Polyhexacyclic compounds as METTL3 inhibitors

Abstract

This invention relates to compounds of formula (I) that act as inhibitors of the activity of METTL3 (N6-adenosine-methyltransferase 70 kDa subunit): X-Y-Z (I), wherein X, Y, and Z are each as defined herein. The invention also relates to methods for preparing these compounds, pharmaceutical compositions comprising them, and their use in treating proliferative diseases (e.g., cancer) and autoimmune diseases involving METTL3 activity, as well as other diseases or conditions.

Description

Technical Field

[0001] This invention relates to certain compounds that function as inhibitors of METTL3 (N6-adenosine-methyltransferase 70 kDa subunit) activity. The invention also relates to methods for preparing these compounds, pharmaceutical compositions comprising them, and their use in treating proliferative diseases (e.g., cancer), autoimmune diseases, neurological disorders, infectious diseases, inflammatory diseases, and other diseases or conditions involving METTL3 activity. Background Technology

[0002] N6-methyladenosine (m6A) is the most common and abundant covalent modification of messenger RNA, regulated by its "writer," "eraser," and "reader" mechanisms (Meyer & Jaffrey 2014, Niu Yet et al., 2013, Yue et al., 2015). Approximately 0.1% to 0.5% of all mRNA adenosines are modified with m6A (Li Y et al., 2015). In vitro data show that m6A affects fundamental aspects of mRNA biology, primarily mRNA expression, splicing, stability, localization, and translation (Meyer et al., 2015; Sledz & Jinek 2016). M6A modification is tissue-specific, and its occurrence profile varies significantly in non-disease-prone tissues (e.g., brain, heart, kidney) as well as in disease-prone tissues and cells (lung, kidney, breast, and leukemia cancer cells) (Meyer et al., 2012).

[0003] The m6A modification and its erasers and writers, such as FTO, ALKBH5, methyltransferase-like 3 (METTL3) and METTL14, are associated with major diseases such as solid organ cancer, leukemia, type 2 diabetes, neuropsychiatric disorders and depression (Chandola et al 2015; Koranda et al 2018).

[0004] RNA methyltransferase METTL3 is a major, but not the only, enzyme catalyzing m6A modification of RNA. It exists as a heterotrimeric complex with METTL14 (Liu et al 2014, Wang et al 2016) and Wilm's Tumour Associated Protein (WTAP) (Ping et al 2014). Catalytic activity is present in METTL3, which transfers methyl groups from the cofactor S-adenosylmethionine to the substrate RNA, while METTL14 promotes substrate RNA binding. WTAP localizes the complex to specific nuclear regions and also localizes RNA substrates to the complex (Wang X et al 2016).

[0005] METTL3 has been reported to play a role in many aspects of cancer development (Fry et al 2018). Genetic knockdown of METTL3 in lung cancer cell lines (A549, H1299, and H1792) and HeLa cells resulted in reduced growth, survival, and invasion of human lung cancer cells (Lin S et al 2016). METTL3 is significantly upregulated in human bladder cancer (Cheng et al 2019). Knockdown of METTL3 significantly reduced in vitro proliferation, invasion, and survival of bladder cancer cells, as well as in vivo tumorigenicity. AF4 / FMR2 family member 4 (AFF4), two key regulators of the NF-κB pathway (IKBKB and RELA), and MYC have also been identified as direct targets of METTL3-mediated m6A modification. In renal cell carcinoma lines (CAK-1, CAK-2, and ACHN), genetic knockdown reduces cell proliferation via the phosphatidylinositol 3-kinase (PI3K) / AKT / mammalian target of rapamycin (mTOR) signaling pathway (Li X et al 2017).

[0006] Recently, Barbieri et al. (2017) defined a group of RNA-modifying enzymes essential for AML leukemia and identified the key leukemic pathway of the METTL3 RNA methyltransferase. In this pathway, METTL3 is stably recruited by the CCAAT-box-binding transcription factor CEBPZ to the promoters of a specific set of active genes, leading to m6A methylation of their respective mRNAs and enhancing translation. An important target is the oncogene SP1, which regulates c-MYC expression in several cancers. Consistent with these findings, METTL3 has been reported to co-transcribe its target with methylation.

[0007] The pathway described by Barbieri et al. is crucial for AML leukemia because its three components are required for AML cell growth: (i) the m6A RNA methyltransferase METTL3; (ii) the transcription factor CEBPZ, which targets this enzyme to its promoter; and (iii) SP1, whose translation depends on m6A modification via METTL3. In summary, Barbieri et al.'s observations define METTL3 enzyme activity as a novel candidate target for the treatment of AML.

[0008] In separate, independent studies, METTL3 has been reported to play a crucial role in controlling the myeloid differentiation of normal hematopoietic cells and leukemia cells in mammals (Vu et al 2017). Forced expression of wild-type METTL3, rather than mutant METTL3 (which is defective in catalytic activity), significantly promoted cell proliferation and inhibited differentiation in human cord blood-derived CD34+ hematopoietic stem / progenitor cells (HSPCs). Genetic knockdown of METTL3 had the opposite effect. METTL3 was highly expressed in AML compared to normal HSPCs or other cancer types. Knockdown of METTL3 in human AML cell lines significantly induced cell differentiation and apoptosis and inhibited leukemia progression in mice xenografted with MOLM-13AML cells. The biological function of METTL3 may be attributed to its m6A-dependent promotion of the translation of its mRNA targets, such as MYC, BCL-2, and PTEN.

[0009] Recently, METTL3-mediated m6A modification has been shown to play a crucial role in T cell homeostasis and signal-dependent induced mRNA degradation in CD4-positive T cell lineages (Li et al., 2017). The absence of METTL3 in mouse T cells disrupts T cell homeostasis and differentiation. In a mouse adoptive transfer model of lymphopenia, primordial METTL3-deficient T cells were unable to undergo homeostatic expansion and remain in a primordial state for up to 12 weeks, thereby preventing colitis. Consistent with these observations, mRNAs encoding the SOCS family genes encoding the STAT signaling repressors SOCS1, SOCS3, and CISH were m6A-tagged, exhibiting slower mRNA decay and increased mRNA and protein expression levels in METTL3-deficient primordial T cells. This enhanced SOCS family activity thus inhibited IL-7-mediated STAT5 activation and T cell homeostatic proliferation and differentiation. Therefore, METTL3-mediated m6A methylation plays an important role in the inducible degradation of Socs mRNA in response to IL-7 signaling, in order to reprogram primordial T cells for proliferation and differentiation, suggesting its role in autoimmunity.

[0010] Recent research has revealed that METTL3 depletion leads to alterations in the replication of various viruses (Winkler et al.). Following viral infection or stimulation of cells with inactivated viruses, the loss of the m6A "writer" METTL3 results in increased induction of interferon-stimulated genes. Consequently, the replication of various viruses is suppressed in an interferon signaling-dependent manner. Notably, IFNB mRNA is modified with m6A and stabilizes after METTL3 inhibition. m6A acts as a negative regulator of the interferon response by directing rapid switching of interferon mRNA and thus promoting viral replication.

[0011] METTL3-dependent m6A regulation on the HBV and HCV viral genomes is mediated by RIG-IRNA sensors that recognize the viral genome. METTL3 depletion enhances viral dsRNA recognition and induces antiviral immune responses (Kim et al.).

[0012] Therefore, METTL3 inhibitors could offer novel treatment options for a range of infectious and inflammatory diseases. In particular, they offer potential therapeutic applications for viral diseases, such as DNA and RNA viruses.

[0013] Furthermore, METTL3-dependent m6A regulation on endogenous mRNA is recognized by MAVS-dependent RNA sensors. METTL3 depletion enhances endogenous dsRNA recognition and induces autoimmune responses (Gao et al.). This suggests that antitumor immune responses can be enhanced by METTL3 inhibition.

[0014] Therefore, METTL3 inhibitors may also provide new treatment options to enhance anti-tumor immune responses.

[0015] References

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[0040] One object of the present invention is to provide an inhibitor of METTL3 activity. Summary of the Invention

[0041] In one aspect, the present invention provides compounds as defined herein or pharmaceutically acceptable salts thereof.

[0042] In another aspect, the present invention provides pharmaceutical compositions as defined herein, comprising a compound as defined herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0043] In another aspect, the present invention provides compounds as defined herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for therapeutic purposes.

[0044] In another aspect, the present invention provides compounds as defined herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for the treatment of proliferative disorders.

[0045] In another aspect, the present invention provides compounds as defined herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for the treatment of cancer. In one specific embodiment, the cancer is human cancer.

[0046] In another aspect, the present invention provides compounds as defined herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for inhibiting METTL3 activity.

[0047] In another aspect, the present invention provides compounds as defined herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for promoting immune responses (e.g., antiviral or antitumor immune responses).

[0048] In another aspect, the present invention provides compounds as defined herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for enhancing innate immune responses in subjects.

[0049] In another aspect, the present invention provides compounds as defined herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for enhancing or strengthening antitumor immune responses during immuno-oncology therapy.

[0050] In another aspect, the present invention provides compounds as defined herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for the treatment of autoimmune diseases.

[0051] In another aspect, the present invention provides compounds as defined herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for the treatment of nervous system disorders.

[0052] In another aspect, the present invention provides compounds as defined herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for the treatment of infectious diseases.

[0053] In another aspect, the present invention provides compounds as defined herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for the treatment of viral infections. Suitably, the viral infection is an RNA virus infection. Suitably, the viral infection is human papillomavirus (HPV) or hepatitis.

[0054] In another aspect, the present invention provides compounds as defined herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for the treatment of inflammatory diseases.

[0055] In another aspect, the present invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating proliferative disorders.

[0056] In another aspect, the present invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating cancer. In one specific embodiment, the medicament is used to treat human cancer.

[0057] In another aspect, the present invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for inhibiting METTL3 activity.

[0058] In another aspect, the present invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for promoting immune responses (e.g., antiviral or antitumor immune responses).

[0059] In another aspect, the present invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for enhancing innate immune responses in subjects.

[0060] In another aspect, the present invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for enhancing or strengthening antitumor immune responses during immuno-oncology therapy.

[0061] In another aspect, the present invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of autoimmune diseases.

[0062] In another aspect, the present invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating nervous system disorders.

[0063] In another aspect, the present invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating infectious diseases.

[0064] In another aspect, the present invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating viral infections. Suitably, the viral infection is an RNA virus infection. Suitably, the viral infection is human papillomavirus (HPV) or hepatitis.

[0065] In another aspect, the present invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating inflammatory diseases.

[0066] In another aspect, the present invention provides a method for inhibiting METTL3 activity in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as defined herein.

[0067] In another aspect, the present invention provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound or pharmaceutically acceptable salt as defined herein or a pharmaceutical composition as defined herein.

[0068] In another aspect, the present invention provides a method for inhibiting metastasis in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound or pharmaceutically acceptable salt as defined herein or a pharmaceutical composition as defined herein.

[0069] In another aspect, the present invention provides a method for promoting an immune response (e.g., an antiviral or antitumor immune response) in a subject in which such a need exists, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein, or a pharmaceutical composition as defined herein.

[0070] In another aspect, the present invention provides a method for enhancing an innate immune response in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein, or a pharmaceutical composition as defined herein.

[0071] In another aspect, the present invention provides a method for enhancing or strengthening an antitumor immune response during immuno-oncology therapy, the method comprising administering to a subject in need a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein, or a pharmaceutical composition as defined herein.

[0072] In another aspect, the present invention provides a method for treating proliferative disorders, the method comprising administering to a subject in need a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein, or a pharmaceutical composition as defined herein.

[0073] In another aspect, the present invention provides a method for treating cancer, the method comprising administering to a subject in need a therapeutically effective amount of a compound or pharmaceutically acceptable salt, as defined herein, or a pharmaceutical composition, as defined herein.

[0074] In another aspect, the present invention provides a method for treating autoimmune diseases, the method comprising administering to a subject in need a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein, or a pharmaceutical composition as defined herein.

[0075] In another aspect, the present invention provides a method for treating a neurological disorder, the method comprising administering to a subject in need a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein, or a pharmaceutical composition as defined herein.

[0076] In another aspect, the present invention provides a method for treating an infectious disease, the method comprising administering to a subject in need a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein, or a pharmaceutical composition as defined herein.

[0077] In another aspect, the present invention provides a method for treating a viral infection, the method comprising administering to a subject in need a therapeutically effective amount of a compound or pharmaceutically acceptable salt, as defined herein, or a pharmaceutical composition, as defined herein. Suitably, the viral infection is an RNA virus infection. Suitably, the viral infection is human papillomavirus (HPV) or hepatitis.

[0078] In another aspect, the present invention provides a method for treating inflammatory diseases, the method comprising administering to a subject in need a therapeutically effective amount of a compound or pharmaceutically acceptable salt as defined herein, or a pharmaceutical composition as defined herein.

[0079] In another aspect, the invention provides combinations comprising compounds as defined herein or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents.

[0080] The present invention also provides methods for synthesizing compounds or pharmaceutically acceptable salts as defined herein.

[0081] In another aspect, the present invention provides compounds or pharmaceutically acceptable salts as defined herein, which can be obtained by or directly by synthetic methods as defined herein.

[0082] In another aspect, the present invention provides novel intermediates as defined herein, which are suitable for use in any of the synthetic methods described herein.

[0083] Preferred, suitable, and optional features of any particular aspect of the invention are also preferred, suitable, and optional features of any other aspect. Detailed Implementation

[0084] definition

[0085] Unless otherwise stated, the following terms used in the specification and claims have the meanings listed below.

[0086] It should be understood that the term “treatment” includes prevention and relief of symptoms of an identified condition. Therefore, “treatment” for a state, disorder, or condition includes: (1) preventing or delaying the occurrence of clinical symptoms of the state, disorder, or condition in persons who may have or are susceptible to the state, disorder, or condition but have not yet experienced or exhibited clinical or subclinical symptoms of the state, disorder, or condition; (2) suppressing the state, disorder, or condition, i.e., arresting, reducing, or delaying the onset or recurrence of the disease (in the case of maintenance treatment) or at least one of its clinical or subclinical symptoms; or (3) alleviating or reducing the disease, i.e. leading to the resolution of the state, disorder, or condition or at least one of its clinical or subclinical symptoms.

[0087] "Therapeutic effective dose" refers to the amount of a compound that is sufficient to achieve such a therapeutic effect when administered to a mammal to treat a disease. The "therapeutic effective dose" will vary depending on the compound, the disease and its severity, and the age and weight of the mammal to be treated.

[0088] In this specification, the term "alkyl" includes both straight-chain and branched alkyl groups. References to a single alkyl group, such as "propyl," specify only the straight-chain form, while references to a single branched alkyl group, such as "isopropyl," specify only the branched form. For example, "C..." 1-6 "alkyl" includes C 1-4 Alkyl, C 1-3 Alkyl, propyl, isopropyl, and tert-butyl. Similar conventions apply to other groups, such as "phenyl (C 1-6 "alkyl" includes phenyl (C 1-4 Alkyl), benzyl, 1-phenylethyl and 2-phenylethyl.

[0089] The terms “(m-nC)” or “Cm-n” or “(m-nC) group” or “Cm-n”, used alone or as a prefix, refer to any group having m to n carbon atoms.

[0090] As used herein, the term "alkenyl" refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyl" and "substituted alkenyl," the latter referring to an alkenyl moiety having a substituent that replaces a hydrogen atom on one or more carbons of the alkenyl group. Such substituents may be present on one or more carbons, including or not included in one or more double bonds. Furthermore, as discussed below, such substituents include all substituents contemplated for alkyl groups, unless stability is limited. For example, substitution of the alkenyl group with one or more alkyl, carbocyclic, aryl, heterocyclic, or heteroaryl groups is contemplated.

[0091] As used herein, the term "alkynyl" refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyl" and "substituted alkynyl," the latter referring to an alkynyl moiety having a substituent that replaces a hydrogen atom on one or more carbons of the alkynyl group. Such substituents may be present on one or more carbons, including or not included in one or more triple bonds. Furthermore, as discussed above, such substituents include all substituents contemplated for alkyl groups, unless stability is limited. For example, it is contemplated that the alkynyl group be substituted with one or more alkyl, carbocyclic, aryl, heterocyclic, or heteroaryl groups.

[0092] An alkylene group is an alkyl group located between two other chemical groups and used to connect the two other chemical groups. Therefore, "C 1-3"Alkylene" refers to a straight-chain saturated divalent hydrocarbon group with 1 to 3 carbon atoms or a branched saturated divalent hydrocarbon group with 3 atoms, such as methylene, ethylene, propylene, etc.

[0093] Term "C" m-n "Cycloalkyl" refers to a hydrocarbon ring containing m to n carbon atoms, such as "C 3-6 "Cycloalkyl" refers to a hydrocarbon ring containing 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The term "C"... m-n "Cycloalkyl" also encompasses non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spirobicyclic carbocyclic systems. The term "C" m-n "Cycloalkyl" includes both monovalent and divalent substances. A monocyclic "C" m-n The cycloalkyl ring contains about 3 to 12 (suitably 3 to 8, most preferably 5 to 6) cyclic carbon atoms. The bicyclic "C" ring... m-n "Cycloalkyl" contains 7 to 17 cyclic carbon atoms, suitably 7 to 12 cyclic carbon atoms. Bicyclic "C" m-n The cycloalkyl ring can be a fused, spiro, or bridged ring system.

[0094] The term "cycloalkoxy" refers to a cycloalkyl-O- group, wherein the cycloalkyl group is as previously defined, for example, C0. 3-4 Cycloalkoxy (or -OC) 3-4 Cycloalkyl refers to a hydrocarbon ring containing 3 to 4 carbon atoms bonded to an oxygen atom, for example:

[0095]

[0096] The term "halogen" or "halogenated" refers to fluorine, chlorine, bromine, and iodine.

[0097] The terms "heterocyclic group," "heterocyclic," or "heterocycle" refer to a non-aromatic, saturated or partially saturated monocyclic, fused, bridged, or spirobicyclic heterocyclic ring system. The term heterocyclic group includes both monovalent and divalent substances. Monocyclic heterocycles contain about 3 to 12 (suitably 3 to 7, most preferably 5 to 6) ring atoms, with 1 to 5 (suitably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. Bicyclic heterocycles contain 7 to 17 member atoms, suitably 7 to 12 member atoms. Bicyclic heterocycles can be fused, spiro, or bridged ring systems. Some examples of heterocyclic groups include cyclic ethers such as ethylene oxide, oxobutyryl, tetrahydrofuranyl, and dicyclic ethers. Alkyl and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, aziridine, pyrrolidinyl, piperidinyl, piperazine, tetrahydrotriazine, tetrahydropyrazolyl, etc. Typical sulfur-containing heterocycles include tetrahydrothiophene, dihydro-1,3-dithiol, tetrahydro-2H-thiaran, and hexahydrothiepine. Other heterocycles include dihydro-oxathiolyl, tetrahydro- azole group, tetrahydro- diazole group, tetrahydrodihydride azole group, tetrahydro- Thiazolyl, hexahydrotriazine, tetrahydro- Azine group, morpholino group, thiomorpholino group, tetrahydropyrimidinyl group, di Dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl are all examples of heterocyclic compounds. For sulfur-containing heterocycles, sulfur oxide heterocycles containing SO or SO2 groups are also included. Some examples include sulfoxide and sulfone forms of tetrahydrothiophene and thiomorpholinyl, such as tetrahydrothiophene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values ​​for heterocyclic groups with one or two oxo (=O) or thio (=S) substituents are, for example, 2-oxopyrrolyl, 2-thiopyrrolyl, 2-oxopyrazoleyl, 2-thioimidazolyl, 2-oxopyridinyl, 2,5-dioxopyrrolyl, 2,5-dioxopyridinyl, or 2,6-dioxopyridinyl. Specific heterocyclic groups are saturated monocyclic 3- to 7-membered heterocyclic groups containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or sulfur, such as azo-heterocyclic butyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothiophenyl, tetrahydrothiophenyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl, or homopiperazinyl. As those skilled in the art will understand, any heterocycle can be linked to another group by any suitable atom (e.g., by a carbon or nitrogen atom). However, references to piperidinyl or morpholinyl herein refer to piperidin-1-yl or morpholin-4-yl rings linked by a cyclic nitrogen atom.

[0098] "Carbon-linked heterocyclic group" means a heterocyclic group as defined above, which is linked by a carbon atom rather than a heteroatom (such as nitrogen).

[0099] "Spirocyclic ring system" refers to a compound having at least two rings, wherein the rings have only one common atom and are not connected by a bridge.

[0100] A "fused ring system" refers to a compound in which two rings share two adjacent atoms. In other words, these rings share a single covalent bond.

[0101] "Bridged ring system" refers to a ring system in which two rings share more than two atoms, see, for example, Jerry March, Advanced Organic Chemistry, 4th ed., Wiley Interscience, pp. 131-133, 1992. Some examples of bridging heterocyclic ring systems include azabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, azabicyclo[2.2.2]octane, azabicyclo[3.2.1]octane, and quinine ring.

[0102] The term "heteroaryl" or "heteroaromatic" refers to an aromatic monocyclic, bicyclic, or polycyclic compound containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur (e.g., 1 to 4, particularly 1, 2, or 3). The term heteroaryl includes both monovalent and divalent compounds. Some examples of heteroaryls are monocyclic and bicyclic groups containing five to twelve ring members, and more typically five to ten ring members. Heteroaryls can be, for example, 5- or 6-membered monocyclic or 9- or 10-membered bicyclic, such as a bicyclic structure formed by fused five- and six-membered rings or two fused six-membered rings. Each ring may contain up to about four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain up to three heteroatoms, more typically up to two, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one cyclic nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic (as in the case of imidazole or pyridine) or substantially non-basic (as in the case of indole or pyrrole nitrogen). Typically, the number of basic nitrogen atoms present in a heteroaryl group (including any amino substituents in the ring) will be less than five.

[0103] Some examples of heteroaryl groups include furanyl, pyrroleyl, and thiophenyl. azole group, iso Azolyl, imidazole, pyrazolyl, thiazolyl, isothiazolyl, Diazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indoleyl, isoyindoleyl, benzothiopheneyl, benzo[] Azolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazole, purine, benzofurazanyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinolinyl, pteridinyl, naphthinyl, carbazole, phenazinyl, benzoisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furano[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o- Zinazinyl, 1H-pyrazolo[4,3-d] Azolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl. "Heteroaryl" also encompasses partially aromatic bicyclic or polycyclic systems in which at least one ring is an aromatic ring and one or more other rings are non-aromatic, saturated, or partially saturated rings, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, or sulfur. Some examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothiophene, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]di Alkenyl, benzo[1,3]-m-dioxacyclopentenyl, 2,2-dioxo-1,3-dihydro-2-benzothiophene, 4,5,6,7-tetrahydrobenzofuranyl, dihydroindolyl, 1,2,3,4-tetrahydro-1,8-naphthidyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, and 3,4-dihydro-2H-pyrido[3,2-b][1,4] Azine group.

[0104] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, furazanyl, and others. azole group, diazole group, Triazole group, iso Azolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl.

[0105] Examples of six-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridinyl, pyrimidinyl, and triazinyl.

[0106] The bicyclic heteroaryl group can be, for example, selected from the following groups:

[0107] A benzene ring fused with a 5- or 6-membered ring containing 1, 2, or 3 heteroatoms;

[0108] A pyridine ring fused with a 5- or 6-membered ring containing 1, 2, or 3 cyclic heteroatoms;

[0109] A pyrimidine ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0110] A pyrrole ring fused with a 5- or 6-membered ring containing 1, 2, or 3 cyclic heteroatoms;

[0111] A pyrazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0112] A pyrazine ring fused with a 5- or 6-membered ring containing 1 or 2 cyclic heteroatoms;

[0113] An imidazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0114] Fused with 5- or 6-membered rings containing 1 or 2 heteroatoms azole ring;

[0115] heterocyclic compounds fused with 5- or 6-membered rings containing 1 or 2 heteroatoms azole ring;

[0116] A thiazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0117] An isothiazole ring fused with a 5- or 6-membered ring containing 1 or 2 heteroatoms;

[0118] Thiophene rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

[0119] Furan rings fused with 5- or 6-membered rings containing 1, 2, or 3 heteroatoms;

[0120] Cyclohexyl rings fused with 5- or 6-membered heteroaromatic rings containing 1, 2, or 3 cyclic heteroatoms; and

[0121] A cyclopentyl ring fused with a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 cyclic heteroatoms.

[0122] Specific examples of bicyclic heteroaryl groups comprising a six-membered ring fused with a five-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, and benzo[…]. azole group, benzo[a] Azolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indoleyl, isoindoleyl, indoleyl, dihydroindoleyl, isodihydroindoleyl, purineyl (e.g., adenineyl, guanineyl), indoleyl, benzo-m-dioxacyclopentenyl, and pyrazolopyridyl.

[0123] Specific examples of bicyclic heteroaryl groups comprising two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isocherenyl, chromanyl, isocherenyl, and benzo[a]diyl. Alkyl, quinazine, benzo[] Azinyl, benzodiazinyl, pyridopyridyl, quinoxalinyl, quinazolinyl, cyclolinyl, phthalazinyl, naphthidyl, and pteridylyl.

[0124] The term "aryl" refers to a ring or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent compounds. Some examples of aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl. In one specific embodiment, the aryl group is phenyl.

[0125] The term "optionally substituted" refers to substituted and unsubstituted groups, structures, or molecules.

[0126] When the optional substituents are selected from “one or more” groups, it should be understood that the definition includes all substituents selected from one of the specified groups or substituents selected from two or more specified groups.

[0127] The phrase “compounds of the present invention” means those compounds disclosed herein, both generally and specifically.

[0128] The compounds of the present invention

[0129] In one aspect, the present invention relates to compounds of formula (I) shown below, or pharmaceutically acceptable salts thereof:

[0130] XYZ

[0131] (I)

[0132] in:

[0133] X is selected from:

[0134]

[0135]

[0136] in

[0137] Q1 is selected from NH and NC. 1-4 Alkyl, O, or S;

[0138] Q 2a Selected from N or CR 2a ;

[0139] Q 2b Selected from N or CR 2b ;

[0140] Q 2c Selected from N or CR 2c ;

[0141] Q 2d Selected from N or CR 2d ;

[0142] Q3 is selected from N or CR 1b ;

[0143] Q4 is selected from N or CR 1x ;

[0144] The prerequisites are Q1 and Q. 2a Q 2b Q 2c Q 2dNo more than 3 of Q3 and Q4 are nitrogen; R 1a Selected from:

[0145] (i)C 1-4 Alkyl or C 1-4 Alkyl groups, each optionally converted by a halogen, cyano group, hydroxyl group, or C group. 3-6 cycloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, aryl, or heteroaryl substitutions; or

[0146] (ii) The following groups:

[0147] -(CR 1c R 1d ) p -NR 1e R 1f ;

[0148] in

[0149] p is an integer selected from 0, 1, 2, or 3.

[0150] R 1c and R 1d Selected independently from:

[0151] (i) Hydrogen (including deuterium),

[0152] (ii)C 1-6 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da One or more substituents are substituted, where R 1ca and R 1da Is it H or C? 1-2 Alkyl; and wherein C 3-6 cycloalkyl and -OC 3-6 The cycloalkyl group may optionally be further substituted with a halogen, cyano or hydroxyl group;

[0153] (iii)C 3-4 Cycloalkyl or 3- to 5-membered heterocyclic groups, each optionally C 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ca R 1daor -S(O) 0-2 R 1ca R 1da Replace, where R 1ca and R 1da Is it H or C? 1-2 Alkyl groups; and

[0154] (iv) or R 1c With R 1d They are linked together to form 3- to 6-membered cycloalkyl or heterocyclic or spirocyclic systems, each optionally selected from C14. 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da One or more substituents are substituted, wherein R 1ca and R 1da Is it H or C? 1-2 alkyl;

[0155] R 1e and R 1f Each is selected independently from:

[0156] (i) Hydrogen (including deuterium);

[0157] (ii)C 1-6 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa One or more substituents are substituted, wherein R 1ea and R 1fa Is it H or C? 1-2 alkyl;

[0158] (iii) Groups having the following formula:

[0159] -(CR 1g R 1h ) q -T1

[0160] in:

[0161] q is 0, 1, 2, 3, 4, 5, or 6;

[0162] R1g and R 1h Selected independently from:

[0163] a) Hydrogen;

[0164] b)C 1-6 Alkyl groups, optionally selected from cyano, hydroxy, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, -OC 3-6 cycloalkyl, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha One or more substituents are substituted, where R 1ga and R 1ha Is it H or C? 1-2 Alkyl; and wherein -OC 3-6 The cycloalkyl group may optionally be replaced by a halogen, a cyano group, or a hydroxyl group;

[0165] c) Aryl-C 1-6 Alkyl, heteroaryl C 1-6 Alkyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl C 1-6 Alkyl groups, each optionally selected from C10, ... 1-2 Alkyl, cyano, C 1-2 Halogenated alkyl, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha One or more substituents are substituted, wherein R 1ga and R 1ha Is it H or C? 1-2 Alkyl; or

[0166] d) or R 1g With R 1h Optionally linked together, such that they, together with the carbon atoms to which they are attached, form 3 to 6-membered cycloalkyl or heterocyclic rings, optionally selected from C14. 1-2 Alkyl, cyano, C 1-2 Halogenated alkyl, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha One or more substituents are substituted, wherein R1ga and R 1ha Is it H or C? 1-2 alkyl;

[0167] Furthermore, T1 is selected from hydrogen, cyano, hydroxyl, and NR. 1t R 2t or -S(O) 0-2 R 1t R 2t (where R) 1t and R 2t Is it H or C? 1-4 Alkyl), C 3-8 cycloalkyl, C 2-3 alkenyl, C 2-3 Alkynyl, aryl, heterocyclic, heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridging C 3-8 cycloalkyl, bridged bicyclic C 5-12 Cycloalkyl or bridged heterocyclic ring systems, each optionally selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 3t R 4t or -S(O) 0-2 R 3t R 4t One or more substituents are substituted, wherein R 3t and R 4t Is it H or C? 1-2 alkyl;

[0168] (iv) or R 1e With R 1f The linkages allow them to form monocyclic or bicyclic heterocyclic rings together with the nitrogen atoms to which they are attached, optionally selected from C14. 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, NR 1i R 1j or -S(O) 0-2 R 1i R 1j One or more substituents are substituted, wherein R 1i and R 1j Is it H or C? 1-4 Alkyl groups, and / or those derived from R 1e and R 1f The formed monocyclic or bicyclic heterocyclic ring may optionally be combined with C 3-6 Cycloalkyl or heterocyclic cyclospirofusion, which is then optionally selected from C 1-4 Alkyl, C1-4 Halogenated alkyl, cyano, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, NR 1i R 1j or -S(O) 0- 2R 1i R 1j One or more substituents are substituted, wherein R 1i and R 1j Is it H or C? 1-4 alkyl;

[0169] R 1b Selected from hydrogen, cyano, halogen or C 1-3 alkyl;

[0170] R 1x Selected from hydrogen, cyano, halogen or C 1-3 alkyl;

[0171] R 2a R 2b R 2c and R 2d Independently selected from hydrogen, cyano, halogen, or the following groups:

[0172] -L 2a -L 2b -Q2

[0173] L 2a Does not exist or is arbitrarily C 1-2 alkyl or oxo-substituted C 1-3 Alkylene;

[0174] L 2b It does not exist or is selected from O, S, SO, SO2, N(R) n ), C(O), C(O)O, OC(O), C(O)N(R n ), N(R n C(O), N(R) n )C(O)N(R o ), S(O)2N(R n ) or N(R n SO2, where R n and R o Each is independently selected from hydrogen or C. 1-2 Alkyl; and

[0175] Q2 is hydrogen, cyano, C 1-6 Alkyl, C 3-6Cycloalkyl, aryl, heterocyclic, or heteroaryl, each optionally selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxyl, amino, carboxyl, carbamoyl, aminosulfonyl, C 1-4 Alkyl, NR p R q OR p C(O)R p C(O)OR p OC(O)R p C(O)N(R) p )R q 、N(R r )C(O)R p S(O) y R p (where y is 0, 1, or 2), SO2N(R) p )R q 、N(R r SO2R p Or (CH2) z NR p R q (where z is 1, 2, or 3) one or more substituents are substituted, where R p and R q Each is independently selected from hydrogen or C. 1-4 Alkyl; Y is selected from:

[0176]

[0177]

[0178] in:

[0179] R 3a1 R 3b1 R 3c1 R 3d1 R 3e1 R 3f1 R 3g1 R 3h1 R 3i1 R 3j1 R 3k1 R 3l1 R 3m1 R 3n1 R 3o1 R 3p1 R 3q1 R 3r1 and R 3s1 Independently selected from hydrogen (including deuterium), C 1-6 Alkyl, C 3-4 cycloalkyl, hydroxyl and halogen; and wherein C 1-6 Alkyl or C3-4 The cycloalkyl group is optionally substituted with one or more substituents selected from halogen, amino, cyano and hydroxyl groups;

[0180] R 3a2 R 3b2 R 3c2 R 3d2 R 3e2 R 3f2 R 3g2 R 3h2 R 3i2 R 3j2 R 3k2 R 3l2 R 3m2 R 3n2 R 3o2 R 3p2 R 3q2 R 3r2 and R 3s2 It is hydrogen or halogen;

[0181] The premise is R 3a1 R 3b1 R 3i1 R 3l1 R 3o1 R 3r1 R 3a2 R 3b2 R 3i2 R 3l2 R 3o2 and R 3s1 It cannot be a halogen when n=1 or when n=2 and the carbon atom it is attached to is attached to an oxygen or nitrogen atom;

[0182] Or R 3a1 With R 3a2 R 3b1 With R 3b2 R 3c1 With R 3c2 R 3d1 With R 3d2 R 3e1 With R 3e2 R 3f1 With R 3f2 R 3g1 With R 3g2 R 3h1 With R 3h2 R 3i1 With R 3i2 R 3j1 With R 3j2 R 3k1 With R 3k2 R 3l1 With R 3l2 R3m1 With R 3m2 R 3n1 With R 3n2 R 3o1 With R 3o2 R 3p1 With R 3p2 R 3q1 With R 3q2 、or R 3r1 With R 3r2 、or R 3s1 With R 3s2 They can connect, allowing them to form spirofused C atoms together with the carbon atoms they are attached to. 3-4 Cycloalkyl groups, optionally substituted with one or more substituents selected from halogen, methyl, amino, cyano and hydroxyl groups;

[0183] n is 0, 1, or 2;

[0184] Z is selected from one of the following structures:

[0185] i)

[0186]

[0187] in:

[0188] B1 is A5, where A5 is selected from CR. 16 and N, where R 16 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 5 or 6-membered heteroaryl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl, 3- to 4-membered heterocyclic groups and C 3-4 Cycloalkoxy;

[0189] B2 is A6, where A6 is selected from N or CR. 17 , where R 17 R H2 R H4 and R H5 Selected from hydrogen, hydroxyl, halogen, cyano, C 1-5 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5 or 6 nucleotide or heteroaryl, C 3-6 cycloalkyl, -OC 3-6Cycloalkyl, heterocyclic, -O-heterocyclic (carbon-linked), where m is an integer from 1 to 6 -(OCH2CH2). m -NR q R r -(OCH2CH2) m -OCH3,NR q R r , -C(O)-NR q R r -C(O)OR q ,

[0190] Where R q and R r Each is independently hydrogen, C 1-5 Alkyl, C 3-6 Cycloalkyl groups, heterocyclic groups linked to 3 to 6 carbons, or R q With R r They are linked together, forming 3- to 6-membered heterocyclic rings together with the nitrogen atoms they are attached to;

[0191] Where any C 1-5 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5 or 6 nucleotide or heteroaryl, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclic, or -O-heterocyclic (carbon-linked) groups are optionally further selected from C 1-2 Alkyl, cyano, C 1-2 Halogenated alkyl, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa One or more substituents are substituted, wherein R 1ea and R 1fa Is it H or C? 1-2 alkyl;

[0192] B3 is N or CR Z1 , where R Z1 Selected from hydrogen, C 1-4 Alkyl, cyano, halogen, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 3-6 cycloalkyl and -OC 3-6 cycloalkyl, wherein C 3-6 cycloalkyl and -OC 3-6The cycloalkyl group may optionally be substituted with one or more of halogen, methyl or methoxy;

[0193] B4 is selected from C or N;

[0194] B5 is selected from CR zi1b or NR B5N ,in:

[0195] R Zi1b Selected from hydrogen, C 1-4 Alkyl, cyano, halogen, NH2 and C 1-4 alkoxy groups; and

[0196] R B5N Selected from hydrogen or C 1-4 alkyl;

[0197] B7 is N, NR Z2N or CR Z2 , where R Z2 Selected from hydrogen, C 1-4 Alkyl, cyano, halogen, NH2 and C 1-4 alkoxy groups; and R Z2N Selected from hydrogen or C 1-4 alkyl;

[0198] B8 is selected from C or N;

[0199] The premise is that no more than four of B1 to B8 are N.

