Polyheterocyclic compounds as mettl3 inhibitors

Abstract

METTL3 (N6 Adenosine Methyltransferase 70kDa Subunit) To provide an inhibitor of enzyme activity.SOLUTION: For example, N - ({2 - [(4, 4-dimethylpiperidin-l-yl) methyl] - 1H - indol-6-yl} methyl) - 4-oxo - 4H - pyrido [l, 2-a] pyrimidine-2-carboxamide is shown to have the following structure. The invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions containing them and to their use in the treatment of proliferative disorders such as cancers and auto-immune diseases and other diseases or conditions in which METTL3 activity is implicated.SELECTED DRAWING: None

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to a class of compounds that function as inhibitors of certain METTL3 (N6-adenosine methyltransferase 70 kDa subunit) activity. The invention also relates to methods for making the compounds, pharmaceutical compositions containing them, and their use in the treatment of proliferative disorders such as cancer, autoimmune diseases, neurological diseases, infectious and inflammatory diseases, and other diseases or conditions in which METTL3 activity is implicated. [Background technology]

[0002] Background of the Invention N6-methyladenosine (m6A) is the most common and abundant covalent modification of messenger RNA and is regulated by the 'writers', 'erasers', and 'readers' of this mark (Meyer & Jaffrey 2014, Niu Y et al., 2013, Yue et al., 2015). Approximately 0.1–0.5% of all mRNA adenosines are m6A modified (Li Y et al., 2015). In vitro data indicate that m6A influences fundamental aspects of mRNA biology, primarily mRNA expression, splicing, stability, localization, and translation (Meyer et al., 2015; Sledz & Jinek 2016). The m6A modification is tissue-specific, with significant variability in its occurrence profile between unaffected tissues (e.g., brain, heart, kidney) and affected tissues and cells (lung, kidney, breast, and leukemic 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 cancers, leukemia, type 2 diabetes, neuropsychiatric-related behavioral disorders and depressive disorders (Chandola et al., 2015; Koranda et al., 2018).

[0004] The RNA methyltransferase METTL3 is the major, but not the only, enzyme responsible for the m6A modification of RNA. It exists as a heterotrimeric complex with METTL14 (Liu et al., 2014, Wang et al., 2016) and Wilms' tumor-associated protein (WTAP) (Ping et al., 2014). The catalytic activity attributed to METTL3, which transfers a methyl group from the cofactor S-adenosylmethionine to the substrate RNA and METTL14, facilitates substrate RNA binding. WTAP localizes the complex to specific nuclear regions and also localizes the RNA substrate to the complex (Wang X et al., 2016).

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

[0006] Recently, Barbieri et al. (2017) identified a set of RNA-modifying enzymes essential for AML leukemia and identified the METTL3 RNA methyltransferase critical leukemia pathway. In this pathway, METTL3 is recruited to the promoters of a specific set of active genes by the CCAAT box-binding transcription factor CEBPZ, leading to m6A methylation of each mRNA and increased translation. One key target is SP1, an oncogene in several cancers that regulates c-MYC expression. Consistent with these findings, it has been reported that METTL3 can co-transcriptionally methylate its targets.

[0007] The pathway described by Barbieri et al. is important in AML leukemia because three of its components, (i) the m6A RNA methyltransferase METTL3; (ii) the transcription factor CEBPZ, which targets this enzyme to promoters; and (iii) SP1, whose translation depends on the m6A modification by METTL3, are essential for AML cell proliferation. Together, the observations by Barbieri et al. identify METTL3 enzymatic activity as a novel potential target for the treatment of AML.

[0008] Another independent study reported that METTL3 plays an essential role in regulating normal hematopoiesis and myeloid differentiation of leukemia cells in mammals (Vu et al., 2017). Forced expression of wild-type METTL3, but not mutant METTL3 (catalytically deficient), significantly promoted cell proliferation and inhibited cell differentiation of human umbilical cord blood-derived CD34+ hematopoietic stem / progenitor cells (HSPCs). Genetic knockdown of METTL3 had the opposite effect. METTL3 is highly expressed in AML compared with normal HSPCs or other types of cancer. METTL3 knockdown in human AML cell lines significantly induced cell differentiation and apoptosis, blocking leukemia progression in mice xenografted with MOLM-13 AML cells. The biological function of METTL3 may be due to its promotion of the translation of mRNA targets such as MYC, BCL-2, and PTEN in an m6A-dependent manner.

[0009] Recently, METTL3-mediated m6A modification has been shown to play a critical role in T cell homeostasis and signal-dependent induction of mRNA decay in CD4+ T cell lineages (Li et al., 2017). METTL3 deletion in mouse T cells disrupts T cell homeostasis and differentiation. In a lymphopenic mouse adoptive transfer model, naive Mettl3-deficient T cells failed homeostatic expansion and remained naive for up to 12 weeks, thereby preventing colitis. Consistent with this observation, the mRNAs of the SOCS family genes encoding the STAT signaling inhibitor proteins SOCS1, SOCS3, and CISH were marked by m6A and showed slow mRNA decay and increased mRNA and protein expression levels in Mettl3-deficient naive T cells. This increased SOCS family activity consequently inhibited IL-7-mediated STAT5 activation and T cell homeostatic proliferation and differentiation. Thus, METTL3-mediated m6A methylation plays a critical role in the inducible degradation of Socs mRNA in response to IL-7 signaling for reprogramming of naive T cells for proliferation and differentiation, implying a role in autoimmunity.

[0010] Recent studies have confirmed that METTL3 depletion alters the reproduction of various viruses (Winkler et al.). After viral infection or cell stimulation with inactivated virus, depletion of m6A 'writer' METTL3 led to increased interferon-stimulated gene induction. As a result, the reproduction of various viruses was suppressed in an interferon signaling-dependent manner. Notably, IFNB mRNA was m6A-modified and stabilized after METTL3 abrogation. m6A serves as a negative regulator of the interferon response by directing rapid turnover of interferon mRNA, thereby promoting viral reproduction.

[0011] METTL3-dependent m6A expression in HBV and HCV viral genomes regulates viral genome recognition by the RIG-I RNA sensor. Depletion of METTL3 enhances viral dsRNA recognition and induces antiviral immune responses (Kim et al.).

[0012] Therefore, METTL3 inhibitors offer novel therapeutic approaches for the treatment of a wide range of infectious and inflammatory diseases, and in particular offer the potential for the treatment of viral diseases (e.g., DNA and RNA viruses).

[0013] Furthermore, METTL3-dependent m6A expression on endogenous mRNAs regulates their recognition by MAVS-dependent RNA sensors. METTL3 depletion enhances endogenous dsRNA recognition and induces autoimmune responses (Gao et al.). This suggests that antitumor immune responses should be enhanced by METTL3 inhibition.

[0014] Therefore, METTL3 inhibitors may also provide a novel therapeutic approach to enhance anti-tumor immune responses. [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millan-Zambrano G, Robson SC, Aspris D, Migliori V, Bannister AJ, Han N, De Braekeleer E, Ponstingl H, Hendrick A, Vakoc CR, Vassiliou GS, Kouzarides T. Nature. 2017 Dec 7;552(7683):126-131.

[0016] [Non-patent document 2] Chandola U, Das R, Panda B. Brief Funct Genomics. 2015 May;14(3):169-79.

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[0036] [Non-Patent Document 22] Geon-Woo Kim, Hasan Imam, Mohsin Khan, Aleem Siddiqui, J Biol Chem, (27 Jul 2020; online publication ahead of print).

[0037] [Non-Patent Document 23] Yimeng Gao, Radovan Vasic, Yuanbin Song, Rhea Teng, Chengyang Liu, Rana Gbyli, Giulia Biancon, Raman Nelakanti, Kirsten Lobben, Eriko Kudo, Wei Liu, Anastasia Ardasheva, Xiaoying Fu, Xiaman Wang, Poorval Joshi, Veronica Lee, Burak Dura, Gabriella Viero, Akiko Iwasaki, Rong Fan, Andrew Xiao, Richard A Flavell, Hua-Bing Li, Toma Tebaldi, Stephanie Halene; Immunity (16 June 2020; Volume 52; 6; p887-1132).

[0038] [Non-Patent Document 24] Rosa M Rubio, Daniel P Depledge, Christopher Bianco, Letitia Thompson, Ian Mohr; Genes Dev. 2018 Dec 1;32(23-24):1472-1484. [Summary of the Invention] [Problems to be Solved by the Invention]

[0039] An object of the present invention is to provide an agent that inhibits METTL3 activity. [Means for solving the problem]

[0040] Summary of the Invention In certain aspects, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0041] In another aspect, the present invention provides a pharmaceutical composition as defined herein, comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0042] In another aspect, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0043] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative condition.

[0044] In another aspect, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of cancer. In certain embodiments, the cancer is a human cancer.

[0045] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in inhibiting METTL3 activity.

[0046] In another aspect, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in promoting an immune response (e.g., an anti-viral or anti-tumor immune response).

[0047] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in increasing the innate immune response in a subject.

[0048] In another aspect, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in increasing or enhancing an anti-tumor immune response during immuno-oncology therapy.

[0049] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of an autoimmune disease.

[0050] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a neurological disease.

[0051] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of an infectious disease.

[0052] In another aspect, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in treating a viral infection. Preferably, the viral infection is an RNA viral infection. Preferably, the viral infection is human papillomavirus (HPV) or hepatitis.

[0053] In another aspect, the present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of an inflammatory disease.

[0054] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a proliferative condition.

[0055] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancer. In certain embodiments, the medicament is for use in the treatment of human cancer.

[0056] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of METTL3 activity.

[0057] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for promoting an immune response (e.g., an anti-viral or anti-tumor immune response).

[0058] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in increasing the innate immune response in a subject.

[0059] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in increasing or enhancing an anti-tumor immune response during immuno-oncology therapy.

[0060] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an autoimmune disease.

[0061] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a neurological disease.

[0062] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an infectious disease.

[0063] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating a viral infection. Preferably, the viral infection is an RNA viral infection. Preferably, the viral infection is human papillomavirus (HPV) or hepatitis.

[0064] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an inflammatory disease.

[0065] In another aspect, the present invention provides a method for inhibiting METTL3 activity in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

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

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

[0068] In another aspect, the present invention provides a method of promoting an immune response (e.g., an anti-viral or anti-tumor immune response) in a subject in need of treatment, comprising administering to the subject an effective amount of a therapeutic compound or pharmaceutically acceptable salt thereof as defined herein, or a pharmaceutical composition as defined herein.

[0069] In another aspect, the present invention provides a method of increasing the innate immune response in a subject in need of treatment, comprising administering to the subject an effective amount of a therapeutic compound or pharmaceutically acceptable salt thereof as defined herein, or a pharmaceutical composition as defined herein.

[0070] In another aspect, the present invention provides a method for increasing or enhancing an anti-tumor immune response during immuno-oncology therapy, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt thereof as defined herein, or a pharmaceutical composition as defined herein.

[0071] In another aspect, the present invention provides a method of treating a proliferative disorder, comprising administering to a subject in need thereof an effective amount of a therapeutic compound or pharmaceutically acceptable salt thereof as defined herein, or a pharmaceutical composition as defined herein.

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

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

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

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

[0076] In another aspect, the present invention provides a method for treating a viral infection, comprising administering an effective amount of a compound or pharmaceutically acceptable salt thereof as defined herein or a pharmaceutical composition as defined herein to a subject in need thereof. Preferably, the viral infection is an RNA virus infection. Preferably, the viral infection is human papillomavirus (HPV) or hepatitis.

[0077] In another aspect, the present invention provides a method of treating an inflammatory disease, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein.

[0078] In certain embodiments, the present invention provides a combination comprising a compound as defined herein, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.

[0079] The present invention further provides methods of synthesizing the compounds or pharmaceutically acceptable salts defined herein.

[0080] In another aspect, the present invention provides a compound or pharmaceutically acceptable salt as defined herein obtained or obtained or directly by a synthetic method as defined herein.

[0081] In another aspect, the present invention provides novel intermediates as defined herein that are suitable for use in any of the processes described herein.

[0082] The preferred, suitable and optional features of any one particular embodiment of the present invention are also preferred, suitable and optional features of all other embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0083] Detailed Description of the Invention definition Unless otherwise stated, the following terms used in the specification and claims have the meanings indicated.

[0084] It is clear that the reference to "treating" or "treatment" includes prevention of a condition and alleviation of established symptoms. "Treating" or "treatment" of a condition, disorder, or condition therefore includes (1) preventing or delaying the appearance of clinical symptoms of the condition, disorder, or condition as they develop in a person who is susceptible to or predisposed to having the condition, disorder, or condition, but who has not yet experienced or displayed clinical or subclinical symptoms of the condition, disorder, or condition; (2) arresting the condition, disorder, or condition, i.e., halting, alleviating, or delaying the onset of the disease or recurrence (in the case of maintenance treatment) or at least one of its clinical or subclinical symptoms; or (3) remission or attenuation of the disease, i.e., inducing regression of the condition, disorder, or condition, or at least one of its clinical or subclinical symptoms.

[0085] "Therapeutically effective amount" means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The therapeutically effective amount will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal being treated.

[0086] In this specification, the term "alkyl" includes both straight-chain and branched-chain alkyl groups. References to individual alkyl groups, such as "propyl," are specific for the straight-chain version only, and references to individual branched-chain alkyl groups, such as "isopropyl," are specific for the branched-chain version only. For example, "C 1-6 "Alkyl" is C 1-4 Alkyl, C 1-3 This includes alkyl, propyl, isopropyl, and t-butyl. A similar convention applies to other radicals, such as "phenyl (C 1-6 alkyl)" is phenyl (C1-4 alkyl), benzyl, 1-phenylethyl and 2-phenylethyl.

[0087] The term "(m-nC)" or "Cm-n" or "(m-nC) group" or "Cm-n" used alone or as a prefix, refers to any group having m through n carbon atoms.

[0088] 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 of which refers to an alkenyl moiety having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may be located on one or more carbons that may or may not be included in one or more double bonds. Furthermore, such substituents include all of those contemplated for alkyl groups below, except when stability is impaired. For example, substitution of alkenyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0089] 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 of which refers to an alkynyl moiety having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may be located on one or more carbons that may or may not be included in one or more triple bonds. Furthermore, such substituents include all of those contemplated for alkyl groups above, except when stability is impaired. For example, substitution of alkynyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

[0090] An "alkylene" group is an alkyl group that is positioned between and serves to connect two other chemical groups. 1-3 "Alkylene" means a linear saturated divalent hydrocarbon radical of one to three carbon atoms or a branched saturated divalent hydrocarbon radical of three atoms, e.g., methylene, ethylene, propylene, and the like.

