IL-17A low molecular weight modulator, method for manufacturing the same, and method for using the same

Abstract

This application describes IL-17A modulator compounds useful for treating IL-17A-mediated inflammatory syndromes, disorders, or diseases.

Description

[Technical Field]

[0001] (Related applications) This application claims priority to China Patent Application No. 202310573188.8, entitled “Novel IL-17A Low Molecular Weight Modulator,” filed with the China National Intellectual Property Administration on 18 May 2023, and China Patent Application No. 202311013032.0, entitled “Novel IL-17A Low Molecular Weight Modulator,” filed with August 11, 2023, as well as to U.S. Provisional Applications No. 63 / 504,649, entitled “IL-17A Low Molecular Weight Modulator, Method of Manufacturing the Same and Method of Use,” filed with the United States Patent and Trademark Office on 26 May 2023, and U.S. Provisional Applications No. 63 / 520,980, entitled “IL-17A Low Molecular Weight Modulator, Method of Manufacturing the Same and Method of Use,” filed with August 22, 2023, the entirety of these applications is incorporated herein by reference.

[0002] This specification discloses novel compounds that modulate interleukin-17A and pharmaceutically active compounds thereof. It also discloses therapeutic uses of such compounds, for example, in the treatment and / or improvement of inflammatory syndromes, disorders, or diseases mediated by IL-17A. [Background technology]

[0003] The interleukin-17 (IL-17) cytokine family (including IL-17A to IL-17F) promotes the maintenance of both adaptive and innate immunity. Released cytokines act via membrane-bound IL-17 receptors (IL-17RA to IL-17RE) to activate the IL-17 signaling pathway. Abnormal expression of IL-17 may be involved in inflammatory and autoimmune diseases such as psoriasis, psoriatic arthritis, rheumatoid arthritis, and multiple sclerosis.

[0004] IL-17A is the most studied member of the IL-17 family. It has been established as a pro-inflammatory cytokine that plays an important role in immune and autoimmune-related diseases, including psoriasis, asthma, psoriatic arthritis, and rheumatoid arthritis. IL-17A is the main cytokine that forms homodimers or heterodimers with IL-17A or IL-17F and is mainly secreted from Th17 cells. It transmits signals through the membrane-bound receptors IL-17RA and IL-17RC, regulates the IL-17A signaling pathway, and induces multiple inflammatory and immune responses. Therefore, IL-17A has emerged as a major concern in the treatment of inflammation-related diseases.

Summary of the Invention

[0005] It was considered that excessive inflammation in autoimmune diseases could be suppressed by inhibiting the IL-17A / IL-17RA protein-protein interaction (PPI). There are multiple ways to inhibit IL-17A signaling that targets the IL-17A protein or receptor. Clinically, multiple monoclonal antibodies (mAbs) have already been approved for various immune diseases. Although there is currently no example of an orally administrable small molecule IL-17A inhibitor that has advanced to the late clinical trial stage, it holds the potential to expand treatment options for many patients who cannot use biological agents, making it a promising area for drug discovery. Therefore, the development of new small molecule IL-17A modulators (e.g., inhibitors) is required. One aspect of the present application relates to a compound of formula I, a pharmaceutically acceptable salt of the compound, a deuterium-substituted form of the compound, and an isomer of the compound. JPEG2026519467000002.jpg45104Ring C is aryl, 5-6 member heteroaryl, C x , x , x , x , 3-10 , x , 3-10 cycloalkyl, C 3-10 heterocyclyl, R x -C 3-10 cycloalkyl, R x -C 3-10 heterocyclyl, R x -aryl, and R x -5-6 member heteroaryl. R xis halogen or -C 1-6 It is alkyl. Ring C has any one or more R 1 It may be replaced with . Each R 1 These are independently OH, CN, and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -CO-C 1-6 Alkyl, -CO-C 1-6 Haloalkyl, -CO-NR 3a R 3b , C 3-10 Cycloalkyl, C 3-10 Heterocyclyl, C 6-10 They are independently selected from the group consisting of aryls and 5-10 membered heteroaryls. Each R 1 These are halogens, oxo, -OH, -CN, and -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -C 1-6 Haloalkyl, -C 3-10 Cycloalkyl, heterocyclyl, -C 6-10 Aryl, 5-10 member heteroaryl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl and -SC 1-6 Each molecule may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl groups. n is either 0 or 1. R 2 is -C 0-1 Alkyl-C 3-9 Cycloalkyl, -C 1-6 Alkyl and -C 1-2 Alkyl-OC 1-3 Selected from the group consisting of alkyl groups, -C 0-1 Alkyl-C 3-9 Cycloalkyl, -C 1-6 Alkyl or -C 1-2 Alkyl-OC1-3 Alkyl is C 3-6 The molecule may be optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halogen, CH3, CHF2, CF3, OH, and oxo. X 1 It is NH, O, or S. X 2 is N, O, or S. 2 It can arbitrarily bond to an atom in ring A, forming another ring adjacent to ring A. X 3 is O or -CR c R d That is. R c and R d Each of these is independently H, halogen, and -C 1-6 Selected from the group consisting of alkyl groups. Ring A is selected from the following group. JPEG2026519467000003.jpg38113Z 1 , Z 2 and Z 3 These are independent of each other: -N=, -N(=O)=, and -C(R a Selected from the group consisting of )=, R a H, F, Cl, Br, I, -C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, OH, CN, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 3-10 The group is selected from heterocyclyls, aryls, and 5-10 membered heteroaryls. Ring B condensed to ring A is selected from the group consisting of 4-7 member heterocycloalkyl, 4-7 member heterocycloaryl, 4-7 member cycloalkyl, and 4-7 member cycloalkenyl, and each of these 4-7 member heterocycloalkyl, 4-7 member heterocycloaryl, 4-7 member cycloalkyl, and 4-7 member cycloalkenyl is optionally a saturated or unsaturated bridging ring. Ring B may optionally be substituted with one or more Rs. b Each R b is independently selected from the group consisting of CN, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-6 alkyl, -O-C 1-6 haloalkyl, -CO-C 1-6 alkyl, COOC 1-6 alkyl, -CO-C 1-6 haloalkyl, -CO-NR 3a R 3b 、-CH2-NR 3a R 3b 、-NR 3a -CO-C 1-6 alkyl, -NR 3a -COOC 1-6 alkyl, -NR 3a -CO-C 1-6 haloalkyl, -NR 3a -CO-NR 3a R 3b 、C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, heterocyclyl, C 6-10 aryl, 5-10 member heteroaryl, -C 1-6 alkyl-C 3-10 cycloalkyl, -C 1-6 alkyl-heterocyclyl, -C 1-6 alkyl-C 6-10 aryl, -C 1-6 alkyl-5-10 member heteroaryl, F, -CH3, -CHF2, -CF3, and OH, and two R b groups may optionally be joined to form C 3-10 cycloalkyl, or heterocyclyl, or C 6-10 aryl, or 5-10 member heteroaryl. Each R b may optionally be halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, -O-C 1-6 alkyl, -O-C 1-6 haloalkyl, -CO-C 1-6 alkyl, COOC1-6 Alkyl, -CO-C 1-6 Haloalkyl, -CO-NR 3a R 3b -CH2-NR 3a R 3b , C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 The molecule may be substituted with one or more substituents independently selected from the group consisting of aryls and 5-10 membered heteroaryls. Ring B is R 3 Replaced with R 3 -CONR 3a R 3b -S(O)-NR 3a R 3b -S(O)2-NR 3a R 3b , -C 0-6 Alkyl-CONR 3a R 3b , -C 0-6 Alkyl-NR 3a R 3b , -N(R 3a )-COR 3a , -N(R 3a )-CONR 3a R 3b , -C 0-6 Alkyl-SONR 3a R 3b , -C 0-6 Alkyl-SO2NR 3a R 3b -C(S)-NR 3a R 3b CN, 5-10 member heteroaryl, -COR 3a , -P(O)(OR 3a )(OR 3b ), -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 1-6 Alkyl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -OC 1-6Selected from the group consisting of alkyl, aryl, heterocyclyl, alkylheterocyclyl, alkylaryl, and alkylcycloalkyl, -5-10 member heteroaryl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 1-6 Alkyl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -OC 1-6 Alkyl, aryl, heterocyclyl, alkylheterocyclyl, alkylaryl, or alkylcycloalkyl may optionally contain halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl and -OC 1-6 They may be substituted with one or more substituents independently selected from the group consisting of haloalkyls. R 3a and R 3b These are C 1-6 Alkyl, C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, C 0-2 Alkyl-C 3-6 A group independently selected from cycloalkyls and 5-6 membered heterocyclines, or R 3a and R 3b It can be arbitrarily combined into C 3-10 Cycloalkyl, heterocyclyl, C 6-10 It can form aryl or 5-10 member heteroaryl compounds. 1-6 Alkyl, C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, C 0-2 Alkyl-C 3-6 Cycloalkyl, 5-6 membered heterocyclyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, or 5-10 membered heteroaryl, is a halogen, C 1-6 Alkyl alkyl groups, and C 1-6It may be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl groups.

[0006] In another embodiment, the present invention relates to the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, a deuterium-substituted derivative thereof, or an isomer thereof in the manufacture of a pharmaceutical product for treating and / or improving an inflammatory syndrome, disorder, or disease mediated by IL-17A. [Modes for carrying out the invention]

[0007] (Detailed explanation) I. 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. A dash at the beginning or end of a chemical group is a convenient symbol indicating a bond to the parent group, and chemical groups can be written with or without one or more dashes without losing their usual meaning. A prefix such as "Cu-v" or "Cu-Cv" indicates that the following group has u to v carbon atoms, where u and v are integers. For example, "C 1-6 "Alkyl" or "C1-C6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0008] "Alkyl" refers to a monovalent or divalent straight-chain or branched saturated hydrocarbon group. For example, an alkyl group consists of 1 to 10 carbon atoms (i.e., C 1-10 Alkyl), 1 to 8 carbon atoms (i.e., C 1-8 Alkyl), 1 to 6 carbon atoms (i.e., C 1-6 Alkyl) or 1 to 4 carbon atoms (i.e., C 1-4It may have alkyl groups. Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl(t-Bu, t-butyl, -C(CH3)3), 1-pentyl(n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl(-CH(CH3)CH2CH2CH3), 3-pentyl(-CH(CH2CH3)2), 2-methyl-2-butyl(-C(CH3)2CH2CH3), 3-methyl-2-butyl(-CH(CH3)CH(CH3)2), 3-methyl-1-butyl(-CH2CH2CH(CH3)2), 2-methyl -1-butyl(-CH2CH(CH3)CH2CH3), 1-hexyl(-CH2CH2CH2CH2CH2CH3), 2-hexyl(-CH(CH3)CH2CH2CH2CH3), 3-hexyl(-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl(-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl(-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl(-CH(CH3)CH Examples include, but are not limited to, 2CH(CH3)2), 3-methyl-3-pentyl(-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl(-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl(-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl(-CH(CH3)C(CH3)3), and octyl(-(CH2)7CH3). The alkyl group may be unsubstituted or substituted.

[0009] "Alkoxy" refers to an -O-alkyl group, where alkyl is defined above. For example, C 1-4 An alkoxy refers to an -O-alkyl group having one to four carbon atoms. The alkoxy group may be unsubstituted or substituted.

[0010] An "alkoxyalkyl" is an alkoxy group bonded to an alkyl group as defined above. For example, C 2-6 Alkoxyalkyl groups include -CH2-OMe, -CH2-O-iPr, -CH2-CH2-OMe, -CH2-CH2-O-CH2-CH3, and -CH2-CH2-O-tBu. Alkoxyalkyl groups may be unsubstituted or substituted.

[0011] An "alkenyl" is a monovalent or divalent linear or branched hydrocarbon radical having at least one carbon-carbon double bond. For example, an alkenyl group has 2 to 8 carbon atoms (i.e., C 2-8 Alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkenyls), or 2-4 carbon atoms (i.e., C 2-4 The alkenyl group may be present. Examples of alkenyl groups include, but are not limited to, ethenyl (-CH=CH2), allyl (-CH2CH=CH2), and -CH2CH=CH-CH3. The alkenyl group may be unsubstituted or substituted.

[0012] "Alkynyl" refers to a monovalent or divalent linear or branched hydrocarbon group having at least one carbon-carbon triple bond. For example, an alkynyl group has 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl), 2-6 carbon atoms (i.e., C 2-6 Alkynyl, or 2-4 carbon atoms (i.e., C 2-4 It may have an alkynyl group. Examples of alkynyl groups include, but are not limited to, acetylenyl (-C≡CH), propargyl (-CH2C≡CH), and -CH2-C≡C-CH3. The alkynyl group may be unsubstituted or substituted.

[0013] "Halogens" refer to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0014] A "haloalkyl" is an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted with the same or different halogens, and the alkyl group is divalent. The alkyl group and halogen may be any of those described above. In some embodiments, a haloalkyl group defines the number of carbon atoms in the alkyl group. For example, C 1-4 Haloalkyl groups include CF3, CH2F, CHF2, CH2CF3, CH2CH2CF3, CCl2CH2CH2CH3, and C(CH3)2(CF2H). Haloalkyl groups may be unsubstituted or substituted.

[0015] A "haloalkoxy" is an alkoxy as defined herein, wherein one or more hydrogen atoms of the alkyl group in the alkoxy are independently substituted by the same or different halogen atoms, and the alkyl group is divalent. The alkoxy group and halogen may be any of those described above. In some embodiments, the haloalkoxy defines the number of carbon atoms in the alkyl group. For example, C 1-4 Haloalkoxy groups include OCF3, OCH2F, OCH2CF3, OCH2CH2CF3, OCl2CH2CH2CH3, and OC(CH3)2(CF2H). Haloalkoxy groups may be unsubstituted or substituted.

[0016] A "cycloalkyl" is a monovalent or divalent monocyclic whole-carbocyclic system, or a multi-condensed whole-carbocyclic system, where each ring is a non-aromatic saturated or unsaturated ring. For example, in some embodiments, cycloalkyls have 3 to 12 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, or 3 to 4 carbon atoms. Exemplary monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. Cycloalkyls also include multi-condensed ring systems (e.g., ring systems containing two rings) having about 7 to 12 carbon atoms. The rings in a multi-condensed ring system may be linked to each other via condensation bonds, spiro bonds, or bridging bonds, where valence requirements permit. Exemplary polycyclic cycloalkyl groups include octahydropentalene, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.2.2]octo-2-ene, and spiro[2.5]octane. Cycloalkyl groups may be unsubstituted or substituted.

[0017] "Alkylcycloalkyl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted with the same or different cycloalkyl groups. The alkyl groups and cycloalkyl groups may be any of those described above. In some embodiments, the number of carbon atoms in the alkyl and cycloalkyl groups is, for example, C 1-6 Alkyl-C 3-12 They can be specified separately, such as cycloalkyl. Alkylcycloalkyl groups may be unsubstituted or substituted.

[0018] As used herein, “aryl” refers to a single monovalent or divalent all-carbon aromatic ring, or a poly-condensed all-carbon ring system in which the rings are aromatic. For example, in some embodiments, the aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. The phenyl group is an example of an aryl. The aryl also includes poly-condensed ring systems (e.g., ring systems containing 2, 3, or 4 rings) having approximately 9 to 20 carbon atoms in which the rings are aromatic. The rings constituting a poly-condensed ring system may be linked to one another via condensation bonds, where valence constraints allow. Furthermore, when referring to a ring-membered aryl having a specific range of atomic numbers (e.g., a 6 to 10-membered ring aryl), it is understood that the range of atomic numbers refers to the total number of atoms in the aryl ring. For example, a 6-membered ring aryl includes phenyl, and a 10-membered ring aryl includes naphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. The aryl group may be unsubstituted or substituted.

[0019] "Alkylaryl" as defined herein refers to an alkyl group in which one or more hydrogen atoms of the alkyl group are independently substituted with the same or different aryl groups. The alkyl group and aryl group may be any of the above, and the alkyl group is divalent. In some embodiments, the alkylaryl group has 7 to 24 carbon atoms, 7 to 16 carbon atoms, 7 to 13 carbon atoms, or 7 to 11 carbon atoms. The alkylaryl group defined by the number of carbon atoms refers to the total number of carbon atoms of the constituent alkyl group and aryl group combined. For example, C7 alkylaryl refers to benzyl, C 11 Alkylaryls include 1-methylnaphthyl and n-pentylphenyl. In some embodiments, the number of carbon atoms in the alkyl and aryl portions can be specified separately. For example, C 1-6 Alkyl-C 6-10Examples include aryl groups. Non-limiting examples of alkylaryl groups include, but are not limited to, benzyl, 2,2-dimethylphenyl, n-pentylphenyl, 1-methylnaphthyl, and 2-ethylnaphthyl. Alkylaryl groups may be unsubstituted or substituted.

