Compounds that are active against nuclear receptors

Abstract

To provide compounds that have improved physicochemical properties and have potent action of modulating nuclear retinoic acid receptor-related orphan receptors (RORs), particularly RORα and / or RORγ.SOLUTION: The invention provides fluoropyrimidine derivatives represented by the compound in the figure, optically active substances thereof, or salts of them.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority under § 119(e) of U.S. Provisional Patent Application No. 62 / 951,239, filed on 20 December 2019, and that disclosure is incorporated herein by reference in its entirety.

[0002] The embodiments and models described herein relate to compounds active against nuclear receptors, pharmaceutical compositions comprising such compounds, and methods for treating inflammatory, metabolic, tumor, and autoimmune diseases or disorders using such compounds. [Background technology]

[0003] Nuclear receptors are a family of transcription factors involved in regulating physiological functions such as cell differentiation, embryonic development, and organ physiology. Nuclear receptors have also been identified as important pathological regulators in diseases such as cancer, diabetes, and autoimmune disorders.

[0004] Examples of nuclear receptors include nuclear retinoic acid receptor-associated orphan receptors (RORs). RORs contain four main domains: the N-terminal A / B domain, the DNA-binding domain, the hinge domain, and the ligand-binding domain. Ligand binding to the ligand-binding domain is thought to cause conformational changes in the downstream domains. Various isoforms exist, and these isoforms differ only in the N-terminal A / B domain (Non-Patent Literature 1).

[0005] ROR consists of three members, known as ROR alpha (RORα or RORa), ROR beta (RORβ or RORb), and ROR gamma (RORγ or RORc).

[0006] RORα is expressed in many tissues, including cerebellar Purkinje cells, liver, thymus, skeletal muscle, skin, lungs, adipose tissue, and kidneys. RORα regulates neurogenesis, bone metabolism, and arteriosclerosis (Non-Patent Literature 1). Furthermore, RORα plays a role in immune responses, such as regulating interleukin (IL) 17A expression in T helper (Th) 17 cells and the function of regulatory T (Treg) cells (Non-Patent Literature 2; Non-Patent Literature 3).

[0007] RORβ exhibits a restricted expression pattern limited to specific areas of the brain (cerebral cortex, thalamus, hypothalamus, and pineal gland) and the retina (Non-Patent Literature 1). RORβ is associated with epilepsy and, together with RORa, is also associated with bipolar disorder (Non-Patent Literature 4; Non-Patent Literature 5).

[0008] RORγ exhibits a broad expression pattern and was the last of the three members to be discovered. To date, two different protein isoforms have been recorded: RORγ1 and RORγ2 (RORγ2 is also known as RORγt). Generally, RORγ is used to describe RORγ1 and / or RORγt. RORγ1 is expressed in many tissues, mainly in the kidneys, liver, and skeletal muscle. In contrast, RORγt expression is limited to several cell types of the immune system as well as lymphoid organs such as the thymus and secondary lymphoid tissues ((Non-Patent Literature 6); (Non-Patent Literature 1)).

[0009] RORγt has been identified as an important regulator of Th17 cell differentiation and IL-17 production by γδT cells, Th17 cells, T-cytotoxic (Tc)17 cells, and innate lymphoid cell type 3 (ILC3) cells (Non-Patent Literature 7). Th17 cells are a subset of T helper cells that preferentially produce cytokines IL-17A, IL-17F, IL-21, and IL-22 (Non-Patent Literature 2). T cells lacking RORγt cannot differentiate into Th17 cells even under Th17 polarization culture conditions, but overexpression of RORγt in naive CD4+ T cells was sufficient to promote the expression of Th17-related cytokines and chemokines (Non-Patent Literature 8; Non-Patent Literature 9). IL-23 is a critical checkpoint in the generation, maintenance, and activation of pathogenic Th17 cells. In response to IL-23 signaling, RORγt, in cooperation with a network of transcription factors (STAT3, IRF4, and BATF), initiates the complete differentiation program of Th17 cells (Non-Patent Literature 8).

[0010] Th17 cells and the IL-17 immune response have been shown to be associated with the pathology of many human inflammatory and autoimmune disorders. Therapeutic strategies targeting the IL-23-IL-17 system have been developed for many autoimmune diseases, and some of them have already demonstrated clinical efficacy in certain diseases (Non-Patent Literature 10; Non-Patent Literature 11).

[0011] Therefore, there is evidence that RORα, RORβ, and RORγ play a role in the pathogenesis of many diseases.

[0012] It would be desirable to provide compounds that modulate the activity of RORα and / or RORγ for use in the treatment of inflammatory, metabolic, and autoimmune diseases.

[0013] Patent Documents 1 and 2 describe compounds that modulate the activity or ROR-gamma receptor. However, there remains a need for potent ROR-gamma modulators with improved physicochemical properties. [Prior art documents] [License]

[0014] [License 1] International Publication No. 2016020288 パンフレット [License 2] International Publication No. 2016020295 パンフレット [License 3] U.S. Patent No. 7,931,909 [Non-licensed literature]

[0015] [Non-licensed Document 1] Jetten,2009,Nuclear Receptor Signaling [Non-licensed Document 2] Castro PLOS 2017 [Non-licensed Document 3] Malhotra 2018 [Non-licensed Document 4] Rudolf 2016 [Non-licensed Document 5] Lai 2015 [Non-licensed Document 6] Hirose 1994 [Non-licensed Document 7] Gaffen 2014 [Non-licensed Document 8] Gaffen 2014, Nat Rev Immunol [Non-licensed Document 9] Yang 2014, Trend Pharmacol Sci [Non-licensed Document 10] Patel 2015 [Non-licensed Document 11] Krueger 2018 Exp Dermatol [Non-licensed Document 12] Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999

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Non-licensed Document 22

Non-licensed Document 23

[0016] This disclosure provides compounds active against nuclear receptors. The disclosure also discloses compounds active against nuclear receptors, pharmaceutical compositions containing such compounds, and the use of such compounds in therapies. In one aspect, in the present specification, a compound of formula (I)

Chemical formula

[0017] In one embodiment, the Specified herein provides a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt of a compound of formula (I) or a stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

[0018] In one embodiment, this specification includes asthma, acne, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, Helicobacter pylori infection, allergic diseases such as allergic rhinitis, allergic conjunctivitis and uveitis, sprue and food allergies, atopic dermatitis, lichen planus, cystic fibrosis, lung graft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, ichthyosis, bullous diseases, hidradenitis suppurativa, steatosis, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and lupus erythematosus. Provided are compounds of formula (I) or stereoisomers thereof, or pharmaceutically acceptable salts of compounds of formula (I) or stereoisomers thereof, for use in the treatment and / or prevention of symptoms of diseases or disorders selected from the group consisting of Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune ocular diseases, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjögren's syndrome, optic neuritis, type 1 diabetes, neuromyelitis optica, myasthenia gravis, Guillain-Barré syndrome, Graves' disease, scleritis, obesity, obesity-induced insulin resistance, type 2 diabetes, and cancer.

[0019] Furthermore, the advantageous features of various embodiments are defined in the dependent claims and the description detailed below. [Modes for carrying out the invention]

[0020] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art. All patents, applications, published applications, and other documents referenced herein are incorporated by reference as a whole. If there are multiple definitions of a term herein, the definition in this section shall prevail unless otherwise stated.

[0021] When used in this specification, R, R1, R2, R3, R4, R5, R6, R7, R8, R9, and R 10 These include, but are not limited to, any "R" group that can be bonded to a given atom. Examples of R groups include, but are not limited to, hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heteroalicyclyl. When two "R" groups are covalently bonded to the same atom or adjacent atoms, they "together" or "combined" as defined herein to form a cycloalkyl, aryl, heteroaryl, or heteroalicyclyl group. For example, but are not limited to, NR a R b Base R a and R b However, when indicated as "together" or "combined," it means that they are covalently bonded to each other at their terminal atoms to form a nitrogen-containing ring: [ka]

[0022] As will be readily apparent to those skilled in the art, any given group disclosed herein may further contain more hydrogen than that provided by the R group, which is the hydrogen bonded to that group.

[0023] Whenever a group is described as "unsubstituted or substituted," if substituted, the substituent (which may be present one or more times, such as one, two, three, or four times) is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl))alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, and aminos including monosubstituted and disubstituted amino groups, as well as their protected derivatives. If a substituent on a group is considered "substituted," then the substituent itself is substituted by one or more of the specified substituents. When a referenced substituent is substituted, it means that one or more hydrogen atoms on the referenced substituent may be replaced with groups individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl))alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, and amino groups including monosubstituted and disubstituted amino groups, as well as their protected derivatives.Protecting groups capable of forming protected derivatives of the above substituents are known to those skilled in the art and can be found in literature incorporated herein by reference (Non-Patent Document 12) as a whole.

[0024] When used in this specification, "C m ~C n (C m to C n )", "C m ~C n (C m -C n )" or "C m~n "m" and "n" are integers, and refer to the number of carbon atoms in the group in question. That is, a group can contain from "m" to "n" carbon atoms. Therefore, for example, the "C1-C6 alkyl" group refers to all alkyl groups having 1 to 6 carbon atoms, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, CH3CH(CH)3CH2-, CH3CH(CH)3CH2-, and (CH3)3C-. If "m" and "n" are not specified for a group, the broadest range described in these definitions is assumed.

[0025] As used herein, “alkyl” refers to a fully saturated (without double or triple bonds) linear or branched hydrocarbon chain group. Alkyl groups may have 1 to 20 carbon atoms (wherever it appears herein, the numerical range such as “1 to 20” refers to each integer within a given range; for example, “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and up to 20 and 20 carbon atoms, but this definition also includes the existence of the term “alkyl” for which no numerical range is specified). Alkyl groups may also be “C 1~6 These can be medium-sized alkyl groups having 1 to 10 carbon atoms, such as "C1-C4 alkyl". Alkyl groups can also be smaller alkyl groups having 1 to 4 carbon atoms. The alkyl groups of the compound are "C1-C4 alkyl", "C 1~4It may be designated as "alkyl" or a similar name. For illustrative purposes only, "C1-C4 alkyl" or "C 1~4 The term "alkyl" indicates that the alkyl chain contains 1 to 4 carbon atoms; that is, alkyl chains are selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are by no means limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, and hexyl. If substituted, the substituents are one or more groups individually and independently selected from alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl) alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, and aminos including monosubstituted and disubstituted amino groups, as well as their protected derivatives.

[0026] As used herein, “alkenyl” refers to an alkyl group containing one or more double bonds in a linear or branched hydrocarbon chain. If two or more double bonds are present, they may or may not be conjugated. An alkenyl group may have 2 to 20 carbon atoms (wherever it appears herein, the numerical range such as “2 to 20” refers to each integer within a given range; for example, “2 to 20 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, and so on, up to 20 and 20 carbon atoms, but this definition also includes the existence of the term “alkenyl” for which no numerical range is specified). If substituted, the substituents are one or more groups individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, mercapto, alkylthio, cyano, halogen, nitro, haloalkyl, hydroxyalkyl, haloalkoxy, and amino groups including monosubstituted and disubstituted amino groups, as well as protected derivatives thereof.

[0027] As used herein, “alkynyl” refers to an alkyl group containing one or more triple bonds in a linear or branched hydrocarbon chain. An alkynyl group may have 2 to 20 carbon atoms (wherever it appears herein, the numerical range such as “2 to 20” refers to each integer within a given range; for example, “2 to 20 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc., up to 20 and 20 carbon atoms, but this definition also includes the existence of the term “alkynyl” for which no numerical range is specified). An alkynyl group may or may not be substituted. If substituted, the substituent may be selected from the same groups disclosed above with respect to alkenyl group substitution.

[0028] As used herein, “hetero” means one or more carbon atoms that may be bonded to a group, and the relevant hydrogen atoms in the bonded group are independently replaced by the same or different heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur.

[0029] As used herein, “heteroalkyl” alone or in combination with other terms refers to a linear or branched alkyl group consisting of a specified number of carbon atoms, in which one or more carbon atoms, such as 1, 2, 3, or 4 carbon atoms, and associated hydrogen atoms are independently replaced by the same or different heteroatoms selected from nitrogen, oxygen, and sulfur. The replaced carbon atoms may be located in the middle or at the end of the alkyl group. An example of a heteroalkyl group is C 1~6 Examples include heteroalkyls, where one or more carbon atoms are replaced by heteroatoms selected from the group consisting of nitrogen, oxygen, and nitrogen, such as -S-alkyl, -O-alkyl, -NH-alkyl, and -alkylene-O-alkyl. Heteroalkyls may be substituted.

[0030] As used herein, “aryl” refers to a carbocyclic (all-carbon) ring or a fused ring (a ring sharing two adjacent carbon atoms) having a completely delocalized π-electron system. In some embodiments described herein, the aryl group is C 1~10The group is an aryl group, which may or may not be substituted. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. The aryl group may be substituted. If substituted, the hydrogen atom is replaced by a substituent that is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl))alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, and aminos including monosubstituted and disubstituted amino groups, as well as one or more groups from their protected derivatives. When substituted, substituents on the aryl group can form non-aromatic rings condensed to the aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl groups.

[0031] As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic ring system (a ring system having a completely delocalized π-electron system) in which at least one atom in the ring system is a heteroatom, i.e., an element other than carbon, including but not limited to nitrogen, oxygen, and sulfur. In some embodiments described herein, the heteroaryl is C 6~10Examples of heteroaryl compounds include, but are not limited to, heteroaryl compounds in which 1 to 4 carbon atoms are replaced by 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of monocyclic "heteroaryls" include, but are not limited to, furan, thiophene, phthalazine, pyrrole, oxazole, oxadiazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, tetrazole, and triazine. Examples of polycyclic "heteroaryls" include, but are not limited to, quinoline, isoquinoline, quinazoline, quinoxaline, indole, purine, benzofuran, benzothiophene, and benzopyranone (e.g., coumarin, chromone, and isocoumarin). Heteroaryls may be substituted. If substituted, the hydrogen atom is replaced by a substituent that is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl))alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, C-amide, N-amide, S-sulfonamide, N-sulfonamide, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, hydroxyalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, and aminos including monosubstituted and disubstituted amino groups, as well as one or more groups from their protected derivatives. When substituted, substituents on the heteroaryl group can form non-aromatic rings condensed to the aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl groups.

[0032] "Aralkyl" or "arylalkyl" refers to an aryl group linked as a substituent via an alkylene group. The alkylene and aryl groups of aralkyl may be substituted. Examples include, but are not limited to, benzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group.

[0033] A "heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group linked as a substituent via an alkylene group. The alkylene and heteroaryl groups of a heteroaralkyl may be substituted. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, pyrazolylalkyl, and imidazolylalkyl, as well as their substitutions and benzo-condensation analogs. In some cases, the alkylene group is a lower alkylene group.

[0034] "Alkylene" is a linear tethering group that forms a bond connecting molecular fragments via terminal carbon atoms. Alkylene can have 1 to 20 carbon atoms. Alkylene is also called "C 1~6 These may be medium-sized alkylenes having 1 to 10 carbon atoms, such as "C1-C4 alkylenes". Alkylenes can also be lower alkylenes having 1 to 4 carbon atoms. Alkylenes include "C1-C4 alkylenes", "C 1~4 They may be designated as "alkylene" or similar names. Non-limiting examples include the methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), and butylene (-(CH2)4-) groups. In the case of methylene, the two linked fragments are linked to the same carbon atom. Lower alkylenes may be substituted.

[0035] As used herein, "heteroalkylene," alone or in combination with other terms, refers to an alkylene group consisting of a specified number of carbon atoms, where one or more carbon atoms, such as 1, 2, 3, or 4 carbon atoms, are independently replaced by the same or different heteroatoms selected from oxygen, sulfur, and nitrogen. Examples of heteroalkylenes include, but are not limited to, -CH2-O-, -CH2-CH2-O-, -CH2-CH2-CH2-O-, -CH2-NH-, -CH2-CH2-NH-, -CH2-CH2-NH-CH2-, -O-CH2-CH2-O-CH2-CH2-O-, and -O-CH2-CH2-O-CH2-CH2-.

[0036] As used herein, "alkylidene" refers to a divalent group such as =CR'R'', which is bonded to one carbon of another group that forms a double bond. Examples of alkylidene groups include, but are not limited to, methylidene (=CH2) and ethylidene (=CHCH3). As used herein, "arylalkylidene" refers to an alkylidene group in which either R' or R'' is an aryl group. The alkylidene group may be substituted.

[0037] As used herein, "alkoxy" refers to a group-OR where R is alkyl, such as methoxy, ethoxy, n-propoxy, cyclopropoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amoxy, tert-amoxy, etc. The alkoxy may be substituted.

[0038] As used herein, “alkylthio” refers to formula -SR where R is an alkyl as defined above, such as methyl mercapto, ethyl mercapto, n-propyl mercapto, 1-methylethyl mercapto (isopropyl mercapto), n-butyl mercapto, iso-butyl mercapto, sec-butyl mercapto, tert-butyl mercapto, etc. Alkylthio may be substituted.

[0039] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, where R is an aryl as defined above, such as phenoxy, naphthalenyloxy, azlenyloxy, anthracenyloxy, naphthalenylthio, phenylthio, etc. Both aryloxy and arylthio may be substituted.

[0040] As used herein, “alkenyloxy” refers to formula-OR where R is an alkenyl as defined above, e.g., vinyloxy, propenyloxy, n-butenyloxy, iso-butenyloxy, sec-pentenyloxy, tert-pentenyloxy, etc. Alkenyloxy may be substituted.

[0041] As used herein, "acyl" refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl atom linked as a substituent via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acrylic. The acyl may be substituted.

[0042] As used herein, "cycloalkyl" refers to a completely saturated (double-bond-free) monocyclic or polycyclic hydrocarbon ring system. If composed of two or more rings, the rings may be bonded together by condensation, crosslinking, or spirobonding. Cycloalkyl groups include C3-C6 and other C3-C6 groups. 10 This range may apply. The cycloalkyl group may or may not be substituted. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. If substituted, the substituent may be alkyl or, unless otherwise indicated, may be selected from those shown above with respect to alkyl group substitution. If substituted, substitution on the cycloalkyl group may form an aromatic ring condensed on the cycloalkyl group, including aryl and heteroaryl groups.

[0043] As used herein, “cycloalkenyl” refers to a cycloalkyl group containing one or more double bonds in the ring, but if there are two or more, they cannot form a completely delocalized π-electron system in the ring (otherwise the group would be “aryl” as defined herein). If it consists of two or more rings, the rings may be linked together in the form of condensation, bridging, or spirobonding. Cycloalkenyl groups are C3-C8 or C5-C 10 C3~C etc. 10 It could be within the range of C. 3~8 As for cycloalkenyls, C 4~8 Cycloalkenyl, C 5~8 Cycloalkenyl or C 6~8 Examples include cycloalkenyls. The cycloalkenyl group may or may not be substituted. If substituted, the substituent may be alkyl or, unless otherwise indicated, may be selected from the groups disclosed above with respect to alkyl substitution. If substituted, substitution on the cycloalkenyl group may form an aromatic ring condensed on the cycloalkenyl group, including aryl and heteroaryl groups.

[0044] As used herein, "cycloalkynyl" refers to a cycloalkyl group containing one or more triple bonds in the ring. When composed of two or more rings, the rings may be bonded together in the form of condensation, crosslinking, or spirobonding. The cycloalkynyl group is C8-C 12 The range may be as follows. The cycloalkynyl group may or may not be substituted. If substituted, the substituent may be alkyl or, unless otherwise indicated, may be selected from the groups disclosed above with respect to alkyl substitution. If substituted, substitution on the cycloalkynyl group may form an aromatic ring condensed on the cycloalkynyl group, including aryl and heteroaryl groups.

[0045] As used herein, "heteroalicyclyl" refers to a 3- to 18-membered ring consisting of carbon atoms and 1 to 5 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The heteroalicyclyl group is C2-C 10The range may be C2 to C9 in some embodiments, and in other embodiments, it may be C2 to C8. In some embodiments, the "heteroalicyclyl" may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be bonded together in the form of condensation, bridging, or spirobonding; and the nitrogen, carbon, and sulfur atoms in the "heteroalicyclyl" may be oxidized; the nitrogen may be quaternized; and the rings may also be provided that they do not form a π-electron system that is completely delocalized across the entire ring. The compounds may contain one or more double bonds, examples of which are 2H-benzo[b][1,4]oxazine-3(4H)-one, 3,4-dihydroquinoline-2(1H)-one, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-benzo[b][1,4]oxazine, 2,3-dihydrobenzo[d]oxazole, 2,3-dihydro-1H-benzo[d]imidazole, indoline, and 1,3-dihydro-2H-benzo[d]imidazole-2-one, and benzo[d]oxazole-2(3H)-one. The heteroalicyclyl group may or may not be substituted. If substituted, the substituent may be one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, oxo, alkoxy, aryloxy, acyl, ester, O-carboxy, mercapto, alkylthio, arylthio, cyano, halogen, C-amide, N-amide, S-sulfonamide, N-sulfonamide, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, haloalkyl, hydroxyalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamide, and aminos including monosubstituted and disubstituted amino groups, as well as protected derivatives thereof.Examples of such "heteroalicyclyls" include, but are not limited to, azepinyl, dioxolanil, imidazolinil, morpholinil, oxetanil, oxylanil, piperidinyl N-oxide, piperidinil, piperazinil, pyrrolidinil, pyranil, 4-piperidonyl, pyrazolidinil, 2-oxopyrrolidinil, tetrahydrofuranil, tetrahydropyranil, thiamorpholinil, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone. When substituted, substitution on the heteroalicyclyl group may form an aromatic ring condensed on the heteroalicyclyl group, including aryl and heteroaryl groups.

