Small molecule modulators of IL-17A, methods of preparation and methods of use thereof

Abstract

Described herein are compounds of IL-17A modulators useful in the treatment of IL-17A-mediated inflammatory syndrome, conditions or diseases.

Description

[0001] Citation of relevant applications

[0002] This application claims the full benefits of Chinese Patent Application No. 202310267210.6, filed with the State Intellectual Property Office of China on March 14, 2023, and U.S. Provisional Application No. 63 / 492,386, filed with the United States Patent and Trademark Office on March 27, 2024, the entire contents of which are incorporated herein by reference.

[0003] field

[0004] This application discloses compounds that regulate IL-17A and pharmaceutical compositions thereof. Therapeutic uses of such compounds are also disclosed herein, for example, for treating and / or improving IL-17A-mediated inflammatory syndromes, conditions, or diseases.

[0005] background

[0006] The interleukin-17 (IL-17) cytokine family, including IL-17A through IL-17F, promotes the maintenance of both adaptive and innate immunity. Released cytokines exert their effects through their membrane-bound IL-17 receptors (IL-17R), a family with five receptors (IL-17RA through IL-17RE), and activate the IL-17 signaling pathway. Dysregulation of IL-17 expression may contribute to inflammatory and autoimmune diseases such as psoriasis, psoriatic arthritis, rheumatoid arthritis, and multiple sclerosis.

[0007] Interleukin-17A (IL-17A) is the most studied member of the IL-17 family. It is a recognized pro-inflammatory cytokine that plays a crucial role in immune and autoimmune-related diseases, including psoriasis, asthma, psoriatic arthritis, and rheumatoid arthritis. IL-17A forms homodimers or heterodimers with IL-17A or IL-17F and is a major cytokine primarily secreted by Th17 cells. It signals through its membrane-bound receptors IL-17RA and IL-17RC and regulates the IL-17A signaling pathway, triggering various inflammatory and immune responses. Therefore, IL-17A has become an important area of ​​research in the treatment of inflammation-related diseases.

[0008] Blocking the IL-17A / IL-17RA protein-protein interaction (PPI) is hypothesized to reduce excessive inflammation in autoimmune diseases. Several approaches exist to block IL-17A signaling by targeting the IL-17A protein or receptor. Clinically, several monoclonal antibodies (mAbs) have been approved for various autoimmune diseases. While no oral small molecule IL-17A inhibitors have yet entered late-stage clinical trials, they represent an attractive area of ​​discovery because their development could expand treatment options for many patients who lack access to biologics. Therefore, there is a need for new small molecule IL-17A modulators (e.g., inhibitors).

[0009] Overview

[0010] This application relates, in part, to compounds of formula I:

[0011]

[0012] Its pharmaceutically acceptable salts, its deuterated compounds, and its stereoisomers,

[0013] in

[0014] R1 is selected from aryl, 5-6 heteroaryl, -C 1-3 alkyl-aryl or -C 1-3 alkyl-5-6-membered heteroaryl; wherein R1 is optionally surrounded by one or more R 1a replace;

[0015] Where R 1a Independently selected from halogens, oxometalates, -OH, -CN, and -C 1-6 Alkyl or -C 0-2 Alkyl-C 3-6 cycloalkyl; wherein each R 1a Optionally, it may be substituted by one or more substituents, each independently selected from halogens;

[0016] R2 and R3 are each independently selected from H and -C. 1-6 Alkyl, aryl, C 3-10 cycloalkyl, -C 0-2 Alkyl-C 3-10 Cycloalkyl, 5-10 membered heterocyclic groups, -C 0-2 Alkyl-C 5-10 Aryl or -C 0-2 Alkyl-5-10-membered heterocyclic groups; or R2 and R3 combined with the atoms they are attached to to form C 3-10 cycloalkyl or 5-10 membered heterocyclic groups; wherein the C 3-10 The cycloalkyl or 5-10 membered heterocyclic group is optionally replaced by one or more groups, each independently selected from halogens, -C 1-9Alkyl or -C 1-8 Substituents of haloalkyl groups;

[0017] Where G is selected from:

[0018]

[0019] Where m = 0, 1, or 2;

[0020] n = 0, 1, or 2;

[0021] Where Z is N or -C(R7)-;

[0022] Wherein ring A is a 9-10 membered heteroaryl group; wherein ring A is optionally composed of one or more groups, each independently selected from halogen, oxo, -OH, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 Substitution of aryl or 5-10 heteroaryl groups;

[0023] Where Y is selected from O, S, SO, S(O)2, or

[0024] R4 and R5 are each independently selected from H, OH, and -C. 1-9 Alkyl, -C 1-8 Halogenated alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -COR 6a -C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 alkyl-heterocyclic, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 Aryl, 5-10 heteroaryl, -C 1-4 Alkyl-SO2-C 1-4 Alkyl or -C 1-4 Alkyl-SO2-C 3-8 cycloalkyl;

[0025] R4 and R5 are each optionally selected independently from one or more of H, halogen, oxo, -OH, -CN, and -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10The aryl or 5-10-membered heteroaryl groups are substituted; or R4 and R5 are bonded to the atoms to which they are attached to form a 3-10-membered heterocyclic group; wherein the 3-10-membered heterocyclic group is optionally substituted by one or more substituents, each independently selected from halogens, -C 1-9 Alkyl or -C 1-8 Substituents of haloalkyl groups;

[0026] R6 is independently selected from H and C. 1-9 Alkyl, C 1-8 Halogenated alkyl, -C 1-6 Alkyl-alkoxy, -C 1-6 Alkyl-cycloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, 5-10 quinone heteroaryl, CO2R 6a COR 6a CON(R) 6a (R) 6b ), -S(O)R 6a -S(O)(NH)R 6a -S(O)2R 6a -S(O)2OR 6a -S(O)2N(R 6a (R) 6b ) or -S(O)(NR 6a )R 6a ;

[0027] R6 may optionally be selected independently from one or more halogens, oxo groups, -OH, -CN, and -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 1-6 Halogenated alkyl, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 Substitution of aryl or 5-10 heteroaryl groups;

[0028] Where R 6a and R 6b Each is independently selected from H and C. 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl or 5-10 heteroaryl; or R 6a and R 6b They combine with the atoms they are attached to to form C 3-10cycloalkyl or 5-10 membered heterocyclic groups; wherein the C 3-10 The cycloalkyl or 5-10 membered heterocyclic group is optionally replaced by one or more groups, each independently selected from halogens, -C 1-9 Alkyl or -C 1-8 Substituents of haloalkyl groups;

[0029] Where R 6a and R 6b Each can be optionally selected by one or more elements independently chosen from halogen, oxo, -OH, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 1-6 Halogenated alkyl, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 Aryl, 5-10 heteroaryl, -C 1-4 Alkyl-C 3-8 cycloalkyl or -C 1-4 Substitution of alkyl-heterocyclic groups;

[0030] R7 is selected from H, halogen, oxo, -OH, -CN, and -C. 1-9 Alkyl, -C 1-8 Halogenated alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 2-6 alkenyl, -C 2-6 Alkyne group, -CO2R 7a -COR 7a -CONHR 7a , -NO2, -NH2, -N3, -SH, -O(C 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -NH(C) 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -N(C) 1-9 alkyl)2 or -N(C 1-8 (halogenated alkyl)2;

[0031] Where R 7a Selected from H, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 alkyl-heterocyclic, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl or 5-10 heteroaryl; and wherein the 5-10 heteroaryl or heterocyclic group is optionally substituted by one or more substituents, each independently selected from N, O or S.

[0032] On the other hand, this application relates to compositions comprising compounds of formula I, pharmaceutically acceptable salts thereof, deuterated derivatives thereof, and isomers thereof.

[0033] On the other hand, this application relates to a method for regulating IL-17A, comprising administering to an individual requiring the method an effective amount of a composition comprising a compound of formula I of this application, a pharmaceutically acceptable salt thereof, a deuterated derivative thereof or an isomer thereof, or a composition comprising a compound of formula I of this application, a pharmaceutically acceptable salt thereof, a deuterated derivative thereof or an isomer thereof.

[0034] On the other hand, this application relates to the use of compounds of formula I, pharmaceutically acceptable salts thereof, deuterated derivatives thereof, or isomers thereof in the preparation of medicaments for modulating IL-17A.

[0035] On the other hand, this application relates to a method of treating an inflammatory disease or disease state, comprising administering to an individual requiring the method an effective amount of a pharmaceutical composition comprising a compound of formula I of this application, a pharmaceutically acceptable salt thereof, a deuterated derivative thereof or an isomer thereof, or a composition comprising a compound of formula I of this application, a pharmaceutically acceptable salt thereof, a deuterated derivative thereof or an isomer thereof.

[0036] Detailed Explanation

[0037] I. Definition

[0038] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Dashes at the beginning or end of chemical groups are for convenience in indicating the connection point with the parent compound; chemical groups may or may not be described with one or more dashes without losing their ordinary meaning. Prefixes such as "C" u-v "or "C u -C v "" indicates that the following groups have 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.