[0020] In this specification, “heterocyclyl,” “heterocyclic,” or “heterocycloalkyl” refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic system having at least one heteroatom (i.e., at least one cyclic heteroatom selected from oxygen, nitrogen, and sulfur) in the ring. Unless otherwise specified, a heterocyclyl group has 3 to about 20 cyclic atoms, for example, 3 to 12 cyclic atoms, for example, 4 to 12 cyclic atoms, 4 to 10 cyclic atoms, or 3 to 8 cyclic atoms, or 3 to 6 cyclic atoms, or 3 to 5 cyclic atoms, or 4 to 6 cyclic atoms, or 4 to 5 cyclic atoms. Preferably, a heterocyclyl group has 3 to about 20 cyclic atoms. Therefore, this term includes a single saturated or partially unsaturated ring (e.g., a 3, 4, 5, 6, or 7-membered ring) having approximately 1 to 6 cyclic carbon atoms and approximately 1 to 4 cyclic heteroatoms (selected from the group consisting of oxygen, nitrogen, and sulfur present in the ring). Rings in a system of multiple fused rings (e.g., bicyclic heterocyclils) may be linked to one another via condensation bonds, spirobonds, or bridging bonds, where valence requirements permit. Heterocyclils include azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, thietan, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-1-azaspiro[3.3]heptan-6-yl These include tan-1-yl, 2-thia-6-azaspiro[3.3]heptan-6-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2-azabicyclo[3.1.0]hexane-2-yl, 3-azabicyclo[3.1.0]hexanyl, 2-azabicyclo[2.1.1]hexanyl, 2-azabicyclo[2.2.1]heptan-2-yl, 4-azaspiro[2.4]heptanyl, 5-azaspiro[2.4]heptanyl, etc. The heterocyclyl group may be unsubstituted or substituted.

[0021] "Alkyl heterocyclyl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently substituted with the same or different heterocyclyl groups. The alkyl group and heterocyclyl group may be any of those described above, and the alkyl group is divalent. In some embodiments, the number of atoms in the alkyl moiety and the heterocyclyl moiety may be specified separately. For example, C 1-6 It is an alkyl-3-12 member heterocycline (with 1 to 4 heteroatoms, each independently N, O, or S). The alkyl heterocycline group may be unsubstituted or substituted.

[0022] A "5-10 membered heteroaryl" refers to a single aromatic ring having at least one non-carbon atom in the ring, selected from the group consisting of oxygen, nitrogen, and sulfur. A "5-10 membered heteroaryl" also includes a multi-condensed ring system having at least one such aromatic ring, which will be described later. Therefore, a "5-10 membered heteroaryl" includes a single aromatic ring having approximately 1 to 9 carbon atoms and approximately 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may exist in oxidized forms, as long as the ring is aromatic. Exemplary 5-10 membered heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. A "5-10 membered heteroaryl" also includes a multiple condensed ring system (e.g., a ring system containing 2, 3, or 4 rings), where the 5-10 membered heteroaryl group defined above condenses with one or more rings selected from 5-10 membered heteroaryls (e.g., to form 1,8-naphthilidinyl) and aryls (e.g., to form benzimidazolyl or indazolyl) to form a multiple condensed ring system. Therefore, a 5-10 membered heteroaryl (single aromatic ring or multiple condensed ring system) can have about 1 to 20 carbon atoms and about 1 to 6 heteroatoms within the 5-10 membered heteroaryl ring. For example, tetrazolyl has 1 carbon atom and 4 nitrogen heteroatoms within the ring. Each ring in a multiple condensed ring system can be linked to one another via condensation bonds, as long as valence constraints allow. It should be understood that the individual rings in a multiple condensed ring system can be linked to each other in any order. It should be understood that bonding sites in 5-10 membered heteroaryl or 5-10 membered heteroaryl multiple condensed ring systems can be located on any suitable atom of the 5-10 membered heteroaryl or 5-10 membered heteroaryl multiple condensed ring system, including carbon atoms and heteroatoms (e.g., nitrogen). Furthermore, when referring to a membered ring with a specific range of atomic numbers (e.g., a 5-10 membered heteroaryl), it should be understood that this range refers to the total number of ring atoms in the 5-10 membered heteroaryl, including carbon atoms and heteroatoms.Furthermore, it should be understood that the rings in a multiple fused ring system may include aryl rings fused to heterocycles (e.g., 3, 4, 5, 6, or 7-membered rings) that have saturated or partially unsaturated bonds. Heterocycles have approximately 1 to 9 cyclic carbon atoms and approximately 1 to 4 cyclic heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. For example, thiazolyls are included in 5-10 membered heteroaryls, and quinolinyls are included in 5-10 membered heteroaryls. Exemplary 5-10 membered heteroaryl groups include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridadinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, and tetrazolyl. The 5-10 membered heteroaryl group may be unsubstituted or substituted.

[0023] "Alkyl heteroaryl" means an alkyl group as defined herein in which one or more hydrogen atoms of the alkyl group are independently substituted with the same or different heteroaryl groups, and the alkyl group is divalent. The alkyl group and heteroaryl group may be any of those described above. In some embodiments, the number of atoms in the alkyl group and the heteroaryl group are specified separately. For example, C 1-6 Examples include alkyl-5-10 membered heteroaryl groups (having 1 to 4 heteroatoms, each independently N, O, or S). The alkyl heteroaryl group may be unsubstituted or substituted.

[0024] In this specification, "oxo" refers to =O.

[0025] In this specification, “substitution” means that one or more hydrogen atoms in a group are independently substituted by one or more substituents (e.g., one, two, three, or four or more) as shown.

[0026] "The compounds of this application" include the compounds disclosed herein, for example, compounds of this application include compounds of formula I, including the compounds of the examples. In some embodiments, "the compounds of this application" includes compounds of formula I.

[0027] "Pharmacologically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, humectants, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers approved by the U.S. Food and Drug Administration as permissible for use in humans or livestock.

[0028] As used herein, “therapeutic effective dose” or “effective dose” means an amount effective in eliciting a desired biological or medical response, and includes an amount of the compound sufficient to affect the treatment of a disease when administered to a subject for the treatment of that disease. The effective dose varies depending on the compound, the disease, its severity, and the age and weight of the subject being treated. The effective dose may include a variety of amounts. As understood in the art, the effective dose may be one or more doses. That is, a single dose or multiple doses may be required to achieve the desired therapeutic endpoint. The effective dose may be considered in the context of administering one or more therapeutic agents, and a single dose of an agent may be considered an effective dose if, when used in combination with one or more other agents, a desirable or beneficial result can be obtained or is obtained. The appropriate dose of a compound administered concomitantly may be reduced as necessary due to the combined effects of the compounds (e.g., additional or synergistic effects).

[0029] In this specification, “simultaneous administration” means administering a unit dose of the compound disclosed herein before or after the administration of a unit dose of one or more additional therapeutic agents, for example, administering the compound disclosed herein within a few seconds, minutes, or hours after the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of the compound of this application is administered first, and then within a few seconds or minutes, a unit dose of one or more additional therapeutic agents is administered. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, and then within a few seconds or minutes, a unit dose of the compound of this application is administered. In some embodiments, a unit dose of the compound of this application is administered first, and then several hours later (e.g., 1 to 12 hours), a unit dose of one or more additional therapeutic agents is administered. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, and then after a certain period of time (e.g., 1 to 12 hours), a unit dose of the compound of this application is administered. The concomitant administration of the compounds disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of the compounds disclosed herein with one or more additional therapeutic agents, resulting in a therapeutically effective amount of each agent being present in the subject's body.

[0030] pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided.

[0031] "Pharmacologically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms, and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

[0032] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, as free bases. A pharmaceutically acceptable salt is a non-toxic salt of the free base form of a compound having the desired pharmacological activity of the free base. These salts can be derived from inorganic or organic acids or bases. For example, a compound containing basic nitrogen can be prepared as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monophosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptaneates, propioates, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, butin-1,4-dioate, and hexin-1 Examples include ,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besilates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, and mandelates. A list of other suitable pharmacologically acceptable salts is published in "Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pennsylvania, 2006."

[0033] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include suitable bases, e.g., alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, N(C1-C4 alkyl)4 +This also includes salts derived from other sources. Additionally, it includes base addition salts such as sodium salts and potassium salts.

[0034] The compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, are also provided. In these compounds, 1 to n hydrogen atoms bonded to a carbon atom are deuterium atoms ( 2 Deuterium may be substituted with deuterium (also called H or D), where n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium is a non-radioactive isotope of hydrogen. Such compounds may increase resistance to metabolism and, therefore, may be useful in extending the half-life of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, when administered to mammals. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds are synthesized by means known in the art, for example, by using starting materials in which one or more hydrogen atoms are substituted with deuterium. The compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, are also provided, in which 1 to n hydrogen atoms bonded to carbon atoms may be independently substituted with 1 to n corresponding isotopes. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, respectively. 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I is one example.11 C, 18 F, 15 O, and 13 Substitution with positron-emitting isotopes such as 1N may be useful in positron emission topography (PET) studies to investigate substrate acceptor occupancy. The isotope-labeled compound of formula I can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the following examples, using a suitable isotope-labeling reagent instead of a previously used unlabeled reagent.

[0035] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more chiral centers, and thus may give rise to enantiomers, tautomers, diastereomers, and other stereoisomers, as well as deuterated analogs thereof, which can be defined, from an absolute stereochemical standpoint, as (R)- or (S)-, or (D)- or (L)- for amino acids. The chemical formulas shown herein are intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of racemics (or racemics of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). Where a compound described herein has an olefinic double bond or other geometrically asymmetric center, unless otherwise specified, the compound shall include both E and Z geometric isomers. Similarly, all tautomers shall also be included. Where a compound is represented in a chiral form, it is understood that the embodiments include, but are not limited to, concentrated forms of a particular diastereomer or enantiomer. Where chirality is not specified but is present, it is understood that the embodiments relate to either a concentrated form of a particular diastereomer or enantiomer, or a racemic mixture of such a compound. In this specification, “scalemic mixture” refers to a mixture of stereoisomers in a ratio other than 1:1.

[0036] In this specification, “stereoisomer” refers to a compound composed of the same atoms bonded together by the same bonds, but with different three-dimensional structures and therefore incompatible. This application encompasses various stereoisomers and mixtures thereof, and also includes “enantiomers,” which refer to two stereoisomers having molecules that are mirror images of each other and cannot be superimposed.

[0037] In this specification, “tautomerism” refers to the transfer of a proton from one atom in a molecule to another atom in the same molecule. In some embodiments, this application includes tautomers of the said compounds.

[0038] In this specification, “solvate” refers to the result of the interaction between a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0039] As used herein, “hydrate” refers to a compound of this disclosure that is chemically bonded with one or more water molecules.

[0040] "Prevention" or "prevention" means any treatment that suppresses the manifestation of the clinical symptoms of a disease or condition. In some embodiments, the compound may be administered to subjects (including humans) who are at risk of having the disease or condition, or who have a family history of the disease or condition.

[0041] In this specification, “prodrug” refers to a derivative of a drug that, upon administration to the human body, is converted to the parent drug by some chemical or enzymatic pathway. In some embodiments, the prodrug is a biologically inactive derivative of the drug that, upon administration to the human body, is converted to the biologically active parent drug by some chemical or enzymatic pathway.

[0042] As used herein, “treatment,” “to treat,” or “to treat” refers to an approach to obtain a beneficial or desired outcome. For the purposes of this application, beneficial or desired outcomes include, but are not limited to, the alleviation of symptoms associated with a disease or condition and / or a reduction in the severity of symptoms and / or prevention of symptom exacerbation. In one embodiment, “treatment” or “to treat” includes one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by a disease or condition and / or reducing the severity of a disease or condition); b) delaying or preventing the onset of one or more symptoms associated with a disease or condition (e.g., stabilizing a disease or condition, slowing the exacerbation or progression of a disease or condition); and c) alleviating a disease or condition, e.g., regression of clinical symptoms, improvement of the condition, delaying the progression of a disease, improving quality of life, and / or extending survival. As used herein, “individual at risk” refers to an individual at risk of developing the condition to be treated. An “individual at risk” may have a detectable disease or condition, and may or may not exhibit a detectable disease prior to treatment by the methods described herein. "At risk" means that an individual has one or more so-called risk factors, which are measurable parameters known in the art that correlate with the occurrence of a disease or condition. Individuals with one or more of these risk factors are more likely to develop a disease or condition than individuals without these risk factors.

[0043] II. Compounds One aspect of this application relates to a compound of formula I, pharmaceutically acceptable salts thereof, deuterium-substituted compounds, and isomers. JPEG2026519467000004.jpg43101 Ring C is aryl, 5-6 member heteroaryl, C 3-10 Cycloalkyl, C 3-10 Heterocycline, R x -C 3-10 Cycloalkyl, R x -C 3-10 Heterocycline, R x -aryl, and Rx -5-6 member heteroaryl, R x is halogen or -C 1-6 It is alkyl. Ring C has any one or more R 1 It may be replaced with . Each R 1 OH, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -CO-C 1-6 Alkyl, -CO-C 1-6 Haloalkyl, -CO-NR 3a R 3b , C 3-10 Cycloalkyl, C 3-10 Heterocyclyl, C 6-10 They are independently selected from the group consisting of aryls and 5-10 membered heteroaryls. Each R 1 These are halogens, oxo, -OH, -CN, and -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -C 1-6 Haloalkyl, -C 3-10 Cycloalkyl, heterocyclyl, -C 6-10 Aryl, 5-10 member heteroaryl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl and -SC 1-6 Each molecule may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl groups. n is either 0 or 1. R 2 is -C 0-1 Alkyl-C 3-9 Cycloalkyl, -C 1-6 Alkyl and -C 1-2 Alkyl-OC 1-3 Selected from the group consisting of alkyl groups. -C 0-1 Alkyl-C 3-9 Cycloalkyl, -C 1-6Alkyl, or -C 1-2 Alkyl-OC 1-3 Alkyl is C 3-6 The molecule may be optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halogen, CH3, CHF2, CF3, OH, and oxo. X 1 It is NH, O, or S. X 2 is N, O, or S, and X 2 It can arbitrarily bond to an atom in ring A, forming another ring adjacent to ring A. X 3 is O or -CR c R d R c and R d Each of these is independently H, halogen, and -C 1-6 Selected from the group consisting of alkyl groups. Ring A is, Selected from the group consisting of JPEG2026519467000005.jpg37103. Z 1 , Z 2 and Z 3 These are independent of each other: -N=, -N(=O)=, and -C(R a Selected from the group consisting of )=, R a H, F, Cl, Br, I, -C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, OH, CN, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 3-10 The group is selected from heterocyclyls, aryls, and 5-10 membered heteroaryls. Ring B condensed to ring A is selected from the group consisting of 4-7 member heterocycloalkyl, 4-7 member heterocycloaryl, 4-7 member cycloalkyl, and 4-7 member cycloalkenyl, and each of these 4-7 member heterocycloalkyl, 4-7 member heterocycloaryl, 4-7 member cycloalkyl, and 4-7 member cycloalkenyl is optionally a saturated or unsaturated bridging ring. Ring B contains one or more R b It may be arbitrarily substituted. Each R b , CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -CO-C 1-6 Alkyl, COOC 1-6 Alkyl, -CO-C 1-6 Haloalkyl, -CO-NR 3a R 3b -CH2-NR 3a R 3b , -NR 3a -CO-C 1-6 Alkyl, -NR 3a -COOC 1-6 Alkyl, -NR 3a -CO-C 1-6 Haloalkyl, -NR 3a -CO-NR 3a R 3b , C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-heterocyclyl, -C 1-6 Alkyl-C 6-10 Ariel, -C 1-6 Two R groups are independently selected from the group consisting of alkyl-5-10 member heteroaryl, F, -CH3, -CHF2, -CF3, and OH. b The bases can be arbitrarily bonded to C 3-10 Cycloalkyl, or heterocyclyl, or C 6-10It can form aryls or 5-10 member heteroaryls. Each R b These can be halogen, CN, or C. 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -CO-C 1-6 Alkyl, COOC 1-6 Alkyl, -CO-C 1-6 Haloalkyl, -CO-NR 3a R 3b -CH2-NR 3a R 3b , C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 The molecule may be substituted with one or more substituents independently selected from the group consisting of aryls and 5-10 membered heteroaryls. Ring B is R 3 Replaced with R 3 -CONR 3a R 3b -S(O)-NR 3a R 3b -S(O)2-NR 3a R 3b , -C 0-6 Alkyl-CONR 3a R 3b , -C 0-6 Alkyl-NR 3a R 3b , -N(R 3a )-COR 3a , -N(R 3a )-CONR 3a R 3b , -C 0-6 Alkyl-SONR 3a R 3b , -C 0-6 Alkyl-SO2NR 3a R 3b -C(S)-NR 3a R 3b CN, 5-10 member heteroaryl, -COR 3a , -P(O)(OR 3a )(OR 3b ), -S(O)-C1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 1-6 Alkyl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -OC 1-6 Selected from the group consisting of alkyl, aryl, heterocyclyl, alkylheterocyclyl, alkylaryl, and alkylcycloalkyl. -5-10 member heteroaryl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 1-6 Alkyl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -OC 1-6 Alkyl, aryl, heterocyclyl, alkylheterocyclyl, alkylaryl, or alkylcycloalkyl are halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl and -OC 1-6 The molecule may be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl groups. R 3a and R 3b C 1-6 Alkyl, C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, C 0-2 Alkyl-C 3-6 A group consisting of cycloalkyls and 5-6 membered heterocyclines is independently selected, or R 3a and R 3b It can be arbitrarily combined into C 3-10 Cycloalkyl, heterocyclyl, C 6-10 It can form aryl or 5-10 member heteroaryl compounds. 1-6 Alkyl, C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, C 0-2 Alkyl-C 3-6 Cycloalkyl, 5-6 membered heterocyclyl, C 3-10Cycloalkyl, heterocyclyl, C 6-10 Aryl, or 5-10 membered heteroaryl, is a halogen, C 1-6 Alkyl, and C 1-6 The molecule may be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl groups.

