Amide compounds

Abstract

Provided herein are novel compounds (e.g., Formula I), pharmaceutical compositions, and methods of use for treating a variety of diseases or disorders, such as inflammatory diseases or disorders. Formula I.

Description

[0001] In various embodiments, this disclosure generally relates to novel compounds, compositions comprising said novel compounds, methods for preparing said novel compounds, and methods for using said novel compounds, for example, for modulating IL-17A / F activity and / or for treating or preventing diseases or conditions described herein. Background Technology

[0002] Interleukin (IL)-17 is a family of pro-inflammatory cytokines consisting of six known members (IL-17 A through F). IL-17 family cytokines are essential for maintaining adaptive and innate immunity. Among the IL-17 family, IL-17A and IL-17F are the most studied members, capable of forming homodimers and heterodimers (IL-17AA, IL-17AF, and IL-17FF). IL-17 A / F can be released by several cell types, including helper T17 (Th17) cells, γ / δ T cells, mast cells, and neutrophils, with Th17 cells being the primary source. Upon release, IL-17A / F cytokines function through their corresponding IL-17 receptors, which are formed from homodimers or heterodimers of IL-17 receptor A and IL-17 receptor C (IL-17RA and IL-17RC). Specifically, activation of the IL-17 receptor triggers classical signaling and gene expression through multiple signaling pathways (e.g., nuclear factor κB, mitogen-activated protein kinase, and CCAAT / enhancer-binding protein-B), leading to the subsequent production of inflammatory cytokines, including IL-8, IL-6, IL-1β, TNF-α, and numerous chemokines and other effectors. While contributing to host defense responses against bacterial and fungal infections, elevated IL-17A / F cytokines are also key players in autoimmune pathogenesis, acting through amplified inflammatory cascades and subsequent tissue damage in various autoimmune diseases, including but not limited to psoriasis (Ps), psoriatic arthritis (PsA), ankylosing spondylitis (AS), hidradenitis suppurativa (HS), bone erosion, allogeneic transplant rejection, and multiple sclerosis. Furthermore, IL-17A and Th17 cells are also associated with certain cancers, such as multiple myeloma and hepatocellular carcinoma (HCC).

[0003] Targeting IL-17 A and / or F has shown clinical efficacy in treating autoimmune and / or inflammatory diseases and conditions. For example, biologic therapies targeting IL-17 antibody therapy have made significant progress and demonstrated clinical benefit in treating autoimmune diseases. Monoclonal antibodies (mAbs) targeting IL-17A (e.g., secukinumab and ixekizumab) and antibodies targeting the IL-17 receptor (e.g., brodalumab) have been approved by the U.S. Food and Drug Administration for the treatment of patients with autoimmune conditions such as Ps, PsA, and AS. Despite these advances, there is a need for small molecule modulators of IL-17 that can provide alternative and / or orally available treatments for IL-17-related diseases. Summary of the Invention

[0004] In various embodiments, this disclosure is based in part on the finding that certain novel amide compounds can modulate IL-17A and / or IL-17F and can be used to treat or prevent diseases or conditions associated with IL-17A and / or IL-17F, such as autoimmune and / or inflammatory diseases or conditions described herein.

[0005] In some embodiments, this disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0006]

[0007] Formula I,

[0008] The variables are defined herein. In some embodiments, the compound of formula I may have a structure according to a subformula selected from formulas I-E1, IA, IA-1, IA-2, IA-3, I-1, I-2, I-3, I-4, I-1a, I-1b, I-1b-1, I-1c, I-1c-1, I-1d, I-1d-1, I-4a, I-4a-1, I-4a-2, I-4-D2, I-4a-D2, I-4a-1-D2, or I-4a-2-D2, as defined herein. In some embodiments, this disclosure also provides a compound selected from Table 1 herein, or a pharmaceutically acceptable salt thereof. In some embodiments, this disclosure also provides a compound selected from Examples 1-174 herein, or a pharmaceutically acceptable salt thereof.

[0009] Some embodiments of this disclosure relate to a pharmaceutical composition comprising one or more compounds of this disclosure (e.g., compounds of formula I (e.g., formula I-E1, IA, IA-1, IA-2, IA-3, I-1, I-2, I-3, I-4, I-1a, I-1b, I-1b-1, I-1c, I-1c-1, I-1d, I-1d-1, I-4a, I-4a-1, I-4a-2, I-4-D2, I-4a-D2, I-4a-1-D2 or I-4a-2-D2), any of Examples 1-174, any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof), and optionally a pharmaceutically acceptable excipient. The pharmaceutical compositions described herein can be formulated for different routes of administration, such as for oral administration or parenteral injection.

[0010] Some embodiments of this disclosure relate to a method of treating a disease or condition associated with IL-17A and / or IL-17F, such as the inflammatory diseases or conditions described herein and / or autoimmune diseases or conditions, such as psoriasis, psoriatic arthritis, or ankylosing spondylitis. In some embodiments, the method comprises administering to a subject in need a therapeutically effective amount of a compound of the present disclosure (e.g., a compound of formula I (e.g., formula I-E1, IA, IA-1, IA-2, IA-3, I-1, I-2, I-3, I-4, I-1a, I-1b, I-1b-1, I-1c, I-1c-1, I-1d, I-1d-1, I-4a, I-4a-1, I-4a-2, I-4-D2, I-4a-D2, I-4a-1-D2 or I-4a-2-D2), any of Examples 1-174, any compound listed in Table 1 herein, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.

[0011] In some embodiments, this disclosure provides a method for treating an inflammatory disease or condition in a subject of need. In some embodiments, the method comprises administering to the subject of need a therapeutically effective amount of a compound of this disclosure (e.g., a compound of formula I (e.g., formula I-E1, IA, IA-1, IA-2, IA-3, I-1, I-2, I-3, I-4, I-1a, I-1b, I-1b-1, I-1c, I-1c-1, I-1d, I-1d-1, I-4a, I-4a-1, I-4a-2, I-4-D2, I-4a-D2, I-4a-1-D2 or I-4a-2-D2), any of Examples 1-174, any compound listed in Table 1 herein, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof. In some embodiments, the inflammatory disease or symptom is selected from plaque psoriasis, guttate psoriasis, inverted psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis, and non-infectious uveitis.

[0012] The administration described herein is not limited to any particular route of administration. For example, in some embodiments, the administration may be oral, nasal, percutaneous, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, or parenteral. In some embodiments, the administration is oral. In some embodiments, the administration is parenteral injection, such as intravenous injection.

[0013] The compounds disclosed herein can be used as a monotherapy or in combination therapy. In some embodiments according to the methods described herein, one or more compounds of this disclosure can be administered as the sole active ingredient.

[0014] It should be understood that the foregoing description of the invention and the following detailed description are exemplary and explanatory, and do not limit the invention herein. Detailed Implementation

[0015] In various embodiments, novel compounds, pharmaceutical compositions, methods of preparation, and methods of use are provided herein. The compounds disclosed herein are generally IL-17A / F modulators, which may also be used to treat a variety of diseases or conditions, such as those described herein, for example, the autoimmune and / or inflammatory diseases or conditions described herein, such as psoriasis. As shown in the Examples section, representative compounds of this document have shown effective inhibition in both IL17AA and IL17-AF assays, representing one of the advantages associated with the compounds described herein.

[0016] compound

[0017] Formula I

[0018] In some embodiments, this disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof:

[0019]

[0020] Formula I

[0021] in:

[0022] R 1 C is an optional substitute 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl or optionally substituted heteroaryl;

[0023] Z represents empty, C(O), -C(O)-O-, or -C(O)-N(G). Z )-, where Z is -C(O)-O- or -C(O)-N(G Z When )-, the carbonyl group is bonded to the adjacent NH group in formula I, and where G Z It is hydrogen, and the C is optionally substituted. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl or optionally substituted 3-8 membered rings;

[0024] R 2 It is an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted alkyl group;

[0025] Ring A is a phenylene or a 5- or 6-membered heteroarylene (e.g., pyridylene, pyridazinyl, pyrimidinyl, etc.), which is optionally altered by R, where the valence allows. 7 Replace 1-4 instances;

[0026] R 3 and R 4 Each is independently F, CN, G 1A or J 1 -J 2 -J 3 -G 1B J 1 J 2 and J 3 Each is independently empty, O, NG 1B ,C(O),S,SO,SO2 or P(O)G 1B The condition is J 1 J 2 and J 3At least one of them is not empty, and among them:

[0027] G 1B Each time it appears, it is independently either hydrogen or G. 1A ,and

[0028] G 1A Each time it appears, it is an independently substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl or optionally substituted 3-8 membered rings (preferably optionally substituted C) 3-8 (Carbocyclic or optionally substituted 4-8 membered heterocycles);

[0029] Or R 3 and R 4 It is connected together with the carbon atoms of both of them to form an optionally substituted 3-8 membered carbon ring or 4-8 membered heterocycle;

[0030] L 1 It is an empty, optional substitution of C 1-4 Alkylene or optionally substituted C 1-4 Heteroalkyl,

[0031] R 5 It is hydrogen, deuterium, or C with optional substitution. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne or optionally substituted 3- to 8-membered rings;

[0032] Or R 3 Or R 4 With R 5 They can be linked together with intermediate atoms to form optionally substituted 3-8 membered carbon rings or 4-8 membered heterocycles;

[0033] R 6 It's OG 2A 、N(G 2A )C(O)G 2A 、N(G 2A )C(O)OG 2B 、N(G 2A )C(O)NG 2A G 2A 、N(G 2A SO2G 2B or N(G) 2A SO2NG 2A G 2A G 2A Each time it appears, it is independently either hydrogen or G. 2B ; and among them G2B Each time it appears, it is an independently substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl or optionally substituted 3-14 membered rings (e.g., optionally substituted C) 3-8 (Carbon ring, optionally substituted 5- or 6-membered heteroaryl ring, or optionally substituted 4- to 8-membered heterocycle).

[0034] Y is C(O) or SO2;

[0035] R 8 It's NG 3 G 3 Optionally substituted 4-14 membered heterocycles or optionally substituted heteroaryl rings, wherein:

[0036] G 3 Each time it appears, it is independently hydrogen, with optional substitution of C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl or optionally substituted 3-8 membered rings; or two Gs 3 Together with the nitrogen atoms attached to both, they form optionally substituted 4-8 membered heterocycles;

[0037] R 7 Each time it appears, it is independently of deuterium, halogen, CN, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl, optionally substituted 3-8 membered rings or J 4 -J 5 -J 6 -G 4 J 4 J 5 and J 6 Each is independently empty, O, NG 4 ,C(O),S,SO,SO2 or P(O)G 4 J 4 J 5 and J 6 At least one of them is not empty, and G is among them. 4 Each time it appears, it is independently hydrogen, with optional substitution of C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6Heteroalkyl or optionally substituted 3-8 membered rings; or two R... 7 They can be connected to form optional 4-8 member rings;

[0038] Or R 7 An example and R 3 Or R 4 It connects with the intermediate atom to form an optionally substituted 5-8 membered carbon ring or heterocycle; and

[0039] “n” is an integer selected from 0 to 4.

[0040] Compounds of Formula I (including any applicable formulas as described herein) contain one or more asymmetric centers and / or axial chirality, and therefore can exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. In some embodiments, where applicable, compounds of Formula I can exist as individual enantiomers and / or diastereomers, or mixtures of stereoisomers, including racemic mixtures and mixtures enriched with one or more stereoisomers. In some embodiments, where applicable, compounds of Formula I (including any applicable formulas as described herein) can exist as a single enantiomer substantially free of other enantiomers, such as an enantiomer excess (“ee”) greater than 60%, preferably greater than 80% ee, greater than 90% ee, greater than 95% ee, greater than 98% ee, or greater than 99% ee. In some embodiments, where applicable, compounds of Formula I (including any applicable formulas as described herein) can also exist as mixtures of stereoisomers in any ratio, such as racemic mixtures.

[0041] For example, in some embodiments, the compound of formula I may be characterized by having a structure according to formula I-E1:

[0042]

[0043] Formula I-E1,

[0044] The variables are defined herein. In some embodiments, a compound having a structure according to formula I-E1 can be used as a relative to R. 2 The attached chiral carbon is substantially free of another enantiomer, such as the as-drawn enantiomer, such that the enantiomer excess (“ee”) is greater than 60%, preferably greater than 80% ee, greater than 90% ee, greater than 95% ee, greater than 98% ee, or greater than 99% ee.

[0045] In some embodiments, Formula I compounds (including any applicable formulas as described herein) may be present as isotopically labeled compounds, specifically deuterated analogs, wherein one or more hydrogen atoms in the Formula I compound are substituted with deuterium atoms of higher abundance than their native abundance, such as CD3 analogs when the compound has a CH3 group. For clarity, when substituents or variants or other structures as defined herein specifically refer to groups containing deuterium, D, or deuterium, it should be understood that the deuterium at each indicated position is greater than the native abundance of deuterium (approximately 0.0156 mol%), for example, the deuterium content at the indicated position may be at least 1 mol%, 10 mol%, 50 mol%, 90 mol%, 98 mol%, or 99 mol% deuterium. Not wishing to be bound by theory, it is believed that in certain cases, deuteration substitution can produce deuterated analogs with better pharmacokinetic properties. Deuterated analogues can typically be prepared using commercially available deuterating agents, which typically have a high deuterium content of up to 99 mol% or more. In some embodiments, the Formula I compound (including any applicable formula as described herein) exists as a non-isotopically labeled compound; in other words, all atoms in the compound have their respective natural abundances, for example, no hydrogen atoms in the compound are substituted with deuterium atoms whose abundance is higher than their natural abundance.

[0046] It will be apparent to those skilled in the art that, in certain circumstances, compounds of Formula I may exist as mixtures of tautomers or trans-isomers. This disclosure is not limited to any particular tautomer or trans-isomer. Rather, this disclosure covers any and all tautomers or trans-isomers of such tautomers or trans-isomers, whether or not explicitly drawn or mentioned.

[0047] Typically, Z in Formula I or any applicable formula herein is C(O). For example, in a preferred embodiment, a compound of Formula I may have a structure according to Formula IA:

[0048]

[0049] Formula IA,

[0050] The variables are defined in this article.

[0051] In some embodiments, Z in Equation I or any applicable sub-equation of this document may also be empty, i.e., in Equation I... Part of it is In some embodiments, in Formula I The part can be a heteroarylamino, that is, Z is empty and R 1It is a heteroaryl group, for example, in some embodiments, the one in Formula I The portion is a 5- or 6-membered heteroarylamino group, wherein the 5- or 6-membered heteroaryl ring is optionally substituted by, for example, one or two substituents, each of which is independently a halogen, CN, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl group. In some embodiments, the 5- or 6-membered heteroaryl ring may be selected from pyridine, pyridazine, pyrimidine, pyrazine, thiadiazole, oxadiazole, oxazole, imidazole, pyrazole, and isoxazole, which may optionally be substituted as described herein. In some specific embodiments, the alkoxy group in Formula I... The moiety may be a pyridazinylamino group, wherein the pyridazine ring may optionally be substituted by one or two substituents, each of which is independently a halogen, CN, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkoxy groups, such as those in Formula I The parts can be selected from: .

[0052] In some embodiments, Z in any applicable formula of Equation I or any applicable formula herein may also be -C(O)-O- or -C(O)-N(G) Z )-, and in formula I Parts can be or In some embodiments, G Z It can be hydrogen, C 1-6 Alkyl or 3-5 membered ring, wherein the C 1-6 The alkyl or 3-5 membered ring may be unsubstituted or substituted with one or more substituents as described herein. For example, suitable substituents may be oxo, halogenated, or optionally C-shaped rings substituted with deuterium, halogen, and / or OH. 1-3 Alkyl or optionally C 1-3 3- to 5-membered rings substituted with alkyl, halogen, and / or OH groups. For example, in some embodiments, the rings in Formula I... Parts can be , where R 1 Defined in this article, such as C 3-10 The carbocyclic group (e.g., cyclopropyl or cyclobutyl), optionally substituted with one or more substituents as described herein, for example, substituted with one or more substituents independently selected from: halogen, CN, OH, NH2, R A1 OR A1 SR A1 NHR A1 NR A1 R A1 C(O)RA1 C(O)NHR A1 or C(O)NR A1 R A1 , where R A1 Defined in this article.

[0053] Typically, R in Equation I or any applicable sub-equation in this document 1 It is an optionally substituted heteroaryl group. For example, in some preferred embodiments, R in Formula I or any applicable formula herein... 1 It is an optionally substituted 5- or 6-membered heteroaryl group, more preferably a substituted 5- or 6-membered heteroaryl group. In some embodiments, R 1 It is selected from the following 5- or 6-membered heteroaryl groups: pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan, thiophene, imidazole, oxadiazole, thiadiazole, triazole, tetraazole, pyridine, pyrimidine, pyrazine, and pyridazine, each of which may optionally be substituted. In some preferred embodiments, R 1 It is an optionally substituted 5-membered heteroaryl group, for example, pyrazole (e.g., ), isoxazole (e.g., ) or oxadiazole (e.g., When substituted, the optionally substituted heteroaryl group, such as the 5- or 6-membered heteroaryl group, may preferably be substituted by one or more substituents, provided that the valence allows, wherein each substituent is independently selected from halogens, CN, OH, NH2, R. A1 OR A1 SR A1 NHR A1 NR A1 R A1 NR A1 SO2R A1 C(O)R A1 C(O)NHR A1 C(O)NR A1 R A1 S(O) q R A1 S(O) q NR A1 R A1 and S(O)(=NR) A1 )R A1

[0054] in:

[0055] q is 1 or 2; and

[0056] R A1 It is C independently each time it appears. 1-6 Alkyl, C 3-10Carbon rings or 4-10 membered heterocycles, wherein:

[0057] The C 1-6 The alkyl group is optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, OH, CN, C. 1-6 Heteroalkyl, oxo, and 3-8 membered rings (e.g., cyclopropyl, cyclobutyl, oxetane, tetrahydrofuranyl, etc.), wherein the C 1-6 The heteroalkyl group and the 3-8 membered ring are optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, oxo, OH, C-membered rings optionally substituted with deuterium, halogen and / or OH. 1-3 Alkyl or optionally C 1-3 3-5 membered rings substituted with alkyl, halogen, and / or OH groups; and

[0058] The C 3-10 The carbocyclic ring or 4-10-membered heterocycle is optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, OH, CN, C. 1-6 Alkyl, C 1-6 Heteroalkyl, oxo, and 3-8 membered rings, wherein the C 1-6 Alkyl, C 1-6 The heteroalkyl group and the 3-8 membered ring are optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, oxo, OH, C-membered rings optionally substituted with deuterium, halogen and / or OH. 1-3 Alkyl or optionally C 1-3 3-5 membered rings substituted with alkyl, halogen and / or OH.

[0059] In some preferred embodiments, R A1 Each time it appears, it is independently (1) a C group that is optionally substituted by one or more substituents independently selected from deuterium, F and OH. 1-4 Alkyl; or (2) C substituted with one or more substituents independently selected from deuterium, methyl, F and OH. 3-6 cycloalkyl; or (3) a 4-6 membered heterocyclic group optionally substituted with one or more substituents independently selected from deuterium, methyl, F and OH; or (4) (C 1-3 (alkylene)-(3-6 membered ring), wherein the C 1-3 The alkylene group and the 3-6 membered ring are each independently and optionally substituted by one or more substituents independently selected from deuterium, methyl, CD3, F, and OH, wherein the 3-6 membered ring is C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups, for example, an R A1 It can be cyclopropylmethyl, cyclobutylmethyl, , or In some preferred embodiments, R A1Each time it appears independently, it is (i) C that is optionally replaced by deuterium and / or F. 1-4 Alkyl groups, such as methyl, CD3, ethyl, CD2CD3, isopropyl, difluoromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, or 2,2-difluoroethyl; (ii) (C 1-2 (alkylene)-C 3-5 cycloalkyl, such as cyclopropylmethyl, wherein the C 1-2 Alkylene and C 3-5 Each cycloalkyl group is independently and optionally substituted with methyl, deuterium, and / or F; for example, an R A1 yes , or ; or (iii) C substituted with methyl and / or F. 3-4 Cycloalkyl. In some preferred embodiments, R A1 Each time it appears, it is independently C, which is optionally replaced by deuterium and / or F. 1- 4-alkyl or C-substituted with F 3-4 Cycloalkyl. In some specific embodiments, R A1 Each time it appears, it is independently methyl, CD3, ethyl, isopropyl, difluoromethyl, 2,2-difluoroethyl, cyclopropylmethyl, or cyclopropyl. In some specific embodiments, R A1 Each time it appears independently, it is methyl, CD3, ethyl, CD2CD3, isopropyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl. cyclopropylmethyl, cyclobutylmethyl , , , , , Or cyclopropyl.

[0060] In some embodiments, R in Equation I or any applicable sub-equation herein 1 It can be a 5- or 6-membered heteroaryl group selected from the following: pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan, thiophene, imidazole, oxadiazole, thiadiazole, triazole, tetraazole, pyridine, pyrimidine, pyrazine, and pyridazine, which is unsubstituted or substituted by one or two substituents independently selected from the following: halogen, CN, R. A1 OR A1 , where R A1 Defined and preferred herein. In some embodiments, R in Formula I or any applicable formula herein. 1It can be selected from the following 5-membered heteroaryl groups: pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan, thiophene, imidazole, oxadiazole, thiadiazole, triazole, or tetraazole, which are unsubstituted or selected by one or two independently selected R groups. A1 Replace, where R A1 Defined and preferred herein. Although it is obvious, it should be further clarified that when the variables in any applicable sub-formula of Equation I or any applicable sub-formula herein have the stated definitions, it should be understood that such applicable sub-formulas include any sub-formula of Equation I of this document that does not define variables that contradict the stated definitions.

[0061] In some preferred embodiments, R in Formula I or any applicable formula herein 1 It can have according to The structure, where R A1 Defined and preferred herein. For example, in some embodiments, R A1 It can be (1) a C that is optionally substituted by one or more substituents independently selected from deuterium, F and OH. 1-4 Alkyl; or (2) C substituted with one or more substituents independently selected from deuterium, methyl, F and OH. 3-6 (3) a cycloalkyl group; (4) a 4-6 membered heterocyclic group optionally substituted with one or more substituents independently selected from deuterium, methyl, F and OH; or (4) (C 1-3 (alkylene)-(3-6 membered ring), wherein the C 1-3 The alkylene group and the 3-6 membered ring are each independently and optionally substituted by one or more substituents independently selected from deuterium, methyl, CD3, F, and OH, wherein the 3-6 membered ring is C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups, for example, R A1 It can be cyclopropylmethyl, cyclobutylmethyl, , or In some embodiments, R A1 It can be (i) C that is optionally replaced by deuterium and / or F. 1-4 Alkyl groups, such as methyl, CD3, ethyl, isopropyl, difluoromethyl, 2,2-difluoroethyl; (ii) (C 1-2 (alkylene)-C 3-5 cycloalkyl groups, such as cyclopropylmethyl, cyclobutylmethyl, etc., wherein the C 1-2 Alkylene and C 3-5 Each cycloalkyl group is optionally and independently substituted with methyl, deuterium, and / or F; for example, R A1 yes , or ; or (iii) C substituted with methyl and / or F.3-4 Cycloalkyl. In some embodiments, R A1 C can be optionally replaced by deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with F 3-4 Cycloalkyl. In some specific embodiments, R in Formula I or any applicable formula herein. 1 It can be , , , , , , or In some specific embodiments, R in Equation I or any applicable sub-equation herein... 1 You can choose from: In some specific embodiments, R in Equation I or any applicable sub-equation herein... 1 You can choose from: .

[0062] In some preferred embodiments, R in Formula I or any applicable formula herein 1 It can have according to or The structure, where R A1 Defined and preferred herein. For example, in some embodiments, R A1 It can be (1) a C that is optionally substituted by one or more substituents independently selected from deuterium, F and OH. 1-4 Alkyl; (2) C substituted with one or more substituents independently selected from deuterium, methyl, F and OH 3-6 (3) a cycloalkyl group; (4) a 4-6 membered heterocyclic group optionally substituted with one or more substituents independently selected from deuterium, methyl, F and OH; or (4) (C 1-3 (alkylene)-(3-6 membered ring), wherein the C 1-3 The alkylene group and the 3-6 membered ring are each independently and optionally substituted by one or more substituents independently selected from deuterium, methyl, CD3, F, and OH, wherein the 3-6 membered ring is C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups, for example, R A1 It can be cyclopropylmethyl, cyclobutylmethyl, , or In some embodiments, R A1 It can be (i) C that is optionally replaced by deuterium and / or F. 1-4 Alkyl; (ii) (C 1-2 (alkylene)-C 3-5cycloalkyl, such as cyclopropylmethyl, wherein the C 1-2 Alkylene and C 3-5 Each cycloalkyl group is optionally substituted independently with methyl, deuterium and / or F; or (iii) C is optionally substituted with methyl and / or F. 3-4 Cycloalkyl. In some embodiments, R A1 C can be optionally replaced by deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with F 3-4 Cycloalkyl. In some more specific embodiments, R in Formula I or any applicable formula herein. 1 It can be , or .

[0063] In some embodiments, the compound of formula I may be characterized by having a structure according to formulas I-A1, I-A2, and I-A3:

[0064]

[0065] Formula I-A1,

[0066]

[0067] Formula I-A2,

[0068]

[0069] Formula I-A3,

[0070] The variables are defined herein. For example, in some embodiments, R in equation I-A1, I-A2, or I-A3 A1 C can be optionally substituted with one or more substituents independently selected from deuterium, F, and OH. 1-4 Alkyl group, or C group optionally substituted with one or more substituents independently selected from the following. 3-6 Cycloalkyl groups: deuterium, methyl, F, and OH. In some embodiments, R in formula I-A1, I-A2, or I-A3 A1 It can be (i) C that is optionally replaced by deuterium and / or F. 1-4 Alkyl groups, such as methyl, CD3, ethyl, isopropyl, difluoromethyl, 2,2-difluoroethyl; (ii) (C 1-2 (alkylene)-C 3-5 cycloalkyl, such as cyclopropylmethyl, wherein the C 1-2 Alkylene and C 3-5 Each cycloalkyl group is optionally substituted independently with methyl, deuterium, and / or F; or (iii) C is optionally substituted with methyl and / or F. 3-4Cycloalkyl. In some embodiments, R in formula I-A1, I-A2 or I-A3 A1 C can be optionally replaced by deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with F 3-4 Cycloalkyl. In some more specific embodiments, R in formula I-A1, I-A2, or I-A3 A1 It can be methyl, CD3, ethyl, isopropyl, difluoromethyl, 2,2-difluoroethyl, cyclopropylmethyl, or cyclopropyl. In some specific embodiments, R in formula I-A1, I-A2, or I-A3 A1 It is methyl, CD3, ethyl, CD2CD3, isopropyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl. cyclopropylmethyl, cyclobutylmethyl , , , , , Or cyclopropyl.

[0071] In some embodiments, R in Equation I or any applicable sub-equation herein 1 It could also be C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group, optionally substituted by one or more substituents as described herein, for example, substituted by one or more substituents independently selected from: halogen, CN, OH, NH2, R A1 OR A1 SR A1 NHR A1 NR A1 R A1 C(O)R A1 C(O)NHR A1 or C(O)NR A1 R A1 , where R A1 Defined in this article.

[0072] In some embodiments, R in Equation I or any applicable sub-equation herein 1 It can also be a carbon cyclic group, such as C 3-10 The carbocyclic group (e.g., cyclopropyl or cyclobutyl), optionally substituted with one or more substituents as described herein, for example, substituted with one or more substituents independently selected from: halogen, CN, OH, NH2, R A1 OR A1 SR A1 NHR A1 NRA1 R A1 C(O)R A1 C(O)NHR A1 or C(O)NR A1 R A1 , where R A1 Defined herein. For example, in some embodiments, R 1 It can be or Typically, in such embodiments, Z is C(O) or -C(O)-O-. For example, in some embodiments, ZR in Formula I 1 It can be or .

[0073] In some embodiments, R in Equation I or any applicable sub-equation herein 1 It can also be a heterocyclic group, such as a 4-10 membered heterocyclic group having 1-3 independently selected cyclic heteroatoms chosen from O, N, and S, optionally substituted by one or more substituents as described herein, for example substituted by one or more independently selected substituents from: halogen, CN, OH, NH2, R A1 OR A1 SR A1 NHR A1 NR A1 R A1 C(O)R A1 C(O)NHR A1 or C(O)NR A1 R A1 , where R A1 Defined in this article.

[0074] In some embodiments, R in Equation I or any applicable sub-equation herein 1 It can also be an aryl group, such as a phenyl group, which is optionally substituted with one or more substituents as described herein, for example, substituted with one or more substituents independently selected from: halogen, CN, OH, NH2, R A1 OR A1 SR A1 NHR A1 NR A1 R A1 C(O)R A1 C(O)NHR A1 or C(O)NR A1 R A1 , where R A1 Defined in this article.

[0075] In formula I (or any applicable formula herein, such as IA, I-A1, I-A2, or I-A3), ring A is typically phenylene, optionally surrounded by 1-4 R groups. 7 Substitution, i.e., n is 0-4. For example, in some preferred embodiments, the compound of formula I may be characterized by having a structure according to formula I-1:

[0076]

[0077] Formula I-1,

[0078] The variables are defined in this article.

[0079] In some embodiments, in Formula I (e.g., any applicable formula herein, such as IA, I-A1, I-A2, or I-A3), ring A is a 6-membered heteroaryl group (e.g., pyridinyl, pyridazinyl, pyridazinyl, pyrimidinyl, etc.). For example, in some embodiments, ring A and (R 7 ) n Together we can have , , or The structure is given, where n is 0-3 as allowed by valence and R... 7 As defined in this article.

[0080] The integer n in Equation I can be in the range of 0-4, usually 0, 1 or 2.

[0081] In some embodiments, in equation I (e.g., any applicable sub-equation, such as equation IA, I-A1, I-A2, I-A3, I-1, I-2, I-3, I-4, etc.), the integer n can be 0.

[0082] In some embodiments, in Equation I (e.g., any applicable sub-equation, such as Equations IA, I-A1, I-A2, I-A3, I-1, I-2, I-3, I-4, etc.), the integer n can be 1. For example, in some embodiments, in Equation I... Parts can be , where R 7 As defined herein, preferably, R 7 Located adjacent to the NHC(O) portion plotted in Formula I. In some embodiments, in Formula I... Parts can be , , , , or , where R 7 Defined in this article.

[0083] In some embodiments, in formula I (e.g., any applicable formula, such as formula IA, I-A1, I-A2, I-A3, I-1, I-2, I-3, I-4, etc.), the integer n may be greater than 1, such as 2 or 3, if the valence allows.

[0084] In some embodiments, in Formula I (e.g., any applicable formula herein, such as IA, I-A1, I-A2, or I-A3), ring A may also be a 5-membered heteroaryl group.

[0085] Typically, in equation I or any applicable formula in this paper such as equation IA, I-A1, I-A2, I-A3, I-1, I-2, I-3, I-4, etc., R 2 It is an optionally substituted 3-14 membered carbocyclic group, which can be monocyclic or polycyclic (including bicyclic, tricyclic, etc.). When substituted, the 3-14 membered carbocyclic group is preferably substituted by one or more substituents, each of which is independently deuterium, halogen, CN, oxo, or OR. A2 SR A2 NR A2 R A2 C(O)R A2 C(O)OR A2 C(O)NR A2 R A2 S(O)R A2 SO2R A2 SO2NR A2 R A2 OC(O)R A2 NR A2 C(O)R A2 NR A2 SO2R A2 ,PO(R A2 (R) A2 ) or R B2 ,

[0086] Where R A2 Each time it appears, it is independently either hydrogen or R. B2 ,and

[0087] Where R B2 Each time it appears, it is independently an optionally substituted group selected from the following: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group or 3-7 membered carbocyclic ring or 4-7 membered heterocyclic ring, wherein when substituted...

[0088] The C 1-6 Alkyl, C2-6 alkenyl or C 2-6 The alkynyl group is preferably substituted by one or more substituents independently selected from the following: deuterium, halogen, OH, CN, C. 1-6 Heteroalkyl, oxo, and 3-8 membered rings, wherein the C 1-6 The heteroalkyl group and the 3-8 membered ring are optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, oxo, OH, C-membered rings optionally substituted with deuterium, halogen and / or OH. 1-3 Alkyl or optionally C 1-3 3-5 membered rings substituted with alkyl, halogen, and / or OH groups; and

[0089] The 3-7 membered carbon ring or 4-7 membered heterocycle is preferably substituted by one or more substituents independently selected from the following: deuterium, halogen, OH, CN, C. 1-6 Alkyl, C 1-6 Heteroalkyl, oxo, and 3-8 membered rings, wherein the C 1-6 Alkyl, C 1-6 The heteroalkyl group and the 3-8 membered ring are optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, oxo, OH, C-membered rings optionally substituted with deuterium, halogen and / or OH. 1-3 Alkyl or optionally C 1-3 3-5 membered rings substituted with alkyl, halogen and / or OH.