[0039] "Alkyl" is a monovalent or divalent straight-chain or branched saturated hydrocarbon group. For example, alkyl groups can have 1 to 10 carbon atoms (i.e., C64-C ... 1-10 Alkyl groups or 1 to 8 carbon atoms (i.e., C64) 1-8 Alkyl groups or 1 to 6 carbon atoms (i.e., C64) 1-6 Alkyl groups or 1 to 4 carbon atoms (i.e., C46) 1-4Alkyl groups. Examples of alkyl groups include, but are not limited to: methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH3), 2-propyl (i-Pr, i-Propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), and 2-butyl (s-Bu, s-butyl). , -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH3), 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 (-CH2C H2CH(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)CH2CH 3) 4-Methyl-2-pentyl (-CH(CH3)CH2CH(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 can be unsubstituted or substituted.

[0040] The term "heteroalkyl" itself, or in combination with other terms, refers to a stable straight-chain or branched hydrocarbon alkyl group consisting of at least one heteroatom selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. The heteroatom can be located at any internal position of the heteroalkyl group, such as -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH, -CS-CH 2-CH3 -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3. Up to two heteroatoms can be consecutive, for example -CH2-NH-OCH3.

[0041] "Alkenyl" refers to a monovalent or divalent straight-chain or branched hydrocarbon group having at least one carbon-carbon double bond. For example, alkenyl groups can have 2 to 8 carbon atoms (i.e., C2C2). 2-8 Alkenyl) or 2 to 6 carbon atoms (i.e., C) 2-6 alkenyl) or 2 to 4 carbon atoms (i.e., C) 2-4 Alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH2), allyl (-CH2CH=CH2), and -CH2-CH=CH-CH3. Alkenyl groups can be unsubstituted or substituted.

[0042] "Alynyl" refers to a monovalent or divalent straight-chain or branched hydrocarbon group having at least one carbon-carbon triple bond. For example, an alkynyl group can have 2 to 8 carbon atoms (i.e., C64-C ... 2-8 (alkynyl group) or 2 to 6 carbon atoms (i.e., C64) 2-6 (alkynyl group) or 2 to 4 carbon atoms (i.e., C) 2-4 (Alynyl group). Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (-CH2C≡CH), and -CH2-C≡C-CH3. Alynyl groups can be unsubstituted or substituted.

[0043] "Halogen" refers to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0044] "Haloalkyl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently replaced by a halogen, which may be the same or different, such that the alkyl group is divalent. The alkyl group and the halogen can be any of those listed above. In some embodiments, haloalkyl defines the number of carbon atoms in the alkyl moiety, for example, C1. 1-4 Alkyl halogens include CF3, CH2F, CHF2, CH2CF3, CH2CH2CF3, CCl2CH2CH2CH3, and C(CH3)2(CF2H). Alkyl halogens can be unsubstituted or substituted.

[0045] "Alkoxy" refers to the -O-alkyl group, where alkyl is as defined above. For example, C 1-4 An alkoxy group refers to an -O-alkyl group having 1 to 4 carbon atoms. Alkoxy groups can be unsubstituted or substituted.

[0046] "Haloalkoxy" is an alkoxy group as defined herein, wherein one or more hydrogen atoms in the alkoxy group are independently replaced by a halogen, which may be the same or different, such that the alkyl group is divalent. The alkoxy group and the halogen can be any of those listed above. In some embodiments, the haloalkoxy group defines the number of carbon atoms in the alkyl group, for example, C... 1-4Halogenated alkoxy groups include OCF3, OCH2F, OCH2CF3, OCH2CH2CF3, OCCl2CH2CH3, and OC(CH3)2(CF2H). Halogenated alkoxy groups can be unsubstituted or substituted.

[0047] "Cycloalkyl" is a single monovalent or divalent all-carbon ring or a system of multiple fused all-carbon rings, wherein in each case the ring is a non-aromatic saturated or unsaturated ring. For example, in some embodiments, the cycloalkyl has 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 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. Cycloalkyl also includes multiple condensed ring systems having about 7 to 12 carbon atoms (e.g., ring systems comprising 2 rings). Where valence requirements permit, the rings of multiple condensed ring systems may be connected to each other by fusion, spirocyclic, or bridging bonds. Exemplary polycyclic cycloalkyl groups include octahydrocyclopentadiene, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[2.2]oct-2ene, and spiro[2.5]octane. The cycloalkyl group can be unsubstituted or substituted.

[0048] As used herein, "aryl" refers to a single, monovalent or divalent all-carbon aromatic ring or a system of multiple fused all-carbon rings, wherein 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. Aryl groups include phenyl. Aryl groups also include polyfused ring systems having about 9 to 20 carbon atoms (e.g., ring systems comprising 2, 3, or 4 rings), wherein multiple rings are aromatic. When valence requirements permit, the rings of a polyfused ring system can be linked to each other by fused bonds. It should also be understood that when referring to a ternaryl group within an atomic range (e.g., 6-10 aryl groups), the atomic range refers to the total number of ring atoms of the aryl group. For example, a 6-membered aryl group includes phenyl, and a 10-membered aryl group includes naphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, etc. Aryl groups can be unsubstituted or substituted.

[0049] "alkylaryl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently replaced by an aryl group, which may be the same or different. The alkyl and aryl groups can be any of those described above, such that 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 present in the combination of constituting alkyl and aryl groups. For examples of alkylaryl groups, C7 alkylaryl refers to benzyl, while C7 alkylaryl refers to Benzyl. 11Alkyl aryl groups include 1-methylnaphthyl and n-pentylphenyl. In some embodiments, the number of carbon atoms in the alkyl and aryl moieties can be specified separately, for example, C... 1-6 Alkyl-C 6-10 Aryl. Non-limiting examples of alkylaryl groups include, but are not limited to, benzyl, 2,2-dimethylphenyl, n-pentylphenyl, 1-methylnaphthyl, 2-ethylnaphthyl, etc. Alkylaryl groups can be unsubstituted or substituted.

[0050] As used herein, “heterocyclic group” or “heterocyclic alkyl group” 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 stated, a heterocyclic group has 3 to about 20 ring atoms, for example 3 to 12 ring atoms, for example 4 to 12 ring atoms, 4 to 10 ring atoms, or 3 to 8 ring atoms, or 3 to 6 ring atoms, or 3 to 5 ring atoms, or 4 to 6 ring atoms, or 4 to 5 ring atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., 3, 4, 5, 6, or 7-membered ring) having about 1 to 6 ring carbon atoms and about 1 to 3 cyclic heteroatoms selected from oxygen, nitrogen, and sulfur in the ring. When valence requirements permit, the rings of a polyfused ring (e.g., bicyclic heterocyclic group) system can be linked to each other by fusion, spirocyclic, and bridging bonds. Heterocyclic compounds include, but are not limited to, aziridine, imidazoline, morpholine, ethylene oxide (epoxide), oxacyclobutane, thioheterobutane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinine ring, 2-oxa-6-azaspiro[3.3]hept-6-yl, 6-oxa-1-azaspiro[3.3]hept-1-yl, 2-Thia-6-azaspiro[3.3]hept-1-yl, 2,6-diazaspiro[3.3]hept-2-yl, 2-azabicyclo[3.1.0]hex-2-yl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo[2.1.1]hexyl, 2-azabicyclo[2.2.1]hept-2-yl, 4-azaspiro[2.4]heptyl, 5-azaspiro[2.4]heptyl, etc. The heterocyclic group can be unsubstituted or substituted.

[0051] The term "heterenyl" itself, or in combination with other terms, refers to a stable straight-chain or branched hydrocarbon alkyl group consisting of at least one heteroatom selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Heteratomes can be located in any internal position within the heteroalkenyl group. Up to two heteroatoms can be consecutive.

[0052] The term "heteroyne group," either alone or in combination with other terms, refers to a stable straight-chain or branched hydrocarbon alkynyl group consisting of at least one heteroatom selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Heteroatoms can be located at any internal position within the heteroyne group. Up to two heteroatoms can be consecutive.

[0053] "5-10-membered heteroaryl" or "heteroaryl" refers to a single aromatic ring having at least one non-carbon atom in the ring, wherein said atom is selected from oxygen, nitrogen, and sulfur; "5-10-membered heteroaryl" also includes polycyclic aromatic ring systems having at least one such aromatic ring, which are further described below. Thus, "5-10-membered heteroaryl" comprises a single aromatic ring having about 1-6 carbon atoms and about 1-4 heteroatoms selected from oxygen, nitrogen, and sulfur. Sulfur and nitrogen atoms may also be present in oxidized forms, provided the ring is aromatic. Exemplary 5-10-membered heteroaryl ring systems include, but are not limited to, pyridinyl, pyrimidinyl, oxazolyl, or furanyl. "5-10-membered heteroaryl" also includes polycyclic ring systems (e.g., ring systems containing 2, 3, or 4 rings), wherein a 5-10-membered heteroaryl as defined above is fused with one or more rings selected from 5-10-membered heteroaryl (to form, for example, 1,8-naphthidyl) and aryl (to form, for example, benzimidazolyl or indazole) to form a polycyclic ring system. Thus, a 5-10-membered heteroaryl (single aromatic ring or polycyclic ring system) can have about 1-20 carbon atoms and about 1-6 heteroatoms within the 5-10-membered heteroaryl ring. For example, a tetrazolyl ring has 1 carbon atom and 4 nitrogen heteroatoms within the ring. When valence requirements permit, the rings of a polycyclic ring system can be linked to each other by fusion bonds. It should be understood that the individual rings of a polycyclic ring system can be linked relative to each other in any order. It should be understood that the connection point of a 5-10 membered heteroaryl or a 5-10 membered heteroaryl polycyclic ring system can be at any suitable atom of the 5-10 membered heteroaryl or the 5-10 membered heteroaryl polycyclic ring system, including carbon atoms and heteroatoms (e.g., nitrogen). It should also be understood that when referring to a unit of an atomic range (e.g., 5-10 membered heteroaryl), the atomic range refers to the total ring atoms of the 5-10 membered heteroaryl and includes carbon atoms and heteroatoms. It should also be understood that the ring of a polycyclic ring system can include an aromatic ring fused with a heterocycle having saturated or partially unsaturated bonds (e.g., 3, 4, 5, 6, or 7 membered rings), said heterocycle having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from oxygen, nitrogen, and sulfur. For example, 5-10 membered heteroaryls include thiazolyl groups, and 5-10 membered heteroaryls include quinolinyl groups. Exemplary 5-10-membered heteroaryl groups include, but are not limited to, pyridyl, pyrroloyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thiophenyl, indolyl, imidazolyl, azole, isozolyl, thiazolyl, furanyl, diazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzozolyl, inzolyl, quinoxalinyl, quinazolinyl, benzofuranyl, benzimidazolyl, thionaphthyl, pyrrolo[2,3-b]pyridyl, quinazolinyl-4(3H)-one, triazolyl, and tetrazolyl. The 5-10-membered heteroaryl groups can be unsubstituted or substituted.

