CBL-B inhibitor and application method thereof

Abstract

Compounds and methods for modulating or inhibiting CBL-B are provided.

Description

[0001] Cross-references

[0002] This patent application claims the benefit of International Application No. PCT / CN2022 / 106243, filed on July 18, 2022, International Application No. PCT / CN2023 / 073202, filed on January 19, 2023, and International Application No. PCT / CN2023 / 098931, filed on June 7, 2023, the entireties of which are incorporated herein by reference. Background of the Invention

[0004] Dysregulated signaling is a hallmark of cellular transformation and tumorigenesis. The proto-oncogene Casitas B-lineage lymphoma (Cbl or c-Cbl) encodes an E3 ubiquitin ligase that downregulates PTK-directed cellular signaling through ubiquitination, thereby targeting these kinases for degradation in the lysosome or proteasome. Cbl is a member of the Cbl protein family and is therefore characterized by a highly conserved N-terminal region that contains the structural components required for ubiquitin ligase activity. While only one Cbl protein exists in simpler eukaryotic organisms such as Caenorhabditis elegans and Dictyostelium discoideum, three Cbl proteins exist in mammals: Cbl, Cbl-b, and Cbl-c.

[0005] The conserved N-terminus of Cbl family proteins contains a substrate tyrosine kinase binding domain (TKBD), a linker helix region (LHR), and a ring (RING) domain. The TKBD confers specificity to Cbl ligase activity by selectively recruiting phosphorylated substrates containing (N / D)XpY(S / T)XXP, DpYR, or RA(V / I)XNQpY(S / T) motifs. The ring domain mediates the transfer of ubiquitin (Ub) from the E2 Ub conjugating enzyme to the substrate. Within the LHR lies a conserved tyrosine residue (Tyr371 in Cbl) that is crucial for regulating ligase activity. Phosphorylation of this residue enhances ligase activity and is crucial for ubiquitination of the receptor PTK. In addition to their highly conserved N-termini, Cbl and Cbl-b possess extensive C-termini that confer adaptor-like functions to these proteins through their ability to mediate diverse protein-protein interactions. These proteins contain a proline-rich region that mediates interactions with SH3 domain-containing proteins and a tyrosine-rich region that, upon phosphorylation, serves as a binding motif for other SH2 domain-containing proteins. Cbl and Cbl-b terminate in a ubiquitin-associated domain that is essential for homo- and heterodimerization of these two Cbl proteins.

[0006] Cbl-b is an important brake on T cell immune responses. Unlike Cbl, which primarily regulates thymocyte development, Cbl-b regulates peripheral T cell activation primarily by negatively regulating the TCR (T cell receptor) signaling pathway. Specifically, Cbl-b inhibits VAV1 activation upon TCR engagement and requires CD28 co-stimulation for proliferation and IL-2 production in naive T cells. Cbl-b also ubiquitinates PIK3R1 / p85, inhibiting its recruitment to CD28 and TCRζ, thereby inhibiting the activation of PI3K, a key kinase involved in T cell activation and differentiation. Furthermore, in activated T cells, Cbl-b inhibits PLCG1 activation and calcium mobilization upon restimulation, thereby promoting T cell anergy. Thus, under physiological conditions, Cbl-b limits unnecessary T cell overactivation. 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 anergy, exhaustion, and rejection are widespread in the tumor microenvironment. Therefore, unleashing the full power of T cells by releasing the Cbl-b brake has great potential as an immunotherapy for cancer.

[0007] Therefore, there is a need for new cancer therapies, particularly cancer therapies that use Cbl-b inhibitors. SUMMARY OF THE INVENTION

[0009] Disclosed herein are compounds, or pharmaceutically acceptable salts thereof, that are Cbl-b inhibitors.

[0010] Disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0011]

[0012] Formula (I), as described herein;

[0013] The condition is no Where * indicates the point of attachment to the ring containing X, Y, Z and W, and ** indicates the point of attachment to -CR 8 R 9 -Connection point.

[0014] Also provided herein are compounds of formula (III) or pharmaceutically acceptable salts thereof:

[0015]

[0016] Formula (III), as described herein.

[0017] Also provided herein are compounds of formula (II) or pharmaceutically acceptable salts thereof:

[0018]

[0019] Formula (II), as described herein;

[0020] The condition is no Where * indicates the point of attachment to the -C(=O)-NH- group, and ** indicates the point of attachment to the -CR 8 R 9 - the point of attachment of the group;

[0021] and provided that the compound of formula (II) is not

[0022] Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0023] Also disclosed herein are methods of modulating immune cell activity, comprising contacting the immune cell with an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0024] Also disclosed herein are methods of treating cancer, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0025] Also disclosed herein are methods of treating cancer responsive to inhibition of Cbl-b activity, comprising administering to an individual in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is a lymphoma, leukemia, or myeloma. In some embodiments, the cancer is a non-hematological cancer. In some embodiments, the cancer is a sarcoma, carcinoma, or melanoma. In some embodiments, the cancer is a solid tumor.

[0027] Also disclosed herein are methods of inhibiting abnormal cell proliferation, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0028] Also disclosed herein are methods of modulating an immune response comprising administering to an individual in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0029] Also disclosed herein are methods of inhibiting Cbl-b activity, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0030] Also disclosed herein are methods of treating a disease or condition associated with Cbl-b activity, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0031] Incorporated by Reference

[0032] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Detailed Description of the Invention

[0034] definition

[0035] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments. However, it will be understood by those skilled in the art that the present invention can be practiced without these details. In other cases, well-known structures are not given or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout the specification and the subsequent claims, the words "comprises," "comprising," and their variations should be interpreted as open-ended, inclusive, i.e., "including but not limited to." In addition, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0036] References in this specification to "some embodiments" or "an embodiment" mean that a particular feature, structure or characteristic associated with the embodiment is included in at least one embodiment. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing throughout this specification do not necessarily all refer to the same embodiment. In addition, the particular features, structures or characteristics may be combined in any suitable manner in one or more embodiments. Furthermore, 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 terms "or" and "alternatively" are generally used in a sense that includes "and / or" unless the context clearly indicates otherwise.

[0037] Unless otherwise specified, the following terms used herein have the following meanings:

[0038] "Oxo" refers to =0.

[0039] "Carboxyl" refers to -COOH.

[0040] "Cyano" refers to -CN.

[0041] "Alkyl" refers to a straight or branched, saturated hydrocarbon monovalent group having 1 to about 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 a numerical range appears herein, such as "C1-C6 alkyl" or "C 1-6 The term "alkyl" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although the definition also encompasses occurrences of the term "alkyl" without specifying a numerical range. In some embodiments, the alkyl group is C 1-10 In some embodiments, the alkyl group is C 1-6 In some embodiments, the alkyl group is C 1-5 In some embodiments, the alkyl group is C 1-4 In some embodiments, the alkyl group is C 1-3 Alkyl. Unless otherwise clearly stated in this specification, alkyl can be optionally substituted, for example, substituted by the following groups: oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl etc. In some embodiments, alkyl is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkyl is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkyl is optionally substituted by halogen.

[0042] "Alkenyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The group can be in the cis or trans conformation about the double bond and is understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever a numerical range such as "C2-C6 alkenyl" or "C 2-6 "Alkenyl" means that the alkenyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkenyl" without specifying a numerical range. Unless otherwise specified in the specification, the alkenyl group can be optionally substituted, for example, by the following groups: oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkenyl group is optionally substituted with halogen, -CN, -OH or -OMe. In some embodiments, the alkenyl group is optionally substituted with halogen.

[0043] "Alkynyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever a numerical range such as "C2-C6 alkynyl" or "C 2-6 The term "alkynyl" means that the alkynyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term "alkynyl" without specifying a numerical range. Unless otherwise specified in the specification, the alkynyl group can be optionally substituted, for example, by the following groups: oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl group is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkynyl group is optionally substituted with halogen, -CN, -OH or -OMe. In some embodiments, the alkynyl group is optionally substituted with halogen.

[0044] " alkylene " refers to the divalent hydrocarbon chain of straight or branched chain. Unless otherwise clearly stated in this specification, alkylene can be optionally substituted, for example, substituted by the following groups: oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl etc. In some embodiments, alkylene is optionally substituted by oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkylene is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkylene is optionally substituted by halogen.

[0045] " alkoxy " refers to the group of formula -O-alkyl, wherein alkyl is as defined above. Unless otherwise clearly stated in this specification, alkoxy can be optionally substituted, for example, substituted by the following groups: oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl etc. In some embodiments, alkoxy is optionally substituted by halogen ,-CN ,-COOH, COOMe ,-OH ,-OMe ,-NH Or -NO Replacement. In some embodiments, alkoxy is optionally substituted by halogen ,-CN ,-OH or-OMe. In some embodiments, alkoxy is optionally substituted by halogen.

[0046] "Aryl" refers to a group derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused ring system (when fused with a cycloalkyl or heterocycloalkyl group, the aryl group is bonded through an aromatic ring atom) or a bridged ring system. In some embodiments, the aryl group is a 6-10 membered aryl group. In some embodiments, the aryl group is a 6-membered aryl group (phenyl). Aryl groups include, but are not limited to, aryl groups derived from the following hydrocarbon ring systems: anthracene, naphthylene, phenanthrylene, anthracene, azulene, benzene, Fluoranthene, fluorene, asymmetric indacene (as-indacene), symmetric indacene (s-indacene), indane, indene, naphthalene, phenalene (phenalene), phenanthrene, pleiadene (pleiadene), pyrene (pyrene) and triphenylene. Unless otherwise clearly stated in this specification, aryl can be optionally substituted, for example, substituted by the following groups: halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl etc. In some embodiments, aryl is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, aryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, aryl is optionally substituted by halogen.

[0047] "Cycloalkyl" refers to a partially saturated or fully saturated, monocyclic or polycyclic carbocyclic ring that can include a fused ring system (when fused to an aryl or heteroaryl group, the cycloalkyl group is bonded through a non-aromatic ring atom), a spirocyclic ring system, or a bridged ring system. In some embodiments, the cycloalkyl group is fully saturated. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having 3 to 15 carbon atoms (e.g., C3-C 15 Fully saturated cycloalkyl or C3-C 15 cycloalkenyl), cycloalkyl having 3 to 10 carbon atoms (e.g., C3-C 10 Fully saturated cycloalkyl or C3-C 10In some embodiments, the cycloalkyl group is a 3-10 fully saturated cycloalkyl or a 3-10 membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 3-6 fully saturated cycloalkyl or a 3-6 membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 5-6 fully saturated cycloalkyl or a 5-6 membered cycloalkenyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane and bicyclo[3.3.2]decane, as well as 7,7-dimethyl-bicyclo[2.2.1]heptane. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless otherwise clearly stated in this specification, cycloalkyl is optionally substituted, for example, substituted by the following groups: oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl etc. In some embodiments, cycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl ,-CN ,-COOH, COOMe ,-CF ,-OH ,-OMe ,-NH or-NO Replacement. In some embodiments, cycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl ,-CN ,-CF ,-OH or-OMe Replacement. In some embodiments, cycloalkyl is optionally substituted by halogen.

[0048] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0049] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0050] "Haloalkoxy" refers to a radical of the formula -O-haloalkyl, wherein haloalkyl is as defined above. In some embodiments, the haloalkoxy radical contains 1 to 3 halogens. In some embodiments, the haloalkoxy radical contains 1 to 3 fluorines. In some embodiments, the haloalkoxy radical is -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCH2CHF2, or -OCH2CH2F.

[0051] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxy groups. In some embodiments, the alkyl group is substituted with one hydroxy group. In some embodiments, the alkyl group is substituted with 1, 2, or 3 hydroxy groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0052] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with 1, 2, or 3 amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0053] " assorted alkyl " refers to such alkyl, wherein one or more skeleton atoms of alkyl are selected from atoms other than carbon, such as oxygen, nitrogen (such as-NH-,-N (alkyl)-), sulphur, phosphorus or its combination.Assorted alkyl is connected with the rest of molecule at the carbon atom of assorted alkyl. In one aspect, assorted alkyl is C1-C6 assorted alkyl, wherein the assorted alkyl is made up of atoms (such as oxygen, nitrogen (such as-NH-,-N (alkyl)-), sulphur, phosphorus or its combination) other than 1 to 6 carbon atoms and one or more carbon, wherein the assorted alkyl is connected with the rest of molecule at the carbon atom of assorted alkyl. The example of this type of assorted alkyl is such as-CH2OCH3,-CH2CH2OCH3,-CH2CH2OCH2CH2OCH3,-CH(CH3)OCH3,-CH2NHCH3,-CH2N(CH3)2,-CH2CH2NHCH3 or-CH2CH2N(CH3)2. Unless otherwise expressly stated in this specification, heteroalkyl is optionally substituted, for example, by the following groups: oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl etc. In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF , -OH, -OMe, -NH or -NO . In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF , -OH or -OMe. In some embodiments, heteroalkyl is optionally substituted by halogen.

[0054] "Heterocycloalkyl" refers to a 3- to 24-membered partially saturated or fully saturated ring group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl contains 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocycloalkyl contains 1 to 3 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 1 or 2 nitrogen atoms. In some embodiments, the heterocycloalkyl contains 1 nitrogen. In some embodiments, the heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless otherwise expressly stated herein, a heterocycloalkyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused ring system (when fused to an aryl or heteroaryl group, the heterocycloalkyl group is bonded through a non-aromatic ring atom), a spirocyclic ring system, or a bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyl groups include, but are not limited to, heterocycloalkyl groups having 2 to 15 carbon atoms (e.g., C2-C 15 Fully saturated heterocycloalkyl or C2-C 15 heterocycloalkenyl), heterocycloalkyl having 2 to 10 carbon atoms (e.g., C2-C 10 Fully saturated heterocycloalkyl or C2-C 10heterocycloalkyl group), a heterocycloalkyl group having 2 to 8 carbon atoms (e.g., a C2-C8 fully saturated heterocycloalkyl group or a C2-C8 heterocycloalkenyl group), a heterocycloalkyl group having 2 to 7 carbon atoms (e.g., a C2-C7 fully saturated heterocycloalkyl group or a C2-C7 heterocycloalkenyl group), a heterocycloalkyl group having 2 to 6 carbon atoms (e.g., a C2-C6 fully saturated heterocycloalkyl group or a C2-C6 heterocycloalkenyl group), a heterocycloalkyl group having 2 to 5 carbon atoms (e.g., a C2-C5 fully saturated heterocycloalkyl group or a C2-C5 heterocycloalkenyl group), or a heterocycloalkyl group having 2 to 4 carbon atoms (e.g., a C2-C4 fully saturated heterocycloalkyl group or a C2-C4 heterocycloalkenyl group). Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl, [1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidine, thiazolidine The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. In some embodiments, heterocycloalkyl has 2 to 10 carbon atoms in the ring. It should be understood that when referring to the number of carbon atoms in heterocycloalkyl, the number of carbon atoms in heterocycloalkyl is different from the total number of atoms (i.e., the backbone atoms of the heterocycloalkyl ring) that constitute the heterocycloalkyl (including heteroatoms). In some embodiments, heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl.Unless otherwise clearly stated in this specification, Heterocycloalkyl can be optionally substituted, as described below, for example, substituted by the following groups: oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, Heterocycloalkyl, heteroaryl etc. In some embodiments, Heterocycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl ,-CN ,-COOH, COOMe ,-CF ,-OH ,-OMe ,-NH or-NO Replacement. In some embodiments, Heterocycloalkyl is optionally substituted by halogen, methyl, ethyl ,-CN ,-CF ,-OH or-OMe Replacement. In some embodiments, Heterocycloalkyl is optionally substituted by halogen.

[0055] "Heteroaryl" refers to a 5- to 14-membered ring system radical containing 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and containing at least one aromatic ring. In some embodiments, the heteroaryl group contains 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group contains 1 to 3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl group contains 1 to 3 nitrogen atoms. In some embodiments, the heteroaryl group contains 1 or 2 nitrogen atoms. In some embodiments, the heteroaryl group contains 1 nitrogen. The heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include a fused ring system (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl group is bonded through an aromatic ring atom) or a bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally 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, aza benzoxazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzo benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepine 1-Phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl and thienyl. Unless otherwise expressly stated herein, heteroaryl groups may be optionally substituted, for example, by halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF , -OH, -OMe, -NH , or -NO . In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF , -OH, or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0056] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes situations in which the event or situation occurs and situations in which it does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. In addition, 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 fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, such groups are not intended to introduce any sterically impractical and / or synthetically unfeasible substitutions or substitution patterns. Therefore, any substituent described is generally understood to have a molecular weight of up to about 1,000 daltons, and more typically, a molecular weight of up to about 500 daltons.

[0057] When referring to optional substituents, the term "one or more" means that the main group is optionally substituted by 1, 2, 3 or 4 substituents or more substituents. In some embodiments, the main group is optionally substituted by 1, 2, 3 or 4 substituents. In some embodiments, the main group is optionally substituted by 1, 2 or 3 substituents. In some embodiments, the main group is optionally substituted by 1 or 2 substituents. In some embodiments, the main group is optionally substituted by one substituent. In some embodiments, the main group is optionally substituted by two substituents.

[0058] "Effective amount" or "therapeutically effective amount" refers to that amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, effective to produce the desired therapeutic effect.

[0059] As used herein, the term "treating," ...

[0060] As used herein, a "disease or condition associated with cbl-b activity" or a "cbl-b-mediated disease or condition" refers to any disease or other deleterious condition in which cbl-b or a mutant thereof is known or suspected to play a role.

[0061] Compound

[0062] Described herein are compounds or pharmaceutically acceptable salts thereof for use in treating a disease or condition associated with Cbl-b.

[0063] Disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0064]

[0065] in:

[0066] U is -N- or -CR 1 -;

[0067] R 1 Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl;

[0068] R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl;

[0069] L 1 Does not exist or is -CR 3 R 4 -;

[0070] R 3 and R 4 are independently hydrogen, halogen, -CN, -OH, -ORa 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0071] or R 3 and R 4 together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more R;

[0072] or R 3 and R 4 Together they form an oxo group;

[0073] R 5 and R 6 are independently hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 5a replace;

[0074] or R 5 and R 6 together to form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted by one or more R 5a replace;

[0075] Each R 5a are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NR b )R b 、-NR c Rd 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、-P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0076] or two R on the same atom 5a Together they form an oxo group;

[0077] X is -N- or -CR X -;

[0078] R X Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl;

[0079] Y is -N- or -CR Y -;

[0080] R Y Is hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR b C(=O)NR c R d 、-NRb C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, cycloalkyl optionally substituted with one or more halogen, or heterocycloalkyl optionally substituted with one or more halogen;

[0081] Z is -N- or -CR Z -;

[0082] R Z Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl;

[0083] or R X and R Y together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R;

[0084] or R Y and R Z together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R;

[0085] W is -N- or -CR W -;

[0086] R W Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl;

[0087] Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0088] Each R 7 are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NR b )R b 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、-P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0089] or two R on the same atom 7 Together they form an oxo group;

[0090] n is 0, 1, 2, 3, 4, 5, or 6;

[0091] R 8 and R 9 are independently hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0092] or R 8 and R 9 together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more R;

[0093] or R 8 and R 9 Together they form an oxo group;

[0094] Ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0095] Each R 10 are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NR b )R b 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、-P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl); wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0096] or two R on the same atom 10 Together they form an oxo group;

[0097] m is 0, 1, 2, 3, 4, 5, or 6;

[0098] Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl), wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0099] Each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl), wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0100] R c and R d each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl), wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0101] or R c and R d together with the atoms to which they are attached form heterocycloalkyl, which is optionally substituted with one or more R; and

[0102] Each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl) 2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl;

[0103] Or two R on the same atom form an oxo group;

[0104] The condition is no Where * indicates the point of attachment to the ring containing X, Y, Z and W, and ** indicates the point of attachment to -CR 8 R 9 -Connection point.

[0105] Disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0106]

[0107] in:

[0108] U is -N- or -CR 1 -;

[0109] R 1 Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl;

[0110] R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl;

[0111] L 1 Does not exist or is -CR 3 R 4 -;

[0112] R 3 and R 4 are independently hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0113] or R 3 and R 4 together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more R;

[0114] or R 3 and R 4 Together they form an oxo group;

[0115] R 5 and R 6 are independently hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 5a replace;

[0116] or R 5 and R 6 together to form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted by one or more R 5a replace;

[0117] Each R 5aare independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NR b )R b 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、-P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0118] X is -N- or -CR X -;

[0119] R X Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl;

[0120] Y is -N- or -CR Y -;

[0121] R Y Is hydrogen, halogen, -CN, -OH, -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 haloalkenyl, C2-C6 alkynyl, cycloalkyl optionally substituted with one or more halogen, or heterocycloalkyl optionally substituted with one or more halogen;

[0122] Z is -N- or -CR Z -;

[0123] R Z Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl;

[0124] W is -N- or -CR W -;

[0125] R W Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl;

[0126] Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0127] Each R 7 are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NR b )R b 、-NRc R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、-P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0128] or two R on the same atom 7 Together they form an oxo group;

[0129] n is 0, 1, 2, 3, 4, 5, or 6;

[0130] R 8 and R 9 are independently hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0131] or R 8 and R 9 together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more R;

[0132] or R 8 and R 9 Together they form an oxo group;

[0133] Ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0134] Each R 10 are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NR b )R b 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、-P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl); wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0135] or two R on the same atom 10 Together they form an oxo group;

[0136] m is 0, 1, 2, 3, 4, 5, or 6;

[0137] Each R ais independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl), wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0138] Each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl), wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0139] R c and R d each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl), wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0140] or R c and R d together with the atoms to which they are attached form heterocycloalkyl, which is optionally substituted with one or more R; and

[0141] Each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl) 2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl;

[0142] Or two R on the same atom form an oxo group;

[0143] The condition is no Where * indicates the point of attachment to the ring containing X, Y, Z and W, and ** indicates the point of attachment to -CR 8 R 9 -Connection point.

[0144] In some embodiments of the compound of Formula (I), X is -N-. In some embodiments of the compound of Formula (I), X is -CR X -.

[0145] In some embodiments of the compound of Formula (I), Y is -N-. In some embodiments of the compound of Formula (I), Y is -CR Y -.

[0146] In some embodiments of the compound of Formula (I), Z is -N-. In some embodiments of the compound of Formula (I), Z is -CR Z -.

[0147] In some embodiments of the compound of Formula (I), W is -N-. In some embodiments of the compound of Formula (I), W is -CR W -.

[0148] In some embodiments of the compound of Formula (I), the compound has Formula (Ia):

[0149]

[0150] In some embodiments of the compound of Formula (I), the compound has Formula (Ib):

[0151]

[0152] In some embodiments of the compound of Formula (I), the compound has Formula (Ic):

[0153]

[0154] In some embodiments of the compound of Formula (I), the compound has Formula (Id):

[0155]

[0156] In some embodiments of the compound of Formula (I), (Ia), (Ic), or (Id), R X is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ic) or (Id), R X is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ic) or (Id), R X is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ic) or (Id), R X Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ic) or (Id), R X It's hydrogen.

[0157] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y Is hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NRb S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl C2-C6 alkynyl, cycloalkyl optionally substituted by one or more halogen, or heterocycloalkyl optionally substituted by one or more halogen.

[0158] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, cycloalkyl optionally substituted by one or more halogen, or heterocycloalkyl optionally substituted by one or more halogen.

[0159] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl optionally substituted by one or more halogen, or heterocycloalkyl optionally substituted by one or more halogen.

[0160] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl or cycloalkyl optionally substituted by one or more halogen.

[0161] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R YIt is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or C1-C6 haloalkoxy.

[0162] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y It is hydrogen, C3-C6 cycloalkyl or C1-C6 haloalkoxy.

[0163] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y is hydrogen, -OR a , C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl; and R a It is a C1-C6 haloalkyl group.

[0164] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y is hydrogen, -OR a or C3-C6 cycloalkyl; and R a It is a C1-C6 haloalkyl group.

[0165] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C2-C6 haloalkenyl, C2-C6 alkynyl or cycloalkyl optionally substituted with one or more halogen.

[0166] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl or cycloalkyl optionally substituted with one or more halogen.

[0167] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl or cycloalkyl optionally substituted by one or more halogen.

[0168] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y is hydrogen, -OR a or cycloalkyl optionally substituted with one or more halogens.

[0169] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y is hydrogen, -OR a or cycloalkyl.

[0170] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y Yes-OR a In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y is C1-C6 haloalkoxy. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Id), R Y is C1-C3 haloalkoxy. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Id), R Y It is -OCH2F.

[0171] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y is a C3-C6 cycloalkyl group. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Id), R Y It is cyclopropyl.

[0172] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl optionally substituted with one or more halogen, or heterocycloalkyl optionally substituted with one or more halogen.

[0173] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y It is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl.

[0174] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted by one or more halogen, or 3- to 6-membered heterocycloalkyl optionally substituted by one or more halogen.

[0175] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or 3- to 6-membered heterocycloalkyl.

[0176] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Id), R Y It is hydrogen, methyl, ethyl, -OCH3, -OCH2F, Cl, F, -CH=CH2, -CF=CH2, CN, -C(=O)NH2, C(=O)NHCH3 or -CH2OH.

[0177] In some embodiments of the compound of Formula (I), (Ia), (Ib), or (Ic), R Z is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), R Z is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), R Z is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), R Z Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), R Z In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), R Z is hydrogen or halogen. In some embodiments of the compound of Formula (I), (Ia), (Ib) or (Ic), R Z It's a halogen.

[0178] In some embodiments of the compound of Formula (I) or (Ia), R X and R Ytogether form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; each of which is optionally substituted with one or more R. In some embodiments of the compound of Formula (I) or (Ia), R X and R Y together form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted with one or more R. In some embodiments of the compound of Formula (I) or (Ia), R X and R Y Together they form a cycloalkyl group optionally substituted with one or more R. In some embodiments of the compound of Formula (I) or (Ia), R X and R Y Together they form heterocycloalkyl optionally substituted with one or more R.

[0179] In some embodiments of the compound of Formula (I) or (Ia), R Y and R Z together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; each of which is optionally substituted with one or more R. In some embodiments of the compound of Formula (I) or (Ia), R Y and R Z together form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted with one or more R. In some embodiments of the compound of Formula (I) or (Ia), R Y and R Z Together they form a C5-C6 cycloalkyl group optionally substituted with one or more R. In some embodiments of the compound of Formula (I) or (Ia), R Y and R Z Together they form a 5- or 6-membered heterocycloalkyl optionally substituted with one or more R.

[0180] In some embodiments of the compound of Formula (I) or (Ia)-(Id), R W is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Id), R W is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R W is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R W Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R W It's hydrogen.

[0181] In some embodiments of the compound of Formula (I), yes

[0182] In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 8 and R 9 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein said alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia)-(Id), R 8 and R 9 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Id), R 8 and R 9 are each independently hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 8 and R 9 are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 8 and R 9 In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 8 and R 9 together form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted with one or more R. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 8 and R 9 Together they form an oxo group.

[0183] In some embodiments of the compound of Formula (I) or (Ia)-(Id), Ring B is cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), Ring B is cycloalkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), Ring B is heterocycloalkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), Ring B is 5- or 6-membered heterocycloalkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), Ring B is azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), Ring B is piperidinyl.

[0184] In some embodiments of the compound of Formula (I) or (Ia)-(Id), each R 10 are independently halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl); wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted by one or more R.

[0185] In some embodiments of the compound of Formula (I) or (Ia)-(Id), each R 10 are independently halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl).

[0186] In some embodiments of the compound of Formula (I) or (Ia)-(Id), each R 10 are independently halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl).

[0187] In some embodiments of the compound of Formula (I) or (Ia)-(Id), each R 10 are independently halogen, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or C1-C6 alkylene (cycloalkyl).

[0188] In some embodiments of the compound of Formula (I) or (Ia)-(Id), each R 10 are independently halogen, -OH, -OR a , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or C1-C6 alkylene (cycloalkyl).

[0189] In some embodiments of the compound of Formula (I) or (Ia)-(Id), each R 10 are independently halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl); wherein the alkyl, alkylene, alkynyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted by one or more R.

[0190] In some embodiments of the compound of Formula (I) or (Ia)-(Id), each R 10 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C1-C6 alkylene (C3-C6 cycloalkyl) or C1-C6 alkylene (heterocycloalkyl); wherein said alkyl, alkylene, alkynyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds of formula (I) or (Ia)-(Id), each R 10 is independently halogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), each R 10 is independently C1-C6 alkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), each R 10 are independently F, methyl, OH, -CH=CH2、 Cyclopropyl, -OCHF2 or -CH2F.

[0191] In some embodiments of the compound of Formula (I) or (Ia)-(Id), both R 10together form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; each of which is optionally substituted with one or more R. In some embodiments of the compound of Formula (I) or (Ia)-(Id), two R 10 Together they form a C3-C6 cycloalkyl or a 3- to 6-membered heterocycloalkyl; each of which is optionally substituted by one or more R.