[0200] ii)

[0201]

[0202] Y2 is A7, where A7 is selected from CR. 18 and N; where R 18 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl, 3- to 4-membered heterocyclic groups and C 3-4 Cycloalkoxy;

[0203] Y3 is N or CR z1a , where R Z1a Selected from hydrogen, hydroxyl, C 1-4 Alkyl, cyano, halogen, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 3-6 cycloalkyl and -OC 3-6 cycloalkyl, wherein C 3-6cycloalkyl and -OC 3-6 The cycloalkyl group may optionally be substituted with one or more of halogen, methyl or methoxy;

[0204] Y4 is either C or N;

[0205] Y5 is CR Y5 or NR Y5N ,in:

[0206] R Y5 Selected from hydrogen, C 1-4 Alkyl, cyano, halogen, NH2 and C 1-4 Alkoxy;

[0207] R Y5N Selected from hydrogen or C 1-4 alkyl;

[0208] Y6 is CR Zi2e Or N, where R Zi2e Selected from hydrogen, C 1-4 Alkyl, cyano, halogen, NH2 and C 1-4 Alkoxy;

[0209] Y7 is O, S, CR Z2a Or N, where R Z2a Selected from hydrogen, C 1-4 Alkyl, cyano, halogen, NH2 and C 1-4 Alkoxy;

[0210] Y8 is either C or N;

[0211] Y9 is CR Z3a Or N; where

[0212] R Z3a Selected from hydrogen, C 1-4 Alkyl, cyano, halogen, NH2 and C 1-4 Alkoxy;

[0213] The premise is that no more than four of Y1 to Y8 are N.

[0214] (iii)

[0215]

[0216] X1 is N or CR Z9 , where R Z9 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0217] X2 is selected from N or CR4, where:

[0218] R4 is selected from hydrogen, halogen, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy (e.g., hydrogen, halogen, cyano and methyl);

[0219] X3 is N;

[0220] X4 is either N or C;

[0221] X5 is selected from N, CR5, and CRx. 5a R X5b ,in:

[0222] R5 is selected from hydrogen, halogen, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups (e.g., hydrogen, halogen, cyano, and methyl);

[0223] Rx 5a and R X5b Independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups (e.g., hydrogen, halogen, cyano, and methyl);

[0224] or:

[0225] X6 is A1 and X7 is A2; or

[0226] X6 is A8 and X7 is A9 or A 11 ,in:

[0227] A1 is selected from CR 12 and N; where

[0228] R 12 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups (e.g., hydrogen, halogen, cyano, and C) 1-4 alkyl);

[0229] A2 is selected from CR 13 and N, where:

[0230] R 13 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4Halogenated alkoxy groups (e.g., hydrogen, halogen, cyano, methoxy, and methyl);

[0231] A8 is selected from CR 19 R 20 and NR 21 ;in:

[0232] R 19 and R 20 Independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups (e.g., hydrogen, halogen, cyano, and C) 1-4 alkyl);

[0233] R 21 Is it hydrogen or C? 1-4 alkyl.

[0234] A9 is selected from CR 22 R 23 and NR 24 ;

[0235] Where R 22 and R 23 Independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups (e.g., hydrogen, halogen, cyano, and methyl);

[0236] R 24 Selected from hydrogen or C 1-4 alkyl;

[0237] A 11 Selected from CR 28 R 29 and NR 30 ;

[0238] R 28 and R 29 Selected from hydrogen, halogen, methoxy, and methyl;

[0239] R 30 Selected from hydrogen or C 1-4 alkyl.

[0240] X8 is selected from CR6, N, or CR. X6a R X6b ;

[0241] R6 is selected from hydrogen, halogen, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C1-4 alkyl

[0242] Oxygen and C 1-4 Halogenated alkoxy groups;

[0243] R X6a and R X6b Each is independently selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 halogen

[0244] Alkyl, C 1-4 Alkoxy and C 1-4 Halogenated alkoxy groups;

[0245] X9 is either N or C;

[0246] The premise is that no more than four of X2 to X9 are N.

[0247] (iv)

[0248]

[0249] Z 10 Is it N or CR? Z10 , where R Z10 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0250] Z 11 Is it N or CR? Z11 , where R Z11 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0251] Z 12 Is it N or CR? Z12 , where R Z12 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0252] Z 13 Is it N or CR? Z13 , where R Z13 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C1-4 Halogenated alkoxy groups;

[0253] Z 14 Is it N or CR? Z14 , where R Z14 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0254] Z 15 Is it N or CR? Z15 , where R Z15 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0255] Z 16 Is it N or CR? Z16 , where R Z16 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0256] The premise is Z 10 To Z 16 No more than three of them are N;

[0257] (v)

[0258]

[0259] Q7 is CR7 or N;

[0260] Q8 is CR8 or N;

[0261] Q9 is CR9 or N;

[0262] Q 10 It is CR 10 Or N;

[0263] Q 11 It is CR 11 Or N;

[0264] Q 11a It is NR 11N or CR 11a R 11b ;

[0265] Among them, R7, R8, R9, R 10 R11 R 11a and R 11b Each is independently selected from hydrogen, NH2, halogen, cyano, and C. 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-6 Alkyl groups, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3, and -C(O)NR v1 R v2 , where R v1 and R v2 Independently selected from hydrogen and methyl, and; and R 11N Selected from hydrogen, NH2, halogen, cyano and C 1-6 alkyl;

[0266] or

[0267] R9 and R 10 They can be linked together, forming fused 5- or 6-membered saturated or unsaturated ring systems together with the atoms they are linked to, or R 10 With R 11 They can be linked together to form a fused 5- or 6-membered saturated or unsaturated ring system together with the atoms they are linked to, wherein the fused 5- or 6-membered saturated or unsaturated ring system may optionally be selected from C. 1-2 Alkyl, cyano, C 1-2 Halogenated alkyl, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ia R 1ja or -S(O) 0- 2R 1ia R 1ja One or more substituents are substituted, wherein R 1ia and R 1ja Is it H or C? 1-2 alkyl;

[0268] The premise is Q7 to Q 11 No more than three of them are N.

[0269] In another aspect, the present invention relates to compounds of formula (I) shown below, or pharmaceutically acceptable salts thereof:

[0270] XYZ

[0271] (I)

[0272] in:

[0273] X is selected from:

[0274]

[0275] in

[0276] Q1 is selected from NH, N-C1-4 alkyl, O, or S;

[0277] Q 2a Selected from N or CR 2a ;

[0278] Q 2b Selected from N or CR 2b ;

[0279] Q 2c Selected from N or CR 2c ;

[0280] Q 2d Selected from N or CR 2d ;

[0281] Q3 is selected from N or CR 1b Q4 is selected from N or CR. 1x ;

[0282] The prerequisites are Q1 and Q. 2a Q 2b Q 2c Q 2d No more than 3 of Q3 and Q4 are nitrogen; R 1a Selected from:

[0283] (i)C 1-4 Alkyl or C 1-4 Alkyl groups, each optionally converted by a halogen, cyano group, hydroxyl group, or C group. 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, aryl, or heteroaryl substitutions; or

[0284] (ii) The following groups:

[0285] -(CR 1c R 1d ) p -NR 1e R 1f ;

[0286] in

[0287] p is an integer selected from 0, 1, 2, or 3.

[0288] R 1c and R 1d Selected independently from:

[0289] (i) Hydrogen (including deuterium),

[0290] (ii)C 1-6Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da One or more substituents are substituted, where R 1ca and R 1da Is it H or C? 1-2 Alkyl; and wherein C 3-6 cycloalkyl and -OC 3-6 The cycloalkyl group may optionally be further substituted with a halogen, cyano or hydroxyl group;

[0291] (iii)C 3-4 Cycloalkyl or 3- to 5-membered heterocyclic groups, each optionally C 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da Replace, where R 1ca and R 1da Is it H or C? 1-2 alkyl;

[0292] (iv) or R 1c With R 1d They are linked together to form 3- to 6-membered cycloalkyl or heterocyclic or spirocyclic systems, each optionally selected from C14. 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da One or more substituents are substituted, wherein R 1ca and R 1da Is it H or C? 1-2 alkyl;

[0293] R 1e and R 1f Each is selected independently from:

[0294] (i) Hydrogen (including deuterium);

[0295] (ii)C 1-6 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa One or more substituents are substituted, where R 1ea and R 1fa Is it H or C? 1-2 alkyl;

[0296] (iii) Groups having the following formula:

[0297] -(CR 1g R 1h ) q -T1

[0298] in:

[0299] q is 0, 1, 2, 3, 4, 5, or 6;

[0300] R 1g and R 1h Selected independently from:

[0301] a) Hydrogen;

[0302] b)C 1-6 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, -OC 3-6 cycloalkyl, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha One or more substituents are substituted, where R 1ga and R 1ha Is it H or C? 1-2 Alkyl; and wherein -OC 3-6 The cycloalkyl group is optionally substituted with a halogen, cyano, or hydroxyl group; or

[0303] c) Aryl-C 1-6 Alkyl, heteroaryl C 1-6 Alkyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl C 1-6 Alkyl groups, each optionally selected from C10, ... 1-2 Alkyl, cyano, C 1-2Halogenated alkyl, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha One or more substituents are substituted, wherein R 1ga and R 1ha Is it H or C? 1-2 alkyl;

[0304] d) or R 1g With R 1h Optionally linked together, such that they, together with the carbon atoms to which they are attached, form 3 to 6-membered cycloalkyl or heterocyclic rings, optionally selected from C14. 1-2 Alkyl, cyano, C 1-2 Halogenated alkyl, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha One or more substituents are substituted, wherein R 1ga and R 1ha Is it H or C? 1-2 alkyl;

[0305] Furthermore, T1 is selected from hydrogen, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano, hydroxyl, NR 1t R 2t or -S(O) 0-2 R 1t R 2t (where R) 1t and R 2t Is it H or C? 1-4 Alkyl), C 3-8 cycloalkyl, C 2-3 alkenyl, C 2-3 Alkynyl, aryl, heterocyclic, mono- or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridging C 3-8 cycloalkyl, bridged bicyclic C 5-12 Cycloalkyl or bridged heterocyclic ring systems, each optionally selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, C 3-6 cycloalkyl, NR 3t R 4tor -S(O) 0-2 R 3t R 4t One or more substituents are substituted, wherein R 3t and R 4t Is it H or C? 1-2 alkyl;

[0306] (iv) or R 1e With R 1f The linkages allow them to form monocyclic or bicyclic heterocyclic rings together with the nitrogen atoms to which they are attached, optionally selected from C14. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, NR 1i R 1j or -S(O) 0-2 R 1i R 1j One or more substituents are substituted, wherein R 1i and R 1j Is it H or C? 1-4 Alkyl groups, and / or those derived from R 1e and R 1f The formed monocyclic or bicyclic heterocyclic ring may optionally be combined with C 3-6 Cycloalkyl or heterocyclic cyclospirofusion, which is then optionally selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, NR 1i R 1j or -S(O) 0-2 R 1i R 1j One or more substituents are substituted, wherein R 1i and R 1j Is it H or C? 1-4 alkyl;

[0307] Any alkyl, alkoxy, or C 3-6 The cycloalkyl group is further optionally selected from cyano, hydroxyl, halogen, NR. 1k R 1l or -S(O) 0-2 R 1k R 1l One or more substituents are substituted, wherein R 1k and R 1l Is it H or C? 1-4 alkyl;

[0308] R 1b Selected from hydrogen, cyano, halogen or C 1-3 alkyl;

[0309] R 1x Selected from hydrogen, cyano, halogen or C 1-3 alkyl;

[0310] R 2a R 2b R 2c and R 2d Independently selected from hydrogen, cyano, halogen, or the following groups:

[0311] -L 2a -L 2b -Q2

[0312] in

[0313] L 2a Does not exist or is arbitrarily C 1-2 alkyl or oxo-substituted C 1-3 Alkylene;

[0314] L 2b It does not exist or is selected from O, S, SO, SO2, N(R) n ), C(O), C(O)O, OC(O), C(O)N(R n ), N(R n C(O), N(R) n )C(O)N(R o ), S(O)2N(R n ) or N(R n SO2, where R n and R o Each is independently selected from hydrogen or C. 1-2 Alkyl; and

[0315] Q2 is hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, aryl, heterocyclic, or heteroaryl, each optionally selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxyl, amino, carboxyl, carbamoyl, aminosulfonyl, C 1-4 Alkyl, NR p R q OR p C(O)R p C(O)OR p OC(O)R p C(O)N(R) p )R q 、N(R r )C(O)R pS(O) y R p (where y is 0, 1, or 2), SO2N(R) p )R q 、N(R r SO2R p Or (CH2) z NR p R q (where z is 1, 2, or 3) one or more substituents are substituted, where R p and R q Each is independently selected from hydrogen or C. 1-4 Alkyl; Y is selected from:

[0316]

[0317]

[0318] in:

[0319] R 3a1 R 3b1 R 3c1 R 3d1 R 3e1 R 3f1 R 3g1 R 3h1 R 3i1 R 3j1 R 3k1 R 3l1 R 3m1 R 3n1 R 3o1 R 3p1 R 3q1 R 3r1 and R 3s1 Independently selected from hydrogen (including deuterium), C 1-6 Alkyl, C 3-4 cycloalkyl, hydroxyl and halogen; and wherein C 1-6 Alkyl or C 3-4 The cycloalkyl group is optionally substituted with one or more substituents selected from halogen, amino, cyano and hydroxyl groups;

[0320] R 3a2 R 3b2 R 3c2 R 3d2 R 3e2 R 3f2 R 3g2 R 3h2 R 3i2 R 3j2 R 3k2 R 3l2 R3m2 R 3n2 R 3o2 R 3p2 R 3q2 R 3r2 and R 3s2 It is hydrogen or halogen;

[0321] The premise is R 3a1 R 3b1 R 3i1 R 3l1 R 3o1 R 3r1 R 3a2 R 3b2 R 3i2 R 3l2 R 3o2 and R 3s1 It cannot be a halogen when n=1 or when n=2 and the carbon atom it is attached to is attached to an oxygen or nitrogen atom;

[0322] Or R 3a1 With R 3a2 R 3b1 With R 3b2 R 3c1 With R 3c2 R 3d1 With R 3d2 R 3e1 With R 3e2 R 3f1 With R 3f2 R 3g1 With R 3g2 R 3h1 With R 3h2 R 3i1 With R 3i2 R 3j1 With R 3j2 R 3k1 With R 3k2 R 3l1 With R 3l2 R 3m1 With R 3m2 R 3n1 With R 3n2 R 3o1 With R 3o2 R 3p1 With R 3p2 R 3q1 With R 3q2 、or R 3r1 With R 3r2 、or R 3s1 With R 3s2 They can connect, allowing them to form spirofused C atoms together with the carbon atoms they are attached to. 3-4Cycloalkyl groups, optionally substituted with one or more substituents selected from halogen, methyl, amino, cyano and hydroxyl groups;

[0323] n is 0, 1, or 2;

[0324] Z is selected from:

[0325]

[0326]

[0327]

[0328] in:

[0329] R4 is selected from hydrogen, halogen, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups (e.g., hydrogen, halogen, cyano, and methyl);

[0330] R5 is selected from hydrogen, halogen, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups (e.g., hydrogen, halogen, cyano, and methyl);

[0331] R6 is selected from hydrogen, halogen, cyano, and C. 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups (e.g., hydrogen, halogen, cyano, and methyl);

[0332] R8, R9, R 10 and R 11 Independently selected from hydrogen, NH2, halogen, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-6 Alkyl groups, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3, and -C(O)NR v1 R v2 , where R v1 and R v2 Independently selected from hydrogen and methyl; or

[0333] R9 and R 10 They can be linked together, forming fused 5- or 6-membered saturated or unsaturated ring systems together with the atoms they are linked to, or R 10 With R 11They can be linked together to form a fused 5- or 6-membered saturated or unsaturated ring system together with the atoms they are linked to, wherein the fused 5- or 6-membered saturated or unsaturated ring system may optionally be selected from C. 1-2 Alkyl, cyano, C 1-2 Halogenated alkyl, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ia R 1ja or -S(O) 0- 2R 1ia R 1ja One or more substituents are substituted, wherein R 1ia and R 1ja Is it H or C? 1-2 alkyl;

[0334] R7 and R 11N Independently selected from hydrogen, NH2, halogen, cyano, and C 1-6 alkyl;

[0335] R Z1 and R Z1a Selected from hydrogen, C 1-4 Alkyl, cyano, halogen, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 3-6 cycloalkyl and -OC 3-6 cycloalkyl, wherein C 3-6 cycloalkyl and -OC 3-6 The cycloalkyl group may optionally be substituted with one or more of halogen, methyl or methoxy;

[0336] R Z2 and R Z2a Selected from hydrogen, C 1-4 Alkyl, cyano, halogen, NH2 and C 1-4 Alkoxy;

[0337] R Z3a Selected from hydrogen, C 1-4 Alkyl, cyano, halogen, NH2 and C 1-4 Alkoxy;

[0338] R Zi1b Selected from hydrogen, C 1-4 Alkyl, cyano, halogen, NH2 and C 1-4 Alkoxy;

[0339] R Zi2e Selected from hydrogen, C 1-4 Alkyl, cyano, halogen, NH2 and C 1-4 Alkoxy;

[0340] R Y5N and R Z2N Selected from hydrogen or C 1-4 alkyl;

[0341] R Z9 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0342] R Z10 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0343] R Z11 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0344] R Z12 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0345] R Z13 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0346] R Z14 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0347] R Z15 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0348] R Z16 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups;

[0349] A1 is selected from CR 12 and N;

[0350] A2 is selected from CR 13 and N;

[0351] A5 is selected from CR 16 and N;

[0352] A6 is selected from CR 17 and N;

[0353] A7 is selected from CR 18 and N;

[0354] A8 is selected from CR 19 R 20 and NR 21 ;

[0355] A9 is selected from CR 22 R 23 and NR 24 ;

[0356] A 11 Selected from CR 28 R 29 and NR 30 ;

[0357] R 12 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups (e.g., hydrogen, halogen, cyano, and C) 1-4 alkyl);

[0358] R 13 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups (e.g., hydrogen, halogen, cyano, methoxy, and methyl);

[0359] R 16 and R 18 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-4 cycloalkyl, 3- to 4-membered heterocyclic groups and C3-4- Cycloalkoxy;

[0360] R 17 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5 or 6 nucleotide or heteroaryl, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclic, -O-heterocyclic (carbon-linked), where m is an integer from 1 to 6 -(OCH2CH2) m -OCH3, NR q R r , where R q and R r Each is independently hydrogen, C 1-5 Alkyl, C 3-6 Cycloalkyl groups, heterocyclic groups linked to 3 to 6 carbons, or R q With R r They are linked together, forming 3- to 6-membered heterocyclic rings together with the nitrogen atoms they are attached to; wherein any C 1-5 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5 or 6 nucleotide or heteroaryl, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclic, or -O-heterocyclic (carbon-linked) groups are optionally further selected from C 1-2 Alkyl, cyano, C 1-2 Halogenated alkyl, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ea R 1fa or -S(O) 0- 2R 1ea R 1fa One or more substituents are substituted, wherein R 1ea and R 1fa Is it H or C? 1-2 alkyl;

[0361] R 19 and R 20 Selected from hydrogen, halogen, cyano and C 1-4 alkyl;

[0362] R 22 and R 23 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups (e.g., hydrogen, halogen, cyano, and methyl);

[0363] R 28 and R 29 Selected from hydrogen, halogen, methoxy, and methyl;

[0364] R 21 R 24 and R 30 Is it hydrogen or C? 1-4 alkyl.

[0365] Specific compounds of the present invention include, for example, compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of the following and any associated substituents has any meaning as defined in any of paragraphs (1) to (193) above or below:

[0366] X,Y,Z,R 1a ,R 1b ,R 1c ,R 1d ,R 1e ,R 1f ,R 2a ,R 2b ,R 2c ,R 2d Q1,Q 2a Q 2b Q 2c Q 2d Q3, Q4, R 3a1 ,R 3a2 ,R 3b1 ,R 3b2 ,R 3c1 ,R 3c2 ,R 3d1 ,R 3d2 ,R 3e1 ,R 3e2 ,R 3f1 ,R 3f2 ,R 3g1 ,R 3g2 ,R 3h1 ,R 3h2 ,R 3i1 ,R 3i2 ,R 3j1 ,R 3j2 ,R 3k1 ,R 3k2 ,R 3ln ,R 3l2 ,R 3m1 ,R 3m2 ,R 3n1 ,R3n2 ,R 3o1 ,R 3o2 ,R 3p1, R 3p2 ,n,R4,R5,R X5a ,R X5b R6, R7, R8, R9, R 10 ,R 11 ,R 11N ,R 12 ,R 13 ,R 16 ,R 17 ,R 18 ,R 19 ,R 20 ,R 21 ,R 22 ,R 23 ,R 24 ,R 28 ,R 29 ,R 30 R Z1 ,R Z1a ,R Z1b ,R Z1c ,R Z1d ,R Z2 ,R Z2a ,R Z3a ,R Zi1b ,R Zi2e ,R Z9 ,R Z10 ,R Z11 ,R Z12 ,R Z13 ,R Z14 ,R Z15 R Z16 A1, A2, A5, A6, A7, A8, A9, A 11 :

[0367] (1) Q1 is selected from O, NH or NC 1-4 alkyl.

[0368] (2) Q1 is selected from NH or NC 1-4 alkyl.

[0369] (3) Q1 is selected from NH or N-CH3.

[0370] (4) Q1 is NH.

[0371] (5)Q 2a It is CR 2a ;

[0372] (6)Q 2b It is CR 2b ;

[0373] (7)Q 2c It is CR 2c ;

[0374] (8)Q 2d It is CR 2d ;

[0375] (9) Q3 is CR 1b ;

[0376] (10) Q4 is CR 1x ;

[0377] (11)X is selected from:

[0378]

[0379] Among them, Q1 and R 1a R 1b R 1x R 2a R 2b R 2c R 2d As defined in this article.

[0380] (12)X is selected from:

[0381]

[0382] Among them, Q1 and R 1a R 1b R 2a R 2b R 2c and R 2d As defined in this article.

[0383] (13)X is selected from:

[0384]

[0385] Among them, Q1 and R 1a R 1b R 2a R 2b and R 2d As defined in this article.

[0386] (14)X is selected from:

[0387]

[0388] Among them, Q1 and R 1a R 1b R 2a R 2b and R 2dAs defined in this article.

[0389] (15)X is:

[0390]

[0391] Among them, Q1 and R 1a R 1b R 2a R 2b and R 2d As defined in this article.

[0392] (16)X is:

[0393]

[0394] Among them, Q1 and R 1a R 1b R 2a and R 2d As defined in this article.

[0395] (17)R 1b R 2a R 2b R 2c and R 2d Each is independently selected from hydrogen and C. 1-2 Alkyl or halogen.

[0396] (18)X is selected from:

[0397]

[0398] Among them, Q1 and R 1a As defined in this article.

[0399] (19)X is selected from:

[0400]

[0401] Among them, Q1 and R 1a As defined in this article.

[0402] (20)X is selected from:

[0403]

[0404] Among them, Q1 and R 1a As defined in this article.

[0405] (21)X is selected from:

[0406]

[0407]

[0408] Where R 1a As defined in this article.

[0409] (22)X is selected from:

[0410]

[0411] Where R 1a As defined in this article.

[0412] (23)R 1a Selected from:

[0413] (i)C 1-4 Alkyl groups, optionally prefixed with halogen, cyano, hydroxyl, or C 3-6 cycloalkyl, C 1-4- Alkoxy, C 1-4 Halogenated alkoxy, aryl, or heteroaryl substitutions; or

[0414] (ii) The following groups:

[0415] -(CR 1c R 1d ) p -NR 1e R 1f ;

[0416] in

[0417] p is an integer selected from 0, 1, 2 or 3;

[0418] R 1c and R 1d Selected independently from:

[0419] (i) Hydrogen (including deuterium),

[0420] (ii)C 1-6 Alkyl groups, optionally selected from cyano, hydroxy, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, C 3-6 cycloalkyl, -OC 3-6 cycloalkyl, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da One or more substituents are substituted, where R 1ca and R 1da Is it H or C? 1-2 Alkyl; and wherein C 3-6 cycloalkyl and -OC 3-6 The cycloalkyl group may optionally be further substituted with a halogen, cyano or hydroxyl group;

[0421] (iii)C 3-4 Cycloalkyl or 3- to 5-membered heterocyclic groups, each optionally C 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da Replace, where R 1ca and R 1da Is it H or C? 1-2 Alkyl groups; and

[0422] (iv) or R 1c With R 1d They are linked together to form 3- to 6-membered cycloalkyl or heterocyclic or spirocyclic systems, each optionally selected from C14. 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da One or more substituents are substituted, wherein R 1ca and R 1da Is it H or C? 1-2 alkyl;

[0423] R 1e and R 1f Each is selected independently from:

[0424] (i) Hydrogen (including deuterium);

[0425] (ii)C 1-6 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa One or more substituents are substituted, where R 1ea and R 1fa Is it H or C? 1-2 alkyl;

[0426] (iii) Groups having the following formula:

[0427] -(CR1g R 1h )q-T1

[0428] in:

[0429] q is 0, 1, 2, 3, 4, 5, or 6;

[0430] R 1g and R 1h Selected independently from:

[0431] a) Hydrogen;

[0432] b)C 1-6 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, -OC 3-6 cycloalkyl, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha One or more substituents are substituted, where R 1ga and R 1ha Is it H or C? 1-2 Alkyl; and wherein -OC 3-6 The cycloalkyl group may optionally be replaced by a halogen, a cyano group, or a hydroxyl group;

[0433] c) Aryl-C 1-6 Alkyl, heteroaryl C 1-6 Alkyl, C 3-6 cycloalkyl or C 3-6 cycloalkyl C 1-6 Alkyl groups, each optionally selected from C10, ... 1-2 Alkyl, cyano, C 1-2 Halogenated alkyl, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha One or more substituents are substituted, wherein R 1ga and R 1ha Is it H or C? 1-2 Alkyl; or

[0434] d) or R 1g With R 1h Optionally linked together, such that they, together with the carbon atoms to which they are attached, form 3 to 6-membered cycloalkyl or heterocyclic rings, optionally selected from C14. 1-2 Alkyl, cyano, C 1-2 Halogenated alkyl, hydroxyl, C1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha One or more substituents are substituted, wherein R 1ga and R 1ha Is it H or C? 1-2 alkyl;

[0435] Furthermore, T1 is selected from hydrogen, cyano, hydroxyl, and NR. 1t R 2t or -S(O) 0-2 R 1t R 2t (where R) 1t and R 2t Is it H or C? 1-4 Alkyl), C 3-8 cycloalkyl, C 2-3 alkenyl, C 2-3 Alkynyl, aryl, heterocyclic, heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridging C 3-8 cycloalkyl, bridged bicyclic C 5-12 Cycloalkyl or bridged heterocyclic ring systems, each optionally selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 3t R 4t or -S(O) 0-2 R 3t R 4t One or more substituents are substituted, wherein R 3t and R 4t Is it H or C? 1-2 alkyl;

[0436] Or R 1e With R 1f The linkages allow them to form monocyclic or bicyclic heterocyclic rings together with the nitrogen atoms to which they are attached, optionally selected from C14. 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, NR 1i R 1j or -S(O) 0-2 R 1i R 1j One or more substituents are substituted, wherein R 1i and R1j Is it H or C? 1-4 Alkyl groups, and / or those derived from R 1e and R 1f The formed monocyclic or bicyclic heterocyclic ring may optionally be combined with C 3-6 Cycloalkyl or heterocyclic cyclospirofusion, which is then optionally selected from C 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, NR 1i R 1j or -S(O) 0-2 R 1i R 1j One or more substituents are substituted, wherein R 1i and R 1j Is it H or C? 1-4 alkyl;

[0437] (24)R 1a Selected from:

[0438] (i)C 1-4 Alkyl groups, optionally prefixed with halogen, cyano, hydroxyl, or C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, aryl, or heteroaryl substitutions; or

[0439] (ii) The following groups:

[0440] -(CR 1c R 1d ) p -NR 1e R 1f ;

[0441] in

[0442] p is an integer selected from 1 or 2;

[0443] R 1c and R 1d Selected independently from:

[0444] (i) Hydrogen (including deuterium),

[0445] (ii)C 1-3 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, -OC 3-6 cycloalkyl, NR 1ca R 1da or -S(O) 0-2 R1ca R 1da One or more substituents are substituted, where R 1ca and R 1da Is it H or C? 1-2 Alkyl; and wherein C 3-6 cycloalkyl and -OC 3-6 The cycloalkyl group may optionally be replaced by a halogen, a cyano group, or a hydroxyl group;

[0446] (iii)C 3-4 Cycloalkyl or 3- to 5-membered heterocyclic groups, each optionally C 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da Replace, where R 1ca and R 1da Is it H or C? 1-2 Alkyl groups; and

[0447] (iv) or R 1c With R 1d They are linked together to form a 3- to 5-membered cycloalkyl or heterocyclic or spirocyclic system with the carbon atoms to which they are attached, each optionally selected from C14. 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da One or more substituents are substituted, wherein R 1ca and R 1da Is it H or C? 1-2 alkyl;

[0448] R 1e and R 1f Each is selected independently from:

[0449] (i) Hydrogen (including deuterium);

[0450] (ii)C 1-6 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ea R 1fa or -S(O)0-2 R 1ea R 1fa One or more substituents are substituted, where R 1ea and R 1fa Is it H or C? 1-2 alkyl;

[0451] (iii) Groups having the following formula:

[0452] -(CR 1g R 1h ) q -T1

[0453] in:

[0454] q is 0, 1, 2, or 3;

[0455] R 1g and R 1h Selected independently from:

[0456] a) Hydrogen (including deuterium); or

[0457] b)C 1-3 Alkyl groups, optionally substituted with one or more of the following substituents: cyano; oxo; hydroxyl; C 1-3 Alkoxy; Halogen; C 1-4 Halogenated alkoxy groups; -OC 3-4 cycloalkyl, wherein -OC 3-4 The cycloalkyl group is optionally substituted with a halogen, cyano, or hydroxyl group; NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da , where R 1ca and R 1da Is it H or C? 1-2 Alkyl NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha , where R 1ga and R 1ha Is it H or C? 1-2 alkyl;

[0458] c) or R 1g With R 1h Optionally linked together, such that they, together with the carbon atoms to which they are attached, form 3 to 6-membered cycloalkyl or heterocyclic rings, optionally selected from C14. 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR1ga R 1ha or -S(O) 0-2 R 1ga R 1ha One or more substituents are substituted, wherein R 1ga and R 1ha Is it H or C? 1-2 alkyl;

[0459] Furthermore, T1 is selected from hydrogen, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano, hydroxyl, NR 1t R 2t or -S(O) 0-2 R 1t R 2t (where R) 1t and R 2t Is it H or C? 1-4 Alkyl), C 3-8 cycloalkyl, C 2-3 alkenyl, C 2-3 Alkynyl, aryl, heterocyclic, mono- or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridging C 3-8 cycloalkyl, bridged bicyclic C 5-12 Cycloalkyl or bridged heterocyclic ring systems, each optionally selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, C 3-6 cycloalkyl, NR 3t R 4t or -S(O) 0-2 R 3t R 4t One or more substituents are substituted, wherein R 3t and R 4t Is it H or C? 1-2 alkyl;

[0460] (iv) or R 1e With R 1f The linkages allow them to form monocyclic or bicyclic heterocyclic rings together with the nitrogen atoms to which they are attached, optionally selected from C14. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, NR 1i R 1j or -S(O) 0-2 R 1i R 1jOne or more substituents are substituted, wherein R 1i and R 1j Is it H or C? 1-4 Alkyl groups, and / or those derived from R 1e and R 1f The formed monocyclic or bicyclic heterocyclic ring may optionally be combined with C 3-6 Cycloalkyl or heterocyclic cyclospirofusion, which is then optionally selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, NR 1i R 1j or -S(O) 0-2 R 1i R 1j One or more substituents are substituted, wherein R 1i and R 1j Is it H or C? 1-4 alkyl;

[0461] Any alkyl, alkoxy, or C 3-6 The cycloalkyl group is further optionally selected from cyano, hydroxyl, halogen, NR. 1k R 1l or -S(O) 0-2 R 1k R 1l One or more substituents are substituted, wherein R 1k and R 1l Is it H or C? 1-4 alkyl;

[0462] (25)R 1a It is a group of the following formula:

[0463] -(CR 1c R 1d ) p -NR 1e R 1f ;

[0464] in

[0465] p is an integer selected from 1 or 2;

[0466] R 1c and R 1d Selected independently from:

[0467] (i) Hydrogen (including deuterium); or

[0468] (ii)C 1-3 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-3Alkoxy, halogen, C 1-3 Halogenated alkoxy groups, -OC 3-4 One or more substituents of cycloalkyl or NH2 are substituted; wherein -OC 3-6 The cycloalkyl group may optionally be replaced by a halogen, a cyano group, or a hydroxyl group.

