CBL-B inhibitors and methods of use thereof

Abstract

Described herein are inhibitors of Cassias B-line lymphoma (Cbl) and pharmaceutical compositions comprising the inhibitors. The subject compounds and compositions are useful for the treatment of diseases or conditions associated with Cbl-b activity, such as cancer.

Description

[0001] Cross-references

[0002] This patent application claims the benefits of international applications filed on September 28, 2023, PCT / CN2023 / 122735, PCT / CN2024 / 071520, January 10, 2024, PCT / CN2024 / 075999, February 5, 2024, PCT / CN2024 / 096583, May 31, 2024, and August 21, 2024, PCT / CN2024 / 113575, which are incorporated herein by reference in their entirety.

[0003] field

[0004] This disclosure provides compounds that can be used as inhibitors of Cavitas B-lineage lymphoma (Cbl), pharmaceutical compositions comprising them, and their use in treating diseases or conditions associated with Cbl-b activity.

[0005] background

[0006] Signal transduction dysregulation is a key feature of cell transformation and tumorigenesis. The proto-oncogene Casites B-cell lymphoma (Cbl) encodes an E3 ubiquitin ligase, which downregulates PTK-directed cellular signaling via ubiquitination, thereby targeting kinases involved in lysosomal or proteasomal degradation. Cbl is a member of the Cbl protein family and is therefore characterized by a highly conserved N-terminal region containing the structural components required for ubiquitin ligase activity. In simpler eukaryotes such as Caenorhabditis elegans (C. elegans), this dysregulation is also observed. Caenorhabditis elegans ) and *Discotyledon* ( Dictyostelium discoideum Only one Cbl protein exists in the body, but three Cbl proteins exist in mammals, including Cbl, Cbl-b and Cbl-c.

[0007] Cbl-b is an important brake on the T-cell immune response. Unlike Cbl, which primarily regulates thymocyte development, Cbl-b mainly regulates peripheral T-cell activation by negatively modulating the TCR (T-cell receptor) signaling pathway. Specifically, Cbl-b inhibits VAV1 activation during TCR engagement and compels CD28 co-stimulation to promote naive T-cell proliferation and IL-2 production. Cbl-b also ubiquitinates PIK3R1 / p85, which inhibits their recruitment to CD28 and TCRζ, thereby suppressing PI3K activation, a key kinase involved in T-cell activation and differentiation. Furthermore, in activated T-cells, Cbl-b inhibits PLACG1 activation and calcium mobilization upon restimulation, thereby promoting T-cell unresponsiveness. Thus, Cbl-b limits unnecessary T-cell overactivation under physiological conditions. Indeed, Cbl-b KO mice exhibit increased T-cell proliferation, spontaneous autoimmunity characterized by autoantibody production, and infiltration of activated T and B lymphocytes into multiple organs. On the other hand, T cell unresponsiveness, exhaustion, and exclusion are widespread in the tumor microenvironment. Therefore, releasing the full energy of T cells by releasing the Cbl-b brakes holds great promise as an immuno-oncology anticancer therapy.

[0008] Therefore, there is a need for new cancer therapies, especially those using Cbl-b inhibitors.

[0009] Overview

[0010] In one aspect, this disclosure provides compounds of formula (I), (II), (III) or (IV) disclosed herein, or pharmaceutically acceptable salts thereof:

[0011]

[0012]

[0013]

[0014] .

[0015] This document also discloses compounds of formula (Ia), (IIa) or (IIIa) as disclosed herein, or pharmaceutically acceptable salts thereof:

[0016] ,

[0017] ,

[0018] .

[0019] This document also discloses compounds of formula (Ib), formula (Ic), formula (Id), formula (IIb), formula (IIc), formula (IId), formula (IIe), or formula (IIIb), or pharmaceutically acceptable salts thereof:

[0020] ,

[0021] ,

[0022] ,

[0023] ,

[0024] ,

[0025] ,

[0026] ,

[0027] .

[0028] This document also discloses pharmaceutical compositions comprising the compounds disclosed herein (e.g., compounds of formula (I), (Ia), (Ib), (Ic) or (Id), compounds of formula (II), (IIa), (IIb), (IIc), (IId) or (IIe), compounds of formula (III), (IIIa) or (IIIb), compounds of formula (IV), or compounds listed in Table 1, Table 2 or Table 3) or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.

[0029] This article also discloses a method for regulating the activity of immune cells, the method comprising contacting the immune cells with an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0030] This article also discloses methods for treating cancer, which include administering an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof to an individual in need.

[0031] This article also discloses a method for treating cancers that respond to inhibition of Cbl-b activity, the method comprising administering to an individual in need an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0032] This article also discloses a method for inhibiting abnormal cell proliferation, the method comprising administering to an individual in need an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0033] This article also discloses methods for modulating immune responses, which include administering an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof to an individual in need.

[0034] This document also discloses a method for inhibiting Cbl-b activity, the method comprising administering to an individual in need an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0035] This document also discloses methods for treating diseases or conditions associated with Cbl-b activity, the methods comprising administering to an individual in need an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0036] By incorporating via reference

[0037] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication, patent or patent application were specifically cited and incorporated herein by reference.

[0038] Detailed Explanation

[0039] definition

[0040] In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the invention can be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, the word “comprising” and its variations, such as “including” and “containing,” in the specification and the following claims shall be interpreted in an open, inclusive sense, that is, as “including, but not limited to.” Furthermore, the headings provided herein are for convenience only and do not constitute an explanation of the scope or meaning of the claimed invention.

[0041] Throughout this specification, references to "some embodiments" or "one embodiment" mean that a particular feature, structure, or characteristic associated with that embodiment is included in at least one embodiment. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in different places in this specification do not necessarily refer to the same embodiment. Furthermore, in one or more embodiments, a particular feature, structure, or characteristic may be combined in any suitable manner. Additionally, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. It should also be noted that the term "or" is generally used as it is meant, including "and / or," unless the context clearly indicates otherwise.

[0042] Unless otherwise stated, the following terms used herein have the following meanings.

[0043] The definitions of specific functional groups and chemical terms are described in more detail below. For the purposes of this disclosure, chemical elements are identified according to the periodic table (CAS edition), Handbook of Chemistry and Physics, 75th edition, inner cover, and specific functional groups are generally as defined therein. Furthermore, the general principles of organic chemistry, as well as specific functional groups and reactivity, are described in the following references: Organic Chemistry, Thomas Sorrell, 2nd edition, University ScienceBooks, Sausalito, 2006; Smith and March, March's Advanced Organic Chemistry, 6th edition, John Wiley & Sons, Inc., New York, 2007; Larock, Comprehensive Organic Transformations, 3rd edition, VCH Publishers, Inc., New York, 2018; Carruthers, Some Modern Methods of Organic Synthesis, 4th edition, Cambridge University Press, Cambridge, 2004; the entire contents of each of these are incorporated herein by reference.

[0044] Linking substituents are described in various parts of this disclosure. When the structure clearly requires a linking group, the Markush variable listed for that group should be understood as a linking group. For example, if the structure requires a linking group and the Markush group definition for that variable lists "alkyl", then that "alkyl" should be understood to represent a linked alkylene.

[0045] When the bond to a substituent is shown as an intersecting bond between two atoms in the ring, the substituent can bond to any atom in the ring. When a substituent is listed without specifying which atom it bonds to the rest of the compound in a given structure, the substituent can bond to any atom in the structure. Combinations of substituents and / or variables are permitted, provided that such combinations produce stable compounds.

[0046] When any variable (e.g., R) i When a group appears more than once in any component or structural formula of a compound, its definition for each occurrence is independent of its definition for each occurrence in other cases. Therefore, for example, if a group shows 0-2 R... iIf a radical is substituted, the radical can be optionally replaced by at most two R groups. i Substitution of atomic groups, and each time R appears i Independently selected from R i The definition of [the compound]. Furthermore, combinations of substituents and / or variables are permitted, provided that such combinations produce stable compounds.

[0047] The term "C" used in this article i -C j "or "C i - j "C" represents a range of carbon atoms, where i and j are integers, and the range includes the endpoints (i.e., i and j) and every integer point between the two endpoints, where j is greater than i. For example, C1-C6 represents a range of 1-6 carbon atoms, including 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, and 6 carbon atoms. In some implementations, the term "C" is used to indicate the range of carbon atoms. 1-12 "Indicates 1-12, especially 1-10, especially 1-8, especially 1-6, especially 1-5, especially 1-4, especially 1-3 or especially 1-2 carbon atoms.

[0048] "Oxytochemical" refers to the compound oxygen (O).

[0049] "Cyano" refers to -CN.

[0050] Whether used as part of another term or independently, "amino" refers to the -NR group. a R b , where R a and R b The group is independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclic or other suitable organic groups, and each of these groups may optionally be substituted.

[0051] Whether used as part of another term or independently, "hydroxyl" or "hydroxyl" refers to -OH.

[0052] Whether used as part of another term or independently, "alkyl" refers to a saturated monovalent hydrocarbon residue having a straight or branched chain having 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups, such as heptyl, octyl, etc. Whenever it appears herein, numerical ranges such as “C1-C6 alkyl” or “C1-6 alkyl” mean that the alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, but this definition also covers any occurrence of the term “alkyl” without a specified numerical range. In some embodiments, the alkyl group is C1- 10 Alkyl group. In some embodiments, the alkyl group is C1-6 alkyl. In some embodiments, the alkyl group is C1-5 alkyl. In some embodiments, the alkyl group is C1-4 alkyl. In some embodiments, the alkyl group is C1-3 alkyl. Unless otherwise specifically stated in this specification, the alkyl group may optionally be substituted, for example, substituted by one or more substituents such as oxo, halogen, amino, cyano, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxyl ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl group is optionally substituted by one or more substituents such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group is optionally substituted by one or more substituents such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl group is optionally substituted by a halogen.

[0053] Whether used as part of another term or independently, "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon residue having one or more carbon-carbon double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. This group can be in cis or trans configuration, or surrounding the double bond. E or ZConfiguration should be understood to include two isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears herein, numerical ranges such as "C2-C6 alkenyl" or "C2-6 alkenyl" mean that the alkenyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also covers any occurrence of the term "alkenyl" without a specified numerical range. Unless otherwise specified in this specification, the alkenyl group may optionally be substituted, for example, by one or more substituents such as oxo, halogen, amino, cyano, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group is optionally substituted with one or more substituents such as oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl group is optionally substituted with one or more substituents such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group is optionally substituted with a halogen.

[0054] Whether used as part of another term or independently, "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon residue having one or more carbon-carbon triple bonds and having 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, etc. Whenever it appears herein, numerical ranges such as "C2-C6 alkynyl" or "C2-6 alkynyl" mean that the alkynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but this definition also covers any occurrence of the term "alkynyl" without a specified numerical range. Unless otherwise specified in this specification, the alkynyl group may optionally be substituted, for example, by one or more substituents such as oxo, halogen, amino, cyano, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxyl ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl group is optionally substituted with one or more substituents such as oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl group is optionally substituted with one or more substituents such as halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl group is optionally substituted with a halogen.

[0055] "alkylidenyl" is an alkyl group defined above, linked by a terminal divalent carbon. Exemplary alkylidenyl groups include, but are not limited to, methyleneidenyl (H2C=), ethoxyidenyl (CH3CH=), propyleneidenyl (e.g., =C(CH3)2 and =CHCH2CH3), hexoxyidenyl (e.g., CH3(CH2)4CH=), etc. For example, in the following compounds:

[0056] The alkylidene group (i.e., the ethoxyne group) is surrounded by a box as shown by the arrow.

[0057] Whether used as part of another term or independently, "alkoxy" or "alkoxyl" refers to the formula -OR a The group, wherein R a Alkyl group as defined herein. Whenever appearing herein, numerical ranges such as “C1-C6 alkoxy” or “C1-6 alkoxy” mean that the alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms; however, this definition also covers any occurrence of the term “alkoxy” without a specified numerical range. In some embodiments, the alkoxy group is C1- 10 Alkoxy group. In some embodiments, the alkoxy group is C1-6 alkoxy. In some embodiments, the alkoxy group is C1-5 alkoxy. In some embodiments, the alkoxy group is C1-4 alkoxy. In some embodiments, the alkoxy group is C1-3 alkoxy. In some embodiments, the alkoxy group is C1-2 alkoxy. In some embodiments, the alkoxy group is methoxy. Unless otherwise specifically stated in this specification, the alkoxy group may optionally be substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy group is optionally substituted with halogen.

[0058] Whether used as part of another term or independently, "aryl" refers to a group derived from a hydrocarbon ring system comprising 6-30 carbon atoms and at least one aromatic ring. Aryl groups can be monocyclic or polycyclic (including, but not limited to, bicyclic, tricyclic, or tetracyclic) ring systems, which may include fused ring systems (e.g., an aryl ring fused to a cycloalkyl or another aryl ring) or bridged ring systems. In some embodiments, the aryl group is 6- to 10-membered aryl. In some embodiments, the aryl group is 6-membered aryl (phenyl). Aryl groups include, but are not limited to, aryl groups derived from hydrocarbon ring systems of anthracene, azurite, benzene, benzo[a], fluorene, as-indacene, s-indacene, indene, indene, naphthalene, phenalene, pleiadene, pyrene, and benzo[9,10]phenanthrene. Unless otherwise specified in this specification, the aryl group may optionally be substituted, for example, by one or more substituents, such as halogens, amino groups, cyano groups, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid ester groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, the aryl group is optionally substituted by one or more substituents, such as halogens, methyl groups, ethyl groups, -CN groups, -COOH groups, COOMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, the aryl group is optionally substituted by one or more substituents, such as halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, or -OMe groups. In some embodiments, the aryl group is optionally substituted by a halogen.

[0059] Whether used as part of another term or independently, "cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused ring systems (e.g., a cycloalkyl ring fused to another cycloalkyl ring), spirocyclic systems, or bridged ring systems. In some embodiments, the cycloalkyl group is fully saturated. In some embodiments, the cycloalkyl group is partially saturated. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having 3-15 carbon atoms (C3-C4). 15 Fully saturated cycloalkyl or C3-C 15 Cycloalkenyl), cycloalkyl groups with 3-10 carbon atoms (C3-C4) 10 Fully saturated cycloalkyl or C3-C 10Cycloalkyl groups are 3- to 10-membered fully saturated cycloalkyl groups or 3- to 6-membered cycloalkyl groups. In some embodiments, the cycloalkyl group is a 3- to 6-membered fully saturated cycloalkyl group or 5- to 6-membered cycloalkyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornel, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specified in this specification, the cycloalkyl group is optionally substituted, for example, by one or more substituents, such as oxo, halogen, amino, cyano, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl group is optionally substituted by one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the cycloalkyl group is optionally substituted by one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl group is optionally substituted by a halogen.

[0060] "Cycloalkylalkyl" refers to a cycloalkyl group linked to an alkyl group, including -cycloalkyl-alkyl and cycloalkyl-alkyl-. In some embodiments, cycloalkylalkyl refers to -cycloalkyl-alkyl. In some embodiments, cycloalkylalkyl refers to cycloalkyl-alkyl-.

[0061] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0062] "Halogenated alkyl" refers to an alkyl group defined above that has been substituted with one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0063] "Haloalkoxy" refers to an alkoxy group as defined above that has been substituted with one or more halogen groups as defined above.

[0064] "Halogenated alkynyl" refers to an alkynyl group as defined above that has been replaced by one or more halogen groups as defined above.

[0065] "Hydroxyalkyl" means an alkyl group as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0066] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amino groups. In some embodiments, the alkyl group is substituted with one amino group. In some embodiments, the alkyl group is substituted with one, two, or three amino groups. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0067] "Carboxylate group" refers to the -C(O)O- group. "Substituted carboxylate group" refers to -C(O)OG, where G is a carboxylate protecting group. Carboxylate protecting groups are well known to those skilled in the art. A comprehensive list of protecting groups for carboxylate functional groups can be found in Protective Groups in Organic Synthesis, Greene, TW; Wuts, PGM, John Wiley & Sons, New York, NY, (3rd edition, 1999), and carboxylate protecting groups can be added or removed using the methods given therein.

[0068] "Heteroalkyl" means an alkyl group in which one or more skeletal atoms are selected from non-carbon atoms such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl group is attached to the carbon atom of the heteroalkyl group to the remainder of the molecule. In one aspect, a heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group consists of 1-6 carbon atoms and one or more non-carbon atoms such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, wherein the heteroalkyl group is attached to the carbon atom of the heteroalkyl group to the remainder of the molecule. Examples of such heteroalkyl groups are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specified in this specification, heteroalkyl groups are optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl groups are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyl groups are optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl groups are optionally substituted with halogens.

[0069] "Heteroalkenyl" refers to an alkenyl group in which one or more skeletal atoms are selected from non-carbon atoms such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. The heteroalkenyl group is attached to the carbon atom of the heteroalkenyl group to the remainder of the molecule. In one aspect, the heteroalkenyl group is a C2-C6 heteroalkenyl group, wherein the heteroalkenyl group consists of 2-6 carbon atoms and one or more non-carbon atoms such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof, wherein the heteroalkenyl group is attached to the carbon atom of the heteroalkenyl group to the remainder of the molecule. Examples of such heteroalkenyl groups are, for example, -CH=CHOCH3, -CH=CHOCH2CH2OCH3, -CH2CH2OCH=CHOCH3, -C(=CH2)OCH3, -CH=NCH3, -CH2N=CH2, -CH=CHNHCH3, or -CH=CHN(CH3)2. Unless otherwise specified in this specification, the heteroalkenyl group is optionally substituted with, for example, oxo, halogen, amino, cyano, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkenyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkenyl group is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkenyl group is optionally substituted with halogen.

[0070] "Hydynyl" refers to an ynyl group in which one or more skeletal atoms are selected from non-carbon atoms such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. The ynylyl group is attached to the carbon atom of the ynylyl group to the remainder of the molecule. In one aspect, the ynylyl group is a C2-C6 ynylyl group, wherein the ynylyl group consists of 2-6 carbon atoms and one or more non-carbon atoms such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof, wherein the ynylyl group is attached to the carbon atom of the ynylyl group to the remainder of the molecule. Examples of such ynylyl groups are, for example, -C≡COCH3, -C≡COCH2CH2OCH3, -CH2CH2OC≡COCH3, -C≡C-NHCH3, or -C≡CN(CH3)2. Unless otherwise specifically stated in this specification, the ynylyl group may optionally be substituted with, for example, oxo, halogen, amino, cyano, nitro, hydroxyl, alkyl, alkenyl, ynylyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the xyrynyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2 group. In some embodiments, the xyrynyl group is optionally substituted with an oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe group. In some embodiments, the xyrynyl group is optionally substituted with a halogen.

[0071] Whether used as part of another term or independently, "heterocyclic" or "heterocyclic alkyl" refers to a 3- to 24-membered partially or fully saturated cyclic group comprising 2-23 carbon atoms and 1-8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocyclic alkyl is fully saturated. In some embodiments, the heterocyclic alkyl comprises 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl comprises 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocyclic alkyl comprises 1-3 nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises 1 or 2 nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises 1 nitrogen atom. In some embodiments, the heterocyclic alkyl comprises 1 nitrogen atom and 1 oxygen atom. Unless otherwise specifically stated in this specification, the heterocyclic alkyl can be a monocyclic or polycyclic (including, but not limited to, bicyclic, tricyclic, or tetracyclic) cyclic system. In some embodiments, the polycyclic heterocyclic alkyl group may include a fused ring system (e.g., a heterocyclic alkyl group fused to a cycloalkyl group or another heterocyclic alkyl group), a spirocyclic system, or a bridged ring system; and the nitrogen, carbon, or sulfur atom in the heterocyclic alkyl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Representative heterocyclic alkyl groups include, but are not limited to, heterocyclic alkyl groups having 2-15 carbon atoms (C2-C4). 15 Fully saturated heterocyclic alkyl or C2-C 15 Heterocyclic alkenyl groups, heterocyclic alkyl groups with 2-10 carbon atoms (C2-C4) 10 Fully saturated heterocyclic alkyl or C2-C 10Heterocyclic alkenyl groups, heterocyclic alkyl groups with 2-8 carbon atoms (C2-C8 fully saturated heterocyclic alkyl groups or C2-C8 heterocyclic alkenyl groups), heterocyclic alkyl groups with 2-7 carbon atoms (C2-C7 fully saturated heterocyclic alkyl groups or C2-C7 heterocyclic alkenyl groups), heterocyclic alkyl groups with 2-6 carbon atoms (C2-C6 fully saturated heterocyclic alkyl groups or C2-C6 heterocyclic alkenyl groups), heterocyclic alkyl groups with 2-5 carbon atoms (C2-C5 fully saturated heterocyclic alkyl groups or C2-C5 heterocyclic alkenyl groups), or heterocyclic alkyl groups with 2-4 carbon atoms (C2-C4 fully saturated heterocyclic alkyl groups or C2-C4 heterocyclic alkenyl groups). Examples of such heterocyclic alkyl groups include, but are not limited to, aziridinyl, aziridine, oxacyclobutane, dioxopentane, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, decahydroisoindolyl, 2-oxopiperidinyl, 2-oxopiperidinyl, 2-oxopiperidinyl, oxazolyl, piperidinyl, piperazine, 4-piperidinoneyl, pyrrolyl, pyrazolyl, quininecycloyl, thiazoalkyl, tetrahydrofuranyl, and trithionylhexyl. Alkyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisophenylfuran-1-yl, methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl, and 2-oxo-1,3-m-dioxacyclopenten-4-yl. The term heterocyclic alkyl also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In some embodiments, the heterocyclic alkyl has 2-10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl group, the number of carbon atoms in the heterocyclic alkyl group is not the same as the total number of atoms constituting the heterocyclic alkyl group (i.e., the skeletal atoms of the heterocyclic alkyl ring) (including heteroatoms). In some embodiments, the heterocyclic alkyl group is a 3- to 8-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 7-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered fully saturated heterocyclic alkyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 8-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 7-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 3- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 4- to 6-membered heterocyclic alkenyl group. In some embodiments, the heterocyclic alkyl group is a 5- to 6-membered heterocyclic alkenyl group.Unless otherwise specified in this specification, heterocyclic alkyl groups may optionally be substituted as described below, for example, by one or more substituents, such as oxo, halogen, amino, cyano, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylic acid ester, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, etc. In some embodiments, the heterocyclic alkyl group is optionally substituted by one or more substituents, such as oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocyclic alkyl group is optionally substituted by one or more substituents, such as halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclic alkyl group is optionally substituted by a halogen.

[0072] "Heterocyclic alkyl" is a heterocyclic group linked to an alkyl group, including -heterocyclic-alkyl and -heterocyclic-alkyl. In some embodiments, heterocyclic alkyl refers to -heterocyclic-alkyl. In some embodiments, heterocyclic alkyl refers to -heterocyclic-alkyl.