[0044] In some embodiments, ring B is condensed with ring A, Selected from the group consisting of JPEG2026519467000006.jpg196167. R b1 , R b2 , R b3 , R b4 , R b5 , R b6 and R b7 is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -CO-C 1-6 Alkyl, COOC 1-6 Alkyl, -CO-C 1-6 Haloalkyl, -CO-NR 3a R 3b -CH2-NR 3a R 3b -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-heterocyclyl, -C 1-6 Alkyl-C 6-10 Ariel, -C 1-6 Each is independently selected from the group consisting of alkyl-5-10 member heteroaryl, H, F, -CH3, -CHF2, -CF3, and OH. b1 , R b2 , R b3 , R b4 , R b5 , R b6 , Rb7 and R 3 Any two of these can be combined into C 3-10 Cycloalkyl or heterocyclyl, or C 6-10 It can form aryl or 5-10 member heteroaryl groups. b1 and X b2 Each of these is independently C, N, O, or S.

[0045] In some embodiments, R b1 and R b2 Each is independent of the others. Selected from the group consisting of JPEG2026519467000007.jpg39167.

[0046] In some embodiments, R 3 The base is -CONR 3a R 3b -S(O)-NR 3a R 3b -S(O)2-NR 3a R 3b , -C 1-6 Alkyl-CONR 3a R 3b , -C 1-6 Alkyl-NR 3a R 3b , -N(R 3a )-COR 3a , -N(R 3a )-CONR 3a R 3b , -C 1-6 Alkyl-SONR 3a R 3b , -C 1-6 Alkyl-SO2NR 3a R 3b , CN, -COR 3a , and -OC 1-6 Selected from the group consisting of alkyl groups. 3 is halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl and -OC 1-6 The molecule may be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl groups.

[0047] In some embodiments, R 3 The base is -CONR 3a R 3b , -C 1-6 Alkyl-CONR 3a R 3b , -C 1-6 Alkyl-NR 3a R 3b , -N(R 3a )COR 3a , -N(R 3a )CONR 3a R 3b , and -COR 3a It is selected from the group consisting of the following.

[0048] In some embodiments, R 3a and R 3b H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, C 0-6 Alkyl-C 3-6 A group consisting of cycloalkyls and 5-6 membered heterocyclines is independently selected, or R 3a and R 3b It can be arbitrarily combined into C 3-10 It can form cycloalkyl and heterocyclyl groups. 1-6 Alkyl, C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, C 0-2 Alkyl-C 3-6 Cycloalkyl, 5-6 membered heterocyclyl, C 3-10 Cycloalkyl and heterocyclyl compounds are halogens, C 1-6 Alkyl and C 1-6 The molecule may be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl groups.

[0049] In some embodiments, R 3a and R 3b H, C 1-6Alkyl, and C 1-6 It is independently selected from the group consisting of haloalkyls.

[0050] In some embodiments, R 3a and R 3b These can be arbitrarily combined, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Forming aryl or 5-10 member heteroaryls, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, or 5-10 membered heteroaryl, is a halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, and C 1-6 They may be substituted with one or more substituents independently selected from the group consisting of haloalkyls.

[0051] In some embodiments, R 3 The basis is, The image is JPEG2026519467000008.jpg3541, and ring D is C 3-10 It is a cycloalkyl or 3-10 membered heterocycline. 4 is N or CH. Ring D is oxo, halogen, C 1-6 Alkyl, -OC 1-6 Alkyl, and C 1-6 They may be optionally substituted with haloalkyl groups. A heterocyclyl has 1 to 4 heteroatoms, each of which is independently N, O, or S.

[0052] In some embodiments, R 3 The basis is, Selected from the group consisting of JPEG2026519467000009.jpg151167.

[0053] In some embodiments, ring C is an aryl, a 5-6 membered heteroaryl, and C 3-10 Selected from the group consisting of cycloalkyl groups.

[0054] In some embodiments, ring C is a 5-6 membered heteroaryl.

[0055] In some embodiments, ring C is Selected from the group consisting of JPEG2026519467000010.jpg2966.

[0056] In some embodiments, ring C is The file is JPEG2026519467000011.jpg2726.

[0057] In the compound according to claim 1, its pharmaceutically acceptable salt, deuterium-substituted derivative, and isomer, the ring C is C 3-10 It is a cycloalkyl. This cycloalkyl is a halogen, C 1-6 Alkyl, and C 1-6 The molecule may be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl groups.

[0058] In some embodiments, X 3 It is O.

[0059] In some embodiments, X 3 -CR c R d That is the case.

[0060] In some embodiments, R b H, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Two R compounds are independently selected from the group consisting of alkyl heterocyclyl, F, and OH. b The bases can be arbitrarily bonded to C 3-10 They can form cycloalkyl or heterocyclines. Each R b Optionally, halogen, C1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-10 The molecules may be optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl and heterocyclyl molecules.

[0061] In some embodiments, R b H, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-10 Cycloalkyl, heterocyclyl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Two R compounds are independently selected from the group consisting of alkyl-heterocyclines. b The bases can be arbitrarily bonded to C 3-10 They can form cycloalkyl or heterocyclines. Each R b Optionally, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 3-10 The molecule may be substituted with one or more substituents independently selected from the group consisting of cycloalkyl and heterocyclyl molecules.

[0062] In some embodiments, R 1 These are halogen, oxo, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -C 1-6 Haloalkyl and -C 3-10 It is independently selected from the group consisting of cycloalkyls.

[0063] In some embodiments, R 1 is halogen, -C 1-6 Alkyl, -C 1-6 Haloalkyl and -C3-10 It is independently selected from the group consisting of cycloalkyls.

[0064] In some embodiments, R 1 is -C 1-6 Alkyl, -C 1-6 Haloalkyl and -C 3-10 It is independently selected from the group consisting of cycloalkyls.

[0065] In some embodiments, R 2 is -C 0-1 Alkyl-C 3-9 It is a cycloalkyl compound. -C 0-1 Alkyl-C 3-9 Cycloalkyl is C 3-6 The molecule may be optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halogen, CH3, CHF2, CF3, OH, and oxo.

[0066] In some embodiments, R 2 teeth, Selected from the group consisting of JPEG2026519467000012.jpg32134, R 2a and R 2b H, halogen, C 1-3 Selected from the group consisting of alkyl groups, Also, R 2 is one or more halogens and C 1-6 It may be optionally substituted with alkyl.

[0067] In some embodiments, R 2 teeth, Selected from the group consisting of JPEG2026519467000013.jpg35102.

[0068] In some embodiments, R 2 teeth, Selected from the group consisting of JPEG2026519467000014.jpg3254.

[0069] In some embodiments, R 3 teeth, Selected from the group consisting of JPEG2026519467000015.jpg145167.

[0070] In some embodiments, the compounds of this application are selected from the group consisting of the compounds of formulas IA-1, IA-2, IA-3, and IA-4, their pharmaceutically acceptable salts, deuterium-substituted compounds, and isomers. JPEG2026519467000016.jpg82167

[0071] In some embodiments, the compounds of this application are selected from the group consisting of the compounds of formulas IA-5, IA-6, IA-7, and IA-8. JPEG2026519467000017.jpg78167Z 4 is O, S, S=O, S(=O)², or NR b1 And, X 1 is O, S, or NH, and Z 1 , Z 2 or Z 3 These are independently N or -C-Ra.

[0072] In some embodiments, the compounds of this application are selected from the group consisting of compounds of the following formulas IA-9, IA-10, IA-11, and IA-12. JPEG2026519467000018.jpg76167Z 4 is O, S, S=O, S(=O)², or NR b1 That is the case. X 1 It is O, S, or NH. Z 1 , Z 2 or Z 3 These are independently N or -CR a That is the case. The ring C is aryl, 5-6 member heteroaryl, C 3-10 Cycloalkyl, C 3-10Heterocyclyl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-C 3-10 Heterocyclyl, -C 1-6 Alkyl-aryl, or -C 1-6 It is an alkyl-5-6 member heteroaryl. aryl, 5-6 member heteroaryl, C 3-10 Cycloalkyl, C 3-10 Heterocyclyl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-C 3-10 Heterocyclyl, -C 1-6 Alkyl-aryl, or -C 1-6 Alkyl-5-6 member heteroaryls are halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy and C 1-6 Each molecule may be optionally substituted with one or more substituents independently selected from the group consisting of alkoxys.

[0073] In some embodiments, the compounds of this application are selected from the group consisting of compounds of the following formula IA-13. JPEG2026519467000019.jpg4799Z 4 is O, -C(R b1 R b2 )-,-N(R b1 )-is. X 5 It is N or CH. R b1 , R b2 , R b3 and R b4 is -C 1-6 Alkyl, -C 1-6 Haloalkyl, OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -CO-C 1-6 Alkyl, COOC 1-6 Alkyl, -CO-C 1-6 Haloalkyl, -CO-NR 3a R 3b-CH2-NR 3a R 3b , -C 2-6 Alkenyl, -C 2-6 Alkinyl, -C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-heterocyclyl, -C 1-6 Alkyl-C 6-10 Ariel, -C 1-6 A molecule is independently selected from the group consisting of alkyl-5-10 member heteroaryls, H, F, -CH3, -CHF2, -CF3, and OH. b3 and R b4 It can be arbitrarily combined into C 3-10 It can form cycloalkyl or heterocycline molecules. 3-10 Cycloalkyl or heterocyclyl is oxo, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl and -OC 1-6 The molecule may be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl groups. R 3a and R 3b H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, C 0-6 Alkyl-C 3-6 A group independently selected from cycloalkyls and 5-6 membered heterocyclines, or R 3a and R 3b It can be arbitrarily combined into C 3-10 It can form cycloalkyl and heterocyclyl groups. 1-6 Alkyl, C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, C 0-2 Alkyl-C 3-6 Cycloalkyl, 5-6 membered heterocyclyl, C3-10 Cycloalkyl and heterocyclyl compounds are halogens, C 1-6 Alkyl and C 1-6 The molecule may be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl groups. n a The values ​​are 0, 1, and 2.

[0074] In some embodiments, R b3 and R b4 H, -C 1-6 Alkyl, -C 1-6 Haloalkyl, OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -C 3-10 Cycloalkyl, heterocyclyl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, and -C 1-6 It is independently selected from the group consisting of alkyl-heterocyclines. Also, R b3 and R b4 It can be arbitrarily combined into C 3-10 It can form cycloalkyl or heterocycline molecules. 3-10 Cycloalkyl or heterocyclyl compounds contain halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl and -OC 1-6 The molecule may be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl groups.

[0075] In some embodiments, R b4 is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-10 Cycloalkyl, heterocyclyl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, and -C 1-6 Selected from the group consisting of alkyl-heterocyclines. 3-10 Cycloalkyl or heterocyclyl compounds contain halogens, C 1-6 Alkyl, C 1-6Haloalkyl, -OC 1-6 Alkyl and -OC 1-6 The molecule may be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl groups.

[0076] In some embodiments, R b4 is -C 1-6 Alkyl, -C 3-10 Selected from the group consisting of cycloalkyl and heterocyclyl compounds. 3-10 Cycloalkyl or heterocyclyl compounds contain halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl and -OC 1-6 The molecule may be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl groups.

[0077] In some embodiments, X 5 It is N.

[0078] In some embodiments, X 5 It is CH.

[0079] In some embodiments, the compounds of this application are selected from the group consisting of compounds of the following formula IA-18. JPEG2026519467000020.jpg4790

[0080] In some embodiments, Z 4 The group is selected from the group consisting of O and CH2.

[0081] In some embodiments, Z 4 It is O.

[0082] In some embodiments, Z 4 It is CH2.

[0083] In some embodiments, the compounds of this application are selected from the group consisting of compounds of the following formula IA-14. JPEG2026519467000021.jpg4893

[0084] In some embodiments, n a The values ​​are 0 and 1.

[0085] In some embodiments, R b4 is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-10 Cycloalkyl, heterocyclyl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Selected from the group consisting of alkyl heterocyclyl, H, and F. 3-10 Cycloalkyl or heterocyclyl is a halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl and -OC 1-6 The molecule may be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl groups.

[0086] In some embodiments, the compounds of this application are selected from the group consisting of compounds of the following formula IA-15. JPEG2026519467000022.jpg5394X 5 O, -N(R x5 )-,-C(R x6 R x7 Selected from the group consisting of )-, S, S(O), and S(O)2. m1 and m2 are 0, 1, 2, and 3, respectively. n a The values ​​are 0, 1, and 2. R x5 H, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 3-10 Cycloalkyl, -CO-C 1-6 Alkyl and -CO-C 1-6 Selected from the group consisting of haloalkyls. R x6 and Rx7 H, halogen, C 1-6 Alkyl, C 1-6 It is independently selected from the group consisting of haloalkyls.

[0087] In some embodiments, the compounds of this application are selected from the group consisting of compounds of the following formula IA-16. JPEG2026519467000023.jpg4789n a The values ​​are 0, 1, and 2.

[0088] In some embodiments, R b4 is -C 1-6 Alkyl, -C 1-6 Haloalkyl, -C 3-10 Cycloalkyl, heterocyclyl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Selected from the group consisting of alkyl heterocyclyl, H, and F. 3-10 Cycloalkyl or heterocyclyl compounds contain halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl and -OC 1-6 The molecule may be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl groups.

[0089] In some embodiments, the compounds of this application are selected from the group consisting of compounds of the following formula IA-17. JPEG2026519467000024.jpg4995X 5 is O, -N(R x5 )-,-C(R x6 R x7 )-, S, S(O), and S(O)2, m1 and m2 are 0, 1, 2, and 3, respectively. n a The values ​​are 0, 1, and 2. R x5 H, C 1-6 Alkyl, C 1-6 Haloalkyl, -CO-C1-6 Alkyl, -C 3-10 Cycloalkyl and -CO-C 1-6 It is a haloalkyl group. R x6 and R x7 H, halogen, C 1-6 Alkyl, C 1-6 It is a haloalkyl group.

[0090] In some embodiments, the compounds of this application are selected from the group consisting of compounds of the following formula IA-19. JPEG2026519467000025.jpg5790

[0091] Compounds of formula II: JPEG2026519467000026.jpg47109 Its pharmaceutically acceptable salts, deuterium-substituted derivatives, and isomers, Ring C is an aryl or 5-6 member heteroaryl. Ring C has any one or more R 1 It may be replaced with R 1 C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, C 3-10 Heterocyclyl, C 6-10 Selected from the group consisting of aryls and 5-10 membered heteroaryls, R 1 These can be halogen, oxo, -OH, -CN, or -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Haloalkoxy, -C 1-6 Haloalkyl, -C 3-10 Cycloalkyl, heterocyclyl, -C 6-10 The aryl group may be optionally substituted with a 5-10 member heteroaryl group. R c and R d Each is independently selected from the group consisting of H and halogens. n is either 0 or 1. R 2 is -C 0-1 Alkyl-C 3-9 Cycloalkyl, -C 1-6 Alkyl and -C 1-2 Alkyl-OC 1-3 Selected from the group consisting of alkyl groups, -C 0-1 Alkyl-C 3-9 Cycloalkyl, -C 1-6 Alkyl or -C 1-2 Alkyl-OC 1-3 Alkyl is C 3-6 It may be optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halogen, CH3, CHF2, CF3, OH, and oxo. X 1 is NH, O, or S. X 2 X is N, O, or S. 2 It can arbitrarily bond to an atom in ring A, forming another ring adjacent to ring A. Ring A is, Selected from the group consisting of JPEG2026519467000027.jpg39108, Z 1 , Z 2 and Z 3 These are N, N=O, and -CR, respectively, independently. a Selected from the group consisting of R a The group is selected from H, F, Cl, -CH3, -CHF2, -CF3, OH, -OCH3, and -OCF3. Ring B condensed to ring A is selected from the group consisting of 4-7 member heterocycloalkyl, 4-7 member heterocycloaryl, 4-7 member cycloalkyl, and 4-7 member cycloalkenyl, and each of the 4-7 member heterocycloalkyl, 4-7 member heterocycloaryl, 4-7 member cycloalkyl, and 4-7 member cycloalkenyl is optionally a saturated or unsaturated bridging ring. Ring B has any one or more R b It may also be replaced with each R b C is independent1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-heterocyclyl, -C 1-6 Alkyl-C 6-10 Ariel, -C 1-6 Selected from the group consisting of alkyl-5-10 member heteroaryls, F, -CH3, -CHF2, -CF3, and OH, with two R b The bases can be arbitrarily bonded to C 3-10 Cycloalkyl, or heterocyclyl, or C 6-10 Each R can form an aryl or a 5-10 member heteroaryl. b may be substituted with one or more halogens as desired. Ring B is R 3 Replaced with R 3 teeth, Selected from the group consisting of JPEG2026519467000028.jpg32167, R 3a and R 3b Each is independent of C 1-6 Alkyl, C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, C 0-2 Alkyl-C 3-6 R is independently selected from the group consisting of cycloalkyl and 5-6 membered heterocyclyl groups. 3a and R 3b These can be arbitrarily combined, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 It can form aryls or 5-10 membered heteroaryls.

