bicyclic heterocyclyl each contain one or more R Ｏ２ It is arbitrarily replaced with, Each R Ｏ２ These are independently: Halo, OH, -CN, C １～４ Alkoxy, C １～４ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyrill, or 4-7 member monocyclic or bicyclic heterocycline, where C １～４ Alkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyclyl, and 4-7 membered monocyclic or bicyclic heterocyclyl each contain one or more halos, C １～６ Alkyl, or -O-C １～６ It is optionally substituted with alkyl, Each R Ｏ３ H and C are independent of each other. １～６ Alkyl, C １～４ Haloalkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyrill, or 4-7 membered monocyclic heterocycline, where R Ｏ３ The C represented by １～６ Alkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyclyl, and 4-7 membered monocyclic heterocyclyl each contain one or more R Ｏ２ It is arbitrarily replaced with, R Ｏ４ H, C １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyrill, or 4-7 member monocyclic heterocycline, where R Ｏ４ The C represented by １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyclyl, and 4-7 member monocyclic heterocyclyl are classified as halo, oxo, -CN, and -OR, respectively. Ｏ１ , -NR Ｎ１ R Ｎ２ , C １～６ Alkyl, C １～４ They are optionally substituted with one or more substituents independently selected from haloalkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyrill, and 4-7 membered monocyclic heterocyclyl. R Ｎ１ and R Ｎ２ These are H and C, which are independent of each other. １～６ Alkyl, 4-7 membered monocyclic heterocyclyl, 5 or 6 membered heteroaryl, or C ３～６ It is a cycloalkyl, where R Ｎ１ and R Ｎ２ The C represented by １～６ Alkyls are, respectively, C １～４ It is optionally substituted with an alkoxy or phenyl, and R Ｎ１ and R Ｎ２ The C represented by ３～６ Cycloalkyls, 4- to 7-membered monocyclic heterocyclines, and 5 or 6-membered heteroaryls are, respectively, C １～４ It is optionally substituted with alkyl, Each R Ｎ３ H or C １～６ It is alkyl, Each R Ｎ４ H or C １～６ A pharmaceutically acceptable salt thereof of the compound or any alkyl compound.

2. Ring A is an aromatic ring or aromatic heterocycle formed by condensation of ring B, which is a five-membered aromatic heterocycle. X １ However, it is N or CH, X ２ However, N or CR ２ And, X ３ However, N or CR ３ And, X ４ However, N or CR ４ And, The C ring is phenyl or a 5-6 member heteroaryl, and each of these has one or more R groups. Ｃ It is arbitrarily replaced by, Each R Ｃ However, independently, Halo, -CN, -NR Ｎ１ R Ｎ２ , -NR Ｎ３ -C(O)-R ７ , -NR Ｎ４ -SO ２ -R ７ , -C(O)-R ７ , -SO ２ -R ７ , -OR Ｏ１ , C １～６ Alkyl, 3-7 membered monocyclic carbocyclyl, or 4-9 membered monocyclic or bicyclic heterocyclyl, where R Ｃ The C represented by １～６ Alkyl, 3-7 membered monocyclic carbocyclyl, and 4-9 membered monocyclic or bicyclic heterocyclyl each contain one or more R Ｃ１ It is arbitrarily substituted with, or two R Ｃ However, together with the atoms in between, they form a 3- to 7-membered monocyclic carbocyclyl which is arbitrarily substituted with one or more halos. Each R Ｃ１ However, independently, halo, oxo, -CN, -OR Ｏ１ , -NR Ｎ１ R Ｎ２ , -C(O)-R ７ , -C(O)-OR Ｏ３ , -SO ２ -R ７ , C １～６ Alkyl, phenyl, 5-6 member heteroaryl, or 4-7 member monocyclic heterocyclyl, where R Ｃ１ The C represented by １～６ Alkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered monocyclic heterocyclils are classified as halo, oxo, -CN, and -OR, respectively. Ｏ１ , -NR Ｎ１ R Ｎ２ , C １～６ Alkyl, C １～４ They are optionally substituted with one or more substituents independently selected from haloalkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyrill, and 4-8 membered monocyclic heterocyclyl. R １ However, C １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyrill, or 4-7 member monocyclic heterocycline, where R １ The C represented by １～６ Alkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyrill, and 4-7 membered monocyclic heterocyclyl each contain one or more R ８ It is arbitrarily replaced by, R １Ａ However, H or C １～３ Is it alkyl? or R １ and R １Ａ However, together with the atoms to which they are bonded, they form a monocyclic heterocycle of 5 or 6 members. R ２ However, it is H or halo, R ３ However, H, -NR Ｎ１ R Ｎ２ -CN, Halo, -C(O)-R ７ , -C(O)-OR Ｏ３ , -SO ２ -R ７ , -OR Ｏ４ , C １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyclyl, or 4-9 member monocyclic or bicyclic heterocyclyl, where R ３ The C represented by １～６ Alkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyclyl, and 4-9 membered monocyclic or bicyclic heterocyclyl each have one or more R groups. ９ It is arbitrarily replaced with, R ４ However, it is H or halo, Each R ７ However, independently, C １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyrill, or 4-7 member monocyclic heterocycline, where R ７ The C represented by １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyclyl, and 4-7 member monocyclic heterocyclyl are respectively classified as halo, oxo, -CN, and -OR. Ｏ１ , -NR １ａ R １ｂ , C １～６ Alkyl, C １～４ It is optionally substituted with one or more substituents independently selected from haloalkyl groups, 3- to 7-membered monocyclic