[0073] Whether used as part of another term or independently, "heteroaryl" refers to a 5- to 14-membered cyclic group comprising 1-13 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group comprises 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group comprises 1-3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl group comprises 1-3 nitrogen atoms. In some embodiments, the heteroaryl group comprises 1 or 2 nitrogen atoms. In some embodiments, the heteroaryl group comprises 1 nitrogen atom. The heteroaryl group can be a monocyclic or polycyclic (e.g., bicyclic, tricyclic, or tetracyclic) cyclic system. In some embodiments, the polycyclic heteroaryl group may comprise a fused ring system (e.g., a monocyclic heteroaryl group fused with a cycloalkyl, heterocyclic, aryl ring, or another heteroaryl ring, or a monocyclic aryl group fused with a heterocyclic or heteroaryl ring) or a bridged ring system; and the nitrogen, carbon, or sulfur atom in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, azatriyl, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzo-m-dioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxadienyl, 1,4-benzodioxylalkyl, benzonaphthuryl, benzooxazolyl, benzo-m-dioxacyclopentenyl, benzodioxenyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiopheneyl (benzothiophene), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazole, cenyl, dibenzofuranyl, dibenzothiopheneyl, furanyl, furanoneyl, isothiazolyl, imidazolyl, Indazole, indolyl, isoindolyl, dihydroindolyl, isodihydroindolyl, isoquinolinyl, indoleyl, isoxazolyl, naphridinyl, oxadiazolyl, 2-oxoazapyridine, oxazolyl, ethylene oxide, 1-pyridinyl oxide, 1-pyrimidinyl oxide, 1-pyrazinyl oxide, 1-pyridazinyl oxide, 1-phenyl-1H-pyrroleyl, phenazinyl, phenothiazinyl, phenothiazinyl, 2,3-diazanaphthyl, pteridinyl, purine, pyrroleyl, pyrazolyl, pyridoneyl, pyridinyl, hydroxypyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophene (i.e., thiophene).Unless otherwise specified in this specification, heteroaryl groups may optionally be substituted, for example, by one or more substituents, such as halogens, amino groups, cyano groups, nitro groups, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxylic acid ester groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, etc. In some embodiments, the heteroaryl group is optionally substituted by one or more substituents, such as halogens, methyl groups, ethyl groups, -CN groups, -COOH groups, COOMe groups, -CF3 groups, -OH groups, -OMe groups, -NH2 groups, or -NO2 groups. In some embodiments, the heteroaryl group is optionally substituted by one or more substituents, such as halogens, methyl groups, ethyl groups, -CN groups, -CF3 groups, -OH groups, or -OMe groups. In some embodiments, the heteroaryl group is optionally substituted by a halogen.

[0074] The term "partially saturated" refers to a group that contains at least one double or triple bond and is intended to cover a ring with multiple unsaturated sites, but not to include aromatic (i.e., completely unsaturated) groups.

[0075] The terms “optional,” “optional,” or “optionally” mean that the event or situation described below may or may not occur, and the description includes both scenarios where said event or situation occurs and scenarios where said event or situation does not occur. For example, “optionally substituted alkyl” means “alkyl” or “substituted alkyl” as defined above. Furthermore, the optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between full and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that for any group containing one or more substituents, such groups are not intended to introduce any spatially impractical and / or synthetically infeasible substitution or substitution pattern. Therefore, any substituents described are generally understood to have a maximum molecular weight of about 1,000 Daltons, and more typically, a molecular weight of up to about 500 Daltons.

[0076] The term "one or more" when referring to optional substituents means that the subject group is optionally substituted by 1, 2, 3, 4, or more substituents. In some embodiments, the subject group is optionally substituted by 1, 2, 3, or 4 substituents. In some embodiments, the subject group is optionally substituted by 1, 2, or 3 substituents. In some embodiments, the subject group is optionally substituted by 1 or 2 substituents. In some embodiments, the subject group is optionally substituted by one substituent. In some embodiments, the subject group is optionally substituted by two substituents.

[0077] "Effective dose" or "therapeutic effective dose" refers to the amount of a compound administered to an individual mammal in a single dose or as part of a series of doses to effectively produce the desired therapeutic effect.

[0078] As used in this article, the term "treatment" includes relieving, reducing or improving at least one symptom of a disease or condition, preventing additional symptoms, suppressing a disease or condition, such as preventing the development of a disease or condition, alleviating a disease or condition, causing a disease or condition to subside, relieving the condition caused by a disease or condition, or stopping the symptoms of a disease or condition.

[0079] As used herein, “disease or condition associated with cbl-b activity” or “cbl-b-mediated disease or disorder” means any disease or other harmful condition in which cbl-b or its mutants are known or suspected to be at play.

[0080] compound

[0081] This article describes compounds or pharmaceutically acceptable salts thereof for the treatment of diseases or conditions associated with Cbl-b.

[0082] This article discloses compounds of formula (I), (II), or (III):

[0083] ,

[0084] ,

[0085] ,

[0086] ,

[0087] Or its pharmaceutically acceptable salt.

[0088] in:

[0089] R 1 Each is independently selected from halogen, cyano, and -OR. a -SR a -NR b R c Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are optionally substituted by one or more R;

[0090] Ring A is a cycloalkyl, heterocyclic, aryl, or heteroaryl group;

[0091] R 2 and R 3 Each is independently selected from hydrogen, halogen, cyano, -ORa -SR a -NR b R c Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are optionally substituted by one or more R;

[0092] Ring B is a cycloalkyl or heterocyclic group;

[0093] R 4 Each is independently selected from halogen, cyano, oxo, -OR a -SR a -NR b R c Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, or haloalkyl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, or haloalkyl is optionally substituted with one or more R; or

[0094] Two Rs 4 Together with the same atom to which they are all connected, they form C2-C6 alkylidene groups that are optionally substituted by one or R;

[0095] The ring C is aryl or heteroaryl;

[0096] R 5 Each is independently selected from halogen, cyano, and -OR. a -SR a -NR b R c Alkyl, alkenyl, ynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, alkenyl, ynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more R groups; or

[0097] Ring D is , , , , or Among them, ring D The end represents the connection point between ring D and ring C, and Indicates a single bond or a double bond;

[0098] Z 1 It is C(H) 1-2 Or N(H) 0-1 ;

[0099] Z 2 It is C(H) 1-2 N(H)0-1 , O or S;

[0100] W is C(H) 0-1 Or N;

[0101] Y is N(H) 0-1 O, S, C(O), S(O) 1-2 Or P(O) 1-2 ;

[0102] J is C(H) 0-1 Or N;

[0103] X is C(H) 0-1 Or N;

[0104] T is C(H) 0-1 Or N;

[0105] Ring E is a heterocyclic or heteroaryl group;

[0106] The ring G is a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more R groups;

[0107] R 6 Each is independently selected from halogen, cyano, and -OR. a -SR a -NR b R c Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, or heterocyclic, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, haloalkyl, cycloalkyl, or heterocyclic is optionally substituted with one or more R;

[0108] R 7 and R 8 Each is independently selected from hydrogen, deuterium, halogen, cyano, -OR a -SR a -NR b R c Alkyl, haloalkyl, or cycloalkyl;

[0109] V is CH or N;

[0110] R 9 and R 10 Each is independently selected from hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, or heterocyclic alkyl, wherein the cycloalkyl, heterocyclic, cycloalkylalkyl, and heterocyclic alkyl are optionally substituted with one or more R; or

[0111] R 9 and R 10Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are optionally substituted with one or more R;

[0112] R a The group is selected from hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are independently and optionally substituted by one or more R.

[0113] R b and R c Each is independently selected from hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are independently and optionally substituted by one or more R; or

[0114] R b and R c Together with the atoms to which they are attached, they form heterocyclic groups, which are optionally substituted with one or more R atoms;

[0115] Ring D1 is ,in Indicates a single bond or a double bond;

[0116] Ring E1 is a 5- to 6-membered heteroaryl or a 5- to 6-membered heterocyclic group;

[0117] Z 3 It is C(H) 1-2 Or N(H) 0-1 ;

[0118] Z 4 It is C(H) 1-2 N(H) 0-1 , O or S;

[0119] Z 5 It is C(H) 1-2 N(H) 0-1 , O or S;

[0120] W 1 It is C(H) 0-1 Or N;

[0121] W 2 It is C(H) 0-1 Or N;

[0122] R 600 Each is independently selected from halogen, cyano, heterocyclic, and -SR groups. a-NH2, -N(alkyl)2, -NH(cycloalkyl), -C(O)NH2, -C(O)NH(alkyl), unsubstituted alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, -alkynyl-N(alkyl)2, haloalkynyl, -alkynyl-heterocyclic or cycloalkyl, wherein the heterocyclic and cycloalkyl groups are optionally substituted by one or more R';

[0123] Or two Rs 600 Together with the atoms to which they are attached, they form cycloalkyl, heterocyclic, or heteroaryl groups, which are optionally substituted with one or more R groups;

[0124] R 700 It is a halogen, alkyl, haloalkyl, cycloalkyl, or heterocyclic group, wherein the alkyl, haloalkyl, cycloalkyl, and heterocyclic group are optionally substituted by one or more R independently;

[0125] R and R' are each independently a halogen, cyano, oxo, -OH, -S(=O)(alkyl), -S(=O)2(alkyl), -S(=O)2N(alkyl)2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -NH2, -N(alkyl)2, -NH(alkyl), -C(=O)(alkyl), -C(=O)OH, -C(=O)O(alkyl), alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, or heterocyclic group;

[0126] m is 0, 1, 2, 3 or 4;

[0127] n is 0, 1, 2, or 3;

[0128] p is 0, 1, 2, or 3;

[0129] q is 0, 1, 2, or 3;

[0130] j is 0, 1, 2, 3, 4, 5, or 6;

[0131] g is 0, 1, 2, 3, 4, 5, or 6;

[0132] k is 0, 1, 2, or 3;

[0133] u is 0, 1, or 2;

[0134] h is 0 or 1; and

[0135] i is 0, 1, or 2.

[0136] In some embodiments of compounds of formula (I), (II), (III), or (IV), ring A is a heteroaryl group. In some embodiments, ring A is a 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, or 5- to 6-membered heteroaryl. In some embodiments, ring A is a 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl, or 5-membered heteroaryl. In some embodiments, ring A is a monocyclic heteroaryl. In some embodiments, ring A is a polycyclic heteroaryl.

[0137] In some embodiments of compounds of formula (I), (II), (III), or (IV), ring A is a 5- to 7-membered monocyclic heteroaryl. In some embodiments, ring A is a 5- to 6-membered monocyclic heteroaryl. In some embodiments, ring A is a 5-membered monocyclic heteroaryl. In some embodiments, ring A is a 6-membered monocyclic heteroaryl.

[0138] In some embodiments of compounds of formula (I), (II), (III) or (IV), ring A is triazolyl, isoxazolyl, pyrroleyl, thiophenyl, furanyl, pyrazolyl, imidazoyl, thiazoyl, isothiazolyl, thiadiazolyl, oxadiazolyl or dihydropyrrolotriazolyl.

[0139] In some embodiments of compounds of formula (I), (II), (III) or (IV), ring A is or .

[0140] In some embodiments of compounds of formula (I), (II), (III) or (IV), R 1 Each is independently selected from -CN, -OH, and -OR. a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, or heterocycloalkyl. In some embodiments, R 1 Each is independently selected from C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments, R 1 Each is independently selected from C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl, C1-C2 haloalkyl, C1 haloalkyl, C2 haloalkyl, C3 haloalkyl, C4 haloalkyl, or C5 haloalkyl. In some embodiments, R1 Each is independently selected from CH3, CF2H or CFH2.

[0141] In some embodiments of compounds of formula (I), (II), (III), or (IV), m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0142] In some embodiments of compounds of formula (I), (II), (III) or (IV), yes or R 1A and R 1B Each is independently selected from hydrogen or R 1 .

[0143] In some embodiments of compounds of formula (I), (II), (III) or (IV), yes , , or .

[0144] In some embodiments of compounds of formula (I), (II), (III), or (IV), n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[0145] In some embodiments of compounds of formula (I), (II), (III) or (IV), R 2 and R 3 Each is independently selected from hydrogen, halogen, cyano, -OR a -SR a -NR b R c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 2-6 Heterene, C 2-6 Neyne group, C 1-6 Haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclic, C 6-10 Aryl or 5- to 9-membered heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally substituted with one or more R. In some embodiments, R 2 and R 3 Each is independently selected from hydrogen, halogen, cyano, C1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic groups, wherein the alkyl, haloalkyl and cycloalkyl groups are optionally substituted with one or more R groups.

[0146] In some embodiments of compounds of formula (I), (II), (III), or (IV), ring B is a cycloalkyl group. In some embodiments, ring B is a C group. 3-9 cycloalkyl, C 3-8 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl or C 3-4 Cycloalkyl. In some embodiments, ring B is a C9-cycloalkyl, C8-cycloalkyl, C7-cycloalkyl, C6-cycloalkyl, C5-cycloalkyl, C4-cycloalkyl, or C3-cycloalkyl. In some embodiments, ring B is a monocyclic cycloalkyl. In some embodiments, ring B is a polycyclic cycloalkyl.

[0147] In some embodiments of compounds of formula (I), (II), (III), or (IV), ring B is cyclobutyl. In some embodiments, ring B is cyclobutenyl. In some embodiments, ring B is cyclopropyl.

[0148] In some embodiments of compounds of formula (I), (II), (III), or (IV), ring B is a heterocyclic group. In some embodiments, ring B is a 3- to 9-membered heterocyclic group, a 3- to 8-membered heterocyclic group, a 3- to 7-membered heterocyclic group, a 3- to 6-membered heterocyclic group, a 3- to 5-membered heterocyclic group, a 3- to 4-membered heterocyclic group, a 5- to 6-membered heterocyclic group, a 3-membered heterocyclic group, a 4-membered heterocyclic group, a 5-membered heterocyclic group, a 6-membered heterocyclic group, a 7-membered heterocyclic group, an 8-membered heterocyclic group, or a 9-membered heterocyclic group. In some embodiments, ring B is a monocyclic heterocyclic group. In some embodiments, ring B is a polycyclic heterocyclic group. In some embodiments, the heterocyclic group comprises one or two O atoms or N atoms. In some embodiments, the heterocyclic group comprises one O atom. In some embodiments, the heterocyclic group comprises one N atom.

[0149] In some embodiments of compounds of formula (I), (II), (III), or (IV), p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0150] In some embodiments of compounds of formula (I), (II), (III) or (IV), R 4 Each is independently selected from halogen, cyano, oxo, -OR a -SRa -NR b R c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 2-6 Heterene, C 2-6 pyrynyl or C 1-6 The alkyl group, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, and haloalkyl groups are optionally substituted with one or more R. In some embodiments, R 4 Each was independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 Haloalkyl, wherein the alkyl, alkenyl, ynyl, and haloalkyl groups are optionally substituted with one or more R groups. In some embodiments, R groups are... 4 Each was independently selected from C 1-3 Alkyl, C 2-3 alkenyl, C 2-3 alkynyl or C 1-3 Haloalkyl, wherein the alkyl, alkenyl, ynyl, and haloalkyl groups are optionally substituted with one or more R groups. In some embodiments, R groups are... 4 Each is a cyano group.

[0151] In some embodiments of the compounds of formula (I) or (II), yes , , , , , or In some implementation schemes, yes In some implementation schemes, yes In some implementation schemes, yes In some implementation schemes, yes In some implementation schemes, yes In some implementation schemes, yes In some implementation schemes, yes .

[0152] In some embodiments of the compounds of formula (III) or (IV), yes , , or .

[0153] In some embodiments of compounds of formula (I), (II), (III), or (IV), the two R 4 Together with the same atom to which they are all bonded, they form a C2-C6 alkylidene group, which is optionally substituted with one or more R atoms. In some embodiments, two R atoms are substituted with one R atom. 4 Together with the same atom to which they are all bonded, they form a C2-C6 alkylidene group, which is optionally substituted with one or more halogens. In some embodiments, the two R... 4 Together with the same atom to which they are all bonded, they form a C2-C4 alkylidene group, which is optionally substituted with one or more halogens. In some embodiments, the two R... 4 They are formed together with the same atom to which they are all connected. It may be optionally replaced by one or more halogens.

[0154] In some embodiments of the compounds of formula (I) or (II), yes or In some implementation schemes, yes In some implementation schemes, yes .

[0155] In some embodiments of compounds of formula (III) or (IV), yes or .

[0156] In some embodiments of the compound of formula (IV), R 700 It is halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3- to 6-membered heterocyclic groups, wherein the alkyl, haloalkyl, cycloalkyl, and heterocyclic groups are optionally substituted independently by one or more R groups. In some embodiments, R... 700 It is F, Cl, Br, I, -CH3, -CH2CH3, -CF3, -CHF2, -CHF2CH3, cyclopropyl or cyclobutyl.

[0157] In some embodiments of compounds of formula (I), (II), (III), or (IV), the ring C is aryl. In some embodiments, the ring C is C. 6-12 Aryl, C 6-11 Aryl, C 6-10 Aryl, C 6-9 Aryl, C6-8 Aryl or C 6-7 Aryl. In some embodiments, the ring C is C 12 Aryl, C 11 Aryl, C 10 Aryl, C9-aryl, C8-aryl, C7-aryl, or C6-aryl. In some embodiments, the cyclic C is a monocyclic aryl. In some embodiments, the cyclic C is a polycyclic aryl.

[0158] In some embodiments of compounds of formula (I), (II), (III) or (IV), the ring C is phenyl.

[0159] In some embodiments of compounds of formula (I), (II), (III), or (IV), the ring C is And ring C The end indicates the connection point between ring C and ring D or ring D1.

[0160] In some embodiments of compounds of formula (I), (II), (III), or (IV), the ring C is a heteroaryl group. In some embodiments, the ring C is a 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, or 5- to 6-membered heteroaryl. In some embodiments, the ring C is a 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl, or 5-membered heteroaryl. In some embodiments, the ring C is a monocyclic heteroaryl. In some embodiments, the ring C is a polycyclic heteroaryl.

[0161] In some embodiments of compounds of formula (I), (II), (III), or (IV), ring C is a 5- to 7-membered monocyclic heteroaryl. In some embodiments, ring C is a 5- to 6-membered monocyclic heteroaryl. In some embodiments, ring C is a 5-membered monocyclic heteroaryl. In some embodiments, ring C is a 6-membered monocyclic heteroaryl.

[0162] In some embodiments of compounds of formula (I), (II), (III) or (IV), the ring C is pyridyl.

[0163] In some embodiments of compounds of formula (I), (II), (III), or (IV), the ring C is And ring C The end indicates the connection point between ring C and ring D or ring D1.

[0164] In some embodiments of compounds of formula (I), (II), (III) or (IV), R 5 Each is independently selected from halogen, cyano, and -OR. a -SR a -NRb R c C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, aryl, or heteroaryl groups, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted with one or more R groups. In some embodiments, R groups are... 5 Each was independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, wherein the alkyl, haloalkyl, cycloalkyl or heterocyclic group is optionally substituted with one or more R.

[0165] In some embodiments of compounds of formula (I), (II), (III), or (IV), q is 0, 1, 2, or 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0166] In some embodiments of compounds of formula (I), (II), (III) or (IV), yes R 5A R 5B and R 5C Each is independently selected from hydrogen or R 5 And ring C The end indicates the connection point between ring C and ring D or ring D1.

[0167] In some embodiments of compounds of formula (I), (II), (III) or (IV), yes , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or And ring C The end indicates the connection point between ring C and ring D or ring D1.

[0168] In some embodiments, the compound has formula (Ia), formula (IIa), or formula (IIIa):

[0169] ,

[0170] ,

[0171] ,

[0172] U 1 It is O, S, NH or CH2; and U 2 U 3 U 4 and U 5 Each can be either N or CH independently.

[0173] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), m is 1, and R 1 It is an alkyl or haloalkyl group.

[0174] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), m is 1, and R 1 It is an alkyl group. In some embodiments, R 1 It is a C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl. In some embodiments, R 1 It is C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl.

[0175] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), m is 1, and R 1 It is -CH3.

[0176] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), m is 1, and R 1 It is a haloalkyl group. In some embodiments, R 1 It is a C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl, or C1-C2 haloalkyl. In some embodiments, R 1 It is independently a C6 haloalkyl, C5 haloalkyl, C4 haloalkyl, C3 haloalkyl, C2 haloalkyl or C1 haloalkyl.

[0177] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), m is 1, and R 1 It is -CHF2.

[0178] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), m is 1, and R 1 It is -CH2F.

[0179] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), n is 0.

[0180] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), n is 1, and R 2 and R 3Both are hydrogen.

[0181] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), p is 1, and R 4 It is an alkyl or alkynyl group.

[0182] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), p is 1, and R 4 It is an alkyl group. In some embodiments, R 4 It is a C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl. In some embodiments, R 4 It is C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl.

[0183] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), p is 1, and R 4 It is -CH3.

[0184] In some implementations, p is 1, and R 4 It is an alkynyl group. In some implementations, R 4 It is C2-C6 ynyl, C2-C5 ynyl, C2-C4 ynyl, or C2-C3 ynyl. In some embodiments, R 4 It is C6 ynyl, C5 ynyl, C4 ynyl, C3 ynyl or C2 ynyl.

[0185] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), p is 1, and R 4 It is an acetylene group.

[0186] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), p is 2, and both R 4 They are formed together with the same atom to which they are all connected. It may be optionally replaced by one or more halogens.

[0187] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), p is 2, and both R 4 They are formed together with the same atom to which they are all connected. or .

[0188] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), q is 0.

[0189] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), q is 1, and R 5 Yes - OR a .

[0190] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), q is 1, R 5 Yes - OR a And R a It is an alkyl, haloalkyl, or cycloalkyl group.

[0191] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), R a It is an alkyl group. In some embodiments, R aIt is a C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl. In some embodiments, R a It is C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl.

[0192] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), R a It is a haloalkyl group. In some embodiments, R a It is a C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl, or C1-C2 haloalkyl. In some embodiments, R a It is independently a C6 haloalkyl, C5 haloalkyl, C4 haloalkyl, C3 haloalkyl, C2 haloalkyl or C1 haloalkyl.

[0193] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), R a It is a cycloalkyl group. In some embodiments, R a It is C 3-9 cycloalkyl, C 3-8 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl or C 3-4 Cycloalkyl. In some embodiments, R a It is a C9 cycloalkyl, C8 cycloalkyl, C7 cycloalkyl, C6 cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, or C3 cycloalkyl. In some embodiments, R a It is a monocyclic cycloalkyl group.

[0194] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), R 5 It is -OCH3, -OCH2CH3, -OCH2F, , , or .

[0195] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), q is 1, and R 5 It is a cycloalkyl group.

[0196] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), R 5 It is C 3-9 cycloalkyl, C 3-8 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl or C 3-4 Cycloalkyl. In some embodiments, R 5 It is a C9 cycloalkyl, C8 cycloalkyl, C7 cycloalkyl, C6 cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, or C3 cycloalkyl. In some embodiments, R 5 It is a monocyclic cycloalkyl group.

[0197] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), q is 1, and R 5 It is cyclopropyl.