[0046] "(cycloalkyl)alkyl" refers to a cycloalkyl group linked as a substituent via an alkylene group. The alkylene and cycloalkyl groups of (cycloalkyl)alkyl may be substituted. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, and cycloheptylmethyl. In some cases, the alkylene group is a lower alkylene group.

[0047] "(cycloalkenyl)alkyl" refers to a cycloalkenyl group linked as a substituent via an alkylene group. The alkylene and cycloalkenyl in (cycloalkenyl)alkyl may be substituted. In some cases, the alkylene group is a lower alkylene group.

[0048] "(cycloalkynyl)alkyl" refers to a cycloalkynyl group linked as a substituent via an alkylene group. The alkylene and cycloalkynyl in (cycloalkynyl)alkyl may be substituted. In some cases, the alkylene group is a lower alkylene group.

[0049] As used herein, "halo" or "halogen" refers to F (fluoro), Cl (chloro), Br (bromo), or I (iodine).

[0050] As used herein, "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogens. Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethyl, trifluoromethyl, and 1-chloro-2-fluoromethyl, 2-fluoroisobutoxy. Haloalkyls may or may not be substituted, and in some embodiments, C 1~6 This relates to medium-sized haloalkyls, such as haloalkyls, that have 1 to 10 carbon atoms.

[0051] As used herein, "haloalkoxy" refers to an RO- group in which R is a haloalkyl group. Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy. Haloalkoxys may be substituted.

[0052] As used herein, the term hydroxyalkyl refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl group. Such groups include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, and hydroxyhexyl. The hydroxyalkyl group may or may not be substituted, and in some embodiments, C 1~6 This relates to hydroxyalkyl groups of medium size, such as hydroxyalkyl groups, which have 1 to 10 carbon atoms.

[0053] The "O-carboxyl" group refers to an "RC(=O)O-" group where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl))alkyl, as defined herein. The O-carboxyl may be substituted.

[0054] The "C-carboxyl" group refers to a "-C(=O)OR" group where R may be the same as the one defined for O-carboxyl. The C-carboxyl group may be substituted.

[0055] The "trihalomethanesulfonyl" group refers to the "X3CSO2-" group where X is a halogen.

[0056] Dashed line connection [ka] The dashed line represents an arbitrarily chosen unsaturation between the atoms forming the bond. This bond can be unsaturated (e.g., C=C, C=N, C=O) or saturated (e.g., CC, CN, CO). The dashed line bond exists in ring systems that can form parts of an aromatic ring system.

[0057] When used herein, bold straight lines (not wedges) or dashed lines are used to connect them. [ka] This refers to the related stereochemistry that includes all possible stereoisomers at that position.

[0058] When used herein, and unless otherwise indicated, the wedge joints (bold, dashed, or otherwise) [ka] This refers to absolute stereochemistry, which refers to the specific stereoisomer depicted at that position.

[0059] The "nitro" group refers to the "-NO2" group.

[0060] The "cyano" group refers to the "-CN" group.

[0061] The "cyanato" group refers to the "-OCN" group.

[0062] The "isocyanato" group refers to the "-NCO" group.

[0063] The "thiocyanate" group refers to the "-SCN" group.

[0064] The "carbonyl" group refers to the "-C(=O)-" group.

[0065] The "thiocarbonyl" group refers to the "-C(=S)-" group.

[0066] The "oxo" group refers to the "=O" group.

[0067] The "hydroxy" group or "hydroxyl" group refers to the "-OH" group.

[0068] The "isothiocyanate" group refers to the "-NCS" group.

[0069] The "sulfinyl" group refers to a "-S(=O)-R" group where R can be the same as the one defined for O-carboxyl groups. The sulfinyl group may be substituted.

[0070] The "sulfonyl" group refers to an "SO2R" group where R may be the same as that defined for an O-carboxyl group. The sulfonyl group may be substituted.

[0071] The "S-sulfonamide" group is R A and R B Each of these can be independent of the others and be the same as defined for the R group as defined for the O-carboxyl group, or substituted or unsubstituted C 3~8 Cycloalkyl, substituted, or unsubstituted C 3~8A cycloalkenyl, substituted or unsubstituted C 3~8 A cycloalkyl, substituted or unsubstituted C 3~8 A ring system selected from the group consisting of a cycloalkenyl, a substituted or unsubstituted heteroalicyclyl, a substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl that can be combined to form a "-SO2NR A R B " group. The S-sulfonamide may be substituted.

[0072] The "N-sulfonamide" group refers to an "RSO2N(R A )-" group, where R and R A can each be the same as defined for the R group as defined for O-carboxy. The N-sulfonamide may be substituted.

[0073] The "trihalomethanesulfonamide" group refers to an "X3CSO2N(R)-" group having X as a halogen, and R can be the same as defined for O-carboxy. The trihalomethanesulfonamide may be substituted.

[0074] The "C-amide" group refers to an R A and R B that can each be the same as defined for the R group as defined for O-carboxy, or a "-C(=O)NR 3~8 A cycloalkyl, substituted or unsubstituted C 3~8 A cycloalkenyl, substituted or unsubstituted C 3~8 A cycloalkyl, substituted or unsubstituted C 3~8 A cycloalkenyl, substituted or unsubstituted heteroalicyclyl, substituted or unsubstituted aryl, and a substituted or unsubstituted heteroaryl that can be combined to form a ring system selected from the group consisting of "-C(=O)NR A R B " group. The C-amide may be substituted.

[0075] The "N-amide" group is R and R A Each of these can independently be the same as the one defined for the R group as defined for the O-carboxyl group, "RC(=O)NR" A - Refers to the group. The N-amide may be substituted.

[0076] An "ester" refers to a "-C(=O)OR" group where R can be the same as the one defined for O-carboxyl groups. Esters may be substituted.

[0077] A lower alkoxyalkyl group refers to an alkoxy group linked via a lower alkene group. Lower alkoxyalkyl groups may be substituted.

[0078] "Amine" or "amino" refers to "RNH2" (primary amine), "R2NH" (secondary amine), and "R3N" (tertiary amine). The amino group may be substituted.

[0079] A lower aminoalkyl group refers to an amino group linked via a lower alkene group. Lower aminoalkyl groups may be substituted.

[0080] In the compounds herein, unsubstituted or monosubstituted amine groups may be converted to amides using techniques well known to those skilled in the art, any hydroxyl group may be converted to an ester, and any carboxyl group may be converted to either an amide or an ester (see, for example, Non-Patent Document 12).

[0081] When used herein, any abbreviations relating to protecting groups, amino acids, and other compounds shall, unless otherwise indicated, follow their common use, recognized abbreviations, or those of the IUPAC-IUB Biochemical Nomenclature Committee (see Non-Patent Document 13).

[0082] List of abbreviations DMF Dimethylformamide DMSO (Dimethyl Sulfoxide) MeOH methanol EtOH Ethanol THF (Tetrahydrofuran) DCM: Dichloromethane, Methylene Chloride DCE 1,2-Dichloroethane LRMS low resolution mass spectrometry HPLC (High-Pressure Liquid Chromatography) Prep-HPLC Preparative High-Pressure Liquid Chromatography h time min EA ethyl acetate EDC·HCl 3-((ethylimino)methyleneamino)-N,N-dimethylpropane-1-aminium chloride DIEA (Diisopropylethylamine) TEA (Triethylamine) TFA (Trifluoroacetic Acid) HCl (hydrochloric acid, hydrogen chloride) HOBt 1-Hydroxybenzotriazole hydrate HOAt 1-hydroxy-7-azabenzotriazole HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate DMAP 4-(dimethylamino)pyridine DAST (Diethylamino) Sulfate Trifluoride DMP Des-Martin Periodinane, 1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one TBAF Tetrabutylammonium fluoride trihydrate TBDMSCl tert-butyldimethylsilyl chloride MsCl methanesulfonyl chloride NAS nucleophilic aromatic substitution nBuLi n-butyllithium iPr isopropyl Boc tert-butyloxycarbonyl Flash CC Flash Column chromatography on overnight rt room temperature AQ water-based ND Not decided Cbz Carboxybenzyl Hex (hexane) Heptane DEA (Diethylamine) PE (Petroleum Ether) DAD Diode Array Detector TOF Flight Time IPA Isopropanol Pg protecting group

[0083] In any compound disclosed herein having one or more chiral centers, where absolute stereochemistry is not explicitly shown, it is understood that each center may independently be in an R configuration, an S configuration, or a mixture thereof. Therefore, the compounds provided herein may be enantiomerically pure or stereoisomerically mixed. Furthermore, the compounds provided herein may be scalemic mixtures. In addition, in any compound having one or more double bonds that produce geometric isomers that can be defined as E or Z, it is understood that each double bond may independently be E, Z, or a mixture thereof. Similarly, all tautomers are also intended to be included.

[0084] As used herein, the term "rac" means "racemic," "racemic mixture," etc., as understood by those skilled in the art. For example, a racemic mixture contains a mixture of equal amounts of enantiomers of chiral molecules. Typically, racemic mixtures do not exhibit optical activity.

[0085] As used herein, the term "rel" refers to a relative, not absolute, arrangement of chiral centers with respect to any other chiral center within the same compound, as will be understood by those skilled in the art.

[0086] As used herein, “tautomer” and “tautomerous” refer to alternating forms of the compounds disclosed herein with different proton positions. Non-limiting examples include enol-keto and imine-enamine tautomers, or tautomerous forms of heteroaryl groups containing ring atoms bonded to both the ring-NH- and ring-N- moieties, such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole.

[0087] It is understood that isotopes may be present in the compounds described herein. Each chemical element as represented in the compound structure may contain any isotope of that element. For example, in the compounds described herein, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, in this specification, references to compounds encompass all possible isotopic forms unless otherwise clearly indicated by the context.

[0088] As used herein, references to elements, regardless of their description or chemical structure, include all isotopes of that element unless otherwise specified. For example, the term "hydrogen" or "H" in chemical structures as used herein, unless otherwise indicated by the use of a specific isotope, 1 Not just H, but Deuterium ( 2 H), tritium ( 3 It is understood that this also includes H), and mixtures thereof. Other specific non-limiting examples of elements in which isotopes are included include carbon, phosphorus, iodine, and fluorine.

[0089] As used herein, “pharmaceutically acceptable salt” refers to a salt of a compound that does not inhibit the biological activity and properties of the compound. A pharmaceutically acceptable salt can be obtained by the reaction of a compound disclosed herein with an acid or a base. Examples of salts formed with a base include ammonium salts (NH4 +Examples include, but are not limited to, alkali metal salts such as sodium or potassium; alkaline earth salts such as calcium or magnesium; salts of organic bases such as dicyclohexylamine, piperidine, piperazine, methylpiperazine, N-methyl-D-glucamine, diethylamine, ethylenediamine, tris(hydroxymethyl)methylamine; and salts of amino acids such as arginine and lysine, but are not limited to those. Useful acid-based salts include, but are not limited to, acetates, adipines, aspartates, ascorbicates, benzoates, butyrates, caprinates, caproates, caprylates, cansylates, citrates, decanoates, formates, fumarates, glucons, glutarates, glycolates, hexanoates, laurates, lactates, maleates, nitrates, oleates, oxalates, octanoates, propaneates, palmitates, phosphates, sebacinates, succinates, stearates, sulfates, methanesulfonates, ethanesulfonates, p-toluenesulfonates, salicylates, tartrates, and tosylates.

[0090] pharmaceutically acceptable solvents and hydrates are one or more water molecules as solvents, or 1 to about 100, or 1 to about 10, or 1 to about 2, 3, or 4 solvents or complexes of water molecules with compounds.

[0091] As used herein, “prodrug” refers to a compound that may not be pharmaceutically active but is converted to an active drug upon in vivo administration. Prodrugs may be designed to alter the metabolic stability or transport properties of a drug, mask side effects or toxicity, enhance the flavor of a drug, or alter other properties or characteristics of a drug. Prodrugs are often useful because they can be administered more easily than their parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. Prodrugs may also have better solubility than the active parent drug in a pharmaceutical composition. An example of a prodrug, not limited to these, is a compound disclosed herein, which is administered as an ester ("prodrug") to facilitate absorption across cell membranes, where water solubility is detrimental to mobility, but where water solubility is advantageous, and the compound is metabolically hydrolyzed once to a carboxylic acid (the active entity) inside the cell. A further example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized in vivo to release the active parent compound. With knowledge of pharmacodynamic processes and in vivo drug metabolism, those skilled in the art can design prodrugs of compounds once pharmaceutically active compounds are known (see, for example, Non-Patent Document 14).

[0092] As used herein, “modulating” receptor activity means either activating it, i.e., increasing its cellular function beyond the basal level measured in the particular environment in which it is found, or inactivating it, i.e., reducing its cellular function below the basal level measured in the environment in which it is found and / or rendering it completely incapable of performing its cellular function, even in the presence of its natural binding partner. The natural binding partner is an endogenous molecule that is an agonist for the receptor.

[0093] An "agonist" is defined as a compound that increases the basal activity of a receptor (i.e., receptor-mediated signal transduction).

[0094] As used herein, “partial agonist” refers to a compound that has affinity for a receptor but is not an agonist, and when bound to the receptor, it induces, to a small degree, the pharmacological response that is normally associated with the receptor, even when the majority of the receptor is occupied by the compound.

[0095] An "inverse agonist" is defined as a compound that, while not technically an antagonist, reduces or inhibits the basal activity of a receptor, thereby exhibiting negative endogenous activity as an agonist.

[0096] As used herein, “antagonist” refers to a compound that binds to a receptor and forms a complex that does not produce any response, as if the receptor were not occupied. Antagonists attenuate the effect of an agonist on the receptor. Antagonists may bind reversibly or irreversibly and efficiently quench the receptor's activity continuously or at least until the antagonist is metabolized or dissociated or removed by other means, such as physical or biological processes.

[0097] As used herein, “subject” refers to an animal that is the subject of treatment, observation, or experimentation. “Animal” includes cold-blooded and warm-blooded vertebrates and invertebrates, such as birds, fish, crustaceans, reptiles, and especially mammals. “Mammals” include, but are not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates such as monkeys, chimpanzees, and apes, and especially humans.

[0098] As used herein, “patient” means a subject being treated by a healthcare professional, such as an MD or DVM, in an attempt to cure or at least reverse the effects of a particular disease or disorder, or to prevent the disease or disorder from occurring in its original place.

[0099] As used herein, “carrier” refers to a compound that facilitates the uptake of a compound into a cell or tissue. For example, but not limited to, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into target cells or tissues.

[0100] As used herein, “diluent” refers to a component in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the mass of a potent drug whose mass is too small for manufacture or administration. It may also be a liquid for dissolving a drug to be administered by injection, oral ingestion, or inhalation. Common forms of diluents in the art are buffered aqueous solutions, such as phosphate-buffered saline that mimics the composition of human blood, but are not limited thereto.

[0101] As used herein, “excipient” refers to an inert substance added to a pharmaceutical composition to provide the composition with, but not limited to, properties, consistency, stability, binding ability, lubrication, or disintegration ability. “Diluent” is a type of excipient.

[0102] A “receptor” is intended to include any molecule present inside or on the surface of a cell that can affect the cellular function when inhibited or stimulated by a ligand. Typically, a receptor includes an extracellular domain with ligand-binding properties, a transmembrane domain that anchors the receptor in the cell membrane, and an intracellular domain that generates a cellular signal in response to ligand binding (“signaling”). Receptors also include any intracellular molecule that generates a signal in response to binding. Receptors also include any molecule that has the characteristic structure of a receptor but does not have an identifiable ligand. In addition, receptors include cleaved, modified, or mutated receptors, or any molecule that contains part or all of the sequence of a receptor.

[0103] A "ligand" is intended to include any substance that interacts with the receptor.

[0104] "Selective" or "selectivity" is defined as the ability of a compound to produce a desired response from a particular receptor type, subtype, class, or subclass, while producing less or no response from other receptor types. "Selective" or "selectivity" of one or more specific subtypes of a compound means the ability of the compound to increase the activity of that subtype while increasing the activity of other subtypes less, little, or no.

[0105] As used herein, "simultaneous administration" of pharmacologically active compounds refers to the delivery of two or more separate chemical entities, whether in vitro or in vivo. Simultaneous administration means the simultaneous delivery of separate drugs; the simultaneous delivery of a mixture of drugs; and the delivery of a second or additional drug after the delivery of one drug. Drugs administered simultaneously are usually intended to work in combination with each other.

[0106] As used herein, the term “effective dose” means the amount of an active compound or medicinal product that elicits a biological or medical response in a tissue, system, animal or human, including relief or mitigation of symptoms of a disease being treated, as determined by a researcher, veterinarian, doctor of medicine or other clinician.

[0107] As used herein, “prevent /

[0108] compound In one embodiment, the present disclosure relates to a compound of formula (I). [ka] , its stereoisomer, or a pharmaceutically acceptable salt of the compound or stereoisomer (in the formula, Y1, Y2, and Y3 are independently -N- or -CR8-; m is independently selected from 0, 1, and 2; R is hydrogen, C 1~6 Alkyl and C 1~4 Selected from the group consisting of hydroxyalkyl groups; R 0a and R 0b Hydrogen and C are independent of each other. 1~4 Alkyl, C 1~4 Hydroxyalkyl, and C 1~4 Selected from the group consisting of haloalkyls; R 1a and R 1b These are independently hydrogen, hydroxyl, halogen, amino, and C 1~4 Alkyl, C 1~4 Hydroxyalkyl, and C 1~4 Selected from the group consisting of haloalkyls; R2 is hydrogen, hydroxyl, amino, cyano, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, -C(=O)NH2, -C(=O)OH, -C(=O)OC 1~4 Selected from the group consisting of alkyl and substituted or unsubstituted heteroaryls; Ring C is a 3- to 10-membered heteroalicyclyl ring system containing, in addition to the one N atom shown in the C ring of the compound of formula I, 0, 1, or 2 heteroatoms independently selected from N, O, and S; Each R3 is hydrogen, halogen, hydroxyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl; and C 1~4 Independently selected from the group consisting of hydroxyhaloalkyl; R5 does not exist, or it is hydrogen or C 1~4It is alkyl; R6 is hydrogen, -CN, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~4 Hydroxyhaloalkyl, C 1~4 Alkoxy, C 1~4 Selected from the group consisting of haloalkoxys, substituted or unsubstituted heteroaryls; R7 is hydrogen, hydroxyl, -CN, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~4 Alkoxy, C 1~4 Selected from the group consisting of haloalkoxys; Each R8 represents hydrogen, hydroxyl, -CN, halogen, and C. 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~4 Alkoxy, and C 1~4 Independently selected from the group consisting of haloalkoxys; and If R7 is hydrogen and each R8 present is hydrogen, then R6 is always -CN, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~4 Hydroxyhaloalkyl, C 1~4 Alkoxy, C 1~4 A heteroaryl is selected from the group consisting of haloalkoxys, substituted or unsubstituted heteroaryls, and if substituted, the heteroaryl is C 1~4 Alkyl, C 1~4 Hydroxyalkyl, C 2~4 Alkenil, C 2~4 Alkinyl, Hydroxy, C 1~4 Alkoxy, cyano, halogen, C 1~4 Haloalkyl, C 1~4 Haloalkoxy and C 1~6 This relates to a group that is substituted with 1 to 3 groups independently selected from the group consisting of hydroxyhaloalkyl groups.

[0109] In some embodiments disclosed herein, R is hydrogen.

[0110] In some embodiments disclosed herein, R 0a R is selected from the group consisting of hydrogen, methyl, -CH2OH, -CH2CH2OH, -CH2F, and -CHF2. In some embodiments, R 0b is hydrogen, C 1~4 Alkyl, C 1~4 Hydroxyalkyl, and C 1~4 Selected from the group consisting of haloalkyls. In other embodiments, R 0a is selected from the group consisting of hydrogen, methyl, -CH2OH, -CH2CH2OH, -CH2F, and -CHF2, and R 0b is hydrogen, C 1~4 Alkyl, C 1~4 Hydroxyalkyl, and C 1~4 Selected from the group consisting of haloalkyls. In other embodiments, R 0a and R 0b At least one of them is hydrogen, for example, R 0a is selected from the group consisting of hydrogen, methyl, -CH2OH, and -CH2CH2OH, and R 0b is hydrogen. In some embodiments, R 0a is hydrogen. In many embodiments, R 0a and R 0b It is hydrogen.

[0111] In some embodiments disclosed herein, R 1a is selected from the group consisting of hydroxyl, fluoro and -CF3, and R 1b R is selected from the group consisting of hydrogen, fluoro, and methyl, for example, 1a is hydroxyl or fluoro, and R 1b is hydrogen or fluoro, for example, R 1a and R 1b Both are fluoro, or R 1a is hydroxyl and R 1b is hydrogen. In some embodiments, R 1ais hydroxyl or fluoro. In many embodiments, R 1a is hydroxyl. In many embodiments, R 1b It is hydrogen.