carbocyclines, and 4- to 7-membered monocyclic heterocyclines. Each R ８ However, independently, halo, oxo, -CN, -OR Ｏ１ , C １～６ Alkyl, C １～４ They are haloalkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyclyl, or 4-7 member monocyclic heterocyclyl. Each R ９ However, independently, halo, oxo, -OR Ｏ１ , -NR Ｎ１ R Ｎ２ , -CN, -C(O)-OR Ｏ３ , -S Ｏ２ -R １０ , C １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyrill, or 4-7 member monocyclic heterocycline, where R ９ The C represented by １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyclyl, and 4-7 member monocyclic heterocyclyl are respectively classified as halo, oxo, -CN, and -OR. Ｏ１ , -NR Ｎ１ R Ｎ２ , C １～６ Alkyl, C １～４ They are optionally substituted with one or more substituents independently selected from haloalkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyrill, and 4-7 membered monocyclic heterocyclyl. Each R Ｏ１ However, independently, H and C １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic or bicyclic carbocyclyl, or 4-7 member monocyclic or bicyclic heterocyclyl, where R Ｏ１ The C represented by １～６ Alkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic or bicyclic carbocyclyl, and 4-7 membered monocyclic or bicyclic heterocyclyl each contain one or more R groups. Ｏ２ It is arbitrarily replaced with, Each R Ｏ２ However, independently, Halo, OH, -CN, C １～４ Alkoxy, C １～４ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyrill, or 4-7 member monocyclic or bicyclic heterocycline, where C １～４ Alkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyrill, and 4-7 membered monocyclic or bicyclic heterocyclil each contain one or more halos, C １～６ Alkyl, or -O-C １～６ It is optionally substituted with alkyl, Each R Ｏ３ However, independently, H and C １～６ Alkyl, C １～４ Haloalkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyrill, or 4-7 membered monocyclic heterocycline, where R Ｏ３ The C represented by １～６ Alkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyrill, and 4-7 membered monocyclic heterocyclyl each contain one or more R Ｏ２ It is arbitrarily replaced with, R Ｏ４ However, H, C １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyrill, or 4-7 member monocyclic heterocycline, where R Ｏ４ The C represented by １～６ Alkyl, phenyl, 5-6 member heteroaryl, 3-7 member monocyclic carbocyclyl, and 4-7 member monocyclic heterocyclyl are respectively classified as halo, oxo, -CN, and -OR. Ｏ１ , -NR Ｎ１ R Ｎ２ , C １～６ Alkyl, C １～４ They are optionally substituted with one or more substituents independently selected from haloalkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered monocyclic carbocyrill, and 4-7 membered monocyclic heterocyclyl. R Ｎ１ and R Ｎ２ However, H and C are independent of each other. １～６ Alkyl, or C ３～６ It is a cycloalkyl, where R Ｎ１ and R Ｎ２ The C represented by １～６ Each alkyl group is C １～４ It is arbitrarily substituted with alkoxy, Each R Ｎ３ However, independently, H or C １～６ It is alkyl, Each R Ｎ４ However, independently, H or C １～６ The compound according to claim 1, wherein it is alkyl.

3. R １Ａ However, H or -CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. The compound is of formula (II), (III), (IV), (V), or (VI): 【Chemistry 2】 The compound according to claim 1, or represented by a pharmaceutically acceptable salt thereof.

5. R ２ However, it is H or F, or R ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein H is present.

6. (i) Ring C is a phenyl, a 5- or 6-membered monocyclic heterocyclyl, or a 5- to 6-membered heteroaryl, each of which has 1 to 3 R Ｃ It is arbitrarily replaced by, (ii) Ring C is phenyl or a 5-6 member heteroaryl, each of which has 1-3 R Ｃ It is arbitrarily replaced by, (iii) Ring C is selected from pyridinonyl, pyridadinonyl, pyrazinonyl, imidazolyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyridinyl, pyrimidinyl, thiadiazolyl, thiazolyl, and triazinyl, each of which has one or three R Ｃ It is arbitrarily replaced by, (iv) Ring C is selected from imidazolyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl, pyridinyl, pyrimidinyl, thiadiazolyl, thiazolyl, and triazinyl, each of which has one or three R Ｃ It is arbitrarily replaced by, (v) Ring C is selected from imidazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrimidinyl, thiadiazolyl, thiazolyl, and triazinyl, each of which has one or three R Ｃ It is arbitrarily replaced by, (vi) Ring C is selected from pyrazinyl, pyrimidinyl, and thiazolyl, each of which has one or three R Ｃ It is arbitrarily replaced by, (vii) Ring C is 【Transformation 3】 Selected from, in the formula, 【Chemistry 4】 This represents a bond to ring B, where n is 0, 1, 2, or 3, or (viiii) Ring C is, 【Transformation 5】 Selected from, in the formula, 【Transformation 6】 This represents a bond to ring B, where n is 0, 1, 2, or 3. (ix) Ring C is 【Transformation 7】 Selected from, (x) Ring C is 【Chemistry 8-1】 【Chemistry 8-2】 Selected from, in the formula, 【Chemistry 9】 This represents the bond to ring B, and the two R in ring C Ｃ The bases may be the same or different, (xi) Ring C is 【Chemistry 10-1】 【Chemistry 10-2】 Selected