[0198] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), q is 1, and R 5 Yes -NR b R c In some implementations, R b It is hydrogen, and R c It is hydrogen. In some implementations, R b It is hydrogen, and R c It is an alkyl, haloalkyl, cycloalkyl, or heterocyclic group, wherein the alkyl, cycloalkyl, and heterocyclic group are optionally substituted by one or more R groups independently. In some embodiments, R... b It is hydrogen, and R cIt is a C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclic group, wherein the alkyl, cycloalkyl, and heterocyclic group are optionally and independently substituted by one or more R. In some embodiments, R b It is hydrogen, and R c It is an alkyl, haloalkyl, or cycloalkyl group. In some embodiments, R... c It is an alkyl group, wherein the alkyl group is optionally substituted independently with one or more R. In some embodiments, R c It is an alkyl group. In some embodiments, R c It is a C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl, wherein the alkyl group is optionally and independently substituted with one or more R. In some embodiments, R c It is a C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl. In some embodiments, R c It is a C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl. In some embodiments, R c It is a haloalkyl group. In some embodiments, R c It is a C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl, or C1-C2 haloalkyl. In some embodiments, R c Independently, it is a C6 haloalkyl, C5 haloalkyl, C4 haloalkyl, C3 haloalkyl, C2 haloalkyl, or C1 haloalkyl. In some embodiments, R c It is a cycloalkyl group. In some embodiments, R c It is C 3-9 cycloalkyl, C 3-8 cycloalkyl, C 3-7 cycloalkyl, C 3-6 cycloalkyl, C 3-5 cycloalkyl or C 3-4 Cycloalkyl. In some embodiments, R c It is a C9 cycloalkyl, C8 cycloalkyl, C7 cycloalkyl, C6 cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, or C3 cycloalkyl. In some embodiments, R c It is a monocyclic cycloalkyl group. In some embodiments, R c It is a single-ring C 3-6 Cycloalkyl, monocyclic C 3-5 cycloalkyl or monocyclic C 3-4 Cycloalkyl. In some embodiments, R c It is a heterocyclic group. In some implementations, R cIt is a 3- to 6-membered heterocyclic group, a 3- to 5-membered heterocyclic group, a 3- to 4-membered heterocyclic group, a 5- to 6-membered heterocyclic group, a 6-membered heterocyclic group, a 5-membered heterocyclic group, a 4-membered heterocyclic group, or a 3-membered heterocyclic group.

[0199] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), q is 1, and R 5 Selected from NH2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2F, -NHCH2CHF2, -NHCH2CH2OH, , or .

[0200] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb) or (IV), R is independently a halogen, cyano, oxo, -OH, -S(=O) (alkyl), -S(=O)2 (alkyl), -S(=O)2N (alkyl)2, -S(=O)2NH (alkyl), -S(=O)2N (alkyl)2, -NH2, -N (alkyl)2, -NH (alkyl), -C(=O) (alkyl), -C(=O)OH, -C(=O)O (alkyl), alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl or heterocyclic. In some embodiments of the compounds disclosed herein, R is each independently a halogen, cyano, -OH, -NH2, -NHCH3, -N(CH3)2, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl. In some embodiments of the compounds disclosed herein, R is each independently a halogen, cyano, -OH, C1-C6 alkyl, C1-C6 alkoxy, or C1-C6 haloalkyl. In some embodiments, R is each independently a halogen, cyano, -OH, or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R is each independently a halogen, -OH, or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R is each independently a halogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R is each independently a halogen. In some embodiments, R is independently a halogen, cyano, oxo, -OH, -S(=O)(C1-C6 alkyl), -S(=O)2(C1-C6 alkyl), -S(=O)2N(C1-C6 alkyl)2, -S(=O)2NH(C1-C6 alkyl), -S(=O)2N(C1-C6 alkyl)2, -NH2, -N(C1-C6 alkyl)2, -NH(C1-C6 alkyl), -C(=O)(C1-C6 alkyl), -C(=O)OH, -C(=O)O(C1-C6 alkyl), C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclic group.In some embodiments, R is independently a halogen, cyano, -OH, C1-C6 alkyl (e.g., -CH3 or -CH2CH3), C1-C6 alkoxy (e.g., -OCH3 or -OCH2CH3), C1-C6 hydroxyalkyl (e.g., -CF3 or -CH2CF3), C3-C6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl), or a 3- to 6-membered heterocyclic group (e.g.). , or wait).

[0201] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), q is 1, and R 5 It is an alkyl or haloalkyl group, wherein the alkyl or haloalkyl group is optionally substituted with one or more R.

[0202] In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (IIe), (III), (IIIa), (IIIb), or (IV), q is 1, and R 5 It is -CHF2, -CH2CHF2, or -CF3.

[0203] In some embodiments of compounds of formula (Ia), (Ib), (Ic), (Id), (IIa), (IIb), (IIc), (IId), (IIe), (IIIa) or (IIIb), yes , , , , , , , , , , , , , , , , , , , , , , , or .

[0204] In some embodiments of the compound of formula (I), ring D is Among them, ring D The end indicates the connection point between ring D and ring C.

[0205] In some embodiments of the compound of formula (I), ring D is Among them, ring D The end represents the connection point between ring D and ring C, and u is 1.

[0206] In some embodiments of the compound of formula (I), ring D is Z 1 It is -C(H) 1-2 -, Z 2 It is -C(H) 1-2 - and ring D The end indicates the connection point between ring D and ring C.

[0207] In some embodiments of the compound of formula (I), yes Among them, ring D The end indicates the connection point between ring D and ring C.

[0208] In some embodiments of the compound of formula (I), yes And R 6 Each is independently a halogen, -OR a Alkyl or haloalkyl, wherein the alkyl and haloalkyl are each optionally substituted independently by one or more R, and the ring D is The terminator indicates the junction point between ring D and ring C. In some embodiments, R is independently a halogen, cyano, oxo, or -OH group.

[0209] In some embodiments of the compound of formula (I), yes And R 6 Each is independently a halogen, -OR a C1-C6 alkyl or C1-C6 haloalkyl, wherein the alkyl and haloalkyl groups are each optionally substituted independently by one or more R groups, and the ring D is... The terminator indicates the junction point between ring D and ring C. In some embodiments, R is independently a halogen, cyano, oxo, or -OH group.

[0210] In some embodiments of the compound of formula (I), R 6 One or more of them are halogens.

[0211] In some embodiments of the compound of formula (I), j is 1, and R 6 Yes, it is -F.

[0212] In some embodiments of the compound of formula (I), R 6 One or more independently are -OR a In some implementations, R a It is an alkyl or haloalkyl group, each of which is optionally substituted independently by one or more R groups. In some embodiments, each R group is independently a halogen, cyano, oxo, or -OH group.

[0213] In some embodiments of the compound of formula (I), R 6 One or more independently are -OR a R a It is an alkyl group. In some embodiments, R a Independently, they are C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl, each optionally substituted by one or more R. In some embodiments, R a Independently, it is a C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl group, each of which is optionally substituted by one or more R groups. In some embodiments, each R group is independently a halogen, cyano, oxo, or -OH group.

[0214] In some embodiments of the compound of formula (I), j is 1, and R 6 It is -OCH3.

[0215] In some embodiments of the compound of formula (I), R 6 One or more of them are independently C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl, each of which is optionally substituted by one or more R. In some embodiments, R 6 One or more of them are independently C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl or C1 alkyl, each of which is optionally substituted by one or more R. In some embodiments, each R is independently halogen, cyano, oxo or -OH.

[0216] In some embodiments of the compound of formula (I), j is 1, and R 6 It is -CH3.

[0217] In some embodiments of the compound of formula (I), R 6One or more of them are independently C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl, or C1-C2 haloalkyl, each of which is optionally substituted by one or more R. In some embodiments, R 6 One or more of them are independently C6 haloalkyl, C5 haloalkyl, C4 haloalkyl, C3 haloalkyl, C2 haloalkyl, or C1 haloalkyl, each of which is optionally substituted by one or more R. In some embodiments, each R is independently a halogen, cyano, oxo, or -OH.

[0218] In some embodiments of the compound of formula (I), j is 1, and R 6 It is a C1-C6 haloalkyl, C1-C5 haloalkyl, C1-C4 haloalkyl, C1-C3 haloalkyl, or C1-C2 haloalkyl. In some embodiments, j is 1, and R 6 It is a C1 haloalkyl group. In some embodiments, j is 1, and R 6 It is either -CF3 or -CHF2.

[0219] In some embodiments of the compound of formula (I), yes or R 6A R 6B R 6C and R 6D Each is independently selected from hydrogen or R 6 And ring D The end indicates the connection point between ring D and ring C.

[0220] In some embodiments of the compound of formula (I), R 6A It is hydrogen.

[0221] In some embodiments of the compound of formula (I), R 6B It is hydrogen, halogen, cyano, -OR a -SR a -NR b R c Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, or heterocyclic, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, haloalkyl, cycloalkyl, or heterocyclic group is optionally substituted with one or more R. In some embodiments, R 6B It is hydrogen, halogen, cyano, -OR a -SR a -NR b R c C 1-6 Alkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 1-6 Heteroalkyl, C 2-6 Heterene, C 2-6 Neyne group, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, and heterocyclic groups are optionally substituted with one or more R. In some embodiments, R 6B It is hydrogen, halogen, -OR a C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, wherein the alkyl, haloalkyl, cycloalkyl, and heterocyclic groups are optionally substituted with one or more R. In some embodiments, R 6B It can be hydrogen, halogen, CF3, CH3, OCH3, CHF2, or cyclopropyl.

[0222] In some embodiments of the compound of formula (I), R 6C It is hydrogen, halogen, cyano, -OR a -SR a -NR b R c Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, or heterocyclic, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, haloalkyl, cycloalkyl, or heterocyclic group is optionally substituted with one or more R. In some embodiments, R 6C It is hydrogen, halogen, C 1-6 Alkyl or C 1-6 The alkyl group and the haloalkyl group are optionally substituted with one or more R. In some embodiments, R 6B It is hydrogen, F, Cl, Br, I, or CH3.

[0223] In some embodiments of the compound of formula (I), R 6D It is hydrogen.

[0224] In some embodiments of the compound of formula (I), ring D is Among them, ring D The end indicates the connection point between ring D and ring C.

[0225] In some embodiments of the compound of formula (I), ring D is Among them, ring D The end represents the connection point between ring D and ring C, and i is 1.

[0226] In some embodiments of the compound of formula (I), ring D is W is N, and Y is C(O), and ring D is The end represents the connection point between ring D and ring C. In some implementations, i is 1.

[0227] In some embodiments of the compound of formula (I), ring D is Where ring E is a 6-membered heteroaryl group, and ring D is... The end represents the connection point between ring D and ring C. In some implementations, i is 1.

[0228] In some embodiments of the compound of formula (I), ring D is X is C, and T is C, and the ring D is The end represents the connection point between ring D and ring C. In some implementations, i is 1.

[0229] In some embodiments of the compound of formula (I), ring D is Among them, ring D The end indicates the connection point between ring D and ring C.

[0230] In some embodiments of the compound of formula (I), ring D is Ring G is a cycloalkyl, heterocyclic, or heteroaryl group, and ring D is... The end represents the connection point between ring D and ring C. In some implementations, i is 1.

[0231] In some embodiments of the compounds of formula (I), ring G is a cycloalkyl group. In some embodiments, ring G is C 5-11 cycloalkyl, C 5-10 cycloalkyl, C 5-9 cycloalkyl, C 5-8 cycloalkyl, C 5-7 cycloalkyl or C 5-6 Cycloalkyl. In some embodiments, the ring G is C. 11 cycloalkyl, C 10 Cycloalkyl, C9 cycloalkyl, C8 cycloalkyl, C7 cycloalkyl, C6 cycloalkyl, or C5 cycloalkyl. In some embodiments, ring G is a monocyclic cycloalkyl.

[0232] In some embodiments of the compounds of formula (I), ring G is a heterocyclic group. In some embodiments, ring G is a 5- to 10-membered heterocyclic group, a 5- to 9-membered heterocyclic group, a 5- to 8-membered heterocyclic group, a 5- to 7-membered heterocyclic group, or a 5- to 6-membered heterocyclic group. In some embodiments, ring G is a 10-membered heterocyclic group, a 9-membered heterocyclic group, an 8-membered heterocyclic group, a 7-membered heterocyclic group, a 6-membered heterocyclic group, or a 5-membered heterocyclic group. In some embodiments, ring G is a monocyclic heterocyclic group.

[0233] In some embodiments of the compounds of formula (I), ring G is a 5- to 7-membered monocyclic heterocyclic group. In some embodiments, ring G is a 5- to 6-membered monocyclic heterocyclic group. In some embodiments, ring G is a 5-membered monocyclic heterocyclic group. In some embodiments, ring G is a 6-membered monocyclic heterocyclic group.

[0234] In some embodiments of the compounds of formula (I), ring G is a heteroaryl group. In some embodiments, ring G is a 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, or 5- to 6-membered heteroaryl. In some embodiments, ring G is a 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl, or 5-membered heteroaryl. In some embodiments, ring G is a monocyclic heteroaryl. In some embodiments, ring G is a polycyclic heteroaryl. In some embodiments, ring G is a bicyclic heteroaryl.

[0235] In some embodiments of the compounds of formula (I), ring G is a 5- to 7-membered monocyclic heteroaryl. In some embodiments, ring G is a 5- to 6-membered monocyclic heteroaryl. In some embodiments, ring G is a 5-membered monocyclic heteroaryl. In some embodiments, ring G is a 6-membered monocyclic heteroaryl.

[0236] In some embodiments of the compound of formula (I), Selected from:

[0237] , , , , , , , , , , , , , , , , or Among them, ring D The end indicates the connection point between ring D and ring C.

[0238] In some embodiments of the compound of formula (I), j is 0, 1, or 2, and R 6 Each is independently a halogen, alkyl, or haloalkyl.

[0239] In some embodiments of the compound of formula (I), R 6 Each is an independent halogen. In some implementations, R6 Each is either fluorine or chlorine.

[0240] In some embodiments of the compound of formula (I), ring D is Among them, ring D The end indicates the connection point between ring D and ring C.

[0241] In some embodiments of the compound of formula (I), ring D is Among them, ring D The end represents the connection point between ring D and ring C, and i is 1.

[0242] In some embodiments of the compound of formula (I), ring D is W is -N-, Y is -C(O)-, and ring D is The end represents the connection point between ring D and ring C. In some implementations, i is 1.

[0243] In some embodiments of the compound of formula (I), ring D is Ring E is a 6-membered heteroaryl group, and ring D is... The end represents the connection point between ring D and ring C. In some implementations, i is 1.

[0244] In some embodiments of the compound of formula (I), ring D is J is CH, X is C, T is C, and ring D is The end represents the connection point between ring D and ring C. In some implementations, i is 1.

[0245] In some embodiments of the compound of formula (I), ring D is Among them, ring D The end indicates the connection point between ring D and ring C.

[0246] In some embodiments of the compounds of formula (I), ring G is a cycloalkyl group. In some embodiments, ring G is C 5-11 cycloalkyl, C 5-10 cycloalkyl, C 5-9 cycloalkyl, C 5-8 cycloalkyl, C 5-7 cycloalkyl or C 5-6 Cycloalkyl. In some embodiments, the ring G is C. 11 cycloalkyl, C 10 Cycloalkyl, C9 cycloalkyl, C8 cycloalkyl, C7 cycloalkyl, C6 cycloalkyl, or C5 cycloalkyl. In some embodiments, ring G is a monocyclic cycloalkyl.

[0247] In some embodiments of the compounds of formula (I), ring G is a heterocyclic group. In some embodiments, ring G is a 5- to 10-membered heterocyclic group, a 5- to 9-membered heterocyclic group, a 5- to 8-membered heterocyclic group, a 5- to 7-membered heterocyclic group, or a 5- to 6-membered heterocyclic group. In some embodiments, ring G is a 10-membered heterocyclic group, a 9-membered heterocyclic group, an 8-membered heterocyclic group, a 7-membered heterocyclic group, a 6-membered heterocyclic group, or a 5-membered heterocyclic group. In some embodiments, ring G is a monocyclic heterocyclic group.

[0248] In some embodiments of the compounds of formula (I), ring G is a 5- to 7-membered monocyclic heterocyclic group. In some embodiments, ring G is a 5- to 6-membered monocyclic heterocyclic group. In some embodiments, ring G is a 5-membered monocyclic heterocyclic group. In some embodiments, ring G is a 6-membered monocyclic heterocyclic group.

[0249] In some embodiments of the compounds of formula (I), ring G is a heteroaryl group. In some embodiments, ring G is a 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, or 5- to 6-membered heteroaryl. In some embodiments, ring G is a 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl, or 5-membered heteroaryl. In some embodiments, ring G is a monocyclic heteroaryl. In some embodiments, ring G is a polycyclic heteroaryl. In some embodiments, ring G is a bicyclic heteroaryl.

[0250] In some embodiments of the compounds of formula (I), ring G is a 5- to 7-membered monocyclic heteroaryl. In some embodiments, ring G is a 5- to 6-membered monocyclic heteroaryl. In some embodiments, ring G is a 5-membered monocyclic heteroaryl. In some embodiments, ring G is a 6-membered monocyclic heteroaryl.

[0251] In some embodiments of the compound of formula (I), Selected from:

[0252] , , , , , , , , , , , ,

[0253] Among them, ring D The end indicates the connection point between ring D and ring C;

[0254] R 6a and R 6bEach is R independently 6 ;

[0255] j1 is 0, 1, or 2; and

[0256] j2 is 0, 1, 2, 3 or 4.

[0257] In some embodiments of the compound of formula (I), j1 and j2 are both 0.

[0258] In some embodiments of the compound of formula (I), j1 is 1, j2 is 0, and R 6a It is an alkyl group. In some embodiments, R 6a It is a C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl. In some embodiments, R 6 It is independently a C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl or C1 alkyl.

[0259] In some embodiments of the compound of formula (I), j1 is 1, j2 is 0, and R 6a It is -CH3.

[0260] In some embodiments of the compound of formula (I), k is 0.

[0261] In some embodiments of the compound of formula (I), k is 1, and R 7 and R 8 Each is independently selected from hydrogen or alkyl groups.

[0262] In some embodiments of the compound of formula (I), k is 1, and R 7 and R 8 Both are hydrogen.

[0263] In some embodiments of the compound of formula (I), k is 1, R 7 It is hydrogen, and R 8 It is an alkyl group. In some embodiments, R 8 It is a C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl. In some embodiments, R 8 It is C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, or C1 alkyl.

[0264] In some embodiments of the compound of formula (I), k is 1, R 7 It is hydrogen, and R 8 It is -CH3.

[0265] In some embodiments of the compound of formula (I), k is 1, and R 7 and R8 All are alkyl groups. In some embodiments, R 7 and R 8 Independently, it is a C1-C6 alkyl, C1-C5 alkyl, C1-C4 alkyl, C1-C3 alkyl, or C1-C2 alkyl. In some embodiments, R 7 and R 8 It is independently a C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl or C1 alkyl.

[0266] In some embodiments of the compound of formula (I), k is 1, and R 7 and R 8 Both are -CH3.

[0267] In some embodiments of the compound of formula (I), V is N.

[0268] In some embodiments of the compound of formula (I), V is N, R 9 It is hydrogen, and R 10 It is a cycloalkyl or cycloalkyl group, each optionally substituted by one or more R, and each R is independently selected from halogen, alkyl or haloalkyl.

[0269] In some embodiments of the compound of formula (I), V is N, R 9 It is hydrogen, and R 10 It is a cycloalkyl group, optionally substituted with one or more Rs, each R being independently selected from halogens, alkyl groups, or haloalkyl groups. In some embodiments, R... 10 It is a -C1-C3 alkyl-C 3-9 Cycloalkyl, -C1-C3 alkyl-C 3-8 Cycloalkyl, -C1-C3 alkyl-C 3-7 Cycloalkyl, -C1-C3 alkyl-C 3-6 Cycloalkyl, -C1-C3 alkyl-C 3-5 cycloalkyl or -C1-C3 alkyl-C 3-4 Cycloalkyl groups, each optionally substituted independently with one or more R groups. In some embodiments, R groups are... 5 It is a -C1-C3 alkyl-C9 cycloalkyl, -C1-C3 alkyl-C8 cycloalkyl, -C1-C3 alkyl-C7 cycloalkyl, -C1-C3 alkyl-C6 cycloalkyl, -C1-C3 alkyl-C5 cycloalkyl, -C1-C3 alkyl-C4 cycloalkyl, or -C1-C3 alkyl-C3 cycloalkyl, each optionally substituted independently by one or more R. In some embodiments, R is independently a halogen, alkyl, or haloalkyl.

[0270] In some embodiments of the compound of formula (I), V is N, R 9 It is hydrogen, and R10 yes .

[0271] In some embodiments of the compound of formula (I), V is N, R 9 It is hydrogen, and R 10 It is a cycloalkyl group optionally substituted with one or more Rs, and each R is independently selected from halogens, alkyl groups, or haloalkyl groups. In some embodiments, R... 10 It is -C 3-9 cycloalkyl, -C 3-8 cycloalkyl, -C 3-7 cycloalkyl, -C 3-6 cycloalkyl, -C 3-5 cycloalkyl or -C 3-4 Cycloalkyl groups, each optionally substituted independently with one or more R groups. In some embodiments, R groups are... 5 It is a -C9 cycloalkyl, -C8 cycloalkyl, -C7 cycloalkyl, -C6 cycloalkyl, -C5 cycloalkyl, -C4 cycloalkyl, or -C3 cycloalkyl, each of which is optionally substituted by one or more R independently. In some embodiments, each R is independently a halogen, alkyl, or haloalkyl.

[0272] In some embodiments of the compound of formula (I), V is N, R 9 It is hydrogen, and R 10 yes or .

[0273] In some embodiments of the compound of formula (I), V is N, and R 9 and R 10 Together with the atoms to which they are attached, they form a heterocyclic group, which is optionally substituted by one or more Rs, each of which is independently selected from halogens, alkyl groups, or haloalkyl groups.

[0274] In some embodiments of the compound of formula (I), V is N, and R 9 and R 10 Together with the atoms to which they are attached, they form 5- to 10-membered heterocyclic groups, 5- to 9-membered heterocyclic groups, 5- to 8-membered heterocyclic groups, 5- to 7-membered heterocyclic groups, or 5- to 6-membered heterocyclic groups, each of which is independently and optionally substituted with one or more Rs. In some embodiments, R... 9 and R 10 Together with the atoms they are attached to, they form 10-membered heterocyclic groups, 9-membered heterocyclic groups, 8-membered heterocyclic groups, 7-membered heterocyclic groups, 6-membered heterocyclic groups, or 5-membered heterocyclic groups, each of which is independently and optionally substituted by one or more Rs. In some embodiments, R... 9 and R 10Together with the atoms they are attached to, they form 5- to 7-membered monocyclic heterocyclic groups, which are optionally substituted with one or more R atoms. In some embodiments, R atoms are... 9 and R 10 Together with the atoms they are attached to, they form 5- to 6-membered monocyclic heterocyclic groups, which are optionally substituted with one or more R atoms. In some embodiments, R atoms are... 9 and R 10 Together with the atoms they are attached to, they form a 5-membered monocyclic heterocyclic group, which is optionally substituted with one or more R atoms. In some embodiments, R atoms are... 9 and R 10 Together with the atoms to which they are attached, they form a 6-membered monocyclic heterocyclic group, which is optionally substituted with one or more Rs. In some embodiments, each R is independently selected from halogens, alkyl groups, or haloalkyl groups.

[0275] In some embodiments of the compound of formula (I), V is N, and R 9 and R 10 Together with the atoms they are attached to, they form piperidine, which is optionally substituted with one or more R atoms.

[0276] In some embodiments of the compound of formula (I), V is N, and R 9 and R 10 Together with the atoms they are attached to, they form piperidine, which is replaced by a -CH3 group.

[0277] In some embodiments of compounds of formula (II), (III), or (IV), ring E1 is a 5- or 6-membered heteroaryl or a 5- or 6-membered heterocyclic group. In some embodiments, ring E1 is a 6-membered heteroaryl or a 6-membered heterocyclic group. In some embodiments, ring E1 is a 5-membered heteroaryl or a 5-membered heterocyclic group.

[0278] In some embodiments of compounds of formula (II), (III), or (IV), ring D1 is .

[0279] In some embodiments of compounds of formula (II), (IIa), (III), (IIIa) or (IV), ring D1 is selected from:

[0280] , , , , , , , , , , , , , and .