[0054] "alkylheteroaryl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are independently replaced by a heteroaryl group, which may be the same or different, such that the alkyl group is divalent. The alkyl group and the heteroaryl group can be any of those described above. In some embodiments, the number of atoms in the alkyl and heteroaryl moieties are specified separately, for example, C1 having 1 to 4 heteroatoms, each independently N, O, or S. 1-6 Alkyl-5 to 10-membered heteroaryl groups. Alkyl heteroaryl groups can be unsubstituted or substituted.

[0055] The term "oxo" as used in this article refers to =O

[0056] This refers to a key that can be a single key or a double key.

[0057] As used herein, “substituted” means that one or more hydrogen atoms of a group are independently replaced by one or more substituents (e.g., 1, 2, 3 or 4 or more) as shown.

[0058] "Compounds of this application" includes compounds disclosed herein, such as compounds of formula I, including the compounds of the examples. In some embodiments, "compounds of this application" includes compounds of formula I.

[0059] "Pharmaceutical acceptable excipients" include, but are not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration for acceptable use in humans or livestock.

[0060] As used herein, “therapeutic effective amount” or “effective amount” means an amount that effectively elicits the desired biological or medical response, including amounts of compounds sufficient to achieve such treatment of a disease when administered to an individual. Effective amounts will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the individual being treated. Effective amounts can encompass a range of amounts. As understood in the art, an effective amount can be one or more doses; that is, a single or multiple doses may be required to achieve the desired therapeutic endpoint. An effective amount may be considered when administering one or more therapeutic agents, and a single agent may be considered to be administered at an effective amount if, in combination with one or more other agents, a desired or beneficial result can be obtained. The appropriate dose of any co-administered compound may optionally be reduced due to the combined effects of the compounds (e.g., additive or synergistic effects).

[0061] As used herein, “co-administration” means administering a unit dose of the disclosed compound before or after administering a unit dose of one or more other therapeutic agents, such as administering the disclosed compound within seconds, minutes, or hours after administering one or more other therapeutic agents. For example, in some embodiments, a unit dose of the disclosed compound is administered first, followed by a unit dose of one or more other therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of the disclosed compound within seconds or minutes. In some embodiments, a unit dose of the disclosed compound is administered first, followed by a unit dose of one or more other therapeutic agents after several hours (e.g., 1-12 hours). In other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of the disclosed compound after several hours (e.g., 1-12 hours). Co-administration of the disclosed compound with one or more other therapeutic agents generally means administering the disclosed compound and one or more other therapeutic agents simultaneously or sequentially, such that a therapeutically effective amount of each agent is present in the individual.

[0062] Pharmaceutically acceptable salts, hydrates, solvates, tautomers, polymorphs, and prodrugs of the compounds described herein are also provided.

[0063] "Pharmaceutically acceptable" or "physiologically acceptable" means compounds, salts, compositions, dosage forms and other materials used to prepare pharmaceutical compositions suitable for veterinary or human use.

[0064] The compounds described herein can be prepared and / or formulated as pharmaceutically acceptable salts or, where appropriate, as free bases. Pharmaceutically acceptable salts are non-toxic salts of compounds in the free base form, possessing the desired pharmacological activity of a free base. These salts can be derived from inorganic or organic acids or bases. For example, compounds containing basic nitrogen can be prepared as pharmaceutically acceptable salts by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propynates, oxalates, malonates, succinates, octanoates, sebates, fumarates, maleates, butynedates, etc. 1,4-Diositate, Hexyn-1,6-Diositate, Benzoate, Chlorobenzoate, Methylbenzoate, Dinitrobenzoate, Hydroxybenzoate, Methoxybenzoate, Phthalate, Sulfonate, Methylsulfonate, Propylsulfonate, Benzenesulfonate, Xylenesulfonate, Naphthalene-1-sulfonate, Naphthalene-2-sulfonate, Phenylacetate, Phenylacetate, Phenylacetate, Citrate, Lactate, γ-Hydroxybutyrate, Hydroxyacetate, Tartrate, and Mandelate. A list of other pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott, Wiliams and Wilkins, Philadelphia, Pa, 2006.

[0065] Examples of pharmaceutically acceptable salts of the compounds disclosed herein also include salts derived from suitable bases, such as alkali metals (e.g., sodium, potassium), alkaline earth metals (e.g., magnesium), ammonium, and N(C1-C4 alkyl)4 salts. + It also includes base salts, such as sodium or potassium salts.

[0066] Also provided are the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein one to n hydrogen atoms bonded to a carbon atom may be replaced by a deuterium atom or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds (also known as “deuterated substitutes” or “deuterated compounds”) can increase metabolic resistance and are therefore used to increase 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 methods well known in the art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0067] Also provided are the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, wherein one to n atoms can be independently substituted by one 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. 2 H, 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. Using positron emission of isotopes, for example 11 C 18 F, 15 O and 13 N-substitution can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of formula IA-1 can generally be prepared using conventional techniques known to those skilled in the art or by methods similar to those described in the examples below, using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent.

[0068] The compounds of embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers, thus producing enantiomers, tautomers, diastereomers, and other stereoisomers, which can be defined according to absolute stereochemistry as (R)-, (S)-, (D)-, or (L)- of amino acids, and their deuterated analogs. The chemical formulas shown in this application 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 / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, and unless otherwise stated, it is intended that the compounds include both E and Z geometric isomers. Similarly, it is intended that all tautomer forms be included. When a compound is represented in its chiral form, it should be understood that embodiments include, but are not limited to, specific diastereomers or enantiomer-enriched forms. When chirality is not specified but present, it should be understood that embodiments relate to specific diastereomers or enantiomer-enriched forms; or racemic or non-racemic mixtures of such compounds. As used herein, a “scalemic mixture” is a mixture of stereoisomers in a ratio not of 1:1.

[0069] As used herein, “stereoisomers” refers to compounds composed of identical atoms bonded by the same bonds but with different three-dimensional structures, and these are not interchangeable. This application considers various stereoisomers and mixtures thereof, and includes “enantiomers,” which refer to two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0070] As used herein, "tautomer" refers to a proton transfer from one atom of a molecule to another atom of the same molecule. In some embodiments, this application includes tautomers of the compounds.

[0071] As used herein, "solvent" refers to the result of the interaction between the solvent and the compound. Solvents of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

[0072] As used herein, “hydrate” refers to the compounds of this disclosure that are chemically associated with one or more water molecules.

[0073] "Prevention" or "preventing" refers to any treatment of a disease or disease state that prevents the development of clinical symptoms of the disease or disease state. In some embodiments, the compound may be based on individuals (including humans) at risk or with a family history of the disease or disease state.

[0074] As used in this article, "prodrug" refers to a drug derivative that, upon administration to the human body, is converted into the parent drug via a chemical or enzymatic pathway. In some implementations, a prodrug is a biologically inactive derivative of the drug that, upon administration to the human body, is converted into the biologically active parent drug via a chemical or enzymatic pathway.

[0075] As used herein, “treatment” or “treat” refers to a method of achieving a beneficial or desired outcome. For the purposes of this application, beneficial or desired outcomes include, but are not limited to, alleviating symptoms and / or reducing the severity of symptoms and / or preventing the worsening of symptoms associated with a disease or disease state. In one embodiment, “treatment” includes one or more of the following: a) suppressing a disease or disease state (e.g., reducing one or more symptoms caused by the disease or disease state, and / or reducing the severity of the disease or disease state); b) slowing or preventing the development of one or more symptoms associated with said disease or disease state (e.g., stabilizing said disease or disease state, delaying the worsening or progression of said disease or disease state); and c) alleviating a disease or disease state, for example, causing the disappearance of clinical symptoms, improving the disease state, delaying the progression of the disease, improving quality of life, and / or prolonging survival. As used herein, “individual at risk” refers to an individual at risk of developing a disease state to be treated. An individual “at risk” may or may not have a detectable disease or disease state, and may or may not have a detectable disease prior to treatment with the methods described herein. "Being at risk" means that an individual has one or more so-called risk factors, which are measurable parameters associated with the development of a disease or disease state and are known in the art. Individuals with one or more of these risk factors are more likely to develop a disease or disease state than individuals without these risk factors.