[0090] For example, in some preferred embodiments, R 2 It is a substituted monocyclic C 3-8 Cycloalkyl, for example, monocyclic C-shaped compounds optionally substituted with one or more substituents. 3-8 Cycloalkyl, wherein the one or more substituents are each independently deuterium, halogen, CN, oxo, OR A2 SR A2 NR A2 R A2 C(O)R A2 C(O)OR A2 C(O)NR A2 R A2 S(O)R A2 SO2R A2 SO2NR A2 R A2 OC(O)R A2 NR A2 C(O)R A2 NR A2 SO2R A2 ,PO(R A2 (R) A2 ) or R B2 , where R A2 and RB2 Defined herein. In some preferred embodiments, when replaced, the monocyclic C 3-8 The cycloalkyl group may be substituted with one or more substituents, each of which is independently deuterium, halogen, OH, oxo, or optionally by one or more G groups. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Alkoxy, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy. In some embodiments, R 2 It is an unsubstituted monocyclic C 3-8 Cycloalkyl groups, such as cyclopentyl, cyclohexyl, or cycloheptyl. In some embodiments, R 2 It is a single-ring C 3-7 Cycloalkyl groups, such as cyclohexyl or cycloheptyl, are optionally substituted with one or more substituents, each of which is independently deuterium, F, or optionally G. S2 Replacement C 1-3 Alkyl, wherein G S2 Each occurrence is independently of deuterium, F, or OH. In some preferred embodiments, G S1 or G S2 It can be F. In some embodiments, R 2 It is a monocyclic C that is optionally substituted with one or more (e.g., 1 or 2) methyl groups. 3-7 Cycloalkyl. In some embodiments, R 2 It is a monocyclic C that is optionally replaced by one or more (e.g., 1 or 2) F. 3-7 Cycloalkyl. In some embodiments, R 2 It is a monocyclic C that is optionally replaced by one or more (e.g., 1) CF3. 3-7 Cycloalkyl. In some embodiments, R 2 yes , , or In some embodiments, R 2 Selected from the following: In some embodiments, R 2 Selected from the following: For example, in some specific embodiments, the compound of formula I-1 may be characterized by having a structure according to formula I-1a:

[0091]

[0092] Formula I-1a,

[0093] The variables are defined in this article.

[0094] In some preferred embodiments, R 2 It can also be a polycyclic C with optional substitution. 4-10 Carbocyclic groups, such as spiro[2,5]octyl, indanyl, etc., and, for example, polycyclic C groups optionally substituted with one or more substituents. 4-10 The carbocyclic group, wherein each of the one or more substituents is independently deuterium, halogen, CN, oxo, or OR. A2 SR A2 NR A2 R A2 C(O)R A2 C(O)OR A2 C(O)NR A2 R A2 S(O)R A2 SO2R A2 SO2NR A2 R A2 OC(O)R A2 NR A2 C(O)R A2 NR A2 SO2R A2 ,PO(R A2 (R) A2 ) or R B2 , where R A2 and R B2 Defined herein. In some preferred embodiments, when replaced, the polycyclic C 4-10 The carbocyclic group may be substituted by one or more substituents, each of which is independently deuterium, halogen, OH, oxo, or optionally by one or more G groups. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Alkoxy, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkyl groups. For clarity, the polycyclic C groups in this article... 4-10 A carbocyclic group includes a ring system, wherein one ring is an aromatic ring, provided that the ring system as a whole is non-aromatic. For example, and Both are examples of unsubstituted C9 carbon cyclic groups.

[0095] In some embodiments, R 2 It can be a spiral, fused, or bridged double ring C 4-10 cycloalkyl, for example, or It is optionally substituted with one or more substituents, each of which is independently deuterium, halogen, OH, oxo, and optionally substituted with one or more G. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Alkoxy, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkyl group. For example, in some embodiments, R 2 Selected from: In some embodiments, R 2 Selected from: For example, in some preferred embodiments, the compound of formula I-1 may be characterized by having a structure according to formula I-1c:

[0096]

[0097] Formula I-1c,

[0098] Where t is 0, 1, or 2, and R 100 Each time it appears, it is independently a halogen, optionally replaced by deuterium or F, of C. 1-3 Alkyl groups or C groups optionally substituted with deuterium or F 1-3 Alkoxy groups, and other variables defined herein. In equation I-1c, when t is not 0, R 100 This should be understood as a substituent for the cyclohexyl or cyclopropyl moiety of a bicyclic structure. In some embodiments, t is 0. In some embodiments, t is 2. In some embodiments, R 100 It is F each time it appears. In some preferred embodiments, the compound of formula I-1 may be characterized by having a structure according to formula I-1c-1:

[0099]

[0100] Formula I-1c-1,

[0101] The variables are defined in this article.

[0102] In some preferred embodiments, R in formula I or any applicable formula herein such as formula IA, I-A1, I-A2, I-A3, I-1, I-2, I-3, I-4, etc. 2 It may be an optionally substituted alkyl group. Preferably, in such embodiments, R in Formula I or any applicable formula herein is... 2 It can be a substituted methyl group, wherein one or both hydrogen atoms are independently surrounded by an alkyl, heteroalkyl, or 3-12 membered ring structure (e.g., selected from C).3-7 A monocyclic ring consisting of a carbocyclic ring, a 4-8 membered heterocyclic ring, a phenyl ring, or a 5- or 6-membered heteroaryl ring; or a spirocyclic, fused, or bridged 5- to 12-membered bicyclic ring, wherein each ring is independently substituted with a carbocyclic ring, a heterocyclic ring, a phenyl ring, or a 5- or 6-membered heteroaryl ring, wherein each of these is further optionally substituted. In some embodiments, the substituted methyl group is replaced by two independently selected, optionally substituted 3- to 12-membered ring structures selected from (1) C 3-7 A monocyclic ring consisting of a carbocyclic ring, a 4-8 membered heterocyclic ring, a phenyl ring, or a 5- or 6-membered heteroaryl ring; or (2) a spirocyclic, fused, or bridged 5- to 12-membered bicyclic ring, wherein each ring is independently a carbocyclic ring, a heterocyclic ring, a phenyl ring, or a 5- or 6-membered heteroaryl ring. In some embodiments, the substituted methyl group is replaced by a substituent, which is optionally a 3- to 12-membered ring structure selected from the following: (1) selected from C 3-7 A monocyclic ring consisting of a carbocyclic, 4-8 membered heterocyclic, phenyl, or 5- or 6-membered heteroaryl group; or (2) a spirocyclic, fused, or bridged 5- to 12-membered bicyclic ring, wherein each ring is independently a carbocyclic, heterocyclic, phenyl, or 5- or 6-membered heteroaryl group; and optionally another substituent, which is an optionally substituted alkyl or heteroalkyl group. When substituted, the optionally substituted 3- to 12-membered ring structure or the optionally substituted alkyl or heteroalkyl group is preferably substituted by one or more substituents independently selected from: deuterium, halogen, OH, oxo, optionally substituted by one or more G groups. S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl or optionally substituted 3-7 membered ring structures (e.g., carbocyclic, heterocyclic, phenyl, or heteroaryl), wherein G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy, wherein the optionally substituted 3-7 membered ring structure is optionally substituted by one or more substituents, each of which is independently deuterium, halogen, CN, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups, C groups optionally substituted with deuterium and / or F 1-4 Heteroalkyl or optionally substituted with deuterium, F, OH and / or methyl cyclopropyl or cyclobutyl.

[0103] In some preferred embodiments, R in formula I or any applicable formula herein such as formula IA, I-A1, I-A2, I-A3, I-1, I-2, I-3, I-4, etc. 2 It can have The structure, where R 10 and R 11 Each is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted C 3-7A carbocyclic or optionally substituted phenyl group, wherein R 10 and R 11 At least one of them is not hydrogen, preferably, R 10 and R 11 Neither of them is hydrogen. 10 and R 11 They can be the same or different. When replaced, R 10 Or R 11 The optionally substituted groups may preferably be substituted by one or more substituents independently selected from the following: deuterium, halogen, OH, oxo, optionally substituted by one or more G groups. S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl or optionally substituted 3-7 membered ring structures (e.g., carbocyclic, heterocyclic, phenyl, or heteroaryl), wherein G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy, wherein the optionally substituted 3-7 membered ring structure is optionally substituted by one or more substituents, each of which is independently deuterium, halogen, CN, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups, C groups optionally substituted with deuterium and / or F 1-4 Heteroalkyl or optionally substituted with deuterium, F, OH and / or methyl cyclopropyl or cyclobutyl.

[0104] In some specific embodiments, the compound of formula I-1 may be characterized by having a structure according to formula I-1b:

[0105]

[0106] Formula I-1b,

[0107] The variables are defined in this article.

[0108] In some embodiments, R 10 It is arbitrarily controlled by one or more Gs S1 Replacement C 1-4 Alkyl, wherein G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkyl group.

[0109] In some embodiments, R 10 It is (1) C 3-6 cycloalkyl; or (2)-(C 1-3 alkylene)-(C 3-6 cycloalkyl), wherein the C 1-3 Alkylene and C3-6 Each of the cycloalkyl groups is optionally substituted with, for example, one or more substituents, each of which is independently deuterium, halogen, OH, oxo, and optionally substituted with one or more G groups. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Heteroalkyl, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy. In some embodiments, the C 1-3 The alkylene group is unsubstituted. In some embodiments, G S1 It is F each time it appears. In some embodiments, the C 3-6 Cycloalkyl groups are unsubstituted or C16 groups independently selected from F1 and optionally substituted by F1. 1-3 Alkyl substituents. For example, in some preferred embodiments, R 10 It is cyclopropyl, methylcyclopropyl, or cyclobutyl.

[0110] In some embodiments, R 10 It is (1) phenyl; or (2)-(C) 1-3 (alkylene)-phenyl, wherein the C 1-3 Each of the alkylene and phenyl groups is optionally substituted with, for example, one or more substituents, each of which is independently deuterium, halogen, OH, CN, or optionally with one or more G groups. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Heteroalkyl, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy. In some embodiments, the C 1-3 The alkylene group is unsubstituted. In some embodiments, G S1 In each occurrence, it is F. In some embodiments, the phenyl group is unsubstituted or C substituted with one or more halogens independently selected from halogens (e.g., F or Cl) and optionally F. 1-3 Alkyl substituents. For example, in some preferred embodiments, R 10 It is phenyl. In some embodiments, R 10 It is a substituted phenyl group, for example, a halogen-substituted phenyl group, such as a phenyl group substituted by one or two halogens independently selected from F and Cl.

[0111] In some embodiments, R 11 It is (1) C3-6 cycloalkyl; or (2)-(C 1-3 alkylene)-(C 3-6 cycloalkyl), wherein the C 1-3 Alkylene and C 3-6 Each of the cycloalkyl groups is optionally substituted with, for example, one or more substituents, each of which is independently deuterium, halogen, OH, oxo, and optionally substituted with one or more G groups. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Heteroalkyl, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy. In some embodiments, the C 1-3 The alkylene group is unsubstituted. In some embodiments, G S1 It is F in each occurrence. In some embodiments, C 3-6 Cycloalkyl groups are unsubstituted or C16 groups independently selected from F1 and optionally substituted by F1. 1-3 Alkyl substituents. For example, in some preferred embodiments, R 11 It is cyclopropyl, methylcyclopropyl, or cyclobutyl.

[0112] In some embodiments, R 11 It is (1) phenyl; or (2)-(C) 1-3 (alkylene)-phenyl, wherein the C 1-3 Each of the alkylene and phenyl groups is optionally substituted with, for example, one or more substituents, each of which is independently deuterium, halogen, OH, CN, or optionally with one or more G groups. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Heteroalkyl, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy. In some embodiments, the C 1-3 The alkylene group is unsubstituted. In some embodiments, G S1 In each occurrence, it is F. In some embodiments, the phenyl group is unsubstituted or C substituted with one or more halogens independently selected from halogens (e.g., F or Cl) and optionally F. 1-3 Alkyl substituents. For example, in some preferred embodiments, R 11 It is phenyl. In some embodiments, R 11It is a substituted phenyl group, for example, a halogen-substituted phenyl group, such as a phenyl group substituted by one or two halogens independently selected from F and Cl.

[0113] In some embodiments, R 10 and R 11 C is independently, optionally substituted with, for example, one or more substituents. 3-6 Cycloalkyl, wherein each of the one or more substituents is independently deuterium, halogen, OH, oxo, or optionally distilled by one or more Gs. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Heteroalkyl, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkyl groups. In some embodiments, G S1 It is F each time it appears. In some embodiments, the C 3-6 Cycloalkyl groups are unsubstituted or C16 groups independently selected from F1 and optionally substituted by F1. 1-3 Alkyl substituents.

[0114] In some embodiments, R 10 and R 11 The phenyl group is independently and optionally substituted with, for example, one or more substituents, each of which is independently deuterium, halogen, OH, oxo, CN, or optionally substituted with one or more G. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Heteroalkyl, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkyl groups. In some embodiments, G S1 In each occurrence, it is F. In some embodiments, the phenyl group is unsubstituted or C substituted with one or more halogens independently selected from halogens (e.g., F or Cl) and optionally F. 1-3 Alkyl substituents. In some embodiments, the phenyl group is unsubstituted or halogenated, such as a phenyl group substituted with one or two halogens independently selected from F and Cl.

[0115] In some embodiments, R 10 It is C 3-6 Cycloalkyl, and R 11 It is a phenyl group, wherein the C 3-6The cycloalkyl and phenyl groups are independently and optionally substituted with, for example, one or more substituents, each of which is independently deuterium, halogen, OH, oxo, CN, or optionally substituted with one or more G groups. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Heteroalkyl, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkyl groups. In some embodiments, G S1 It is F each time it appears. In some embodiments, the C 3-6 Cycloalkyl groups are unsubstituted or C16 groups independently selected from F1 and optionally substituted by F1. 1-3 Alkyl substituents. In some embodiments, the phenyl group is unsubstituted or C-substituted with one or more alkyl groups independently selected from halogens (e.g., F or Cl) and optionally F-substituted. 1-3 Alkyl substituents. In some embodiments, the phenyl group is unsubstituted or halogenated, such as a phenyl group substituted with one or two halogens independently selected from F and Cl.

[0116] In some embodiments, R 10 C is an optional substitute 1-4 Alkyl groups, for example, optionally containing one or more G S1 Replacement C 1-4 Alkyl, and R 11 It is C 3-6 cycloalkyl or phenyl, wherein the C 3-6 The cycloalkyl and phenyl groups are independently and optionally substituted with, for example, one or more substituents, each of which is independently deuterium, halogen, OH, oxo, CN, or optionally substituted with one or more G groups. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Heteroalkyl, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkyl groups. In some embodiments, G S1 It is F in each occurrence. In some embodiments, R 11 It is C 3-6 cycloalkyl, and the C 3-6 Cycloalkyl groups are unsubstituted or C16 groups independently selected from F1 and optionally substituted by F1. 1-3 Alkyl substituents. In some embodiments, R 11It is a phenyl group, and the phenyl group is unsubstituted or C12 independently selected from halogens (e.g., F or Cl) and optionally substituted with F. 1-3 Alkyl substituents.

[0117] In some embodiments, R 10 and R 11 The phenyl group is independently selected from cyclopropyl, methylcyclopropyl, cyclobutyl, phenyl, and phenyl groups substituted with one or two halogens independently selected from F and Cl.

[0118] In some embodiments, R 10 and R 11 They are the same. For example, in some embodiments, R 10 and R 11 Both are cyclopropyl. In some embodiments, R 10 and R 11 Both are cyclobutyl. In some embodiments, R 10 and R 11 Both are phenyl.

[0119] In some specific embodiments, the compound of formula I-1b may be characterized by having a structure according to formula I-1b-1:

[0120]

[0121] Formula I-1b-1,

[0122] The variables are defined in this article.

[0123] In some embodiments, R 10 and R 11 different.

[0124] In some embodiments, R in Equation I or any applicable sub-equation herein 2 The heterocyclic group may also be optionally substituted, including monocyclic or polycyclic heterocyclic groups. For clarity, the polycyclic heterocycle described herein may have two or more rings, wherein one or more of the rings may be phenyl or heteroaryl rings or carbocyclic rings, provided that the ring system is not aromatic overall and contains at least one cyclic heteroatom. For example, the polycyclic heterocyclic group may be selected from rings such as fused heteroarylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkyl, and tricyclic systems such as spirochetes.

[0125] In some preferred embodiments, R in formula I or any applicable formula herein such as formula IA, I-A1, I-A2, I-A3, I-1, I-2, I-3, I-4, etc. 2It can be a 10-14 membered polycyclic heterocyclic group having 1-3 independently selected cyclic heteroatoms chosen from S, O, and N, and wherein, when substituted, the 10-14 membered polycyclic heterocyclic group is preferably substituted by one or more substituents, each of which is independently deuterium, halogen, CN, oxo, or OR. A2 SR A2 NR A2 R A2 C(O)R A2 C(O)OR A2 C(O)NR A2 R A2 S(O)R A2 SO2R A2 SO2NR A2 R A2 OC(O)R A2 NR A2 C(O)R A2 NR A2 SO2R A2 ,PO(R A2 (R) A2 ) or R B2 ,

[0126] Where R A2 Each time it appears, it is independently either hydrogen or R. B2 ,and

[0127] Where R B2 Each time it appears, it is independently an optionally substituted group selected from the following: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group or 3-7 membered carbocyclic ring or 4-7 membered heterocyclic ring, wherein when substituted...

[0128] The C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is preferably substituted by one or more substituents independently selected from the following: deuterium, halogen, OH, CN, C. 1-6 Heteroalkyl, oxo, and 3-8 membered rings, wherein the C 1-6 The heteroalkyl group and the 3-8 membered ring are optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, oxo, OH, C-membered rings optionally substituted with deuterium, halogen and / or OH. 1-3 Alkyl or optionally C 1-3 3-5 membered rings substituted with alkyl, halogen, and / or OH groups; and

[0129] The 3-7 membered carbon ring or 4-7 membered heterocycle is preferably substituted by one or more substituents independently selected from the following: deuterium, halogen, OH, CN, C. 1-6 Alkyl, C 1-6 Heteroalkyl, oxo, and 3-8 membered rings, wherein the C 1-6 Alkyl, C 1-6 The heteroalkyl group and the 3-8 membered ring are optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, oxo, OH, C-membered rings optionally substituted with deuterium, halogen and / or OH. 1-3 Alkyl or optionally C 1-3 3-5 membered rings substituted with alkyl, halogen and / or OH.

[0130] In some embodiments, the 10-14 membered polycyclic heterocyclic group having 1-3 independently selected cyclic heteroatoms chosen from S, O, and N is optionally substituted with one or more substituents, each of which is independently a halogen, CN, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkoxy group. In some embodiments, the 10-14 membered polycyclic heterocyclic group has a fused ring structure from a 5-7 membered heterocycle and a phenyl or 6-membered heteroaryl ring, and optionally forms an additional ring having a spiro, fused, or bridged structure of the 5-7 membered heterocycle. For example, in some embodiments, the 10-14 membered polycyclic heterocyclic group is a bicyclic fused ring from a 6-membered heterocycle (e.g., a 6-membered heterocycle having a cyclic heteroatom that is itself O, N, or S) and a phenyl ring, such as... Optionally substituted as defined herein. For clarity, when substituted, the substitution can occur on the phenyl ring moiety or the dihydropyran moiety; other permissible substitutions of optionally substituted polycyclic rings herein should be understood similarly unless otherwise specified or contrary to the context. In some embodiments, the 10-14 membered polycyclic heterocyclic group has a bicyclic fused ring from a 6-membered heterocycle having a heteroatom that is itself O, N, or S and a phenyl ring, optionally further comprising a spiropropyl ring to the 6-membered heterocycle, i.e., the spiropropyl ring, if present, shares a carbon atom with the 6-membered heterocycle. In some embodiments, the 10-14 membered polycyclic heterocyclic group has a bicyclic fused ring from a 6-membered heterocycle having a heteroatom that is itself O, N, or S and a phenyl ring, and a spiropropyl ring sharing a carbon atom with the 6-membered heterocycle. For example, in some embodiments, the 10-14 membered polycyclic heterocyclic group is , which is optionally replaced as defined herein. In some embodiments, R in formula I or any applicable formula herein such as formula IA, I-A1, I-A2, I-A3, I-1, I-2, I-3, I-4, etc. 2 It can be , or More preferably, .

[0131] In some preferred embodiments, the compound of formula I-1 may be characterized by having a structure according to formula I-1d:

[0132]

[0133] Formula I-1d,

[0134] Where q is 0, 1, or 2, and R 20 Each time it appears, it is independently a halogen, optionally replaced by deuterium or F, of C. 1-3 Alkyl groups or C groups optionally substituted with deuterium or F 1-3 Alkoxy groups, and other variables defined herein. In equation I-1d, when q is not 0, R 20 This should be understood as a substituent for the benzene ring portion of a tricyclic structure. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, R 20 It is F each time it appears. In some embodiments, the compound of formula I-1 may be characterized by having a structure according to formula I-1d-1:

[0135]

[0136] Equation I-1d-1,

[0137] The variables are defined in this article.

[0138] In some embodiments, in Equation I or any applicable sub-equation of this document, R 3 and R 4 G is independent 1A In some embodiments, R 3 and R 4 One of them is G 1A And R 3 and R 4 Another one in the formula J is defined as follows: 1 -J 2 -J 3 -G 1B J indicates. 1 J 2 and J 3 The combination of is not particularly restricted, and it can preferably be (a) when J 1 J 2 and J 3 The two in the middle are spacetime, O and NG. 1B ,C(O),S,SO,SO2 or P(O)G1B The connector; or (b) when J 1 J 2 and J 3 One of them is spacetime, amide (C(O)NG) 1B ), ester (C(O)O), sulfonamide (SO2NG) 1B (c) When J 1 J 2 and J 3 When neither is empty, carbamate (OC(O)NG) 1B ), urea (NG) 1B C(O)NG 1B ), aminosulfonylamino (NG) 1B SO2NG 1B Connectors such as )

[0139] In some embodiments, in Equation I or any applicable sub-equation of this document, R 3 and R 4 Each is independently and arbitrarily controlled by one or more Gs S2 Replacement C 1-4 Alkyl groups or optionally one or more G S2 Replacement C 1-4 Heteroalkyl, of which G S2 Each time it appears, it is independently deuterium, F, or OH. In some embodiments, G S2 It is F each time it appears.

[0140] In some embodiments, R 3 C is C that is optionally replaced by deuterium and / or F. 1-4 Alkyl group. For example, in some embodiments, R 3 It is unreplaced C 1-4 Alkyl groups or C atoms substituted with one or more (e.g., 1, 2, or 3) F atoms. 1-4 Alkyl group. For example, in some embodiments, R 3 It can be methyl.

[0141] In some embodiments, R 4 C is C that is optionally replaced by deuterium and / or F. 1-4 Alkyl group. For example, in some embodiments, R 4 It is unreplaced C 1-4 Alkyl groups or C atoms substituted with one or more (e.g., 1, 2, or 3) F atoms. 1-4 Alkyl, for example, R 4 It is a methyl group.

[0142] In some embodiments, R 4 It is C 3-6 cycloalkyl or -(C1-3 alkylene)-(C 3-6 cycloalkyl), wherein the C 3-6 Each of the cycloalkyl groups is optionally substituted with one or more substituents, each of which is independently deuterium, halogen, OH, oxo, and optionally substituted with one or more G groups. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Heteroalkyl, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkyl group.

[0143] In some embodiments, R 3 and R 4 Both are independently selected from C that is optionally replaced by deuterium and / or F. 1-4 Alkyl group. For example, in some embodiments, R 3 and R 4 Both are independent, unreplaced C 1-4 Alkyl groups or C atoms substituted with one or more (e.g., 1, 2, or 3) F atoms. 1-4 Alkyl group. For example, in some embodiments, R 3 and R 4 Both can be methyl.

[0144] In some preferred embodiments, in formula I or any applicable formulas such as formulas IA, I-A1, I-A2, I-A3, I-1, I-2, I-3, I-4, etc., R 3 and R 4 It is connected together with the carbon atoms to which both are attached to form optionally substituted 3-7 membered carbon rings. For example, in some preferred embodiments, R 3 and R 4 It connects together with the carbon atoms to which both are attached to form an optionally substituted cyclopropyl ring, for example, an unsubstituted cyclopropylene ring. Or F-substituted cyclopropylene, for example, .

[0145] In some preferred embodiments, the compound of formula I may be characterized by having a structure according to formula I-3:

[0146]

[0147] Formula I-3,

[0148] The variables are defined in this article.

[0149] In some preferred embodiments, in formula I or any applicable formula herein such as formula IA, I-A1, I-A2, I-A3, I-1, I-2, etc., R 3 and R 4 Together with the carbon atoms to which both are attached, they form a 4-8 membered heterocycle having one or two independent cyclic heteroatoms selected from O, N, and S, wherein the sulfur atom, if present, is optionally oxidized, and the 4-8 membered heterocycle is optionally substituted, for example, R. 3 and R 4 It connects together with the carbon atoms to which both are attached to form optional substitutions. or .

[0150] In some preferred embodiments, in formula I or any applicable formula herein such as formula IA, I-A1, I-A2, I-A3, I-1, I-3, etc., L 1 It is empty. For example, in some preferred embodiments, the compound of formula I may have a structure according to formula I-2:

[0151]

[0152] Formula I-2,

[0153] The variables are defined in this article.

[0154] In some embodiments, L 1 C can be arbitrarily replaced 1-4 Alkylene. In some embodiments, L 1 C can be arbitrarily replaced 1-4 Heteroalkyl groups.

[0155] In formula I or any of the applicable formulas in this paper such as IA, I-A1, I-A2, I-A3, I-1, I-2, I-3, I-4, etc., R 5 Typically, hydrogen or C is optionally replaced by F. 1-4 Alkyl group (e.g., methyl or fluorine-substituted methyl). In some preferred embodiments, R 5 It is hydrogen.

[0156] In some embodiments, R 5 It can also be C, which can be arbitrarily replaced. 2-6 alkenyl, optionally substituted C 2-6 Alkyne or optionally substituted 3-8 membered rings, such as optionally substituted 3-5 membered carbon rings or 4-5 membered heterocycles.

[0157] In some embodiments, R 3 and R 4 One of them with R 5Together with the intermediate atom, they connect to form optionally substituted 3-8 membered carbon rings or 4-8 membered heterocycles, and R 3 and R 4 Another one is defined in this article.

[0158] In formula I or any of the applicable formulas in this paper such as IA, I-A1, I-A2, I-A3, I-1, I-2, I-3, I-4, etc., R 6 Usually N(G) 2A )C(O)G 2B 、N(G 2A )C(O)OG 2B 、N(G 2A )C(O)NG 2A G 2B 、N(G 2A SO2G 2B or N(G) 2A SO2NG 2A G 2B G 2A and G 2B As defined herein, preferably,

[0159] G 2A Each time it appears, it is independently hydrogen or an optionally substituted C. 1-6 Alkyl; and

[0160] G 2B It is R X1 (C) 1-4 (alkylene)-R X1 or (C) 1-4 (heteroalkyl)-R X1 Wherein C 1-4 The heteroalkylene group is optionally substituted with an oxygen and contains 1-3 heteroatoms independently selected from S, O, or N, wherein the S atom, if present, is optionally oxidized.

[0161] Where R X1 C is an optional substitute 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl or optionally substituted 3-14 membered rings (e.g., optionally substituted C) 3-8 (Carbon ring, optionally substituted 5- or 6-membered heteroaryl ring, or optionally substituted 4- to 8-membered heterocycle).

[0162] When G is replaced, 2A Or R X1The optionally substituted group is preferably substituted by one or more substituents, each of which is independently deuterium, halogen, OH, oxo (where applicable), CN, or optionally substituted by one or more G. S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl or optionally with one or more G S3 Substituted 3-6 membered rings (e.g., cyclopropyl), where G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl group.

[0163] In some embodiments, in formula I or any applicable formula herein such as formula IA, I-A1, I-A2, I-A3, I-1, I-2, I-3, I-4, etc., R 6 It can be N(G) 2A )C(O)G 2B G 2A and G 2B Defined and preferred herein. For example, in some embodiments, R 6 It can be NHC(O)G 2B G 2B Defined and preferred herein. For example, in some embodiments, R 6 It can be or .

[0164] In some embodiments, G 2A Each time it appears, it is independently hydrogen or optionally accompanied by one or more G atoms. S2 Replacement C 1-4 Alkyl, wherein G S2 Each time it appears, it is independently of deuterium, F, or OH.

[0165] In some embodiments, G 2B It is R X1 , where R X1 Defined and preferred in this document.

[0166] In some embodiments, G 2B Yes (C) 1-4 (alkylene)-R X1 , such as (C 1-2(alkylene)-R X1 , where R X1 Defined and preferred in this document.

[0167] In some embodiments, G 2B Yes (C) 1-4 (heteroalkyl)-R X1 , where R X1 Defined and preferred in this document.

[0168] In some preferred embodiments, R X1 It is arbitrarily controlled by one or more Gs S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl or optionally with one or more G S3 Substituted 3-10 membered rings (e.g., carbocyclic, heterocyclic, or heteroaryl rings), wherein G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl group. For example, in some embodiments, R X1 It is arbitrarily controlled by one or more Gs S1 Replacement C 1-4 Alkyl group. In some embodiments, R X1 It is arbitrarily controlled by one or more Gs S1 Replacement C 1-4 Heteroalkyl. In some embodiments, R X1 It is arbitrarily controlled by one or more Gs S3 Replacement C 3-7 Carbon ring. In some embodiments, R X1 It is arbitrarily controlled by one or more Gs S3 Replaced 4-7 membered heterocycles.

[0169] In some embodiments, G 2B It is R X1 or (C) 1-4 (alkylene)-R X1 , where R X1 It is arbitrarily controlled by one or more Gs S1 Replacement C 1-4 Alkyl, optionally with one or more G S3 Replacement C 3-7 Carbon ring, optionally bound by one or more G S3The substituted 5- or 6-membered heteroaryl ring; or optionally, the ring is replaced by one or more G... S3 Substituted 4-7 membered heterocycles, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl group.

[0170] In some embodiments, G 2B It is arbitrarily controlled by one or more Gs S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl or optionally with one or more G S3 Substituted 3-10 membered rings (e.g., carbocyclic, heterocyclic, or heteroaryl rings), wherein G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl groups. In some embodiments, G 2B G is as defined in this article. 2C or G 2D .

[0171] In some embodiments, in formula I or any applicable formula herein such as formula IA, I-A1, I-A2, I-A3, I-1, I-2, I-3, I-4, etc., R 6 It can be NHC(O)G 2C 、NHC(O)OG 2C or NHC(O)NHG 2C And G 2C It is arbitrarily controlled by one or more Gs S1 Replacement C 1-4 Alkyl groups (e.g., methyl or ethyl), optionally with one or more G S3 Replacement C 3-6 cycloalkyl (e.g., cyclobutyl), optionally with one or more G S3 The substituted 4-7 membered heterocycle (e.g., oxetane) or optionally substituted by one or more G S3 Substituted 5- or 6-membered heteroaryl groups, wherein G S1Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl group. In some preferred embodiments, R 6 It is NHC(O)G 2C G 2C Defined herein. In some embodiments, R 6 Selected from In some embodiments, R 6 Selected from .

[0172] In some embodiments, in formula I or any applicable formula herein such as formula IA, I-A1, I-A2, I-A3, I-1, I-2, I-3, I-4, etc., R 6 It can be NHC(O)G 2D G 2D It is (1) C that is optionally replaced by one or more deuterium and / or F. 1-4 Alkyl; or (2) C substituted with methyl and / or F. 3-6 Cycloalkyl groups. For example, in some specific embodiments, G 2D C is optionally replaced by one or more deuterium and / or F. 1-4 Alkyl groups, such as ethyl groups. In some preferred embodiments, R 6 yes .

[0173] In Formula I or any applicable formula herein, Y is typically C(O). For example, in some preferred embodiments, the Formula I compound may have a structure according to Formula I-4:

[0174]

[0175] Formula I-4,

[0176] The variables are defined in this article.

[0177] In some embodiments, the compound of formula I may have a structure according to formula I-4-D2:

[0178]

[0179] Formula I-4-D2,

[0180] The variables are defined in this article.

[0181] For example, in some embodiments, the compound of formula I-4 may have a structure according to formula I-4a:

[0182]

[0183] Formula I-4a,

[0184] The variables are defined in this article.

[0185] In some more specific embodiments, the compound of formula I-4a may have a structure according to formula I-4a-1 or I-4a-2:

[0186]

[0187] Formula I-4a-1

[0188]

[0189] Formula I-4a-2,

[0190] The variables are defined in this article.

[0191] In some embodiments, the compound of formula I-4-D2 may have a structure according to formula I-4a-D2:

[0192]

[0193] Formula I-4a-D2,

[0194] The variables are defined in this article.

[0195] In some more specific embodiments, the compound of formula I-4a-D2 may have a structure according to formula I-4a-1-D2 or 1-4a-2-D2:

[0196]

[0197] Formula I-4a-1-D2

[0198]

[0199] Formula I-4a-2-D2,

[0200] The variables are defined in this article.

[0201] In some embodiments, Y may be an SO2 group.

[0202] In some embodiments, ring A in Formula I may be an unsubstituted phenylene or an unsubstituted 6-membered heteroaryl group (e.g., pyridinyl, pyridazinyl, pyrimidinyl, etc.), i.e., n is 0.

[0203] In some embodiments, ring A in Formula I may be a phenylene or a 6-membered heteroaryl group (e.g., pyridylene, pyridazinylene, pyrimidinylene, etc.), which is R-dependent where the valence allows. 7 One to four instances of substitution are performed, i.e., n is 1 to 4. Typically, when substituted, the phenylene or 6-membered heteroaryl group is replaced by one or two R groups as defined herein. 7 replace.

[0204] Various groups can be suitable R of applicable formula I or the sub-formula of this article. 7 These include deuterium, halogens, cyano, alkyl, alkenyl, alkynyl, heteroalkyl, cyclic structures such as carbocyclic or heterocyclic, alcohols, amines, alkoxy, esters, amides, sulfones, sulfonamides, etc.

[0205] In some embodiments, two R 7 They can be linked to form optionally substituted 4-8 membered rings, such as 4-8 membered carbon rings or heterocyclic or phenyl rings, or 5- or 6-membered heteroaryl rings. In some embodiments, R 7 An example and R 3 Or R 4 It connects with the intermediate atom to form an optionally substituted 5-8 membered carbon ring or heterocycle. In such embodiments, any remaining R 7 It can be independently selected from deuterium, halogen, CN, or optionally substituted C as defined herein. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl, optionally substituted 3-8 membered rings or J 4 -J 5 -J 6 -G 4 .