[0469] (iii)C 3-4 cycloalkyl groups, optionally C 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy or NR 1ca R 1da Replace; and

[0470] (iv) or R 1c With R 1d They are linked together to form a 3- to 5-membered cycloalkyl or heterocyclic or spirocyclic system with the carbon atoms to which they are attached, each optionally selected from C14. 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2- Halogenated alkoxy groups, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da One or more substituents are substituted, wherein R 1ca and R 1da Is it H or C? 1-2 alkyl;

[0471] R 1e and R 1f Each is selected independently from:

[0472] (i) Hydrogen (including deuterium);

[0473] (ii)C 1-6 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 The haloalkoxy group or one or more substituents of NH2 are used for substitution.

[0474] (iii) Groups having the following formula:

[0475] -(CR 1g R 1h ) q -T1

[0476] in:

[0477] q is 0, 1, 2, or 3;

[0478] R 1g and R 1h Selected independently from:

[0479] a) Hydrogen (including deuterium); or

[0480] b)C 1-6 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, -OC 3-6 cycloalkyl, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da One or more substituents are substituted, where R 1ca and R 1da Is it H or C? 1-2 Alkyl NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha , where R 1ga and R 1ha Is it H or C? 1-2 Alkyl; and wherein -OC 3-6 The cycloalkyl group may optionally be replaced by a halogen, a cyano group, or a hydroxyl group;

[0481] c) or R 1g With R 1h Optionally linked together, such that they, together with the carbon atoms to which they are attached, form 3 to 6-membered cycloalkyl or heterocyclic rings, optionally selected from C14. 1-2 Alkyl, C 1-2- Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha One or more substituents are substituted, wherein R 1ga and R 1ha Is it H or C? 1-2 alkyl;

[0482] Furthermore, T1 is selected from hydrogen, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano, hydroxyl, NR 1t R 2t or -S(O) 0-2 R1t R 2t (where R) 1t and R 2t Is it H or C? 1-4 Alkyl), C 3-8 cycloalkyl, C 2-3 alkenyl, C 2-3 Alkynyl, aryl, heterocyclic, mono- or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridging C 3-8 cycloalkyl, bridged bicyclic C 5-12 Cycloalkyl or bridged heterocyclic ring systems, each optionally selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, C 3-6 cycloalkyl, NR 3t R 4t or -S(O) 0-2 R 3t R 4t One or more substituents are substituted, wherein R 3t and R 4t Is it H or C? 1-2 alkyl;

[0483] (iv) or R 1e With R 1f The linkages allow them to form monocyclic or bicyclic heterocyclic rings together with the nitrogen atoms to which they are attached, optionally selected from C14. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, NR 1i R 1j or -S(O) 0-2 R 1i R 1j One or more substituents are substituted, wherein R 1i and R 1j Is it H or C? 1-4 Alkyl groups, and / or those derived from R 1e and R 1f The formed monocyclic or bicyclic heterocyclic ring may optionally be combined with C 3-6 Cycloalkyl or heterocyclic cyclospirofusion, which is then optionally selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, NR 1i R1j or -S(O) 0-2 R 1i R 1j One or more substituents are substituted, wherein R 1i and R 1j Is it H or C? 1-4 alkyl;

[0484] Any alkyl, alkoxy, or C 3-6 The cycloalkyl group is further optionally selected from cyano, hydroxyl, halogen, NR. 1k R 1l or -S(O) 0-2 R 1k R 1l One or more substituents are substituted, wherein R 1k and R 1l Is it H or C? 1-4 alkyl.

[0485] (26)R 1a It is a group of the following formula:

[0486] -(CR 1c R 1d ) p -NR 1e R 1f ;

[0487] in

[0488] p is an integer selected from 1 or 2;

[0489] R 1c and R 1d Selected independently from:

[0490] (i) Hydrogen (including deuterium),

[0491] (ii)C 1-3 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-3 Alkoxy, halogen, C 1-43 Halogenated alkoxy groups, -OC 3-4 One or more substituents of cycloalkyl or NH2 are substituted; wherein -OC 3-6 The cycloalkyl group may optionally be replaced by a halogen, a cyano group, or a hydroxyl group.

[0492] (iii) or R 1c With R 1d They are linked together to form a 3- to 5-membered cycloalkyl or heterocyclic or spirocyclic system with the carbon atoms to which they are attached, each optionally selected from C14. 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da One or more substituents are substituted, wherein R 1ca and R 1da Is it H or C? 1-2 alkyl;

[0493] R 1e Selected from:

[0494] (i) Hydrogen (including deuterium);

[0495] (ii)C 1-3 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 The haloalkoxy group and NH2 are substituted with one or more substituents;

[0496] And R 1f Selected from:

[0497] (i)C 1-6 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 The haloalkoxy group and NH2 are substituted with one or more substituents;

[0498] (ii) Groups having the following formula:

[0499] -(CR 1g R 1h ) q -T1

[0500] in:

[0501] q is 1, 2, or 3;

[0502] R 1g and R 1h Selected independently from:

[0503] a) Hydrogen (including deuterium); or

[0504] b)C 1-6 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, -OC 3-6 cycloalkyl, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1daOne or more substituents are substituted, where R 1ca and R 1da Is it H or C? 1-2 Alkyl NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha , where R 1ga and R 1ha Is it H or C? 1-2 Alkyl; and wherein -OC 3-6 The cycloalkyl group may optionally be replaced by a halogen, a cyano group, or a hydroxyl group;

[0505] c) or R 1g With R 1h Optionally linked together, such that they, together with the carbon atoms to which they are linked, form a 3- to 4-membered cycloalkyl or heterocyclic ring, which is optionally selected from C. 1-2 Alkyl, C 1-2- Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2- Halogenated alkoxy groups, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha One or more substituents are substituted, wherein R 1ga and R 1ha Is it H or C? 1-2 alkyl;

[0506] Furthermore, T1 is selected from hydrogen, halogens, and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano, hydroxyl, NR 1t R 2t or -S(O) 0-2 R 1t R 2t (where R) 1t and R 2t Is it H or C? 1-4 Alkyl), C 3-8 cycloalkyl, C 2-3 alkenyl, C 2-3 Alkynyl, aryl, heterocyclic, mono- or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridging C 3-8 cycloalkyl, bridged bicyclic C 5-12 Cycloalkyl or bridged heterocyclic ring systems, each optionally selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, C3-6 cycloalkyl, NR 3t R 4t or -S(O) 0-2 R 3t R 4t One or more substituents are substituted, wherein R 3t and R 4t Is it H or C? 1-2 alkyl;

[0507] Or R 1e With R 1f The linkages allow them to form monocyclic or bicyclic heterocyclic rings together with the nitrogen atoms to which they are attached, optionally selected from C14. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, NR 1i R 1j or -S(O) 0-2 R 1i R 1j One or more substituents are substituted, wherein R 1i and R 1j Is it H or C? 1-4 Alkyl groups, and / or those derived from R 1e and R 1f The formed monocyclic or bicyclic heterocyclic ring may optionally be combined with C 3-6 Cycloalkyl or heterocyclic cyclospirofusion, which is then optionally selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, NR 1i R 1j or -S(O) 0-2 R 1i R 1j One or more substituents are substituted, wherein R 1i and R 1j Is it H or C? 1-4 alkyl;

[0508] Any alkyl, alkoxy, or C 3-6 The cycloalkyl group is further optionally selected from cyano, hydroxyl, halogen, NR. 1k R 1l or -S(O) 0-2 R 1k R 1l One or more substituents are substituted, wherein R 1k and R1l Is it H or C? 1-4 alkyl.

[0509] (27)R 1a It is a group of the following formula:

[0510] -(CR 1c R 1d ) p -NR 1e R 1f

[0511] in

[0512] p is an integer selected from 1 or 2;

[0513] R 1c and R 1d Selected independently from:

[0514] (i) Hydrogen (including deuterium),

[0515] (ii)C 1-3 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-3 Alkoxy, halogen, C 1-3 Halogenated alkoxy groups, -OC 3-4 One or more substituents of cycloalkyl or NH2 are substituted; wherein -OC 3-6 The cycloalkyl group may optionally be replaced by a halogen, a cyano group, or a hydroxyl group.

[0516] (iii) or R 1c With R 1d They are linked together to form a 3- to 5-membered cycloalkyl or heterocyclic or spirocyclic system with the carbon atoms to which they are attached, each optionally selected from C14. 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2 One or more substituents of the haloalkoxy group are substituted;

[0517] R 1e Selected from:

[0518] (i) Hydrogen (including deuterium);

[0519] (ii)C 1-3 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 The haloalkoxy group and NH2 are substituted with one or more substituents;

[0520] R 1f It is a group having the following formula:

[0521] -(CR 1g R 1h ) q -T1

[0522] in:

[0523] q is 1, 2, or 3;

[0524] R 1g and R 1h Selected independently from:

[0525] a) Hydrogen (including deuterium); or

[0526] b)C 1-3 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, -OC 3-6 One or more substituents of the cycloalkyl group are substituted, wherein -OC 3-6 The cycloalkyl group may optionally be replaced by a halogen, a cyano group, or a hydroxyl group;

[0527] c) or R 1g With R 1h Optionally linked together, such that they, together with the carbon atoms to which they are linked, form a 3- to 4-membered cycloalkyl or heterocyclic ring, which is optionally selected from C. 1-2 Alkyl, C 1-2- Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2- One or more substituents of the haloalkoxy group are substituted;

[0528] Furthermore, T1 is selected from halogens and C. 1-4 Alkyl, C 1-4 Halogenated alkyl, cyano, hydroxyl, NR 1t R 2t or -S(O) 0-2 R 1t R 2t (where R) 1t and R 2t Is it H or C? 1-4 Alkyl), C 3-8 cycloalkyl, C 2-3 alkenyl, C 2-3 Alkynyl, aryl, heterocyclic, mono- or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridging C 3-8 cycloalkyl, bridged bicyclic C 5-12 Cycloalkyl or bridged heterocyclic ring systems, each optionally selected from C 1-2 Alkyl, C 1-2- Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C1-2 Halogenated alkoxy groups, C 3-6 cycloalkyl, NR 3t R 4t or -S(O) 0-2 R 3t R 4t One or more substituents are substituted, wherein R 3t and R 4t Is it H or C? 1-2 alkyl;

[0529] Or R 1e With R 1f The linkages allow them to form monocyclic or bicyclic heterocyclic rings together with the nitrogen atoms to which they are attached, optionally selected from C14. 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, NR 1i R 1j or -S(O) 0-2 R 1i R 1j One or more substituents are substituted, wherein R 1i and R 1j Is it H or C? 1-4 Alkyl groups, and / or those derived from R 1e and R 1f The formed monocyclic or bicyclic heterocyclic ring may optionally be combined with C 3-6 Cycloalkyl or heterocyclic cyclospirofusion, which is then optionally selected from C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-4 Alkoxy, halogen, C 1-4 Halogenated alkoxy groups, NR 1i R 1j or -S(O) 0-2 R 1i R 1j One or more substituents are substituted, wherein R 1i and R 1j Is it H or C? 1-4 alkyl;

[0530] Any alkyl, alkoxy, or C 3-6 The cycloalkyl group is further optionally selected from cyano, hydroxyl, halogen, NR. 1k R 1l or -S(O) 0-2 R 1k R 1l One or more substituents are substituted, wherein R1k and R 1l Is it H or C? 1-4 alkyl.

[0531] (28)R 1a It is a group of the following formula:

[0532] -(CR 1c R 1d ) p -NR 1e R 1f ;

[0533] in

[0534] p is an integer selected from 1 or 2;

[0535] R 1c and R 1d Selected independently from:

[0536] (i) Hydrogen (including deuterium),

[0537] (ii)C 1-3 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-3 Alkoxy, halogen, C 1-3 Halogenated alkoxy groups, -OC 3-4 One or more substituents of cycloalkyl or NH2 are substituted; wherein -OC 3-6 The cycloalkyl group may optionally be replaced by a halogen, a cyano group, or a hydroxyl group.

[0538] (iii) or R 1c With R 1d They are linked together to form a 3- to 5-membered cycloalkyl or heterocyclic or spirocyclic system with the carbon atoms to which they are attached, each optionally selected from C14. 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2 One or more substituents of the haloalkoxy group are substituted;

[0539] R 1e Selected from:

[0540] (i) Hydrogen (including deuterium);

[0541] (ii)C 1-3 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 The haloalkoxy group and NH2 are substituted with one or more substituents;

[0542] R 1f It is a group having the following formula:

[0543] -(CR 1g R 1h ) q -T1

[0544] in:

[0545] q is 1 or 2;

[0546] R 1g and R 1h Selected independently from:

[0547] a) Hydrogen (including deuterium); or

[0548] b)C 1-3 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 The haloalkoxy group is substituted with one or more substituents of the -O-C3 cycloalkyl group, wherein the -O-C3 cycloalkyl group is optionally substituted with a halogen, a cyano or a hydroxyl group;

[0549] And T1 is selected from C 1-4 Alkyl, C 3-8 Cycloalkyl, aryl, heterocyclic, heteroaryl, spirocyclic, carbocyclic, or heterocyclic ring systems, bridged C 3-8 cycloalkyl, bridged bicyclic C 5-12 Cycloalkyl or bridged heterocyclic ring systems, each optionally selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy or C 3-6 One or more substituents of the cycloalkyl group are substituted;

[0550] Or R 1e With R 1f The linkages allow them to form monocyclic or bicyclic heterocyclic rings together with the nitrogen atoms to which they are attached, optionally selected from C14. 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1i R 1j or -S(O) 0-2 R 1i R 1j One or more substituents are substituted, wherein R 1i and R 1j Is it H or C? 1-2 Alkyl groups, and / or those derived from R 1e and R1f The formed monocyclic or bicyclic heterocyclic ring may optionally be combined with C 3-6 Cycloalkyl or heterocyclic cyclospirofusion, which is then optionally selected from C 1-2 Alkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1i R 1j or -S(O) 0-2 R 1i R 1j One or more substituents are substituted, wherein R 1i and R 1j Is it H or C? 1-2 alkyl;

[0551] Any alkyl, alkoxy, or C 3-6 The cycloalkyl group is further optionally selected from cyano, hydroxyl, halogen, NR. 1k R 1l or -S(O) 0-2 R 1k R 1l One or more substituents are substituted, wherein R 1k and R 1l Is it H or C? 1-4 alkyl.

[0552] (29)R 1a It is a group of the following formula:

[0553] -(CR 1c R 1d ) p -NR 1e R 1f ;

[0554] in

[0555] p is an integer selected from 1 or 2;

[0556] R 1c and R 1d Selected independently from:

[0557] (i) Hydrogen (including deuterium), or

[0558] (ii)C 1-3 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 The alkyl halooxy group or one or more substituents of the -O-C3 cycloalkyl group are used for substitution.

[0559] R 1e Selected from hydrogen (including deuterium) or C 1-2Alkyl; and

[0560] R 1f It is a group having the following formula:

[0561] -(CR 1g R 1h ) q -T1

[0562] in:

[0563] q is 1 or 2;

[0564] R 1g and R 1h Selected independently from:

[0565] a) Hydrogen (including deuterium); or

[0566] b)C 1-2 Alkyl groups, optionally selected from cyano, oxo, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2 One or more substituents of the haloalkoxy group are substituted;

[0567] And T1 is selected from C 1-4 Alkyl, C 3-8 Cycloalkyl, aryl, heterocyclic, mono- or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic cyclic systems, bridged C 3-8 cycloalkyl, bridged bicyclic C 5-12 Cycloalkyl or bridged heterocyclic ring systems, each optionally selected from C 1-2 Alkyl, C 1-2- Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy or C 3-6 One or more substituents of the cycloalkyl group are substituted;

[0568] Or R 1e With R 1f The linkages allow them to form monocyclic or bicyclic heterocyclic rings together with the nitrogen atoms to which they are attached, optionally selected from C14. 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2 One or more substituents of the haloalkoxy group are substituted, and / or R is used. 1e and R 1f The formed monocyclic or bicyclic heterocyclic ring may optionally be combined with C 3-6 Cycloalkyl or heterocyclic cyclospirofusion, which is then optionally selected from C 1-2 Alkyl, C 1-2- Haloalkyl, C3-6 Cycloalkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2 One or more substituents of the haloalkoxy group are used; wherein any alkyl, alkoxy or C group is used. 3-6 The cycloalkyl group is further optionally selected from cyano, hydroxyl, halogen, NR. 1k R 1l or -S(O) 0-2 R 1k R 1l One or more substituents are substituted, wherein R 1k and R 1l Is it H or C? 1-4 alkyl.

[0569] (30)R 1a It is a group of the following formula:

[0570] -(CR 1c R 1d p-NR 1e R 1f ;

[0571] in

[0572] p is an integer selected from 1 or 2;

[0573] R 1c and R 1d Independently selected from hydrogen (including deuterium) or C 1-2 alkyl;

[0574] R 1e Selected from hydrogen (including deuterium) or C 1-2 Alkyl; and

[0575] R 1f It is a group having the following formula:

[0576] -(CR 1g R 1h ) q -T1

[0577] in:

[0578] q is 1 or 2;

[0579] R 1g and R 1h Independently selected from hydrogen (including deuterium) or C 1-2 alkyl;

[0580] And T1 is selected from C 1-4 Alkyl, C 3-4 Cycloalkyl, heterocyclic, mono- or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic cyclic systems, bridged C 3-cycloalkyl, bridged bicyclic C 5-12 Cycloalkyl or bridged heterocyclic ring systems, each optionally selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy or C 3-6 One or more substituents of the cycloalkyl group are substituted;

[0581] Or R 1e With R 1f The linkages allow them to form monocyclic or bicyclic heterocyclic rings together with the nitrogen atoms to which they are attached, optionally selected from C14. 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2 One or more substituents of the haloalkoxy group are substituted, and / or R is used. 1e and R 1f The formed monocyclic or bicyclic heterocyclic ring may optionally be combined with C 3-6 Cycloalkyl or heterocyclic cyclospirofusion, which is then optionally selected from C 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2 One or more substituents of the haloalkoxy group are substituted; wherein any alkyl, alkoxy, or C group is substituted. 3-6 The cycloalkyl group is further optionally selected from cyano, hydroxyl, halogen, NR. 1k R 1l or -S(O) 0-2 R 1k R 1l One or more substituents are substituted, wherein R 1k and R 1l Is it H or C? 1-4 alkyl.

[0582] (31)R 1a It is a group of the following formula:

[0583] -(CR 1c R 1d ) p -NR 1e R 1f ;in

[0584] p is 1;

[0585] R 1c and R 1d Independently selected from hydrogen (including deuterium) or C1-2 alkyl;

[0586] R 1e Selected from hydrogen (including deuterium) or C 1-2 Alkyl; and

[0587] R 1f It is a group having the following formula:

[0588] -(CR 1g R 1h ) q -T1

[0589] in:

[0590] q is 1 or 2;

[0591] R 1g and R 1h Independently selected from hydrogen (including deuterium) or C 1-2 alkyl;

[0592] And T1 is selected from C 3-4 Cycloalkyl, heterocyclic, mono- or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic cyclic systems, bridged C 3-8 cycloalkyl, bridged bicyclic C 5-12 Cycloalkyl or bridged heterocyclic ring systems, each optionally selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2- Halogenated alkoxy or C 3-6 One or more substituents of the cycloalkyl group are substituted;

[0593] Or R 1e With R 1f The linkages allow them to form monocyclic or bicyclic heterocyclic rings together with the nitrogen atoms to which they are attached, optionally selected from C14. 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2 One or more substituents of the haloalkoxy group are substituted, and / or R is used. 1e and R 1f The formed monocyclic or bicyclic heterocyclic ring may optionally be combined with C 3-6 Cycloalkyl or heterocyclic cyclospirofusion, which is then optionally selected from C 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2One or more substituents of the haloalkoxy group are used, wherein any alkyl, alkoxy, or C group is used. 3-6 The cycloalkyl group is further optionally selected from cyano, hydroxyl, halogen, NR. 1k R 1l or -S(O) 0-2 R 1k R 1l One or more substituents are substituted, wherein R 1k and R 1l Is it H or C? 1-4 alkyl.

[0594] (32)R 1a It is a group of the following formula:

[0595] -(CR 1c R 1d ) p -NR 1e R 1f ;in

[0596] p is 1;

[0597] R 1c and R 1d Independently selected from hydrogen (including deuterium) or C 1-2 alkyl;

[0598] R 1e Selected from hydrogen (including deuterium) or C 1-2 Alkyl; and

[0599] R 1f It is a group having the following formula:

[0600] -(CR 1g R 1h ) q -T1

[0601] in:

[0602] q is 1;

[0603] R 1g and R 1h Independently selected from hydrogen (including deuterium) or C 1-2 alkyl;

[0604] And T1 is selected from C 3-4 Cycloalkyl, heterocyclic, spirocyclic, or heterocyclic ring systems, bridged C 3-8 cycloalkyl, bridged bicyclic C 5-12 Cycloalkyl or bridged heterocyclic ring systems, each optionally selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C1-2 Halogenated alkoxy or C 3-6 One or more substituents of the cycloalkyl group are substituted.

[0605] Any alkyl or alkoxy group may optionally be further substituted with one or more substituents selected from cyano, hydroxy, or halogen.

[0606] (33)R 1a It is a group of the following formula:

[0607] -(CR 1c R 1d ) p -NR 1e R 1f ;in

[0608] p is 1;

[0609] R 1c and R 1d Independently selected from hydrogen (including deuterium) or C 1-2 Alkyl; and

[0610] R 1e With R 1f The linkages allow them to form monocyclic or bicyclic heterocyclic rings together with the nitrogen atoms to which they are attached, optionally selected from C14. 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2 One or more substituents of the haloalkoxy group are substituted, and / or R is used. 1e and R 1f The formed monocyclic or bicyclic heterocyclic ring may optionally be combined with C 3-6 Cycloalkyl or heterocyclic cyclospirofusion, which is then optionally selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2 One or more substituents of the haloalkoxy group are substituted.

[0611] (34)R 1a yes

[0612]

[0613] T1 is defined as described in this article.

[0614] (35)R 1a It is a group of the following formula:

[0615]

[0616] Where T1 is selected from C 3-4 Cycloalkyl, heterocyclic, spirocyclic, or heterocyclic ring systems, bridged C 3-8 cycloalkyl, bridged bicyclic C 5-12 Cycloalkyl or bridged heterocyclic ring systems, each optionally selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2 One or more substituents of the haloalkoxy group are substituted;

[0617] (36)R 1a Selected from:

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628] (37)R 1a Selected from:

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638] (38)R 1a Selected from:

[0639]

[0640]

[0641]

[0642]

[0643] (39)R 1a Selected from:

[0644]

[0645] (40)R 1a Selected from:

[0646]

[0647] (40a)R 1a Selected from:

[0648]

[0649] (41)R 1a Selected from:

[0650]

[0651] (41a)R 1a yes:

[0652]

[0653] (41b)R 1a yes:

[0654]

[0655] (41c)R 1a yes:

[0656]

[0657] (42)R 1a yes:

[0658]

[0659] (43)R 1b Selected from hydrogen, halogen or C 1-2 alkyl.

[0660] (44)R 1b It is hydrogen.

[0661] (45)R 1x Selected from hydrogen, halogen or C 1-2 alkyl.

[0662] (46)R 1x It is hydrogen.

[0663] (47)R 2a R 2b R 2c and R 2d Independently selected from hydrogen, cyano, halogen, or the following groups:

[0664] -L 2a -L 2b -Q2

[0665] L 2a Does not exist or is arbitrarily C 1-2 alkyl or oxo-substituted C 1-3 Alkylene;

[0666] L 2b It does not exist or is selected from O, S, N(R) n ), C(O), C(O)O, OC(O), C(O)N(R n ), N(R n C(O), N(R) n )C(O)N(R o ), where R n and R o Each is independently selected from hydrogen or C. 1-2 Alkyl; and

[0667] Q2 is hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, aryl, heterocyclic, or heteroaryl, each optionally selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxyl, amino, carboxyl, carbamoyl, aminosulfonyl, C 1-4 Alkyl, NR p R q OR p C(O)R p One or more substituents are substituted, wherein R p and R q Each is independently selected from hydrogen or C. 1-4 Alkyl group. (48)R 2a R 2b R 2c and R 2dIndependently selected from hydrogen, cyano, halogen, or the following groups:

[0668] -L 2a -L 2b -Q2

[0669] L 2a Does not exist or is arbitrarily C 1-2 Alkyl-substituted C 1-3 Alkylene;

[0670] L 2b It does not exist or is selected from O, S, N(R) n ), C(O); and

[0671] Q2 is hydrogen, cyano, C 1-6 Alkyl, C 3-6 Cycloalkyl, aryl, heterocyclic, or heteroaryl groups, each optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, and hydroxyl.

[0672] (49)R 2a R 2b R 2c and R 2d Independently selected from hydrogen, cyano, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, aryl, heterocyclic, or heteroaryl groups, each optionally substituted with one or more substituents selected from halogen, trifluoromethyl, trifluoromethoxy, amino, cyano, and hydroxyl.

[0673] (50)R 2a R 2b R 2c and R 2d Independently selected from hydrogen, cyano, halogen, or C 1-3 alkyl.

[0674] (51)R 2a R 2b R 2c and R 2d It is independently selected from hydrogen or halogen.

[0675] (52)R 2a R 2b R 2c and R 2d It is hydrogen.

[0676] (53)R 3a1 R 3b1 R 3c1 R3d1 R 3e1 R 3f1 R 3g1 R 3h1 R 3i1 R 3j1 R 3k1 R 3l1 R 3m1 R 3n1 R 3o1 R 3p1 R 3q1 R 3r1 and R 3s1 Independently selected from hydrogen and C 1-6 Alkyl, C 3-4 cycloalkyl, hydroxyl and halogen; and wherein C 1-6 Alkyl or C 3-4 The cycloalkyl group is optionally substituted with one or more substituents selected from halogen, amino, cyano, and hydroxyl groups; and R 3a2 R 3b2 R 3c2 R 3d2 R 3e2 R 3f2 R 3g2 R 3h2 R 3i2 R 3j2 R 3k2 R 3l2 R 3m2 R 3n2 R 3o2 R 3p2 R 3q2 R 3r2 and R 3s2 It is hydrogen;

[0677] (54)R 3a1 R 3b1 R 3c1 R 3d1 R 3e1 R 3f1 R 3g1 R 3h1 R 3i1 R 3j1 R 3k1 R 3l1 R 3m1 R 3n1 R 3o1 R 3p1 R 3q1 R 3r1 and R 3s1 Independently selected from hydrogen and C 1-6 Alkyl; and wherein C 1-6The alkyl group is optionally substituted with one or more hydroxyl substituents;

[0678] (55)R 3a1 R 3b1 R 3c1 R 3d1 R 3e1 R 3f1 R 3g1 R 3h1 R 3i1 R 3j1 R 3k1 R 3l1 R 3m1 R 3n1 R 3o1 R 3p1 R 3q1 R 3r1 and R 3s1 Independently selected from hydrogen and methyl; and wherein the methyl group is optionally substituted by one or more hydroxyl substituents;

[0679] (56)R 3a1 R 3b1 R 3c1 R 3d1 R 3e1 R 3f1 R 3g1 R 3h1 R 3i1 R 3j1 R 3k1 R 3l1 R 3m1 R 3n1 R 3o1 R 3p1 R 3q1 R 3r1 and R 3s1 Independently selected from hydrogen and methyl; wherein the methyl group is substituted with a hydroxyl group;

[0680] (57)R 3a2 R 3b2 R 3c2 R 3d2 R 3e2 R 3f2 R 3g2 R 3h2 R 3i2 R 3j2 R 3k2 R 3l2 R 3m2 R 3n2 R 3o2 R 3p2 R 3q2 R3r2 and R 3s2 It is hydrogen;

[0681] (58)R 3a1 With R 3a2 R 3b1 With R 3b2 R 3c1 With R 3c2 R 3d1 With R 3d2 R 3e1 With R 3e2 R 3f1 With R 3f2 R 3g1 With R 3g2 R 3h1 With R 3h2 R 3i1 With R 3i2 R 3j1 With R 3j2 R 3k1 With R 3k2 R 3l1 With R 3l2 R 3m1 With R 3m2 R 3n1 With R 3n2 R 3o1 With R 3o2 R 3p1 With R 3p2 R 3q1 With R 3q2 R 3r1 With R 3r2 and R 3s1 With R 3s2 It is hydrogen.

[0682] (59)R 3a1 With R 3a2 R 3b1 With R 3b2 R 3c1 With R 3c2 R 3d1 With R 3d2 R 3e1 With R 3e2 R 3f1 With R 3f2 R 3g1 With R 3g2 R 3h1 With R 3h2 R 3i1 With R 3i2 R 3j1 With R 3j2 R 3k1 With R 3k2 R3l1 With R 3l2 R 3m1 With R 3m2 R 3n1 With R 3n2 R 3o1 With R 3o2 R 3p1 With R 3p2 and R 3q1 With R 3q2 R 3r1 With R 3r2 and R 3s1 With R 3s2 Connect to form a helical fused C 3-4 Cycloalkyl groups, optionally substituted with one or more substituents selected from halogens, amino groups, cyano groups, and hydroxyl groups.

[0683] (60) n is 0, 1 or 2;

[0684] (61) n is 1 or 2;

[0685] (62) n is 1;

[0686] (63) Y is Where R 3a1 R 3a2 and n are as defined in this article;

[0687] (64) Y is Where n is defined in this paper;

[0688] (65)Y is Where R 3b1 R 3b2 and n are as defined in this article;

[0689] (66)Y is Where R 3c1 R 3c2 and n are as defined in this article;

[0690] (67) Y is Where R 3d1 R 3d2 and n are as defined in this article;

[0691] (68) Y is Where R 3e1 R 3e2 and n are as defined in this article;

[0692] (69) Y is

[0693] (70)Y is Where R 3f1 R3f2 and n are as defined in this article;

[0694] (71) Y is Where R 3g1 R 3g2 and n are as defined in this article;

[0695] (72) Y is Where R 3h1 R 3h2 and n are as defined in this article;

[0696] (73) Y is Where R 3i1 R 3i2 and n are as defined in this article;

[0697] (74) Y is Where R 3j1 R 3j2 and n are as defined in this article;

[0698] (75) Y is Where R 3k1 R 3k2 and n are as defined in this article;

[0699] (76) Y is Where R 3l1 R 3l2 and n are as defined in this article;

[0700] (77)Y is Where R 3m1 R 3m2 and n are as defined in this article;

[0701] (78) Y is Where R 3n1 R 3n2 and n are as defined in this article;

[0702] (79) Y is Where R 3o1 R 3o2 and n are as defined in this article;

[0703] (80)Y is Where R 3p1 R 3p2 and n are as defined in this article;

[0704] (81) Y is Where R 3q1 R 3q2 and n are as defined in this article;

[0705] (82) Y is Where R 3r1 R 3r2 and n are as defined in this article;

[0706] (83) Y is Where R 3s1 R 3s2 and n are as defined in this article;

[0707] (84) Y is selected from:

[0708]

[0709] (85)Y is selected from:

[0710]

[0711] Where R 3a1 R 3a2 R 3b1 R 3b2 R 3e1 R 3e2 R 3i1 R 3i2 R 3j1 and R 3j2 As defined in this article.

[0712] (86) Y is selected from:

[0713]

[0714] (87) Y is selected from:

[0715]

[0716] (88)Y is selected from

[0717] (89) Y is

[0718] (90) R4, R5 and R6 are independently selected from hydrogen and halogens;

[0719] (91) R4, R5, and R6 are hydrogen;

[0720] (92) When Z is When, then R7, R9 and R 11N Independently selected from hydrogen, halogens, and cyano groups;

[0721] (93) When Z is When, then R7, R9 and R 11N It is hydrogen;

[0722] (94) When Z is When, then R8, R9, R 10 and R 11 Independently selected from hydrogen, NH2, halogen, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-6 Alkyl groups, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3, and -C(O)NR v1 R v2 , where R v1 and R v2 Independently selected from hydrogen and methyl; or R9 and R 10 They can be linked together to form fused 5- or 6-member saturated or unsaturated ring systems, or R 10 With R 11 They can be linked together to form fused 5- or 6-member saturated or unsaturated ring systems.

[0723] (95) When Z is When, then R8, R9, R 10 and R 11 Independently selected from hydrogen, NH2, halogen, cyano, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups and C 1-3 alkyl.

[0724] (95a) When Z is When R8 is selected from hydrogen, cyano, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3 and -C(O)NR v1 R v2 , where R v1 and R v2 Independently selected from hydrogen and methyl; R9 is hydrogen; R 10 Selected from halogens, C 1-4 Alkoxy or C 1-4 Haloalkoxy; and R 11 It is hydrogen.