[0281] In some embodiments of compounds of formula (II), (IIa), (III), (IIIa) or (IV), g is 0, 1 or 2.

[0282] In some embodiments of compounds of formula (II), (IIa), (III) or (IIIa), yes , , , , , , , , , , , , , or , where R 600a1 R 600a2 R 600a3 and R 600a4 Each is independently selected from hydrogen or R 600 .

[0283] In some embodiments of compounds of formula (II), (IIa), (IIb), (III) or (IIIa), (IIIb) or (IV), R 600 Each is independently selected from halogen, cyano, heterocyclic, and -SR groups. a -NH2, -N(alkyl)2, -NH(cycloalkyl), -C(O)NH2, -C(O)NH(alkyl), unsubstituted alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, -alkynyl-N(alkyl)2, haloalkynyl, -alkynyl-heterocyclic or cycloalkyl, wherein the heterocyclic and cycloalkyl groups are optionally substituted by one or more R'. In some embodiments, R 600 Each is independently selected from halogen, cyano, piperazine, -SR a -NH2, -N(alkyl)2, -NH(cycloalkyl), -C(O)NH2, -C(O)NH(alkyl), unsubstituted alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, -alkynyl-N(alkyl)2, haloalkynyl, -alkynyl-heterocyclic or cycloalkyl. In some embodiments, R 600Each group is independently selected from halogens, cyano groups, heterocyclic groups, -C(O)NH2, unsubstituted alkyl groups, alkynyl groups, haloalkyl groups, hydroxyalkyl groups, haloalkoxy groups, -alkynyl-N(alkyl)2 groups, haloalkynyl groups, -alkynyl-heterocyclic groups, or cycloalkyl groups, wherein the heterocyclic and cycloalkyl groups are optionally substituted by one or more R' groups. In some embodiments, R' is selected from halogens, cyano groups, heterocyclic groups, -C(O)NH2 groups, unsubstituted alkyl groups, alkynyl groups, cycloalkyl groups, unsubstituted alkyl ... 600 Each is independently selected from halogens, cyano groups, -C(O)NH2, and unsubstituted C. 1-6 Alkyl (e.g., unsubstituted C) 1-5 Alkyl, unsubstituted C 1-4 Alkyl, unsubstituted C 1-3 Alkyl or unsubstituted C 1-2 Alkyl groups, etc.), C 2-6 alkynyl groups (e.g., C) 2-5 alkynyl group, C 2-4 alkynyl or C 2-3 (alkyne group, etc.), C 1-6 Haloalkyl (e.g., C10) 1-5 Haloalkyl, C 1-4 Haloalkyl, C 1-3 Halogenated alkyl or C 1-2 (halogenated alkyl groups, etc.), C 1-6 Hydroxyalkyl (e.g., C) 1-5 Hydroxyalkyl, C 1-4 Hydroxyalkyl, C 1-3 Hydroxyalkyl or C 1-2 hydroxyalkyl, etc.), C 1-6 Halogenated alkoxy groups (e.g., C15) 1-5 Halogenated alkoxy groups, C 1-4 Halogenated alkoxy groups, C 1-3 Halogenated alkoxy or C 1-2 (e.g., halogenated alkoxy groups), -C 2-6 alkynyl-N(C) 1-6 Alkyl)2, C 2-6 Halogenated alkynyl groups (e.g., C10) 2-5 Halogenated alkynyl group, C 2-4 Halogenated alkynyl or C 2-3 (halogenated alkynyl groups, etc.), -C 2-6 alkynyl-(3- to 6-membered heterocyclic group), C 3-6 cycloalkyl (e.g., C10) 3-5 cycloalkyl or C 3-4 The heterocyclic group (e.g., 3- to 5- or 3- to 4-membered heterocyclic group) or cycloalkyl group is optionally substituted with one or more R'. In some embodiments, R 600 Each is independently selected from halogen, cyano, C 1-3 Alkyl, C 1-3 Hydroxyalkyl, -C 2-3 alkynyl-N(C) 1-3Alkyl)2, C 2-3 Halogenated alkynyl groups and -C 2-3 Alkynyl-(5- to 6-membered heterocyclic group). In some embodiments, R 600 Each is C 3-6 Cycloalkyl groups (e.g., C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C...) 3-5 cycloalkyl or C 5-6 Cycloalkyl groups, etc., optionally substituted with one or more (e.g., two or three, etc.) R'. In some embodiments, R... 600 Each is a 3- to 6-membered heterocyclic group (e.g., 3-membered heterocyclic group, 4-membered heterocyclic group, 5-membered heterocyclic group, 6-membered heterocyclic group, 3- to 5-membered heterocyclic group, or 5- to 6-membered heterocyclic group, etc.), which is optionally replaced by one or more (e.g., two or three, etc.) R'. In some embodiments, R 600 Each is a piperazine, piperidinyl, or aziridine group, optionally substituted with one or more (e.g., two or three, etc.) R'. In some embodiments, R... 600 Each is a spirocyclic bicyclic heterocyclic group (e.g., 6- to 15-membered spirocyclic bicyclic heterocyclic group, 6-membered spirocyclic bicyclic heterocyclic group, 7-membered spirocyclic bicyclic heterocyclic group, 8-membered spirocyclic bicyclic heterocyclic group, or 9-membered spirocyclic bicyclic heterocyclic group), each optionally replaced by one or more (e.g., two or three, etc.) R'. In some embodiments, R 600 Each is a bridged bicyclic heterocyclic group (e.g., 6- to 15-membered bridged bicyclic heterocyclic group, 6-membered bridged bicyclic heterocyclic group, 7-membered bridged bicyclic heterocyclic group, 8-membered bridged bicyclic heterocyclic group, or 9-membered bridged bicyclic heterocyclic group), which is optionally replaced by one or more (e.g., two or three, etc.) R'. In some embodiments, R 600 Each is a fused bicyclic heterocyclic group (e.g., a 6- to 15-membered fused bicyclic heterocyclic group, a 6-membered fused bicyclic heterocyclic group, a 7-membered fused bicyclic heterocyclic group, an 8-membered fused bicyclic heterocyclic group, or a 9-membered fused bicyclic heterocyclic group), each optionally replaced by one or more (e.g., two or three, etc.) R'. In some embodiments, R 600 Each is , , or Each of them may be optionally replaced by one or more (e.g., two or three, etc.) R'.

[0284] In some embodiments of compounds of formula (II), (IIa), (IIb), (III), or (IIIa), (IIIb), or (IV), R' is independently a halogen, cyano, oxo, -OH, -S(=O) (alkyl), -S(=O)2 (alkyl), -S(=O)2N (alkyl)2, -S(=O)2NH (alkyl), -S(=O)2N (alkyl)2, -NH2, -N (alkyl)2, -NH (alkyl), -C(=O) (alkyl), -C(=O)OH, -C(=O)O (alkyl), alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, or heterocyclic group. In some embodiments, R' is independently a halogen, cyano, oxo, -OH, -NH2, alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, or heterocyclic group. In some implementations, R' is independently a halogen, -OH, -NH2, or C. 1-6 Alkyl (e.g., C10) 1-5 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl or C1 alkyl, etc.), C 1-6 Haloalkyl (e.g., C10) 1-5 Haloalkyl, C 1-4 Haloalkyl, C 1-3 Halogenated alkyl or C 1-2 (halogenated alkyl groups, etc.) or C 1-6 Hydroxyalkyl (e.g., C) 1-5 Hydroxyalkyl, C 1-4 Hydroxyalkyl, C 1-3 Hydroxyalkyl or C 1-2 (Hydroxyalkyl, etc.). In some embodiments, R' is independently a halogen, -OH, -NH2, -CH3, or -CH2CH3. In some embodiments, -CH3 is -CD3.

[0285] In some embodiments of compounds of formula (II), (IIa), (IIb), (III) or (IIIa), (IIIb) or (IV), R 600 Each is independently selected from -Cl, -F, -CN, -CH3, -CH(CH3)2, -CH2OH, -CF3, -CHF2, -CF2CF3, -CH(CH3)CF2, -CH2CHF2, -OCH2F, -OCHF2, -OCClF2, -C(O)NH2, , , , , , , , , , , , , , , , , , or In some implementation schemes, yes In some implementation schemes, yes In some implementation schemes, yes .

[0286] In some embodiments of compounds of formula (II), (IIa), (III), or (IIIa), or (IV), yes , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or In some implementation schemes, yes .

[0287] In some embodiments of compounds of formula (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IV), the two R 600 Together with the atoms to which they are attached, they form cycloalkyl, heterocyclic, or heteroaryl groups, each of which is optionally substituted with one or more R groups.

[0288] In some embodiments of compounds of formula (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IV), the two R 600 Together with the atoms they are attached to, they form cycloalkyl groups, which are optionally substituted with one or more R atoms. In some embodiments, two R atoms are substituted with one R atom. 600 Together with the atoms they are attached to, they form C 3-6 Cycloalkyl groups (e.g., C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C...) 3-5 cycloalkyl or C 5-6 (e.g., cycloalkyl groups), which are optionally substituted with one or more R groups.

[0289] In some embodiments of compounds of formula (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IV), the two R 600 Together with the atoms they are attached to, they form a heterocyclic group, which is optionally substituted with one or more R atoms. In some embodiments, two R atoms are substituted with one R atom. 600 Together with the atoms to which they are attached, they form 5- to 10-membered heterocyclic groups, 5- to 9-membered heterocyclic groups, 5- to 8-membered heterocyclic groups, 5- to 7-membered heterocyclic groups, or 5- to 6-membered heterocyclic groups, each optionally substituted with one or more Rs. In some embodiments, two Rs... 600 Together with the atoms they are attached to, they form 10-membered heterocyclic groups, 9-membered heterocyclic groups, 8-membered heterocyclic groups, 7-membered heterocyclic groups, 6-membered heterocyclic groups, or 5-membered heterocyclic groups, each optionally substituted with one or more Rs. In some embodiments, two Rs... 600 Together with the atoms to which they are attached, they form monocyclic heterocyclic groups, which are optionally substituted with one or more R atoms.

[0290] In some embodiments of compounds of formula (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IV), the two R 600 Together with the atoms they are attached to, they form 5- to 7-membered monocyclic heterocyclic groups, which are optionally substituted with one or more Rs. In some embodiments, two Rs... 600 Together with the atoms they are attached to, they form 5- to 6-membered monocyclic heterocyclic groups, which are optionally substituted with one or more Rs. In some embodiments, two Rs... 600 Together with the atoms they are attached to, they form a 5-membered monocyclic heterocyclic group, which is optionally substituted with one or more R atoms. In some embodiments, two R atoms are substituted with one R atom. 600 Together with the atoms to which they are attached, they form a 6-membered monocyclic heterocyclic group, which is optionally substituted with one or more R atoms.

[0291] In some embodiments of compounds of formula (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IV), the two R 600 Together with the atoms they are attached to, they form heteroaryl groups, which are optionally substituted with one or more R groups. In some embodiments, two R groups are substituted with one R group. 600 Together with the atoms they are attached to, they form 5- to 10-membered heteroaryl, 5- to 9-membered heteroaryl, 5- to 8-membered heteroaryl, 5- to 7-membered heteroaryl, or 5- to 6-membered heteroaryl, each optionally substituted with one or more Rs. In some embodiments, two Rs... 600 Together with the atoms they are attached to, they form 10-membered heteroaryl, 9-membered heteroaryl, 8-membered heteroaryl, 7-membered heteroaryl, 6-membered heteroaryl, or 5-membered heteroaryl, each optionally substituted with one or more Rs. In some embodiments, two Rs... 600 Together with the atoms they are attached to, they form a monocyclic heteroaryl group, which is optionally substituted with one or more R atoms. In some embodiments, two R atoms are substituted with one R atom. 600 Together with the atoms they are attached to, they form polycyclic heteroaryl groups, which are optionally substituted with one or more R groups. In some embodiments, two R groups are substituted with one R group. 600 Together with the atoms they are attached to, they form bicyclic heteroaryl groups, which are optionally substituted with one or more R groups.

[0292] In some embodiments of compounds of formula (II), (IIa), (IIb), (III), (IIIa), (IIIb), or (IV), the two R 600 Together with the atoms they are attached to, they form 5- to 7-membered monocyclic heteroaryl groups, which are optionally substituted with one or more R groups. In some embodiments, two R groups are substituted with one R group. 600Together with the atoms they are attached to, they form 5- to 6-membered monocyclic heteroaryl groups, which are optionally substituted with one or more R groups. In some embodiments, two R groups are substituted with one or more R groups. 600 Together with the atoms they are attached to, they form a 5-membered monocyclic heteroaryl group, which is optionally substituted with one or more R atoms. In some embodiments, two R atoms are substituted with one R atom. 600 Together with the atoms to which they are attached, they form a 6-membered monocyclic heteroaryl group, which is optionally substituted with one or more R atoms.

[0293] In some embodiments of compounds of formula (II), (IIa), (III), (IIIa) or (IV), Selected from , , or R 600a Each is R independently 600 g1 is 0, 1, or 2; and g2 is 0, 1, 2, 3, or 4.

[0294] In some embodiments of compounds of formula (II), (IIa), (III), (IIIa) or (IV), yes , or .

[0295] In some embodiments of compounds of formula (I), (II), (III) or (IV), compounds selected from the following formulas are provided herein:

[0296] ,

[0297] ,

[0298] ,

[0299] ,

[0300] ,

[0301] ,

[0302] ,

[0303] ,

[0304] ,

[0305] ,

[0306] Or a pharmaceutically acceptable salt thereof, wherein g is 0, 1, 2, 3 or 4, R 1 To R 10 R 6A To R 6D R 600 R 600a V, rings G, m, n, p, q, k, and g1 are as defined in this paper.

[0307] In some embodiments of compounds of formula (I), (II), (III) or (IV), compounds selected from the following formulas are provided herein:

[0308] ,

[0309] ,

[0310] ,

[0311] ,

[0312] ,

[0313] ,

[0314] ,

[0315] ,

[0316] ,

[0317] ,

[0318] Or a pharmaceutically acceptable salt thereof, wherein g is 0, 1, 2, 3 or 4, R 1 To R 10 V, R 5A To R 5C R 6A To R 6D R 600 R 600a Rings G, n, k, and g1 are as defined in this paper.

[0319] In some embodiments of compound formula (II) or (III), compounds selected from the following formulas are provided herein:

[0320] ,

[0321] ,

[0322] Or a pharmaceutically acceptable salt thereof, wherein R 600a1 R600a2 R 600a3 and R 600a4 Each is independently selected from hydrogen or R 600 n, R 1A R 2 R 3 R 4 and R 5A As defined in this article.

[0323] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are one of the compounds in Table 1, Table 2 or Table 3.

[0324] Table 1 Exemplary Compounds

[0325]

[0326]

[0327]

[0328]

[0329] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are one of the compounds listed in Table 2.

[0330] Table 2 Exemplary Compounds

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are one of the compounds listed in Table 3.

[0339] Table 3 Exemplary Compounds

[0340]

[0341]

[0342]

[0343]

[0344] Other forms of the compounds disclosed herein

[0345] Isomers / stereoisomers

[0346] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis (cis, syn, zusammen (Z)), trans (trans, anti, entgegen (E)) isomers and corresponding mixtures thereof. In some cases, the compounds described herein have one or more chiral centers, and each center exists in an R or S configuration. The compounds described herein include all diastereomers, enantiomers, and epimers, and corresponding mixtures thereof. In other embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination, or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as their respective stereoisomers by reacting a racemic mixture of compounds with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers possess different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and these differences are utilized to separate the diastereomers. In some embodiments, diastereomers are separated by chiral chromatography or, preferably, by a separation / resolution technique based on solubility differences. In some embodiments, optically pure enantiomers are recovered along with the resolving agent by any practical method that does not lead to racemization. Carbon-carbon bonds in the provided compounds can be represented herein by solid lines (…). wedge bond ), dashed wedge key ( ), bold key ( ) or dashed key ( The term is used to describe the bonds connected to the asymmetric carbon atom using solid lines. This is intended to indicate all possible stereoisomers (e.g., specific enantiomers, racemic mixtures, etc.) associated with that carbon atom. Wedge-shaped bonds are used... ) or dashed wedge key ( ) indicates absolute stereochemistry. Bold bonds are used ( ) or dashed key ( ) indicates relative stereochemistry.

[0347] Isotope-enriched compounds

[0348] Unless otherwise indicated, the compounds described herein can exhibit their natural isotopic abundances, or one or more of the atoms can be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variants of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, designated as 1 H (protium), 2 H (deuterium), and 3 H (tritium). Protium is the most abundant hydrogen isotope in nature. Enrichment of deuterium can provide some therapeutic advantages, such as increased in vivo half-life and / or exposure, or can provide compounds for studying in vivo drug elimination and metabolic pathways.

[0349] For example, the compounds described herein can be artificially enriched with one or more particular isotopes. In some embodiments, the compounds described herein can be artificially enriched with one or more isotopes that are not predominantly present in nature. In some embodiments, the compounds described herein can be artificially enriched with one or more isotopes selected from deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). In some embodiments, the compounds described herein are artificially enriched with one or more isotopes selected from the following: 2 H, 11 C, 13 C, 14 C, 15 C, 12 N, 13 N, 15 N, 16 N, 16 O, 17 O, 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 131 Br, 131 I, and 125I. In some embodiments, the abundance of enriched isotopes is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% on a molar basis.

[0350] In some embodiments, the compound is deuterated at at least one position. In some embodiments, some or all of the compounds disclosed herein are... 1 H atoms are 2 H atom substitution.

[0351] Methods for synthesizing deuterium-containing compounds are known in the art and are included by way of non-limiting example only, including the methods described in U.S. Patent Nos. 5,846,514 and 6,334,997 and the synthetic methods described below. For example, deuterium-substituted compounds can be synthesized using various methods, such as those described in the following literature: Dean, Dennis C. (ed.), Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21) 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2) 9-32.

[0352] Deuterated raw materials are readily available and used in the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A wide range of deuterium-containing reagents and building blocks are commercially available from chemical suppliers, such as Aldrich Chemical Co.

[0353] Pharmaceutically acceptable salts

[0354] In some embodiments, the compounds described herein are present in their pharmaceutically acceptable salt form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts present in the form of a pharmaceutical composition.

[0355] In some embodiments, the compounds described herein have acidic or basic groups, and thus react with a variety of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or by reacting the purified compound in its free form with a suitable acid or base and isolating the resulting salt.

[0356] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with inorganic or organic acids. These salts include: acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionates, decanoates, diglucuronates, dihydrophosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, fumarates, glucohepanoates, glycerophosphates, glycolates, hemisulfates, heptahydrates, hexyn-1,6-dicitates, hydroxybenzoates, γ-hydroxybenzoates. Butyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, pyrosulfonate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0357] Furthermore, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the compounds in their free base form with pharmaceutically acceptable inorganic or organic acids, said inorganic or organic acids including, but not limited to: inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; and organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, etc. Acids, including 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-en-1-carboxylic acid, glucoheponic acid, 4,4'-methylenebis(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecyl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. In some embodiments, other acids, such as oxalic acid, although not pharmaceutically acceptable on their own, may be used to prepare salts as intermediates for obtaining the compounds described herein and their pharmaceutically acceptable acid addition salts.

[0358] In some embodiments, the compounds described herein that contain free acid groups react with suitable bases, such as pharmaceutically acceptable metal cation hydroxides, carbonates, bicarbonates, sulfates, ammonia, or pharmaceutically acceptable primary, secondary, tertiary, or quaternary ammonium compounds. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, and N2SO4. + (C 1-4 Alkyl)4, etc.

[0359] Representative organic amines used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, such quaternization yields water- or oil-soluble or water- or oil-dispersible products.

[0360] tautomer

[0361] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the structural formulas described herein. Tautomers are compounds that can interconvert through hydrogen atom migration, accompanied by the conversion of single bonds and adjacent double bonds. In bond arrangements where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomer forms of the compounds disclosed herein are considered. The exact proportions of tautomers depend on a variety of factors, including temperature, solvent, and pH.

[0362] Treatment

[0363] This document discloses methods for modulating the activity of immune cells (e.g., T cells, B cells, or NK cells), for example, by contacting immune cells with an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof or a combination thereof to modulate the activity of immune cells (e.g., T cells, B cells, or NK cells).

[0364] This article also discloses methods for treating cancer, which include administering an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof to an individual in need.

[0365] This article also discloses a method for treating cancers that respond to inhibition of Cbl-b activity, the method comprising administering to an individual in need an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0366] This article also discloses a method for inhibiting abnormal cell proliferation, the method comprising administering to an individual in need an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0367] This article also discloses methods for modulating immune responses, which include administering an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof to an individual in need.

[0368] This document also discloses a method for inhibiting Cbl-b activity, the method comprising administering to an individual in need an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0369] This document also discloses methods for treating diseases or conditions associated with Cbl-b activity, the methods comprising administering to an individual in need an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0370] In some implementations, the disease or condition associated with Cbl-b activity is cancer.

[0371] In some embodiments, the cancer is a hematologic malignancy. In some embodiments, the cancer is lymphoma, leukemia, or myeloma. In some embodiments, the cancer is a non-hematologic malignancy. In some embodiments, the cancer is sarcoma, carcinoma, or melanoma. In some embodiments, the cancer is a solid tumor.

[0372] Hematologic malignancies include, but are not limited to: one or more types of leukemia, such as B-cell acute lymphoblastic leukemia (“BALL”), T-cell acute lymphoblastic leukemia (“TALL”), and acute lymphoblastic leukemia (ALL); one or more chronic leukemias, including, but not limited to chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL); other hematologic malignancies or hematologic disorders, including, but not limited to, B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or large cell-follicular lymphoma, malignant lymphoproliferative disorders, MALT lymphoma, mantle cell lymphoma, and marginal zone lymphoma. Multiple myeloma, myelodysplastic syndrome, non-Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell tumor, Waldenström macroglobulinemia, and "preleukemia" are a diverse collection of hematologic diseases resulting from the ineffective production (or dysplasia) of bone marrow hematopoietic cells.

[0373] Non-hematologic cancers include, but are not limited to, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell carcinoma, melanoma, stomach cancer, brain cancer, lung cancer (e.g., NSCLC), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.

[0374] Dosage

[0375] In some embodiments, a composition containing one or more compounds described herein is administered for a therapeutic treatment. In some therapeutic applications, the composition is administered to a patient who already has a disease or condition in an amount sufficient to cure or at least partially suppress at least one symptom of said disease or condition. The effective amount for this purpose depends on the severity and course of said disease or condition, prior therapy, the patient's health status, weight and response to the drug, and the judgment of the treating physician. The therapeutically effective amount may optionally be determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0376] Application route

[0377] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ocular, nasal, and topical administration. Furthermore, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0378] In some embodiments, the compounds described herein are administered locally rather than systemically, for example, by direct injection into an organ, typically in the form of a reservoir formulation or a sustained-release formulation. In certain embodiments, long-acting formulations are administered via implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, such as in liposomes coated with organ-specific antibodies. In these embodiments, the liposomes target the organ and are selectively absorbed by it. In still other embodiments, the compounds described herein are provided in the form of a rapid-release formulation, a prolonged-release formulation, or a medium-release formulation.

[0379] Pharmaceutical Compositions / Formulations

[0380] In accordance with standard pharmaceutical practice, the compounds described herein are administered, alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, as a pharmaceutical composition to an individual in need. In some embodiments, the compounds described herein are administered to animals.