from, in the formula, 【Chemistry 11】 This represents the bond to ring B, and the two R in ring C Ｃ The bases may be the same or different, (xi) Ring C is, 【Chemistry 12】 Selected from, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. (i) Each R Ｃ However, it became independent, Halo, -NR Ｎ１ R Ｎ２ , -NR Ｎ３ -C(O)-R ７ , -NR Ｎ４ -SO ２ -R ７ , -C(O)-R ７ , -OR Ｏ１ , C １～６ Alkyl, alkenyl, C ３～６ Cycloalkyl, phenyl, 5-12 membered monocyclic or bicyclic heteroaryl, or 4-8 membered monocyclic or bicyclic heterocyclil, or two R Ｃ However, together with the atoms in between, they form a 3- to 7-membered monocyclic carbocyclyl which is arbitrarily substituted with one or two halos, where R Ｃ The C represented by １～６ Alkyl, C ３～６ Cycloalkyl groups, 5-12 membered monocyclic or bicyclic heteroaryl groups, and 4-8 membered monocyclic or bicyclic heterocyclil groups each have 1-3 R groups. Ｃ１ It is arbitrarily replaced, and in some cases (a) R Ｃ The C represented by ３～６ The cycloalkyl group is selected from cyclobutyl, cyclopentyl, cyclopropyl, and cyclohexyl, R Ｃ The 5-12 member monocyclic or bicyclic heteroaryl represented by is furanil, pyrazolyl, imidazoyl, triazolyl, isoxazole, pyridinyl, pyrimidinyl, isoindolinyl, 3H-imidazo[4,5-b]pyridinyl, 1H-benzo[d][1,2,3]triazolyl, and R Ｃ The 4- to 8-membered monocyclic or bicyclic heterocyclil represented by is selected from azetidinyl, 2,6-diazaspiro[3.3]heptanyl, isothiazolidinyl, isothiazolidinedioxide, morpholinyl, oxabicycloheptanyl, oxetanyl, piperidinyl, piperidinyl, pyrrolidinyl, pyrrolidinonyl, tetrahydrofuranyl, pyridine-2(1H)-oil, tetrahydro-2H-pyranyl, 2-oxabicyclo[2.1.1]hexanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 7-oxabicyclo[2.2.1]heptanyl, where C ３～６ Each of the cycloalkyl, 5-12 membered monocyclic or bicyclic heteroaryl, and 4-8 membered monocyclic or bicyclic heterocyclil has 1-3 R Ｃ１ It is arbitrarily substituted with, or two R Ｃ However, together with the atoms in between, they form a cyclopentyl substituted with one or two halos, or (b) R Ｃ The C represented by ３～６ The cycloalkyl and the 4-8 membered monocyclic or bicyclic heterocyclils are given by the following formula: 【Chemistry 13-1】 【Chemistry 13-2】 It is represented by, During the ceremony, 【Chemistry 14】 This represents a bond to ring C, where n is 0, 1, 2, or 3, or (c) R Ｃ The C represented by ３～６ Cycloalkyls and the aforementioned 4-8 membered monocyclic or bicyclic heterocyclines are 【Chemistry 15-1】 【Chemistry 15-2】 Selected independently from, During the ceremony, 【Chemistry 16】 However, this represents a bond to ring C, and there are two R Ｃ１ The bases may be the same or different, (ii) Each R Ｃ However, it became independent, Halo, -NR Ｎ１ R Ｎ２ , -NR Ｎ３ -C(O)-R ７ , -NR Ｎ４ -SO ２ -R ７ , -C(O)-R ７ , -OR Ｏ１ , C １～６ Alkyl, C ３～６ A cycloalkyl or a 4-8 membered monocyclic or bicyclic heterocycline, where R Ｃ The C represented by １～６ Alkyl, C ３～６ Cycloalkyl groups and 4-8 membered monocyclic or bicyclic heterocyclines each have 1-3 R groups. Ｃ１ It is arbitrarily replaced, and in some cases, (a) R Ｃ The C represented by ３～６ The cycloalkyl and the 4-8 membered monocyclic or bicyclic heterocyclils are given by the following formula: 【Chemistry 17】 It is represented by, During the ceremony, [Chemistry 18] This represents a bond to ring C, where n is 0, 1, 2, or 3, or (b) R Ｃで The C represented ３～６ Cycloalkyls and the aforementioned 4-8 membered monocyclic or bicyclic heterocyclines are 【Chemistry 19】 Selected independently from, During the ceremony, 【Chemistry 20】 However, this represents a bond to ring C, and there are two R Ｃ１ The bases may be the same or different, (iii) R Ｃ At least one of them is C １～３ It is a haloalkyl, preferably R Ｃ At least one of them is -CF ２ CH ３ is, or (iv) Each R Ｃ is -F, -Cl, -CH ３ , -CH ２ F, -CHF ２ , -CF ３ , -CH ２ -CH ３ , -CH ２ -CH ２ F, -CH ２ -CHF ２ , -CH ２ -CF ３ , -CHF-CH ２ F, -CH ２ -CHF ２ , -CH ２ -CH ２ -CH ２ F, -CH ２ -CF ３ , -C(CH ３ ) ３ , -CF ２ CH ３ , -CHF-CH ３ , -CH(CH ３ ) ２ , -CF(CH ３ ) ２ , -C(CH ３ ) ２ -CH ２ F, -CH(CH ３ )-CHF ２ , -CH(CH ３ )-CF ３ X , -C(CH ３ ) ２ -CF ３ , -CH ２ -CH ２ -CN, -CH ２ OCH ３ , -CH ２ -C(CH ３ ) ２ -CN, -C(CH ３ ) ) ２ -OH, -CH(CH ３ )-OCH ３ , -C(CH ３ ) ２ -OCH ３ , -C(CH ３ ) ２ -CH ２ -OCH ３ 、-CH(OH)-CH ３ 、-C(CH ３ )(OH)-CF ３ 、-EH=EH ２ ,-OCH ３ 、-O-CHF ２ 、-C(CH ３ )(OCH ３ )-CH ２ -OCH ３ 、-O-CF ３ ,-EH(OEH ３ )-シクロロッピル、-OH、-O-CH ２ CH ３ 、-O-CH ２ CHF ２ 、-O-EH(EH ３ ) ２ 、-O-EH(EF ３ ) ２ 、-O-CH ２ -OCH ３ 、-O-EH(EH ３ )-OCH ３ 、-O-EH(EH ３ )-CH ２ -OCH ３ 、-O-CH ２ -CH ２ -O-CH ３ 、-O-CH ２ --H(H) ３ )-OCH ３ 、-CF(CH ３ )-CH ２ -OCH ３ 、-EH(CF ３ )-NH ２ ,-EH(OEH ３ )-C(CH ３ ) ３ 、-NHC(O)-CH ３ ,-NH-S ２ -CH ３ 、-NH ２ 、-NHCH ３ 、-N(CH ３ ) ２ ,-NHCH(CH ３ ) ２ 、-NHCH ２ CH ２ CH ３ , - NHCH ２ C (CH ３ ) ２ OCH ３ , cyclopropyl, -CHF-cyclopropyl, -CF(CH ３ )-cyclopropyl,-CH(OCH ３ )-Cyclopropyl,-C(CH ３ ) (OCH ３ )-cyclopropyl,-CF(OCH ３ )-Cyclopropyl,-NH-Cyclohexyl,-NH-Cyclopropyl,-NH-N-Methylpiperidine,-NH-CH ２ -Cyclopropyl, -NH-CH ２ -CH ２ - OCH ３ , -N(CH ３ ) - CH ２ -CH ２ - OCH ３ , -CH(NH ２ ) - CF ３ , 【Chemistry 21-1】 【Chemistry 21-2】 【Chemistry 21-3】 Selected independently from, in the formula, 【Chemistry 22】 However, this represents a bond to ring C. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. (i) Each R Ｃ１ However, independently, Halo, -CN, -OR Ｏ１ , -NR Ｎ１ R Ｎ２ , -C(O)-R ７ , -C(O)-OR Ｏ３ , -SO ２ -R ７ , C １～６ Alkyl, C ３～６ A cycloalkyl or a 4-6 membered monocyclic heterocycline, where R Ｃ１ The C represented by １～６ Alkyl is halo and -OR ａ１ It is optionally substituted with 1 to 3 substituents independently selected from the original compound. R ａ１ However, H, C １～４ Alkyl, or 4-6 membered heterocyclyl, (ii) Each R Ｃ１ However, independently, Halo, -CN, -OR Ｏ１ , -NR Ｎ１ R Ｎ２ , -C(O)-R ７ , -C(O)-OR Ｏ３ , -SO ２ -R ７ , C １～６ Alkyl or 4-6 membered monocyclic heterocyclyl, where R Ｃ１ The C represented by １～６ Alkyl is halo and -OR ａ１ It is optionally substituted with 1 to 3 substituents independently selected from the original compound. R ａ１ However, H, C １～４ Alkyl, or 4-6 membered heterocyclyl, (iii) Each R Ｃ１ However, F, Cl, -CN, OH, -OCH ３ , -OCHF ２ , -NH ２ , -N(CH ３ ) ２ ien-CH ３ ien-CH ２ F, -CHF ２ , -CF ３ ien-CH ２ -OH, -CH ２ -CH ３ , -CH(CH ３ ) ２ ien-CH ２ -O-CH ３ ien-CH ２ -CH ２ - OCH ３ ,-C(O)-CH ３ , -C(O)-OC(CH ３ ) ３ , -SO ２ -CH ３ cyclopropyl, 【Chemistry 23】 Selected independently from, in the formula, 【Chemistry 24】 However, R Ｃ Represents a connection to, or (iv) each R Ｃ１ is F, -CN, OH, -OCH ３ , -OCHF ２ , -NH ２ , -N(CH ３ ) ２ , -CH ３ , -CH ２ F, -CHF ２ , -CF<​​​​​​​​​​​​​​​​​​​​​ 【Chemistry 25】 Selected independently from, in the formula, 【Chemistry 26】 However, R Ｃ Represents a connection to The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

9. (i) R １ However, H, C １～４ Alkyl, -OR １Ａ , -NR Ｎ１ R Ｎ２ , or C ３～６ It is a cycloalkyl, where R １ The C represented by １～４ Alkyl and C ３～６ The cycloalkyl groups are, respectively, halo, -CN, and C. １～３ Alkoxy, C １～３ Alkyl and C １～３ One to three R molecules independently selected from haloalkyl groups. ８ It is arbitrarily replaced by, R １Ａ However, C １～４ It is alkyl, R Ｎ１ and R Ｎ２ However, each is independent of H or C １～４ Alkyl, or (ii) R １ However, C １～４ Alkyl or C ３～６ It is a cycloalkyl, where R １ The C represented by １～４ Alkyl and C ３～６ The cycloalkyl groups are, respectively, halo, -CN, and C. １～３ Alkoxy, C １～３ Alkyl and C １～３ One to three R molecules independently selected from haloalkyl groups. ８ It is arbitrarily replaced by, (iii) R １ However, halo, -CN, C １～３ Alkoxy, C １～３ Alkyl and C １～３ One to three R molecules independently selected from haloalkyl groups. ８ C arbitrarily substituted by １～４ Alkyl and / or R ８ However, in each occurrence, independently, Halo, -CN, C １～３ It is an alkoxy, preferably each R ８ However, F, -CN, and -OCH ３ Selected independently of, (iv)R １ However, -H, -CH ３ , -CD ３ ien-CH ２ -CH ３ ien-CH ２ - CHF ２ ien-CH ２ -CH ２ -CN, -CH ２ -CH ２ - OCH ３ , -OCH ３ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ cyclopropyl, 【Chemistry 27】 Selected from, (v) R １ However, -CH ３ ien-CH ２ -CH ３ ien-CH ２ - CHF ２ ien-CH ２ -CH ２ -CN, -CH ２ -CH ２ - OCH ３ cyclopropyl, 【Chemistry 28】 Selected from, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. (i) R ３ However, H, -NR Ｎ１ R Ｎ２ , Halo, -C(O)-R ７ , -C(O)-OR Ｏ３ , -SO ２ -R ７ , -OR Ｏ４ , C １～６ Alkyl, Alkenyl C ３～６ A cycloalkyl, a 5 or 6-membered heteroaryl, or a 4- to 10-membered monocyclic or bicyclic heterocycline, where R ３ The C represented by １～６ Alkyl, C ３～６ Cycloalkyl groups and 4- to 9-membered monocyclic or bicyclic heterocyclines each have 1 to 3 R groups. ９ It is arbitrarily replaced by, (ii) R ３ However, H, -NR Ｎ１ R Ｎ２ , Halo, -C(O)-R ７ , -C(O)-OR Ｏ３ , -SO ２ -R ７ , -OR Ｏ４ , C １～６ Alkyl, C ３～６ A cycloalkyl, a 4- to 9-membered monocyclic or bicyclic heterocycline, where R ３ The C represented by １～６ Alkyl, C ３～６ Cycloalkyl groups and 4- to 9-membered monocyclic or bicyclic heterocyclines each have 1 to 3 R groups. ９ It is arbitrarily replaced by, (iii) R ３ However, each has one or three R ９ C arbitrarily substituted by ３～６ It is a cycloalkyl or a 4-10 membered monocyclic or bicyclic heterocycline, or (iv)R ３ However, each has one or three R ９ C arbitrarily substituted by ３～６ It is a cycloalkyl or a 4- to 9-membered monocyclic or bicyclic heterocycline, or (v) R ３ However, pyrazolyl, pyridinyl, azetidinyl, cyclobutyl, cyclopentyl, cyclopropyl, 2-oxaspiro[3.3]heptanyl, 1,7-diazaspiro[4.4]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 7-oxa-2-azaspiro[3.5]nonanyl, 1-oxa-7-azaspiro[4.4]nonanyl, 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]nonanyl , 1,6-diazaspiro[3.3]heptanyl, 1-oxa-6-azaspiro[3.3]heptanyl, 3,6-diazabicyclo[3.2.0]heptanyl, 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]heptanyl, 1,6-diazaspiro[3.4]octanyl, 1,7-diazaspiro[4.4]nonanyl, 2-oxa-7-azaspiro[4.4]nonanyl, octahydropyrano[2,3-c ]pyrrolyl, octahydro-1H-pyrrolo[3,4-b]pyridinyl, octahydropyrrolo[3,4-b][1,4]oxazinyl, octahydropyrrolo[3,4-b]pyrrolyl, 3-oxa-6-azabicyclo[3.1.1]heptanyl, hexahydro-1H-fl[3,4-c]pyrrolyl, 1,4-oxazepanyl, 6-oxa-2-azabispiro[3.5]nonanyl, 5-oxa-2-azabispiro[3.4]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-oxa-7-azabicyclo[3.