[0725] (96) When Z is When R8 is hydrogen, cyano, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3, or -C(O)NR, then R8 is hydrogen, cyano, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3, or -C(O)NR. v1 R v2 , where R v1 and R v2 Independently selected from hydrogen and methyl; R9 is hydrogen; R 10 It is C 1-4 Alkoxy or C 1-4 Haloalkoxy; and R 11 It is hydrogen.

[0726] (97) When Z is In this case, R8 is hydrogen or cyano; R9 is hydrogen; R 10 It is C 1-4 alkoxy groups; and R 11 It is hydrogen.

[0727] (97a) When Z is When, then R8, R9 and R 11 It is hydrogen, and R 10 It is a methoxy group.

[0728] (98) When Z is When, then R8, R9, R 10 and R 11 It is hydrogen.

[0729] (99)R Z1 and R Z1a Selected from hydrogen, C 1-4 Alkyl, cyano, halogen, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 3-6 cycloalkyl and -OC 3-6 cycloalkyl, wherein C 3-6 cycloalkyl and -OC 3-6 The cycloalkyl group may optionally be substituted with one or more of halogen, methyl or methoxy;

[0730] (100)R Z1 and R Z1a Selected from hydrogen, C 1-2 Alkyl, cyano, halogen, C 1-2 Haloalkyl, C 1-2 Halogenated alkoxy groups, C 1-2 Alkoxy;

[0731] (101)R Z1 and R Z1a Selected from hydrogen, C 1-2 Alkyl, cyano, and halogen;

[0732] (102)R Z1 and R Z1a It is hydrogen;

[0733] (103)R Z2 R Z2a R Z3a R Zi1b and R Zi2e Independently selected from hydrogen and C 1-4 Alkyl, cyano, halogen or C 1-4 Alkoxy;

[0734] (104)R Z2 R Z2a R Z3a R Zi1b and R Zi2e Independently selected from hydrogen, cyano, or halogen;

[0735] (105)R Z2 R Z2a R Z3a R Zi1b and R Zi2e It is hydrogen;

[0736] (106)R B5N R Y5N R Z2N and R 11N Selected from hydrogen or methyl;

[0737] (107)R B5N R Y5N R Z2N and R 11N It is hydrogen;

[0738] (108)R Z4 R Z5 R Z6 R Z7 R Z8 R Z9 R Z10 R Z11 R Z12 R Z13 R Z14 R Z15 and R Z16 Independently selected from hydrogen, halogens, and cyano groups;

[0739] (109)R Z4 R Z5 R Z6 R Z7 R Z8 R Z9 R Z10 R Z11 R Z12 R Z13 R Z14 R Z15 and R Z16 Independently selected from hydrogen and halogens;

[0740] (110)R Z4 R Z5 R Z6 R Z7 R Z8 R Z9 R Z10 RZ11 R Z12 R Z13 R Z14 R Z15 R Z16 It is hydrogen;

[0741] (111) Appropriately,

[0742] When X6 is A1, A1 is CR. 12 ;

[0743] When X7 is A2, A2 is CR. 13 ;

[0744] B1 is A5, where A5 is CR 16 ;

[0745] B2 is A6, where A6 is CR 17 ;

[0746] Y2 is A7, where CR is... 18 ;

[0747] When X6 is A8, A8 is CR. 19 R 20 ;

[0748] When X7 is A9, A9 is CR. 22 R 23 ;

[0749] When X7 is A 11 At that time, A 11 It is CR 28 R 29 ;

[0750] And R 12 R 13 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 28 and R 29 As defined in this article.

[0751] (112)R 12 R 13 R 16 R 19 R 20 R 21 R 22 and R 23 Independently selected from hydrogen, halogen, cyano, and methyl;

[0752] (113)R 12 R 13 R 16 R 19 R 20 R 21 R 22 and R 23 It is hydrogen;

[0753] (114)R 12 Selected from hydrogen, halogen, cyano and C 1-4 alkyl;

[0754] (115)R 12 Selected from hydrogen and halogens;

[0755] (116)R 12 Selected from hydrogen and chlorine;

[0756] (117)R 12 It is hydrogen;

[0757] (118)R 13 Selected from hydrogen, halogen, cyano, and methyl;

[0758] (119)R 13 It is hydrogen;

[0759] (120)R 13 Selected from hydrogen, methoxy, and methyl;

[0760] (121)R 16 and R 18 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkyl and C 1-4 Halogenated alkoxy groups;

[0761] (122)R 16 and R 18 Selected from hydrogen, halogen, cyano and C 1-4 alkyl;

[0762] (123)R 16 and R 18 Selected from hydrogen and halogens;

[0763] (124)R 16 and R 18 It is hydrogen;

[0764] (125)R 17 Selected from hydrogen, halogen, cyano, C 1-5 Alkyl, C 1-4 Haloalkyl, C 1-4Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5 or 6 nucleotide or heteroaryl, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclic, -O-heterocyclic (carbon-linked), where m is an integer from 1 to 6 -(OCH2CH2) m -OCH3, NR q R r , where R q and R r Each is independently hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl groups, heterocyclic groups linked to 3 to 6 carbons, or R q With R r They are linked together, forming 3- to 6-membered heterocyclic rings together with the nitrogen atoms they are attached to;

[0765] Where any C 1-5 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5 or 6 nucleotide or heteroaryl, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclic, or -O-heterocyclic (carbon-linked) groups are optionally further selected from C 1-2 Alkyl, cyano, C 1-2 Halogenated alkyl, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa One or more substituents are substituted, wherein R 1ea and R 1fa Is it H or C? 1-2 alkyl.

[0766] (126)R 17 Selected from hydrogen, halogen, cyano, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 2-3 alkenyl, C 2-3 alkynyl, phenyl, 5 or 6 nucleotide or heteroaryl, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclic, -O-heterocyclic (carbon-linked), where m is an integer from 1 to 6 -(OCH2CH2)m -OCH3, NR q R r , where R q and R r Each is independently hydrogen, C 1-2 Alkyl, or R q With R r They are linked together, forming 3- to 6-membered heterocyclic rings together with the nitrogen atoms they are attached to;

[0767] Where any C 1- Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5 or 6 nucleotide or heteroaryl, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclic, or -O-heterocyclic (carbon-linked) groups are optionally further selected from C 1-2 Alkyl, cyano, C 1-2 Halogenated alkyl, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa One or more substituents are substituted, wherein R 1ea and R 1fa Is it H or C? 1-2 alkyl.

[0768] (127)R 17 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5- or 6-membered heteroaryl, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclic, -O-heterocyclic (carbon-linked), -(OCH2CH2) m -OCH3 (where m is 1, 2, or 3), NR q R r , where R q and R r Each is independently hydrogen, C 1-4 Alkyl; or R q With R r They are linked together, forming 3- to 6-membered heterocyclic rings together with the nitrogen atoms they are attached to;

[0769] Where any C1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5 or 6 nucleotide or heteroaryl, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclic, or -O-heterocyclic (carbon-linked) groups are optionally further selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen and C 1-2 One or more substituents of the haloalkoxy group are substituted.

[0770] (128)R 17 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, -OC 3-4 Cycloalkyl, heterocyclic, -(OCH2CH2) m -OCH3 (where m is 1, 2, or 3), NR q R r , where R q and R r Each is independently hydrogen or C 1-2 alkyl;

[0771] Where any C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 cycloalkyl, -OC 3-4 Cycloalkyl and heterocyclic systems are optionally further selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen and C 1-2 One or more substituents of the haloalkoxy group are substituted.

[0772] (129)R 17 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 alkenyl, C 2-4 Alkyne group and 5 or 6 aryl or heteroaryl group; wherein any C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 The alkynyl, 5- or 6-membered aryl or heteroaryl groups are optionally further selected from C 1-2Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen and C 1-2 One or more substituents of the haloalkoxy group are substituted.

[0773] (130)R 17 Selected from hydrogen, halogens, C 1-4 Alkoxy, C 2-4 Alkyne group and 5 or 6 aryl or heteroaryl groups.

[0774] (131)R 17 Selected from hydrogen, C 1-4 Alkoxy, bromine, ethynyl, and pyrazolyl.

[0775] (132)R 28 and R 29 Selected from hydrogen or halogen, methoxy, and methyl;

[0776] (133)R 28 and R 29 It is hydrogen;

[0777] (134)R 21 R 24 and R 30 Independently selected from hydrogen or methyl;

[0778] (135)R 21 R 24 and R 30 It is hydrogen;

[0779] (136)Z is selected from

[0780]

[0781] Where X2, X3, X4, X5, X6, X7, X8 and X9 are as defined in this document;

[0782] (137)Z is

[0783]

[0784] Where X2, X4, X5, X6, X7, X8 and X9 are as defined in this document;

[0785] (138)Z is

[0786]

[0787] X2 is CR4:

[0788] X4 is either C or N;

[0789] X5 is CR5:

[0790] X6 is A1, where A1 is CR 12

[0791] X7 is A2, where A2 is CR. 13

[0792] X8 is either N or CR6.

[0793] X9 is either N or C;

[0794] Among them, R4, R5, R6, R 12 and R 13 As defined in this article;

[0795] (139)Z is R4, R5, R6, A1, and A2 are defined as described in this paper;

[0796] (140)Z is

[0797] Where X2, X4, X5, X6, X7, X8 and X9 are as defined in this document;

[0798] (141)Z is

[0799]

[0800] X2 is CR4:

[0801] X4 is N;

[0802] X5 is CR5:

[0803] X6 is A1, where A1 is CR 12

[0804] X7 is A2, where A2 is CR. 13

[0805] The X8 is a CR6.

[0806] X9 is either N or C;

[0807] Among them, R4, R5, R6, R 12 R 13 X7, X8, and X9 are as defined in this document;

[0808] (142)Z is R4, R5, R6, A1, and A2 are defined as described in this paper;

[0809] (143)Z is B1, B2, B3, B4, B5, B7 and B8 are as defined in this document;

[0810] (144)Z is:

[0811]

[0812] in

[0813] B1 is A5, where A5 is N or CR. 16 ;

[0814] B2 is A6, where A6 is CR 17

[0815] B3 is N or CR Z1 ;

[0816] B4 is either N or C;

[0817] B5 is selected from CR zi1b or NR B5N

[0818] B7 is N, NR Z2N or CR Z2 ;

[0819] B8 is selected from C or N;

[0820] Where R 16 R 17 R Z1 R zi1b R B5N R Z2 As defined in this article;

[0821] (145) Z is:

[0822]

[0823] in

[0824] B1 is A5, where A5 is CR 16 ;

[0825] B2 is A6, where A6 is CR 17

[0826] B3 is CR Z1 ;

[0827] B4 is either N or C;

[0828] B5 is selected from CR zi1b or NR B5N

[0829] B7 is N, NH or CR Z2 ;

[0830] B8 is C;

[0831] Where R16 R 17 R Z1 R zi1b R B5N R Z2 As defined in this article;

[0832] (146)Z is Among them, A5, A6, R Z1 and R Z2 As defined in this article;

[0833] (147)Z is Among them, A5, A6, R Z1 R Z2 It is R Zi1b As defined in this article;

[0834] (148)Z is Among them, A5, A6, R Z1 R Z2N and R Zi1b As defined in this article;

[0835] (149) Z is: Where R Z1 R Z2 R Zi1b A5 and A6 are as defined in this document;

[0836] (150)Z is: Where R Z2 A5 and A6 are as defined in this document;

[0837] (151) Z is: Where R Z1d R Z2d A6 is as defined in this article;

[0838] (152)Z is

[0839]

[0840] Among them, Q7, Q8, Q9, Q 10 and Q 11 As defined in this article;

[0841] (153)Z is

[0842]

[0843] Among them, Q8, Q9, Q 10 and Q 11 As defined in this article;

[0844] (154)Z is selected from:

[0845]

[0846] Among them, R7, R8, R9, R 10 and R 11 As defined in this article;

[0847] (155)Z is Among them, R8, R9, R 10 and R 11 As defined in this article;

[0848] (156)Z is in:

[0849] R8 is selected from hydrogen, cyano, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3 and -C(O)NR. v1 R v2 , where R v1 and R v2 Independently selected from hydrogen and methyl;

[0850] R 10 Selected from halogens, C 1-4 Alkoxy or C 1-4 Halogenated alkoxy groups;

[0851] R9 and R 11 As defined in this article;

[0852] (157)Z is Where R8 is hydrogen or cyano, and R 10 It is C 1-4 Alkoxy;

[0853] (157a)Z is

[0854] (158)Z is

[0855] (159)Z is Among them, A7, R Y5N R Z1a R Z2a and R Z3a As defined in this article;

[0856] (160)Z is R4, R5, A8, and A9 are defined as described in this document;

[0857] (161)Z is Among them, R4, R5, R6, A8 and A 11 As defined in this article;

[0858] (162)Z is

[0859]

[0860] Among them, Q8, Q9, Q 10 and Q 11a As defined in this article;

[0861] (163)Z is

[0862] Among them, R7, R9 and R 11N As defined in this article;

[0863] (164)Z is

[0864]

[0865] in

[0866] X1 is N or CR Z9 ;

[0867] X2 is CR4:

[0868] X3 is N;

[0869] X4 is C;

[0870] X5 is CR5:

[0871] X6 is A1, where A1 is CR 12

[0872] X7 is A2, where A2 is CR. 13

[0873] X8 is either N or CR6.

[0874] X9 is either N or C;

[0875] Where R Z9 R4, R5, R6, R 12 and R 13 As defined in this article.

[0876] (165)Z is

[0877]

[0878] in

[0879] Y2 is A7, where A7 is CR. 18 ;

[0880] Y3 is N or CR Z1a ;

[0881] Y4 is C or N

[0882] Y5 is NR Y5N ;

[0883] Y6 is CR Zi2e Or N;

[0884] Y7 is CR Z2a Or N;

[0885] Y8 is either C or N;

[0886] Y9 is CR Z3a Or N;

[0887] Where R 18 R z1a R Y5N R Zi2e R Z2a and R Z3a As defined in this article;

[0888] (166)Z is

[0889]

[0890] in

[0891] Y2 is A7, where A7 is CR. 18 ;

[0892] Y4 is C or N

[0893] Y5 is NR Y5N ;

[0894] Y6 is CR Zi2e Or N;

[0895] Y7 is CR Z2a Or N;

[0896] Y8 is either C or N;

[0897] Y9 is CR Z3a Or N;

[0898] Where R 18 R z1a R Y5N R Zi2e R Z2a and R Z3a As defined in this article;

[0899] (167)Z is: Where R Y5N R Z1a R Z2a R Z3a A7 is as defined in this article;

[0900] (168) Z is: Where R Z1a R Z2a R Z3a A7 is as defined in this article;

[0901] (169)Z is: Where R Y5N R Z2a R Z3a R Zi2e A7 is as defined in this article;

[0902] (170)Z is: Where R Z2a R Z3a R Zi2e A7 is as defined in this article;

[0903] (171)Z is

[0904]

[0905] in

[0906] Y2 is A7, where A7 is CR. 18 ;

[0907] Y4 is N

[0908] Y5 is CR Y5 ;

[0909] Y6 is CR Zi2e ;

[0910] Y7 is either O or S;

[0911] Y8 is C;

[0912] Y9 is N;

[0913] Where R 18 R Y5 R Zi2e As defined in this article;

[0914] (172) Z is:

[0915]

[0916] Among them, A7 and R Zi2e As defined in this article;

[0917] (173)Z is: Among them, R4, R5, R6, R Z9 R 12 and R 13As defined in this article;

[0918] (174)Z is: Among them, R4, R5, R6, R 19 R 22 and R Z9 As defined in this article;

[0919] (175)Z is

[0920]

[0921] Where X2, X3, X4, X5, X6, X7, X8 and X9 are as defined in this document;

[0922] (176) Z is: Among them, R4, R5, R6, R 12 R 13 and R Z9 As defined in this article;

[0923] (177)Z is

[0924] Z 10 Z 11 Z 12 Z 13 Z 14 Z 15 and Z 16 As defined in this article;

[0925] (178)Z is

[0926]

[0927] in

[0928] Z 10 It is CR Z10 ,

[0929] Z 11 It is N;

[0930] Z 12 It is CR Z12 ;

[0931] Z 13 It is CR Z13 ;

[0932] Z 14 Is it N or CR? Z14 ;

[0933] Z 15 Is it N or CR? Z15 ;

[0934] Z 16 It is CR Z16 ;

[0935] Where R Z10 R Z12 R Z13 R Z14 R Z15 and R Z16 As defined in this article;

[0936] (179)Z is

[0937]

[0938] in

[0939] Z 10 It is CR Z10 ,

[0940] Z 11 It is CR Z10 Or N;

[0941] Z 12 It is CR Z12 ;

[0942] Z 13 It is CR Z13 ;

[0943] Z 14 It is N;

[0944] Z 15 Is it N or CR? Z15 ;

[0945] Z 16 It is CR Z16 ;

[0946] Where R Z10 R Z12 R Z13 R Z14 R Z15 and R Z16 As defined in this article;

[0947] (180)Z is: Z 10 Z 12 Z 13 Z 14 Z 15 and Z 16 As defined in this article;

[0948] (181)Z is: Z 13 Z 14 Z15 and Z 16 As defined in this article;

[0949] (182)Z is: Where R Z10 R Z12 R Z13 R Z14 R Z15 and R Z16 As defined in this article;

[0950] (183)Z is: Z 10 Z 11 Z 12 Z 13 Z 15 and Z 16 As defined in this article,

[0951] (184)Z is: Where R Z10a R Z11a R Z12a R Z13a R Z15a and R Z16a As defined in this article;

[0952] (185)Z is selected from:

[0953]

[0954] B1, B2, B3, B4, B5, B7, B8, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, X1, X2, X3, X4, X5, X6, X7, X8, and X9 are the terms used in this paper.

[0955] (186)Z is selected from:

[0956]

[0957]

[0958]

[0959] in:

[0960] A1, A2, A5, A6, A7, A8, A9, A 11 , R4, R5, R6, R7, R8, R9, R 10 R 11 R 11N R 12 R 13 R 19R 22 R Y5N R Z1 R Z2 R z9 R Z10 R Z11 R Z12 R Z13 R Z14 R Z15 R Z16 R Z2a R Z3a R Z1a R Zi1b and R Zi2e As defined in this article;

[0961] (187)Z is selected from:

[0962]

[0963]

[0964] Among them, A1, A2, A5, A6, A7, A8, A9, A 11 , R4, R5, R6, R7, R8, R9, R 10 R 11 R 11N R 12 R 13 R 19 R 22 R Z1 R Z2 R z9 R Z10 R Z11 R Z12 R Z13 R Z14 R Z15 R Z16 R Z2a R Z3a R Z1a R Zi1b and R Zi2e As defined in this article;

[0965] (188)Z is selected from:

[0966]

[0967]

[0968] A1, A2, A5, A6, A7, A8, A9, A 11 , R4, R5, R6, R7, R8, R9, R 10R 11 R Y5N R Z1 R Z2 R Z10 R Z12 R Z13 R Z14 R Z15 R Z16 R Z2a R Z3a R Z1a R Zi1b and R Zi2e As defined in this article;

[0969] (189)Z is selected from:

[0970]

[0971] Among them, A1, A2, A5, A6, A7, A8, A9, A 11 , R4, R5, R6, R7, R8, R9, R 10 R 11 R Y5N R Z1 R Z2 R Z10 R Z12 R Z13 R Z14 R Z15 R Z16 R Z2a R Z3a R Z1a R Zi1b and R Zi2e As defined in this article.

[0972] (190)Z is selected from:

[0973]

[0974] Among them, A1, A2, A5, A6, A7, A8, A9, A 11 , R4, R5, R6, R7, R8, R9, R 10 R 11 R Y5N R Z1 R Z2 R Z10 R Z12, R Z13 R Z14 R Z15 R Z16 R Z2a R Z3a R Z1aR Zi1b and R Zi2e As defined in this article.

[0975] (191)Z is selected from:

[0976]

[0977] Among them, R8, R 10 R 17 R 18 and R Z1 As defined in this article.

[0978] (192)Z is selected from:

[0979]

[0980]

[0981]

[0982]

[0983] (193)Z is selected from:

[0984]

[0985] Suitablely, as defined herein, a heteroaryl or heterocyclic group is a monocyclic heteroaryl or heterocyclic group comprising one, two, or three heteroatoms selected from N, O, or S.

[0986] Suitablely, a heteroaryl group is a 5- or 6-membered aryl or heteroaryl ring containing one, two, or three heteroatoms selected from N, O, or S.

[0987] Suitablely, the heterocyclic group is a 4, 5, or 6-membered heterocyclic ring containing one, two, or three heteroatoms selected from N, O, or S. Most preferably, the heterocyclic group is a 5 or 6-membered ring containing one, two, or three heteroatoms selected from N, O, or S [e.g., morpholino (e.g., 4-morpholino), oxetane, methyloxetane (e.g., 3-methyloxetane), pyrrolidone (e.g., pyrrolidone-2-one)].

[0988] Appropriately, the aryl group is phenyl.

[0989] In one implementation, X is

[0990]

[0991] Y is selected from:

[0992] And Z is selected from:

[0993]

[0994] in:

[0995] (i)R 1a R 1b R 2a R 2b and R 2d As defined in this article;

[0996] (ii)R 3a1 R 3a2 R 3b1 R 3b2 R 3i1 R 3i2 R 3j1 R 3j2 and n as defined in this paper; and

[0997] (iii)A1, A2, A5, A6, A7, R4, R5, R6, R8, R9, R 10 R 11 R z1 R Z2 R Z10 R Z12 R Z13 R Z14 R Z15 R Z16 R Z2a R Z3a R Zi2e R Zi1b and R Z2 As defined in this article.

[0998] In one implementation scheme

[0999] X is

[1000]

[1001] Y is

[1002]

[1003] Z is

[1004]

[1005] in:

[1006] (i)R 1a R 1b R 2a R 2b and R 2d As defined in this article;

[1007] (ii)n、R 3a1 R 3a2 R 3j1 R 3j2 As defined herein; and

[1008] (iii)A1, A2, A5, A6, A7, R4, R5, R6, R8, R9, R 10 R 11 R Z1 R Z2 R Z2a R Z3a R Zi2e R Zi1b As defined in this article.

[1009] In one implementation scheme

[1010] X is

[1011]

[1012] Y is

[1013]

[1014] Z is

[1015]

[1016] in:

[1017] (i)R 1a R 1b R 2a R 2b and R 2d As defined in this article;

[1018] (ii)n、R 3a1 and R 3a2 As defined herein; and

[1019] (iii)A1, A2, A5, A6, A7, R4, R5, R6, R8, R9, R 10 R 11 R Z1 R Z2 R Z2a R Z3a R Zi2e R Zi1b As defined in this article.

[1020] In one implementation scheme:

[1021] X is

[1022]

[1023] Y is

[1024] and

[1025] Z is

[1026]

[1027] in:

[1028] (i)R 1a R 1b R 2a R 2b and R 2d As defined in this article;

[1029] (ii)n、R 3j1 and R 3j2 As defined herein; and

[1030] (iii)A1, A2, A5, A6, A7, R4, R5, R6, R8, R9, R 10 R 11 R Z1 R Z2 R Z2a R Z3a R Zi2e R Zi1b As defined in this article.

[1031] In one implementation scheme

[1032] X is

[1033] Y is and

[1034] Z is

[1035] (i) where R 1a R 1b R 2a R 2b and R 2d As defined in this article;

[1036] (ii)n、R 3a1 and R 3a2 As defined herein; and

[1037] (iii)A5, A6, R Z1 and R Z2 As defined in this article.

[1038] In one implementation scheme

[1039] X is

[1040] Y is and

[1041] Z is

[1042] (i) where R 1a R 1b R 2a R 2b and R 2d As defined in this article;

[1043] (ii)n、R 3a1 and R 3a2 As defined herein; and

[1044] (iii) A1, A2, R4, R5 and R6 are as defined herein.

[1045] In one implementation scheme

[1046] X is

[1047] Y is and

[1048] Z is

[1049] (i) where R 1a R 1b R 2a R 2b and R 2d As defined in this article;

[1050] (ii)n、R 3a1 and R 3a2 As defined herein; and

[1051] (iii)A5, A6, R Z1 R Zi1b and R Z2 As defined in this article.

[1052] In one implementation scheme

[1053] X is

[1054] Y is and

[1055] Z is

[1056] (i) where R 1a R1b R 2a R 2b and R 2d As defined in this article;

[1057] (ii)n、R 3a1 and R 3a2 As defined herein; and

[1058] (iii)A Z6 R Z2e R Z3e and R Zi2e As defined in this article.

[1059] In one implementation scheme

[1060] X is

[1061] Y is and

[1062] Z is

[1063] (i) where R 1a R 1b R 2a R 2b and R 2d As defined in this article;

[1064] (ii)n、R 3a1 and R 3a2 As defined herein; and

[1065] (iii)A5, A6, R Z1 and R Z2 As defined in this article.

[1066] In one implementation scheme

[1067] X is

[1068] Y is and

[1069] Z is

[1070] (i) where R 1a R 1b R 2a R 2b and R 2d As defined in this article;

[1071] (ii)n、R 3a1 and R 3a2 As defined herein; and

[1072] (iii) A1, A2, R4, R5 and R6 are as defined herein.

[1073] In one implementation scheme

[1074] X is

[1075] Y is and

[1076] Z is

[1077] (i) where R 1a R 1b R 2a and R 2d As defined in this article;

[1078] (ii)n、R 3a1 and R 3a2 As defined herein; and

[1079] (iii)A5, A6, R Z1 R Zi1b and R Z2 As defined in this article.

[1080] In one implementation scheme

[1081] X is

[1082] Y is and

[1083] Z is

[1084] (iv) where R 1a R 1b R 2a R 2b and R 2d As defined in this article;

[1085] (v)n、R 3a1 and R 3a2 As defined herein; and

[1086] (vi)A Z6 R Z2e R Z3e and R Zi2e As defined in this article.

[1087] In one implementation scheme

[1088] X is

[1089] Y is and

[1090] Z is

[1091] (i) where R 1a R 1b R 2a R 2b and R 2d As defined in this article;

[1092] (ii)n、R 3j1 and R 3j2 As defined herein; and

[1093] (iii)A5, A6, R Z1 and R Z2 As defined in this article.

[1094] In one implementation scheme

[1095] X is

[1096] Y is and

[1097] Z is

[1098] (i) where R 1a R 1b R 2a and R 2d As defined in this article;

[1099] (ii)n、R 3j1 and R 3j2 As defined herein; and

[1100] (iii)A5, A6, R Z1 and R Z2 As defined in this article.

[1101] In one implementation scheme

[1102] X is

[1103] Y is and

[1104] Z is

[1105] (i) where R 1a R 1b R 2a R 2b and R 2dAs defined in this article;

[1106] (ii)n、R 3j1 and R 3j2 As defined herein; and

[1107] (iii) A1, A2, R4, R5 and R6 are as defined herein.

[1108] In one implementation scheme

[1109] X is

[1110] Y is and

[1111] Z is

[1112] (iv) where R 1a R 1b R 2a and R 2d As defined in this article;

[1113] (v)n、R 3j1 and R 3j2 As defined herein; and

[1114] (vi) A1, A2, R4, R5 and R6 are as defined herein.

[1115] In one implementation scheme

[1116] X is

[1117] Y is and

[1118] Z is

[1119] (i) where R 1a R 1b R 2a R 2b and R 2d As defined in this article;

[1120] (ii)n、R 3j1 and R 3j2 As defined herein; and

[1121] (iii)A5, A6, R Z1 R Zi1b and R Z2 As defined in this article.

[1122] In one implementation scheme

[1123] X is

[1124] Y is and

[1125] Z is

[1126] (i) where R 1a R 1b R 2a R 2b and R 2d As defined in this article;

[1127] (ii)n、R 3j1 and R 3j2 As defined herein; and

[1128] (iii)A5, A6, R Z1 R Zi1b and R Z2 As defined in this article.

[1129] In one implementation scheme

[1130] X is

[1131] Y is and

[1132] Z is

[1133] in:

[1134] (i)R 1a R 1b R 2a R 2b and R 2d As defined in this article;

[1135] (ii)n、R 3j1 and R 3j2 As defined herein; and

[1136] (iii)A7, R Z2a R Z3a and R Zi2e As defined in this article.

[1137] In one implementation scheme

[1138] X is

[1139] Y is and

[1140] Z is

[1141] in:

[1142] (i)R 1a R 1b R 2a R 2b and R 2d As defined in this article;

[1143] (ii)n、R 3j1 and R 3j2 As defined herein; and

[1144] (iii)A7, R Z2a R Z3a and R Zi2e As defined in this article.

[1145] In one implementation scheme

[1146] X is

[1147] Y is and

[1148] Z is

[1149] in:

[1150] (iv)R 1a R 1b R 2a R 2b and R 2d As defined in this article;

[1151] (v)n、R 3j1 and R 3j2 As defined herein; and

[1152] (vi)R8, R9, R 10 and R 11 As defined in this article.

[1153] In one implementation scheme

[1154] X is

[1155]

[1156] Y is

[1157]

[1158] Z is

[1159]

[1160] in:

[1161] (iv)R 1a R 1b R 2a R 2b and R 2d As defined in this article;

[1162] (v)n、R 3a1 R 3a2 R 3j1 R 3j2 As defined herein; and

[1163] (vi)R8, R9, R 10 R 11 As defined in this article.

[1164] In one implementation scheme:

[1165] When X6 is A1, A1 is CR. 12 ;

[1166] When X7 is A2, A2 is CR. 13 ;

[1167] B1 is A5, where A5 is CR 16 ;

[1168] B2 is A6, where A6 is CR 17 ;

[1169] Y2 is A7, where A7 is CR. 18 ;

[1170] When X6 is A8, A8 is CR. 19 R 20 ;

[1171] When X7 is A9, A9 is CR. 22 R 23 ;

[1172] When X7 is A 11 At that time, A 11 It is CR 28 R 29 ;

[1173] And R 12 R 13 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R28 and R 29 As defined in this article.

[1174] In one implementation: A1 is CR 12 A2 is CR 13 A5 is CR 16 A6 is CR 17 A7 is CR 18 A8 is CR 19 R 20 A9 is CR 22 R 23 A 11 It is CR 28 R 29 ;where R 12 R 13 R 16 R 17 R 18 R 19 R 20 R 21 R 22 R 23 R 28 and R 29 As defined in this article.

[1175] In one implementation scheme:

[1176] (i)R4, R5,R X5a R X5b R Y5 R6, R7, R8, R9, R 10 R 11 R 11a R 11b R Z2 R Z2a R Z3a R Zi1b R Zi2e R Z9 R Z10 R Z11 R Z12 ,R Z12a R Z13 R Z14 ,R Z15 and R Z16 Independently selected from hydrogen, methyl, cyano, or halogen; and

[1177] R B5N R Y5N R Z2N and R 11N Selected from methyl or hydrogen;

[1178] (ii)RZ1 and R Z1a Selected from hydrogen, C 1-4 Alkyl, cyano, halogen, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 1-4 Alkoxy, C 3-6 cycloalkyl and -OC 3-6 cycloalkyl;

[1179] (iii)R 12 R 13 R 16 R 18 R 19 R 20 R 21 R 22 R 23 R 24 and R 30 Independently selected from hydrogen, halogen, cyano, and methyl;

[1180] (iv)R 17 Selected from hydrogen, halogen, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5 or 6 nucleotide or heteroaryl, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclic, -(OCH2CH2) where m is an integer from 1 to 6 m -OCH3, NR q R r , where R q and R r Each is independently hydrogen, C 1-4 Alkyl, or R q With R r They are linked together, forming 3- to 6-membered heterocyclic rings together with the nitrogen atoms they are attached to; wherein any C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5 or 6 nucleotide or heteroaryl, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclic, or -O-heterocyclic (carbon-linked) groups are optionally further selected from C 1-2 Alkyl, cyano, C 1-2 Halogenated alkyl, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ea R1fa or -S(O) 0-2 R 1ea R 1fa One or more substituents are substituted, wherein R 1ea and R 1fa Is it H or C? 1-2 alkyl.

[1181] (v)R 21 R 24 and R 30 Independently selected from hydrogen or methyl;

[1182] (vi)R 28 and R 29 Selected from hydrogen or halogen, methoxy and methyl.

[1183] In one implementation scheme:

[1184] (i)R4,R5,R X5a ,R X5b ,R Y5 ,R B5N ,R Y5N R6, R7, R8, R9, R 10 ,R 11 ,R 11a ,,R 11b ,R 11N ,R Z2 ,R Z2N

[1185] R Z2a ,R Z3a ,R Zi1b ,R Zi2e ,R Z9 ,R Z10 ,R Z11 ,R Z12 ,R Z12a ,R Z13 ,R Z14 ,R Z15 and R Z16 It is hydrogen;

[1186] (ii)R Z1 and R Z1a Selected from hydrogen, cyano, halogen, C 1-2 Haloalkyl, C 1-2 Halogenated alkoxy groups, C 1-2 Alkoxy, C 3-6 cycloalkyl and -OC 3-6 cycloalkyl;

[1187] (iii)R 12 R 13 R 16R 18 R 19 R 20 R 21 R 22 R 23 R 24 and R 30 It is hydrogen;

[1188] (iv)R 17 Selected from hydrogen, halogen, cyano, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Halogenated alkoxy groups, C 2-3 alkenyl, C 2-3 alkynyl, phenyl, 5 or 6 nucleotide or heteroaryl, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclic, -(OCH2CH2) where m is an integer from 1 to 6 m -OCH3, NR q R r , where R q and R r Each is independently hydrogen, C 1-2 Alkyl, or R q With R r They are linked together, forming 3- to 6-membered heterocyclic rings together with the nitrogen atoms they are attached to; wherein any C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl, phenyl, 5 or 6 nucleotide or heteroaryl, C 3-6 cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclic, or -O-heterocyclic (carbon-linked) groups are optionally further selected from C 1-2 Alkyl, cyano, C 1-2 Halogenated alkyl, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy groups, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa One or more substituents are substituted, wherein R 1ea and R 1fa Is it H or C? 1-2 alkyl;

[1189] (v)R 21 R 24 and R 30 It is hydrogen;

[1190] (vi)R 28and R 29 It is hydrogen.

[1191] Appropriately, X is defined as in any of paragraphs (11) to (22) above. More appropriately, X is defined as in paragraphs (14), (15), (16) or (22). Most appropriately, X is defined as in paragraph (22).