[0112] In some embodiments disclosed herein, R2 is hydrogen, halogen, hydroxyl, cyano, methyl, ethyl, -CH2OH, -CH2CH2OH, and -C(=O)OC 1~2 The alkyl group is selected from the group consisting of hydrogen, fluoro, hydroxyl, methyl, -CH2OH, and -C(=O)OCH3. In some embodiments, R2 is selected from the group consisting of hydrogen, fluoro, and hydroxyl, for example, hydroxyl.

[0113] In some embodiments, R 1a , R 1b And at least one of R2 is a substituent other than hydrogen. In some embodiments, R 1a , R 1b And two of R2 are substituents other than hydrogen, for example, R 1a and R 1b Is it fluoro, or R 1a R is hydroxyl, and R2 is hydroxyl. In some embodiments, R 1a is hydroxyl and R 1b And R2 is hydrogen.

[0114] In some embodiments disclosed herein, the ring system C is selected from the group consisting of 4-membered heteroalicyclyl, 5-membered heteroalicyclyl, and 6-membered heteroalicyclyl; examples include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 2-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.1.0]hexanyl. In some embodiments, the ring system C is morpholinyl or pyrrolidinyl, which may be unsubstituted or, in some embodiments, substituted with R3. In some embodiments, C is morpholinyl. R3 may be absent (m is 0), or there may be one or two (m is 1 or 2). In some embodiments, m is 0. If two are present, each R3 may be bonded to the same atom. Each R3 is C 1~4 Alkyl, C 1~4 The group consists of haloalkyls and halogens, with specific examples being methyl, fluoro, and difluoro. In some embodiments, R3 is a halogen or methyl, and m is 1 or 2. In some embodiments, the ring system C is morpholinyl, i.e., R3 is absent (m is 0).

[0115] For clarity, R4 is not used within this disclosure.

[0116] In some embodiments of this disclosure, R5 cannot exist when the heteroalicyclyl ring system C is a bicyclic, tricyclic, or tetracyclic ring system and the carbon atom to which R5 is bonded is a bridgehead atom. R5 also cannot exist when the carbon atom to which it is bonded is part of a double bond.

[0117] In some embodiments disclosed herein, R5 is either absent (for example, when the ring system C is a bicyclic ring such as 2-azabicyclo[3.1.0]hexanyl, which makes R5 unavailable (absent)) or hydrogen. In some embodiments, R5 is hydrogen.

[0118] In some embodiments disclosed herein, R6 is selected from the group consisting of hydrogen, halogen, C 1~4 haloalkyl, C 1~4 haloalkoxy, C 1~4 hydroxyalkyl, C 1~4 hydroxyhaloalkyl, and substituted or unsubstituted 5-member heteroaryl. For example, R6 is selected from the group consisting of hydrogen, halogen, -CF3, -CHF2, -CCH3F2, -OCF3, -OCHF2, -C(CF3)2OH, and 5-member heteroaryl, and 5-member heteroaryl substituted with one or two methyls.

[0119] In many embodiments, R6 is -CF3.

[0120] In some embodiments disclosed herein, R7 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -CF3, -OCHF2, -CHF2 and -OCF3. For example, R7 is selected from the group consisting of hydrogen, fluoro, CF3, and hydroxyl. In some embodiments, R7 is hydrogen.

[0121] In some embodiments disclosed herein, Y1, Y2 and Y3 are each independently -CH. In some embodiments, Y1 is -N-, and Y2 and Y3 are each independently -CH-. In some embodiments, Y2 is -N-, and Y1 and Y3 are each independently -CH-. In some embodiments, Y3 is -N-, and Y1 and Y2 are each independently CH. In some embodiments, Y3 is -CH-, and Y1 and Y2 are -N-. In some embodiments, Y1 is -CH-, and Y2 and Y3 are each independently -CR8-, wherein each R8 is selected from the group consisting of hydrogen, methyl, fluoro, hydroxyl and -CF3, or each R8 is hydrogen.

[0122] In some embodiments disclosed herein, R6 is hydrogen and at least one of Y2 or Y3 is -CR8, where R8 is selected from the group consisting of -CN, hydroxyl, halogen, C 1~4 alkyl, C 1~4 haloalkyl, C 1~4 hydroxyalkyl, C 1~4 alkoxy, and C 1~4 haloalkoxy.

[0123] In one embodiment of formula (I), R is hydrogen; R 0a and R 0b are independently hydrogen or methyl; R 1a is selected from the group consisting of hydrogen, fluoro, and hydroxyl; R 1b is hydrogen or fluoro; R2 is selected from the group consisting of hydrogen, fluoro, and hydroxyl; ring C is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, 2-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.1.0]hexanyl; m is selected from the group consisting of 0, 1, and 2; R3 is selected from the group consisting of hydrogen, fluoro, and methyl; R5 is absent or hydrogen; R6 is selected from the group consisting of hydrogen, -CF3, -OCF3, and -Cl; R7 is hydrogen or fluoro; Y1, Y2, and Y3 are each -CH-; or Y1 is -CH-, Y2 is -CH-, and Y3 is -C(OH)-; or Y1 is -CH-, Y2 is -CH-, and Y3 is -N-; or Y1 is -CH-, Y2 is -C(CF3)-, and Y3 is -CH-; or Y1 is -CH-, Y2 is -N-, and Y3 is -CH-.

[0124] In one embodiment of formula (I), R is hydrogen; R 0a is selected from the group consisting of hydrogen, methyl, -CH2OH, -CH2CH2OH, and R 0b is hydrogen, for example, both R 0a and R 0b are hydrogen; R 1ais selected from the group consisting of hydroxyl, fluoro and -CF3 and R 1b R is selected from the group consisting of hydrogen, fluoro, and methyl, for example, 1a is hydroxyl or fluoro, and R 1b R1 is hydrogen or fluoro; R2 is selected from the group consisting of hydrogen, fluoro and hydroxyl, for example, hydroxyl; ring system C is morpholinyl or pyrrolidinyl, which may be unsubstituted or substituted with one or two R3 groups in some embodiments, for example, methyl, fluoro or difluoro; R5 is hydrogen; R6 is -CF3; R7 is selected from the group consisting of hydrogen, fluoro, -CF3 and hydroxyl, for example, hydrogen; Y2 is -N- and Y1 and Y3 are independently -CH-, or Y3 is -N- and Y1 and Y2 are independently -CH-, or Y1 is -CH- and Y2 and Y3 are independently -CR8-, and each R8 is selected from the group consisting of hydrogen, methyl, fluoro, hydroxyl and -CF3, for example, each R8 is hydrogen.

[0125] In one embodiment, the compound, stereoisomer, or salt according to formula (I) is one of the following compounds: [ka] (In the formula, R 1a is fluoro or hydroxyl; R 1b is hydrogen or fluorine; R2 is either hydrogen or hydroxyl; R6 is -CF3; and Y2 and Y3 are each independently selected from the group consisting of -N-, -CH-, and -CF-. For example, both Y2 and Y3 are -CH-, or Y2 is -CH- and Y3 is -CF. Or for example, both Y2 and Y3 are each -CH-, or Y2 is -CH- and Y3 is -CF- and R 1ais hydroxyl and R 1b is hydrogen, or R 1a It is fluoro, and R 1b It is hydrogen or fluorocarbon.

[0126] In one embodiment, the compound, stereoisomer, or salt according to formula (I) is 2-(4-(((5-fluoro-6-((S)-3-(5-trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)propanamide, (S)-2-(4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, (S)-2-(4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)-2-methylpropanamide, (S)-2-(4-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, (S)-2-(4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, (S)-2-(4-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethoxy)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((3RS,4RS)-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, the first isomer to elute, 2-((3R*,4R*)-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, the second isomer to elute, (S)-2-(4-fluoro-4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, the first isomer to elute, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, the second isomer to elute, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, the first isomer to elute, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, the second isomer to elute, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((S)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, the first isomer to elute, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((S)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, the second isomer to elute, 2-((3R*,4S*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, the first isomer to elute, 2-((3R*,4S*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, the second isomer to elute, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, the first isomer to elute, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, the second isomer to elute, (R)-2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-4-hydroxypiperidine-1-yl)acetamide, 2-((R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, the first isomer to elute, 2-((R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, the second isomer to elute, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, the first isomer to elute, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, the second isomer to elute, 2-((3RS,4RS)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, the first isomer to elute, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, the second isomer to elute, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, the first isomer to elute, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, the second isomer to elute, 2-((R*)-4-(((6-((R)-4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, the first isomer to elute, 2-((R*)-4-(((6-((R)-4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, the second isomer to elute, 2-((3RS,4RS)-4-(((6-((R)-4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, rel-2-((3R,4R)-4-(((5-fluoro-6-((3S,5R)-3-methyl-5-(3-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide or rel-2-((3R,4R)-4-(((5-fluoro-6-((3R,5S)-3-methyl-5-(3-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, the first isomer to elute, rel-2-((3R,4R)-4-(((5-fluoro-6-((3S,5R)-3-methyl-5-(3-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide or rel-2-((3R,4R)-4-(((5-fluoro-6-((3R,5S)-3-methyl-5-(3-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, second isomer, rel-2-((3R,4R)-4-(((5-fluoro-6-((3S,5R)-3-methyl-5-(3-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide or rel-2-((3R,4R)-4-(((5-fluoro-6-((3R,5S)-3-methyl-5-(3-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, the first isomer to elute, rel-2-((3R,4R)-4-(((5-fluoro-6-((3S,5R)-3-methyl-5-(3-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide or rel-2-((3R,4R)-4-(((5-fluoro-6-((3R,5S)-3-methyl-5-(3-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, second isomer, rel-2-((3R,4R)-4-(((5-fluoro-6-((3S,5R)-3-methyl-5-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide or rel-2-((3R,4R)-4-(((5-fluoro-6-((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, the first isomer to elute, rel-2-((3R,4R)-4-(((5-fluoro-6-((3S,5R)-3-methyl-5-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide or rel-2-((3R,4R)-4-(((5-fluoro-6-((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, second isomer, rel-2-((3R,4R)-4-(((5-fluoro-6-((3S,5R)-3-methyl-5-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide or rel-2-((3R,4R)-4-(((5-fluoro-6-((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, the first isomer to elute, rel-2-((3R,4R)-4-(((5-fluoro-6-((3S,5R)-3-methyl-5-(4-(trifluoromethyl)phenyl)morpholino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide or rel-2-((3R,4R)-4-(((5-fluoro-6-((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)morpholino)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)acetamide, the isomer eluting second, (S)-2-(4-(((5-fluoro-6-(3-(4-(trifluoromethoxy)phenyl)morpholino)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)-5-fluoropyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, (R)-2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, rac-2-(4-(((5-fluoro-6-((2R,4R)-4-fluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)azetidin-1-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)acetamide, rac-2-((3R,4R)-4-(((6-(2-(4-chlorophenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3RS,4RS)-4-(((5-fluoro-6-((1S*,5R*)-1-(6-(trifluoromethyl)pyridine-3-yl)-2-azabicyclo[3.1.0]hexane-2-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, rac-2-((3R,4R)-4-(((5-fluoro-6-(2-(6-(trifluoromethyl)pyridine-3-yl)-3-azabicyclo[3.1.0]hexane-3-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, rac-2-((3R,4R)-4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)azetidine-1-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((5-fluoro-6-((S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((5-fluoro-6-((R)-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((R)-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((R)-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, and 2-((R*)-4-(((6-((R)-4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide It is selected from the group consisting of the following.

[0127] In some cases, the compound, stereoisomer, or salt of a stereoisomer according to formula (I) is 2-((3R*,4R*)-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, the first isomer to elute, 2-((3R*,4R*)-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, the second isomer to elute, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, the first isomer to elute, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, the second isomer to elute, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, the first isomer to elute, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, the second isomer to elute, 2-((R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, the first isomer to elute, 2-((R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, the second isomer to elute, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, the first isomer to elute, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, the second isomer to elute, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, the first isomer to elute, and 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, second isomer It is selected from the group consisting of the following.

[0128] In one embodiment, the compound or stereoisomer according to formula (I), or a salt of the compound or stereoisomer, 2-(4-(((5-fluoro-6-((S)-3-(5-trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)propanamide, (S)-2-(4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, (S)-2-(4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)-2-methylpropanamide, (S)-2-(4-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, (S)-2-(4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, (S)-2-(4-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethoxy)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((3RS,4RS)-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, (S)-2-(4-fluoro-4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((S)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((3R*,4S*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, (R)-2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-4-hydroxypiperidine-1-yl)acetamide, 2-((R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-((3RS,4RS)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-((R*)-4-(((6-((R)-4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, 2-((3RS,4RS)-4-(((6-((R)-4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, rel-2-((3R,4R)-4-(((5-fluoro-6-((3S,5R)-3-methyl-5-(3-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, rel-2-((3R,4R)-4-(((5-fluoro-6-((3R,5S)-3-methyl-5-(3-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, rel-2-((3R,4R)-4-(((5-fluoro-6-((3S,5R)-3-methyl-5-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, rel-2-((3R,4R)-4-(((5-fluoro-6-((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, (S)-2-(4-(((5-fluoro-6-(3-(4-(trifluoromethoxy)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, (R)-2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, rac-2-(4-(((5-fluoro-6-((2R,4R)-4-fluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)azetidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, rac-2-((3R,4R)-4-(((6-(2-(4-chlorophenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3RS,4RS)-4-(((5-fluoro-6-((1S*,5R*)-1-(6-(trifluoromethyl)pyridine-3-yl)-2-azabicyclo[3.1.0]hexane-2-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, rac-2-((3R,4R)-4-(((5-fluoro-6-(2-(6-(trifluoromethyl)pyridine-3-yl)-3-azabicyclo[3.1.0]hexane-3-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, rac-2-((3R,4R)-4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)azetidine-1-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((5-fluoro-6-((S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((5-fluoro-6-((R)-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((R)-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((R)-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, and 2-((R*)-4-(((6-((R)-4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide It is selected from the group consisting of the following.

[0129] In some cases, a compound, stereoisomer, or salt is 2-(4-(((5-fluoro-6-(3-(5-trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)propanamide, 2-(4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)-2-methylpropanamide, 2-(4-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethoxy)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-fluoro-4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3,3-difluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3,3-difluoro-4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-4-hydroxypiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-methyl-5-(3-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-methyl-5-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(4-(trifluoromethoxy)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(4-fluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)azetidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(2-(4-chlorophenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(1-(6-(trifluoromethyl)pyridine-3-yl)-2-azabicyclo[3.1.0]hexane-2-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(6-(trifluoromethyl)pyridine-3-yl)-3-azabicyclo[3.1.0]hexane-3-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)azetidine-1-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-(3,3-difluoro-4-(((5-fluoro-6-(3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3,3-difluoro-4-(((5-fluoro-6-(2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, and 2-(4-(((6-(4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide It is selected from the group consisting of the following.

[0130] In one embodiment, the compound or stereoisomer, or a salt of the compound or stereoisomer, 2-((3R*,4R*)-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, and 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide It is selected from the group consisting of the following.

[0131] In one embodiment, the compound or stereoisomer, or a salt of the compound or stereoisomer, 2-(4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(3,3-difluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, and 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide It is selected from the group consisting of the following.

[0132] In various cases, compounds, stereoisomers, or salts are, [ka] [ka] It is selected from the group consisting of the following.

[0133] In some embodiments, whenever a halogen is specified as a substituent, the halogen is selected from fluoro or chloro.

[0134] The embodiments and specific disclosures used herein are intended to illustrate different options of the Disclosure, and the embodiments may be combined with other applicable embodiments.

[0135] Specific examples of the compounds are disclosed in Table 1 below.

[0136] [Table 1]

[0137] [Table 2]

[0138] [Table 3]

[0139] Table 4

[0140] Table 5

[0141] Table 6

[0142] Table 7

[0143] Table 8

[0144] Table 9

[0145] Table 10

[0146] Table 11

[0147] Table 12

[0148] Table 13

[0149] [Table 14]

[0150] [Table 15]

[0151] [Table 16]

[0152] In a related embodiment, a prodrug of the compound of formula (I) as described herein is provided.

[0153] The compounds disclosed herein are active and have, for example, RORγ Gal4 <1000 nM, for example <500 nM, for example <100 nM, etc., and have substantially lower logP (reduced logP such as 1.5, for example 2.0, for example 2.5 log units) than the compounds disclosed in (Patent Document 1) and (Patent Document 2). In certain embodiments, LogD and LogP are substantially lower than those of the compounds in (Patent Document 1) and (Patent Document 2). Accordingly, the compounds disclosed herein have improved lipophilicity at similar titers. Accordingly, the compounds disclosed herein may be improved modifiers of RORγ, having, for example, attractive interaction with the hydrophobic binding site of the ligand-binding domain (LBD) of RORγ (e.g., higher binding ability) and lower logP and / or lower logD.

[0154] Pharmaceutical composition In another aspect, the disclosure relates to a pharmaceutical composition comprising physiologically acceptable surfactants, carriers, diluents, excipients, smoothing agents, suspending agents, thin-film forming materials, and coating aids, or combinations thereof; and compounds as disclosed herein, for example, compounds of formulas (I), (II), and (III) as disclosed herein, or salts, stereoisomers, or salts of stereoisomers thereof. The compounds of formulas (I), (II), and (III) contained in the pharmaceutical composition may also be any of the compounds in the preferred embodiments described above. In another aspect, the disclosure relates to a pharmaceutical composition comprising physiologically acceptable surfactants, carriers, diluents, excipients, smoothing agents, suspending agents, thin-film forming materials, and coating aids, or combinations thereof; and any one of the compounds of formulas I, II, or III disclosed herein. Acceptable carriers or diluents, as well as other additives, to be combined with one or more compounds of formulas I, II, or III as disclosed herein for therapeutic use, are well known in the pharmaceutical field and are described, for example, in Non-Patent Literature 15, which is incorporated herein by reference as a whole. Preservatives, stabilizers, colorants, sweeteners, fragrances, flavorings, and taste enhancers may be provided in the pharmaceutical composition. For example, esters of sodium benzoate, ascorbic acid, and p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used.In various embodiments, alcohols, esters, sulfated aliphatic alcohols, etc., may be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicates, magnesium aluminate, magnesium aluminometasilicate, synthetic aluminum silicate, calcium carbonate, sodium bicarbonate, calcium hydrogen phosphate, calcium carboxymethylcellulose, etc., may be used as excipients; magnesium stearate, talc, hydrogenated oils, etc., may be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, and soy sauce may be used as suspending agents or lubricants; cellulose phthalate acetate as a derivative of carbohydrates such as cellulose or sugar, and methyl acetate-methacrylate copolymer as a derivative of polyvinyl may be used as suspending agents; and plasticizers such as phthalate esters may be used as suspending agents.

[0155] The term “pharmaceutical composition” refers to a mixture of a compound disclosed herein with other chemical components, such as a diluent or carrier. Pharmaceutical compositions facilitate the administration of a compound to a living organism. Multiple techniques for administering compounds exist in the art, including but not limited to oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, or salicylic acid. Similarly, pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic base, such as ammonia, sodium carbonate, sodium bicarbonate, or sodium hydroxide.

[0156] The term "carrier" defines a chemical substance that facilitates the uptake of a compound into a cell or tissue. For example, dimethyl sulfoxide (DMSO), though not limited to these, is a commonly used carrier to facilitate the uptake of many organic compounds into the cells or tissues of living organisms.

[0157] The term "diluent" defines a chemical substance diluted in water that dissolves a target compound and stabilizes the compound in a biologically active form. Salts dissolved in buffer solutions are used as diluents in the art. One commonly used buffer solution is phosphate-buffered saline, which mimics the salt conditions of human blood. Because buffer salts can control the pH of the solution at low concentrations, buffered diluents rarely alter the biological activity of a compound.

[0158] The term "physiologically acceptable" defines a carrier or diluent that does not inhibit the biological activity and properties of a compound.

[0159] The pharmaceutical compositions described herein may be administered to human patients either by themselves or, in the case of combination therapy, in pharmaceutical compositions mixed with other active ingredients or suitable carriers or excipients. Techniques for formulation and administration of the compounds of this application can be found in (Non-Patent Document 15).

[0160] Preferred routes of administration include, for example, oral, rectal, transmucosal, topical, or intestinal administration; intramuscular, subcutaneous, intravenous, intrathecal injection, and parenteral delivery including intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injection. The compound may also be administered in sustained-release or controlled-release dosage forms for long-term and / or periodic pulsed administration at a predetermined rate, including depot injections, osmotic pumps, pills, and transdermal (including electrotransport) patches.

[0161] Pharmaceutical compositions may be manufactured in ways known by conventional processes such as mixing, dissolving, granulation, dragée production, micronization, emulsification, encapsulation, encapsulation, or tableting.

[0162] Pharmaceutical compositions for use as described herein may be formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate the processing of the active compound into a pharmaceutically usable formulation. The appropriate dosage form depends on the chosen route of administration. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art, for example, in Non-Patent Document 15 above.