[0091] The term “C m-n "Cycloalkyl" means a hydrocarbon ring containing m to n carbon atoms, e.g., "C 3-6 "Cycloalkyl" means a hydrocarbon ring containing 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. m-n "Cycloalkyl" also includes non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic carbocyclic ring systems. m-n "Cycloalkyl" includes both monovalent and divalent species. m-n A "cycloalkyl" ring contains about 3 to 12 (preferably 3 to 8, most preferably 5 to 6) ring carbon atoms. m-n Cycloalkyl" contains 7 to 17 ring carbon atoms, preferably 7 to 12 ring carbon atoms. m-n The "cycloalkyl" rings may be fused, spiro or bridged ring systems.

[0092] The term "cycloalkoxy" means a cycloalkyl-O- group, in which the cycloalkyl group is as defined above, e.g., C 3-4 Cycloalkoxy (or -OC 3-4 Cycloalkyl) refers to a hydrocarbon ring bonded via an O atom and containing 3 to 4 carbon atoms, e.g. [ka] means.

[0093] The term "halo" or "halogeno" refers to fluoro, chloro, bromo and iodo.

[0094] The terms "heterocyclyl," "heterocyclic," or "heterocycle" refer to non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring systems. The term heterocyclyl includes both monovalent and divalent species. Monocyclic heterocyclic rings contain about 3 to 12 (preferably 3 to 7, most preferably 5 to 6) ring atoms and 1 to 5 (preferably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. Bicyclic heterocyclic rings contain 7 to 17 member atoms, preferably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic rings contain about 7 to about 17 ring atoms, preferably 7 to 12 ring atoms. Bicyclic heterocyclic rings can be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, etc. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepin. Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydrooxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. Regarding sulfur-containing heterocycles, oxidized sulfur heterocycles containing SO or SO groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, e.g., tetrahydrothienyl 1,1-dioxide and thiomorpholinyl 1,1-dioxide. Suitable values ​​for heterocyclyl groups having one or two oxo (=O) or thioxo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.Particular heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclyls containing one, two, or three heteroatoms selected from nitrogen, oxygen, or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl, or homopiperazinyl. As will be appreciated by those skilled in the art, any heterocycle can be bonded to other groups through any suitable atom, such as through a carbon or nitrogen atom. However, references herein to piperidino or morpholino refer to piperidin-1-yl or morpholin-4-yl rings bonded through the ring nitrogen.

[0095] A "carbon-linked heterocyclyl" is a heterocyclic group, as defined above, attached via a carbon atom rather than a heteroatom such as nitrogen.

[0096] By "spirocyclic ring system" is meant a compound that is at least two rings that have only one atom in common and that are not joined by a bridge.

[0097] By "fused ring system" is meant a compound in which two rings share two adjacent atoms, in other words, the rings share one covalent bond.

[0098] By "bridged ring system" is meant a ring system in which two rings share more than two atoms (see, for example, Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131-133, 1992.) Examples of bridged heterocyclyl ring systems include aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane, and quinuclidine.

[0099] The term "heteroaryl" or "heteroaromatic" refers to an aromatic mono-, bi-, or polycyclic ring containing one or more (e.g., 1 to 4, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. The term heteroaryl includes both monovalent and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, and more typically 5 to 10 ring members. A heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, e.g., a bicyclic structure formed from a 5-membered ring and a 6-membered fused ring, or two fused 6-membered rings. Each ring can generally contain up to about four heteroatoms selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring contains up to three heteroatoms, more typically up to two, e.g., one heteroatom. In certain embodiments, a heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl ring can be basic, as in the case of an imidazole or pyridine, or essentially non-basic, as in the case of an indole or pyrrole nitrogen. Generally, the number of basicities present in a heteroaryl group, including any amino group substituents on the ring, is less than 5.

[0100] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, and isoquinolyl. These include aryl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, and imidazo[1,2-b][1,2,4]triazinyl. "Heteroaryl" also covers partially aromatic bi- or polycyclic ring systems in which at least one ring is aromatic and one or more of the other rings is non-aromatic, saturated or partially saturated, so long as at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl, and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

[0101] Examples of 5-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0102] Examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0103] Bicyclic heteroaryl groups include, for example: a benzene ring fused to a five- or six-membered ring containing one, two, or three ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing one, two, or three ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; a pyrrole ring fused to a five- or six-membered ring containing one, two, or three ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; a pyrazine ring fused to a five- or six-membered ring containing one or two ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; a thiophene ring fused to a five- or six-membered ring containing one, two, or three ring heteroatoms; a furan ring fused to a five- or six-membered ring containing one, two, or three ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing one, two, or three ring heteroatoms; and A cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing one, two, or three ring heteroatoms It may be a group selected from:

[0104] Illustrative examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl groups.

[0105] Illustrative examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0106] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and the like. In a specific embodiment, aryl is phenyl.

[0107] The term "optionally substituted" refers to both substituted and unsubstituted groups, structures, or molecules.

[0108] When optional substituents are selected from "one or more" groups, this definition is intended to include all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups.

[0109] The term "compounds of the invention" means the compounds disclosed herein both generically and specifically.

[0110] Compounds of the Invention In certain embodiments, the present invention relates to a compound of formula (I) as shown below, or a pharmaceutically acceptable salt thereof: [ka] where: X is [ka] is selected from where: Q1 is NH, NC 1-4 alkyl, O or S; Q 2a is N or CR 2a Selected from; Q 2b is N or CR 2b Selected from; Q 2c is N or CR 2c Selected from; Q 2d is N or CR 2d Selected from; Q3 is N or CR 1b Selected from; Q4 is N or CR 1x is selected from; and Q1, Q 2a , Q 2b , Q 2c , Q 2d , Q3 and Q4 shall not exceed three nitrogen atoms; R 1a teeth (i) each optionally containing halo, cyano, hydroxy, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 C optionally substituted with haloalkoxy, aryl or heteroaryl 1-4 Alkyl or C1-4 is alkoxy; or (ii) Formula: -(CR 1c R 1d ) p -NR 1e R 1f is selected from the group where: p is an integer selected from 0, 1, 2, or 3; R 1c and R 1d is independent (i) hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da C substituted with one or more substituents selected from 1-6 alkyl, where R 1ca and R 1da is H or C 1-2 alkyl; and C 3-6 Cycloalkyl and -OC 3-6 cycloalkyl optionally further substituted with halo, cyano or hydroxy; (iii)C 3-4 cycloalkyl or 3- to 5-membered heterocyclyl, each of which is optionally C 1-4 Alkyl, C 1-4 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da where R 1ca and R 1da is H or C 1-2 alkyl; and (iv) or R 1c and R 1d are joined together with the carbon atoms to which they are attached to form a 3- to 6-membered cycloalkyl or heterocyclic or spirocyclic ring system, each of which optionally is C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da wherein R 1ca and R 1da is H or C 1-2 Alkyl Selected from; R 1e and R 1f are each independently (i) Hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa C substituted with one or more substituents selected from 1-6 Alkyl optionally cyano, oxo, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa C substituted with one or more substituents selected from 1-6 alkyl, where R 1ea and R 1fa is H or C 1-2 those that are alkyl; Formula (iii): -(CR 1g R 1h )q -T1 is a group where q is 0, 1, 2, 3, 4, 5 or 6; R 1g and R 1h is independent a) hydrogen; b) optionally cyano, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, -OC 3-6 Cycloalkyl, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha C substituted with one or more substituents selected from 1-6 alkyl, where R 1ga and R 1ha is H or C 1-2 alkyl; and -OC 3-6 cycloalkyl optionally substituted with halo, cyano or hydroxy; 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 of which is optionally C 1-2 Alkyl, Cyano, C 1-2 Haloalkyl, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha wherein R 1ga and R 1ha is H or C 1-2 alkyl; or d) or R 1g and R 1hare optionally linked to each other so as to form, together with the carbon atoms to which they are attached, a 3- to 6-membered cycloalkyl or heterocyclic ring, which is optionally C 1-2 Alkyl, Cyano, C 1-2 Haloalkyl, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha wherein R 1ga and R 1ha is H or C 1-2 Alkyl Selected from; and T1 is hydrogen, cyano, hydroxy, NR 1t R 2t or -S(O) 0-2 R 1t R 2t (where R 1t and R 2t is H or C 1-4 alkyl), C 3-8 Cycloalkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, aryl, heterocyclyl, heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C 3-8 Cycloalkyl, Bridged Bicyclic C 5-12 cycloalkyl or bridged heterocyclic ring systems, each of which is optionally C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 3t R 4t or -S(O) 0-2 R 3t R 4t wherein R 3t and R 4t is H or C 1-2 those that are alkyl; (iv) or R 1eand R 1f are bonded to each other so as to form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic ring, which optionally is C 1-4 Alkyl, C 1-4 Haloalkyl, cyano, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, NR 1i R 1j or -S(O) 0-2 R 1i R 1j wherein R 1i and R 1j is H or C 1-4 alkyl and / or R 1e and R 1f The monocyclic or bicyclic heterocyclic ring formed by 3-6 spiro-fused to a cycloalkyl or heterocyclic ring, which in turn is optionally 1-4 Alkyl, C 1-4 Haloalkyl, cyano, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, NR 1i R 1j or -S(O) 0-2 R 1i R 1j wherein R 1i and R 1j is H or C 1-4 Alkyl Selected from; R 1b is hydrogen, cyano, halo or C 1-3 alkyl; R 1x is hydrogen, cyano, halo or C 1-3 alkyl; R 2a , R 2b , R 2c and R 2d are independently hydrogen, cyano, halo, or a group of the formula: -L 2a -L 2b -Q2 are independently selected from the group L 2a does not exist or in some cases C 1-2 C substituted with alkyl or oxo 1-3 is alkylene; L 2b is absent or 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 are each independently hydrogen or C 1-2 alkyl; and Q2 is hydrogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, 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 (wherein z is 1, 2, or 3), wherein Rp and R q are each independently hydrogen or C 1-4 alkyl; Y is: [ka] is selected from where: 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 are independently hydrogen (including deuterium), C 1-6 Alkyl, C 3-4 cycloalkyl, hydroxy, and halo; and C alkyl or C 3-4 cycloalkyl optionally substituted with one or more substituents selected from halo, amino, cyano, and hydroxy; 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 is hydrogen or halo; However, R 3a1 , R 3b1 , R 3i1 , R3l1 , R 3o1 , R 3r1 , R 3a2 , R 3b2 , R 3i2 , R 3l2 , R 3o2 and R 3s1 where n=1 or n=2 and cannot be halo when the carbon atom to which they are attached is attached to an oxygen or nitrogen atom; or R 3a1 and R 3a2 , R 3b1 and R 3b2 , R 3c1 and R 3c2 , R 3d1 and R 3d2 , R 3e1 and R 3e2 , R 3f1 and R 3f2 , R 3g1 and R 3g2 , R 3h1 and R 3h2 , R 3i1 and R 3i2 , R 3j1 and R 3j2 , R 3k1 and R 3k2 , R 3l1 and R 3l2 , R 3m1 and R 3m2 , R 3n1 and R 3n2 , R 3o1 and R 3o2 , R 3p1 and R 3p2 , R 3q1 and R 3q2 or R 3r1 and R 3r2 or R 3s1 and R 3s2 together with the carbon atoms to which they are attached to form spiro-fused C 3-4 may be joined together to form a cycloalkyl, which is optionally substituted with one or more substituents selected from halo, methyl, amino, cyano, and hydroxy; n is 0, 1 or 2; Z is selected from one of the following structures: i) [ka] where: B1 is A5, where A5 is CR 16 and N, where R 16 is hydrogen, halo, 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 Haloalkoxy, C 3-4 Cycloalkyl, 3-4 membered heterocyclyl and C 3-4 cycloalkoxy; B2 is A6, where A6 is N or CR 17 where R 17、 R H2 , R H4 and R H5 is hydrogen, hydroxy, halo, 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-membered or heteroaryl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclyl, -O-heterocyclyl (carbon bond), -(OCH2CH2) m -NR q R r , -(OCH2CH2) m -OCH3 (where m is an integer from 1 to 6), NR q R r , -C(O)-NR q R r , -C(O)OR q is selected from where R q and R r are each independently hydrogen, C 1-5 Alkyl, C3-6 cycloalkyl, 3- to 6-membered carbon-bonded heterocyclyl, or R q and R r are linked to each other so as to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered heterocyclic ring; where C 1-5 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5- or 6-membered or heteroaryl, C 3-6 Cycloalkyl, -OC 3-6 Any of cycloalkyl, heterocyclyl, or -O-heterocyclyl (carbon bond) may optionally be C 1-2 Alkyl, Cyano, C 1-2 Haloalkyl, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa and further substituted with one or more substituents selected from: 1ea and R 1fa is H or C 1-2 is alkyl; B3 is N or CR Z1 where R Z1 is hydrogen, C 1-4 Alkyl, cyano, halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkoxy, C 3-6 Cycloalkyl and -OC 3-6 cycloalkyl, wherein C 3-6 Cycloalkyl and -OC 3-6 cycloalkyl optionally substituted with one or more of halo, methyl, or methoxy; B4 is selected from C or N; B5 is CR zi1b or NR B5N Selected from, where: R Zi1b is hydrogen, C1-4 Alkyl, cyano, halo, NH2 and C 1-4 alkoxy; and R B5N is hydrogen or C 1-4 alkyl; B7 is N, NR Z2N or CR Z2 where R Z2 is hydrogen, C 1-4 Alkyl, cyano, halo, NH2 and C 1-4 alkoxy; and R Z2N is hydrogen or C 1-4 alkyl; B8 is selected from C or N; However, there are no more than four Ns in B1 to B8; ii) [ka] where: Y2 is A7, where A7 is CR 18 and N; where R 18 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl, 3-4 membered heterocyclyl and C 3-4 cycloalkoxy; Y3 is N or CR z1a where R Z1a is hydrogen, hydroxy, C 1-4 Alkyl, cyano, halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkoxy, C 3-6 Cycloalkyl and -OC 3-6 cycloalkyl, wherein C 3-6 Cycloalkyl and -OC 3-6 cycloalkyl optionally substituted with one or more of halo, methyl, or methoxy; Y4 is C or N; Y5 is CR Y5 or NR Y5N where: R Y5 is hydrogen, C 1-4 Alkyl, cyano, halo, NH2 and C 1-4 selected from alkoxy; R Y5N is hydrogen or C 1-4 alkyl; Y6 is CR Zi2e or N, where R Zi2e is hydrogen, C 1-4 Alkyl, cyano, halo, NH2 and C 1-4 selected from alkoxy; Y7 is O, S, CR Z2a or N, where R Z2a is hydrogen, C 1-4 Alkyl, cyano, halo, NH2 and C 1-4 selected from alkoxy; Y8 is C or N; Y9 is CR Z3a or N; where R Z3a is hydrogen, C 1-4 Alkyl, cyano, halo, NH2 and C 1-4 selected from alkoxy; However, there are no more than four Ns among Y1 to Y8; (iii) [ka] where: X1 is N or CR Z9 where R Z9 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy; X2 is selected from N or CR4, where: R4 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4Alkoxy, C 1-4 selected from haloalkoxy (e.g., hydrogen, halo, cyano, and methyl); X3 is N; X4 is N or C; X5 is N, CR5 and CRx 5a R X5b Selected from, where: R5 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkoxy (e.g., hydrogen, halo, cyano, and methyl); Rx 5a and R X5b are independently hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkoxy (e.g., hydrogen, halo, cyano, and methyl); X6 is A1 and X7 is A2; or X6 is A8, X7 is A9 or A 11 where: A1 is CR 12 and N; R 12 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 Haloalkoxy (e.g., hydrogen, halo, cyano, and C 1-4 alkyl); A2 is CR 13 and N, where R 13 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy (e.g., hydrogen, halo, cyano, methoxy, and methyl); A8 is CR 19 R 20and N.R. 21 Selected from; where R 19 and R 20 are independently hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy (e.g., hydrogen, halo, cyano, and C 1-4 alkyl); R 21 is hydrogen or C 1-4 is alkyl; A9 is CR 22 R 23 and N.R. 24 Selected from; where R 22 and R 23 are independently hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkoxy (e.g., hydrogen, halo, cyano, and methyl); R 24 is hydrogen or C 1-4 alkyl; A 11 is CR 28 R 29 and N.R. 30 Selected from; R 28 and R 29 is selected from hydrogen, halo, methoxy and methyl; R 30 is hydrogen or C 1-4 alkyl; X8 is CR6, N or CR X6a R X6b Selected from; where R6 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy; R X6a and R X6bare each independently hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy and C 1-4 haloalkoxy; X9 is N or C; However, there are no more than four Ns among X2 to X9; (iv) [ka] where: Z 10 is N or CR Z10 where R Z10 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy; Z 11 is N or CR Z11 where R Z11 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy; Z 12 is N or CR Z12 where R Z12 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy; Z 13 is N or CR Z13 where R Z13 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy; Z 14 is N or CR Z14 where R Z14is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy; Z 15 is N or CR Z15 where R Z15 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy; Z 16 is N or CR Z16 where R Z16 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy; However, Z 10 ~Z 16 There are no more than three Ns in (v) [ka] where: Q7 is CR7 or N; Q8 is CR8 or N; Q9 is CR9 or N; Q 10 is CR 10 or N; Q 11 is CR 11 or N; Q 11a is NR 11N or CR 11a R 11b and; where R7, R8, R9, R 10 , R 11 , R 11a and R 11b are each independently hydrogen, NH2, halo, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C1-6 Alkyl, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3 and -C(O)NR v1 R v2 where R v1 and R v2 are independently selected from hydrogen and methyl; and R 11N are hydrogen, NH2, halo, cyano and C 1-6 alkyl; or R9 and R 10 may be linked to each other so as to form, together with the atoms to which they are attached, a fused 5- or 6-membered saturated or unsaturated ring system or R 10 and R 11 may be linked to each other so as to form, together with the atoms to which they are attached, a fused 5- or 6-membered saturated or unsaturated ring system, or wherein any of the fused 5- or 6-membered saturated or unsaturated ring systems optionally includes C 1-2 Alkyl, Cyano, C 1-2 Haloalkyl, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ia R 1ja or -S(O) 0-2 R 1ia R 1ja wherein R 1ia and R 1ja is H or C 1-2 is alkyl; However, Q7~Q 11 There are no more than three N's.