[0206] In some embodiments, R 7 One or more instances of J can be defined by the general formula J as shown in this paper. 4 -J 5 -J 6 -G 4 J indicates. 4 J 5 and J 6 The combination of is not particularly restricted, and it can preferably be (a) when J 4 J 5 and J 6 The two in the middle are spacetime, O and NG. 4 ,C(O),S,SO,SO2 or P(O)G 4 The connector; or (b) when J 4 J 5 and J 6One of them is spacetime, amide (C(O)NG) 4 ), ester (C(O)O), sulfonamide (SO2NG) 4 (c) When J 4 J 5 and J 6 When neither is empty, carbamate (OC(O)NG) 4 ), urea (NG) 4 C(O)NG 4 ), aminosulfonylamino (NG) 4 SO2NG 4 Connectors such as )

[0207] In some embodiments, R 7 Each occurrence is independently of deuterium, halogen (e.g., F, Cl, or Br), CN, or C optionally substituted with deuterium and / or F. 1-6 Alkyl groups, C groups optionally substituted with deuterium and / or F 2-6 Alkenyl groups, C groups optionally substituted with deuterium and / or F 2-6 Alkyne group, C group optionally substituted with deuterium and / or F 1-6 Heteroalkyl groups, optionally substituted 3-7 membered carbon rings, or heterocycles having one or two cyclic heteroatoms, OG 4 NG 4 G 4 SG 4 C(O)G 4 or C(O)NG 4 G 4 G 4 Each time it appears, it is independently hydrogen, optionally substituted with deuterium and / or F, of C. 1-6 Alkyl or optionally substituted 3-7 membered carbon rings or heterocycles having one or two cyclic heteroatoms, wherein each of the optionally substituted 3-7 membered carbon rings or heterocycles is optionally substituted by one or more substituents independently selected from: deuterium, F, OH, C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl group.

[0208] In some more specific embodiments, R 7 Each time it appears, it is independently F, Cl, or C, which is optionally replaced by F. 1-4 Alkyl groups, C groups optionally substituted with F 2-4 Alkenyl, C optionally substituted with F 2-4 Alkyne group or C group optionally substituted with F 1-4 Heteroalkyl. In some specific embodiments, the compounds in Formula I or its derivatives... Parts can be , wherein F is located at the ortho position of amide NH in formula I.

[0209] In some embodiments, R in Equation I (e.g., any applicable sub-equation in the applicable sub-equation) 8 It's NG 3 G 3 G 3 Defined in this article.

[0210] In some embodiments, R in Equation I (e.g., any applicable sub-equation in the applicable sub-equation) 8 It's NG 3A G 3B ,in:

[0211] Among them G 3A It is hydrogen or an optional substituted C 1-6 Alkyl; and

[0212] G 3B It is R X2 (C) 1-4 (alkylene)-R X2 or (C) 1-4 (heteroalkyl)-R X2 Wherein C 1-4 The heteroalkylene group is optionally substituted with an oxygen and contains 1-3 heteroatoms independently selected from S, O, or N, wherein the S atom, if present, is optionally oxidized.

[0213] Where R X2 C is an optional substitute 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl or optionally substituted 3-14 membered rings (e.g., optionally substituted C) 3-8 (Carbon ring or optionally substituted 4-8 membered heterocycles).

[0214] When G is replaced, 3A Or R X2 The optionally substituted group is preferably substituted by one or more substituents, each of which is independently deuterium, halogen, OH, oxo (where applicable), CN, or optionally substituted by one or more G. S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl or optionally with one or more G S3 Substituted 3-6 membered rings (e.g., cyclopropyl), where G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F.1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl group.

[0215] In some embodiments, G 3B It is R X2 , where R X2 Defined and preferred in this document.

[0216] In some embodiments, G 3B Yes (C) 1-4 (alkylene)-R X2 , such as (C 1-2 (alkylene)-R X2 , where R X2 Defined and preferred in this document.

[0217] In some embodiments, G 3B Yes (C) 1-4 (heteroalkyl)-R X2 , where R X2 Defined and preferred in this document.

[0218] In some preferred embodiments, R X2 It is arbitrarily controlled by one or more Gs S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl or optionally with one or more G S3 Substituted 3-10 membered rings (e.g., carbocyclic, heterocyclic, or heteroaryl rings), wherein G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl group. For example, in some embodiments, R X2 It is arbitrarily controlled by one or more Gs S1 Replacement C 1-4 Alkyl group. In some embodiments, R X2 It is arbitrarily controlled by one or more Gs S1 Replacement C 1-4 Heteroalkyl. In some embodiments, R X2 It is arbitrarily controlled by one or more Gs S3 Replacement C 3-7Carbon ring. In some embodiments, R X2 It is arbitrarily controlled by one or more Gs S3 Replaced 4-7 membered heterocycles. For example, in some embodiments, R 8 It can be .

[0219] In some embodiments, R in Equation I (e.g., any applicable sub-equation in the applicable sub-equation) 8 It is an optionally substituted 4-8 membered heterocycle having 1-3 cyclic heteroatoms, wherein one of the cyclic heteroatoms is a cyclic nitrogen bonded to Y, and any remaining cyclic heteroatoms are independently selected from N, O and S, wherein the sulfur atom, if present, is optionally oxidized.

[0220] In some embodiments, R in Equation I (e.g., any applicable sub-equation in the applicable sub-equation) 8 It has a structure represented by M-1, (M-1), the structure being optionally substituted with a ring selected from the following: azacyclobutane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine 1,1,dioxide and azaspiro[3,3]heptane,

[0221] When substituted, the optionally substituted ring is preferably substituted by one or more substituents, each of which is independently deuterium, halogen, OH, oxo (where applicable), CN, or R. X3 OR X3 C(O)R X3 SO2R X3 (C) 1-4 (alkylene)-R X3 or (C) 1-4 (heteroalkyl)-R X3 Wherein C 1-4 The heteroalkylene group is optionally substituted with an oxo group and contains 1-3 heteroatoms independently selected from S, O, or N, wherein the S atom, if present, is optionally oxidized, or the two substituents are linked together with the atoms they are bonded to form a 3-6 membered ring, which may be spiro, fused, or bridged.

[0222] Where R X3 Each time it appears, it is independently and optionally controlled by one or more Gs. S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl or optionally with one or more G S3 Substituted 3-6 membered rings (e.g., cyclopropyl, phenyl, etc.), wherein G S1Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl group. For example, in some embodiments, R 8 It can be , , or .

[0223] In some embodiments, R in Equation I (e.g., any applicable sub-equation in the applicable sub-equation) 8 It can have a structure represented by M-2. (M-2)

[0224] Where R 30 It is hydrogen, optionally by one or more G S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl, optionally with one or more G S3 Substituted 3-6 membered rings (e.g., cyclopropyl, phenyl, etc.) or (C 1-2 alkylene)-(3-6-membered ring), wherein the 3-6-membered ring (e.g., cyclopropyl) is optionally surrounded by one or more G S3 Replace, where G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkoxy

[0225] k is 0, 1, or 2, and

[0226] R 31 Each time it appears, it is independently deuterated, oxidized, or optionally substituted with F, C. 1-4 Alkyl, or two R 31 Linked with intermediate atoms to form rings, such as fused or spiropropyl or bridged rings, or an R 31 and R 30 It connects with intermediate atoms to form a ring. For example, in some embodiments, R 8 It can have a structure selected from the following:

[0227] Where k1 is 0 or 1, and R 31 As defined above.

[0228] In some embodiments, in M-2, R 30 It is hydrogen.

[0229] In some embodiments, in M-2, R 30 It is arbitrarily controlled by one or more Gs S1 Replacement C 1-4 Alkyl, or R 30 It is cyclopropyl or (C 1-2 alkylene)-(cyclopropyl), wherein the cyclopropyl group is optionally surrounded by one or more G S1 Replace, where G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkyl group. For example, in some embodiments, R 30 It is C that is either unsubstituted or substituted by F. 1-4 Alkyl groups, such as methyl groups. In some specific embodiments, R 30 It is CH3, CD3, ethyl groups optionally substituted with 1-3 F atoms (e.g., CH2CF2H, CH2CF3, etc.), methoxyethyl, cyclopropylmethyl, cyclopropyl, etc. For example, in some embodiments, R 8 It can have a structure selected from the following: .

[0230] In some embodiments, k is 0 in M-2.

[0231] In some embodiments, in M-2, k is 1 or 2, and R 31 Each time it appears, it is optionally controlled by one or more Gs. S1 Replacement C 1-4 Alkyl, wherein G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy, for example, R 31 It is methyl in every instance.

[0232] In some embodiments, R in Equation I (e.g., any applicable sub-equation in the applicable sub-equation) 8 It can have a structure represented by M-3. (M-3)

[0233] in

[0234] R 32It is hydrogen, halogen, CN, optionally with one or more Gs S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl or optionally with one or more G S3 Substituted 3-6 membered rings (e.g., cyclopropyl, phenyl, etc.).

[0235] R 33 It is hydrogen, halogen, CN, OH, NH2, optionally with one or more G S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy, C 1-4 Monoalkylamines or C 2-4 Dialkylamine) or optionally with one or more G S3 Substituted 3-6 membered rings (e.g., cyclopropyl, phenyl, etc.).

[0236] Or R 32 and R 33 It is attached together with the carbons to which it is attached to form a C(=O) or optionally substituted 3-6 membered ring (e.g., cyclopropyl, cyclobutyl, oxetane, etc.).

[0237] Among them G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkoxy

[0238] j is 0, 1, or 2, and

[0239] R 34 Each time it appears, it is independently oxidized, deuterated, halogenated, CN, or C optionally substituted with F. 1-4 Alkyl, or two R 34 Or an R 34 and R 32 and R 33 One of them is linked with an intermediate atom to form a ring, such as a spiropropyl or a fused or bridged ring, such as R. 8 yes , wait.

[0240] In some embodiments, in M-3, R 32It is hydrogen, F, optionally with one or more Gs S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Alkoxy, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy, for example, R 32 It includes F, CH3, CHF2, CF3, difluoromethoxy, etc.

[0241] In some embodiments, in M-3, R 33 It is hydrogen, OH, halogen (e.g., F), CN, or optionally by one or more Gs. S1 Replacement C 1-4 Alkyl, wherein G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy, for example, R 33 These include hydrogen, F, CH3, OH, etc. For example, in some embodiments, R... 8 It can have , , , , , or The structure.

[0242] In some embodiments, in M-3, j is 0.

[0243] In some embodiments, in M-3, j is 1 or 2, and R 34 Each time it appears, it is independently OH, halogen, CN, or optionally accompanied by one or more Gs. S1 Replacement C 1-4 Alkyl, wherein G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkyl group.

[0244] In some embodiments, in formula I, R 8 It is an optionally substituted 4-14 membered heterocyclic ring or an optionally substituted heteroaryl ring.

[0245] In some embodiments, in formula I, R 8 It is an optionally substituted 4-7 membered heterocycle having one or two cyclic heteroatoms, each independently being N, O, or S, wherein the sulfur atom, if present, is optionally oxidized.

[0246] When substituted, the 4-7 membered heterocycle is preferably substituted by one or more substituents, each of which is independently deuterium, halogen, OH, oxo (where applicable), CN, or R. X4 OR X4 C(O)R X4 SO2R X4 (C) 1-4 (alkylene)-R X4 or (C) 1-4 (heteroalkyl)-R X4 Wherein C 1-4 The heteroalkylene group is optionally substituted with an oxygen and contains 1-3 heteroatoms independently selected from S, O, or N, wherein the S atom is optionally oxidized.

[0247] Where R X4 Each time it appears, it is independently and optionally controlled by one or more Gs. S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl or optionally with one or more G S3 Substituted 3-6 membered rings (e.g., cyclopropyl, phenyl, etc.), wherein G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl group.

[0248] The exemplary definition of each variable in this document also includes any definitions shown for the corresponding variable in the specific compounds listed in Table 1 of this document and those shown in the exemplary embodiments 1 to 28 listed herein.

[0249] In some embodiments, this disclosure also provides a compound according to any one of the exemplary embodiments 1 to 28:

[0250] Example 1. A compound of formula I-2 or a pharmaceutically acceptable salt thereof:

[0251]

[0252] Formula I-2

[0253] in:

[0254] R 1It is selected from the following 5-membered heteroaryl groups: pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan, thiophene, imidazole, oxadiazole, thiadiazole, triazole, or tetraazole, which are unsubstituted or selected by one or two independently R groups. A1 Replace, where R A1 It is (i) C that is optionally replaced by deuterium and / or F. 1-4 Alkyl; (ii) (C 1-2 (alkylene)-C 3-4 cycloalkyl, such as cyclopropylmethyl, wherein the C 1-2 Alkylene and C 3-4 Each cycloalkyl group is optionally substituted independently with methyl, deuterium and / or F; or (iii) C is optionally substituted with methyl and / or F. 3-4 cycloalkyl;

[0255] R 2 Selected from:

[0256] i) Single-ring C 3-8 Cycloalkyl, optionally substituted with one or more substituents, each of which is independently deuterium, halogen, OH, oxo, and optionally substituted with one or more G... S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Alkoxy;

[0257] ii) Multicyclic C 4-10 A carbocyclic group, optionally substituted with one or more substituents, each of which is independently deuterium, halogen, OH, oxo, and optionally substituted with one or more G groups. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 alkoxy; or

[0258] iii) The structure, in which (1)R 10 It is arbitrarily controlled by one or more Gs S1 Replacement C 1-4 Alkyl, and R 11 It is C 3-6 cycloalkyl or phenyl; (2) R 10 It is C 3-6 Cycloalkyl, and R 11 It is phenyl; (3) R 10 and R 11 C is independent 3-6 cycloalkyl; or (4) R 10 and R 11It is independently a phenyl; wherein the C in each of (1)-(4) is phenyl 3-6 The cycloalkyl or phenyl group is independently and optionally substituted with one or more substituents, each of which is independently deuterium, halogen, OH, oxo, and optionally substituted with one or more G groups. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Heteroalkyl; or

[0259] iv) A 10-14 membered polycyclic heterocyclic group having 1-3 independently selected cyclic heteroatoms chosen from S, O, and N, wherein the 10-14 membered polycyclic heterocyclic group has a fused ring structure from a 5-7 membered heterocycle and a phenyl or 6-membered heteroaryl ring, optionally forming an additional ring having a spiro, fused, or bridged structure of the 5-7 membered heterocycle, and wherein the 10-14 membered polycyclic heterocyclic group is optionally substituted by one or more substituents, each of which is independently a halogen, CN, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkoxy;

[0260] Ring A is a phenylene or a 6-membered heteroaryl group (e.g., pyridylene, pyridazinyl, pyrimidinyl, etc.), which is optionally altered by R, depending on the valence. 7 Replace one or two instances;

[0261] Y is C(O);

[0262] R 3 and R 4 Each is independently and arbitrarily controlled by one or more Gs S2 Replacement C 1-4 Alkyl groups or optionally one or more G S2 Replacement C 1-4 Heteroalkyl, or

[0263] R 3 and R 4 The carbon atoms attached to both of them are connected together to form an optionally substituted 3-7 membered carbon ring or an optionally substituted 4-8 membered heterocycle having one or two independent cyclic heteroatoms selected from O, N and S, wherein the sulfur atom, if present, is optionally oxidized.

[0264] R 5 It is hydrogen;

[0265] R 6 It is N(G) 2A )C(O)G 2B ;

[0266] R7 Each time it appears, it is independently F, Cl, or C, which is optionally replaced by F. 1-4 Alkyl groups, C groups optionally substituted with F 2-4 Alkenyl, C optionally substituted with F 2-4 Alkyne group or C group optionally substituted with F 1-4 Heteroalkyl;

[0267] R 8 It's NG 3 G 3 Or optionally substituted 4-8 membered heterocycles, wherein G 3 Each time it appears, it is independently hydrogen, with optional substitution of C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl or optionally substituted 3-8 membered rings; or two Gs 3 Together with the nitrogen atoms to which both are attached, they form optionally substituted 4-8 membered heterocycles; and

[0268] “n” is 0, 1, or 2.

[0269] in:

[0270] G 2A Each time it appears, it is independently hydrogen or optionally accompanied by one or more G atoms. S2 Replacement C 1-4 alkyl,

[0271] G 2B It is R X1 (C) 1-4 (alkylene)-R X1 or (C) 1-4 (heteroalkyl)-R X1 Wherein C 1-4 The heteroalkylene group is optionally substituted with an oxo group and contains 1-3 heteroatoms independently selected from S, O, or N, wherein the S atom, if present, is optionally oxidized.

[0272] R X1 It is arbitrarily controlled by one or more Gs S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl, optionally with one or more G S3 Replacement C 3-7 Carbon ring, optionally bound by one or more G S3 The substituted 5- or 6-membered heteroaryl ring; or optionally, the ring is replaced by one or more G... S3 Substituted 4-7 membered heterocycles;

[0273] G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy;

[0274] G S2 Each time it appears, it is independently deuterium, F, or OH; and

[0275] G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl group.

[0276] Example 2. The compound according to Example 1 or a pharmaceutically acceptable salt thereof, characterized in that it has a structure according to formula I-4 or I-4-D2:

[0277]

[0278] Formula I-4,

[0279]

[0280] Formula I-4-D2,

[0281] Where R 1 R 2 R 5 R 6 R 7 R 8 And n is as defined in Example 1.

[0282] Example 3. The compound or a pharmaceutically acceptable salt thereof according to Example 1 or 2, wherein R 1 Based on The structure.

[0283] Example 4. The compound or a pharmaceutically acceptable salt thereof according to Example 1 or 2, wherein R 1 Based on or The structure.

[0284] Example 5. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 4, R A1 Each time it appears independently, it is (i) C that is optionally replaced by deuterium and / or F. 1-4 Alkyl groups, such as methyl, CD3, ethyl, isopropyl, difluoromethyl, 2,2-difluoroethyl; (ii) cyclopropylmethyl; or (iii) C groups optionally substituted with F. 3-4Cycloalkyl groups, such as cyclopropyl groups.

[0285] Example 6. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 5, wherein R 2 It is a single-ring C 3-7 Cycloalkyl, optionally substituted with one or more substituents, each of which is independently deuterium, F, or optionally G. S2 Replacement C 1-3 alkyl.

[0286] Example 7. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 5, wherein R 2 yes , , , or .

[0287] Example 8. A compound according to any one of Examples 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from: .

[0288] Example 9. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 5, wherein R 2 yes .

[0289] Example 10. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 5, wherein R 2 have The structure, and R 10 and R 11 The phenyl group is independently selected from cyclopropyl, methylcyclopropyl, cyclobutyl, phenyl, and phenyl groups substituted with one or both halogens independently selected from F and Cl.

[0290] Example 11. The compound or a pharmaceutically acceptable salt thereof according to Example 10, wherein R 10 and R 11 They are the same.

[0291] Example 12. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 5, wherein R 2 yes , or .

[0292] Example 13. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 5, wherein R 2 yes .

[0293] Example 14. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 13, wherein R 6 It is NHC(O)G 2B G 2B Defined in Example 1.

[0294] Example 15. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 14, characterized in that it has a structure according to formula I-4a or I-4a-D2.

[0295]

[0296] Formula I-4a

[0297]

[0298] Formula I-4a-D2.

[0299] Example 16. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 15, wherein R 6 It is NHC(O)G 2C , or G 2B It is G 2C And G 2C It is arbitrarily controlled by one or more Gs S1 Replacement C 1-4 Alkyl, optionally with one or more G S3 Replacement C 3-6 cycloalkyl, optionally with one or more G S3 The substituted 4-7 membered heterocycle or optionally replaced by one or more G S3 Substituted 5- or 6-membered heteroaryl groups, wherein G S1 and G S3 As defined in Example 1.

[0300] Example 17. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 16, characterized in that it has a structure according to formula I-4a-1 or I-4a-1-D2:

[0301]

[0302] Formula I-4a-1,

[0303]

[0304] Formula I-4a-1-D2.

[0305] Example 18. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 17, wherein R 6 It is NHC(O)G 2D , or G 2B It is G 2D And G 2D C is optionally replaced by one or more deuterium and / or F. 1-4 alkyl.

[0306] Example 19. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 17, wherein R 6 It is NHC(O)G 2D , or G 2B It is G 2D And G 2D C is optionally substituted with methyl and / or F. 3-6 Cycloalkyl.

[0307] Example 20. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 19, characterized in that it has a structure according to formula I-4a-2 or I-4a-2-D2:

[0308]

[0309] Formula I-4a-2

[0310]

[0311] Formula I-4a-2-D2.

[0312] Example 21. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 20, wherein n is 0 or 1 where applicable.

[0313] Example 22. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 21, wherein R 7 Each time it appears, it is independently F, Cl, or C, which is optionally replaced by F. 1-4 Alkyl groups or C groups optionally substituted with F 1-4 Alkoxy groups, such as R 7 It is F each time it appears.

[0314] Example 23. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 22, wherein R 8 It has a structure based on M-1, (M-1), the structure being optionally substituted with a ring selected from the following: aziridine, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine 1,1,dioxide and azirspiro[3,3]heptane, wherein the optionally substituted ring is optionally substituted with one or more substituents as described herein, for example, as described in the original filing of claim 49.

[0315] Example 24. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 22, wherein R 8 It has a structure based on M-2, (M-2), where R 30 R 31 And k are defined herein, for example, as defined in any one of the original filings, claims 50 to 53.

[0316] Example 25. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 22, wherein R 8 It has a structure based on M-3, (M-3), where R 32 R 33 R 34 The terms j are defined herein, for example, as defined in any of claims 54 to 58 of the original filing.

[0317] Example 26. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 25, wherein G S1 It is F in each occurrence; and G. S2 It is F each time it appears.

[0318] Example 27. The compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 26, wherein each variable in Formula I-2 may be independently selected from any of the corresponding specific groups shown in the compounds in Table 1.

[0319] Example 28. A compound or a pharmaceutically acceptable salt thereof according to any one of Examples 1 to 26, wherein, where applicable, each variable in Formula I-2 may have its corresponding definition as defined herein and within the definition in Example 1.

[0320] In some embodiments, this disclosure also provides compounds selected from Table 1 below, their deuterated analogs, their stereoisomers, or their pharmaceutically acceptable salts:

[0321] Table 1. List of compounds

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382] It should be understood that the wriggly bond in the structure indicates that the chiral center to which the wriggly bond is attached can be in an R configuration or an S configuration, and stereoisomers and any mixtures thereof are contemplated in this disclosure. This disclosure also specifically contemplates stereoisomers of any of the compounds listed above, particularly those having R in different stereochemical configurations. 2 Those with functional groups.

[0383] In some embodiments, to the extent applicable, the genus of compounds described herein also excludes any single compound specifically known prior to this disclosure. In some embodiments, to the extent applicable, any subgenus or species of compounds that were entirely within the genus of compounds described herein prior to this disclosure may also be excluded from such genus herein.

[0384] In view of this disclosure, the compounds of this disclosure can be readily synthesized by those skilled in the art. Exemplary synthesis is also shown in the Examples section. Certain synthetic starting materials or intermediates that can be used to prepare the compounds of this disclosure may be prepared according to the disclosed procedures, such as those described in US 2020 / 0247785, WO 2020 / 146194, WO 2021 / 055376, WO 2023 / 283453, WO 2022 / 007461, etc.

[0385] 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, and 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, “Protective Groups in Organic Synthesis,” 4th edition, PGM Wuts; TW Greene, John Wiley, 2007, and the references cited therein. The reagents used in the reactions described herein are generally known compounds, or can be prepared by known procedures or obvious modifications thereof. For example, many reagents are available from commercial suppliers such as Sigma-Aldrich (Milwaukee, Wisconsin, USA). Other reagents can be prepared using procedures described in the following standard reference texts or their obvious modifications: *Fischer 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 Supplements (Elsevier Science Publishers, 1989); *Organic Reactions*, Volumes 1-40 (John Wiley and Sons, 1991); *March's Advanced Organic Chemistry* (Wiley, 7th Edition); and *Larock's Comprehensive Organic Transformations* (Wiley-VCH). (1999) and any of the available updates up to the date of this application.

[0386] Pharmaceutical Composition

[0387] Some embodiments relate to a pharmaceutical composition comprising one or more compounds disclosed herein.

[0388] The pharmaceutical composition may optionally contain a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises a compound of the present disclosure (e.g., a compound of formula I (e.g., a compound of formula I-E1, IA, IA-1, IA-2, IA-3, I-1, I-2, I-3, I-4, I-1a, I-1b, I-1b-1, I-1c, I-1c-1, I-1d, I-1d-1, I-4a, I-4a-1, I-4a-2, I-4-D2, I-4a-D2, I-4a-1-D2 or I-4a-2-D2), any one of Examples 1-174, or listed in Table 1 herein). The pharmaceutically acceptable excipients are any compound of the compound or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are known in the art. Suitable excipients, without limitation, include, for example, encapsulating materials or additives such as antioxidants, binders, buffers, carriers, coatings, colorants, diluents, disintegrants, emulsifiers, extenders, fillers, flavorings, humectants, lubricants, fragrances, preservatives, propellants, release agents, sterilizing agents, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st edition, AR Gennaro (Lippincott, Williams & Wilkins, Baltimore, Md., 2005; incorporated herein by reference), which discloses a variety of excipients for formulating pharmaceutical compositions and known techniques for preparing pharmaceutical compositions.

[0389] Pharmaceutical compositions may include any one or more of the compounds disclosed herein. For example, in some embodiments, a pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, for example, in a therapeutically effective amount. In any of the embodiments described herein, a pharmaceutical composition may comprise a therapeutically effective amount (e.g., for treating the autoimmune and / or inflammatory diseases or conditions described herein) of a compound selected from any of Examples 1-174 or any specific compound disclosed in Table 1 herein, or a pharmaceutically acceptable salt thereof. In some preferred embodiments, a pharmaceutical composition may comprise a compound selected from the compounds according to Examples 1-174, wherein the IC50 of said compound is... 50 The value is less than 100 nM, more preferably less than 50 nM, as measured according to biological example 1.

[0390] The pharmaceutical compositions described herein can be formulated for delivery via any known route of delivery, including but not limited to oral, nasal, transdermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, or parenteral administration.

[0391] In some embodiments, the pharmaceutical composition may be formulated for oral administration. The oral formulation may be presented in discrete units, such as capsules, pills, sachets, lozenges, or tablets, each of which contains a predetermined amount of the active compound; in the form of powder or granules; in the form of a solution or suspension of an aqueous or non-aqueous liquid; or in the form of an oil-in-water or water-in-oil emulsion. Excipients used to prepare compositions for oral administration are known in the art. Suitable excipients, without limitation, include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butanediol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethyl cellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, peanut oil, hydroxypropyl methylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl cellulose, sodium phosphate, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearate fumarate, sucrose, surfactants, talc, tragacanth gum, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0392] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., intravenous injection or infusion, subcutaneous or intramuscular injection). The parenteral formulation may be, for example, an aqueous solution, a suspension, or an emulsion. Excipients used to prepare the parenteral formulation are known in the art. Suitable, non-limiting excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, wheat germ oil, peanut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water, and mixtures thereof.

[0393] The compounds disclosed herein can be used alone, in combination with each other, or in combination with one or more other therapeutic agents. When used in combination with one or more other therapeutic agents, the compounds disclosed herein or the pharmaceutical compositions herein can be administered to a subject simultaneously or sequentially with such other therapeutic agents in any order. In some embodiments, a pharmaceutical composition may comprise one or more compounds of the present disclosure and one or more other therapeutic agents in a single composition. In some embodiments, a pharmaceutical composition comprising one or more compounds of the present disclosure may be included in a kit that also comprises a separate pharmaceutical composition comprising one or more other therapeutic agents.

[0394] Pharmaceutical compositions may include various amounts of the compounds disclosed herein, depending on various factors such as the intended use and potency of the compounds and selectivity. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compounds disclosed herein. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compounds disclosed herein and a pharmaceutically acceptable excipient. As used herein, a therapeutically effective amount of the compounds disclosed is an amount effective in treating a disease or condition as described herein, such as an autoimmune and / or inflammatory disease or condition, such as psoriasis, which may depend on the recipient of treatment, the condition being treated, the symptoms or disease and their severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is co-administered.

[0395] Treatment methods / uses

[0396] The compounds disclosed herein have a variety of uses. For example, the compounds disclosed herein can be used as therapeutic and / or preventative agents of diseases or conditions associated with IL-17A and / or IL-17F, and more specifically, therapeutically active agents of diseases or conditions associated with IL-17A, such as those associated with IL-17AA or IL-17AF. Accordingly, some embodiments of this disclosure also relate to methods of treating or preventing diseases or conditions associated with IL-17A and / or IL-17F in a subject of need using one or more of the compounds disclosed herein or pharmaceutical compositions herein, such as methods of treating autoimmune diseases or conditions or inflammatory diseases or conditions in a subject of need.

[0397] In some embodiments, this disclosure provides a method for modulating IL-17A and / or IL-17F in a subject of need, the method comprising administering to the subject one or more compounds of this disclosure (e.g., compounds of formula I (e.g., I-E1, IA, IA-1, IA-2, IA-3, I-1, I-2, I-3, I-4, I-1a, I-1b, I-1b-1, I-1c, I-1c-1, I-1d, I-1d-1, I-4a, I-4a-1, I-4a-2, I-4-D2, I-4a-D2, I-4a-1-D2 or I-4a-2-D2), any of Examples 1-174, any of the compounds listed in Table 1 herein, or pharmaceutically acceptable salts thereof), or pharmaceutical compositions thereof.

[0398] In some embodiments, this disclosure provides a method for treating or preventing IL-17A and / or IL-17F-mediated diseases or conditions in a subject of need, the method comprising administering to the subject one or more compounds of this disclosure (e.g., compounds of formula I (e.g., I-E1, IA, IA-1, IA-2, IA-3, I-1, I-2, I-3, I-4, I-1a, I-1b, I-1b-1, I-1c, I-1c-1, I-1d, I-1d-1, I-4a, I-4a-1, I-4a-2, I-4-D2, I-4a-D2, I-4a-1-D2, or I-4a-2-D2), any of Examples 1-174, any of the compounds listed in Table 1 herein, or pharmaceutically acceptable salts thereof), or pharmaceutical compositions thereof. Such diseases include inflammatory diseases and conditions, proliferative diseases (e.g., cancer), autoimmune diseases, and other diseases described herein.

[0399] In some embodiments, this disclosure provides a method of treating an inflammatory disease or condition in a subject of need, the method comprising administering to the subject one or more compounds of this disclosure (e.g., compounds of formula I (e.g., I-E1, IA, IA-1, IA-2, IA-3, I-1, I-2, I-3, I-4, I-1a, I-1b, I-1b-1, I-1c, I-1c-1, I-1d, I-1d-1, I-4a, I-4a-1, I-4a-2, I-4-D2, I-4a-D2, I-4a-1-D2 or I-4a-2-D2), any of Examples 1-174, any of the compounds listed in Table 1 herein, or pharmaceutically acceptable salts thereof), or pharmaceutical compositions thereof. In some embodiments, the inflammatory disease or condition is selected from plaque psoriasis, guttate psoriasis, inverted psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis, and non-infectious uveitis.

[0400] In some embodiments, this disclosure provides a method of treating an autoimmune disease or condition in a subject of need, the method comprising administering to the subject one or more compounds of this disclosure (e.g., compounds of formula I (e.g., I-E1, IA, IA-1, IA-2, IA-3, I-1, I-2, I-3, I-4, I-1a, I-1b, I-1b-1, I-1c, I-1c-1, I-1d, I-1d-1, I-4a, I-4a-1, I-4a-2, I-4-D2, I-4a-D2, I-4a-1-D2, or I-4a-2-D2), any of Examples 1-174, any of the compounds listed in Table 1 herein, or pharmaceutically acceptable salts thereof), or pharmaceutical compositions thereof. In some embodiments, the autoimmune disease or condition is psoriasis, psoriatic arthritis, or ankylosing spondylitis. In some embodiments, the autoimmune disease or condition is psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, bone erosion, allogeneic transplant rejection, or multiple sclerosis.

[0401] In some embodiments, this disclosure provides a method of treating a subject in need of psoriasis, the method comprising administering to the subject one or more compounds of this disclosure (e.g., compounds of formula I (e.g., I-E1, IA, IA-1, IA-2, IA-3, I-1, I-2, I-3, I-4, I-1a, I-1b, I-1b-1, I-1c, I-1c-1, I-1d, I-1d-1, I-4a, I-4a-1, I-4a-2, I-4-D2, I-4a-D2, I-4a-1-D2 or I-4a-2-D2), any of Examples 1-174, any of the compounds listed in Table 1 herein, or pharmaceutically acceptable salts thereof), or pharmaceutical compositions thereof.

[0402] The compounds disclosed herein can be used alone or in combination with one or more other therapeutic agents. When used in combination with one or more other therapeutic agents, the compounds disclosed herein or the pharmaceutical compositions herein can be administered to a subject simultaneously or sequentially with such other therapeutic agents in any order.

[0403] Dosing regimens, including those used in the methods described herein, can be varied and adjusted depending on the recipient of treatment, the condition, symptom or disease being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether another drug is administered concurrently.

[0404] definition

[0405] It should be understood that appropriate valences are maintained for all parts and their combinations.

[0406] It should also be understood that specific embodiments of the variable parts of this document may be the same as or different from another specific embodiment having the same identifier.