3. 1) Nonanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3,6-diazabicyclo[3.2.0]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 2λ ２ ,6-diazaspiro[3.3]heptanil, 1λ ２ , 7λ ２ - Selected from diazaspiro[4.4]nonanyl, oxetanyl, piperidinyl, piperazinyl, piperazine-2-onyl, pyrrolidinyl, pyrrolidine-2-onyl, and tetrahydropyranyl, each of which contains 1 to 3 R ９ It is arbitrarily replaced by, (vi)R ３ However, azetidinyl, cyclobutyl, cyclopentyl, cyclopropyl, 2,5-diazabicyclo[2.2.1]heptanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3,6-diazabicyclo[3.2.0]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 3,8-diazabicyclo[3.2.1]octanyl, morpholinyl, octahydropyrrolo[3,4-c]pyrrolyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 2λ ２ ,6-diazaspiro[3.3]heptanil, 1λ ２ , 7λ ２ - Selected from diazaspiro[4.4]nonanyl, oxetanyl, piperidinyl, piperazinyl, piperazine-2-onyl, pyrrolidinyl, pyrrolidine-2-onyl, and tetrahydropyranyl, each of which contains 1 to 3 R ９ It is arbitrarily replaced by, (vii)R ３ However, these are selected from pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, and 3,6-diazabicyclo[3.1.1]heptanyl, each of which contains 1 to 3 R ９ It is arbitrarily replaced by, (viiii)R ３ However, 1 to 3 R ９ Pyrrolidinyl optionally substituted by, or (ix)R ３ but, 【Chemistry 29-1】 【Chemistry 29-2】 【Chemistry 29-3】 Selected from, in the formula, 【Transformation 30】 This represents a bond to ring B, where m is 0, 1, 2, 3, or 4, or (x)R ３ but, 【Chemistry 31】 Selected from, (xi)R ３ but, 【Chemistry 32-1】 【Chemistry 32-2】 【Chemistry 32-3】 【Chemistry 32-4】 Selected from, in the formula, 【Transformation 33】 However, this represents a bond to ring B, or (xii)R ３ が、 【Chemistry 34-1】 【Chemistry 34-2】 Selected from, in the formula, 【Chemistry 35】 However, this represents a bond to ring B, or (xiii)R ３ However, H, -NR Ｎ１ R Ｎ２ , Halo, -C(O)-R ７ , -C(O)-OR Ｏ３ , -SO ２ -R ７ , -OR Ｏ４ , or 1 to 3 R ９ C arbitrarily replaced by １～６ It is alkyl. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. (i) Each R ９ However, independently, halo, -OH, -OC １～４ Alkyl, -NR ａ２ R ａ３ , -CN, -C(O)-OR ａ１ , -SO ２ -R ａ１ , C １～４ Alkyl, or C ３～６ It is a cycloalkyl, where R ９ The C represented by １～４ Alkyl and C ３～６ The cycloalkyls are, respectively, halo and C. １～３ It is optionally substituted with 1 to 3 substituents independently selected from the alkoxy, R ａ１ , R ａ２ , and R ａ３ However, each is independent of C １～３ Alkyl, or (ii) Each R ９ However, independently, Haro, -OR ａ１ , -NR ａ２ R ａ３ , -CN, -C(O)-OR ａ１ , -SO ２ -R ａ１ , C １～４ Alkyl, C ３～６ A cycloalkyl or a 4-10 membered monocyclic or bicyclic heterocycline, where R ９ The C represented by １～４ Alkyl, 4-10 membered monocyclic or bicyclic heterocyclyl, and C ３～６ The cycloalkyl groups are, respectively, halo, -OH, -CN, and C. １～４ Alkyl and C １～３ It is optionally substituted with 1 to 3 substituents independently selected from the alkoxy, R ａ１ , R ａ２ , and R ａ３ However, H and C are independent of each other. ３～４ Cycloalkyl, or C １～３ It is alkyl, and here, R ａ１ , R ａ２ , and R ａ３ The C represented by ３～４ Cycloalkyl, C １～４ It is optionally substituted with alkyl, R ａ１ , Ｒａ２ , and R ａ３ The C represented by １～３ The alkyl group is optionally substituted with phenyl, or (iii) Each R ９ However, independently, Haro, -OR ａ１ , -NR ａ２ R ａ３ , -CN, -C(O)-OR ａ１ , -SO ２ -R ａ１ , C １～４ Alkyl, C ３～６ A cycloalkyl or a 4- to 7-membered monocyclic heterocycline, where R ９ The C represented by １～４ Alkyl and C ３～６ The cycloalkyls are, respectively, halo and C. １～３ It is optionally substituted with 1 to 3 substituents independently selected from the alkoxy, R ａ１ , R ａ２ , and R ａ３ However, each is independent of H or C １～３ Alkyl, or (iv) Each R ９ is F, OH, -OCH ３ , -OCH ２ CH ３ , -OCH(CH ３ ) ２ , -OCHF ２ , -OCF ３ , -OCD ３ -O-cyclopropyl, -NHCH ３ , -NH ２ , -N(CH ３ ) ２ , -N (CD ３ ) ２ , -N(CH ２ CH ３ ) ２ , -N(CH ３ ) (CH ２ CH ３ ), -NHCH(CH ３ ) ２ , - NHCH ２ CH ３ -CN, -CH ３ ien-CH ２ F, -CF ３ , -C(O)-OCH ２ CH ３ , -SO ２ -CH ３ ien-CH ２ - OCH ３ ien-CH ２ -CH ２ - OCH ３ ien-CH ２ -CH ３ ien-CH ２ -CN, pyrrolidinyl, morpholinyl, azetidinyl, cyclopropyl, -CHF ２ ien-CH ２ -CF ３ , 【Transformation 36】 Selected independently of, (v) Each R ９ is F, -OH, -OCH ３ , -OCHF ２ , -OCF ３ , -N(CH ３ ) ２ -CN, -CH ３ , -CF ３ , -C(O)-OCH ２ CH ３ , -SO ２ -CH ３ ien-CH ２ - OCH ３ ien-CH ２ -CH ２ - OCH ３ ien-CH ２ -CH ３ Cyclopropyl, -CHF ２ , and -CH ２ -CF ３ Selected independently of, (vi) Each R ９ is F, OH, -OCH ３ , -OCHF ２ , -OCF ３ , - NHCH ３ , -NH ２ , -N(CH ３ ) ２ , -N(CH ２ CH ３ ) ２ , -N(CH ３ ) (CH ２ CH ３ ), -NHCH(CH ３ ) ２ -CN, -CH ３ , -CF ３ , -C(O)-OCH ２ CH ３ , -SO ２ -CH ３ ien-CH ２ - OCH ３ ien-CH ２ -CH ２ - OCH ３ ien-CH ２ -CH ３ Pyrrolidinyl, Morpholinyl, Cyclopropyl, -CHF ２ , and -CH ２ -CF ３ Selected independently of, (vii)R ９ Two of these atoms, along with the atom between them, are combined into a halo, C １～４ Alkyl and C １～４ It forms a 4-6 membered monocyclic heterocycline which is optionally substituted with one or two substituents independently selected from the haloalkyl group. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. (i)R ３ が、H、C-、-CN、-CH ３ 、-CH ２ F、-CHF ２ 、-CF ３ 、-CH ２ -CH ３ 、-CH ２ CF ３ 、-CHF-CH ３ ,-EH(EH ３ ) ２ 、-EH(CF ３ ) ２ 、-CHF-CH ２ F、-CH ２ -CH ２ -CN、-H ２ -CH ２ -CH ３ ,-EH(EH ３ )-CH ２ -CH ３ 、-CH ２ --H(H) ３ ) ２ 、-CH ２ -シクロローピル、-CH ２ -ホーホリニル、-CH ２ OH、-H ２ -OCH ３ 、-C(CH ３ )-CH ２ -CH ３ ,-EH(EH ３ )-CF ３ ,-EH(EH ３ )-OCH ３ 、-CH ２ N(CH) ３ ) ２ 、-EH=EH ２ 、-NH ２ 、-NHCH ３ 、-NHCH ２ CH ３ 、-N(CH ３ ) ２ -OCH ３ 、-N(CH ３ )-CH ２ -CH ２ -OCH ３ 、-N(CH ３ )CH ２ C(CH) ３ ) ２ OCH ３ 、-C(O)-OCH ３ 、-C(O)-OCH ２ CH ３ 、-E ２ -CH ３ 、-O-EH(EH ３ ) ２ 、-O-CH ２ -CH ２ -OCH ３ 、 【Chemistry 37】 Selected from, in the formula, 【Transformation 38】 However, this represents a bond to ring B, or (｡｡)ｲ ３ が、H、Cl、-CH ３ 、-CH ２ F、-CHF ２ 、-CF ３ 、-CH ２ -CH ３ 、-CHF-CH ３ ,-EH(EH ３ ) ２ 、-CHF-CH ２ F、-CH ２ -CH ２ -CN、-H ２ -CH ２ -CH ３ 、-CH ２ --H(H) ３ ) ２ 、-CH ２ -シクロローピル、-CH ２ -OCH ３ ,-EH(EH ３ )-CH ２ -CH ３ ,-EH(EH ３ )-CF ３ ,-EH(EH ３ )-OCH ３ 、-N(CH ３ ) ２ ,-OCH ３ 、-N(CH ３ )-CH ２ -CH ２ -OCH ３ 、-C(O)-OCH ３ 、-E ２ -CH ３ 、-O-EH(EH ３ ) ２ 、-O-CH ２ -CH ２ -OCH ３ 、 【Chemistry 39】 Selected from, in the formula, 【Chemistry 40】 However, this represents a bond to ring B. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. (i) Each R ７ However, independently, C １～６ Alkyl, C ３～６ A cycloalkyl or a 4-6 membered monocyclic heterocycline, where R ７ The C represented by １～６ Alkyl, C ３～６ Cycloalkyls and 4-6 membered monocyclic heterocyclines are, respectively, halo and C. １～３ Alkyl and C １～３ It is optionally substituted with one to three substituents independently selected from the haloalkyl group, or (ii) Each R ７ but, -CH ３ 、 【Chemistry 41】 Selected independently of The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. (1) Each R Ｏ１ is independently H, C １～６ alkyl, a 3- to 6-member monocyclic or bicyclic carbocyclyl, a 4- to 6-member monocyclic heterocyclyl, or a 6-member heteroaryl, where the C Ｏ１ alkyl, 3- to 6-member monocyclic or bicyclic carbocyclyl, 4- to 6-member monocyclic heterocyclyl, and 6-member heteroaryl represented by R １～６ are each optionally substituted by 1 to 3 R Ｏ２ s, and preferably each R Ｏ１ is H, -CH ３ , -CHF ２ , -CF ３ , -CH ２ -CH ３ , -CH ２ -CHF ２ , -CH ２ -CF ３ , -CH ２ -CH ２ -CH ３ , -CH(CH ３ ) ２ , -CH(CF ３ ) ２ , -CH ２ -CH ２ -OCH ３ , -CH(CH ３ )-CH ２ -OCH ３ , -CH ２ -CH(CH ３ )-OCH ３ ​ 【Chemistry 42】 Selected independently of (2) Each R Ｏ２ However, independently, Halo, OH, -CN, C １～４ Alkoxy, C １～４ Alkyl, 3-5 membered monocyclic carbocyrill, 4-7 membered monocyclic or bicyclic heterocyclyl, or phenyl, where C １～４ Alkyl, 3-5 membered monocyclic carbocyryl, 4-7 membered monocyclic or bicyclic heterocyclyl, and phenyl are each C １～３ Alkoxy, C １～３ They are optionally substituted with haloalkoxys or 1 to 3 halos, preferably each R Ｏ２ However, F, -CN, OH, -OCH ３ ien-CH ３ ,-CHF ２ , -CF ３ , 【Chemistry 43】 Selected independently from, in the formula, 【Chemistry 44】 However, R Ｏ１ Represents a connection to (3) Each R Ｏ３ However, independently, Halo and C １～４ C is optionally substituted with 1 to 3 substituents independently selected from the haloalkyl group. １～６ They are alkyl, preferably each R Ｏ３ However, independently, -CH ３ ien-CH ２ CH ３ , or -C(CH ３ ) ３ That is, (4) R Ｏ４ However, each of them is Halo and C １～３ C is optionally substituted with 1 to 3 substituents independently selected from the alkoxy. １～４ Alkyl or C ３～６ It is a cycloalkyl, preferably R Ｏ４ However, -CH ３ ien-CH ２ -CH ３ , -CH(CH ３ ) ２ ien-CH ２ -CH ２ - OCH ３ , and 【Chemistry 45】 Selected from, (5) Caution Ｎ１ and R Ｎ２ However, H and C are independent of each other. １～３ C arbitrarily substituted with alkoxy ３～６ Cycloalkyl or C １～４ It is alkyl, preferably R Ｎ１ and R Ｎ２ However, independently of each other, H and -CH ３ , -CH(CH ３ ) ２ ien-CH ２ -CH ２ - OCH ３ , or representing cyclohexyl (6) R Ｎ３ However, H is, and (7) R Ｎ４ However, H The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