[1192] Appropriately, Q1 is defined as in any of paragraphs (1) to (4) above. Most appropriately, Q1 is defined as in paragraph (3) or (4).

[1193] Appropriately, Q 2a As defined in paragraph (5).

[1194] Appropriately, Q 2b As defined in paragraph (6).

[1195] Appropriately, Q 2c As defined in paragraph (7).

[1196] Appropriately, Q 2d As defined in paragraph (8).

[1197] Appropriately, Q3 is defined as in paragraph (9).

[1198] Appropriately, Q4 is defined as in paragraph (10).

[1199] Appropriately, R 1a As defined in any of paragraphs (23) through (42) above. Appropriately, R 1a As defined in any of paragraphs (30) through (35) or (36) through (42). More appropriately, R 1a As defined in paragraphs (32) through (35) or (40) through (42). Most appropriately, R 1a As defined in any of paragraphs (40) through (42), such as paragraphs (40a), (41a), (41b), (41c) or (42).

[1200] Appropriately, R 1b As specified in any of paragraphs (43) to (44). Most appropriately, R 1b As defined in paragraph (44).

[1201] Appropriately, R 1x As specified in either paragraph (45) or (46). Most appropriately, R 1x As defined in paragraph (46).

[1202] Appropriately, R 2a R 2b R 2cand R 2d As defined by any of paragraphs (47) to (52) above. Most appropriately, R 2a R 2b and R 2c As defined in paragraphs (51) or (52).

[1203] Where appropriate, Y is defined as in any of the paragraphs (63) to (89) above. Most appropriately, Y is defined as in any of the paragraphs (86), (87), (88) or (89).

[1204] Suitablely, n is defined as any of the paragraphs (60) to (62) above. Most suitablely, n is defined as in paragraph (62), i.e., n is 1.

[1205] Appropriately, R 3a1 ,R 3b1 ,R 3c1 ,R 3d1 ,R 3e1 ,R 3f1 ,R 3g1 ,R 3h1 ,R 3i1 ,R 3j1 ,R 3k1 ,R 3l1 ,R 3m1 ,R 3n1 ,R 3o1 R 3p1 R 3q1 R 3r1 and R 3s1 As defined in any of paragraphs (53) to (56) and paragraphs (58) to (59) above. Most appropriately, R 3a1 ,R 3b1 ,R 3c1 ,R 3d1 ,R 3e1 ,R 3f1 R 3g1 R 3h1 R 3i1 R 3j1 R 3k1 R 3l1 K 3m1 R 3n1 K 3o1 ,,R 3p1 R 3q1 R 3r1 and R 3s1 As defined in paragraphs (56) or (58).

[1206] Appropriately, R 3a2 ,R 3b2 ,R 3c2 ,R3d2 ,R 3e2 R 3f2 R 3g2 R 3h2 R 3i2 R 3j2 R 3k2 ,R 3l2 ,R 3m2 ,R 3n2 ,R 3o2 .R 3p2 R 3q2 R 3r2 and R 3s2 As defined by any of the paragraphs (57), (58), and (59) above. Most appropriately, R 3a2 ,R 3b2 R 3c2 ,R 3d2 ,R 3e2 R 3f2 R 3g2 R 3h2 R 3i2 R 3j2 R 3k2 ,R 3l2 ,R 3m2 ,R 3n2 ,R 3o2 ,R 3p2 R 3q2 R 3r2 and R 3s2 As defined in paragraphs (57) or (58) above.

[1207] Suitablely, Z is defined as any one of the paragraphs (136) to (193) above. More suitablely, Z is defined as in paragraphs (187) to (193). Most suitablely, Z is defined as any one of the paragraphs (190) to (193).

[1208] Suitablely, R4, R5 and R6 are defined as in either paragraph (90) or (91). Most suitablely, R4, R5 and R6 are defined as in paragraph (91), i.e., R4, R5 and R6 are hydrogen.

[1209] Appropriately, when Z is: When, then R7, R9 and R 11N As defined in either of paragraphs (92) and (93) above. Most appropriately, R7, R9, and R 11N As defined in paragraph (93).

[1210] Appropriately, when Z is hour,

[1211] Then R8, R9, R 10 and R11 As defined in any of paragraphs (94) to (98) above. More appropriately, R8, R9, R 10 and R 11 As specified in any of paragraphs (95) to (98) above. Most appropriately, R8, R9, R 10 and R 11 As defined in paragraphs (97), (97a), or (98).

[1212] Appropriately, R Z1 and R Z1a As defined by any of paragraphs (99) through (102). Most appropriately, R Z1 and R Z1a As defined in paragraph (102).

[1213] Appropriately, R Z2 R Z2a R Z3a R Zi1b and R Zi2e As specified in any of paragraphs (103) through (105). Most appropriately, R Z2 R Z2a R Z3a R Z3e R Zi1b and R Zi2e As defined in paragraph (105).

[1214] Appropriately, R B5N R Y5N R Z2N and R 11N As defined in paragraphs (106) or (107). Most appropriately, R B5N R Y5N R Z2N and R 11N As defined in paragraph (106).

[1215] Appropriately, R Z4 ,R Z5 ,R Z6 ,R Z7 ,R Z8 ,R Z9 ,R Z10 ,R Z11 ,R Z12 ,R Z13 ,R Z14 ,R Z15 , and R Z16 As defined in any of paragraphs (108) through (110). Most appropriately, R Z4 ,R Z5 ,R Z6 ,RZ7 ,R Z8 ,R Z9 R Z10 ,R Z11 ,R Z12 ,R Z13 ,R Z14 ,R Z15 , and R Z16 As defined in paragraph (110).

[1216] Appropriately, A1, A2, A5, A6, A7, A8, A9 and A 11 As defined in paragraph (111).

[1217] Appropriately, R 12 R 13 R 16 R 19 R 20 R 21 R 22 and R 23 As defined in either paragraph (112) or (113) above. Most appropriately, R 12 R 13 R 16 R 19 R 20 R 21 R 22 and R 23 As defined in paragraph (113).

[1218] Appropriately, R 12 As defined by any of paragraphs (114) through (117) above. Most appropriately, R 12 As defined in paragraph (117), that is, R 12 It is hydrogen.

[1219] Appropriately, R 13 As defined by any of paragraphs (118) through (120) above. Most appropriately, R 13 As defined in paragraph (119).

[1220] Appropriately, R 16 and R 18 As defined by any of paragraphs (121) through (124) above. Most appropriately, R 16 and R 18 As defined in paragraph (124), that is, R 16 and R 18 It is hydrogen.

[1221] Appropriately, R 17As defined in any of paragraphs (125) through (131) above. More appropriately, R 17 As specified in any of paragraphs (128) through (131). Most appropriately, R 17 As defined in any of paragraphs (129) to (131).

[1222] Appropriately, R 28 and R 29 As defined by any of paragraphs (132) to (133) above. Most appropriately, R 28 and R 29 As defined in paragraph (133).

[1223] Appropriately, R 21 R 24 and R 30 As defined by any of paragraphs (134) to (135) above. Most appropriately, R 21 R 24 and R 30 As defined in paragraph (135).

[1224] Appropriately, R4, R5, R X5a ,R X5b R6, R7, R8, R9, R 10 R 11 R 11N R Z1 R Z1a ,R Z2 R Z2a ,R Z3a R Zi1b ,R Zi1c ,R Zi2e ,R Z9 ,R Z10 ,R Z11 ,R Z12 ,R Z13 ,R Z14 ,R Z15 and R Z16 Independently selected from hydrogen or methyl. Most preferably, R4, R5, R X5a ,R X5b R6, R7, R8, R9, R 10 ,R 11 ,R 11 N,R Z1 ,R Z1a ,R Z2 ,R Z2a ,R Z3a ,R Zi1b ,R Zi1c ,R Zi2e ,R Z9,R Z10 ,R Z11 ,R Z12 ,R Z13 ,R Z14 ,R Z15 and R Z16 It is hydrogen.

[1225] In the specific groups of the compounds of the present invention or their pharmaceutically acceptable salts, Y is as defined in paragraph (63), i.e., the compounds have the following structural formula (II) (sub-definition of formula (I):

[1226]

[1227] Where X and R 3a1 R 3a2 , n, and Z each have any of the meanings defined in this article.

[1228] In one embodiment of the compound of formula (II):

[1229] X is defined as in any of the paragraphs (11) to (22) above;

[1230] R 3a1 As defined in any of the paragraphs (53) to (56) and paragraphs (58) to (59) above;

[1231] R 3a2 As defined in any of the paragraphs (57), (58) and (59) above;

[1232] n is defined as in any of paragraphs (60) to (62) above; and

[1233] Z is defined as any of the paragraphs (136) to (193) above.

[1234] In one embodiment of the compound of formula (II):

[1235] X is as defined in paragraph (22) above;

[1236] R 3a1 As defined in paragraph (56) above;

[1237] R 3a2 As defined in paragraph (57) above;

[1238] n is as defined in paragraph (62) above; and

[1239] Z is defined as any of the paragraphs (136) to (193) above.

[1240] In specific groups of the compound of formula (II):

[1241] X is as defined in paragraphs (20), (21) or (22) above, and R 1a As defined in any of paragraphs (23) to (42) above;

[1242] R 3a1 As defined in paragraph (56) above;

[1243] R 3a2 As defined in paragraph (57) above;

[1244] n is as defined in paragraph (62) above; and

[1245] Z is defined as any of the paragraphs (136) to (193) above.

[1246] In specific groups of the compound of formula (II):

[1247] X is as defined in paragraph (22) above, and R 1a As defined in any of paragraphs (36) to (42) above;

[1248] R 3a1 As defined in paragraph (56) above;

[1249] R 3a2 As defined in paragraph (57) above;

[1250] n is as defined in paragraph (62) above; and

[1251] Z is defined as any of the paragraphs (136) to (193) above.

[1252] In specific groups of the compound of formula (II):

[1253] X is as defined in paragraph (22) above, and R 1a As defined in paragraphs (32) or (35) above;

[1254] R 3a1 As defined in paragraph (56) above;

[1255] R 3a2 As defined in paragraph (57) above;

[1256] n is as defined in paragraph (62) above; and

[1257] Z is defined as any of the paragraphs (136) to (193) above.

[1258] In one embodiment of the compound of formula (II):

[1259] X is as defined in paragraph (14) above;

[1260] R 3a1 As defined in any of the paragraphs (53) to (56) and paragraphs (58) to (59) above;

[1261] R 3a2 As defined in any of the paragraphs (57), (58) and (59) above;

[1262] n is defined as in any of paragraphs (60) to (62) above; and

[1263] Z is defined as in any of the paragraphs (142), (146) and (156) above.

[1264] In the specific groups of the compounds of the present invention or their pharmaceutically acceptable salts, Y is as defined in paragraph (73), i.e., the compounds have the following structural formula (III) (sub-definition of formula (I):

[1265]

[1266] Where X and R 3i1 R 3i2 , n, and Z each have any of the meanings defined in this article.

[1267] In one embodiment of the compound of formula (III):

[1268] X is defined as in any of the paragraphs (11) to (22) above;

[1269] R 3i1 As defined in any of the paragraphs (53) to (56) and paragraphs (58) to (59) above;

[1270] R 3i2 As defined in any of the paragraphs (57), (58) and (59) above;

[1271] n is defined as in any of paragraphs (60) to (62) above; and

[1272] Z is defined as any of the paragraphs (136) to (193) above.

[1273] In one embodiment of the compound of formula (III):

[1274] X is as defined in paragraph (22) above;

[1275] R 3i1 As defined in paragraph (56) above;

[1276] R 3i2As defined in paragraph (57) above;

[1277] n is as defined in paragraph (62) above; and

[1278] Z is defined as any of the paragraphs (136) to (193) above.

[1279] In specific groups of the compound of formula (III):

[1280] X is as defined in paragraphs (20), (21) or (22) above, and R 1a As defined in any of paragraphs (23) to (42) above;

[1281] R 3i1 As defined in paragraph (56) above;

[1282] R 3i2 As defined in paragraph (57) above;

[1283] n is as defined in paragraph (62) above; and

[1284] Z is defined as any of the paragraphs (136) to (193) above.

[1285] In specific groups of the compound of formula (III):

[1286] X is as defined in paragraph (22) above, and R 1a As defined in any of the paragraphs (30) to (35) or (36) to (42) above;

[1287] R 3i1 As defined in paragraph (56) above;

[1288] R 3i2 As defined in paragraph (57) above;

[1289] n is as defined in paragraph (62) above; and

[1290] Z is defined as any of the paragraphs (136) to (193) above.

[1291] In the specific groups of the compounds of the present invention or their pharmaceutically acceptable salts, Y is as defined in paragraph (64), i.e., the compounds have the following structural formula (IV) (sub-definition of formula (I):

[1292]

[1293] Where X, n, and Z each have any of the meanings defined in this article.

[1294] In one embodiment of the compound of formula (IV):

[1295] X is defined as in any of the paragraphs (11) to (22) above;

[1296] n is defined as in any of paragraphs (60) to (62) above; and

[1297] Z is defined as any of the paragraphs (136) to (193) above.

[1298] In one embodiment of the compound of formula (IV):

[1299] X is as defined in paragraph (22) above;

[1300] n is as defined in paragraph (62) above; and

[1301] Z is defined as any of the paragraphs (136) to (193) above.

[1302] In specific groups of the compound of formula (IV):

[1303] X is as defined in paragraphs (20), (21) or (22) above, and R 1a As defined in any of paragraphs (23) to (42) above;

[1304] n is as defined in paragraph (62) above; and

[1305] Z is defined as any of the paragraphs (136) to (193) above.

[1306] In specific groups of the compound of formula (IV):

[1307] X is as defined in paragraph (22) above, and R 1a As defined in any of the paragraphs (30) to (35) or (36) to (42) above;

[1308] n is as defined in paragraph (62) above; and

[1309] Z is defined as any of the paragraphs (136) to (193) above.

[1310] In the specific groups of the compounds of the present invention or their pharmaceutically acceptable salts, Y is as defined in paragraph (74), i.e., the compounds have the following structural formula (V) (sub-definition of formula (I):

[1311]

[1312] Where X and R 3j1 R 3j2 , n, and Z each have any of the meanings defined in this article.

[1313] In one embodiment of the compound of formula (V):

[1314] X is defined as in any of the paragraphs (11) to (22) above;

[1315] R 3j1 As defined in any of the paragraphs (53) to (56) and paragraphs (58) to (59) above;

[1316] R 3j2 As defined in any of the paragraphs (57), (58) and (59) above;

[1317] n is defined as in any of paragraphs (60) to (62) above; and

[1318] Z is defined as any of the paragraphs (136) to (193) above.

[1319] In one embodiment of the compound of formula (V):

[1320] X is as defined in paragraph (22) above;

[1321] R 3j1 As defined in paragraph (56) above;

[1322] R 3j2 As defined in paragraph (57) above;

[1323] n is as defined in paragraph (62) above; and

[1324] Z is defined as any of the paragraphs (136) to (193) above.

[1325] In specific groups of the compound of formula (V):

[1326] X is as defined in paragraphs (20), (21) or (22) above, and R 1a As defined in any of paragraphs (23) to (42) above;

[1327] R 3j1 As defined in paragraph (56) above;

[1328] R 3j2 As defined in paragraph (57) above;

[1329] n is as defined in paragraph (62) above; and

[1330] Z is defined as any of the paragraphs (136) to (193) above.

[1331] In specific groups of the compound of formula (V):

[1332] X is as defined in paragraph (22) above, and R 1a As defined in any of the paragraphs (30) to (35) or (36) to (42) above;

[1333] R 3j1 As defined in paragraph (56) above;

[1334] R 3j2 As defined in paragraph (57) above;

[1335] n is as defined in paragraph (62) above; and

[1336] Z is defined as any of the paragraphs (136) to (193) above.

[1337] In the specific groups of the compounds of the present invention or their pharmaceutically acceptable salts, X is defined as in paragraph (15), i.e., the compound has the following structural formula (VI) (sub-definition of formula (I):

[1338]

[1339] Where R 1a R 1b R 2a R 2b R 2d Y and Z each have any of the meanings defined in this article.

[1340] In one embodiment of the compound of formula (VI):

[1341] Q1 is defined as any one of paragraphs (1) to (4);

[1342] R 1a As defined in any of paragraphs (23) to (42) above;

[1343] R 1b As defined in any of paragraphs (43) to (44) above;

[1344] R 2a R 2b and R 2d As defined in any of paragraphs (47) to (52) above;

[1345] Y is defined as in any of the paragraphs (63) to (89) above; and

[1346] Z is defined as any of the paragraphs (136) to (193) above.

[1347] In one embodiment of the compound of formula (VI):

[1348] Q1 is defined as in either paragraph (3) or (4);

[1349] R 1a As defined in any of paragraphs (30) to (35) above;

[1350] R 1b As defined in paragraph (44) above;

[1351] R 2a R 2b and R 2d As defined in paragraphs (51) or (52);

[1352] Y is as defined in paragraphs (86), (87), (88), or (89) above; and

[1353] Z is defined as in any of the paragraphs (186) to (193) above.

[1354] In one embodiment of the compound of formula (VI):

[1355] Q1 is defined as in either paragraph (3) or (4);

[1356] R 1a As defined in any of paragraphs (38) to (42) above;

[1357] R 1b As defined in paragraph (44) above;

[1358] R 2a R 2b and R 2d As defined in paragraphs (51) or (52);

[1359] Y is as defined in paragraphs (86), (87), (88), or (89) above; and

[1360] Z is defined as any of the paragraphs (136) to (193) above.

[1361] In one embodiment of the compound of formula (VI):

[1362] Q1 is defined as in paragraphs (3) or (4);

[1363] R 1a As defined in any of paragraphs (38) to (42) above;

[1364] R 1b As defined in paragraph (44) above;

[1365] R 2a R 2band R 2d As defined in paragraphs (51) or (52);

[1366] Y is defined as in any of the paragraphs (85) to (89) above; and

[1367] Z is defined as any of the paragraphs (189) to (193) above.

[1368] In specific groups of the compound of formula (VI):

[1369] Q1 is defined as in paragraph (4);

[1370] R 1a As defined in paragraphs (32) or (35) above;

[1371] R 1b As defined in paragraph (44) above;

[1372] R 2a R 2b and R 2d As defined in paragraph (52);

[1373] Y is as defined in paragraph (89) above;

[1374] Z is defined as any of the items in paragraph (193) above.

[1375] In specific groups of the compound of formula (XI):

[1376] Q1 is defined as in paragraph (4);

[1377] R 1a As defined in any of the paragraphs (40a), (41a), (41b), (41c) or (42) above;

[1378] R 1b As defined in paragraph (44) above;

[1379] R 2a R 2b and R 2d As defined in paragraph (52);

[1380] Y is as defined in paragraph (89) above; and

[1381] Z is defined as in paragraph (193) above.

[1382] In the specific groups of the compounds of the present invention or their pharmaceutically acceptable salts, X is defined as in paragraph (15) and Y is defined as in paragraph (63), i.e., the compound has the following structural formula (VII) (sub-definition of formula (I):

[1383]

[1384] Where R 1a R 1b R 2a R 2b R 2d R 3a1 R 3a2 , n, and Z each have any of the meanings defined in this article.

[1385] In one embodiment of the compound of formula (VII):

[1386] Q1 is defined as any one of paragraphs (1) to (4);

[1387] R 1a As defined in any of paragraphs (23) to (42) above;

[1388] R 1b As defined in any of paragraphs (43) to (44) above;

[1389] R 2a R 2b and R 2d As defined in any of paragraphs (47) to (52) above;

[1390] R 3a1 As defined in any of the paragraphs (53) to (56) and paragraphs (58) to (59) above;

[1391] R 3a2 As defined in any of the paragraphs (57), (58) and (59) above;

[1392] n is defined as in any of the paragraphs (60), (61) and (62) above;

[1393] Z is defined as any of the paragraphs (136) to (193) above.

[1394] In one embodiment of the compound of formula (VII):

[1395] Q1 is defined as in either paragraph (3) or (4);

[1396] R 1a As defined in any of paragraphs (30) to (35) above;

[1397] R 1b As defined in paragraph (44) above;

[1398] R 2a R 2b and R2d As defined in paragraphs (51) or (52);

[1399] R 3a1 As defined in paragraph (56) above;

[1400] R 3a2 As defined in paragraph (57) above;

[1401] n is as defined in paragraph (62) above; and

[1402] Z is defined as any one of the paragraphs (186) to (191) above.

[1403] In one embodiment of the compound of formula (VII):

[1404] Q1 is defined as in either paragraph (3) or (4);

[1405] R 1a As defined in any of paragraphs (38) to (42) above;

[1406] R 1b As defined in paragraph (44) above;

[1407] R 2a R 2b and R 2d As defined in paragraphs (51) or (52);

[1408] R 3a1 As defined in paragraph (56) above;

[1409] R 3a2 As defined in paragraph (57) above;

[1410] n is as defined in paragraph (62) above; and

[1411] Z is defined as any of the paragraphs (136) to (193) above.

[1412] In one embodiment of the compound of formula (VII):

[1413] Q1 is defined as in either paragraph (3) or (4);

[1414] R 1a As defined in any of paragraphs (38) to (42) above;

[1415] R 1b As defined in paragraph (44) above;

[1416] R 2a R 2b and R 2dAs defined in paragraphs (51) or (52);

[1417] R 3a1 As defined in paragraph (56) above;

[1418] R 3a2 As defined in paragraph (57) above;

[1419] n is as defined in paragraph (62) above; and

[1420] Z is defined as any one of the paragraphs (186) to (191) above.

[1421] In one embodiment of the compound of formula (VII):

[1422] Q1 is defined as in either paragraph (3) or (4);

[1423] R 1a As defined in paragraphs (32) or (35) above;

[1424] R 1b As defined in paragraph (44) above;

[1425] R 2a R 2b and R 2d As defined in paragraphs (51) or (52);

[1426] R 3a1 As defined in paragraph (56) above;

[1427] R 3a2 As defined in paragraph (57) above;

[1428] n is as defined in paragraph (62) above; and

[1429] Z is defined as any one of the paragraphs (186) to (191) above.

[1430] In one embodiment of the compound of formula (VII):

[1431] Q1 is defined as in either paragraph (3) or (4);

[1432] R 1a As defined in any of paragraphs (38) to (42) above;

[1433] R 1b As defined in paragraph (44) above;

[1434] R 2a R 2b and R 2dAs defined in paragraphs (51) or (52);

[1435] R 3a1 As defined in paragraph (56) above;

[1436] R 3a2 As defined in paragraph (57) above;

[1437] n is as defined in paragraph (62) above; and

[1438] Z is defined as in paragraph (193) above.

[1439] In the specific groups of the compounds of the present invention or their pharmaceutically acceptable salts, X is defined as in paragraph (15) and Z is defined as in paragraph (146), i.e., the compound has the following structural formula (VIII) (sub-definitions of formula (I):

[1440]

[1441] Where X and R 1a R 1b R 2a R 2b R 2d Y, A5, A6, R Z1 and R Z2 Each has any of the meanings defined in this article.

[1442] In one embodiment of the compound of formula (VIII):

[1443] Q1 is defined as any one of paragraphs (1) to (4);

[1444] R 1a As defined in any of paragraphs (23) to (42) above;

[1445] R 1b As defined in any of paragraphs (43) to (44) above;

[1446] R 2a R 2b and R 2d As defined in any of paragraphs (47) to (52) above;

[1447] Y is defined as in any of the paragraphs (63) to (89) above;

[1448] R Z1 As defined in any of paragraphs (99) to (102) above;

[1449] R Z2 As defined in any of paragraphs (103) to (105) above;

[1450] A5 is CR 16 And R 16 As defined in any of paragraphs (121) to (124) above; and

[1451] A6 is CR 17 And R 17 As defined in any of paragraphs (125) to (131) above.

[1452] In one embodiment of the compound of formula (VIII):

[1453] Q1 is defined as in paragraphs (3) or (4);

[1454] R 1a As defined in any of paragraphs (30) to (35) above;

[1455] R 1b As defined in paragraph (44) above;

[1456] R 2a R 2b and R 2d As defined in paragraphs (51) or (52);

[1457] Y is defined as in any of the paragraphs (85) to (89) above; and

[1458] R Z1 As defined in any of paragraphs (101) to (102) above;

[1459] R Z2 As defined in any of paragraphs (104) to (105) above;

[1460] A5 is CR 16 And R 16 As defined in any of paragraphs (123) to (124) above; and

[1461] A6 is CR 17 And R 17 As defined in any of paragraphs (128) to (131) above.

[1462] In one embodiment of the compound of formula (VIII):

[1463] Q1 is defined as in paragraphs (3) or (4);

[1464] R 1a As defined in any of paragraphs (38) to (42) above;

[1465] R 1bAs defined in paragraph (44) above;

[1466] R 2a R 2b and R 2d As defined in paragraphs (51) or (52);

[1467] Y is defined as in any of the paragraphs (85) to (89) above; and

[1468] R Z1 As defined in any of paragraphs (101) to (102) above;

[1469] R Z2 As defined in any of paragraphs (104) to (105) above;

[1470] A5 is CR 16 And R 16 As defined in any of paragraphs (123) to (124) above; and

[1471] A6 is CR 17 And R 17 As defined in any of paragraphs (128) to (131) above.

[1472] In specific groups of the compound of formula (VIII):

[1473] Q1 is defined as in paragraph (4);

[1474] R 1a As defined in any of the paragraphs (40a), (41a), (41b), (41c) or (42) above;

[1475] R 1b As defined in paragraph (44) above;

[1476] R 2a R 2b and R 2d As defined in paragraph (52);

[1477] Y is defined as in any of the paragraphs (87), (88) or (89) above;

[1478] R Z1 As defined in any of the paragraphs above (102);

[1479] R Z2 As defined in paragraph (105) above;

[1480] A5 is CR 16 And R 16 As defined in paragraph (124) above; and

[1481] A6 is CR 17 And R 17 As defined in any of paragraphs (130) to (131) above.

[1482] In specific groups of the compound of formula (VIII):

[1483] Q1 is defined as in paragraph (4);

[1484] R 1a As defined in paragraphs (32) or (35) above;

[1485] R 1b As defined in paragraph (44) above;

[1486] R 2a R 2b and R 2d As defined in paragraph (52);

[1487] Y is defined as in any of the paragraphs (87), (88) or (89) above;

[1488] R Z1 As defined in any of the paragraphs above (102);

[1489] R Z2 As defined in paragraph (105) above;

[1490] A5 is CR 16 And R 16 As defined in paragraph (124) above; and

[1491] A6 is CR 17 And R 17 As defined in any of paragraphs (130) to (131) above.

[1492] In the specific groups of the compounds of the present invention or their pharmaceutically acceptable salts, X is defined as in paragraphs (14), (15) or (16) and Z is defined as in paragraph (142), i.e., the compound has the following structural formula (IX) or (X) (sub-definitions of formula (I):

[1493]

[1494] Where R 1a R 1b R 2a R 2b R 2d Q1, Y, A1, A2, R4, R5, and R6 each have any of the meanings defined herein.

[1495] In one embodiment of the compound of formula (IX):

[1496] Q1 is defined as any one of paragraphs (1) to (4);

[1497] R 1a As defined in any of paragraphs (23) to (42) above;

[1498] R 1b As defined in any of paragraphs (43) to (44) above;

[1499] R 2a R 2b and R 2d As defined in any of paragraphs (47) to (52) above;

[1500] Y is defined as in any of the paragraphs (63) to (89) above;

[1501] A1 is CR 12 And R 12 As defined in any of the paragraphs (112), (113), or (114) through (117) above;

[1502] A2 is CR 13 And R 13 As defined in any of the paragraphs (112), (113) or (118) through (120) above;

[1503] R4 is defined as in paragraphs (90) or (91) above;

[1504] R5 is defined as in paragraphs (90) or (91) above; and

[1505] R6 is defined as in paragraphs (90) or (91) above.

[1506] In one embodiment of the compound of formula (IX):

[1507] Q1 is defined as in paragraphs (3) or (4);

[1508] R 1a As defined in any of paragraphs (30) to (35) above;

[1509] R 1b As defined in paragraph (44) above;

[1510] R 2a R 2b and R 2d As defined in paragraphs (51) or (52);

[1511] Y is defined as in any of the paragraphs (85) to (89) above;

[1512] A1 is CR 12 And R 12 As defined in any of paragraphs (114) to (117) above;

[1513] A2 is CR 13 And R 13 As defined in paragraph (120) above;

[1514] R4 is defined as in paragraph (91) above;

[1515] R5 is defined as in paragraph (91) above; and

[1516] R6 is defined as described in paragraph (91) above.

[1517] In one embodiment of the compound of formula (IX):

[1518] Q1 is defined as in paragraphs (3) or (4);

[1519] R 1a As defined in any of paragraphs (38) to (42) above;

[1520] R 1b As defined in paragraph (44) above;

[1521] R 2a R 2b and R 2d As defined in paragraphs (51) or (52);

[1522] Y is defined as in any of the paragraphs (85) to (89) above;

[1523] A1 is CR 12 And R 12 As defined in any of paragraphs (114) to (117) above;

[1524] A2 is CR 13 And R 13 As defined in paragraph (120) above;

[1525] R4 is defined as in paragraph (91) above;

[1526] R5 is defined as in paragraph (91) above; and

[1527] R6 is defined as described in paragraph (91) above.

[1528] In one embodiment of the compound of formula (IX):

[1529] Q1 is defined as in paragraph (4);

[1530] R 1a As defined in any of the paragraphs (40a), (41a), (41b), (41c) or (42) above;

[1531] R 1b As defined in paragraph (44) above;

[1532] R 2a R 2b and R 2d As defined in paragraph (52);

[1533] Y is defined as in either paragraph (88) or (89) above;

[1534] A1 is CR 12 And R 12 As defined in any of paragraphs (116) to (117) above;

[1535] A2 is CR 13 And R 13 As defined in paragraph (120) above;

[1536] R4 is defined as in paragraph (91) above;

[1537] R5 is defined as in paragraph (91) above; and

[1538] R6 is defined as described in paragraph (91) above.

[1539] In one embodiment of the compound of formula (IX):

[1540] Q1 is defined as in paragraph (4);

[1541] R 1a As defined in paragraphs (32) or (35) above;

[1542] R 1b As defined in paragraph (44) above;

[1543] R 2a and R 2d As defined in paragraph (52);

[1544] Y is defined as in either paragraph (88) or (89) above;

[1545] A1 is CR 12 And R 12 As defined in any of paragraphs (116) to (117) above;

[1546] A2 is CR 13 And R 13 As defined in paragraph (120) above;

[1547] R4 is defined as in paragraph (91) above;

[1548] R5 is defined as in paragraph (91) above; and

[1549] R6 is defined as described in paragraph (91) above.

[1550] In one embodiment of the compound of formula (X):

[1551] Q1 is defined as any one of paragraphs (1) to (4);

[1552] R 1a As defined in any of paragraphs (23) to (42) above;

[1553] R 1b As defined in any of paragraphs (43) to (44) above;

[1554] R 2a and R 2d As defined in any of paragraphs (47) to (52) above;

[1555] Y is defined as in any of the paragraphs (63) to (89) above;

[1556] A1 is CR 12 And R 12 As defined in any of the paragraphs (112), (113), or (114) through (117) above;

[1557] A2 is CR 13 And R 13 As defined in any of the paragraphs (112), (113) or (118) through (120) above;

[1558] R4 is defined as in paragraphs (90) or (91) above;

[1559] R5 is defined as in paragraphs (90) or (91) above; and

[1560] R6 is defined as in paragraphs (90) or (91) above.

[1561] In one embodiment of the compound of formula (X):

[1562] Q1 is defined as in paragraphs (3) or (4);

[1563] R 1a As defined in any of paragraphs (38) to (42) above;

[1564] R 1b As defined in paragraph (44) above;

[1565] R 2a and R 2d As defined in paragraphs (51) or (52);

[1566] Y is defined as in any of the paragraphs (85) to (89) above;

[1567] A1 is CR 12 And R 12 As defined in any of paragraphs (114) to (117) above;

[1568] A2 is CR 13 And R 13 As defined in paragraph (120) above;

[1569] R4 is defined as in paragraph (91) above;

[1570] R5 is defined as in paragraph (91) above; and

[1571] R6 is defined as described in paragraph (91) above.

[1572] In one embodiment of the compound of formula (X):

[1573] Q1 is defined as in paragraph (4);

[1574] R 1a As defined in any of the paragraphs (40a), (41a), (41b), (41c) or (42) above;

[1575] R 1b As defined in paragraph (44) above;

[1576] R 2a and R 2d As defined in paragraph (52);

[1577] Y is defined as in either paragraph (88) or (89) above;

[1578] A1 is CR 12 And R 12 As defined in any of paragraphs (116) to (117) above;

[1579] A2 is CR 13 And R 13 As defined in paragraph (120) above;

[1580] R4 is defined as in paragraph (91) above;

[1581] R5 is defined as in paragraph (91) above; and

[1582] R6 is defined as described in paragraph (91) above.

[1583] In one embodiment of the compound of formula (X):

[1584] Q1 is defined as in paragraph (4);

[1585] R 1a As defined in paragraphs (32) or (35) above;

[1586] R 1b As defined in paragraph (44) above;

[1587] R 2a R 2b and R 2d As defined in paragraph (52);

[1588] Y is defined as in either paragraph (88) or (89) above;

[1589] A1 is CR 12 And R 12 As defined in any of paragraphs (116) to (117) above;

[1590] A2 is CR 13 And R 13 As defined in paragraph (120) above;

[1591] R4 is defined as in paragraph (91) above;

[1592] R5 is defined as in paragraph (91) above; and

[1593] R6 is defined as described in paragraph (91) above.

[1594] In the specific groups of the compounds of the present invention or their pharmaceutically acceptable salts, X is defined as in paragraph (15) and Z is defined as in paragraph (147), that is, the compound has the following structural formula (XI) (sub-definitions of formula (I):

[1595]

[1596] Where X and R 1a R 1b R 2a R 2b R 2d Y, A5, A6, R Z1 R Z2 and R Zi1bEach has any of the meanings defined in this article.