[0092] Compounds of formula III: JPEG2026519467000029.jpg47105 and its pharmaceutically acceptable salts, deuterium-substituted forms, and isomers, Ring C is aryl, 5- to 6-membered heteroaryl, C 3-10 cycloalkyl, C 3-10 heterocyclyl, R x -C 3-10 cycloalkyl, R x -C 3-10 heterocyclyl, R x -aryl, and R x -5- to 6-membered heteroaryl, where R x is halogen or -C 1-6 alkyl, Ring C may optionally be substituted with one or more R 1 groups, each R 1 is OH, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -O-C 1-6 alkyl, -O-C 1-6 haloalkyl, -CO-C 1-6 alkyl, -CO-C 1-6 haloalkyl, -CO-NR 3a R 3b 、C 3-10 cycloalkyl, C 3-10 heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, independently selected from the group consisting of, each R 1 is halogen, oxo, -OH, -CN, -C 1-6 alkyl, -C 1-6 alkoxy, -C 1-6 haloalkoxy, -C 1-6 s haloalkyl, -C 3-10 cycloalkyl, heterocyclyl, -C 6-10 aryl, 5- to 10-membered heteroaryl, -S(O)-C 1-6 alkyl, -S(O)₂-C 1-6 alkyl and -S-C 1-6They may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl groups. n is either 0 or 1. R 2 is -C 0-1 Alkyl-C 3-9 Cycloalkyl, -C 1-6 Alkyl and -C 1-2 Alkyl-OC 1-3 Selected from the group consisting of alkyl groups, -C 0-1 Alkyl-C 3-9 Cycloalkyl, -C 1-6 Alkyl or -C 1-2 Alkyl-OC 1-3 Alkyl is C 3-6 It may be optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl, halogen, CH3, CHF2, CF3, OH, and oxo. X 1 is NH, O, or S. X 2 is N, O, or S, and X 2 It can optionally bond to an atom in ring A, forming another ring adjacent to ring A. X 3 is O or -CR c R d R c and R d Each of these is independently H, halogen, and -C 1-6 Selected from the group consisting of alkyl groups, Ring A is, Selected from the group consisting of JPEG2026519467000030.jpg39107, Z 1 , Z 2 and Z 3 These are independent of each other: -N=, -N(=O)=, and -C(R a Selected from the group consisting of )=, R a H, F, Cl, Br, I, -C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenil, C 2-6Alkynyl, OH, CN, -O-C 1-6 Alkyl, -O-C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C 3-10 Selected from the group consisting of heterocyclyl, aryl and 5-10 member heteroaryl, Ring B fused to ring A is selected from the group consisting of 4-7 member heterocycloalkyl, 4-7 member heterocycloaryl, 4-7 member cycloalkyl, and 4-7 member cycloalkenyl, and each 4-7 member heterocycloalkyl, 4-7 member heterocycloaryl, 4-7 member cycloalkyl, and 4-7 member cycloalkenyl is optionally a saturated or unsaturated bridged ring, Ring B is optionally substituted with one or more R b Each R b is independently CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -O-C 1-6 Alkyl, -O-C 1-6 Haloalkyl, -CO-C 1-6 Alkyl, COOC 1-6 Alkyl, -CO-C 1-6 Haloalkyl, -CO-NR 3a R 3b , -CH2-NR 3a R 3b , -NR 3a -CO-C 1-6 Alkyl, -NR 3a -COOC 1-6 Alkyl, -NR 3a -CO-C 1-6 Haloalkyl, -NR 3a -CO-NR 3a R 3b , C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, 5-10 member heteroaryl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-heterocyclyl, -C 1-6 Alkyl-C 6-10 Aryl, -C1-6 Independently selected from the group consisting of alkyl-5-10 member heteroaryl, F, -CH3, -CHF2, -CF3, and OH, and two R b The bases can be arbitrarily bonded to C 3-10 Cycloalkyl, or heterocyclyl, or C 6-10 Each R can form an aryl or a 5-10 member heteroaryl. b Halogen, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -CO-C 1-6 Alkyl, COOC 1-6 Alkyl, -CO-C 1-6 Haloalkyl, -CO-NR 3a R 3b -CH2-NR 3a R 3b , C 2-6 Alkenil, C 2-6 Alkinyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 They may be optionally substituted with one or more substituents independently selected from the group consisting of aryls and 5-10 membered heteroaryls. Ring B is R 3 It is replaced with R 3 -CONR 3a R 3b -S(O)-NR 3a R 3b -S(O)2-NR 3a R 3b , -C 0-6 Alkyl-CONR 3a R 3b , -C 0-6 Alkyl-NR 3a R 3b , -N(R 3a )-COR 3a , -N(R 3a )-CONR 3a R 3b , -C 0-6 Alkyl-SONR 3a R 3b , -C 0-6Alkyl-SO2NR 3a R 3b -C(S)-NR 3a R 3b CN, 5-10 member heteroaryl, -COR 3a , -P(O)(OR 3a )(OR 3b ), -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 1-6 Alkyl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -OC 1-6 Selected from the group consisting of alkyl, aryl, heterocyclyl, alkylheterocyclyl, alkylaryl, and alkylcycloalkyl, -5-10 member heteroaryl, -S(O)-C 1-6 Alkyl, -S(O)2-C 1-6 Alkyl, C 1-6 Alkyl, -C 1-6 Alkyl-C 3-10 Cycloalkyl, -OC 1-6 Alkyl, aryl, heterocyclyl, alkylheterocyclyl, alkylaryl, or alkylcycloalkyl are halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl and -OC 1-6 They may be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl groups. R 3a and R 3b These are C 1-6 Alkyl, C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, C 0-2 Alkyl-C 3-6 A group independently selected from cycloalkyls and 5-6 membered heterocyclines, or R 3a and R 3b It can be arbitrarily combined into C 3-10 Cycloalkyl, heterocyclyl, C 6-10 It can form aryl or 5-10 member heteroaryl compounds, C1-6 Alkyl, C 1-6 Haloalkyl, -C 2-6 Alkenyl, -C 2-6 Alkinyl, C 0-2 Alkyl-C 3-6 Cycloalkyl, 5-6 membered heterocyclyl, C 3-10 Cycloalkyl, heterocyclyl, C 6-10 Aryl, or 5-10 membered heteroaryl, is a halogen, C 1-6 Alkyl, and C 1-6 The molecule may be optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl groups.

[0093] In some embodiments, the compounds of this application are selected from the group consisting of the following compounds. JPEG2026519467000031.jpg229157 JPEG2026519467000032.jpg229163 JPEG2026519467000033.jpg229143 JPEG2026519467000034.jpg220167 JPEG2026519467000035.jpg166167 JPEG2026519467000036.jpg229161 JPEG2026519467000037.jpg221167 JPEG2026519467000038.jpg229156 JPEG2026519467000039.jpg227167 JPEG2026519467000040.jpg206167 JPEG2026519467000041.jpg224167 JPEG2026519467000042.jpg226167JPEG2026519467000043.jpg223167

[0094] Mai. Pharmaceutical composition Another aspect of this application relates to a pharmaceutical composition comprising the compound of this application. In some embodiments, this application provides a pharmaceutical composition comprising the compound of this application and one or more pharmaceutically acceptable excipients.

[0095] In some embodiments, the pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the pharmaceutical composition of this application further comprises one or more additional therapeutic agents.

[0097] The pharmaceutical compositions of this application may be in any form suitable for the intended method of administration. In some embodiments, the pharmaceutical compositions may be in the form of tablets, sachets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs for oral administration.

[0098] In some embodiments, the pharmaceutical composition of this application is provided in a unit dosage form, including but not limited to capsules, sachets, tablets, etc., containing a predetermined amount of the active ingredient. In one embodiment, the pharmaceutical composition is a tablet.

[0099] Pharmaceutical compositions may be prepared by any method well known in the pharmaceutical field. Such methods include the step of combining an active ingredient (e.g., the compound of this application or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients. In some embodiments, pharmaceutical compositions are prepared by uniformly and closely combining the active ingredient with one or more liquid excipients, one or more finely dispersed solid excipients, or both to form a mixture, and optionally molding the mixture into a final product. The techniques and preparations are generally described in "Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pennsylvania, 2006."

[0100] Examples of one or more excipients include, but are not limited to, fillers, binders, volume extenders, lubricants, sweeteners, flavorings, colorants, and preservatives. In some embodiments, the pharmaceutical composition is in tablet form and contains one or more pharmaceutically acceptable excipients suitable for tablet manufacturing. These excipients include, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate or sodium phosphate; granulators and disintegrants such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin, and acacia; and lubricants such as magnesium stearate, stearic acid, and talc. The tablets may be uncoated or coated by known techniques, including microencapsulation, to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a longer-lasting effect. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with wax.

[0101] The amount of active ingredient combined with an inactive ingredient to manufacture a dosage form may vary depending on the intended therapeutic target and method of administration. For example, in some embodiments, an oral dosage form for human administration may contain about 1 to 1000 mg of active ingredient combined with a suitable and convenient amount of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutically acceptable excipients may vary in weight ratio (wt / wt) of the whole composition from about 5% to about 95%.

[0102] In some embodiments, the pharmaceutical compositions of this application do not contain agents that affect the metabolic rate of the active ingredient. In some embodiments, the pharmaceutical compositions of this application do not contain agents that adversely affect (e.g., delay, inhibit, or suppress) the metabolism of the compound of this application, or the metabolism of other active ingredients administered sequentially or simultaneously, separately from the compound of this application. It is also understood that none of the methods, kits, products, etc., detailed herein contain agents that adversely affect (e.g., delay, inhibit, or suppress) the metabolism of the compound of this application, or the metabolism of other active ingredients administered sequentially or simultaneously, separately from the compound of this application.

[0103] IV. Treatment method Another aspect of this application relates to a method for preventing, treating, or improving symptoms of IL-17A-mediated inflammatory syndromes, disorders, or diseases using the compounds of this application. In some embodiments, the method includes administering to a subject in need of such treatment an effective amount of the compound of formula I, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound thereof, or an isomer thereof. [Examples]

[0104] (synthesis) The compounds of this disclosure can be prepared using the methods disclosed herein, their usual modifications as can be seen from the disclosure herein, and methods well known in the art. In addition to the teachings herein, conventionally known synthetic methods can be used. The synthesis of representative compounds of formula I, or pharmaceutically acceptable salts thereof (e.g., compounds having the structure described by one or more of formula I, or compounds having the structure described by other formulas or compounds disclosed herein) can be achieved as described in the following examples.

[0105] General synthesis method

[0106] Typical embodiments of the compounds according to this application can be synthesized using the general reaction schemes and / or examples described below. As will be apparent from the description herein, the general scheme can be modified by substituting the starting materials with other substances having similar structures, thereby obtaining corresponding different products. The synthesis descriptions below provide numerous examples of how to change the starting materials to obtain the corresponding products. The starting materials are usually obtained from commercial sources or synthesized using published methods for synthesizing the compounds of the embodiments of this application. Each substituent can be identified by examining the structure of the compound to be synthesized. In light of the examples herein, identification of the final product is usually revealed by a simple inspection process that identifies the necessary starting materials. Labels of the groups used in the reaction schemes herein (e.g., R 1 , R 2 The labels provided are for illustrative purposes only and, unless otherwise specified, do not necessarily correspond to the names or functions of other labels used to describe the compound of formula I or its embodiments or substructures.

[0107] Synthesis reaction parameters

[0108] The compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are indicated, it will be understood that other process conditions may also be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvent used, but such conditions can be determined by routine optimization procedures for those skilled in the art.

[0109] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Protecting groups suitable for various functional groups, as well as appropriate conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, numerous protecting groups are described in TW Greene and GMWuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and the references cited therein.

[0110] Furthermore, the compounds of this application may contain one or more chiral centers. Therefore, as needed, these compounds can be prepared or isolated as pure stereoisomers, i.e., individual enantiomers or diastereomers, or as mixtures containing stereoisomers. Unless otherwise specified, all stereoisomers (and mixtures containing them) are included within the scope of this disclosure. Pure stereoisomers (or concentrated mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of these compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, etc.

[0111] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). Other compounds can be prepared by procedures or obvious modifications thereof described in standard reference texts such as Fieser and Fieser's "Reagents for Organic Synthesis" Vol. 1–15 (John Wiley, and Sons, 1991), Rodd's "Chemistry of Carbon Compounds" Vol. 1–5 and Supplemental (Elsevier Science Publishers, 1989), "organic Reactions" Vol. 1–40 (John Wiley, and Sons, 1991), March's "Advanced Organic Chemistry" (John Wiley, and Sons, 5th edition, 2001), and Larock's "Comprehensive Organic Transformations" (VCH Publishers Inc., 1989).

[0112] The terms “solvent,” “inert organic solvent,” or “inert solvent” refer to solvents that are inert under the reaction conditions described in conjunction with them (e.g., including benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), N,N-dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, pyridine, etc.). Unless otherwise specified, the solvents used in the reactions of this application are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.

[0113] The term "appropriate amount" means adding enough to achieve the specified function, for example, enough to bring the solution to the desired volume (i.e., 100%).

[0114] The compounds described herein can be synthesized according to the general scheme shown below. It should be understood that in the following scheme, each compound shown may have a protecting group at any step, if necessary. Standard protecting groups are within the understanding of those skilled in the art. Example 1: Preparation of the compound

[0115] In another embodiment, the present invention provides a method for producing compounds of formula I, pharmaceutically acceptable salts, esters, or stereoisomers thereof. The method comprises nine general routes (route 1, route 2, route 3, route 4, route 5, route 6, route 7, route 8, route 9, route 10, route 11, route 12, route 13, route 14, and route 15). Route 1: Asymmetric synthesis of compound 1 using chiral α-methylbenzylamine. JPEG2026519467000044.jpg71167

[0116] (Synthesis of Compounds 1-2) A THF solution of compound 1-1 (1.0 equivalent) and α-methylbenzylamine (1.2 equivalents) was stirred with Ti(OEt)4 (3.0 equivalents) at 85°C until complete conversion was achieved. Subsequently, NaBH4 (1.2 equivalents) was added to the solution at -40°C and stirred at 25°C until complete conversion was achieved. The reaction was stopped with deionized water and extracted with ethyl acetate. The organic phase was acidified with HCl and concentrated under reduced pressure to obtain white crystals. These were washed with EA-MeOH (10:1) solution to obtain pure compound 1-2.

[0117] (Synthesis of compounds 1-3) Compounds 1-2 (1.0 equivalent), BocNH2 (1.5 equivalent), Pd2(dba)3 (5 mol%), X-Phos (20 mol%), and Cs2CO3 (3.0 equivalent) were added to dioxane under a nitrogen atmosphere and stirred at 90-100°C for 3 hours. After cooling, RINKAN and water were added to the mixed solution and stirred for 10 minutes. The organic phase was then separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The concentrate was purified by column chromatography using silica gel to obtain compound 1-3.

[0118] Synthesis of Compounds 1-4

[0119] Compounds 1-3 were dissolved in the minimum amount of ethyl acetate, and dioxane·HCl was added, followed by stirring at 25°C for 2 hours. The reaction solvent was then removed under reduced pressure to obtain ammonia hydrochloride salt in quantitative yield. This salt was used directly without purification. (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cycloheptylacetic acid (1.0 equivalent), HATU (1.5 equivalents), and TEA (1.5 equivalents) were placed in DCM (1M) and stirred at 20-25°C for 1 hour. The above salt (1.0 equivalent) was added and stirred for 2 hours. Water was added and stirred for 15 minutes. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to obtain compounds 1-4.

[0120] Synthesis of Compounds 1-5

[0121] Compounds 1-4 were dissolved in the minimum amount of RINKAN, and dioxane·HCl was added, followed by stirring at 25°C for 2 hours. The reaction solvent was then removed under reduced pressure to obtain the amine hydrochloride in quantitative yield. This salt was used directly without purification. To a solution of 1-isopropyl-1H-pyrazole-5-carboxylic acid (1.0 equivalent) in DCM (1M), HATU (1.5 equivalents) and TEA (1.5 equivalents) were added, and the mixture was stirred at room temperature for 30 minutes. The aforementioned salt (1.0 equivalent) was added to the reaction mixture, and stirring was continued for 2 hours. Water was added, and the mixture was stirred for 10 minutes. The organic phase was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to obtain compounds 1-5.

[0122] Synthesis of Compound 1

[0123] Compounds 1-5 (1.0 equivalent) were hydrolyzed in the presence of a Pd / C catalyst to produce primary ammonias. Next, 4,4,4-trifluorobutyric acid, HATU (1.5 equivalents), and TEA (1.5 equivalents) were mixed in DCM (1M) and stirred at room temperature for 2 hours. Water was added and stirred for 10 minutes. The organic phase was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to obtain compound 1. Route 2: Asymmetric synthesis of compound 1 using chiral sulfinylamide. JPEG2026519467000045.jpg61167

[0124] Synthesis of compound 1-2'

[0125] A THF solution of compound 1-1 (1.0 equivalent) and chiral sulfinylamide (1.2 equivalents) was stirred with Ti(OEt)4 (3.0 equivalents) at 85°C until complete conversion was achieved. Subsequently, NaBH4 (1.2 equivalents) was added to the solution at -40°C and stirred at 25°C until complete conversion was achieved. The reaction was stopped with deionized water and extracted with ethyl acetate. The organic phase was acidified with HCl and concentrated under reduced pressure to obtain compound 1-2' as white crystals (98% yield).

[0126] Synthesis of Compounds 1-3'

[0127] Compounds 1-2' were mixed with 4,4,4-trifluorobutyric acid, HATU (1.5 equivalents), and TEA (1.5 equivalents) in DCM (1M) and stirred at room temperature for 2 hours. Water was added and stirred for 10 minutes. The organic phase was separated, washed with water and saline solution, dried over MgSO4, and concentrated under reduced pressure to obtain compound 1-3'.