15. (i) The compound is of formula (VII) or (VIII): 【Chemistry 46】 or represented by a pharmaceutically acceptable salt thereof, in the formula, Ring C has 1 to 3 R Ｃ It is a six-membered heteroaryl that is arbitrarily substituted by, Each R Ｃ However, independently, -OR Ｏ１ , C １～４ It is an alkyl or a five-membered heterocycline, where R Ｃ The C represented by １～４ Alkyl and 5-membered heterocyclyl each have 1 to 3 R Ｃ１ It is arbitrarily replaced with, Each R Ｃ１ However, independently, halo or -OR Ｏ１ And, R １ However, H or -CH ３ And, R ３ However, H, C １～４ Alkyl, C ３～５ A cycloalkyl or a 5-7 membered monocyclic or bicyclic heterocycline, where R ３ The C represented by １～４ Alkyl, C ３～５ Cycloalkyl groups and 5-7 membered monocyclic or bicyclic heterocyclines each have 1-3 R groups. ９ It is arbitrarily replaced by, Each R ９ However, independently, -OR Ｏ１ , -NR Ｎ１ R Ｎ２ , 5-7 membered monocyclic heterocyclyl, or C １～４ It is alkyl, Each R Ｏ１ However, independently, H and C １～４ Alkyl, or C ３～５ It is a cycloalkyl, where the C １～４ Alkyl and C ３～５ Each of the cycloalkyl groups is R Ｏ２ It is arbitrarily replaced by, Each R Ｏ２ However, independently, -CN or C １～４ It is an alkoxy, R Ｎ１ and R Ｎ２ However, each is independent of H or C １～３ Alkyl, or (ii) The compound is of formula (VII) or (VIII): 【Chemistry 47】 or represented by a pharmaceutically acceptable salt thereof, in the formula, Ring C has 1 to 3 R Ｃ It is a six-membered heteroaryl that is arbitrarily substituted by, Each R Ｃ However, independently, -OR Ｏ１ , C １～４ It is an alkyl or a five-membered heterocycline, where R Ｃ The C represented by １～４ Alkyl and 5-membered heterocyclyl each have 1 to 3 R Ｃ１ It is arbitrarily replaced with, Each R Ｃ１ However, independently, halo or -OR Ｏ１ And, R ３ However, H, C １～４ Alkyl, C ３～５ A cycloalkyl or a 5-7 membered monocyclic or bicyclic heterocycline, where R ３ The C represented by １～４ Alkyl, C ３～５ Cycloalkyl groups and 5-7 membered monocyclic or bicyclic heterocyclines each have 1-3 R groups. ９ It is arbitrarily replaced by, Each R ９ However, independently, -OR Ｏ１ , -NR Ｎ１ R Ｎ２ , 5-7 membered monocyclic heterocyclyl, or C １～４ It is alkyl, Each R Ｏ１ However, independently, H and C １～４ Alkyl, or C ３～５ It is a cycloalkyl, where the C １～４ Alkyl and C ３～５ Each of the cycloalkyl groups is R Ｏ２ It is arbitrarily replaced by, Each R Ｏ２ However, independently, -CN or C １～４ It is an alkoxy, R Ｎ１ and R Ｎ２ However, each is independent of H or C １～３ It is alkyl. The compound according to claim 1.

16. (i) Ring C is pyridinyl, pyrazinyl, or pyrimidinyl, each of which has one or two R Ｃ It is arbitrarily replaced by, in some cases, (a) Ring C is 【Chemistry 48】 Selected from, During the ceremony, 【Chemistry 49】 This represents a bond to ring B, where n is 1 or 2, or (b) Ring C is [Transformation 50] Selected from, During the ceremony, 【Chemistry 51】 This represents the bond to ring B, and the two R in ring C Ｃ The base may be the same or different. (ii) Each R Ｃ However, independently, -OR Ｏ１ , C １～２ Alkyl, C １～２ Haloalkyl, or one R Ｃ１ It is an oxygen-containing five-membered heterocycline that is optionally substituted, and in some cases, (a) R Ｃ However, one R Ｃ１ It is a tetrahydrofuranyl optionally substituted with, or (b) R Ｃ but, 【Chemistry 52】 And in the formula, 【Chemistry 53】 However, this represents a bond to ring C, or (c) Each R Ｃ is, -CH ３ , -CH ２ CH ３ , -CF ２ CH ３ , -CF(CH ３ ) ２ , -OCH ３ , -O-CH ２ -CH ２ , -O-CH ３ , 【Chemistry 54】 Selected independently from, in the formula, 【Transformation 55】 However, this represents a bond to ring C, or (d) each R Ｃが 、-CH ３ 、-CF ２ CH ３ 、-OCH ３ 、-O-CH ２ -CH ２ -O-CH ３ 、 【Transformation 56】 Selected independently from, in the formula, 【Chemistry 57】 However, this represents a bond to ring C, or (e) each R Ｃ is, -CH ３ , -CH ２ CH ３ , -CF ２ CH ３ , -CF(CH ３ ) ２ , -OCH ３ , -O-CH ２ -CH ２ -O-CH ３ , 【Chemistry 58】 Selected independently from, in the formula, 【Chemistry 59】 This represents a bond to ring C, and / or (iii) R ３ However, H, -CH ２ CH ３ , 【Transformation 60】 Selected from, During the ceremony, 【Chemistry 61】 This represents a bond to ring B, where m is 0, 1, or 2, preferably, R ３ However, H, -CH ２ CH ３ , 【Transformation 62】 Selected from, in the formula, 【Transformation 63】 However, this represents a bond to ring B. (iv) Each R ９ , -OH, -OCH ３ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ , -N(CH ３ ) (CH ２ CH ３ ), -N(CH ２ CH ３ ) ２ Pyrrolidinil, Morpholinil, -CH ２ CH ３ , and -CH ３ Selected independently of, (v) R Ｏ１ However, independently of each other, H and -CH ３ ien-CH ２ CH ２ OCH ３ cyclopropyl, 【Chemistry 64】 Selected from, The compound according to claim 15 or a pharmaceutically acceptable salt thereof.