[0163] Injectable preparations can be prepared in conventional forms, such as liquid solutions or suspensions, solid forms suitable for liquid solutions or suspensions before injection, or emulsions. Suitable excipients include, for example, water, physiological saline, dextrose, mannitol, lactose, lecithin, albumin, monosodium glutamate, and cysteine ​​hydrochloride. In addition, if necessary, the injectable pharmaceutical composition may contain trace amounts of non-toxic auxiliary substances such as wetting agents and pH buffering agents. Physiologically compatible buffers include, but are not limited to, Hanks' solution, Ringer's solution, or physiological saline buffer. If necessary, absorption enhancers (e.g., liposomes) may be used.

[0164] For transmucosal administration, appropriate permeabilizing agents may be used in the formulation to allow penetration through the barrier.

[0165] For example, pharmaceutical formulations for parenteral administration by bolus injection or continuous infusion contain an aqueous solution of the active compound in a water-soluble form. Furthermore, suspensions of the active compound can be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or media include fatty oils such as sesame oil, or other organic oils such as soy, grapefruit, or almond oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, enabling the preparation of highly concentrated solutions. Injectable formulations may be provided in unit dosage forms (e.g., ampoules or multi-dose containers) with added preservatives. Compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous media, and may contain formulation agents such as suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be in powder form for compositions with a suitable medium, such as sterile pyrogen-free water, before use.

[0166] For oral administration, compounds can be readily formulated by combining the active compound with a pharmaceutically acceptable carrier well known in the art. Such carriers enable the compounds disclosed herein to be formulated as tablets, pills, coated tablets, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by patients being treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally by grinding the resulting mixture, and processing the granular mixture after adding suitable adjuvants as needed to obtain a tablet or coated tablet core. Suitable excipients include fillers such as sugars containing lactose, sucrose, mannitol, or sorbitol; for example, cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If necessary, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or salts thereof such as alginic acid or sodium alginate may be added. The sugar-coated tablet core is provided with a suitable coating. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solvent, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or sugar-coated tablet coating to characterize different combinations of identification or active compound doses. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, Carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solvent, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the tablet or sugar-coated tablet coating to characterize different combinations of identification or active compound doses.

[0167] Pharmaceutical preparations that can be administered orally include push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain the active ingredient in a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Further stabilizers may be added. All formulations for oral administration should be in a dosage suitable for such administration.

[0168] For buccal administration, the composition may take the form of a conventionally formulated tablet or sugar-coated tablet.

[0169] For administration by inhalation, the compounds for use as described herein are conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer, using a suitable nebulizer, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of pressurized aerosols, the dose unit may be determined by providing a valve for delivering a measured amount. Capsules and cartridges, for example, gelatin capsules and cartridges for use in inhalers or blowers, may be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

[0170] Furthermore, this specification discloses a variety of pharmaceutical compositions well known in the pharmaceutical field for use including intraocular, intranasal, and intraauricular delivery. Suitable penetrating agents for these uses are generally known in the art. Topical ophthalmic compositions may be formulated as aqueous solutions buffered at a pH of 5.0 to 8.0. Other components that may be desirable for use in ophthalmic preparations include preservatives (benzalkonium chloride, stabilized oxychloro complexes marketed as Purite®, or stabilized chlorine dioxide), cosolvents (such as polysorbate 20, 60, and 80, Pluronic® F-68, F-84, and P-103, cyclodextrin, or Solutol), and viscosity enhancers (polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, or hydroxypropylcellulose). The compounds disclosed herein may also be used in intraocular implants as described in Patent Document 3, which is incorporated herein by reference. Examples of pharmaceutical compositions for intraocular delivery include aqueous eye drop solutions of water-soluble active compounds, such as eye drops, or gellan gum ((Non-Patent Literature 16) or hydrogel (Non-Patent Literature 17)); eye drop ointments; eye drop suspensions such as fine particles, small polymeric particles containing drugs suspended in a liquid carrier medium (Non-Patent Literature 18), lipid-soluble formulations (Non-Patent Literature 19), and microspheres (Non-Patent Literature 20); and ophthalmic inserts. All of the above references are incorporated herein by reference as a whole. Such suitable pharmaceutical formulations for intraocular delivery are most often and preferably formulated aseptically and isotonic and buffered for stability and comfort. Pharmaceutical compositions for intranasal delivery may also include droplets and sprays, which are often prepared to simulate nasal secretions in many respects to ensure the maintenance of normal ciliary action.As disclosed in whole in Non-Patent Literature 15, which is incorporated herein by reference, and as is well known to those skilled in the art, preferred formulations are most often and preferably isotonic and slightly buffered to maintain a pH of 5.5 to 6.5, and most often and preferably include an antimicrobial preservative and a suitable drug stabilizer. Pharmaceutical formulations for intraauricular delivery include suspensions and ointments for topical application in the ear. Common solvents for such ear formulations include glycerin and water.

[0171] The compounds disclosed herein may also be formulated into rectal compositions such as suppositories or retained enemas containing conventional suppository bases, such as cocoa butter or other glycerides.

[0172] In addition to the formulations described above, the compound may also be formulated as a depot formulation. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Therefore, for example, the compound may be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin, or as a poorly soluble derivative, such as a poorly soluble salt.

[0173] For hydrophobic compounds, a suitable pharmaceutical carrier may be a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A common cosolvent system used is the VPD cosolvent system, which is a solution of 3% w / v benzyl alcohol composed of anhydrous ethanol up to a volume, 8% w / v nonpolar surfactant Polysorbate 80™, and 65% w / v polyethylene glycol 300. Naturally, the proportions of the cosolvent system may be significantly altered without destroying its solubility and toxicity characteristics. Furthermore, the uniqueness of the cosolvent components can be changed: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be changed; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl polyoridone; and other sugars or polysaccharides may substitute for dextrose.

[0174] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be used. Liposomes and emulsions are well-known examples of delivery media or carriers for hydrophobic drugs. Certain organic solvents, such as dimethyl sulfoxide, may also be used. Furthermore, compounds may be delivered using sustained-release systems, such as a semipermeable matrix of a solid hydrophobic polymer containing the therapeutic agent. Various sustained-release materials have been established and are well known to those skilled in the art. Sustained-release capsules may release compounds for several weeks, up to 100 days, depending on their chemical properties. Depending on the chemical properties and biological stability of the therapeutic reagent, further strategies for protein stabilization may be utilized.

[0175] Drugs intended for intracellular administration can be administered using techniques well known to those skilled in the art. For example, such drugs can be encapsulated in liposomes. All molecules present in the aqueous solution at the time of liposome formation are incorporated into the aqueous interior. The contents of the liposome are protected from the external microenvironment as the liposome fuses with the cell membrane and are efficiently delivered to the cytoplasm. Liposomes can be coated with tissue-specific antibodies. The liposomes will then be targeted to and selectively taken up by the desired organ. Alternatively, small hydrophobic organic molecules can be administered directly into cells.

[0176] Further therapeutic or diagnostic agents may be incorporated into the pharmaceutical composition. Alternatively, the pharmaceutical composition may be combined with other compositions containing other therapeutic or diagnostic agents.

[0177] combination The compounds disclosed herein may also be combined with other active compounds in the treatment and / or prevention of inflammatory, metabolic, tumor, and autoimmune diseases or disorders or their symptoms.

[0178] The combinations provided herein include the compounds disclosed herein and a) Corticosteroids, such as prednisone, methylprednisolone, or beta-methasone; b) Immunosuppressants, such as cyclosporine, tacrolimus methotrexate, hydroxyurea, mycophenolate mofetil, mycophenolic acid, sulfasalazine, 6-thioguanine, or azathioprine; c) Fumarate esters, e.g., dimethyl fumarate; d) Dihydroorotate dehydrogenase (DHODH) inhibitors, e.g., leflunomide; e) Retinoids, for example, acitretin or isotretinoin; f) Anti-inflammatory drugs, such as apremilast, crisabolol, celecoxib, diclofenac, aceclofenac, aspirin, or naproxen; g) JAK inhibitors, e.g., tofacitinib, baricitinib, upadacitinib, ruxolitinib, or delgocitinib; h) Antibiotics, e.g., gentamicin; i) Anticancer drugs, such as lenalidomide, pomalidomide, pembrolizumab, nivolumab, daratumumab, bortezomib, carfilzomib, ixazomib, bendamustine, or ventoclast; j) T-cell blocking agents, e.g., alefacept or efalizumab; k) Tumor necrosis factor-alpha (TNF-alpha) blockers, e.g., etanercept, adalimumab, infliximab, golimumab, certolizumab pegol; l) Interleukin-12 / 23 blockers, e.g., ustekinumab; m) IL-23 blockers, e.g., risankizumab, guselkumab, or tildrakizumab; n) Anti-IL4 / IL13 antagonists, e.g., dupilumab, lebrikizumab, or tralokinumab; o) IL-1β blockers, e.g., canakinumab; p) IL-alpha blockers, e.g., vermekimab; q) CD6 blockers, e.g., itorizumab; r) IL-36 blockers, e.g., BI-655130 or bimekizumab; s) IL-6 antagonists, e.g., tocilizumab; t) Calcinulin inhibitors, e.g., pimecrolimus, tacrolimus, or cyclosporine; u) Treatment with phototherapy agents, e.g., psoralen, methoxypsoralen, or 5-methoxypsoralen + UVA (PUVA) or UVB (with or without tar); v) Fixed combinations of corticosteroids and vitamin D derivatives; w) Fixed combinations of corticosteroids and retinoids; x) Corticosteroid tape; and y)BMS986165, PF-06700841, PF-06826647, picridenosone, tepyramid fumarate, LYC-30937, LEO-32731, BI-730357, PRCL-02, LNP-1955, GSK-2982772, CBP-307, KD-025, MP-1032, petesicatib, JTE-451, Hemay-005, SM-04755, EDP-1815, BI-730460, SFA-002 ER, JNJ-3534, SAR-441169, BOS-172767, SCD-044, ABBV-157, BAY-1834845, AUR-101, R-835, PBF-1650, RTA-1701, AZD-0284, mirikizumab, CD20 antagonist, salicylic acid, coal tar, Mical-1, DUR-928, AM-001, BMX It contains one or more additional active substances, such as drugs selected from -010, TA-102, SNA-125, prepocitinib tosylate, pegcantratinib, ESR-114, NP-000888, SM-04755, BOS-475, SB-414, LEO-134310, CBS-3595, PF-06763809, XCUR-17, or BTX-1308.

[0179] The active compounds in a combination, i.e., the compounds provided herein and other optional active compounds, may be administered together in the same pharmaceutical composition, or in different compositions intended for separate, simultaneous, combined, or sequential administration via the same or different routes.

[0180] use As described above, the compounds or pharmaceutical compositions disclosed herein may be used to modulate the activity of retinoic acid receptor-related orphan receptors (RORs), such as RORα, RORβ, and / or RORγ receptors. Modulators of RORγ are outlined in (Non-Patent Document 21) and (Non-Patent Document 22), which are incorporated herein by reference as a whole. Examples of RORγ receptors are RORγ1 and RORγt receptors. As described above, the compounds or pharmaceutical compositions may also exhibit selective modulation of a particular ROR receptor to a different ROR receptor. For example, according to some embodiments disclosed herein, some compounds or pharmaceutical compositions modulate the activity of the RORγ receptor to a greater extent than they modulate the activity of the RORα and / or RORβ receptors.

[0181] The compounds or pharmaceutical compositions disclosed herein may also be used to modulate the activity of cells that produce IL-17A in a RORγt-dependent manner, such as γδT cells, Th17 cells, Tc17 cells, and ILC3 cells. The compounds or pharmaceutical compositions disclosed herein may also be used to inhibit RORγt function upon IL-23 stimulation and subsequently negatively affect the differentiation and proliferation of Tc17 and Th17 cells, which are then pathogenic.

[0182] The papers that provide useful background information are (Non-Patent Document 23); (Non-Patent Document 24); (Non-Patent Document 25); (Non-Patent Document 26); and (Non-Patent Document 27), all of which are incorporated herein by reference as a whole.

[0183] The compounds or pharmaceutical compositions described herein and above may also be used in therapy to treat inflammatory, metabolic, neoplastic, and autoimmune diseases or disorders or their symptoms. Examples of such diseases or disorders are inflammatory, metabolic, neoplastic, and autoimmune diseases or disorders mediated or affected by IL-17A and / or RORγ. The role of RORγ in the pathogenesis of autoimmune or inflammatory diseases is disclosed in (Non-Patent Document 28); (Non-Patent Document 29); (Non-Patent Document 30); (Non-Patent Document 31); (Non-Patent Document 32); and (Non-Patent Document 33), all of which are incorporated herein by reference as a whole.

[0184] More specific examples of diseases or disorders, or their symptoms, include asthma, bruxism, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, Helicobacter pylori infection, allergic diseases such as allergic rhinitis, allergic conjunctivitis and uveitis, sprue and food allergies, atopic dermatitis, lichen planus, cystic fibrosis, lung graft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, ichthyosis, bullous diseases, and suppurative sweat glands. These include inflammation, steatohepatitis, fatty liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune eye disease, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjögren's syndrome, optic neuritis, type 1 diabetes, neuromyelitis optica, myasthenia gravis, Guillain-Barré syndrome, Graves' disease, scleritis, obesity, obesity-induced insulin resistance, type 2 diabetes, and cancer.

[0185] More preferably, diseases or disorders, or their symptoms, include acne, atopic dermatitis, lichen planus, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, ichthyosis, bullous diseases, hidradenitis suppurativa, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), and lupus erythematosus.

[0186] Examples of symptoms include physical or mental features that are considered to indicate a disease state, particularly those that are evident to the patient, such as preventing or alleviating one or more symptoms commonly experienced in connection with such disease, even if treating or preventing the symptoms is not considered to modulate the disease.

[0187] More specifically, compounds or pharmaceutical compositions having an antagonist or inverse agonist effect on RORγ may be used to reduce the levels of IL-17A and / or interleukins, and other gene products such as cytokines, thereby controlling RORγ. For example, this may be used for asthma, acne, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, Helicobacter pylori infection, allergic diseases such as allergic rhinitis, allergic conjunctivitis and uveitis, sprue and food allergies, atopic dermatitis, lichen planus, cystic fibrosis, lung graft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ichthyosis, bullous diseases, hidradenitis suppurativa, ankylosing spondylitis, psoriasis, psoriatic arthritis, steatosis, fatty liver disease, and non-alcoholic diseases. This may apply to individuals suffering from alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune diabetes, autoimmune ocular disease, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjögren's syndrome, optic neuritis, type 1 diabetes, neuromyelitis optica, myasthenia gravis, Guillain-Barré syndrome, Graves' disease, scleritis, obesity, obesity-induced insulin resistance, and type 2 diabetes.

[0188] Conversely, IL-17A levels may be increased using compounds or pharmaceutical compositions that have an agonist effect on RORγ. Increasing IL-17A levels may be particularly useful in conditions of weakened immune function or in boosting the immune system's response, such as during infection and in cancer.

[0189] The compounds described herein may be used in the manufacture of pharmaceuticals for the treatment and / or prevention of inflammatory, metabolic, tumor, and autoimmune diseases or disorders or their symptoms.

[0190] Method of administration The compound or pharmaceutical composition may be administered to the patient by any suitable means. Non-limiting examples of methods of administration include, in particular, as deemed appropriate by those skilled in the art to bring the compounds disclosed herein into contact with living tissue: (a) administration via oral routes (including administration in the form of capsules, tablets, granules, sprays, syrups, or other such forms); (b) administration via parenteral routes such as rectal, vaginal, urethral, ​​intraocular, nasal, or auricular (including administration as aqueous suspensions, oily preparations, etc., or as infusions, sprays, suppositories, ointments, etc.); (c) administration via subcutaneous, intraperitoneal, intravenous, intramuscular, intradermal, intraorbital, intra-articular, intraspinal, intrasternal injection, etc. (including delivery by infusion pump); (d) local administration such as direct injection in the renal or cardiac region, e.g., depot placement, intratumoral injection, or intra-lymph node injection; (e) local administration; and (f) administration of cells ex vivo followed by insertion of the cells into the patient.

[0191] Suitable pharmaceutical compositions for administration include compositions in which the active ingredient is contained in an amount effective to achieve its intended purpose. The therapeutically effective dose of a compound disclosed herein, as required by dosage, will depend on the route of administration, the type of animal being treated (mammal, including humans), and the physical characteristics of the particular animal under consideration. The dose may be adjusted to achieve the desired effect, but will depend on factors such as body weight, diet, concurrent drug therapy, and other factors that a person skilled in the art of medicine would recognize. More specifically, the therapeutically effective dose means the amount of compound effective in preventing, alleviating, or reversing the symptoms of the disease being treated, or in prolonging survival. Determining the therapeutically effective dose is well within the capabilities of a person skilled in the art, particularly in light of the detailed disclosure provided herein.

[0192] As will be readily apparent to those skilled in the art, the useful in vivo doses and specific modes of administration will vary depending on age, weight, and mammalian species being treated, the specific compounds used, and the specific applications for which these compounds are used. Determining the effective dose level, i.e., the dose level required to achieve the desired outcome, can be achieved by those skilled in the art using conventional pharmacological methods. Typically, human clinical applications of a product begin at a relatively low dose level and increase until the desired effect is achieved. Alternatively, useful doses and routes of administration for compositions identified by the methods described herein using established pharmacological methods can be established using acceptable in vitro studies.

[0193] In non-human animal studies, the application of promising products is initiated at relatively high dose levels, and the dose is reduced until the desired effect is no longer achieved or adverse side effects disappear. Doses may vary widely depending on the desired effect and therapeutic indicator.

[0194] Typically, the dosage may be between approximately 10 micrograms / kg and 100 mg / kg body weight, preferably between approximately 100 micrograms / kg and 10 mg / kg body weight. Alternatively, the dosage may be calculated based on the patient's surface area, as will be understood by those skilled in the art.

[0195] The exact formulation, route of administration, and dosage of the pharmaceutical compositions disclosed herein may be selected by individual physicians in consideration of the patient's condition. (See, for example, Non-Patent Literature 34, incorporated herein by reference in whole, in particular p.1 of Chapter 1). Typically, the dose range of a composition administered to a patient may be about 0.5 to 1000 mg / kg of patient body weight. The dosage may be a single dose or a series of two or more doses administered over a period of one or more days, as required by the patient. Where human doses of a compound have been established for at least some conditions, those same doses, or doses between about 0.1% and about 500%, more preferably between about 25% and about 250%, of the established human doses may be used. Where human doses have not been established, as in the case of a newly discovered pharmaceutical compound, the ED may be used as determined by toxicity and efficacy studies in animals. 50 Or ID 50 The appropriate dosage for humans can be estimated from the value, or other appropriate values ​​obtained from in vitro or in vivo studies.

[0196] It should be noted that the attending physician will know the methods and timing for discontinuing, interrupting, or adjusting administration in the event of toxicity or organ damage. Conversely, the attending physician will also know how to adjust treatment to a higher level if the clinical response is insufficient (excluding toxicity). The scale of the dose administered in the management of the target disorder will vary depending on the severity of the condition being treated and the route of administration. The severity of the condition can be partially assessed, for example, by standard prognosis assessment methods. Furthermore, the dose and possibly the frequency of administration will also vary depending on the individual patient's age, weight, and response. A program equivalent to the one described above may be used in veterinary medicine.

[0197] While the exact dosage will be determined for each drug, in most cases several generalizations regarding dosage can be made. A daily dosage plan for adult human patients may be, for example, an oral dose of 5 to 200 mg between 0.1 mg and 2000 mg of each active ingredient, preferably between 1 mg and 500 mg. Eye drops may be in the range of concentrations between 0.005 and 5 percent. In one embodiment, eye drops may be in the range of 0.01 and 1 percent, or in another embodiment, between 0.01 and 0.3 percent. In other embodiments, intravenous, subcutaneous, or intramuscular doses of each active ingredient are used, between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, for example, 1 to 40 mg. In the case of pharmaceutically acceptable salt administration, the dose may be calculated as free base. In some embodiments, the composition is administered 1 to 4 times per day. Alternatively, the compositions disclosed herein may be administered by continuous intravenous infusion, preferably at doses of up to 1000 mg of each active ingredient per day. As will be understood by those skilled in the art, in certain circumstances, particularly to effectively and aggressively treat invasive diseases or infections, it may be necessary to administer the compounds disclosed herein in amounts exceeding, or far exceeding, the range or frequency of the preferred doses described above. In some embodiments, the compounds will be administered for a period of sustained therapy, for example, one week or more, or for one month or one year.

[0198] Dosage and administration intervals may be individually adjusted to provide plasma or tissue levels of the active portion sufficient to maintain the regulatory effect, or to provide the minimum effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. The dose required to achieve the MEC will depend on the individual characteristics and administration route. However, plasma concentrations may be determined using HPLC assays or bioassays.

[0199] The administration interval may also be determined using the MEC value. The composition should be administered using a regimen that maintains plasma levels above the MEC for 10–90%, preferably 30–90%, and most preferably 50–90% of that time.

[0200] In the case of topical or ex vivo administration or selective uptake, the effective local concentration of the drug may not be related to the plasma concentration.

[0201] The amount of the composition administered may depend on the subject being treated, the subject's weight, the severity of their suffering, the mode of administration, and the prescribing physician's judgment.