[0381] On the other hand, this document provides pharmaceutical compositions comprising the compound described herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically acceptable formulation. A suitable formulation depends on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in the following literature: Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., editors, Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0382] Example

[0383] For illustrative purposes, the following examples are included. The examples provided herein describe the compounds disclosed herein and the synthesis of intermediates for the preparation of said compounds. However, it should be understood that these examples are not limiting of this disclosure, but are merely illustrative of methods for implementing this disclosure. Those skilled in the art will recognize that the described chemical reactions can be readily modified to prepare many other compounds of this disclosure, and alternative methods for preparing the compounds of this disclosure are considered to be within the scope of this disclosure. For example, unspecificated compounds of this disclosure can be successfully synthesized by modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, by using other suitable reagents and building blocks known in the art other than those described, and / or by conventionally adjusting the reaction conditions. Furthermore, those skilled in the art will understand that the various steps described herein or in separate batches of the compounds can be combined. Alternatively, other reactions disclosed herein or other reactions known in the art will be considered suitable for preparing other compounds of this disclosure. Therefore, the following description is not intended to limit the scope of this disclosure, which is determined by the appended claims.

[0384] Compound Synthesis

[0385] Example 1

[0386]

[0387] BH3 (259 mL, 259 mmol, 1.0 M THF solution) was added to a solution of 1-(2-bromopyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid (7 g, 25.9 mmol) in THF (2 mL) at 25°C under N2. The reaction mixture was stirred at 25°C for 1 h. The reaction mixture was quenched by adding MeOH at 25°C. The mixture was concentrated under reduced pressure to give compound 1-1 (3.1 g, 46.7%), which was used directly for the next step without further purification; LCMS: 256.1 / 258.1 [M+H] + .

[0388] DMP (16.6 g, 39.0 mmol) was added to a solution of compound 1-1 (5 g, 19.5 mmol) in DCM (100 mL) at 0°C. The resulting mixture was stirred at 25°C for 12 hours. The mixture was filtered through a Celite pad, and the filtrate was concentrated to give a crude product, which was purified by rapid silica gel chromatography to give compound 1-2 (4.5 g, 90.7%); LCMS: 254.0 / 256.0 [M+H]. + .

[0389] Compounds 1-2 (5 g, 19.7 mmol) were added to a solution of hydroxylamine hydrochloride (1.4 g, 19.7 mmol) and TEA (2.70 mL, 19.7 mmol) in DCM (50 mL) at 0°C. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water (100 mL) and extracted with DCM (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compounds 1-3 (4.5 g, 85.0%), which were used directly for the next step without further purification; LCMS: 269.0 / 271.0 [M+H] + .

[0390] NCS (6.0 g, 44.6 mmol) was added to a solution of compounds 1-3 (4 g, 14.9 mmol) in DMF (50 mL) at 5°C under N2. After stirring at 60°C for 3 hours, the reaction mixture was used directly for the next step without further purification; LCMS: 259.0 [M+H] + .

[0391] Add ( ) to a solution of compounds 1-4 (5 g, 19.4 mmol) in CHCl3 (30 mL) 2E Ethyl 3-(dimethylamino)prop-2-enoate (4.2 g, 29.1 mmol) and TEA (4.03 mL, 29.1 mmol). The mixture was stirred at room temperature for 16 hours. The reaction was quenched by adding saturated NH4Cl (aqueous solution). The mixture was then extracted with DCM (50 mL × 2). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by chromatography to give compounds 1-5 (2.2 g, 35.4%); LCMS: 321.2 [M+H]. + .

[0392] DIBAL-H (2 mL, 2.0 mmol) was slowly added over 1 min to a solution of compounds 1-5 (600 mg, 1.9 mmol) in THF (10 mL) at -78°C. The resulting mixture was stirred at -78°C for 2 h. The reaction mixture was quenched by adding 2 M NaOH (aqueous solution, 2 mL) at 25°C. After dilution with EtOAc (30 mL), the mixture was filtered through a Celite pad, and the filtrate was concentrated to give the crude product, which was purified by reversed-phase chromatography to give compounds 1-6 (200 mg, 38.4%); LCMS: 279.1 [M+H] + .

[0393] TEA (0.08 mL, 0.6 mmol) and MsCl (67.8 mg, 0.6 mmol) were added to a solution of compounds 1-6 (150 mg, 0.5 mmol) in DCM (5 mL) at 25°C. The reaction was stirred at 25°C for 2 hours. The mixture was quenched by adding water (10 mL) and extracted with dichloromethane (10 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compounds 1-7 (160 mg, 83.3%); LCMS: 357.0 [M+H] + .

[0394] NaBH4 (36.0 mg, 0.9 mmol) was added to a solution of compounds 1-7 (170 mg, 0.5 mmol) in DMSO (2 mL) at 25°C. The reaction mixture was stirred at 60°C for 1 h. The reaction mixture was purified by reversed-phase chromatography to give compounds 1-8 (60 mg, 47.9%); LCMS: 263.0 [M+H] + .

[0395] Towards( S Potassium trifluoro[(3-methyl-1-piperidinyl)methyl]borate (1.8 g, 8.365 mmol), 6-bromo-8-(trifluoromethyl)quinazolin-4 ( 3H1.2 g (4.180 mmol) and K₂CO₃ (1.7 g, 12.547 mmol) were added to a solution of dioxane (10 mL) and water (2 mL), along with cataXcium A (0.3 g, 0.836 mmol) and Pd(OAc)₂ (0.1 g, 0.418 mmol). The mixture was stirred at 120 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was partitioned between EtOAc (70 mL) and water (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography to give compounds 1-9 (1.03 g, 76.0%). LCMS: 272.1 [M+H] + .

[0396] Compounds 1-8 (50 mg, 0.19 mmol) and 1-9 were subjected to nitrogen at 25°C and N2. CuI (36.3 mg, 0.19 mmol), K₂CO₃ (52.6 mg, 0.38 mmol), and methyl [(49.5 mg, 0.152 mmol) were added to a solution in dioxane (2 mL). 1R , 2R [2-methylamino]cyclohexylamine (16.2 mg, 0.11 mmol). The reaction was stirred at 120°C for 16 hours. The mixture was filtered through a Celite pad, the filtrate was concentrated to give the crude product, which was purified by preparative-HPLC to give compound 1. LCMS: 552.4 [M+H] + ; 1 H NMR (400 MHz, chloroform-) d ) δ 8.86 – 8.44 (m, 3H)8.09 (s, 1H) 7.95 (s, 1H) 7.43 – 7.27 (m, 2H) 4.43 – 3.39 (m, 2H) 2.95 – 2.79(m, 2H) 2.75 – 2.45 (m, 4H) 2.32 – 1.55 (m, 10H) 1.15 (d, J = 5.6 Hz, 3H)1.06 – 0.70 (m, 4H).

[0397] Example 3

[0398]

[0399] Add cyclopropyltrifluoro- to a solution of 2,6-dichloro-4-methylpyridine (10 g, 61.73 mmol) in water (15 mL) and toluene (150 mL). λ 4 - Potassium boronate (10 g, 67.90 mmol), Pd(OAc)2 (1.4 g, 6.17 mmol), cataXcium A (2.2 g, 6.17 mmol), and Cs2CO3 (60.3 g, 185.18 mmol). The reaction mixture was stirred at 110 °C under N2 for 2 hours. The reaction mixture was partitioned between 100 mL of NH4Cl (aqueous solution) and 200 mL of EtOAc. The organic phase was separated, washed with NH4Cl (aqueous solution) (100 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography to give compound 3-1 (5.1 g, 49.3%). LCMS: 168.1 [M+H] + .

[0400] LDA (22.8 mL, 45.64 mmol) was slowly added to a solution of compound 3-1 (5.1 g, 30.43 mmol) in anhydrous THF (30 mL) at -78 °C and N2. The mixture was stirred at -78 °C for 0.5 h. Methyl methoxyformate (13.7 g, 152.15 mmol) was added dropwise. The mixture was stirred at 0 °C for another 1 h. The mixture was quenched by adding H2O (50 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography to give compound 3-2 (2.1 g, 30.6%). LCMS: 226.1 [M+H] + .

[0401] Cs₂CO₃ (7.2 g, 22.15 mmol) was added to a solution of compound 3-2 (2.5 g, 11.07 mmol) in DMF (25 mL). The mixture was stirred at 0 °C under N₂ for 0.5 h. 1,3-Dibromo-2-methylpropane (7.2 g, 33.23 mmol) was slowly added at 25 °C, and the resulting mixture was stirred at 25 °C under N₂ for 16 h. The mixture was then partitioned between water (80 mL) and EtOAc (80 mL). The organic phase was separated, washed with water (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography to give compound 3-3 (2.1 g, 67.8%). LCMS: 280.2 [M+H] + .

[0402] A solution of LiOH (1.3 g, 30.02 mmol) in H₂O (10 mL) was added to a solution of compound 3-3 (2.1 g, 7.50 mmol) in EtOH (10 mL) at 0 °C. The mixture was stirred at 25 °C for 3 hours. The pH of the mixture was adjusted to 4 with HCl (1 M). The mixture was then extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give crude compound 3-4 (2 g, 100.3%). LCMS: 266.1 [M+H] + .

[0403] A solution of compounds 3-4 (2 g, 7.52 mmol) in SOCl2 (10 mL) was stirred at 80 °C for 1 hour. The mixture was concentrated to obtain a residue, which was then added to DCM (10 mL) and the solution was added dropwise to a solution of ammonia in MeOH (7 M, 20 mL). The resulting mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to obtain a residue, which was purified by rapid silica gel chromatography (ISCO@; 40 g SepaFlash@ silica gel flash column, eluent 0-50% EtOAc / PE @ 40 mL / min) to give compounds 3-5 (1.8 g, 90.3%). LCMS: 265.1 [M+H] + ;

[0404] The solution of compound 3-5 (1.8 g, 6.79 mmol) in DMF-DMA (10 mL) was stirred for 12 hours at 100 °C and N2. The reaction mixture was concentrated under reduced pressure to give crude compound 3-6. LCMS: 320.1 [M+H] + ;

[0405] Hydrazine hydrate (18 mL, 370.06 mmol) was added to a solution of compounds 3-6 (1.8 g, 5.62 mmol) in AcOH (18 mL) at 0 °C and N2. The reaction mixture was stirred at 80 °C for 3 h. The mixture was quenched with H2O (60 mL) and extracted with EtOAc. The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by reversed-phase chromatography (Isolera-Biotage column: Agela C18 40 g; mobile phase A: 10 mM FA aqueous solution, mobile phase B: ACN; flow rate: 40 mL / min; gradient: 30% B-40% B, 15 min; detector: UV 210 nm) to give compounds 3-7. LCMS: 289.1 [M+H] + ;

[0406] K₂CO₃ (765.7 mg, 5.54 mmol) was added to a solution of compounds 3-7 (800 mg, 2.77 mmol) in DMF (10 mL), and the mixture was bubbled with dichlorofluoromethane. The mixture was stirred at 100 °C for 16 hours. The mixture was quenched by adding H₂O (60 mL) and extracted with EtOAc. The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by reversed-phase chromatography to give compounds 3-8. LCMS: 339.0 [M+H] + ;

[0407] Following the steps for synthesizing compound 1 in Example 1, compound 3 was synthesized using compounds 3-8 as corresponding substrates. LCMS: 560.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.98 (s, 1H) 8.47 (s, 1H)8.10 (s, 1H) 7.80 (d, J = 9.4 Hz, 1H) 7.69 (d, J = 8.3 Hz, 1H) 7.60 – 7.28(m, 3H) 3.57 (s, 2H) 2.89 (td, J= 12.1, 3.8 Hz, 2H) 2.76 – 2.65 (m, 3H) 2.61– 2.58 (m, 2H) 2.25 – 2.16 (m, 1H) 1.93 – 1.83 (m, 1H) 1.67 – 1.56 (m, 4H)1.52 – 1.42 (m, 1H) 1.08 (d, J = 4.7 Hz, 3H) 1.01 – 0.96 (m, 4H) 0.88 – 0.77 (m, 4H).

[0408] Example 4

[0409]

[0410] A solution of 2-amino-5-bromo-3-methylbenzoic acid (4.1 g, 17.82 mmol) in formamide (50 mL) was stirred at 170 °C under N2 for 4 h. The reaction mixture was cooled to room temperature and poured into water, resulting in a precipitate. After filtration, the filter cake was dried to give compound 4-1 (3.2 g, 75.1%). LCMS: 239.0 / 241.0 [M+H] + .

[0411] Towards( S Potassium trifluoro[(3-methyl-1-piperidinyl)methyl]borate (1.8 g, 8.365 mmol), compound 4-1 (1 g, 4.182 mmol), and K₂CO₃ (1.7 g, 12.547 mmol) were added to a solution of dioxane (10 mL) and water (2 mL) along with cataXcium A (0.3 g, 0.836 mmol) and Pd(OAc)₂ (0.1 g, 0.418 mmol). The mixture was stirred at 120 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was partitioned between EtOAc (70 mL) and water (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography to give compound 4-3 (870 mg, 76.6%). LCMS: 272.1 [M+H] + .

[0412] To a solution of compound 4-2 (500 mg, 1.84 mmol), (3-(2-bromopyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)methanol (595.4 mg, 1.84 mmol), and K₂CO₃ (509.2 mg, 3.68 mmol) in 1,4-dioxane (5 mL), CuI (351.0 mg, 1.84 mmol) and methyl[(1R,2R)-2-(methylamino)cyclohexyl]amine (523.9 mg, 3.68 mmol) were added. The mixture was stirred at 90 °C and N₂ for 1 h. The reaction mixture was partitioned between water (20 mL) and EtOAc (30 mL). The organic phase was separated, washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography to give compound 4-3 (800 mg, 84.5%). LCMS: 514.3 [M+H] + .

[0413] DMP (743.2 mg, 1.752 mmol) was added to a solution of compound 4-3 (600 mg, 1.168 mmol) in DCM (10 mL). The mixture was stirred at 25 °C for 3 hours. The reaction mixture was partitioned between sodium thiosulfate (20 mL) and DCM (30 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography to give compound 4-4 (500 mg, 83.7%, crude). LCMS: 512.4 [M+H] + .

[0414] Add ( ) to a solution of compound 4-4 (500 mg, 0.97 mmol) and K2CO3 (270.1 mg, 1.95 mmol) in MeOH (10 mL) 1Z )-1-(diazo-1-onthium)-1-[dimethoxy-(oxo)- λ 5 [-phosphino]-prop-1-en-2-acid salt(( 1Z )-1-(diazyn-1-iumyl)-1-[dimethoxy-(oxo)- λ 5[-phosphanyl]-prop-1-en-2-olate (281.6 mg, 1.46 mmol). The mixture was stirred at 25 °C for 3 hours. The reaction mixture was partitioned between NH4Cl (20 mL saturated aqueous solution) and EtOAc (30 mL). The organic phase was separated, washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative-HPLC to give compound 4. LCMS: 508.3 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.62 (d, J = 5.3 Hz, 1H) 8.55 (s, 1H) 8.47(s, 1H) 7.96 (s, 1H) 7.71 – 7.65 (m, 2H) 7.35 (dd, J = 6.1, 0.8 Hz, 1H) 3.53(s, 2H) 3.40 – 3.37 (m, 2H) 3.30 (s, 3H) 3.16 (d, J = 2.3 Hz, 1H) 3.10 – 3.05(m, 1H) 2.79 – 2.70 (m, 4H) 2.57 (s, 3H) 1.91 – 1.84 (m, 1H) 1.67 – 1.55 (m,4H) 1.52 – 1.44 (m, 1H) 0.88 – 0.79 (m, 4H).

[0415] Example 5

[0416]

[0417] A mixture of 2,2,2-trichloroethane-1,1-diol (15 g, 90.689 mmol) and sodium sulfate (85 g, 598.592 mmol) in H₂O (500 mL) was heated to 40°C. 2,3-Dihydro-1,1-diol was slowly added to the stirred mixture. H 5-Indene-5-amine (10 g, 75.075 mmol). The reaction mixture was stirred for 1 hour, and a suspension of hydroxylamine hydrochloride (21 g, 302.158 mmol) was rapidly added to the reaction mixture. The mixture was then stirred at 90°C for 5 hours. The mixture was cooled to room temperature and filtered. The filter cake was washed with water (50 mL × 3) to give compound 5-1 (12 g, 78.3%). LCMS: 205.3 [M+H] + .

[0418] A solution of compound 5-1 (10 g, 48.972 mmol) in H₂SO₄ (80 mL) was stirred at 80 °C for 30 min. The mixture was poured into ice water (50 mL). The mixture was extracted with DCM:MeOH = 10:1 (100 mL × 5). The combined organic layers were dried over anhydrous Na₂SO₄ and concentrated to give compound 5-2 (6 g, 65.4%). LCMS: 188.1 [M + H] + .

[0419] Hydrogen peroxide (7.8 mL, 100.659 mmol) was added dropwise to a solution of compound 5-2 (6 g, 32.051 mmol) in 2M NaOH (60 mL, 120.000 mmol), and the reaction was stirred at room temperature for 3 hours. 1N hydrochloric acid was added to the reaction mixture to adjust the pH to 5. The resulting mixture was extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine, dried, and concentrated to give compound 5-3 (4 g, 70.4%). LCMS: 178.0 [M+H] + .

[0420] Compound 5-4 was synthesized using compound 5-3 as a substrate, following step 1 of Example 4. LCMS: 187.1 [M+H] + .

[0421] Tert-butyl hydroperoxide (11.1 mL, 80.559 mmol) was added dropwise to a vigorously stirred suspension of trioxo-λ6-chromium(VI) (53.7 mg, 0.537 mmol) in DCM (50 mL) at 0 °C. The mixture was warmed to room temperature and stirred for 30 min. Compound 5-4 (1000.0 mg, 5.371 mmol) was slowly added, and the mixture was stirred at room temperature for 12 h. The mixture was concentrated under vacuum to remove DCM. The residue was purified by rapid silica gel chromatography to give compound 5-5 (600 mg, 55.8%); LCMS: 201.1 [M+H] + .

[0422] A mixture of compound 5-5 (580 mg, 2.897 mmol), (1-fluorocyclobutyl)methylamine hydrochloride (606.7 mg, 4.346 mmol), and tetraisopropoxide titanium (6 mL, 20.267 mmol) was stirred in a sealed tube at 80 °C for 12 h. After adding NaBH4 (657.1 mg, 17.383 mmol) and THF (6 mL), the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc (40 mL) and quenched by adding water (2 mL) and MeOH (20 mL) at 10 °C. The mixture was washed with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative-HP to give compound 5-6 (150 mg, 18.0%). LCMS: 288.1 [M+H] + .

[0423] Compound 5 was synthesized using compounds 5-6 as corresponding substrates according to step 9 of Example 1. LCMS: 562.4 [M+H] + .

[0424] Example 6

[0425]

[0426] Add 1,2-dibromoethane (0.9 mL, 10.251 mmol) to a solution of Zn (4.0 g, 61.507 mmol) in dry THF (50 mL) at 25 °C. Stir the reaction mixture at 70 °C for 1 min and cool to 25 °C. Repeat this operation three times. Add trimethylchlorosilane (0.5 mL, 4.100 mmol), and stir the resulting suspension at 25 °C for 15 min. Then heat to 70 °C. Add a solution of tert-butyl 2-bromoacetate (10 g, 51.256 mmol) in dry THF (10 mL) while refluxing the mixture. After the addition is complete, reflux the reaction mixture again for 20 min and cool to 25 °C. Use the mixture directly for the next step.

[0427] Qphos (693.6 mg, 0.976 mmol) was added to a solution of compound 6-1, 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (3000 mg, 9.759 mmol), and Pd2(dba)3 (553.4 mg, 0.976 mmol) in THF (30 mL). The reaction mixture was stirred at 25°C under nitrogen for 2 hours. The mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified by silica gel chromatography to give compound 6-2 (2 g, 69.3%). LCMS: 296.1 [M+H] + .

[0428] Compound 6 was synthesized according to Example 3 using compound 6-2 as the corresponding substrate. LCMS: 629.5 [M+H+ACN] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.99 (s, 1H) 8.51 (s, 1H) 8.17 (s, 1H) 8.13 (s, 1H) 7.86 – 7.79 (m, 2H) 7.73 (d, J = 8.3 Hz, 1H) 7.52 (t, J = 58.6 Hz,1H) 3.59 (s, 2H) 3.00 – 2.90 (m, 2H) 2.76 – 2.60 (m, 4H) 2.35 – 2.30 (m, 1H)1.97 – 1.78 (m, 1H) 1.70 – 1.40 (m, 5H) 1.09 (d, J = 5.9 Hz, 3H) 0.91 – 0.75(m, 4H).

[0429] Examples 7 & 8

[0430]

[0431] LiHMDS (27.4 mL, 27.41 mmol) was added to a solution of 3-methylenecyclobutane-1-onitrile (2.6 g, 27.41 mmol) in THF (20 mL) at -78 °C and N2. The mixture was stirred at -78 °C for 1 h. Then, 2,4,6-trichloropyridine (5 g, 27.41 mmol) was added at -78 °C. The resulting mixture was stirred at -78 °C and N2 for 2 h. The reaction mixture was partitioned between 100 mL of NH4Cl (aqueous solution) and 100 mL of EtOAc. The organic phase was separated, washed with saturated NH4Cl (aqueous solution) (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography to give compound 7-1 (3.7 g, 56.5%). LCMS: 238.9 [M+H] + .

[0432] 1M NaOH (20.9 mL, 20.91 mmol) was added to a solution of compound 7-1 (1 g, 4.18 mmol) in EtOH (10 mL). The reaction was stirred at 100 °C for 16 h. The mixture was adjusted to pH 4 with HCl (3 M) and then extracted with ethyl acetate (40 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated to give the residue. The residue was purified by reversed-phase chromatography to give compound 7-2 (900 mg, 83.3%). LCMS: 258.0 [M+H] + .

[0433] Compound 7-3 was synthesized using compound 7-2 as a substrate according to the method described in Example 3. LCMS: 331.0 [M+H] + .

[0434] To a solution of compound 7-3 (160 mg, 0.48 mmol) in DMSO (3 mL), ethanhydroxamic acid (108.9 mg, 1.45 mmol) and K₂CO₃ (200.4 mg, 1.45 mmol) were added. The reaction mixture was stirred at 80 °C for 16 h. The mixture was adjusted to pH 4 with HCl (1 M) and then extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography to give compound 7-4 (100 mg, 66.2%). LCMS: 313.1 [M+H] + .

[0435] Cs₂CO₃ (104.2 mg, 0.32 mmol) and fluoromethyl 4-methylbenzenesulfonate (130.6 mg, 0.64 mmol) were added to a solution of compound 7-4 (100 mg, 0.32 mmol) in DMF (2 mL). The mixture was stirred at 80 °C for 16 h. The mixture was quenched by adding H₂O (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography to give compound 7-5 (60 mg, 54.4%). LCMS: 344.8 [M+H] + .

[0436] A borane-methyl thiocyanate complex (0.7 mL, 6.963 mmol) was added to a solution of compound 7-5 (480 mg, 1.393 mmol) in THF (5 mL) at -10 °C and N2. The mixture was stirred at 25 °C for 4 h. A solution of sodium 1,3,2-dioxaboriran-2-olate (637.9 mg, 7.798 mmol) in H2O (10 mL) and 1,4-dioxane (2 mL) was added. The reaction mixture was stirred at 65 °C and N2 for 6 h. The reaction mixture was partitioned between H2O (20 mL) and EtOAc (100 mL). The organic phase was separated, washed with NH4Cl (aqueous solution) (30 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography to give compound 7-6 (200 mg, 39.2%). LCMS: 363.0 [M+H] + .