[0076] II.Compounds

[0077] This application relates, in part, to compounds of formula I:

[0078]

[0079] Its pharmaceutically acceptable salts, its deuterated compounds, and its stereoisomers,

[0080] in

[0081] R1 is selected from aryl, 5-6 heteroaryl, -C 1-3 alkyl-aryl or -C 1-3 alkyl-5-6-membered heteroaryl; wherein R1 is optionally surrounded by one or more R 1a replace;

[0082] Where R 1a Independently selected from halogens, oxometalates, -OH, -CN, and -C 1-6 Alkyl or -C 0-2 Alkyl-C 3-6 cycloalkyl; wherein each R 1a Optionally, it may be substituted by one or more substituents, each independently selected from halogens;

[0083] R2 and R3 are each independently selected from H and -C. 1-6 Alkyl, aryl, C 3-10 cycloalkyl, -C 0-2 Alkyl-C 3-10 Cycloalkyl, 5-10 membered heterocyclic groups, -C 0-2 Alkyl-C 5-10 Aryl or -C 0-2 Alkyl-5-10-membered heterocyclic groups; or R2 and R3 combined with the atoms they are attached to to form C 3-10 cycloalkyl or 5-10 membered heterocyclic groups; wherein the C 3-10 The cycloalkyl or 5-10 membered heterocyclic group is optionally replaced by one or more groups, each independently selected from halogens, -C 1-9 Alkyl or -C 1-8 Substituents of haloalkyl groups;

[0084] Where G is selected from:

[0085]

[0086] Where m = 0, 1, or 2;

[0087] n = 0, 1, or 2;

[0088] Where Z is N or -C(R7)-;

[0089] Wherein ring A is a 9-10 membered heteroaryl group; wherein ring A is optionally composed of one or more groups, each independently selected from halogen, oxo, -OH, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 Substitution of aryl or 5-10 heteroaryl groups;

[0090] Where Y is selected from O, S, SO, S(O)2, or

[0091] R4 and R5 are each independently selected from H, OH, and -C. 1-9 Alkyl, -C 1-8 Halogenated alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -COR 6a -C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 alkyl-heterocyclic, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 Aryl, 5-10 heteroaryl, -C 1-4 Alkyl-SO2-C 1-4 Alkyl or -C 1-4 Alkyl-SO2-C 3-8 cycloalkyl;

[0092] R4 and R5 are each optionally selected independently from one or more of H, halogen, oxo, -OH, -CN, and -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 The aryl or 5-10-membered heteroaryl groups are substituted; or R4 and R5 are bonded to the atoms to which they are attached to form a 3-10-membered heterocyclic group; wherein the 3-10-membered heterocyclic group is optionally substituted by one or more substituents, each independently selected from halogens, -C 1-9 Alkyl or -C 1-8 Substituents of haloalkyl groups;

[0093] R6 is independently selected from H and C. 1-9 Alkyl, C 1-8 Halogenated alkyl, -C 1-6 Alkyl-alkoxy, -C 1-6 Alkyl-cycloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, 5-10 quinone heteroaryl, CO2R 6a COR 6a CON(R) 6a (R) 6b ), -S(O)R 6a -S(O)(NH)R 6a -S(O)2R 6a -S(O)2OR 6a-S(O)2N(R 6a (R) 6b ) or -S(O)(NR 6a )R 6a ;

[0094] R6 may optionally be selected independently from one or more halogens, oxo groups, -OH, -CN, and -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 1-6 Halogenated alkyl, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 Substitution of aryl or 5-10 heteroaryl groups;

[0095] Where R 6a and R 6b Each is independently selected from H and C. 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl or 5-10 heteroaryl; or R 6a and R 6b They combine with the atoms they are attached to to form C 3-10 cycloalkyl or 5-10 membered heterocyclic groups; wherein the C 3-10 The cycloalkyl or 5-10 membered heterocyclic group is optionally replaced by one or more groups, each independently selected from halogens, -C 1-9 Alkyl or -C 1-8 Substituents of haloalkyl groups;

[0096] Where R 6a and R 6b Each can be optionally selected by one or more elements independently chosen from halogen, oxo, -OH, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 1-6 Halogenated alkyl, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 Aryl, 5-10 heteroaryl, -C 1-4 Alkyl-C 3-8 cycloalkyl or -C 1-4 Substitution of alkyl-heterocyclic groups;

[0097] R7 is selected from H, halogen, oxo, -OH, -CN, and -C. 1-9 Alkyl, -C 1-8 Halogenated alkyl, -C 1-6Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 2-6 alkenyl, -C 2-6 Alkyne group, -CO2R 7a -COR 7a -CONHR 7a , -NO2, -NH2, -N3, -SH, -O(C 1-9 Alkyl), -O(C) 1-8 Halogenated alkyl), -NH(C) 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -N(C) 1-9 alkyl)2 or -N(C 1-8 (halogenated alkyl)2;

[0098] Where R 7a Selected from H, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 alkyl-heterocyclic, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl or 5-10 heteroaryl; and wherein the 5-10 heteroaryl or heterocyclic group is optionally substituted by one or more substituents, each independently selected from N, O or S.

[0099] In some embodiments, this application relates to compounds of formulas Ia and Ib, their pharmaceutically acceptable salts, their deuterated compounds, and their stereoisomers:

[0100]

[0101]

[0102] In some embodiments, this application relates to compounds of formulas IIa and IIb, their pharmaceutically acceptable salts, their deuterated compounds, and their stereoisomers:

[0103]

[0104] In some implementations, ring A is selected from:

[0105]

[0106] In some embodiments, the compounds of this application have the structure of Formula III:

[0107]

[0108] R1 is selected from aryl or 5-6 heteroaryl groups; wherein R1 is optionally separated by one or more R1a Replace; where each R 1a Independently selected from halogens, -C 1-6 Alkyl or -C 0-2 Alkyl-C 3-6 cycloalkyl; wherein each R 1a Optionally, it may be substituted by one or more substituents, each independently selected from halogens;

[0109] R4 and R5 are each independently selected from H, OH, and -C. 1-9 Alkyl, -C 1-8 Halogenated alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -COR 6a -C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 alkyl-heterocyclic, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 Aryl, 5-10 heteroaryl, -C 1-4 Alkyl-SO2-C 1-4 Alkyl or -C 1-4 Alkyl-SO2-C 3-8 cycloalkyl;

[0110] R4 and R5 are each optionally selected independently from one or more of H, halogen, oxo, -OH, -CN, and -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 The aryl or 5-10-membered heteroaryl groups are substituted; or R4 and R5 are bonded to the atoms to which they are attached to form a 3-10-membered heterocyclic group; wherein the 3-10-membered heterocyclic group is optionally substituted by one or more substituents, each independently selected from halogens, -C 1-9 Alkyl or -C 1-8 Substituents of haloalkyl groups;

[0111] R6 is independently selected from H and C. 1-9 Alkyl, C 1-8 Halogenated alkyl, -C 1-6 Alkyl-alkoxy, -C 1-6 Alkyl-cycloalkoxy, C 3-10 Cycloalkyl, heterocyclic, CO2R 6a COR 6a or CON(R) 6a (R) 6b );

[0112] R6 may optionally be selected from one or more halogens, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 1-6 Halogenated alkyl or -C 3-10 Substitution of cycloalkyl groups.

[0113] In some implementations, R4 and R5 are each independently selected from H and -C. 1-9 Alkyl, -C 1-8 Halogenated alkyl, -C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 alkyl-heterocyclic or -C 3-10 cycloalkyl;

[0114] Alternatively, R4 and R5 may combine with the atoms to which they are attached to form 3-10 membered heterocyclic groups; wherein the 3-10 membered heterocyclic groups may optionally be one or more independently selected from halogens, -C 1-9 Alkyl or -C 1-8 Substitution of alkyl halogens.

[0115] In some implementations, R6 is independently selected from H and C. 1-9 Alkyl, C 1-8 Halogenated alkyl, -C 1-6 Alkyl-alkoxy, -C 1-6 Alkyl-cycloalkoxy, C 3-10 Cycloalkyl, heterocyclic, CO2R 6a COR 6a or CON(R) 6a (R) 6b );

[0116] R6 may optionally be selected from one or more halogens, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 1-6 Halogenated alkyl or -C 3-10 Substitution of cycloalkyl groups.

[0117] In some implementations, R 6a and R 6b Each is independently selected from H and C. 1-9 Alkyl, C 1-8 Haloalkyl, C 3-10 cycloalkyl or heterocyclic groups; or R 6a and R 6b They combine with the atoms they are attached to to form C 3-10 cycloalkyl or 5-10 membered heterocyclic groups; wherein the C3-10 The cycloalkyl or 5-10 membered heterocyclic group is optionally replaced by one or more groups, each independently selected from halogens, -C 1-9 Alkyl or -C 1-8 Substituents of haloalkyl groups;

[0118] Where R 6a and R 6b Each can be optionally selected by one or more independently chosen from halogens, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 1-6 Halogenated alkyl, -C 3-10 Substitution by cycloalkyl or heterocyclic substituents.