[0128] Synthesis of compounds 1-4'

[0129] Compounds 1-3' (1.0 equivalent), BocNH2 (1.5 equivalent), Pd2(dba)3 (10 mol%), X-Phos (20 mol%), and Cs2CO3 (3.0 equivalent) were added to dioxane under a nitrogen atmosphere and stirred at 90-100°C for 3 hours. After cooling, RINKAN and water were added to the mixed solution and stirred for 10 minutes. The organic phase was then separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The concentrate was purified by column chromatography using silica gel to obtain compound 1-4'.

[0130] Synthesis of Compounds 1-5'

[0131] Compounds 1-4' were dissolved in the minimum amount of ethyl acetate, and dioxane·HCl was added, followed by stirring at 25°C for 2 hours. The reaction solvent was then removed under reduced pressure to obtain the amine hydrochloride in quantitative yield. This salt was used directly without purification. (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cycloheptylacetic acid (1.0 equivalent), HATU (1.5 equivalents), and TEA (1.5 equivalents) were placed in DCM (1M) and stirred at 20-25°C for 1 hour. The above salt (1.0 equivalent) was added and stirred for 2 hours. Water was added and stirred for 15 minutes. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to obtain compounds 1-5'.

[0132] Synthesis of Compound 1

[0133] Compound 1-5' was dissolved in the minimum amount of ethyl acetate, and dioxane·HCl was added, followed by stirring at 25°C for 2 hours. The reaction solvent was then removed under reduced pressure to obtain the amine hydrochloride in quantitative yield. This salt was used directly without purification. To a solution of 1-isopropyl-1H-pyrazole-5-carboxylic acid (1.0 equivalent) in DCM (1M), HATU (1.5 equivalents) and TEA (1.5 equivalents) were added, and the mixture was stirred at room temperature for 30 minutes. The above salt (1.0 equivalent) was added to the reaction mixture and stirred for 2 hours. Water was added and the mixture was stirred for 10 minutes. The organic phase was separated, washed with water and brine, dried over MgSO4, and then concentrated under reduced pressure to obtain compound 1. Route 3. Preparation of intermediates 2-6 JPEG2026519467000046.jpg51167 Conditions: a) TMSCN, ZnI2, DCM, room temperature, 16 hours, quantitative; b) SnCl2, HCl / AcOH (1:1), 80°C, 16 hours, 50% yield; c) Chiral auxiliaries (e.g., quinine, (R)-(+)-1-phenylethylamine, (S)-(-)-1-phenylethylamine); e) BocNH2, Cs2CO3, 10% Pd2(dba)3, 20% XPhos, dioxane, 85°C, 3 hours. Following the procedure for intermediate 2-6, the following intermediates were prepared. JPEG2026519467000047.jpg140167

[0134] Synthesis of compound 2-2

[0135] A DCM solution of compound 2-1 (1.0 equivalent) and TMSCN (1.5 equivalents) was stirred with ZnI2 (2 mol%) at room temperature for 16 hours until complete conversion occurred. The reaction mixture was washed with saturated sodium bicarbonate aqueous solution. The organic layer was dried (MgSO4) and concentrated under reduced pressure to obtain compound 2-2 (yield 97%).

[0136] Synthesis of Compounds 2-3

[0137] A mixture of compound 2-2 (1.0 equivalent) and SnCl2·2H2O (4.0 equivalents) was dissolved in a mixed solvent of acetic acid and concentrated hydrochloric acid (1:1) and refluxed overnight. The mixture was extracted with CH2Cl2. The combined organic phase was washed with 2N sodium hydroxide solution. The combined basic washings were extracted with ether and then acidified to pH=2 with 5N hydrochloric acid solution. The acidic aqueous mixture was extracted with ethyl acetate (EA), and the combined organic layer was dried and concentrated under reduced pressure to obtain compound 2-3 (yield 85%).

[0138] Synthesis of Compounds 2-4

[0139] Compounds 2-3 were treated with oxalyl chloride and DMF in DCM at room temperature, and a solution of Evans' auxiliary and TEA was added to the reaction flask. The resulting diastereomers were separated by silica gel column to obtain compound 2-4.

[0140] Synthesis of Compounds 2-5

[0141] Compounds 2-4 were dissolved in DMF, and NaHCO3 (1.2 equivalents) and MeI (1.5 equivalents) were added to the reaction system. The mixture was stirred at room temperature for 4 hours until complete conversion occurred. EA was added, the organic phase was washed with NaHCO3 solution, dried over MgSO4, and concentrated under reduced pressure to obtain compound 2-5 in quantitative yield.

[0142] Synthesis of Compounds 2-6

[0143] Compound 2-5 (1.0 equivalent), BocNH2 (1.5 equivalent), Pd2(dba)3 (10 mol%), X-Phos (20 mol%), and Cs2CO3 (3.0 equivalent) were added to dioxane under a nitrogen atmosphere and stirred at 90-100°C for 3 hours. After cooling, RINKAN and water were added to the mixed solution and stirred for 10 minutes. The organic phase was then separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain compound 2-6. Route 4. Preparation of intermediates 3-4 JPEG2026519467000048.jpg27167

[0144] Synthesis of compound 3-2

[0145] A MeCN solution of compound 3-1 (1.0 equivalent) and tert-butyl bromoacetate (1.2 equivalents) was stirred with Cs2CO3 (1.2 equivalents) at 60°C for 2 hours until complete conversion occurred. The reaction mixture was washed with 1N hydrochloric acid aqueous solution. The organic layer was dried (with MgSO4) and concentrated under reduced pressure to obtain compound 3-2 (97% yield).

[0146] Synthesis of compound 3-3

[0147] Compound 3-2 (1.0 equivalent) was dissolved in a mixed solvent of trifluoroacetic acid and CH2Cl2 (1:1) and stirred at room temperature for 2 hours. The mixture was extracted with CH2Cl2. The combined organic phase was washed with 2N sodium hydroxide solution. The combined basic washings were extracted with ether and then acidified to pH=2 with 5N hydrochloric acid solution. The acidic aqueous mixture was extracted with EA, and Pd / C (10 wt%, 10 mol%) was added to the combined organic layer. An H2 balloon was attached and the mixture was stirred at room temperature for 2 hours. The organic layer was then filtered, dried, and concentrated under reduced pressure to obtain compound 3-3 (99% yield).

[0148] Synthesis of Compounds 3-4

[0149] TEA (1.5 equivalents) was added to a solution of compound 3-3 (1.0 equivalent) in DCM (1M), and the mixture was stirred at room temperature for 30 minutes. The reaction was stopped by the addition of EA. The organic phase was washed with 2N sodium hydroxide solution, then washed with water and saline solution, dried over MgSO4, and concentrated under reduced pressure to obtain a lactam intermediate. The lactam was separated by chiral HPLC using CHIRALPAK ODH to obtain chiral compounds 3-4. Route 5. Preparation of intermediate 4-4 JPEG2026519467000049.jpg27167 Conditions: a) 1.2 equivalents of KNO3, H2SO4, 0°C, 2 hours; b) 10% Pd / C, EA, room temperature, 2 hours; c) 1.2 equivalents of Boc2O, DCM, Na2CO3; d) PhCH2Br, 110°C, 12 hours; e) 10% Pd / C, HOAc, 60°C, 12 hours; f) Separation by chiral HPLC using CHIRALPAK ODH.

[0150] Synthesis of compound 4-2

[0151] A sulfuric acid solution of compound 4-1 (1.0 equivalent) was stirred at 0°C, and KNO3 was added to the solution in small amounts over 2 hours until complete conversion occurred. The reaction was stopped with EA and saline solution. The reaction mixture was washed with saline solution. The organic layer was dried (MgSO4) and concentrated under reduced pressure to obtain compound 4-2 (yield 97%).

[0152] Synthesis of compound 4-3

[0153] Compound 4-2 (1.0 equivalent) was dissolved in EA. Pd / C (10 wt%, 10 mol%) was added, an H2 balloon was attached, and the mixture was stirred at room temperature for 0.5 hours. The organic layer was then filtered, dried, and concentrated under reduced pressure to obtain compound 4-3 (99% yield).

[0154] Synthesis of compound 4-4

[0155] A solution of compound 4-3 (1.0 equivalent) in BnBr (1.1 equivalents) was heated at 110°C for 30 minutes. The reaction mixture solidified, indicating complete conversion. The solid cake was washed with PE and used directly without purification. The resulting product was acidified to pH=2 with 5N hydrochloric acid solution. Pd / C (10 wt%, 10 mol%) was added, and the mixture was stirred at 60°C for 2 hours with an H2 balloon attached. The organic layer was filtered, dried, and concentrated under reduced pressure to obtain racemic compound 4-4 (99% yield). Next, the lactam was separated by chiral HPLC using CHIRALPAK ODH to obtain chiral compound 4-4. Route 6. Preparation of intermediates 5-4 JPEG2026519467000050.jpg79167 Conditions: a) POCl3, room temperature reflux, 8 hours; b) Cs2CO3, PhCH2Br, DMF, room temperature, 12 hours; c) BocNH2, Cs2CO3, 10% Pd2(dba)3, 20% XPhos, 85°C, 3 hours; d) Separation by chiral HPLC using CHIRALPAK ODH.

[0156] Synthesis of compound 5-2

[0157] 1.0 equivalent of methyl 2-oxoacetate was added to a toluene solution of compound 5-1 (1.0 equivalent), and the mixture was stirred at 80°C for 2 hours. Then, 20 equivalents of POCl3 were added, and the mixture was stirred at 120°C for 8 hours. The reaction was stopped at 0°C with EA and NaHCO3. The reaction mixture was washed with saline solution. The organic layer was dried (MgSO4) and concentrated under reduced pressure to obtain compound 5-2 (yield 77%).

[0158] Synthesis of compound 5-3

[0159] Compound 5-2 (1.0 equivalent) was dissolved in DMF, BnBr (1.0 equivalent) was added, and the mixture was stirred with Cs2CO3 (1.2 equivalents) at room temperature for 6 hours until complete conversion occurred. The reaction mixture was stopped, extracted with EA, and washed with brine. The organic layer was dried (MgSO4) and concentrated under reduced pressure to obtain compound 5-3 (95% yield).

[0160] Synthesis of Compound 5-4

[0161] Compound 5-3 (1.0 equivalent), BocNH2 (1.5 equivalents), Pd2(dba)3 (5 mol%), X-Phos (20 mol%), and Cs2CO3 (3.0 equivalents) were added to dioxane under a nitrogen atmosphere and stirred at 90-100°C for 3 hours. After cooling, RINKAN and water were added to the mixed solution and stirred for 10 minutes. The organic phase was then separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain racemic compound 5-4. Racemic compound 5-4 was separated by chiral HPLC using CHIRALPAK ODH to obtain chiral compound 5-4. Route 7. Preparation of compounds 2-9, intermediate 3, intermediate 4, and intermediate 5. JPEG2026519467000051.jpg90137JPEG2026519467000052.jpg95167 Compound 2-7 Series Compound Synthesis

[0162] The corresponding protected aromatic amines (2-6, 3-6, 4-4, 5-4) were each dissolved in the minimum amount of ethyl acetate, and dioxane·HCl was added and the mixture was stirred at 25°C for 2 hours. The reaction solvent was then removed under reduced pressure to obtain the amine hydrochloride in quantitative yield. This salt was used directly without purification. (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cycloheptylacetic acid (1.0 equivalent), HATU (1.5 equivalents), and TEA (1.5 equivalents) were added to DCM (1M) and the mixture was stirred at 20-25°C for 1 hour. The above salt (1.0 equivalent) was added and the mixture was stirred for 2 hours. Water was added and the mixture was stirred for 15 minutes. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to obtain the corresponding N-protected aminoamide (e.g., compound 2-7).

[0163] Synthesis of Compounds 2-8

[0164] Compound 2-7 was dissolved in the minimum amount of siRNA, and dioxane·HCl was added, followed by stirring at 25°C for 2 hours. The reaction solvent was then removed under reduced pressure to obtain the amine hydrochloride in quantitative yield. This salt was used directly without purification. To a solution of 1-isopropyl-1H-pyrazole-5-carboxylic acid (1.0 equivalent) in DCM (1M), HATU (1.5 equivalents) and TEA (1.5 equivalents) were added, and the mixture was stirred at room temperature for 30 minutes. The aforementioned salt (1.0 equivalent) was added to the reaction mixture, and the mixture was stirred for 2 hours. Water was added, and the mixture was stirred for 10 minutes. The organic phase was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to obtain compound 2-8.

[0165] Synthesis of Compounds 2-9, Intermediate 3, Intermediate 4, and Intermediate 5

[0166] To a solution of compound 2-8 (1.0 equivalent) in methanol (1M), 3N NaOH (1M) was added and the mixture was stirred at room temperature for 8 hours. The reaction was stopped with deionized water. The reaction mixture was extracted with ether and subsequently acidified to pH=2 with 5N hydrochloric acid solution. The acidic aqueous mixture was extracted with EA, and the combined organic layer was dried and concentrated under reduced pressure to obtain the carboxylic acid. Next, the carboxylic acid (1.0 equivalent), HATU (1.5 equivalents), 3,3-difluoroazetidine hydrochloride (1.1 equivalents), and TEA (1.5 equivalents) were added to DCM (1M) and the mixture was stirred at 20-25°C for 1 hour. Water was added and the mixture was stirred for 15 minutes. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to obtain compound 2-9 (85% yield). Intermediates 3, 4, and 5 were synthesized in a similar manner. Route 8. Preparation of intermediates 3-1 and 3-2 JPEG2026519467000053.jpg33167

[0167] Intermediate 3 (1.0 equivalent) was dissolved in DMF, BnBr (1.0 equivalent) was added, and the mixture was stirred with Cs2CO3 (1.2 equivalents) at room temperature for 6 hours until complete conversion occurred. The reaction mixture was stopped, extracted with EA, and washed with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to obtain intermediate 3-1 (yield 95%).

[0168] Intermediate 3-1 (1.0 equivalent) was dissolved in HOAc, pyridine BH3 (10 equivalents) was added, and the mixture was stirred at room temperature for 12 hours until complete conversion occurred. The reaction mixture was stopped, extracted with EA, and washed with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure to obtain intermediate 3-2 (95% yield). Route 9. Preparation of Compound 67, Compound 89, and Compound 92 JPEG2026519467000054.jpg134167

[0169] Intermediate 4 was hydrolyzed under a Pd / C catalyst to produce a secondary amine. Next, 4,4,4-trifluorobutyric acid, HATU (1.5 equivalents), and TEA (1.5 equivalents) were mixed in DCM (1M) and stirred at room temperature for 2 hours. Water was added and stirred for 10 minutes. The organic phase was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to obtain compound 89. Compounds 67 and 92 were synthesized by a similar method. Route 10. Preparation of Intermediate 6 JPEG2026519467000055.jpg30167