[0437] Compounds 7 and 8 were synthesized according to the method described in Example 4 above.

[0438] Compound 7:

[0439] LCMS: 578.4 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 9.01 (s, 1H) 8.56 (s,1H) 8.10 (s, 1H) 7.81 (d, J = 8.3 Hz, 1H) 7.70 (d, J= 8.2 Hz, 1H) 7.66 –7.33 (m, 2H) 7.11 (s, 1H) 6.13 (d, J = 52.1 Hz, 2H) 3.58 (s, 2H) 3.14 (d, J =2.2 Hz, 1H) 3.13 – 3.02 (m, 4H) 2.74 – 2.67 (m, 2H) 1.93 – 1.84 (m, 1H) 1.69 – 1.55 (m, 4H) 1.52 – 1.43 (m, 1H) 1.33 – 1.24 (m, 1H) 0.87 – 0.77 (m, 4H).

[0440] Compound 8:

[0441] LCMS: 578.4 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H) 8.56 (d, J = 4.9 Hz, 1H) 8.11 (s, 1H) 7.84 – 7.78 (m, 1H) 7.70 (d, J = 8.3 Hz, 1H)7.68 – 7.38 (m, 2H) 7.05 (s, 1H) 6.13 (d, J = 52.1 Hz, 2H) 3.58 (s, 2H) 3.18– 3.16 (m, 1H) 3.16 – 3.11 (m, 1H) 2.86 – 2.78 (m, 2H) 2.77 – 2.65 (m, 3H)1.90 (t, J = 10.4 Hz, 1H) 1.67 – 1.56 (m, 4H) 1.52 – 1.42 (m, 1H) 1.33 – 1.23(m, 1H) 0.86 – 0.78 (m, 4H).

[0442] Examples 9 & 10

[0443]

[0444] At room temperature, 6-bromo-8-(trifluoromethyl)quinazolin-4 ( 3HCs₂CO₃ (33.4 g, 102.389 mmol) and 4-(chloromethyl)-1-methoxybenzene (23.1 mL, 170.648 mmol) were added to a solution of 10 g (34.130 mmol) in DMF (100 mL). The reaction mixture was stirred at 25 °C for 18 h. The mixture was filtered, and the filter cake was washed with EtOAc (100 mL × 2) to give the crude product. The crude product was slurried with EtOAc at 25 °C for 30 min. The mixture was filtered, and the filter cake was dried to give compound 9-1. (9.3 g, 65.9%). LCMS: 413.1 / 415.1[M+H] + ;

[0445] Add (tributyl-λ) to a solution of compound 9-1 (5 g, 12.101 mmol) in dioxane (100 mL) 4 (-Stanalkyl)methanol (7.8 g, 24.202 mmol) and XPhos Pd G2 (1.0 g, 1.210 mmol). The mixture was stirred at 80 °C and N2 for 12 hours. The reaction mixture was concentrated to give the residue. The residue was purified by rapid silica gel chromatography to give compound 9-2 (3.25 g, 73.7%). LCMS: 365.2 [M+H] + ;

[0446] 1,1,1-triacetoxy-1,3-dihydro-1λ was added to a solution of compound 9-2 (1 g, 2.745 mmol) in DCM (20 mL) at 0 °C. 5 -benzo[ d ][ 1,2 Iodoxacyclopentadien-3-one (1,1,1-triacetoxy-1,3-dihydro-1λ) 5 -benzo[ d ][ 1,2 Iodoxol-3-one (1.7 g, 4.117 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was partitioned between DCM (30 mL) and NaHCO3 (25 mL saturated aqueous solution). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography to give compound 9-3 (508 mg, 51.0%). LCMS: 363.2 [M+H] + ;

[0447] Triethylamine (0.5 mL, 3.312 mmol) was added to a solution of compound 9-3 (600 mg, 1.656 mmol) and 1-methylcyclobutane-1-amine hydrochloride (402.8 mg, 3.312 mmol) in MeOH (8 mL). The mixture was stirred in a microwave oven at 100 °C for 2 min, followed by the addition of sodium cyanoborohydride (208.0 mg, 3.312 mmol), and the mixture was stirred in a microwave oven at 80 °C for 1 h. The mixture was quenched by adding water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography to give compound 9-4 (550 mg, 77.0%). LCMS: 432.3 [M+H] + ;

[0448] A solution of compound 9-4 (654 mg, 1.516 mmol) in TFA (7 mL) was stirred at 80 °C and N2 for 2 hours. The mixture was quenched by adding water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography to give compound 9-5. LCMS: 312.2 [M+H] + ;

[0449] Compounds 9 and 10 were synthesized according to the method described in Example 4 above.

[0450] Compound 9:

[0451] LCMS: 548.3 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.68 – 8.64 (m, 2H)8.46 (s, 1H) 8.41 (s, 1H) 8.25 (s, 1H) 7.80 (s, 1H) 7.50 (dd, J = 5.3, 1.6Hz, 1H) 3.84 (s, 2H) 3.32 – 3.28 (m, 2H) 3.26 (s, 3H) 3.14 (d, J= 2.3 Hz,1H) 3.12 – 3.05 (m, 4H) 2.03 – 1.92 (m, 3H) 1.74 – 1.65 (m, 3H) 1.23 (s, 3H).

[0452] Compound 10:

[0453] LCMS: 548.3 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.64 (d, J = 6.6 Hz, 2H) 8.47 (d, J = 6.4 Hz, 2H) 8.25 (s, 1H) 7.69 (s, 1H) 7.39 (dd, J = 5.3, 1.5Hz, 1H) 3.84 (s, 2H) 3.31 – 3.27 (m, 5H) 3.16 (d, J = 2.2 Hz, 1H) 3.11 – 3.04(m, 1H) 2.79 – 2.71 (m, 2H) 2.03 – 1.94 (m, 3H) 1.74 – 1.65 (m, 3H) 1.29 –1.23 (m, 3H).

[0454] Example 22

[0455]

[0456] NIS (1.04 g, 4.63 mmol) was added to a solution of 2-amino-5-bromobenzoic acid (1 g, 4.63 mmol) in DCM (10 mL). The mixture was stirred at 25 °C under N2 for 48 hours. The reaction solution was poured into water (30 mL) and extracted with DCM (20 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was ground with PE at 25 °C for 30 min. The mixture was filtered, and the filter cake was concentrated to give compound 22-1 (1.2 g). LCMS: 341.8 / 343.8 [M+H] + ;

[0457] A solution of compound 22-1 (1.2 g, 3.51 mmol) in formamide (10 mL) was stirred at 180 °C under N2 for 3 hours. The reaction solution was poured into ice water (50 mL), and the product was precipitated under constant stirring. After filtration, the filter cake was washed with water and EtOAc / PE (1:1), and dried to give crude compound 22-2 (750 mg). LCMS: 350.8 / 352.8 [M+H] + ;

[0458] Cs₂CO₃ (75.2 g, 230.80 mmol) and PMBCl (24.1 g, 153.89 mmol) were added to a solution of compound 22-2 (27 g, 76.94 mmol) in DMF (270 mL). The mixture was stirred at 25 °C under N₂ for 12 h. The reaction solution was poured into water (600 mL) and extracted with EtOAc (400 mL × 3). The combined organic phases were washed with water (300 mL × 2) and brine (300 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was ground with EtOAc at 25 °C for 30 min. The mixture was filtered, and the filtrate was concentrated to give compound 22-3 (31 g). LCMS: 471.0 / 473.0 [M+H] + ;

[0459] To a solution of compound 22-3 (5 g, 10.61 mmol) in dioxane (50 mL), tributyl(vinyl)tin (3.4 g, 10.613 mmol), cesium fluoride (3.2 g, 21.227 mmol), and bis(ethane)methane chloride bis(triphenylphosphine) (0.8 g, 1.061 mmol) were added. The mixture was stirred at 100 °C under N2 for 3 hours. The reaction solution was poured into water (50 mL) and extracted with EtOAc (45 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by rapid silica gel chromatography (Agela @: 40 g SepaFlash @-silica gel flash column, eluent 0 - 20% PE / EtOAc gradient @: 55 mL / min) to give compound 22-4 (2.1 g, 53.3%). LCMS: 371.1 / 373.1 [M+H] + ;

[0460] To a solution of compound 22-4 (2.21 g, 5.954 mmol), 2-hydroxypropane-1,2,3-tricarboxylic acid (1.5 g, 7.740 mmol), and NMO (0.9 g, 7.740 mmol) in water (20 mL), dipotassium dioxidodioxo-λ6-osmium(VI)dihydrate (0.2 g, 0.595 mmol) in tBuOH (20 mL) was added. The mixture was stirred at 25 °C for 2 hours. Then, sodium periodate (2.5 g, 11.907 mmol) was added, and the mixture was stirred at 25 °C for 3 hours. The reaction solution was poured into water (50 mL) and extracted with EtOAc (45 mL × 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by rapid silica gel chromatography (Agela @: 20 g SepaFlash @-silica gel flash column, eluent 0-10% MeOH / DCM gradient @: 40 mL / min) to give compound 22-5 (1.77 g, 74.9%). LCMS: 373.0 / 375.0 [M+H] + ;

[0461] Compound 22-5 was subjected to treatment at 0°C. DAST (1.3 mL, 9.486 mmol) was added to a solution in DCM (20 mL). The reaction mixture was stirred at 25 °C for 3 hours. The mixture was quenched by adding 30 mL of water and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to give the residue. The crude product was purified by rapid silica gel chromatography (Agela @: 20 g SepaFlash @-silica gel flash column, eluent 0-25% EtOAc / PE gradient @: 40 mL / min) to give compound 22-6 (1.5 g, 80.0%). LCMS: 394.8 / 396.8 [M+H] + ;

[0462] Compound 22 was synthesized using compound 22-6 as a substrate according to the method described in Example 9 above. LCMS: 544.4 [M+H] + ; 1 H NMR (400 MHz, DMSO- d6) δ 8.68 – 8.61 (m, 2H) 8.47 (s, 1H)8.27 (s, 1H) 8.05 (s, 1H) 7.71 (s, 1H) 7.63 (t, J = 55.1 Hz, 1H) 7.38 (dd, J = 5.3, 1.4 Hz, 1H) 3.64 (s, 2H) 3.40 – 3.39 (m, 1H) 3.30 (s, 3H) 3.16 (d, J =2.3 Hz, 1H) 3.13 – 3.02 (m, 2H) 2.77 – 2.69 (m, 4H) 1.96 – 1.90 (m, 1H) 1.68 – 1.57 (m, 4H) 1.52 – 1.44 (m, 1H) 0.90 – 0.80 (m, 4H).

[0463] Example 23

[0464]

[0465] To a solution of 2,2,2-trichloroethane-1,1-diol (22.35 g, 135 mmol) in H₂O (750 ml), add Na₂SO₄ (128 g, 901 mmol). When the temperature reaches 45°C, add dropwise 2,3-dihydro- 1H -Indene-4-amine (15 g, 113 mmol). The reaction mixture was stirred for 1 h, and then a suspension of NH₂OH·HCl (31.3 g, 450 mmol) was rapidly added to the reaction mixture. The mixture was stirred at 80°C for 1 h. The mixture was cooled to room temperature, filtered, and the filter cake was washed with water (50 mL × 3). The filter cake was concentrated to give compound 23-1. (22.5 g). LCMS: 205.1 [M+H] + ;

[0466] A solution of compound 23-1 (6 g, 29.383 mmol) in methanesulfonic acid (25 mL, 29.383 mmol) was stirred at 80 °C for 30 min. The reaction mixture was cooled to room temperature, poured into ice water, and filtered. The filter cake was dissolved in warm 1 N NaOH and neutralized with acetic acid. After filtration, the filtrate was acidified with concentrated HCl. The mixture was filtered, and the filter cake was washed with water. The solid was dried to give compound 23-2 (6.0 g). LCMS: 188.0 [M+H] + ;

[0467] Hydrogen peroxide (3 mL, 26.471 mmol) was added to a solution of compound 23-2 (6.6 g, 35.256 mmol) in NaOH (2 M aqueous solution, 70 mL, 140.000 mmol) at room temperature, and the reaction was stirred at room temperature for 2 hours. The mixture was adjusted to pH 4 with 1 N HCl and extracted with EtOAc (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude compound 23-3. LCMS: 178.0 [M+H] + ;

[0468] NBS (8.3 g, 46.558 mmol) was added to a solution of compound 23-3 (5.5 g, 31.038 mmol) in AcOH (25 mL) at room temperature, and the reaction was stirred overnight at room temperature. The reaction mixture was partitioned between water (100 mL) and EtOAc (200 mL). The organic phase was separated, washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (ISCO@; 80 g SepaFlash@ silica gel flash column, eluent 0-60% EtOAc / PE gradient@ 50 mL / min) to give compound 23-4 (2.3 g). LCMS: 256.0 / 258.0 [M+H] + ;

[0469] Compound 23 was synthesized using compound 23-4 as a substrate according to the method described in Example 9 above. LCMS: 570.4 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 9.10 (s, 1H) 8.62 (d, J = 5.3 Hz,1H) 8.49 (s, 1H) 7.95 (s, 1H) 7.74 (s, 1H) 7.64 – 7.34 (m, 2H) 3.50 (s, 2H)3.22 – 3.10 (m, 5H) 3.10 – 3.03 (m, 2H) 2.86 – 2.66 (m, 5H) 2.15 (p, J = 7.6Hz, 2H) 1.96 – 1.88 (m, 1H) 1.69 – 1.55 (m, 4H) 1.49 – 1.40 (m, 1H) 0.90 –0.79 (m, 4H).

[0470] Example 40

[0471]

[0472] At room temperature, 6-bromo-3-(4-methoxybenzyl)-8-(trifluoromethyl)quinazolin-4-( 3H Tributyl(1-ethoxyvinyl)stanane (912.6 mg, 2.527 mmol) and Pd(PPh3)4 (146.0 mg, 0.126 mmol) were added to a solution of 10 mL of dioxane. The reaction was stirred at 110 °C and N2 for 12 h. The mixture was quenched by adding KF (30 mL of saturated aqueous solution) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to give crude compound 40-1 (522 mg). The crude product was used for the next step without further purification. LCMS: 405.1 [M + H] + ;

[0473] HCl (100 mL, 100.000 mmol) was added to a solution of compound 40-1 (18.1 g, 44.758 mmol) in THF (90 mL) at room temperature. The reaction was stirred at 25 °C for 1 h. The mixture was quenched by adding water (45 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to give compound 40-2 (12.5 g, 74.2%). The crude product was used for the next step without further purification. LCMS: 377.1 [M + H] + ;

[0474] Magnesium monobromide methanide (22.3 mL, 23.736 mmol) was added to a solution of compound 40-2 (7 g, 18.602 mmol) in THF (100 mL) at room temperature. The reaction was stirred at 60 °C for 12 h. The mixture was quenched by adding water (45 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (45 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (Agela @: 80 g SepaFlash @-silica gel flash column, eluent 0-30% EtOAc / PE gradient @: 70 mL / min) to give compound 40-3 (4.07 g, 55.8%). LCMS: 393.5 [M+H] + ;

[0475] To a solution of compound 40-3 (4 g, 10.194 mmol) in DCM (40 mL), azidotrimethylsilane (3.3 mL, 25.484 mmol) and ethoxyethanetrifluoroborane (2.6 mL, 20.898 mmol) were added at room temperature. The reaction was stirred at 25 °C for 2 hr. The mixture was quenched by adding water (40 mL) and extracted with EtOAc (40 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous Na₂SO₄, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (Agela @: 40 g SepaFlash @-silica gel flash column, eluent 0-20% EtOAc / PE gradient @: 50 mL / min) to give compound 40-4 (4.06 g, 95.4%). LCMS: 418.3 [M+H] + ;

[0476] Zinc (1.253 g, 19.17 mmol) was added to a solution of compound 40-4 (4 g, 9.58 mmol) in AcOH (40 mL). The mixture was stirred at 50 °C under N2 for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by reversed-phase chromatography (Isolera-Biotage column: Agela C18 80 g; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 50 mL / min; gradient: 20% B to 40% B, 20 min; detector: UV 210 nm) to give compound 40-5 (2.55 g, 68.0% yield).

[0477] Cyclobutanone (0.269 g, 3.83 mmol) was added to a solution of compound 40-5 (1 g, 2.55 mmol) in tetraisopropoxide titanium (10 mL). The mixture was stirred in a sealed test tube at 100 °C for 36 hours. The reaction mixture was used directly for the next step without purification.

[0478] NaBH4 (0.427 g, 11.27 mmol) was added to a solution of compound 40-6 (1 g, 2.255 mmol) in THF (10 mL) at 0 °C. The mixture was stirred at 25 °C under N2 for 2 h. The reaction mixture was partitioned between water (30 mL) and EtOAc (35 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by reversed-phase chromatography (column: Agilent C18, 40 g; mobile phase A: 0.1 % FA / H2O, B: ACN; flow rate: 35 mL / min; gradient: 30-60 %; retention time: 30 min) to give compound 40-7 (500 mg, 49.8% yield). LCMS: 446.1 [M+H] + ;

[0479] TFA (10 mL) was added to a solution of compound 40-7 (450 mg, 1.010 mmol). The mixture was stirred at 80 °C under N2 for 2 hours. The reaction solution was directly concentrated to give the crude product. The crude product was purified by rapid silica gel chromatography (Agela @: 4 g SepaFlash @-silica gel flash column, eluent 0-15% MeOH / DCM gradient @: 20 mL / min) to give compound 40-8. LCMS: 326.1 [M+H] + ;

[0480] Compound 40 was synthesized using compound 40-8 as a substrate according to the method described in Example 4 above. LCMS: 598.3 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 9.10 (s, 1H) 8.67 – 8.62 (m, 2H)8.46 (d, J= 1.9 Hz, 1H) 8.39 – 8.36 (m, 1H) 7.74 (s, 1H) 7.65 – 7.33 (m, 2H)3.42 – 3.36 (m, 2H) 3.18 – 3.16 (m, 1H) 2.93 – 2.86 (m, 1H) 2.84 – 2.76 (m,2H) 2.73 – 2.68 (m, 1H) 1.95 – 1.84 (m, 2H) 1.72 – 1.62 (m, 2H) 1.48 – 1.35(m, 8H).

[0481] Example 45

[0482]

[0483] According to the method for preparing 40-2, 6-bromo-3-(4-methoxybenzyl)-8-methylquinazolin-4-( 3H Compound 45-1 was synthesized using )-ketone as a substrate.

[0484] A solution of compound 45-1 (800 mg, 2.48 mmol) and 1-methylcyclobutane-1-amine (254 mg, 2.98 mmol) in tetraisopropoxide (10 mL) was stirred at 100 °C for 16 h. After cooling to 25 °C, THF (5 mL) and sodium boranuide (563 mg, 14.89 mmol) were added. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with EtOAc (20 mL) and quenched by adding water (5 mL) and MeOH (5 mL) at 10 °C. The suspension was filtered, the filter cake was washed with EtOAc (15 mL × 3), dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by reversed-phase chromatography (Isolera-Biotage column: Agela C18 20 g; mobile phase A: 0.1% FA, mobile phase B: ACN; flow rate: 30 mL / min; gradient: 35% B to 45% B, 15 min; detector: UV 210 nm) to give compound 45-2 (300 mg, 30.9%). LCMS: 392.2 [M+H] + ;

[0485] Formaldehyde (0.021 mL, 0.76 mmol) was added to a solution of compound 45-2 (300 mg, 0.76 mmol) in DCM (5 mL). The resulting mixture was stirred at 25 °C for 1 h. Then STAB (244 mg, 1.15 mmol) was added. The mixture was stirred at 25 °C for 16 h. The mixture was concentrated to give the residue. The residue was purified by rapid silica gel chromatography (ISCO@; 12 g SepaFlash@ silica gel flash column, eluent 0-100% EtOAc / PE @ 20 mL / min) to give compound 45-3 (220 mg, 70.8%). LCMS: 406.0 [M+H] + ;

[0486] Compound 45 was synthesized using compound 45-3 as a substrate according to the method described in Example 1 above. LCMS: 548.3 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.98 (s, 1H) 8.62 (d, J = 5.3 Hz, 1H) 8.54(s, 1H) 8.03 (s, 1H) 7.87 (s, 1H) 7.76 (s, 1H) 7.45 (t, J = 58.6 Hz, 1H) 7.42(dd, J = 5.2, 1.6 Hz, 1H) 3.85 – 3.75 (m, 1H) 2.92 – 2.84 (m, 2H) 2.67 – 2.58(m, 6H) 2.13 (q, J = 9.4 Hz, 1H) 1.92 (s, 3H) 1.90 – 1.60 (m, 5H) 1.30 (d, J = 6.7 Hz, 3H) 1.22 (s, 3H) 1.09 (d, J = 5.6 Hz, 3H).

[0487] Example 46

[0488]

[0489] To 6-bromo-8-iodo-3-(4-methoxybenzyl)quinazolin-4 ( 3H)-ketone (3 g, 6.37 mmol), CuI (0.122 g, 0.637 mmol), and K3PO4 (1.352 g, 6.37 mmol) were added to a solution of sodium methanesulfinate (0.975 g, 9.55 mmol) and DMPHPC (0.149 g, 0.637 mmol) in DMSO (30 mL). The mixture was stirred at 80 °C and N2 for 12 hours. The reaction solution was directly concentrated to give the crude product. The crude product was purified by rapid silica gel chromatography (Agela @: 80 g SepaFlash @-silica gel flash column, eluent 0-50% EtOAc / PE gradient @: 70 mL / min) to give compound 46-1 (330 mg, 12.24% yield). LCMS: 422.8 / 424.8 [M+H] + ;

[0490] Compound 46 was synthesized using compound 46-1 as a substrate according to the method described in Example 9 above. LCMS: 598.3 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.98 (s, 1H) 8.74 (s, 1H) 8.64 (d, J = 5.3 Hz, 1H) 8.42 (d, J = 2.0 Hz, 1H) 8.35 (d, J = 2.0 Hz, 1H) 7.86 (s, 1H)7.48 (dd, J = 5.3, 1.7 Hz, 1H) 7.45 (t, J = 58.7 Hz, 1H) 3.67 (s, 2H) 3.56(s, 3H) 2.94 – 2.82 (m, 2H) 2.80 – 2.69 (m, 2H) 2.69 – 2.58 (m, 3H) 1.95 (t, J = 10.3 Hz, 1H) 1.71 – 1.56 (m, 4H) 1.55 – 1.42 (m, 1H) 1.09 (d, J = 5.7 Hz, 3H) 0.93 – 0.78 (m, 4H).