[1597] In one embodiment of the compound of formula (XI):

[1598] Q1 is defined as any one of paragraphs (1) to (4);

[1599] R 1a As defined in any of paragraphs (23) to (42) above;

[1600] R 1b As defined in any of paragraphs (43) to (44) above;

[1601] R 2a R 2b and R 2d As defined in any of paragraphs (47) to (52) above;

[1602] Y is defined as in any of the paragraphs (63) to (89) above; and

[1603] A5 is CR 16 And R 16 As defined in any of paragraphs (121) to (124) above;

[1604] A6 is CR 17 And R 17 As defined in any of the paragraphs (125) to (131) above;

[1605] R Z1 As defined in any of paragraphs (99) to (102) above;

[1606] R Z2 As defined in any of paragraphs (103) to (105) above; and

[1607] R Zi1b As defined in any of paragraphs (103) to (105) above;

[1608] In one embodiment of the compound of formula (XI):

[1609] Q1 is defined as in paragraphs (3) or (4);

[1610] R 1a As defined in any of paragraphs (38) to (42) above;

[1611] R 1b As defined in paragraph (44) above;

[1612] R 2a R 2b and R2d As defined in paragraphs (51) or (52);

[1613] Y is defined as in any of the paragraphs (85) to (89) above; and

[1614] A5 is CR 16 And R 16 As defined in any of paragraphs (123) to (124) above;

[1615] A6 is CR 17 And R 17 As defined in any of the paragraphs (128) to (131) above;

[1616] R Z1 As defined in any of paragraphs (101) to (102) above;

[1617] R Z2 As defined in any of paragraphs (104) to (105) above; and

[1618] R Zi1b As defined in any of paragraphs (104) to (105) above.

[1619] In one embodiment of the compound of formula (XI):

[1620] Q1 is defined as in paragraphs (3) or (4);

[1621] R 1a As defined in any of paragraphs (30) to (35) above;

[1622] R 1b As defined in paragraph (44) above;

[1623] R 2a R 2b and R 2d As defined in paragraphs (51) or (52);

[1624] Y is defined as in any of the paragraphs (85) to (89) above; and

[1625] A5 is CR 16 And R 16 As defined in any of paragraphs (123) to (124) above;

[1626] A6 is CR 17 And R 17 As defined in any of the paragraphs (128) to (131) above;

[1627] R Z1As defined in any of paragraphs (101) to (102) above;

[1628] R Z2 As defined in any of paragraphs (104) to (105) above; and

[1629] R Zi1b As defined in any of paragraphs (104) to (105) above.

[1630] In specific groups of the compound of formula (XI):

[1631] Q1 is defined as in paragraph (4);

[1632] R 1a As defined in any of the paragraphs (40a), (41a), (41b), (41c) or (42) above;

[1633] R 1b As defined in paragraph (44) above;

[1634] R 2a R 2b and R 2d As defined in paragraph (52);

[1635] Y is defined as in any of the paragraphs (87), (88) or (89) above;

[1636] A5 is CR 16 And R 16 As defined in paragraph (124) above;

[1637] A6 is CR 17 And R 17 As defined in any of paragraphs (130) to (131) above; and

[1638] R Z1 As defined in paragraph (102) above;

[1639] R Z2 As defined in paragraph (105) above; and

[1640] R Zi1b As defined in paragraph (105) above.

[1641] In specific groups of the compound of formula (XI):

[1642] Q1 is defined as in paragraph (4);

[1643] R 1a As defined in paragraphs (32) or (35) above;

[1644] R1b As defined in paragraph (44) above;

[1645] R 2a R 2b and R 2d As defined in paragraph (52);

[1646] Y is defined as in any of the paragraphs (87), (88) or (89) above;

[1647] A5 is CR 16 And R 16 As defined in paragraph (124) above;

[1648] A6 is CR 17 And R 17 As defined in any of paragraphs (130) to (131) above; and

[1649] R Z1 As defined in paragraph (102) above;

[1650] R Z2 As defined in paragraph (105) above; and

[1651] R Zi1b As defined in paragraph (105) above.

[1652] In the specific groups of the compounds of the present invention or their pharmaceutically acceptable salts, X is defined as in paragraph (16), that is, the compound has the following structural formula (XII) (sub-definition of formula (I):

[1653]

[1654] Where X and R 1a R 1b R 2a R 2d Y and Z each have any of the meanings defined in this article.

[1655] In one embodiment of the compound of formula (XII):

[1656] Q1 is defined as any one of paragraphs (1) to (4);

[1657] R 1a As defined in any of paragraphs (23) to (42) above;

[1658] R 1b As defined in any of paragraphs (43) to (44) above;

[1659] R 2a and R 2dAs defined in any of paragraphs (47) to (52) above;

[1660] Y is defined as in any of the paragraphs (63) to (89) above; and

[1661] Z is defined as any of the paragraphs (136) to (193) above.

[1662] In one embodiment of the compound of formula (XII):

[1663] Q1 is defined as in paragraphs (3) or (4);

[1664] R 1a As defined in any of paragraphs (30) to (35) above;

[1665] R 1b As defined in paragraph (44) above;

[1666] R 2a and R 2d As defined in paragraphs (51) or (52) above;

[1667] Y is defined as in any of the paragraphs (85) to (89) above; and

[1668] Z is defined as any of the paragraphs (189) to (193) above.

[1669] In one embodiment of the compound of formula (XII):

[1670] Q1 is defined as in paragraphs (3) or (4);

[1671] R 1a As defined in any of paragraphs (38) to (42) above;

[1672] R 1b As defined in paragraph (44) above;

[1673] R 2a and R 2d As defined in paragraphs (51) or (52);

[1674] Y is defined as in any of the paragraphs (85) to (89) above; and

[1675] Z is defined as any of the paragraphs (189) to (193) above.

[1676] In specific groups of the compound of formula (XII):

[1677] Q1 is defined as in paragraph (4);

[1678] R1a As defined in paragraphs (32) or (35) above;

[1679] R 1b As defined in paragraph (44) above;

[1680] R 2a and R 2d As defined in paragraph (52);

[1681] Y is as defined in paragraph (89) above;

[1682] Z is defined as any of the items in paragraph (193) above.

[1683] In specific groups of the compound of formula (XII):

[1684] Q1 is defined as in paragraph (4);

[1685] R 1a As defined in any of the paragraphs (40a), (41a), (41b), (41c) or (42) above;

[1686] R 1b As defined in paragraph (44) above;

[1687] R 2a and R 2d As defined in paragraph (52);

[1688] Y is as defined in paragraph (89) above; and

[1689] Z is defined as in paragraph (193) above.

[1690] In the specific groups of the compounds of the present invention, Z is defined as in paragraph (155), that is, the compounds have the following structural formula (XIII) (sub-definition of formula (I):

[1691]

[1692] In one embodiment of the compound of formula (XII):

[1693] X is defined as in any of the paragraphs (11) to (22) above;

[1694] Y is defined as in any of the paragraphs (63) to (89) above; and

[1695] R8, R9, R 10 and R 11 As defined in any of paragraphs (94) to (98) above.

[1696] In one embodiment of the compound of formula (XIII):

[1697] X is as defined in paragraphs (14), (15), (16) or (22) above;

[1698] Y is defined as in any of the paragraphs (85) to (89) above;

[1699] R8, R9, R 10 and R 11 As defined in any of paragraphs (94) to (98) above.

[1700] In one embodiment of the compound of formula (XIII):

[1701] X is as defined in paragraphs (14), (15), (16) or (22) above;

[1702] Y is defined as in any of paragraphs (86), (87), (88), or (89);

[1703] R8, R9, R 10 and R 11 As defined in any of paragraphs (95a) to (97) above.

[1704] In specific groups of the compound of formula (XIII):

[1705] X is as defined in paragraphs (14), (15), (16) or (22) above;

[1706] Y is defined as in either paragraph (88) or (89);

[1707] In specific groups of the compound of formula (XIII):

[1708] X is as defined in paragraph (22) above;

[1709] Y is as defined in paragraph (89);

[1710] R8, R9, R 10 and R 11 As defined in paragraphs (96), (97) or (97a).

[1711] Specific compounds of the present invention include any of the compounds exemplified in this application or their pharmaceutically acceptable salts, and in particular any of the following:

[1712] N-({2-[(4,4-dimethylpiperidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-carboxamide

[1713] N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1714] N-[[2-[[(3,3-difluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1715] N-[[2-[[(1-hydroxycyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1716] N-[[2-[[(1-fluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1717] N-[[2-[[(1-methylcyclopropyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1718] N-[[2-(2-azabicyclo[2.1.1]hexane-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1719] N-[[2-(3-azabicyclo[3.1.1]heptane-3-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1720] N-[[2-[[2-(hydroxymethyl)pyrrolidin-1-yl]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1721] N-[[2-(morpholinomethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1722] N-[[2-[(1-adamantylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1723] 4-O-N-[[2-(1-piperidinylmethyl)-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide

[1724] N-[[2-[(4-fluoro-1-piperidinyl)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidin-2-carboxamide

[1725] 4-Oxo-N-[[2-[[[racemic-(1S,2S,4S)-7-oxabicyclo[2.2.1]heptane-5-en-2-yl]methylamino]methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide

[1726] N-[[2-[[(1-hydroxycyclopentyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1727] 4-Oxo-N-[[2-[[[racemic-(1S,2R,4S)-7-oxabicyclo[2.2.1]heptane-5-en-2-yl]methylamino]methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide

[1728] N-[[2-[(1-bicyclo[1.1.1]pentylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1729] N-[[2-[(cyclobutylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1730] N-({2-[({bicyclo[2.2.1]heptane-2-yl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1731] N-[[2-[(cyclopropylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1732] N-[[2-(2-azabicyclo[2.2.2]octane-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1733] N-[[2-[[(2,2-difluorocyclopropyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1734] N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1735] N-[[2-[(cyclohexylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1736] N-[[2-[[(1-hydroxycyclohexyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1737] N-[[2-[(cyclopentylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidin-2-carboxamide

[1738] N-[[2-[(cyclopentylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1739] N-[[2-[[(1-methoxycyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1740] N-[[2-[(isobutylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1741] N-[[2-[(cyclohexylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1742] N-[[2-[(cyclopropylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1743] 4-Oxo-N-[[2-[(prop-2-ynylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide

[1744] N-[[2-[(oxetane-2-ylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1745] N-[[2-[(2,2-dimethylpropylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1746] N-[[2-[(1-bicyclo[1.1.1]pentylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1747] N-{[2-({[(1S,2S)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1748] N-{[2-({[(1R,2R)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1749] N-{[2-({[(1S,2R)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1750] N-{[2-({[(1R,2S)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1751] N-[[2-[(cyclopropylmethylamino)methyl]-5-fluoro-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1752] N-[[2-[(cyclobutylmethylamino)methyl]-5-fluoro-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1753] 4-Oxo-N-[[2-[(2,2,2-trifluoroethylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide

[1754] N-[(2-{[N-(cyclobutylmethyl)acetamido]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1755] 4-O-N-{[2-(piperidin-2-yl)-1H-indol-6-yl]methyl}-4H-pyrido[1,2-a]pyrimidin-2-carboxamide

[1756] N-[(2-{[(cyclobutylmethyl)amino]methyl}-3-fluoro-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1757] N-[(2-{[(cyclobutylmethyl)amino]methyl}-1-methyl-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1758] N-[[2-[(cyclobutylmethylamino)-dideutero-methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1759] N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-indazole-4-carboxamide

[1760] N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[3,2-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1761] N-(1H-indol-6-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1762] N-(1H-indol-2-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1763] N-(indoleazin-2-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1764] N-[(6-{[4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]methyl}-1H-indole-2-yl)methyl]cyclopropylamine

[1765] (1R,2S)-2-[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamino]cyclopentanol

[1766] N-[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methyl]cyclopentanamine

[1767] N-(cyclopropylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamine

[1768] 1-[[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indole-2-yl]methylamino]methyl]cyclobutanol

[1769] N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamine

[1770] N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-b]pyridin-2-yl]methylamine

[1771] N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methylamine

[1772] N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methylamine

[1773] 2-[1-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]triazol-4-yl]pyrido[1,2-a]pyrimidin-4-one

[1774] N-(cyclobutylmethyl)-1-[6-[[4-(6-methoxyimidazo[1,5-a]pyridin-8-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamine

[1775] N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)imidazol-1-yl]methyl]-1H-indol-2-yl]methylamine

[1776] N-(cyclobutylmethyl)-1-[6-[[3-(1H-indazol-4-yl)-1,2,4- [diazol-5-yl]methyl]-1H-indol-2-yl]methylamine

[1777] N-[[2-(2-azaspiro[3.3]heptane-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1778] N-[[2-[(benzylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1779] N-[[2-(3-azabicyclo[3.1.0]hexane-3-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1780] N-[[2-[[cyclobutylmethyl(methyl)amino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1781] N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1782] N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-1,3-benzodiazol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1783] N-[(2-{[(but-2-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-carboxamide

[1784] N-[(2-{[(3-cyclopropylprop-2-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-carboxamide

[1785] N-({2-[({bicyclo[3.1.0]hexane-6-yl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1786] N-[(2-{[({bicyclo[2.1.1]hexane-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1787] N-[(2-{[({3-methylbicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1788] N-({2-[(3-methylazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1789] N-({2-[(3-fluorozacricyclobutan-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1790] N-({2-[(azacyclobutan-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1791] N-{[2-({2-azaspiro[3,4]octane-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1792] N-({2-[(3-hydroxyazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1793] N-({2-[(3,3-dimethylazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1794] 4-Oxo-N-[(2-{[3-(2,2,2-trifluoroethoxy)azacyclobutane-1-yl]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1795] N-[(2-{[3-(difluoromethyl)azacyclobutane-1-yl]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1796] N-({2-[(3-methoxyazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1797] N-[(2-{[3-(tert-butoxy)azacyclobutane-1-yl]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1798] 4-Oxo-N-[(2-{[3-(trifluoromethyl)azacyclobutane-1-yl]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1799] N-({2-[(3-ethoxyazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1800] N-{[2-({2-azaspiro[3.5]nonane-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1801] N-({2-[(2-methylazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1802] N-({2-[(3,3-dimethylpyrrolidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-carboxamide

[1803] N-{[2-({6-fluoro-2-azaspiro[3.3]heptane-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1804] N-{[2-({6,6-difluoro-2-azaspiro[3.3]heptane-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1805] N-({2-[(3-cyclobutylazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1806] N-({2-[(3-cyclopropylazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1807] N-({2-[(3-tert-butylazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1808] N-[(2-{[(1-tert-butylcyclopropyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1809] N-{[2-({[(3-methylcyclobutyl)methyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1810] 4-Oxo-N-[(2-{[(2,3,3-trimethylbutane-2-yl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1811] N-[(2-{[({imidazo[1,2-a]pyridin-2-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1812] N-({2-[(3,3-diethylazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1813] 4-Oxo-N-[(2-{[(pentan-3-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1814] N-{[2-({6-azaspiro[3,4]octane-6-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1815] N-({2-[(2,2-dimethylpyrrolidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-carboxamide

[1816] N-{[2-({octahydrocyclopentan[c]pyrrolo-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-carboxamide

[1817] N-{[2-({5-azaspiro[2,4]heptane-5-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1818] N-[(2-{[({3-methoxybicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1819] 4-Oxo-N-[(2-{[({spiro[2,2]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1820] 4-Oxo-N-({2-[({spiro[2,3]hexane-1-yl}amino)methyl]-1H-indol-6-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1821] N-[(2-{[({3-cyanobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1822] N-{[2-({1-oxa-6-azaspiro[3,4]octane-6-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1823] N-{[2-({2-azaspiro[4.4]nonane-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1824] N-[(2-{[(1-methylcyclopentyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1825] N-{[2-(hydroxymethyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1826] N-[(2-{[(1-cyclobutylcyclopropyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1827] N-{[2-({[(1-methylcyclobutyl)methyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1828] 4-Oxo-N-[(2-{[({spiro[2,3]hexane-5-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1829] N-({2-[({[3-(fluoromethyl)bicyclo[1.1.1]pentan-1-yl]methyl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1830] N-[(2-{[(1-{3-fluorobicyclo[1.1.1]pentan-1-yl}ethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1831] N-({2-[(tert-butylamino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-carboxamide

[1832] 4-(1-{[2-({2-azaspiro[3.3]heptane-2-yl}methyl)-1H-indol-6-yl]methyl}-1H-1,2,3-triazol-4-yl)-1H-indazole

[1833] N-{[2-(2-{2-azaspiro[3.3]heptane-2-yl}ethyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1834] ({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)({6-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine

[1835] N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-5-oxo-5H-[1,3]thiazo[3,2-a]pyrimidine-7-carboxamide

[1836] N-[(2-{[({bicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1837] N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1838] N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-6-yl)methyl]-4-oxo-4H-pyridolo[1,2-a]pyrimidin-2-carboxamide

[1839] N-[(2-{[({3-methylbicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1840] N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-carboxamide

[1841] N-[(2-{[({bicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1842] N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-c]182yridine-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1843] N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H,6H,7H,8H,9H-pyrido[1,2-a]pyrimidine-2-carboxamide

[1844] (cyclobutylmethyl)({6-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-imidazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine

[1845] (cyclobutylmethyl)({6-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine

[1846] N-[(2-{[(2,2-dimethylpropyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

[1847] N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

[1848] (cyclobutylmethyl)({6-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine

[1849] N-[[2-(2-azabicyclo[2.2.1]heptane-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1850] N-[(3-fluoro-1-bicyclo[1.1.1]pentyl)methyl]-1-[6-[(4-imidazo[1,5-a]pyridin-8-yltriazol-1-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methylamine

[1851] (cyclobutylmethyl)[(6-{[1-(1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine

[1852] [(3,3-Difluorocyclobutyl)methyl][(6-{[1-(1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indole-2-yl)methyl]amine]amine

[1853] (cyclobutylmethyl)[(6-{[1-(isoquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine

[1854] (cyclobutylmethyl)({6-[(1-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-4-yl)methyl]-1H-indol-2-yl}methyl)amine

[1855] 3-[1-({2-[({(bicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarboxynitrile;

[1856] 3-[1-({2-[({(3-fluorobicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarboxynitrile;

[1857] 5-Methoxy-3-[1-({2-[({(3-methylbicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-2-pyridinecarboxynitrile;

[1858] 3-{1-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarboxynitrile;

[1859] 3-{1-[(2-{(6-aza-6-spiro[3.4]octyl)methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarboxylonitrile;

[1860] 3-[1-({2-[(4,4-dimethyl-1-piperidinyl)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarboxynitrile;

[1861] N-((2-((6-azaspiro[3.4]octane-6-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide;

[1862] 3-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-5-fluoromethylpyridinenitrile;

[1863] 1-Cyclobutyl-N-((6-((4-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methylamine;

[1864] 5-Chloro-3-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)methylpyridinium;

[1865] 2-((6-azaspiro[3.4]octane-6-yl)methyl)-6-((4-(imidazo[1,5-a]pyridin-8-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-pyrrolo[3,2-c]pyridine.

[1866] Other compounds of the present invention or their pharmaceutically acceptable salts include any of the following:

[1867] 3-[1-({2-[({(bicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarboxynitrile;

[1868] 3-[1-({2-[({(3-fluorobicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarboxynitrile;

[1869] 5-Methoxy-3-[1-({2-[({(3-methylbicyclo[1.1.1]pent-1-yl)methyl}amino)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-2-pyridinecarboxynitrile;

[1870] 3-{1-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarboxynitrile;

[1871] 3-{1-[(2-{(6-aza-6-spiro[3.4]octyl)methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarboxylonitrile; and

[1872] 3-[1-({2-[(4,4-dimethyl-1-piperidinyl)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarboxylonitrile.

[1873] Specific compounds of the present invention include any of the compounds exemplified in this application or their pharmaceutically acceptable salts, and in particular any of the following:

[1874] N-[[2-[[(1-hydroxycyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide;

[1875] N-[[2-[[(1-fluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide;

[1876] N-[[2-[(4,4-dimethyl-1-piperidinyl)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1877] N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1878] N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

[1879] N-(cyclobutylmethyl)-1-[6-[[4-(1H-pyrazolo[4,3-c]pyridin-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamine

[1880] N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamine

[1881] N-(cyclobutylmethyl)-1-[6-[[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamine

[1882] N-[[2-[(2,2-dimethylpropylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1883] N-[[2-[(1-bicyclo[1.1.1]pentylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1884] 1-[[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indole-2-yl]methylamino]methyl]cyclobutanol

[1885] N-[[2-[[(3-fluoro-1-bicyclo[1.1.1]pentyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1886] N-[[2-[[(3,3-difluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1887] N-[(3,3-difluorocyclobutyl)methyl]-1-[6-[[1-(1H-indazol-4-yl)triazol-4-yl]methyl]-1H-indole-2-yl]methylamine

[1888] N-[[2-[(oxetane-2-ylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1889] N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-indazole-4-carboxamide

[1890] N-[[2-[[(1-fluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1891] N-[[2-[(cyclobutylmethylamino)methyl]-3H-benzimidazol-5-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1892] N-(cyclobutylmethyl)-1-[6-[[1-(4-isoquinolinyl)triazol-4-yl]methyl]-1H-indol-2-yl]methylamine

[1893] 4-Oxo-N-[[2-[(prop-2-ynylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide

[1894] N-[[2-[(2,2-dimethylpropylamino)methyl]-1H-indol-6-yl]methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

[1895] N-[[2-[(cyclopropylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1896] N-[[2-[(isobutylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[1897] N-[[2-[(cyclohexylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide.

[1898] The various functional groups and substituents constituting the compound of formula (I) are generally selected such that the molecular weight of the compound of formula (I) does not exceed 1000. More generally, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650. More preferably, the molecular weight is less than 600, and for example 550 or less.

[1899] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of the compounds of the present invention that have sufficient basicity, such as acid addition salts with, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citrate, methanesulfonic acid, or maleic acid. Alternatively, suitable pharmaceutically acceptable salts of the compounds of the present invention that have sufficient acidity are alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tri-(2-hydroxyethyl)amine.

[1900] Compounds with the same molecular formula but differing in the properties of their atoms, their bonding sequence, or their spatial arrangement are called "isomers." Isomers with different spatial arrangements of their atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and those that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetry center and are described by the R- and S-sequence rules of Cahn and Prelog, or by the manner in which the molecules rotate in the plane of polarization, and are called dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[1901] The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be prepared as individual (R)- or (S)- stereoisomers or mixtures thereof. Unless otherwise stated, the description or naming of particular compounds in the specification and claims is intended to include individual enantiomers and mixtures thereof, racemates, or others. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition, J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by decomposition of racemic forms. Some compounds of the present invention may have geometric isomer centers (E- and Z-isomers). It should be understood that the present invention covers all optical, diastereomeric, and geometric isomers and mixtures thereof with antiproliferative activity.

[1902] This invention also covers compounds of the invention as defined herein, which contain one or more isotopic substitutions. For example, H can be any isotopic form, including 1 H, 2 H(D) and 3H(T); C can be any isotopic form, including 12 C 13 C and 14 C; and O can be any isotopic form, including 16 O and 18 O; etc.

[1903] It should also be understood that certain compounds of formula (I) (and compounds of formulas (II), (III) and (IV)) may exist in solvated and non-solvated forms, such as hydrated forms. It should be understood that the present invention covers all such solvated forms having antiproliferative activity.

[1904] It should also be understood that certain compounds of formula (I) (and compounds of formulas (II), (III), and (IV)) may exhibit polymorphism, and the present invention covers all such forms having antiproliferative activity.

[1905] Compounds of formula (I) (and compounds of formulas (II), (III), and (IV)) can exist in many different tautomeric forms, and references to compounds of formula (I) include all such forms. For the avoidance of doubt, when a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are still included in formula (I). Some examples of tautomeric forms include ketone-, enol-, and enlate- forms, such as in, for example, the following tautomeric pairs: ketone / enol (illustrated below), imine / enamine, amide / iminool, amidine / amidinium, nitroso / oxime, thionone / enethiol, and nitro / acid-nitro.

[1906]

[1907] Compounds of formula (I) containing amine functional groups can also form N-oxides. The compounds of formula (I) containing amine functional groups mentioned herein also include N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Some specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Jerry March, Advanced Organic Chemistry, 4th ed., Wiley Interscience, pages. More specifically, N-oxides can be prepared by the LWDeady process (Syn. Comm. 1977, 7, 509-514), in which an amine compound reacts with m-chloroperoxybenzoic acid (mCPBA), for example in an inert solvent (e.g., dichloromethane).

[1908] Compounds of formula (I) can be administered as prodrugs, which decompose in the human or animal body to release the compounds of the present invention. Prodrugs can be used to modify the physical properties and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs can be formed when the compounds of the present invention contain suitable groups or substituents that can be linked to property-modifying groups. Some examples of prodrugs include in vivo cleavable ester derivatives that can be formed at the carboxyl or hydroxyl group in compounds of formula (I) and in vivo cleavable amide derivatives that can be formed at the carboxyl or amino group in compounds of formula (I).

[1909] Therefore, when obtained by organic synthesis, and when obtained in humans or animals by the cleavage of its prodrug, the present invention includes those compounds of formula (I) as defined above. Thus, the present invention includes those compounds of formula (I) produced by organic synthesis methods, and such compounds produced in humans or animals by the metabolism of precursor compounds, i.e., compounds of formula (I) can be synthetically produced or metabolically produced compounds.

[1910] A suitable pharmaceutically acceptable prodrug of a compound of formula (I) is a prodrug that is suitable for administration to humans or animals without undesirable pharmacological activity and without excessive toxicity, based on reasonable medical judgment.

[1911] Several forms of prodrugs have been described, for example in the following documents:

[1912] a) Methods in Enzymology , No. 42 volumes Pages 309-396, edited by K. Widder, et al. (Academic Press, 1985);

[1913] b) Design of Pro-drugs, edited by H. Bundgaard (Elsevier, 1985);

[1914] c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, pp. 113–191 (1991);

[1915] d)H.Bundgaard, Advanced Drug Delivery Reviews , 8 ,1-38(1992);

[1916] e)H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77 ,285(1988);

[1917] f)N.Kakeya, et al., Chem.Pharm.Bull. , 32 ,692(1984);

[1918] g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Volume 14; and

[1919] h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[1920] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) containing a carboxyl group are, for example, esters that are cleavable in vivo. Cleavable esters of compounds of formula (I) containing a carboxyl group are, for example, pharmaceutically acceptable esters that are cleaved in the human or animal body to produce a parent acid. Suitable pharmaceutically acceptable esters for the carboxyl group include C... 1-6 Alkyl esters (e.g., methyl, ethyl, and tert-butyl), C 1-6 Alkoxymethyl esters (e.g., methoxymethyl esters), C 1-6 Alkyloxymethyl esters (e.g., neopentyloxymethyl ester, 3-phthaloyl ester), C 3-8 Cycloalkylcarbonyloxy-C 1-6 Alkyl esters (e.g., cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters), 2-oxo-1,3-dioxolenylmethyl esters (e.g., 5-methyl-2-oxo-1,3-dioxolenyl-4-ylmethyl ester), and C 1-6 Alkoxycarbonyloxy-C 1-6 Alkyl esters (e.g., methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters).

[1921] Suitable pharmaceutically acceptable prodrugs of formula (I) containing a hydroxyl group are, for example, esters or ethers that are cleavable in vivo. Cleavable esters or ethers of formula (I) containing a hydroxyl group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to produce a parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxyl group include inorganic esters, such as phosphate esters (including cyclic phosphoramide esters). Other suitable pharmaceutically acceptable ester-forming groups for the hydroxyl group include C... 1-10 Alkyl groups (e.g., acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups), C 1-10Alkoxycarbonyl (e.g., ethoxycarbonyl), N,N-(C 1-6 2-Carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl. Some examples of cyclic substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C 1-4 Alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups of the hydroxyl group include α-acyloxyalkyl, such as acetoxymethyl and neopentyloxymethyl.

[1922] Suitable pharmaceutically acceptable prodrugs of formula (I) containing a carboxyl group are, for example, amides that are cleavable in vivo, such as amides formed with amines such as ammonia, C 1-4 Alkylamines, such as methylamine, (C 1-4 Alkyl)2-amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C 1-4 Alkoxy-C 2-4 Alkylamines such as 2-methoxyethylamine, phenyl-C 1-4 Alkylamines, such as benzylamine, and amino acids, such as glycine or its esters.

[1923] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) having an amino group are, for example, their in vivo cleavable amide derivatives. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, amides formed with: C 1-10 Alkyl groups include acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Some examples of cyclic substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C 1-4 Alkyl)piperazine-1-ylmethyl.

[1924] The in vivo effects of compounds of formula (I) may be exerted in part through one or more metabolites formed in the human or animal body following administration of the compound of formula (I). As previously mentioned, the in vivo effects of compounds of formula (I) may also be exerted through the metabolism of the prodrug (prodrug).

[1925] While the invention may relate to any compound or specific group of a compound as defined herein by way of optional, preferred or suitable features or in particular embodiments, the invention may also relate to any compound or specific group of a compound that specifically excludes the optional, preferred or suitable features or embodiments described herein.

[1926] Suitablely, the present invention excludes any individual compound that does not have the biological activity defined herein.

[1927] synthesis

[1928] The compounds of the present invention can be prepared by any suitable technique known in the art. Specific methods for preparing these compounds are further described in the appended examples.

[1929] In the synthetic methods described herein and in any reference synthetic methods used to prepare starting materials, it should be understood that those skilled in the art may choose all proposed reaction conditions, including the selection of solvents, reaction atmospheres, reaction temperatures, experimental durations, and workup procedures.

[1930] Technicians in the field of organic synthesis understand that the functionality present in multiple parts of a molecule must be compatible with the reagents and reaction conditions used.

[1931] It should be understood that during the synthesis of the compounds of the present invention in the methods defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent them from undergoing undesirable reactions. Skilled chemists will understand when such protection is needed, and how to place such protecting groups in place and subsequently remove them.

[1932] For some examples of protecting groups, see one of the many general texts on the subject, such as Theodora Green's 'Protective Groups in Organic Synthesis' (published by John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to a skilled chemist suitable for removing the protecting group in question, chosen so as to achieve the removal of the protecting group with minimal interference to groups elsewhere in the molecule.

[1933] Therefore, if the reactants include groups such as amino, carboxyl, or hydroxyl, it is expected that the group will be protected in some of the reactions mentioned herein.

[1934] For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups (e.g., alkanoyl groups, such as acetyl groups), alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl groups), arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl groups), or aromatic acyl groups (e.g., benzoyl groups). The deprotection conditions for these protecting groups necessarily vary depending on the choice of protecting group. Therefore, for example, acyl groups, such as alkanoyl, alkoxycarbonyl, or aromatic acyl groups, can be removed by hydrolysis, for example, with a suitable base, such as an alkali metal hydroxide, such as lithium hydroxide or sodium hydroxide. Alternatively, acyl groups, such as tert-butoxycarbonyl groups, can be removed, for example, by treatment with a suitable acid, such as hydrochloric acid, sulfuric acid, or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl groups, such as benzyloxycarbonyl groups, can be removed, for example, by hydrogenation under catalytic conditions (e.g., palladium on carbon) or by treatment with a Lewis acid (e.g., boron tri(trifluoroacetic acid)). Suitable alternative protecting groups for primary amino groups are, for example, phthaloyl groups, which can be removed by treatment with alkylamines (e.g., dimethylaminopropylamine) or with hydrazine.

[1935] Suitable protecting groups for the hydroxyl group are, for example, acyl groups (e.g., alkanoyl groups such as acetyl, aromatic acyl groups such as benzoyl), or arylmethyl groups such as benzyl. The deprotection conditions for these protecting groups necessarily vary depending on the choice of protecting group. Therefore, for example, the acyl group (e.g., alkanoyl or aromatic acyl) can be removed by hydrolysis with a suitable base such as an alkali metal hydroxide (e.g., lithium hydroxide, sodium hydroxide) or ammonia. Alternatively, the arylmethyl group (e.g., benzyl) can be removed by hydrogenation under conditions of a catalyst (e.g., palladium on carbon).

[1936] Suitable protecting groups for the carboxyl group are, for example, esterification groups, such as methyl or ethyl, which can be removed, for example, by hydrolysis with a base (e.g., sodium hydroxide); or, for example, tert-butyl, which can be removed, for example, by treatment with an acid (e.g., an organic acid such as trifluoroacetic acid); or, for example, benzyl, which can be removed, for example, by hydrogenation under the conditions of a catalyst (e.g., palladium on carbon).

[1937] Resins can also be used as protecting groups.

[1938] The methods used to synthesize compounds of formula I will vary depending on the nature of the variable groups. Suitable methods for their preparation are further described in the accompanying examples.

[1939] Once a compound of formula I has been synthesized by any of the methods defined herein, the method may further include the following additional steps:

[1940] (i) Remove any existing protecting groups;

[1941] (ii) Converting a compound of formula I into another compound of formula I;

[1942] (iii) forming its pharmaceutically usable salt, hydrate, or solvate; and / or

[1943] (iv) Formation of its prodrug.

[1944] The obtained compound of formula I can be separated and purified using techniques known in the art.

[1945] Bioactivity

[1946] The METTL3 enzyme and cell assays described in the appended Examples section can be used to measure the pharmacological effects of the compounds of the present invention.

[1947] Although the pharmacological properties of the compounds of Formula I vary with structural changes, as expected, the compounds of the present invention were found to be active in these METTL3 assays.

[1948] Generally, the compounds of the present invention exhibit an IC50 of 10 μM or lower in the METTL3 enzyme assay described herein. 50 The preferred compounds of the present invention exhibit an IC50 concentration of 5 μM or lower. 50 Furthermore, the most preferred compounds of the present invention exhibit an IC50 concentration of 2 μM or lower. 50 .

[1949] In the METTL3 cell assay described in the Examples section, compounds of formula (I) suitably exhibit activity below 10 μM, while preferred compounds of the present invention show IC50 values ​​of 5 μM or lower. 50 Furthermore, the most preferred compounds exhibit activity at 2 μM or lower.

[1950] Pharmaceutical Composition

[1951] According to another aspect of the invention, a pharmaceutical composition is provided comprising the compound of the invention as defined above or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[1952] The compositions of the present invention may be suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), inhalation (e.g., as fine powders or liquid aerosols), insufflation (e.g., as fine powders), or parenteral use (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[1953] The compositions of the present invention can be obtained using conventional pharmaceutical excipients known in the art through conventional procedures. Therefore, compositions for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[1954] An effective amount of the compounds of the present invention used for treatment is sufficient to treat or prevent the autoimmune diseases mentioned herein and / or to treat or prevent proliferative diseases, slow their progression and / or alleviate symptoms associated with such diseases and / or conditions.