[0407] Where applicable, suitable groups for variables in Formula I compounds or their sub-formulas may be chosen independently. Where applicable, non-limiting useful groups for variables in Formula I compounds or their sub-formulas may include any group of the corresponding group, alone or in any combination, as shown in the examples herein or the specific compounds described in Table 1. Furthermore, it should be understood that the definition of a variable in Formula I may have the same definition for a variable defined in a sub-formula of Formula I. Similarly, unless otherwise specified or contrary to the context, the definition of a sub-formula of Formula I may have the same definition for a variable defined in combination with Formula I or another sub-formula of Formula I.

[0408] The embodiments described in this disclosure can be combined. Such combinations are contemplated and are within the scope of this disclosure. For example, where applicable, R of Formula I can be contemplated. 1 R2 R 3 R 4 R 5 R 6 R 7 R 8 The definitions of any one or more of , Y, Z, ring A and n can be related to R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 The definition of any one or more of Y, Z, ring A and n is used, and compounds derived from said combinations are contemplated within the scope of this disclosure.

[0409] When displayed perpendicular to (or otherwise intersecting with) the keys, the symbol The point where the shown portion connects to the rest of the molecule is indicated. It should be noted that for divalent (or multivalent) structures, one or more adjacent groups or appropriate variables shown in the formula can be indicated by the symbol. In addition to the divalent (or multivalent) structures shown, the connection direction is indicated. When a group or variable that is not immediately attached is not shown for either of the two attachment points in a divalent structure, it should be understood that either direction of attachment to the rest of the molecule is permitted unless otherwise specified or clearly contrary to the context. The connection direction of the divalent structure herein can also be indicated by specifying that one attachment point (or variable) is attached / linked to another attachment point (or variable) in the structure herein, or by specifying the relative position (e.g., ortho, meta, para, etc.) of one group (or variable) to another group (or variable) in the structure herein.

[0410] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition, inner page, and specific functional groups are generally defined as described herein. Additionally, the general principles of organic chemistry, as well as specific functional components and reactivity, are described in the following literature: Thomas Sorrell, *Organic Chemistry*, University Science Books, Sausalito, 1999; Smith and March, *March's Advanced Organic Chemistry*, 5th ed., John Wiley & Sons, Inc., New York, 2001; Larock, *Comprehensive Organic Transformations*, VCH Publishers, Inc., New York, 1989; and Carruthers, *Some Modern Methods of Organic Synthesis*, 3rd ed., Cambridge University Press, Cambridge, 1987. This disclosure is not intended to be limited in any way by the exemplary list of substituents described herein.

[0411] The compounds described herein may contain one or more asymmetric centers and therefore may exist in a variety of stereoisomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched with one or more stereoisomers. Isomers may be separated from mixtures by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC), chiral supercritical fluid chromatography (SFC), and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (edited by EL Eliel, Univ. of Notre Dame Press, Notre Dame, IN, 1972). This disclosure further covers compounds described herein that are in the form of individual isomers substantially free of other isomers and, alternatively, mixtures of various isomers, including racemic mixtures. When specifically plotting stereochemistry, unless otherwise contradicted by the context, it should be understood that, for a particular chiral center or axial chirality, a compound may exist primarily as the stereoisomers plotted, such as by HPLC or SFC area or both less than 20 wt%, less than 10 wt%, less than 5 wt%, less than 1 wt%, or have undetectable amounts of other stereoisomers, for example, an enantiomer excess of the compound may be greater than 60%, greater than 80%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%. The presence and / or amount of stereoisomers can be determined by those skilled in the art in light of this disclosure, including by using chiral HPLC or chiral SFC.As will be understood by those skilled in the art, when an asterisk (*) is shown in the chemical structures herein, unless otherwise contradicted by the context, the corresponding chiral center is specified as either enantiomerically pure or enriched in any configuration, or enantiomerically pure or enriched in the configuration as drawn, such as by HPLC or SFC area or both less than 20 wt%, less than 10 wt%, less than 5 wt%, less than 1 wt%, or having an undetectable amount of other stereoisomers. Furthermore, when no stereochemistry is specifically drawn and no asterisk (*) is used in the chemical structures, unless otherwise contradicted by the context, it should be understood that such structures include the corresponding compounds in any stereoisomeric form, including individual isomers substantially free of other isomers and mixtures of various isomers including racemic mixtures.

[0412] When listing a range of values, it is intended to cover every value within that range and its subranges. For example, "C 1–6 "Aims to cover C1, C2, C3, C4, C5, C6, C 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 .

[0413] As used herein, the term "compound of this disclosure" means any compound described herein according to formula I (e.g., formula I-E1, IA, IA-1, IA-2, IA-3, I-1, I-2, I-3, I-4, I-1a, I-1b, I-1b-1, I-1c, I-1c-1, I-1d, I-1d-1, I-4a, I-4a-1, I-4a-2, I-4-D2, I-4a-D2, I-4a-1-D2 or I-4a-2-D2), any of Examples 1-174, or any of the compounds disclosed in Table 1 herein. Any specific compound of the present disclosure, its isotopically labeled compounds (such as deuterated analogs, wherein one or more hydrogen atoms are replaced by deuterium atoms with a higher abundance than their native abundance, e.g., CD3 analogs when the compound has a CH3 group), its possible regioisomers, possible geometric isomers, possible stereoisomers (including diastereomers, enantiomers, and racemic mixtures), its tautomers, its conformational isomers, its pharmaceutically acceptable esters, and / or its possible pharmaceutically acceptable salts (e.g., acid addition salts such as HCl salts or base addition salts such as Na salts). Hydrates and solvates of the compounds of this disclosure are considered compositions of this disclosure, wherein said compounds are associated with water or a solvent, respectively.

[0414] The compounds disclosed herein can exist in an isotopically labeled or enriched form containing one or more atoms having an atomic mass or mass number different from the most abundant atomic mass or mass number found in nature. The isotopes can be radioactive or non-radioactive isotopes. Isotopes of atoms such as hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine are included, but are not limited to, those of other atoms. 2 H, 3 H, 13 C 14 C 15 N、 18 O、 32 P, 35 S, 18 F, 36 Cl and 125 I. Compounds containing other isotopes of these and / or other atoms are within the scope of this invention.

[0415] As used herein, the phrase "administration," "administering," or other variations thereof refer to the provision of the compound or a prodrug of the compound to an individual in need of treatment.

[0416] As used herein, the term "alkyl" on its own or as part of another group refers to a straight-chain or branched aliphatic saturated hydrocarbon. In some embodiments, an alkyl group may comprise one to twelve carbon atoms (i.e., C64-C ... 1-12 Alkyl group or a specified number of carbon atoms. In one embodiment, the alkyl group is a straight-chain C14 group. 1-10 Alkyl group. In another embodiment, the alkyl group is a branched C-chain. 3-10 Alkyl group. In another embodiment, the alkyl group is a straight-chain C14 group. 1-6 Alkyl group. In another embodiment, the alkyl group is a branched C-chain. 3-6 Alkyl group. In another embodiment, the alkyl group is a straight-chain C14 group. 1-4 Alkyl group. For example, C 1-4 Alkyl groups include methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and isobutyl. As used herein, the term "alkylene" itself, or as part of another group, refers to a divalent radical derived from an alkyl group, i.e., by removing any one hydrogen atom from the alkyl group. For example, non-limiting straight-chain alkylene groups (i.e., (CH2)). x (Including -CH2-CH2-CH) 2- CH2-, -CH2-CH2-CH2-, -CH2-CH2-, etc.

[0417] As used herein, the term "alkenyl," whether used alone or as part of another group, refers to a straight-chain or branched aliphatic hydrocarbon containing one or more, for example, one, two, or three carbon-carbon double bonds. In one embodiment, the alkenyl group is C 2-6 Alkenyl. In another embodiment, the alkenyl group is C. 2-4 Alkenyl. Non-limiting exemplary alkenyl groups include vinyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0418] As used herein, the term "alkynyl" on its own or as part of another group refers to a straight-chain or branched aliphatic hydrocarbon containing one or more, for example, one to three carbon-carbon triple bonds. In one embodiment, the alkynyl group has one carbon-carbon triple bond. In one embodiment, the alkynyl group is C 2-6 Alkyne group. In another embodiment, the alkynyl group is C. 2-4 Alkyne group. Non-limiting exemplary alkyne groups include ethynyl, propynyl, butynyl, 2-butynyl, pentylyl, and hexynyl.

[0419] As used herein, the term "alkoxy" itself, or as part of another group, refers to the formula OR a1 free radicals, of which R a1 It is an alkyl group.

[0420] As used herein, the term "cycloalkoxy" on its own or as part of another group refers to the formula OR a1 free radicals, of which R a1 It is a cycloalkyl group.

[0421] As used herein, the term "haloalkyl" itself, or as part of another group, refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms. In a preferred embodiment, the haloalkyl is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, the haloalkyl is a C18-28-3 ... 1-10 Halogenated alkyl group. In one embodiment, the halogenated alkyl group is C10. 1-6 Halogenated alkyl group. In one embodiment, the halogenated alkyl group is C10. 1-4 Halogenated alkyl groups.

[0422] As used herein, unless otherwise stated, the term "heteroalkyl" on its own or in combination with another term means a stable straight-chain or branched alkyl group, for example having 2 to 14 carbons, such as 2 to 10 carbons in a chain, wherein one or more of the carbons have been selected from S, O 、 The heteroatoms P and N are substituted, and the nitrogen, phosphine, and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Heteroatoms S and O 、 P and N can be placed at any internal position of the heteroalkyl group or at the position where the alkyl group is attached to the rest of the molecule. When a heteroalkyl group is referred to as substituted, the substituent can replace one or more hydrogen atoms attached to the carbon atom and / or heteroatom of the heteroalkyl group. In some embodiments, the heteroalkyl group is C 1-4 Heteroalkyl groups, as defined herein, refer to heteroalkyl groups having 1-4 carbon atoms. C 1-4 Examples of heteroalkyl groups include, but are not limited to, C4 heteroalkyl groups such as -CH2-CH2-N(CH3)-CH3, C3 heteroalkyl groups such as -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, C2 heteroalkyl groups such as -CH2-CH2-OH, -CH2-CH2-NH2, -CH2-NH(CH3), -O-CH2-CH3, and C1 heteroalkyl groups such as -CH2-OH, -CH2-NH2, -O-CH3. Preferably, the C... 1-4 Heteroalkyl (or C) 1-4 Heteroalkyl groups contain one or two heteroatoms, such as one oxygen atom, one nitrogen atom, two oxygen atoms, two nitrogen atoms, or one oxygen atom and one nitrogen atom. Similarly, the term "heteroalkyl group" itself or as part of another substituent refers to a divalent radical derived from a heteroalkyl group, such as, but not limited to, -CH2-CH2-O-CH2.2- CH2- and -O-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatom can also occupy any one or two of the chain ends (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, for alkylene and heteroalkylene linking groups, the direction in which the formula of the linking group is written does not imply the orientation of the linking group. The term "heteroalkyl" is followed by terms such as -NR'R. '' In the case of specific heteroalkyl groups, it should be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, specific heteroalkyl groups are used to increase clarity. Therefore, the term "heteroalkyl" should not be interpreted herein as excluding terms such as -NR'R. '' Specific heteroalkyl groups, etc.

[0423] In some preferred embodiments, unless otherwise specified or contrary to the context, C in this document... 1-6 Heteroalkyl groups can be C 1-6 Alkoxy, NH(C) 1-6 alkyl), N(C) 1-4 Alkyl)(C 1-4 alkyl), -(C 1-5 alkylene)-O-(C 1-5 alkyl), -(C 1-5 alkylene)-NH(C 1-5 alkyl), -(C 1-4 alkylene)-N(C 1-4 Alkyl)(C 1-4 alkyl), -(C 1-5 alkylene)-S-(C 1-5 alkyl), -(C 1-5 alkylene)-SO2-(C 1-5 Alkyl), SO2 (C) 1-6 Alkyl), P(O)(C 1-4 Alkyl)(C 1-4 Alkyl), SO2NH(C) 1-6 Alkyl), SO2N(C) 1-4 Alkyl)(C 1-4 alkyl), -(C 1-5 alkylene)-SO2NH-(C 1-5 alkyl) or -(C 1-4 Alkylene)-SO2N(C 1-4 Alkyl)(C 1-4 Alkyl groups), provided that the total number of carbons is not greater than 6, and any optional substituents are not counted. In some preferred embodiments, the C35 atoms described herein... 1-6 Heteroalkylene groups can be derived from the aforementioned C by removing a hydrogen atom. 1-6 Any one of the heteroalkyl groups.

[0424] In some preferred embodiments, unless otherwise specified or contrary to the context, C in this document... 1-4 Heteroalkyl groups can be C 1-4 Alkoxy, NH(C) 1-4 alkyl), N(C) 1-3 Alkyl)(C 1-3 alkyl), -(C 1-3 alkylene)-O-(C 1-3 alkyl), -(C 1-3 alkylene)-NH(C 1-3 alkyl), -(C 1-2 alkylene)-N(C 1-2 Alkyl)(C 1-2 alkyl), -(C 1-3 alkylene)-S-(C 1-3 alkyl), -(C 1-3 alkylene)-SO2-(C 1-3 Alkyl), SO2 (C) 1-4 Alkyl), P(O)(C 1-3 Alkyl)(C 1-3 Alkyl), SO2NH(C) 1-4 Alkyl), SO2N(C) 1-3 Alkyl)(C 1-3 alkyl), -(C 1-3 alkylene)-SO2NH-(C 1-3 alkyl) or -(C 1-2 Alkylene)-SO2N(C 1-2 Alkyl)(C 1-2 Alkyl groups), provided that the total number of carbon atoms is not greater than 4, and any optional substituents are not counted. In some preferred embodiments, the C atoms herein... 1-4 Heteroalkylene groups can be derived from the aforementioned C by removing a hydrogen atom. 1-4 Any one of the heteroalkyl groups.

[0425] When used alone or as part of another group, "carbocyclic group" or "carbocyclic ring" refers to a non-aromatic ring system having at least 3 carbon atoms, for example, 3 to 10 cyclic carbon atoms ("C"). 3-10A carbocyclic radical is a free radical consisting of a carbocyclic group and a non-aromatic cyclic hydrocarbon group with zero heteroatoms. The carbocyclic group can be monocyclic (“monocyclic carbocyclic”) or contain fused, bridged, or spirocyclic systems, such as bicyclic systems (“bicyclic carbocyclic”), and can be saturated or partially unsaturated. Non-limiting exemplary carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decahydronaphthalene, adamantyl, cyclopentenyl, and cyclohexenyl. As used herein, the term “subcarbocyclic”, when used alone or as part of another group, refers to a divalent free radical derived from a carbocyclic group as defined herein.

[0426] In some embodiments, the "carbocyclic group" is fully saturated and is also referred to as a cycloalkyl group. In some embodiments, the cycloalkyl group may have 3 to 10 cyclic carbon atoms ("C10"). 3-10 cycloalkyl group (“cycloalkylene”). In a preferred embodiment, the cycloalkyl group is monocyclic. As used herein, the term “cycloalkylene” refers, either on its own or as part of another group, to a divalent radical derived from the cycloalkyl group, such as… or wait.

[0427] Unless otherwise defined or contrary to the context, heteroatoms herein refer to atoms selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. More preferably, heteroatoms herein refer to atoms selected from nitrogen, oxygen, and sulfur.

[0428] When used alone or as part of another group, the term "heterocyclic group" or "heterocycle" refers to a radical having a ring carbon atom and at least one ring heteroatom, such as a trivalent or larger radical with one to four ring heteroatoms, or a radical of a trivalent to 14-membered nonaromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclic groups containing one or more nitrogen atoms, the linking point may be a carbon or nitrogen atom, where the valence allows. Heterocyclic groups may be monocyclic ("monocyclic heterocyclic group") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic group"), and may be saturated or partially unsaturated. Heterocyclic groups may also be referred to as heterocyclic alkyl groups when all ring carbon atoms in a heterocyclic group as defined herein are saturated carbons. Heterocyclic bicyclic systems may include one or more heteroatoms in one or both rings, and the linking point may be on any ring. As used herein, the term "subheterocyclic group" when used alone or as part of another group refers to a divalent radical derived from a heterocyclic group as defined herein. Heterocyclic or sub-heterocyclic groups may optionally be attached to the rest of the molecule via carbon or nitrogen atoms.

[0429] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirrocyclopropenyl, ethylene oxide, and thiocyclopropane. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirrocyclobutane, oxacyclobutane, and thiocyclobutane. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxapentyl, oxothiocyclopentyl, dithiocyclopentyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thiophenyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithienyl, and dioxane. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazineyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirheptanyl, oxeheptanyl, and thioheptanyl. Exemplary 5-membered heterocyclic groups fused to a C6 aryl ring (also referred to herein as examples of 5,6-bicyclic heterocycles) include, but are not limited to, indololinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinoneyl, etc. Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as examples of 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0430] When used alone or as part of another group, "aryl" refers to a free radical ("C") having a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in the ring array) with 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system. 6-14 Aryl group (“C6 aryl”); in some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 "Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen cyclic carbon atoms ("C"). 14 "Aryl"; for example, anthraquinone). As used herein, the term "aryl" on its own or as part of another group refers to a divalent radical derived from an aryl group as defined herein.

[0431] When used alone or as part of another group, "aralkyl" refers to an alkyl group that is substituted with one or more aryl groups, preferably with one aryl group. Examples of aralkyl groups include benzyl, phenethyl, etc. When aralkyl is referred to as optionally substituted, the alkyl or aryl portion of the aralkyl group may be optionally substituted.

[0432] When used alone or as part of another group, "heteroaryl" refers to a radical having a 5-14 membered monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in the ring array) having a cyclic carbon atom provided in the aromatic ring system and at least one, preferably 1-4, cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). As used herein, for clarity, pyridones (e.g., pyridin-2-one, ...) R can be a hydrogen or nitrogen substituent), pyrimidinones, etc., such as pyridinones fused with aryl or heteroaryl groups (e.g., (where R can be a hydrogen or nitrogen atom substituent) is considered a heteroaryl ring herein. In heteroaryls containing one or more nitrogen atoms, the linkage can be a carbon or nitrogen atom, where the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. In a bicyclic heteroaryl where one ring does not contain a heteroatom (e.g., indole, quinolinyl, etc.), the linkage can be on either ring, i.e., the ring with a heteroatom (e.g., 2-indole) or the ring without a heteroatom (e.g., 5-indole). As used herein, the term "hybrid aryl" itself, or as part of another group, refers to a divalent radical derived from a heteroaryl as defined herein.

[0433] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrroleyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azircycloheptenyl, oxazircycloheptenyl, and thiocycloheptenyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazole, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0434] When used alone or as part of another group, "heteroaryl" refers to an alkyl group that is substituted with one or more heteroaryl groups, preferably with one heteroaryl group. When a heteroaryl group is referred to as "optionally substituted," the alkyl or heteroaryl portion of the heteroaryl group may be optionally substituted.

[0435] As used herein, unless otherwise stated or otherwise contrary, “ring structure”, “cyclic structure” or simply “ring” having a specified number of ring members, such as “3-10 membered ring structure”, “3-12 membered ring structure” or “5 or 6 membered ring”, should be understood to cover any ring structure (e.g., carbocyclic, heterocyclic, aryl, heteroaryl, etc.) having a specified number of ring members, which can be (1) monocyclic or polycyclic (as is chemically feasible), such as monocyclic or bicyclic (including fused, spiro and bridged bicyclic, and those ring systems in which two monocyclic rings are connected by a single or double bond); (2) aromatic, partially unsaturated or fully saturated; and in the case of a polycyclic structure, each ring can be independently aromatic, partially unsaturated or fully saturated; and (3) free of heteroatoms (i.e., all ring members are carbon atoms) or 1-4 heteroatoms; or in the case of a polycyclic structure, each ring can be independently free of cyclic heteroatoms or 1-4 cyclic heteroatoms (e.g., O, N, S, etc.). When the ring is described as containing cyclic sulfur or nitrogen atoms, the sulfur or nitrogen atoms may optionally be oxidized. One or more cyclic carbon atoms in the ring structure may be present as C (=O). A fully saturated ring is a ring in which the cyclic carbon atoms and any present cyclic heteroatoms (e.g., nitrogen) do not form double or triple bonds with any other atoms. The ring structure may optionally be substituted by one or more substituents described herein. The substituents of the ring structure described herein may also have a cyclic structure, and in some cases, two substituents of the ring structure may be referred to as being linked to form a cyclic structure.

[0436] As is generally understood in the art, for clarity, when a structure can be characterized in multiple ways, a structure is considered a suitable definition of a variable as long as one such representation falls within the scope of the variable's definition herein. For example, when a monovalent variable is defined as an optionally substituted 6-membered ring, the variable encompasses (a) among other structures. or structure It can be considered as a 6-membered monocyclic or bicyclic ring substituted with phenyl; and the structure of (b) It can be viewed as a 6-membered ring, where two substituents are linked to form a cyclopropyl ring (unless optional substituents for the 6-membered ring are specified and not included as an option); however, the variable will not cover... This is because the connecting loop is not a 6-membered ring under any representation of the structure. To further explain, when the variable is instead defined as an arbitrarily substituted monocyclic 6-membered ring, the variable does not cover... Instead, it covers The structure (unless an optional substituent for a 6-membered ring is specified and not included as an option). If the variable is defined as a 6-membered ring optionally substituted with a halogen, the variable can cover the structure, such as ,

[0437] Because each of them can be considered as an unsubstituted or a 6-membered ring substituted with one or two fluorine atoms.

[0438] As is commonly understood in the art, alkylene, alkenylene, ynylene, heteroalkylene, carbocyclic, heterocyclic, arylene, and heteroarylene refer to the corresponding divalent radicals of alkyl, alkenyl, ynylene, heteroalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl, respectively.

[0439] "Optionally substituted" groups, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl, refer to the corresponding unsubstituted or substituted group. Generally, the term "substituted," regardless of whether it is preceded by the term "optionally," means that at least one hydrogen atom present on the group (e.g., a carbon or nitrogen atom) is replaced by a permissible substituent, such as a substituent that, upon substitution, produces a stable compound, such as a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reactions). Unless otherwise stated, a "substituted" group has substituents at one or more substituted positions of the group, and when more than one position in any given structure is substituted, the substituents at each position may be the same or different. Typically, when substituted, the optionally substituted group herein can be substituted by 1-5 substituents. Substituents can be carbon, nitrogen, oxygen, or sulfur substituents, each of which may optionally be isotopically labeled, such as by deuteration, where applicable. Two of the optional substituents may link to form a ring structure, such as an optionally substituted cycloalkyl, heterocyclic, aryl, or heteroaryl ring. Substitution can occur on any available carbon, oxygen, or nitrogen atom and can form a spirocyclic ring. Generally, the substitutions described herein do not produce OO, ON, SS, SN (except for SO2-N bonds), heteroatom-halogen, or -C(O)-S bonds or three or more consecutive heteroatoms, except for O-SO2-O, O-SO2-N, and N-SO2-N, except for some bonds or links in a stable aromatic system where such bonds or links are permissible.

[0440] In a broad sense, permissible substituents herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For a suitable organic compound, permissible substituents may be one or more and may be the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents in the organic compounds described herein that satisfy the valence of the heteroatom. Substituents may include any substituents described herein, such as halogens, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetic acids, or thiocarbamates), alkoxy groups, cycloalkoxy groups, phosphoryl groups, phosphate groups, phosphonates, phosphonites, amino groups, amide groups, amidine groups, imine groups, cyano groups, nitro groups, azide groups, mercapto groups, alkylthio groups, sulfate groups, sulfonates, aminosulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, alkyl groups, alkenyl groups, cycloalkyl groups, heterocyclic groups, aralkyl groups, aryl groups, or heteroaryl groups, each of which may be substituted if appropriate.

[0441] Exemplary substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -aryl-alkyl, -alkylene-heteroaryl, -alkenyl-heteroaryl, -alkynyl-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, -O-heteroaryl, -O-alkylene-heteroaryl, -O-cycloalkyl, -O-heterocyclic alkyl, acyl, -C(O)-alkyl, -C(O)-haloalkyl, -C(O)-aryl, -C(O)-alkylene-aryl, -C(O)-heteroaryl, -C(O)-alkylene-heteroaryl, -C(O)-cycloalkyl, -C(O)-heterocyclic alkyl. Halogen, -NO2, -CN, -SF5, -C(O)OH, -C(O)O-alkyl, -C(O)O-aryl, -C(O)O-alkylene-aryl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)-haloalkyl, -S(O)2-haloalkyl, -S(O)-aryl, -S(O)2-aryl, -S(O)-heteroaryl, -S(O)2-heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, -S(O)2-alkylene-aryl, -S(O)2-alkylene-heteroaryl, -S-cycloalkyl, -S-heterocycloalkyl, -S(O)-cycloalkyl, -S(O)-heterocycloalkyl, - S(O)2-cycloalkyl, -S(O)2-heterocycloalkyl, -S(O)(═NH)-alkyl, -S(O)(═NH)-haloalkyl, -S(O)(═NH)-aryl, -S(O)(═NH)-alkylene-aryl, -S(O)(═NH)-heteroaryl, -S(O)(═NH)-alkylene-heteroaryl, -S(O)(═NH)-cycloalkyl, -S(O)(═NH)-heterocycloalkyl, -S(O)(═Nalkyl)-alkyl, -S(O)(═Nalkyl)-haloalkyl, -S(O)(═Nalkyl)-aryl, -S(O)(═Nalkyl)-alkylene-aryl, -S(O)(═Nalkyl)-heteroaryl, -S(O)(═Nalkyl)-alkylene- Heteroaryl, -S(O)(═Nalkyl)-cycloalkyl, -S(O)(═Nalkyl)-heterocycloalkyl, cycloalkyl, heterocycloalkyl, -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-cycloalkyl, -C(═N-CN)-NH2, -C(═NH)-NH2, -C(═NH)-NH(alkyl), -N(Y1)(Y2), -alkylene-N(Y1)(Y2), -C(O)N(Y1)(Y2) and -S(O)2N(Y1)(Y2), wherein Y1 and Y2 may be the same or different, and are independently selected from the group consisting of: hydrogen, alkyl, haloalkyl, aryl, -alkylene-aryl, heteroaryl, -alkylene-heteroaryl, cycloalkyl, heterocycloalkyl.Furthermore, Y1 and Y2, along with the nitrogen atoms they are attached to, can form heterocycles.

[0442] Some examples of suitable substituents include, but are not limited to, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)ynyl, (C3-C8)... 10Cycloalkyl, halogen (F, Cl, Br or I), halogenated (C1-C8)alkyl (e.g., but not limited to -CF3), -O-(C1-C8)alkyl, -OH, -S-(C1-C8)alkyl, -SH, -NH(C1-C8)alkyl, -N((C1-C8)alkyl)2 group, -NH2, -C(O)NH2, -C(O)NH(C1-C8)alkyl, -C(O)N((C1-C8)alkyl)2, -NHC(O)H, -NHC(O)(C1-C8)alkyl, -NHC(O)(C3-C8)cycloalkyl, -N((C1-C8)alkyl)C(O)H, -N((C1-C8)alkyl) C(O)(C1-C8)alkyl, -NHC(O)NH2, -NHC(O)NH(C1-C8)alkyl, -N((C1-C8)alkyl)C(O)NH2 group, -NHC(O)N((C1-C8)alkyl)2 group, -N((C1-C8)alkyl)C(O)N((C1-C8)alkyl)2 group, -N((C1-C8)alkyl)C(O)NH((C1-C8)alkyl), -C(O)H, -C(O)(C1-C8)alkyl, -CN, -NO2, -S(O)(C1-C8)alkyl, -S(O)2(C1-C8)alkyl, -S(O)2N((C1-C8)alkyl -S(O)2NH(C1-C8)alkyl, -S(O)2NH(C3-C8)cycloalkyl, -S(O)2NH2, -NHS(O)2(C1-C8)alkyl, -N((C1-C8)alkyl)S(O)2(C1-C8)alkyl, -(C1-C8)alkyl-O-(C1-C8)alkyl, -O-(C1-C8)alkyl-O-(C1-C8)alkyl, -C(O)OH, -C(O)O(C1-C8)alkyl, NHOH, NHO(C1-C8)alkyl, -O-halogenated(C1-C8)alkyl (e.g., but not limited to -OCF3), -S(O)2-halogenated(C1-C8)alkyl -S-alkyl (e.g., but not limited to -S(O)2CF3), -S-halogenated (C1-C8)alkyl (e.g., but not limited to -SCF3), -(C1-C6)heterocyclic (e.g., but not limited to pyrrolidine, tetrahydrofuran, pyran, or morpholine), -(C1-C6)heteroaryl (e.g., but not limited to tetrazolium, imidazole, furan, pyrazine, or pyrazole), -phenyl, -NHC(O)O-(C1-C6)alkyl, -N((C1-C6)alkyl)C(O)O-(C1-C6)alkyl, -C(═NH)-(C1-C6)alkyl, -C(═NOH)-(C1-C6)alkyl, or -C(═NO-(C1-C6)alkyl)-(C1-C6)alkyl.

[0443] Exemplary carbon atom substituents include, but are not limited to, deuterium, halogen, -CN, -NO2, -N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkylamino, dialkylamino, amide, sulfonamide, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C 3-10 carbonyl group, C 6-10 Aryl, 3-10 membered heterocyclic groups, 5-10 membered heteroaryl groups, etc. For example, exemplary carbon atom substituents may include F, Cl, -CN, -SO2H, -SO3H, -OH, -OC. 1-6 Alkyl, -NH2, -N(C) 1-6 alkyl)2、-NH(C 1-6 Alkyl), -SH, -SC 1-6 Alkyl group, -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -C(=O)NH2, -C(=O)N(C 1-6 Alkyl)2、-OC(=O)NH(C 1-6 Alkyl), -NHC(=O)(C 1-6 alkyl), -N(C) 1-6 Alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 Alkyl), -NHC(=O)N(C 1-6 alkyl)2、-NHC(=O)NH(C 1-6 Alkyl groups), -NHC(=O)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2、-SO2NH(C 1-6 Alkyl groups, -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 carbonyl group, C 6-10 Aryl, 3-10 heterocyclic, 5-10 heteroaryl; or two paired substituents can be linked to form =O.

[0444] Where valence permits, the nitrogen atom can be substituted or unsubstituted, and includes primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen substituents include, but are not limited to, acyl, ester, sulfone, sulfoxide, and C. 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 The aryl group and 5-14-membered heteroaryl group, or two substituents connected to the nitrogen atom, are linked to form a 3-14-membered heterocyclic group or a 5-14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group may be further substituted as defined herein. In some embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups are well known in the art and include those described in Protecting Groups in Organic Synthesis, 4th Edition, PGMWuts; TW Greene, John Willie Press, 2007, which is incorporated herein by reference. Exemplary nitrogen protecting groups include, but are not limited to, those nitrogen protecting groups that form urethane esters, such as benzyloxycarbonyl (Cbz), p-methoxybenzylcarbonyl (Moz or MeOZ), tert-butoxycarbonyl (BOC), Troc, 9-fluorenylmethoxycarbonyl (Fmoc), etc.; those nitrogen protecting groups that form amides, such as acetyl, benzoyl, etc.; those nitrogen protecting groups that form benzylamines, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, etc.; those nitrogen protecting groups that form sulfonamides, such as toluenesulfonyl, nitrobenzenesulfonyl, etc.; and other nitrogen protecting groups, such as p-methoxyphenyl.

[0445] Exemplary oxygen substituents include, but are not limited to, acyl, ester, sulfonate, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14Aryl and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, ynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group may be further substituted as defined herein. In some embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups are well known in the art and include those described in Protecting Groups in Organic Synthesis, 4th Edition, PGM Wuts; TW Greene, John Willie Press, 2007, which is incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, those oxygen protecting groups that form alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyl, such as 4-methoxybenzyl, methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), etc.; those oxygen protecting groups that form silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), etc.; those oxygen protecting groups that form acetals or ketals, such as tetrahydropyranyl (THP); those oxygen protecting groups that form esters, such as formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methyl methoxyacetate, etc.; and those oxygen protecting groups that form carbonates or sulfonates, such as methanesulfonate / mesylate, benzylsulfonate, and toluenesulfonate (Ts), etc.

[0446] Unless explicitly stated to the contrary, combinations of substituents and / or variables are permitted only if such combinations are chemically permissible and produce stable compounds. A “stable” compound is one that can be prepared and isolated and whose structure and properties are retained or can be made substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject).