[0170] Sodium hydride (60% dispersion in mineral oil, 3.53 g, 88.2 mmol) was washed three times with hexane and then suspended in THF (9 mL). A mixture of 2'-hydroxyacetophenone (22.0 mmol) and the corresponding ester (55.1 mmol) in THF (2.5 mL) was added dropwise to the suspension at room temperature. A vigorous reaction was observed, and the temperature reached reflux. After the total amount was added, the reaction mixture was stirred for a further 5 minutes and then poured onto ice to stop the reaction. The mixture was then further acidified to pH 6 with 6 M hydrochloric acid aqueous solution. The solution was extracted with ethyl acetate, and the combined organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated to obtain 1,3-dione as the crude product. Without purification, a solution of the crude 1,3-dione product (2.50 g, 14.0 mmol) in methanol (30 mL) was treated with concentrated hydrochloric acid (1 mL). The mixture was stirred at room temperature for 14 hours. The mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate (50 mL), and washed sequentially with saturated sodium bicarbonate aqueous solution, water, and saline solution. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, eluent: ethyl acetate / hexane 1:3) to obtain 2-substituted chromen-4-one. 2-substituted chromen-4-one was hydrogenated in methanol with Pd / C and H2 to obtain intermediate 6. Route 11. Preparation of Intermediate 7 JPEG2026519467000056.jpg35144 In a round-bottom flask equipped with a magnetic stirrer, 1-(4-bromo-2-hydroxyphenyl)ethane-1-one (2 g, 9.30 mmol), intermediate 7-1 (1.16 g, 10.23 mmol), pyrrolidine (0.99 g, 13.95 mmol), and methanol (20 mL) were added. The reaction mixture was stirred at 60°C for 16 hours. The progress of the reaction was monitored by TLC (PE / siRNA 10:1). After the reaction was complete, the reaction mixture or solution was concentrated and dried. The dried mixture was partitioned with EA (100 mL) and 3N NaOH aqueous solution (50 mL). The organic layer was separated, washed with water and brine (50 mL), dried over Na2SO4, and evaporated to dryness. After evaporating and removing the solvent, intermediate 7 (yield 60.66%) was obtained as a brown solid. Route 12. Preparation of Intermediate 8 JPEG2026519467000057.jpg59167 Synthesis of Intermediate 8-2 Intermediate 8-1 was synthesized by Knoevenagel condensation with a ketone and methyl cyanoacetate. Next, intermediate 8-1 was added dropwise to a THF solution of Grignard reagent (3-chlorobenzyl)magnesium bromide and heated at 42-45°C for 2 hours with stirring. After cooling in ice water, sulfuric acid (20%) was added dropwise and the mixture was stirred at room temperature until the complex was completely decomposed. The organic layer was separated. The aqueous layer was extracted with diethyl ether. The organic fractions were combined, washed twice with water, and dried over MgSO4. The solvent was vacuum distilled using a 10 cm fractional distillation column to obtain intermediate 8-2. Synthesis of intermediate 8-3 Intermediate 8-2 (16 mmol) was placed in a reaction flask, and concentrated sulfuric acid (8 mL) was added from a dropping funnel while stirring (the mixture was cooled with water to maintain a temperature of 25-30°C). After stirring at room temperature for 3 hours, the mixture was poured onto ice (120 g). The resulting crystals were filtered, washed with water, treated with water (60 mL) and aqueous ammonium hydroxide solution (6 mL), and extracted with diethyl ether. The solvent was removed by distillation. The compound was recrystallized from ethanol-water (2:1) to obtain intermediate 8-3. Synthesis of Intermediate 8 A mixture of intermediate 8-3 (20 mmol), the corresponding acid chloride (20 mmol), and anhydrous toluene (30 mL) was refluxed for 4 hours. The solvent was removed by distillation. The residue was recrystallized from anhydrous ethanol to obtain intermediate 8. Route 13. Preparation of Compounds 167, 176, and 247 JPEG2026519467000058.jpg55167JPEG2026519467000059.jpg78167 Synthesis of compound 167-1 2-bromo-3-methylbutanoic acid (1.1 equivalents), HATU (1.5 equivalents), compound 167-0 (1.0 equivalent), and TEA (1.5 equivalents) were added to DCM (1M) and stirred at 20-25°C for 1 hour. Water was added and stirred for 15 minutes. The organic layer was separated, washed with aqueous hydrochloric acid (1M) and brine, dried over MgSO4, and concentrated under reduced pressure to obtain compound 167-1. Synthesis of compound 167-2 Compound 167-1 was dissolved in THF (0.5 M), and NaH (2.0 equivalents) was added in installments. The reaction was then stirred at 20-25°C for 8 hours until complete conversion occurred. Water (5 equivalents) and EA (0.1 M) were added, and the mixture was stirred for 15 minutes. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to obtain compound 167-2. Synthesis of compound 167-3 Compound 167-2 was dissolved in THF (0.5 M) and slowly added to a solution of lithium aluminum hydride (2 equivalents) in tetrahydrofuran (1 M) at 0°C. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction was stopped with wet sodium sulfate. The reaction mixture was filtered through a high-low bed and washed with tetrahydrofuran (25 ml). The filtrate was completely removed by distillation to obtain compound 167-3. Synthesis of compound 167-4 Compound 167-3 (1.0 equivalent), DCM (0.3 M), ethyl diisopropylamine (10 equivalents), and bis(trichloromethyl) carbonate (1.1 equivalents) were added to a round-bottom flask equipped with a magnetic stirring bar. Water was added and the mixture was stirred for 15 minutes. The organic layer was separated, washed with aqueous hydrochloric acid (1 M) and brine, dried over MgSO4, and then concentrated under reduced pressure to obtain compound 167-4. Synthesis of compound 167-5 Compound 167-4 (1.0 equivalent), tert-butylcarbamate (1.5 equivalents), Pd2(dba)3 (0.1 equivalent), and xanthophos were added to a round-bottom flask equipped with a magnetic stirrer and pretreated by stirring in a minimum amount of 1,4-dioxane. Then, 1,4-dioxane (0.01 M) was added to the mixture. The mixture was stirred at 85°C for 3 hours under a nitrogen balloon. Samples were taken from the reaction mixture using a dropping tube, and the reaction progress was confirmed by TLC (PE / SiO=1:1) and LC-MS. After the reaction was complete, the reaction mixture was concentrated or evaporated under reduced pressure to remove the dioxane. The concentrated reaction mixture was diluted with a solvent and poured into water. The aqueous layer was extracted twice with an organic solvent (20 mL). The combined organic layer was washed with water (30 mL) and dried over Na2SO4. After concentrating and removing the solvent, an oily crude product was obtained. The crude product was purified by silica gel chromatography, and compound 167-5 (yield 90%) was obtained as a yellow solid by elution with PE:Â1 in a 1:1 ratio. Synthesis of compound 167-6 Compound 167-5 was dissolved in the minimum amount of ethyl acetate, and dioxane·HCl was added and the mixture was stirred at 25°C for 2 hours. The reaction solvent was then removed under reduced pressure to obtain the amine hydrochloride in quantitative yield. This salt was used directly without purification. (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cycloheptylacetic acid (1.0 equivalent), HATU (1.5 equivalents), and TEA (1.5 equivalents) were added to DCM (1M) and the mixture was stirred at 20-25°C for 1 hour. The above salt (1.0 equivalent) was added and the mixture was stirred for 2 hours. Water was added and the mixture was stirred for 15 minutes. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to obtain compound 167-6. Synthesis of compound 167 Compound 167-6 was dissolved in the minimum amount of ethyl acetate, and dioxane·HCl was added and the mixture was stirred at 25°C for 2 hours. The reaction solvent was then removed under reduced pressure to obtain the amine hydrochloride in quantitative yield. This salt was used directly without purification. 1-Isopropyl-1H-pyrazole-5-carboxylic acid (1.0 equivalent), HATU (1.5 equivalents), and TEA (1.5 equivalents) were added to DCM (1M) and the mixture was stirred at 20-25°C for 1 hour. The above salt (1.0 equivalent) was added and the mixture was stirred for 2 hours. Water was added and the mixture was stirred for 15 minutes. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to obtain compound 167. Route 14. Synthesis of Compound 169 and Compound 246 JPEG2026519467000060.jpg51167 JPEG2026519467000061.jpg58167 Synthesis of Compound 169-2 Compound 169-0 (1.0 equivalent) and 2,4-dibromoaniline (1.0 equivalent) were dissolved in toluene (1M). Activated silica gel (100 mg / mmol) was added, and the mixture was stirred at 100°C for several hours until complete conversion occurred. Pd(OAc)2 (10 mol%) and rac-BINAP (10 mol%) were added to the mixture, and the mixture was stirred at 100°C for a further 2 hours to obtain compound 169-2. Synthesis of compound 169-3 Compound 169-2 (1.0 equivalent), DCM (0.3 M), ethyl diisopropylamine (10 equivalents), and bis(trichloromethyl) carbonate (1.1 equivalents) were added to a round-bottom flask equipped with a magnetic stirring bar. Water was added and the mixture was stirred for 15 minutes. The organic layer was separated, washed with aqueous hydrochloric acid (1 M) and brine, dried over MgSO4, and then concentrated under reduced pressure to obtain compound 169-3. Synthesis of compound 169-4 Compound 169-3 (1.0 equivalent), tert-butylcarbamate (1.5 equivalents), Pd2(dba)3 (0.1 equivalent), and xanthophos were added to a round-bottom flask equipped with a magnetic stirrer and pretreated by stirring in a minimum amount of 1,4-dioxane. Next, 1,4-dioxane (0.01 M) was added to the above mixture. The mixture was stirred at 85°C for 3 hours under a nitrogen balloon. Samples were taken from the reaction mixture using a dropping tube, and the progress of the reaction was confirmed by TLC (PE / siRNA=1:1) and LC-MS. After the reaction was complete, the reaction mixture was concentrated or evaporated under reduced pressure to remove the dioxane. The concentrated reaction mixture was diluted with a solvent and poured into water. The aqueous layer was extracted twice with an organic solvent (20 mL). The combined organic layer was washed with water (30 mL) and dried over Na2SO4. After concentrating and removing the solvent, an oily crude product was obtained. The crude product was purified by silica gel chromatography, and compound 169-4 (yield 90%) was obtained as a yellow solid by elution with PE:siRNA = 1:1. Synthesis of compound 169-5 Compound 169-4 was dissolved in the minimum amount of ethyl acetate, dioxane·HCl was added, and the mixture was stirred at 25°C for 2 hours. The reaction solvent was then removed under reduced pressure to obtain the amine hydrochloride in quantitative yield. This salt was used directly without purification. (2S)-2-{[(tert-butoxy)carbonyl]amino}-2-cycloheptylacetic acid (1.0 equivalent), HATU (1.5 equivalents), and TEA (1.5 equivalents) were placed in DCM (1M) and stirred at 20-25°C for 1 hour. The above salt (1.0 equivalent) was added and the mixture was stirred for 2 hours. Water was added and the mixture was stirred for 15 minutes. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to obtain compound 169-5. Synthesis of compound 169 Compound 169-5 was dissolved in the minimum amount of ethyl acetate, and dioxane·HCl was added and the mixture was stirred at 25°C for 2 hours. The reaction solvent was then removed under reduced pressure to obtain the amine hydrochloride in quantitative yield. This salt was used directly without purification. 1-Isopropyl-1H-pyrazole-5-carboxylic acid (1.0 equivalent), HATU (1.5 equivalents), and TEA (1.5 equivalents) were added to DCM (1M) and the mixture was stirred at 20-25°C for 1 hour. The above salt (1.0 equivalent) was added and the mixture was stirred for 2 hours. Water was added and the mixture was stirred for 15 minutes. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under reduced pressure to obtain compound 169. Route 15. Synthesis of compounds 189, 190, 191, 192, and 194 N,N'-Disuccinimidyl carbonate (0.51 g, 2 mmol) and pyridine (0.19 g, 2.4 mmol) were added to a solution of 2,2-difluorocyclopropanemethanol (216 mg, 2.00 mmol) in acetonitrile (4 mL). The mixture was stirred overnight at room temperature to obtain a clear solution. Saturated NaHCO3 aqueous solution (5 mL) and saline solution (20 mL) were added to separate the phases. The aqueous phase was extracted with ELISA (2 × 50 mL), and the combined organic phase was washed with saline solution (20 mL), dried over MgSO4, and concentrated under reduced pressure to obtain (2,2-difluorocyclopropyl)methyl 2,5-dioxopyrrolidine-1-yl carbonate (313 mg, yield 62.86%). We proceeded to the next stage without purification. A mixture of 189-4 (25 mg, 0.046 mmol), 189-3 (0.013 g, 0.055 mmol), TEA, and triethylamine (0.014 g, 0.14 mmol) in acetonitrile (1.5 mL) was heated overnight at room temperature. The reaction mixture was washed with water and saline solution, and then extracted with toluene (3 × 5 mL). The combined organic extract was dried over Na₂SO₄ and concentrated under reduced pressure. The concentrate was purified by column chromatography (elution with silica gel, DCM / CH3OH) to obtain compound 189: (2,2-difluorocyclopropyl)methyl N-[(S)-cycloheptyl[(2-(3,3-difluorocyclobutyl)-4-(3-(trifluoromethyl)azetidine-1-carbonyl)-3,4-dihydro-2H-1-benzopyran-7-yl)carbamoyl]methyl]carbamate (3.6 mg, yield 11.55%). Compounds 190, 191, 192, and 194 were synthesized by a similar method. JPEG2026519467000063.jpg 112167 Chiral Resolution The compound of formula I was separated chirally by pre-HPLC. The chromatography column was CHIRALPAK® IA, 10 μm, 30*250 mm, with mobile phase A being HEX and mobile phase B being IPC, UV spectroscopy 254 Nm, and the isoglobin elution program being mobile phase A:mobile phase B = 60:40 (V / V). The following compounds are prepared according to the procedure described herein, using appropriate starting materials and intermediates, and, if necessary, appropriate protecting group chemistry. 1 Confirmed by HNMR and MS. [Table 1] JPEG2026519467000064.jpg229164 JPEG2026519467000065.jpg229162 JPEG2026519467000066.jpg229162 JPEG2026519467000067.jpg229162 JPEG2026519467000068.jpg229162 JPEG2026519467000069.jpg229162 JPEG2026519467000070.jpg229162 JPEG2026519467000071.jpg229162 JPEG2026519467000072.jpg229162 JPEG2026519467000073.jpg229162 JPEG2026519467000074.jpg229162 JPEG2026519467000075.jpg229162 JPEG2026519467000076.jpg229162 JPEG2026519467000077.jpg229162 JPEG2026519467000078.jpg229162 JPEG2026519467000079.jpg229162 JPEG2026519467000080.jpg229162 JPEG2026519467000081.jpg229162 JPEG2026519467000082.jpg229162 JPEG2026519467000083.jpg229162 JPEG2026519467000084.jpg229162 JPEG2026519467000085.jpg229162 JPEG2026519467000086.jpg229162 JPEG2026519467000087.jpg229162 JPEG2026519467000088.jpg229162 JPEG2026519467000089.jpg229162 JPEG2026519467000090.jpg229162 JPEG2026519467000091.jpg229162 JPEG2026519467000092.jpg229162 JPEG2026519467000093.jpg229162 JPEG2026519467000094.jpg229162 JPEG2026519467000095.jpg229162 JPEG2026519467000096.jpg229162 JPEG2026519467000097.jpg229162 JPEG2026519467000098.jpg229162 JPEG2026519467000099.jpg229162 JPEG2026519467000100.jpg229162 JPEG2026519467000101.jpg229162 JPEG2026519467000102.jpg229162 JPEG2026519467000103.jpg229162 JPEG2026519467000104.jpg229162 JPEG2026519467000105.jpg229162 JPEG2026519467000106.jpg229162 JPEG2026519467000107.jpg229162 JPEG2026519467000108.jpg229162 JPEG2026519467000109.jpg229162 JPEG2026519467000110.jpg229162 JPEG2026519467000111.jpg229162 JPEG2026519467000112.jpg229162 JPEG2026519467000113.jpg229162 JPEG2026519467000114.jpg229162 JPEG2026519467000115.jpg229163 [Example 2] JPEG2026519467000116.jpg175167

[0171] compound management 1. The test compound was sequentially diluted 3-fold from 10 mM in DMSO for 10 doses. 2. The reference compound (IL-17A inhibitor-1) was prepared in DMSO by serially diluting it 3-fold from 1 mM for 10 doses. 3. A 1000-fold positive control (1 mM IL-17A inhibitor-1) and a 1000-fold solvent control (100% DMSO) were prepared.

[0172] Assay procedure a) Cells were cultured according to the recommendations of the HEK-Blue® IL-17 technical datasheet. HEK-Blue IL-17 cells were assayed during the logarithmic growth phase. b) The growth medium was aspirated and the cells were washed twice with PBS to remove phenol red. c) The cells were resuspended in the test medium to the appropriate concentration. d) Only cells with a viability rate of over 90% were used in the assay. e) Using Echo655, compound dilutions were transferred in 25 nL increments to a 384-well assay plate. f) HEK-BlueIL-17 cells (25 μL) were seeded at a rate of 8,000 cells / well in a 384-well plate containing rhIL-17A / A. g) Cells were incubated at 37°C in a 5% CO2 atmosphere for 20 hours. h) 2 μL of cell supernatant was transferred to each well of a 384-well assay plate. i) 20 μL of PNPP substrate was added. j) Absorbance at 405 nm was measured using an Envision2105 plate reader.

[0173] Data Analysis For each well, the RLU signal (LUM cmpd ) was calculated. The inhibition rate (%) was calculated as follows: [formula] JPEG2026519467000117.jpg27158 Signal ave_pc: Average signal of the positive control across the entire plate. Signal ave_vc: Average signal of the negative control across the entire plate. The IC50 of the compounds was calculated, and an effect-dose curve was created. Using GraphPad 8.0, the logarithm of the inhibition rate (%) and compound concentration was fitted to a nonlinear regression (dose-response - variable gradient) to calculate the IC50. The results are summarized in Table 2. [Table 2] JPEG2026519467000118.jpg165167 Example 3. Pharmacokinetics of the compound of this application The compounds described in this application were formulated in 40% PEG400 / 10% Solutol / 2% Tween 80 / 48% physiological saline (v / v / v / v) and administered orally (PO) to fasted SD rats at a dose of 10 mg per kilogram of body weight. Plasma samples were collected at 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. Compound concentrations were measured by LC-MS, and pharmacokinetic parameters were calculated using WinNonlin 8.2 with a non-compartmental analysis model. Table 3 shows the PK parameters of representative compounds. [Table 3] JPEG2026519467000119.jpg33167