[0111] In another aspect, the present invention relates to a compound of formula (I) as shown below, or a pharmaceutically acceptable salt thereof: [ka] where: X is [ka] is selected from where: Q1 is NH, NC 1-4 alkyl, O or S; Q 2a is N or CR 2a Selected from; Q 2b is N or CR 2b Selected from; Q 2c is N or CR 2c Selected from; Q 2d is N or CR 2d Selected from; Q3 is N or CR 1b Selected from; Q4 is N or CR 1x is selected from; and Q1, Q 2a , Q 2b , Q 2c , Q 2d , Q3 and Q4 shall not exceed three nitrogen atoms; R 1a teeth: (i) each optionally containing halo, cyano, hydroxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 1-4 Alkoxy, C 1-4 C optionally substituted with haloalkoxy, aryl or heteroaryl 1-4 Alkyl or C 1-4 alkoxy; or (ii) Formula: -(CR 1c R 1d ) p -NR 1e R 1f is selected from the group where: p is an integer selected from 0, 1, 2, or 3; R 1c and R 1d are independently: (i) hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C 1-4Alkoxy, Halo, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da C substituted with one or more substituents selected from 1-6 alkyl, where R 1ca and R 1da is H or C 1-2 alkyl; and C 3-6 Cycloalkyl and -OC 3-6 cycloalkyl optionally further substituted with halo, cyano or hydroxy; (iii)C 3-4 cycloalkyl or 3- to 5-membered heterocyclyl, each of which is optionally C 1-4 Alkyl, C 1-4 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da where R 1ca and R 1da is H or C 1-2 those that are alkyl; (iv) or R 1c and R 1d are joined together with the carbon atoms to which they are attached to form a 3- to 6-membered cycloalkyl or heterocyclic or spirocyclic ring system, each of which optionally is C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da wherein R1ca and R 1da is H or C 1-2 Alkyl Selected from; R 1e and R 1f are each independently: (i) Hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa C substituted with one or more substituents selected from 1-6 Alkyl optionally cyano, oxo, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa C substituted with one or more substituents selected from 1-6 alkyl, where R 1ea and R 1fa is H or C 1-2 those that are alkyl; Formula (iii): -(CR 1g R 1h ) q -T1 is a group wherein q is 0, 1, 2, 3, 4, 5 or 6; R 1g and R 1h are independently: a) hydrogen; b) optionally cyano, oxo, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, -OC 3-6 Cycloalkyl, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1haC substituted with one or more substituents selected from 1-6 alkyl, where R 1ga and R 1ha is H or C 1-2 alkyl; and -OC 3-6 cycloalkyl optionally substituted with halo, cyano, or hydroxy; or 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 of which is optionally C 1-2 Alkyl, Cyano, C 1-2 Haloalkyl, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha wherein R 1ga and R 1ha is H or C 1-2 those that are alkyl; d) or R 1g and R 1h are optionally linked to each other so as to form, together with the carbon atoms to which they are attached, a 3- to 6-membered cycloalkyl or heterocyclic ring, which is optionally C 1-2 Alkyl, Cyano, C 1-2 Haloalkyl, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha wherein R 1ga and R 1ha is H or C 1-2 Alkyl Selected from; And T1 is hydrogen, halo, C1-4 Alkyl, C 1-4 Haloalkyl, cyano, hydroxy, NR 1t R 2t or -S(O) 0-2 R 1t R 2t (where R 1t and R 2t is H or C 1-4 alkyl), C 3-8 Cycloalkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, aryl, heterocyclyl, monocyclic or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C 3-8 Cycloalkyl, Bridged Bicyclic C 5-12 cycloalkyl or bridged heterocyclic ring systems, each of which is optionally C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, C 3-6 Cycloalkyl, NR 3t R 4t or -S(O) 0-2 R 3t R 4t wherein R 3t and R 4t is H or C 1-2 those that are alkyl; (iv) or R 1e and R 1f are bonded to each other so as to form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic ring, which optionally is C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, NR 1i R 1j or -S(O) 0-2 R 1i R 1j wherein R1i and R 1j is H or C 1-4 alkyl and / or R 1e and R 1f The monocyclic or bicyclic heterocyclic ring formed by 3-6 spiro-fused to a cycloalkyl or heterocyclic ring, which in turn is optionally 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, NR 1i R 1j or -S(O) 0-2 R 1i R 1j wherein R 1i and R 1j is H or C 1-4 is alkyl; where alkyl, alkoxy or C 3-6 Any of the cycloalkyls may optionally be cyano, hydroxy, halo, NR 1k R 1l or -S(O) 0-2 R 1k R 1l and further substituted with one or more substituents selected from: 1k and R 1l is H or C 1-4 Alkyl Selected from; R 1b is hydrogen, cyano, halo or C 1-3 alkyl; R 1x is hydrogen, cyano, halo or C 1-3 alkyl; R 2a , R 2b , R 2c and R 2d are independently hydrogen, cyano, halo, or a group of the formula: -L 2a -L 2b -Q2 are independently selected from the group where: L 2a does not exist or in some cases C 1-2 C substituted with alkyl or oxo 1-3 is alkylene; L 2b is absent or 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 are each independently hydrogen or C 1-2 alkyl; and Q2 is hydrogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, 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 (wherein z is 1, 2, or 3), wherein Rp and R q are each independently hydrogen or C 1-4 alkyl; Y is: [ka] is selected from where: 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 are independently hydrogen (including deuterium), C 1-6 Alkyl, C 3-4 cycloalkyl, hydroxy, and halo; and C alkyl or C 3-4 cycloalkyl optionally substituted with one or more substituents selected from halo, amino, cyano, and hydroxy; 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 is hydrogen or halo; However, R 3a1 , R 3b1 , R 3i1 , R3l1 , R 3o1 , R 3r1 , R 3a2 , R 3b2 , R 3i2 , R 3l2 , R 3o2 and R 3s1 where n=1 or n=2 and cannot be halo when the carbon atom to which they are attached is attached to an oxygen or nitrogen atom; or R 3a1 and R 3a2 , R 3b1 and R 3b2 , R 3c1 and R 3c2 , R 3d1 and R 3d2 , R 3e1 and R 3e2 , R 3f1 and R 3f2 , R 3g1 and R 3g2 , R 3h1 and R 3h2 , R 3i1 and R 3i2 , R 3j1 and R 3j2 , R 3k1 and R 3k2 , R 3l1 and R 3l2 , R 3m1 and R 3m2 , R 3n1 and R 3n2 , R 3o1 and R 3o2 , R 3p1 and R 3p2 , R 3q1 and R 3q2 or R 3r1 and R 3r2 or R 3s1 and R 3s2 together with the carbon atoms to which they are attached to form spiro-fused C 3-4 may be joined together to form a cycloalkyl, which is optionally substituted with one or more substituents selected from halo, methyl, amino, cyano, and hydroxy; n is 0, 1 or 2; Z is: [ka] [ka] is selected from where: R4 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkoxy (e.g., hydrogen, halo, cyano, and methyl); R5 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkoxy (e.g., hydrogen, halo, cyano, and methyl); R6 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 selected from haloalkoxy (e.g., hydrogen, halo, cyano, and methyl); R8, R9, R 10 and R 11 are independently hydrogen, NH2, halo, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-6 Alkyl, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3 and -C(O)NR v1 R v2 where R v1 and R v2 are independently selected from hydrogen and methyl; or R9 and R 10 may be linked to each other so as to form, together with the atoms to which they are attached, a fused 5- or 6-membered saturated or unsaturated ring system or R 10 and R 11may be linked to each other so as to form, together with the atoms to which they are attached, a fused 5- or 6-membered saturated or unsaturated ring system, or wherein any of the fused 5- or 6-membered saturated or unsaturated ring systems optionally includes C 1-2 Alkyl, Cyano, C 1-2 Haloalkyl, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ia R 1ja or -S(O) 0-2 R 1ia R 1ja wherein R 1ia and R 1ja is H or C 1-2 is alkyl; R7 and R 11N are independently hydrogen, NH2, halo, cyano and C 1-6 alkyl; R Z1 and R Z1a is hydrogen, C 1-4 Alkyl, cyano, halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkoxy, C 3-6 Cycloalkyl and -OC 3-6 cycloalkyl, wherein C 3-6 Cycloalkyl and -OC 3-6 cycloalkyl optionally substituted with one or more of halo, methyl, or methoxy; R Z2 and R Z2a is hydrogen, C 1-4 Alkyl, cyano, halo, NH2 and C 1-4 selected from alkoxy; R Z3a is hydrogen, C 1-4 Alkyl, cyano, halo, NH2 and C 1-4 selected from alkoxy; R Zi1b is hydrogen, C 1-4 Alkyl, cyano, halo, NH2 and C 1-4 selected from alkoxy; R Zi2e is hydrogen, C 1-4 Alkyl, cyano, halo, NH2 and C 1-4 selected from alkoxy; R Y5N and R Z2N is hydrogen or C 1-4 selected from alkyl; R Z9 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy; R Z10 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy; R Z11 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy; R Z12 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy; R Z13 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy; R Z14 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy; R Z15 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C1-4 Alkoxy, C 1-4 haloalkoxy; R Z16 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy; A1 is CR 12 and N; A2 is CR 13 and N; A5 is CR 16 and N; A6 is CR 17 and N; A7 is CR 18 and N; A8 is CR 19 R 20 and N.R. 21 Selected from; A9 is CR 22 R 23 and N.R. 24 Selected from; A 11 is CR 28 R 29 and N.R. 30 Selected from; R 12 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy (e.g., hydrogen, halo, cyano, and C 1-4 alkyl); R 13 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy (e.g., hydrogen, halo, cyano, methoxy, and methyl); R 16 and R 18 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4Alkoxy, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 3-4 Cycloalkyl, 3-4 membered heterocyclyl and C 3-4 cycloalkoxy; R 17 is hydrogen, halo, cyano, C 1-4 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-membered or heteroaryl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclyl, -O-heterocyclyl (carbon bond), -(OCH2CH2) m -OCH3 (where m is an integer from 1 to 6), NR q R r where R q and R r are each independently hydrogen, C 1-5 Alkyl, C 3-6 cycloalkyl, 3- to 6-membered carbon-bonded heterocyclyl, or R q and R r are linked to each other so as to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered heterocyclic ring; 1-5 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5- or 6-membered or heteroaryl, C 3-6 Cycloalkyl, -OC 3-6 Any of cycloalkyl, heterocyclyl, or -O-heterocyclyl (carbon bond) may optionally be C 1-2 Alkyl, Cyano, C 1-2 Haloalkyl, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1faand further substituted with one or more substituents selected from: 1ea and R 1fa is H or C 1-2 is alkyl; R 19 and R 20 are hydrogen, halo, cyano and C 1-4 alkyl; R 22 and R 23 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 haloalkoxy (e.g., selected from hydrogen, halo, cyano, and methyl); R 28 and R 29 is selected from hydrogen, halo, methoxy and methyl; R 21 , R 24 and R 30 is hydrogen or C 1-4 It is alkyl.