17. (1) Ring C is 【Transformation 65】 Selected from, R Ｃ However, C １～３ Alkyl or C １～３ It is an alkoxy, R ３ However, these are selected from pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, and 3,6-diazabicyclo[3.1.1]heptanyl, each of which contains 1 to 2 R ９ It is arbitrarily replaced by, R ９ However, they became independent, Hello, C １～４ Alkyl, OH, -OC １～４ Alkyl, or -NR ａ２ R ａ３ And, R ａ２ and R ａ３ However, each is independent of H or C １～３ Alkyl, or (2) Ring C is 【Chemical Formula 66】 Selected from, R Ｃ However, in each occurrence, independently, C １～３ Alkyl, C １～３ Haloalkyl, or C １～３ It is an alkoxy, R ３ However, these are selected from pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptanyl, and 3,6-diazabicyclo[3.1.1]heptanyl, each of which contains 1 to 2 R ９ It is arbitrarily replaced by, R ９ However, they became independent, Hello, C １～４ Alkyl, OH, -OC １～４ Alkyl, or -NR ａ２ R ａ３ And, R ａ２ and R ａ３ However, each is independent of H or C １～３ It is alkyl, and in some cases, (i) R in equation (C2) Ｃ However, C １～２ Alkyl or C １～２ It is an alkoxy, R in equation (C3) Ｃ However, C １～２ It is a haloalkyl, Regarding equation (C4), R Ｃ One of them is C １～２ It is a haloalkyl, and the others are C １～３ Alkyl or C １～３ It is an alkoxy, or (ii) R ３ but, 【Transformation 67】 Selected from, R ９ However, C １～３ Alkyl, -OC １～３ Alkyl, or -NR ａ２ R ａ３ And m is 0, 1, or 2, or (iii) R in equation (C3) Ｃ However, -CF ２ CH ３ And for equation (C4), R Ｃ One of them is -CF ２ CH ３ And other R Ｃ However, C １～３ Alkyl or C １～３ It is an alkoxy, m is 1 or 2, R ９ However, in each occurrence, independently, C １～３ Alkyl, -OC １～３ Alkyl, or -NR ａ２ R ａ３ is, or (iv) Ring C is 【Transformation 68】 And, R Ｃ However, C １～２ Alkyl or C １～２ It is an alkoxy, R ３ but, 【Transformation 69】 And, R ９ However, in each occurrence, independently, C １～２ Alkyl or -NR ａ２ R ａ３ And, R ａ２ and R ａ３ However, C １～２ It is alkyl, R Ｃ However, -CH ３ ien-CH ２ CH ３ , or -OCH ３ is, or (v) R ９ However, -CH ３ or -N(CH ３ ) ２ That is, The compound according to claim 15 or a pharmaceutically acceptable salt thereof.

18. (i) The compound is of formula (VIIA'): 【Transformation 70】 or represented by a pharmaceutically acceptable salt thereof, in the formula, R １ However, H or -CH ３ And, R Ｃ１ａ However, C is replaced by 1 to 3 halos. １～３ It is alkyl, R Ｃ１ｂ However, C １～３ It is alkyl, R ３ but, 【Chemistry 71】 Selected from, Each R ９ However, independently, -NR Ｎ１ R Ｎ２ , C １～４ Alkyl, morpholinyl, or pyrrolidinyl, R Ｎ１ and R Ｎ２ However, each is independent of H or C １～３ Alkyl, or (ii) The compound is of formula (VIIA): 【Chemistry 72】 or represented by a pharmaceutically acceptable salt thereof, in the formula, R Ｃ１ａ However, C is replaced by 1 to 3 halos. １～３ It is alkyl, R Ｃ１ｂ However, C １～３ It is alkyl, R ３ but, 【Transformation 73】 Selected from, Each R ９ However, independently, -NR Ｎ１ R Ｎ２ , C １～４ Alkyl, morpholinyl, or pyrrolidinyl, R Ｎ１ and R Ｎ２ However, each is independent of H or C １～３ It is alkyl, and in some cases, R Ｃ１ａ However, -CF ２ CH ３ And R Ｃ１ｂ However, -CH ３ or CH ２ CH ３ is, or Each R ９ However, it became independent, -NH ２ , - NHCH ３ , -N(CH ３ ) ２ , -N(CH ３ ) (CH ２ CH ３ ), -N(CH ２ CH ３ ) ２ , 【Chemistry 74】 -CH ３ , or -CH ２ CH ３ That is, The compound according to claim 1.

19. The aforementioned compound is given by the following formula: 【Chemistry 75】 or represented by a pharmaceutically acceptable salt thereof, in the formula, R Ｃ１ａ However, C is replaced by 1 to 3 halos. １～３ It is alkyl, R Ｃ１ｂ However, C １～３ It is an alkoxy, n1 is 0 or 1, R ３ but, 【Transformation 76】 And, R ９ However, -NR Ｎ１ R Ｎ２ And, R Ｎ１ and R Ｎ２ However, each is independent of H or C １～３ It is alkyl, and in some cases, R Ｃ１ａ However, -CF ２ CH ３ or -CF(CH ３ ) ２ And n1 is either 0 or n1 is 1, R Ｃ１ｂ However, -OCH ３ and / or R ９ However, -NHCH(CH ３ ) ２ That is, The compound according to claim 1.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21. A pharmaceutical composition for treating a disease or disorder that is effective by inhibition of tyrosine kinase 2 (TYK2), comprising a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, cutaneous lupus erythematosus, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, The above-mentioned pharmaceutical composition is for the treatment of head trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes mellitus (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxin 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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