[0119] In some implementations, R1 is selected from

[0120]

[0121] In some implementations, R2 and R3 are independently selected from H and -C. 1-6 Alkyl, C 3-10 cycloalkyl or -C 0-2 Alkyl-C 3-10 Cycloalkyl groups; or R2 and R3 combined with the atoms they are attached to form C 3-10 cycloalkyl; wherein the C 3-10 The cycloalkyl group may optionally be replaced by one or more halogens.

[0122] In some embodiments, the compounds of this application are selected from the following compounds:

[0123]

[0124]

[0125]

[0126]

[0127] III. Treatment Methods

[0128] Another aspect of this application relates to methods for preventing, treating, or improving symptoms of IL-17A-mediated inflammatory syndromes, conditions, or diseases using the compounds of this application. In some embodiments, the method includes the step of administering to an individual in need of such treatment an effective amount of a compound of formula I, Ia, Ib, IIa, IIb, or a pharmaceutically acceptable salt thereof. Example

[0129] synthesis

[0130] The compounds disclosed herein can be prepared using the methods disclosed herein and their conventional modifications, which will be readily apparent given the content of this disclosure and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can be used. The synthesis of typical Formula I compounds or their pharmaceutically acceptable salts, such as compounds having structures described by one or more Formula I compounds, or other formulas or compounds disclosed herein, can be carried out as described in the following examples.

[0131] General Synthesis

[0132] Typical embodiments of the compounds according to this application can be synthesized using the general reaction schemes and / or examples described below. Given the description herein, it will be apparent that the general scheme can be modified by substituting the starting materials with other materials having similar structures to produce correspondingly different products. The description of the synthesis subsequently provides numerous examples of how the starting materials can be varied to provide the respective products. The starting materials are typically obtained from commercial sources or synthesized using methods already disclosed for synthesizing compounds as embodiments of this application, and examination of the structure of the compound to be synthesized will provide the identity of each substituent. The identity of the final product will generally be revealed by simple examination methods (examples given herein) that make the identification of the necessary starting materials apparent. The group designations (e.g., R1, R2) used in the reaction schemes herein are for illustrative purposes only and, unless otherwise stated, need not be matched by name or function to designations used elsewhere to describe compounds of Formula I or aspects or fragments thereof.

[0133] Synthesis reaction parameters

[0134] The compounds disclosed herein can be prepared from readily available starting materials using, for example, the following general methods and procedures. It should be understood that while typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions can also be used unless otherwise stated. Optimal reaction conditions can vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0135] 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. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, many protecting groups are described in, for example, TW Greene and GMWuts (1999), Protecting Groups in Organic Synthesis, 3rd edition, Wiley, New York, and the references cited therein.

[0136] Furthermore, the compounds of this application may contain one or more chiral centers. Therefore, pure stereoisomers can be prepared or isolated, either as individual enantiomers or diastereomers, or as mixtures rich in stereoisomers, if desired. Unless otherwise stated, all such stereoisomers (and enriched mixtures) are included within the scope of this disclosure. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active raw materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0137] The starting materials used in the following reactions are generally known compounds or can be prepared by known methods or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). Others can be prepared by procedures or obvious modifications thereof, as described in standard reference textbooks such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformation (VCH Publisher Inc., 1989).

[0138] The terms “solvent,” “inert organic solvent,” or “inert solvent” refer to solvents that are inert under the reaction conditions described therein (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), N,N-dimethylformamide (“DMF”), chloroform, dichloromethane (or dichloromethane), diethyl ether, methanol, pyridine, etc.). Unless otherwise stated, 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.

[0139] The term "qs" refers to adding an amount sufficient to achieve the function, for example, bringing the solution to the desired volume (i.e., 100%).

[0140] The compounds provided herein can be synthesized according to the general schemes provided below. In the schemes below, it should be understood that each compound shown may have the required protecting group at any step. Standard protecting groups are entirely within the scope of those skilled in the art.

[0141] Preparation Example 1: Synthesis of Intermediates

[0142] Int-1(S,S): (3S,4S)-1-benzyl-4-(4-((tert-butoxycarbonyl)amino)phenyl)pyrrolidine-3-carboxylic acid methyl ester and Int-1(R,R): (3R,4R)-1-benzyl-4-(4-((tert-butoxycarbonyl)amino)phenyl)pyrrolidine-3-carboxylic acid methyl ester

[0143]

[0144] Under nitrogen atmosphere and at -78 °C, a solution of P,P-bis(2,2,2-trifluoroethyl)phosphonoacetate (1.78 mL, 8.4 mmol) and 18-crown-6 (3.96 g, 15 mmol) in THF (20 mL) was treated with KHMDS (0.5 M, toluene solution, 16.8 mL, 8.4 mmol) and stirred for 30 min at this temperature. A solution of compound 1-1 (1.1 g, 6 mmol) in THF (2 mL) was added dropwise to this suspension, and the reaction mixture was stirred at -78 °C for 2 h. The organic phase was washed with NH4Cl solution and water and brine, dried over MgSO4, and concentrated under vacuum. Purification by silica gel column chromatography yielded Int 1-2, 0.7 g, 47.9% yield. m / z = 241.0 [M+H] + .

[0145] Compounds 1-2 (600 mg, 2.49 mmol), N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methylamine (709 mg, 2.99 mmol), and trifluoroacetic acid (TFA) (93.6 mg, 0.82 mmol) were dissolved in DCM (10 mL) and stirred at 20–25 °C for 2 days. The reaction mixture was added to NaHCO3 solution (10 mL), and the organic phase was washed with water and brine. The solution was dried over MgSO4 and concentrated under vacuum. Purification by silica gel column chromatography yielded Int 1-3, 0.82 g, yield: 88.0%. m / z = 374.1 [M+H] + .

[0146] Under nitrogen atmosphere, Int Cis-1-3 (800 mg, 2.14 mmol), BocNH2 (275 mg, 2.35 mmol), Pd2(dba)3 (18.3 mmol, 0.2 mmol), X-Phos (19 mg, 0.4 mmol), and Cs2CO3 (1.04 g, 3.21 mmol) were added to dioxane and stirred at 90–100 °C for 3 hours. After cooling, EtOAc (20 mL) and water (20 mL) were added to the mixture and stirred for 10 minutes. The organic phase was then separated, washed with water and brine, dried over MgSO4, and concentrated under vacuum. Purification by column chromatography on silica gel yielded cis-Int 1, 0.64 g, yield: 72.9%, m / z = 411.2 [M+H]. + Cis-Int 1 was purified by chiral column (Welch XT C18 150mm*21.2mm, 5μm) to obtain Int-1(S,S):(3S,4S)-1-benzyl-4-(4-((tert-butoxycarbonyl)amino)phenyl)pyrrolidine-3-carboxylate methyl ester and Int-1(R,R):(3R,4R)-1-benzyl-4-(4-((tert-butoxycarbonyl)amino)phenyl)pyrrolidine-3-carboxylate methyl ester.

[0147] Int 2(R,S): (3R,4S)-1-benzyl-4-(4-((tert-butoxycarbonyl)amino)phenyl)pyrrolidine-3-carboxylic acid methyl ester and Int 2(S,R): (3R,4S)-1-benzyl-4-(4-((tert-butoxycarbonyl)amino)phenyl)pyrrolidine-3-carboxylic acid methyl ester

[0148]

[0149]

[0150] After generating Int-1(S,S), racemic trans-Int-2 can be prepared via E-olefin. The title compound is obtained after purification by a chiral column (Welch XT C18 150mm*21.2mm, 5μm).

[0151] Int 3: (3S,4R)-1-benzyl-4-(5-((tert-butoxycarbonyl)amino)pyridin-2-yl)pyrrolidine-3-carboxylic acid methyl ester

[0152]

[0153] After generating Int-1(S,S), Int 3 is obtained by replacing 1-1 with 5-bromopyridinecarboxaldehyde.

[0154] Int 4: (3S,4S)-1-benzyl-4-(6-((tert-butoxycarbonyl)amino)-2-fluoropyridin-3-yl)pyrrolidine-3-carboxylic acid methyl ester

[0155]

[0156] After generating Int-1(S,S), Int4 is obtained by replacing 1-1 with 6-bromo-2-fluoronicotinaldehyde.

[0157] Int 5: (3S,4S)-1-benzyl-4-(4-((tert-butoxycarbonyl)amino)-2-(trifluoromethyl)phenyl)pyrrolidine-3-carboxylic acid methyl ester

[0158]

[0159] After generating Int-1(S,S), Int 5 is obtained by replacing 1-1 with 4-bromo-2-(trifluoromethyl)benzaldehyde.

[0160] Int 6: Methyl 4-(4-aminophenyl)tetrahydrothiophene-3-carboxylate

[0161]

[0162] At room temperature, a solution of Tf₂O (1.94 g, DCM solution, 6.87 mmol) was added dropwise to a solution of 6-1 (1.0 g, 6.24 mmol) and N,N-diethylethylamine (TEA) (0.95 g, 9.36 mmol) in 10 mL of dichloromethane (DCM) and stirred for 2 hours. Water (10 mL) was added to the mixture and stirred for 10 minutes. The organic layer was separated, washed with water and brine, dried over MgSO₄, and concentrated under vacuum. Purification by silica gel column chromatography yielded Int 6-2, 1.2 g, yield: 65.6%.