[0112] Particular compounds of the present invention are, for example, compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein, unless otherwise specified, 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 3l1 , R 3l2 , R 3m1、 R 3m2 , R 3n1 , R 3n2 , 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 and any associated substituents each having the meaning defined above or in any of paragraphs (1) to (193) below:

[0113] (1) Q1 is O, NH, or NC 1-4 alkyl.

[0114] (2) Q1 is NH or NC 1-4 alkyl.

[0115] (3) Q1 is selected from NH or N-CH3.

[0116] (4) Q1 is NH.

[0117] (5)Q 2a is CR 2a is.

[0118] (6)Q 2b is CR 2b is.

[0119] (7)Q 2c is CR 2c is.

[0120] (8)Q 2d is CR 2d is.

[0121] (9) Q3 is CR 1b is.

[0122] (10) Q4 is CR 1x is.

[0123] (11) X is: [ka] is selected from Here, Q1, R 1a , R 1b , R 1x , R 2a , R 2b , R 2c , R 2d is as defined herein.

[0124] (12) X is: [ka] Selected from; Here, Q1, R 1a , R 1b , R 2a , R 2b , R 2c and R 2d is as defined herein.

[0125] (13) X is: [ka] is selected from Here, Q1, R 1a , R 1b , R 2a , R 2b and R 2d is as defined herein.

[0126] (14) X is: [ka] is selected from Here, Q1, R 1a , R 1b , R 2a , R 2b and R 2d is as defined herein.

[0127] (15)X is: [ka] and; Here, Q1, R 1a , R 1b , R 2a , R 2b and R 2d is as defined herein.

[0128] (16)X is: [ka] and; Here, Q1, R 1a , R 1b , R 2a and R 2d is as defined herein.

[0129] (17)R 1b , R 2a , R 2b , R 2c and R 2d are each independently hydrogen, C 1-2 It is selected from alkyl or halo.

[0130] (18)X is: [ka] Selected from; where Q1 and R 1a is as defined herein.

[0131] (19)X is: [ka] Selected from; where Q1 and R 1a is as defined herein.

[0132] (20)X is: [ka] Selected from; where Q1 and R 1a is as defined herein.

[0133] (21)X is: [ka] [ka] Selected from where R 1a is as defined herein.

[0134] (22)X is: [ka] Selected from; where R 1a is as defined herein.

[0135] (23)R 1a teeth: (i) optionally halo, cyano, hydroxy, C 3-6 Cycloalkyl, C 1-4 Alkoxy, C 1-4 C substituted with haloalkoxy, aryl or heteroaryl 1-4 alkyl; or (ii) Formula: -(CR 1c R 1d ) p -NR 1e R 1f ; is selected from the group where: p is an integer selected from 0, 1, 2, or 3; R 1c and R 1d are independently: (i) hydrogen (including deuterium); (ii) optionally cyano, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da C substituted with one or more substituents selected from 1-6 alkyl, where R 1ca and R 1da is H or C 1-2 alkyl; and C 3-6 Cycloalkyl and -OC 3-6cycloalkyl optionally further substituted with halo, cyano or hydroxy; (iii)C 3-4 cycloalkyl or 3- to 5-membered heterocyclyl, each of which is optionally C 1-4 Alkyl, C 1-4 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da where R 1ca and R 1da is H or C 1-2 alkyl; and (iv) or R 1c and R 1d are joined together with the carbon atoms to which they are attached to form a 3- to 6-membered cycloalkyl or heterocyclic or spirocyclic ring system, each of which optionally is C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da wherein R 1ca and R 1da is H or C 1-2 Alkyl Selected from; R 1e and R 1f are each independently: (i) Hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0-2 R 1ea R1fa C substituted with one or more substituents selected from 1-6 Alkyl optionally cyano, oxo, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa C substituted with one or more substituents selected from 1-6 alkyl, where R 1ea and R 1fa is H or C 1-2 those that are alkyl; Formula (iii): -(CR 1g R 1h ) q -T1 is a group where: q is 0, 1, 2, 3, 4, 5 or 6; R 1g and R 1h are independently: a) hydrogen; b) optionally cyano, oxo, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, -OC 3-6 Cycloalkyl, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha C substituted with one or more substituents selected from 1-6 alkyl, where R 1ga and R 1ha is H or C 1-2 alkyl; and -OC 3-6 cycloalkyl optionally substituted with halo, cyano or hydroxy; c) Aryl-C 1-6 Alkyl, heteroaryl C 1-6 Alkyl, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl C 1-6alkyl groups, each of which is optionally C 1-2 Alkyl, Cyano, C 1-2 Haloalkyl, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha wherein R 1ga and R 1ha is H or C 1-2 alkyl; or d) or R 1g and R 1h are optionally linked to each other so as to form, together with the carbon atoms to which they are attached, a 3- to 6-membered cycloalkyl or heterocyclic ring, which is optionally C 1-2 Alkyl, Cyano, C 1-2 Haloalkyl, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha wherein R 1ga and R 1ha is H or C 1-2 Alkyl Selected from; and T1 is hydrogen, cyano, hydroxy, NR 1t R 2t or -S(O) 0-2 R 1t R 2t (where R 1t and R 2t is H or C 1-4 alkyl), C 3-8 Cycloalkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, aryl, heterocyclyl, heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C 3-8 Cycloalkyl, Bridged Bicyclic C5-12 cycloalkyl or bridged heterocyclic ring systems, each of which is optionally C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 3t R 4t or -S(O) 0-2 R 3t R 4t wherein R 3t and R 4t is H or C 1-2 Alkyl Select from; or R 1e and R 1f are bonded to each other so as to form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic ring, which optionally is C 1-4 Alkyl, C 1-4 Haloalkyl, cyano, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, NR 1i R 1j or -S(O) 0-2 R 1i R 1j wherein R 1i and R 1j is H or C 1-4 alkyl and / or R 1e and R 1f The monocyclic or bicyclic heterocyclic ring formed by 3-6 spiro-fused to a cycloalkyl or heterocyclic ring, which in turn is optionally 1-4 Alkyl, C 1-4 Haloalkyl, cyano, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, NR 1i R 1j or -S(O) 0-2 R 1i R 1jwherein R 1i and R 1j is H or C 1-4 It is alkyl.

[0136] (24)R 1a teeth: (i) optionally halo, cyano, hydroxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 1-4 Alkoxy, C 1-4 C substituted with haloalkoxy, aryl or heteroaryl 1-4 alkyl; or (ii) Formula: -(CR 1c R 1d ) p -NR 1e R 1f ; is selected from the group where: p is an integer selected from 1 or 2; R 1c and R 1d are independently: (i) hydrogen (including deuterium); (ii) In some cases, C 1-3 C substituted with one or more substituents selected from alkyl 1-3 alkyl, where R 1ca and R 1da is H or C 1-2 alkyl; and C 3-6 Cycloalkyl and -OC 3-6 cycloalkyl optionally substituted with halo, cyano, or hydroxy; (iii)C 3-4 cycloalkyl or 3- to 5-membered heterocyclyl, each of which is optionally C 1-4 Alkyl, C 1-4 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ca R 1da or -S(O) 0-2 R1ca R 1da where R 1ca and R 1da is H or C 1-2 alkyl; and (iv) or R 1c and R 1d are linked together so as to form, together with the carbon atoms to which they are attached, a 3- to 5-membered cycloalkyl or heterocyclic ring or spirocyclic ring system, each of which optionally is C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da wherein R 1ca and R 1da is H or C 1-2 Alkyl Selected from; R 1e and R 1f are each independently: (i) Hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa C substituted with one or more substituents selected from 1-6 Alkyl optionally cyano, oxo, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa C substituted with one or more substituents selected from 1-6 alkyl, where R 1ea and R1fa is H or C 1-2 those that are alkyl; Formula (iii): -(CR 1g R 1h ) q -T1 is a group where: q is 0, 1, 2 or 3; R 1g and R 1h are independently: a) hydrogen (including deuterium); or b) In some cases, C 1-3 C substituted with one or more substituents selected from alkyl 1-3 alkyl, where -OC 3-4 Cycloalkyl is optionally substituted with halo, cyano, or hydroxy; NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da , where R 1ca and R 1da is H or C 1-2 NR is alkyl 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha , where R 1ga and R 1ha is H or C 1-2 those that are alkyl; c) or R 1g and R 1h are optionally linked to each other so as to form, together with the carbon atoms to which they are attached, a 3- to 6-membered cycloalkyl or heterocyclic ring, which is optionally C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1hawherein R 1ga and R 1ha is H or C 1-2 Alkyl Selected from; And T1 is hydrogen, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, cyano, hydroxy, NR 1t R 2t or -S(O) 0-2 R 1t R 2t (where R 1t and R 2t is H or C 1-4 alkyl), C 3-8 Cycloalkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, aryl, heterocyclyl, monocyclic or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C 3-8 Cycloalkyl, Bridged Bicyclic C 5-12 cycloalkyl or bridged heterocyclic ring systems, each of which is optionally C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, C 3-6 Cycloalkyl, NR 3t R 4t or -S(O) 0-2 R 3t R 4t wherein R 3t and R 4t is H or C 1-2 those that are alkyl; (iv) or R 1e and R 1f are bonded to each other so as to form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic ring, which optionally is C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C 1-4Alkoxy, Halo, C 1-4 Haloalkoxy, NR 1i R 1j or -S(O) 0-2 R 1i R 1j wherein R 1i and R 1j is H or C 1-4 alkyl and / or R 1e and R 1f The monocyclic or bicyclic heterocyclic ring formed by 3-6 spiro-fused to a cycloalkyl or heterocyclic ring, which in turn is optionally 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, NR 1i R 1j or -S(O) 0-2 R 1i R 1j wherein R 1i and R 1j is H or C 1-4 Alkyl Selected from; where alkyl, alkoxy or C 3-6 Any of the cycloalkyls may optionally be cyano, hydroxy, halo, NR 1k R 1l or -S(O) 0-2 R 1k R 1l and further substituted with one or more substituents selected from: 1k and R 1l is H or C 1-4 It is alkyl.

[0137] (25)R 1a is the expression: -(CR 1c R 1d ) p -NR 1e R 1f ; is a group wherein p is an integer selected from 1 or 2; R 1c and R 1d are independently: (i) hydrogen (including deuterium); or (ii) optionally cyano, oxo, hydroxy, C 1-3 Alkoxy, Halo, C 1-3 Haloalkoxy, -OC 3-4 C substituted with one or more substituents selected from cycloalkyl or NH 1-3 alkyl; where -OC 3-6 cycloalkyl optionally substituted with halo, cyano or hydroxy; (iii) In some cases, C 1-4 Alkyl, C 1-4 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy or NR 1ca R 1da C is replaced by 3-4 cycloalkyl; and (iv) or R 1c and R 1d are linked together so as to form, together with the carbon atoms to which they are attached, a 3- to 5-membered cycloalkyl or heterocyclic ring or spirocyclic ring system, each of which optionally is C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da wherein R 1ca and R 1da is H or C 1-2 Alkyl Selected from; R 1e and R 1f are each independently: (i) Hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 C substituted with one or more substituents selected from haloalkoxy, NH 1-6 alkyl; Formula (iii): -(CR 1g R 1h ) q -T1 is a group wherein q is 0, 1, 2 or 3; R 1g and R 1h are independently: a) hydrogen (including deuterium); or b) optionally cyano, oxo, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, -OC 3-6 Cycloalkyl, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da C substituted with one or more substituents selected from 1-6 alkyl, where R 1ca and R 1da is H or C 1-2 NR is alkyl 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha , where R 1ga and R 1ha is H or C 1-2 alkyl; and -OC 3-6 cycloalkyl optionally substituted with halo, cyano or hydroxy; c) or R 1g and R 1h are optionally linked to each other so as to form, together with the carbon atoms to which they are attached, a 3- to 6-membered cycloalkyl or heterocyclic ring, which is optionally C 1-2 Alkyl, C1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha wherein R 1ga and R 1ha is H or C 1-2 Alkyl Selected from; And T1 is hydrogen, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, cyano, hydroxy, NR 1t R 2t or -S(O) 0-2 R 1t R 2t (where R 1t and R 2t is H or C 1-4 alkyl), C 3-8 Cycloalkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, aryl, heterocyclyl, monocyclic or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C 3-8 Cycloalkyl, Bridged Bicyclic C 5-12 cycloalkyl or bridged heterocyclic ring systems, each of which is optionally C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, C 3-6 Cycloalkyl, NR 3t R 4t or -S(O) 0-2 R 3t R 4t wherein R 3t and R 4t is H or C 1-2 those that are alkyl; (iv) or R 1e and R 1fare bonded to each other so as to form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic ring, which optionally is C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, NR 1i R 1j or -S(O) 0-2 R 1i R 1j wherein R 1i and R 1j is H or C 1-4 alkyl and / or R 1e and R 1f The monocyclic or bicyclic heterocyclic ring formed by 3-6 spiro-fused to a cycloalkyl or heterocyclic ring, which in turn is optionally 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, NR 1i R 1j or -S(O) 0-2 R 1i R 1j wherein R 1i and R 1j is H or C 1-4 Alkyl Selected from; where alkyl, alkoxy or C 3-6 Any of the cycloalkyls may optionally be cyano, hydroxy, halo, NR 1k R 1l or -S(O) 0-2 R 1k R 1l and further substituted with one or more substituents selected from: 1k and R 1l is H or C 1-4 It is alkyl.