[0447] Unless otherwise specified or contrary to the context, the optionally substituted group as defined in conjunction with Formula I may be (A) unsubstituted; or (B) substituted with one or more substituents, each of which is independently deuterium, halogen, CN, or Y. 1 -Y 2 -Y 3 -Y 4 , where Y 1 Y 2 and Y 3 Each is independently empty, O, NY 4 ,C(O),S,SO,SO2,S(O)(=NY 4 C, optionally substituted with deuterium, F and / or OH 1-4 Alkylene or P(O)Y4 , where Y 4 Each time it appears, it is independently hydrogen, optionally accompanied by one or more Y atoms. 10 Replacement C 1-6 Alkyl group, optionally with one or more Y 10 Replacement C 2-6 alkenyl, optionally with one or more Y 10 Replacement C 2-6 alkynyl group, optionally with one or more Y groups 10 Replacement C 1-6 Heteroalkyl or optionally Y 10 The 3-14 member rings are replaced, where Y 10 Each time it appears, it is independently of deuterium, halogen, oxo (where applicable), CN, or Y. 20 -Y 21 -Y 22 -Y 23 , where Y 20 Y 21 and Y 22 Each is independently empty, O, NY 23 ,C(O),S,SO,SO2,S(O)(=NY 23 C, optionally substituted with deuterium, F and / or OH 1-4 Alkylene or P(O)Y 23 , where Y 23 Each time it appears, it is independently hydrogen, optionally accompanied by one or more Y atoms. 30 Replacement C 1-6 Alkyl group, optionally with one or more Y 30 Replacement C 2-6 alkenyl, optionally with one or more Y 30 Replacement C 2-6 alkynyl group, optionally with one or more Y groups 30 Replacement C 1-6 Heteroalkyl or optionally Y 30 The replaced 3-8 member ring, where Y 30 Each time it appears independently of deuterium, halogen, oxo (where applicable), CN, OH, NH2, optionally by one or more Y. 31 Replacement C 1-4 Alkyl group, optionally with one or more Y 31 Replacement C 1-4 Heteroalkyl or optionally Y 31 The replaced 3-5 member ring, where Y 31 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F1-4 Heteroalkyl; or (C) two or more substituents of the corresponding optionally substituted group, and / or one of the substituents of the corresponding optionally substituted group connected to another variable herein to form a ring (e.g., spirocyclic, fused, or bridged ring), which is optionally substituted by one or more substituents as defined in (B), and any remaining substituents of the corresponding optionally substituted group as defined in (B). In some preferred embodiments, the optionally substituted group as defined in conjunction with Formula I may be unsubstituted or substituted by one or more substituents as defined in (B). 1 Y 2 and Y 3 The combination is not particularly limited, and it can preferably be (a) when Y 1 Y 2 and Y 3 The two in the middle are spacetime, O and NY. 4 ,C(O),S,SO,SO2 or P(O)Y 4 The connector; or (b) when Y 1 Y 2 and Y 3 One of them is spacetime, amide (C(O)NY) 4 ), ester (C(O)O), sulfonamide (SO2NY) 4 (c) When Y 1 Y 2 and Y 3 When neither is empty, carbamate (OC(O)NY) 4 ), urea (NY 4 C(O)NY 4 ), aminosulfonylamino (NY 4 SO2NY 4 Connectors such as Y. 20 Y 21 and Y 22 The combination should be understood similarly.

[0448] Unless otherwise specified or contrary to the context, when a group herein is defined as optionally substituted with one or more substituents selected from the defined list of substituents or simply the defined list of substituents, the group is generally unsubstituted or substituted with one, two, three, or four substituents as defined, but in some embodiments, the group may also be substituted with more than four substituents. For example, an alkyl group optionally substituted with one or more substituents independently selected from deuterium, F, and OH is generally unsubstituted or substituted with one to four substituents, each independently of deuterium, F, or OH. Similarly, an alkyl group optionally substituted with deuterium and / or F is generally unsubstituted or substituted with one to four substituents, each independently of deuterium or F.

[0449] Unless otherwise specified or contrary to the context, the 3-8 membered ring herein may be (i) a 3-8 membered carbon ring; (ii) a 4-8 membered heterocycle having 1-3 cyclic heteroatoms, each of which is independently O, S and N, wherein the sulfur atom, if present, is optionally oxidized; (iii) a phenyl ring; or (iv) a 5- or 6-membered heteroaryl ring having 1-4 cyclic heteroatoms, each of which is independently O, S and N.

[0450] Unless otherwise specified or contrary to the context, the 3-5 membered ring herein can be (i) a 3-5 membered carbon ring, such as cyclopropyl, cyclobutyl, etc.; (ii) a 4-5 membered heterocycle having 1-2 cyclic heteroatoms, each of which is independently O, S, and N, wherein the sulfur atom, if present, is optionally oxidized, such as oxobutane, azirone, etc.; or (iii) a 5-membered heteroaryl ring having 1-4 cyclic heteroatoms, each of which is independently O, S, and N.

[0451] In some embodiments, the “optionally substituted” alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, carbocyclic, carbocyclic, cycloalkyl, cycloalkylene, alkoxy, cycloalkoxy, heterocyclic or heterocyclic groups herein may be independently unsubstituted or substituted by one, two, three or four independently selected from the following substituents: deuterium, F, Cl, -OH, CN, protected hydroxyl, oxo (where applicable), NH2, protected amino, NH(C 1-4 alkyl groups or their protected derivatives, N(C) 1-4 Alkyl)(C 1-4 Alkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, phenyl, 5- or 6-membered heteroaryl containing one, two, or three cyclic heteroatoms independently selected from O, S, and N, or 3- to 7-membered heterocyclic groups containing one or two cyclic heteroatoms independently selected from O, S, and N, wherein any of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxyphenyl, heteroaryl, and heterocyclic groups is optionally substituted by one, two, or three substituents independently selected from: deuterium, F, -OH, oxo (where applicable), C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl groups (e.g., CF3), C 1-4 alkoxy and fluorine-substituted C 1-4Alkyl groups. In some embodiments, the “optionally substituted” aryl, arylene, heteroaryl, or heteroarylene groups herein may be independently unsubstituted or substituted by one, two, three, or four independently selected substituents from: deuterium, F, Cl, -OH, -CN, NH2, protected amino, NH(C 1-4 alkyl groups or their protected derivatives, N(C) 1-4 Alkyl)(C 1-4 Alkyl), -S(=O)(C 1-4 alkyl), -SO2(C 1-4 Alkyl), C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Alkoxy, C 3-6 cycloalkyl, C 3-6 Cycloalkoxy, phenyl, 5- or 6-membered heteroaryl containing one, two, or three cyclic heteroatoms independently selected from O, S, and N, or 3- to 7-membered heterocyclic groups containing one or two cyclic heteroatoms independently selected from O, S, and N, wherein any of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxyphenyl, heteroaryl, and heterocyclic groups is optionally substituted by one, two, or three substituents independently selected from: deuterium, F, -OH, oxo (where applicable), C 1-4 Alkyl, fluorine-substituted C 1-4 Alkyl, C 1-4 alkoxy and fluorine-substituted C 1-4 Alkyl group.

[0452] "Halogen" or "halogen" refers to fluorine (fluorine, -F), chlorine (chlorine, -Cl), bromine (bromine, -Br) or iodine (iodine, -I).

[0453] The term "pharmaceutically acceptable salt" refers to salts that, to the extent of reasonable medical judgment, are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art.

[0454] The term "tautomer" or "tautomeric" refers to two or more interconvertible compounds resulting from tautomerization. The exact ratio of tautomers depends on several factors, including, for example, temperature, solvent, and pH. Tautomerization is known to those skilled in the art. Exemplary tautomerizations include keto-enol, amide-imide, lactam-lactam-lactam, enamine-imide, and enamine-(different enamines) tautomerizations.

[0455] As used herein, the term “subject” (which may be referred to herein as “patient”) means an animal, preferably a mammal, and most preferably a human, that is the object of treatment, observation or experimentation.

[0456] As used herein, the terms "treat / treating / treatment," etc., refer to the elimination, reduction, or improvement of a disease or symptom and / or associated symptoms. While not excluded, treating a disease or symptom does not require the complete elimination of said disease, symptom, or associated symptoms. As used herein, the terms "treat / treating / treatment," etc., can include "preventive treatment," which refers to reducing the likelihood of the development of a disease or symptom, or the likelihood of recurrence of a previously controlled disease or symptom, in subjects who do not have such a disease or symptom but are at risk or prone to relapse. The term "treatment" and its synonyms contemplate the administration of a therapeutically effective amount of the compounds described herein to subjects who require such treatment.

[0457] The term "effective amount" refers to an amount of compound or combination of compounds, as described herein, sufficient to achieve the intended application, including but not limited to the prevention or treatment of a disease. Therapeutic effective amounts can vary depending on the intended application (in vitro or in vivo) or the subject and the condition of the disease being treated (e.g., the subject's weight, age, and sex), the severity of the disease, the route of administration, etc., which can be readily determined by those skilled in the art. The term also applies to doses that will induce a specific response in target cells and / or tissues. Specific doses will vary depending on the particular compound selected, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which the compound is administered, and the physical delivery system carrying the compound.

[0458] As used herein, unless explicitly stated or clearly understood from the context that this is not intended, the singular forms “a / an” and “the” include plural referents.

[0459] The term "and / or" as used herein, such as in phrases like "A and / or B," is intended to include both A and B; A or B; A (alone); and B (alone). Similarly, the term "and / or" as used herein, such as in phrases like "A, B, and / or C," is intended to cover each of the following embodiments: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0460] Headings and subheadings are used for convenience and / or formal compliance only, do not limit the subject matter, and are not associated with an interpretation of the subject matter description. In various embodiments, features described under one heading or subheading of this disclosure may be combined with features described under other headings or subheadings. Furthermore, not all features under a single heading or subheading are necessarily used in embodiments.

[0461] Example

[0462] Abbreviations: Unless otherwise expressly indicated or clearly contrary to the context, the abbreviations used in the Examples section should be understood to have their ordinary meaning in the art. Some abbreviations used in the Examples section of this document are shown below.

[0463]

[0464] The various starting materials, intermediates, and compounds described in the examples herein can be separated and purified using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography, where appropriate. Characterization of these compounds can be performed using conventional methods, such as by melting point determination, mass spectrometry, nuclear magnetic resonance, and various other spectroscopic analyses. Unless otherwise expressly indicated or clearly contrary to the context, abbreviations used in the Examples section should be understood to have their ordinary meaning in the art. The examples are merely illustrative and do not limit the claimed invention in any way.

[0465] Exemplary embodiments of the steps for synthesizing the products described herein are described in more detail below. Some of the intermediates and examples in this document have one or more chiral centers. Stereoisomers, including enantiomers and diastereomers, can be prepared by chiral synthesis and / or chiral resolution. Some of the absolute stereochemistry in the Examples section of this document (whether indicated as provisional or not) is assigned based on literature or other evidence, or is arbitrary. It should be understood that if the assigned stereochemistry is later found to be incorrect, the expected structure should be the corresponding compound with the correct stereochemistry. This disclosure specifically contemplates all potential stereoisomers from the synthetic examples.

[0466] Intermediate A

[0467] N-(1-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propionamide （A）

[0468]

[0469] Step 1: 1-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxynitrile (A-1)

[0470] Under N2, NaOH (50% in water, 12.5 mL) and TBAB (0.80 g, 2.5 mmol) were added to a stirred mixture of 2-(4-bromo-3-fluorophenyl)acetonitrile (5.00 g, 23 mmol) and 1,2-dibromoethane (1.5 mL) in toluene (12.5 mL). After stirring at room temperature under N2 for 16 hours, the mixture was treated with water and extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to give 1-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxynitrile (5.00 g). 1 HNMR (400 MHz, DMSO-d6) δ 7.73 (dd, J = 8.4 Hz, 7.6 Hz, 1H), 7.29 (dd, J =10.4 Hz, 2.4 Hz, 1H), 7.21 (m, 1H), 1.79 (m, 2H), 1.67-1.55 (m, 2H).

[0471] Step 2: 1-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxaldehyde (A-2)

[0472] DIBAL-H (1 M in n-hexane, 52 mL, 52 mmol) was added dropwise to a stirred solution of 1-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxynitrile (6.30 g, 26 mmol) in DCM (63 mL) at -78 °C under N2. After stirring at -78 °C for 1 hour under N2, the mixture was quenched with water and extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to give 1-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxaldehyde (4.10 g). 1 H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 7.53 (dd, J = 8.0 Hz, 7.2 Hz, 1H), 7.08 (dd, J = 9.2Hz, 2.0 Hz, 1H), 7.00 (m, 1H), 1.64-1.56 (m, 2H), 1.45-1.37 (m, 2H).

[0473] Step 3: 2-Amino-2-(1-(4-bromo-3-fluorophenyl)cyclopropyl)acetonitrile (A-3)

[0474] NH3 (7 N in MeOH, 24.1 mL, 169 mmol) and Ti(Oi-Pr)4 (5.75 g, 20 mmol) were added dropwise to a stirred solution of 1-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxaldehyde (4.10 g, 17 mmol) in MeOH (80 mL) under N2 at 0 °C. After stirring under N2 at 0 °C for 1 h, TMSCN (6.69 g, 67 mmol) was added dropwise at 0 °C. After stirring for another 16 h at room temperature, the mixture was treated with water and extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc = 1:1) to give 2-amino-2-(1-(4-bromo-3-fluorophenyl)cyclopropyl)acetonitrile (1.7 g). LCMS (ESI, m / z): [M+H] + 269.0.

[0475] Step 4: 2-Amino-2-(1-(4-bromo-3-fluorophenyl)cyclopropyl)acetic acid (A-4)

[0476] A mixture of 1.70 g (6.3 mmol) of 2-amino-2-[1-(4-bromo-3-fluorophenyl)cyclopropyl]acetonitrile in concentrated HCl (20 mL) was stirred at 100 °C for 2 hours. The resulting mixture was concentrated under reduced pressure to give a crude product that could be used directly in the next step. LCMS (ESI, m / z): [M+H] + 288.0.

[0477] Step 5: 2-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-propamidoacetic acid (A-5)

[0478] Propionic anhydride (1.08 g, 8.33 mmol) was added dropwise to a stirred mixture of 2-amino-2-(1-(4-bromo-3-fluorophenyl)cyclopropyl)acetic acid (0.80 g, 2.78 mmol) and DIEA (2.15 g, 16.7 mmol) in DCM (10 mL) at room temperature under N2. After stirring for 1 hour, the mixture was concentrated under reduced pressure to give a crude product directly usable in the next step. LCMS (ESI, m / z): [M+H] + 344.0.

[0479] Step 6: N-(1-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl) Propionamide (A)

[0480] HATU (1.99 g, 5.23 mmol) and DIEA (1.35 g, 10.5 mmol) were added to a stirred mixture of 2-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-propamidoacetic acid (0.90 g, 2.62 mmol) and 1-methylpiperazine (0.79 g, 7.84 mmol) in DMF (10 mL) at room temperature under N2. After stirring for 16 hours, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give intermediate A (430 mg). LCMS (ESI, m / z): [M+H] + 426.3.

[0481] Intermediates B and C

[0482] (R)-N-(1-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propyl Amide (B) and (S)-N-(1-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propyl Amide (C)

[0483]

[0484] The racemic N-(1-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propionamide (intermediate A, 180 mg, 0.423 mmol) was purified by SFC under the following conditions (CHIRAL ART Cellulose-SA column, NH4OH) to give two separate enantiomers, intermediate B (peak 1) and intermediate C (peak 2). Intermediate B (peak 1): LCMS (ESI, m / z): [M+H] + 426.1. Intermediate C (peak 2): LCMS (ESI, m / z): [M+H] + 426.1.

[0485] Intermediate D

[0486] 2-(4-bromo-3-fluorophenyl)-2-methylpropionitrile (D)

[0487]

[0488] Under N2 at 0 °C, NaH (mineral oil containing 60% dispersion, 0.93 g, 23.4 mmol) was added dropwise to a stirred solution of 2-(4-bromo-3-fluorophenyl)acetonitrile (2.00 g, 9.34 mmol) in DMF (20 mL). After stirring at 0 °C for 1 h, CH3I (3.32 g, 23.4 mmol) was added dropwise. After stirring for another 1 h, the mixture was quenched with saturated NH4Cl (aqueous solution) at 0 °C and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to give intermediate D (1.00 g). LCMS (ESI, m / z): [M+H] + 242.1.

[0489] Intermediate E

[0490] N-(3-(4-bromo-3-fluorophenyl)-3-methyl-1-(4-methylpiperazin-1-yl)-1-oxobut-2-yl)propionamide （E）

[0491]

[0492] Intermediate E is synthesized from D following a synthetic sequence similar to that used in synthesis A. LCMS (ESI, m / z): [M+H] + 428.1.

[0493] intermediate F

[0494] (S)-N-(2-amino-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide （F）

[0495]

[0496] Step 1: (S)-(2-amino-1-(4,4-difluorocyclohexyl)-2-oxoethyl) tert-butyl carbamate (F-1)

[0497] DIEA (330 mg, 2.6 mmol) and NH4Cl (32.8 mg, 0.61 mmol) were added to a stirred mixture of (S)-2-((tert-butoxycarbonyl)amino)-2-(4,4-difluorocyclohexyl)acetic acid (150 mg, 0.51 mmol) and HATU (292 mg, 0.77 mmol) in DMF (1 mL) at room temperature under N2. After stirring for 16 hours, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude product directly for the next step. LCMS (ESI, m / z): [M+H-56] +237.2.

[0498] Step 2: (S)-2-amino-2-(4,4-difluorocyclohexyl)acetamide hydrochloride (F-2)

[0499] At room temperature, HCl solution (4 M in 1,4-dioxane, 1.20 mL) was added to a stirred mixture of (S)-(2-amino-1-(4,4-difluorocyclohexyl)-2-oxoethyl)carbamate (140 mg, 0.48 mmol) in 1,4-dioxane (0.2 mL). After stirring for 1 hour, the mixture was concentrated under reduced pressure to give a crude product as an HCl salt, which can be used directly in the next step. LCMS (ESI, m / z): [M+H] + 193.3.

[0500] Step 3: (S)-N-(2-amino-1-(4,4-difluorocyclohexyl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5- Formamide (F)

[0501] HATU (325 mg, 0.86 mmol) was added to a stirred mixture of (S)-2-amino-2-(4,4-difluorocyclohexyl)acetamide hydrochloride (130 mg, 0.57 mmol), 2-ethylpyrazol-3-carboxylic acid (87.8 mg, 0.63 mmol), and DIEA (221 mg, 1.7 mmol) in DMF (1.3 mL) at room temperature. After stirring for 2 hours, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EtOAc = 1:10) to give intermediate F (100 mg). LCMS (ESI, m / z): [M+H] + 315.3.

[0502] Synthesize the intermediates in the table below using conditions similar to those for intermediate F.

[0503]

[0504] Intermediate J

[0505] (R)-2-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-((tert-butoxycarbonyl)amino)acetic acid (J)

[0506]

[0507] Step 1: (R)-N-((1-(4-bromo-3-fluorophenyl)cyclopropyl)methylene)-2-methylpropane-2-sulfinamide （J-1）

[0508] At room temperature under N2, pyridinium p-toluenesulfonate (1.5 g, 5.9 mmol) and CuSO4 (23.6 g, 148 mmol) were added fractionally to a stirred solution of 1-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxaldehyde (9.0 g, 37 mmol) and (R)-2-methylpropane-2-sulfinamide (5.8 g, 48 mmol) in DCM (90 mL). After stirring for 16 hours, the mixture was filtered. The filtrate was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (3:1) to give (R)-N-((1-(4-bromo-3-fluorophenyl)cyclopropyl)methylene)-2-methylpropane-2-sulfinamide (12 g). LCMS (ESI, m / z): [M+H] + 346.1.

[0509] Step 2: (R)-N-((R)-(1-(4-bromo-3-fluorophenyl)cyclopropyl)(cyano)methyl)-2-methylpropane-2-imide sulfonamide (J-2) and (R)-N-((S)-(1-(4-bromo-3-fluorophenyl)cyclopropyl)(cyano)methyl)-2-methylpropane-2-imide Sulfonamide (J-2-B)

[0510] TMSCN (3.2 g, 32 mmol) was added dropwise to a stirred mixture of (R)-N-((1-(4-bromo-3-fluorophenyl)cyclopropyl)methylene)-2-methylpropane-2-sulfinamide (10.0 g, 29 mmol) and CsF (4.8 g, 32 mmol) in THF (100 mL) at -50 °C under N2. After stirring at room temperature for 16 h, the mixture was treated with saturated NH4Cl solution and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give the mixture. The diastereomer mixture was separated by preparative achiral HPLC under the following conditions (column: DAICEL DCpak P4VP 5*25 cm, 5 µm; mobile phase A: CO2, mobile phase B: MeOH (1%-2 M-NH3-MeOH); flow rate: 140 mL / min; gradient: isocratic 26% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm) to obtain peak 1 of (R)-N-((S)-(1-(4-bromo-3-fluorophenyl)cyclopropyl)(cyano)methyl)-2-methylpropane-2-sulfinamide (J-2-B, 2.6 g) and peak 2 of (R)-N-((R)-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-(cyano)methyl)-2-methylpropane-2-sulfinamide (J-2, 5.7 g). LCMS (ESI, m / z): [M+H] + 373.1.

[0511] Step 3: (R)-2-amino-2-(1-(4-bromo-3-fluorophenyl)cyclopropyl)acetic acid hydrochloride (J-3)

[0512] A solution of (R)-N-((R)-(1-(4-bromo-3-fluorophenyl)cyclopropyl)(cyano)methyl)-2-methylpropane-2-sulfinamide (4.4 g, 12 mmol) in concentrated hydrochloric acid (40 mL) was stirred at 100 °C for 16 hours under N2. The mixture was concentrated under reduced pressure to give (R)-2-amino-2-(1-(4-bromo-3-fluorophenyl)cyclopropyl)acetic acid (4.2 g) as an HCl salt. LCMS (ESI, m / z): [M+H] + 288.1.

[0513] Step 4: (R)-2-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-((tert-butoxycarbonyl)amino)acetic acid (J)

[0514] Di-tert-butyl dicarbonate (4.7 g, 21 mmol) was added dropwise to a stirred solution of (R)-2-amino-2-(1-(4-bromo-3-fluorophenyl)cyclopropyl)acetic acid hydrochloride (4.2 g, 13 mmol) and DIEA (7.5 g, 58 mmol) in ACN (42 mL). After stirring at room temperature for 1 hour, the mixture was purified by reversed-phase column chromatography under the following conditions (column: WelFlash™ C18-I, 20–40 μm, 330 g; eluent A: water; eluent B: ACN; gradient: 25%–45% B over 25 minutes; flow rate: 60 mL / min; detector: 220 / 254 nm) to give intermediate J (3.3 g). LCMS (ESI, m / z): [M+H-56] + 332.2.

[0515] intermediate K

[0516] 1-(4-Bromo-3-fluorophenyl)cyclobutane-1-carboxaldehyde (K)

[0517]

[0518] Intermediate K was prepared from 2-(4-bromo-3-fluorophenyl)acetonitrile under conditions similar to those used in the synthesis of intermediate A-2. 1 HNMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 7.56-7.52 (m, 1H), 6.94-6.91 (m, 1H), 6.83-6.80 (m, 1H), 2.76-2.70 (m, 2H), 2.41-2.34 (m, 2H), 2.10-1.90 (m, 2H).

[0519] intermediate L

[0520] (R)-2-(1-(4-bromo-3-fluorophenyl)cyclobutyl)-2-((tert-butoxycarbonyl)amino)acetic acid (L)

[0521]

[0522] Intermediate L was synthesized from K under conditions similar to those for B substitution synthesis. LCMS (ESI, m / z): [M+H] + 402.1.

[0523] intermediate M

[0524] (R)-2-((R)-1-(4-bromo-3-fluorophenyl)-2,2-difluorocyclopropyl)-2-((tert-butoxycarbonyl)amino)ethyl Acid (M)

[0525]

[0526]

[0527] Step 1: Ethyl 2-(4-bromo-3-fluorophenyl)acrylate (M-1)

[0528] A mixture of ethyl 2-(4-bromo-3-fluorophenyl)acrylate (2.0 g, 7.7 mmol), paraformaldehyde (700 mg, 23.1 mmol), K₂CO₃ (3.2 g, 23 mmol), and TBAI (129 mg, 0.35 mmol) in toluene (25 mL) was stirred at 60 °C for 1 hour. The resulting mixture was filtered, and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to give ethyl 2-(4-bromo-3-fluorophenyl)acrylate (1.1 g). GCMS m / z 271.9 [M].

[0529] Step 2: Ethyl 1-(4-bromo-3-fluorophenyl)-2,2-difluorocyclopropane-1-carboxylate (M-2)

[0530] A mixture of ethyl 2-(4-bromo-3-fluorophenyl)acrylate (500 mg, 1.8 mmol) and NaI (82 mg, 0.55 mmol) in THF (5 mL) was stirred at 65 °C for 10 min under N2. TMSCF3 (781 mg, 5.5 mmol) was added dropwise. After stirring at 65 °C for another 8 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (99:1) to give ethyl 1-(4-bromo-3-fluorophenyl)-2,2-difluorocyclopropane-1-carboxylate (200 mg). GCMS m / z 322.1 [M].

[0531] Step 3: (1-(4-bromo-3-fluorophenyl)-2,2-difluorocyclopropyl)methanol (M-3)

[0532] Under N2 at 0 °C, LiAlH4 (2 M in THF, 1.86 mmol, 0.93 mL) was added dropwise to a mixture of ethyl 1-(4-bromo-3-fluorophenyl)-2,2-difluorocyclopropane-1-carboxylate (200 mg, 0.62 mmol) in THF (2 mL). After stirring for 2 h, the mixture was quenched with water and an aqueous solution of NaOH (15% solution), diluted with EtOAc and treated with MgSO4. The mixture was filtered and the filtrate was concentrated under reduced pressure to give (1-(4-bromo-3-fluorophenyl)-2,2-difluorocyclopropyl)methanol (170 mg). GCMS m / z 279.9 [M].

[0533] Step 4: 1-(4-bromo-3-fluorophenyl)-2,2-difluorocyclopropane-1-carboxaldehyde (M-4)

[0534] A mixture of (1-(4-bromo-3-fluorophenyl)-2,2-difluorocyclopropyl)methanol (200 mg, 0.71 mmol) and DMP (513 mg, 1.2 mmol) in DCM (10 mL) was stirred at room temperature for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 1-(4-bromo-3-fluorophenyl)-2,2-difluorocyclopropane-1-carboxaldehyde (130 mg). GCMS m / z 278.0 [M].

[0535] Step 5: (R)-N-((1-(4-bromo-3-fluorophenyl)-2,2-difluorocyclopropyl)methylene)-2-methylpropane-2- sulfinamide (M-5)

[0536] Ti(OEt)4 (29.4 g, 0.13 mol) was added dropwise to a mixture of 1-(4-bromo-3-fluorophenyl)-2,2-difluorocyclopropane-1-carboxaldehyde (9 g, 32 mmol) and (R)-2-methylpropane-2-sulfinamide (4.3 g, 36 mmol) in DCM (90 mL) at room temperature under N2. After stirring under reflux for 1 h, the mixture was treated with water, filtered through a diatomaceous earth pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (8:1) to give (R)-N-((1-(4-bromo-3-fluorophenyl)-2,2-difluorocyclopropyl)methylene)-2-methylpropane-2-sulfinamide (7.6 g). LCMS (ESI, m / z): [M+H] + 382.4.

[0537] Step 6: (R)-N-((R)-((R)-1-(4-bromo-3-fluorophenyl)-2,2-difluorocyclopropyl)(cyano)methyl)-2- Methylpropane-2-sulfinamide (M-6) and (R)-N-((R)-((S)-1-(4-bromo-3-fluorophenyl)-2,2-difluorocyclopropyl) (cyano)methyl)-2-methylpropane-2-sulfinamide (M-6-B)

[0538] At -50 °C, TMSCN (0.63 g, 6.12 mmol) was added dropwise to a mixture of (R)-N-((1-(4-bromo-3-fluorophenyl)-2,2-difluorocyclopropyl)methylene)-2-methylpropane-2-sulfinamide (1.8 g, 4.7 mmol) and CsF (0.95 g, 6.3 mmol) in THF (20 mL). After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to give the product mixture. The diastereomer mixture was separated by a preparative achiral SFC (column: DAICEL DCpak P4VP 3*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH (1% 2M NH3-MeOH); flow rate: 65 mL / min; gradient (B%): isocratic 28% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm) to obtain peak 1, which represents a pair of diastereomers, and peak 2, which represents a second pair of diastereomers. Peak 2 was passed through preparative chiral HPLC (column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2 M NH3-MeOH), mobile phase B: MeOH:DCM=1:1; flow rate: 20 mL / min; gradient (B%): isocratic 20%B; wavelength: 254 / 220 nm) to obtain peak 1 provisionally assigned as (R)-N-((R)-((R)-1-(4-bromo-3-fluorophenyl)-2,2-difluorocyclopropyl)-(cyano)methyl)-2-methylpropane-2-sulfinamide and peak 2 provisionally assigned as (R)-N-((R)-((S)-1-(4-bromo-3-fluorophenyl)-2,2-difluorocyclopropyl)(cyano)-methyl)-2-methylpropane-2-sulfinamide). LCMS (ESI, m / z): [M+H] + 411.2.

[0539] Under conditions similar to the substitution synthesis of intermediate B, intermediate M was synthesized from intermediate M-6 via steps 7 and 8. LCMS (ESI, m / z): [MH] - 424.0.

[0540] intermediate N

[0541] 1-(methyl-d3)-1H-pyrazole-5-carboxylic acid (N)

[0542]

[0543] Step 1: 1-(methyl-d3)-1H-pyrazole-5-carboxylic acid ethyl ester (N-1)

[0544] A mixture of ethyl 1H-pyrazole-5-carboxylate (8.0 g, 57 mmol), iodomethane-d3 (9.9 g, 69 mmol), and K2CO3 (15.8 g, 114 mmol) in DMF (80 mL) was stirred at room temperature under N2 for 4 hours. The mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to give ethyl 1-(methyl-d3)-1H-pyrazole-5-carboxylate (4 g). LCMS (ESI, m / z): [M+H] + 158.1.

[0545] Step 2: 1-(methyl-d3)-1H-pyrazole-5-carboxylic acid (N)

[0546] Ethyl 1-(methyl-d3)-1H-pyrazole-5-carboxylate (400 mg, 2.5 mmol) and LiOH·H2O (320 mg, 7.6 mmol) were stirred in a mixture of THF (4 mL) and H2O (4 mL) at room temperature for 2 hours. After removing most of the THF under reduced pressure, the residue was acidified to pH 2–3 with HCl solution (3 M in water) and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give intermediate N (300 mg). LCMS (ESI, m / z): [M+H] + 130.1.

[0547] Under conditions similar to those used in the synthesis of N, intermediate O in the table below was synthesized from ethyl 1H-pyrazole-5-carboxylate.

[0548]

[0549] intermediate P

[0550] (R)-1-(1-(3,3-difluorocyclobutyl)ethyl)-1H-pyrazole-5-carboxylic acid (P)

[0551]

[0552] Step 1: 1-(1-(3,3-difluorocyclobutyl)ethyl)-1H-pyrazole-5-carboxylic acid ethyl ester (P-1)

[0553] DIAD (3.1 g, 15 mmol) was added dropwise to a mixture of 1-(3,3-difluorocyclobutyl)ethyl-1-ol (700 mg, 5.1 mmol), PPh3 (4.0 g, 15 mmol), and ethyl 1H-pyrazole-5-carboxylate (793 mg, 5.7 mmol) in THF (2 mL) at room temperature under N2. After stirring for 4 hours, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (12:1) to give ethyl 1-(1-(3,3-difluorocyclobutyl)ethyl)-1H-pyrazole-5-carboxylate (780 mg). LCMS (ESI, m / z): [M+H] + 259.1.

[0554] Step 2: 1-(1-(3,3-difluorocyclobutyl)ethyl)-1H-pyrazole-5-carboxylic acid (P-2)

[0555] Ethyl 1-(1-(3,3-difluorocyclobutyl)ethyl)-1H-pyrazole-5-carboxylic acid (780 mg, 3.0 mmol) and LiOH (362 mg, 15.1 mmol) were stirred in THF (7 mL) and H₂O (7 mL) at room temperature for 4 hours. The mixture was acidified to pH 4–5 with aqueous HCl (1 M) and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 1-(1-(3,3-difluorocyclobutyl)ethyl)-1H-pyrazole-5-carboxylic acid. LCMS (ESI, m / z): [M+H] + 231.1.

[0556] Step 3: (R)-1-(1-(3,3-difluorocyclobutyl)ethyl)-1H-pyrazole-5-carboxylic acid (P)

[0557] Intermediate P-2 was resolved by preparative chiral HPLC under the following conditions (column: CHIRAL ART Cellulose-SZ 3*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH (0.1%-DEA); flow rate: 75 mL / min; gradient (B%): isocratic 10%B; temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm) to obtain peak 1 arbitrarily designated as intermediate P and peak 2 arbitrarily designated as PB. LCMS (ESI, m / z): [M+H] + 231.1

[0558] The intermediates listed in the table below were synthesized from 1H-pyrazole-5-carboxylic acid ethyl ester under conditions similar to those of the P-2 synthesis.

[0559]

[0560] intermediate U

[0561] (S)-2-((tert-butoxycarbonyl)amino)-2-((S)-3,3-difluorocyclohexyl)acetic acid (U)

[0562]

[0563] Step 1: (S)-2-((diphenylmethylene)amino)-2-((S)-3-oxocyclohexyl)tert-butyl acetate (U-1)

[0564] Reference: Chinchilla, R. et al., ARKIVOC, 2005, 6, 222-232.

[0565] Under N2 at -78°C, cyclohexyl-2-en-1-one (5.2 g, 54 mmol) was added dropwise over 15 minutes to a stirred mixture of 2-((diphenylmethylene)amino)acetic acid tert-butyl ester (5.0 g, 17 mmol), cesium hydroxide (28.4 g, 169 mmol), and (1S,2S,4S,5R)-2-((R)-(allyloxy)(quinolin-4-yl)methyl)-1-(anthracite-9-ylmethyl)-5-vinylquinine cyclo-1-bromium (CAS: 200132-54-3, 1.1 g, 1.7 mmol) in DCM (70 mL). After stirring at -78°C for 30 minutes and then at -60°C for 6 hours, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to give (S)-2-((diphenylmethylene)amino)-2-((S)-3-oxocyclohexyl)acetate tert-butyl ester (3.5 g). LCMS (ESI, m / z): [M+H] + 392.3.

[0566] Step 2: (S)-2-((S)-3,3-difluorocyclohexyl)-2-((diphenylmethylene)amino)tert-butyl acetate (U- 2）

[0567] A solution of (S)-2-((diphenylmethylene)amino)-2-((S)-3-oxocyclohexyl)acetate tert-butyl ester (2.2 g, 5.6 mmol) and BAST (11 mL, 56 mmol) in a DCE (20 mL) was stirred at 0 °C under N2 for 30 min, followed by stirring at 70 °C for 16 h. The mixture was quenched with saturated NaHCO3 solution at 0 °C and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column: C18 silica gel, 90 g; mobile phase: water containing ACN (10 mmol / L NH4HCO3); flow rate: 60 mL / min, 0% to 100% gradient over 40 minutes) to give (S)-2-((S)-3,3-difluorocyclohexyl)-2-((diphenylmethylene)amino)acetic acid tert-butyl ester (1.4 g). LCMS (ESI, m / z): [M+H) + 414.2.