[0163] Under nitrogen atmosphere, compound 6-2 (1.0 g, 3.42 mmol), 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborhecyclopentane (0.85 g, 3.42 mmol), Pd(dppf)₂Cl₂ (0.28 g, 0.34 mmol), and Cs₂CO₃ (2.23 g, 6.84 mmol) were added to a dioxane / H₂O mixture (10 mL / 2.5 mL) and stirred at 90–95 °C for 2 hours. After cooling, EtOAc (20 mL) and water (20 mL) were added to the mixture, and the mixture was stirred for 10 minutes. The organic layer was separated, washed with water and brine, dried over MgSO₄, and concentrated under vacuum. Purification by silica gel column chromatography yielded Int 6-3, 0.65 g, 71.6% yield.

[0164] Compound 6-3 (0.65 g, 2.45 mmol) and Pd / C (10% by weight, 0.065 g) were added to methanol (10 mL) under hydrogen atmosphere and stirred overnight at 25–30 °C. After filtration, the solution was collected and concentrated under vacuum to give compound Int 6, 0.85 g, 95.0%. m / z = 238.1 [M+H] + .

[0165] Int 7: methyl 4-(4-aminophenyl)tetrahydrothiophene-3-carboxylate 1,1-dioxide

[0166]

[0167] To a methanol (3 mL) solution of Int 6 (0.3 g, 1.26 mmol), add H₂O₂ (30%, 1 mL) and titanium isopropylidene (0.5 mL), and stir at 40–45 °C for 3 hours. Add Na₂S₂O₃ solution (10 mL) and stir for 30 minutes. Separate the organic phase, wash with water and brine, dry with MgSO₄, and concentrate under vacuum to give Int 7, 0.25 g, yield: 73.4%. m / z = 270.1 [M + H] + .

[0168] Int 8: 4-(2-((S)-((tert-butoxycarbonyl)amino)(4,4-difluorocyclohexyl)methyl)-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)pyrrolidine-3-carboxylic acid methyl ester

[0169]

[0170]

[0171] Compound 8-1 (2.0 g, 6.82 mmol), HATU (3.11 g, 8.18 mmol), and TEA (1.0 g, 10.23 mmol) were added to DCM (15 ml) and stirred at 20–25 °C for 1 hour. Compound 8-2 (1.18 g, 6.82 mmol) was added and stirred for 4 hours. Water (15 ml) was added and stirred for 15 minutes. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under vacuum to give 8-3, 1.87 g, yield: 61.0%. m / z = 449.1 [M+H] + .

[0172] At 0–5 °C, a solution of O-(trimethylammonium sulfonyl)hydroxylamine (1.29 g, 6.01 mmol) in DCM (5 ml) was added to a solution of compound 8–3 (1.80 g, 4.01 mmol) in DCM (20 ml), and the mixture was stirred for 1 hour. The mixture was then heated to 40–45 °C and stirred overnight. Water (20 ml) was added to the mixture, and the mixture was stirred for 15 minutes. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under vacuum. Purification by silica gel column chromatography yielded Int8–4, 0.55 g, yield: 30.8%. m / z = 446.1 [M+H] + .

[0173] Under nitrogen atmosphere, compounds 8-4 (0.55 g, 1.23 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborhecyclopentane) (0.328 g, 1.29 mmol), Pd(dppf)2Cl2 (0.11 g, 0.14 mmol), and AcOK (0.18 g, 1.85 mmol) were added to dioxane (10 ml), and the mixture was stirred at 80–85 °C for 2 hours. After cooling, 1-benzyl 3-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (0.50 g, 1.23 mmol), H2O (2 ml), and Cs2CO3 (0.80 g, 2.46 mmol) were added to the mixture, and the mixture was stirred at 90–95 °C for 3 hours. After cooling, add EtOAc (20 ml) and H2O (20 ml) and stir for 15 minutes. Separate the organic layer, wash with water and brine, dry with MgSO4 and concentrate under vacuum. Purify by silica gel column chromatography to obtain Int 8-5, 0.35 g, yield: 45.3%.

[0174] Compound 8-5 (0.35 g, 0.56 mmol) and Pd / C (10% by weight, 0.035 g) were added to methanol (10 mL) under hydrogen atmosphere and stirred overnight at 25–30 °C. The solution was filtered and concentrated under vacuum to give compound Int 8, 0.27 g, 96.3%. m / z = 495.3 [M+H] + .

[0175] Triazole derivatives (Int 9-11) can be prepared using appropriate reagents according to the method in Int 8.

[0176]

[0177] Int 12: (S)-(3-chloro-1-(4,4-difluorocyclohexyl)-2-oxopropyl)tert-butyl carbamate

[0178]

[0179]

[0180] LDA (2.0 M, THF / hexane (12:25) solution, 26 mL, 51.3 mmol) was added to a solution of 12-1 (5 g, 17.1 mmol) and bromochloromethane (11.0 g, 85.5 mmol) in THF (25 mL), and the mixture was stirred at -78 °C for 3 hours. The organic phase was washed with NH4Cl solution and brine, dried over MgSO4, and concentrated under vacuum. Purification by silica gel column chromatography yielded Int 12, 3.7 g, yield: 66.6%. m / z = 326.1 [M+H] + .

[0181] Int 13: (S)-((7-bromoimidazolo[1,2-b]pyridazin-2-yl)(4,4-difluorocyclohexyl)methyl)tert-butyl carbamate

[0182]

[0183] 5-Bromopyridazine-3-amine (1.0 g, 5.75 mmol), Int 12 (2.81 g, 8.62 mmol), and NaHCO3 (1.9 g, 23 mmol) were added to t-BuOH (15 mL) and stirred in a sealed tube at 130–135 °C for 48 hours. After cooling, EtOAc (25 mL) and H2O (25 mL) were added to the mixture and stirred for 15 minutes. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated under vacuum to obtain the product. The product was purified by silica gel column chromatography to give Int 13, 1.32 g, yield: 51.6%. m / z = 445.1 [M+H] + .

[0184] Imidazole derivatives Int 14 and Int 15 can be prepared using appropriate reagents according to the method in Int 13.

[0185] Int 14: (S)-((7-bromoimidazolo[1,2-a]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)tert-butyl carbamate

[0186]

[0187] Int 15: (S)-((7-bromoimidazolo[1,2-c]pyrimidin-2-yl)(4,4-difluorocyclohexyl)methyl)tert-butyl carbamate

[0188]

[0189] Int 16: (S)-((7-bromoquinazolin-2-yl)(4,4-difluorocyclohexyl)methyl)tert-butyl carbamate

[0190]

[0191] POCl3 (0.77 g, 5 mmol) was added dropwise to a DCM (10 mL) solution of 16-1 (1.0 g, 5.0 mmol), TEA (1.01 g, 10 mmol), and 12-1 (1.47 g, 5.0 mmol) at 0–5 °C and stirred for 2 hours. The reaction was quenched with saturated Na2CO3 solution, and the organic phase was washed with water and brine, dried over MgSO4, and concentrated under vacuum. Purification by silica gel column chromatography yielded Int 16-2, 1.96 g, yield: 82.5%. m / z = 475.1 [M+H] + .

[0192] Compound 16-2 (1.5 g, 3.16 mmol) and NH4OAc (4.87 g, 63.2 mmol) were added to AcOH (10 mL) and stirred at 75–85 °C for 4 hours. After cooling, the reaction mixture was quenched with saturated Na2CO3 solution, and EtOAc (20 mL) was added to the reaction mixture. The organic phase was then separated, washed with water and brine, dried over MgSO4, and concentrated under vacuum. Purification by silica gel column chromatography yielded Int 16, 0.93 g, yield: 64.6%. m / z = 456.1 [M+H] + .

[0193] Int 17:(S)-((6-bromobenzo[d]oxazol-2-yl)(4,4-difluorocyclohexyl)methyl)tert-butyl carbamate (Int 17)

[0194]

[0195] Compound 17-1 (2.0 g, 7.97 mmol), compound 12-1 (2.34 g, 7.97 mmol), HATU (3.63 g, 9.56 mmol), and DIPEA (2.06 g, 15.94 mmol) were added to DCM (20 ml) and stirred at room temperature for 3 hours. H₂O (20 ml) was added to the mixture and stirred for 15 minutes. The organic layer was separated, washed with water and brine, dried over MgSO₄, and concentrated under vacuum to give compound 17-2, 3.86 g, 92.0%. m / z = 525.0 [M+H] + .

[0196] Under a nitrogen atmosphere, compound 17-2 (2.5 g, 4.75 mmol), CuI (0.9 g, 0.48 mmol), 1,10-phenanthroline (180.5 mg, 0.96 mmol), and Cs₂CO₃ (2.32 g, 7.13 mmol) were added to 1,2-dimethoxyethane (30 mL), and the reaction was refluxed for 24 hours. After cooling, H₂O (30 mL) and DCM (30 mL) were added to the mixture, and the mixture was stirred for 15 minutes. The organic layer was separated, washed with water and brine, dried over MgSO₄, and concentrated under vacuum to give the product. The product was purified by silica gel column chromatography to give Int 17, 0.50 g, yield: 23.6%. m / z = 445.1 [M+H] + .

[0197] Int 18:(S)-((6-bromobenzo[d]thiazolyl-2-yl)(4,4-difluorocyclohexyl)methyl)tert-butyl carbamate (Int 18)

[0198]

[0199] Compound 17-2 (0.8 g, 1.52 mmol) and Lawesson's reagent (0.60 g, 1.52 mmol) were added to toluene (10 mL) and refluxed for 4 hours. After cooling, H₂O (10 mL) and EtOAc (10 mL) were added and stirred for 10 minutes. The organic layer was separated, washed with water and brine, dried over MgSO₄, and concentrated under vacuum to give the product. The product was purified by silica gel column chromatography to give Int 18-1, 0.21 g, yield: 25.5%. m / z = 541.0 [M+H] + .