[0491] Example 47

[0492]

[0493] A solution of 2-amino-3-(trifluoromethyl)benzoic acid (1 g, 4.87 mmol) in formamide (10 mL) was stirred at 170 °C under N2 for 4 hours. The reaction solution was poured into ice water (50 mL), and the product was precipitated under constant stirring. The mixture was filtered, the filter cake was washed with water, and concentrated under reduced pressure to give crude compound 47-1 (730 mg, 69.93% yield). LCMS: 215.1 [M+H] + ;

[0494] Compound 47-1 (200 mg, 0.934 mmol), 2-chloro-6-(fluoromethoxy)-4-(( 1s , 3s )-3-methyl-1-(4-methyl- 4H -1,2,4-triazol-3-yl)cyclobutyl)pyridine (348 mg, 1.121 mmol) and K2CO3 (258 mg, 1.868 mmol) were added to a solution of dioxane (5 mL) with CuI (178 mg, 0.934 mmol) and ( 1R, 2R 1,2-Cyclohexanediamine (266 mg, 1.868 mmol). The mixture was stirred at 120 °C under N2 for 1 h. The reaction mixture was partitioned between ethyl acrylate (12 mL) and water (10 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (Waters 3767 / QDA, column: XBridge C18, 19). 250 mm, 10 μm; Mobile phase A: 10 mmol / L NH4HCO3 / H2O, B: ACN; Flow rate: 20 mL / min; Gradient: 50-50%; Retention time: 7.1-7.7 min), yielding compound 47 as the main peak. LCMS: 489.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.79 (s, 1H) 8.50 (d, J = 7.3Hz, 1H) 8.37 (s, 1H) 8.27 (d, J = 7.2 Hz, 1H) 7.76 (t, J = 7.7 Hz, 1H) 7.54(d, J = 1.1 Hz, 1H) 7.10 (d,J = 1.2 Hz, 1H) 6.14 (d, J = 52.1 Hz, 2H) 3.27(s, 3H) 2.94 – 2.84 (m, 2H) 2.65 – 2.56 (m, 3H) 1.09 (d, J = 5.3 Hz, 3H).

[0495] Example 66

[0496]

[0497] 2,6-dichloro-4-(( 1s , 3s )-3-methyl-1-(4-methyl- 4H A solution of 1,2,4-triazol-3-yl)cyclobutyl)pyridine (10 g, 33.6 mmol) in ethylamine (100 mL, 2 M THF solution) was stirred at 110 °C and N2 for 72 hours. The mixture was concentrated to give the residue. The residue was purified by rapid silica gel chromatography (Agela @: 120 g SepaFlash @-silica gel flash column, eluent 0 - 5% DCM / MeOH gradient @: 85 mL / min) to give compound 66-1. (6 g, 58.3% yield). LCMS: 306.1 [M+H] + ;

[0498] CuI (125 mg, 0.654 mmol) was added to a solution of compounds 66-1 (200 mg, 0.654 mmol), 47-1 (210 mg, 0.981 mmol), and K₂CO₃ (181 mg, 1.308 mmol) in 1,4-dioxane (5 mL). Racemic -(1R,2R) -N1,N2-Dimethylcyclohexane-1,2-diamine (186 mg, 1.308 mmol). The mixture was stirred at 120 °C under N2 for 12 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL × 2), dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by preparative HPLC (Gilson GX-281, column: XSelect CHS C18, 19). 250 mm, 10 μm; Mobile phase A: 10 mmol NH4HCO3, B: ACN; Flow rate: 20 L / min; Gradient: 53-53%; Retention time: 8-9.5 min, yielding compound 66 as the main peak. LCMS: 484.1 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.71 (s, 1H) 8.48 (d, J = 8.0 Hz, 1H) 8.36 (s, 1H) 8.25 (d, J = 6.9 Hz, 1H) 7.73 (t, J =7.8 Hz, 1H) 6.99 (t, J = 5.3 Hz, 1H) 6.87 (d, J = 1.2 Hz, 1H) 6.45 (d, J =1.2 Hz, 1H) 3.28 (s, 3H) 3.26 – 3.19 (m, 2H) 2.82 – 2.71 (m, 2H) 2.62 – 2.52(m, 3H) 1.11 (t, J = 7.2 Hz, 3H) 1.07 (d, J = 5.8 Hz, 3H).

[0499] Example 82

[0500]

[0501] To a solution of 6-bromo-8-(trifluoromethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)quinazolin-4(3H)-one (1 g, 2.362 mmol) in 1,4-dioxane (10 mL), (tributyltinyl)methanol (1.517 g, 4.72 mmol)) and XPhos Pd G2 (0.186 g, 0.236 mmol) were added at room temperature. The reaction mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (Agela @: 12 g SepaFlash @-silica gel flash column, eluent 0 - 15% MeOH / DCM gradient @: 30 mL / min) to give compound 82-1 (800 mg, 90% yield). LCMS: 375.1 [M+H] + ;

[0502] DMP (1584 mg, 3.73 mmol) was added to a solution of 82-1 (932 mg, 2.489 mmol) in DCM (10 mL) at 0 °C. The mixture was stirred at 25 °C under N2 for 1 hour. The reaction mixture was then partitioned between water and DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and the residue was purified by rapid silica gel chromatography (Agela: 12 g SepaFlash @-silica gel flash column, eluent 0-20% EtOAc / PE gradient @: 30 mL / min) to give compound 82-2 (631 mg, 68.1% yield). LCMS: 373.0 [M+H] + ;

[0503] Potassium tert-butoxide (2.352 mL, 2.352 mmol) was added to a solution of Ph3P(CH2OMe)Br (911 mg, 2.352 mmol) in THF (10 mL), and the mixture was stirred at 0 °C for 30 min. Then, THF (10 mL) and compound 82-2 (730 mg, 1.960 mmol) were added, and the mixture was stirred at 10 °C for 12 h. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (Agela: 12 g SepaFlash @-silica gel flash column, eluent 0-20% EtOAc / PE gradient @: 30 mL / min) to give compound 82-3 (323 mg, 41.1% yield). LCMS: 401.0 [M+H] + ;

[0504] HCl (4 mL, 24.00 mmol) was added to a solution of compound 82-3 (323 mg, 0.807 mmol) in THF (5 mL). The mixture was stirred at 60 °C and N2 for 1 hour. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (Agela @: 4 g SepaFlash @-silica gel flash column, eluent 0-25% EtOAc / PE gradient @: 20 mL / min) to give crude compound 82-4 (42 mg, 13.48% yield). The crude product was used for the next step without further purification. LCMS: 387.0 [M+H] + ;

[0505] Compound 82-4 was subjected to treatment at 0°C. DAST (0.021 ml, 0.155 mmol) was added to a solution of (30 mg, 0.078 mmol) in DCM (3 mL). The reaction was stirred at 25 °C for 3 hours. The mixture was quenched by adding water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give compound 82-5 as a white solid. The crude product was used for the next step without further purification. LCMS: 409.1 [M+H] + ;

[0506] To a solution of compound 82-5 (40 mg, 0.098 mmol) in THF (2 mL), HCl (2 mL, 12.00 mmol) was added. The mixture was stirred at 70 °C and N2 for 12 hours. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (Agela @: 4 g SepaFlash @-silica gel flash column, eluent 0 - 15% MeOH / DCM gradient @: 20 mL / min) to give crude compound 82-6. The crude product was used for the next step without further purification. LCMS: 279.0 [M+H] + ;

[0507] Compound 82 was synthesized using 82-6 and 6-chloro-N-ethyl-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine-2-amine as substrates, according to the method described in Example 66 above. LCMS: 548.2 [M+H] + ;

[0508] Example 85

[0509]

[0510] SEM-Cl (4.62 mL, 26.0 mmol) and Cs₂CO₃ (12.73 g, 39.1 mmol) were added to a solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1 g, 6.51 mmol) in DMF (15 mL). The mixture was stirred at 20 °C and N₂ for 12 h. The mixture was quenched by adding water (50 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (ISCO@; 12 g SepaFlash@ silica gel flash column, eluent 0-25% EtOAc / PE @ 30 mL / min) to give compound 85-1 (470 mg, 25.4% yield). LCMS: 283.9 [M+H] + ;

[0511] To a solution of compound 85-1 (470 mg, 1.656 mmol) in DMSO (8 mL), N-hydroxyacetamide (373 mg, 4.97 mmol) and K₂CO₃ (687 mg, 4.97 mmol) were added. The mixture was stirred at 80 °C under N₂ for 2 hours. The reaction mixture was partitioned between EtOAc (12 mL) and water (20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (ISCO@; 12 g SepaFlash@ silica gel flash column, eluent 0-100% EtOAc / PE @ 30 mL / min) to give compound 85-2 (320 mg, 72.8% yield). LCMS: 266.1 [M+H] + ;

[0512] Compound 85-3 was synthesized using compound 85-2 and 6-chloro-N-ethyl-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine-2-amine as substrates, according to the method described in Example 66 above. LCMS: 535.4 [M+H] + ;

[0513] TBAF (39.1 mg, 0.150 mmol) was added to a solution of compound 85-3 (80 mg, 0.150 mmol) in THF (2 mL). The mixture was stirred at 70 °C for 2 hours. The reaction mixture was partitioned between EtOAc (12 mL) and NH4Cl (saturated aqueous solution, 20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (Waters 3767QDA, column: XBridge C18, 19). 250 mm, 10 μm; Mobile phase A: 10 mmol / L NH4HCO3 / H2O, B: ACN; Flow rate: 20 mL / min; Gradient: 28-28%; Retention time: 6.7-7.8 min), yielding compound 85. LCMS: 404.9 [M+H] + ; 1 H NMR (400MHz, DMSO- d 6 ) δ 12.24 (s, 1H) 8.34 (s, 1H) 8.21 (s, 1H) 7.45 (s, 1H) 6.91 (t, J = 4.8 Hz, 1H) 6.72 (s, 1H) 6.43 (d, J = 1.8 Hz, 1H) 6.40 (s, 1H) 3.29 (s,3H) 3.21 – 3.28 (m, 2H) 2.83 – 2.71 (m, 2H) 2.53 (s, 3H) 1.14 – 1.08 (m, 3H)1.07 (d, J = 5.5 Hz, 3H).

[0514] Example 90

[0515]

[0516] To a solution of (tert-butoxycarbonyl)(8-iodo-4-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-3,4-dihydroquinazolin-7-yl)carbamate (1 g, 1.619 mmol) in DMF (10 mL), (dibutyl(propyl)tinyl)ethynyl)trimethylsilane (0.665 g, 1.781 mmol) and Pd(PPh3)4 (0.187 g, 0.162 mmol) were added. The mixture was stirred at 90 °C and N2 for 12 hours. The reaction mixture was poured into water (30 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (Agela: 12 g SepaFlash @-silica gel flash column, eluent 0-20% EtOAc / PE gradient @: 30 mL / min) to give compound 90-1 (740 mg, 78% yield). LCMS: 588.5 [M+H] + ;

[0517] Cs₂CO₃ (831 mg, 2.55 mmol) was added to a solution of compound 90-1 (500 mg, 0.851 mmol) in DMF (10 mL), and the mixture was stirred at 80 °C under N₂ for 12 h. The resulting mixture was stirred at 120 °C for 2 h. The reaction mixture was poured into water (30 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (Agela: 4 g SepaFlash @ silica gel flash column, eluent 0 - 30% EtOAc / PE gradient @: 20 mL / min) to give compound 90-2. LCMS: 316.2 [M+H] + ;

[0518] TBAF (85 mg, 0.323 mmol) was added to a solution of compound 90-2 (102 mg, 0.323 mmol) in THF (3 mL). The mixture was stirred at 70 °C under a nitrogen atmosphere for 12 hours. The reaction mixture was purified by reversed-phase chromatography to give compound 90-3. The crude product was used for the next step without further purification. LCMS: 186.1 [M+H] + ;

[0519] Compound 90 was synthesized using 90-3 and 6-chloro-N-ethyl-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine-2-amine as substrates, according to the method described in Example 66 above. LCMS: 455.2 [M+H] + ; 1 HNMR (400 MHz, DMSO- d 6 ) δ 11.78 (s, 1H) 8.60 (s, 1H) 8.36 (s, 1H) 7.88 (d, J =8.6 Hz, 1H) 7.60 (d, J = 8.3 Hz, 1H) 7.55 – 7.52 (m, 1H) 6.98 – 6.92 (m, 2H)6.85 (d, J = 1.0 Hz, 1H) 6.41 (d, J = 1.0 Hz, 1H) 3.29 (s, 3H) 3.26 – 3.21(m, 2H) 3.21 – 3.12 (m, 2H) 2.83 – 2.76 (m, 2H) 2.59 – 2.54 (m, 3H) 1.12 (t, J = 7.2 Hz, 3H) 1.08 (d, J = 5.9 Hz, 3H).

[0520] Example 132

[0521]

[0522] LDA (61.7 mL, 123 mmol) was added to a solution of 2,6-dichloro-4-methylpyridine (10 g, 61.7 mmol) in THF (100 mL). The mixture was stirred at -78°C for 30 min. Then dimethyl carbonate (15.57 g, 173 mmol) was added, and the mixture was stirred at 0°C for 1 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (ISCO@; 120 g SepaFlash@ silica gel flash column, eluent 0-25% EtOAc / PE@ 80 mL / min) to give crude compound 132-1 (8.8 g, 64.8% yield). LCMS: 220.0 [M+H] + ;

[0523] Cs₂CO₃ (11.49 g, 35.3 mmol) was added to a solution of compound 132-1 (7.76 g, 35.3 mmol) in DMF (70 mL). The mixture was stirred at 0°C for 30 min. Then, bromocyclobutane (33.2 mL, 353 mmol) was added to the solution, and the mixture was stirred at 20°C for 16 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (ISCO@; 80 g SepaFlash@ silica gel flash column, eluent 0-25% EtOAc / PE @ 60 mL / min) to give compound 132-2 (2.4 g, 24.83% yield). 1 H NMR (400 MHz, DMSO- d 6 )δ 7.51 (s, 2H) 3.86 (s, 1H) 3.59 (s, 3H) 2.90 – 2.79 (m, 1H) 2.10 – 2.01 (m,1H) 1.83 – 1.64 (m, 5H).

[0524] Compound 132-3 was synthesized using compound 132-2 as a substrate according to the method described in Example 3 above. LCMS: 297.1 [M+H] + ;

[0525] A solution of compound 132-3 (819 mg, 2.76 mmol) in EtNH2 / THF (10 mL, 10.00 mmol) was stirred at 110 °C for 96 hours. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography to give compound 132-4. LCMS: 306.2 [M+H] + ;

[0526] Compound 132-4 was used as a substrate according to the method in Example 66 above, and then separated by SFC (Waters SFC 80 column: DAICELCHIRALPAK® AD 250mm). Compound 132 was synthesized using a mobile phase system of 30 mm, 10 μm; mobile phase A: supercritical CO2; mobile phase B: IPA (+0.1% 7.0 mol / L ammonia in MEOH solution); A:B: 80:20, flow rate: 50 mL / min, circulation time: 5.3 min. LCMS: 484.2 [M+H] + Chiral analysis conditions: Waters UPCC CA-185, column: DAICELCHIRALPAK® AD 100mm 3.0 mm, 3.0 μm; Mobile phase A: supercritical CO2; Mobile phase B: IPA (+0.1% DEA); Flow rate 15 mL / min; Retention time (as the second peak) = 2.017 min. 1 H NMR (400MHz, DMSO- d 6) δ 8.70 (s, 1H) 8.48 (d, J = 7.1 Hz, 1H) 8.37 (s, 1H) 8.25 (d, J = 7.5 Hz, 1H) 7.73 (t, J = 7.8 Hz, 1H) 6.99 (t, J = 5.2 Hz, 1H) 6.80 (s, 1H)6.39 (s, 1H) 4.18 (d, J = 10.5 Hz, 1H) 3.48 (s, 3H) 3.25 – 3.18 (m, 2H) 3.17 – 3.10 (m, 1H) 2.11 – 2.03 (m, 1H) 1.93 – 1.77 (m, 4H) 1.76 – 1.66 (m, 1H)1.11 (t, J = 7.2 Hz, 3H).

[0527] Example 144

[0528]

[0529] Oxaloyl dichloro(5 mL, 57.7 mmol) and DMF(0.3 mL, 3.84 mmol) were added to a solution of 1-(2,6-dichloropyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid (10 g, 38.4 mmol) in DCM (100 mL). The reaction was stirred at 15 °C for 2 h. The mixture was concentrated under reduced pressure to give the crude product. The crude product was used for the next step without further purification. LCMS: 274.2 [M+H]+ (as a methyl ester)

[0530] A solution of compound 144-1 (10.7 g, 38.4 mmol) in DCM (40 mL) was added dropwise to ammonia (7 M MeOH solution, 18.2 mL, 126.9 mmol). The mixture was stirred at 0 °C for 1 hour. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by rapid silica gel chromatography (ISCO@; 80 g SepaFlash@ silica gel flash column, eluent 0-10% MeOH / DCM @ 80 mL / min) to give compound 144-2 (6.3 g, 63.3% yield). LCMS: 300.0 [M+H] + ;

[0531] A solution of compound 144-2 (500 mg, 1.93 mmol), K₂CO₃ (800 mg, 5.79 mmol), and PMBNHEt (638 mg, 3.86 mmol) in DMF (10 mL) was stirred at 130 °C for 16 h. The mixture was quenched by adding H₂O (150 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (ISCO @; 40 g SepaFlash @ silica gel flash column, eluent 0-100% MeOH / DCM gradient @ 50 mL / min) to give compound 144-3 (800 mg, 13.36% yield). LCMS: 388.2 [M+H] + ;

[0532] Compound 144-3 A solution of (60 mg, 0.155 mmol) in DMF-DMA (4 mL, 29.9 mmol) was stirred at 100 °C for 16 hours. The mixture was concentrated under reduced pressure to give the crude product. The crude product was used for the next step without further purification. LCMS: 443.3 [M+H] + ;

[0533] Hydrazine hydroxide (1 mL, 0.113 mmol) was added to a solution of compound 144-4 (50 mg, 0.113 mmol) in AcOH (2 mL) at 0 °C. The mixture was stirred at 80 °C under a nitrogen atmosphere for 3 h. The mixture was quenched by adding H₂O (20 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (ISCO @; 4 g SepaFlash @ silica gel flash column, eluent 0-15% MeOH / DCM gradient @ 15 mL / min) to give compound 144-5 (40 mg, 86% yield). LCMS: 412.4 [M+H] + ;

[0534] To a solution of compound 144-5 (40 mg, 0.097 mmol) in THF (10 mL), NaH (8 mg, 0.194 mmol) was added. The mixture was stirred at 0 °C for 30 min, and then fluoroiodomethane (24 mg, 0.146 mmol) was added at 0 °C. The resulting mixture was stirred at 20 °C for 16 h. The mixture was quenched by adding H2O (10 mL) and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography (ISCO @; 4 g SepaFlash @ silica gel flash column, eluent 0-100% EtOAc / PE gradient @ 18 mL / min) to give compound 144-6. The crude product was used for the next step without further purification. LCMS: 444.0 [M+H] + ;

[0535] Compound 144-6 (10 mg, 0.023 mmol), 8-(trifluoromethyl)quinazolin-4 ( 3HCuI (5 mg, 0.025 mmol) and methyl[(1R,2R)-2-(methylamino)cyclohexyl]amine (7 mg, 0.045 mmol) were added to a solution of 1,4-dioxane (4 mL). The mixture was stirred at 120 °C under a nitrogen atmosphere for 16 hours. The reaction mixture was poured into water (15 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the residue. The residue was purified by rapid silica gel chromatography to give compound 144-7. The crude product was used for the next step without further purification. LCMS: 622.3 [M+H] + .

[0536] TFA (2 mL, 26.0 mmol) was added to a solution of 144-7 (5 mg, 8.04 µmol) in DCM (2 mL). The reaction mixture was stirred at 20 °C for 3 hours. The reaction mixture was poured into NaHCO3 (15 mL saturated aqueous solution) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The mixture was filtered, and the filtrate was purified by preparative HPLC (Waters 3767 / QDA column: Sunfire C18,19). 250 mm, 10 μm; Mobile phase A: 0.1% NH4HCO3 / H2O, B: ACN; Flow rate: 20 mL / min; Gradient: 62-72% (retention time = 9.4-11.2 min, main peak), yielding compound 144. LCMS: 502.4 [M+H] + ; 1 H NMR (400 MHz, DMSO- d 6) δ 8.71(s, 1H) 8.68 (s, 1H) 8.48 (d, J = 7.1 Hz, 1H) 8.25 (d, J = 7.6 Hz, 1H) 7.74(t, J = 7.8 Hz, 1H) 7.00 (t, J = 5.3 Hz, 1H) 6.93 (d, J = 1.1 Hz, 1H) 6.48(d, J = 1.1 Hz, 1H) 5.74 (d, J= 51.3 Hz, 2H) 3.28 – 3.19 (m, 2H) 2.84 – 2.73(m, 2H) 2.62 – 2.52 (m, 3H) 1.11 (t, J = 7.2 Hz, 3H) 1.07 (d, J = 5.5 Hz, 3H).

[0537] The following compounds were synthesized using a method similar to that described above.

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550] Biological assay

[0551] Example A. Binding determination based on HTRF

[0552] Determination method:

[0553] The affinity of candidate compounds for Cbl-b protein was evaluated using an HTRF-based binding assay. CBL-B (GST-Tag) was purchased from BPS (catalog number 80415). Fluorescently labeled Cbl-b binding probes were manufactured internally. Monoclonal antibodies against the GST-Tb cavitation compound were obtained from Cisbio (61GSTTLB). In short, the compounds were diluted and transferred using an echo sensor to an Opti-384F black plate (PE, 6007279). 1x assay buffer (HEPES pH 7.5 50 mM, NaCl 50 mM, MgCl2 5 mM, TCEP 1 mM, Tween-20 0.01%), 2x protein mixture (10 nM), and 2x probe mixture (120 nM) were prepared. 10 μL of the 2x protein mixture (or 1x assay buffer as a protein-free control) was added to the assay plate. After incubation at 25°C for 30 min, 10 μl of 2x probe mixture was added, and incubation was continued at 25°C for 2 h. Data was read using Envision and acquired with an Ex340 / Em495 / 520. IC was calculated using XLFit Excel plugin version 4.3.1. 50 The equation is:

[0554] 4-parameter logical model or S-shaped dose-response model

[0555] fit = (A+((BA) / (1+((C / x)^D))))

[0556] inv = (C / ((((BA) / (yA))-1)^(1 / D)))

[0557] res = (y-fit)

[0558] result :

[0559] Data for exemplary compounds are shown in Table 4.

[0560] Table 4

[0561]

[0562] a : A: < 20 nM; B: 20 ​​~ 200 nM; C: 200 ~ 500 nM; D: > 500 nM.

[0563] Other compounds disclosed in this paper also exhibited Cbl-b inhibitory activity.

[0564] Example B. ELISA-based phosphorylation-CBLB assay

[0565] Determination method:

[0566] Coat a 384-well ELISA plate (781074, Greiner) with 25 μL of E2 (UbcH5b) to a final concentration of 20 μg / ml, centrifuge at 1000 rpm for 1 min, and incubate at 37 °C for 90 min. After protein coating, wash the ELISA plate, discard the solution, and dry. Add 100 μL of PBST, incubate for 5 min, and repeat three times. Transfer 100 μL of blocking buffer to each well. Incubate at 25 °C for 90 min, wash the plate, and wait for the reaction. Incubate the compound with CBL-B and Src-Zap70. Serially dilute the compound in a 384 PP plate using DMSO. Transfer 0.3 μL of the diluted compound to a 384-well reaction plate (6007290, PE) using ECHO, add 15 μL of CBL-B, and incubate at 25 °C for 10 min. Then add 15 μL of Src-Zap70 & ATP and incubate at 25 °C for 120 min, ensuring the final DMSO concentration is 1% (double replicate) (final concentration: 50 mM MgCl2 (pH 7.0), 5 mM MgCl2, 100 mM NaCl, 0.01% Triton X-100, 0.01% BSA, 1 mM MTT, 1.5 nM CBL-B, 10 nM Src-Zap70, and 1 mM ATP). Transfer 20 μL of the above reaction mixture from a 384-well plate to an ELISA plate and incubate at 25 °C for 120 min. After washing the plate, transfer 25 μL of SA-HRP (16000X) to an ELISA plate and incubate at 25 °C for 60 min, then wash the plate. Transfer 25 μL of ECL Plus WB substrate (solutions A and B, 1:1 ratio) to an ELISA plate and incubate at 25 °C for 5 min. Read the luminescence signal from the BMG microplate reader (PHERAstar FSX). Wells coated with E2 and DMSO were used as high controls, and wells coated with E2 and the first concentration of the reference compound were used as low controls. Calculate the inhibition rate (%inhibition) of each compound in each well = 100. (High control - compound well) / (High control - low control). IC50 of the nonlinear regression equation was determined by fitting with XLfit 5.5.0. 50 value.