[0202] The compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicity of certain compounds, or subsets of compounds, that share certain chemical parts can be established by determining their in vitro toxicity to mammals, preferably cell lines such as human cell lines. The results of such tests are often a prediction of toxicity in mammals, or more specifically, in animals such as humans. Alternatively, the toxicity of certain compounds in animal models such as mice, rats, rabbits, or monkeys can be determined using known methods. The efficacy of certain compounds can be established using several accepted methods, such as in vitro methods, animal models, or human clinical trials. Accepted in vitro models exist for almost all classes of conditions, including but not limited to cancer, cardiovascular disease, and various immune disorders. Similarly, acceptable animal models can be used to establish the efficacy of chemicals for treating such conditions. When selecting a model to determine efficacy, those skilled in the art can be guided by state-of-the-art techniques for selecting appropriate models, doses, and routes of administration, as well as control systems. Naturally, human clinical trials can also be used to determine the efficacy of compounds in humans.

[0203] The composition may be provided in a pack or dispenser device that can contain, if necessary, one or more unit dosage forms containing the active ingredient. The pack may include, for example, metal or plastic foil such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice relating to the form of container as defined by the government agency that regulates the manufacture, use, or sale of the drug, the notice reflecting agency approval of the form of the drug for human or veterinary administration. Such notice may be, for example, a label approved by the U.S. Food and Drug Administration for a prescription drug, or an insert for an approved product. Compositions containing the compounds disclosed herein, formulated in a suitable pharmaceutical carrier, may also be prepared, placed in a suitable container, and labeled for the treatment of a specified condition.

[0204] Overview As described above with respect to specific descriptive embodiments, this specification is not intended to be limited to any particular form described herein. Any combination of the embodiments described above should be understood to be within the scope of this disclosure. Rather, this disclosure is limited only by the appended claims, and other embodiments other than the specific embodiments described above are equally possible within those appended claims.

[0205] In the claims, the term “includes / includes” does not exclude the existence of other types or processes. Furthermore, individual features may be included in different claims, but they may be advantageously combined in some cases, and inclusion in different claims does not mean that the combination of features is unfeasible and / or unfavorable. In addition, singular references do not exclude plurals. Terms such as “a,” “an,” “first,” “second,” etc., do not exclude plurals. The phrases “at least one” or “one or more” refer to one or a number greater than one, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0206] Wherever a chemical name or structure is given, it has always been generated using conventional methods or preferred software methods. The names of the compounds were generated by ChemDraw Professional, version 17.1.0.105(19).

[0207] In this disclosure, in the structural diagrams, the labels "or1", "or2", "&1", or "&2" for each stereocenter specify the "stereochemical group" to which the center belongs.

[0208] In the case of an "or" group, its meaning is that it represents a structure in which one stereoisomer has either the stereochemical group (e.g., (R, S)) as depicted, or a stereoisomer in which the chiral center of the group has the opposite configuration (S, R).

[0209] In the case of the "&" group, the "&" combined with a given number (e.g., &1) indicates a mixture of marked asymmetrically substituted atoms. When the numbering brings together several asymmetrically substituted atoms, this indicates their relative configurations. If they are represented as (R,S), then the opposite configuration (S,R) also exists with respect to the designated contributing group. [Examples]

[0210] experiment The following embodiments are merely examples and should not be construed as limiting the scope of this disclosure. Rather, this disclosure is limited only by the appended claims.

[0211] General chemical procedures overview Unless otherwise specified, starting materials were obtained from private manufacturers such as AbBchem, ABCR, Alfa Aesar, Anaspec, Anichem, Apollo Scientific, ASDI-Inter, Asiba Pharmatech, Astach, ArkPharm, Bachem, Chem-Impex, ChemCollect, Chembridge, Combi-Blocks, Enamine, FCH, Fluka, Fluorochem, Frontier Scientific, HDH Pharma, InFarmatik, InterBioScreen, Life Chemicals, Manchester Organics, Matrix, MercaChem, NetChem, Oakwood Chemical, PepTech, Pharmcore, PrincetonBio, Sigma-Aldrich, TRC, Tyger Scientific, and Ukrorgsyn, and used without further purification. Solvents such as DMF, DMSO, and DCM were used directly or dried on molecular sieves.

[0212] device NMR 1 ¹H NMR spectra were recorded using CD3OD, CDCl3, or DMSO-d6 solvents on the following Bruker Avance 300 spectrometers (300 MHz), Bruker Avance III 400 spectrometer (400 MHz), Bruker Avance Neo (400 MHz), Bruker Avance III 600 (600 MHz), and Varian V NMR spectrometer (400 MHz). Chemical shifts are reported in ppm(δ) using the residual solvent as an internal standard; CDCl3: 7.26 ppm; CD3OD: 3.31 ppm; DMSO-d6: 2.50 ppm. Coupling constants (J) are given in Hz.

[0213] Analytical U / HPLC The following instruments were used for analytical U / HPLC: Waters Acquity system with Acquity BEH C18 (1.7 μm, 2.1 x 50 mm) featuring a linear gradient of a two-component solvent system using DAD at a flow rate of 0.5 mL / min and ambient temperature, combined with MS detection SQD I. Agilent Infinity I / II -TOF6230B / CLND Antek 8060 with a linear gradient acquity BEH C18 (1.7 μm, 2.1 x 50 mm) using a two-component solvent system with a flow rate of 0.75 mL / min in combination with DAD. Agilent 1200 Series-1260 Infinity with a Waters XBridge C18 (5 μm, 4.6 x 50 mm) with a linear gradient of a two-component solvent system using a flow rate of 1.5 mL / min and UV detection at 214 nm or 254 nm, combined with MS detection (Agilent). Shimadzu Nexera with a Waters XBridge C18 (5 μm, 4.6 x 50 mm) for linear gradient of a two-component solvent system using a flow rate of 1.5 mL / min and UV detection at 214 nm or 254 nm, combined with MS detection (Shimadzu). Waters Acquity system with a linear gradient of a two-component solvent system using DAD at a flow rate of 0.65 mL / min and ambient temperature, combined with an MS detection Waters detector, and featuring an Acquity BEH C18 (1.7 μm, 2.1 x 50 mm).

[0214] Preparative HPLC The following instruments were used for preparative HPLC: Waters Acquity system with a Supelco DISCOVERY C18 (5μm, 25cm x 21.2mm) using a linear gradient of a two-component solvent system with a flow rate of 45 mL / min and UV detection at 254 nm, combined with MS detection on a Waters Micromass ZQ Quadrupole MS. Shimadzu Nexera X2 with a Merck Chromolith SpeedROD RP-18E (5μm, 10x100mm) for linear gradient detection of a two-component solvent system using flow rates between 4 and 7 mL / min and UV detection at 254 nm, combined with MS detection on Shimadzu LCMS-2020. The Waters Masslynx system features a Waters XBridge C18 column (5 μm, 19 x 150 mm) with a linear gradient of a two-component solvent system using a flow rate of 15 mL / min and UV detection at 214 nm or 254 nm, combined with MS detection (Waters). The Gilson GX-281 TRILUTION features a linear gradient of a two-component solvent system with a Phenomenex Gemini NX-C18 column (5 μm, 21.2 x 150 mm) using a flow rate of 15 mL / min and UV detection at 214 nm or 254 nm, combined with MS detection (Waters).

[0215] The following straight gradients were used: HCO2H-(H2O / CH3CN / HCO2H(100 / 0 / 0.1%~0 / 100 / 0.1%)) NH4OAc-(H2O / CH3CN / NH4OAc(100 / 0 / 0.02%~0 / 100 / 0.02%)) TFA-(H2O / CH3CN / TFA(100 / 0 / 0.1%~0 / 100 / 0.1%)) NH4HCO3-(H2O / CH3CN / NH4HCO3(100 / 0 / 0.1%~0 / 100 / 0.1%)) NH4OH-(H2O / CH3CN / NH4OH(100 / 0 / 0.1%~0 / 100 / 0.1%)) HCO2NH4-(H2O / 50%MeOH+50%CH3CN / HCO2H / NH3(95 / 5 / 0.05% / 0.01%~5 / 95 / 0.05% / 0.01%))

[0216] Flash CC was most frequently performed on Isolera® automated systems. Flash CC and preparative TLC were performed using SiO2 unless otherwise specified. However, C18 columns were also used (water-acetonitrile / MeOH (1:1) gradient, with or without 0.1% v / v ammonium formate in both phases, using 0-100% acetonitrile / MeOH (1:1)).

[0217] Analytical chiral chromatography The analysis was performed on a Waters UPC2 system connected to a Waters QDa MS detector and a DAD detector equipped with a chiral column using gradient elution at a flow rate of 1 mL / min. Available chiral columns were CHIRALPAK (3 μm, 4.6 x 100 mm) IA, IB, IC, and ID, as well as Trefoil AMY1 (2.5 μm, 2.1 x 150 mm).

[0218] The following linear gradients were used for analytical UPC2: CO2 / MeOH / DEA(99 / 1 / 0.2%~60 / 40 / 0.2%)) CO2 / EtOH / DEA(99 / 1 / 0.2%~60 / 40 / 0.2%) CO2 / IPA / DEA(99 / 1 / 0.2%~60 / 40 / 0.2%)

[0219] Preparative Chiral Chromatography Prior to chiral separation, the compounds were purified using a suitable solvent by the standard method previously described.

[0220] Preparative chiral separation was performed using either a Gilson (306, GX-281 trilution, 156-UV / Vis, Waters 3100 MSD) or Waters SFC-80 with a chiral column in a specified solvent, using flow rates between 10 and 50 mL / min (simply 50 g / min for SCF) and detection at either 214 or 230 nm; available chiral columns were Reprosil AMS (5 μm, 20 mm x 250 mm), Lux C2 (5 μm, 21.2 mm x 250 mm), Lux C4 (5 μm, 21.2 mm x 250 mm), Chiralpak® columns IA, IB, IC, ID, IF, or IG (5 μm, 20 mm x 250 mm), or Chiralcel® OJ-H or OD-H. The appropriate column and elution conditions used for each compound are described in the experimental section.

[0221] Synthesis method The compounds disclosed herein may be synthesized by one of the following three general methods: General Method H, General Method I, and General Method J.

[0222] General method H [ka] The cyclic amine H1 was reacted with a suitable base (such as DIEA, TEA, or K2CO3) with 4,5,6-trifluoropyrimidine (at room temperature or slightly higher, i.e., 30°C). If H1 was substituted at both the 2 and 6 positions, more severe conditions were required (i.e., microwave reactor at 100°C for 10 hours). After the reaction was considered complete, intermediate H2 was work-treated and purified by chromatography (flash CC or preparative HPLC) or used as a crude product in the next step. Subsequently, intermediate H2, the base (such as DIEA, TEA, or Cs2CO3), and the primary amine H3 were dissolved in a solvent (such as DMSO or DMSO-water, water, or water-ethanol mixture), and the temperature was raised to 70-100°C overnight or until the reaction was considered complete. Next, intermediate H4 was obtained by work-treatment and purification, and this was subjected to deprotection. Next, the product from deprotected H5 (as a free base, TFA salt, or hydrochloride) was used in HA, HB, or HC in the general methods described below.

[0223] H3 amines were commercially available, but all other compounds were described as being synthesized.

[0224] Example H5-1: Synthesis of (S)-5-fluoro-N-(piperidine-4-ylmethyl)-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-amine, H5-1. [ka] a) DIEA, DMSO b) DIEA, DMSO c) HCl, dioxane

[0225] (S)-4-(5,6-difluoropyrimidine-4-yl)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholine, H2-1 [ka] 4,5,6-trifluoropyrimidine (2.0 g, 15 mmol) and H1-1 (4.0 g, 15 mmol) were dissolved in DMSO, and then DIEA (10.5 mL, 60 mmol) was added. The reaction mixture was stirred overnight at room temperature, then poured into water, and the mixture was extracted four times with EA. Next, the EA phase was washed twice with aq LiCl (5%) and once with brine, then dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash CC (Hept:EA) to obtain H2-1 (4.9 g, 14 mmol). LCMS: MS calculated value: 346; MS measured value: 347 ([M+1] + ).

[0226] (S)-4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-carboxylate tert-butyl, H4-1 [ka] Compounds H3-1 (2.8 g, 8.1 mmol) and H2-1 (1.8 g, 8.8 mmol) were added to a solution of DIEA (8 mL, 40 mmol) in dry DMSO (30 mL) at room temperature. The reaction mixture was then heated to 50 °C for 2 hours, the heating was stopped, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into aq LiCl (5%) and subsequently extracted three times with EA. The combined organic phase was washed twice with aq LiCl (5%) and once with brine, dried to (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash CC (EA:Hept) to obtain H4-1 (3.7 g, 6.8 mmol). LCMS:MSCalcd:540;MS measured value:541([M+1] + ).

[0227] (S)-5-fluoro-N-(piperidine-4-ylmethyl)-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-amine, H5-1 [ka] HCl (60 mL, 2 M) in dioxane was added to H4-1 (3.6 g, 6.7 mmol). This resulted in a sticky mass, which was dissolved by adding aq HCl (15 mL, 2 M). The reaction mixture was then stirred at room temperature for 2 hours and concentrated under vacuum. The residue was dissolved in saturated NaHCO3 and EA was added. Since the clear phase was not discernible, the mixture was centrifuged for 10 minutes, after which the phases could be separated. The aqueous phase was extracted three times with EA. The combined organic phases were washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum to obtain crude H5-1 (2.9 g, 6.6 mmol). LCMS: MS calculated value: 440; MS measured value: 441 ([M+1] + ).

[0228] Next, intermediate H5 was converted to the corresponding acetamide using one of three different pathways; After alkylation of the corresponding alpha-bromoester with a suitable base (such as TEA, DIEA, or K2CO3), the corresponding acid was obtained by hydrolysis, and finally, EDC·HCl coupling was performed with ammonium chloride and a suitable base. After alkylation of the alpha-bromoester with a suitable base, ammonia-based aminolysis was performed. HC 2-bromoacetamide was directly alkylated with a suitable base such as TEA, DIEA, or K2CO3.

[0229] General method HA [ka] To obtain H7, H5 was treated with either methyl 2-bromoacetate, methyl 2-bromopropanoate, or methyl 2-bromo-2-methylpropanoate, and a suitable base, i.e., TEA. The methyl ester was then hydrolyzed with LiOH in a mixture of water / THF / MeOH to obtain the acid (or its Li salt) H8. Subsequently, the final product H6 was obtained by a reaction between H8, HOAt, EDC·HCl, and NH4Cl in a suitable solvent.

[0230] Example HA: Synthesis of 2-(4-(((5-fluoro-6-((S)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)propanamide, H6-1 [ka] a) DIEA, methyl 2-bromopropanoate, DCM. b) LiOH, THF, MeOH. c) DIEA, NH4Cl, HOAt, EDC·HCl, DMF.

[0231] 2-(4-(((5-fluoro-6-((S)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)propanoate methyl, H7-1 [ka] A solution of methyl 2-bromopropanoate (80 μL, 0.72 mmol) in DCM (2 mL) was added dropwise to a stirred solution of DCM (10 mL), DIEA (0.63 mL), and H5-1 (0.26 g, 0.6 mmol), and the mixture was cooled on an ice bath. The ice bath was removed, and the reaction mixture was stirred for 72 hours. Next, an additional 20 μL, 0.18 mmol of 2-bromopropanoate was added, and the reaction mixture was stirred at 30°C for 24 hours. After concentrating the reaction mixture under vacuum, saturated NaHCO3 was added, and the resulting mixture was extracted three times with EA. The combined organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash CC (DCM:MeOH) to obtain H7-1 (220 mg, 0.42 mmol). LCMS: MS calculated value: 526; MS measured value: 527 ([M+1] + ).

[0232] 2-(4-(((5-fluoro-6-((S)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)propanoic acid, H8-1 [ka] A solution of aq LiOH (0.4 mL, 2 M) was added to a solution of H7-1 (220 mg, 0.4 mmol) in THF:MeOH (1:1, 4 mL). The reaction mixture was stirred overnight at room temperature. The mixture was then concentrated under vacuum to obtain the crude product H8-1 (271 mg), which was used without purification. LCMS: MS calculated value: 512; MS measured value: 513 ([M+1] + ).

[0233] 2-(4-(((5-fluoro-6-((S)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)propanamide, H6-1 [ka] H8-1 (271 mg) was added to solutions of DMF and DIEA (10 and 0.5 mL, respectively). Then, the following were added: NH4Cl (66 mg, 1.23 mmol), HOAt (84 mg, 0.6 mmol), and EDC·HCl (117 mg, 0.6 mmol). The reaction mixture was stirred overnight at room temperature. Next, further NH4Cl (66 mg, 1.23 mmol) and EDC·HCl (117 mg, 0.6 mmol) were added, and the reaction mixture was stirred again at room temperature for a further 24 hours. The reaction mixture was concentrated under vacuum, and a saturated aqueous solution of NaHCO3 was added to the residue. The mixture was extracted three times with EA. The combined EA phase was washed twice with aq LiCl (5%) and once with brine, dried, filtered, and concentrated under vacuum to obtain the crude product. Next, this was purified by flash carbon dioxide (DCM:MeOH) to obtain H6-1 (149 mg, 0.29 mmol). LCMS: MS calculated value: 511; MS measured value: 512 ([M+1] + ).

[0234] The following compounds were prepared according to the general method HA.

[0235] [Table 17]

[0236] General method HB: [ka] The methyl ester intermediate H7 was subjected to aminolysis in MeOH to obtain H6.

[0237] Example HB: Synthesis of (S)-2-(4-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, H6-4 [ka] a) DIEA, 2-bromoacetate. b) NH3, MeOH.

[0238] (S)-2-(4-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)methyl acetate, H7-2 [ka] A solution of methyl 2-bromoacetate (67 mg, 0.44 mmol in 1.5 mL DCM) was slowly added to an ice-cold solution of (S)-5-fluoro-N-((4-fluoropiperidine-4-yl)methyl)-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-amine H5-2 (167 mg, 0.36 mmol in 7 mL DCM containing 380 μL DIEA). After addition, the ice bath was removed, the reaction mixture was allowed to reach room temperature, and then stirred overnight at room temperature. The reaction mixture was concentrated under vacuum, saturated aqueous solution of NaHCO3 was added, and the mixture was extracted three times with EA. The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash CC (DCM:MeOH) to obtain H7-2 (180 mg, 0.34 mmol). LCMS: MS calculated value: 529; MS measured value: 530 ([M+1] + ).

[0239] (S)-2-(4-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, H6-4 [ka] H7-2 (180 mg, 0.34 mg) was dissolved in MeOH (3 mL), cooled on an ice bath, and then NH3 (g) was passed through the solution and bubbling occurred. The vial was sealed and the reaction mixture was stirred at room temperature overnight. Next, the vial was cooled on an ice bath (-10°C), the vial was opened, and the mixture was stirred while slowly heating to room temperature. The mixture was concentrated under reduced pressure to obtain H6-4 (170 mg, 0.33 mg). LCMS: MS calculated value: 514; MS measured value: 515 ([M+1] + ).

[0240] The following compounds were prepared according to the general method HB.

[0241] [Table 18]

[0242] [Table 19]

[0243] General method HC: [ka] Intermediate H5 was treated with 2-bromoacetamide and a suitable base such as DIEA, Na2CO3, or K2CO3 to obtain the final compound H6.

[0244] Example HC: Synthesis of (S)-2-(4-fluoro-4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, H6-8. [ka] 65 mg, 0.5 mmol of K2CO3 was followed by 30 mg, 0.22 mmol of 2-bromoacetamide in a solution of ((S)-4-(5,6-difluoropyrimidine-4-yl)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholine H5-3 (30 mg, 0.07 mmol) in dry THF. The reaction mixture was stirred at room temperature for 4 hours, followed by overnight at 30°C. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC to obtain H6-8 (17.4 mg, 0.034 mmol).

[0245] The following compounds were prepared according to the general method HC.

[0246] [Table 20]

[0247] [Table 21]

[0248] [Table 22]

[0249] [Table 23]

[0250] [Table 24]

[0251] [Table 25]

[0252] [Table 26]

[0253] [Table 27]

[0254] [Table 28]

[0255] General Method I [ka] The compound was also prepared by adding 2-(4-(aminomethyl)piperidine-1-yl)acetamide to intermediate H2 (synthesized as outlined in General Method H). The NAS reaction was carried out in DMSO at 80–100°C under the same conditions (using a suitable base such as DIEA or TEA). The reaction mixture was then concentrated and purified directly by chromatography.

[0256] Example I: Synthesis of (S)-2-(4-(((5-fluoro-6-(3-(4-(trifluoromethoxy)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, H6-23 [ka] a) DIEA, DMSO. A solution of (S)-4-(5,6-difluoropyrimidine-4-yl)-3-(4-(trifluoromethoxy)phenyl)morpholine H2-2 (160 mM, 1 equivalent in DMSO), 2-(4-(aminomethyl)piperidine-1-yl)acetamide I-1 (160 mM, 1 equivalent in DMSO), and DIEA (pure, 6 equivalents). The reaction mixture was shaken at 80°C overnight, followed by 100°C for 4 hours. The reaction mixture was then cooled and concentrated under vacuum. Subsequent analysis and purification of the resulting residue by HPLC yielded pure title compound H6-23 (62%). LCMS: MS calculated value: 512; MS measured value: 513 ([M+1] + ).