[1955] The amount of active ingredient in combination with one or more excipients to produce a single dosage form will necessarily vary depending on the individual being treated and the specific route of administration. For example, formulations intended for oral administration to humans typically contain, for example, 0.5 mg to 0.5 g of the active ingredient (more suitably 0.5 to 100 mg, e.g., 1 to 30 mg) mixed with an appropriate and convenient amount of excipients, which may be from about 5% to about 98% of the total composition weight.

[1956] According to well-known medical principles, the dosage of a compound of formula (I) used for therapeutic or preventative purposes will vary naturally depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[1957] When the compounds of the present invention are used for therapeutic or preventative purposes, they are typically administered in doses ranging from, for example, 0.1 mg / kg to 75 mg / kg body weight, if necessary. Lower doses are generally administered when administered via an enteral route. Thus, for example, for intravenous or intraperitoneal administration, doses ranging from, for example, 0.1 mg / kg to 30 mg / kg body weight are typically used. Similarly, for inhalation administration, doses ranging from, for example, 0.05 mg / kg to 25 mg / kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of the compounds of the present invention.

[1958] Therapeutic uses and applications

[1959] This invention provides compounds that function as inhibitors of METTL3 activity.

[1960] Therefore, the present invention provides a method for inhibiting METTL3 activity in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1961] The present invention also provides a method for treating a disease or condition involving METTL3 activity in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Suitably, the disease or condition involving METTL3 activity is cancer, such as lung cancer, kidney cancer, solid organ cancer, pancreatic cancer or leukemia, type 2 diabetes, neuropsychiatric disorders, infections (e.g., viral infections), or depression.

[1962] The present invention provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting cells with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof.

[1963] The present invention provides a method for treating proliferative disorders, the method comprising administering to a subject in need a therapeutically effective amount of a compound, as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[1964] This invention provides a method for treating cancer, the method comprising administering to a subject in need a therapeutically effective amount of a compound, as defined herein, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. Suitably, the cancer is lung cancer, kidney cancer, solid organ cancer, pancreatic cancer, or leukemia, suitably AML leukemia or chronic myeloid leukemia.

[1965] The present invention provides a method for treating leukemia, the method comprising administering to a subject in need a therapeutically effective amount of a compound, as defined herein, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1966] The present invention provides a method for treating AML leukemia, the method comprising administering to a subject in need a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[1967] This invention provides a method for treating autoimmune diseases, the method comprising administering to a subject in need a therapeutically effective amount of a compound, as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof. Suitably, autoimmune diseases are colitis, multiple sclerosis, rheumatoid arthritis, lupus, cirrhosis, or dermatitis.

[1968] The present invention provides a method for treating neurological disorders, the method comprising administering to a subject in need a therapeutically effective amount of a compound, as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[1969] The present invention provides a method for treating infectious diseases, the method comprising administering to a subject in need a therapeutically effective amount of a compound, as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[1970] In another aspect, the present invention provides a method for treating a viral infection, the method comprising administering to a subject in need a therapeutically effective amount of a compound or pharmaceutically acceptable salt, as defined herein, or a pharmaceutical composition, as defined herein. Suitably, the viral infection is an RNA virus infection. Suitably, the viral infection is human papillomavirus (HPV) or hepatitis.

[1971] The present invention provides a method for treating inflammatory diseases, the method comprising administering to a subject in need a therapeutically effective amount of a compound, as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[1972] METTL3 inhibitors are also potential therapeutic agents for treating diseases associated with the reactivation of the silent X chromosome (Patil et al, Nature, 2016 Sep 15; 537(7620):369-373). Therefore, they are potential effective treatments for Rett syndrome.

[1973] The present invention also provides a method for treating diseases associated with the reactivation of a silenced X chromosome, the method comprising administering to a subject in need a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[1974] The present invention also provides a method for treating Rett syndrome, the method comprising administering to a subject in need a therapeutically effective amount of a compound, as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[1975] The present invention provides compounds as defined herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for therapeutic purposes.

[1976] This invention provides compounds as defined herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for the treatment of proliferative disorders.

[1977] This invention provides compounds as defined herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for the treatment of cancer. In one specific embodiment, the cancer is human cancer. Suitably, the cancer is lung cancer, kidney cancer, solid organ cancer, pancreatic cancer, or leukemia, suitably AML leukemia or chronic myeloid leukemia.

[1978] The present invention provides compounds as defined herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for the treatment of leukemia.

[1979] The present invention provides compounds as defined herein or pharmaceutically acceptable salts or pharmaceutical compositions thereof for the treatment of AML leukemia.

[1980] The present invention provides compounds as defined herein or pharmaceutically acceptable salts or pharmaceutical compositions thereof for inhibiting METTL3 activity.

[1981] This invention provides compounds as defined herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for the treatment of autoimmune diseases. Suitably, autoimmune diseases are colitis, multiple sclerosis, rheumatoid arthritis, lupus, cirrhosis, or dermatitis.

[1982] This invention provides compounds as defined herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for the treatment of nervous system disorders.

[1983] The present invention provides compounds as defined herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for the treatment of infectious diseases.

[1984] This invention provides compounds as defined herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for the treatment of inflammatory diseases.

[1985] In another aspect, the present invention provides compounds as defined herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions as defined herein, for the treatment of viral infections. Suitably, the viral infection is an RNA virus infection. Suitably, the viral infection is human papillomavirus (HPV) or hepatitis.

[1986] This invention provides compounds as defined herein or pharmaceutically acceptable salts thereof for treating diseases or conditions involving METTL3 activity. Suitably, the diseases or conditions involving METTL3 activity are cancers, such as lung cancer, kidney cancer, solid organ cancer, pancreatic cancer or leukemia, type 2 diabetes, neuropsychiatric disorders or depression.

[1987] This invention provides compounds as defined herein, or pharmaceutically acceptable salts or pharmaceutical compositions thereof, for the treatment of diseases associated with the reactivation of the silent X chromosome.

[1988] The present invention provides compounds as defined herein or pharmaceutically acceptable salts or pharmaceutical compositions thereof for the treatment of Rett syndrome.

[1989] This invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating proliferative disorders.

[1990] This invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating cancer. Suitably, the medicament is used to treat human cancer. Suitably, the cancer is lung cancer, kidney cancer, solid organ cancer, pancreatic cancer, or leukemia, suitably AML leukemia or chronic myeloid leukemia.

[1991] This invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of leukemia.

[1992] This invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of AML leukemia.

[1993] This invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of autoimmune diseases. Suitably, autoimmune diseases are colitis, multiple sclerosis, rheumatoid arthritis, lupus, cirrhosis, or dermatitis.

[1994] This invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of nervous system disorders.

[1995] This invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating inflammatory diseases.

[1996] In another aspect, the present invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating viral infections. Suitably, the viral infection is an RNA virus infection. Suitably, the viral infection is human papillomavirus (HPV) or hepatitis.

[1997] This invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating infectious diseases.

[1998] This invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for inhibiting METTL3 activity.

[1999] This invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating diseases or conditions involving METTL3 activity. Suitably, the diseases or conditions involving METTL3 activity are cancers, such as lung cancer, kidney cancer, solid organ cancer, pancreatic cancer or leukemia, type 2 diabetes, neuropsychiatric disorders or depression.

[2000] This invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating diseases associated with the reactivation of the silent X chromosome.

[2001] This invention provides the use of compounds as defined herein or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of Rett syndrome.

[2002] The term "proliferative disorder" is used interchangeably throughout this document and refers to unwanted or uncontrolled cell proliferation, such as tumor growth or proliferative growth, whether in vitro or in vivo, of undesirable, excessive, or abnormal cells. Examples of proliferative disorders include, but are not limited to, pre-malignant and malignant cell proliferation, including but not limited to malignant tumors and neoplasms, cancer, leukemia, psoriasis, bone diseases, fibroproliferative disorders (e.g., connective tissue), and atherosclerosis. Any type of cell can be treated, including but not limited to those from the lungs, colon, breast, ovary, prostate, liver, pancreas, brain, and skin.

[2003] The antiproliferative effects of the compounds of this invention have particular applications in the treatment of human cancer (due to their inhibition of METTL3 activity).

[2004] Anticancer effects can be produced through one or more mechanisms, including but not limited to regulation of cell proliferation, inhibition of angiogenesis (formation of new blood vessels), inhibition of metastasis (spread of tumors from their source), inhibition of invasion (spread of tumor cells to adjacent normal structures), or promotion of apoptosis (programmed cell death).

[2005] In one specific embodiment of the present invention, the proliferative condition to be treated is cancer.

[2006] Application route

[2007] The compounds of the present invention or pharmaceutical compositions comprising these compounds may be administered to the subject via any convenient route of administration, whether systemically / peripherally or superficially (i.e., at the desired site of action).

[2008] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; percutaneous (including, for example, by patches, ointments, etc.); mucosal (including, for example, by patches, ointments, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by using, for example, by aerosols, such as inhalation or blowing into the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by vaginal suppositories); parenteral, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal; and by implantation of a depot or reservoir, for example, subcutaneously or intramuscularly.

[2009] Combination therapy

[2010] The antiproliferative therapy defined above can be used as a standalone treatment, or in addition to the compounds of the present invention, it can also involve conventional surgery, radiation therapy, or chemotherapy. Such chemotherapy may include one or more antitumor agents from the following classes:

[2011] (i) Other antiproliferative / antitumor drugs and combinations thereof used in medical oncology, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide, and nitrosourea); antimetabolites (e.g., gemcitabine); and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, and cytosine. Arabinoside and hydroxyurea; antitumor antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, actinomycin, and mithramycin); antimitotic agents (e.g., vinca alkaloids). Alkaloids, such as vincristine, vinblastine, vindesine, and vinorelbine; taxanes, such as taxol and taxotere; and polokinase inhibitors; and topoisomerase inhibitors (e.g., epipodophyllotoxin, such as etoposide and teniposide, amsacrine, topotecan, and camptothecin).

[2012] (ii) Cell growth inhibitors, such as anti-estrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), anti-androgens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), and progestins (e.g., megestrol acetate). (iii) Anti-invasive agents [e.g., c-Src kinase family inhibitors, such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazol-5-carboxamide (dasatinib, BMS-354825; J. Med. Chem. ,2004, 47 ,6658-6661) and bosutinib (SKI-606), as well as metalloproteinase inhibitors such as marimastat, urokinase plasminogen activator receptor function inhibitors or heparanase antibodies;

[2013] (iv) Growth factor function inhibitors: Such inhibitors include, for example, growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin]). TM[], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erbitux, C225], and any growth factor or growth factor receptor antibody disclosed by Stern et al. (Critical reviews in Oncology / haematology, 2005, Vol. 54, pp. 11-29); such inhibitors also include tyrosine kinase inhibitors, such as epidermal growth factor family inhibitors (e.g., EGFR family tyrosine kinase inhibitors, such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoline-4-amine (CI) 1033), ERB2 tyrosine kinase inhibitors, such as lapatinib; hepatocyte growth factor family inhibitors; insulin-derived growth factor family inhibitors; platelet-derived growth factor family inhibitors, such as imatinib and / or nilotinib (AMN107); serine / threonine kinase inhibitors (e.g., Ras / Raf signaling inhibitors, such as farnesyltransferase inhibitors, such as sorafenib (BAY)). 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336), inhibitors of cell signaling via MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (e.g. AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459) and cyclin-dependent kinase inhibitors, such as CDK2 and / or CDK4 inhibitors;

[2014] (v) Anti-angiogenic agents, such as agents that inhibit the action of vascular endothelial growth factor (VEGF), [e.g., the anti-VEGF antibody bevacizumab (Avastin)]. TMAnd, for example, VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidine-1-ylpropoxy)quinazoline (AZD2171; Example 240 in WO 00 / 47212), compounds such as those in international patent applications WO97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO Compounds disclosed in 98 / 13354 and compounds that act through other mechanisms (e.g., linomide, integrin αvβ3 inhibitors and angiostatin));

[2015] (vi) Vascular damaging agents such as Combretastatin A4 and compounds disclosed in international patent applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669, WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213;

[2016] (vii) Endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan;

[2017] (viii) Antisense therapy, such as those targeting the targets listed above, such as ISIS2503 (anti-ras antisense);

[2018] (ix) Gene therapy methods, including, for example, methods to replace abnormal genes (e.g., abnormal p53 or abnormal BRCA1 or BRCA2), GDEPT (gene-directed enzyme prodrug therapy) methods (e.g., methods using cytosine deaminase, thymidine kinase or bacterial nitroreductase), and methods to improve patients' tolerance to chemotherapy or radiation therapy (e.g., multidrug-resistant gene therapy).

[2019] (x) Immunotherapy methods, including, for example, in vitro and in vivo methods for enhancing the immunogenicity of a patient's tumor cells (e.g., transfection with cytokines such as interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factor), methods for reducing T cell dysfunction, methods using transfected immune cells (e.g., dendritic cells transfected with cytokines), methods using tumor cell lines transfected with cytokines, and methods using anti-idiotype antibodies; and

[2020] (xi) Medications used to treat AML leukemia, including, for example, cytarabine, FLT3 inhibitors, BCL2 inhibitors (e.g., venetoclax) or IDH1 / 2 inhibitors.

[2021] In one specific implementation, the antiproliferative treatment defined above, in addition to the compounds of the present invention, may involve conventional surgery, radiation therapy, or chemotherapy.

[2022] Such combination therapy can be achieved by administering the individual components of the treatment simultaneously, sequentially, or separately. Such combination products utilize compounds of the invention within the dosage range described above, and other pharmaceutically active agents within their approved dosage ranges.

[2023] According to this aspect of the invention, a combination is provided comprising the compound of the invention as defined above or a pharmaceutically acceptable salt thereof, and another antitumor agent for treating cancer (e.g., cancer involving solid tumors).

[2024] According to this aspect of the invention, combinations are provided comprising the compounds of the invention as defined above or pharmaceutically acceptable salts thereof, and any of the antitumor agents listed above, for the treatment of proliferative conditions (e.g., cancers involving solid tumors).

[2025] In another aspect of the invention, compounds of the invention or pharmaceutically acceptable salts thereof are provided for use in combination with another antitumor agent for the treatment of cancer, said other antitumor agent optionally selected from one listed above.

[2026] In this document, when the term "combination" is used, it should be understood that it refers to simultaneous, separate, or sequential application. In one aspect of the invention, "combination" means simultaneous application. In another aspect of the invention, "combination" means separate application. In yet another aspect of the invention, "combination" means sequential application. In the case of continuous or separate application, delaying the application of the second component should not diminish the beneficial effects of the combination.

[2027] According to another aspect of the invention, a pharmaceutical composition is provided comprising a compound of the invention or a pharmaceutically acceptable salt thereof in combination with an antitumor agent (optionally selected from one listed above), in combination with a pharmaceutically acceptable diluent or carrier.

[2028] In another embodiment, the present invention relates to a treatment combination comprising compounds as defined herein and other agents for treating AML leukemia, such as cytarabine, FLT3 inhibitors, BCL2 inhibitors, or IDH1 / 2 inhibitors. Suitably, the agent for treating AML leukemia is a BCL2 inhibitor, such as venetoclax.

[2029] Example

[2030] The following abbreviations were used in the examples:

[2031] AIBN-azobisisobutyronitrile

[2032] DBU–1,8-diazabicyclo[5.4.0]undec-7-ene

[2033] DCE – dichloroethane

[2034] DCM – dichloromethane

[2035] DIBAL – Diisobutylaluminum hydride

[2036] DIPEA–N-ethyl-N-isopropyl-prop-2-amine

[2037] DMAP–4-dimethylaminopyridine

[2038] DMF – dimethylformamide

[2039] DMSO – dimethyl sulfoxide

[2040] DPPA – diphenylphosphohydride

[2041] HATU–[dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium; hexafluorophosphate

[2042] HPLC – High Performance Liquid Chromatography

[2043] IPA – Isopropyl alcohol

[2044] LCMS – Liquid Chromatography-Mass Spectrometry

[2045] NBS–N-bromosuccinimide

[2046] NMP–N-methyl-2-pyrrolidone

[2047] Phase sep cartridge – Telos phase separator 6mL

[2048] RBF – Round Bottom Flask

[2049] RM – Reaction mixture

[2050] RT – Retention Time

[2051] STAB – Sodium Triacetoxyborohydride

[2052] T3P–propylphosphonic anhydride

[2053] TBAF – Tetra-n-Butylammonium Fluoride

[2054] TEA – Triethylamine

[2055] TFA – Trifluoroacetic acid

[2056] TFAA – Trifluoroacetic anhydride

[2057] THF – Tetrahydrofuran

[2058] The following methods were used in the embodiments:

[2059] LCMS Method A refers to low pH analysis performed over 1.2 minutes at a flow rate of 1.2 mL / min using a mobile phase consisting of 0.1% formic acid in a 5% to 100% gradient of MeCN in water. The stationary phase consisted of Kinetex Core-Shell C18, 2.1 mm × 50 mm, 5 μm. The experiment was run at 40 °C.

[2060] LCMS Method B refers to high pH analysis performed over 2.1 minutes at a flow rate of 1.0 mL / min using a mobile phase consisting of 2 mM ammonium bicarbonate buffered to pH 10 in MeCN at a gradient of 5% to 100% in water. The stationary phase consisted of Phenomenex Gemini-NX C18, 2.0 × 50 mm, 3 μm. The experiment was run at 40 °C.

[2061] LCMS Method C refers to high pH analysis performed over 5.8 minutes at a flow rate of 0.6 mL / min using a mobile phase consisting of 2 mM ammonium bicarbonate buffered to pH 10 in a 5% to 100% gradient of MeCN in water. The stationary phase was provided by Waters. BEHTM C18, 2.1 × 100 mm, 1.7 μm composition. Experiments were conducted at 40 °C.

[2062] LCMS Method D refers to high pH analysis performed over 5.9 minutes at a flow rate of 0.6 mL / min using a mobile phase consisting of 2 mM ammonium bicarbonate buffered to pH 10 in MeCN at a gradient of 5% to 100% in water. The stationary phase consisted of Phenomenex Gemini–NX C18, 2.0 × 100 mm, 3 μm. The experiment was run at 40 °C.

[2063] LCMS Method E refers to low pH analysis performed over 5.3 minutes at a flow rate of 0.6 mL / min using a mobile phase consisting of 0.1% formic acid in a 5% to 100% gradient of MeCN in water. The stationary phase consisted of Phenomenex Kinetix-XBC18, 2.1 mm × 100 mm, 1.7 μm. The experiment was run at 40 °C.

[2064] LCMS method F refers to high pH analysis performed at a flow rate of 1.0 mL / min over 0.75 minutes using a mobile phase consisting of 2 mM ammonium bicarbonate buffered to pH 10 in a 5% to 100% gradient of MeCN in water. The stationary phase is supplied by Waters. BEHTM C18, 2.1 × 100 mm, 1.7 μm composition. Experiments were conducted at 40 °C.

[2065] Method G refers to low pH analysis performed over 3.00 minutes using a mobile phase consisting of a 3% to 100% gradient of 0.1% formic acid in water: acetonitrile (10:90) with 0.1% formic acid in water (pH = 2.70), at a flow rate of 0.8 mL / min. The stationary phase consisted of a C18 column, 50 × 2.1 mm, 1.6 μm. The experiment was run at 35 °C.

[2066] Method H refers to high pH analysis performed over 3.0 minutes at a flow rate of 0.5 mL / min using a mobile phase consisting of 5 mM ammonium bicarbonate (pH 7.35) in a gradient of MeCN in water. The stationary phase consisted of C18, 50 × 2.1 mm, 2.5 μm. The experiment was conducted at 35 °C.

[2067] Method I refers to high pH analysis performed over 3.0 minutes at a flow rate of 0.5 mL / min using a mobile phase consisting of 5 mM ammonium bicarbonate (pH 7.35) in a gradient of MeCN in water. The stationary phase consisted of C18, 50 × 2.1 mm, 2.5 μm. The experiment was conducted at 35 °C.

[2068] Method J refers to high pH analysis performed over 1.35 minutes at a flow rate of 1 mL / min using a mobile phase consisting of 2 mM ammonium bicarbonate buffered to pH 10 in a 1% to 100% gradient of MeCN. The stationary phase was supplied by Waters. BEHTMC18, 2.1 × 30 mm, 1.7 μm composition. Experiments were conducted at 40 °C.

[2069] Method K refers to low pH analysis performed over 5.4 minutes at a flow rate of 0.6 mL / min using a mobile phase consisting of a 5% to 100% gradient of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. The stationary phase consisted of a Phenomenex Kinetex Core-Shell C850 × 2.1 mm, 2.6 μm column (protected by a "safety guard" column). The experiment was run at 40 °C.

[2070] Method L refers to low pH analysis performed over 1.1 minutes at a flow rate of 0.9 mL / min using a mobile phase consisting of a 5% to 100% gradient of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. The stationary phase was supplied by Waters. The composition was BEHTM C18 2.1×50mm, 1.7μm. The experiment was conducted at 40℃.

[2071] Method M refers to low pH analysis performed over 2.25 minutes at a flow rate of 1.2 mL / min using a mobile phase consisting of a 5% to 100% gradient of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. The stationary phase consisted of Phenomenex Kinetex Core-Shell C850 x 2.1 mm, 2.6 μm modules. The experiment was run at 40 °C.

[2072] LC04_ABF3 refers to high pH analysis performed over 2.70 minutes at a flow rate of 1.0 mL / min using a mobile phase consisting of 5 mM ammonium bicarbonate buffered to pH 10 in acetonitrile gradients in water from 50% to 100%. The stationary phase was provided by Waters. The C18 material is 4.6 × 50 mm in size and 3.5 μm in diameter. The experiment was conducted at 30 °C.

[2073] LC04_ABR2 refers to high pH analysis performed over 9.0 minutes at a flow rate of 1.0 mL / min using a mobile phase consisting of 5 mM ammonium bicarbonate buffered to pH 10 in acetonitrile gradients from 10% to 100% in water. The stationary phase was provided by Waters. BEH TM The C18 material is 4.6 × 150 mm in size and 3.5 μm in diameter. The experiment was conducted at 30 °C.

[2074] LC03_ABR2 refers to high pH analysis performed over 3.0 minutes at a flow rate of 0.5 mL / min using a mobile phase consisting of 5 mM ammonium bicarbonate buffered to pH 10 in acetonitrile gradients from 3% to 100% in water. The stationary phase was provided by Waters. BEH TM The composition is C18 2.1×50mm, 2.5μm. The experiment was conducted at 30℃.

[2075] UC02_FAR1 refers to low pH analysis performed over 3.00 minutes using a mobile phase consisting of a 3% to 100% gradient of 0.1% formic acid in water (pH = 2.70) and acetonitrile in water (10:90) at a flow rate of 0.8 mL / min. The stationary phase is supplied by Waters. BEHTM The composition is C18 2.1×50mm, 2.5μm. The experiment was conducted at 30℃.

[2076] The following preparative HPLC method was used in the examples:

[2077] Preparation method A refers to low-pH purification using a mobile phase consisting of 0.1% formic acid in MeCN at a gradient of 10% to 95% in water, carried out over 14.4 minutes at a flow rate of 40 mL / min. The stationary phase consisted of Waters Sunfire C18, 30 × 100 mm, 10 μm.

[2078] Preparation method B refers to high-pH purification using a mobile phase consisting of 0.2% ammonium hydroxide in a 30% to 95% gradient of MeCN in water, carried out over 10 minutes at a flow rate of 40 mL / min. The stationary phase consisted of Waters XBridge™ C18 OBD™, 30 × 100 mm, 10 μm.

[2079] Intermediate 1: 4-O-pyrido[1,2-a]pyrimidine-2-carboxylic acid

[2080]

[2081] Methyl 4-oxopyrido[1,2-a]pyrimidin-2-carboxylate [Tetrahedron (2014), 70(17), 2761-2765] (3.94 g, 19.3 mmol) was dissolved in a solution of hydrogen chloride (8 M, 7.5 mL) at room temperature (note the exothermic reaction upon addition), and the mixture was heated under reflux for 2 hours. The mixture was cooled to room temperature, and the precipitate was collected by filtration and dried under vacuum to give the title compound (3.00 g, 81%) as a white solid.

[2082] Method A: LC-MS (electrospray): m / z = 191.1 (M+H) + RT = 0.32 minutes Example 1: N-({2-[(4,4-dimethylpiperidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[2083]

[2084] Step 1: 2-(4,4-dimethylpiperidin-1-carbonyl)-1H-indole-6-carboxynitrile

[2085]

[2086] HATU (809 mg, 2.13 mmol) was added to a mixture of 6-cyano-1H-indole-2-carboxylic acid (330 mg, 1.77 mmol) and DIPEA (1.5 mL, 8.86 mmol) in DMF (26 mL). The mixture was stirred at ambient temperature for 5 min, followed by the addition of 4,4-dimethylpiperidine hydrochloride (292 mg, 1.95 mmol), and the mixture was stirred at ambient temperature for 1 h. The mixture was extracted with EtOAc and H2O, and the layers were separated. The mixture was then extracted with EtOAc (3 × 10 mL), and the organic layer was washed with brine, dried over MgSO4, and concentrated. Purification by alkaline reversed-phase HPLC gave the title compound (100 mg, 20%) as a yellow solid.

[2087] Method A: LC-MS (electrospray): m / z = 281.95 (M+H) + RT = 1.20 minutes

[2088] Step 2: [2-[(4,4-dimethyl-1-piperidinyl)methyl]-1H-indol-6-yl]methylamine

[2089]

[2090] Lithium aluminum hydride (2M in THF, 0.22 mL, 0.44 mmol) was added to a solution of 2-(4,4-dimethylpiperidin-1-carbonyl)-1H-indole-6-carboxynitrile (100 mg, 0.355 mmol) in anhydrous THF (2 mL). The mixture was stirred at 0 °C, then warmed to room temperature and stirred for 1 hour. Additional lithium aluminum hydride (2M in THF, 0.22 mL, 0.44 mmol) was added, and the mixture was stirred at ambient temperature for 67 hours. The reaction was cooled to 0 °C and treated dropwise with H₂O (2 mL), NaOH (1M, 2 mL), and H₂O (6 mL). The mixture was stirred for 10 minutes, filtered, and the filter cake was washed with THF. The filtrate was concentrated and purified by acidic reversed-phase chromatography to give the title compound (86 mg, 89%) as a yellow solid.

[2091] Method A: LC-MS (electrospray): m / z = 272.1 (M+H) + RT = 0.31 minutes

[2092] Step 3: N-({2-[(4,4-dimethylpiperidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[2093]

[2094] HATU (80 mg, 0.210 mmol) was added to a mixture of 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid intermediate 1 (60%, 61 mg, 0.19 mmol) and DIPEA (0.15 mL, 0.88 mmol) in DMF (2.6 mL). The mixture was stirred at ambient temperature for 5 min, followed by the addition of [2-[(4,4-dimethyl-1-piperidinyl)methyl]-1H-indol-6-yl]methylamine (48 mg, 0.18 mmol), and the mixture was stirred at ambient temperature for 1 h. Additional HATU (45 mg) was added, and stirring continued for 2 h. The mixture was partitioned between EtOAc and H2O, the layers were separated, and the mixture was extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine, dried over MgSO4, and concentrated under vacuum. The crude material was purified by preparative HPLC (Method B) to obtain the title compound (4.0 mg, 5.1%) as a white solid.

[2095] Method B: LC-MS (electrospray): m / z = 444.3(M+H) + RT = 4.59 minutes Example 2: N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[2096]

[2097] Step 1: 3-Amino-4-(3,3-diethoxyprop-1-yn-1-yl)benzylnitrile

[2098]

[2099] Pd₂(PPh₃)₂Cl₂ (230 mg, 0.328 mmol) and triphenylphosphine (172 mg, 0.656 mmol) were added to a solution of 3-amino-4-iodobenzonitrile (8.00 g, 32.8 mmol) in anhydrous THF (40 mL) and triethylamine (80 mL, 0.574 mol) at ambient temperature. The solution was degassed by bubbling nitrogen into it for 20 minutes. Copper iodide (I) (125 mg, 0.66 mmol) and 3,3-diethoxyprop-1-yne (5.04 g, 39.3 mmol) were then added sequentially, and the reaction mixture was stirred under a nitrogen atmosphere for 18 hours. The precipitate (triethylamine hydrochloride) was collected by filtration and washed with EtOAc (approximately 20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on SiO2 [Biotage KP-Sil 100 g, eluted with 0% to 50% EtOAc in heptane]. Fractions containing the product were combined and concentrated under vacuum to give the title compound (8.19 g, quantified) as an orange oil.

[2100] Method B: LC-MS (electrospray): m / z = 262.3(M+H) + RT = 1.65 minutes.

[2101] Step 2: 2-(diethoxymethyl)-1H-indole-6-carboxynitrile

[2102]

[2103] Potassium tert-butoxide (6.98 g, 62.2 mmol) was added to a stirred solution of 3-amino-4-(3,3-diethoxyprop-1-ynyl)benzylnitrile (8.00 g, 31.1 mmol) in NMP (99 mL) at 0 °C (the solution color changed from orange to deep red). After warming to room temperature, the solution was stirred at ambient temperature for 16 hours. A saturated aqueous solution of ammonium chloride (25 mL) was added, and the resulting mixture was partitioned between EtOAc (250 mL) and water (250 mL). The layers were separated, and the organic layer was washed twice with water (2 × 200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to give a brown oil. The first aqueous layer was extracted again with EtOAc (200 mL), and the layers were separated. The organic layer was washed twice with water (2 × 200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum to give an orange oil. The crude material was purified by chromatography on SiO2 [BIOTAGE KP-Sil 100 g, eluted with 0% to 50% EtOAc in heptane]. Fractions containing the product were combined and concentrated under vacuum. The residue (yellow solid) was recrystallized from EtOAc / heptane to give the title compound as a colorless crystalline solid (5.86 g, 24.0 mmol, 77%).

[2104] Method B: LC-MS (electrospray): m / z = 262.3(M+H) + RT = 1.69 minutes.

[2105] Step 3: [2-(diethoxymethyl)-1H-indol-6-yl]methylamine

[2106]

[2107] Ammonia (7M, 20 mL, 0.14 mmol) in MeOH was added to a degassed solution of 2-(diethoxymethyl)-1H-indole-6-carboxynitrile (5.8 g, 24 mmol) in ethanol (70 mL), and the reactants were degassed and backfilled with nitrogen three times. Raney nickel (approximately 5.4 g, 0.1 mmol, assuming 50%) was added, and the reactants were evacuated and backfilled with nitrogen three times. For the last evacuation, the flask was evacuated and placed under a hydrogen atmosphere and stirred at ambient temperature for 3 hours. More Raney nickel (approximately 2.7 g) was added, and the reactants were evacuated and placed under a hydrogen atmosphere and stirred at ambient temperature for 16 hours. The catalyst was removed by filtration (through Kieselguhr) and washed with methanol (50 mL). The filtrate was concentrated under reduced pressure to give the title compound (5.96 g, 100%) as a colorless oil that crystallized upon standing.

[2108] Method C: LC-MS (electrospray): m / z = 247.3 (MH) - RT = 2.74 minutes.

[2109] Step 4: N-[(2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[2110]

[2111] HATU (910 mg, 2.39 mmol) was added to a stirred solution of 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (455 mg, 2.39 mmol) (intermediate 1) and DIPEA (1.0 mL, 5.98 mmol) in DMF (10 mL). The color changed from colorless to green and a suspension was formed. After stirring for another 30 minutes at ambient temperature, a solution of [2-(diethoxymethyl)-1H-indol-6-yl]methylamine (500 mg, 1.99 mmol) in DMF (5 mL) was added dropwise to the reactants. The color changed from green to red and the reactants became homogeneous. The mixture was stirred overnight at ambient temperature.

[2112] The mixture was partitioned between EtOAc (100 mL) and a saturated NaHCO3 solution (50 mL). The organic layer was separated, washed with water (80 mL) and brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to obtain a viscous red oil.

[2113] The crude product was dissolved in THF (10 mL), water (1 mL) and acetic acid (0.5 mL) were added, and the mixture was stirred at ambient temperature for 2 hours.

[2114] THF was removed under vacuum and water (10 mL) was added to the resulting mixture, resulting in the precipitation of another solid. The brown solid was collected by washing with water (2 × 5 mL) followed by ether (3 × 5 mL) and dried under vacuum to give the title compound (520 mg, 75%) as a brown solid.

[2115] Method C: LC-MS (electrospray): m / z = 347.2 (M+H) + RT = 2.37 minutes.

[2116] Step 5: N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[2117]

[2118] At ambient temperature, N-[(2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide (185 mg, 0.53 mmol), DCE (5 mL), and 1-cyclobutylmethylamine (0.13 mL, 1.0 mmol) were placed into a pressure vial. The vial was sealed, and the mixture was stirred at 65 °C for 2 hours. After cooling to room temperature, sodium triacetoxyborohydride (340 mg, 1.85 mmol) was added, and the mixture was heated to 65 °C for 2 hours.

[2119] The mixture was partitioned between EtOAc (40 mL) and a saturated sodium bicarbonate solution (30 mL). The organic layer was separated, washed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue (pale yellow oil) was purified by reversed-phase chromatography (basic method, SNAP ULTRA 30 g column, eluted with MeCN + 0.1% NH₃ / H₂O + 0.1% NH₃, 10% to 90%). The fraction containing the desired product was lyophilized overnight to give the title compound (85 mg, 38%) as a grayish-white solid.

[2120] Method C: LC-MS (electrospray): m / z = 416.4 (M+H) + RT = 3.14 minutes.