Claims

1. Compounds of formula I, pharmaceutically acceptable salts thereof, deuterium-substituted compounds, and isomers, Ring C is aryl, 5-6 member heteroaryl, C ３－１０ cycloalkyl, C ３－１０ heterocyclyl, R ｘ -C ３－１０ cycloalkyl, R ｘ -C ３－１０ heterocyclyl, R ｘ -aryl and R ｘ -5-6 member heteroaryl, and R ｘ is halogen or -C １－６ alkyl, Ring C has any one or more R １ Replaced by, Each R １ OH, CN, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, -CO-C １－６ Alkyl, -CO-C １－６ Haloalkyl, -CO-NR ３ａ R ３ｂ , C ３－１０ Cycloalkyl, C ３－１０ Heterocyclyl, C ６－１０ Independently selected from the group consisting of aryls and 5-10 membered heteroaryls, Each R １ These are halogen, oxo, -OH, -CN, and -C １－６ Alkyl, -C １－６ Alkoxy, -C １－６ Haloalkoxy, -C １－６ Haloalkyl, -C ３－１０ Cycloalkyl, heterocyclyl, -C ６－１０ Aryl, 5-10 member heteroaryl, -S(O)-C １－６ Alkyl, -S(O) ２ -C １－６ Alkyl and -S-C １－６ They are optionally substituted with one or more substituents independently selected from the group consisting of alkyl groups, n is either 0 or 1, R ２ is, -C ０－１ Alkyl-C ３－９ Cycloalkyl, -C １－６ Alkyl and -C １－２ Alkyl-O-C １－３ Selected from the group consisting of alkyl groups, the -C ０－１ Alkyl-C ３－９ Cycloalkyl, the above-C １－６ Alkyl or the aforementioned -C １－２ Alkyl-O-C １－３ Alkyl is C ３－６ Cycloalkyl, halogen, CH ３ CHF ２ CF ３ Optionally substituted with one or more substituents independently selected from the group consisting of , OH, and oxo, X １ is NH, O, or S, X ２ is N, O, or S, and X ２ It can optionally bond to an atom in ring A, forming another ring adjacent to ring A. X ３ is O or -CR ｃ R ｄ And R ｃ and R ｄ These are H, halogen, and -C, respectively, independently. １－６ Selected from the group consisting of alkyl groups, Ring A is, Selected from the group consisting of, Z １ Z ２ and Z ３ These are independent of each other: -N=, -N(=O)=, and -C(R ａ Selected from the group consisting of ) = R ａ H, F, Cl, Br, I, -C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkynyl, OH, CN, -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ３－１０ Selected from the group consisting of heterocyclyls, aryls, and 5-10 membered heteroaryls, Ring B condensed to ring A is selected from the group consisting of 4-7 member heterocycloalkyl, 4-7 member heterocycloaryl, 4-7 member cycloalkyl, and 4-7 member cycloalkenyl, and each of the 4-7 member heterocycloalkyl, 4-7 member heterocycloaryl, 4-7 member cycloalkyl, and 4-7 member cycloalkenyl is optionally a saturated or unsaturated crosslinking ring. Ring B is optionally substituted with one or more Rs ｂ and each R ｂ is CN, C １－６ alkyl, C １－６ haloalkyl, -O-C １－６ alkyl, -O-C １－６ haloalkyl, -CO-C １－６ alkyl, -COOC １－６ alkyl, -CO-C １－６ haloalkyl, -CO-NR ３ａ R ３ｂ 、-CH ２ -NR ３ａ R ３ｂ 、-NR ３ａ -CO-C １－６ alkyl, -NR ３ａ -COOC １－６ alkyl, -NR ３ａ -CO-C １－６ haloalkyl, -NR ３ａ -CO-NR ３ａ R ３ｂ 、C ２－６ alkenyl, C ２－６ alkynyl, C ３－１０ cycloalkyl, heterocyclyl, C ６－１０ aryl, 5-10 member heteroaryl, -C １－６ alkyl-C ３－１０ cycloalkyl, -C １－６ alkyl-heterocyclyl, -C １－６ alkyl-C ６－１０ aryl, -C １－６ alkyl-5-10 member heteroaryl, F, -CH ３ 、-CHF ２ 、-CF ３ 、and OH, respectively independently selected from the group consisting of, and two R ｂ groups may optionally be joined to form C ３－１０ cycloalkyl, heterocyclyl, C ６－１０ aryl, or 5-10 member heteroaryl, and each R ｂ is halogen, CN, C １－６ alkyl, C １－６ haloalkyl, -O-C １－６ alkyl, -O-C １－６ haloalkyl, -CO-C １－６ Alkyl, COOC １－６ Alkyl, -CO-C １－６ Haloalkyl, -CO-NR ３ａ R ３ｂ ien-CH ２ -NR ３ａ R ３ｂ , C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, C ６－１０ Optionally substituted with one or more substituents independently selected from the group consisting of aryls and 5-10 membered heteroaryls, Ring B is R ３ Replaced with R ３ H-CONR ３ａ R ３ｂ , -S(O)-NR ３ａ R ３ｂ , -S(O) ２ -NR ３ａ R ３ｂ , -C ０－６ Alkyl-CONR ３ａ R ３ｂ , -C ０－６ Alkyl-NR ３ａ R ３ｂ , -N(R ３ａ )-COR ３ａ , -N(R ３ａ ) - CONR ３ａ R ３ｂ , -C ０－６ Alkyl-SONR ３ａ R ３ｂ , -C ０－６ Alkyl-SO ２ NR ３ａ R ３ｂ , -C(S)-NR ３ａ R ３ｂ CN, 5-10 member heteroaryl, -COR ３ａ , -P(O)(OR ３ａ ) ( OR ３ｂ ), -S(O)-C １－６ Alkyl, -S(O) ２ -C １－６ Alkyl, C １－６ Alkyl, -C １－６ Alkyl-C ３－１０ Cycloalkyl, -O-C １－６ Selected from the group consisting of alkyl, aryl, heterocyclyl, alkylheterocyclyl, alkylaryl, and alkylcycloalkyl, the 5-10 member heteroaryl and the -S(O)-C １－６ Alkyl, the aforementioned -S(O) ２ -C １－６ alkyl, the C １－６ Alkyl, the above-C １－６ Alkyl-C ３－１０ Cycloalkyl, the -O-C １－６ Alkyl, the aryl, the heterocyclyl, the alkylheterocyclyl, the alkylaryl, or the alkylcycloalkyl may optionally contain halogens, C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl and -O-C １－６ Substituted with one or more substituents independently selected from the group consisting of haloalkyls, R ３ａ and R ３ｂ C １－６ Alkyl, C １－６ Haloalkyl, -C ２－６ Alkenyl, -C ２－６ Alkinyl, C ０－２ Alkyl-C ３－６ A group consisting of cycloalkyls and 5-6 membered heterocyclines is independently selected, or R ３ａ and R ３ｂ This can be arbitrarily combined into C ３－１０ Cycloalkyl, heterocyclyl, C ６－１０ Forming an aryl or 5-10 member heteroaryl, the C １－６ alkyl, the C １－６ Haloalkyl, the above-C ２－６ Alkenyl, the above-C ２－６ Alkinyl, the C ０－２ Alkyl-C ３－６ Cycloalkyl, the 5-6 membered heterocyclyl, the C ３－１０ Cycloalkyl, the heterocyclyl, the C ６－１０ The aryl, or the 5-10 member heteroaryl, may optionally contain halogens, C １－６ Alkyl and C １－６ Substituted with one or more substituents independently selected from the group consisting of haloalkyl groups, Compounds characterized by the above, pharmaceutically acceptable salts thereof, deuterium-substituted compounds, and isomers thereof.

2. Ring B condenses with ring A and is selected from the following group: R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ , R ｂ６ and R ｂ７ is, -C １－６ Alkyl, -C １－６ Haloalkyl, O-C １－６ Alkyl, -O-C １－６ Haloalkyl, -CO-C １－６ Alkyl, COOC １－６ Alkyl, -CO-C １－６ Haloalkyl, -CO-NR ３ａ R ３ｂ ien-CH ２ -NR ３ａ R ３ｂ , -C ２－６ Alkenyl, -C ２－６ Alkinyl, -C ３－１０ Cycloalkyl, heterocyclyl, C ６－１０ Aryl, 5-10 member heteroaryl, -C １－６ Alkyl-C ３－１０ Cycloalkyl, -C １－６ Alkyl-heterocyclyl, -C １－６ Alkyl-C ６－１０ Ariel, -C １－６ Alkyl-5-10 membered heteroaryl, H, F, -CH ３ ,-CHF ２ , -CF ３ Independently selected from the group consisting of , and OH, and R ｂ１ , R ｂ２ , R ｂ３ , R ｂ４ , R ｂ５ , R ｂ６ , R ｂ７ and R ３ Any two of these can be combined, C ３－１０ Cycloalkyl, heterocyclyl, C ６－１０ Forming an aryl or 5-10 membered heteroaryl, X ｂ１ and X ｂ２ The compound according to claim 1, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof, wherein each of the elements is independently C, N, O, or S.

3. R ｂ１ and R ｂ２ Each is independent of the others. Selected from the group consisting of, The compound according to claim 2, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

4. R ３ The base is -CONR ３ａ R ３ｂ , -S(O)-NR ３ａ R ３ｂ , -S(O) ２ -NR ３ａ R ３ｂ , -C １－６ Alkyl-CONR ３ａ R ３ｂ , -C １－６ Alkyl-NR ３ａ R ３ｂ , -N(R ３ａ )-COR ３ａ , -N(R ３ａ ) - CONR ３ａ R ３ｂ , -C １－６ Alkyl-SONR ３ａ R ３ｂ , -C １－６ Alkyl-SO ２ NR ３ａ R ３ｂ ,CN,-COR ３ａ , and -O-C １－６ Selected from the group consisting of alkyl groups, R ３ is halogen, C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl and -O-C １－６ The compound according to claim 1, optionally substituted with one or more substituents independently selected from the group consisting of haloalkyls, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

5. R ３ The base is -CONR ３ａ R ３ｂ , -C １－６ Alkyl-CONR ３ａ R ３ｂ , -C １－６ Alkyl-NR ３ａ R ３ｂ , -N(R ３ａ )-COR ３ａ , -N(R ３ａ ) - CONR ３ａ R ３ｂ , and -COR ３ａ A compound according to claim 4, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer, selected from the group consisting of the above.

6. R ３ａ and R ３ｂ H, C １－６ Alkyl, C １－６ Haloalkyl, -C ２－６ Alkenyl, -C ２－６ Alkinyl, C ０－６ Alkyl-C ３－６ A group consisting of cycloalkyls and 5-6 membered heterocyclines is independently selected, or R ３ａ and R ３ｂ This can be arbitrarily combined into C ３－１０ Forming cycloalkyl and heterocyclyl groups, the C １－６ alkyl, the C １－６ Haloalkyl, the above-C ２－６ Alkenyl, the above-C ２－６ Alkinyl, the C ０－２ Alkyl-C ３－６ Cycloalkyl, the 5-6 membered heterocyclyl, the C ３－１０ Cycloalkyls and the heterocyclyls are halogens, C １－６ Alkyl and C １－６ The compound according to claim 1, optionally substituted with one or more substituents independently selected from the group consisting of haloalkyls, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

7. R ３ａ and R ３ｂ H, C １－６ Alkyl and C １－６ Compounds according to claim 6, each independently selected from the group consisting of haloalkyls, pharmaceutically acceptable salts thereof, deuterium-substituted compounds, and isomers thereof.

8. R ３ａ and R ３ｂ These can be arbitrarily combined to form C ３－１０ Cycloalkyl, heterocyclyl, C ６－１０ Forming aryl and 5-10 member heteroaryls, the C ３－１０ Cycloalkyl, the heterocyclyl, the C ６－１０ The aryl, or the 5-10 member heteroaryl, may optionally contain halogens, C １－６ Alkyl, -O-C １－６ Alkyl and C １－６ The compound according to claim 6, substituted with one or more substituents independently selected from the group consisting of haloalkyls, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

9. R ３ The basis is, And, Ring D is C ３－１０ It is a cycloalkyl or 3-10 membered heterocycline, X ４ is N or CH, and ring D is optionally oxo, halogen, or C １－６ Alkyl, -O-C １－６ Alkyl and C １－６ The compound according to claim 1, wherein the compound is substituted with a haloalkyl group, the heterocyclyl having 1 to 4 heteroatoms, each of which is independently N, O, or S, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

10. R ３ The basis is, A compound according to claim 1, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof, selected from the group consisting of the above.

11. Ring C consists of aryl, 5-6 member heteroaryl, and C ３－１０ A compound according to claim 1, selected from the group consisting of cycloalkyls, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

12. The compound according to claim 11, wherein ring C is a 5-6 membered heteroaryl compound, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

13. Ring C is, A compound according to claim 11, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer, selected from the group consisting of the above.

14. Ring C is, The compound according to claim 13, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

15. Ring C is C ３－１０ It is a cycloalkyl, and the cycloalkyl is a halogen, C １－６ Alkyl and C １－６ The compound according to claim 1, optionally substituted with one or more substituents independently selected from the group consisting of haloalkyls, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

16. X ３ The compound according to claim 1, wherein is O, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

17. X ３ ga-CR ｃ R ｄ The compound according to claim 1, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

18. R ｂ H, C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, C ６－１０ Aryl, 5-10 member heteroaryl, -C １－６ Alkyl-C ３－１０ Cycloalkyl, -C １－６ Independently selected from the group consisting of alkyl-heterocyclyl, F, and OH, and two R ｂ The bases can be arbitrarily combined, C ３－１０ Forms a cycloalkyl or heterocycline, and each R ｂ is halogen, C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, C ３－１０ The compound according to claim 1, optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl and heterocyclyl, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

19. R ｂ H, C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, C ３－１０ Cycloalkyl, heterocyclyl, -C １－６ Alkyl-C ３－１０ Cycloalkyl and -C １－６ Independently selected from the group consisting of alkyl-heterocyclines, two R ｂ The bases can be arbitrarily combined, C ３－１０ Forms a cycloalkyl or heterocycline, and each R ｂ is halogen, C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, C ３－１０ The compound according to claim 1, optionally substituted with one or more substituents independently selected from the group consisting of cycloalkyl and heterocyclyl, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

20. R １ These are halogen, oxo, and -C １－６ Alkyl, -C １－６ Alkoxy, -C １－６ Haloalkoxy, -C １－６ Haloalkyl and -C ３－１０ A compound according to claim 1, independently selected from the group consisting of cycloalkyls, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

21. R １ is halogen, -C １－６ Alkyl, -C １－６ Haloalkyl and -C ３－１０ A compound according to claim 20, independently selected from the group consisting of cycloalkyls, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

22. R １ is, -C １－６ Alkyl, -C １－６ Haloalkyl and -C ３－１０ A compound according to claim 21, independently selected from the group consisting of cycloalkyls, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

23. R ２ Ha-C ０－１ Alkyl-C ３－９ It is a cycloalkyl, and the -C ０－１ Alkyl-C ３－９ Cycloalkyl is C ３－６ Cycloalkyl, halogen, CH ３ CHF ２ CF ３ The compound according to claim 1, optionally substituted with one or more substituents independently selected from the group consisting of OH and oxo, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

24. R ２ teeth, Selected from the group consisting of, R ２ａ and R ２ｂ These are H, halogen, and C １－３ Selected from the group consisting of alkyl groups, R ２ Optionally, one or more halogens and C １－６ The compound according to claim 23, which is substituted with an alkyl group, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

25. R ２ teeth, A compound according to claim 24, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer, selected from the group consisting of the above.

26. R ２ teeth, A compound according to claim 25, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer, selected from the group consisting of the above.

27. The compound according to any one of claims 1 to 25, wherein the compound has a structure selected from the group consisting of formulas I-A-1, I-A-2, I-A-3, and I-A-4, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

28. The compound has a structure selected from the group consisting of formulas I-A-5, I-A-6, I-A-7, and I-A-8. Z ４ はO、S、S=O、S(=O) ２ , or NR ｂ１ And, X １ is O, S, or NH, and Z １ Z ２ or Z ３ These are independently N or -CR-R ａ The compound according to any one of claims 1 to 25, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

29. The compound has a structure selected from the group consisting of formulas I-A-9, I-A-10, I-A-11, and I-A-12. Z ４ はO、S、S=O、S(=O) ２ , or NR ｂ１ And, X １ is O, S, or NH, Z １ Z ２ or Z ３ Each is independently N or -CR-R ａ and The ring C is aryl, 5-6 member heteroaryl, C ３－１０ Cycloalkyl, C ３－１０ Heterocyclyl, -C １－６ Alkyl-C ３－１０ Cycloalkyl, -C １－６ Alkyl-C ３－１０ Heterocyclyl, -C １－６ Alkyl-aryl, or -C １－６ It is an alkyl-5-6 member heteroaryl, and the aryl, the 5-6 member heteroaryl, and the C ３－１０ Cycloalkyl, the C ３－１０ Heterocycline, the above-C １－６ Alkyl-C ３－１０ Cycloalkyl, the above-C １－６ Alkyl-C ３－１０ Heterocycline, the above-C １－６ Alkyl-aryl, or the aforementioned -C １－６ Alkyl-5-6 member heteroaryls are halogens, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Haloalkoxy and C １－６ A compound according to any one of claims 1 to 25, optionally substituted with one or more substituents independently selected from the group consisting of alkoxys, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

30. The compound has the structure of formula I-A-13, Z ４ is O, -C(R ｂ１ R ｂ２ )-,-N(R ｂ１ ) - and X ５ is N or CH, R ｂ１ , R ｂ２ , R ｂ３ and R ｂ４ is, -C １－６ Alkyl, -C １－６ Haloalkyl, O-C １－６ Alkyl, -O-C １－６ Haloalkyl, -CO-C １－６ Alkyl, COOC １－６ Alkyl, -CO-C １－６ Haloalkyl, -CO-NR ３ａ R ３ｂ ien-CH ２ -NR ３ａ R ３ｂ , -C ２－６ Alkenyl, -C ２－６ Alkinyl, -C ３－１０ Cycloalkyl, heterocyclyl, C ６－１０ Aryl, 5-10 member heteroaryl, -C １－６ Alkyl-C ３－１０ Cycloalkyl, -C １－６ Alkyl-heterocyclyl, -C １－６ Alkyl-C ６－１０ Ariel, -C １－６ Alkyl-5-10 membered heteroaryl, H, F, -CH ３ ,-CHF ２ , -CF ３ Independently selected from the group consisting of , and OH, and R ｂ３ and R ｂ４ This can be arbitrarily combined into C ３－１０ Forming a cycloalkyl or heterocycline, the C ３－１０ The cycloalkyl or heterocyclyl is oxo, halogen, C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl and -O-C １－６ They are optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl groups, R ３ａ and R ３ｂ H, C １－６ Alkyl, C １－６ Haloalkyl, -C ２－６ Alkenyl, -C ２－６ Alkinyl, C ０－６ Alkyl-C ３－６ Independently selected from the group consisting of cycloalkyls and 5-6 membered heterocyclines, or R ３ａ and R ３ｂ This can be arbitrarily combined into C ３－１０ Forming cycloalkyl and heterocyclyl groups, the C １－６ alkyl, the C １－６ Haloalkyl, the above-C ２－６ Alkenyl, the above-C ２－６ Alkinyl, the C ０－２ Alkyl-C ３－６ Cycloalkyl, the 5-6 membered heterocyclyl, the C ３－１０ Cycloalkyls and the heterocyclyls are halogens, C １－６ Alkyl and C １－６ They are optionally substituted with one or more substituents independently selected from the group consisting of haloalkyls, and n ａ The compound according to any one of claims 1 to 25, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof, wherein is 0, 1, and 2.