[0192] In some embodiments of compounds of Formula (I) or (Ia)-(Id), m is 0, 1, 2, or 3. In some embodiments of compounds of Formula (I) or (Ia)-(Id), m is 1 or 2. In some embodiments of compounds of Formula (I) or (Ia)-(Id), m is 1, 2, or 3. In some embodiments of compounds of Formula (I) or (Ia)-(Id), m is 0, 1, or 2. In some embodiments of compounds of Formula (I) or (Ia)-(Id), m is 1 or 2. In some embodiments of compounds of Formula (I) or (Ia)-(Id), m is 0. In some embodiments of compounds of Formula (I) or (Ia)-(Id), m is 1. In some embodiments of compounds of Formula (I) or (Ia)-(Id), m is 2. In some embodiments of compounds of Formula (I) or (Ia)-(Id), m is 3.

[0193] In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes

[0194] In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes

[0195] In some embodiments of the compound of Formula (I) or (Ia)-(Id), L 1 In some embodiments of the compound of Formula (I) or (Ia)-(Id), L 1 Yes-CR 3 R 4 -.

[0196] In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 3 and R 4are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein said alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia)-(Id), R 3 and R 4 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Id), R 3 and R 4 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkylcycloalkyl, or heterocycloalkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 3 and R 4 are each independently hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 3 and R 4 In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 3 and R 4 together form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted with one or more R. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 3 and R 4 Together they form an oxo group.

[0197] In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 6 Is hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 6 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 6 Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 6 It's hydrogen.

[0198] In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 5Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 5a replace.

[0199] In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 5 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R 5a In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 5 is cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl are each independently optionally substituted by one or more R 5a In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 5 is optionally replaced by one or more R 5a In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 5 is optionally replaced by one or more R 5a Substituted 3- to 6-membered heterocycloalkyl.

[0200] In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 5 and R 6 together forming optionally one or more R 5a In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 5 and R 6 together forming optionally one or more R 5a Substituted C3-C6 cycloalkyl.

[0201] In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 5 and R 6 together forming optionally one or more R 5a In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 5 and R 6 together forming optionally one or more R 5aSubstituted 5- to 6-membered heterocycloalkyl.

[0202] In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 5 and R 6 together forming optionally one or more R 5a Substituted cyclobutyl.

[0203] In some embodiments of the compound of Formula (I) or (Ia)-(Id), each R 5a are independently halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein said alkyl, alkynyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compound of formula (I) or (Ia)-(Id), each R 5a is independently halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl or C2-C6 alkynyl; wherein the alkyl and alkynyl are each independently optionally substituted with one or more R.

[0204] In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes

[0205] In some embodiments of the compound of Formula (I) or (Ia)-(Id), U is -N-. In some embodiments of the compound of Formula (I) or (Ia)-(Id), U is -CR 1 -.

[0206] In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 1Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 1 is C1-C6 alkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 1 It's hydrogen.

[0207] In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 2 is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 2 Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 2 is C1-C6 alkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 2 is hydrogen. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 2 is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), R 2 It is a C1-C6 haloalkyl group.

[0208] In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes

[0209] In some embodiments of compounds of Formula (I) or (Ia)-(Id), Ring A is cycloalkyl or heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), Ring A is aryl or heteroaryl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), Ring A is aryl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), Ring A is phenyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), Ring A is heteroaryl.

[0210] In some embodiments of compounds of Formula (I) or (Ia)-(Id), Ring A is a bicyclic cycloalkyl, bicyclic heterocycloalkyl, bicyclic aryl, or bicyclic heteroaryl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), Ring A is a bicyclic cycloalkyl or bicyclic heterocycloalkyl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), Ring A is a bicyclic aryl or bicyclic heteroaryl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), Ring A is a bicyclic heteroaryl. In some embodiments of compounds of Formula (I) or (Ia)-(Id), wherein Ring A is a 6-6 fused ring. In some embodiments of compounds of Formula (I) or (Ia)-(Id), Ring A is a 6-6 fused ring containing 1-4 ring nitrogen atoms. In some embodiments of the compound of Formula (I) or (Ia)-(Id), Ring A is a 6-6 fused ring containing 2 ring nitrogen atoms. In some embodiments of the compound of Formula (I) or (Ia)-(Id), Ring A is a 6-6 fused ring containing 3 ring nitrogen atoms.

[0211] In some embodiments of the compound of Formula (I) or (Ia)-(Id), Ring A is benzothiazolyl, benzimidazolyl, indazolyl, pyrazolopyridinyl, thiazolopyridinyl, quinoxalinyl, or pyridopyrazinyl.

[0212] In some embodiments of the compound of Formula (I) or (Ia)-(Id), Ring A is indazolyl or pyrazolopyridinyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), Ring A is indazolyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), Ring A is pyrazolopyridinyl.

[0213] In some embodiments of the compound of Formula (I) or (Ia)-(Id), Ring A is tetrahydroisoquinolinyl, dihydrophthalazinyl, dihydroisoquinolinyl, dihydroquinazolinyl, dihydropyridopyrimidinyl, dihydropyrroloimidazolyl, dihydroimidazopyridinyl, dihydrothienopyridazinyl, dihydroindazolyl, tetrahydropyrrolopyridinyl, or dihydropyrrolopyridine.

[0214] In some embodiments of the compound of Formula (I) or (Ia)-(Id), Ring A is tetrahydroisoquinolinyl, dihydrophthalazinyl, dihydroisoquinolinyl, dihydroquinazolinyl, dihydropyrroloimidazolyl, dihydroimidazopyridinyl, dihydrothienopyridazinyl, dihydroindazolyl, tetrahydropyrrolopyridinyl, or dihydropyrrolopyridine.

[0215] In some embodiments of the compound of Formula (I) or (Ia)-(Id), Ring A is dihydroquinazolinyl or dihydropyridopyrimidinyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), Ring A is dihydroquinazolinyl. In some embodiments of the compound of Formula (I) or (Ia)-(Id), Ring A is dihydropyridopyrimidinyl.

[0216] In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes in

[0217] X 1 、X 2 、X 3 、X 4 and X 5 are independently N or CR 7’ ; and R 7’ is hydrogen or R 7 .

[0218] In some embodiments, X 1 It's CR 7’ In some embodiments, X 1 It's N.

[0219] In some embodiments, X 2 It's CR 7’ In some embodiments, X 2 It's N.

[0220] In some embodiments, X 3 It's CR 7’ In some embodiments, X 3 It's N.

[0221] In some embodiments, X 4 It's CR 7’ In some embodiments, X 4 It's N.

[0222] In some embodiments, X 5 It's CR 7’ In some embodiments, X 5 It's N.

[0223] In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes

[0224] In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes R 7’ is hydrogen or R 7 In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes R 7’ is hydrogen or R 7 .

[0225] In some embodiments of the compound of Formula (I) or (Ia)-(Id), each R 7 are independently halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein each alkyl group is independently optionally substituted with one or more R; or two R on the same atom 7 In some embodiments of the compound of Formula (I) or (Ia)-(Id), each R 7 are independently halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl or C1-C6 haloalkyl; wherein each alkyl is independently optionally substituted with one or more R; or two R on the same atom 7 In some embodiments of the compound of Formula (I) or (Ia)-(Id), each R 7 are independently -OH, C1-C6 alkyl or C1-C6 haloalkyl; or two R on the same atom 7 In some embodiments of the compound of Formula (I) or (Ia)-(Id), each R 7 are independently C1-C6 haloalkyl; or two R on the same atom 7 Together they form an oxo group.

[0226] In some embodiments of the compound of Formula (I) or (Ia)-(Id), each R 7’ are independently hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of the compound of formula (I) or (Ia)-(Id), each R 7’ are independently hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl or C1-C6 haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of the compound of formula (I) or (Ia)-(Id), each R 7’ is independently hydrogen, -OH, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Id), each R 7’ are independently hydrogen or C1-C6 haloalkyl.

[0227] In some embodiments of compounds of Formula (I) or (Ia)-(Id), n is 0, 1, 2, 3, or 4. In some embodiments of compounds of Formula (I) or (Ia)-(Id), n is 0, 1, 2, or 3. In some embodiments of compounds of Formula (I) or (Ia)-(Id), n is 1, 2, or 3. In some embodiments of compounds of Formula (I) or (Ia)-(Id), n is 1, 2, 3, or 4. In some embodiments of compounds of Formula (I) or (Ia)-(Id), n is 2, 3, or 4. In some embodiments of compounds of Formula (I) or (Ia)-(Id), n is 2 or 3. In some embodiments of compounds of Formula (I) or (Ia)-(Id), n is 0. In some embodiments of compounds of Formula (I) or (Ia)-(Id), n is 1. In some embodiments of compounds of Formula (I) or (Ia)-(Id), n is 2. In some embodiments of the compound of Formula (I) or (Ia)-(Id), n is 3. In some embodiments of the compound of Formula (I) or (Ia)-(Id), n is 4.

[0228] In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes

[0229] In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes

[0230] In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes In some embodiments of the compound of Formula (I) or (Ia)-(Id), yes

[0231] Disclosed herein are compounds of formula (III) or pharmaceutically acceptable salts thereof:

[0232]

[0233] in:

[0234] U is -N- or -CR 1 -;

[0235] R 1 Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl;

[0236] R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl;

[0237] L 1 Does not exist or is -CR 3 R 4 -;

[0238] R3 and R 4 are independently hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0239] or R 3 and R 4 together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more R;

[0240] or R 3 and R 4 Together they form an oxo group;

[0241] R 5 and R 6 are independently hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 5a replace;

[0242] or R 5 and R 6 together to form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted by one or more R 5a replace;

[0243] Each R 5a are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NRb )R b 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、-P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0244] or two R on the same atom 5a Together they form an oxo group;

[0245] X is -N- or -CR X -;

[0246] R X Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl;

[0247] Y is -N- or -CR Y -;

[0248] R Y Is hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR bC(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl C2-C6 alkynyl, cycloalkyl optionally substituted with one or more halogen, or heterocycloalkyl optionally substituted with one or more halogen;

[0249] Z is -N- or -CR Z -;

[0250] R Z Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl;

[0251] or R X and R Y together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R;

[0252] or R Y and R Z together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R;

[0253] W is -N- or -CR W -;

[0254] R W Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl;

[0255] X 3 、X 4 and X 5 are independently N or CR 7’ ;

[0256] Each R 7’ are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NR b )R b 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、-P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0257] R 8 and R 9 are independently hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0258] or R 8 and R 9 together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more R;

[0259] or R 8 and R 9 Together they form an oxo group;

[0260] Ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0261] Each R 10 are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NR b )R b 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、-P(=O)(R b)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R; or two R on the same atom 10 Together they form an oxo group;

[0262] m is 0, 1, 2, 3, 4, 5, or 6;

[0263] Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl), wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0264] Each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl), wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0265] R c and R d each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl), wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0266] or Rc and R d together with the atoms to which they are attached form heterocycloalkyl, which is optionally substituted with one or more R; and

[0267] Each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl) 2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl;

[0268] Or two R on the same atom form an oxo group.

[0269] In some embodiments of the compound of formula (III), Y is -N-. In some embodiments of the compound of formula (III), Y is -CR Y -.

[0270] In some embodiments of the compound of formula (III), Z is -N-. In some embodiments of the compound of formula (III), Z is -CR Z -.

[0271] In some embodiments of the compound of formula (III), W is -N-. In some embodiments of the compound of formula (III), W is -CR W -.

[0272] In some embodiments of the compound of Formula (III), the compound has Formula (IIIa):

[0273]

[0274] In some embodiments of the compound of Formula (III), the compound has Formula (IIIb):

[0275]

[0276] In some embodiments of the compound of Formula (III), the compound has Formula (IIIc):

[0277]

[0278] In some embodiments of the compound of Formula (III), the compound has Formula (IIId):

[0279]

[0280] In some embodiments of the compound of Formula (III), (IIIa), (IIIc), or (IIId), R X is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (III), (IIIa), (IIIc) or (IIId), R X is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (III), (IIIa), (IIIc) or (IIId), R X is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (III), (IIIa), (IIIc) or (IIId), R X Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (III), (IIIa), (IIIc) or (IIId), R X It's hydrogen.

[0281] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, cycloalkyl optionally substituted by one or more halogen, or heterocycloalkyl optionally substituted by one or more halogen.

[0282] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl optionally substituted by one or more halogen, or heterocycloalkyl optionally substituted by one or more halogen.

[0283] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl or cycloalkyl optionally substituted by one or more halogen.

[0284] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y It is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or C1-C6 haloalkoxy.

[0285] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y is hydrogen, -OR a , C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl; and R a It is a C1-C6 haloalkyl group.

[0286] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C2-C6 haloalkenyl, C2-C6 alkynyl or cycloalkyl optionally substituted with one or more halogen.

[0287] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d, C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, or cycloalkyl optionally substituted with one or more halogens.

[0288] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl, or cycloalkyl optionally substituted with one or more halogens.

[0289] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y is hydrogen, -OR a , or cycloalkyl optionally substituted with one or more halogens.

[0290] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y is hydrogen, -OR a In some embodiments of the compound of Formula (III), (IIIa), (IIIb) or (IIId), R Y is C1-C6 haloalkoxy. In some embodiments of the compound of formula (III), (IIIa), (IIIb) or (IIId), R Y It is a C1-C3 haloalkoxy group.

[0291] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y Yes-OR a In some embodiments of the compound of Formula (III), (IIIa), (IIIb) or (IIId), R Y Yes-OR a , and R a is C1-C6 haloalkyl. In some embodiments of the compound of formula (III), (IIIa), (IIIb) or (IIId), R Y It is -OCH2F.

[0292] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R YIn some embodiments of the compound of Formula (III), (IIIa), (IIIb) or (IIId), R Y It is cyclopropyl.

[0293] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl optionally substituted with one or more halogen, or heterocycloalkyl optionally substituted with one or more halogen.

[0294] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y It is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl.

[0295] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl optionally substituted by one or more halogen, or heterocycloalkyl optionally substituted by one or more halogen.

[0296] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl.

[0297] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl.

[0298] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y It is hydrogen or C1-C6 alkyl.

[0299] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIId), R Y It's hydrogen.

[0300] In some embodiments of the compound of Formula (III), (IIIa), (IIIb), or (IIIc), R Zis hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (III), (IIIa), (IIIb) or (IIIc), R Z is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (III), (IIIa), (IIIb) or (IIIc), R Z is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (III), (IIIa), (IIIb) or (IIIc), R Z Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (III), (IIIa), (IIIb) or (IIIc), R Z In some embodiments of the compound of Formula (III), (IIIa), (IIIb) or (IIIc), R Z is hydrogen or halogen. In some embodiments of the compound of Formula (III), (IIIa), (IIIb) or (IIIc), R Z It's a halogen.

[0301] In some embodiments of the compound of Formula (III) or (IIIa), R X and R Y Together they form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; each of which is optionally substituted with one or more R. In some embodiments of the compound of Formula (III) or (IIIa), R X and R Y together form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted with one or more R. In some embodiments of the compound of formula (III) or (IIIa), R X and R Y Together they form a cycloalkyl group optionally substituted with one or more R. In some embodiments of the compound of Formula (III) or (IIIa), R X and R Y Together they form heterocycloalkyl optionally substituted with one or more R.

[0302] In some embodiments of the compound of Formula (III) or (IIIa), R Y and R Z Together they form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; each of which is optionally substituted with one or more R. In some embodiments of the compound of Formula (III) or (IIIa), R Y and RZ together form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted with one or more R. In some embodiments of the compound of formula (III) or (IIIa), R Y and R Z Together they form a cycloalkyl group optionally substituted with one or more R. In some embodiments of the compound of Formula (III) or (IIIa), R Y and R Z Together they form heterocycloalkyl optionally substituted with one or more R.

[0303] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R W is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of Formula (III) or (IIIa)-(IIId), R W is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), R W is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), R W Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), R W It's hydrogen.

[0304] In some embodiments of the compound of formula (III), yes

[0305] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 8 and R 9 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein said alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds of Formula (III) or (IIIa)-(IIId), R 8 and R 9are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of Formula (III) or (IIIa)-(IIId), R 8 and R 9 are each independently hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), R 8 and R 9 are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 8 and R 9 In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 8 and R 9 together form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted with one or more R. In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 8 and R 9 Together they form an oxo group.

[0306] In some embodiments of compounds of Formula (III) or (IIIa)-(IIId), Ring B is cycloalkyl or heterocycloalkyl. In some embodiments of compounds of Formula (III) or (IIIa)-(IIId), Ring B is cycloalkyl. In some embodiments of compounds of Formula (III) or (IIIa)-(IIId), Ring B is heterocycloalkyl. In some embodiments of compounds of Formula (III) or (IIIa)-(IIId), Ring B is 5- or 6-membered heterocycloalkyl.

[0307] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), Ring B is azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl. In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), Ring B is piperidinyl.

[0308] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), each R 10 are independently halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl); wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted by one or more R.

[0309] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), each R 10 are independently halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl).

[0310] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), each R 10 are independently halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl).

[0311] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), each R 10 are independently halogen, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or C1-C6 alkylene (cycloalkyl).

[0312] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), each R 10 are independently halogen, -OH, -OR a , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or C1-C6 alkylene (cycloalkyl).

[0313] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), each R 10 are independently halogen, -CN, -OH, -ORa 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl); wherein the alkyl, alkylene, alkynyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted by one or more R.

[0314] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), each R 10 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl); wherein said alkyl, alkylene, alkynyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds of formula (III) or (IIIa)-(IIId), each R 10 is independently halogen or C1-C6 alkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), each R 10 are independently C1-C6 alkyl.

[0315] In some embodiments of compounds of Formula (III) or (IIIa)-(IIId), m is 0, 1, 2, or 3. In some embodiments of compounds of Formula (III) or (IIIa)-(IIId), m is 1 or 2. In some embodiments of compounds of Formula (III) or (IIIa)-(IIId), m is 1, 2, or 3. In some embodiments of compounds of Formula (III) or (IIIa)-(IIId), m is 0, 1, or 2. In some embodiments of compounds of Formula (III) or (IIIa)-(IIId), m is 1 or 2. In some embodiments of compounds of Formula (III) or (IIIa)-(IIId), m is 0. In some embodiments of compounds of Formula (III) or (IIIa)-(IIId), m is 1. In some embodiments of compounds of Formula (III) or (IIIa)-(IIId), m is 2. In some embodiments of compounds of Formula (III) or (IIIa)-(IIId), m is 3. In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), m is 4.

[0316] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), yes In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), yes

[0317] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), L 1 In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), L 1 Yes-CR 3 R 4 -.

[0318] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 3 and R 4 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; wherein said alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds of Formula (III) or (IIIa)-(IIId), R 3 and R 4 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of Formula (III) or (IIIa)-(IIId), R 3 and R 4 Each is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkylcycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), R 3 and R 4 are each independently hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), R 3 and R 4 In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 3 and R 4 together form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted with one or more R. In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 3 and R 4 Together they form an oxo group.

[0319] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 6 Is hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), R 6 Is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), R 6 Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), R 6 It's hydrogen.

[0320] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 5 Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 5a replace.

[0321] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 5 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R 5a In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 5 is cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl are each independently optionally substituted by one or more R 5a In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 5 is optionally replaced by one or more R 5a In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 5 is optionally replaced by one or more R 5a Substituted heterocycloalkyl.

[0322] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 5 and R 6 together forming optionally one or more R 5a Substituted cycloalkyl.

[0323] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 5 and R 6 together forming optionally one or more R 5a Substituted heterocycloalkyl.

[0324] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 5 and R 6 together forming optionally one or more R 5a Substituted cyclobutyl.

[0325] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), each R 5a are independently halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkynyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted by one or more R.

[0326] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), each R 5a are independently halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein said alkyl, alkynyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds of formula (III) or (IIIa)-(IIId), each R 5a is independently halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl or C2-C6 alkynyl; wherein the alkyl and alkynyl are each independently optionally substituted with one or more R.

[0327] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), yes In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), yes In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), yes In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), yes In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), yes In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), yes

[0328] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), U is -N-. In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), U is -CR 1 -.

[0329] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 1 Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), R 1 Is C1-C6 alkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), R 1 It's hydrogen.

[0330] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 2 Is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), R 2 Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), R 2 Is C1-C6 alkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), R 2 In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), R 2 is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), R2 It is a C1-C6 haloalkyl group.

[0331] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), yes In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), yes In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), yes In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), yes In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), yes

[0332] In some embodiments of the compound of Formula (III), (IIIa), (IIIc), or (IIId), X 3 It's CR 7’ In some embodiments of the compound of Formula (III), (IIIa), (IIIc) or (IIId), X 3 It's N.

[0333] In some embodiments of the compound of Formula (III), (IIIa), (IIIc), or (IIId), X 4 It's CR 7’ In some embodiments of the compound of Formula (III), (IIIa), (IIIc) or (IIId), X 4 It's N.

[0334] In some embodiments of the compound of Formula (III), (IIIa), (IIIc), or (IIId), X 5 It's CR 7’ In some embodiments of the compound of Formula (III), (IIIa), (IIIc) or (IIId), X 5 It's N.

[0335] In some embodiments of the compound of Formula (III), (IIIa), (IIIc), or (IIId), yes In some embodiments of the compound of Formula (III), (IIIa), (IIIc), or (IIId), yes In some embodiments of the compound of Formula (III), (IIIa), (IIIc), or (IIId), yes In some embodiments of the compound of Formula (III), (IIIa), (IIIc), or (IIId), yes In some embodiments of the compound of Formula (III), (IIIa), (IIIc), or (IIId), yes

[0336] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), each R 7’ are independently hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds of formula (III) or (IIIa)-(IIId), each R 7’ are independently hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl or C1-C6 haloalkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), each R 7’ is independently hydrogen, -OH, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), each R 7’ is independently hydrogen or C1-C6 haloalkyl. In some embodiments of the compound of formula (III) or (IIIa)-(IIId), each R 7’ is independently hydrogen or -CF3.

[0337] In some embodiments of the compound of Formula (III) or (IIIa)-(IIId), yes

[0338] Also provided herein are compounds of formula (II) or pharmaceutically acceptable salts thereof:

[0339]

[0340] in:

[0341] U is -N- or -CR 1 -;

[0342] R 1 Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl;

[0343] R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl;

[0344] L 1 Does not exist or is -CR 3 R 4 -;

[0345] R 3 and R 4 are independently hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0346] or R 3 and R 4 together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more R;

[0347] R 5 and R 6 are independently hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R5a replace;

[0348] or R 5 and R 6 together to form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted by one or more R 5a replace;

[0349] Each R 5a are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NR b )R b 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、-P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0350] X is -N- or -CR X -;

[0351] R X Is hydrogen, halogen, -CN, -OH, -OR a 、-NR cR d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl;

[0352] Y is -N- or -CR Y -;

[0353] R Y Is hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl C2-C6 alkynyl, cycloalkyl optionally substituted with one or more halogen, or heterocycloalkyl optionally substituted with one or more halogen;

[0354] Z is -N- or -CR Z -;

[0355] R Z Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl;

[0356] W is -N- or -CR W -;

[0357] R W Is hydrogen, halogen, -CN, -OH, -ORa 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl;

[0358] Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0359] Each R 7 are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NR b )R b 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d 、-P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0360] or two R on the same atom 7 Together they form an oxo group;

[0361] n is 0, 1, 2, 3, 4, 5, or 6;

[0362] R 8 and R 9 are independently hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0363] or R 8 and R 9 together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more R;

[0364] Ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0365] Each R 10 are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NR b )R b 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d、-P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0366] or two R on the same atom 10 Together they form an oxo group;

[0367] m is 0, 1, 2, 3, 4, 5, or 6;

[0368] Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl), wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0369] Each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl), wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0370] R c and R d each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl) or C1-C6 alkylene(heteroaryl), wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R;

[0371] or R cand R d together with the atoms to which they are attached form heterocycloalkyl, which is optionally substituted with one or more R; and

[0372] Each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl) 2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl;

[0373] Or two R on the same atom form an oxo group;

[0374] The condition is no Where * indicates the point of attachment to the -C(=O)-NH- group, and ** indicates the point of attachment to the -CR 8 R 9 - connection point;

[0375] and provided that the compound of formula (II) is not

[0376]

[0377] Also provided herein are compounds of formula (II) or pharmaceutically acceptable salts thereof:

[0378]

[0379] in:

[0380] U is -CR 1 -;and

[0381] R 2 , L 1 、R 5 、R 6 , X, Y, Z, W, Ring A, R 7 、n、R 8 、R 9, Ring B, R 10 and m have the meanings defined herein.

[0382] In some embodiments of the compound of Formula (II), R Y Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl;

[0383] In some embodiments of the compound of formula (II), X is -N-. In some embodiments of the compound of formula (II), X is -CR X -.

[0384] In some embodiments of the compound of formula (II), Y is -N-. In some embodiments of the compound of formula (II), Y is -CR Y -.

[0385] In some embodiments of the compound of formula (II), Z is -N-. In some embodiments of the compound of formula (II), Z is -CR Z -.

[0386] In some embodiments of the compound of formula (II), W is -N-. In some embodiments of the compound of formula (II), W is -CR W -.

[0387] In some embodiments of the compound of Formula (II), the compound has Formula (IIa):

[0388]

[0389] In some embodiments of the compound of Formula (II) or (IIa), R X is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (II) or (IIa), R X is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (II) or (IIa), R X is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (II) or (IIa), R XIs hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (II) or (IIa), R X It's hydrogen.

[0390] In some embodiments of the compound of Formula (II) or (IIa), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, cycloalkyl optionally substituted by one or more halogen, or heterocycloalkyl optionally substituted by one or more halogen.

[0391] In some embodiments of the compound of Formula (II) or (IIa), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl optionally substituted by one or more halogen, or heterocycloalkyl optionally substituted by one or more halogen.

[0392] In some embodiments of the compound of Formula (II) or (IIa), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl or cycloalkyl optionally substituted by one or more halogen.

[0393] In some embodiments of the compound of Formula (II) or (IIa), R Y is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl or C1-C6 alkoxy, wherein the alkoxy is optionally substituted with one or more halogens.

[0394] In some embodiments of the compound of Formula (II) or (IIa), R Y is hydrogen, -OR a , C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl; and R a It is a C1-C6 haloalkyl group.

[0395] In some embodiments of the compound of Formula (II) or (IIa), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C2-C6 haloalkenyl, C2-C6 alkynyl or cycloalkyl optionally substituted with one or more halogen.

[0396] In some embodiments of the compound of Formula (II) or (IIa), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2C2-C6 alkynyl or cycloalkyl optionally substituted by one or more halogen.

[0397] In some embodiments of the compound of Formula (II) or (IIa), R Y is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2C2-C6 alkynyl or cycloalkyl optionally substituted by one or more halogen.

[0398] In some embodiments of the compound of Formula (II) or (IIa), R Y is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl optionally substituted with one or more halogen, or heterocycloalkyl optionally substituted with one or more halogen.

[0399] In some embodiments of the compound of Formula (II) or (IIa), R Y It is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl.

[0400] In some embodiments of the compound of Formula (II) or (IIa), R Y is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl optionally substituted by one or more halogen, or heterocycloalkyl optionally substituted by one or more halogen.

[0401] In some embodiments of the compound of Formula (II) or (IIa), R Y is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl.

[0402] In some embodiments of the compound of Formula (II) or (IIa), R Y is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl.

[0403] In some embodiments of the compound of Formula (II) or (IIa), R Y Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (II) or (IIa), R Y It's hydrogen.

[0404] In some embodiments of the compound of Formula (II) or (IIa), R Z is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (II) or (IIa), R Z is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (II) or (IIa), R Z is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (II) or (IIa), R Z Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (II) or (IIa), R Z It's hydrogen.

[0405] In some embodiments of the compound of Formula (II) or (IIa), R W is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (II) or (IIa), R W is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (II) or (IIa), R W is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (II) or (IIa), R W Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (II) or (IIa), R W It's hydrogen.

[0406] In some embodiments of the compound of Formula (II) or (IIa), R 8 and R 9 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein said alkyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compound of formula (II) or (IIa), R 8 and R 9 Each is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (II) or (IIa), R 8 and R 9 are each independently hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (II) or (IIa), R 8 and R 9 are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (II) or (IIa), R 8 and R 9 In some embodiments of the compound of Formula (II) or (IIa), R 8 and R 9 together form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted with one or more R. In some embodiments of the compound of Formula (II) or (IIa), R 8 and R 9 Together they form an oxo group.

[0407] In some embodiments of the compound of formula (II) or (IIa), Ring B is cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (II) or (IIa), Ring B is cycloalkyl. In some embodiments of the compound of formula (II) or (IIa), Ring B is heterocycloalkyl. In some embodiments of the compound of formula (II) or (IIa), Ring B is 5- or 6-membered heterocycloalkyl.

[0408] In some embodiments of the compound of Formula (II) or (IIa), Ring B is azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl. In some embodiments of the compound of Formula (II) or (IIa), Ring B is piperidinyl.

[0409] In some embodiments of the compound of Formula (II) or (IIa), each R 10 are independently halogen, -CN, -OH, -ORa 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl); wherein the alkyl, alkylene, alkynyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted by one or more R.

[0410] In some embodiments of the compound of Formula (II) or (IIa), each R 10 is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl); wherein said alkyl, alkylene, alkynyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compound of formula (II) or (IIa), each R 10 is independently halogen or C1-C6 alkyl. In some embodiments of the compound of formula (II) or (IIa), each R 10 are independently C1-C6 alkyl.