[0138] (26)R 1a is the expression: -(CR 1c R 1d ) p -NR 1e R 1f is a group wherein p is an integer selected from 1 or 2; R 1c and R 1d are independently: (i) hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C 1-3 Alkoxy, Halo, C 1-43 Haloalkoxy, -OC 3-4 C substituted with one or more substituents selected from cycloalkyl or NH 1-3 alkyl; where -OC 3-6 cycloalkyl optionally substituted with halo, cyano or hydroxy; (iii) or R 1c and R 1d are linked together so as to form, together with the carbon atoms to which they are attached, a 3- to 5-membered cycloalkyl or heterocyclic ring or spirocyclic ring system, each of which optionally is C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da wherein R 1ca and R 1da is H or C 1-2 Alkyl Selected from; R 1e teeth: (i) Hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C 1-2Alkoxy, Halo, C 1-2 C substituted with one or more substituents selected from haloalkoxy and NH 1-3 Alkyl is selected from; and R 1f teeth: (i) optionally cyano, oxo, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 C substituted with one or more substituents selected from haloalkoxy and NH 1-6 alkyl; (ii) Formula: -(CR 1g R 1h ) q -T1 is a group wherein q is 1, 2 or 3; R 1g and R 1h are independently: a) hydrogen (including deuterium); or b) optionally cyano, oxo, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, -OC 3-6 Cycloalkyl, NR 1ca R 1da or -S(O) 0-2 R 1ca R 1da C substituted with one or more substituents selected from 1-6 alkyl, where R 1ca and R 1da is H or C 1-2 NR is alkyl 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha , where R 1ga and R 1ha is H or C 1-2 alkyl; and -OC 3-6 cycloalkyl optionally substituted with halo, cyano or hydroxy; c) or R 1g and R 1hare optionally linked to each other so as to form, together with the carbon atoms to which they are attached, a 3- to 4-membered cycloalkyl or heterocyclic ring, which is optionally C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ga R 1ha or -S(O) 0-2 R 1ga R 1ha wherein R 1ga and R 1ha is H or C 1-2 Alkyl Selected from; And T1 is hydrogen, halo, C 1-4 Alkyl, C 1-4 Haloalkyl, cyano, hydroxy, NR 1t R 2t or -S(O) 0-2 R 1t R 2t (where R 1t and R 2t is H or C 1-4 alkyl), C 3-8 Cycloalkyl, C 2-3 Alkenyl, C 2-3 Alkynyl, aryl, heterocyclyl, monocyclic or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C 3-8 Cycloalkyl, Bridged Bicyclic C 5-12 cycloalkyl or bridged heterocyclic ring systems, each of which is optionally C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, C 3-6 Cycloalkyl, NR 3t R 4t or -S(O) 0-2 R 3t R 4t wherein R 3t and R4t is H or C 1-2 Alkyl Select from; or R 1e and R 1f are bonded to each other so as to form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic ring, which optionally is C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, NR 1i R 1j or -S(O) 0-2 R 1i R 1j wherein R 1i and R 1j is H or C 1-4 alkyl and / or R 1e and R 1f The monocyclic or bicyclic heterocyclic ring formed by 3-6 spiro-fused to a cycloalkyl or heterocyclic ring; which in turn optionally includes C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, NR 1i R 1j or -S(O) 0-2 R 1i R 1j wherein R 1i and R 1j is H or C 1-4 is alkyl; where alkyl, alkoxy or C 3-6 Any of the cycloalkyls may optionally be cyano, hydroxy, halo, NR 1k R 1l or -S(O) 0-2 R 1k R 1land further substituted with one or more substituents selected from: 1k and R 1l is H or C 1-4 It is alkyl.

[0139] (27)R 1a is the expression: -(CR 1c R 1d ) p -NR 1e R 1f is a group wherein p is an integer selected from 1 or 2; R 1c and R 1d are independently: (i) hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C 1-3 Alkoxy, Halo, C 1-3 Haloalkoxy, -OC 3-4 C substituted with one or more substituents selected from cycloalkyl or NH 1-3 alkyl; where -OC 3-6 cycloalkyl optionally substituted with halo, cyano or hydroxy; (iii) or R 1c and R 1d are bonded to each other so as to form, together with the carbon atoms to which they are attached, a 3- to 5-membered cycloalkyl or heterocyclic ring or spirocyclic ring system, each of which optionally is C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, halo or C 1-2 substituted with one or more substituents selected from haloalkoxy Selected from; R 1e teeth: (i) Hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C 1-2 Alkoxy, Halo, C 1-2C substituted with one or more substituents selected from haloalkoxy and NH 1-3 Alkyl Selected from; R 1f is the expression: -(CR 1g R 1h ) q -T1 is a group wherein q is 1, 2 or 3; R 1g and R 1h are independently: a) hydrogen (including deuterium); or b) In some cases, C 1-3 C substituted with one or more substituents selected from alkyl 1-3 alkyl, where -OC 3-6 cycloalkyl optionally substituted with halo, cyano or hydroxy; c) or R 1g and R 1h are optionally linked to each other so as to form, together with the carbon atoms to which they are attached, a 3- to 4-membered cycloalkyl or heterocyclic ring, which is optionally C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, halo or C 1-2 substituted with one or more substituents selected from haloalkoxy Selected from; And T1 is halo, C 1-4 Alkyl, C 1-4 Haloalkyl, cyano, hydroxy, NR 1t R 2t or -S(O) 0-2 R 1t R 2t (where R 1t and R 2t is H or C 1-4 alkyl), C 3-8 Cycloalkyl, C 2-3 Alkenyl, C 2-3Alkynyl, aryl, heterocyclyl, monocyclic or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C 3-8 Cycloalkyl, Bridged Bicyclic C 5-12 cycloalkyl or bridged heterocyclic ring systems, each of which is optionally C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, C 3-6 Cycloalkyl, NR 3t R 4t or -S(O) 0-2 R 3t R 4t wherein R 3t and R 4t is H or C 1-2 Is it alkyl? or R 1e and R 1f are bonded to each other so as to form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic ring, which optionally is C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C 1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, NR 1i R 1j or -S(O) 0-2 R 1i R 1j wherein R 1i and R 1j is H or C 1-4 alkyl and / or R 1e and R 1f The monocyclic or bicyclic heterocyclic ring formed by 3-6 spiro-fused to a cycloalkyl or heterocyclic ring, which in turn is optionally 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C1-4 Alkoxy, Halo, C 1-4 Haloalkoxy, NR 1i R 1j or -S(O) 0-2 R 1i R 1j wherein R 1i and R 1j is H or C 1-4 is alkyl; where alkyl, alkoxy or C 3-6 Any of the cycloalkyls may optionally be cyano, hydroxy, halo, NR 1k R 1l or -S(O) 0-2 R 1k R 1l and further substituted with one or more substituents selected from: 1k and R 1l is H or C 1-4 It is alkyl.

[0140] (28)R 1a is the expression: -(CR 1c R 1d ) p -NR 1e R 1f ; is a group wherein p is an integer selected from 1 or 2; R 1c and R 1d are independently: (i) hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C 1-3 Alkoxy, Halo, C 1-3 Haloalkoxy, -OC 3-4 C substituted with one or more substituents selected from cycloalkyl or NH 1-3 alkyl; where -OC 3-6 cycloalkyl optionally substituted with halo, cyano or hydroxy; (iii) or R 1c and R 1dare bonded to each other so as to form, together with the carbon atoms to which they are attached, a 3- to 5-membered cycloalkyl or heterocyclic ring or spirocyclic ring system, each of which optionally is C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, halo or C 1-2 substituted with one or more substituents selected from haloalkoxy Selected from; R 1e teeth: (i) Hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 C substituted with one or more substituents selected from haloalkoxy and NH 1-3 Alkyl Selected from; R 1f is the expression: -(CR 1g R 1h ) q -T1 is a group wherein q is 1 or 2; R 1g and R 1h are independently: a) hydrogen (including deuterium); or b) optionally cyano, oxo, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 C substituted with one or more substituents selected from haloalkoxy, -O-C cycloalkyl 1-3 alkyl, wherein -O-C3 cycloalkyl is optionally substituted with halo, cyano, or hydroxy; And T1 is C 1-4 Alkyl, C 3-8 Cycloalkyl, aryl, heterocyclyl, heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C 3-8 Cycloalkyl, Bridged Bicyclic C 5-12 cycloalkyl or bridged heterocyclic ring systems, each of which is optionally C1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy or C 3-6 substituted with one or more substituents selected from cycloalkyl; or R 1e and R 1f are bonded to each other so as to form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic ring, which optionally is C 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1i R 1j or -S(O) 0-2 R 1i R 1j wherein R 1i and R 1j is H or C 1-2 alkyl and / or R 1e and R 1f The monocyclic or bicyclic heterocyclic ring formed by 3-6 spiro-fused to a cycloalkyl or heterocyclic ring, which in turn is optionally 1-2 Alkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1i R 1j or -S(O) 0-2 R 1i R 1j wherein R 1i and R 1j is H or C 1-2 is alkyl; where alkyl, alkoxy or C 3-6 Any of the cycloalkyls may optionally be cyano, hydroxy, halo, NR 1k R 1lor -S(O) 0-2 R 1k R 1l and further substituted with one or more substituents selected from: 1k and R 1l is H or C 1-4 It is alkyl.

[0141] (29)R 1a is the expression: -(CR 1c R 1d ) p -NR 1e R 1f ; is a group wherein p is an integer selected from 1 or 2; R 1c and R 1d are independently: (i) hydrogen (including deuterium) or (ii) optionally cyano, oxo, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 C substituted with one or more substituents selected from haloalkoxy, -O-C cycloalkyl 1-3 Alkyl Selected from; R 1e is hydrogen (including deuterium) or C 1-2 alkyl; and R 1f is the expression: -(CR 1g R 1h ) q -T1 is a group wherein q is 1 or 2; R 1g and R 1h are independently: a) hydrogen (including deuterium); or b) optionally cyano, oxo, hydroxy, C 1-2 Alkoxy, halo or C 1-2 C substituted with one or more substituents selected from haloalkoxy 1-2 Alkyl Selected from; And T1 is C 1-4 Alkyl, C 3-8 Cycloalkyl, aryl, heterocyclyl, monocyclic or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C 3-8 Cycloalkyl, Bridged Bicyclic C 5-12 cycloalkyl or bridged heterocyclic ring systems, each of which is optionally C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy or C 3-6 substituted with one or more substituents selected from cycloalkyl; or R 1e and R 1f are bonded to each other so as to form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic ring, which optionally is C 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C 1-2 Alkoxy, halo or C 1-2 haloalkoxy and / or R 1e and R 1f The monocyclic or bicyclic heterocyclic ring formed by 3-6 spiro-fused to a cycloalkyl or heterocyclic ring, which in turn is optionally 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C 1-2 Alkoxy, halo or C 1-2 haloalkoxy; wherein alkyl, alkoxy or C 3-6 Any of the cycloalkyls may optionally be cyano, hydroxy, halo, NR 1k R 1l or -S(O) 0-2 R 1k R 1l and further substituted with one or more substituents selected from:1k and R 1l is H or C 1-4 It is alkyl.

[0142] (30)R 1a is the expression: -(CR 1c R 1d ) p -NR 1e R 1f ; is a group wherein p is an integer selected from 1 or 2; R 1c and R 1d are independently hydrogen (including deuterium) or C 1-2 alkyl; R 1e is hydrogen (including deuterium) or C 1-2 alkyl; and R 1f is the expression: -(CR 1g R 1h ) q -T1 is a group wherein q is 1 or 2; R 1g and R 1h are independently hydrogen (including deuterium) or C 1-2 alkyl; And T1 is C 1-4 Alkyl, C 3-4 Cycloalkyl, heterocyclyl, monocyclic or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C 3- Cycloalkyl, Bridged Bicyclic C 5-12 cycloalkyl or bridged heterocyclic ring systems, each of which is optionally C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy or C 3-6 substituted with one or more substituents selected from cycloalkyl; or R 1eand R 1f are bonded to each other so as to form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic ring, which optionally is C 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C 1-2 Alkoxy, halo or C 1-2 haloalkoxy and / or R 1e and R 1f The monocyclic or bicyclic heterocyclic ring formed by 3-6 spiro-fused to a cycloalkyl or heterocyclic ring, which in turn is optionally 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C 1-2 Alkoxy, halo or C 1-2 haloalkoxy; wherein alkyl, alkoxy or C 3-6 Any of the cycloalkyls may optionally be cyano, hydroxy, halo, NR 1k R 1l or -S(O) 0-2 R 1k R 1l and further substituted with one or more substituents selected from: 1k and R 1l is H or C 1-4 It is alkyl.

[0143] (31)R 1a is the expression: -(CR 1c R 1d ) p -NR 1e R 1f ; is a group wherein p is 1; R 1c and R 1d are independently hydrogen (including deuterium) or C 1-2 alkyl; R1e is hydrogen (including deuterium) or C 1-2 alkyl; and R 1f is the expression: -(CR 1g R 1h ) q -T1 is a group wherein q is 1 or 2; R 1g and R 1h are independently hydrogen (including deuterium) or C 1-2 alkyl; And T1 is C 3-4 Cycloalkyl, heterocyclyl, monocyclic or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C 3-8 Cycloalkyl, Bridged Bicyclic C 5-12 cycloalkyl or bridged heterocyclic ring systems, each of which is optionally C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy or C 3-6 substituted with one or more substituents selected from cycloalkyl; or R 1e and R 1f are bonded to each other so as to form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic ring, which optionally is C 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C 1-2 Alkoxy, halo or C 1-2 haloalkoxy and / or R 1e and R 1f The monocyclic or bicyclic heterocyclic ring formed by 3-6 spiro-fused to a cycloalkyl or heterocyclic ring; which in turn optionally includes C 1-2 Alkyl, C 1-2 Haloalkyl, C3-6 Cycloalkyl, cyano, hydroxy, C 1-2 Alkoxy, halo or C 1-2 haloalkoxy, wherein any alkyl, alkoxy or C 3-6 Cycloalkyl is optionally cyano, hydroxy, halo, NR 1k R 1l or -S(O) 0-2 R 1k R 1l and further substituted with one or more substituents selected from: 1k and R 1l is H or C 1-4 It is alkyl.

[0144] (32)R 1a is the expression: -(CR 1c R 1d ) p -NR 1e R 1f ; is a group wherein p is 1; R 1c and R 1d are independently hydrogen (including deuterium) or C 1-2 alkyl; R 1e is hydrogen (including deuterium) or C 1-2 alkyl; and R 1f is the expression: -(CR 1g R 1h ) q -T1 is a group wherein q is 1; R 1g and R 1h are independently hydrogen (including deuterium) or C 1-2 alkyl; And T1 is C 3-4 Cycloalkyl, heterocyclyl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C 3-8 Cycloalkyl, Bridged Bicyclic C5-12 cycloalkyl or bridged heterocyclic ring systems, each of which is optionally C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy or C 3-6 cycloalkyl; wherein any alkyl or alkoxy is optionally further substituted with one or more substituents selected from cyano, hydroxy, or halo.

[0145] (33)R 1a is the expression: -(CR 1c R 1d ) p -NR 1e R 1f ; is a group wherein p is 1; R 1c and R 1d are independently hydrogen (including deuterium) or C 1-2 alkyl; and R 1e and R 1f are bonded to each other so as to form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic ring, which optionally is C 1-2 Alkyl, C 1-2 Haloalkyl, C 3-6 Cycloalkyl, cyano, hydroxy, C 1-2 Alkoxy, halo or C 1-2 haloalkoxy and / or R 1e and R 1f The monocyclic or bicyclic heterocyclic ring formed by 3-6 spiro-fused to a cycloalkyl or heterocyclic ring, which in turn is optionally 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, halo or C 1-2and substituted with one or more substituents selected from haloalkoxy.

[0146] (34)R 1a teeth [ka] and where T1 is as defined herein.