31. R ｂ３ and R ｂ４ H, -C １－６ Alkyl, -C １－６ Haloalkyl, O-C １－６ Alkyl, -O-C １－６ Haloalkyl, -C ３－１０ Cycloalkyl, heterocyclyl, -C １－６ Alkyl-C ３－１０ Cycloalkyl and -C １－６ Independently selected from the group consisting of alkyl-heterocyclines, R ｂ３ and R ｂ４ They can be arbitrarily combined into C ３－１０ Forming a cycloalkyl or heterocycline, the C ３－１０ The cycloalkyl or heterocyclyl is a halogen, C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl and -O-C １－６ The compound according to claim 30, optionally substituted with one or more substituents independently selected from the group consisting of haloalkyls, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

32. R ｂ４ is, -C １－６ Alkyl, -C １－６ Haloalkyl, -C ３－１０ Cycloalkyl, heterocyclyl, -C １－６ Alkyl-C ３－１０ Cycloalkyl and -C １－６ Selected from the group consisting of alkyl-heterocyclines, the C ３－１０ The cycloalkyl or heterocyclyl is a halogen, C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl and -O-C １－６ The compound according to claim 30, optionally substituted with one or more substituents independently selected from the group consisting of haloalkyls, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

33. R ｂ４ is, -C １－６ Alkyl, -C ３－１０ Selected from the group consisting of cycloalkyl and heterocyclyl, the C ３－１０ The cycloalkyl or heterocyclyl is a halogen, C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl and -O-C １－６ The compound according to claim 30, optionally substituted with one or more substituents independently selected from the group consisting of haloalkyls, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

34. X ５ The compound according to claim 30, wherein is N, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

35. X ５ The compound according to claim 30, wherein is CH, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

36. The compound has the structure of formula I-A-18. A compound according to any one of claims 1 to 25, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

37. Z ４ O and CH ２ A compound according to any one of claims 29 to 36, selected from the group consisting of the above, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

38. Z ４ The compound according to claim 37, wherein is O, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

39. Z ４ ga CH ２ The compound according to claim 37, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

40. The compound has the structure of formula I-A-14. A compound according to any one of claims 1 to 25, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

41. n ａ The compound according to claim 40, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof, wherein the coefficient of the compound is 0 and 1.

42. R ｂ４ is, -C １－６ Alkyl, -C １－６ Haloalkyl, -C ３－１０ Cycloalkyl, heterocyclyl, -C １－６ Alkyl-C ３－１０ Cycloalkyl, -C １－６ Selected from the group consisting of alkyl-heterocyclyl, H, and F, the C ３－１０ The cycloalkyl or heterocyclyl is a halogen, oxo, C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl and -O-C １－６ The compound according to claim 40, optionally substituted with one or more substituents independently selected from the group consisting of haloalkyls, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

43. The compound has the structure of formula I-A-15, X ５ O, -N(R ｘ５ )-,-C(R ｘ６ R ｘ７ )-, S, S(O), and S(O) ２ Selected from the group consisting of, m1 and m2 are 0, 1, 2, and 3, n ａ These are 0, 1, and 2, R ｘ５ H, C １－６ Alkyl, C １－６ Haloalkyl, -C ３－１０ Cycloalkyl, -CO-C １－６ Alkyl and -CO-C １－６ Selected from the group consisting of haloalkyls, R ｘ６ and R ｘ７ H, halogen, C １－６ Alkyl and C １－６ Compounds according to any one of claims 1 to 25, independently selected from the group consisting of haloalkyls, pharmaceutically acceptable salts thereof, deuterium-substituted compounds, and isomers thereof.

44. The compound has the structure of formula I-A-16, n ａ The compound according to any one of claims 1 to 25, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof, wherein is 0, 1, and 2.

45. R ｂ４ is, -C １－６ Alkyl, -C １－６ Haloalkyl, -C ３－１０ Cycloalkyl, heterocyclyl, -C １－６ Alkyl-C ３－１０ Cycloalkyl, -C １－６ Selected from the group consisting of alkyl-heterocyclyl, H, and F, the C ３－１０ The cycloalkyl or heterocyclyl is a halogen, C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl and -O-C １－６ The compound according to claim 44, optionally substituted with one or more substituents independently selected from the group consisting of haloalkyls, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

46. The compound has the structure of formula I-A-17, X ５ is O, -N(R ｘ５ )-,-C(R ｘ６ R ｘ７ )-, S, S(O), and S(O) ２ And, m1 and m2 are 0, 1, 2, and 3, n ａ These are 0, 1, and 2, R ｘ５ H, C １－６ Alkyl, C １－６ Haloalkyl, -CO-C １－６ Alkyl, -C ３－１０ Cycloalkyl and -CO-C １－６ It is a haloalkyl, and R ｘ６ and R ｘ７ H, halogen, C １－６ Alkyl, C １－６ A compound according to any one of claims 1 to 25, which is a haloalkyl compound, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

47. The compound has the structure of formula I-A-19. A compound according to any one of claims 1 to 25, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

48. Compounds of formula II, pharmaceutically acceptable salts thereof, deuterium-substituted compounds, and isomers, Ring C is an aryl or 5-6 member heteroaryl, Ring C has any one or more R １ Replaced by, R １ C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, C ３－１０ Heterocyclyl, C ６－１０ Selected from the group consisting of aryls and 5-10 membered heteroaryls, R １ These are halogen, oxo, -OH, -CN, and -C １－６ Alkyl, -C １－６ Alkoxy, -C １－６ Haloalkoxy, -C １－６ Haloalkyl, -C ３－１０ Cycloalkyl, heterocyclyl, -C ６－１０ It can be optionally substituted with aryl or 5-10 member heteroaryl compounds. R ｃ and R ｄ Each is independently selected from the group consisting of H and halogens. n is either 0 or 1, R ２ is, -C ０－１ Alkyl-C ３－９ Cycloalkyl, -C １－６ Alkyl and -C １－２ Alkyl-O-C １－３ Selected from the group consisting of alkyl groups, the -C ０－１ Alkyl-C ３－９ Cycloalkyl, the above-C １－６ Alkyl or the aforementioned -C １－２ Alkyl-O-C １－３ Alkyl is C ３－６ Cycloalkyl, halogen, CH ３ CHF ２ CF ３ Optionally substituted with one or more substituents independently selected from the group consisting of , OH, and oxo, X １ is NH, O, or S, X ２ is N, O, or S, and X ２ It can arbitrarily bond to an atom within ring A, forming another ring adjacent to ring A. Ring A is, Selected from the group consisting of, Z １ Z ２ and Z ３ These are N, N=O, and -CR-R, respectively, independently. ａ Selected from the group consisting of R ａ H, F, Cl, -CH ３ ,-CHF ２ , -CF ３ ,OH,-OCH ３ , and -OCF ３ Selected from the group consisting of, Ring B condensed to ring A is selected from the group consisting of 4-7 member heterocycloalkyl, 4-7 member heterocycloaryl, 4-7 member cycloalkyl, and 4-7 member cycloalkenyl, and each of the 4-7 member heterocycloalkyl, 4-7 member heterocycloaryl, 4-7 member cycloalkyl, and 4-7 member cycloalkenyl is optionally a saturated and unsaturated crosslinking ring. Ring B contains one or more R ｂ It is arbitrarily replaced by each R ｂ C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, C ６－１０ Aryl, 5-10 member heteroaryl, -C １－６ Alkyl-C ３－１０ Cycloalkyl, -C １－６ Alkyl-heterocyclyl, -C １－６ Alkyl-C ６－１０ Ariel, -C １－６ Alkyl-5-10 membered heteroaryl, F,-CH ３ ,-CHF ２ , -CF ３ Independently selected from the group consisting of , and OH, two R ｂ The bases can be arbitrarily combined, C ３－１０ Cycloalkyl, heterocyclyl, C ６－１０ Forming an aryl or 5-10 membered heteroaryl, each R ｂ It is optionally replaced with one or more halogens, Ring B is R ３ Replaced with R ３ teeth, Selected from the group consisting of, R ３ａ and R ３ｂ C １－６ Alkyl, C １－６ Haloalkyl, -C ２－６ Alkenyl, -C ２－６ Alkinyl, C ０－２ Alkyl-C ３－６ A cycloalkyl group and a 5-6 membered heterocycline group are independently selected, R ３ａ and R ３ｂ These can be arbitrarily combined to form C ３－１０ Cycloalkyl, heterocyclyl, C ６－１０ Compounds characterized by forming an aryl or 5-10 membered heteroaryl group, pharmaceutically acceptable salts thereof, deuterium-substituted compounds, and isomers.

49. Compounds of formula III, pharmaceutically acceptable salts thereof, deuterium-substituted compounds, and isomers, The ring C is aryl, 5-6 member heteroaryl, C ３－１０ Cycloalkyl, C ３－１０ Heterocycline, R ｘ -C ３－１０ Cycloalkyl, R ｘ -C ３－１０ Heterocycline, R ｘ - Aryl, and R ｘ -5-6 member heteroaryl, R ｘ is halogen or -C １－６ It is alkyl, Ring C has any one or more R １ Replaced by, Each R １ These are independently OH, CN, and C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkinyl, -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, -CO-C １－６ Alkyl, -CO-C １－６ Haloalkyl, -CO-NR ３ａ R ３ｂ , C ３－１０ Cycloalkyl, C ３－１０ Heterocyclyl, C ６－１０ Selected from the group consisting of aryls and 5-10 membered heteroaryls, Each R １ These are halogen, oxo, -OH, -CN, and -C １－６ Alkyl, -C １－６ Alkoxy, -C １－６ Haloalkoxy, -C １－６ Haloalkyl, -C ３－１０ Cycloalkyl, heterocyclyl, -C ６－１０ Aryl, 5-10 member heteroaryl, -S(O)-C １－６ Alkyl, -S(O) ２ -C １－６ Alkyl and -S-C １－６ They are optionally substituted with one or more substituents independently selected from the group consisting of alkyl groups, n is either 0 or 1, R ２ is, -C ０－１ Alkyl-C ３－９ Cycloalkyl, -C １－６ Alkyl and -C １－２ Alkyl-O-C １－３ Selected from the group consisting of alkyl groups, the -C ０－１ Alkyl-C ３－９ Cycloalkyl, the above-C １－６ Alkyl or the aforementioned -C １－２ Alkyl-O-C １－３ Alkyl is C ３－６ Cycloalkyl, halogen, CH ３ CHF ２ CF ３ Optionally substituted with one or more substituents independently selected from the group consisting of , OH, and oxo, X １ is NH, O, or S, X ２ is N, O, or S, and X ２ It can optionally bond to an atom in ring A, forming another ring adjacent to ring A. X ３ is O or -CR ｃ R ｄ And R ｃ and R ｄ Each of these is independently H, halogen, and -C. １－６ Selected from the group consisting of alkyl groups, Ring A is, Selected from the group consisting of, Z １ Z ２ and Z ３ These are independent of each other: -N=, -N(=O)=, and -C(R ａ Selected from the group consisting of ) = R ａ H, F, Cl, Br, I, -C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenil, C ２－６ Alkynyl, OH, CN, -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, C ３－１０ Cycloalkyl, C ３－１０ Selected from the group consisting of heterocyclyls, aryls, and 5-10 membered heteroaryls, Ring B condensed to ring A is selected from the group consisting of 4-7 member heterocycloalkyl, 4-7 member heterocycloaryl, 4-7 member cycloalkyl, and 4-7 member cycloalkenyl, and each of the 4-7 member heterocycloalkyl, 4-7 member heterocycloaryl, 4-7 member cycloalkyl, and 4-7 member cycloalkenyl is optionally a saturated or unsaturated crosslinking ring. Ring B contains one or more R ｂ It is arbitrarily replaced by each R ｂ , CN, C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, -CO-C １－６ Alkyl, COOC １－６ Alkyl, -CO-C １－６ Haloalkyl, -CO-NR ３ａ R ３ｂ ien-CH ２ -NR ３ａ R ３ｂ , -NR ３ａ -CO-C １－６ Alkyl, -NR ３ａ - COOC １－６ Alkyl, -NR ３ａ -CO-C １－６ Haloalkyl, -NR ３ａ -CO-NR ３ａ R ３ｂ , C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, C ６－１０ Aryl, 5-10 member heteroaryl, -C １－６ Alkyl-C ３－１０ Cycloalkyl, -C １－６ Alkyl-heterocyclyl, -C １－６ Alkyl-C ６－１０ Ariel, -C １－６ Alkyl-5-10 membered heteroaryl, F,-CH ３ ,-CHF ２ , -CF ３ Independently selected from the group consisting of , and OH, two R ｂ The bases can be arbitrarily combined, C ３－１０ Cycloalkyl, heterocyclyl, C ６－１０ Forming an aryl or 5-10 membered heteroaryl, each R ｂ is halogen, CN, C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl, -O-C １－６ Haloalkyl, -CO-C １－６ Alkyl, COOC １－６ Alkyl, -CO-C １－６ Haloalkyl, -CO-NR ３ａ R ３ｂ ien-CH ２ -NR ３ａ R ３ｂ , C ２－６ Alkenil, C ２－６ Alkinyl, C ３－１０ Cycloalkyl, heterocyclyl, C ６－１０ Optionally substituted with one or more substituents independently selected from the group consisting of aryls and 5-10 membered heteroaryls, Ring B is R ３ Replaced with R ３ is, -CONR ３ａ R ３ｂ , -S(O)-NR ３ａ R ３ｂ , -S(O) ２ -NR ３ａ R ３ｂ , -C ０－６ Alkyl-CONR ３ａ R ３ｂ , -C ０－６ Alkyl-NR ３ａ R ３ｂ , -N(R ３ａ )-COR ３ａ , -N(R ３ａ ) - CONR ３ａ R ３ｂ , -C ０－６ Alkyl-SONR ３ａ R ３ｂ , -C ０－６ Alkyl-SO ２ NR ３ａ R ３ｂ , -C(S)-NR ３ａ R ３ｂ CN, 5-10 member heteroaryl, -COR ３ａ , -P(O)(OR ３ａ ) ( OR ３ｂ ), -S(O)-C １－６ Alkyl, -S(O) ２ -C １－６ Alkyl, C １－６ Alkyl, -C １－６ Alkyl-C ３－１０ Cycloalkyl, -O-C １－６ Selected from the group consisting of alkyl, aryl, heterocyclyl, alkylheterocyclyl, alkylaryl, and alkylcycloalkyl, the -5-10 member heteroaryl and the -S(O)-C １－６ Alkyl, the aforementioned -S(O) ２ -C １－６ alkyl, the C １－６ Alkyl, the above-C １－６ Alkyl-C ３－１０ Cycloalkyl, the -O-C １－６ Alkyl, the aryl, the heterocyclyl, the alkylheterocyclyl, the alkylaryl, or the alkylcycloalkyl is a halogen, C １－６ Alkyl, C １－６ Haloalkyl, -O-C １－６ Alkyl and -O-C １－６ They are optionally substituted with one or more substituents independently selected from the group consisting of haloalkyl groups, R ３ａ and R ３ｂ C １－６ Alkyl, C １－６ Haloalkyl, -C ２－６ Alkenyl, -C ２－６ Alkinyl, C ０－２ Alkyl-C ３－６ A group consisting of cycloalkyls and 5-6 membered heterocyclines is independently selected, or R ３ａ and R ３ｂ This can be arbitrarily combined into C ３－１０ Cycloalkyl, heterocyclyl, C ６－１０ Forming an aryl or 5-10 member heteroaryl, the C １－６ alkyl, the C １－６ Haloalkyl, the above-C ２－６ Alkenyl, the above-C ２－６ Alkinyl, the C ０－２ Alkyl-C ３－６ Cycloalkyl, the 5-6 membered heterocyclyl, the C ３－１０ Cycloalkyl, the heterocyclyl, the C ６－１０ The aryl, or the 5-10 membered heteroaryl, is a halogen, C １－６ Alkyl and C １－６ A compound characterized by being optionally substituted with one or more substituents independently selected from the group consisting of haloalkyls, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, and an isomer thereof.

50. Having a structure selected from the following group: Compounds characterized by the above, pharmaceutically acceptable salts thereof, deuterium-substituted compounds, and isomers thereof.

51. A pharmaceutical composition comprising a compound according to any one of claims 1 to 50, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, or an isomer thereof, and a pharmaceutically acceptable excipient.

52. A method for regulating IL-17A in a subject, A method characterized by comprising the step of administering to the subject an effective amount of a compound according to any one of claims 1 to 50, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, or an isomer thereof, or a pharmaceutical composition according to claim 51.

53. A method for treating an inflammatory disease or condition in a subject, A method characterized by comprising the step of administering to the subject an effective amount of a compound according to any one of claims 1 to 50, a pharmaceutically acceptable salt thereof, a deuterium-substituted compound, or an isomer thereof, or a pharmaceutical composition according to claim 51.

54. The method according to claim 53, wherein the inflammatory disease or condition is selected from the group consisting of psoriasis vulgaris, guttate psoriasis, psoriasis reversal, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis, and non-infectious uveitis.

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