[0411] In some embodiments of the compound of Formula (II) or (IIa), m is 0, 1, 2, or 3. In some embodiments of the compound of Formula (II) or (IIa), m is 1 or 2. In some embodiments of the compound of Formula (II) or (IIa), m is 1, 2, or 3. In some embodiments of the compound of Formula (II) or (IIa), m is 0, 1, or 2. In some embodiments of the compound of Formula (II) or (IIa), m is 1 or 2. In some embodiments of the compound of Formula (II) or (IIa), m is 0. In some embodiments of the compound of Formula (II) or (IIa), m is 1. In some embodiments of the compound of Formula (II) or (IIa), m is 2. In some embodiments of the compound of Formula (II) or (IIa), m is 3. In some embodiments of the compound of Formula (II) or (IIa), m is 4.

[0412] In some embodiments of the compound of Formula (II) or (IIa), yes In some embodiments of the compound of Formula (II) or (IIa), yes

[0413] In some embodiments of the compound of Formula (II) or (IIa), L 1In some embodiments of the compound of Formula (II) or (IIa), L 1 Yes-CR 3 R 4 -.

[0414] In some embodiments of the compound of Formula (II) or (IIa), R 3 and R 4 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein said alkyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compound of formula (II) or (IIa), R 3 and R 4 Each is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (II) or (IIa), R 3 and R 4 Each is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkylcycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (II) or (IIa), R 3 and R 4 are each independently hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (II) or (IIa), R 3 and R 4 In some embodiments of the compound of Formula (II) or (IIa), R 3 and R 4 together form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted with one or more R. In some embodiments of the compound of Formula (II) or (IIa), R 3 and R 4 Together they form an oxo group.

[0415] In some embodiments of the compound of Formula (II) or (IIa), R 6 Is hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (II) or (IIa), R 6 Is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of formula (II) or (IIa), R 6Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (II) or (IIa), R 6 It's hydrogen.

[0416] In some embodiments of the compound of Formula (II) or (IIa), R 5 Is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 5a replace.

[0417] In some embodiments of the compound of Formula (II) or (IIa), R 5 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R 5a In some embodiments of the compound of Formula (II) or (IIa), R 5 is cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl are each independently optionally substituted by one or more R 5a In some embodiments of the compound of Formula (II) or (IIa), R 5 is optionally replaced by one or more R 5a In some embodiments of the compound of Formula (II) or (IIa), R 5 is optionally replaced by one or more R 5a Substituted heterocycloalkyl.

[0418] In some embodiments of the compound of Formula (II) or (IIa), R 5 and R 6 together forming optionally one or more R 5a Substituted cycloalkyl.

[0419] In some embodiments of the compound of Formula (II) or (IIa), R 5 and R 6 together forming optionally one or more R 5a Substituted heterocycloalkyl.

[0420] In some embodiments of the compound of Formula (II) or (IIa), R 5 and R 6Together they form optionally substituted with one or more R 5a of cyclobutyl.

[0421] In some embodiments of the compound of Formula (II) or (IIa), each R 5a are independently halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein said alkyl, alkynyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compound of formula (II) or (IIa), each R 5a is independently halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl or C2-C6 alkynyl; wherein the alkyl and alkynyl are each independently optionally substituted with one or more R.

[0422] In some embodiments of the compound of Formula (II) or (IIa), yes In some embodiments of the compound of Formula (II) or (IIa), yes

[0423] In some embodiments of the compound of Formula (II) or (IIa), U is -N-. In some embodiments of the compound of Formula (II) or (IIa), U is -CR 1 -.

[0424] In some embodiments of the compound of Formula (II) or (IIa), R 1 Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (II) or (IIa), R 1 Is C1-C6 alkyl. In some embodiments of the compound of formula (II) or (IIa), R 1 It's hydrogen.

[0425] In some embodiments of the compound of Formula (II) or (IIa), R 2 Is hydrogen or C1-C6 alkyl. In some embodiments of the compound of formula (II) or (IIa), R 2 Is C1-C6 alkyl. In some embodiments of the compound of formula (II) or (IIa), R 2 It's hydrogen.

[0426] In some embodiments of the compound of formula (II) or (IIa), Ring A is cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (II) or (IIa), Ring A is aryl or heteroaryl. In some embodiments of the compound of formula (II) or (IIa), Ring A is aryl. In some embodiments of the compound of formula (II) or (IIa), Ring A is phenyl. In some embodiments of the compound of formula (II) or (IIa), Ring A is heteroaryl.

[0427] In some embodiments of the compound of formula (II) or (IIa), Ring A is a bicyclic cycloalkyl, a bicyclic heterocycloalkyl, a bicyclic aryl, or a bicyclic heteroaryl. In some embodiments of the compound of formula (II) or (IIa), Ring A is a bicyclic cycloalkyl or a bicyclic heterocycloalkyl. In some embodiments of the compound of formula (II) or (IIa), Ring A is a bicyclic aryl or a bicyclic heteroaryl. In some embodiments of the compound of formula (II) or (IIa), Ring A is a bicyclic heteroaryl.

[0428] In some embodiments of the compound of Formula (II) or (Ha), Ring A is benzothiazolyl, benzimidazolyl, indazolyl, pyrazolopyridinyl, thiazolopyridinyl, quinoxalinyl, or pyridopyrazinyl.

[0429] In some embodiments of the compound of Formula (II) or (IIa), Ring A is tetrahydroisoquinolinyl, dihydrophthalazinyl, dihydroisoquinolinyl, dihydroquinazolinyl, dihydropyrroloimidazolyl, dihydroimidazopyridinyl, dihydrothienopyridazinyl, dihydroindazolyl, tetrahydropyrrolopyridinyl, or dihydropyrrolopyridine.

[0430] In some embodiments of the compound of Formula (II) or (IIa), each R 7 are independently halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein each alkyl group is independently optionally substituted with one or more R; or two R on the same atom 7 Together they form oxo. In some embodiments of the compound of Formula (II) or (IIa), each R 7 are independently halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl or C1-C6 haloalkyl; wherein each alkyl is independently optionally substituted with one or more R; or two R on the same atom 7Together they form oxo. In some embodiments of the compound of Formula (II) or (IIa), each R 7 are independently -OH, C1-C6 alkyl or C1-C6 haloalkyl; or two R on the same atom 7 Together they form oxo. In some embodiments of the compound of Formula (II) or (IIa), each R 7 are independently C1-C6 haloalkyl; or two R on the same atom 7 Together they form an oxo group.

[0431] In some embodiments of the compound of Formula (II) or (IIa), n is 0, 1, 2, 3, or 4. In some embodiments of the compound of Formula (II) or (IIa), n is 0, 1, 2, or 3. In some embodiments of the compound of Formula (II) or (IIa), n is 1, 2, 3, or 4. In some embodiments of the compound of Formula (II) or (IIa), n is 2, 3, or 4. In some embodiments of the compound of Formula (II) or (IIa), n is 2 or 3. In some embodiments of the compound of Formula (II) or (IIa), n is 0. In some embodiments of the compound of Formula (II) or (IIa), n is 1. In some embodiments of the compound of Formula (II) or (IIa), n is 2. In some embodiments of the compound of Formula (II) or (IIa), n is 3. In some embodiments of the compound of Formula (II) or (IIa), n is 4.

[0432] In some embodiments of the compound of Formula (II) or (IIa), yes

[0433] In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl), wherein the alkyl, alkylene, cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl, wherein said alkyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each Ra is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a R is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl. a is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a are independently C1-C6 alkyl.

[0434] In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl), wherein said alkyl, alkylene, cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl, wherein said alkyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. b R is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R b is hydrogen. In some embodiments of the compounds disclosed herein, each R b are independently C1-C6 alkyl.

[0435] In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene (cycloalkyl) or C1-C6 alkylene (heterocycloalkyl), wherein said alkyl, alkylene, cycloalkyl and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R c and R d In some embodiments of the compounds disclosed herein, R c and R d Each is independently a C1-C6 alkyl group.

[0436] In some embodiments of the compounds disclosed herein, R c and R d Together with the atoms to which they are attached, they form a heterocycloalkyl group optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d Together with the atoms to which they are attached they form a heterocycloalkyl.

[0437] In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl; or two R on the same atom form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl; or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy; or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy; or two R on the same atom form an oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen or C1-C3 alkyl.

[0438] In some embodiments of the compounds disclosed herein, R, R 1 、R 2 、R 3 、R 4 、R 5 、R 5a 、R 6 、R 7 、R 8 、R 9 、R 10 、R X 、R Y 、R Z 、R W 、R a 、R b 、R c and R d One or more of the groups contains a percentage of deuterium that is above the natural deuterium abundance.

[0439] In some embodiments of the compounds disclosed herein, one or more of the following groups 1 H is replaced by one or more deuteriums: R, R 1 、R 2 、R 3 、R 4 、R 5 、R 5a 、R 6 、R 7 、R 8 、R 9 、R 10 、R X 、R Y 、R Z 、R W 、R a 、R b 、R c and R d .

[0440] In some embodiments of the compounds disclosed herein, R, R 1 、R 2 、R 3 、R 4 、R 5 、R 5a 、R 6 、R 7 、R 8 、R 9 、R 10 、R X 、R Y 、R Z 、R W 、R a 、R b 、R c and R d The deuterium abundance of each of 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% by mole.

[0441] In some embodiments of the compounds disclosed herein, one or more of Ring A or Ring B 1 H is replaced by one or more deuteriums.

[0442] Any combination of the above-described groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the art to provide stable moieties and compounds.

[0443] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is one of the compounds in Table 1.

[0444] Table 1

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463] *Trans and cis isomers were not separated.

[0464] **The trans and cis isomers or diastereomers were separated and the absolute stereochemistry was not determined. ***The trans and cis isomers were separated and the absolute stereochemistry at the cyclobutyl position was determined.

[0465] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is one of the compounds in Table 2.

[0466] Table 2

[0467]

[0468]

[0469]

[0470]

[0471] Other forms of the compounds disclosed herein

[0472] Isomers / stereoisomers

[0473] 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 described herein include all cis (cis, syn, zusammen (Z)), trans (trans, anti, entgegen (E)) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center exists in the R configuration or the S configuration. The compounds described herein include all diastereoisomers, enantiomers and epimers and their corresponding mixtures. In other embodiments of the compounds and methods provided herein, the enantiomers and / or diastereoisomer mixtures produced by a single preparation step, combination or mutual conversion can be used for the applications described herein. In some embodiments, the racemic mixture of the compound is reacted with an optically active resolving agent to form a pair of diastereomeric compounds, the diastereoisomers are separated and the optically pure enantiomers are recovered, thereby preparing the compounds described herein as their individual stereoisomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.), and these differences are exploited for separation. In some embodiments, diastereomers are separated by chiral chromatography, or preferably by separation / resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomers are then recovered together with the resolving agent by any practical method that does not result in racemization.

[0474] Labeled compounds

[0475] In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds in the form of pharmaceutical compositions. Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those described herein, but have one or more atoms replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example, 2 H(D), 3 H. 13 C. 14 C. l5 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds described herein and pharmaceutically acceptable salts thereof containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present disclosure. Certain isotopically labeled compounds, for example, into which radioactive isotopes, such as 3 H and 14 C, can be used in drug and / or substrate tissue distribution assays. 3 H, and carbon-14, i.e. 14 C isotopes are particularly preferred due to their ease of preparation and detection.

[0476] In some embodiments, the deuterium abundance in each substituent disclosed herein 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% by mole. In some embodiments, one or more substituents disclosed herein contain deuterium at a percentage greater than the natural deuterium abundance. In some embodiments, one or more of one or more substituents disclosed herein 1 H is replaced by one or more deuteriums.

[0477] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0478] Pharmaceutically acceptable salts

[0479] In some embodiments, the compounds described herein exist in the form of pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts in the form of pharmaceutical compositions.

[0480] The compounds described herein possess acidic or basic groups and, therefore, react with any of a variety of inorganic or organic bases, and 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 separately reacting the purified compound in free form with a suitable acid or base and isolating the salt thus formed.

[0481] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with inorganic or organic acids or inorganic bases, such salts include acetates, acrylates, adipates, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, hexanoate, octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, gluconoheptate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate salt, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0482] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; 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, , 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-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids, such as oxalic acid, while not pharmaceutically acceptable themselves, may be used to prepare salts that can be used as intermediates in obtaining the compounds disclosed herein and their pharmaceutically acceptable acid addition salts.

[0483] In some embodiments, the compounds described herein containing free acid groups are reacted with a suitable base, such as a pharmaceutically acceptable metal cation hydroxide, carbonate, bicarbonate, sulfate, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amine. Representative salts include alkali or alkaline earth metal salts such as lithium, sodium, potassium, calcium and magnesium, as well as aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 Alkyl)4, etc.

[0484] Representative organic amines for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include quaternization products of any basic nitrogen-containing groups they contain. In some embodiments, water- or oil-soluble or dispersible products may be obtained by such quaternization.

[0485] Tautomers

[0486] 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 be interconverted by hydrogen atom migration accompanied by the conversion of single bonds and adjacent double bonds. In bonding arrangements where tautomerization is possible, a chemical equilibrium of tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on a variety of factors, including temperature, solvent, and pH.

[0487] Treatment

[0488] Disclosed herein are methods of modulating the activity of immune cells (eg, T cells, B cells, or NK cells) by contacting the immune cells with an effective amount of a Cbl-b inhibitor described herein, or a pharmaceutically acceptable salt thereof, or a composition thereof.

[0489] Also provided are in vitro methods for producing immune cells with regulated activity (referred to herein as "modified immune cells"), wherein the modified immune cells can be administered to an individual in need (e.g., an individual with cancer) by an ex vivo method. Further provided are in vivo methods for regulating responses in an individual in need (e.g., an individual with cancer), wherein the method comprises administering an effective amount of a Cbl-b inhibitor as described herein, or a composition thereof. In addition, the present disclosure provides in vitro methods for producing amplified lymphocyte populations in an individual after in vivo lymphatic modulation, wherein the lymphatic modulation is the result of administering an effective amount of a Cbl-b inhibitor as described herein, or a composition thereof, to the individual. The amplified lymphocyte population can then be administered to the individual. The amplified lymphocyte population can then be administered to the individual with cancer. In some embodiments, the modified immune cells or amplified lymphocyte populations are produced by a biological sample comprising immune cells obtained from an individual, such as a blood sample comprising peripheral blood mononuclear cells or a tumor biopsy comprising tumor infiltrating lymphocytes (TILs).

[0490] Also disclosed herein are methods of treating cancer, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0491] Also disclosed herein are methods of treating cancer responsive to inhibition of Cbl-b activity, comprising administering to an individual in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0492] Also disclosed herein are methods of inhibiting abnormal cell proliferation, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0493] Also disclosed herein are methods of modulating an immune response comprising administering to an individual in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0494] Also disclosed herein are methods of inhibiting Cbl-b activity, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0495] Also disclosed herein are methods of treating a disease or condition associated with Cbl-b activity, comprising administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0496] In some embodiments, the disease or disorder associated with Cbl-b activity is cancer.

[0497] In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is a lymphoma, leukemia, or myeloma. In some embodiments, the cancer is a non-hematological cancer. In some embodiments, the cancer is a sarcoma, carcinoma, or melanoma. In some embodiments, the cancer is a solid tumor.

[0498] Hematologic cancers include, but are not limited to, one or more leukemias, such as B-cell acute lymphoblastic leukemia ("BALL"), T-cell acute lymphoblastic leukemia ("TALL"), acute lymphoblastic leukemia (ALL); one or more chronic leukemias, including, but not limited to, chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL); additional hematologic cancers or hematologic disorders, including, but not limited to, B-cell promyelocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's 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, marginal zone lymphoma, multiple myeloma, myelodysplasia and myelodysplastic syndrome, non-Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, and "preleukemia," a group of blood disorders caused by ineffective production (or dysplasia) of myeloid blood cells.

[0499] Non-hematological cancers include, but are not limited to, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell carcinoma, melanoma, gastric 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.

[0500] dose

[0501] In certain embodiments, the compositions containing the compounds described herein are administered for therapeutic therapy. In certain therapeutic applications, compositions are administered to patients already suffering from a disease or condition in an amount sufficient to cure or at least partially suppress at least one symptom of the disease or condition. The effective amount for this purpose depends on the severity and course of the disease or condition, previous therapy, the patient's health, body weight, and response to the drug, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose-ranging clinical trials.

[0502] In certain embodiments, when the patient's condition does not improve in the judgment of the physician, the compound will be administered chronically, that is, for an extended period of time, including throughout the patient's life, to improve or control or limit the symptoms of the patient's disease or condition.

[0503] Once the patient's condition improves, a maintenance dose is administered as necessary. Subsequently, in certain embodiments, the dose or the frequency of administration, or both, is reduced based on the changes in symptoms.

[0504] The amount of a given active agent corresponding to this amount will vary depending on factors such as the specific compound, the disease state and its severity, the characteristics of the individual or host in need of treatment (e.g., weight, sex), but will still be determined according to the specific circumstances related to the case, including, for example, the specific active agent being administered, the route of administration, the condition being treated, and the individual or host being treated.

[0505] In some embodiments, the dosage for adult treatment is generally 0.01 mg to 5000 mg per day. In some embodiments, the daily dosage suitable for the compounds described herein or their pharmaceutically acceptable salts is about 0.01 to about 50 mg / kg body weight. In various embodiments, the daily dosage and unit dosage vary according to many variables, including but not limited to the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0506] Route of administration

[0507] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0508] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner, for example, by injecting the compound directly into an organ, typically in the form of a depot formulation or a sustained-release formulation. In a specific embodiment, the long-acting formulation is administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. In addition, in other embodiments, the drug is delivered in the form of a targeted drug delivery system, for example, in the form of a liposome coated with an organ-specific antibody. In such an embodiment, the liposome is targeted to an organ and selectively absorbed by the organ. In another embodiment, the compounds described herein are provided in the form of a rapid-release formulation, in the form of an extended-release formulation, or in the form of a moderate-release formulation.

[0509] Pharmaceutical compositions / preparations

[0510] The compounds described herein are administered to an individual in need thereof, alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent, as a pharmaceutical composition, in accordance with standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.

[0511] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compound into a pharmaceutically acceptable formulation. The appropriate formulation depends on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed. (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0512] In some embodiments, the pharmaceutically acceptable excipient is selected from the group consisting of carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, antifoaming agents, antioxidants, preservatives, and any combination thereof.

[0513] The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0514] combination

[0515] Disclosed herein are methods of treating diseases or disorders associated with cbl-b using a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with an additional therapeutic agent.

[0516] In some embodiments, the additional therapeutic agent is administered simultaneously with the compounds disclosed herein. In some embodiments, the additional therapeutic agent and the compounds disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered before the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered after the compounds disclosed herein are administered.

[0517] In some embodiments, the additional therapeutic agent is an anti-cancer agent.

[0518] In some embodiments, the additional therapeutic agent is a cancer vaccine.

[0519] In some embodiments, the additional therapeutic agent is an oncolytic virus. Example

[0520] The following examples serve to illustrate, but not to limit, the claimed invention.The following examples further illustrate the present invention, but of course should not be construed as limiting its scope in any way.

[0521] The following synthetic schemes are provided for illustrative purposes only and are not intended to be limiting. The following examples illustrate various methods for preparing the compounds described herein. It will be understood that those skilled in the art will be able to prepare these compounds by similar methods or by combining other methods known to those skilled in the art. It will also be understood that those skilled in the art will be able to prepare the compounds in a manner similar to the methods described below by using appropriate starting materials and modifying the synthetic routes as needed. Typically, starting materials and reagents can be obtained from commercial suppliers, synthesized from sources known to those skilled in the art, or prepared as described herein.

[0522] Embodiment 1:

[0523]

[0524] Step 1: Preparation of compound 1-1

[0525] To a solution of 2-(2-(trifluoromethyl)phenyl)acetonitrile (23.0 g, 124.2 mmol) in THF (200 mL) was added BH3-Me2S (10 M, 24.8 mL) dropwise over 30 mins at 0 ° C. The mixture was then heated to reflux for 16 h. The reaction mixture was quenched by adding MeOH (300 mL) at 25 ° C. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 1-1. LCMS: 189.9 [M+H] + ;

[0526] Step 2: Preparation of compound 1-2

[0527] To a solution of compound 1-1 (16.0 g, 84.6 mmol) in CHCl₃ (200 mL) was added ethyl chloroformate (10.8 g, 99.9 mmol, 9.51 mL) and a 1 M aqueous Na₂CO₃ solution (160.0 mL) at 0°C. The resulting mixture was stirred at 25°C for 2 h. The reaction mixture was diluted with H₂O (200 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 1-2. 1 H NMR: (400MHz, DMSO-d6) δ7.71-7.59(m,2H),7.49-7.39(m,2H),7.33-7.18(m,1H),3. 97(q,J=7.1Hz,2H),3.27-3.17(m,2H),2.89(t,J=7.3Hz,2H),1.14(t,J=7.1Hz,3H);

[0528] Step 3: Preparation of compound 1-3

[0529] To a solution of compound 1-2 (8.00 g, 30.6 mmol) in POCl3 (20 mL) was added PO5 (8.69 g, 61.3 mmol). The resulting mixture was stirred at 115 ° C for 2 h. The reaction mixture was concentrated under reduced pressure to remove POCl3. At 25 ° C, the residue was carefully poured into H2O (50 mL) and then diluted with H2O (50 mL). The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 1-3. LCMS: 216.1 [M+H] + ; 1 H NMR:(400MHz,DMSO-d6)δ8.24(br s,1H),8.16(d,J=7.8Hz,1H),7.88(d,J=7.8Hz,1H),7.56(t,J=7.8Hz,1H),3.41(dt,J=2.9,6.6Hz,2H),3.03(t,J=6.4Hz,2H);

[0530] Step 4: Preparation of compound 1-4

[0531] To a solution of compound 1-3 (413.0 mg, 1.92 mmol) in H2SO4 (10 mL) was added NBS (409.9 mg, 2.30 mmol). The mixture was stirred at 25°C for 16 h. The reaction mixture was added dropwise to ice water (20 mL) at 0°C, and the mixture was extracted with DCM (10 mL x 2). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. Compound 1-4 was used directly in the next step without further purification. LCMS: 292.0 / 294.0 [MH] - ;

[0532] Step 5: Preparation of compound 1-5

[0533] To a solution of compound 1-4 (150.0 mg, 0.5 mmol) in dioxane (4 mL) and H2O (1 mL) was added [[(3S)-3-fluoropyrrolidin-1-yl]methyl]trifluoroboric acid (213.3 mg, 1.02 mmol, K +Salt), K3PO4 (324.8 mg, 1.53 mmol) and Ruphos-Pd-G4 (43.4 mg, 51.0 μmol). The mixture was stirred at 80°C for 16 h under N2. The reaction mixture was concentrated. The residue was purified by flash silica gel column chromatography to obtain compound 1-5. LCMS: 317.2 [M+H] + ;

[0534] Step 6: Preparation of (S)-7-((3-fluoropyrrolidin-1-yl)methyl)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-(trifluoromethyl)-3,4-dihydroisoquinolin-1(2H)-one

[0535] A mixture of compound 1-5 (80.0 mg, 252.9 μmol), 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (92.9 mg, 303.5 μmol), CuI (9.63 mg, 50.6 μmol), DMEDA (8.92 mg, 101.2 μmol, 10.9 μL) and K2CO3 (69.9 mg, 505.9 μmol) in dioxane (2 mL) was degassed and bubbled with N2 three times, and then the mixture was stirred at 100 ° C. under N2 atmosphere for 16 h. The reaction mixture was partitioned between brine (3 mL) and EtOAc (3 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give Example 1 as an HCl salt. LCMS: 542.4 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ12.20-11.54(m,1H),9.70-9.39(m,1H),8.51(br s,1H),8.40(br s,1H),7.62-7.31(m,3H),7.17(d,J=7.5Hz,1H),5.62-5.30(m,1H),4.59(br s,2H),4.11-3.98(m,2H),3.91-3.70(m,1H),3.47(s,4H),3.30(br s,3H),3.22-3.11(m,2H),3.00-2.87(m,1H),2.69-2.57(m,1H),2.45-2.29(m,3H),2.28-2.15(m,1H),1.20-0.99(m,3H).

[0536] Examples 2 and 3:

[0537]

[0538] According to the method of Example 1, Compound 1-4 (3.6 g, 12.242 mmol) and (S)-trifluoro((3-methylpiperidin-1-yl)methyl)borate potassium (335.28 mg, 1.530 mmol) were used as substrates to synthesize Examples 2 and 3. Chiral SFC analysis was performed under the following conditions: AD (100 x 3.0 mm, 3.0 μm) column, eluted with mobile phase (A: supercritical CO2; B: EtOH (0.1% DEA); gradient: 5% B for 0.5 min, then from 5% to 40% B in 5 min, then 40% B for 2.5 min), with a flow rate of 1.5 mL / min, at 35°C, and the pressure was set to 1800 psi.

[0539] Example 2:

[0540] LCMS: 552.2 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6)δ8.30(s,1H),8.17(s,1H),7.85-7.80(m,1H),7.49-7. 39(m,2H),7.33-7.27(m,1H),7.23-7.15(m,1H),4.01(t,J=6.4Hz,2H),3.55(s ,2H),3.30-3.20(m,7H),2.90-2.78(m,2H),2.73-2.66(m,2H),2.36-2.31(m,1 H),1.98-1.82(m,1H),1.75-1.43(m,5H),1.11-1.05(m,3H),0.89-0.77(m,4H). t R =4.49 minutes, chiral purity: 99.6%.

[0541] Example 3:

[0542] LCMS: 552.2 [M+H] + ; 1H NMR: (400MHz, DMSO-d6) δ8.37(s,1H),8.17(s,1H),7.82(s,1H),7.40(t,J= 7.8Hz,1H),7.30-7.24(m,2H),7.04(d,J=8.1Hz,1H),3.99(t,J=6.2Hz,2H) ,3.55(s,2H),3.29-3.05(m,7H),2.78-2.64(m,2H),2.37-2.18(m,3H),1.9 4-1.86(m,1H),1.68-1.49(m,5H),1.10(d,J=6.4Hz,3H),0.86-0.79(m,4H). t R = 4.20 min, chiral purity: 99.5%.

[0543] Embodiment 4:

[0544]

[0545] Step 1: Preparation of compound 4-1

[0546] To a solution of 4-fluoro-3-(trifluoromethyl)benzoic acid (6 g, 28.831 mmol) in HNO3 (50 mL) was added sulfuric acid (7.7 mL, 144.155 mmol) at 0°C, and the mixture was stirred at 75°C for 5 h. The reaction mixture was quenched with ice water (40 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were dried, filtered, and concentrated to give compound 4-1. LCMS: 251.9 [MH] - .

[0547] Step 2: Preparation of compound 4-2

[0548] To a solution of compound 4-1 (3 g, 11.853 mmol) in THF (35 mL) was added Pd / C (1.26 g, 11.853 mmol). The resulting mixture was stirred at 25°C under H2 (15 psi) for 12 h. The suspension was filtered and the filter cake was washed with MeOH (100 mL). The combined filtrates were concentrated to give compound 4-2. LCMS: 222.0 [MH] - .

[0549] Step 3: Preparation of compound 4-3

[0550] To a solution of compound 4-2 (2 g, 8.963 mmol) in DCM (20 mL) were added HATU (6.82 g, 17.927 mmol) and DIEA (4 mL), and the mixture was stirred at room temperature for 30 minutes. Then, (3S)-3-methylpiperidinium hydrochloride (2.43 g, 17.927 mmol) was added to the mixture, and the mixture was stirred at 25 ° C for another 12 h. The reaction was quenched with water (100 mL). The resulting mixture was extracted with DCM (100 mL×2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 4-3. LCMS: 305.2 [M+H] + .

[0551] Step 4: Preparation of compound 4-4

[0552] To a solution of compound 4-3 (500 mg, 1.643 mmol) in THF (10 mL) was slowly added a 1.0 M solution of borane tetrahydrofuran complex in THF (8 mL, 8.216 mmol), and the mixture was stirred at 40 ° C. under a N2 atmosphere for 12 h. The reaction mixture was quenched with MeOH (50 mL) and stirred at 80 ° C. for 8 h, and then the mixture was concentrated in vacuo to give compound 4-4. LCMS: 291.2 [M+H] + .

[0553] Step 5: Preparation of compound 4-5

[0554] To a solution of compound 4-4 in DMF (10 mL) was added potassium ethyl xanthate (635.15 mg, 3.962 mmol). The reaction was stirred at 120°C for 12 h. The mixture was directly purified by reverse phase column chromatography to afford compound 4-5. LCMS: 347.1 [M+H] + ;

[0555] Step 6: Preparation of compound 4-6

[0556] A mixture of compound 4-5 (400 mg, 1.155 mmol) in DCM (5 mL) and SOCl2 (10 mL) was stirred at room temperature for 12 h. The reaction mixture was quenched at 0°C by adding 100 mL of saturated NaHCO3 (aq). The resulting mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 4-6. LCMS: 349.1 [M+H] + .