[0257] The following compounds were prepared according to general method I.

[0258] [Table 29]

[0259] [Table 30]

[0260] General method J [ka] The compound was also synthesized using a one-pot, two-step synthesis procedure. The secondary amine H1 and trifluoropyrimidine were added to a solution of DIEA in DMSO and stirred at room temperature for 3 hours to produce H2 in situ. Then, I was added along with additional DIEA, and the reaction was heated overnight to 80°C. The reaction mixture was cooled to room temperature and concentrated. The remaining residue was then purified by preparative HPLC to obtain H6.

[0261] Example J: Synthesis of rac-2-((3R,4R)-4-(((6-(2-(4-chlorophenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, H6-29. [ka] a) DMSO, DIEA. b)DMSO, DIEA. A solution of 4,5,6-trifluoropyrimidine (160 mM, 1 equivalent in DMSO) and DIEA (pure, 6 equivalents) was added to a solution of 2-(4-chlorophenyl)pyrrolidine and H1-15 (160 mM, 1 equivalent in DMSO). The reaction mixture was shaken at ambient temperature for 3 hours. Then, a DMSO solution of rac-2-((3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-yl)acetamide hydrochloride I-2 (160 mM, 1 equivalent) and DIEA (pure, 4 equivalents) was added, and the reaction mixture was shaken overnight at 80°C. Next, the reaction mixture was cooled and then concentrated under reduced pressure. Subsequent analysis and purification by HPLC yielded H6-29 (48%).

[0262] The following compounds were prepared according to general method J.

[0263] [Table 31]

[0264] Synthesis of intermediates The H1 components were synthesized according to the general method described in (Patent Document 2) or as outlined below.

[0265] H1 and H3 components were commercially available unless otherwise noted below.

[0266] Finally, the "I" intermediate was synthesized from the corresponding commercially available components as follows.

[0267] Synthesis of (R)-2-(4,4-difluoropyrrolidine-2-yl)-5-(trifluoromethyl)pyridine, H1-5 [ka] a) TBDMSCl, imidazole, DMF. b) Boc2O, DMAP, TEA, CH3CN. c) 2-bromo-5-(trifluoromethyl)pyridine, n-BuLi, toluene. d) NaBH4, MeOH. e) MsCl, TEA, THF. f) TBAF, THF. g) DMP, DCM. h) DAST, DCM. i) Chiralpak IG. j) TFA, DCM.

[0268] Synthesis of (R)-4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-one, iH1-5-2. [ka] Imidazole (9.09 g, 134 mmol) and TBDMSCl were added at 0°C to a mixture of (R)-4-hydroxypyrrolidine-2-one (9.0 g, 89.1 mmol) in DMF (50 mL). The reaction mixture was then stirred at 25°C for 3 hours, followed by the addition of water (200 mL). The resulting precipitate was collected by filtration and dried under vacuum to obtain compound iH1-5-2 (15.5 g, 80.7%) as a white solid. 1H-NMR(300MHz,DMSO-d6):δ 7.55(d,J=0.9Hz,1H),4.51-4.48(m,1H),3.50-3.46(m,1H),3.01-2.98(m, 1H),2.47-2.42(m,1H),1.95-1.89(m,1H),0.85(s,9H),0.11-0.05(m,6H).

[0269] Synthesis of 4-((tert-butyldimethylsilyl)oxy)-2-oxopyrrolidine-1-carboxylic acid (R)-tert-butyl, iH1-5-3 [ka] TEA (7.49 mL, 53.7 mmol), DMAP (5.47 g, 44.8 mmol), and (Boc)2O (12.5 mL, 53.7 mmol) were sequentially added at 0°C to a solution of compound iH1-5-2 (9.64 g, 44.8 mmol) in CH3CN (90 mL). The reaction mixture was stirred overnight at room temperature, and then partitioned between EA and water. The separated organic layer was washed with saturated NH4Cl and brine, dried to (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash CC (Hex:EA=3:1) to obtain compound iH1-5-3 (13.4 g, 95%) as a light brown solid. 1 H-NMR(300MHz,DMSO-d6):δ 4.44-4.41(m,1H),3.87-3.82(m,1H),3.49-3.45(m,1H),2.85-2.79(m ,1H),2.24-2.16(m,1H),1.44-1.42(m,9H),0.84(s,9H),0.07(s,6H).

[0270] Synthesis of (2-((tert-butyldimethylsilyl)oxy)-4-oxo-4-(5-(trifluoromethyl)pyridine-2-yl)butyl)carbamate(R)-tert-butyl, iH1-5-4 [ka] Under an N2 atmosphere, n-BuLi (25.4 mL, 2.5 M, 63.5 mmol) was added dropwise to a solution of 2-bromo-5-(trifluoromethyl)pyridine (10.7 g, 47.61 mmol) in dry toluene (100 mL) at -70°C. After stirring for 2 hours, iH1-5-3 (10 g, 31.7 mmol) dissolved in dry toluene (30 mL) was added dropwise, and the reaction mixture was stirred at -70°C for 2 hours. The reaction mixture was warmed to room temperature and quenched with H2O (300 mL). The mixture was extracted with EA (3 x 200 mL), washed with brine (3 x 200 mL), dried to (Na2SO4), filtered, and concentrated under vacuum to obtain crude iH1-5-4 (18 g, crude, >100%).

[0271] Synthesis of ((2R)-2-((tert-butyldimethylsilyl)oxy)-4-hydroxy-4-(5-(trifluoromethyl)pyridine-2-yl)butyl)carbamate tert-butyl, iH1-5-5 [ka] Crude iH1-5-4 (18g, 39.0 mmol) was dissolved in MeOH (100 mL) cooled to 0°C, and then NaBH4 (2.4g, 63.5 mmol) was added. After stirring at room temperature for 2 hours, the mixture was quenched with H2O (200 mL). The mixture was extracted with EA (3 x 100 mL), the combined organic phase was washed with brine (200 mL x 2), dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash CC (EA:PE = 1:10~1:3) to obtain iH1-5-5 (4.3g, 23.8%) as yellow oil. LCMS: MS calculated value: 464; MS measured value: 465 ([M+1] + ).

[0272] Synthesis of 4-((tert-butyldimethylsilyl)oxy)-2-(5-(trifluoromethyl)pyrrolidine-2-yl)pyrrolidine-1-carboxylic acid (4R)-tert-butyl, iH1-5-6 [ka] Under an N2 atmosphere, TEA (4.68 g, 46.3 mmol) and MsCl (2.64 g, 23.2 mmol) were added at 0°C to a solution of iH1-5-5 (2.15 g, 4.63 mmol) in dry THF (30 mL). The reaction mixture was stirred at 80°C for 2 days, cooled to room temperature, and quenched with H2O (200 mL). The mixture was extracted with EA (3 x 100 mL), the combined organic phase was washed with brine (2 x 200 mL), dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash CC (EA:PE = 1:10~1:3) to obtain iH1-5-6 (1.05 g, 51%) as a yellow oil. LCMS: MS calculated value: 446; MS measured value: 447 ([M+1] + ).

[0273] Synthesis of 4-hydroxy-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-carboxylic acid (4R)-tert-butyl, iH1-5-7 [ka] TBAF (7.9 g, 25.1 mmol) was added to a solution of compound iH1-5-6 (5.6 g, 12.6 mmol) in dry THF (30 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then quenched by adding H2O (200 mL), and the mixture was extracted with EA (3 x 100 mL). The combined organic layer was washed with brine (2 x 100 mL), dried, filtered, and concentrated under vacuum. The residue was purified by flash CC (EA:PE = 1:3~4:5) to obtain iH1-5-7 (2.73 g, 65.5%) as a yellow solid. LCMS: MS calculated value: 332; MS measured value: 333 ([M+1] + ).

[0274] Synthesis of 4-oxo-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-carboxylate tert-butyl, iH1-5-8 [ka] DMP (20.8 g, 49.1 mmol) was added at 0°C to a solution of compound iH1-5-7 (3.26 g, 9.82 mmol) in DCM (40 mL). The reaction mixture was stirred at room temperature for 12 hours, followed by the addition of H2O (200 mL). The mixture was extracted with EA (3 x 100 mL). The combined organic phase was washed with aqueous NaHSO3 solution and brine (2 x 100 mL), dried to (Na2SO4), and concentrated under vacuum. The residue was purified by flash CC (EA:PE = 1:10~1:3) to obtain iH1-5-8 (2.1 g, 64.8%) as a yellow oil. LCMS: MS calculated value: 330.1; MS measured value: 331.3 ([M+1] + ).

[0275] Synthesis of 4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-carboxylate tert-butyl, iH1-5-9, and chiral separation into iH1-5-9-1 and iH1-5-9-2. [ka] Under an N2 atmosphere, DAST was added at -70°C to a solution of iH1-5-8 (2.1 g, 6.36 mmol) in dry DCM (30 mL). The reaction mixture was slowly allowed to reach room temperature, followed by stirring at room temperature for 12 hours. The mixture was quenched with saturated NaHCO3 and extracted with EA (3 x 100 mL). The organic phase was washed with brine (2 x 100 mL), dried to (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash CC (EA:PE = 1:10~1:3) to obtain compound iH1-5-9 (1.5 g, 67%) as a yellow oil. LCMS: MS calculated value: 352; MS measured value: 353 ([M+1] + ).

[0276] Subsequently, iH1-5-9 was separated into enantiomers using chiral chromatography (Chiralpak IG, Hex:EtOH=90:10), iH1-5-9-1 470mg (the first isomer to dissolve) iH1-5-9-2 960mg (second isomer to be eluted) I obtained it.

[0277] Synthesis of trifluoroacetic acid (R)-2-(4,4-difluoropyrrolidine-2-yl)-5-(trifluoromethyl), H1-5 [ka] TFA (5 ml) was added to a solution of iH1-5-9-1 (470 mg, 1.33 mmol) in DCM (10 mL). After stirring at room temperature for 2 hours, the mixture was concentrated under vacuum to obtain crude H1-5 (790 mg, >100%). LCMS: MS calculated value: 252; MS measured value: 253 ([M+1] + ).

[0278] Synthesis of rac-(3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)morpholine, H1-7. [ka] a) Boc2O, DMAP, Imidazole, THF. b) n-BuLi, 1-bromo-4-(trifluoromethyl)benzene, THF. c) TFA, DCM. d) NaBH4, MeOH. e) Chiralcel OD-H.

[0279] Synthesis of 3-methyl-5-oxomorpholine-4-carboxylate tert-butyl, iH1-7-2. [ka] Under an N2 atmosphere, a round-bottom flask was packed with 6-methylpiperidine-2-one (10 g, 86.4 mmol), dry THF (50 mL), ditert-butyl dicarbonate (26.5 g, 120 mmol), and DMAP (1.1 g, 8.2 mmol), and the contents were stirred overnight. Imidazole (5.9 g, 86.9 mmol) was added, and the mixture was stirred for a further 30 minutes, after which EA (60 mL) was added. The mixture was washed with aqueous HCl (15 mL, 1%) and aqueous NaHCO3 (20 mL), the organic phase was dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash CC (EA:PE = 1:10) to obtain iH1-7-2 (8 g, 37 mmol) as oil.

[0280] Synthesis of (1-(2-oxo-2-(4-(trifluoromethyl)phenyl)ethoxy)propan-2-yl)carbamate tert-butyl, iH1-7-3 [ka] Under an N2 atmosphere, n-BuLi (25 mL, 2.5 M) was added at -78°C to a solution of 1-bromo-4-(trifluoromethyl)benzene (3.5 g, 15.6 mmol) in dry THF (50 mL). After stirring at -60°C for 30 minutes, iH1-7-2 (4.0 g, 18.7 mmol) was added. The reaction mixture was stirred at -60°C for 1 hour, quenched with saturated NH4Cl, and allowed to reach room temperature. The mixture was extracted with EA, the combined organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash CC (EA:PE = 30:70) to obtain iH1-7-3 (2.4 g, 6.4 mmol) as oil.

[0281] Synthesis of 3-methyl-5-(4-(trifluoromethyl)phenyl)-3,6-dihydro-2H-1,4-oxazine, iH1-7-4 [ka] iH1-7-3 (2.4 g, 6.4 mmol) was added to a mixture of TFA / DCM (20 mL / 10 mL) and stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to obtain crude iH1-7-4 (4 g) as a yellow oil.

[0282] Synthesis of 3-methyl-5-(4-(trifluoromethyl)phenyl)morpholine, iH1-7-5, and isolation of rac-(3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)morpholine, H1-7, and separation of H1-7-1 and H1-7-2. [ka] NaBH4 (0.47 g, 12.4 mmol) was added at 0°C to a solution of crude iH-7-4 (1 g) in MeOH (20 mL). The reaction mixture was then stirred at room temperature for 12 hours, quenched by adding water, and the resulting mixture was extracted with EA. The combined organic phases were washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum. The residue was purified by flash CC (PE:EA = 3-30% EA) to obtain iH1-7-5 (200 mg, 0.82 mmol) as oil.

[0283] Next, H1-7 was purified (Chiralcel® OD-H, Hex:IPA=98:2), H1-7-1 (80 mg, the first isomer to dissolve), H1-7-2 (80 mg, second isomer to be eluted) I obtained it.

[0284] H1-6-1 and H1-6-2 were synthesized as outlined for H1-7-1 and H1-7-2, but 1-bromo-3-(trifluoromethyl)benzene was used instead of 1-bromo-4-(trifluoromethyl)benzene.

[0285] Synthesis of 1-(6-(trifluoromethyl)pyridine-3-yl)-2-azabicyclo[3.1.0]hexane, H1-13 and isolation of the stereoisomer H1-13-2. [ka]

[0286] Synthesis of N-benzyl-N-(buta-3-en-1-yl)-6-(trifluoromethyl)nicotinamide, iH1-13-2. [ka] Under an N2 atmosphere, HATU was added after TEA to a solution of 1,N-benzylbuta-3-en-1-amine (12 g, 75 mmol) and 2,6-(trifluoromethyl)nicotinic acid (14.3 g, 75 mmol) in dry DMF. The reaction mixture was then stirred overnight at room temperature, quenched with H2O, and subsequently extracted with EA. The combined organic phase was washed with H2O and brine, and then concentrated. The resulting residue was purified by flash CC (EA:PE = 1:3) to obtain iH1-13-2 (12 g, 36 mmol).

[0287] Synthesis of 2-benzyl-1-(6-(trifluoromethyl)pyridine-3-yl)-2-azabicyclo[3.1.0]hexane, iH1-13-3 [ka] Ti(OiPr)4 was added to an ice-cold solution of iH1-13-2 (12 g, 36 mmol) in dry THF. Then, a solution of cyclopentyl magnesium chloride (100 mL, 2 M) was slowly added to maintain the reaction temperature below 10°C. Next, the reaction mixture was stirred overnight at room temperature and quenched with saturated aqueous NH4Cl solution. The mixture was filtered, and the filtrate was extracted with EA. The EA phase was washed with H2O and brine, and then concentrated. The residue was purified by flash CC (EA:PE = 1:15) to obtain iH1-13-3 (3.8 g, 12 mmol).

[0288] Synthesis of 1-(6-(trifluoromethyl)pyridine-3-yl)-2-azabicyclo[3.1.0]hexane, H1-13 and isolation of H1-13-2. [ka] At room temperature, ACE-Cl (1-chloroethyl chloroformate) was added to a solution of iH1-13-3 (3.2 g, 10 mmol) in DCE (50 mL), and the solution was heated under reflux for 19 hours. Next, the DCE was removed, MeOH (50 mL) was added, and the reaction mixture was refluxed for 3 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to obtain H1-13 (500 mg, 2.2 mmol).

[0289] After purification of iH1-13 (CHIRALPAK IC, Hex:EtOH=90:10), two stereoisomers were obtained. H1-13-1 First dissolution peak (100 mg) H1-13-2 Second peak to dissolve (100mg)

[0290] Synthesis of 2-(6-(trifluoromethyl)pyridine-3-yl)-3-azabicyclo[3.1.0]hexane, H1-14. [ka] a) iPrMgCl, 5-bromo-2-(trifluoromethyl)pyridine, NaBH3CN, THF. b) BH3·THF, THF.

[0291] Synthesis of 4-(6-(trifluoromethyl)pyridine-3-yl)-3-azabicyclo[3.1.0]hexane-2-one, iH1-14-2 [ka] Under an inert atmosphere, a solution of iPrMgCl (45 mL, 2 M) was added to a solution of 5-bromo-2-(trifluoromethyl)pyridine (19 g, 80 mmol) in dry THF (100 mL) at 0°C, and the mixture was stirred for 4 hours. The Grignard reagent in the solution was then cooled to -78°C, followed by the addition of a solution of 3-azabicyclo[3.1.0]hexane-2,4-dione (4.6 g, 40 mmol) in dry THF. The reaction mixture was allowed to reach room temperature and stirred at ambient temperature for 8 hours. Then, NaBH3CN (2.5 g, 40 mmol) was added, followed by HCl (13 mL, 0.16 mol), and the reaction mixture was stirred for a further 4 hours. The resulting mixture was extracted using DCM. The DCM phase was washed with brine, dried, filtered, and concentrated under vacuum. The residue was purified by flash carbon dioxide (EA:PE=1:1) to obtain iH1-14-2 (5g, 20.6 mmol) as a yellow solid.

[0292] Synthesis of 2-(6-(trifluoromethyl)pyridine-3-yl)-3-azabicyclo[3.1.0]hexane, H1-14. [ka] BH3 in THF was added to a solution of iH1-14-2 (1 g, 4.1 mmol) in dry THF (10 mL), and the reaction mixture was stirred overnight. The mixture was then quenched with aqueous HCl (2 M, 50 mL) and stirred for a further 1 hour. The pH was adjusted to approximately 9 with NaHCO3, and the mixture was extracted by DCM. The DCM phase was washed with brine and concentrated under vacuum. Next, the residue was purified by preparative HPLC to obtain H1-14 (100 mg, 0.43 mmol) as a white solid.

[0293] Synthesis of 2-(4-(aminomethyl)piperidine-1-yl)acetamide hydrochloride, I-1. [ka] a) DIEA, methyl 2-bromopropanate, DCM. b) HCl, dioxane.

[0294] Synthesis of ((1-(2-amino-2-oxoethyl)piperidine-4-yl)methyl)carbamate tert-butyl, II-1-2 [ka] 2-bromoacetamide (724 mg, 5.3 mmol) was added dropwise to an ice-cooled solution of (piperidine-4-ylmethyl)carbamate tert-butyl II-1-1 (1.1 g, 5 mmol) in a mixture of DCM (40 mL) and DIEA (5.2 mL). The ice bath was removed and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under vacuum, and the residue was purified by flash CC (MeOH:DCM). After concentration under reduced pressure, the crude product was mixed with a saturated aqueous solution of NaHCO3. The mixture was extracted four times with EA. The combined organic phase was washed once with a saturated aqueous solution of NaHCO3, dried to (Na2SO4), filtered, and concentrated under vacuum to obtain II-1-2 (1.0 g, 3.9 mmol). LCMS: MS calculated value: 171; MS measured value: 172 ([M+1] + ). 1 H NMR(300MHz, methanol-d4)δ 3.02-2.87(m,6H),2.13(td,J=11.5,2.4Hz,2H),1.75-1.65(m,2H),1.45(s,9H),1.41(s,1H),1.30(qd,J=12.0,3.8Hz,2H).

[0295] 2-(4-(aminomethyl)piperidine-1-yl)acetamide hydrochloride, I-1 [ka] Compound iI-1-2 (1.0 g, 3.9 mmol) was added to HCl in dioxane (4 M, 4 mL). The reaction mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure, and dried under high vacuum (<1 mmHg). This yielded crude I-1 (960 mg, 3.9 mmol), which was used without further purification. LCMS: MS calculated value: 171; MS measured value: 172 ([M+1] + ).

[0296] Synthesis of rac-2-((3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-yl)acetamide hydrochloride, I-2. [ka] a) CbzCl, NaHCO3. b) TFA, DCM. c) DMF, 2-bromoacetamide, K2CO3. d) Pd / C, H2, HCl.

[0297] Synthesis of (3R,4R)-4-((((benzyloxy)carbonyl)amino)methyl)-3-hydroxypiperidine-1-carboxylate rac-tert-butyl, II-2-2 [ka] NaHCO3 (3.4 g, 40.5 mmol) and Cbz-Cl (2.7 g, 16.2 mmol) were added to a solution of (3S,4S)-4-(aminomethyl)-3-hydroxypiperidine-1-carboxylic acid rac-tert-butyl II-2-1 (4.6 g, 13.5 mmol) in THF / H2O (10 mL / 3 mL). The reaction mixture was then stirred at 35°C for 16 hours. H2O (20 mL) was added, and the mixture was extracted with DCM (3 x 30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under vacuum to obtain II-2-2 as a colorless oil (3.8 g, 77% yield), which was used directly in the next step without further purification. LCMS: MS calculated value: 364; MS measured value: 365 ([M+1] + ).