[2121] Example 6: N-[[2-[[(1-methylcyclopropyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[2122]

[2123] (1-Methylcyclopropyl)methylamine hydrochloride (70 mg, 0.577 mmol) was added to a solution of N-[(2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide (100 mg, 0.289 mmol) in a pressure vial in a DCE (7 mL), and the reaction mixture was stirred at 60 °C for 3 hours. (1-Methylcyclopropyl)methylamine hydrochloride (70 mg, 0.577 mmol) and N-ethyl-N-isopropyl-propyl-2-amine (0.30 mL, 1.73 mmol) were added, and the reaction mixture was stirred at 60 °C for 1 hour. The mixture was cooled to room temperature and added dropwise over 5 minutes to a solution of NaBH4 (11 mg, 0.289 mmol) in ethanol (2.5 mL). The mixture was stirred overnight at ambient temperature. NaBH4 (11 mg, 0.289 mmol) was added dropwise to ethanol (2.5 mL), and the reaction mixture was stirred at ambient temperature for another 1 hour. The mixture was quenched with water (30 mL), extracted with DCM (3 × 40 mL), passed through a Telos phase separator, and concentrated under vacuum. The residue was purified by preparative HPLC (Method B), and the fractions containing the product were combined, concentrated under vacuum, and freeze-dried overnight to give the title compound (70 mg, 59%) as a pale yellow solid.

[2124] Method C: LC-MS (electrospray): m / z = 416.5 (M+H) + RT = 3.16 minutes

[2125] The compounds in Table 1 were prepared using commercial amines or the intermediates described herein in the same manner as in Example 2.

[2126] Table 1

[2127]

[2128]

[2129]

[2130]

[2131]

[2132]

[2133]

[2134]

[2135]

[2136]

[2137]

[2138]

[2139]

[2140]

[2141]

[2142]

[2143]

[2144]

[2145]

[2146]

[2147] Example 42: 4-oxo-N-[[2-[(2,2,2-trifluoroethylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide

[2148]

[2149] 2,2,2-Trifluoroethylamine (25 μL, 0.318 mmol) was added to a solution of N-[(2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide (55 mg, 0.159 mmol) in DCE (4 mL) and 1,1,1,3,3,3-hexafluoro-2-propanol (2 mL) in a pressure vial, and the mixture was stirred at 50 °C for 1 hour. The mixture was cooled to room temperature and treated again with 2,2,2-trifluoroethylamine (25 μL, 0.318 mmol) and stirred at 50 °C for 2.5 hours. The mixture was cooled to room temperature and added dropwise over 5 minutes to a solution of NaBH4 (18 mg, 0.476 mmol) in ethanol (2 mL). The mixture was stirred overnight at ambient temperature. The mixture was retreated with NaBH4 (18 mg, 0.476 mmol) and stirred at ambient temperature for 1 hour and 15 minutes. The mixture was quenched with water (30 mL) and extracted with DCM (3 × 40 mL). The combined organic layers were passed through an Isolute phase separator and concentrated under vacuum. The crude material was purified by preparative HPLC (Method B) to give the title compound (40.2 mg, 59%) as a grayish-white solid.

[2150] Method C: LC-MS (electrospray): m / z = 430.3(M+H) + RT = 2.94 minutes

[2151] Example 70: N-[[2-[[cyclobutylmethyl(methyl)amino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[2152]

[2153] At ambient temperature, N-ethyl-N-isopropyl-propan-2-amine (0.25 mL, 1.44 mmol) and methyl iodide (30 μL, 0.481 mmol) were added to a solution of N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide (200 mg, 0.481 mmol) in chloroform (3 mL) and 2-propanol (1 mL), and the mixture was stirred for 4 hours. The mixture was concentrated to dryness under reduced pressure. The residue was dissolved in MeOH (3 mL) and purified by preparative HPLC (Method B). The fractions containing the product were combined and concentrated to dryness under reduced pressure. The residue was dissolved in a 1:1 mixture of acetonitrile and water (4 mL) and lyophilized to give the title compound (65 mg, 31%) as a pale yellow solid.

[2154] Method C: LC-MS (electrospray): m / z = 430.4 (M+H) + RT = 3.62 minutes

[2155] Example 43: N-[(2-{[N-(cyclobutylmethyl)acetamido]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[2156]

[2157] Acetic anhydride (36 μL, 0.385 mmol) was added to a solution of N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide (Example 2) (150 mg, 0.350 mmol) and N-ethyl-N-isopropyl-propyl-2-amine (0.18 mL, 1.05 mmol) in DCM (5 mL) at ambient temperature, and the mixture was stirred for 2 hours. The mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (Method B) to give the title compound (139 mg, 85.9%) as a white solid.

[2158] Method E: LC-MS (electrospray): m / z = 458.2 (M+H) + RT = 3.01 minutes

[2159] Example 44: 4-oxo-N-{[2-(piperidin-2-yl)-1H-indol-6-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[2160]

[2161] Step 1: 2-[2-(2-amino-4-cyano-phenyl)ethynyl]piperidine-1-carboxylic acid tert-butyl ester

[2162]

[2163] At room temperature, bis(triphenylphosphine)palladium(II) chloride (30 mg, 0.0430 mmol) and triphenylphosphine (23 mg, 0.0861 mmol) were added to a solution of 3-amino-4-iodobenzonitrile (1.05 g, 4.30 mmol) in anhydrous THF (5 mL) and triethylamine (10 mL, 71.7 mmol). The solution was degassed by bubbling nitrogen into the solution for 15 min. Copper(I) iodide (16 mg, 0.0861 mmol) and tert-butyl 2-ethynylpiperidin-1-carboxylic acid (0.99 g, 4.73 mmol) were then added sequentially, and the reaction mixture was stirred under a nitrogen atmosphere for 4 h. The precipitate (triethylamine hydroiodide) was collected by filtration and washed with EtOAc (approximately 20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography on SiO2 (eluting with 0% to 50% EtOAc in heptane). Fractions containing the product were combined and concentrated under vacuum. The orange solid was ground together with heptane. The resulting solid was collected by filtration, washed with heptane (about 25 mL), and dried in a vacuum oven at 45 °C for 2 hours to give the title compound (1.03 g, 70%) as a white solid.

[2164] Method C: LC-MS (electrospray): m / z = 651.5 (2M+H) + RT = 4.21 minutes

[2165] Step 2: 2-(6-cyano-1H-indol-2-yl)piperidin-1-carboxylic acid tert-butyl ester

[2166]

[2167] Potassium 2-methylprop-2-olate (0.69 g, 6.15 mmol) was added to a stirred solution of 2-[2-(2-amino-4-cyano-phenyl)ethynyl]piperidin-1-carboxylic acid tert-butyl ester (1.00 g, 3.07 mmol) in anhydrous NMP (12 mL) at 0 °C (the color of the solution changed from colorless to orange within seconds). After warming to room temperature under a nitrogen atmosphere for 16 hours, ammonium chloride (saturated, 5 mL) was added and the resulting mixture was partitioned between EtOAc (100 mL) and water (80 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (50 mL). The combined organic layers were washed with water (2 × 50 mL) and brine (30 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The residue (brown solid) was purified by chromatography on SiO₂ (eluting with 0% to 50% EtOAc in heptane). The fractions containing the product were combined and concentrated under vacuum. The residue (orange solid) was ground together with heptane. The resulting solid was collected by vacuum filtration, washed with heptane (10 mL), and dried in a vacuum oven at 45 °C for 2 hours to give the title compound (875 mg, 87%) as a white solid.

[2168] Method C: LC-MS (electrospray): m / z = 326.3 (M+H) + RT = 4.19 minutes

[2169] Step 3: 2-[6-(aminomethyl)-1H-indol-2-yl]piperidine-1-carboxylic acid tert-butyl ester

[2170]

[2171] The title compound (785 mg, 83%) was prepared from tert-butyl 2-(6-cyano-1H-indol-2-yl)piperidine-1-carboxylic acid using the chemical method described in step 3 of Example 2.

[2172] Method E: LC-MS (electrospray): m / z = 330.2(M+H) + RT = 2.22 minutes.

[2173] Step 4: 2-{6-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)methyl]-1H-indol-2-yl}piperidin-1-carboxylic acid tert-butyl ester

[2174]

[2175] HATU (246 mg, 0.647 mmol) was added to a solution of 4-oxopyrido[1,2-a]pyrimidin-2-carboxylic acid (135 mg, 0.711 mmol) (intermediate 1), N-ethyl-N-isopropyl-prop-2-amine (0.11 mL, 0.647 mmol) and 2-[6-(aminomethyl)-1H-indol-2-yl]piperidin-1-carboxylic acid tert-butyl ester (213 mg, 0.647 mmol) in anhydrous DMF (4 mL), and the mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between EtOAc (60 mL) and water (40 mL). The organic layer was separated, washed with water (40 mL) and brine (20 mL), dried (Na2SO4), filtered, and concentrated to dryness under vacuum. The residue was purified by chromatography on SiO2 (eluting with 0% to 100% EtOAc in heptane). The fractions containing the product were combined and concentrated under vacuum to give the title compound (313 mg, 92%) as a yellow oil.

[2176] Method C: LC-MS (electrospray): m / z = 502.4 (M+H) + RT = 3.89 minutes

[2177] Step 5: 4-oxo-N-{[2-(piperidin-2-yl)-1H-indol-6-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[2178]

[2179] A solution of 2-{6-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)methyl]-1H-indol-2-yl}piperidin-1-carboxylic acid tert-butyl ester (96%, 313 mg, 0.599 mmol) in dioxane in 4M HCl (4.5 mL) was stirred at 40 °C for 2 hours [the solution turned deep red and gas production ceased]. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was dissolved in MeOH (3 mL) and analyzed by preparative HPLC (Method B). Fractions containing the product were combined and concentrated to dryness under vacuum. The residue was dissolved in acetonitrile (2 mL) and water (2 mL) and lyophilized to give the title compound (120 mg, 49%) as a pale yellow solid.

[2180] Method C: LC-MS (electrospray): m / z = 402.5(M+H) + RT = 2.77 minutes

[2181] Example 45: N-[(2-{[(cyclobutylmethyl)amino]methyl}-3-fluoro-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[2182]

[2183] Step 1: N-[(3-fluoro-2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[2184]

[2185] 1-Chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octanebis(tetrafluoroborate) (515 mg, 1.45 mmol) was added to a solution of N-[(2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidin-2-carboxamide (95%, 530 mg, 1.45 mmol) in anhydrous NMP (10 mL) at room temperature, and the mixture was stirred for 3 days. The mixture was diluted with EtOAc (100 mL), washed with water (50 mL) and brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method B). Fractions containing the product were combined and concentrated to dryness to give the title compound (97 mg, 15%) as a beige solid.

[2186] Method C: LC-MS (electrospray): m / z = 365.3 (M+H) + RT = 2.60 minutes

[2187] Step 2: N-[(2-{[(cyclobutylmethyl)amino]methyl}-3-fluoro-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[2188]

[2189] The title compound (40 mg, 43.5%) was prepared in the same manner as in step 5 of Example 2.

[2190] Method C: LC-MS (electrospray): m / z = 434.4 (M+H) + RT = 3.29 minutes

[2191] Example 46: N-[(2-{[(cyclobutylmethyl)amino]methyl}-1-methyl-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[2192]

[2193] Step 1: 2-(diethoxymethyl)-1-methyl-1H-indole-6-carboxynitrile

[2194]

[2195] A solution of 2-(diethoxymethyl)-1H-indole-6-carboxynitrile (650 mg, 2.66 mmol) in DMF (1 mL) was added to a slurry of sodium hydride (60%, 266 mg, 6.65 mmol) in DMF (1 mL) at 0 °C. The reaction mixture was warmed to room temperature for 10 min, then cooled back to 0 °C. Methyl iodine (0.33 mL, 5.32 mmol) was added dropwise to the slurry and the reaction mixture was stirred at 0 °C for 5 min, then warmed to room temperature. The reaction mixture was stirred for 1 h. The mixture was cooled to 0 °C and quenched by adding water (3 mL) dropwise. The mixture was diluted with EtOAc (5 mL) and the layers were separated. The aqueous layer was extracted twice more with EtOAc (2 × 5 mL). The organic layers were combined and washed with brine (5 mL), dried over MgSO4, filtered, and concentrated under vacuum to give a crude product as a yellow oil. The crude material was purified by chromatography on SiO2 [0% to 50% EtOAc / heptane] to give the title compound (624 mg, 90%) as a white solid.

[2196] Method B: LC-MS (electrospray): m / z = 259.1 (M+H) + RT = 0.68 minutes

[2197] Step 2: 1-[2-(diethoxymethyl)-1-methyl-1H-indol-6-yl]methylamine

[2198]

[2199] The title compound (570 mg, 90%) was prepared in the same manner as in step 3 of Example 2.

[2200] Method B: LC-MS (electrospray): m / z = 263.3(M+H) + RT = 1.75 minutes

[2201] Step 3: N-[(2-formyl-1-methyl-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[2202]

[2203] T3P (50%, 1.6 mL, 2.61 mmol) was added to a solution of 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (454 mg, 2.39 mmol) (intermediate 1), [2-(diethoxymethyl)-1-methyl-indol-6-yl]methylamine (570 mg, 2.17 mmol) and DIPEA (1.9 mL, 10.9 mmol) in DMF (10 mL), and the mixture was stirred overnight at ambient temperature. The mixture was then treated with T3P (50%, 1.6 mL, 2.61 mmol) and DIPEA (1.9 mL, 10.9 mmol) and stirred at ambient temperature for 2 hours. The mixture was extracted with DCM and H2O, the layers were separated, and the organic layer was passed through a TELOS phase separator and concentrated. The crude material was purified by chromatography on SiO2 [0% to 100% EtOAc / heptane] to give the title compound (369 mg, 46%) as a grayish-white solid.

[2204] Method A: LC-MS (electrospray): m / z = 361.1 (M+H) + RT = 1.06 minutes

[2205] Step 4: N-[(2-{[(cyclobutylmethyl)amino]methyl}-1-methyl-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide

[2206]

[2207] 1-Cyclobutylmethylamine (87 mg, 1.02 mmol) was added to a solution of N-[(2-formyl-1-methyl-indole-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide (184 mg, 0.511 mmol) in 1,1,1,3,3,3-hexafluoro-2-propanol (18.437 mL), and the mixture was stirred at ambient temperature for 30 minutes. 1-Cyclobutylmethylamine (87 mg, 1.02 mmol) was added, and the mixture was stirred at ambient temperature for 1 hour, followed by heating at 40 °C for 2 hours. Another 1-cyclobutylmethylamine (87 mg, 1.02 mmol) was added, and the mixture was stirred at ambient temperature overnight. NaBH4 (58 mg, 1.53 mmol) was added to the mixture, followed by a few drops of MeOH, and the mixture was stirred at ambient temperature for 30 minutes. The mixture was quenched with MeOH (10 mL) at 0 °C and concentrated under vacuum. The residue was partitioned and separated between saturated NaHCO3 (aqueous solution) (10 mL) and DCM (10 mL). The aqueous phase was extracted with DCM (2 × 10 mL), and the combined organic phases were passed through a TELOS phase separator and concentrated under vacuum. The residue was purified by preparative HPLC (Method B) to give the title compound (119 mg, 54.3%) as a pale yellow solid.

[2208] Method C: LC-MS (electrospray): m / z = 430.6 (M+H) + RT = 3.42 minutes

[2209] Example 47: N-[[2-[(cyclobutylmethylamino)-dideuterated-methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[2210]

[2211] Step 1: 6-Cyano-1H-indole-2-carboxylic acid

[2212]

[2213] 1M sodium hydroxide (7.5 mL, 7.49 mmol) was added to a suspension of methyl 6-cyano-1H-indole-2-carboxylic acid (1.00 g, 5.00 mmol) in MeOH (15 mL) at ambient temperature. The mixture was stirred at 40 °C for 2 hours. After cooling to room temperature, the reactants were acidified with 2M HCl (5 mL) and water (20 mL) was added. The resulting precipitate was collected by vacuum filtration, washed with water (50 mL), and dried overnight in a vacuum oven at 45 °C to give the title compound (926 mg, 95%) as a pale yellow solid.

[2214] Method A: LC-MS (electrospray): m / z = 185.2 (MH)⁻, RT = 0.98 minutes

[2215] Step 2: 6-Cyano-N-(cyclobutylmethyl)-1H-indole-2-carboxamide

[2216]

[2217] Di(imidazol-1-yl) ketone (529 mg, 3.26 mmol) was added to a solution of 6-cyano-1H-indole-2-carboxylic acid (97%, 626 mg, 3.26 mmol) in DMF (5 mL) at ambient temperature. The mixture was stirred at 70 °C (generating a large amount of gas) for 1 hour. The mixture was cooled to room temperature and 1-cyclobutylmethylamine (361 mg, 4.24 mmol) was added. The mixture was stirred at ambient temperature for 3 hours. The mixture was diluted with EtOAc (10 mL) and the solid was filtered off. Water (50 mL) and diethyl ether (50 mL) were added to the filtrate with stirring. The resulting precipitate was collected by vacuum filtration, washed with water (20 mL) and diethyl ether (20 mL), and dried overnight in a vacuum oven at 45 °C to give the title compound (550 mg, 63%) as an off-white solid.

[2218] Method A: LC-MS (electrospray): m / z = 253.9 (M+H) + RT = 1.14 minutes

[2219] Step 3: 6-(aminomethyl)-N-(cyclobutylmethyl)-1H-indole-2-carboxamide

[2220]

[2221] The title compound (487 mg, 94%) was prepared in the same manner as in step 3 of Example 2.

[2222] Method C: LC-MS (electrospray): m / z = 258.1 (M+H) + RT = 2.56 minutes

[2223] Step 4: 1-[6-(aminomethyl)-1H-indol-2-yl]-N-(cyclobutylmethyl)-1,1-dideuterated-methylamine

[2224]

[2225] To tetrahydro ( 2Lithium aluminate (1-) (221 mg, 5.83 mmol) was added in a single dose of 6-(aminomethyl)-N-(cyclobutylmethyl)-1H-indole-2-carboxamide (150 mg, 0.583 mmol) to a cooled (ice bath) suspension in anhydrous 1,4-dioxane (5 mL). The ice bath was removed, and the mixture was stirred under reflux for 3 hours (heat block temperature 110 °C). The mixture was cooled to 0 °C (ice bath) and quenched by dropwise addition of a mixture of THF (10 mL) and water (1 mL), followed by the addition of 2 M NaOH (0.2 mL). The mixture was stirred at ambient temperature for 30 minutes. The solids were removed by filtration (Kieselguhr) and washed with THF (20 mL). The filtrate was dried (Na2SO4), filtered, and concentrated to dryness under reduced pressure. The residue was dissolved in chloroform (2 mL) and heptane (10 mL) was added. The precipitate was collected by vacuum filtration, washed with heptane (5 mL), and dried in a vacuum oven at 45 °C for 2 hours to give the title compound (114 mg, 69%) as a pale yellow solid.

[2226] Method C: LC-MS (electrospray): m / z = 246.2 (M+H) + RT = 2.96 minutes

[2227] Step 5: N-[[2-[(cyclobutylmethylamino)-dideutero-methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide

[2228]

[2229] HATU (170 mg, 0.448 mmol) was added to a solution of 4-oxopyrido[1,2-a]pyrimidin-2-carboxylic acid (78 mg, 0.408 mmol) (intermediate 1), 1-[6-(aminomethyl)-1H-indol-2-yl]-N-(cyclobutylmethyl)-1,1-dideuterated-methylamine (86%, 116 mg, 0.408 mmol), and DIPEA (0.21 mL, 1.22 mmol) in DMF (3 mL). The reaction mixture was stirred overnight at ambient temperature. The mixture was partitioned between EtOAc (600 mL) and a saturated NaHCO3 solution (20 mL). The organic layer was separated, washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by open-access preparative HPLC method A. The fractions containing the product were combined and concentrated under vacuum until most of the acetonitrile was removed (water bath temperature 45°C, pressure 100 mbar). The clear solution was alkalized with a saturated aqueous sodium carbonate solution and extracted with 3:1 chloroform / 2-propanol (3 × 40 mL). The combined extracts were washed with brine (40 mL), dried (Na₂SO₄), filtered, and concentrated to dryness under reduced pressure. The residue was ground together with acetonitrile. The solid was collected by vacuum filtration, washed with acetonitrile (10 mL), and dried overnight in a vacuum oven at 45°C to give the title compound (63 mg, 36%) as a white solid.

[2230] Method C: LC-MS (electrospray): m / z = 418.5 (M+H) + RT = 3.14 minutes

[2231] Example 48: N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-indazole-4-carboxamide

[2232]

[2233] At ambient temperature, N-[(2-formyl-1H-indol-6-yl)methyl]-1-tetrahydropyran-2-yl-indazole-4-carboxamide (150 mg, 0.373 mmol), DCE (4.3 mL), and 1-cyclobutylmethylamine (0.091 mL, 0.745 mmol) were placed into a pressure vial. The vial was sealed, and the mixture was stirred at 65 °C for 2 hours. After cooling to room temperature, sodium triacetoxyborohydride (184 mg, 0.866 mmol) was added, and the mixture was heated to 65 °C for 2 hours. The mixture was partitioned between EtOAc (40 mL) and a saturated sodium bicarbonate solution (30 mL). The organic layer was separated, washed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The orange residue was purified by basic reversed-phase chromatography (SNAP Ultra 30g column, MeCN + 0.1% NH3 / H2O + 0.1% NH3, 10% to 90%). The fraction containing the purified product was concentrated under vacuum to give a beige residue. The crude substance was redissolved in MeOH (1 mL) and DCM (4 mL), and 4M HCl (1 mL) in dioxane was added. The reaction mixture was stirred at ambient temperature for 5 hours. The solvent was removed under vacuum, and the crude pink solid was purified using a 2g-SCX column eluted first with MeOH (10 mL) and then with 2M ammonia (10 mL) in MeOH solution. The second filtrate was concentrated under vacuum to give the desired product as a grayish-white solid. The compound was lyophilized overnight to give the title compound (78 mg, 53%) as a grayish-white powder.

[2234] Method C: LC-MS (electrospray): m / z = 388.3 (M+H) + RT = 2.96 minutes

[2235] Intermediate 2: N-(cyclobutylmethyl)-N-prop-2-ynyl-carbamate tert-butyl ester

[2236]

[2237] Sodium hydride (60%, 852 mg, 21.3 mmol) was added to a solution of tert-butyl propionate (3.00 g, 19.3 mmol) in anhydrous DMF (30 mL) at 0 °C. The mixture was stirred for 10 min, followed by the addition of (bromomethyl)cyclobutane (2.4 mL, 21.3 mmol). The resulting mixture was then stirred overnight at ambient temperature. The mixture was diluted with water (50 mL) and extracted with diethyl ether (3 × 50 mL). The co...

Claims

1. Compounds of formula (IX) shown below, or their pharmaceutically acceptable salts: in: Q1 is selected from NH or N-CH3; R 1a is a radical of the formula: in: p is an integer selected from 1 or 2; R 1c and R 1d are independently selected from hydrogen or C 1-2 alkyl; R 1e selected from hydrogen or C 1-2 alkyl; and R 1f is a group of the formula: in: q is 1 or 2; R 1g and R 1h are independently selected from hydrogen or C 1-2 alkyl; And T1 is selected from: C 1-4 Alkyl, C 3-8 cycloalkyl groups, 3- to 7-membered monocyclic heterocyclic groups, and bridged bicyclic C groups 5-12 Cycloalkyl or 7- to 12-membered bridged heterocyclic groups; wherein each is optionally selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy or C 3-6 One or more substituents of the cycloalkyl group are substituted; Or R 1e With R 1f The linkages allow them to form 3- to 7-membered monocyclic heterocyclic rings or 7- to 12-membered bicyclic heterocyclic rings together with the nitrogen atoms to which they are attached, optionally selected from C. 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2 One or more substituents of the haloalkoxy group are substituted, and / or R is used. 1e and R 1f The resulting 3- to 7-membered monocyclic heterocyclic rings can be selectively combined with C. 3-6 Cycloalkyl or 3- to 7-membered heterocyclic cyclospirofusion, which is then optionally selected from C 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2 One or more substituents of the haloalkoxy group are substituted; wherein any alkyl, alkoxy, or C group is substituted. 3-6 The cycloalkyl group is further optionally selected from cyano, hydroxyl, halogen, NR. 1k R 1l or -S(O) 0-2 R 1k R 1l One or more substituents are substituted, wherein R 1k and R 1l Is it H or C? 1-4 alkyl; R 1b selected from hydrogen, halogen or C 1-2 alkyl; R 2a , R 2b , and R 2d are independently selected from hydrogen, cyano, halogen, or C 1-3 alkyl; Y is selected from: in: R 3a1 , R 3i1 and R 3j1 are selected from hydrogen and methyl; R 3a2 R 3i2 and R 3j2 It is hydrogen; and n is 1 or 2; R4 is selected from hydrogen and halogens; R5 is selected from hydrogen and halogens; R6 is selected from hydrogen and halogens; A1is CR 12 R 12 is selected from hydrogen, halogen, cyano and C 1-4 alkyl; and A2is CR 13 , R 13 is selected from hydrogen, halogen, cyano, methoxy and methyl.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: R 1b , R 2a , R 2b , and R 2d are hydrogen; and Q1 is selected from NH or N-CH3.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: R 1b , R 2a , R 2b , and R 2d are hydrogen; and Q1 is NH.

4. The compound of claim 1 or 2, wherein R 1a is a group of the formula: ； in p is 1; R 1c and R 1d are independently selected from hydrogen or C 1-2 alkyl; R 1e selected from hydrogen or C 1-2 alkyl; and R 1f is a group of the formula: in: q is 1 or 2; R 1g and R 1h are independently selected from hydrogen or C 1-2 alkyl; And T1 is selected from C 3-4 cycloalkyl groups, 3- to 7-membered monocyclic heterocyclic groups, and bridged bicyclic C groups 5-12 Cycloalkyl or bridged 7- to 12-membered bicyclic heterocyclic groups, each optionally selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2- Halogenated alkoxy or C 3-6 One or more substituents of the cycloalkyl group are substituted; Or R 1e With R 1f The linkages allow them to form 3- to 7-membered monocyclic heterocyclic rings or 7- to 12-membered bicyclic heterocyclic rings together with the nitrogen atoms to which they are attached, optionally selected from C. 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2 One or more substituents of the haloalkoxy group are substituted, and / or R is used. 1e and R 1f The resulting 3- to 7-membered monocyclic heterocyclic rings can be selectively combined with C. 3-6 Cycloalkyl or 3- to 7-membered heterocyclic cyclospirofusion, which is then optionally selected from C 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2 One or more substituents of the haloalkoxy group are used, wherein any alkyl, alkoxy, or C group is used. 3-6 The cycloalkyl group is further optionally selected from cyano, hydroxyl, halogen, NR. 1k R 1l or -S(O) 0-2 R 1k R 1l One or more substituents are substituted, wherein R 1k and R 1l Is it H or C? 1-4 alkyl.

5. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1a is a group of the formula: in R 1c and R 1d are independently selected from hydrogen or C 1-2 alkyl; R 1e selected from hydrogen or C 1-2 alkyl; and R 1f is a group of the formula: in: q is 1; R 1g and R 1h are independently selected from hydrogen or C 1-2 alkyl; And T1 is selected from C 3-4 cycloalkyl groups, 3- to 7-membered monocyclic heterocyclic groups, and bridged bicyclic C groups 5-12 Cycloalkyl or 7- to 12-membered bridged heterocyclic groups, wherein each is optionally selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen, C 1-2 Halogenated alkoxy or C 3-6 One or more substituents of the cycloalkyl group are substituted. Any alkyl or alkoxy group may optionally be further substituted with one or more substituents selected from cyano, hydroxy, or halogen.

6. The compound of claim 1 or 2, wherein R 1a is a group of the formula: in p is 1; R 1c and R 1d Independently selected from hydrogen or C 1-2 Alkyl; and R 1e With R 1f The linkages allow them to form 3- to 7-membered monocyclic heterocyclic rings or 7- to 12-membered bicyclic heterocyclic rings together with the nitrogen atoms to which they are attached, optionally selected from C. 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2 One or more substituents of the haloalkoxy group are substituted, and / or R is used. 1e and R 1f The resulting 3- to 7-membered monocyclic heterocyclic rings can be selectively combined with C. 3-6 Cycloalkyl or 3- to 7-membered heterocyclic cyclospirofusion, which is then optionally selected from C 1-2 Alkyl, C 1-2 Halogenated alkyl, cyano, hydroxyl, C 1-2 Alkoxy, halogen or C 1-2 One or more substituents of the haloalkoxy group are substituted.

7. The compound of claim 1 or 2, wherein R 1a is selected from: 。 8. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 1b is hydrogen.

9. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2a , R 2b and R 2d are independently selected from hydrogen or halogen.

10. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is selected from: 。 11. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is selected from: or .

12. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Y is: 。 13. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R4 is hydrogen.

14. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R5 is hydrogen.

15. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R6 is hydrogen.

16. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 12 is selected from hydrogen and halogen.

17. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 12 is hydrogen.

18. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R 13 Selected from hydrogen, methoxy, and methyl.

19. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 13 is hydrogen.

20. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: R4, R5, and R6 are hydrogen; A1is CR 12 wherein R 12 is selected from hydrogen or chloro; A2is CR 13 wherein R 13 is hydrogen or methoxy.

21. A compound or a pharmaceutically acceptable salt thereof, said compound or pharmaceutically acceptable salt thereof selected from any one of the following: N-({2-[(4,4-dimethylpiperidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[[(3,3-difluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[[(1-hydroxycyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[[(1-fluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[[(1-methylcyclopropyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-(2-azabicyclic[ 2.1.1]hexane-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-(3-azabicyclic[ 3.1.1]Heptane-3-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[[2-(hydroxymethyl)pyrrolidin-1-yl]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-(morpholinomethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(1-adamantylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[[2-(1-piperidinylmethyl)-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(4-fluoro-1-piperidinyl)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[[2-[[[racemic-(1S,2S,4S)-7-oxabicyclo[2.2.1]heptane-5-en-2-yl]methylamino]methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[[(1-hydroxycyclopentyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[[2-[[[racemic-(1S,2R,4S)-7-oxabicyclo[2.2.1]heptane-5-en-2-yl]methylamino]methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(1-bicyclo[1.1.1]pentylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(cyclobutylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[({bicyclo[2.2.1]heptane-2-yl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(cyclopropylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-(2-azabicyclo[2.2.2]octane-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[[(2,2-difluorocyclopropyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[({3-fluorobicyclic[ 1.1.1]pentan-1-yl)methyl)amino]methyl]-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(cyclohexylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[[(1-hydroxycyclohexyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(cyclopentylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(cyclopentylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[[(1-methoxycyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(isobutylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(cyclohexylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(cyclopropylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[[2-[(prop-2-ynylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(oxetane-2-ylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(2,2-dimethylpropylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(1-bicyclo[1.1.1]pentylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({[(1S,2S)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({[(1R,2R)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({[(1S,2R)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({[(1R,2S)-2-hydroxycyclopentyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(cyclopropylmethylamino)methyl]-5-fluoro-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(cyclobutylmethylamino)methyl]-5-fluoro-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[[2-[(2,2,2-trifluoroethylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[N-(cyclobutylmethyl)acetamido]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-{[2-(piperidin-2-yl)-1H-indol-6-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[(cyclobutylmethyl)amino]methyl}-3-fluoro-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[(cyclobutylmethyl)amino]methyl}-1-methyl-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(cyclobutylmethylamino)-dideutero-methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-(2-azaspiro[3.3]heptane-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(benzylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-(3-azabicyclo[3.1.0]hexane-3-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[[cyclobutylmethyl(methyl)amino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[(but-2-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[(3-cyclopropylprop-2-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[({bicyclo[3.1.0]hexane-6-yl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[({bicyclo[2.1.1]hexane-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[({3-methylbicyclo[ 1.1.1]pentan-1-yl)methyl)amino]methyl]-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-methylazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-fluorozacricyclobutan-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(azacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({2-azaspiro[3.4]octane-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-hydroxyazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3,3-dimethylazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(2-{[3-(2,2,2-trifluoroethoxy)azacyclobutane-1-yl]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[3-(difluoromethyl)azacyclobutane-1-yl]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-methoxyazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[3-(tert-butoxy)azacyclobutane-1-yl]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(2-{[3-(trifluoromethyl)azacyclobutane-1-yl]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-ethoxyazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({2-azaspiro[3.5]nonane-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(2-methylazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3,3-dimethylpyrrolidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({6-fluoro-2-azaspiro[3.3]heptane-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({6,6-difluoro-2-azaspiro[3.3]heptane-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-cyclobutylazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-cyclopropylazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-tert-butylazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[(1-tert-butylcyclopropyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({[(3-methylcyclobutyl)methyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(2-{[(2,3,3-trimethylbutane-2-yl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[({imidazo[1,2-a]pyridin-2-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3,3-diethylazacyclobutane-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(2-{[(pent-3-yn-1-yl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({6-azaspiro[3.4]octane-6-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(2,2-dimethylpyrrolidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({octahydrocyclopentan[c]pyrrolo-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({5-azaspiro[2.4]heptane-5-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[({3-methoxybicyclo[ 1.1.1]pentan-1-yl)methyl)amino]methyl]-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(2-{[({spiro[2,2]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-({2-[({spiro[2.3]hexane-1-yl}amino)methyl]-1H-indol-6-yl}methyl)-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[({3-cyanobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({1-oxa-6-azaspiro[3.4]octane-6-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({2-azaspiro[4.4]nonane-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[(1-methylcyclopentyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-(hydroxymethyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[(1-cyclobutylcyclopropyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({[(1-methylcyclobutyl)methyl]amino}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-Oxo-N-[(2-{[({spiro[2.3]hexane-5-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[({[3-(fluoromethyl)bicyclo[ 1.1.1]pentan-1-yl]methyl}amino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[(1-{3-fluorobicyclic[ 1.1.1]pentan-1-yl)ethyl)amino]methyl]-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(tert-butylamino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-(2-{2-azaspiro[3.3]heptane-2-yl}ethyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H,6H,7H,8H,9H-pyrido[1,2-a]pyrimidine-2-carboxamide; and N-[[2-(2-azabicyclo[2.2.1]heptane-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide.

22. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, and one or more pharmaceutically acceptable excipients.

23. Use of the compound of any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 22 for the preparation of a medicament for treating cancer, wherein the cancer is selected from lung cancer, kidney cancer, pancreatic cancer or leukemia.

24. Use of the compound of any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 22 in the preparation of a medicament for the treatment of leukemia.

25. Use of the compound of any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 22 for the preparation of a medicament for the treatment of AML leukemia or chronic myeloid leukemia.

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