[0557] Step 7: Preparation of (S)-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-5-((3-methylpiperidin-1-yl)methyl)-7-(trifluoromethyl)benzo[d]thiazole

[0558] To a solution of compound 4-6 (100 mg, 0.287 mmol) and 4-methyl-3-(3-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)-4H-1,2,4-triazole (202.56 mg, 0.573 mmol) in dioxane (3 mL) and H2O (0.3 mL) were added K2CO3 (79.24 mg, 0.573 mmol) and Pd(dppf)Cl2 (20.98 mg, 0.029 mmol). Under a nitrogen atmosphere, the mixture was stirred at 100°C for 12 h. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC to give Example 4. LCMS: 540.4 [M+H] + ; 1 H NMR: (400MHz, CDCl3) δ8.33-7.83(m,4H),7.77(s,1H),7.53-7.43(m,2H),3.71(s,2H),3.24(d,J=12.7Hz,3H),2. 95(s,2H),2.82-2.64(m,3H),2.44-2.04(m,2H),1.89-1.61(m,6H),1.17(t,J=6.0Hz,3H),0.88(d,J=4.5Hz,4H).

[0559] Example 5: Preparation of (S)-3-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-7-((3-methylpiperidin-1-yl)methyl)-5-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridine

[0560]

[0561] Step 1: Preparation of compound 5-1

[0562] To a mixture of 1H-pyrazol-4-amine (10.5 g, 126.369 mmol) in toluene (50 mL) was added ethyl 4,4,4-trifluoro-3-oxobutanoate (25.59 g, 139.006 mmol) and 4-methylbenzenesulfonic acid (2.18 g, 12.637 mmol). The mixture was then stirred at 120 ° C for 16 h. After cooling to room temperature, the solution was filtered. The filtrate was concentrated to obtain compound 5-1. LCMS: 250.2

[0563] [M+H] + .

[0564] Step 2: Preparation of compound 5-2

[0565] A mixture of compound 5-1 (5 g, 20.065 mmol) in diphenyl ether (10 mL) was stirred at 260°C for 1 hour. The reaction mixture was cooled to room temperature and triturated with MTBE (10 mL) at 25°C for 2 hours. The mixture was filtered. The filter cake was collected. The filtrate was concentrated to give compound 5-2. LCMS: 204.1 [M+H] + .

[0566] Step 3: Preparation of compound 5-3

[0567] A mixture of compound 5-2 (1.0 g, 4.923 mmol) in POCl3 (10 mL) was stirred at 90°C for 1 hour. The reaction mixture was cooled, and phosphorus oxychloride was removed under reduced pressure. The residue was poured into water and adjusted to pH 8-9 with 10% sodium carbonate solution. The mixture was extracted with ethyl acetate (150 ml x 3), and the combined organic layers were dried and concentrated to give compound 5-3. LCMS: 222.1 [M+H] + .

[0568] Step 4: Preparation of compound 5-4

[0569] To a solution of (S)-trifluoro((3-methylpiperidin-1-yl)methyl)borate potassium (741.76 mg, 3.386 mmol) and compound 5-3 (500 mg, 2.257 mmol) in dioxane (15 mL) and H2O (3 mL) were added Cs2CO3 (2206.13 mg, 6.771 mmol), Catacxium A (80.92 mg, 0.226 mmol) and Pd(OAc)2 (25.34 mg, 0.113 mmol), and the resulting mixture was stirred at 120°C under N2 for 12 h. The reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel column chromatography to give compound 5-4. LCMS: 299.2 [M+H] + .

[0570] Step 5: Preparation of compound 5-5

[0571] To a solution of compound 5-4 (230 mg, 0.771 mmol) in chloroform (5 mL) and TFA (175.82 mg, 1.542 mmol) was added NIS (173.47 mg, 0.771 mmol). The reaction solution was stirred at 20°C for 2 h. The mixture was adjusted to pH = 8 with NaHCO3 (aq.), and then saturated Na2S2O3 (aq.) (20 mL) was added. After 10 minutes, the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layers were concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 5-5. LCMS: 425.1 [M+H] + .

[0572] Step 6: Preparation of Example 5

[0573] To a solution of compound 5-5 (50 mg, 0.118 mmol) and 4-methyl-3-(3-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)-4H-1,2,4-triazole (83.37 mg, 0.236 mmol) in dioxane (3 mL) and H2O (0.3 mL) were added K2CO3 (32.58 mg, 0.236 mmol) and Pd(dppf)Cl2 (8.62 mg, 0.012 mmol). Under a nitrogen atmosphere, the mixture was stirred at 100 ° C. for 16 h. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC to give Example 5. LCMS: 524.3 [M+H] + ; 1 H NMR: (400MHz, CDCl3) δ11.58(brs,1H),8.84(s,1H),8.40-8.21(m,1H),7.98(m,1H),7.56-7.42(m,2H),7.23-7.09(m,1H),3.98(br s,2H),3.31(s,3H),3.05-2.95(m,2H),2.84-2.59(m,3H),1.90-1.71(m,2 H), 1.58 (s, 6H), 1.16 (d, J = 5.5Hz, 3H), 1.01 (s, 1H), 0.90 (d, J = 4.4Hz, 3H).

[0574] Example 6:

[0575]

[0576] Step 1: Preparation of compound 6-1

[0577] To a solution of methyl 2-(acetoxymethyl)-5-bromo-3-(trifluoromethyl)benzoate (2 g, 5.632 mmol) in MeOH (6 mL) was added MeONa (0.06 g, 1.126 mmol) at room temperature. The mixture was stirred at room temperature for 2 h, then poured into a 1M HCl solution (3 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried, filtered, and concentrated under reduced pressure to yield compound 6-1. 1 H NMR: (400MHz, CDCl3) δ8.25(s,1H),8.04(s,1H),5.42(s,2H).

[0578] Step 2: Preparation of compound 6-2

[0579] To a solution of compound 6-1 (730 mg, 2.598 mmol) in CCl4 (7 mL) were added NBS (554.81 mg, 3.117 mmol) and BPO (62.86 mg, 0.260 mmol). The reaction mixture was stirred at 85 ° C for 10 h. The reaction was quenched by adding H2O (10 mL). The mixture was extracted with DCM (20 mL × 3). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to give compound 6-2, which was used without further purification. 1 HNMR: (400MHz, CDCl3) δ8.27(s,1H),8.11(s,1H),7.46(s,1H).

[0580] Step 3: Preparation of compound 6-3

[0581] To a solution of compound 6-2 (855 mg, 2.376 mmol) in EtOH (10 mL) was added hydrazine hydrate (0.577 mL, 11.878 mmol). The mixture was stirred at 80 ° C for 18 h. The reaction mixture was cooled to room temperature and diluted with cold water. Then, a solid precipitated. The mixture was filtered and the filter cake was collected to obtain compound 6-3. LCMS: 293.0 [M+H] + .

[0582] Step 4: Preparation of compound 6-4

[0583] Compound 6-4 was synthesized according to step 4 in Example 5. LCMS: 326.2 [M+H] + ;

[0584] Step 5: Preparation of Example 6

[0585] To a solution of compound 6-4 (150 mg, 0.461 mmol) in dioxane (2 mL) were added 2,5-diazahexane (16.26 mg, 0.184 mmol), K2CO3 (127.44 mg, 0.922 mmol), 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (141.18 mg, 0.461 mmol) and CuI (17.56 mg, 0.092 mmol). Under an N2 atmosphere, the mixture was stirred at 100°C for 12 h. Then, the mixture was concentrated to obtain a residue. The residue was purified by preparative HPLC to obtain Example 6. LCMS: 551.4 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6)δ8.6(s,2H),8.5-8.1(m,2H),7.7-7.2(m,4H),3.8(s,2H),3.3-3.2(m,3H),3.2-3.0(m ,1H),3.0-2.7(m,3H),2.6-2.5(m,2H),2.5-2.1(m,2H),1.9-1.4(m,5H),1.2-1.0(m,3H),0.8(d,J=6.1Hz,4H).

[0586] Example 7:

[0587]

[0588] Step 1: Preparation of compound 7-1

[0589] To a solution of 2-methyl-1-nitro-3-(trifluoromethyl)benzene (15 g, 73.121 mmol) in concentrated H2SO4 (150 mL) was added 1,3-dibromo-4,4-dimethyl-2-oxotetrahydro-1H-imidazole-5-one (12.54 g, 43.872 mmol) at 0°C. The reaction mixture was then stirred at room temperature for 3 h. The reaction mixture was poured into ice water (200 mL). After 10 minutes, the mixture was extracted with ethyl acetate (300 mL × 3). The combined organic layers were washed with saturated NaHCO3 (aq.), filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 7-1. 1 H NMR: (400MHz, CDCl3) δ 8.04 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 1.8 Hz, 1H), 2.51 (d, J = 1.4 Hz, 3H).

[0590] Step 2: Preparation of compound 7-2

[0591] To a solution of compound 7-1 (1.00 g, 3.521 mmol) and benzoyl peroxide (0.09 g, 0.352 mmol) in tetrachloromethane (30 mL) was added NBS (0.66 g, 3.697 mmol). The mixture was stirred at 80 ° C for 18 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash silica gel column chromatography to obtain compound 7-2. LCMS: 383.9 [M+Na] + .

[0592] Step 3: Preparation of compound 7-3

[0593] Under N2, compound 7-2 (1 g, 2.755 mmol) and To a mixture of molecular sieves (200 mg) in MeCN (10 mL) was added 4-methyl-1,4-oxazacyclohexane 4-oxide (0.68 g, 5.841 mmol), and the resulting mixture was stirred for 1.5 h. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with H2O and 1N HCl. The organic layer was washed with 70 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 7-3.

[0594] Step 4: Preparation of compound 7-4

[0595] To a solution of compound 7-3 (300 mg, 0.101 mmol) in propan-2-ol (6 mL) was added 3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline (26.83 mg, 0.111 mmol), and the mixture was stirred at 80 ° C for 4 h. Then, tributylphosphine (93.95 mg, 0.464 mmol) was added, and the resulting mixture was stirred at 80 ° C for 16 h. The mixture was cooled to room temperature and diluted with EtOAc (10 mL). The organic matter was washed with brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel column chromatography to give compound 7-4. LCMS: 490.0 [M+1] + .

[0596] Step 5: Preparation of Example 7

[0597] To a solution of compound 7-4 (50 mg, 0.101 mmol), potassium (S)-trifluoro((3-methylpiperidin-1-yl)methyl)borate (44.68 mg, 0.204 mmol), and Cs2CO3 (99.67 mg, 0.306 mmol) in dioxane (2 mL) and H2O (1 mL) was added Ruphos Pd G4 (9.81 mg, 0.010 mmol). Under N2, the reaction mixture was stirred at 90°C for 16 h. The mixture was concentrated to give a residue, which was purified by preparative HPLC to give Example 7. LCMS: 523.2 [M+H] + ; 1 H NMR: (400MHz, methanol-d4)δ8.5-8.3(m,2H),8.0-7.4(m,6H),4.0(s,2H),3.4-3.4(m,3H),3.2-2.9( m,4H),2.8-2.4(m,4H),2.2-2.0(m,1H),1.9-1.6(m,4H),1.2(d,J=6.1Hz,3H),1.1-0.9(m,4H).

[0598] Example 8:

[0599]

[0600] Step 1: Preparation of compound 8-1

[0601] To a solution of 2-fluoro-1-nitro-3-(trifluoromethyl)benzene (6.67 g, 31.899 mmol) in TFA (20 mL) and H2SO4 (30 mL) was added NBS (6.81 g, 38.278 mmol). The reaction mixture was stirred at 60 ° C for 12 h. The mixture was cooled to room temperature and diluted with ice water (100 mL). Then, the mixture was extracted with ethyl acetate (40 mL × 3). The organic layer was separated and washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a residue, which was purified by silica gel chromatography to obtain compound 8-1.

[0602] Step 2: Preparation of compound 8-2

[0603] At 25°C under N2, a solution of compound 8-1 (2 g, 6.944 mmol) in MeOH (5 mL) was added with a MeOH solution of MeNH2 (9.2 mL, 69.444 mmol). The reaction was stirred at 25°C for 18 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to give compound 8-2. LCMS: 299.0 [M+H] + .

[0604] Step 3: Preparation of compound 8-3

[0605] To a solution of compound 8-2 (200 mg, 0.669 mmol) in EtOH (1 mL) and EA (2 mL) was added stannous chloride dihydrate (450.90 mg, 2.004 mmol) at 25°C under N2. The reaction was stirred at 70°C for 3 h. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase column chromatography to obtain compound 8-3. LCMS: 269.0 [M+H] + .

[0606] Step 4: Preparation of compound 8-4

[0607] To a solution of 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (1 g, 3.266 mmol) in 1,4-dioxane (12 mL) was added (tributyltin)methanol (1.58 g, 4.899 mmol) and XPhos Pd G2 (0.26 g, 0.327 mmol) at room temperature. Under N2, the reaction mixture was stirred at 90 ° C for 18 h. The mixture was filtered through a celite pad, and the filtrate was concentrated to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 8-4. LCMS: 258.3 [M+H] + .

[0608] Step 5: Preparation of compound 8-5

[0609] To a solution of compound 8-4 (789 mg, 3.066 mmol) in DCM (10 mL) was added DMP (197.78 mg, 0.466 mmol) at 0°C, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with Na2SO3 (aq., 10 mL) and extracted with DCM (15 mL×2). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 8-5. LCMS: 256.3 [M+H] + .

[0610] Step 6: Preparation of compound 8-6

[0611] At room temperature, to a stirred solution of compound 8-5 (300 mg, 1.115 mmol) and compound 8-3 (284.67 mg, 1.115 mmol) in DMF (5 mL) and H2O (1 mL) was added potassium persulfate (Oxone) (411.24 mg, 0.669 mmol) in portions over 15 minutes. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel column chromatography to give compound 8-6. LCMS: 503.8 [M+H] + .

[0612] Step 7: Preparation of Example 8

[0613] Example 8 was synthesized according to step 5 in Example 7. LCMS: 537.3 [M+H] + ; 1 H NMR: (400 MHz, chloroform-d) δ 8.1-7.7 (m, 4H), 7.6-7.4 (m, 3H), 4.2 (s, 2H), 3.9 (s, 3H), 3.5-3.1 (m, 5H), 3.0-2.6 (m, 4H), 2.5-2.2 (m, 2H), 2.1-1.7 (m, 5H), 1.2 (d, J = 4.4 Hz, 3H), 1.0-0.8 (m, 4H).

[0614] Example 9:

[0615]

[0616] Step 1: Preparation of compound 9-1

[0617] To a solution of dimethyl 4-bromophthalate (5 g, 18.310 mmol) in 1,2-dichloroethane (50 mL) at 0°C, cesium fluoride (0.56 g, 3.662 mmol) and trimethyl(trifluoromethyl)silane (3.2 mL, 21.972 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The mixture was then partitioned between ethyl acetate (100 mL) and water (15.0 mL). The organic phase was separated, washed with brine (15.0 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide compound 9-1.

[0618] Step 2: Preparation of compound 9-2

[0619] To a solution of compound 9-1 (4 g, 12.860 mmol) in THF (5 mL) was added hydrazine hydrate (1.3 mL, 25.719 mmol) at room temperature, and the mixture was stirred at 75°C for 12 h. The mixture was concentrated to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 9-2. LCMS: 293.0 [M+H] + .

[0620] Step 3: Preparation of compound 9-3

[0621] To a mixture of compound 9-2 (300 mg, 1.024 mmol) and potassium (S)-trifluoro((3-methylpiperidin-1-yl)methyl)borate (224.30 mg, 1.024 mmol) in H2O (0.5 mL) and dioxane (5 mL) were added K3PO4 (434.60 mg, 2.048 mmol) and Ruphos Pd G4 (435.30 mg, 0.512 mmol), and the mixture was stirred at 100°C for 12 h. Then, the mixture was partitioned between ethyl acetate (100 mL) and water (15.0 mL). The organic phase was separated, washed with brine (15.0 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 9-3. LCMS: 326.2 [M+H] + ;

[0622] Step 4: Preparation of Example 9

[0623] To a solution of compound 9-3 (50 mg, 0.154 mmol), 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (47.06 mg, 0.154 mmol) in dioxane (5 mL) were added CuI (5.85 mg, 0.031 mmol), K2CO3 (42.48 mg, 0.307 mmol) and 2,5-diazahexane (5.42 mg, 0.061 mmol). Under N2, the mixture was stirred at 100 ° C. for 12 h. The mixture was concentrated under reduced pressure to give a residue, which was further purified by preparative HPLC to give Example 9. LCMS: 551.4 [M+H] + ; 1 H NMR: (400 MHz, chloroform-d) δ 8.7-8.0 (m, 4H), 7.9-7.3 (m, 4H), 4.4-4.0 (m, 2H), 3.6-3.1 (m, 5H), 3.0-2.3 (m, 6H), 2.2-1.6 (m, 5H), 1.3-1.1 (m, 3H), 1.1 (s, 1H), 0.9 (d, J = 5.4 Hz, 3H).

[0624] Embodiment 10:

[0625]

[0626] Step 1: Preparation of compound 10-1

[0627] To a solution of compound 6-3 (500 mg, 1.706 mmol) in dioxane (8 mL) was added (tributyltin)methanol (1095 mg, 3.412 mmol) and XPhos Pd G2 (8 mg, 0.010 mmol). Under N2, the reaction was stirred at 80 ° C overnight. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 10-1. LCMS: 245.0 [M+H] + .

[0628] Step 2: Preparation of compound 10-2

[0629] To a solution of compound 10-1 (200 mg, 0.819 mmol) in DCM (10 mL) was added DMP (521 mg, 1.229 mmol), and the reaction was stirred at room temperature for 2 h. The reaction was diluted with DCM (20 mL), then washed with saturated Na2SO3 (10 M), saturated NaHCO3 aqueous solution (10 mL), and brine. The organic layer was purified by flash silica gel chromatography to obtain compound 10-2. LCMS: 243.0 [M+H] + .

[0630] Step 3: Preparation of compound 10-3

[0631] To a solution of compound 10-2 (100 mg, 0.413 mmol) in dioxane (5 mL) were added 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (151.74 mg, 0.496 mmol), K2CO3 (114.14 mg, 0.826 mmol), DMEDA (14.56 mg, 0.165 mmol) and CuI (15.73 mg, 0.083 mmol). Under N2, the reaction was stirred at 100 ° C for 16 hours. The residue was purified by flash silica gel column chromatography to give compound 10-3. LCMS: 468.1 [M+H] + .

[0632] Step 4: Preparation of Example 10

[0633] To a solution of compound 10-3 (16 mg, 0.034 mmol) in DCE (2 mL) was added CH COONa (3 mg, 0.041 mmol) and AcOH (one drop). The mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (21 mg, 0.103 mmol) was added to the mixture, and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give a residue, which was further purified by preparative HPLC to give Example 10. LCMS: 553.2 [M+H] + ; 1 H NMR: (400 MHz, chloroform-d) δ 8.63 (s, 1H), 8.56 (s, 1H), 8.26 (s, 1H), 7.70 (s, 1H), 7.58-7.34 (m, 4H), 3.93-3.65 (m, 5H), 3.26 (s, 3H), 2.92-2.64 (m, 6H), 2.38-1.99 (m, 3H), 1.18-1.09 (m, 6H).

[0634] Example 11:

[0635]

[0636] Step 1: Preparation of compound 11-1

[0637] According to the method of Example 4, Example 11 was synthesized using compound 4-2 (300 mg, 1.345 mmol) and (2R)-2-methyl-1,4-oxaziridine (136.00 mg, 1.345 mmol) as substrates. LCMS: 542.2 [M+H] + ; 1HNMR: (400MHz, DMSO-d6) δ8.40-8.29(m,2H),8.08-7.97(m,1H),7.89-7.82 (m,2H),7.69-7.47(m,2H),3.83-3.64(m,3H),3.61-3.48(m,2H),3.26-3.1 9(m,3H),2.98-2.87(m,2H),2.77-2.56(m,4H),2.39-2.26(m,1H),2.18-2. 06(m,1H),1.83(t,J=10.7Hz,1H),1.15-1.08(m,3H),1.04(d,J=6.2Hz,3H).

[0638] Example 12:

[0639]

[0640] Step 1: Preparation of compound 12-1

[0641] To a solution of 7-bromoisoquinolin-1(2H)-one (1 g, 4.463 mmol) in THF (20 mL) was added potassium 2-methylpropan-2-olate (in THF, 4.9 mL, 4.909 mmol) at 0 ° C. The solution was stirred for 20 minutes. Then, 1-chloro-2,5-dioxane (0.56 g, 4.463 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 40 minutes. The mixture was concentrated in vacuo to give a residue, which was further purified by flash silica gel chromatography to give compound 12-1.

[0642] Step 2: Preparation of compound 12-2

[0643] To a solution of compound 12-1 (1.4 g, 4.485 mmol) in MeCN (10 mL) were added [bis(trifluoroacetoxy)iodo]benzene (5.81 g, 13.455 mmol), copper acetate (0.45 g, 2.242 mmol), potassium fluoride (0.78 g, 13.455 mmol) and trimethyl(trifluoromethyl)silane (3.0 mL, 20.182 mmol). The resulting mixture was stirred at 40 ° C for 12 h. Then, the mixture was partitioned between ethyl acetate (100 mL) and water (15.0 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue, which was further purified by flash silica gel chromatography to give compound 12-2. LCMS: 380.1 [M+H] + .

[0644] Step 3: Preparation of compound 12-3

[0645] To a solution of compound 12-2 (200 mg, 0.526 mmol) and (S)-trifluoro((3-methylpiperidin-1-yl)methyl)borate potassium (115.27 mg, 0.526 mmol) in H2O (0.5 mL) and dioxane (5 mL) were added Ruphos Pd G4 (50.61 mg, 0.053 mmol) and Cs2CO3 (514.24 mg, 1.578 mmol). The resulting mixture was stirred at 90 ° C for 18 h. Then, the mixture was partitioned between ethyl acetate (100 mL) and water (20.0 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to give a residue. The residue was purified by flash silica gel column chromatography to give compound 12-3. LCMS: 413.3 [M+H] + .

[0646] Step 4: Preparation of compound 12-4

[0647] A mixture of compound 12-3 (200 mg, 0.485 mmol) in H2SO4 (1 mL) was stirred at 90°C for 5 h. The mixture was concentrated in vacuo to give the crude compound 12-4, which was used in the next step without further purification. LCMS: 325.3 [M+H] + .

[0648] Step 5: Preparation of Example 12

[0649] To a solution of compound 12-4 (30 mg, 0.092 mmol) and 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (28.32 mg, 0.092 mmol) in dioxane (1 mL) were added K2CO3 (25.43 mg, 0.184 mmol), CuI (3.50 mg, 0.018 mmol) and DMEDA (3.24 mg, 0.037 mmol). Under N2, the mixture was stirred at 120 ° C. for 12 h. The mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to give Example 12. LCMS: 550.4 [M+H] + ; 1H NMR: (400 MHz, chloroform-d) δ 8.38 (s, 1H), 8.09-7.81 (m, 2H), 7.64 (s, 1H), 7.55-7.21 (m, 5H), 3.78-3.48 (m, 2H), 3.37-3.22 (m, 3H), 2.98-2.60 (m, 6H), 2.13-1.61 (m, 7H), 1.15 (d, J = 4.7 Hz, 3H), 0.96-0.89 (m, 1H), 0.85 (d, J = 5.8 Hz, 3H).

[0650] Example 13:

[0651]

[0652] To a solution of compound 6-4 (30 mg, 0.092 mmol) in dioxane (2 mL) was added 3-((3-(3-bromophenyl)oxetan-3-yl)methyl)-4-methyl-4H-1,2,4-triazole (28 mg, 0.092 mmol), K2CO3 (25.49 mg, 0.184 mmol), DMEDA (4.06 mg, 0.046 mmol) and CuI (3.51 mg, 0.018 mmol). Under N2, the reaction was stirred at 100 ° C. for 16 h. The residue was purified by preparative HPLC to give Example 13. LCMS: 553.2 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ8.54(s,2H),8.33-8.26(m,1H),8.22(s,1H),7.55-7.38(m,2H),7.22(s,1H),7.01(s,1H),4.95( d,J=6.1Hz,2H),4.86(d,J=6.0Hz,2H),3.51(s,2H),2.95(s,3H),2.79-2.43(m,6H),1.76-1.53(m,4H),0.97-0.76(m,4H).

[0653] Example 14 & 15:

[0654]

[0655] Step 1: Preparation of compound 14-1

[0656] To a solution of 1-benzyl-3-methylpiperidin-4-one (5 g, 24.597 mmol) in DCM (50 mL) was added DAST (16.2 mL, 122.983 mmol) at room temperature. The resulting solution was heated to 40 ° C and stirred for 14 h. After cooling to room temperature, the reaction mixture was added dropwise to ice water (100 mL), followed by the addition of saturated aqueous NaHCO 3 solution (20 mL). The resulting mixture was extracted with DCM (3×100 mL), and the combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4, filtered, and concentrated under reduced pressure to give a residue, which was further purified by silica gel chromatography to give compound 14-1. LCMS: 226.2 [M+H] + .

[0657] Step 2: Preparation of compound 14-2

[0658] To a solution of compound 14-1 (0.9 g, 3.995 mmol) in MeOH (20 mL) was added Pd / C (1.28 g) and 1,1,2-trichloroethane (2.66 g, 19.975 mmol). The reaction was stirred at room temperature under H2 for 12 h. The reaction mixture was concentrated under reduced pressure to give compound 14-2. LCMS: 136.0 [M+H] + .

[0659] Step 3: Preparation of compound 14-3

[0660] To a solution of compound 14-2 (500 mg, 3.329 mmol) in THF (20 mL) was added potassium (bromomethyl)trifluoroborate (193.16 mg, 0.962 mmol), KHCO (787.49 mg, 7.866 mmol), and KI (43.53 mg, 0.262 mmol). The reaction was stirred at 80° C. for 4 h. The reaction mixture was concentrated to give compound 14-3, which was used directly in the next step.

[0661] Step 4: Preparation of compound 14-4

[0662] To a solution of compound 6-3 (200 mg, 0.683 mmol) in dioxane / water (5 mL, 4:1) were added Cs2CO3 (444 mg, 1.365 mmol), compound 14-3 (174 mg, 0.683 mmol) and Ruphos Pd G4 (6 mg, 0.007 mmol). The resulting mixture was stirred at 100 ° C for 16 h. The residue was purified by silica gel chromatography to give compound 14-4. LCMS: 362.0 [M+H] + ;

[0663] Step 5: Preparation of compound 14-4a / 14-4b

[0664] By preparative SFC ( Compound 14-4 was further separated on an IG (250×25 mm, 10 μm) column using a mobile phase (A: supercritical CO 2 ; B: MEOH (+0.1% 7.0 mol / l ammonia in MEOH solution); A / B=90 / 10) at a flow rate of 80 mL / min at room temperature and a pressure setting of 100 bar to obtain compound 14-4a (6.72 minutes) and compound 14-4b (7.9 minutes). LCMS: 362.0 [M+H] + .

[0665] Step 6: Preparation of Example 14 and Example 15

[0666] Under N2, a solution of compound 14-4a (20 mg, 0.055 mmol), 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (16 mg, 0.055 mmol), K2CO3 (22 mg, 0.166 mmol), DMEDA (2 mg, 0.022 mmol) and CuI (2.5 mg, 0.011 mmol) in dioxane (3 mL) was stirred at 100 ° C. for 16 h. The mixture was purified by preparative HPLC to give Example 14. LCMS: 587.2 [M+H] + ; 1 H NMR: (400MHz, chloroform-d) δ8.62(s,1H),8.56(s,1H),8.18(s,1H),8.06-7.91(m,1H),7.70(s,1H),7.58-7.43(m,2H),7.37(d,J=7.6Hz,1H),3.7 4(s,2H),3.36-3.16(m,3H),2.90(s,2H),2.77(s,1H),2.69(d,J=5.8Hz,4H),2.47-1.99(m,5H),1.24-1.09(m,3H),1.01(d,J=5.8Hz,3H).

[0667] Example 15 was synthesized using compound 14-4b as a substrate according to a method similar to that of Example 14. LCMS: 587.2 [M+H] + ; 1H NMR: (400MHz, chloroform-d) δ8.62(s,1H),8.56(s,1H),8.18(s,1H),8.07-7.92(m,1H),7.70(s,1H),7.60-7.43(m,2H),7.37(d,J=7.9Hz,1H),3.74(s ,2H),3.33-3.14(m,3H),2.96-2.82(m,2H),2.82-2.74(m,1H),2.74-2. 63(m,4H),2.46-1.94(m,5H),1.25-1.08(m,3H),1.01(d,J=5.9Hz,3H).

[0668] Example 16:

[0669]

[0670] Step 1: Preparation of compound 16-1

[0671] To a solution of 3-((3-(3-bromophenyl)oxetan-3-yl)methyl)-4-methyl-4H-1,2,4-triazole (150 mg, 0.487 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (247.20 mg, 0.973 mmol), and KOAc (95.54 mg, 0.973 mmol) in dioxane (3 mL) was added Pd(dppf)Cl2 (35.61 mg, 0.049 mmol). The mixture was stirred at 80°C under N2 for 16 h. The reaction mixture was cooled to room temperature, quenched with water (5 mL), and extracted with dichloromethane (10 mL x 2). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by preparative TLC to give compound 16-1. LCMS: 356.0 [M+H] + .