[0147] (35)R 1a is the expression: [ka] is the basis of where T1 is C 3-4 Cycloalkyl, heterocyclyl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C 3-8 Cycloalkyl, Bridged Bicyclic C 5-12 cycloalkyl or bridged heterocyclic ring systems, each of which is optionally C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, halo or C 1-2 and substituted with one or more substituents selected from haloalkoxy.

[0148] (36)R 1a teeth: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from.

[0149] (37)R 1a teeth: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] is selected from.

[0150] (38)R 1a teeth: [ka] [ka] [ka] is selected from.

[0151] (39)R 1a teeth: [ka] is selected from.

[0152] (40)R 1a teeth: [ka] is selected from.

[0153] (40a)R 1a teeth: [ka] is selected from.

[0154] (41)R 1a teeth: [ka] is selected from.

[0155] (41a)R 1a teeth: [ka] is.

[0156] (41b)R 1a teeth: [ka] is.

[0157] (41c)R 1a teeth: [ka] is.

[0158] (42)R 1a teeth: [ka] is.

[0159] (43)R 1b is hydrogen, halo or C 1-2 alkyl.

[0160] (44)R 1b is hydrogen.

[0161] (45)R 1x is hydrogen, halo or C 1-2 alkyl.

[0162] (46)R 1x is hydrogen.

[0163] (47)R 2a , R 2b , R 2c and R 2d are independently hydrogen, cyano, halo, or a group of the formula: -L 2a -L 2b -Q2 wherein L 2a does not exist or in some cases C 1-2 C substituted with alkyl or oxo 1-3 is alkylene; L 2b does not exist or 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 are each independently hydrogen or C 1-2 alkyl; and Q2 is hydrogen, cyano, C 1-6 Alkyl, C 3-6cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, C 1-4 Alkyl, NR p R q , OR p , C(O)R p wherein R p and R q are each independently hydrogen or C 1-4 alkyl.

[0164] (48)R 2a , R 2b , R 2c and R 2d are independently hydrogen, cyano, halo, or a group of the formula: -L 2a -L 2b -Q2 wherein: L 2a is absent or optionally substituted with C alkyl 1-3 is alkylene; L 2b does not exist or O, S, N(R n ), C(O); and Q2 is hydrogen, cyano, C 1-6 Alkyl, C 3-6 cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, amino, cyano, and hydroxy.

[0165] (49)R 2a , R 2b , R 2c and R 2d are independently hydrogen, cyano, C 1-6 Alkoxy, C 1-6 Haloalkoxy, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C3-6 and selected from cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally substituted with one or more substituents selected from halo, trifluoromethyl, trifluoromethoxy, amino, cyano, and hydroxy.

[0166] (50)R 2a , R 2b , R 2c and R 2d are independently hydrogen, cyano, halo, or C 1-3 alkyl.

[0167] (51)R 2a , R 2b , R 2c and R 2d is independently selected from hydrogen or halo.

[0168] (52)R 2a , R 2b , R 2c and R 2d is hydrogen.

[0169] (53)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 are independently hydrogen, C 1-6 Alkyl, C 3-4 cycloalkyl, hydroxy, and halo; and C alkyl or C 3-4 cycloalkyl is optionally substituted with one or more substituents selected from halo, amino, cyano, and hydroxy; and R 3a2 , R3b2 , 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 is hydrogen.

[0170] (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 are independently hydrogen and C 1-6 and C1-6 alkyl optionally substituted with one or more hydroxy substituents.

[0171] (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 3s1is independently selected from hydrogen and methyl; and methyl is optionally substituted with one or more hydroxy substituents.

[0172] (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 is independently selected from hydrogen and methyl; and the methyl is substituted with one hydroxy substituent.

[0173] (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 , R 3r2 and R 3s2 is hydrogen.

[0174] (58)R 3a1 and R 3a2 , R 3b1 and R 3b2 , R 3c1 and R 3c2 , R 3d1 and R 3d2 , R 3e1 and R 3e2 , R 3f1 and R 3f2 , R3g1 and R 3g2 , R 3h1 and R 3h2 , R 3i1 and R 3i2、 R 3j1 and R 3j2 , R 3k1 and R 3k2 , R 3l1 and R 3l2 , R 3m1 and R 3m2 , R 3n1 and R 3n2 , R 3o1 and R 3o2 , R 3p1 and R 3p2 , R 3q1 and R 3q2 , R 3r1 and R 3r2 and R 3s1 and R 3s2 is hydrogen.

[0175] (59)R 3a1 and R 3a2 , R 3b1 and R 3b2 , R 3c1 and R 3c2 , R 3d1 and R 3d2 , R 3e1 and R 3e2 , R 3f1 and R 3f2 , R 3g1 and R 3g2 , R 3h1 and R 3h2 , R 3i1 and R 3i2、 R 3j1 and R 3j2 , R 3k1 and R 3k2 , R 3l1 and R 3l2 , R 3m1 and R 3m2 , R 3n1 and R 3n2 , R 3o1 and R 3o2 , R 3p1 and R 3p2 and R 3q1 and R3q2 , R 3r1 and R 3r2 and R 3s1 and R 3s2 is bonded to form a spiro-fused C 3-4 Forms a cycloalkyl, which is optionally substituted with one or more substituents selected from halo, amino, cyano and hydroxy.

[0176] (60) n is 0, 1 or 2.

[0177] (61) n is 1 or 2.

[0178] (62)n is 1.

[0179] (63) Y is [ka] where R 3a1 , R 3a2 and n is as defined herein.

[0180] (64) Y is [ka] where n is as defined herein.

[0181] (65) Y is [ka] where R 3b1 , R 3b2 and n is as defined herein.

[0182] (66) Y is [ka] where R 3c1 , R 3c2 and n is as defined herein.

[0183] (67) Y is [ka] where R 3d1 , R 3d2 and n is as defined herein.

[0184] (68) Y is [ka] where R 3e1 , R 3e2 and n is as defined herein.

[0185] (69) Y is [ka] is.

[0186] (70) Y is [ka] where R 3f1 , R 3f2 and n is as defined herein.

[0187] (71) Y is [ka] where R 3g1 , R 3g2 and n is as defined herein.

[0188] (72) Y is [ka] where R 3h1 , R 3h2 and n is as defined herein.

[0189] (73) Y is [ka] where R 3i1 , R 3i2 and n is as defined herein.

[0190] (74) Y is [ka] where R 3j1 , R 3j2 and n is as defined herein.

[0191] (75) Y is [ka] where R 3k1 , R 3k2 and n is as defined herein.

[0192] (76) Y is [ka] where R 3l1 , R 3l2 and n is as defined herein.

[0193] (77) Y is [ka] where R 3m1 , R 3m2 and n is as defined herein.

[0194] (78) Y is [ka] where R 3n1 , R 3n2 and n is as defined herein.

[0195] (79) Y is [ka] where R 3o1 , R 3o2 and n is as defined herein.

[0196] (80) Y is [ka] where R 3p1 , R 3p2 and n is as defined herein.

[0197] (81) Y is [ka] where R 3q1 , R 3q2 and n is as defined herein.

[0198] (82) Y is [ka] where R 3r1 , R 3r2 and n is as defined herein.

[0199] (83) Y is [ka] where R 3s1 , R 3s2 and n is as defined herein.

[0200] (84)Y is: [ka] is selected from.

[0201] (85)Y is: [ka] where R is selected from 3a1 , R 3a2 , R 3b1 , R 3b2 , R 3e1 , R 3e2 , R 3i1 , R 3i2 , R 3j1 and R 3j2 is as defined herein.

[0202] (86)Y is: [ka] is selected from.

[0203] (87)Y is: [ka] is selected from.

[0204] (88) Y is [ka] is selected from.

[0205] (89) Y is [ka] is.

[0206] (90) R4, R5 and R6 are independently selected from hydrogen and halo.

[0207] (91) R4, R5 and R6 are hydrogen.

[0208] (92) Z [ka] When R7, R9 and R 11N is independently selected from hydrogen, halo, and cyano.

[0209] (93) Z [ka] When R7, R9 and R 11N is hydrogen.

[0210] (94) Z [ka] When R8, R9, R 10 and R 11 are independently hydrogen, NH2, halo, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 1-6 Alkyl, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3 and -C(O)NR v1 R v2 where R v1 and R v2 are independently selected from hydrogen and methyl; or R and R 10 may together form a fused 5- or 6-membered saturated or unsaturated ring system, or R 10 and R 11 may be taken together to form a fused 5- or 6-membered saturated or unsaturated ring system.

[0211] (95) Z [ka] When R8, R9, R 10 and R 11 are independently hydrogen, NH2, halo, cyano, C 1-4 Alkoxy, C 1-4 Haloalkoxy and C 1-3 alkyl.

[0212] (95a)Z is [ka] When R8 is hydrogen, cyano, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3 and -C(O)NR v1 R v2 where R v1 and R v2 are independently selected from hydrogen and methyl; R is hydrogen; R 10 is halo, C 1-4 Alkoxy or C 1-4 haloalkoxy; and R 11 is hydrogen.

[0213] (96) Z [ka] When R8 is hydrogen, cyano, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3 and -C(O)NR v1 R v2 , where R v1 and R v2 are independently selected from hydrogen and methyl; R is hydrogen; R 10 is C 1-4 Alkoxy or C 1-4 haloalkoxy; and R 11 is hydrogen.

[0214] (97) Z [ka] When R is hydrogen or cyano; R is hydrogen; 10 is C 1-4 alkoxy; and R 11 is hydrogen.

[0215] (97a)Z is [ka] When R8, R9 and R 11 is hydrogen and R 10 is methoxy.

[0216] (98) Z [ka] When R8, R9, R 10 and R 11 is hydrogen.

[0217] (99)R Z1 and R Z1a is hydrogen, C 1-4 Alkyl, cyano, halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkoxy, C 3-6 Cycloalkyl and -OC 3-6 cycloalkyl, wherein C 3-6 Cycloalkyl and -OC 3-6 The cycloalkyl is optionally substituted with one or more of halo, methyl or methoxy.

[0218] (100)R Z1 and R Z1a is hydrogen, C 1-2 Alkyl, cyano, halo, C 1-2 Haloalkyl, C 1-2 Haloalkoxy, C 1-2 Alkoxy is selected from:

[0219] (101)R Z1 and R Z1a is hydrogen, C 1-2 It is selected from alkyl, cyano and halo.

[0220] (102)R Z1 and R Z1a is hydrogen.

[0221] (103)R Z2 , R Z2a , R Z3a , R Zi1b and R Zi2e are independently hydrogen, C 1-4 Alkyl, cyano, halo or C 1-4Alkoxy is selected from:

[0222] (104)R Z2 , R Z2a , R Z3a , R Zi1b and R Zi2e is independently selected from hydrogen, cyano, or halo.

[0223] (105)R Z2 , R Z2a , R Z3a , R Zi1b and R Zi2e is hydrogen.

[0224] (106)R B5N , R Y5N、 R Z2N and R 11N is selected from hydrogen or methyl.

[0225] (107)R B5N , R Y5N、 R Z2N and R 11N is hydrogen.

[0226] (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 is independently selected from hydrogen, halo, and cyano.

[0227] (109)R Z4 , R Z5 , R Z6 , R Z7 , R Z8 , R Z9 , R Z10 , R Z11 , R Z12 , R Z13 , R Z14 , R Z15and R Z16 is independently selected from hydrogen and halo.

[0228] (110)R Z4 , R Z5 , R Z6 , R Z7 , R Z8 , R Z9 , R Z10 , R Z11 , R Z12 , R Z13 , R Z14 , R Z15 , R Z16 is hydrogen.

[0229] (111) Preferably, When X6 is A1, A1 is CR 12 and; When X7 is A2, A2 is CR 13 and; B1 is A5, where A5 is CR 16 and; B2 is A6, where A6 is CR 17 and; Y2 is A7, where CR 18 and; When X6 is A8, A8 is CR 19 R 20 and; When X7 is A9, A9 is CR 22 R 23 and; X7 is A 11 When A 11 is CR 28 R 29 and; And here, 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 is as defined herein.

[0230] (112)R 12 , R 13 , R 16 , R 19 , R 20 , R 21 , R 22 and R 23 is independently selected from hydrogen, halo, cyano, and methyl.

[0231] (113)R 12 , R 13 , R 16 , R 19 , R 20 , R 21 , R 22 and R 23 is hydrogen.

[0232] (114)R 12 are hydrogen, halo, cyano and C 1-4 alkyl.

[0233] (115)R 12 is selected from hydrogen and halo.

[0234] (116)R 12 is selected from hydrogen and chloro.

[0235] (117)R 12 is hydrogen.

[0236] (118)R 13 is selected from hydrogen, halo, cyano and methyl.

[0237] (119)R 13 is hydrogen.

[0238] (120)R 13 is selected from hydrogen, methoxy and methyl.

[0239] (121)R 16 and R 18 is hydrogen, halo, cyano, C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 Haloalkyl and C 1-4 haloalkoxy.

[0240] (122)R 16 and R 18 are hydrogen, halo, cyano and C 1-4 alkyl.

[0241] (123)R 16 and R 18 is selected from hydrogen and halo.

[0242] (124)R 16 and R 18 is hydrogen.

[0243] (125)R 17 is hydrogen, halo, 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-membered or heteroaryl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclyl, -O-heterocyclyl (carbon bond), -(OCH2CH2) m -OCH3 (where m is an integer from 1 to 6), NR q R r where R q and R r are each independently hydrogen, C 1-4 Alkyl, C 3-6 cycloalkyl, 3- to 6-membered carbon-bonded heterocyclyl, or R q and R r are linked to each other so as to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered heterocyclic ring; where C 1-5 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4Alkynyl, phenyl, 5- or 6-membered or heteroaryl, C 3-6 Cycloalkyl, -OC 3-6 Any of cycloalkyl, heterocyclyl, or -O-heterocyclyl (carbon bond) may optionally be C 1-2 Alkyl, Cyano, C 1-2 Haloalkyl, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa and further substituted with one or more substituents selected from: 1ea and R 1fa is H or C 1-2 It is alkyl.

[0244] (126)R 17 is hydrogen, halo, cyano, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Haloalkoxy, C 2-3 Alkenyl, C 2-3 alkynyl, phenyl, 5- or 6-membered or heteroaryl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclyl, -O-heterocyclyl (carbon bond), -(OCH2CH2) m -OCH3 (where m is an integer from 1 to 6), NR q R r where R q and R r are each independently hydrogen, C 1-2 Alkyl or R q and R r are linked to each other so as to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered heterocyclic ring; where C 1- Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5- or 6-membered or heteroaryl, C 3-6Cycloalkyl, -OC 3-6 Any of cycloalkyl, heterocyclyl, or -O-heterocyclyl (carbon bond) may optionally be C 1-2 Alkyl, Cyano, C 1-2 Haloalkyl, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa and further substituted with one or more substituents selected from: 1ea and R 1fa is H or C 1-2 It is alkyl.