[0200] The subsequent reaction involves the preparation of Int 17 to complete the preparation of Int 18.

[0201] Int 19 and Int 20 can be prepared using appropriate reagents according to the methods of Int 17 and Int 18.

[0202] Int 19: (S)-((5-bromobenzo[d]oxazol-2-yl)(4,4-difluorocyclohexyl)methyl)tert-butyl carbamate (Int 19) and Int 20: (S)-((5-bromobenzo[d]thiazolyl)(4,4-difluorocyclohexyl)methyl)tert-butyl carbamate (Int 20)

[0203]

[0204] Preparation Example 2: Synthesis of Compound 1

[0205] Compound 1: (3S,4S)-3-(4-((S)-2-cycloheptyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)acetamido)phenyl)-4-(3,3-difluorozacriane-1-carboxyl)pyrrolidine-1-carboxylic acid methyl ester

[0206]

[0207] TFA (5 ml) was added to a DCM (15 ml) solution of Int 1 (1.2 g, 2.92 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to obtain an oil. This oil was dissolved in DCM (15 ml), and then a saturated NaHCO3 solution (15 ml) was added. The organic phase was separated, washed with water and brine, dried over MgSO4, and concentrated under vacuum to give compound 1-1, 0.83 g, yield: 91.5%. m / z = 311.2 [M+H] + .

[0208] HATU (1.47 g, 3.87 mmol) and TEA (0.52 g, 5.16 mmol) were added to a DCM solution of (S)-2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetic acid (0.77 g, 2.84 mmol) in 20 mL, and the mixture was stirred at room temperature for 30 min. Compound 1-1 (0.80 g, 2.58 mmol) was added to the mixture and stirred for 2 h. Water (20 mL) was added and the mixture was stirred for 10 min. The organic phase was separated, washed with water and brine, dried over MgSO4, and concentrated under vacuum to give compound 1-2, 1.03 g, yield: 70.9%. m / z = 564.3 [M+H] + .

[0209] TFA (3 ml) was added to a DCM (10 ml) solution of Int 1-2 (1.0 g, 1.77 mmol), and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to obtain an oil. This oil was dissolved in DCM (10 ml), and then a saturated NaHCO3 solution (10 ml) was added. The organic phase was separated, washed with water and brine, dried over MgSO4, and concentrated under vacuum to give compounds 1-3, 0.78 g, yield: 94.8%. m / z = 464.3 [M+H] + .

[0210] HATU (0.32 g, 0.83 mmol) and TEA (0.15 g, 1.5 mmol) were added to a DCM solution of 1-isopropyl-1H-pyrazole-5-carboxylic acid (0.13 g, 0.83 mmol) in 10 mL of water, and the mixture was stirred at room temperature for 30 min. Compound I-1 (0.35 g, 0.75 mmol) was added to the mixture and stirred for 2 h. Water (10 mL) was added and the mixture was stirred for 10 min. The organic phase was separated, washed with water and brine, dried over MgSO4, and concentrated under vacuum to give compounds 1-4, 0.37 g, yield: 81.7%. m / z = 564.3 [M+H] + .

[0211] LiOH (59 mg, 2.47 mmol) was added to a MeOH / H₂O (4 mL / 1 mL) solution of compounds 1-4 (0.37 g, 0.62 mmol), and the mixture was stirred at room temperature for 1 hour. Citric acid solution (2 M, 10 mL) was added to the mixture, followed by EtOAc (20 mL), and the mixture was stirred for 10 minutes. The organic phase was separated, washed with water and brine, dried over MgSO₄, and concentrated under vacuum to give compounds 1-5, 0.31 g, yield: 85.8%. m / z = 586.3 [M+H] + .

[0212] HATU (71 mg, 0.19 mmol) and TEA (34 mg, 0.34 mmol) were added to a DCM solution (5 mL) of (S)-2-((tert-butoxycarbonyl)amino)-2-cycloheptylacetic acid (0.1 g, 0.17 mmol) and stirred at room temperature for 30 min. 3,3-Difluoroazacyclobutane (19.1 mg, 0.2 mmol) was added to the mixture and stirred for 2 h. Water (50 mL) was added and stirred for 10 min. The organic phase was separated, washed with water and brine, dried over MgSO4, and concentrated under vacuum to give compounds 1-6, 75 mg, yield: 66.5%. m / z = 661.4 [M+H] + .

[0213] Pd / C (10 mg by weight) was added to a MeOH solution of 1-6 (75 mg, 0.11 mmol) and stirred at room temperature for 4 hours under a hydrogen atmosphere. After filtration, the solution was concentrated under vacuum to give compounds 1-7, which were used for the next reaction without purification.

[0214] At 0-5℃, methyl chloroformate (12.7 mg) in 5 ml of DCM solution was added dropwise to a 1-7 DCM solution and stirred for 1 hour. Water (10 ml) was added and stirred for 10 minutes. The organic phase was separated, washed with water and brine, dried with MgSO4, and concentrated into an oil under vacuum. The oil was then analyzed by preparative liquid chromatography (ACN: 0.5% TFA, SunFire). @ Prep C18 OBD TM The oily substance was purified using a chromatography plate (5 μM × 19 mm × 150 mm) to give compound 1,41 mg, in a yield of 58.2%. LCMS: [M + H] + :629.3.

[0215] The following compounds were prepared according to the preparation method described herein, using appropriate starting materials and intermediates, and, where necessary, appropriate protecting group chemistry methods. Their structures were analyzed... 1 HNMR confirmed.

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229]

[0230]

[0231]

[0232]

[0233]

[0234]

[0235]

[0236]

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255]

[0256] Example 3 Evaluation of in vitro bioactivity

[0257]

[0258]

[0259] Compound Management

[0260] 1. Dilute the test compound 3-fold sequentially in DMSO at 10 mM for 10 doses.

[0261] 2. Preparation of reference compound (IL-17A-inhibitor-1) by 10 doses of 3-fold serial dilution from 1 mM in DMSO.

[0262] 3. Prepare 1000× positive control (1mM IL-17A-inhibitor-1) and 1000× vector control (100% DMSO).

[0263] Test Procedure

[0264] a) Follow the recommended HEK-Blue TM IL-17 technical data sheet for cultured cells. HEK-Blue IL-17 levels were measured in HEK-Blue cells during the exponential growth phase.

[0265] b) Absorb the growth medium and wash the cells twice with PBS to remove phenol red.

[0266] c) Resuspend the cells in the test medium to the appropriate concentration.

[0267] d) Only cells with a viability greater than 90% were used for the assay.

[0268] e) Use an Echo 655 to transfer 25 nm of the compound dilution to a 384-well assay plate.

[0269] f) Seed 25 μl of HEK-Blue IL-17 cells at 8,000 cells / well into 384-well plates containing rhIL-17A / A.

[0270] g) Incubate the cells at 37°C under a 5% CO2 atmosphere for 20 hours.

[0271] h) Transfer 2 μl of cell supernatant to each well of the 384-well assay plate.

[0272] i) Add 20 μl of PNPP substrate.

[0273] j) Measure the absorbance at 405 nm using an Envision 2105 plate reader.

[0274] Data Analysis

[0275] Calculate the RLU signal (LUM) for each aperture. cmpd ).

[0276] Calculate the inhibition percentage as follows:

[0277]

[0278] Signal Ave_PC : The average signal of the positive control on the plate.

[0279] Signal Ave_VC : The average signal of the negative control on the plate.

[0280] Calculate the IC of the compound 50 And plot the effect-dose curve of the compound:

[0281] IC was calculated by fitting the inhibition percentage and log of the compound concentration to a nonlinear regression (dose response - variable slope) using Graphpad 8.0. 50 .

[0282] The results are summarized in Table 2.

[0283] Table 2: Relative biological activities of compounds in HEK-Bule cell assays

[0284]

[0285]