[0672] Step 2: Preparation of Example 16

[0673] To a solution of compound 4-6 (9.82 mg, 0.028 mmol) and compound 16-1 (20 mg, 0.059 mmol) in dioxane (1 mL) and H 2 O (0.2 mL) were added K 2 CO 3 (7.78 mg, 0.056 mmol) and Pd (dppf) Cl 2 (2.06 mg, 0.003 mmol). Under a nitrogen atmosphere, the mixture was stirred at 80 ° C for 12 h. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC to give Example 16. LCMS: 542.2 [M+H] + ;1 H NMR: (400 MHz, chloroform-d) δ 8.30 (s, 1H), 8.03-7.80 (m, 2H), 7.78-7.62 (m, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.05-6.89 (m, 1H), 5.31-5.01 (m, 4H), 3.62 (s, 2H), 2.93 (s, 3H), 2.00-1.70 (m, 5H), 1.34-1.17 (m, 4H), 0.98-0.78 (m, 5H).

[0674] Example 17:

[0675]

[0676] Step 1: Preparation of compound 17-1

[0677] To a solution of 4-bromo-2-nitro-6-(trifluoromethyl)aniline (500 mg, 1.754 mmol) in EtOH (5 mL) and EA (2.5 mL) was added stannous chloride dihydrate (427.48 mg, 1.895 mmol) under N2 at 25°C. The reaction was stirred at 70°C for 3 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by reverse phase column chromatography to give compound 17-1. LCMS: 254.0 [M+H] + .

[0678] Step 2: Preparation of Example 17

[0679] According to the method of Example 8, using compound 17-1 and compound 8-5 as substrates, Example 17 was synthesized. LCMS: 523.0 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ8.41-8.26(m,1H),8.23-7.98(m,2H),7.71(s,1H),7.58-7.27(m,3H),3.60(s,2H),3.21-3.14(m,4H),2.97-2.86(m,2H ),2.74(t,J=7.9Hz,2H),2.62-2.53(m,3H),1.90(t,J=10.7Hz,1H),1.7 1-1.54(m,4H),1.53-1.41(m,1H),1.16-1.06(m,3H),0.91-0.77(m,4H).

[0680] Examples 18 and 19:

[0681]

[0682] To a solution of compound 6-4 (50 mg, 0.154 mmol), K2CO3 (42.48 mg, 0.307 mmol), 3-((3-bromophenyl)(cyclobutyl)methyl)-4-methyl-4H-1,2,4-triazole (70.59 mg, 0.231 mmol) in 1,4-dioxane (2 mL) were added 2,5-diazahexane (5.42 mg, 0.061 mmol) and CuI (5.85 mg, 0.031 mmol). Under a N2 atmosphere, the mixture was stirred at 100 ° C for 16 h. The mixture was concentrated to give a residue. The residue was purified by preparative HPLC to give the expected compound, which was further separated by SFC to give Examples 18 and 19. Chiral SFC analysis was performed according to the following conditions: The column was loaded with 1B (100×3.0 mm, 3.0 μm) and eluted with mobile phase (A: supercritical CO 2 ; B: MeOH (0.1% DEA); 40% B for 8 minutes) at a flow rate of 1.5 mL / min at 35° C. and the pressure was set to 1800 psi.

[0683] Example 18:

[0684] LCMS: 551.6 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ8.54(d,J=6.6Hz,2H),8.34(s,1H),8.26(s,1H),7.54-7.43(m,3H),7.33(d,J=7.2Hz,1H),4.29(d,J=10.4Hz,1H), 3.73(s,2H),3.44(s,3H),3.23-3.11(m,1H),2.76-2.66(m,2H),2.15- 1.95(m,2H),1.83-1.41(m,6H),1.29-1.18(m,4H),0.88-0.78(m,4H). t R = 4.40 min; chiral purity: 99.9%.

[0685] Example 19:

[0686] LCMS: 551.6 [M+H] + ; 1H NMR: (400MHz, DMSO-d6) δ8.53(d,J=6.3Hz,2H),8.34(s,1H),8.26(s,1H),7.55-7.43(m,3H),7.36-7.31(m,1H),4.29(d,J=10.4Hz,1H),3.73(s ,2H),3.44(s,3H),3.21-3.14(m,1H),2.70(d,J=21.7Hz,2H),2.03(d,J =46.9Hz,2H),1.85-1.42(m,6H),1.28-1.19(m,4H),0.87-0.78(m,4H). t R = 4.65 minutes; chiral purity: 99.9%.

[0687] Example 20:

[0688]

[0689] To a solution of compound 10-3 (30 mg, 0.064 mmol) and 3-ethynylpiperidinium chloride (11.18 mg, 0.077 mmol) in MeOH (1 mL) and DCM (1 mL) was added AcOH (1 drop). The mixture was stirred at room temperature for 0.5 h, and then 2-methylpyridine borane (10.27 mg, 0.096 mmol) was added. The reaction mixture was then stirred at room temperature for 16 h. The mixture was further purified by preparative HPLC to give Example 20. LCMS: 561.4 [M+H] + ; 1 H NMR: (400 MHz, chloroform-d) δ 8.73-8.45 (m, 2H), 8.14-7.92 (m, 1H), 7.73-7.26 (m, 5H), 3.97-3.39 (m, 2H), 3.36-3.07 (m, 4H), 3.01-2.55 (m, 7H), 2.44-1.67 (m, 7H), 1.18-1.11 (m, 3H).

[0690] Example 21:

[0691]

[0692] Example 21 was synthesized according to a method similar to Example 20. LCMS: 549.2 [M+H] + ; 1H NMR: (400MHz, chloroform-d) δ8.64(s,1H),8.56(s,1H),8.37(s,1H),8.06-7.96(m,1H),7.72-7.45(m,3H),7.36(d,J=7.8Hz,1H),5.52(s,1H),4 .07-3.75(m,2H),3.35-3.13(m,4H),3.06-2.79(m,4H),2.73-2.62(m,4H),2.33-2.18(m,2H),1.68-1.56(m,3H),1.14(t,J=5.4Hz,3H).

[0693] Example 22:

[0694]

[0695] Step 1: Preparation of compound 22-1

[0696] To a solution of piperidine hydrochloride (714.09 mg, 5.872 mmol) in THF (10 mL) was added potassium (bromomethyl)trifluoroborate (1179.10 mg, 5.872 mmol), K2CO3 (1623.02 mg, 11.744 mmol), and KI (97.48 mg, 0.587 mmol). The mixture was stirred at 80 ° C for 4 h. The solid was removed by filtration, and the filtrate was concentrated to give compound 22-1, which was used directly in the next step.

[0697] Step 2: Preparation of compound 22-2

[0698] To a solution of compound 22-1 (400 mg, 1.952 mmol), 7-bromo-5-(trifluoromethyl)phthalazin-1(2H)-one (160 mg, 0.546 mmol) and Cs2CO3 (533.69 mg, 1.638 mmol) in dioxane (5 mL) and H2O (1 mL) were added Pd(OAc)2 (12.26 mg, 0.055 mmol) and butyldi-1-adamantylphosphine (19.58 mg, 0.055 mmol). The resulting mixture was stirred at 90 ° C for 16 h. The mixture was concentrated to give a residue, which was purified by reverse phase chromatography to give compound 22-2. LCMS: 312.1 [M+H] + .

[0699] Step 3: Preparation of Example 22

[0700] To a solution of compound 22-2 (50 mg, 0.161 mmol) in dioxane (2 mL) were added DMEDA (56.63 mg, 0.642 mmol), K2CO3 (44.39 mg, 0.321 mmol), 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole (49.18 mg, 0.161 mmol) and CuI (30.59 mg, 0.161 mmol). Under N2 atmosphere, the mixture was stirred at 100 ° C. for 16 h. The residue was purified by preparative HPLC to give Example 22. LCMS: 537.3 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ8.83-8.18(m,4H),7.64-7.33(m,4H),3.99-3.44(m,2H),3.27- 3.20(m,3H),2.92-2.76(m,2H),2.68-2.24(m,6H),1.80-1.34(m,7H),1.15-0.98(m,3H).

[0701] Example 23:

[0702]

[0703] Step 1: Preparation of compound 23-1

[0704] To a solution of methyl 2-methyl-3-(trifluoromethyl)benzoate (5 g, 22.917 mmol) in AcOH (50 mL) was added Br2 (1.4 mL, 25.209 mmol), HNO3 (9.6 mL, 229.169 mmol), and AgNO3 (5.06 g, 29.792 mmol). The reaction was stirred at room temperature overnight. The reaction was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated, washed with saturated NaCl solution (3 × 50 mL), dried, filtered, and concentrated to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 23-1.

[0705] Step 2: Preparation of compound 23-2

[0706] To a solution of compound 23-1 (4.2 g, 14.138 mmol) in DMF (40 mL) was added (dimethylamino)dimethoxymethane (5.05 g, 42.414 mmol). The reaction mixture was stirred at 110°C overnight. The reaction was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with saturated NaCl solution (3 × 50 mL), dried, filtered, and concentrated to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 23-2.

[0707] Step 3: Preparation of compound 23-3

[0708] To a solution of 7-bromo-5-(trifluoromethyl)-1H-isochromene-1-one (200 mg, 0.683 mmol) in MeOH (2 mL) was added methanolic ammonia solution (0.20 mL, 1.433 mmol). The reaction mixture was stirred at 60 ° C overnight. Then, the mixture was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with saturated NaCl solution (3×50 mL), dried, filtered and concentrated to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 23-3. LCMS: 291.0 [MH] - .

[0709] Step 4: Preparation of Example 23

[0710] According to the method in Example 1, using compound 23-3 and (S)-trifluoro((3-methylpiperidin-1-yl)methyl)borate potassium as substrates, Example 23 was synthesized. LCMS: 550.3 [M+H] + ; 1 H NMR: (400 MHz, chloroform-d) δ 8.81-8.56 (m, 2H), 8.21 (s, 1H), 7.63-7.48 (m, 2H), 7.44 (s, 1H), 7.40-7.29 (m, 2H), 6.89 (d, J = 7.7 Hz, 1H), 4.37-4.27 (m, 2H), 3.63 (s, 1H), 3.55-3 .15(m,4H),3.02-2.75(m,2H),2.73-2.46(m,3H),2.41-2.19(m,1H),2.14-1.71(m, 4H), 1.37-1.23 (m, 1H), 1.26-1.10 (m, 3H), 1.08-0.98 (m, 1H), 0.94 (d, J = 6.4Hz, 3H).

[0711] Example 24:

[0712]

[0713] Step 1: Preparation of compound 24-1

[0714] Under N2 atmosphere, K2CO3 (21.53 g, 155.817 mmol) and 3-bromopropan-1-ol (14 mL, 156 mmol) were added to a solution of methyl 5-bromo-2-hydroxybenzoate (24 g, 103.878 mmol) in dry DMF (240 mL). The mixture was stirred at 60 ° C for 4 h. The reaction solution was quenched by pouring it into 100 mL of saturated NH4Cl, and then the mixture was diluted with 100 mL of EtOAc. The aqueous phase was extracted four times with EtOAc (150 mL×3). The combined organic phase was washed with 150 mL of brine, dried, filtered to remove the solid and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain compound 24-1. LCMS: 288.8 [M+H] + .

[0715] Step 2: Preparation of compound 24-2

[0716] To a solution of compound 24-1 (15 g, 51.880 mmol) in MeCN (150 mL) were added water (12.5 mL), TEMPO (2.43 g, 15.564 mmol), and (diacetoxyiodo)benzene (50.44 g, 155.639 mmol). The reaction mixture was stirred at room temperature for 3 h. Upon completion, 2-methyl-2-butene (181.94 g, 2593.989 mmol), water (12.5 mL), and NaH2PO4 (62.23 g, 518.798 mmol) were added, respectively. The resulting mixture was cooled to 0°C, and then NaClO2 (37.54 g, 415.038 mmol) was added. The reaction was stirred vigorously at 0°C for 1 h. The reaction was quenched by pouring into 1100 mL of saturated Na2S2O3. The aqueous layer was extracted with EA (1500 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over anhydrous Na2SO4 and concentrated to give a residue. The residue was purified by silica gel chromatography to give compound 24-2. LCMS: 300.8 [MH] - .

[0717] Step 3: Preparation of compound 24-3

[0718] A mixture of compound 24-2 (2 g, 6.598 mmol) in chlorosulfonic acid (12 mL, 0.759 mmol) was stirred at 0°C for 1 h. The resulting mixture was quenched by pouring it into ice water. The mixture was extracted with DCM (25 mL x 3). The combined organic layers were washed with brine (25 mL), dried over anhydrous Na2SO4, and concentrated to obtain a residue. The residue was purified by silica gel chromatography to obtain compound 24-3. LCMS: 284.9 [M+H] + .

[0719] Step 4: Preparation of compound 24-4

[0720] To a solution of compound 24-3 (680 mg, 2.385 mmol) in DCM (10 mL) was added ethane-1,2-dithiol (562 mg, 5.962 mmol) and boron trifluoride etherate (846 mg, 5.963 mmol). The mixture was stirred at room temperature for 16 h. The aqueous layer was extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated to obtain a residue. The residue was purified by silica gel chromatography to obtain compound 24-4. LCMS: 360.7 [M+H] + .

[0721] Step 5: Preparation of compound 24-5

[0722] A mixture of NIS (423 mg, 1.882 mmol) in DCM (5 mL) was cooled to -78 ° C, and then a solution of HF-Py (373 mg, 3.764 mmol) and compound 24-4 (340 mg, 0.941 mmol) in DCM (5 mL) was added. The reaction was stirred at -78 ° C for 1 h, then warmed to 0 ° C and stirred for another 30 minutes. The residue was purified by silica gel chromatography to give compound 24-5. LCMS: 306.8 [M+H] + .

[0723] Step 6: Preparation of compound 24-6

[0724] To a solution of compound 24-5 (190 mg, 0.619 mmol) in dioxane (6 mL) and H 2 O (1.5 mL) were added (S)-3-methyl-1-((trifluoro-14-boryl)methyl)piperidinium potassium salt (407 mg, 1.856 mmol), Cs 2 CO 3 (605 mg, 1.856 mmol) and RuPhos Pd G 4 (53 mg, 0.062 mmol), and the resulting mixture was stirred at 90° C. under a nitrogen atmosphere for 16 h. The residue was purified by reverse phase column chromatography to give compound 24-6. LCMS: 340.5 [M+H]+ .

[0725] Step 7: Preparation of compound 24-7

[0726] To a solution of compound 24-6 (130 mg, 0.383 mmol) in MeOH (2 mL) and H2O (0.5 mL) was added NaOH (45.97 mg, 1.149 mmol). The mixture was stirred at room temperature for 16 h. The mixture was acidified to pH = 6 with 2N HCl and then concentrated to obtain a residue. The residue was purified by reverse phase column chromatography to obtain compound 24-7. LCMS: 326.3 [M+H] + .

[0727] Step 8: Preparation of Example 24

[0728] To a solution of compound 24-7 (80 mg, 0.246 mmol) and 3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline (60 mg, 0.246 mmol) in pyridine (2 mL) was added EDCI (71 mg, 0.369 mmol). The mixture was stirred at room temperature for 2 h. The residue was purified by preparative HPLC to give Example 24. LCMS: 550.5 [M+H] + ; 1 HNMR: (400MHz, DMSO-d6) δ10.19(d,J=7.0Hz,1H),9.39-7.36(m,5H),7.32(q,J=7.7,7.0Hz,1H),7.12-6.76(m,1H),4.51-4.37(m,2H),3. 44(s,2H),3.31(s,3H),3.25-3.05(m,3H),2.79-2.62(m,3H),2.36-2 .13(m,2H),2.01-1.32(m,7H),1.14-1.04(m,3H),0.91-0.77(m,4H).

[0729] Example 25:

[0730]

[0731] Step 1: Preparation of compound 25-1

[0732] A mixture of 2,2-difluorobenzo[d][1,3]dioxolane-4-carboxylic acid (500 mg, 2.474 mmol) in H2SO4 (2.5 mL) was added to HNO3 (0.25 mL) and stirred at 0°C for 3 h. After completion, the mixture was poured into ice water. The organic phase was separated, washed with water (10 mL), dried, and filtered to give compound 25-1, which was used in the next step without further purification. LCMS: 248.0 [M+H] + ;

[0733] Step 2: Preparation of compound 25-2

[0734] To a solution of compound 25-1 (200 mg, 0.809 mmol) in DMF (5 mL) was added iodomethane (0.2 mL) and KCO (335.56 mg, 2.428 mmol) under N₂. The mixture was stirred at room temperature for 2 h. The mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 25-2. 1 H NMR (400MHz, CDCl3) δ 8.69 (d, J = 2.3 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 4.03 (s, 3H).

[0735] Step 3: Preparation of compound 25-3

[0736] A mixture of compound 25-2 (2 g, 7.659 mmol), Fe (4.28 g, 76.587 mmol) and NH4Cl (4.1 g, 76.587 mmol) in EtOH (20 mL) and H2O (5 mL) was stirred at 80°C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to remove the solvent to give compound 25-3, which was used in the next step without further purification. LCMS: 232.1 [M+H] + ; Step 4: Preparation of compound 25-4

[0737] To a solution of compound 25-3 (980 mg, 4.240 mmol) in H2SO4 (0.2 mL) and H2O (5 mL) was added a mixture of sodium nitrite (438.74 mg, 6.360 mmol) in H2O (5 mL). The resulting mixture was stirred at 0°C for 1 hour. After adding a mixture of potassium iodide (2.1 g, 12.719 mmol) in H2O (5 mL), the mixture was stirred at 80°C for another 15 minutes. The mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 25-4. 1 H NMR (400MHz, CDCl3) δ8.02 (d, J = 1.7 Hz, 1H), 7.54 (d, J = 1.7 Hz, 1H), 3.97 (s, 3H).

[0738] Step 5: Preparation of Example 25

[0739] According to the method in Example 24, using compound 25-4 as a substrate, Example 25 was synthesized. LCMS: 536.4 [MH] -；1 H NMR: (400MHz, chloroform-d) δ8.26(s,1H),7.96(s,1H),7.83(s,1H),7.76(s,1H),7.51(d,J=8.0Hz,1H),7.40-7.31(m,2H),7.11(d,J=7.7H z,1H),3.51(s,2H),3.23(s,3H),2.95-2.83(m,2H),2.79-2.60(m,4H),2.04-1.54(m,7H),1.15(d,J=5.4Hz,3H),0.94-0.80(m,4H).

[0740] Examples 26 and 27:

[0741]

[0742] Step 1: Preparation of compound 26-1

[0743] At 25 ° C, under N2, 3-iodooxetane (471.33 mg, 2.562 mmol) and potassium 2-methylpropan-2-ol (373.71 mg, 3.330 mmol) were added to a solution of methyl 2-(3-nitrophenyl)acetate (500 mg, 2.562 mmol) in DMF (10 mL) at 25 ° C. The mixture was stirred at 25 ° C. for 1 hour. At 0 ° C., the mixture was added dropwise to an aqueous solution of NH4Cl (30 mL) over 10 minutes while stirring. The aqueous layer was extracted with ethyl acetate (40 mL×3). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel chromatography to give compound 26-1. LCMS: 252.0 [M+H] + .

[0744] Step 2: Preparation of compound 26-2

[0745] To a solution of compound 26-1 (570 mg, 2.269 mmol) in EtOH (2 mL) was added hydrazine hydrate (0.772 mL, 15.881 mmol). The mixture was then stirred at 60 ° C for 12 h. The mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash silica gel column chromatography to obtain compound 26-2. 1 H NMR: (400MHz, CDCl3) δ8.16(d,J=7.9Hz,2H),7.67(d,J=7.6Hz,1H),7.54(t,J=7.7Hz,1 H),7.15(s,1H),5.01-4.54(m,2H),4.50-4.22(m,2H),3.97-3.85(m,3H),3.48(s,1H).

[0746] Step 3: Preparation of compound 26-3

[0747] To a solution of compound 26-2 (356 mg, 1.417 mmol) in THF (10 mL) was added methyl isothiocyanate (414.38 mg, 5.668 mmol). The mixture was stirred at 80°C for 2 h. The reaction mixture was filtered and concentrated under reduced pressure to give compound 26-3, which was used directly in the next step. LCMS: 325.2 [M+H] + .

[0748] Step 4: Preparation of compound 26-4

[0749] Compound 26-3 (459 mg, 1.415 mmol) was added to a solution of KOH (397.00 mg, 7.075 mmol) in H2O (2 mL). The mixture was stirred at 25 ° C for 12 h. The reaction mixture was partitioned between dichloromethane (15 mL) and H2O (6 mL). The pH of the aqueous layer was adjusted to 5-7 by 1M HCl (aq). The mixture was extracted with dichloromethane (20 ml × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 26-4. LCMS: 307.0 [M+H] + .

[0750] Step 5: Preparation of compound 26-5

[0751] To a solution of compound 26-4 (315 mg, 1.028 mmol) in ethanol (10 mL) was added Raney-Ni at room temperature. The mixture was then stirred at 78°C for 40 minutes. The mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 26-5. LCMS: 267.1 [M+Na] + .

[0752] Step 6: Preparation of compound 26-6

[0753] After preparing compound 26-5, according to the method of Example 24, methyl 3-bromo-5-(trifluoromethyl)benzoate (200 mg, 0.707 mmol) was used as a substrate to synthesize Example 26 and Example 27. Chiral SFC analysis was performed under the following conditions: OD (250 × 4.6 mm, 4.0 μm) column, eluted with mobile phase (A: supercritical CO2; B: MeOH (0.1% DEA); gradient: 5% B for 0.5 min, then from 5% to 40% B in 5 min, then 40% B for 2.5 min), with a flow rate of 1.5 mL / min, at 35 ° C, and the pressure was set to 1800 psi.

[0754] Example 26:

[0755] LCMS: 528.2 [M+H] + ; 1H NMR: (400 MHz, chloroform-d) δ 8.64 (s, 1H), 8.22-7.95 (m, 3H), 7.89 (d, J = 7.5 Hz, 1H), 7.73 (s, 1H), 7.58-7.32 (m, 2H), 7.00 (s, 1H), 5.01 (t, J = 6.7 Hz, 1H), 4.69 (t, J = 6.7 Hz, 1H) ,4.61-4.49(m,1H),4.42(d,J=11.0Hz,1H),4.35-4.26(m,1H),4.08-3.95(m,1H), 3.67(s,2H),3.40(s,3H),3.14-2.70(m,2H),1.93-0.97(m,6H),0.98-0.74(m,4H). t R = 3.64 minutes; chiral purity: 100%.

[0756] Example 27:

[0757] LCMS: 528.2 [M+H] + ; 1 H NMR: (400 MHz, chloroform-d) δ 8.86 (s, 1H), 8.12 (s, 1H), 8.04-7.87 (m, 3H), 7.74 (s, 1H), 7.49-7.33 (m, 2H), 7.03 (d, J = 6.8 Hz, 1H), 5.00-4.95 (m, 1H), 4.69 (t, J = 6.7 Hz, 1H), 4.59-4.48(m,1H),4.41(d,J=10.9Hz,1H),4.32-4.21(m,1H),4.12-3.90(m,1H),3 .61(s,2H),3.40(s,3H),2.97-2.65(m,2H),2.09-1.19(m,6H),0.97-0.78(m,4H). t R = 4.15 minutes; chiral purity: 99.0%.

[0758] Examples 28 and 29:

[0759]

[0760] Step 1: Preparation of compound 28-1

[0761] A mixture of 5-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (200.0 mg, 696.8 μmol), 3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline (185.7 mg, 766.5 μmol), HATU (291.5 mg, 766.5 μmol) and DIEA (270.2 mg, 2.09 mmol, 364.1 μL) in DCM (5 mL) was degassed and bubbled with N2 three times, and then the mixture was stirred at 25 ° C. under N2 atmosphere for 16 h. The reaction mixture was concentrated under reduced pressure to remove DCM. The residue was purified by flash silica gel column chromatography to give compound 28-1. LCMS: 513.1 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ10.64-10.74(m,1H)8.30-8.40(m,1H)8.15-8.24(m,2H)7.64-7.75(m,1H)7.31-7.56 (m,2H)6.98-7.20(m,1H)3.57-3.69(m,2H)3.40-3.50(m,1H)3.10-3.22(m,5H)1.08(dd,J=10.51,6.75Hz,3H)

[0762] Step 2: Preparation of Examples 28 and 29

[0763] A mixture of compound 28-1 (150.0 mg, 293.4 μmol), (S)-trifluoro((3-methylpiperidin-1-yl)methyl)borate potassium (105.6 mg, 586.7 μmol), PdCl2(dtbpf) (9.56 mg, 14.7 μmol) and K3PO4 (124.5 mg, 586.7 μmol) in dioxane (5 mL) and H2O (1 mL) was degassed and bubbled with N2 3 times, and then the mixture was stirred at 90 ° C. under N2 atmosphere for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give a mixture, which was further separated by SFC to give Examples 28 and 29. Chiral SFC analysis was performed according to the following conditions: OJ (100 × 3.0 mm, 3.0 μm) column, eluted with mobile phase (A: supercritical CO2; B: MeOH (0.1% DEA); gradient: 5% B for 0.5 min, then from 5% to 40% B in 5 min, then 40% B for 2.5 min), with a flow rate of 1.5 mL / min, at 35 ° C, and the pressure was set to 1800 psi.

[0764] Example 28:

[0765] LCMS: 544.3 [M+H] + ; 1 H NMR: (400MHz, CDCl3) δ8.32(s,1H),7.95(s,1H),7.80(d,J=5.1Hz,1H),7.79-7.49(m,2H),7.40-7.27(m,2H),7.11(d,J=7.9Hz,1H),3.58(s,2H), 3.22(s,3H),2.88(dd,J=10.1,6.6Hz,2H),2.70-2.58(m,3H),2.39-1.87 (m,2H),1.84-1.60(m,6H),1.14(d,J=5.3Hz,3H),0.87(d,J=4.1Hz,4H). t R = 1.88 minutes; chiral purity: 96.0%.

[0766] Example 29:

[0767] LCMS: 544.4 [M+H] + ; 1 H NMR: (400MHz, CDCl3) δ8.27 (s, 1H), 8.02 (s, 1H), 7.81 (d, J = 5.3Hz, 1H), 7.59 (d, J=7.7Hz,1H),7.53(d,J=8.2Hz,1H),7.32(dd,J=15.2,7.2Hz,2H),6.99(d,J=8.2 Hz,1H),3.56(s,2H),3.26(s,3H),3.20-3.09(m,2H),2.91-2.46(m,3H),2.32(t ,J=10.6Hz,2H),2.05-1.64(m,6H),1.13(d,J=6.6Hz,3H),0.86(d,J=5.4Hz,4H). t R = 2.20 min; chiral purity: 100%.

[0768] Example 30:

[0769]

[0770] According to Example 28, using 3-bromo-5-(trifluoromethyl)benzoic acid as a substrate, Example 30 was synthesized. LCMS: 526.4 [M+H] + ; 1H NMR: (400MHz, DMSO-d6) δ10.45(s,1H),8.38(s,1H),8.15(d,J=10.38Hz,2H),7.84(s,1H),7.74( d,J=8.13Hz,1H),7.51(s,1H),7.36(t,J=7.94Hz,1H),6.98(d,J=7.25Hz,1H),3.60(s,2H),3.22( s,3H),3.06-3.15(m,2H),2.68-2.76(m,2H),2.32-2.47(m,2H),2.15-2.30(m,2H),1.92(t,J=10 .38Hz,1H),1.54-1.70(m,4H),1.44-1.53(m,1H),1.10(d,J=6.50Hz,3H),0.82(d,J=6.00Hz,3H).

[0771] Example 31:

[0772]

[0773] Step 1: Preparation of compound 31-1

[0774] To a solution of methyl 2-(3-bromophenyl)acetate (2.00 g, 8.73 mmol) in DMF (20 mL) was added t-BuOK (1.27 g, 11.35 mmol) at 0°C. The mixture was stirred at 0°C for 30 minutes, and then iodocyclobutane (1.41 g, 10.5 mmol, 989.1 μL) was added at 0°C. The mixture was stirred at 25°C for 16 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 31-1. LCMS: 283.2 [M+H] + ; 1 HNMR: (400 MHz, chloroform-d) δ7.34-7.49 (m, 2H), 7.15-7.26 (m, 2H), 3.68 (s, 3H), 3.52 (d, J = 10.88 Hz, 1H), 2.88-3.06 (m, 1H), 2.12-2.28 (m, 1H), 1.79-1.95 (m, 4H), 1.59-1.68 (m, 1H).

[0775] Step 2: Preparation of compound 31-2

[0776] To a solution of compound 31-1 (1.00 g, 3.53 mmol) in EtOH (10 mL) was added hydrazine hydrate (2.65 g, 53.0 mmol, 2.57 mL). The mixture was stirred at 80 ° C for 16 h. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product of compound 31-2, which was used directly in the next step without further purification. LCMS: 283.0 [M+H] + .