[0568] Step 3: (S)-2-amino-2-((S)-3,3-difluorocyclohexyl)acetic acid hydrochloride (U-3)

[0569] A solution of (S)-2-((S)-3,3-difluorocyclohexyl)-2-((diphenylmethylene)amino)-tert-butyl acetate (1.1 g, 2.7 mmol) in THF (2 mL) and HCl aqueous solution (6 M, 20 mL) was stirred at room temperature for 20 hours and concentrated under reduced pressure. The residue was washed with DCM to give (S)-2-amino-2-((S)-3,3-difluorocyclohexyl)acetic acid HCl salt (0.8 g). LCMS (ESI, m / z): [M+H] + 194.1.

[0570] Step 4: (S)-2-((tert-butoxycarbonyl)amino)-2-((S)-3,3-difluorocyclohexyl)acetic acid (U)

[0571] At 0 °C, Boc₂O (1.4 g, 6.2 mmol) was added dropwise to a solution of (S)-2-amino-2-((S)-3,3-difluorocyclohexyl)acetate hydrochloride (0.8 g, 3.5 mmol) and DIEA (22 mL, 12 mmol) in ACN (10 mL). After stirring at room temperature for 1 hour, the mixture was purified by reversed-phase rapid chromatography under the following conditions (column: C18 silica gel, 90 g; mobile phase: deionized water containing ACN; flow rate: 60 mL / min, 0% to 30% gradient over 40 minutes) to give intermediate U (0.75 g). LCMS (ESI, m / z): [M+H-56] + 237.9.

[0572] intermediate V

[0573] (2S)-2-((tert-butoxycarbonyl)amino)-2-((5S)-1,1-difluorospiro[2.5]oct-5-yl)acetic acid (V)

[0574]

[0575] Step 1: (S)-2-amino-2-((S)-3-oxocyclohexyl)tert-butyl acetate (V-1)

[0576] A solution of (S)-2-((diphenylmethylene)amino)-2-((S)-3-oxocyclohexyl)acetate tert-butyl ester (9.0 g, 23 mmol) in THF (90 mL) and HCl aqueous solution (4 M, 90 mL) was stirred at room temperature for 2 hours. After completion, the mixture was extracted with n-heptane to remove impurities. The aqueous layer was neutralized to pH = 6 with saturated NaHCO3 solution and concentrated under reduced pressure to give (S)-2-amino-2-((S)-3-oxocyclohexyl)acetate tert-butyl ester. LCMS (ESI, m / z): [M+H] + 228.1.

[0577] Step 2: (S)-2-((tert-butoxycarbonyl)amino)-2-((S)-3-oxocyclohexyl)tert-butyl acetate (V-2)

[0578] A solution of (S)-2-amino-2-((S)-3-oxocyclohexyl)acetate tert-butyl ester (10 g, 44 mmol), (Boc)₂O (22.1 g, 100 mmol), NaHCO₃ (18.5 g, 220 mmol), and NaCl (25.7 g, 440 mmol) in CHCl₃ was stirred at 60 °C for 5 hours. After stirring, the mixture was treated with water and extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1 to 10:3) to give (S)-2-((tert-butoxycarbonyl)amino)-2-((S)-3-oxocyclohexyl)acetate tert-butyl ester (1 g). LCMS (ESI, m / z): [M+H-56-56] + 216.1.

[0579] Step 3: (S)-2-((tert-butoxycarbonyl)amino)-2-((S)-3-methylenecyclohexyl)tert-butyl acetate (V- 3）

[0580] TMSCHN2 (2 M in hexane, 3.7 mL, 7.4 mmol) was added dropwise to a mixture of (S)-2-((tert-butoxycarbonyl)amino)-2-((S)-3-oxocyclohexyl)acetate tert-butyl ester (1.0 g, 3.1 mmol), RhCl(PPh3)3 (10 mg, 0.01 mmol), and PPh3 (880 mg, 3.4 mmol) in 1,4-dioxane (20 mL) and isopropanol (3.5 mL) at 60 °C under N2. After stirring at 60 °C for 16 h, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to give (S)-2-((tert-butoxycarbonyl)amino)-2-((S)-3-methylenecyclohexyl)acetate tert-butyl ester (550 mg). LCMS (ESI, m / z): [M+H-56-56] + 214.1.

[0581] Step 4: (2S)-2-amino-2-((5S)-1,1-difluorospiro[2.5]oct-5-yl)tert-butyl acetate (V-4)

[0582] A solution of (S)-2-((tert-butoxycarbonyl)amino)-2-((S)-3-methylenecyclohexyl)acetate tert-butyl (500 mg, 1.54 mmol), (bromodifluoromethyl)trimethylsilane (1.18 g, 5.82 mmol), and TBAB (19 mg, 0.058 mmol) in toluene (6 mL) was stirred at 110 °C for 0.5 h under N2. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column: C18 silica gel, 90 g; mobile phase: water containing MeCN (0.05% NH4HCO3), 60% to 80% gradient over 30 min) to give (2S)-2-amino-2-((5S)-1,1-difluorospiro[2.5]oct-5-yl)acetate tert-butyl (220 mg). LCMS (ESI, m / z): [M+H] + 275.9.

[0583] Step 5: (2S)-2-amino-2-((5S)-1,1-difluorospiro[2.5]oct-5-yl)acetic acid (V-5)

[0584] A solution of (2S)-2-amino-2-((5S)-1,1-difluorospiro[2.5]oct-5-yl)acetic acid tert-butyl ester (210 mg, 0.763 mmol) and TFA (0.5 mL) in DCM (2 mL) was stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure to give (2S)-2-amino-2-((5S)-1,1-difluorospiro[2.5]oct-5-yl)acetic acid. LCMS (ESI, m / z): [M+H] + 220.1.

[0585] Step 6: (2S)-2-((tert-butoxycarbonyl)amino)-2-((5S)-1,1-difluorospiro[2.5]oct-5-yl)acetic acid （V）

[0586] A solution of (2S)-2-amino-2-((5S)-1,1-difluorospiro[2.5]oct-5-yl)acetic acid (165 mg, 0.75 mmol), (Boc)₂O (254 mg, 1.16 mmol), and DIEA (251 mg, 1.94 mmol) in ACN (0.5 mL) was stirred at room temperature for 6 hours. The mixture was purified by reversed-phase rapid chromatography under the following conditions (column: C18 silica gel, 48 g; mobile phase: water containing MeCN (0.05% NH₄HCO₃), 10% to 25% gradient over 10 minutes) to give intermediate V (40 mg). LCMS (ESI, m / z): [M+H] + 319.8.

[0587] intermediate W

[0588] (S)-2-(((benzyloxy)carbonyl)amino)-2-((3R,5S)-1,1-difluorospiro[2.5]oct-5-yl)acetic acid (W)

[0589]

[0590] Step 1: (S)-2-((diphenylmethylene)amino)-2-((S)-3-methylenecyclohexyl)tert-butyl acetate (W- 1）

[0591] Intermediate W-1 was synthesized from U-1 under conditions similar to those used in the synthesis of V-3. LCMS (ESI, m / z): [M+H] + 390.3.

[0592] Step 2: (S)-2-amino-2-((S)-3-methylenecyclohexyl)tert-butyl acetate (W-2)

[0593] Intermediate W-2 was synthesized from W-1 under conditions similar to those of V-1 synthesis. LCMS (ESI, m / z): [M+H] + 226.1.

[0594] Step 3: (S)-2-(((benzyloxy)carbonyl)amino)-2-((S)-3-methylenecyclohexyl)tert-butyl acetate (W- 3）

[0595] At 0 °C, CbzCl (1.1 g, 6.5 mmol) was added dropwise to a stirred solution of (S)-2-amino-2-((S)-3-methylenecyclohexyl)acetate tert-butyl (1.0 g, 4.4 mmol) and TEA (2.0 g, 19.5 mmol) in DCM (0.5 mL). After stirring at room temperature for 16 h, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column: C18 silica gel, 90 g; mobile phase: water containing MeCN (0.05% NH4HCO3), 40% to 80% gradient over 60 min) to give (S)-2-(((benzyloxy)carbonyl)amino)-2-((S)-3-methylenecyclohexyl)acetate tert-butyl (1.5 g). LCMS (ESI, m / z): [M+H-56] + 304.0.

[0596] Step 4: (S)-2-(((benzyloxy)carbonyl)amino)-2-((3R,5S)-1,1-difluorospiro[2.5]oct-5-yl)ethyl tert-butyl ester (W-4) and (S)-2-(((benzyloxy)carbonyl)amino)-2-((3S,5S)-1,1-difluorospiro[2.5]oct-5-yl) tert-butyl acetate (W-4-B)

[0597] A mixture of (S)-2-(((benzyloxy)carbonyl)amino)-2-((S)-3-methylenecyclohexyl)acetate tert-butyl (1.5 g, 4.2 mmol), (bromodifluoromethyl)trimethylsilane (2.5 g, 12.3 mmol), and TBAB (40 mg, 0.12 mmol) in toluene (5 mL) was stirred at 110 °C for 1 h under N2. The mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column: C18 silica gel, 90 g; mobile phase: water containing MeCN (0.05% NH4HCO3), 50% to 70% gradient over 30 min) to give a mixture of diastereomers. The mixture was separated by SFC under the following conditions (column: CHIRALPAK IG 3*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH (1%-2M-NH3-MeOH); flow rate: 90 mL / min; gradient (B%): isocratic 12% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm) to obtain peak 1 tentatively assigned to (S)-2-(((benzyloxy)carbonyl)amino)-2-((3S,5S)-1,1-difluorospiro[2.5]octyl-5-yl)tert-butyl acetate (W-4-B) and peak 2 tentatively assigned to (S)-2-(((benzyloxy)carbonyl)amino)-2-((3R,5S)-1,1-difluorospiro[2.5]octyl-5-yl)tert-butyl acetate (W-4). LCMS (ESI, m / z): [M+H-56] + 354.1.

[0598] Step 5: (S)-2-(((benzyloxy)carbonyl)amino)-2-((3R,5S)-1,1-difluorospiro[2.5]oct-5-yl)ethyl Acid (W)

[0599] Intermediate W was synthesized from W-4 under conditions similar to those used in the synthesis of V-5. LCMS (ESI, m / z): [M+H] + 354.1.

[0600] Intermediate X

[0601] (S)-2-amino-2-((S)-spiro[2.5]oct-5-yl)acetonitrile (X)

[0602]

[0603] Step 1: Spiro[2.5]octane-5-carboxaldehyde (X-1)

[0604] Under N2 at -78°C, to bromo(methoxymethyl)triphenyl-l 5t-BuOK (1 M in THF, 230 mL, 230 mmol) was added dropwise to a solution of phosphine (79 g, 204 mmol) in THF (800 mL). After stirring at -78 °C for 2 h, spiro[2,5]oct-5-one (22 g, 177 mmol) was added dropwise. After stirring at room temperature for 16 h, an aqueous solution of HCl (6 M, 100 mL) was added. The mixture was stirred for 2 h, treated with water, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give spiro[2,5]octane-5-carboxaldehyde.

[0605] Step 2: (S)-4-methyl-N-(spiro[2.5]oct-5-methylene)benzenesulfinamide (X-2)

[0606] A mixture of spiro[2.5]octane-5-carboxaldehyde (20 g, 145 mmol), (S)-4-methylbenzenesulfinamide (22.5 g, 145 mmol), and Ti(OEt)4 (99.2 g, 435 mol) in DCM (200 mL) was refluxed and stirred under N2 for 4 hours. The mixture was treated with water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel rapid column chromatography, eluting with PE / EtOAc (5:1) to give (S)-4-methyl-N-(spiro[2.5]octane-5-methylene)benzenesulfinamide (20 g). LCMS (ESI, m / z): [M+H] + 276.1.

[0607] Step 3: (S)-N-((1S)-cyano(spiro[2.5]oct-5-yl)methyl)-4-methylbenzenesulfinamide (X-3)

[0608] TMSCN (23 g, 232 mmol) was added to a solution of (S)-4-methyl-N-(spiro[2.5]oct-5-methylene)benzenesulfinamide (20 g, 73 mmol), CsF (15.2 g, 100 mmol), and TMSCN in THF (10 mL) at -50 °C under N2. After stirring at room temperature for 16 hours, the mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (3:1) to give (S)-N-((1S)-cyano(spiro[2.5]oct-5-yl)methyl)-4-methylbenzenesulfinamide (20 g). LCMS (ESI, m / z): [M+H] + 303.1.

[0609] Step 4: (S)-N-((S)-cyano((S)-spiro[2.5]oct-5-yl)methyl)-4-methylbenzenesulfinamide (X-4) And (S)-N-((S)-cyano((R)-spiro[2.5]oct-5-yl)methyl)-4-methylbenzenesulfinamide (X-4-B)

[0610] (S)-N-((1S)-cyano(spiro[2.5]oct-5-yl)methyl)-4-methylbenzenesulfinamide was passed through an SFC under the following conditions (column: CHIRALPAK IG 5*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH (0.3% 7 M NH3-MEOH); flow rate: 180 mL / min; gradient (B%): isocratic 36% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm). The mixture was separated at nm to obtain peak 1 of a mixture of (S)-N-((S)-cyano((S)-spiro[2.5]oct-5-yl)methyl)-4-methylbenzenesulfinamide (X-4) and peak 2 of a mixture of the two minor isomers. Peak 1 was further separated by SFC under the following conditions (column: CHIRAL ARTCellulose-SZ 3*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH (0.3% 7 M NH3-MEOH); flow rate: 85 mL / min; gradient (B%): isocratic 14% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm) to obtain a first peak of (S)-N-((S)-cyano((S)-spiro[2.5]oct-5-yl)methyl)-4-methylbenzenesulfinamide (X-4) and a second peak of (S)-N-((S)-cyano((R)-spiro[2.5]oct-5-yl)methyl)-4-methylbenzenesulfinamide (X-4-B). LCMS (ESI, m / z): [M+H] + 303.1.

[0611] Step 5: (S)-2-amino-2-((S)-spiro[2.5]oct-5-yl)acetonitrile (X)

[0612] A solution of (S)-N-((S)-cyano((S)-spiro[2.5]oct-5-yl)methyl)-4-methylbenzene-sulfinamide (1 g, 3.31 mmol) and HCl (4 M in 1,4-dioxane, 1 mL) in MeOH (1 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, treated with water, and washed with Et2O to remove impurities. The aqueous layer was adjusted to pH 8-9 with saturated NaHCO3 and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give intermediate X (520 mg). LCMS (ESI, m / z): [M+H] + 165.1.

[0613] intermediate Y

[0614] (S)-2-amino-2-((S)-3,3-dimethylcyclohexyl)acetonitrile (Y)

[0615]

[0616] Under synthetic conditions similar to X-3, Y-1, a commercially available ketone synthesis intermediate, was synthesized from it.

[0617] Intermediate Y-1 was separated by SFC under the following conditions (system: Waters SFC 150, column name: DAICELCHIRALPAK® OD-10, column size: 25*250 mm 10 μm, mobile phase A: supercritical CO2, mobile phase B: MeOH (0.05% NH3·MeOH), A:B = 90:10, wavelength: 214 nm / 254 nm, flow rate: 60 mL / min, column temperature: room temperature) to obtain peak 1 of a mixture of (S)-N-((S)-cyano((S)-3,3-dimethylcyclohexyl)methyl)-4-methylbenzenesulfinamide (Y-2) and a minor isomer, and peak 2 of a mixture of (S)-N-((S)-cyano((R)-3,3-dimethylcyclohexyl)methyl)-4-methylbenzenesulfinamide (Y-2-B) and another minor isomer. Peak 1 was further separated by SFC under the following conditions (system: Waters SFC 150, column name: DAICEL CHIRALPAK® AS-10, column size: 25*250mm 10 μm, mobile phase A: supercritical CO2, mobile phase B: MeOH (0.05% NH3·MeOH), A:B = 80:20, wavelength: 214 nm / 254 nm, flow rate: 60 mL / min, column temperature: room temperature) to obtain the main peak of (S)-N-((S)-cyano((S)-3,3-dimethylcyclohexyl)methyl)-4-methylbenzenesulfinamide (Y-2). LCMS (ESI, m / z): [M+H] + 305.2.

[0618] Under synthesis conditions similar to those for X, intermediate Y is synthesized from Y-2. LCMS (ESI, m / z): [M+H] + 167.1.

[0619] Intermediate Z and BA

[0620] (S)-2-amino-2-((R)-4,4-difluorocycloheptyl)acetonitrile hydrochloride (Z) and (S)-2-amino-2-((S)-4, 4-Difluorocycloheptyl)acetonitrile hydrochloride (BA)

[0621]

[0622] Under conditions similar to those for the synthesis of intermediate X-3, intermediate Z-1 is synthesized from a commercially available ketone.

[0623] Intermediate Z-1 was purified by SFC under the following conditions (column: CHIRAL ART Amylose-C NEO 5*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH (1%-2 M-NH3-MeOH); flow rate: 140 mL / min; gradient: isocratic 28% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm) to obtain the first main peak tentatively assigned to (S)-N-((S)-cyano((R)-4,4-difluorocycloheptyl)methyl)-4-methylbenzenesulfinamide (Z-2) and the second main peak tentatively assigned to (S)-N-((S)-cyano((S)-4,4-difluorocycloheptyl)methyl)-4-methylbenzenesulfinamide (BA-2). LCMS (ESI, m / z): [M+H] + 327.1.

[0624] Under synthesis conditions similar to X, intermediate Z is synthesized from Z-2, and intermediate BA is synthesized from BA-2. LCMS(ESI, m / z): [M+H] + 189.1.

[0625] Intermediate BB and BC

[0626] (S)-2-amino-2-((R)-7,7-difluorospiro[2.5]oct-5-yl)acetonitrile (BB) and (S)-2-amino-2-((S)- 7,7-Difluorospiro[2.5]oct-5-yl)acetonitrile (BC)

[0627]

[0628]

[0629] Step 1: tert-butyl 3-methoxy-5-oxocyclohexyl-3-ene-1-carboxylate (BB-1)

[0630] Under nitrogen atmosphere at 0 °C, DMAP (12 g, 98.3 mmol) and Boc₂O (46 g, 210 mmol) were added in portions to a stirred mixture of 3-methoxy-5-oxocyclohexane-3-ene-1-carboxylic acid (12 g, 70.5 mmol) in t-BuOH (100 mL). After stirring at room temperature for 16 h, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to give tert-butyl 3-methoxy-5-oxocyclohexane-3-ene-1-carboxylic acid (16 g). LCMS (ESI, m / z): [M+H] + 227.1

[0631] Step 2: 7-oxospiro[2.5]octane-5-carboxylic acid tert-butyl ester (BB-2)

[0632] Tetraisopropoxide (8.2 g, 29 mmol) was added in portions to a stirred mixture of tert-butyl 3-methoxy-5-oxocyclohexyl-3-ene-1-carboxylate (15 g, 66 mmol) in diethyl ether (375 mL) at -10 °C under N2. After stirring for 10 min, ethyl magnesium bromide (3 M in diethyl ether, 75 mL, 225 mmol) was added in portions over 2 hours at -10 °C. After stirring for another 2 hours at room temperature, the mixture was quenched with saturated NH4Cl solution. The resulting mixture was filtered and extracted with diethyl ether. The combined organic layers were washed with water, dried over anhydrous Na2SO4, and filtered. The resulting filtrate was treated with TsOH (0.38 g, 2.2 mmol). After stirring for 16 hours at room temperature, the mixture was washed with saturated NaHCO3, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (5:1) to give tert-butyl 7-oxospiro[2.5]octane-5-carboxylate (2.5 g). 1 H NMR (400 MHz, CDCl3) δ 2.89-2.79 (m, 1H), 2.63-2.50 (m, 3H), 2.13-2.04 (m, 1H), 1.82-1.76 (m, 1H), 1.51-1.47 (m, 1H), 1.44 (s, 9H), 0.55-0.48 (m, 1H), 0.45-0.33 (m, 3H).

[0633] Step 3: tert-butyl 7,7-difluorospiro[2.5]octane-5-carboxylate (BB-3)

[0634] DAST (14.4 g, 89.3 mmol) was added dropwise to a solution of 7-oxospiro[2.5]octane-5-carboxylate (2.5 g, 11.2 mmol) in DCM (30 mL) at -78 °C under N2. After stirring at 50 °C for 16 h, the mixture was quenched with saturated NH4Cl and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to give 7,7-difluorospiro[2.5]octane-5-carboxylate (1.2 g). 1H NMR (400 MHz, CDCl3) δ 2.75-2.64 (m,1H), 2.44-2.31 (m, 1H), 2.21-2.04 (m, 1H), 1.92-1.73 (m, 2H), 1.49-1.46 (m,2H), 1.44 (s, 9H), 0.54-0.34 (m, 4H).

[0635] Step 4: 7,7-Difluorospiro[2.5]octane-5-carboxylic acid (BB-4)

[0636] Under conditions similar to those used in the synthesis of V-5, intermediate BB-4 was synthesized from BB-3.

[0637] Step 5: (7,7-Difluorospiro[2.5]oct-5-yl)methanol (BB-5)

[0638] A mixture of 7,7-difluorospiro[2.5]octane-5-carboxylic acid (1 g, 4.2 mmol) in a borane-tetrahydrofuran complex (1 M in THF, 10 mL) was stirred at 60 °C for 16 hours. The mixture was quenched with MeOH (20 mL) at 0 °C and concentrated under reduced pressure to give (7,7-difluorospiro[2.5]octane-5-yl)methanol.

[0639] Step 6: 7,7-Difluorospiro[2.5]octane-5-carboxaldehyde (BB-6)

[0640] Oxaloyl chloride (533 mg, 4.2 mmol) was added dropwise to a solution of DMSO (333 mg, 4.3 mmol) in DCM (20 mL) at -78 °C under N2. After stirring at -78 °C for 15 min, (7,7-difluorospiro[2.5]oct-5-yl)methanol (600 mg, 3.4 mmol) was added dropwise to a solution of DCM (10 mL) over 5 min. After stirring for another 1 h, Et3N (861 mg, 8.5 mmol) was added dropwise. The mixture was stirred at -78 °C for 30 min, treated with KH2PO4 (20% in H2O, 10 mL) and water (10 mL) and extracted with DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 7,7-difluorospiro[2.5]octane-5-carboxaldehyde.

[0641] Under synthesis conditions similar to those of X-3, intermediate BB-8 was synthesized from BB-6.

[0642] Intermediate BB-8 was separated by SFC under the following conditions (column: CHIRALPAK IG 3*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH (0.3% 7 M NH3-MeOH); flow rate: 80 mL / min; gradient: isocratic 14% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm) to obtain a first main peak of (S)-N-((S)-cyano((R)-7,7-difluorospiro[2.5]oct-5-yl)methyl)-4-methylbenzenesulfinamide (BB-9) and a second main peak of (S)-N-((S)-cyano((S)-7,7-difluorospiro[2.5]oct-5-yl)methyl)-4-methylbenzenesulfinamide (BC-9). LCMS (ESI, m / z): [M+H] + 339.1.

[0643] Under synthesis conditions similar to X, intermediate BB was synthesized from BB-9, and intermediate BC was synthesized from BC-9. LCMS (ESI, m / z): [M+H] + 201.1.

[0644] intermediate BD

[0645] (S)-2-amino-2-((S)-8,8-difluorospiro[2.5]oct-5-yl)acetonitrile (BD)

[0646]

[0647] Step 1: 12,12-Difluoro-6,9-dioxane ... 5 .3 3 Dodecane (BD-2)

[0648] Under conditions similar to those used in the synthesis of BB-3, intermediate (BD-2) was synthesized from BD-1 (Chemical Communications, 1998, 12, 1287-1288).

[0649] Step 2: 8,8-Difluorospiro[2.5]oct-5-one (BD-3)

[0650] 12,12-difluoro-6,9-dioxane-1,4-[2.1.4] 5 .3 3 A mixture of dodecane (1.3 g, 6.4 mmol) and TsOH (0.66 g, 3.8 mmol) in acetone (10 mL) and H2O (3 mL) was stirred at 60 °C for 16 hours. The mixture was concentrated under reduced pressure, treated with water, and extracted with EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 8,8-difluorospiro[2.5]oct-5-one (700 mg).

[0651] Under conditions similar to those for the synthesis of X-2, intermediate BD-5 was synthesized from BD-3 via steps 3 and 4.

[0652] Step 5: (S)-N-((1S)-cyano(8,8-difluorospiro[2.5]oct-5-yl)methyl)-4-methylbenzenesulfinamide (BD-6)

[0653] TMSCN (153 mg, 1.5 mmol) was added to a mixture of (S)-N-((8,8-difluorospiro[2.5]oct-5-yl)methylene)-4-methylbenzenesulfinamide (240 mg, 0.77 mmol) and Gd(OTf)3 (47 mg, 0.077 mmol) in DCM (2.4 mL) at 0 °C under N2. After stirring at room temperature for 4 hours, the mixture was treated with ice water and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to give (S)-N-((1S)-cyano(8,8-difluorospiro[2.5]oct-5-yl)methyl)-4-methylbenzenesulfinamide (150 mg). LCMS (ESI, m / z): [M+H] + 339.1.

[0654] Step 6: (S)-N-((S)-cyano((S)-8,8-difluorospiro[2.5]oct-5-yl)methyl)-4-methylbenzenesulfinyl Amine (BD-7) and (S)-N-((S)-cyano((R)-8,8-difluorospiro[2.5]oct-5-yl)methyl)-4-methylbenzenesulfinamide (BD-7-B)

[0655] Intermediate BD-6 was separated by preparative chiral HPLC under the following conditions (column: Chiral ART Cellulose-SA, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2 M NH3-MeOH), mobile phase B: EtOH:DCM = 1:1; flow rate: 20 mL / min; gradient (B%): isocratic 10% B; wavelength: 254 nm / 220 nm) to obtain a first main peak of (S)-N-((S)-cyano((S)-8,8-difluorospiro[2.5]oct-5-yl)methyl)-4-methylbenzenesulfinamide (BD-7) and a second main peak of (S)-N-((S)-cyano((R)-8,8-difluorospiro[2.5]oct-5-yl)methyl)-4-methylbenzenesulfinamide (BD-7-B). LCMS (ESI, m / z): [M+H] + 339.1. BD-7: 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 4.53 (d, J = 8.4 Hz, 1H), 4.02-3.99 (m, 1H), 2.49 (s, 3H), 2.28-2.19 (m, 1H), 2.11-1.64 (m, 5H), 1.23-1.16 (m, 1H), 1.12-1.06 (m, 1H), 0.77-0.71 (m, 1H), 0.51-0.38 (m, 2H). BD-7-B: 1 H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 4.54 (d, J = 8.0Hz, 1H), 4.05-4.00 (m, 1H), 2.47 (s, 3H), 2.28-2.17 (m, 1H), 2.13-2.01 (m,3H), 1.94-1.78 (m, 1H), 1.69-1.62 (m, 1H) 1.30-1.21 (m, 1H), 1.12-1.06 (m,1H), 0.79-0.72 (m, 1H), 0.50-0.38 (m, 2H).

[0656] Step 7: (S)-2-amino-2-((S)-8,8-difluorospiro[2.5]oct-5-yl)acetonitrile (BD)

[0657] Intermediate BD was synthesized from BD-7 under synthesis conditions similar to those of X. LCMS (ESI, m / z): [M+H] + 201.1.

[0658] Under conditions similar to those for synthesis X, the intermediates listed in the table below are synthesized from the corresponding ketones.

[0659]

[0660] Intermediate BI

[0661] (S)-2-amino-2-((S)-7-fluorospiro[trypanan-3,1'-cyclopropane]-4-yl)acetonitrile (BI)

[0662]

[0663] The intermediate BI-1 was synthesized according to “WO2022 / 007462, 2022, A1”.

[0664] Step 1: 7-Fluoro-4-(methoxymethylene)spiro[trypanan-3,1'-cyclopropane] (BI-2)

[0665] Under N2 at 0 °C, n-BuLi (2.5 M in n-hexane, 68 mL, 169 mmol) was added dropwise to a mixture of (methoxymethyl)triphenylphosphine chloride (58.1 g, 169 mmol) and THF (125 mL). After stirring for 1 hour, THF (125 mL) containing 7-fluorospiro[trypanan-3,1'-cyclopropane]-4-one (25.0 g, 130 mmol) was added dropwise. The mixture was stirred at 60 °C for 2 hours, treated with saturated NH4Cl and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (10:1) to give 7-fluoro-4-(methoxymethylene)spiro[trypanan-3,1'-cyclopropane] (30.0 g). For [M], GCMSm / z 220.1.

[0666] Step 2: 7-Fluorospiro[trypanan-3,1'-cyclopropane]-4-carboxaldehyde (BI-3)

[0667] At 0 °C, HCl (6 M in water, 125 mL) was added to a mixture of 7-fluoro-4-(methoxymethylene)spiro[trypanan-3,1'-cyclopropane] (25 g, 114 mmol) in THF (125 mL). After stirring at 60 °C for 3 h, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated NaHCO3 and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 7-fluorospiro[trypanan-3,1'-cyclopropane]-4-carboxaldehyde. For [M], GCMS m / z = 206.0.

[0668] Step 3: (S)-N-((7-fluorospiro[trypanan-3,1'-cyclopropane]-4-yl)methylene)-2-methylpropane-2-sulfinyl Amine (BI-4)

[0669] A mixture of 25.0 g (121 mmol) of 7-fluorospiro[trypanan-3,1'-cyclopropane]-4-carboxaldehyde, (S)-2-methylpropane-2-sulfinamide (14.7 g (121 mmol)) and Ti(OEt)4 (51 mL (242 mmol) in THF (250 mL) was stirred at 60 °C for 1 hour under N2. The mixture was treated with water / EtOAc, filtered, and the filtrate was extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (3:1) to give (S)-N-((7-fluorospiro[trypanan-3,1'-cyclopropane]-4-yl)methylene)-2-methylpropane-2-sulfinamide (18.0 g). LCMS (ESI, m / z): [M+H] + 310.1.

[0670] Step 4: (S)-N-((S)-cyano((S)-7-fluorospiro[3,1'-cyclopropane]-4-yl)methyl)-2-methylpropane Alkyl-2-sulfinamide (BI-5)

[0671] TMSCN (14 mL, 110 mmol) was added to a mixture of (S)-N-((7-fluorospiro[tryptan-3,1'-cyclopropane]-4-yl)methylene)-2-methylpropane-2-sulfinamide (17.0 g, 55 mmol) and CsF (16.7 g, 110 mmol) in MTBE (85 mL) at 0 °C under N2. After stirring at room temperature for 16 h, the precipitate was collected by filtration and washed with MTBE. The solid was treated with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by grinding with MTBE to give chiral pure (S)-N-((S)-cyano((S)-7-fluorospiro[tryptan-3,1'-cyclopropane]-4-yl)methyl)-2-methylpropane-2-sulfinamide (6.0 g). LCMS (ESI, m / z): [M+H] + 337.0.

[0672] Step 5: (S)-2-amino-2-((S)-7-fluorospiro[3,1'-cyclopropane]-4-yl)acetonitrile hydrochloride (BI)

[0673] A mixture of (S)-N-((S)-cyano((S)-7-fluorospiro[trypanan-3,1'-cyclopropane]-4-yl)methyl)-2-methylpropane-2-sulfinamide (485 mg, 1.43 mmol) and HCl (4.0 M in 1,4-dioxane, 1.6 mL) in methanol (4.8 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. The residue was purified by milling with MTBE to give intermediate BI (400 mg) as an HCl salt. LCMS (ESI, m / z): [M+H] + 233.1.

[0674] intermediate BJ

[0675] (S)-2-amino-2-((S)-6,7-difluorospiro[trypanan-3,1'-cyclopropane]-4-yl)acetonitrile (BJ)

[0676]

[0677] Intermediate BJ was synthesized as an HCl salt under conditions similar to those used in the synthesis of intermediate BI. LCMS (ESI, m / z): [M+H] + 251.0.

[0678] intermediates BK and BL

[0679] (S)-2-amino-2-((S)-7-fluorochrome-4-yl)acetonitrile hydrochloride (BK) and (S)-2-amino-2-((R)-7- Fluorochrome-4-yl)acetonitrile hydrochloride (BL)

[0680]

[0681] Under synthetic conditions similar to X-3, the commercially available ketone synthesis intermediate BK-1 was synthesized.

[0682] Intermediate BK-1 was separated by preparative achiral SFC under the following conditions (column: GreenSep Basic 3 * 15 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH (1% - 2 M-NH3-MeOH); flow rate: 65 mL / min; gradient: isocratic 18% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm) to obtain a main peak of a mixture of BK-2 and BL-2. The mixture was separated by SFC under the following conditions (column: (S, S)-WHELK-O1 3 * 25 cm, 5 μm; mobile phase A: CO2, mobile phase B: ACN:MeOH = 1:1 (1% 2 M NH3-MEOH); flow rate: 90 mL / min; gradient: isocratic 14% B; column temperature (°C): 35; back pressure (bar): 100; wavelength: 220 nm) to obtain a first peak of (S)-N-((S)-cyano((S)-7-fluorochromo-4-yl)methyl)-2-methylpropane-2-sulfinamide (BK-2) and a second peak of (S)-N-((S)-cyano((R)-7-fluorochromo-4-yl)methyl)-2-methylpropane-2-sulfinamide (BL-2). LCMS (ESI, m / z): [M+H] + 311.1.