[0245] (127)R 17 is hydrogen, halo, cyano, C 1-4 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-membered heteroaryl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclyl, -O-heterocyclyl (carbon bond), -(OCH2CH2) m -OCH3 (where m is 1, 2 or 3), NR q R r where R q and R r are each independently hydrogen, C 1-4 alkyl; or R q and R r are linked to each other so as to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered heterocyclic ring; where C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5- or 6-membered or heteroaryl, C 3-6 Cycloalkyl, -OC 3-6Any of cycloalkyl, heterocyclyl, or -O-heterocyclyl (carbon bond) may optionally be C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, halo and C 1-2 It is further substituted with one or more substituents selected from haloalkoxy.

[0246] (128)R 17 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, -OC 3-4 Cycloalkyl, heterocyclyl, -(OCH2CH2) m -OCH3 (where m is 1, 2 or 3), NR q R r where R q and R r are each independently hydrogen or C 1-2 is alkyl; where C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, -OC 3-4 Both cycloalkyl and heterocyclyl systems may optionally be C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, halo and C 1-2 It is further substituted with one or more substituents selected from haloalkoxy.

[0247] (129)R 17 is hydrogen, halo, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4alkynyl and 5- or 6-membered aryl or heteroaryl; 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 alkynyl, 5- or 6-membered aryl or heteroaryl, optionally C 1-2 Alkyl, C 1-2 Haloalkyl, cyano, hydroxy, C 1-2 Alkoxy, halo and C 1-2 It is further substituted with one or more substituents selected from haloalkoxy.

[0248] (130)R 17 is hydrogen, halo, C 1-4 Alkoxy, C 2-4 Selected from alkynyl and 5- or 6-membered aryl or heteroaryl.

[0249] (131)R 17 is hydrogen, C 1-4 It is selected from alkoxy, bromo, ethynyl and pyrazole.

[0250] (132)R 28 and R 29 is selected from hydrogen or halo, methoxy and methyl.

[0251] (133)R 28 and R 29 is hydrogen.

[0252] (134)R 21 , R 24 and R 30 are independently selected from hydrogen or methyl.

[0253] (135)R 21 , R 24 and R 30 is hydrogen.

[0254] (136)Z is [ka] Selected from; where X2, X3, X4, X5, X6, X7, X8 and X9 are as defined herein.

[0255] (137)Z is [ka] and; where X2, X4, X5, X6, X7, X8 and X9 are as defined herein.

[0256] (138)Z is [ka] and; X2 is CR4; X4 is C or N; X5 is CR5; X6 is A1, where A1 is CR 12 and; X7 is A2, where A2 is CR 13 and; X8 is N or CR6, X9 is N or C; where R4, R5, R6, R 12 and R 13 is as defined herein.

[0257] (139)Z is [ka] where R 4、 R5, R6, A1 and A2 are as defined herein.

[0258] (140)Z is [ka] and; where X2, X4, X5, X6, X7, X8 and X9 are as defined herein.

[0259] (141)Z is [ka] and X2 is CR4; X4 is N; X5 is CR5: X6 is A1, where A1 is CR 12 and; X7 is A2, where A2 is CR 13 and; X8 is CR6; X9 is N or C; where R4, R5, R6, R 12 , R 13 , X7, X8 and X9 are as defined herein.

[0260] (142)Z is [ka] where R 4、 R5, R6, A1 and A2 are as defined herein.

[0261] (143)Z is [ka] where B1, B2, B3, B4, B5, B7 and B8 are as defined herein.

[0262] (144)Z is: [ka] where: B1 is A5, where A5 is N or CR 16 and; B2 is A6, where A6 is CR 17 and; B3 is N or CR Z1 and; B4 is N or C; B5 is CR zi1b or NR B5N Selected from; B7 is N, NR Z2N or CR Z2 and; B8 is selected from C or N; where R 16 , R 17 , R Z1 , R zi1b , R B5N , R Z2 is as defined herein.

[0263] (145)Z is: [ka] where: B1 is A5, where A5 is CR 16 and; B2 is A6, where A6 is CR 17 and; B3 is CR Z1 and; B4 is N or C; B5 is CR zi1b or NR B5N Selected from; B7 is N, NH or CR Z2 and; B8 is C; where R 16 , R 17 , R Z1 , R zi1b , R B5N , R Z2 is as defined herein.

[0264] (146)Z is [ka] where A5, A6, R Z1 and R Z2 is as defined herein.

[0265] (147)Z is [ka] where A5, A6, R Z1 , R Z2 and R Zi1b is as defined herein.

[0266] (148)Z is [ka] where A5, A6, R Z1 , R Z2N and R Zi1b is as defined herein.

[0267] (149)Z is [ka] where R Z1 , R Z2 , R Zi1b , A5 and A6 are as defined herein.

[0268] (150)Z is [ka] where R Z2 , A5 and A6 are as defined herein.

[0269] (151)Z is [ka] where R Z1d , R Z2d and A6 is as defined herein.

[0270] (152)Z is [ka] where Q7, Q8, Q9, Q10 and Q 11 is as defined herein.

[0271] (153)Z is [ka] where Q8, Q9, Q 10 and Q 11 is as defined herein.

[0272] (154)Z is: [ka] where R7, R8, R9, R 10 and R 11 is as defined herein.

[0273] (155)Z is [ka] where R8, R9, R 10 and R 11 is as defined herein.

[0274] (156)Z is [ka] where: R8 is hydrogen, cyano, -CH2OCH3, -CH2SO2CH3, -SO2CH3, -NHC(O)CH3 and -C(O)NR v1 R v2 where R v1 and R v2 are independently selected from hydrogen and methyl; R 10 is halo, C 1-4 Alkoxy or C 1-4 haloalkoxy; R9 and R 11 is as defined herein.

[0275] (157)Z is [ka] where R8 is hydrogen or cyano, and R 10 is C 1-4 It is an alkoxy.

[0276] (157a)Z is [ka] is.

[0277] (158)Z is [ka] is.

[0278] (159)Z is [ka] where A7, R Y5N , R Z1a , R Z2a and R Z3a is as defined herein.

[0279] (160)Z is [ka] where R4, R5, A8 and A9 are as defined herein.

[0280] (161)Z is [ka] where R4, R5, R6, A8 and A 11 is as defined herein.

[0281] (162)Z is [ka] where Q8, Q9, Q 10 and Q 11a is as defined herein.

[0282] (163)Z is [ka] where R7, R9 and R 11N is as defined herein.

[0283] (164)Z is [ka] where: X1 is N or CR Z9 and; X2 is CR4; X3 is N; X4 is C; X5 is CR5; X6 is A1, where A1 is CR 12 and; X7 is A2, where A2 is CR 13 and; X8 is N or CR6, X9 is N or C; where R Z9 , R4, R5, R6, R 12 and R 13 is as defined herein.

[0284] (165)Z is [ka] where: Y2 is A7, where A7 is CR 18 and; Y3 is N or CR Z1a and; Y4 is C or N; Y5 is NR Y5N and; Y6 is CR Zi2e or N; Y7 is CR Z2a or N; Y8 is C or N; Y9 is CR Z3a or N; where R 18 , R z1a , R Y5N , R Zi2e , R Z2a and R Z3a is as defined herein.

[0285] (166)Z is [ka] where: Y2 is A7, where A7 is CR 18 and; Y4 is C or N; Y5 is NR Y5N and; Y6 is CR Zi2e or N; Y7 is CR Z2a or N; Y8 is C or N; Y9 is CR Z3a or N; where R 18 , R z1a , R Y5N , R Zi2e , R Z2a and R Z3a is as defined herein.

[0286] (167)Z is [ka] where R Y5N , R Z1a , R Z2a , R Z3a and A7 is as defined herein.

[0287] (168)Z is [ka] where R Z1a , R Z2a , R Z3a and A7 is as defined herein.

[0288] (169)Z is [ka] where R Y5N , R Z2a , R Z3a , R Zi2e and A7 is as defined herein.

[0289] (170)Z is [ka] where R Z2a , R Z3a , R Zi2e and A7 is as defined herein.

[0290] (171)Z is [ka] where: Y2 is A7, where A7 is CR 18 and; Y4 is N; Y5 is CR Y5 and; Y6 is CR Zi2e and; Y7 is O or S; Y8 is C; Y9 is N; where R 18 , R Y5 , R Zi2e is as defined herein.

[0291] (172)Z is: [ka] where A7 and R Zi2e is as defined herein.

[0292] (173)Z is [ka] where R4, R5, R6, R Z9 , R 12 and R 13 is as defined herein.

[0293] (174)Z is [ka] where R4, R5, R6, R 19 , R 22 and R Z9 is as defined herein.

[0294] (175)Z is [ka] where X2, X3, X4, X5, X6, X7, X8 and X9 are as defined herein.

[0295] (176)Z is [ka] where R4, R5, R6, R 12 , R 13 and R Z9 is as defined herein.

[0296] (177)Z is [ka] where Z 10 , Z 11 , Z 12 , Z13 , Z 14 , Z 15 and Z 16 is as defined herein.

[0297] (178)Z is [ka] where: Z 10 is CR Z10 and; Z 11 is N; Z 12 is CR Z12 and; Z 13 is CR Z13 and; Z 14 is N or CR Z14 and; Z 15 is N or CR Z15 and; Z 16 is CR Z16 and; where R Z10 , R Z12 , R Z13 , R Z14 , R Z15 and R Z16 is as defined herein.

[0298] (179)Z is [ka] where: Z 10 is CR Z10 and; Z 11 is CR Z10 or N; Z 12 is CR Z12 and; Z 13 is CR Z13 and; Z 14 is N; Z 15 is N or CR Z1 and 5; Z 16 is CR Z16 and; where R Z10 , R Z12 , R Z13 , R Z14 , R Z15 and R Z16 is as defined herein.

[0299] (180)Z is [ka] where Z 10 , Z 12 , Z 13 , Z 14 , Z 15 and Z 16 is as defined herein.

[0300] (181)Z is [ka] where Z 13 , Z 14 , Z 15 and Z 16 is as defined herein.

[0301] (182)Z is [ka] where R Z10 , R Z12 , R Z13 , R Z14 , R Z15 and R Z16 is as defined herein.

[0302] (183)Z is [ka] where Z 10 , Z11 , Z 12 , Z 13 , Z 15 and Z 16 is as defined herein.

[0303] (184)Z is [ka] where R Z10a , R Z11a , R Z12a , R Z13a , R Z15a and R Z16a is as defined herein.

[0304] (185)Z is: [ka] where B is selected from 1、 B 2、 B 3、 B 4、 B 5、 B 7、 B 8、 Y 2、 Y 3、 Y 4、 Y 5、 Y 6、 Y 7、 Y 8、 Y 9、 X1, X2, X3, X4, X5, X6, X7, X8 and X9 are as defined herein.

[0305] (186)Z is: [ka] [ka] [ka] is selected from, where: A1, A2, A5, A 6、 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 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 is as defined herein.

[0306] (187)Z is: [ka] [ka] where A1, A2, A5, A 6、 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 is as defined herein.

[0307] (188)Z is: [ka] where A1, A2, A5, A 6、 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 is as defined herein.

[0308] (189)Z is [ka] Selected from; Here, A1, A2, A5, A 6、 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 is as defined herein.

[0309] (190)Z is [ka] where A1, A2, A5, A 6、 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 is as defined herein.

[0310] (191)Z is [ka] where R8, R 10 , R 17 , R 18 and R Z1 is as defined herein.

[0311] (192)Z is [ka] [ka] [ka] [ka] is selected from.

[0312] (193)Z is: [ka] is selected from.

[0313] Preferably, a heteroaryl or heterocyclyl group as defined herein is a monocyclic heteroaryl or heterocyclyl group containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0314] Suitably, heteroaryl is a 5- or 6-membered aryl or heteroaryl ring containing 1, 2 or 3 heteroatoms selected from N, O or S.

[0315] Preferably, the heterocyclyl group is a 4-, 5- or 6-membered heterocyclyl ring containing 1, 2 or 3 heteroatoms selected from N, O or S. Most preferably, the heterocyclyl group is a 5- or 6-membered ring containing 1, 2 or 3 heteroatoms selected from N, O or S [e.g., morpholinyl (e.g., 4-morpholinyl), oxetane, methyloxetane (e.g., 3-methyloxetane), pyrrolidinone (e.g., pyrrolidin-2-one)].

[0316] Preferably, the aryl group is phenyl.

[0317] In some embodiments, X is [ka] and; Y is: [ka] is selected from; and Z is: [ka] is selected from, where: (i)R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (ii)R 3a1 , R 3a2、 R 3b1 , R 3b2, R 3i1 , R 3i2 , R 3j1、 R 3j2 and n is as defined herein; and (iii) A1, A2, A5, A6, A7, R4, R 5、 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 is as defined herein.

[0318] In one embodiment, X is [ka] and Y is [ka] and Z is [ka] where: (i)R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (ii) n, R 3a1 , R 3a2、 R 3j1 , R 3j2 is as defined herein; and (iii) A1, A2, A5, A6, A7, R4, R 5、 R6, R8, R9, R 10 , R 11 , R Z1, R Z2 , R Z2a , R Z3a , R Zi2e , R Zi1b is as defined herein.

[0319] In one embodiment, X is [ka] and Y is [ka] and Z is [ka] where: (i)R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (ii) n, R 3a1 and R 3a2 is as defined herein; and (iii) A1, A2, A5, A6, A7, R4, R 5、 R6, R8, R9, R 10 , R 11 , R Z1 , R Z2 , R Z2a , R Z3a , R Zi2e , R Zi1b is as defined herein.

[0320] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and; where: (i)R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (ii) n, R 3j1 and R 3j2 is as defined herein; and (iii) A1, A2, A5, A6, A7, R4, R 5、 R6, R8, R9, R 10 , R 11 , R Z1 , R Z2 , R Z2a , R Z3a , R Zi2e , R Zi1b is as defined herein.

[0321] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and; (i) where R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (ii) n, R 3a1 and R 3a2 is as defined herein; and (iii) A5, A6, R Z1 and R Z2is as defined herein.

[0322] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and (i) where R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (ii) n, R 3a1 and R 3a2 is as defined herein; and (iii) A1, A2, R4, R5 and R6 are as defined herein.

[0323] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and (i) where R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (ii) n, R3a1 and R 3a2 is as defined herein; and (iii) A5, A6, R Z1 , R Zi1b and R Z2 is as defined herein.

[0324] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and (i) where R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (ii) n, R 3a1 and R 3a2 is as defined herein; and (iii)A Z6 , R Z2e , R Z3e and R Zi2e is as defined herein.