[0777] Step 3: Preparation of compound 31-3

[0778] To a solution of compound 31-2 (600.0 mg, 2.12 mmol) in THF (10 mL) was added methylimino(thioxo)methane (619.7 mg, 8.48 mmol, 579.2 μL). The mixture was stirred at 25°C for 16 h. The reaction mixture was concentrated under reduced pressure to remove THF to obtain crude compound 31-3, which was used in the next step without further purification. LCMS: 357.8 [M+H] + .

[0779] Step 4: Preparation of compound 31-4

[0780] To a solution of compound 31-3 (1.50 g, 4.21 mmol) in water (5 mL) was added NaOH (673.6 mg, 16.8 mmol). The mixture was stirred at 20°C for 16 h. At 25°C, the reaction mixture was adjusted to pH = 7 using 1M HCl, then diluted with water (50 mL) and extracted with DCM (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound 31-4, which was used directly in the next step without further purification. LCMS: 339.9 [M+H] + .

[0781] Step 5: Preparation of compound 31-5

[0782] To a solution of compound 31-4 (700.0 mg, 2.07 mmol) in DCM (10 mL) was added H2O2 (994.1 μL, 10.4 mmol, 30% purity) and AcOH (1.49 g, 24.8 mmol, 1.42 mL) at 0°C. The mixture was stirred at 20°C for 12 h. At 25°C, the reaction was quenched by the addition of aqueous Na2SO3 solution (100 mL), and the mixture was then extracted with DCM (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude compound 31-5, which was used directly in the next step without further purification. LCMS: 307.8 [M+H] + .

[0783] Step 6: Preparation of compound 31-6

[0784] To a solution of compound 31-5 (300.0 mg, 979.7 μmol) in ACN (5 mL) were added Cu2O (28.0 mg, 195.9 μmol, 20.0 μL) and NH3-H2O (2.97 mL, 25.5 mmol, 33% purity). The mixture was stirred at 110 ° C. under microwave irradiation for 2 h. The reaction mixture was partitioned between water (50 mL) and ethyl acetate (100 mL). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 31-6. LCMS: 242.9 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ8.30 (s, 1H), 6.92 (t, J = 7.69Hz, 1H), 6.25-6.45 (m, 3H), 5.03 (br s,2H),3.92(d,J=10.51Hz,1H),3.35(s,3H),3.01-3.16(m,1H),2.01-2.15(m,1H),1.71-1.85(m,4H),1.56-1.69(m,1H).

[0785] Step 7: Preparation of Example 31

[0786] To a solution of compound 31-6 (70.0 mg, 288.9 μmol) and compound 26-7 (87.0 mg, 288.9 μmol) in DCM (1 mL) were added DIEA (112.0 mg, 866.6 μmol, 150.9 μL) and HATU (109.8 mg, 288.9 μmol). The mixture was stirred at 25 ° C for 16 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to obtain Example 31. LCMS: 526.3 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ10.44(s,1H),8.33(s,1H),8.15(d,J=9.90Hz,2H),7.84(s,1H),7.71(d,J=8.6 8Hz,1H),7.54(s,1H),7.31(t,J=7.82Hz,1H),7.04(d,J=7.70Hz,1H),4.16(d,J=10.64Hz,1H),3.61(br s,2H),3.40(s,4H),3.09-3.24(m,1H),2.61-2.77(m,2H),2.06-2.17(m,1H),1.93(t,J=10. 03Hz, 1H), 1.74-1.83 (m, 4H), 1.54-1.71 (m, 5H), 1.48 (q, J = 12.35Hz, 1H), 0.72-0.85 (m, 3H).

[0787] Intermediate 1:

[0788]

[0789] Step 1: Preparation of Int 1-1

[0790] To a solution of 4-bromo-2-nitro-6-(trifluoromethyl)benzene-1-carbaldehyde (1.0 g, 3.356 mmol) in toluene (10 mL) was added PTSA (0.2 g, 1.007 mmol) and ethylene glycol (0.94 mL, 16.779 mmol) at room temperature. The solution was stirred at 110°C for 12 hours. Upon completion, water (30 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (40 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous NaSO, filtered, concentrated in vacuo, and purified by column chromatography to afford Int 1-1 (1.1 g, 95.8%). 1H NMR (400MHz, CDCl3) δ8.00 (d, J = 1.7Hz, 1H), 7.80 (d, J = 1.6Hz, 1H), 6.11 (s, 1H), 4.13–3.88 (m, 4H).

[0791] Step 2: Preparation of Int 1-2

[0792] Int 1-2 was synthesized according to step 2 in Example 22. LCMS: 375.2 [M+H] + ;

[0793] Step 3: Preparation of Intermediate 1

[0794] To a solution of Int 1-2 (430 mg, 1.149 mmol) in acetonitrile (6 mL) was added H2SO4 (0.24 mL, 4.594 mmol), and the mixture was stirred at 60 ° C for 2 hours. After concentration, the residue was dissolved in DCM (10 mL). To the resulting solution was added 20 mL of NH3 / MeOH (7N). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure to remove the solvent to give a residue, which was purified by silica gel chromatography to give the title intermediate (240 mg, 63.3%). LCMS: 331.1 [M+H] + .

[0795] Example 32:

[0796]

[0797] Step 1: Preparation of compound 32-1

[0798] To a solution of methyltriphenylphosphonium bromide (13.9 g, 38.85 mmol) in THF (50 mL) was added t-BuOK (31.79 mL, 1 M in THF, 31.79 mmol). The resulting mixture was heated to 40 ° C for 45 minutes. After cooling to 0 ° C, a solution of 1-(3-bromophenyl)-3-oxocyclobutane-1-carboxylic acid methyl ester (10 g, 35.32 mmol) in THF (50 mL) was added. The reaction was stirred at room temperature overnight. The reaction mixture was poured into brine (30 mL) and the mixture was diluted with EtOAc (60 mL) and water (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash chromatography to obtain compound 32-1. 1H NMR: (400MHz, CDCl3) δ7.46 (d, J=1.6Hz, 1H), 7.38 (dd, J=7.6, 1.5Hz, 1H), 7.22 (dt, J=1 5.4,7.6Hz,2H),4.92–4.80(m,2H),3.67(s,3H),3.57–3.46(m,2H),3.22–3.09(m,2H).

[0799] Step 2: Preparation of compound 32-2

[0800] Borane-THF (65.3 mL) was added to a solution of compound 32-1 (10.8 g, 38.41 mmol) in dry THF (150 mL) at -10 ° C. The resulting mixture was stirred at room temperature for 4 hours. After cooling to -20 ° C, MeOH (43.2 mL) was added. After stirring for 15 minutes, sodium hydroxide (32.0 mL, 96.03 mmol) and hydrogen peroxide (0.89 mL, 1.78 mmol) were added. The mixture was stirred for another 2 hours, and then a saturated sodium sulfite solution (100 mL) was added. The mixture was diluted with EtOAc (70 mL) and water (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography to give compound 32-2. LCMS: [M+H] + =299.0 / 301.0.

[0801] Step 3: Preparation of compound 32-3

[0802] Compound 32-2 was used as a substrate and compound 32-3 was synthesized according to steps 2 to 5 of the preparation of Example 31. Step 4: Preparation of compound 32-4

[0803] To a solution of compound 32-3 (1300 mg, 4.03 mmol) in dioxane (25 mL) was added dicyclohexyl {3,6-dimethoxy-2-[2,4,6-tri(propyl-2-yl)phenyl]phenyl}phosphine (433.2 mg, 0.807 mmol), tert-butyl carbamate (944.9 mg, 8.070 mmol), Cs2CO3 (3943.6 mg, 12.104 mmol) and Pd2(dba)3 (369.5 mg, 0.403 mmol). The mixture was stirred at 100 ° C. under N2 overnight. After completion, the reaction mixture was partitioned between EA (100 mL) and H2O (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography to give compound 32-4. LCMS: [M+H] + =359.2.

[0804] Step 5: Preparation of compound 32-5

[0805] A solution of compound 32-4 (1147 mg, 3.200 mmol) in TFA (15 mL) and DCM (5 mL) was stirred at room temperature for 30 minutes. HO (100 mL) and EtOAc (300 mL) were added to the solution. The organic phase was separated and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase chromatography to give compound 32-5; LCMS: [M+H] + =259.2.

[0806] Step 6: Preparation of compound 32-6

[0807] To a solution of compound 32-5 (200 mg, 0.774 mmol) in IPA (1.5 mL) was added intermediate 1 (255.7 mg, 0.774 mmol). The mixture was stirred at 80 ° C for 4 hours. Then, tributylphosphine (516.9 mg, 2.555 mmol) was added and the resulting mixture was stirred at 80 ° C for another 16 hours. After completion, the mixture was distributed between H2O (100 mL) and EtOAc (300 mL), the organic phase was separated and washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give compound 32-6. LCMS: [M+H] + =539.4.

[0808] Step 7: Preparation of compound 32-7

[0809] To a solution of compound 32-6 (150 mg, 0.278 mmol) in DCM (3 mL) was added DMP (177.1 mg, 0.418 mmol), and the mixture was stirred at 20° C. for 1 hour. The reaction mixture was diluted with DCM (20 mL), then washed with saturated Na 2 SO 3 (10 M), saturated aqueous NaHCO 3 (10 mL), and brine, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography to give compound 32-7. LCMS: [M+H] + =537.3.

[0810] Step 8: Preparation of Example 32

[0811] To a solution of compound 32-7 (100 mg, 0.186 mmol) in MeOH (3 mL) was added K2CO3 (51.5 mg, 0.373 mmol) and (1Z)-1-(diazo-1-iumyl)-1-[dimethoxy(oxo)-λ5-phosphanyl]-prop-1-ene-2-olate ((1Z)-1-(diazyn-1-iumyl)-1-[dimethoxy(oxo)-λ5-phosphanyl]prop-1-en-2-olate) (35.8 mg, 0.186 mmol). Under N2, the mixture was stirred at 0°C for 3 hours. The reaction was then filtered through a pad of celite, and the filtrate was concentrated to give a residue, which was purified by reverse phase preparative HPLC to give Example 32. LCMS: [M+H] + =533.4; 1 HNMR(400MHz, chloroform-d)δ8.49(s,1H),8.13–7.97(m,2H),7.91(s,1H),7.84 –7.76(m,1H),7.63–7.48(m,2H),7.40–7.28(m,1H),3.76(d,J=11.4Hz,2 H),3.42(t,J=9.4Hz,2H),3.35–3.16(m,6H),3.16–3.07(m,1H),2.96–2 .87(m,2H),2.26–2.20(m,1H),1.90–1.47(m,4H),0.88(d,J=6.2Hz,4H).

[0812] Example 33:

[0813]

[0814] Step 1: Preparation of compound 33-1

[0815] To a solution of compound 32-2 (1.5 g, 5.013 mmol) and CH3I (2845.6 mg, 20.053 mmol) in DMF (15 mL) was added NaH (802.1 mg, 20.053 mmol) at 0°C, and the mixture was stirred at 0°C for 3 hours. The reaction was diluted with EtOAc (30 mL) and water (50 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 33-1.

[0816] Step 2: Preparation of compound 33-2

[0817] Compound 33-2 was synthesized using compound 33-1 as a substrate according to steps 2 to 5 of the preparation of Example 31. LCMS: 336.1 / 338.1 [M+H] + .

[0818] Step 3: Preparation of compound 33-3

[0819] A solution of compound 33-2 (482 mg, 1.434 mmol) and Cu2O (202.1 mg, 1.434 mmol) in NH4OH (1 mL, 26.000 mmol) and ACN (1 mL) was stirred at 110 ° C overnight. The reaction mixture was partitioned between water (30 mL) and EtOAc (30 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase preparative HPLC to obtain compound 33-3. LCMS: 273.0 [M+H] + .

[0820] Step 4: Preparation of Example 33

[0821] The title compound was synthesized according to step 6 of Example 32 using compound 33-3 as a substrate. LCMS: 553.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ9.25(s,1H),8.42–8.31(m,1H),8.11–8.03(m,1H),7.97(s,1H),7.89(s,1H),7.62–7.49(m,2 H),7.24(d,J=8.0Hz,1H),3.59(s,2H),3.41–2.60(m,16H),1.99–1.89(m,1H),1.73–1.32(m,4H),0.86–0.78(m,4H).

[0822] Intermediate 2:

[0823]

[0824] Step 1: Preparation of Int 2-1

[0825] Int 2-1 was synthesized according to compound 10-1. LCMS: 245.1 [M+H] + ;

[0826] Step 2: Preparation of Int 2-2

[0827] Int 2-2 was synthesized according to step 3 in Example 38. LCMS: 245.1 [M+H] + ;

[0828] Step 3: Preparation of Intermediate 2

[0829] To a solution of Int 2-2 (100 mg, 0.213 mmol) in DCM (3 mL) was added DMP (135.2 mg, 0.319 mmol) at 0°C. The mixture was stirred at room temperature under N2 for 1 hour. The mixture was filtered and the filter cake was washed with DCM (5 mL x 2). The filtrate was concentrated to give the crude product, which was further purified by reverse phase preparative HPLC to give the title compound. LCMS: 469.1 [M+H] + .

[0830] According to Step 4 in Example 10, the following compounds were synthesized using Intermediate 2 as a substrate.

[0831]

[0832]

[0833] Step 1: Preparation of Int 3-1

[0834] In a sealed tube, a mixture of 2-amino-5-bromo-3-(trifluoromethyl)benzoic acid (1 g, 3.521 mmol) in azanecarbaldehyde (10 mL) was stirred at 110 ° C overnight. After completion, the mixture was partitioned between EtOAc (30 mL) and H2O (30 mL). The aqueous phase was extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to give Int 3-1 (250 mg, 19.39%). LCMS: 292.9 [M+H] + .

[0835] Step 2: Preparation of Intermediate 3

[0836] The title compound was synthesized according to step 2 in Example 22. LCMS: 326.0 [M+H] + .

[0837] Example 35:

[0838]

[0839] Step 1: Preparation of compound 35-1

[0840] To a solution of 2,4,6-trichloropyridine (3 g, 16.447 mmol) in DMF (50 mL) was added dimethyl malonate (2.4 g, 18.092 mmol) and Cs2CO3 (10.7 g, 32.895 mmol) at room temperature. The mixture was stirred at 70°C for 18 hours. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to give compound 3 (2.4 g, 52.5%). LCMS: 278.0 [M+H] + .

[0841] Step 2: Preparation of compound 35-2

[0842] To a mixture of compound 35-1 (2.13 g, 7.659 mmol) and K2CO3 (3.2 g, 22.977 mmol) in DMF (20 mL) was added 3-bromoprop-1-ene (1.9 g, 15.702 mmol) dropwise at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction was quenched by adding water, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to give compound 35-2 (2.20 g, 90.2%). LCMS: 318.0 [M+H] + .

[0843] Step 3: Preparation of compound 35-3

[0844] To a mixture of compound 35-2 (2 g, 6.287 mmol) in THF (10 mL) was added DIBAL-H (25 mL, 25 mmol) dropwise at -20 ° C. The mixture was stirred at room temperature for 16 hours. At -20 ° C, the reaction was quenched by the dropwise addition of MeOH and stirred at -10 ° C for 10 minutes. At 10 ° C, the mixture was poured into an aqueous solution of Rochelle's salt and stirred for another 15 minutes. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to give compound 35-3 (1100 mg, 66.8%). LCMS: 262.0 [M+H] + .

[0845] Step 4: Preparation of compound 35-4

[0846] To a solution of compound 35-3 (2.1 g, 8.012 mmol) in toluene (20 mL) was added PPh3 (4.2 g, 16.024 mmol) at room temperature. After stirring for 10 minutes, a toluene (60 mL) solution of DEAD (1608.4 mg, 6.868 mmol) and zinc bis[(diethylamino)methanedithioate] (4.3 g, 12.018 mmol) was added dropwise. The mixture was stirred at room temperature for 16 hours. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography to give compound 35-4 (1.5 g, 76.7%). LCMS: 244.1 [M+H] + .

[0847] Step 5: Preparation of compound 35-5

[0848] To a solution of compound 35-4 (852 mg, 3.49 mmol) in EtOAc (4 mL), CH 3 CN (4 mL) and H 2 O (6.4 mL) was added RuCl 3 (36 mg, 0.175 mmol). After stirring at room temperature for 20 minutes, NaIO 4 (2.9 g, 13.961 mmol) was added portionwise under an ice bath. The reaction mixture was stirred for another 1.5 hours. After completion, 50 mL of water was added to the mixture, and the aqueous layer was then extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography to give compound 35-5. LCMS: 262.0 [M+H] + Step 6: Preparation of compound 35-6

[0849] Compound 35-6 was synthesized using compound 35-5 as a substrate according to steps 2 to 5 of the preparation of Example 31. LCMS: 299.0 [M+H] + .

[0850] Step 7: Preparation of compound 35-7

[0851] At 25 ° C, under N2, to a solution of compound 35-6 (20 mg, 0.067 mmol) and intermediate 3 (22 mg, 0.067 mmol) in dioxane (2 mL) was added methyl [(1R, 2R) -2- (methylamino) cyclohexyl] amine (9 mg, 0.067 mmol), K2CO3 (18.5 mg, 0.135 mmol) and CuI (6.4 mg, 0.034 mmol). The reaction was stirred at 120 ° C for 16 hours. The mixture was filtered through a celite pad, and the filtrate was concentrated to give a residue. The residue was purified by reverse phase preparative HPLC to give compound 35-7. LCMS: 588.4 [M + H] + .

[0852] Step 8: Preparation of Example 35

[0853] To a solution of compound 35-7 (120 mg, 0.204 mmol) in DMF (2 mL) was added TEA (0.14 mL, 1.020 mmol), Pd(dppf)Cl (74.7 mg, 0.102 mmol) and HCOOH (46.9 mg, 1.020 mmol) at 25 ° C. under N2. The reaction mixture was stirred at 70 ° C. for 1 hour. After completion, the reactant was filtered through a celite pad, and the filtrate was concentrated to give a residue, which was purified by reverse phase preparative HPLC to give the title compound. LCMS: 554.0 [M+H] + ; 1 HNMR (400MHz, chloroform-d) δ8.64(s,1H),8.50(d,J=5.1Hz,1H),8.42(s,1H),8.15(s,1H),7.97(s,1H),7.46(s,1H),7.05(d,J=5.0Hz,1H),5.09 (dd,J=31.3,6.4Hz,4H),3.61(s,3H),3.18(s,2H),2.75(dd,J=19.6,9.3Hz,2H),2.01–1.87(m,2H),1.81–1.49(m,6H),0.92–0.76(m,4H).

[0854] Intermediate 4:

[0855]

[0856] Step 1: Preparation of Int 4-1

[0857] To a stirred solution of 2,6-dichloro-4-methylpyridine (63 g, 388.889 mmol) in anhydrous THF (500 mL) was slowly added LDA (388.89 mL, 777.778 mmol) at -78 ° C under N2. The mixture was stirred at -78 ° C for 0.5 h. A solution of methyl methoxyformate (81.94 mL, 972.222 mmol) in dry THF (130 mL) was added dropwise. The solution was stirred at 0 ° C for 1 hour. The reaction was quenched with aqueous NH4Cl solution (500 mL). The resulting mixture was extracted with EtOAc (200 mL×3). The combined organic phases were washed with aqueous sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. After filtration, the organic layer was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography to give Int 4-1. LCMS: 220.1 [M+H] + .

[0858] Step 2: Preparation of Int 4-2

[0859] To a solution of Int 4-1 (50.0 g, 231.364 mmol) in DMF (510 mL) was added NaH (20.4 g, 509 mmol) in portions at 0°C. The mixture was stirred at 0°C for 30 minutes. Then, the solution was stirred at 25°C for 2 hours. After completion, the mixture was poured into an aqueous ammonium chloride solution (700 mL). The mixture was then extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by column chromatography to give Int 4-2. LCMS: 274.1 [M+H] + .

[0860] Step 3: Preparation of Intermediate 4

[0861] Intermediate 4 was synthesized using Int 4-2 as a substrate according to steps 2 to 5 of the preparation of Example 31. LCMS: 297.1 [M+H] + .

[0862] Example 38:

[0863]

[0864] Step 1: Preparation of compound 38-1

[0865] To a solution of intermediate 4 (400 mg, 1.346 mmol) in DMSO (6 mL) was added K2CO3 (558.0 mg, 4.038 mmol) and N-hydroxyacetamide (303.2 mg, 4.038 mmol). The mixture was stirred at 80°C for 18 hours. The mixture was purified by reverse phase preparative HPLC to give compound 38-1. LCMS: 279.2 [M+H] + .

[0866] Step 2: Preparation of compound 38-2

[0867] To a solution of compound 38-1 (250 mg, 0.897 mmol) in DMF (3 mL) was added Cs2CO3 (292.2 mg, 0.897 mmol). The mixture was stirred at 0 ° C for 10 minutes, and then 4-methylbenzenesulfonic acid fluoromethyl ester (366.3 mg, 1.794 mmol) was added. Under N2, the resulting mixture was heated to 80 ° C for 2 hours. The mixture was purified by reverse phase preparative HPLC to give compound 38-2. LCMS: 311.2 [M+H] + .

[0868] Step 3: Preparation of Example 38

[0869] To a solution of compound 38-2 (100 mg, 0.322 mmol) in dioxane (2 mL) were added intermediate 3 (73.3 mg, 0.225 mmol), CuI (30.6 mg, 0.161 mmol), K2CO3 (88.9 mg, 0.644 mmol) and methyl[(1R,2R)-2-(methylamino)cyclohexyl]amine (45.8 mg, 0.322 mmol). Under N2, the mixture was stirred at 120°C for 18 hours. After concentration under reduced pressure, the residue was purified by reverse phase preparative HPLC to give the title compound. LCMS: 600.4 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.74(s,1H),8.53–8.38(m,1H),8.22–8.00(m,2H),7.74–7.56(m,1H),6.98–6.69(m,1H),6.14–5.88 (m,2H),3.66–3.31(m,5H),3.29–2.85(m,2H),2.82–2.66(m,4H),2.38–1.89(m,2H),1.83–1.13(m,8H),0.94–0.81(m,4H).

[0870] Intermediate 5:

[0871]

[0872] Step 1: Preparation of Int 5-1

[0873] To a solution of 6-bromo-2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-(trifluoromethyl)-2H-indazole (288 mg, 0.587 mmol) in dioxane (5 mL) was added (tributyltin)methanol (565.79 mg, 1.762 mmol) and XPhos Pd G2 (3.21 mg, 0.004 mmol). The mixture was stirred at 80 ° C for 5 hours. Then, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel chromatography to give compound 3-5 (145 mg). LCMS: 442.2 [M+H] + .

[0874] Step 6: Preparation of Intermediate 5

[0875] To a solution of Int 5-1 (50 mg, 0.113 mmol) in DCM (2 mL) was added 1,1-diacetoxy-3-oxo-1,3-dihydrobenzo[d][1,2]iodooxolan-1-yl acetate (72.06 mg, 0.170 mmol). The mixture was stirred at 20 °C for 1 hour. The reaction was diluted with DCM (20 mL), washed with saturated Na2SO3 (10 M), saturated aqueous NaHCO3 (10 mL) and brine (10 mL), then concentrated to give Intermediate 5, which was used directly without further purification. LCMS: 440.2 [M+H] + .

[0876] According to Step 4 in Example 10, the following compounds were synthesized using Intermediate 5 or Intermediate 8 as a substrate.

[0877]

[0878] Example 41:

[0879]

[0880] The title compound was synthesized according to step 3 in Example 38. LCMS: 586.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ8.72–8.57(m,1H),8.50–8.31(m,2H),8.16(s,1H),7.94–7.42(m,2H),4.76–

[0881] 4.58(m,2H),3.58(s,3H),3.30–3.11(m,4H),2.97–2.58(m,4H),2.04–1.84(m,1H),1.70–

[0882] 1.41(m,5H),1.30–1.03(m,2H),0.91–0.73(m,4H).

[0883] Example 42:

[0884]

[0885] Step 1: Preparation of compound 42-1

[0886] To a solution of (S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (5 g, 23.223 mmol) in DCM (20 mL) was added DMP (11.8 mg, 27.868 mmol) at 0°C. The mixture was stirred at room temperature for 2 hours under N2. The mixture was filtered and the filter cake was washed with DCM. The filtrate was concentrated to give a residue, which was further purified by flash silica gel chromatography to give compound 42-1 (4.375 g, 88.3%). 1 H NMR: (400MHz, CDCl3) δ9.69 (s, 1H), 3.90 (s, 1H), 3.64 (d, J = 12.3Hz, 1H), 3.32 (dd, J = 13.5, 8.3Hz, 1H), 3.08(ddd,J=13.0,9.3,3.3Hz,1H),2.42(s,1H),1.95(d,J=6.4Hz,1H),1.77–1.52(m,3H),1.45(s,9H).

[0887] Step 2: Preparation of compound 42-2

[0888] To a solution of compound MTPPC (10.5 g, 30.767 mmol) in THF (20 mL) was added KHMDS (3.5 g, 30.767 mmol) at 0°C. The mixture was stirred at 0°C for 30 minutes. Then, compound 42-1 (4.375 g, 20.511 mmol) dissolved in THF (13 mL) was added to the mixture at -20°C. The mixture was stirred at 25°C for 12 hours. The reaction mixture was partitioned between water (20 mL) and EtOAc (15 mL). The organic phase was separated, washed with 15 mL (15 mL × 3) of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The combined crude product was purified by flash silica gel column chromatography to obtain compound 42-2 (3.761 g, 70.0%).

[0889] Step 3: Preparation of compound 42-3

[0890] To a solution of compound 42-2 (3 g, 12.433 mmol) in MeOH (30 mL) was added HCl (1 ml, 1.000 mmol), and the mixture was stirred at room temperature under N2 for 6 hours. The reaction mixture was partitioned between water (20 mL) and EA (15 mL). The organic phase was separated, washed with brine (3 times) (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The crude product was used directly in the next step without further purification.

[0891] Step 4: Preparation of compound 42-4

[0892] To a solution of compound 42-3 (2700 mg, 11.879 mmol) in MeOH (30 mL) was added K2CO3 (3283.2 mg, 23.757 mmol) and Bestmann reagent (2738.2 mg, 14.254 mmol) at 0°C. Under N2, the mixture was stirred at room temperature for 12 hours. The reaction mixture was partitioned between water (30 mL) and EtOAc (30 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 42-4 (471 mg, 17.8%).

[0893] Step 5: Preparation of compound 42-5

[0894] A mixture of compound 42-4 (200 mg, 0.896 mmol) in HCl / dioxane (4 M, 6 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give crude compound 42-5. LCMS: 124.1 [M+H] + The crude product was used in the next step without further purification.

[0895] Step 6: Preparation of Example 42

[0896] The title compound was synthesized according to the method of step 4 in Example 10 using compound 42-5 and intermediate 5 as substrates. LCMS: 547.4 [M+H] + ; 1H NMR(400MHz, methanol-d4)δ9.10(s,1H),8.52(s,1H),8.19(s,1H),8.11(s,1H) ,8.06–7.98(m,1H),7.71–7.64(m,2H),7.63–7.57(m,1H),4.55(s,2H),3. 66–3.52(m,2H),3.38(s,3H),3.08–2.82(m,4H),2.75–2.63(m,3H),2.37– 2.21(m,2H),2.13–1.92(m,4H),1.85–1.69(m,1H),1.18(d,J=5.9Hz,3H).

[0897] Intermediate 6:

[0898]

[0899] Step 1: Preparation of intermediate 6-1

[0900] (3,5-Dibromophenyl)acetic acid (40 g, 136.082 mmol) was dissolved in MeOH (400 mL) and stirred at 0°C. H2SO4 (7.253 mL, 136.082 mmol) was added dropwise while stirring. The mixture was then heated to reflux for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 200 mL of water and extracted with EtOAc (300 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give Int 6-1 (41.9 g, 100.0%). 1 H NMR (400MHz, CDCl3) δ7.58 (t, J=1.7Hz, 1H), 7.38 (d, J=1.7Hz, 2H), 3.72 (s, 3H), 3.57 (s, 2H).

[0901] Step 2: Preparation of intermediate 6-2

[0902] Int 6-2 was synthesized according to step 2 in Intermediate 7.

[0903] Step 3: Preparation of intermediate 6-3

[0904] Int 6-3 was synthesized according to steps 2 to 5 of the preparation of Example 31. LCMS: 386.0 [M+H] + .

[0905] Step 4: Preparation of Intermediate 6-4

[0906] A mixture of Int 6-3 (10.6 g, 27.525 mmol), NH2Boc (3.2 g, 27.525 mmol), Xantphos (3.2 g, 5.505 mmol), Pd2(dba)3 (2.5 g, 2.753 mmol) and Cs2CO3 (17.9 g, 55.051 mmol) in dioxane (100 mL) was degassed and bubbled with N2 three times. The mixture was then stirred at 100 ° C under N2 atmosphere overnight. The reactants were filtered through a pad of celite and the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography to give Int6-4 (7 g, 60.4%). LCMS: 423.2 [M+H] + .

[0907] Step 5: Preparation of Intermediate 6

[0908] To a solution of Int 6-4 (2 g, 4.747 mmol) in DCM (15 mL) was added TFA (5 mL) at 25°C, and the mixture was stirred at 25°C for 1 hour. The mixture was concentrated to give Intermediate 6 (1.4 g, 91.8%). LCMS: 321.1 [M+H] + .