[0683] Under synthesis conditions similar to BI, intermediate BK was synthesized from BK-2, and intermediate BL was synthesized from BL-2. LCMS (ESI, m / z): [M+H] + 207.3.

[0684] Synthesize the intermediates in the table below using conditions similar to those for intermediate F.

[0685]

[0686]

[0687] intermediates CG and CH

[0688] N-((S)-2-amino-1-((3R,5S)-1,1-difluorospiro[2.5]oct-5-yl)-2-oxoethyl)-1-ethyl- 1H-pyrazole-5-carboxamide (CG) and N-((S)-2-amino-1-((3S,5S)-1,1-difluorospiro[2.5]oct-5-yl)-2-oxo (Ethyl)-1-Ethyl-1H-pyrazole-5-carboxamide (CH)

[0689]

[0690] Intermediate CG-1 was synthesized from V under conditions similar to those of the F synthesis. Intermediate CG-1 was then subjected to preparative chiral HPLC under the following conditions (column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2 MNH3-MeOH), mobile phase B: EtOH:DCM = 1:1; flow rate: 20... Separation was performed at a concentration of mL / min; gradient (B%): isocratic 15; wavelength: 254 / 220 nm to obtain peak 1 tentatively assigned to N-((S)-2-amino-1-((3S,5S)-1,1-difluorospiro[2.5]oct-5-yl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (CH) and peak 2 tentatively assigned to N-((S)-2-amino-1-((3R,5S)-1,1-difluorospiro[2.5]oct-5-yl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (CG). LCMS (ESI, m / z): [M+H] + 341.1.

[0691] Intermediate CG (alternative synthesis)

[0692] N-((S)-2-amino-1-((3R,5S)-1,1-difluorospiro[2.5]oct-5-yl)-2-oxoethyl)-1-ethyl- 1H-pyrazole-5-carboxamide (CG)

[0693]

[0694] Under conditions similar to those of the F-synthesis, intermediate CG was synthesized from intermediate W via amide coupling, Cbz deprotection, and amide coupling. LCMS (ESI, m / z): [M+H] + 341.1.

[0695] intermediate CI

[0696] N-((S)-2-amino-1-((S)-7-fluorospiro[3,1'-cyclopropyl]-4-yl)-2-oxoethyl)-1-ethyl- 1H-pyrazole-5-carboxamide (CI)

[0697]

[0698] Step 1: N-((S)-cyano((S)-7-fluorospiro[3,1'-cyclopropane]-4-yl)methyl)-1-ethyl-1H-pyridine Zyrazole-5-carboxamide (CI-1)

[0699] A mixture of (S)-2-amino-2-((S)-7-fluorospiro[trypanan-3,1'-cyclopropane]-4-yl)acetonitrile hydrochloride (130 mg, 0.48 mmol), 1-ethyl-1H-pyrazole-5-carboxylic acid (78 mg, 0.56 mmol), DIEA (0.39 mL, 2.2 mmol), and HATU (319 mg, 0.84 mmol) in DMF (2 mL) was stirred at 0 °C for 2 hours. The mixture was purified by reversed-phase rapid chromatography under the following conditions (column: C18 silica gel; mobile phase: water containing ACN (0.05% NH4HCO3), 10% to 50% gradient over 30 minutes) to give N-((S)-cyano((S)-7-fluorospiro[trypanan-3,1'-cyclopropane]-4-yl)methyl)-1-ethyl-1H-pyrazole-5-carboxamide (150 mg). LCMS (ESI, m / z): [M+H] + 355.1.

[0700] Step 2: N-((S)-2-amino-1-((S)-7-fluorospiro[trypanan-3,1'-cyclopropyl]-4-yl)-2-oxoethyl)- 1-Ethyl-1H-pyrazole-5-carboxamide (CI)

[0701] At 0 °C, H₂O₂ (30% in H₂O, 0.5 g, 4.4 mmol) was added dropwise to a stirred mixture of N-((S)-cyano((S)-7-fluorospiro[trypanan-3,1'-cyclopropyl]-4-yl)methyl)-1-ethyl-1H-pyrazole-5-carboxamide (150 mg, 0.42 mmol) and K₂CO₃ (175 mg, 1.3 mmol) in DMSO (1.5 mL). After stirring at room temperature for 2 h, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / EtOAc (1:3) to give intermediate CI (150 mg). LCMS (ESI, m / z): [M+H] + 373.2.

[0702] Under conditions similar to those for the synthesis of CI, the intermediates listed in the table below are synthesized from the corresponding aminonitriles.

[0703]

[0704]

[0705]

[0706] Intermediate B (substitution synthesis)

[0707] (R)-N-(1-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propyl Amide (B)

[0708]

[0709] Step 1: (R)-(1-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl tert-butyl carbamate (B-1A)

[0710] A solution of (R)-2-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-((tert-butoxycarbonyl)-amino)acetic acid (5.0 g, 13 mmol), 1-methylpiperazine (1.4 g, 14 mmol), DIEA (9.0 mL, 52 mmol), and HATU (7.4 g, 19 mmol) in DMF (50 mL) was stirred at 0 °C under N2 for 1 hour. The mixture was purified by reversed-phase rapid chromatography under the following conditions (column: C18 silica gel; mobile phase: water containing ACN (10 mmol / L NH4HCO3), 20% to 60% gradient over 30 minutes) to give (R)-(1-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)carbamate tert-butyl ester (5.0 g). LCMS (ESI, m / z): [M+H] + 470.1.

[0711] Step 2: (R)-2-amino-2-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-1-(4-methylpiperazin-1-yl)ethyl-1- Ketohydrochloride (B-2A)

[0712] A mixture of (R)-(1-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)carbamate tert-butyl ester (5 g, 11 mmol) and HCl solution (4.0 M in 1,4-dioxane, 50 mL) in 1,4-dioxane was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to give (R)-2-amino-2-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-1-(4-methylpiperazin-1-yl)ethyl-1-one hydrochloride as an HCl salt. LCMS (ESI, m / z): [M+H] + 370.1.

[0713] Step 3: (R)-N-(1-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl (B) propionamide

[0714] At 0 °C under N2, propionic anhydride (3.5 g, 27 mmol) was added to a solution of (R)-2-amino-2-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-1-(4-methylpiperazin-1-yl)ethyl-1-one hydrochloride (5.0 g, 12 mmol) and DIEA (11.8 mL, 66 mmol) in DCM (50 mL). After stirring at room temperature for 1 hour, the mixture was treated with water and extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give intermediate B (4 g). LCMS (ESI, m / z): [M+H] + 426.1.

[0715] Under conditions similar to those used in the synthesis of B, the intermediate DN-FB is synthesized from the corresponding amino acids. For intermediate FC, the final step uses an acyl chloride instead of an anhydride.

[0716]

[0717]

[0718]

[0719]

[0720] intermediate FD

[0721] (R)-N-(1-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-(1,1-difluoro-6-azaspiro[2.5]oct-6-yl)- 2-Oxoethyl)oxetane-3-carboxamide (FD)

[0722]

[0723] Under conditions similar to those used in the B-2A synthesis, intermediate FD was synthesized from J via HATU-mediated amide coupling, Boc deprotection, and HATU-mediated amide coupling. LCMS (ESI, m / z): [M+H] + 501.1.

[0724] Synthesize the intermediates in the table below using conditions similar to those for intermediate FD.

[0725]

[0726] intermediate FK

[0727] N-((R)-1-(1-(4-((S)-2-amino-2-((S)-spiro[2.5]oct-5-yl)acetamido)-3-fluorophenyl) Cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propionamide (FK)

[0728]

[0729] Step 1: ((S)-cyano((S)-spiro[2.5]oct-5-yl)methyl)tert-butyl carbamate (FK-1)

[0730] A solution of (S)-2-amino-2-((S)-spiro[2.5]oct-5-yl)acetonitrile (4.0 g, 24 mmol), (Boc)₂O (10.6 g, 49 mmol), and NaHCO₃ (6.1 g, 73 mmol) in 1,4-dioxane (40 mL) and H₂O (5 mL) was stirred at room temperature for 1 hour. The mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (5:1) to give tert-butyl ((S)-cyano((S)-spiro[2.5]oct-5-yl)methyl)carbamate (4.0 g). LCMS (ESI, m / z): [M+H-56] + 209.

[0731] Step 2: ((S)-2-amino-2-oxo-1-((S)-spiro[2.5]oct-5-yl)ethyl)tert-butyl carbamate (FK-2)

[0732] At room temperature, H2O2 (30% in H2O, 2.6 g, 23 mmol) was added dropwise to a mixture of ((S)-cyano((S)-spiro[2.5]oct-5-yl)methyl)carbamate (3.0 g, 11 mmol) and K2CO3 (1.6 g, 11 mmol) in DMSO (30 mL). After stirring for 4 hours, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give ((S)-2-amino-2-oxo-1-((S)-spiro[2.5]oct-5-yl)ethyl)carbamate (3.0 g). LCMS (ESI, m / z): [M+H] + 283.1.

[0733] Step 3: ((S)-2-((2-fluoro-4-(1-(((R)-2-(4-methylpiperazin-1-yl)-2-oxo-1-propamidoethyl) (FK-3)-(S ...

[0734] A mixture of ((S)-2-amino-2-oxo-1-((S)-spiro[2.5]oct-5-yl)ethyl)carbamate tert-butyl ester (1.6 g, 5.7 mmol), (R)-N-(1-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propionamide (2.4 g, 5.6 mmol), K3PO4 (2.4 g, 11 mmol), DMEDA (500 mg, 5.7 mmol), and CuI (1.1 g, 5.8 mmol) in 1,4-dioxane (40 mL) was degassed and backfilled with N2. After stirring at 100 °C for 6 hours, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column: C18 silica gel, 90 g; mobile phase: water containing MeCN (0.05% NH4HCO3), 40% to 60% gradient over 30 minutes) to give tert-butyl ((S)-2-((2-fluoro-4-(1-(((R)-2-(4-methylpiperazin-1-yl)-2-oxo-1-propamidoethyl)cyclopropyl)phenyl)amino)-2-oxo-1-((S)-spiro[2.5]oct-5-yl)ethyl)carbamate (2.0 g). LCMS (ESI, m / z): [M+H] + 628.5.

[0735] Step 4: N-((R)-1-(1-(4-((S)-2-amino-2-((S)-spiro[2.5]oct-5-yl)acetamido)-3-fluoro (Phenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propionamide (FK)

[0736] TMSOTf (7.1 g, 32 mmol) was added dropwise to a stirred solution of ((S)-2-((2-fluoro-4-(1-(((R)-2-(4-methylpiperazin-1-yl)-2-oxo-1-propamidoethyl)cyclopropyl)phenyl)amino)-2-oxo-1-((S)-spiro[2.5]oct-5-yl)ethyl)carbamate (2.0 g, 3.2 mmol) and 2,6-dimethylpyridine (4.1 g, 38 mmol) in DCM (20 mL). After stirring for 1 hour at room temperature, the mixture was treated with water and concentrated under reduced pressure. The residue was purified by reversed-phase rapid chromatography under the following conditions (column: C18 silica gel; mobile phase: water containing MeCN (0.05% NH4HCO3), 30% to 60% gradient over 30 minutes) to give intermediate FK (1.6 g). LCMS (ESI, m / z): [M+H) + 528.4.

[0737] Under conditions similar to those used in the synthesis of FK, intermediate FL is synthesized from X, and intermediate FM is synthesized from BI. Following the last two steps, intermediate FN is synthesized by reacting F-1 with B, followed by Boc deprotection. Following the last two steps, intermediate FO-FQ is synthesized by reacting the precursor of BV with the corresponding bromide, followed by Boc deprotection.

[0738]

[0739]

[0740] Example 1

[0741] N-((1S)-1-cycloheptyl-2-((2-fluoro-4-(1-(2-(4-methylpiperazin-1-yl)-2-oxo-1-propionamidyl) Ethyl)cyclopropyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (1)

[0742]

[0743] Step 1: ((1S)-1-cycloheptyl-2-((2-fluoro-4-(1-(2-(4-methylpiperazin-1-yl)-2-oxo-1-propionyl) Aminoethyl)cyclopropyl)phenyl)amino)-2-oxoethyl)tert-butyl carbamate (1-1)

[0744] At room temperature under N2, N-(1-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propionamide (200 mg, 0.47 mmol), (S)-(2-amino-1-cycloheptyl-2-oxoethyl)carbamate tert-butyl ester (152 mg, 0.56 mmol) and N2 were reacted. 1 N 2 CuI (89 mg, 0.47 mmol) and K3PO4 (209 mg, 0.99 mmol) were added to a stirred mixture of 1,4-dioxane (4 mL) and dimethyl ethane-1,2-diamine (41 mg, 0.47 mmol). The mixture was degassed and then stirred at 100 °C for 2 hours under N2. After completion, the reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give tert-butyl ((1S)-1-cycloheptayl-2-((2-fluoro-4-(1-(2-(4-methylpiperazin-1-yl)-2-oxo-1-propamidoethyl)cyclopropyl)phenyl)amino)-2-oxoethyl)carbamate (200 mg). LCMS (ESI, m / z): [M+H] + 616.5.

[0745] Step 2: N-(1-(1-(4-((S)-2-amino-2-cycloheptaylacetamyl)-3-fluorophenyl)cyclopropyl)-2-(4- Methylpiperazine-1-yl)-2-oxoethyl)propionamide (1-2)

[0746] Under N2 at 0 °C, TMSOTf (360 mg, 1.62 mmol) and 2,6-dimethylpyridine (208 mg, 1.94 mmol) were added dropwise to a stirred solution of ((1S)-1-cycloheptayl-2-((2-fluoro-4-(1-(2-(4-methylpiperazin-1-yl)-2-oxo-1-propamidoethyl)cyclopropyl)phenyl)amino)-2-oxoethyl)carbamate (100 mg, 0.16 mmol) in DCM (2 mL). After stirring for 20 min, the mixture was concentrated under reduced pressure to give a crude product for direct use in the next step. LCMS (ESI, m / z): [M+H] + 516.4.

[0747] Step 3: N-((1S)-1-cycloheptyl-2-((2-fluoro-4-(1-(2-(4-methylpiperazin-1-yl)-2-oxo-1-propane) Aminoethyl)cyclopropyl)phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide (1)

[0748] At room temperature and under N2, HOBt (35 mg, 0.26 mmol), EDCI (50 mg, 0.26 mmol), and TEA (70 mg, 0.70 mmol) were added to a stirred mixture of N-(1-(1-(4-((S)-2-amino-2-cycloheptylacetamyl)-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propionamide (90 mg, 0.17 mmol) and 1-isopropyl-1H-pyrazole-5-carboxylic acid (40 mg, 0.26 mmol) in DMF (1 mL). After stirring for 1 hour, the mixture was directly purified by preparative HPLC (0.05% NH4HCO3) to obtain Example 1. 1H NMR (400 MHz, DMSO-d6) δ9.87 (s, 1H), 8.43 (d, J = 8.8 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.71 (t, J= 8.4 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.20-7.11 (m, 2H), 6.91 (d, J = 2.0Hz, 1H), 5.38 (m, 1H), 5.19 (d, J = 8.8 Hz, 1H), 4.61 (t, J = 8.4 Hz, 1H), 3.45-3.27 (m, 4H), 2.29-2.07 (m, 9H), 1.98 (m, 1H), 1.79-1.34 (m, 18H), 1.03-0.94 (m, 4H), 0.89-0.72 (m, 2H), 0.61 (m, 1H); LCMS (ESI, m / z): [M+H] + 652.6.

[0749] Examples 2 and 3

[0750] N-((S)-1-cycloheptyl-2-((2-fluoro-4-(1-(((R)-2-(4-methylpiperazin-1-yl)-2-oxo-1-propionyl) (2) and N-((S)- 1-Cycloheptyl-2-((2-Fluoro-4-(1-((S)-2-(4-methylpiperazin-1-yl)-2-oxo-1-propamidoethyl)cyclopropyl) (3) Phenyl)amino)-2-oxoethyl)-1-isopropyl-1H-pyrazole-5-carboxamide

[0751]

[0752] Example 1 was further separated by chiral HPLC under the following conditions (CHIRALPAK IG column, NH4OH) to obtain Examples 2 and 3. Example 2 (peak 2): 11H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.71 (t, J = 8.4 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.19 - 7.12 (m, 2H), 6.91 (d, J = 1.6 Hz, 1H), 5.38 (m, 1H), 5.19 (d, J = 8.8 Hz, 1H), 4.61 (t, J = 8.4 Hz, 1H), 3.48 - 3.28 (m, 4H), 2.25 - 2.05 (m, 9H), 1.95 (m, 1H), 1.77 - 1.32 (m, 18H), 1.01 - 0.93 (m, 4H), 0.90 - 0.70 (m, 2H), 0.61 (m, 1H); LCMS (ESI, m / z): [M+H] + 652.6. Example 3 (Peak 1): 1 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.43 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.71 (t, J = 8.4 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.19 - 7.12 (m, 2H), 6.91 (d, J = 2 Hz, 1H), 5.42 - 5.35 (m, 1H), 5.19 (d, J = 8.8 Hz, 1H), 4.61 (t, J = 8.4 Hz, 1H), 3.48 - 3.28 (m, 4H), 2.25 - 2.05 (m, 9H), 1.95 (m, 1H), 1.77 - 1.32 (m, 18H), 1.01 - 0.93 (m, 4H), 0.90 - 0.70 (m, 2H), 0.61 (m, 1H); LCMS (ESI, m / z): [M+H] + 652.6.

[0753] Example 4

[0754] N-((S)-1-(4,4-difluorocyclohexyl)-2-((2-fluoro-4-(1-((R)-2-(4-methylpiperazin-1-yl)-2-oxo) (4) 1-Propamidoethyl)cyclopropyl)phenyl)amino)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide

[0755]

[0756] Under N2, DMEDA (4 mg, 0.05 mmol) was added to a mixture of (R)-N-(1-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propionamide (20.0 mg, 0.047 mmol), (2S)-2-(4,4-difluorocyclohexyl)-2-[(2-ethylpyrazol-3-yl)carbamoyl]acetamide (18.0 mg, 0.056 mmol), CuI (9 mg, 0.05 mmol), and K3PO4 (21.0 mg, 0.099 mmol) in 1,4-dioxane (0.5 mL). The mixture was degassed and then stirred under N2 at 100 °C for 16 hours. After completion, the reaction mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 7:1) to obtain an impure product. The material was further purified by preparative HPLC (0.055% NH₄HCO₃) to obtain Example 4. 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.59(d, J = 8.0 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.73 (m, 1H), 7.48 (d, J = 2.0Hz, 1H), 7.25-7.08 (m, 2H), 7.00 (d, J = 2.0 Hz, 1H), 5.17 (d, J = 8.8 Hz,1H), 4.65 (t, J = 8.4 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H), 3.46-3.29 (m, 4H),2.26-1.66 (m, 16H), 1.55-1.32 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H), 1.03- 0.91(m, 4H), 0.88-0.72 (m, 2H), 0.60 (m, 1H); LCMS (ESI, m / z): [M+H] + 660.3.

[0757] Examples 5 and 6 are synthesized from intermediates B or E using synthesis conditions similar to those in Example 4.

[0758]

[0759] Example 7

[0760] 1-Ethyl-N-((S)-2-((2-fluoro-4-(1-((R)-2-(4-methylpiperazin-1-yl)-2-oxo-1-propionamide) (S)-7-fluorospiro[3,1'-cyclopropyl]-4-yl)-2-oxoethyl)-1H- Pyrazole-5-carboxamide (7)

[0761]

[0762] A mixture of N-((S)-2-amino-1-((S)-7-fluorospiro[3,1'-cyclopropyl]-4-yl)-2-oxoethyl)-1-ethyl-1H-pyrazole-5-carboxamide (61 mg, 0.16 mmol), (R)-N-(1-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propionamide (70 mg, 0.16 mmol), CuI (31 mg, 0.16 mmol), DMEDA (14 mg, 0.16 mmol), and K3PO4 (73 mg, 0.34 mmol) in 1,4-dioxane (0.8 mL) was degassed and backfilled with N2. After stirring at 100 °C for 6 hours, the mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM / MeOH = 10:1) to obtain an impure product. The material was further purified by preparative HPLC (0.05% NH₄HCO₃) to obtain Example 7. 1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.91 (d, J = 9.2 Hz,1H), 8.03 (d, J = 8.8 Hz, 1H), 7.70 (t, J = 8.4 Hz, 1H), 7.47 (d, J = 2.0 Hz,1H), 7.30-7.16 (m, 3H), 6.98 (d, J = 2.0 Hz, 1H), 6.63-6.59 (m, 1H), 6.52-6.48 (m, 1H), 5.22 (d, J = 8.8 Hz, 1H), 5.13-5.05 (m, 2H), 4.32 (m, 2H),3.50-3.31 (m, 5H), 2.57-2.53 (m, 1H), 2.25-1.95 (m, 9H), 1.15 (t, J = 7.2 Hz,3H), 1.05-0.92 (m, 4H), 0.90-0.75 (m, 3H), 0.68-0.48 (m, 3H), 0.32-0.25 (m,1H); LCMS (ESI, m / z): [M+H] + 718.3.

[0763] Use conditions similar to those in Example 7 to synthesize the instances in the table below.

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800] Example 144

[0801] 1-Ethyl-N-((S)-2-((2-fluoro-4-(1-((R)-2-(4-methylpiperazin-1-yl)-2-oxo-1-propionamide) (S)-(2,5)octyl-5-yl)ethyl)-1H-pyrazole-5-carboxamide (144)

[0802]

[0803] A solution of N-((R)-1-(1-(4-((S)-2-amino-2-((S)-spiro[2.5]oct-5-yl)acetamyl)-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propionamide (300 mg, 0.569 mmol), 1-ethyl-1H-pyrazole-5-carboxylic acid (80 mg, 0.57 mmol), HATU (324 mg, 0.853 mmol), and DIEA (220 mg, 1.71 mmol) in DMF (4 mL) was stirred at room temperature for 2 hours. The mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (20:1) to give an impure product. The material was further purified by preparative HPLC (0.05% NH4HCO3) to obtain Example 144. 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H),8.44 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.69 (t, J = 8.4 Hz, 1H),7.47 (d, J = 2.0 Hz, 1H), 7.19-7.11 (m, 2H), 6.97 (d, J = 2.0 Hz, 1H), 5.19(d, J = 8.8 Hz, 1H), 4.56 (t, J = 8.4 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H), 3.48-3.32 (m, 4H), 2.22-1.94 (m, 10H), 1.72-1.46 (m, 4H), 1.41-1.10 (m, 5H), 1.02-0.93 (m, 5H), 0.87-0.74 (m, 3H), 0.63-0.59 (m, 1H), 0.28-0.15 (m, 4H); LCMS (ESI, m / z): [M+H] + 650.4.

[0804] Use conditions similar to those in Example 144 to synthesize the instances in the table below.

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812] Example 167

[0813] 3,3-Difluorocyclobutyl((S)-2-((2-fluoro-4-(1-((R)-2-(4-methylpiperazin-1-yl)-2-oxo-1-propane) Aminoethyl)cyclopropyl)phenyl)amino)-2-oxo-1-((S)-spiro[2.5]oct-5-yl)ethyl)carbamate butyl ester （167）

[0814]

[0815] Step 1: 3,3-Difluorocyclobutyl(4-nitrophenyl) carbonate (167-1)

[0816] 4-Nitrophenyl chloroformate (1.9 g, 9.4 mmol) was added to a solution of 3,3-difluorocyclobut-1-ol (500 mg, 4.6 mmol) and pyridine (1.5 g, 19 mmol) in ACN (3 mL) at 0 °C under N2. After stirring at room temperature for 3 h, the mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (7:1) to give 3,3-difluorocyclobutyl(4-nitrophenyl) carbonate (1 g). 1 H NMR (400 MHz, CDCl3) δ 8.36-8.28 (m, 2H), 7.46-7.37 (m, 2H), 5.12-5.01 (m, 1H), 3.24-3.07 (m, 2H), 2.98-2.79 (m, 2H).

[0817] Step 2: 3,3-Difluorocyclobutyl((S)-2-((2-fluoro-4-(1-((R)-2-(4-methylpiperazin-1-yl)-2-oxo) (S-1-propamidoethyl)cyclopropyl)phenyl)amino)-2-oxo-1-((S)-spiro[2.5]oct-5-yl)ethyl)aminomethyl Butyl ester (167)

[0818] 3,3-Difluorocyclobutyl(4-nitrophenyl)carbonate (103 mg, 0.38 mmol) was added to a solution of N-((R)-1-(1-(4-((S)-2-amino-2-((S)-spiro[2.5]oct-5-yl)acetamido)-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propionamide (40 mg, 0.076 mmol) and DIEA (196 mg, 1.5 mmol) in ACN (2 mL). After stirring at room temperature for 16 hours, the mixture was treated with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (9:1) to give an impure product. The material was further purified to Example 167 by preparative HPLC (0.05% NH4HCO3). 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.01 (d, J = 8.8 Hz,1H), 7.67 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.22-7.11 (m, 2H), 5.19 (d, J = 8.8 Hz, 1H), 4.83-4.72 (m, 1H), 4.11 (t, J = 8.4 Hz, 1H), 3.49-3.26 (m, 4H), 3.06-2.94 (m, 2H), 2.70-2.54 (m, 2H), 2.27-2.04 (m, 8H), 2.02-1.92 (m, 1H), 1.90-1.73 (m, 1H), 1.70-1.52 (m, 3H), 1.47 (m, 1H), 1.30 (m,1H), 1.15 (m, 1H), 1.02-0.73 (m, 8H), 0.62-0.57 (m, 1H), 0.30-0.11 (m, 4H);LCMS (ESI, m / z): [M+H] + 662.4.

[0819] Example 168

[0820] N-((S)-2-((4-(1-((R)-2-(1,1-difluoro-6-azaspiro[2.5]oct-6-yl)-1-(2-methoxyethyl) (amido)-2-oxoethyl)cyclopropyl)-2-fluorophenyl)amino)-2-oxo-1-((S)-spiro[2.5]oct-5-yl)ethyl)- 1-Ethyl-1H-pyrazole-5-carboxamide (168)

[0821]

[0822] Step 1: (R)-(1-(1-(4-bromo-3-fluorophenyl)cyclopropyl)-2-(1,1-difluoro-6-azaspiro[2.5]octyl-6- tert-butyl 2-oxoethyl carbamate (168-1)

[0823] Intermediate 168-1 was synthesized under conditions similar to those used in the synthesis of B-1A. LCMS (ESI, m / z): [M+H] + 517.2.

[0824] Step 2: ((R)-2-(1,1-difluoro-6-azaspiro[2.5]oct-6-yl)-1-(1-(4-((S)-2-(1-ethyl- 1H-pyrazole-5-carboxamido)-2-((S)-spiro[2.5]oct-5-yl)acetamyl)-3-fluorophenyl)cyclopropyl)-2-oxoethyl tert-butyl carbamate (168-2)

[0825] Intermediate 168-2 was synthesized under conditions similar to those used in the synthesis of FK-3. LCMS (ESI, m / z): [M+H] + 741.5.

[0826] Step 3: N-((S)-2-((4-(1-((R)-1-amino-2-(1,1-difluoro-6-azaspiro[2.5]octyl-6-yl)- 2-Oxoethyl)cyclopropyl)-2-fluorophenyl)amino)-2-oxo-1-((S)-spiro[2.5]oct-5-yl)ethyl)-1-ethyl- 1H-pyrazole-5-carboxamide (168-3)

[0827] Intermediate 168-3 was synthesized under conditions similar to those used in the synthesis of V-5. LCMS (ESI, m / z): [M+H] + 641.2.

[0828] Step 4: N-((S)-2-((4-(1-((R)-2-(1,1-difluoro-6-azaspiro[2.5]octyl-6-yl)-1-(2-methyl) (Oxyacetamido)-2-oxoethyl)cyclopropyl)-2-fluorophenyl)amino)-2-oxo-1-((S)-spiro[2.5]oct-5-yl) (Ethyl)-1-Ethyl-1H-pyrazole-5-carboxamide (168)

[0829] Synthesize Example 168 under conditions similar to those of Example 144. 1 H NMR (400 MHz, DMSO-d6) δ9.91 (s, 1H), 8.44 (d, J = 8.0 Hz, 1H), 7.71-7.64 (m, 2H), 7.46 (d, J = 2.0Hz, 1H), 7.19-7.10 (m, 2H), 6.96 (d, J = 2.0 Hz, 1H), 5.10 (t, J = 7.6 Hz,1H), 4.55 (t, J = 8.4 Hz, 1H), 4.46 (q, J = 6.8 Hz, 2H), 3.86 (m, 2H), 3.65-3.34 (m, 4H), 3.32 (s, 3H), 2.08-2.00 (m, 1H), 1.72-1.46 (m, 7H), 1.38-1.17(m, 8H), 1.05-0.94 (m, 3H), 0.85-0.77 (m, 3H), 0.28-0.15 (m, 4H); LCMS (ESI,m / z): [M+H] + 713.5.

[0830] Example 169

[0831] N-((R)-1-(1-(4-((S)-2-((6-chloropyridazine-3-yl)amino)-2-((S)-spiro[2.5]oct-5-yl)ethyl (Amide)-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propionamide (169)

[0832]

[0833] A mixture of N-((R)-1-(1-(4-((S)-2-amino-2-((S)-spiro[2.5]oct-5-yl)acetamyl)-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propionamide (40 mg, 0.076 mmol), 3,6-dichloropyridazine (22 mg, 0.15 mmol), Cs₂CO₃ (74 mg, 0.23 mmol), Pd-PEPPSI-IHeptCl 3-chloropyridine (7 mg, 0.008 mmol) in 1,4-dioxane (1 mL) was degassed and backfilled with N₂. After stirring at 100 °C for 16 hours, the mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give an impure product. The material was further purified by preparative HPLC (0.05% NH4HCO3) to obtain Example 169. 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.64 (t,J = 8.4 Hz, 1H), 7.37 (d, J = 9.6 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.17-7.09 (m, 2H), 7.07 (d, J = 9.2 Hz, 1H), 5.18 (d, J = 8.8 Hz, 1H), 4.71 (t, J= 7.6 Hz, 1H), 3.49-3.32 (m, 4H), 2.23-2.05 (m, 8H), 2.01-1.91 (m, 2H), 1.75-1.67 (m, 2H), 1.61 (t, J = 12.4 Hz, 2H), 1.42-1.21 (m, 2H), 1.02-0.93 (m,5H), 0.87-0.73 (m, 3H), 0.62-0.57 (m, 1H) , 0.31-0.15 (m, 4H); LCMS (ESI, m / z): [M+H] + 640.4.

[0834] Example 170

[0835] N-((R)-1-(1-(4-((S)-2-((6-(difluoromethyl)pyridazine-3-yl)amino)-2-((S)-spiro[2.5]octyl- 5-yl)acetamyl)-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propionamide (170)

[0836]

[0837] A solution of N-((R)-1-(1-(4-((S)-2-amino-2-((S)-spiro[2.5]oct-5-yl)acetamyl)-3-fluorophenyl)cyclopropyl)-2-(4-methylpiperazin-1-yl)-2-oxoethyl)propionamide (100 mg, 0.190 mmol), 3-chloro-6-(difluoromethyl)pyridazine (31 mg, 0.19 mmol), and CsF (43 mg, 0.29 mmol) in DMSO (1 mL) was stirred at 130 °C for 5 hours under N2. The mixture was treated with water and extracted with EtOAc. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (20:1) to give an impure product. The material was purified by preparative HPLC (0.05% NH4HCO3) followed by preparative chiral HPLC (column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2 M NH3-MeOH), mobile phase B: EtOH:DCM=1:1; flow rate: 20 mL / min; gradient (B%): 60% isocratic; wavelength: 254 / 220 nm) to obtain Example 170. 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.66 (t, J = 8.4 Hz, 1H), 7.55-7.48 (m, 2H), 7.18-6.81 (m, 4H), 5.18 (d, J =8.8 Hz, 1H), 4.84 (t, J = 7.6 Hz, 1H), 3.45-3.26 (m, 4H), 2.22-1.95 (m, 10H), 1.75-1.58 (m, 4H), 1.41-1.22 (m, 2H), 1.02-0.93 (m, 5H), 0.85-0.72 (m, 3H),0.59 (m, 1H), 0.29-0.17 (m, 4H); LCMS (ESI, m / z): [M+H] + 656.4.

[0838] Example 171 was synthesized using conditions similar to those used in synthesis 170. Examples 172 and 173 were synthesized using conditions similar to those used in synthesis 169. Example 174 was synthesized using Gphos, G6, Pd, TES, and Gphos as catalysts for the CN coupling reaction.

[0839]

[0840]

[0841] Biological Example 1. IL17-AA HEK Cell Reporter Gene Assay

[0842] Human embryonic kidney HEK293 cells with a stably integrated embryonic alkaline phosphatase (SEAP) reporter gene (Invivogen, catalog number hkb-il17) that is secreted in a signal-dependent manner by the human IL-17 receptor (RA / RC) signal were seeded in DMEM (Hyclone) containing 10% heat-inactivated FBS (Thermo Fisher) and 100 U / mL PenStrep (Solarbio). Cells were treated with serially diluted compounds and stimulated overnight with recombinant human IL17-AA protein (R&D, catalog number 7955-IL-025). SEAP activity was then detected from the cell culture supernatant according to the manufacturer's instructions. Inhibition data were calculated by comparing the wells with 0% inhibition mediator control (Hc) and 100% inhibition unstimulated control (Lc) according to the following equation:

[0843] Inhibition % = (RHc - R sample) / (RHc - RLc) * 100

[0844] Then, dose-response curves were generated to determine the cellular response (IC50) after XLFit suppression of 50%. 50 The required concentration (Equation 201).

[0845] For IL-17AA HEK Blue activity, the values ​​in parentheses are: A < 50 nM; 50 nM < B < 500 nM; >500 nM < C < 20000 nM.