[0298] (((3R,4R)-3-hydroxypiperidine-4-yl)methyl)carbamate rac-benzyl, iI-2-3 [ka] TFA (5 mL) was added to a solution of iI-2-2 (3.8 g, 10.7 mmol) in DCM (10 mL), and the reaction mixture was stirred at room temperature for 5 hours. The mixture was concentrated under vacuum to obtain iI-2-3 as a brown oil (3.2 g), which was used directly in the next step without further purification. LCMS: MS calculated value: 264; MS measured value: 265 ([M+1] + ).

[0299] (((3R,4R)-1-(2-amino-2-oxoethyl)-3-hydroxypiperidine-4-yl)methyl)carbamate rac-benzyl, iI-2-4 [ka] K2CO3 (4.43 g, 32.1 mmol) and 2-bromoacetamide (1.77 g, 12.8 mmol) were added to a solution of crude iI-2-3 (3.21 g, 10.7 mmol) in DMF (10 mL), and the reaction mixture was stirred at 35 °C for 16 hours. Next, H2O (120 mL) was added, and the mixture was extracted with EA (3 x 30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by HPLC to obtain trans iI-2-4 as a white solid (500 mg, 1.6 mmol). LCMS: MS calculated value: 321; MS measured value: 322 ([M+1] + ).

[0300] rac-2-((3R,4R)-4-(aminomethyl)-3-hydroxypiperidine-1-yl)acetamide hydrochloride, I-2 [ka] Pd / C (10%, 100 mg) was added to a solution of iI-2-4 (500 g, 1.56 mmol) in MeOH (30 mL), and the reaction was stirred at 35°C for 3 hours under an H2 atmosphere (50 psi). The mixture was filtered and concentrated under reduced pressure to obtain crude I-2 as a white solid (300 mg). The solid was then stirred in HCl / 1,4-dioxane (4 M) to obtain the hydrochloride as a white solid (54 mg, yield 15%). 1 H-NMR(400MHz,CD3OD):δ 3.85(s,2H),δ3.70-3.76(m,1H),δ 3.38-3.49(m,2H),δ 3.08-3.13(m,1H),δ 2.96-3.13(m,1H),δ 2.86-2.91(m,1H),δ 2.77-2.83(m,1H),δ 1.95-1.99(m,1H),δ 1.81-1.82(m,1H),δ 1.51-1.62(m,1H). MS calculated value: 187; MS measured value: 188 ([M+1] + ).

[0301] [Table 32]

[0302] [Table 33]

[0303] [Table 34]

[0304] [Table 35]

[0305] [Table 36]

[0306] [Table 37]

[0307] [Table 38]

[0308] [Table 39]

[0309] Biological evaluation The activity of the compounds was evaluated using the RORγ reporter assay (also known as the Gal4 assay). Both the Gal4 and Th17 assays (another preferred assay) are cell assays that monitor the functional activity of the compounds being assayed.

[0310] The compounds disclosed herein were also evaluated in a mouse in vivo pharmacodynamic model (anti-CD3-inducible plasma IL-17A).

[0311] In addition, the compounds disclosed herein can be evaluated in various mouse disease models, such as experimental autoimmune encephalomyelitis (EAE) models (animal models related to multiple sclerosis) and collagen-induced arthritis (CIA) models (animal models related to rheumatoid arthritis).

[0312] Th17 assay (another suitable assay) Human peripheral blood mononuclear cells (PBMCs) were isolated from the buffy coat of healthy human volunteers using the Ficoll paque PLUS kit (GE Healthcare, catalog no. 17-1440-02) as instructed by the manufacturer. Naive CD4+ T cells were isolated using the naive CD4+ T cell kit, human (Milteny Biotec, catalog no. 130-094-131). The following modifications were made to the manufacturer's protocol: 1) incubation of the biotin-antibody cocktail and anti-biotin microbeads was extended to 30 minutes, and 2) cells were washed with 40 mL of Miltenyi buffer. Differentiation of Th17 cells by test compounds (or solvent for control, 0.1% DMSO) during overall differentiation in 96-well plates (400,000 cells / well, 160 μl RPMI 1640 + 10% fetal bovine serum) coated with anti-CD3 (BD ​​Pharmingen, 5 μg / ml) containing 5 μg / ml anti-CD28 (BD Pharmingen), 10 ng / ml IL-2 (R&D Systems), 2.5 ng / ml TGFβ-1 (R&D Systems), 20 ng / ml IL-1β (R&D Systems), 20 ng / ml IL-6 (R&D Systems), 30 ng / ml IL-23 (R&D Systems), 2.5 μg / ml anti-IL-4 (R&D Systems), and 1 μg / ml anti-IFNγ (R&D Systems). The test compounds were tested in triplicates diluted 1000-fold in culture medium (final DMSO concentration 0.1%). They were incubated at 37°C, 5% CO2, and 95% humidity for 7 days, with 2-fluoro-4'-[[4-(4-pyridinylmethyl)-1-piperazinyl]methyl]-α,α-bis(trifluoromethyl)-[1,1'-biphenyl]-4-methanol (SR2211 Calbiochem, catalog number 557353) used as a positive control. For negative controls, cells were differentiated to Th0 using 5 μg / ml anti-CD28 (BD Pharmingen), 10 ng / ml IL-2 (R&D Systems), 2 μg / ml anti-IL4 (R&D Systems), and 2 μg / ml anti-IFNγ (R&D Systems).IL-17 levels in the supernatant were measured by ELISA (R&D Systems). Representative results from the Th17 assay are shown in Table 2.

[0313] [Table 40]

[0314] RORγ reporter assay (Gal4) The HEK293 cell line is transiently co-transfected with two plasmids (one containing a RORγ ligand-binding domain fused to a galactose-responsive transcription factor (Gal4), and the other containing a luciferase reporter gene and a Gal-binding site (UAS)). This configuration allows for the determination of RORγ activity in the cell line through the measurement of luminescence.

[0315] RORγ reporter cell suspensions were dispensed into plates and incubated at 37°C and 5% CO2 for 2 hours. The culture medium consisted of DMEM / F-12 medium (Gibco) supplemented with 10% thermally inactivated FBS (Sigma-Aldrich), non-essential amino acids (Sigma-Aldrich), 2 mM Glutamax (Gibco), and 100 U / mL penicillin (Sigma-Aldrich). Dose-response curves for the compounds were prepared in 100% DMSO and further diluted 100-fold in culture medium. The compound solutions were added to plates containing cells (final DMSO concentration of 0.1%) and incubated at 37°C and 5% CO2 for 24 hours. Luciferase detection reagent was added to each well, and relative luminescence units (RLU) were quantified from each assay well using a plate-reading luminometer.

[0316] After calculating the mean RLU±SD values ​​for all treatment sets, the percentage decrease in RORγ activity in response to the corresponding test compound was calculated. The following formula was used: Activity = 100 * [1 - [x test compound / mean medium]] theoretical minimum decrease (0% decrease). For all experiments, the activity values ​​were plotted against compound concentration in a single plot and adjusted to a 4-parameter logistic curve to obtain absolute IC50 values ​​with 95% confidence intervals. These calculations were performed in excel-fit software using the X-204 model curve.

[0317] The results of the RORγ reporter (Gal4) assay are shown in Table 3 below.

[0318] [Table 41]

[0319] As can be seen from Table 3 above, the fluoropyrimidine derivatives of this disclosure were found to exhibit favorable activity across RORγ reporter (Gal4) assays.

[0320] According to the embodiment, IC in the RORγ reporter assay (Gal4) 50 Compounds having a <1000 nM value are disclosed herein.

[0321] According to another preferred embodiment, IC in the RORγ reporter assay (Gal4) 50 Compounds having a <500 nM value are disclosed herein.

[0322] According to another, more preferred embodiment, IC in the RORγ reporter assay (Gal4) 50 Compounds having a <100nM value are disclosed herein.

[0323] Collagen-induced arthritis (CIA) trial Collagen-induced arthritis (CIA) is an animal model of rheumatoid arthritis used to evaluate the efficacy of test compounds. CIA was induced in male DBA / 1J mice (Jackson Laboratories) at Washington Biotechnology Inc. (Baltimore) by subcutaneous injection of 50 μl of bovine collagen / Freund's complete adjuvant emulsion at the base of the tail. After 21 days, mice were boosted by further subcutaneous injection of 50 μl of collagen / Freund's incomplete adjuvant emulsion. For treatment, the compound or solvent (2% DMSO, 10% HP-β-CD in MilliQ water) was administered orally twice daily at various doses selected from 3, 10, and 30 mg / kg, starting from the CIA induction day (prevention setting) or after disease onset (day 27, treatment setting). Treatment continued until day 41, and animals were scored three times a week. Each foot was scored, and the sum of all four scores was recorded as the Arthritis Index (AI). The maximum possible AI was 16. 0 = no visible effects of arthritis; 1 = edema and / or erythema of one toe; 2 = edema and / or erythema of two joints; 3 = edema and / or erythema of more than two joints; 4 = severe arthritis of the entire foot and toes, including limb deformity and joint ankylosis. The Arthritis Index for each treatment can be expressed as the mean score relative to each treatment group + / - SEM. Compounds H6-13-2 and H6-11-2 were tested in the model. With a 10mpk po bid, the H6-13-2 Arthritis Index (AI) reduced the effect of mouse aIL-17A antibody by 83%. With H6-11-2 administered in a 10mpk po bid, the AI ​​reduced the effect of mouse aIL-17A antibody by 61%.

[0324] In vivo IL-17A induction in mouse anti-CD3 models Male C57BL / 6JRj mice (7 weeks old) were purchased from Janvier Labs and housed at the Almirall animal facility throughout the experiment. The animals were conditioned for 5 days in a new environment of 22°C ± 2°C, 55% ± 10% relative humidity, and a 12-hour:12-hour light:dark cycle. The animals were housed in polycarbonate cages and had free access to water and unpurified stock diet (2014 Teklad Global 14% Protein Rodent Maintenance Diet, Envigo) throughout the entire experiment. Animal care was carried out in accordance with European Commission Directive 2010 / 63 / EU and the laws of Catalonia and Spain. All procedures were carried out in accordance with the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines and with approval from the Animal Experiment Ethics Committee of Almirall (Barcelona, ​​Spain).

[0325] Mice were intraperitoneally injected with 7.5 μg of anti-CD3e (clone 145-2C11 from Pharmingen BD) at 0 hours (day 0) and 48 hours (day 3). The group that did not induce induction was injected with PBS instead of anti-CD3e. At the end of the experiment (4 hours after anti-CD3e injection), the animals were anesthetized with isofluorane (Baxter), and 0.5–1 mL of blood samples were collected by intracardiac puncture in heparinized tubing. Plasma samples were stored at -80°C for subsequent analysis.

[0326] The test compound was freshly suspended in sterile 0.5% methylcellulose 0.1% tween-80 solution (10 mL / kg body weight). The compound was administered by oral forced administration according to the selected dosage and body weight; control animals received the same volume of solvent. Treatment was administered twice daily from day 0 to day 3, with the final dose given one hour before anti-CD3e injection.

[0327] The plasma levels of IL-17A were measured by ELISA (R&D Systems) according to the manufacturer's instructions. The results were calculated as the percentage decrease of plasma IL-17A with respect to the difference between the non-induced group and the anti-CD3e-induced group by the following formula: Inhibition = 100 * [1 - [(x - mean non-induced) / (mean control vehicle - mean non-induced)]]. The IL-17A inhibition for each treatment can be expressed as the mean for each treatment group ± S.E.M. Statistical analysis of the data was performed using Dunnett's multiple comparison test after one-way ANOVA when appropriate. Differences were considered significant when p ≤ 0.05.

[0328] Results:

[0329]

Table 42

[0330] In summary, the compounds disclosed herein have been found to at least modulate the activity of RORγ. The compounds disclosed herein are active and have, for example, Gal4 < 1000 nM such as 500 < nM and < 100 nM. Furthermore, in comparative property studies, they exhibit improved lipophilicity as revealed by a decrease in LogP and / or LogD compared to previously described highly potent compounds; see, for example, Tables 4a - c. In these tables, all numbers (except Gal4 activity) were calculated; the method is indicated in the column headings.

[0331] ''

Table 43

[0332]

Table 44

[0333]

Table 45

[0334] The RORγ Gal4 data used to create the comparisons in Tables 4a and 4b are based on the Gal4 data created for the listed compounds (data not available in Patent Document 2). LipE is not reported in Table 4c because, with the exception of the compounds used in Tables 4a and 4b, the Gal4 data was only available as % inhibition. In relation to Tables 4a-4c above, Tables 5 and 6 are considered relevant as they show comparisons between known compounds that are structurally similar to the compounds of this disclosure.

[0335] [Table 46]

[0336] [Table 47]

[0337] ALogP and LipE are calculated using Canvas, which is part of the Schroedinger software suite (Release 2019-1).

[0338] As mentioned herein, the compounds disclosed herein may therefore be improved modifiers of RORγ, possessing, for example, attractive interactions (e.g., high binding ability) with the hydrophobic binding site of the ligand-binding domain (LBD) of the RORγ receptor and improved physicochemical properties as described above.