Claims

1. Compounds of Formula I: Its pharmaceutically acceptable salts, its deuterated compounds, and its stereoisomers, in R1 is selected from aryl, 5-6 heteroaryl, -C 1-3 alkyl-aryl or -C 1-3 alkyl-5-6-membered heteroaryl; wherein R1 is optionally surrounded by one or more R 1a replace; Where R 1a Independently selected from halogens, oxometalates, -OH, -CN, and -C 1-6 Alkyl or -C 0-2 Alkyl-C 3-6 cycloalkyl; wherein each R 1a Optionally, it may be substituted by one or more substituents, each independently selected from halogens; R2 and R3 are each independently selected from H and -C. 1-6 Alkyl, aryl, C 3-10 cycloalkyl, -C 0-2 Alkyl-C 3-10 Cycloalkyl, 5-10 membered heterocyclic groups, -C 0-2 Alkyl-C 5-10 Aryl or -C 0-2 Alkyl-5-10-membered heterocyclic groups; or R2 and R3 combined with the atoms they are attached to form C 3-10 cycloalkyl or 5-10 membered heterocyclic groups; wherein the C 3-10 The cycloalkyl or 5-10 membered heterocyclic group is optionally replaced by one or more groups, each independently selected from halogens, -C 1-9 Alkyl or -C 1-8 Substituents of haloalkyl groups; Where G is selected from: Where m = 0, 1, or 2; n = 0, 1, or 2; Where Z is N or -C(R7)-; Wherein ring A is a 9-10 membered heteroaryl group; wherein ring A is optionally composed of one or more groups, each independently selected from halogen, oxo, -OH, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 Substitution of aryl or 5-10 heteroaryl groups; Where Y is selected from O, S, SO, S(O)2, or R4 and R5 are each independently selected from H, OH, and -C. 1-9 Alkyl, -C 1-8 Halogenated alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -COR 6a -C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 Alkyl-heterocyclic, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 Aryl, 5-10 heteroaryl, -C 1-4 Alkyl-SO2-C 1-4 Alkyl or -C 1-4 Alkyl-SO2-C 3-8 cycloalkyl; R4 and R5 are each optionally selected independently from one or more of H, halogen, oxo, -OH, -CN, and -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 The aryl or 5-10-membered heteroaryl groups are substituted; or R4 and R5 are bonded to the atoms to which they are attached to form a 3-10-membered heterocyclic group; wherein the 3-10-membered heterocyclic group is optionally substituted by one or more substituents, each independently selected from halogens, -C 1-9 Alkyl or -C 1-8 Substituents of haloalkyl groups; R6 is independently selected from H and C. 1-9 Alkyl, C 1-8 Halogenated alkyl, -C 1-6 Alkyl-alkoxy, -C 1-6 Alkyl-cycloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl, 5-10 quinone heteroaryl, CO2R 6a COR 6a CON(R) 6a (R) 6b ), -S(O)R 6a -S(O)(NH)R 6a -S(O)2R 6a -S(O)2OR 6a -S(O)2N(R 6a (R) 6b ) or -S(O)(NR 6a )R 6a ; R6 may optionally be selected independently from one or more halogens, oxo groups, -OH, -CN, and -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 1-6 Halogenated alkyl, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 Substitution of aryl or 5-10 heteroaryl groups; Where R 6a and R 6b Each is independently selected from H and C. 1-9 Alkyl, C 1-8 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, heterocyclic, C 6-10 aryl or 5-10 heteroaryl; or R 6a and R 6b They combine with the atoms they are attached to to form C 3-10 cycloalkyl or 5-10 membered heterocyclic groups; wherein the C 3-10 The cycloalkyl or 5-10 membered heterocyclic group is optionally replaced by one or more groups, each independently selected from halogens, -C 1-9 Alkyl or -C 1-8 Substituents of haloalkyl groups; Where R 6a and R 6b Each can be optionally selected by one or more elements independently chosen from halogen, oxo, -OH, -CN, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 1-6 Halogenated alkyl, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 Aryl, 5-10 heteroaryl, -C 1-4 Alkyl-C 3-8 cycloalkyl or -C 1-4 Substitution of alkyl-heterocyclic groups; R7 is selected from H, halogen, oxo, -OH, -CN, and -C. 1-9 Alkyl, -C 1-8 Halogenated alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 2-6 alkenyl, -C 2-6 Alkyne group, -CO2R 7a -COR 7a -CONHR 7a , -NO2, -NH2, -N3, -SH, -O(C 1-9 alkyl), -O(C) 1-8 Halogenated alkyl), -NH(C) 1-9 alkyl), -NH(C) 1-8 Halogenated alkyl), -N(C) 1-9 alkyl)2 or -N(C 1-8 (halogenated alkyl)2; Where R 7a Selected from H, -C 1-6 Alkyl, -C 1-6 Halogenated alkyl, -C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 alkyl-heterocyclic, C 3-10 cycloalkyl, heterocyclic, C 6-10 Aryl or 5-10 heteroaryl; and wherein the 5-10 heteroaryl or heterocyclic group is optionally substituted by one or more substituents, each independently selected from N, O or S.

2. The compound of claim 1, its pharmaceutically acceptable salt, its deuterated compound, and its stereoisomers, wherein the compound has the structures of formulas Ia and Ib:

3. The compound of claim 1, its pharmaceutically acceptable salt, its deuterated compound, and its stereoisomers, wherein the compound has structures of formulas IIa and IIb:

4. The compound of claim 1 or 3, its pharmaceutically acceptable salt, its deuterated compound, and its stereoisomers, wherein ring A is selected from:

5. The compound of claim 1, its pharmaceutically acceptable salt, its deuterated compound, and its stereoisomers, wherein the compound has a structure of formula III: R1 is selected from aryl or 5-6 heteroaryl groups; wherein R1 is optionally separated by one or more R 1a Replace; where each R 1a Independently selected from halogens, -C 1-6 Alkyl or -C 0-2 Alkyl-C 3-6 cycloalkyl; wherein each R 1a Optionally, it may be substituted by one or more substituents, each independently selected from halogens; R4 and R5 are each independently selected from H, OH, and -C. 1-9 Alkyl, -C 1-8 Halogenated alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl group, -COR 6a -C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 Alkyl-heterocyclic, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 Aryl, 5-10 heteroaryl, -C 1-4 Alkyl-SO2-C 1-4 Alkyl or -C 1-4 Alkyl-SO2-C 3-8 cycloalkyl; R4 and R5 are each optionally selected independently from one or more of H, halogen, oxo, -OH, -CN, and -C. 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 3-10 Cycloalkyl, heterocyclic, -C 6-10 The aryl or 5-10-membered heteroaryl groups are substituted; or R4 and R5 are bonded to the atoms to which they are attached to form a 3-10-membered heterocyclic group; wherein the 3-10-membered heterocyclic group is optionally substituted by one or more substituents, each independently selected from halogens, -C 1-9 Alkyl or -C 1-8 Substituents of haloalkyl groups; R6 is independently selected from H and C. 1-9 Alkyl, C 1-8 Halogenated alkyl, -C 1-6 Alkyl-alkoxy, -C 1-6 Alkyl-cycloalkoxy, C 3-10 Cycloalkyl, heterocyclic, CO2R 6a COR 6a or CON(R) 6a (R) 6b ); R6 may optionally be selected from one or more halogens, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 1-6 Halogenated alkyl or -C 3-10 Substitution of cycloalkyl groups.

6. The compound according to any one of claims 1 to 5, wherein R4 and R5 are each independently selected from H, -C 1-9 Alkyl, -C 1-8 Halogenated alkyl, -C 1-4 Alkyl-C 3-8 cycloalkyl, -C 1-4 alkyl-heterocyclic or -C 3-10 Cycloalkyl groups; or R4 and R5 bonded to the atoms to which they are attached to form 3-10 membered heterocyclic groups; wherein the 3-10 membered heterocyclic groups are optionally composed of one or more atoms each independently selected from halogens, -C 1-9 Alkyl or -C 1-8 Substitution of alkyl halogens.

7. The compound according to any one of claims 1 to 6, wherein R6 is independently selected from H and C. 1-9 Alkyl, C 1-8 Halogenated alkyl, -C 1-6 Alkyl-alkoxy, -C 1-6 Alkyl-cycloalkoxy, C 3-10 Cycloalkyl, heterocyclic, CO2R 6a COR 6a or CON(R) 6a (R) 6b ); R6 may optionally be selected from one or more halogens, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 1-6 Halogenated alkyl or -C 3-10 Substitution of cycloalkyl groups.

8. The compound according to any one of claims 1 to 7, wherein R 6a and R 6b Each is independently selected from H and C. 1-9 Alkyl, C 1-8 Haloalkyl, C 3-10 cycloalkyl or heterocyclic groups; or R 6a and R 6b They combine with the atoms they are attached to to form C 3-10 cycloalkyl or 5-10 membered heterocyclic groups; wherein the C 3-10 The cycloalkyl or 5-10 membered heterocyclic group is optionally replaced by one or more groups, each independently selected from halogens, -C 1-9 Alkyl or -C 1-8 Substituents of haloalkyl groups; Where R 6a and R 6b Each can be optionally selected by one or more independently chosen from halogens, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Halogenated alkoxy groups, -C 1-6 Halogenated alkyl, -C 3-10 Substitution by cycloalkyl or heterocyclic substituents.

9. The compound according to any one of claims 1 to 8, wherein R1 is selected from...

10. The compound according to any one of claims 1 to 9, wherein R2 and R3 are independently selected from H and -C. 1-6 Alkyl, C 3-10 cycloalkyl or -C 0-2 Alkyl-C 3-10 Cycloalkyl groups; or R2 and R3 combined with the atoms they are attached to form C 3-10 cycloalkyl; wherein the C 3-10 The cycloalkyl group may optionally be replaced by one or more halogens.

11. A compound, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, and its stereoisomers, wherein said compound is selected from:

12. A pharmaceutical composition comprising: The compound according to any one of claims 1 to 11, and Pharmaceutically acceptable excipients.

13. A method for regulating IL-17A, comprising administering to an individual requiring the method a therapeutically effective amount of the pharmaceutical composition of claim 12 or the compound of any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a stereoisomer thereof.

14. A method for treating an inflammatory disease or disease state, comprising administering to an individual requiring the method a therapeutically effective amount of the pharmaceutical composition of claim 12 or the compound of any one of claims 1 to 11, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, or a stereoisomer thereof.

15. The method of claim 13, wherein the inflammatory disease or disease state is selected from plaque psoriasis, guttate psoriasis, inverted psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, palmoplantar psoriasis, non-infectious uveitis, psoriasis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, and / or COPD.

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