[0846]

[0847]

[0848]

[0849] Biological Example 2. IL17-AF HEK Cell Reporter Gene Assay

[0850] Human embryonic kidney HEK293 cells with a stably integrated embryonic alkaline phosphatase (SEAP) reporter gene (Ingenie, catalog number hkb-il17) that is secreted in a signal-dependent manner by the human IL-17 receptor (RA / RC) were seeded in DMEM (Hyclon) containing 10% heat-inactivated FBS (Thermo Fisher Scientific) and 100 U / mL PenStrep (Solepro). Cells were treated with serially diluted compounds and stimulated overnight with recombinant human IL17-AF protein (R&D, catalog number 5837-IL-010). SEAP activity was then detected from the cell culture supernatant according to the manufacturer's instructions. Inhibition data were calculated by comparing the wells with 0% inhibition mediator control (Hc) and 100% inhibition unstimulated control (Lc) according to the following equation:

[0851] Inhibition % = (RHc - R sample) / (RHc - RLc) * 100

[0852] Then, dose-response curves were generated to determine the cellular response (IC50) after XLFit suppression of 50%. 50 The required concentration (Equation 201).

[0853] Examples 2, 7, 9, 11, 26, 31, 33, 45, 49, 54, 59, 88, 93, 95, 96, 102, 111, 120, 123, 125, 128, 132, 135, 139, 140, 141, 143, 144, 147, and 158 exhibited IC50 values ​​less than 100 nM in IL-17AF HEK Blue. 50 value.

[0854] The summary and abstract section may set forth one or more exemplary embodiments of the invention as conceived by the inventors, but not all exemplary embodiments, and therefore is not intended to limit the invention and the appended claims in any way.

[0855] The invention has been described above using functional building blocks, which illustrate implementations of specified functions and their relationships. For ease of description, the boundaries of these functional building blocks have been arbitrarily defined herein. Alternative boundaries can be defined as long as the specified functions and their relationships are properly performed.

[0856] Regarding aspects of the invention described as belonging to a genus, each individual species is considered a separate aspect of the invention. If aspects of the invention are described as "comprising" features, embodiments that are "consisting of" or "substantially composed of" features are also contemplated.

[0857] The foregoing description of the specific embodiments so fully reveals the general nature of the invention that, without requiring excessive experimentation or departing from the general concept of the invention, others can readily modify and / or adapt various applications of such specific embodiments by applying knowledge of the art. Therefore, based on the teachings and guidance presented herein, such adaptations and modifications are intended to fall within the meaning and scope of equivalents of the disclosed embodiments. It should be understood that phrases or terms herein are for descriptive and not limiting purposes, and that the terminology or phrases in this specification should be interpreted by those skilled in the art based on the teachings and guidance.

[0858] The breadth and scope of this invention should not be limited by any of the exemplary embodiments described above.

[0859] All aspects, embodiments, and options described herein can be combined in any and all variations.

[0860] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if specifically and individually indicated that each individual publication, patent, or patent application is incorporated by reference. In the event of any conflict between any meaning or definition of a term in this document and any meaning or definition of the same term in the documents incorporated by reference, the meaning or definition given to the term in this document shall prevail.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: Formula I in: R 1 C is an optional substitute 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkynyl, optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl or optionally substituted heteroaryl; Z represents empty, C(O), -C(O)-O-, or -C(O)-N(G). Z )-, where Z is -C(O)-O- or -C(O)-N(G Z When )-, the carbonyl group is bonded to the adjacent NH group in formula I, and where G Z It is hydrogen, and the C is optionally substituted. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl or optionally substituted 3-8 membered rings; R 2 It is an optionally substituted carbocyclic group, an optionally substituted heterocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group, or an optionally substituted alkyl group; Ring A is a phenylene or a 5- or 6-membered heteroarylene (e.g., pyridylene, pyridazinyl, pyrimidinyl, etc.), which is optionally altered by R, where the valence allows. 7 Replace 1-4 instances; R 3 and R 4 Each is independently F, CN, G 1A or J 1 -J 2 -J 3 -G 1B J 1 J 2 and J 3 Each is independently empty, O, NG 1B ,C(O),S,SO,SO2 or P(O)G 1B The condition is J 1 J 2 and J 3 At least one of them is not empty, and among them: G 1B Each time it appears, it is independently either hydrogen or G. 1A ,and G 1A Each time it appears, it is an independently substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl or optionally substituted 3-8 membered rings (preferably optionally substituted C) 3-8 (Carbocyclic or optionally substituted 4-8 membered heterocycles); Or R 3 and R 4 It is connected together with the carbon atoms of both of them to form an optionally substituted 3-8 membered carbon ring or 4-8 membered heterocycle; L 1 It is an empty, optional substitution of C 1-4 Alkylene or optionally substituted C 1-4 Heteroalkyl, R 5 It is hydrogen, deuterium, or C with optional substitution. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Alkyne or optionally substituted 3- to 8-membered rings; Or R 3 Or R 4 With R 5 They can be linked together with intermediate atoms to form optionally substituted 3-8 membered carbon rings or 4-8 membered heterocycles; R 6 It's OG 2A 、N(G 2A )C(O)G 2A 、N(G 2A )C(O)OG 2B 、N(G 2A )C(O)NG 2A G 2A 、N(G 2A SO2G 2B or N(G) 2A SO2NG 2A G 2A G 2A Each time it appears, it is independently either hydrogen or G. 2B ; and among them G 2B Each time it appears, it is an independently substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl or optionally substituted 3-14 membered rings (e.g., optionally substituted C) 3-8 (Carbon ring, optionally substituted 5- or 6-membered heteroaryl ring, or optionally substituted 4- to 8-membered heterocycle). Y is C(O) or SO2; R 8 It's NG 3 G 3 Optionally substituted 4-14 membered heterocycles or optionally substituted heteroaryl rings, wherein: G 3 Each time it appears, it is independently hydrogen, with optional substitution of C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl or optionally substituted 3-8 membered rings; or two Gs 3 Together with the nitrogen atoms attached to both, they form optionally substituted 4-8 membered heterocycles; R 7 Each time it appears, it is independently of deuterium, halogen, CN, or optionally substituted C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl, optionally substituted 3-8 membered rings or J 4 -J 5 -J 6 -G 4 J 4 J 5 and J 6 Each is independently empty, O, NG 4 ,C(O),S,SO,SO2 or P(O)G 4 J 4 J 5 and J 6 At least one of them is not empty, and G is among them. 4 Each time it appears, it is independently hydrogen, with optional substitution of C. 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl or optionally substituted 3-8 membered rings; or two R... 7 They can be connected to form optional 4-8 member rings; Or R 7 An example and R 3 Or R 4 It connects with the intermediate atom to form an optionally substituted 5-8 membered carbon ring or heterocycle; and "n" is an integer selected from 0 to 4.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that... It has a structure according to formula I-E1: Formula I-E1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring A is phenylene, and the compound is characterized by having a structure according to formula I-1: Formula I-1.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that... It has a structure according to Equation I-2: Formula I-2.

5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that... It has a structure according to Equation I-3: Formula I-3.

6. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that... It has a structure according to formula I-4 or I-4-D2: Formula I-4 Formula I-4-D2.

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Z is C(O).

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 1 It is an optionally substituted 5- or 6-membered heteroaryl group, preferably a substituted 5- or 6-membered heteroaryl group.

9. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 1 It is selected from the following 5- or 6-membered heteroaryl groups: pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyrrole, furan, thiophene, imidazole, oxadiazole, thiadiazole, triazole, tetraazole, pyridine, pyrimidine, pyrazine, and pyridazine, each of which is optionally substituted by one or more substituents independently selected from the following: halogen, CN, OH, NH2, R A1 OR A1 SR A1 NHR A1 NR A1 R A1 NR A1 SO2R A1 C(O)R A1 C(O)NHR A1 C(O)NR A1 R A1 S(O) q R A1 S(O) q NR A1 R A1 and S(O)(=NR) A1 )R A1 , in q is 1 or 2; and R A1 It is C independently each time it appears. 1-6 Alkyl, C 3-10 Carbon rings or 4-10 membered heterocycles, wherein: The C 1-6 The alkyl group is optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, OH, CN, C. 1-6 Heteroalkyl, oxo, and 3-8 membered rings (e.g., cyclopropyl, cyclobutyl, etc.), wherein the C 1-6 The heteroalkyl group and the 3-8 membered ring are optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, oxo, OH, C-membered rings optionally substituted with deuterium, halogen and / or OH. 1-3 Alkyl or optionally C 1-3 3-5 membered rings substituted with alkyl, halogen, and / or OH groups; and The C 3-10 The carbocyclic ring or 4-10-membered heterocycle is optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, OH, CN, C. 1-6 Alkyl, C 1-6 Heteroalkyl, oxo, and 3-8 membered rings, wherein the C 1-6 Alkyl, C 1-6 The heteroalkyl group and the 3-8 membered ring are optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, oxo, OH, C-membered rings optionally substituted with deuterium, halogen and / or OH. 1-3 Alkyl or optionally C 1-3 3-5 membered rings substituted with alkyl, halogen and / or OH.

10. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 1 Based on The structure, where R A1 As defined in claim 9.

11. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein R 1 Based on or The structure, where R A1 As defined in claim 9.

12. The compound according to any one of claims 9 to 11, or a pharmaceutically acceptable salt thereof, wherein R A1 Each time it appears, it is independently (1) a C group that is optionally substituted by one or more substituents independently selected from deuterium, F and OH. 1-4 Alkyl; or (2) C substituted with one or more substituents independently selected from deuterium, methyl, F and OH. 3-6 (3) a 4-6 membered heterocyclic group optionally substituted with one or more substituents independently selected from deuterium, methyl, CD3, F and OH; or (4) (C 1-3 (alkylene)-(3-6 membered ring), wherein the C 1-3 The alkylene group and the 3-6 membered ring are each independently and optionally substituted by one or more substituents independently selected from deuterium, methyl, CD3, F, and OH, wherein the 3-6 membered ring is C 3-6 Cycloalkyl or 4-6 membered heterocyclic groups, for example, an R A1 It can be cyclopropylmethyl, cyclobutylmethyl, , or .

13. The compound according to any one of claims 9 to 11, or a pharmaceutically acceptable salt thereof, wherein R A1 Each time it appears independently, it is (i) C that is optionally replaced by deuterium and / or F. 1-4 Alkyl; (ii) (C 1-2 (alkylene)-C 3-5 cycloalkyl groups, such as cyclopropylmethyl and cyclobutylmethyl, wherein the C 1-2 Alkylene and C 3-5 Each cycloalkyl group is independently and optionally substituted with methyl, deuterium, and / or F; for example, an R A1 yes , or ; or (iii) C substituted with methyl and / or F. 3-4 Cycloalkyl.

14. The compound according to any one of claims 9 to 11, or a pharmaceutically acceptable salt thereof, wherein R A1 Each time it appears independently, it is methyl, CD3, ethyl, CD2CD3, isopropyl, difluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl. cyclopropylmethyl, cyclobutylmethyl , , , , , Or cyclopropyl, for example, R 1 yes , , , , , , , , , , , , , , , , , , , or .

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 2 It is an optionally substituted 3-14 membered carbocyclic group, which is monocyclic or polycyclic, and wherein, when substituted, the 3-14 membered carbocyclic group is preferably substituted by one or more substituents, each of which is independently deuterium, halogen, CN, oxo, or OR. A2 SR A2 NR A2 R A2 C(O)R A2 C(O)OR A2 C(O)NR A2 R A2 S(O)R A2 SO2R A2 SO2NR A2 R A2 OC(O)R A2 NR A2 C(O)R A2 NR A2 SO2R A2 ,PO(R A2 (R) A2 ) or R B2 , Where R A2 Each time it appears, it is independently either hydrogen or R. B2 ,and Where R B2 Each time it appears, it is independently an optionally substituted group selected from the following: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group or 3-7 membered carbocyclic ring or 4-7 membered heterocyclic ring, wherein when substituted... The C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is preferably substituted by one or more substituents independently selected from the following: deuterium, halogen, OH, CN, C. 1-6 Heteroalkyl, oxo, and 3-8 membered rings, wherein the C 1-6 The heteroalkyl group and the 3-8 membered ring are optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, oxo, OH, C-membered rings optionally substituted with deuterium, halogen and / or OH. 1-3 Alkyl or optionally C 1-3 3-5 membered rings substituted with alkyl, halogen, and / or OH groups; and The 3-7 membered carbon ring or 4-7 membered heterocycle is preferably substituted by one or more substituents independently selected from the following: deuterium, halogen, OH, CN, C. 1-6 Alkyl, C 1-6 Heteroalkyl, oxo, and 3-8 membered rings, wherein the C 1-6 Alkyl, C 1-6 The heteroalkyl group and the 3-8 membered ring are optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, oxo, OH, C-membered rings optionally substituted with deuterium, halogen and / or OH. 1-3 Alkyl or optionally C 1-3 3-5 membered rings substituted with alkyl, halogen and / or OH.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R 2 It is a single-ring C 3-8 Cycloalkyl, optionally substituted with one or more substituents, each of which is independently deuterium, halogen, OH, oxo, and optionally substituted with one or more G... S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Alkoxy, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkyl group.

17. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R 2 It is a single-ring C 3-7 Cycloalkyl groups, such as cyclohexyl or cycloheptyl, are optionally substituted with one or more substituents, each of which is independently deuterium, F, or optionally G. S2 Replacement C 1-3 Alkyl, wherein G S2 Each time it appears, it is independently of deuterium, F, or OH, for example, R. 2 yes , , , or , or R 2 Selected from: .

18. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R 2 It is a multi-cyclic C 4-10 The carbocyclic group, such as spiro[2,5]octyl, indane, etc., is optionally substituted with one or more substituents, each of which is independently deuterium, halogen, OH, oxo, and optionally substituted with one or more G groups. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Alkoxy, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkyl group.

19. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R 2 It is a spiral, fused, or bridged double ring C 4-10 cycloalkyl, for example, or It is optionally substituted with one or more substituents, each of which is independently deuterium, halogen, OH, oxo, and optionally substituted with one or more G. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Alkoxy, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy, for example, R 2 Selected from: .

20. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 2 have The structure in which R 10 and R 11 Each is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted C 3-7 A carbocyclic or optionally substituted phenyl group, wherein R 10 and R 11 At least one of them is not hydrogen, preferably, R 10 and R 11 Neither of them is hydrogen.

21. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R 10 It is arbitrarily controlled by one or more Gs S1 Replacement C 1-4 Alkyl, wherein G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy, for example, R 10 It is unreplaced C 1-4 alkyl.

22. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R 10 It is (1) C 3-6 cycloalkyl; or (2)-(C 1-3 alkylene)-(C 3-6 cycloalkyl), wherein the C 1-3 Alkylene and C 3-6 Each of the cycloalkyl groups is optionally substituted with, for example, one or more substituents, each of which is independently deuterium, halogen, OH, oxo, and optionally substituted with one or more G groups. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Heteroalkyl, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy, for example, R 10 It is cyclopropyl, methylcyclopropyl, or cyclobutyl.

23. The compound of claim 20 or a pharmaceutically acceptable salt thereof, wherein R 10 It is (1) phenyl; or (2)-(C) 1-3 (alkylene)-phenyl, wherein the C 1-3 Each of the alkylene and phenyl groups is optionally substituted with, for example, one or more substituents, each of which is independently deuterium, halogen, OH, CN, or optionally with one or more G groups. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Heteroalkyl, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy, for example, R 10 It is a phenyl or halogen-substituted phenyl, such as 2-chlorophenyl.

24. The compound according to any one of claims 20 to 23, or a pharmaceutically acceptable salt thereof, wherein R 11 It is (1) C 3-6 cycloalkyl; or (2)-(C 1-3 alkylene)-(C 3-6 cycloalkyl), wherein the C 1-3 Alkylene and C 3-6 Each of the cycloalkyl groups is optionally substituted with, for example, one or more substituents, each of which is independently deuterium, halogen, OH, oxo, and optionally substituted with one or more G groups. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Heteroalkyl, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy, for example, R 11 It is cyclopropyl, methylcyclopropyl, or cyclobutyl.

25. The compound according to any one of claims 20 to 23, or a pharmaceutically acceptable salt thereof, wherein R 11 It is (1) phenyl; or (2)-(C) 1-3 (alkylene)-phenyl, wherein the C 1-3 Each of the alkylene and phenyl groups is optionally substituted with, for example, one or more substituents, each of which is independently deuterium, halogen, OH, oxo, CN, or optionally with one or more G groups. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Heteroalkyl, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy, for example, R 11 It is a phenyl or halogen-substituted phenyl, such as 2-chlorophenyl.

26. The compound according to any one of claims 20 to 25, or a pharmaceutically acceptable salt thereof, wherein R 10 and R 11 They are the same.

27. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein R 10 and R 11 Both are cyclopropyl, cyclobutyl, or phenyl.

28. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 2 It is an optionally substituted 10-14 membered polycyclic heterocyclic group having 1-3 independently selected cyclic heteroatoms chosen from S, O, and N, wherein when substituted, the 10-14 membered polycyclic heterocyclic group is preferably substituted by one or more substituents, each of which is independently deuterium, halogen, CN, oxo, or OR. A2 SR A2 NR A2 R A2 C(O)R A2 C(O)OR A2 C(O)NR A2 R A2 S(O)R A2 SO2R A2 SO2NR A2 R A2 OC(O)R A2 NR A2 C(O)R A2 NR A2 SO2R A2 ,PO(R A2 (R) A2 ) or R B2 , Where R A2 Each time it appears, it is independently either hydrogen or R. B2 ,and Where R B2 Each time it appears, it is independently an optionally substituted group selected from the following: C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group or 3-7 membered carbocyclic ring or 4-7 membered heterocyclic ring, wherein when substituted... The C 1-6 Alkyl, C 2-6 alkenyl or C 2-6 The alkynyl group is preferably substituted by one or more substituents independently selected from the following: deuterium, halogen, OH, CN, C. 1-6 Heteroalkyl, oxo, and 3-8 membered rings, wherein the C 1-6 The heteroalkyl group and the 3-8 membered ring are optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, oxo, OH, C-membered rings optionally substituted with deuterium, halogen and / or OH. 1-3 Alkyl or optionally C 1-3 3-5 membered rings substituted with alkyl, halogen, and / or OH groups; and The 3-7 membered carbon ring or 4-7 membered heterocycle is preferably substituted by one or more substituents independently selected from the following: deuterium, halogen, OH, CN, C. 1-6 Alkyl, C 1-6 Heteroalkyl, oxo, and 3-8 membered rings, wherein the C 1-6 Alkyl, C 1-6 The heteroalkyl group and the 3-8 membered ring are optionally substituted by one or more substituents independently selected from the following: deuterium, halogen, oxo, OH, C-membered rings optionally substituted with deuterium, halogen and / or OH. 1-3 Alkyl or optionally C 1-3 3-5 membered rings substituted with alkyl, halogen and / or OH.

29. The compound of claim 28 or a pharmaceutically acceptable salt thereof, wherein the optionally substituted 10-14 membered polycyclic heterocyclic group is optionally substituted by one or more substituents, each of the one or more substituents being independently a halogen, CN, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 The alkoxy group, wherein the 10-14 membered polycyclic heterocyclic group has a fused ring structure from a 5-7 membered heterocycle and a phenyl or 6-membered heteroaryl ring, optionally forming an additional ring having a spiro, fused, or bridged structure of the 5-7 membered heterocycle; preferably, the 10-14 membered polycyclic heterocyclic group has a fused ring structure from a 6-membered heterocycle having a cyclic heteroatom that is itself O, N, or S and a phenyl ring, optionally further containing a spiropropyl ring to the 6-membered heterocycle, for example, the optionally substituted 10-14 membered polycyclic heterocyclic group may be , or More preferably, .

30. The compound according to any one of claims 1, 2, 4, 5 and 7 to 29, or a pharmaceutically acceptable salt thereof, wherein, where applicable, ring A and (R) 7 ) n Together , , or The structure is given by n, where n is 0-3, depending on the valence.

31. The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein ring A and (R) 7 ) n Together The structure, where R 7 The amide NH in Formula I is located at the ortho position.

32. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 and 7 to 31, wherein R 3 and R 4 Each is independently and arbitrarily controlled by one or more Gs S2 Replacement C 1-4 Alkyl groups or optionally one or more G S2 Replacement C 1-4 Heteroalkyl, of which G S2 Each time it appears, it is independently of deuterium, F, or OH.

33. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 and 7 to 32, wherein R 3 C is C that is optionally replaced by deuterium and / or F. 1-4 Alkyl, for example, R 3 It is a methyl group.

34. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 and 7 to 33, wherein R 4 C is C that is optionally replaced by deuterium and / or F. 1-4 Alkyl, for example, R 4 It is a methyl group.

35. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 and 7 to 33, wherein R 4 It is C 3-6 cycloalkyl or -(C 1-3 alkylene)-(C 3-6 cycloalkyl), wherein the C 3-6 Each of the cycloalkyl groups is optionally substituted with one or more substituents, each of which is independently deuterium, halogen, OH, oxo, and optionally substituted with one or more G groups. S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Heteroalkyl, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkyl group.

36. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 and 7 to 31, wherein R 3 and R 4 It is attached together with the carbon atoms of both of them to form an optionally substituted 3-7 membered carbon ring, such as a cyclopropyl or cyclobutyl ring.

37. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 and 7 to 31, wherein R 3 and R 4 The carbon atoms attached to both of them are linked together to form a 4-8 membered heterocycle having one or two independent cyclic heteroatoms selected from O, N, and S, wherein the sulfur atom, if present, is optionally oxidized, and the 4-8 membered heterocycle is optionally substituted, for example, R. 3 and R 4 It connects together with the carbon atoms to which both are attached to form optional substitutions. or .

38. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 and 7 to 31, wherein R 3 and R 4 It connects together with the carbon atoms to which both are attached to form an optionally substituted cyclopropyl ring, for example, an unsubstituted cyclopropylene ring. Or F-substituted cyclopropylene, for example, .

39. The compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein L 1 It is empty.

40. The compound according to any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen or C optionally replaced by F. 1-4 Alkyl (e.g., methyl or fluorine-substituted methyl), preferably R 5 It is hydrogen.

41. The compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R 6 It is N(G) 2A )C(O)G 2B 、N(G 2A )C(O)OG 2B 、N(G 2A )C(O)NG 2A G 2B 、N(G 2A SO2G 2B or N(G) 2A SO2NG 2A G 2B ,in G 2A Each time it appears, it is independently hydrogen or an optionally substituted C. 1-6 Alkyl; and G 2B It is R X1 (C) 1-4 (alkylene)-R X1 or (C) 1-4 (heteroalkyl)-R X1 Wherein C 1-4 The heteroalkylene group is optionally substituted with an oxygen and contains 1-3 heteroatoms independently selected from S, O, or N, wherein the S atom, if present, is optionally oxidized. Where R X1 C is an optional substitute 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl or optionally substituted 3-14 membered rings (e.g., optionally substituted C) 3-8 (Carbon ring, optionally substituted 5- or 6-membered heteroaryl ring, or optionally substituted 4- to 8-membered heterocycle). When G is replaced, 2A Or R X1 The optionally substituted group is preferably substituted by one or more substituents, each of which is independently deuterium, halogen, OH, oxo (where applicable), CN, or optionally substituted by one or more G. S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl or optionally with one or more G S3 Substituted 3-6 membered rings (e.g., cyclopropyl), where G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl group.

42. The compound of claim 41 or a pharmaceutically acceptable salt thereof, wherein G 2A Each time it appears, it is independently hydrogen or optionally accompanied by one or more G atoms. S2 Replacement C 1-4 Alkyl, wherein G S2 Each time it appears, it is independently of deuterium, F, or OH.

43. The compound according to claim 41 or 42, or a pharmaceutically acceptable salt thereof, wherein G 2B It is arbitrarily controlled by one or more Gs S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl or optionally with one or more G S3 Substituted 3-10 membered rings (e.g., carbocyclic, heterocyclic, or heteroaryl rings), wherein G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl group.

44. The compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein R 6 It is NHC(O)G 2C 、NHC(O)OG 2C or NHC(O)NHG 2C And G 2C It is arbitrarily controlled by one or more Gs S1 Replacement C 1-4 Alkyl groups (e.g., methyl or ethyl), optionally with one or more G S3 Replacement C 3-6 cycloalkyl (e.g., cyclobutyl), optionally with one or more G S3 The substituted 4-7 membered heterocycle (e.g., oxetane) or optionally substituted by one or more G S3 Substituted 5- or 6-membered heteroaryl groups, wherein G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl group.

45. The compound of claim 44 or a pharmaceutically acceptable salt thereof, wherein R 6 It is NHC(O)G 2D And G 2D It is (1) C that is optionally replaced by one or more deuterium and / or F. 1-4 Alkyl, or (2) C substituted with methyl and / or F. 3-6 cycloalkyl, for example, R 6 yes .

46. ​​The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 45, wherein Y is C(O).

47. The compound according to any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, wherein R 8 It's NG 3A G 3B , Among them G 3A It is hydrogen or an optional substituted C 1-6 Alkyl; and G 3B It is R X2 (C) 1-4 (alkylene)-R X2 or (C) 1-4 (heteroalkyl)-R X2 Wherein C 1-4 The heteroalkylene group is optionally substituted with an oxygen and contains 1-3 heteroatoms independently selected from S, O, or N, wherein the S atom, if present, is optionally oxidized. Where R X2 C is an optional substitute 1-6 Alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 3-6 alkynyl group, optionally substituted C 1-6 Heteroalkyl or optionally substituted 3-14 membered rings (e.g., optionally substituted C) 3-8 (Carbon ring or optionally substituted 4-8 membered heterocycles). When G is replaced, 3A Or R X2 The optionally substituted group is preferably substituted by one or more substituents, each of which is independently deuterium, halogen, OH, oxo (where applicable), CN, or optionally substituted by one or more G. S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl or optionally with one or more G S3 Substituted 3-6 membered rings (e.g., cyclopropyl), where G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl group.

48. The compound according to any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, wherein R 8 It is an optionally substituted 4-8 membered heterocycle having 1-3 cyclic heteroatoms, wherein one of the cyclic heteroatoms is a cyclic nitrogen bonded to Y, and any remaining cyclic heteroatoms are independently selected from N, O and S, wherein the sulfur atom, if present, is optionally oxidized.

49. The compound of claim 48 or a pharmaceutically acceptable salt thereof, wherein R 8 It has a structure represented by M-1, (M-1), the structure being optionally substituted with a ring selected from the following: azacyclobutane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine 1,1,dioxide and azaspiro[3,3]heptane, When substituted, the optionally substituted ring is preferably substituted by one or more substituents, each of which is independently deuterium, halogen, OH, oxo (where applicable), CN, or R. X3 OR X3 C(O)R X3 SO2R X3 (C) 1-4 (alkylene)-R X3 or (C) 1-4 (heteroalkyl)-R X3 Wherein C 1-4 The heteroalkylene group is optionally substituted with an oxo group and contains 1-3 heteroatoms independently selected from S, O, or N, wherein the S atom, if present, is optionally oxidized, or the two substituents are linked together with the atoms they are bonded to form a 3-6 membered ring, which may be spiro, fused, or bridged. Where R X3 Each time it appears, it is independently and optionally controlled by one or more Gs. S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl or optionally with one or more G S3 Substituted 3-6 membered rings (e.g., cyclopropyl, phenyl, etc.), wherein G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl group.

50. The compound according to any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, wherein R 8 It has a structure represented by M-2, (M-2) Where R 30 It is hydrogen, optionally by one or more G S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl, optionally with one or more G S3 Substituted 3-6 membered rings (e.g., cyclopropyl, phenyl, etc.) or (C 1-2 alkylene)-(3-6-membered ring), wherein the 3-6-membered ring (e.g., cyclopropyl) is optionally surrounded by one or more G S3 Replace, where G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkoxy k is 0, 1, or 2, and R 31 Each time it appears, it is independently deuterated, oxidized, or optionally substituted with F, C. 1-4 Alkyl, or two R 31 Linked with intermediate atoms to form rings, such as fused or spiropropyl or bridged rings, or an R 31 and R 30 They connect together with intermediate atoms to form a ring. For example, R 8 It can have a structure selected from the following: Where k1 is 0 or 1, and R 30 As defined above.

51. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R 30 It is hydrogen or optionally composed of one or more G atoms. S1 Replacement C 1-4 Alkyl, or R 30 It is cyclopropyl or (C 1-2 alkylene)-(cyclopropyl), wherein the cyclopropyl group is optionally surrounded by one or more G S1 Replace, where G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy, for example, R 30 It is CH3, CD3, ethyl groups optionally substituted with 1-3 F atoms (e.g., CH2CF2H, CH2CF3, etc.), methoxyethyl, cyclopropylmethyl, cyclopropyl, etc., for example, R 8 It can have a structure selected from the following: 。 52. The compound of claim 50 or 51 or a pharmaceutically acceptable salt thereof, wherein k is 0.

53. The compound according to claim 50 or 51, or a pharmaceutically acceptable salt thereof, wherein k is 1 or 2, and R 31 It is methyl in every instance.

54. The compound of claim 48 or a pharmaceutically acceptable salt thereof, wherein R 8 It has a structure represented by M-3. (M-3) in R 32 It is hydrogen, halogen, CN, optionally with one or more Gs S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl or optionally with one or more G S3 Substituted 3-6 membered rings (e.g., cyclopropyl, phenyl, etc.). R 33 It is hydrogen, halogen, CN, OH, NH2, optionally with one or more G S1 Replacement C 1-4 Alkyl, optionally with one or more G S1 Replacement C 1-4 Heteroalkyl (e.g., C 1-4 Alkoxy, C 1-4 Monoalkylamines or C 2-4 Dialkylamine) or optionally with one or more G S3 Substituted 3-6 membered rings (e.g., cyclopropyl, phenyl, etc.). Or R 32 and R 33 It is attached together with the carbon atoms to form a C(=O) or optionally substituted 3-6 membered ring (e.g., cyclopropyl, cyclobutyl, oxetane, etc.), for example, R 8 yes , wait, Among them G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy; and G S3 Each time it appears, it is independently deuterium, F, OH, or C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkoxy j is 0, 1, or 2, and R 34 Each time it appears, it is independently oxidized, deuterated, halogenated, CN, or C optionally substituted with F. 1-4 Alkyl, or two R 34 Or an R 34 and R 32 and R 33 One of them is linked together with an intermediate atom to form a ring, such as a spiropropyl or a fused or bridged ring.

55. The compound of claim 54 or a pharmaceutically acceptable salt thereof, wherein R 32 It is hydrogen, F, optionally with one or more Gs S1 Replacement C 1-4 Alkyl groups or optionally one or more G S1 Replacement C 1-4 Alkoxy, of which G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy, for example, R 32 It includes F, CH3, CHF2, CF3, difluoromethoxy, etc.

56. The compound according to claim 54 or 55, or a pharmaceutically acceptable salt thereof, wherein R 33 It is hydrogen, OH, halogen (e.g., F), CN, or optionally by one or more Gs. S1 Replacement C 1-4 Alkyl, wherein G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkoxy, for example, R 33 It includes hydrogen, F, CH3, OH, etc., for example, R 8 have , , , , , or The structure.

57. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 54 to 56, wherein j is 0.

58. The compound according to any one of claims 54 to 56, or a pharmaceutically acceptable salt thereof, wherein j is 1 or 2, and R 34 Each time it appears, it is independently OH, halogen, CN, or optionally accompanied by one or more Gs. S1 Replacement C 1-4 Alkyl, wherein G S1 Each time it appears, it is independently deuterium, F, OH, or C substituted with deuterium and / or F. 1-4 Alkyl group.

59. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 58, wherein n is 0, 1 or 2, preferably n is 0 or 1.

60. The compound according to any one of claims 1 to 59, or a pharmaceutically acceptable salt thereof, wherein R 7 Each occurrence is independently a halogen (e.g., F, Cl, or Br), CN, or C optionally substituted with F. 1-6 Alkyl groups, C groups optionally substituted with F 2-6 Alkenyl, C optionally substituted with F 2-6 Alkyne group, C group optionally substituted with F 1-6 Heteroalkyl groups, optionally substituted 3-7 membered carbon rings or 4-7 membered heterocycles with 1-2 cyclic heteroatoms, OG 4 NG 4 G 4 SG 4 C(O)G 4 or C(O)NG 4 G 4 G 4 Each time it appears, it is independently hydrogen, optionally replaced by F, C. 1-6 Alkyl or optionally substituted 3-7 membered carbon rings or heterocycles having 1-2 cyclic heteroatoms, wherein each of the optionally substituted 3-7 membered carbon rings or heterocycles is optionally substituted by one or more substituents independently selected from: deuterium, F, OH, C optionally substituted with deuterium and / or F. 1-4 Alkyl groups or C groups optionally substituted with deuterium and / or F 1-4 Alkyl group.

61. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 59, wherein R 7 Each time it appears, it is independently F, Cl, or C, which is optionally replaced by F. 1-4 Alkyl groups, C groups optionally substituted with F 2-4 Alkenyl, C optionally substituted with F 2-4 Alkyne group or C group optionally substituted with F 1-4 Heteroalkyl groups.

62. A compound selected from Table 1 or Examples 1 to 174, or a pharmaceutically acceptable salt thereof.

63. A pharmaceutical composition comprising a compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

64. A method for modulating IL-17A and / or IL-17F in a subject in need, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 63.

65. A method for treating an inflammatory disease or condition in a subject in need, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 63.

66. The method of claim 65, wherein the inflammatory disease or symptom is selected from plaque psoriasis, guttate psoriasis, inverted psoriasis, pustular psoriasis, erythrodermic psoriasis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, rheumatoid arthritis, palmoplantar psoriasis, spondyloarthritis and non-infectious uveitis.

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