[0339] Furthermore, the compounds disclosed herein have been found to be useful in vivo and consequently useful in treating inflammatory, metabolic, and autoimmune diseases or their symptoms. In embodiments of the present invention, for example, the following items are provided. (Item 1) Compounds according to formula (I) [ka] , its stereoisomer, or a pharmaceutically acceptable salt of the compound or stereoisomer (in the formula, Y1, Y2, and Y3 are independently -N- or -CR8-; m is independently selected from 0, 1, and 2; R is hydrogen, C 1~6 Alkyl and C 1~4 Selected from the group consisting of hydroxyalkyl groups; R 0a and R 0b Hydrogen and C are independent of each other. 1~4 Alkyl, C 1~4 Hydroxyalkyl, and C 1~4 Selected from the group consisting of haloalkyls; R 1a and R 1b These are independently hydrogen, hydroxyl, halogen, amino, and C 1~4 Alkyl, C 1~4 Hydroxyalkyl, and C 1~4 Selected from the group consisting of haloalkyls; R2 is hydrogen, hydroxyl, amino, cyano, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, -C(=O)NH2, -C(=O)OH, -C(=O)OC 1~4 Selected from the group consisting of alkyl and substituted or unsubstituted heteroaryls; Ring C is a 3- to 10-membered heteroalicyclyl ring system containing, in addition to the one N atom shown in the C ring of the compound of formula I, 0, 1, or 2 heteroatoms independently selected from N, O, and S; Each R3 is hydrogen, halogen, hydroxyl, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl; and C 1~4 Independently selected from the group consisting of hydroxyhaloalkyl; R5 does not exist, or it is hydrogen or C 1~4 It is alkyl; R6 is hydrogen, -CN, halogen, C 1~4 Alkyl, C1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~4 Hydroxyhaloalkyl, C 1~4 Alkoxy, C 1~4 Selected from the group consisting of haloalkoxys and substituted or unsubstituted heteroaryls; R7 is hydrogen, hydroxyl, -CN, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~4 Alkoxy, and C 1~4 Selected from the group consisting of haloalkoxys; Each R8 represents hydrogen, hydroxyl, -CN, halogen, and C. 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~4 Alkoxy, and C 1~4 Independently selected from the group consisting of haloalkoxys; and If R7 is hydrogen and each R8 present is hydrogen, then R6 is always -CN, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~4 Hydroxyhaloalkyl, C 1~4 Alkoxy, C 1~4 Selected from the group consisting of haloalkoxys and substituted or unsubstituted heteroaryls; and If substituted, the heteroaryl is C 1~4 Alkyl, C 1~4 Hydroxyalkyl, C 2~4 Alkenil, C 2~4 Alkinyl, Hydroxy, C 1~4 Alkoxy, cyano, halogen, C 1~4 Haloalkyl, C 1~4 Haloalkoxy and C 1~6 (Substituted with 1 to 3 groups independently selected from the group consisting of hydroxyhaloalkyl groups). (Item 2) A compound, stereoisomer, or salt listed in item 1, wherein R is hydrogen. (Item 3) R 0a However, it is selected from the group consisting of hydrogen, methyl, -CH2OH, -CH2CH2OH, -CH2F, and -CHF2; and R 0b However, hydrogen, C 1~4 Alkyl, C 1~4 Hydroxyalkyl, and C 1~4 A compound, stereoisomer, or salt selected from the group consisting of haloalkyls, as described in item 1 or 2. (Item 4) R 0a However, it is selected from the group consisting of hydrogen, methyl, -CH2OH, and -CH2CH2OH, and R 0b A compound, stereoisomer, or salt described in item 1 or 2, wherein the compound is hydrogen. (Item 5) R 0a However, the compounds, stereoisomers, or salts listed in item 4 are hydrogen. (Item 6) R 1a , R 1b and at least one of R2 is not hydrogen, a compound, stereoisomer, or salt as described in any one of items 1 to 5. (Item 7) R 1a However, selected from the group consisting of hydroxyl, fluoro, and -CF3; and R 1b However, a compound, stereoisomer, or salt described in any one of items 1 to 6, selected from the group consisting of hydrogen, fluoro, and methyl. (Item 8) R 1a A compound, stereoisomer, or salt described in any one of items 1 to 7, wherein the compound is hydrogen or fluoro. (Item 9) R 1a A compound, stereoisomer, or salt described in any one of items 1 to 8, which is hydroxyl. (Item 10) R 1b However, a compound, stereoisomer, or salt described in any one of items 1 to 9, which is hydrogen. (Item 11) R2 is hydrogen, halogen, hydroxyl, cyano, methyl, ethyl, -CH2OH, -CH2CH2OH, and -C(=O)OC 1~2 A compound, stereoisomer, or salt selected from the group consisting of alkyl groups, as described in any one of items 1 to 10. (Item 12) A compound, stereoisomer, or salt described in any one of items 1 to 11, wherein R2 is selected from the group consisting of hydrogen, fluoro, hydroxyl, methyl, -CH2OH, and -C(=O)OCH3. (Item 13) A compound, stereoisomer, or salt described in any one of items 1 to 12, wherein R2 is selected from the group consisting of hydrogen, fluoro, and hydroxyl. (Item 14) A compound, stereoisomer, or salt described in any one of items 1 to 13, wherein R2 is hydroxyl. (Item 15) A compound, stereoisomer, or salt described in any one of items 1 to 14, wherein ring C is a 4-membered heteroalicyclyl, a 5-membered heteroalicyclyl, or a 6-membered heteroalicyclyl. (Item 16) A compound, stereoisomer, or salt described in any one of items 1 to 15, wherein ring C is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 2-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.1.0]hexanyl. (Item 17) A compound, stereoisomer, or salt described in any one of items 1 to 16, wherein the C ring is morpholinyl or pyrrolidinyl. (Item 18) A compound, stereoisomer, or salt described in any one of items 1 through 17, wherein m is 0. (Item 19) A compound, stereoisomer, or salt described in any one of items 1 to 17, wherein each R3 is independently halogen or methyl, and m is 1 or 2. (Item 20) A compound, stereoisomer, or salt described in any one of items 1 to 19, wherein the carbon ring is morpholinyl. (Item 21) A compound, stereoisomer, or salt described in any one of items 1-20, wherein R5 is hydrogen. (Item 22) R6 is hydrogen, halogen, C 1~4 Haloalkyl, C 1~4 Haloalkoxy, C 1~4 Hydroxyalkyl, C 1~4 A compound, stereoisomer, or salt described in any one of items 1 to 21, selected from the group consisting of hydroxyhaloalkyls and substituted or unsubstituted five-membered heteroaryls. (Item 23) A compound, stereoisomer, or salt according to any one of items 1 to 22, wherein R6 is selected from the group consisting of hydrogen, halogen, -CF3, -CHF2, -CCH3F2, -OCF3, -OCHF2, -C(CF3)2OH, and five-membered heteroaryls, and five-membered heteroaryls substituted with one or two methyl groups. (Item 24) A compound, stereoisomer, or salt described in any one of items 1 to 23, wherein R6 is -CF3. (Item 25) A compound, stereoisomer, or salt described in any one of items 1 to 24, wherein R7 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, -CF3, -OCHF2, -CHF2, and -OCF3. (Item 26) A compound, stereoisomer, or salt described in any one of items 1 to 25, wherein R7 is selected from the group consisting of hydrogen, fluoro, -CF3, and hydroxyl. (Item 27) A compound, stereoisomer, or salt described in any one of items 1 through 26, wherein R7 is hydrogen. (Item 28) Y1, Y2, and Y3 are independently -CH-, or Y1 is -N- and Y2 and Y3 are independently -CH-; or Y2 is -N- and Y1 and Y3 are independently -CH-; or Y3 is -N- and Y1 and Y2 are independently -CH-; or A compound, stereoisomer, or salt described in any one of items 1 to 27, wherein Y3 is -CH- and Y1 and Y2 are each -N-. (Item 29) A compound, stereoisomer, or salt described in any one of items 1 to 27, wherein Y1 is -CH-, Y2 and Y3 are independently -CR8-, and each R8 is independently selected from the group consisting of hydrogen, methyl, fluoro, hydroxyl, and -CF3. (Item 30) The compounds, stereoisomers, or salts listed in item 29, in which each R8 is hydrogen. (Item 31) Y2 is -N- and Y1 and Y3 are independently -CH-; or A compound, stereoisomer, or salt described in any one of items 1 to 28, wherein Y3 is -N- and Y1 and Y2 are independently -CH-. (Item 32) R6 is hydrogen, at least one of Y2 or Y3 is -CR8-, and R8 is -CN, hydroxyl, halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, C 1~4 Hydroxyalkyl, C 1~4 Alkoxy, and C 1~4 A compound, stereoisomer, or salt selected from the group consisting of haloalkoxys, as described in any one of items 1 to 23. (Item 33) The following formula [ka] (In the formula, R 1a is fluoro or hydroxyl; R 1b is hydrogen or fluorine; R2 is either hydrogen or hydroxyl; R6 is -CF3; and Y2 and Y3 are each independently selected from one compound (selected from the group consisting of -N-, -CH-, and -CF-), which are the compounds, stereoisomers, or salts described in item 1. (Item 34) The compounds, stereoisomers, or salts described in item 33, wherein Y2 and Y3 are each -CH-, or Y2 is -CH- and Y3 is -CF-. (Item 35) R 1a is hydroxyl and R 1b A compound, stereoisomer, or salt described in item 33 or 34, wherein the compound is hydrogen. (Item 36) R 1a is fluoro and R 1b A compound, stereoisomer, or salt described in item 33 or 34, wherein the compound is hydrogen or fluoro. (Item 37) R is hydrogen; R 0a and R 0b These are independently hydrogen or methyl; R 1a However, it is selected from the group consisting of hydrogen, fluoro, and hydroxyl; R 1b However, it is hydrogen or fluorine; R2 is selected from the group consisting of hydrogen, fluoro, and hydroxyl; Ring C is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, 2-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.1.0]hexanyl; m is selected from the group consisting of 0, 1, and 2; R3 is selected from the group consisting of hydrogen, fluoro, and methyl; R5 is either nonexistent or hydrogen; R6 is selected from the group consisting of hydrogen, -CF3, -OCF3, and -Cl; R7 is either hydrogen or fluorine; Y1, Y2, and Y3 are each -CH-; or Y1 is -CH-, Y2 is -CH-, and Y3 is -C(OH)-; or Y1 is -CH-, Y2 is -CH-, and Y3 is -N-; or Y1 is -CH-, Y2 is -C(CF3)-, and Y3 is -CH-; or The compound, stereoisomer, or salt described in item 1, wherein Y1 is -CH-, Y2 is -N-, and Y3 is -CH-. (Item 38) 2-(4-(((5-fluoro-6-((S)-3-(5-trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)propanamide, (S)-2-(4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, (S)-2-(4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)-2-methylpropanamide, (S)-2-(4-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, (S)-2-(4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, (S)-2-(4-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethoxy)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((3RS,4RS)-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, (S)-2-(4-fluoro-4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((S)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((3R*,4S*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, (R)-2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-4-hydroxypiperidine-1-yl)acetamide, 2-((R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-((3RS,4RS)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-((R*)-4-(((6-((R)-4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, 2-((3RS,4RS)-4-(((6-((R)-4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, rel-2-((3R,4R)-4-(((5-fluoro-6-((3S,5R)-3-methyl-5-(3-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, rel-2-((3R,4R)-4-(((5-fluoro-6-((3R,5S)-3-methyl-5-(3-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, rel-2-((3R,4R)-4-(((5-fluoro-6-((3S,5R)-3-methyl-5-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, rel-2-((3R,4R)-4-(((5-fluoro-6-((3R,5S)-3-methyl-5-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, (S)-2-(4-(((5-fluoro-6-(3-(4-(trifluoromethoxy)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, (R)-2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, rac-2-(4-(((5-fluoro-6-((2R,4R)-4-fluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)azetidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, rac-2-((3R,4R)-4-(((6-(2-(4-chlorophenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3RS,4RS)-4-(((5-fluoro-6-((1S*,5R*)-1-(6-(trifluoromethyl)pyridine-3-yl)-2-azabicyclo[3.1.0]hexane-2-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, rac-2-((3R,4R)-4-(((5-fluoro-6-(2-(6-(trifluoromethyl)pyridine-3-yl)-3-azabicyclo[3.1.0]hexane-3-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, rac-2-((3R,4R)-4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)azetidine-1-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((5-fluoro-6-((S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((5-fluoro-6-((R)-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((R)-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((S)-3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((R)-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, and 2-((R*)-4-(((6-((R)-4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide A compound, stereoisomer, or salt described in item 1, selected from the group consisting of the following. (Item 39) 2-(4-(((5-fluoro-6-(3-(5-trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)propanamide, 2-(4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)-2-methylpropanamide, 2-(4-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethoxy)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-fluoro-4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3,3-difluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3,3-difluoro-4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-4-hydroxypiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-methyl-5-(3-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-methyl-5-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(4-(trifluoromethoxy)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(4-fluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)azetidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(2-(4-chlorophenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(1-(6-(trifluoromethyl)pyridine-3-yl)-2-azabicyclo[3.1.0]hexane-2-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(6-(trifluoromethyl)pyridine-3-yl)-3-azabicyclo[3.1.0]hexane-3-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)azetidine-1-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-(3,3-difluoro-4-(((5-fluoro-6-(3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3,3-difluoro-4-(((5-fluoro-6-(2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, and 2-(4-(((6-(4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide A compound, stereoisomer, or salt described in item 1, selected from the group consisting of the following. (Item 40) 2-((3R*,4R*)-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-((R*)-3,3-difluoro-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((3R*,4R*)-3-fluoro-4-(((5-fluoro-6-((S)-3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-((R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, and 2-((3R*,4R*)-4-(((6-((R)-4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide A compound, stereoisomer, or salt described in item 1, selected from the group consisting of the following. (Item 41) 2-(4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(3,3-difluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, and 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide A compound, stereoisomer, or salt described in item 1, selected from the group consisting of the following. (Item 42) [ka] A compound, stereoisomer, or salt described in item 1 having the structure of [the compound]. (Item 43) [ka] A compound, stereoisomer, or salt described in item 1 having the structure of [the compound]. (Item 44) [ka] A compound, stereoisomer, or salt described in item 1 having the structure of [the compound]. (Item 45) [ka] A compound, stereoisomer, or salt described in item 1 having the structure of [the compound]. (Item 46) [ka] A compound, stereoisomer, or salt described in item 1 having the structure of [the compound]. (Item 47) [ka] A compound, stereoisomer, or salt described in item 1 having the structure of [the compound]. (Item 48) A pharmaceutical composition comprising a compound, stereoisomer, or salt described in any one of items 1 to 47 and at least one pharmaceutically acceptable excipient. (Item 49) A compound, stereoisomer, or salt described in any one of items 1 to 47, or a pharmaceutical composition described in item 48, for use as a pharmaceutical. (Item 50) A compound, stereoisomer, or salt described in any one of items 1 to 47, or a pharmaceutical composition described in item 48, for use in the treatment and / or prevention of inflammatory, metabolic, tumor, or autoimmune diseases. (Item 51) A method for treating and / or preventing an inflammatory, metabolic, tumor, or autoimmune disease in a subject suffering from such a disease, comprising administering to the subject a therapeutically effective amount of a compound, stereoisomer, or pharmaceutical composition described in any one of items 1 to 47 or item 48. (Item 52) The aforementioned diseases include asthma, bruxism, chronic obstructive pulmonary disease (COPD), bronchitis, atherosclerosis, Helicobacter pylori infection, allergic diseases such as allergic rhinitis, allergic conjunctivitis and uveitis, sprue and food allergies, atopic dermatitis, lichen planus, cystic fibrosis, lung graft rejection, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, ichthyosis, bullous diseases, hidradenitis suppurativa, steatosis, steatohepatitis, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic Compounds, stereoisomers, or salts or compositions for use as described in item 50 or as described in item 51, selected from the group consisting of non-alcoholic steatohepatitis (NASH), lupus erythematosus, Hashimoto's disease, pancreatitis, autoimmune diabetes mellitus, autoimmune ocular disease, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjögren's syndrome, optic neuritis, type 1 diabetes mellitus, neuromyelitis optica, myasthenia gravis, Guillain-Barré syndrome, Graves' disease, scleritis, obesity, obesity-induced insulin resistance, type 2 diabetes mellitus, and cancer. (Item 53) Compounds, stereoisomers, salts, or compositions for use as described in item 50 or as described in item 51, wherein the disease is selected from the group consisting of acne, atopic dermatitis, lichen planus, multiple sclerosis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, ichthyosis, bullous diseases, hidradenitis suppurativa, ulcerative colitis, colitis, Crohn's disease, inflammatory bowel disease (IBD), and lupus erythematosus. (Item 54) (i) at least one compound, stereoisomer, or salt described in any one of items 1 to 47, and (ii) a) Corticosteroids, such as prednisone, methylprednisolone, or beta-methasone; b) Immunosuppressants, such as cyclosporine, tacrolimus methotrexate, hydroxyurea, mycophenolate mofetil, mycophenolic acid, sulfasalazine, 6-thioguanine, or azathioprine; c) Fumarate esters, e.g., dimethyl fumarate; d) Dihydroorotate dehydrogenase (DHODH) inhibitors, e.g., leflunomide; e) Retinoids, for example, acitretin or isotretinoin; f) Anti-inflammatory drugs, such as apremilast, crisabolol, celecoxib, diclofenac, aceclofenac, aspirin, or naproxen; g) JAK inhibitors, e.g., tofacitinib, baricitinib, upadacitinib, ruxolitinib, or delgocitinib; h) Antibiotics, e.g., gentamicin; i) Anticancer drugs, such as lenalidomide, pomalidomide, pembrolizumab, nivolumab, daratumumab, bortezomib, carfilzomib, ixazomib, bendamustine, or ventoclast; j) T-cell blocking agents, e.g., alefacept or efalizumab; k) Tumor necrosis factor-alpha (TNF-alpha) blockers, e.g., etanercept, adalimumab, infliximab, golimumab, certolizumab pegol; l) Interleukin-12 / 23 blockers, e.g., ustekinumab; m) IL-23 blockers, e.g., risankizumab, guselkumab, or tildrakizumab; n) Anti-IL4 / IL13 antagonists, e.g., dupilumab, lebrikizumab, or tralokinumab; o) IL-1β blockers, e.g., canakinumab; p) IL-alpha blockers, e.g., vermekimab; q) CD6 blockers, e.g., itorizumab; r) IL-36 blockers, e.g., BI-655130 or bimekizumab; s) IL-6 antagonists, e.g., tocilizumab; t) Calcinulin inhibitors, e.g., pimecrolimus, tacrolimus, or cyclosporine; u) Phototherapy, e.g., treatment with psoralen, methoxypsoralen, or 5-methoxypsoralen + UVA (PUVA) or UVB (with or without tar); v) Fixed combinations of corticosteroids and vitamin D derivatives; w) Fixed combinations of corticosteroids and retinoids; x) Corticosteroid tape; and y)BMS986165, PF-06700841, PF-06826647, picridenosone, tepyramid fumarate, LYC-30937, LEO-32731, BI-730357, PRCL-02, LNP-1955, GSK-2982772, CBP-307, KD-025, MP-1032, petesicatib, JTE-451, Hemay-005, SM-04755, EDP-1815, BI-730460, SFA-002 ER, JNJ-3534, SAR-441169, BOS-172767, SCD-044, ABBV-157, BAY-1834845, AUR-101, R-835, PBF-1650, RTA-1701, AZD-0284, mirikizumab, CD20 antagonist, salicylic acid, coal tar, Mical-1, DUR-928, AM-001, BMX-010, TA A combination product comprising one or more additional active ingredients selected from the group consisting of drugs selected from -102, SNA-125, prepocitinib tosylate, pegcantratinib, ESR-114, NP-000888, SM-04755, BOS-475, SB-414, LEO-134310, CBS-3595, PF-06763809, XCUR-17, or BTX-1308.

Claims

1. Compounds according to formula (I) 【Chemistry 1】 , its stereoisomer, or a pharmaceutically acceptable salt of the compound or stereoisomer (wherein Y １ , Y ２ and Y ３ These are independently -N- or -CR ８ - and; m is independently selected from 0, 1, and 2; R is hydrogen, C １～６ Alkyl and C １～４ Selected from the group consisting of hydroxyalkyl groups; R ０ａ and R ０ｂ are independently selected from the group consisting of hydrogen, C １～４ alkyl, C １～４ hydroxyalkyl, and C １～４ haloalkyl; R １ａ and R １ｂ These are independently hydrogen, hydroxyl, halogen, amino, and C. １～４ Alkyl, C １～４ Hydroxyalkyl, and C １～４ Selected from the group consisting of haloalkyls; R ２ C is hydrogen, hydroxyl, amino, cyano, halogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Hydroxyalkyl, -C(=O)NH ２ , -C(=O)OH, -C(=O)OC １～４ Selected from the group consisting of alkyl and substituted or unsubstituted heteroaryls; Ring C is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, 2-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.1.0]hexanyl; Each R ３ is hydrogen, halogen, hydroxyl, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Hydroxyalkyl; and C １～４ Independently selected from the group consisting of hydroxyhaloalkyl; R ５ It does not exist, or hydrogen or C １～４ It is alkyl; R ６ is hydrogen, -CN, halogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Hydroxyalkyl, C １～４ Hydroxyhaloalkyl, C １～４ Alkoxy, C １～４ Selected from the group consisting of haloalkoxys and substituted or unsubstituted heteroaryls; R ７ is hydrogen, hydroxyl, -CN, halogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Hydroxyalkyl, C １～４ Alkoxy, and C １～４ Selected from the group consisting of haloalkoxys; Each R ８ is hydrogen, hydroxyl, -CN, halogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Hydroxyalkyl, C １～４ Alkoxy, and C １～４ Independently selected from the group consisting of haloalkoxys; and R ７ is hydrogen, and each R present ８ Whenever R is hydrogen, ６ -CN, halogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Hydroxyalkyl, C １～４ Hydroxyhaloalkyl, C １～４ Alkoxy, C １～４ Selected from the group consisting of haloalkoxys and substituted or unsubstituted heteroaryls; and If substituted, the heteroaryl is C １～４ Alkyl, C １～４ Hydroxyalkyl, C ２～４ Alkenil, C ２～４ Alkinyl, hydroxy, C １～４ Alkoxy, cyano, halogen, C １～４ Haloalkyl, C １～４ Haloalkoxy and C １～６ (Substituted with 1 to 3 groups independently selected from the group consisting of hydroxyhaloalkyl groups).

2. The compound, stereoisomer, or salt according to claim 1, wherein R is hydrogen.

3. R ０ａ However, hydrogen, methyl, -CH ２ OH, -CH ２ CH ２ OH, -CH ２ F, and -CHF ２ Selected from the group consisting of; and R ０ｂ However, hydrogen, C １～４ Alkyl, C １～４ Hydroxyalkyl, and C １～４ A compound, stereoisomer, or salt according to claim 1 or 2, selected from the group consisting of haloalkyl groups.

4. R １ａ , R １ｂ and R ２ A compound, stereoisomer, or salt according to any one of claims 1 to 3, wherein at least one of the elements is not hydrogen.

5. R １ａ However, hydroxyl, fluoro, and -CF ３ Selected from the group consisting of; and R １ｂ The compound, stereoisomer, or salt according to any one of claims 1 to 4, selected from the group consisting of hydrogen, fluoro, and methyl.

6. R １ｂ The compound, stereoisomer, or salt according to any one of claims 1 to 5, wherein the compound is hydrogen.

7. R ２ However, hydrogen, halogen, hydroxyl, cyano, methyl, ethyl, -CH ２ OH, -CH ２ CH ２ OH and -C(=O)O-C １～２ A compound, stereoisomer, or salt according to any one of claims 1 to 6, selected from the group consisting of alkyl groups.

8. A compound, stereoisomer, or salt according to any one of claims 1 to 7, wherein m is 0.

9. Each R ３ A compound, stereoisomer, or salt according to any one of claims 1 to 7, wherein is independently a halogen or a methyl, and m is 1 or 2.

10. R ５ The compound, stereoisomer, or salt according to any one of claims 1 to 9, wherein the compound is hydrogen.

11. R ６ is selected from the group consisting of hydrogen, halogen, C １～４ haloalkyl, C １～４ haloalkoxy, C １～４ hydroxyalkyl, C １～４ hydroxyhaloalkyl, and substituted or unsubstituted 5-membered heteroaryl, the compound, stereoisomer, or salt according to any one of claims 1 to 10.

12. R ７ is hydrogen, halogen, hydroxyl, cyano, -CF ３ , -OCHF ２ , -CHF ２ and -OCF ３ and is selected from the group consisting of, a compound, stereoisomer, or salt according to any one of claims 1 to 11.

13. Y １ , Y ２ and Y ３ They are independently -CH-, or Y １ is -N- and Y ２ and Y ３ They are independently -CH-, or Y ２ is -N- and Y １ and Y ３ They are independently -CH-, or Y ３ is -N- and Y １ and Y ２ They are independently -CH-, or Y ３ is -CH- and Y １ and Y ２ A compound, stereoisomer, or salt according to any one of claims 1 to 12, wherein each of the elements is -N-.

14. Y １ is -CH-, Y ２ and Y ３ These are independent, and each is -CR ８ - and each R ８ These independently produce hydrogen, methyl, fluoro, hydroxyl, and -CF ３ A compound, stereoisomer, or salt according to any one of claims 1 to 12, selected from the group consisting of the above.

15. Each R ８ The compound, stereoisomer, or salt according to claim 14, wherein the compound is hydrogen.

16. R ６ is hydrogen, Y ２ or Y ３ At least one of them is -CR ８ - and R ８ However, -CN, hydroxyl, halogen, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Hydroxyalkyl, C １～４ Alkoxy, and C １～４ A compound, stereoisomer, or salt according to any one of claims 1 to 11, selected from the group consisting of haloalkoxys.

17. R is hydrogen; R ０ａ and R ０ｂ These are independently hydrogen or methyl; R １ａ However, it is selected from the group consisting of hydrogen, fluoro and hydroxyl; R １ｂ However, it is hydrogen or fluoro; R ２ However, it is selected from the group consisting of hydrogen, fluoro and hydroxyl; Ring C is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl, 2-azabicyclo[3.1.0]hexanyl, and 3-azabicyclo[3.1.0]hexanyl; m is selected from the group consisting of 0, 1, and 2; R ３ However, selected from the group consisting of hydrogen, fluoro and methyl; R ５ However, it either does not exist or is hydrogen; R ６ However, hydrogen, -CF ３ , -OCF ３ Selected from the group consisting of and -Cl; R ７ However, it is hydrogen or fluoro; and Y １ , Y ２ and Y ３ However, the following (1) to (5): (1) Y １ , Y ２ and Y ３ Each of these is -CH-; (2) Y １ is -CH-, Y ２ is -CH- and Y ３ is -C(OH)-; (3) Y １ is -CH-, Y ２ is -CH- and Y ３ is -N-; (4) Y １ is -CH-, Y ２ ga-C(CF ３ ) - and Y ３ is -CH-; and (5) Y １ is -CH-, Y ２ is -N- and Y ３ is -CH- The compound, stereoisomer, or salt according to claim 1, which is any one of the following.

18. 2-(4-(((5-fluoro-6-(3-(5-trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)propanamide, 2-(4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)-2-methylpropanamide, 2-(4-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethoxy)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-fluoro-4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3,3-difluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(3-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3,3-difluoro-4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(3-(5-(trifluoromethyl)pyridine-2-yl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-4-hydroxypiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(5-(trifluoromethyl)pyridine-2-yl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-methyl-5-(3-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-methyl-5-(4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(4-(trifluoromethoxy)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(2-hydroxy-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(4-fluoro-2-(4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)azetidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(2-(4-chlorophenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(1-(6-(trifluoromethyl)pyridine-3-yl)-2-azabicyclo[3.1.0]hexane-2-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(6-(trifluoromethyl)pyridine-3-yl)-3-azabicyclo[3.1.0]hexane-3-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(4-(trifluoromethyl)phenyl)azetidine-1-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((5-fluoro-6-(2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3-fluoro-4-(((5-fluoro-6-(3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-hydroxypiperidine-1-yl)acetamide, 2-(4-(((6-(4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3-fluoropiperidine-1-yl)acetamide, 2-(3,3-difluoro-4-(((5-fluoro-6-(3-(2-fluoro-4-(trifluoromethyl)phenyl)morpholino)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, 2-(3,3-difluoro-4-(((5-fluoro-6-(2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)methyl)piperidine-1-yl)acetamide, and 2-(4-(((6-(4,4-difluoro-2-(2-fluoro-4-(trifluoromethyl)phenyl)pyrrolidine-1-yl)-5-fluoropyrimidine-4-yl)amino)methyl)-3,3-difluoropiperidine-1-yl)acetamide A compound, stereoisomer, or salt according to claim 1, selected from the group consisting of the following. 【Request Item 19】 【Chemistry 3-1】 【Chemistry 3-2】 A compound, stereoisomer, or salt according to claim 1 having the structure of the compound, stereoisomer, or salt described in claim 1.

20. A pharmaceutical composition for use in the treatment and / or prevention of inflammatory, metabolic, tumor, or autoimmune diseases, comprising a compound, stereoisomer, or salt according to any one of claims 1 to 19.

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