[0567] result:

[0568] Data for exemplary compounds are shown in Table 5.

[0569] Table 5

[0570]

[0571] a : A: < 100 nM; B: 100 ~ 500 nM; C: 500 ~ 1000 nM; D: > 1000 nM.

[0572] Example C. IL-2 secretion assay

[0573] Determination method:

[0574] Human PBMCs were thawed from cryopreservation using pre-warmed complete medium containing 10% FBS and 1% PS. After standing at 37°C and 5% CO2 for 30 min, human pan-T cells were isolated from the PBMCs according to the instructions of the isolation kit (Stemcell, 17951). T cells were recovered overnight at 37°C and 5% CO2. The next day, T cells were harvested, and cell suspensions of the desired density were prepared using complete medium containing 10% FBS, 1% PS, and 55 μM β-mercaptoethanol. Cells were then divided into 1×10⁶ cells per well. 5 200 μL of cells were seeded into 96-well plates pre-coated with 5 μg / mL anti-human CD3 antibody (eBioscience, 16-0037-38). Intermediate dilutions of the test compound were prepared in complete culture medium by serially diluting 3-fold in 100% DMSO. Different concentrations of the compound were then added to the 96-well cell culture plates. After 24 hours of incubation, IL-2 secretion in the cell culture supernatant was measured using an ELISA (4A bio, CHE0003) according to the manufacturer's instructions. A standard curve was fitted using a nonlinear fitting formula.

[0575] Y = base + (top - base) / [1 + 10^((LogIC50 - X) × Hill slope)], where Y refers to OD. 450 Data, where X represents the logarithm of the standard sample concentration.

[0576] The IL-2 concentration in the compound-treated samples was calculated by returning to the standard curve. Wells containing cells and 1‰ DMSO were used as a low control, and the activation % was calculated using the following formula: fold change = IL-2 concentration. 化合物处理的 / IL-2 concentration 低对照 Then, a nonlinear regression equation was used to fit the EC values ​​of the compound. 50 curve:

[0577] Y = base + (top - base) / (1 + 10^((LogIC50 - X) × Hill slope)), where Y represents activation and X represents the logarithm of the compound concentration.

[0578] result:

[0579] Data for exemplary compounds are shown in Table 6.

[0580] Table 6

[0581]

[0582] a : A: < 500 nM; B: 500 ~ 1000 nM; C: 1000 ~ 2000 nM; D: > 2000 nM.

[0583] b A: > 15 times; B: 10 ~ 15 times; C: 5 ~ 10 times; D: < 5 times

[0584] Example D: Metabolic stability in liver microsomes

[0585] Determination method:

[0586] Microsomes (final concentration 0.5 mg / mL), 100 mM phosphate buffer (pH 7.4), and the compound (final concentration 1 μM) were added to the assay plate and pre-incubated at 37°C for 10 min. The reaction was initiated by adding NADPH (final concentration 1 mM) and the plate was shaken at a constant temperature of 37°C. After 0, 5, 15, 30, 45, and 60 min, aliquots were taken and the reaction was quenched with cold acetonitrile. The samples were shaken for 10 min and then centrifuged at 4000 rpm for 20 min at 4°C and analyzed by LC-MS / MS. The in vitro intrinsic clearance rate was calculated based on the proportion of compound disappearance. The compounds were synthesized according to the corresponding patents: compound A (Example 85 in WO2024015863) and NX1607 (Example 23 in WO2020264398).

[0587] result:

[0588] Data for exemplary compounds are shown in Table 7, demonstrating that the compounds disclosed in this disclosure exhibit improved liver microsomal metabolic stability compared to NX1607.

[0589] Table 7

[0590]

[0591] Example E: Metabolic stability in hepatocytes

[0592] Determination method:

[0593] Cell viability was assessed after thawing using the trypan blue rejection assay. In 96-well plates, 10 mM of the test compound and 30 mM of the positive control compound were diluted to 1 mM and 3 mM with DMSO. Then, 1 mM of the test compound and 3 mM of the positive control compound were diluted to 100 µM and 300 µM with acetonitrile. The cryopreserved cells were thawed, isolated, and suspended in incubation medium (Williams E medium (phenol red-free)) containing 2 mM L-glutamine and 25 mM HEPES, and then diluted to 0.5 × 10⁻⁶ with pre-warmed incubation medium. 6 Cells / mL. Add 198 μL of preheated cell suspension to a 96-well plate. Transfer 125 μL of stop solution (containing 200 ng / mL tolbutamide and 200 ng / mL labetalol in acetonitrile as internal standards) to a set of pre-labeled 96-well plates. Add 2 μL of dosing solution to each well of the 96-well plate, in duplicate. For T0 samples, immediately add 25 μL of a homogeneous suspension of each sample to a well containing 125 μL of ice-cold stop solution. Incubate all plates at 37°C in a 95% humidified incubator with constant shaking at 650 rpm to initiate the reaction. At 15, 30, 60, and 90 min, mix the samples, and then transfer 25 μL of each sample at each time point to a well containing 125 μL of ice-cold stop solution. At T0 and T90, culture medium control (MC) sample plates (labeled T0-MC and T90-MC) were prepared by adding the same components to each well except for the cell suspension. The plates were immediately added to a plate shaker at 600 rpm for 10 min and centrifuged at 3220 xg for 20 min at 4°C. After centrifugation, based on the plate pattern, 80 μL / well of the supernatant from the sample plates was transferred to another set of pre-labeled 96-well plates containing 240 μL of ultrapure water. The analytical plates were sealed and stored at 4°C until LC-MS / MS analysis was performed.

[0594] result:

[0595] Data for exemplary compounds are shown in Table 8, demonstrating that the compounds disclosed in this disclosure exhibit improved hepatocyte metabolic stability compared to NX1607.

[0596] Table 8

[0597]

[0598] Example F: In vivo pharmacokinetic studies

[0599] Determination method:

[0600] Male C57 mice (n = 3), male SD rats (n = 3), and beagle dogs (n = 2) received a single intravenous (bolus) injection or a single oral (tube-feeding) administration of the compounds in the cocktail formulation. Mice and rats were administered 1 mg / kg (intravenous) and 10 mg / kg (oral) in solution form in different formulations, and dogs were administered 5 mg / kg (oral) in solution form. Blood samples were collected via the cephalic vein at 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after intravenous (iv) administration, or at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after oral tube-feeding administration, 30 μL at each time point. The blood samples were placed in tubes containing K2-EDTA and stored on ice until centrifugation. Within 1 hour of collection, blood samples were centrifuged at 6800 g for 6 minutes at 2–8°C and then frozen at approximately -80°C. Protein precipitation was performed on 20 µL aliquots of plasma samples using 400 µL of methanol containing 100 ng / mL verapamil (IS). The mixture was vortexed for 1 min and centrifuged at 18000 xg for 10 min. 400 µL of the supernatant was transferred to a 96-well plate. 5 µL of the supernatant aliquot was injected for LC-MS / MS analysis using an LC-MS / MS-27 (TQ6500+) instrument. The results were confirmed using quality control samples with measured internal variability. The accuracy of quality control samples with >66.7% variability should be between 80% and 120% of the known values. A set of standard parameters, including the area under the curve (AUC), was calculated using the non-compartmental analysis module in the FDA-approved pharmacokinetic program Phoenix WinNonlin 7.0 (Pharsight, USA). (0-t) and AUC (0-∞) Elimination half-life (T) 1 / 2 ), maximum blood concentration (C max ), oral bioavailability (F).

[0601] result:

[0602] Data for exemplary compounds are shown in Tables 9 / 10 / 11, demonstrating that the compounds disclosed in this disclosure exhibit improved pharmacokinetic properties in preclinical species compared to NX1607.

[0603] Table 9 Mouse Pk

[0604]

[0605] Table 10 Rat Pk

[0606]

[0607] Table 11 Dog Pk

[0608]

[0609] Example G: CT26 efficacy model

[0610] Determination method:

[0611] Cell culture

[0612] CT26.WT tumor cells (ATCC, catalog number CRL-2638™) were maintained in vitro at 37°C in a 5% CO2 atmosphere in air using RPMI 1640 medium supplemented with 10% heat-inactivated fetal bovine serum. Tumor cells were routinely passaged twice weekly via trypsin-EDTA treatment. Cells grown to approximately 70%–80% confluence were harvested, counted, and used for tumor inoculation.

[0613] Tumor inoculation

[0614] Each mouse was subcutaneously inoculated with 0.05 mL of serum-free RPMI-1640 containing 3 × 10⁶ CT26.WT tumor cells in RPMI-1640 solution on the right ventricular side. 5 (number per mouse).

[0615] Random grouping

[0616] The tumor size was ~46.88mm. 3 (40mm 3 -54mm 3 Animals were enrolled and subjected to efficacy studies using stratified randomization based on tumor volume. A total of 64 mice were enrolled and randomly assigned to 8 groups of 8 mice each. The randomization date was defined as day 0.

[0617] Observation results and data collection

[0618] Following tumor inoculation, monitor animal morbidity and mortality daily. During routine monitoring, examine the animals for the effects of tumor growth and treatment on normal behavior, such as activity level, weight gain / loss (measured twice weekly or every Monday / Wednesday / Friday), dull eyes / coat, and any other abnormal effects. Record mortality rates and observed clinical signs in detail for each animal.

[0619] Tumor size was measured in two dimensions using calipers every Monday, Wednesday, and Friday. Tumor volume was expressed in mm³ using the following formula: V = 0.5a × b², where a and b are the major and minor axes of the tumor, respectively. The TGI was calculated accordingly.

[0620] result:

[0621] Data for exemplary compounds are shown in Table 12, demonstrating that representative compounds of this disclosure (e.g., compound 66) exhibit improved in vivo efficacy compared to NX1607 in the CT26 model.

[0622] Table 12

[0623]

Claims

1. Compounds of formula (I), (II), (III), or (IV): ， ， ， ， Or its pharmaceutically acceptable salt. in: R 1 Each is independently selected from halogen, cyano, and -OR. a -SR a -NR b R c Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are optionally substituted by one or more R; Ring A is a cycloalkyl, heterocyclic, aryl, or heteroaryl group; R 2 and R 3 Each is independently selected from hydrogen, halogen, cyano, -OR a -SR a -NR b R c Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are optionally substituted by one or more R; Ring B is a cycloalkyl or heterocyclic group; R 4 Each is independently selected from hydrogen, halogen, cyano, oxo, -OR a -SR a -NR b R c Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, or haloalkyl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, or haloalkyl is optionally substituted with one or more R; or Two Rs 4 Together with the same atom to which they are all connected, they form C2-C6 alkylidene groups, which are optionally substituted by one or more R groups; The ring C is aryl or heteroaryl; R 5 Each is independently selected from halogen, cyano, and -OR. a -SR a -NR b R c Alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally substituted by one or more R; Ring D is , , , , or Among them, ring D The end represents the connection point between ring D and ring C, and Indicates a single bond or a double bond; Z 1 It is C(H) 1-2 Or N(H) 0-1 ; Z 2 It is C(H) 1-2 N(H) 0-1 , O or S; W is C(H) 0-1 Or N; Y is N(H) 0-1 O, S, C(O), S(O) 1-2 Or P(O) 1-2 ; J is C(H) 0-1 Or N; X is C(H) 0-1 Or N; T is C(H) 0-1 Or N; Ring E is a heterocyclic or heteroaryl group; The ring G is a cycloalkyl, heterocyclic, aryl, or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally substituted by one or more R groups; R 6 Each is independently selected from halogen, cyano, and -OR. a -SR a -NR b R c Alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, or heterocyclic, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, haloalkyl, cycloalkyl, or heterocyclic is optionally substituted with one or more R; R 7 and R 8 Each is independently selected from hydrogen, deuterium, halogen, cyano, -OR a -SR a -NR b R c Alkyl, haloalkyl, or cycloalkyl; V is CH or N; R 9 and R 10 Each is independently selected from hydrogen, deuterium, alkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, or heterocyclic alkyl, wherein the cycloalkyl, heterocyclic, cycloalkylalkyl, and heterocyclic alkyl are optionally substituted with one or more R; or R 9 and R 10 Together with the atoms to which they are attached, they form cycloalkyl or heterocyclic groups, wherein the cycloalkyl and heterocyclic groups are optionally substituted with one or more R; R a The group is selected from hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are independently and optionally substituted by one or more R. R b and R c Each is independently selected from hydrogen, alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, haloalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkenyl, ynyl, heteroalkyl, heteroalkenyl, heteroynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl are independently and optionally substituted by one or more R; or R b and R c Together with the atoms to which they are attached, they form heterocyclic groups, which are optionally substituted by one or more R groups; Ring D1 is ,in Indicates a single bond or a double bond; Ring E1 is a 6-membered heteroaryl or a 6-membered heterocyclic group; Z 3 It is C(H) 1-2 Or N(H) 0-1 ; Z 4 It is C(H) 1-2 N(H) 0-1 , O or S; Z 5 It is C(H) 1-2 N(H) 0-1 , O or S; W 1 It is C(H) 0-1 Or N; W 2 It is C(H) 0-1 Or N; R 600 Each is independently selected from halogen, cyano, heterocyclic, and -SR groups. a -NH2, -N(alkyl)2, -NH(cycloalkyl), -C(O)NH2, -C(O)NH(alkyl), unsubstituted alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, hydroxyalkyl, haloalkoxy, -alkynyl-N(alkyl)2, haloalkynyl, -alkynyl-heterocyclic or cycloalkyl, wherein the heterocyclic and cycloalkyl groups are optionally substituted by one or more R'; or Two Rs 600 Together with the atoms to which they are attached, they form cycloalkyl, heterocyclic, or heteroaryl groups, which are optionally substituted with one or more R groups; R 700 It is a halogen, alkyl, haloalkyl, cycloalkyl, or heterocyclic group, wherein the alkyl, haloalkyl, cycloalkyl, and heterocyclic group are optionally substituted by one or more R independently; R and R' are each independently a halogen, cyano, oxo, -OH, -S(=O)(alkyl), -S(=O)2(alkyl), -S(=O)2N(alkyl)2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -NH2, -N(alkyl)2, -NH(alkyl), -C(=O)(alkyl), -C(=O)OH, -C(=O)O(alkyl), alkyl, alkoxy, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, cycloalkyl, or heterocyclic group; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, or 3; p is 0, 1, 2, or 3; q is 0, 1, 2, or 3; j is 0, 1, 2, 3, 4, 5, or 6; g is 0, 1, 2, 3, 4, 5, or 6; k is 0, 1, 2, or 3; u is 0, 1, or 2; h is 0 or 1; and i is 0, 1, or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a heteroaryl group.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein ring A is triazolyl, isoxazolyl, pyrroleyl, thiophenyl, furanyl, pyrazolyl, imidazoyl, thiazoyl, isothiazolyl, thiadiazolyl, oxadiazolyl or dihydropyrrolotriazolyl.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein ring A is or .

5. The compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein ring B is a cycloalkyl group.

6. The compound of any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein ring B is cyclobutyl.

7. The compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein the ring C is an aryl group.

8. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein the ring C is phenyl.

9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein the ring C is And ring C The end indicates the connection point between ring C and ring D.

10. The compound of any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein the ring C is a heteroaryl group.

11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the ring C is a pyridyl group.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein the ring C is And ring C The end indicates the connection point between ring C and ring D.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (Ia), (IIa), or (IIIa): ， ， ， U 1 It is O, S, NH or CH2; and U 2 U 3 U 4 and U 5 Each can be either N or CH independently.

14. The compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 1 It is an alkyl or haloalkyl group.

15. The compound of any one of claims 1-14 or a pharmaceutically acceptable salt thereof, wherein R 1 It is -CH3, -CHF2, or -CH2F.

16. The compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, wherein n is 0.

17. A compound of any one of claims 1-15 or a pharmaceutically acceptable salt thereof, wherein n is 1 and R 2 and R 3 Both are hydrogen.

18. The compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof, wherein p is 1 and R 4 It is an alkyl or alkynyl group.

19. The compound of any one of claims 1-18 or a pharmaceutically acceptable salt thereof, wherein R 4 It is an alkyl group.

20. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein R 4 It is a methyl group.

21. The compound of any one of claims 1-18 or a pharmaceutically acceptable salt thereof, wherein R 4 It is an acetylinyl group.

22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein R 4 It is an acetylene group.

23. The compound of any one of claims 1-17 or a pharmaceutically acceptable salt thereof, wherein p is 2 and both R 4 They are formed together with the same atom to which they are all connected. It may be optionally replaced by one or more halogens.

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof, wherein two R... 4 They are formed together with the same atom to which they are all connected. or .

25. The compound of any one of claims 1-24 or a pharmaceutically acceptable salt thereof, wherein q is 0.

26. The compound of any one of claims 1-24 or a pharmaceutically acceptable salt thereof, wherein q is 1, and R 5 Yes - OR a .

27. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein R a It is an alkyl, haloalkyl, or cycloalkyl group.

28. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from -OCH3, -OCH2CH3, -OCH2F, , , or .

29. The compound of any one of claims 1-24 or a pharmaceutically acceptable salt thereof, wherein q is 1, and R 5 It is a cycloalkyl group.

30. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein R 5 It is cyclopropyl.

31. The compound of any one of claims 1-24 or a pharmaceutically acceptable salt thereof, wherein q is 1, and R 5 Yes -NR b R c .

32. The compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein R b It is hydrogen, and R c It is an alkyl, haloalkyl, cycloalkyl, or heterocyclic group, wherein the alkyl, cycloalkyl, and heterocyclic group are optionally substituted by one or more R groups independently.

33. The compound of claim 32 or a pharmaceutically acceptable salt thereof, wherein R b It is hydrogen, and R c It is an alkyl, haloalkyl, or cycloalkyl group.

34. The compound of claim 32 or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from NH2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2F, -NHCH2CHF2, -NHCH2CH2OH, , or .

35. The compound of claim 34 or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from -NHCH2CH3, -NHCH2CH2F, -NHCH2CHF2 or .

36. The compound of any one of claims 1-35 or a pharmaceutically acceptable salt thereof, wherein said compound has formula (I) and ring D is .

37. The compound of claim 36 or a pharmaceutically acceptable salt thereof, wherein... yes .

38. The compound of claim 37 or a pharmaceutically acceptable salt thereof, wherein R 6 Independently, it is -F, -CH3, -CHF2, -CF3, or -OCH3.

39. A compound of any one of claims 1-35 or a pharmaceutically acceptable salt thereof, wherein said compound has formula (I) and ring D is .

40. The compound of claim 39 or a pharmaceutically acceptable salt thereof, wherein ring D is .

41. The compound of claim 39 or 40 or a pharmaceutically acceptable salt thereof, wherein... Selected from: , , , , , , , , , , , , , , , , or .

42. A compound of any one of claims 1-35 or a pharmaceutically acceptable salt thereof, wherein said compound has formula (I) and ring D is .

43. The compound of claim 42 or a pharmaceutically acceptable salt thereof, wherein ring D is .

44. The compound of claim 42 or 43 or a pharmaceutically acceptable salt thereof, wherein Selected from: , , , , , , , , , , , , R 6a and R 6b Each is R independently 6 ; j1 is 0, 1, or 2; and j2 is 0, 1, 2, 3 or 4.

45. A compound of any one of claims 1-44 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (I) and V is N.

46. ​​The compound of claim 45 or a pharmaceutically acceptable salt thereof, wherein R 9 It is hydrogen, and R 10 It is a cycloalkyl or cycloalkyl group, each optionally substituted by one or more Rs, each R being independently selected from halogens, alkyl groups, or haloalkyl groups.

47. A compound of any one of claims 1-35 or a pharmaceutically acceptable salt thereof, wherein said compound has formula (II), (IIa), (III), (IIIa) or (IV), and ring D1 is .

48. The compound of any one of claims 1-35 or a pharmaceutically acceptable salt thereof, wherein ring D1 is selected from: , , , , , , , , , , , , , and .

49. A compound of any one of claims 1-35 and 47-48, or a pharmaceutically acceptable salt thereof, wherein said compound has formula (II), (IIa), (III), IIIa), or (IV), and R 600 Each is independently selected from halogen, cyano, heterocyclic, -C(O)NH2, unsubstituted alkyl, alkynyl, haloalkyl, hydroxyalkyl, haloalkoxy, -alkynyl-N(alkyl)2, haloalkynyl, -alkynyl-heterocyclic or cycloalkyl, wherein the heterocyclic and cycloalkyl are optionally substituted by one or more R'.

50. The compound of claim 49 or a pharmaceutically acceptable salt thereof, wherein R 600 Each is independently selected from -Cl, -F, -CN, -CH3, -CH(CH3)2, -CH2OH, -CF3, -CF2CF3, -CH(CH3)CF2, -CH2CHF2, -OCH2F, -OCHF2, -OCClF2, -C(O)NH2, , , , , , , , , , , , , , , , , , or .

51. A compound of any one of claims 1-35 and 47-48, or a pharmaceutically acceptable salt thereof, wherein said compound has formula (II), (IIa), (III), (IIIa), or (IV), and two R... 600 Together with the atoms to which they are attached, they form cycloalkyl, heterocyclic, or heteroaryl groups, each of which is optionally substituted with one or more R groups.

52. The compound of claim 51 or a pharmaceutically acceptable salt thereof, wherein... Selected from , or or , R 600a Each is R independently 600 ; g1 is 0, 1, or 2; and g2 is 0, 1, 2, 3 or 4.

53. The compound of claim 1, having a formula selected from the following: ， ， ， ， ， ， ， ， Or its pharmaceutically acceptable salt. Where R 6A R 6B R 6C and R 6D Each is independently selected from hydrogen or R 6 ; R 600a Each is R independently 600 ; g is 0, 1, 2, 3, or 4; and g1 is 0, 1, or 2.

54. The compound of claim 53, having a formula selected from the following: ， ， ， ， ， ， ， ， Or a pharmaceutically acceptable salt thereof, wherein R 1A Each is independently selected from hydrogen or R 1 R 5A Each is independently selected from hydrogen or R 5 R 6A R 6B R 6C and R 6D Each is independently selected from hydrogen or R 6 .

55. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any of the compounds listed in Table 1, Table 2 or Table 3.

56. A pharmaceutical composition comprising a compound of any one of claims 1-55 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.

57. A method for modulating the activity of immune cells, the method comprising contacting immune cells with an effective amount of the compound of any one of claims 1-55 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 56.

58. A method of treating cancer, the method comprising administering to an individual in need an effective amount of a compound of any one of claims 1-55 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 56.

59. A method for treating cancers that respond to inhibition of Cbl-b activity, the method comprising administering to an individual in need an effective amount of a compound of any one of claims 1-55 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 56.

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