[0909] Example 43:

[0910]

[0911] Step 1: Preparation of compound 43-1

[0912] Compound 43-1 was synthesized according to step 6 in Example 32. LCMS: 603.1 [M+H] + .

[0913] Step 2: Preparation of compound 43-2

[0914] Under CO (50 Psi), a solution of compound 43-1 (240 mg, 0.399 mmol), Pd(dppf)Cl2 (146.0 mg, 0.200 mmol) and TEA (0.41 mL, 2.993 mmol) in MeOH (3 mL) was stirred at 60° C. for 12 hours. The residue was purified by flash silica gel column chromatography to give compound 42-2. LCMS: 581.4 [M+H] + .

[0915] Step 3: Preparation of compound 43-3

[0916] A mixture of compound 43-2 (204 mg, 0.351 mmol) and LiOH (14.7 mg, 0.351 mmol) in EtOH (2 mL) and H2O (1 mL) was stirred at 25°C for 2 hours. The mixture was adjusted to pH 2-3 with 1M HCl and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase chromatography to obtain compound 43-3. LCMS: 567.6 [M+H] + .

[0917] Step 4: Preparation of Example 43

[0918] To a solution of compound 43-3 (50 mg, 0.088 mmol) and HATU (50.3 mg, 0.132 mmol) in DMF (1.5 mL) was added methylammonium chloride (7.1 mg, 0.106 mmol) and DIPEA (0.06 mL, 0.353 mmol). The reaction was stirred at 25 °C for 2 hours. The mixture was purified by reverse phase preparative HPLC to afford the title compound. LCMS: 580.6 [M+H] + ; 1 HNMR (400 MHz, CHLOROFORM-d) δ8.59 (s, 1H), 8.34–8.10 (m, 2H), 8.07–7.93 (m, 1H), 7.91–7.72 (m, 2H), 7.65–7.45 (m, 0H), 6.73–6.43 (m, 1H), 3.61 (s, 2H), 3.39–3.18 (m, 5H), 3.12–2.91 (m, 6H), 2.88–2.52 (m, 4H), 2.08–1.89 (m, 1H), 1.85–1.53 (m, 4H), 1.20–1.11 (m, 3H), 0.95–0.76 (m, 4H).

[0919] Example 44:

[0920]

[0921] Step 1: Preparation of compound 44-1

[0922] To a solution of intermediate 4 (300 mg, 1.009 mmol) in DMSO (5 mL) was added potassium fluoride (58.6 mg, 1.009 mmol). The mixture was stirred at 140° C. for 6 hours. The mixture was purified by reverse phase chromatography to give compound 44-1. LCMS: 281.0 [M+H] + .

[0923] Step 2: Preparation of Example 44

[0924] The title compound was synthesized according to step 3 in Example 38. LCMS: 570.6 [M+H] + ; 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.69 (s, 1H), 8.44 (s, 1H), 8.31–8.04 (m, 2H), 7.91–7.69 (m, 1H), 7.16–6.86 (m, 1H), 3.78–3.32 (m, 5H), 3.30–3.11 (m, 1H), 2.97–2.52 (m, 5H), 2.42–1.92 (m, 2H), 1.87–1.54 (m, 7H), 1.23–1.11 (m, 1H), 1.01–0.78 (m, 4H).

[0925] Example 45:

[0926]

[0927] Step 1: Preparation of compound 45-1

[0928] To a solution of intermediate 4 (500 mg, 1.682 mmol) and methylboronic acid (90.7 mg, 1.514 mmol) in dioxane (4 mL) and H2O (1 mL) was added Pd(PPh3)4 (209.3 mg, 0.168 mmol) and potassium carbonate (581.3 mg, 4.206 mmol) at room temperature. The mixture was stirred at 80 ° C for 14 hours. The mixture was filtered through a celite pad, and the filtrate was concentrated to give a crude product. The crude product was purified by reverse phase chromatography to give compound 45-1. LCMS: 277.2 [M+H] + .

[0929] Step 2: Preparation of Example 45

[0930] The title compound was synthesized according to step 3 in Example 38. LCMS: 566.4 [M+H] + ; 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.76–8.68 (m, 1H), 8.44 (s, 1H), 8.20–8.02 (m, 2H), 7.81–7.55 (m, 1H), 7.21–6.97 (m, 1H), 3.67–3.29 (m, 5H), 3.19 (dd, J=14.5, 7.3 Hz, 1H), 2.95–2.86 (m, 2H), 2.83–2.69 (m, 3H), 2.54 (s, 3H), 2.01–1.92 (m, 1H), 1.76–1.58 (m, 8H), 1.16–1.14 (m, 1H), 0.90–0.81 (m, 4H).

[0931] Example 46:

[0932]

[0933] Step 1: Preparation of compound 46-1

[0934] To a solution of 4,6-dichloropyrimidin-5-amine (11.70 g, 71.337 mmol) in EtOAc (100 mL) were added 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (5 g, 35.668 mmol), tetrakis(triphenylphosphine)palladium (2.06 g, 1.783 mmol) and CuI (0.34 g, 1.783 mmol). The reaction was stirred at 80 ° C under N2 for 2 hours. After cooling to room temperature, the reaction was diluted with EtOAc. The organic phase was separated, washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 46-1 (3.1 g, 32.46%). LCMS: 268.0 [M+H] + .

[0935] Step 2: Preparation of compound 46-2

[0936] To a solution of compound 46-1 (3.1 g, 11.580 mmol) in NMP (60 mL) was added t BuOK (2.60 g, 23.159 mmol). The reaction was stirred at 0°C for 3 hours under N2. The reaction solution was diluted with EtOAc. The organic phase was separated, washed with brine (40 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 46-2 (2.7 g, 87.10%). LCMS: 268.0 [M+H] + .

[0937] Step 3: Preparation of compound 46-3

[0938] To a solution of compound 46-2 (6 g, 22.412 mmol) in MeCN (120 mL) was added NIS (6.05 g, 26.895 mmol), and the reaction was stirred at 0°C under N2 for 2 hours. The reaction mixture was diluted with EtOAc. The organic phase was separated, washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 46-3 (6.6 g, 74.8%). LCMS: 394.0 [M+H] + .

[0939] Step 4: Preparation of compound 46-4

[0940] To a solution of compound 46-3 (2 g, 5.081 mmol) in DMF (40 mL) was added Cs2CO3 (5.0 g, 15.244 mmol) and SEMCl (1.3 g, 7.622 mmol). The reaction was stirred at 0°C under N2 for 2 hours. The reaction solution was diluted with EtOAc. The organic phase was separated, washed with brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 46-4 (2 g, 75.1%). LCMS: 524.0 [M+H] + ; Step 5: Preparation of compound 46-5

[0941] To a solution of compound 46-4 (1 g, 1.909 mmol) in DMF (8 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (340.0 mg, 1.909 mmol) and CuI (0.4 g, 2.291 mmol). The reaction was stirred at 80°C under N2 for 16 hours. The reaction was diluted with EtOAc. The organic phase was separated, washed with brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 46-5 (300 mg, 33.7%).

[0942] Step 6: Preparation of compound 46-6

[0943] To a solution of compound 46-5 (850 mg, 1.824 mmol) in DMSO (6 mL) were added K2CO3 (756.2 mg, 5.472 mmol) and N-hydroxyacetamide (274.0 mg, 3.648 mmol). The reaction was stirred at 80 ° C under N2 for 2 hours. After cooling to room temperature, the reaction was diluted with EtOAc. The organic phase was separated, washed with brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 46-6 (550 mg, 67.4%). LCMS: 448.1 [M+H] + ;

[0944] Step 7: Preparation of compound 46-7

[0945] To a solution of compound 46-6 (1300.0 mg, 2.905 mmol) and intermediate 10 (937.0 mg, 3.050 mmol) in dioxane (10 mL) were added CuI (166.0 mg, 0.872 mmol), DMEDA (204.9 mg, 2.324 mmol) and K2CO3 (1084.0 mg, 7.844 mmol). The mixture was stirred at 110 ° C. under N2 for 12 hours. The reaction mixture was partitioned between water (50 mL) and EtOAc (30 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 46-7 (1.7 g, 86.8%). LCMS: 674.3 [M+H] + .

[0946] Step 8: Preparation of compound 46-8

[0947] To a solution of compound 46-7 (1.6 g, 2.375 mmol) in THF (5 mL) was added HCl (1 N, 10 mL) at 0°C. The mixture was stirred at room temperature under N2 for 2 hours. The mixture was filtered and the filtrate was concentrated to give crude compound 46-8 (1.35 g, 96.4%). The crude product was used in the next step without further purification. LCMS: 590.2 [M+H] + .

[0948] Step 9: Preparation of compound 46-9

[0949] To a solution of compound 46-8 (1.3 g, 2.205 mmol) in DCM (15 mL) was added Dess-Martin periodinane (1.2 g, 2.866 mmol) at 0°C. The mixture was stirred at room temperature under N2 for 3 hours. The reaction mixture was quenched with Na2S2O3 (saturated aqueous solution 10 mL) and NaHCO3 (saturated aqueous solution 10 mL). The mixture was extracted with DCM (10 mL×3). The organic phase was separated, washed with water (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 46-9 (1.25 g, 96.5%). LCMS: 588.2 [M+H] + .

[0950] Step 10: Preparation of compound 46-10

[0951] Compound 46-10 was synthesized according to step 4 in Example 10. LCMS: 671.5 [M+H] + ;

[0952] Step 11: Preparation of Example 46

[0953] To a solution of compound 46-10 (66 mg, 0.098 mmol) in DCM (0.5 mL) was added TFA (2 mL, 0.015 mmol) at room temperature. The mixture was stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC to obtain the title compound. LCMS: 541.1 [M+H] + .

[0954] Example 47:

[0955]

[0956] To a solution of Example 41 (30 mg, 0.051 mmol), cyclopropylboronic acid (14 mg, 0.154 mmol), and tricyclohexylphosphine (14.4 mg, 0.051 mmol) in dioxane / water (3 / 1, 2 mL) was added K 3 PO 4 (11 mg, 0.051 mmol) and Pd(OAc) 2 (6 mg, 0.026 mmol). The resulting mixture was stirred at 90 ° C for 16 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to give the crude product. The crude product was purified by reverse phase preparative HPLC to give the title compound. LCMS: 592.0 [M+H] + ; 1 H NMR (400MHz, chloroform-d) δ8.77–8.71(m,1H),8.47(s,1H),8.18–8.03(m,2H),7.69–7.51(m,1H),7.23(s,1H),3.65–3.32(m,5H), 3.25–3.13(m,2H),3.01–2.64(m,4H),2.03–1.44(m,10H),1.15(d,J=6.3Hz,1H),1.01(d,J=8.2Hz,4H),0.90–0.82(m,4H).

[0957] Intermediate 7:

[0958]

[0959] Step 1: Preparation of intermediate 7-1

[0960] A solution of 2-bromo-4-methylpyridine (20 g, 116 mmol) and tert-butoxybis(dimethylaminomethane) (40.5 g, 232 mmol) was stirred at 110 ° C for 15 hours. The reaction solution was cooled and concentrated under reduced pressure to obtain a residue. After adding water (20 mL) and aminooxidanesulfonic acid (2.5 g, 22.106 mmol), the mixture was stirred at room temperature for 1 hour. After filtration, the mixture was extracted with DCM (100 mL × 2). The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to obtain intermediate 7-1. LCMS: 198.0 [M+H] + .

[0961] Step 2: Preparation of Intermediate 7-2

[0962] To a solution of intermediate 7-1 (9.00 g, 45.7 mmol) and 1,3-dibromo-2-methylpropane (9.90 g, 45.7 mmol) in N,N-dimethylformamide (6 mL) was added sodium hydride (2.20 g, 91.4 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched by adding a saturated aqueous solution of NH4Cl. The reaction mixture was extracted with EtOAc (300 mL×2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography to give intermediate 7-2. LCMS: 252.0 [M+H] + .

[0963] Step 3: Preparation of Intermediate 7

[0964] A solution of intermediate 7-2 (7.40 g, 29.5 mmol) and sodium hydroxide (3.5 g, 88.4 mmol) in ethanol (68 mL) and H2O (13 mL) was stirred at 80°C for 16 hours. After completion, the pH was adjusted to 5 by adding 1M HCl at 0°C. The aqueous layer was extracted with EtOAc (400 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the title compound. LCMS: 271.9 [M+H] + .

[0965] Example 48:

[0966]

[0967] Step 1: Preparation of compound 48-1

[0968] A solution of intermediate 7 (8.50 g, 31.5 mmol) in SOCl2 (35 mL) was stirred at 80 ° C for 1 hour. Then, the mixture was concentrated to obtain a residue. A solution of the above residue in DCM (35 mL) was added dropwise to NH3 / MeOH (7N, 35 mL). The mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by flash silica gel column chromatography to obtain compound 48-1 (5.0 g, 70.7%). LCMS: 225.0 [M+H] + .

[0969] Step 2: Preparation of compound 48-2

[0970] A solution of compound 48-1 (5.0 g, 22.3 mmol) in DMF-DMA (20 mL) was stirred at 100°C for 12 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give crude compound 48-2 (5.0 g, crude), which was used in the next step without further purification. LCMS: 280.2 [M+H] + .

[0971] Step 3: Preparation of compound 48-3

[0972] To a solution of compound 48-2 (5.0 g, crude) in HOAc (14 mL) was added hydrazine hydrate (14 mL). The mixture was stirred at 80 ° C for 4 hours. After cooling to room temperature, the reaction mixture was concentrated to give a residue, which was diluted with water (200 mL) and extracted with EtOAc (300 mL × 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by reverse phase HPLC to give compound 48-3 (4 g, 72.3%). LCMS: 249.0 [M+H] + ;

[0973] Step 4: Preparation of compound 48-4

[0974] To a solution of compound 48-3 (2.00 g, 8.07 mmol) in DMF (20 mL) were added sodium 2-chloro-2,2-difluoroacetate (2.50 g, 16.1 mmol) and K2CO3 (2.20 g, 16.1 mmol). The mixture was stirred at 140 ° C for 5 hours. After cooling to room temperature, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL×3). The combined organic layer was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue, which was purified by reverse phase HPLC to give compound 48-4 (0.15 g, 5.0%). LCMS: 299.0 [M+H]+ .

[0975] Step 5: Preparation of Example 48

[0976] The title compound was synthesized according to step 3 in Example 38. LCMS: 588.4 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.66(s,1H),8.64(d,J=5.3Hz,1H),8.39(s,1H),8.18–8 .11(m,1H),7.86(s,1H),7.47(dd,J=5.3,1.7Hz,1H),7.45(t,J=58.7Hz,1H),3.66(s,2H),2.8 7(p,J=6.2,5.5Hz,2H),2.77–2.69(m,2H),2.68–2.55(m,3H),1.95(t,J=11.0Hz,1H),1.71–1. 56(m,4H),1.53–1.43(m,1H),1.09(d,J=5.6Hz,3H),0.93–0.84(m,1H),0.82(d,J=6.1Hz,3H).

[0977] Example 49:

[0978] According to Example 45, the title compound was synthesized using potassium vinyl trifluoroborate and Intermediate 4 as substrates. LCMS: 578.4 [M+H] + ; 1 H NMR (400 MHz, chloroform-d) δ8.84 (s, 1H), 8.47 (s, 1H), 8.22–8.06 (m, 2H), 7.71 (d, J = 6.3 Hz, 1H), 7.27 (s, 1H), 6.73 (dd, J = 17.2, 10.6 Hz, 1H), 6.33 (d, J = 17.2 Hz, 1H), 5.54 (d, J = 10.7 Hz, 1H), 3.67 (s, 2H),3.57(s,3H),3.21(dd,J=15.0,7.2Hz,1H),2.92(dd,J=14.1,8.0Hz,1H),2.87–2.69(m,4H ), 2.00 (s, 2H), 1.82–1.58 (m, 7H), 1.19–1.12 (m, 1H), 0.97–0.87 (m, 1H), 0.86 (d, J = 5.9Hz, 3H).

[0979] Intermediate 8:

[0980]

[0981] The title compound was synthesized according to the method in Intermediate 5. LCMS: 442.0 [M+H] + .

[0982] Example 51:

[0983]

[0984] Step 1: Preparation of compound 51-1

[0985] To a solution of compound 43-1 (60 mg, 0.100 mmol) in THF (2 mL) were added CuI (1.9 mg, 0.010 mmol), trimethylsilylacetylene (195.9 mg, 1.995 mmol), Pd(PPh3)2Cl2 (7.8 mg, 0.010 mmol), and triethylamine (0.07 mL, 0.499 mmol). The mixture was stirred at 70°C under N2 overnight. The reaction solution was directly used for the next step. LCMS: 619.8 [M+H] + .

[0986] Step 2: Preparation of Example 51

[0987] To a solution of compound 51-1 (60 mg, 0.097 mmol) in MeOH (2 mL) was added KCO (40.2 mg, 0.291 mmol). The mixture was stirred at 25°C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase preparative HPLC to obtain Example 51. LCMS: 547.6 [M+H] + ; 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.59 (s, 2H), 7.97 (d, J = 33.1 Hz, 3H), 7.58 (d, J = 20.0 Hz, 2H), 4.33 (q, J = 13.3 Hz, 2H), 3.57 (dd, J = 67.3, 10.4 Hz, 2H), 3.35 (s, 3H), 3.27–2.65 (m, 4H), 2.64–2.34 (m, 2H), 2.33–1.80 (m, 5H), 1.18 (s, 3H), 1.10–1.00 (m, 1H), 0.94 (d, J = 6.1 Hz, 3H).

[0988] Example 52:

[0989]

[0990] To a solution of Example 53 (30 mg, 0.055 mmol) in DMSO (2 mL) was added KCO (15 mg, 0.110 mmol). The mixture was then stirred at room temperature under a nitrogen atmosphere. HO (0.1 mL, 0.882 mmol) was then added, and the resulting mixture was stirred at 25°C for 16 hours. The mixture was filtered through a pad of Celite, and the filtrate was concentrated to afford the crude product. The crude product was purified by reverse phase preparative HPLC to afford the title compound. LCMS: 566.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ9.32(s,1H),8.55–8.45(m,1H),8.40–8.30(m,1H),8.25(s,1H) ),8.21–8.01(m,1H),7.95–7.74(m,2H),7.70–7.48(m,2H),3.59(s,2H),3.25–3.19(m ,3H),2.99–2.94(m,1H),2.78–2.67(m,2H),2.64–2.56(m,2H),2.41–2.26(m,1H),1.9 7–1.88(m,1H),1.70–1.44(m,5H),1.23(s,1H),1.19–0.98(m,3H),0.99–0.67(m,4H).

[0991] Example 53:

[0992]

[0993] To a solution of compound 43-1 (40 mg, 0.067 mmol) in DMF (2 mL) at 0°C under N2 was added Zn(CN)2 (15.6 mg, 0.133 mmol) and Pd(PPh3)4 (7.7 mg, 0.007 mmol). The reaction was stirred at 120°C for 18 hours. The mixture was purified by reverse phase preparative HPLC to afford the title compound. LCMS: 548.3 [M+H] + ; 1 H NMR (400MHz, chloroform-d) δ8.51(s,1H),8.25–7.93(m,4H),7.75–7.55(m,2H),3.85(s,2H),3.33–3.28(m,3H),3.15 –2.88(m,4H),2.83–2.61(m,2H),2.39–2.22(m,2H),1.99–1.70(m,4H),1.27–1.15(m,4H),0.98–0.85(m,4H).

[0994] Intermediate 9:

[0995]

[0996] The title compound was synthesized according to the preparation of Intermediate 10.

[0997] Example 54:

[0998]

[0999] The title compound was synthesized according to step 5 of Example 6 using intermediate 9 and compound 6-4 as substrates. LCMS: 552.4 [M+H] +; 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.94 (s, 1H), 8.73–8.46 (m, 3H), 8.25 (s, 1H), 8.14–7.85 (m, 2H), 3.70 (s, 2H), 3.35–3.22 (m, 3H), 3.01–2.58 (m, 6H), 2.24–1.90 (m, 2H), 1.81–1.61 (m, 5H), 1.29–1.10 (m, 3H), 1.06–0.77 (m, 4H).

[1000] Intermediate 10:

[1001]

[1002] The title compound was synthesized according to steps 2 to 5 of the preparation of Example 31 using intermediate 7 as a substrate. LCMS: 308.9 [M+H] + .

[1003] Example 55:

[1004]

[1005] The title compound was synthesized according to step 5 of Example 6 using intermediate 10 and compound 6-4 as substrates. LCMS: 552.4 [M+H] + ; 1H NMR(400MHz,MeOD)δ8.64–8.60(m,3H),8.36–8.34(m,2H),7.78(s,1H),7.52(d,J=3.9Hz,1H),3.81(s,2H),3.37(s,3H),3.07–2.94(m,2H), 2.90–2.79(m,2H),2.75–2.69(m,3H),2.09–2.06(m,1H),1.80–1.59(m ,5H),1.17(d,J=5.9Hz,3H),0.96–0.94(m,1H),0.88(d,J=6.2Hz,3H).

[1006] Example 57:

[1007]

[1008] The title compound was synthesized according to Step 6 of Example 32 using Intermediate 1 and 3-(3-(fluoro(4-methyl-4H-1,2,4-triazol-3-yl)methyl)oxetan-3-yl)aniline (synthesized according to the literature) as substrates. LCMS: 543.3 [M+H] + ; 1 H NMR (400 MHz, chloroform-d) δ8.42 (s, 1H), 7.91 (s, 1H), 7.85–7.80 (m, 2H), 7.60 (s, 1H), 7.53 (s, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 7.3 Hz, 1H), 6.48 (d, J = 46.2 Hz, 1H), 5 .34(d,J=6.5Hz,1H),5.32–5.25(m,3H),5.08–5.03(m,1H),3.59(s,2H),3.10(s, 3H),2.87–2.70(m,2H),2.04–1.88(m,1H),1.77–1.60(m,5H),0.89–0.79(m,4H).

[1009] Intermediate 11:

[1010]

[1011] Step 1: Preparation of Int 11-1

[1012] To a solution of compound 7-1 (1.00 g, 3.521 mmol) in H2O (3 mL) and EtOH (5 mL) at 25°C under N2 was added NH4Cl (0.56 g, 10.562 mmol) and Fe (0.98 g, 17.604 mmol). The reaction was stirred at 80°C for 2 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated to afford Int 11-1 (500 mg, 55.90%). LCMS: 254.0 [M+H] + .

[1013] Step 2: Preparation of Int 11-2

[1014] To a solution of Int11-1 (900 mg, 3.543 mmol) in acetic acid (10 mL) was added NaNO2 (611.01 mg, 8.857 mmol), and the mixture was stirred at 40°C for 1 hour. The reaction mixture was then poured into water (30 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated to give Int11-2 (800 mg, 85.21%). LCMS: 265.2 [M+H] + .

[1015] Step 3: Preparation of Intermediate 11

[1016] The title compound was synthesized according to step 2 in Example 22. LCMS: 298.2 [M+H] + .

[1017] Example 58:

[1018]

[1019] A solution of Intermediate 10 (286 mg, 0.931 mmol), Intermediate 11 (277 mg, 0.932 mmol) and Cs2CO3 (909 mg, 2.79 mmol) in DMSO (2 mL) was stirred at 120°C for 16 hours. The mixture was purified by reverse phase preparative HPLC (2 times) to give the title compound. LCMS: 524.4 [M+H] + ;

[1020] Example 59:

[1021]

[1022] Step 1: Preparation of compound 59-1

[1023] To a solution of 3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutan-1-ol (500 mg, 1.396 mmol) in NH4OH (9 mL) and ACN (3 mL) was added Cu2O (235.4 mg, 1.622 mmol). The mixture was stirred at 110°C for 3 hours. After filtration, the filter cake was washed with NH4Cl (saturated aqueous solution 10 mL) and DCM:MeOH=10:1 (20 mL×3). The combined organic layers were concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 59-1 (380 mg, 95.9%). LCMS: 245.2 [M+H] + .

[1024] Step 2: Preparation of compound 59-2

[1025] Compound 59-2 was synthesized according to step 6 in Example 32. LCMS: 492.1 / 494.1 [M+H] + .

[1026] Step 3: Preparation of compound 59-3

[1027] Compound 59-3 was synthesized according to step 2 in Example 22. LCMS: 525.5 [M+H] + .

[1028] Step 4: Preparation of Example 59

[1029] To a solution of (bromodifluoromethyl)trimethylsilane (92.9 mg, 0.457 mmol) and compound 59-3 (60 mg, 0.114 mmol) in DCM (1 mL) and water (1 mL) was added potassium fluoridefluorane (71.5 mg, 0.915 mmol). The reaction was stirred at 25 ° C for 16 hours. The reaction mixture was concentrated in vacuo to remove DCM. The residue was purified by reverse phase preparative HPLC to give the title compound. LCMS: 575.4 [M+H] + ; 1H NMR (400MHz, methanol-d4) δ9.20–9.06(m,1H),8.24–8.05(m,4H),8.04–7.85(m,1H),7.76–7.66(m,2H),7.64–7.43(m,1H),4.51(s,2H),4.61–4. 34(m,1H),3.61(s,3H),3.54–3.30(m,4H),3.06–2.92(m,2H),2.90–2 .65(m,2H),2.02–1.71(m,4H),1.34–1.18(m,1H),1.18–0.94(m,3H).

[1030] Example 60:

[1031]

[1032] To a solution of compound 43-1 (20 mg, 0.033 mmol) in dioxane (2 mL) was added (tributyltin)methanol (32.0 mg, 0.100 mmol) and XPhos-Pd-G2 (2.6 mg, 0.003 mmol) at 25°C under N2. The resulting mixture was stirred at 100°C for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase preparative HPLC to obtain the title compound. LCMS: 553.4 [M+H] + ; 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.50 (s, 1H), 8.16–7.72 (m, 4H), 7.59–7.22 (m, 2H), 4.79 (s, 2H), 3.69 (s, 2H), 3.34–3.17 (m, 4H), 3.01–2.57 (m, 6H), 2.18–1.50 (m, 6H), 1.38–1.24 (m, 1H), 1.19–1.13 (m, 3H), 0.97–0.84 (m, 4H).

[1033] Example 62:

[1034]

[1035] Step 1: Preparation of compound 62-1

[1036] To a solution of 5-amino-2-chloroisonicotinic acid (5 g, 28.974 mmol) in DMF (100 mL) was added NIS (9.8 g, 43.461 mmol), and the reaction was stirred at 0 ° C for 10 minutes. The resulting solution was stirred at 80 ° C for 14 hours. After cooling to room temperature, the reaction mixture was poured into a saturated aqueous solution of Na2S2O3. The mixture was diluted with EtOAc (50 mL) and water (300 mL). The organic phase was separated and the aqueous phase was washed with EtOAc (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 62-1 (7.5 g, 86.7%). LCMS: 298.8 [M+H] + .

[1037] Step 2: Preparation of compound 62-2

[1038] To a solution of compound 62-1 (1 g, 3.350 mmol) in THF (1.5 mL) and MeOH (0.5 mL) was added TMSCHN2 (3.35 mL, 6.700 mmol) at 0°C, and the reaction was stirred at 0°C under N2 for 3 hours. The reaction solution was diluted with EtOAc (20 mL) and water (40 mL). The aqueous phase was extracted with EtOAc (10 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 62-2 (800 mg, 76.4%). LCMS: 312.9 [M+H] + .

[1039] Step 3: Preparation of compound 62-3

[1040] To a solution of compound 62-2 (710 mg, 2.272 mmol) in DMF (6 mL) were added CuI (519.4 mg, 2.726 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2182.3 mg, 11.360 mmol). The reaction was then stirred at 80 ° C under N2 for 5 hours. The reaction solution was diluted with EtOAc (15 mL) and water (30 mL). The aqueous phase was extracted with EtOAc (10 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 62-3 (162 mg, 28.0%). LCMS: 437.1 [M+H] + ;

[1041] Step 4: Preparation of compound 62-4

[1042] The title compound was synthesized according to step 2 in Example 22. LCMS: 332.1 [M+H] + ;

[1043] Step 5: Preparation of compound 62-5

[1044] To a solution of compound 62-4 (200 mg, 0.604 mmol) in formamide (3 mL) was added FA (0.3 mL) at 0°C. The mixture was stirred at 180°C for 14 hours. The reaction mixture was diluted with water (10 mL). The aqueous phase was extracted with EtOAc (10 mL×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel column chromatography to obtain compound 62-5. LCMS: 327.1 [M+H] + .

[1045] Step 6: Preparation of Example 62

[1046] The title compound was synthesized according to step 3 in Example 38. LCMS: 552.1 [M+H] + ; 1 H NMR (400 MHz, chloroform-d) δ 8.63 (s, 1H), 8.25 (s, 1H), 8.01 (s, 1H), 7.61–7.53 (m, 2H), 7.40 (s, 1H), 7.30 (s, 1H), 4.09 (s, 2H), 3.26 (s, 3H), 3.14–2.83 (m, 3H), 2.75–2.63 (m, 3H), 2.08–1.98 (m, 2H), 1.83–1.54 (m, 4H), 1.26 (s, 1H), 1.15 (d, J = 5.8 Hz, 3H), 1.06–0.96 (m, 1H), 0.90 (d, J = 6.2 Hz, 3H).

[1047] Example 63:

[1048]

[1049] The title compound was synthesized according to the method of Example 46. LCMS: 540.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ13.22(s,1H),8.47–8.25(m,2H),7.61–7.22(m,5H),4.48(s,2H),3.29–3.24(m,3H),3.17–3.10(m, 1H),3.03–2.76(m,3H),2.63–2.47(m,2H),2.41–2.14(m,2H),1.89–1.61(m,5H),1.11–0.96(m,4H),0.89(d,J=6.4Hz,3H).

[1050] Example 65:

[1051] Example 65 is the cis-trans-isomer of Example 55, which can be separated by preparative HPLC. LCMS: 552.4 [M+H] + ; 1 H NMR (400 MHz, methanol-d4) δ 8.84 (s, 1H), 8.82–8.52 (m, 3H), 8.50 (s, 1H), 7.81–7.41 (m, 2H), 4.62 (s, 2H), 3.45 (s, 3H), 3.28–3.10 (m, 2H), 3.08–2.89 (m, 2H), 2.81–2.64 (m, 2H), 2.61–2.41 (m, 2H), 2.03–1.72 (m, 5H), 1.24–1.14 (m, 4H), 1.00 (d, J = 6.4 Hz, 3H).

[1052] Example 66:

[1053]

[1054] Step 1: Preparation of compound 66-1

[1055] To a mixture of LiBr (624 mg, 7.186 mmol) and TEA (1.8 mL, 13.065 mmol) in THF (5 mL) was added diethyl (2-methoxy-2-oxoethyl)phosphonate (1441 mg, 6.859 mmol) at 0°C. Stirring was continued at 25°C for 2 hours. To this mixture was added a solution of 3-(3-bromophenyl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutan-1-one (1000 mg, 3.266 mmol) in THF (5 mL) at 0°C. The mixture was then stirred at 25°C for 14 hours. After concentration, the residue was purified by chromatography to give compound 66-1 (1100 mg, 89.52%). LCMS: 378.3 / 376.3 [M+H] + .

[1056] Step 2: Preparation of compound 66-2

[1057] To a solution of compound 66-1 (1.4 g, 3.721 mmol) and CuCl (0.22 g, 2.233 mmol) in MeOH (5 mL) was added NaBH4 (0.56 g, 14.884 mmol) at 25 ° C under N2. The reaction was stirred at 25 ° C for 1 hour. After completion, the reactant was filtered through a celite pad and the filtrate was concentrated to obtain a crude product. The residue was purified by flash silica gel column chromatography to obtain compound 66-2 (600 mg, 42.6%). LCMS: 379.9 / 378.2 [M+H] + .

[1058] Step 3: Preparation of compound 66-3

[1059] To a solution of compound 66-2 (600 mg, 1.586 mmol) in anhydrous DCM (10 mL) was added bis(2-methylpropyl)aluminum hydride (4.76 mL, 4.759 mmol) in portions at 0°C. The mixture was stirred at 0°C for 4 hours. The reaction was quenched by adding water at 0°C. The reactant was filtered through a celite pad, and the filtrate was concentrated to obtain a residue. The residue was purified by chromatography to obtain compound 66-3 (300 mg, 56.3%). LCMS: 336.3 / 338.2 [M+H] + ;

[1060] Step 4: Preparation of compound 66-4

[1061] Compound 66-3 (1.62 g, 4.818 mmol) and Cu2O (0.7 g, 4.818 mmol) were dissolved in CH3CN (5 mL) and NH3.H2O (10 mL). The mixture was stirred at 110°C for 1.5 hours under microwave. The mixture was filtered through a pad of celite, and the filtrate was concentrated to obtain a crude product. The crude product was purified by reverse phase chromatography to obtain compound 66-4 (1.1 g, 83.8%). LCMS: 273.4 [M+H] + .

[1062] Step 5: Preparation of compound 66-5

[1063] To a solution of compound 66-4 (990 mg, 3.322 mmol) in isopropanol (12 mL) was added 4-bromo-2-nitro-6-(trifluoromethyl)benzaldehyde (904 mg, 3.322 mmol), and the mixture was stirred at 80 ° C for 4 hours. Then, tributylphosphine (2013 mg, 9.966 mmol) was added, and the resulting mixture was stirred at 80 ° C for 16 hours. The mixture was cooled to room temperature and diluted with EtOAc (50 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel column chromatography to give compound 66-5 (400 mg, 23.1%). LCMS: 520.1 / 522.1 [M+H] + .

[1064] Step 6: Preparation of compound 66-6

[1065] Compound 66-6 was synthesized according to step 2 in Example 22. LCMS: 553.4 [M+H] + ;

[1066] Step 7: Preparation of compound 66-7

[1067] To a solution of DMP (107 mg, 0.253 mmol) in DCM (3 mL) was added compound 66-6 (70 mg, 0.127 mmol) at 0°C under nitrogen, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between DCM (20 mL) and saturated NaHCO3 (aqueous solution, 20 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column to obtain compound 66-7. LCMS: 551.4 [M+H] + .

[1068] Step 8: Preparation of Example 66

[1069] To a solution of compound 66-7 (50 mg, 0.091 mmol) and K2CO3 (25 mg, 0.182 mmol) in MeOH (3 mL) was added (1Z)-1-(diazo-1-ium)-1-[dimethoxy(oxo)-λ5-phosphinoalkyl]-prop-1-ene-2-olate (54 mg, 0.18 mmol) at 0°C under N2. The reaction was stirred at 25°C for 3 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC to give the title compound. LCMS: 547.4 [M+H] + .

[1070] Example 67:

[1071]

[1072] Step 1: Preparation of compound 67-1

[1073] According to step 3 in Example 38, compound 67-1 was synthesized using the corresponding starting materials. LCMS: 597.5 [M+H] + .

[1074] Step 2: Preparation of Example 67

[1075] To a solution of compound 67-1 (50 mg, 0.084 mmol) in MeCN (3 mL) was added H2SO4 (0.01 mL, 0.251 mmol), and the mixture was stirred at 25°C for 3 hours. The mixture was poured into water (10 mL), and the aqueous phase was basified to pH = 8-9 with 1M NaHCO3 (aq.), extracted with DCM (10 mL x 3), and the combined organic layers were concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC to give the title compound. LCMS: 551.4 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ8.59(s,1H),8.34–8.22(m,3H),7.67–7.63(m,1H),7.52 –7.50(m,1H),7.35–7.29(m,2H),4.33–4.24(m,4H),3.82–3.77(m,2H),3.65– 3.60(m,1H),3.50–3.40(m,4H),2.56(t,J=11.1Hz,1H),2.27–2.14(m,2H),2. 10–2.02(m,1H),1.97–1.94(m,2H),1.10–1.02(m,1H),0.96(d,J=5.5Hz,3H).

[1076] Example 68:

[1077]

[1078] Step 1-3: Preparation of compound 68-3

[1079] Compound 68-3 was synthesized according to steps 4 to 6 in Example 66. LCMS: 569.4 [M+H] + .

[1080] Step 4: Preparation of Example 68

[1081] The title compound was synthesized according to step 2 in Example 67. LCMS: 523.2 [M+H] + .

[1082] Example 70:

[1083]

[1084] Step 1: Preparation of compound 70-1

[1085] To a solution of (S)-tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (5 g, 23.223 mmol) in DCM (50 mL) was added DMP (12.8 g, 30.190 mmol). The resulting mixture was stirred at 0°C for 0.5 hours. The reaction mixture was stirred at 25°C for an additional 1.5 hours. The reaction mixture was diluted with a mixture of 1M Na2S2O3 (50 mL) and saturated aqueous NaHCO3 (50 mL) and stirred for 30 minutes. DCM (30 mL) was added, and the organic phase was separated, dried over anhydrous Na2SO4, and concentrated to afford compound 70-1 (2.4 g, 48.5%).

[1086] Step 2: Preparation of compound 70-2

[1087] To a solution of methyltriphenylphosphonium bromide (5.1 g, 14.177 mmol) in THF (12 mL) was added butyllithium (5.67 mL, 14.177 mmol), and the resulting mixture was stirred at -78 ° C. After stirring at 0 ° C for 30 minutes, the mixture was cooled to -78 ° C, and then a solution of compound 70-1 (2.4 g, 11.252 mmol) in THF (12 mL) was added and stirred at room temperature overnight. After completion, the reaction was quenched by adding brine (30 mL). The mixture was extracted with EtOAc (120 mL), and the organic phase was dried over Na2SO4 and concentrated in vacuo to give a residue, which was further purified by flash silica gel chromatography to give compound 70-2 (420 mg, 17.7%). LCMS: 212.3 [M+H] + .

[1088] Step 3: Preparation of compound 70-3

[1089] A solution of compound 70-2 (100 mg, 0.473 mmol) in DCM (1.5 mL) and TFA (0.5 mL) was stirred at 25°C for 1 hour. After completion, the mixture was concentrated to give compound 70-3 (50 mg, 95.0%). LCMS: 112.3 [M+H] + .

[1090] Step 4: Preparation of Example 70

[1091] The title compound was synthesized according to step 4 of Example 10 using intermediate 5 as a substrate. LCMS: 535.1 [M+H] + ; 1 H NMR (400 MHz, CHLOROFORM-d) δ 8.50 (s, 1H), 8.13–7.67 (m, 4H), 7.60–7.31 (m, 3H), 5.80–5.57 (m, 1H), 5.14–4.94 (m, 2H), 3.53–3.26 (m, 2H), 3.24 (s, 3H), 3.05–2.82 (m, 2H), 2.79–2.51 (m, 3H), 2.45–2.31 (m, 1H), 2.01–1.64 (m, 7H), 1.28–1.08 (m, 4H).

[1092] Example 71:

[1093] The title compound is the cis-trans isomer of Example 58, which can be separated by preparative HPLC. LCMS: 524.4 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.64(d,J=5.2Hz,1H),8.46(s,1H),8 .28(s,1H),7.84(s,1H),7.78(s,1H),7.64–7.52(m,1H),4.46(s,2H),3.26 (s,3H),2.90–2.85(m,2H),2.68–2.61(m,3H),2.38–2.32(m,3H),1.87–1. 65(m,5H),1.13(d,J=6.0Hz,3H),1.10–1.02(m,1H),0.88(d,J=6.4Hz,3H).

[1094] Example 72:

[1095]

[1096] Step 1: Preparation of compound 72-1

[1097] A mixture of 2-(3-bromo-4-fluorophenyl)acetic acid (10 g, 42.911 mmol) in MeOH (100 mL) was stirred at 0°C. Concentrated H2SO4 (2.287 mL, 42.911 mmol) was added dropwise while stirring, and the mixture was heated to reflux for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with H2O (50 mL) and extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 72-1 (10.3 g, 97.16%). LCMS: 524.4 [M+H] + .

[1098] Step 2: Preparation of compound 72-2

[1099] To a solution of compound 72-1 (8.7 g, 35.214 mmol) and 1,3-dibromo-2-methylpropane (7.60 g, 35.214 mmol) in DMF (5 mL) was added NaH (3.10 g, 77.471 mmol) at 0°C under N2. The mixture was stirred at 25°C for 2 hours. The reaction mixture was slowly poured into a saturated solution of ammonium chloride (300 mL). The mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give compound 72-2 (7.4 g, 69.8%). LCMS: 301 / 303.0 [M+H] + .

[1100] Step 3: Preparation of compound 72-3

[1101] Compound 72-3 was synthesized according to Step 2 to Step 5 in Example 31. LCMS: 324.0 / 326.0 [M+H] + ;

[1102] Step 4: Preparation of Example 72

[1103] The title compound was synthesized according to Step 4 to Step 6 in Example 66. LCMS: 541.1 [M+H] + .

[1104] Example 73:

[1105]

[1106] Step 1: Preparation of compound 73-1

[1107] To a solution of 2-amino-3-(trifluoromethyl)benzoic acid (10 g, 48.747 mmol) in DCM (100 mL) was added NBS (9.54 g, 53.622 mmol) and the reaction was stirred at 20°C under N2 for 1 hour. After cooling to room temperature, the reaction mixture was poured into saturated NaHCO3 (aqueous solution, 150 mL) and extracted with DCM (100 mL x 3). The combined organic layers were washed with brine (100 mL), then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was triturated with ethyl acetate / petroleum ether (1 / 3, 20 mL) at 25°C for 20 minutes, filtered, and the filter cake was dried to afford compound 73-1 (13.6 g, 98.23%). LCMS: 284.0 / 286.0 [M+H] + .

[1108] Step 2: Preparation of compound 73-2

[1109] To a solution of compound 73-1 (100 mg, 0.373 mmol) in TFA (30 mL) was added NaNO2 (1.09 g, 15.843 mmol) at 0°C, and the mixture was stirred at 0°C for 1 hour. Then, NaN3 (1.03 g, 15.843 mmol) was added to the mixture, and the mixture was stirred at 0°C for another 30 minutes. The resulting mixture was poured into water and the precipitate was collected by filtration to obtain compound 73-2 (3.5 g, 96.19%). LCMS: 310.0 / 312.0 [M+H] + .

[1110] Step 3: Preparation of compound 73-3

[1111] To a solution of compound 73-2 (640 mg, 2....

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: U is -N- or -CR 1 -; R 1 It is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl; R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; L 1 Does not exist or is -CR 3 R 4 -; R 3 and R 4 are independently hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R; or R 3 and R 4 together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more R; or R 3 and R 4 Together they form an oxo group; R 5 and R 6 are independently hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 5a replace; or R 5 and R 6 together to form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted by one or more R 5a replace; Each R 5a are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NR b )R b 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d ,-P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R; or two R on the same atom 5a Together they form an oxo group; X is -N- or -CR X -; R X It is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl; Y is -N- or -CR Y -; R Y It is hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens; Z is -N- or -CR Z -; R Z It is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl; or R X and R Y together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R; or R Y and R Z together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R; W is -N- or -CR W -; R W It is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Each R 7 are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NR b )R b 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d ,-P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R; or two R on the same atom 7 Together they form an oxo group; n is 0, 1, 2, 3, 4, 5, or 6; R 8 and R 9 are independently hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R; or R 8 and R 9 together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more R; or R 8 and R 9 Together they form an oxo group; Ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Each R 10 are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NR b )R b 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d ,-P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R; or two R on the same atom 10 Together they form an oxo group; m is 0, 1, 2, 3, 4, 5, or 6; Each R a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl), wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R; Each R b independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl), wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R; R c and R d each independently represents hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl), wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R; or R c and R d together with the atoms to which they are attached form heterocycloalkyl, which is optionally substituted with one or more R; and Each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl) 2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl; Or two R on the same atom form an oxo group; The condition is no Where * indicates the point of attachment to the ring containing X, Y, Z and W, and ** indicates the point of attachment to -CR 8 R 9 -Connection point.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Ia):

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (Id):

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R X It is hydrogen or C1-C6 alkyl.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R Y It is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl or cycloalkyl optionally substituted by one or more halogens.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R Y It is hydrogen, C3-C6 cycloalkyl or C1-C6 haloalkoxy.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R Y Yes-OR a .

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R Z It is hydrogen or C1-C6 alkyl.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R W It is hydrogen or C1-C6 alkyl.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 Each is independently hydrogen or C1-C6 alkyl.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5- or 6-membered heterocycloalkyl group.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Ring B is azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein each R 10 are independently halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl); wherein the alkyl, alkylene, alkynyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted by one or more R.

14. The compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein each R 10 independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl); wherein the alkyl, alkylene, alkynyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted by one or more R.

15. The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein each R 10 are independently halogen or C1-C6 alkyl.

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2 or 3.

17. The compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein yes 18. The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein yes 19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein L 1 Does not exist.

20. The compound of any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein L 1 Yes-CR 3 R 4 -.

21. The compound of any one of claims 1 to 18 or 20, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Each is independently hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl.

22. The compound of any one of claims 1-18 or 20 or 21, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Each is hydrogen.

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 6 It is hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl or C1-C6 haloalkyl.

24. The compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein R 6 It is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl.

25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R 6 It's hydrogen.

26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 5a replace.

27. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 5 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R 5a replace.

28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R 5 is cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl are each independently optionally substituted by one or more R 5a replace.

29. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 together forming optionally one or more R 5a Substituted cycloalkyl.

30. The compound of any one of claims 1-22 or 29, or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 together to form optionally one or more R 5a Substituted heterocycloalkyl.

31. The compound of any one of claims 1-22 or 29 or 30, or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 together to form optionally one or more R 5a Substituted cyclobutyl.

32. The compound of any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, wherein each R 5a are independently halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkynyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted by one or more R.

33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein each R 5a independently halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl or C2-C6 alkynyl; wherein the alkyl and alkynyl are each independently optionally substituted by one or more R.

34. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein yes 35. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein yes 36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R 1 It's hydrogen.

37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a C1-C6 alkyl group.

38. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein Ring A is a bicyclic cycloalkyl, a bicyclic heterocycloalkyl, a bicyclic aryl, or a bicyclic heteroaryl.

39. The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein Ring A is a bicyclic cycloalkyl or a bicyclic heterocycloalkyl.

40. The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein Ring A is a bicyclic aryl group or a bicyclic heteroaryl group.

41. The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein Ring A is a bicyclic heteroaryl.

42. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein Ring A is benzothiazolyl, benzimidazolyl, indazolyl, pyrazolopyridinyl, thiazolopyridinyl, quinoxalinyl or pyridopyrazinyl.

43. The compound of any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein Ring A is tetrahydroisoquinolinyl, dihydrophthalazinyl, dihydroisoquinolinyl, dihydroquinazolinyl, dihydropyrroloimidazolyl, dihydroimidazopyridinyl, dihydrothienopyridazinyl, dihydroindazolyl, tetrahydropyrrolopyridinyl or dihydropyrrolopyridine.

44. The compound of any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein each R 7 are independently halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; wherein each alkyl is independently optionally substituted with one or more R; or two R on the same atom 7 Together they form an oxo group.

45. The compound of any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein each R 7 are independently -OH, C1-C6 alkyl or C1-C6 haloalkyl; or two R on the same atom 7 Together they form an oxo group.

46. ​​The compound of any one of claims 1-45, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3 or 4.

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2 or 3.

48. The compound of any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein yes 49. A compound of formula (III) or a pharmaceutically acceptable salt thereof: in: U is -N- or -CR 1 -; R 1 It is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl; R 2 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; L 1 Does not exist or is -CR 3 R 4 -; R 3 and R 4 are independently hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R; or R 3 and R 4 together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more R; or R 3 and R 4 Together they form an oxo group; R 5 and R 6 are independently hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally replaced by one or more R 5a replace; or R 5 and R 6 together to form a cycloalkyl or heterocycloalkyl group; each of which is optionally substituted by one or more R 5a replace; Each R 5a are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NR b )R b 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d ,-P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R; or two R on the same atom 5a Together they form an oxo group; X is -N- or -CR X -; R X It is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl; Y is -N- or -CR Y -; R Y It is hydrogen, halogen, -CN, -OH, -OR a 、-NR c R d 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, cycloalkyl optionally substituted with one or more halogens, or heterocycloalkyl optionally substituted with one or more halogens; Z is -N- or -CR Z -; R Z It is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl; or R X and R Y together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R; or R Y and R Z together form a cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one or more R; W is -N- or -CR W -; R W It is hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl or heterocycloalkyl; X 3 , X 4 and X 5 Independently N or CR 7’ ; Each R 7’ are independently hydrogen, halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NR b )R b 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d ,-P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R; R 8 and R 9 are independently hydrogen, halogen, -CN, -OH, -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 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R; or R 8 and R 9 together form a cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one or more R; or R 8 and R 9 Together they form an oxo group; Ring B is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; Each R 10 are independently halogen, -CN, -NO2, -OH, -OR a 、-OC(=O)R a 、-OC(=O)OR b 、-OC(=O)NR c R d 、-SF5、-SH、-SR a 、-S(=O)R a 、-S(=O)2R a 、-S(=O)2NR c R d 、-S(=O)(=NR b )R b 、-NR c R d 、-NR b C(=O)NR c R d 、-NR b C(=O)R a 、-NR b C(=O)OR b 、-NR b S(=O)2R a 、-N=S(=O)(R b )2, -C(=O)R a 、-C(=O)OR b 、-C(=O)NR c R d ,-P(=O)(R b )2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted by one or more R; or two R on the same atom 10 Together they form an oxo group; m is 0, 1, 2, 3, 4, 5, or 6; Each R a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl), wherein the alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R; Each R b independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl), wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R; R c and R d each independently represents hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl), wherein said alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally substituted with one or more R; or R c and R d together with the atoms to which they are attached form heterocycloalkyl, which is optionally substituted with one or more R; and Each R is independently halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl) 2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl; Or two R on the same atom form an oxo group.

50. The compound of claim 49, or a pharmaceutically acceptable salt thereof, wherein X is -N-.

51. The compound of claim 49 or a pharmaceutically acceptable salt thereof, wherein X is -CR X -.

52. The compound of any one of claims 49-51, or a pharmaceutically acceptable salt thereof, wherein Y is -N-.

53. The compound of any one of claims 49-51 or a pharmaceutically acceptable salt thereof, wherein Y is -CR Y -.

54. The compound of any one of claims 49-53, or a pharmaceutically acceptable salt thereof, wherein Z is -N-.

55. The compound of any one of claims 49-54, or a pharmaceutically acceptable salt thereof, wherein Z is -CR Z -.

56. The compound of any one of claims 49-55, or a pharmaceutically acceptable salt thereof, wherein W is -N-.

57. The compound of any one of claims 49-55, or a pharmaceutically acceptable salt thereof, wherein W is -CR W -.

58. The compound of claim 49 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IIId):

59. The compound of any one of claims 49-58 or a pharmaceutically acceptable salt thereof, wherein R X It is hydrogen or C1-C6 alkyl.

60. The compound of any one of claims 49 to 59, or a pharmaceutically acceptable salt thereof, wherein R X It's hydrogen.

61. The compound of any one of claims 49-60, or a pharmaceutically acceptable salt thereof, wherein R Y It is hydrogen, halogen, -CN, -OR a 、-C(=O)NR c R d , C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkenyl, C2-C6 alkynyl or cycloalkyl optionally substituted by one or more halogens.

62. The compound of any one of claims 49-61 or a pharmaceutically acceptable salt thereof, wherein R Y is hydrogen, -OR a or cycloalkyl optionally substituted by one or more halogens.

63. The compound of any one of claims 49-62, or a pharmaceutically acceptable salt thereof, wherein R Y is hydrogen, -OR a or a cycloalkyl group.

64. The compound of any one of claims 49-63 or a pharmaceutically acceptable salt thereof, wherein R Y Yes-OR a .

65. The compound of any one of claims 49-64, or a pharmaceutically acceptable salt thereof, wherein R Y It is -OCH2F.

66. The compound of any one of claims 49-63, or a pharmaceutically acceptable salt thereof, wherein R Y It's hydrogen.

67. The compound of any one of claims 49-66, or a pharmaceutically acceptable salt thereof, wherein R Z It is hydrogen or C1-C6 alkyl.

68. The compound of any one of claims 49-67 or a pharmaceutically acceptable salt thereof, wherein R Z It's hydrogen.

69. The compound of any one of claims 49-68, or a pharmaceutically acceptable salt thereof, wherein R W It is hydrogen or C1-C6 alkyl.

70. The compound of any one of claims 49-69 or a pharmaceutically acceptable salt thereof, wherein R W It's hydrogen.

71. The compound of any one of claims 49-70, or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 Each is independently hydrogen or C1-C6 alkyl.

72. The compound of any one of claims 49-71 or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 Each is hydrogen.

73. The compound according to any one of claims 49 to 72, or a pharmaceutically acceptable salt thereof, wherein Ring B is a 5- or 6-membered heterocycloalkyl group.

74. The compound of any one of claims 49 to 73, or a pharmaceutically acceptable salt thereof, wherein Ring B is azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.

75. The compound of any one of claims 49 to 74, or a pharmaceutically acceptable salt thereof, wherein Ring B is piperidinyl.

76. The compound of any one of claims 49-75, or a pharmaceutically acceptable salt thereof, wherein each R 10 independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, C1-C6 alkylene(cycloalkyl) or C1-C6 alkylene(heterocycloalkyl); wherein the alkyl, alkylene, alkynyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted by one or more R.

77. The compound of any one of claims 49-76 or a pharmaceutically acceptable salt thereof, wherein each R 10 are independently halogen or C1-C6 alkyl.

78. The compound of any one of claims 49-77 or a pharmaceutically acceptable salt thereof, wherein each R 10 are independently C1-C6 alkyl.

79. The compound of any one of claims 49-78, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.

80. The compound of any one of claims 49-71 or a pharmaceutically acceptable salt thereof, wherein yes 81. The compound of any one of claims 49-71 or a pharmaceutically acceptable salt thereof, wherein yes 82. The compound of any one of claims 49-81 or a pharmaceutically acceptable salt thereof, wherein L 1 Does not exist.

83. The compound of any one of claims 49-81 or a pharmaceutically acceptable salt thereof, wherein L 1 Yes-CR 3 R 4 -.

84. The compound of any one of claims 49-81 or 82, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 Each is hydrogen.

85. The compound of any one of claims 49-84, or a pharmaceutically acceptable salt thereof, wherein R 6 It is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl.

86. The compound of any one of claims 49-85, or a pharmaceutically acceptable salt thereof, wherein R 6 It's hydrogen.

87. The compound of any one of claims 49-86, or a pharmaceutically acceptable salt thereof, wherein R 5 is cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl are each independently optionally substituted by one or more R 5a replace.

88. The compound of any one of claims 49-84, or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 together to form optionally one or more R 5a Substituted cycloalkyl.

89. The compound of any one of claims 49-84 or 88, or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 together forming optionally one or more R 5a Substituted heterocycloalkyl.

90. The compound of any one of claims 49-84 or 88, or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 together forming optionally one or more R 5a Substituted cyclobutyl.

91. The compound of any one of claims 49-80 or a pharmaceutically acceptable salt thereof, wherein each R 5a are independently halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkynyl, cycloalkyl and heterocycloalkyl are each independently optionally substituted by one or more R.

92. The compound of any one of claims 49-91 or a pharmaceutically acceptable salt thereof, wherein each R 5a independently halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl or C2-C6 alkynyl; wherein the alkyl and alkynyl are each independently optionally substituted by one or more R.

93. The compound of any one of claims 49-81 or a pharmaceutically acceptable salt thereof, wherein yes 94. The compound of any one of claims 49-81 or a pharmaceutically acceptable salt thereof, wherein yes 95. The compound of any one of claims 49-81 or a pharmaceutically acceptable salt thereof, wherein yes 96. Compound 49-95 or a pharmaceutically acceptable salt thereof according to any one of claims 49 to 95, wherein yes 97. The compound of any one of claims 49-95 or a pharmaceutically acceptable salt thereof, wherein yes 98. The compound of any one of claims 49-95 or a pharmaceutically acceptable salt thereof, wherein yes 99. The compound of any one of claims 49-98 or a pharmaceutically acceptable salt thereof, wherein each R 7’ are independently hydrogen or C1-C6 haloalkyl.

100. The compound of any one of claims 49-99 or a pharmaceutically acceptable salt thereof, wherein each R 7’ is independently hydrogen or -CF3.

101. A compound according to any one of claims 49 to 95, or a pharmaceutically acceptable salt thereof, wherein yes 102. The compound of claim 1 or 49, or a pharmaceutically acceptable salt thereof, selected from the compounds in Table 1 or Table 2.

103. A pharmaceutical composition comprising a compound according to any one of claims 1 to 102 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

104. A method for modulating the activity of an immune cell, the method comprising contacting the immune cell with an effective amount of a compound according to any one of claims 1 to 102 or a pharmaceutically acceptable salt thereof.

105. A method of treating cancer, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-102, or a pharmaceutically acceptable salt thereof.

106. A method of treating a cancer responsive to inhibition of Cbl-b activity, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-102, or a pharmaceutically acceptable salt thereof.

107. The method of claim 105 or 106, wherein the cancer is a hematological cancer.

108. The method of claim 105 or 106, wherein the cancer is lymphoma, leukemia, or myeloma.

109. The method of claim 105 or 106, wherein the cancer is a non-hematological cancer.

110. The method of claim 105 or 106, wherein the cancer is a sarcoma, carcinoma, or melanoma.

111. The method of claim 105 or 106, wherein the cancer is a solid tumor.

112. A method of inhibiting abnormal cell proliferation, the method comprising administering to an individual in need thereof an effective amount of a compound according to any one of claims 1 to 102 or a pharmaceutically acceptable salt thereof.

113. A method of modulating an immune response, the method comprising administering to an individual in need thereof an effective amount of a compound of any one of claims 1-102, or a pharmaceutically acceptable salt thereof.

114. A method of inhibiting Cbl-b activity, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-102 or a pharmaceutically acceptable salt thereof.

115. A method of treating a disease or condition associated with Cbl-b activity, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-102, or a pharmaceutically acceptable salt thereof.

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