[0325] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and; (i) where R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (ii) n, R 3a1 and R 3a2 is as defined herein; and (iii) A5, A6, R Z1 and R Z2 is as defined herein.

[0326] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and (i) where R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (ii) n, R 3a1 and R 3a2 is as defined herein; and (iii) A1, A2, R4, R5 and R6 are as defined herein.

[0327] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and (i) where R 1a , R 1b、 R 2a and R 2d is as defined herein; (ii) n, R 3a1 and R 3a2 is as defined herein; and (iii) A5, A6, R Z1 , R Zi1b and R Z2 is as defined herein.

[0328] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and (iv) where R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (v)n, R 3a1 and R 3a2 is as defined herein; and (vi) A Z6 , R Z2e , R Z3e and R Zi2e is as defined herein.

[0329] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and (i) where R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (ii) n, R 3j1 and R 3j2 is as defined herein; and (iii) A5, A6, R Z1 and R Z2 is as defined herein.

[0330] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and (i) where R 1a , R 1b、 R 2a and R 2d is as defined herein; (ii) n, R 3j1 and R 3j2 is as defined herein; and (iii) A5, A6, R Z1 and R Z2 is as defined herein.

[0331] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and (i) where R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (ii) n, R 3j1 and R 3j2 is as defined herein; and (iii) A1, A2, R4, R5 and R6 are as defined herein.

[0332] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and (iv) where R 1a , R 1b、 R 2a and R2d is as defined herein; (v)n, R 3j1 and R 3j2 is as defined herein; and (vi) A1, A2, R4, R5 and R6 are as defined herein.

[0333] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and (i) where R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (ii) n, R 3j1 and R 3j2 is as defined herein; and (iii) A5, A6, R Z1 , R Zi1b and R Z2 is as defined here

[0334] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and (i) where R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (ii) n, R 3j1 and R 3j2 is as defined herein; and (iii) A5, A6, R Z1 , R Zi1b and R Z2 is as defined here

[0335] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and; where: (i)R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (ii) n, R 3j1 and R 3j2 is as defined herein; and (iii) A7, R Z2a , R Z3a and R Zi2e is as defined herein.

[0336] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and; where: (i)R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (ii) n, R 3j1 and R 3j2 is as defined herein; and (iii) A7, R Z2a , R Z3a and R Zi2e is as defined herein.

[0337] In one embodiment, X is [ka] and; Y is [ka] and Z is [ka] and; where: (iv)R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (v)n, R 3j1 and R 3j2 is as defined herein; and (vi) R8, R9, R10 and R 11 is as defined herein.

[0338] In one embodiment, X is [ka] and Y is [ka] and Z is [ka] and; where: (iv)R 1a , R 1b、 R 2a , R 2b and R 2d is as defined herein; (v)n, R 3a1 , R 3a2、 R 3j1 , R 3j2 is as defined herein; and (vi) R8, R9, R 10 , R 11 is as defined herein.

[0339] In one embodiment, When X6 is A1, A1 is CR 12 and; When X7 is A2, A2 is CR 13 and; B1 is A5, where A5 is CR 16 and; B2 is A6, where A6 is CR 17 and; Y2 is A7, where A7 is CR 18 and; When X6 is A8, A8 is CR 19 R 20 and; When X7 is A9, A9 is CR 22 R 23 and; X7 is A 11 When A 11 is CR 28 R 29 and; And here, 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 is as defined herein.

[0340] In some embodiments, A1 is CR 12 and A2 is CR 13 A5 is CR 16 A6 is CR 17 and A7 is CR 18 and A8 is CR 19 R 20 A9 is CR 22 R 23 and;A 11 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 is as defined herein.

[0341] In one embodiment, (i) R4, R5, R X5a , R X5b , R Y5、 R6, R7, R8, R9, R 10 , R 11 , R 11a , R11b , 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 is independently selected from hydrogen, methyl, cyano, or halo; and R B5N , R Y5N、 R Z2N and R 11N is selected from methyl or hydrogen; (ii)R Z1 and R Z1a is hydrogen, C 1-4 Alkyl, cyano, halo, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 Alkoxy, C 3-6 Cycloalkyl and -OC 3-6 cycloalkyl; (iii)R 12 , R 13 , R 16 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 and R 30 is independently selected from hydrogen, halo, cyano, and methyl; (iv)R 17 is hydrogen, halo, cyano, C 1-4 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-membered or heteroaryl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclyl, -(OCH2CH2)m -OCH3 (where m is an integer from 1 to 6), NR q R r where R q and R r are each independently hydrogen, C 1-4 Alkyl or R q and R r are linked to each other so as to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered heterocyclic ring; 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5- or 6-membered or heteroaryl, C 3-6 Cycloalkyl, -OC 3-6 Any of cycloalkyl, heterocyclyl, or -O-heterocyclyl (carbon bond) may optionally be C 1-2 Alkyl, Cyano, C 1-2 Haloalkyl, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa and further substituted with one or more substituents selected from: 1ea and R 1fa is H or C 1-2 is alkyl, (v)R 21 , R 24 and R 30 are independently selected from hydrogen or methyl; (vi)R 28 and R 29 is selected from hydrogen or halo, methoxy and methyl.

[0342] In one embodiment, (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 , 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 is hydrogen; (ii)R Z1 and R Z1a is hydrogen, cyano, halo, C 1-2 Haloalkyl, C 1-2 Haloalkoxy, C 1-2 Alkoxy, C 3-6 Cycloalkyl and -OC 3-6 cycloalkyl; (iii)R 12 , R 13 , R 16 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 and R 30 is hydrogen; (iv)R 17 is hydrogen, halo, cyano, C 1-2 Alkyl, C 1-2 Haloalkyl, C 1-2 Alkoxy, C 1-2 Haloalkoxy, C 2-3 Alkenyl, C 2-3 Alkynyl, phenyl, 5- or 6-membered or heteroaryl, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, heterocyclyl, -(OCH2CH2) m -OCH3 (where m is an integer from 1 to 6), NR q R r where R q and R r are each independently hydrogen, C1-2 Alkyl or R q and R r are linked to each other so as to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered heterocyclic ring; 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, phenyl, 5- or 6-membered or heteroaryl, C 3-6 Cycloalkyl, -OC 3-6 Any of cycloalkyl, heterocyclyl, or -O-heterocyclyl (carbon bond) may optionally be C 1-2 Alkyl, Cyano, C 1-2 Haloalkyl, hydroxy, C 1-2 Alkoxy, Halo, C 1-2 Haloalkoxy, NR 1ea R 1fa or -S(O) 0-2 R 1ea R 1fa and further substituted with one or more substituents selected from: 1ea and R 1fa is H or C 1-2 is alkyl (v)R 21 , R 24 and R 30 is hydrogen; (vi)R 28 and R 29 is hydrogen.

[0343] Preferably, X is as defined in paragraphs (11) to (22) above. More preferably, X is as defined in paragraphs (14), (15), (16) or (22). Most preferably, X is as defined in paragraph (22).

[0344] Preferably, Q1 is as defined in paragraphs (1) to (4) above. Most preferably, Q1 is as defined in paragraph (3) or (4).

[0345] Preferably, Q 2a is as defined in paragraph (5).

[0346] Preferably, Q 2b is as defined in paragraph (6).

[0347] Preferably, Q 2c is as defined in paragraph (7).

[0348] Preferably, Q 2d is as defined in paragraph (8).

[0349] Preferably, Q3 is as defined in paragraph (9).

[0350] Preferably, Q4 is as defined in paragraph (10).

[0351] Preferably, R 1a is as defined in paragraphs (23) to (42) above. Preferably, R 1a is as defined in any of paragraphs (30) to (35) or (36) to (42). More preferably, R 1a is as defined in any of paragraphs (32) to (35) or (40) to (42). Most preferably, R 1a is as defined in any of paragraphs (40) to (42), e.g., paragraphs (40a), (41a), (41b), (41c) or (42).

[0352] Preferably, R 1b is as defined in any of paragraphs (43) to (44). Most preferably, R 1b is as defined in paragraph (44).

[0353] Preferably, R 1x is as defined in either paragraph (45) or (46). Most preferably, R 1x is as defined in paragraph (46).

[0354] Preferably, R 2a , R 2b, R 2c and R 2d is as defined in paragraphs (47) to (52) above. Most preferably, R 2a , R 2b and R 2c is as defined in paragraph (51) or (52).

[0355] Preferably, Y is as defined in any of paragraphs (63) to (89) above. Most preferably, Y is as defined in any of paragraphs (86), (87), (88) or (89).

[0356] Preferably, n is as defined above in paragraphs (60) to (62). Most preferably, n is as defined above in paragraph (62), i.e., n is 1.

[0357] Preferably, 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 is as defined above in paragraphs (53) to (56) and paragraphs (58) to (59). Most preferably, 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 , R3p1 , R 3q1 , R 3r1 and R 3s1 is as defined in paragraph (56) or (58).

[0358] Preferably, 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 is as defined above in paragraphs (57), (58) and (59). Most preferably, 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 is as defined in paragraph (57) or (58) above.

[0359] Preferably, Z is as defined in any one of paragraphs (136) to (193) above. More preferably, Z is as defined in any one of paragraphs (187) to (193). Most preferably, Z is as defined in any one of paragraphs (190) to (193).

[0360] Preferably, R4, R5 and R6 are as defined in either paragraph (90) or (91). Most preferably, R4, R5 and R6 are as defined in paragraph (91), i.e., R4, R5 and R6 are hydrogen.

[0361] Preferably, Z is [ka] When R7, R9 and R 11N are as defined above in paragraphs (92) and (93). Most preferably, R7, R9 and R 11N is as defined in paragraph (93).

[0362] Preferably, Z is [ka] When R8, R9, R 10 and R 11 are as defined in paragraphs (94) to (98) above. More preferably, R8, R9, R 10 and R 11 are as defined in paragraphs (95) to (98) above. Most preferably, R8, R9, R 10 and R 11 is as defined in paragraph (97), (97a) or (98).

[0363] Preferably, R Z1 and R Z1a is as defined in any of paragraphs (99) to (102). Most preferably, R Z1 and R Z1a is as defined in paragraph (102).

[0364] Preferably, R Z2 , R Z2a , R Z3a , R Zi1b and R Zi2e is as defined in any of paragraphs (103) to (105). Most preferably, RZ2 , R Z2a , R Z3a , R Z3e , R Zi1b and R Zi2e is as defined in paragraph (105).

[0365] Preferably, R B5N , R Y5N、 R Z2N and R 11N is as defined in paragraph (106) or (107). Most preferably, R B5N , R Y5N、 R Z2N and R 11N is as defined in paragraph (106).

[0366] Preferably, 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 is as defined in any of paragraphs (108) to (110). Most preferably, 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 is as defined in paragraph (110).

[0367] Preferably, A1, A2, A5, A6, A7, A8, A9 and A 11 is as defined in paragraph (111).

[0368] Preferably, R 12 , R13 , R 16 , R 19 , R 20 , R 21 , R 22 and R 23 is as defined in paragraph (112) or (113) above. Most preferably, R 12 , R 13 , R 16 , R 19 , R 20 , R 21 , R 22 and R 23 is as defined in paragraph (113).

[0369] Preferably, R 12 is as defined above in paragraphs (114) to (117). Most preferably, R 12 is paragraph (117), i.e. R 12 is hydrogen as defined in

[0370] Preferably, R 13 is as defined above in paragraphs (118) to (120). Most preferably, R 13 is as defined in paragraph (119).

[0371] Preferably, R 16 and R 18 is as defined above in paragraphs (121) to (124). Most preferably, R 16 and R 18 is as defined in paragraph (124), i.e., R 16 and R 18 is hydrogen.

[0372] Preferably, R 17 is as defined above in paragraphs (125) to (131). More preferably, R 17 is as defined in any of paragraphs (128) to (131). Most preferably, R 17 is as defined in any of paragraphs (129) to (131).

[0373] Preferably, R 28 and R 29 is as defined above in paragraphs (132)-(133). Most preferably, R 28 and R 29 is as defined in paragraph (133).

[0374] Preferably, R 21 , R 24 and R 30 is as defined above in paragraphs (134)-(135). Most preferably, R 21 , R 24 and R 30 is as defined in paragraph (135).

[0375] Preferably, 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 are independently selected from hydrogen or methyl. Most preferably, R, R, 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、 RZ11 , R Z12 , R Z13 , R Z14 , R Z15 and R Z16 is hydrogen.

[0376] In a particular group of compounds of the invention, Y is as defined in paragraph (63), i.e., the compounds have the structural formula (II) (a subdefinition of formula (I)) shown below: [ka] [In the formula, X, R 3a1 , R 3a2 , n and Z each have any of the meanings defined herein. or a pharmaceutically acceptable salt thereof.

[0377] In an embodiment of the compound of formula (II), X is as defined in paragraphs (11) to (22) above; R 3a1 is as defined in paragraphs (53) to (56) and (58) to (59) above; R 3a2 is as defined in paragraphs (57), (58) and (59) above; n is as defined in paragraphs (60)-(62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0378] In an embodiment of the compound of formula (II), X is as defined in paragraph (22) above; R 3a1 is as defined in paragraph (56) above; R 3a2 is as defined in paragraph (57) above; n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0379] In a particular group of compounds of formula (II), X is as defined in paragraph (20), (21) or (22) above, and R 1a is as defined in paragraphs (23) to (42) above; R 3a1 is as defined in paragraph (56) above; R 3a2 is as defined in paragraph (57) above; n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0380] In a particular group of compounds of formula (II), X is as defined in paragraph (22) above, and R 1a is as defined in paragraphs (36) to (42) above; R 3a1 is as defined in paragraph (56) above; R 3a2 is as defined in paragraph (57) above; n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0381] In a particular group of compounds of formula (II), X is as defined in paragraph (22) above, and R 1a is as defined in paragraph (32) or (35) above; R 3a1 is as defined in paragraph (56) above; R 3a2 is as defined in paragraph (57) above; n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0382] In an embodiment of the compound of formula (II), X is as defined in paragraph (14) above; R 3a1 is as defined in paragraphs (53) to (56) and (58) to (59) above; R 3a2 is as defined in paragraphs (57), (58) and (59) above; n is as defined in paragraphs (60)-(62) above; and Z is as defined in any of paragraphs (142), (146) and (156) above.

[0383] In a particular group of compounds of the invention, Y is as defined in paragraph (73), i.e., the compounds have the structural formula (III) (a subdefinition of formula (1)) shown below: [ka] [In the formula, X, R 3i1 , R 3i2 , n and Z each have any of the meanings defined herein. or a pharmaceutically acceptable salt thereof.

[0384] In an embodiment of the compound of formula (III), X is as defined in paragraphs (11) to (22) above; R 3i1 is as defined in paragraphs (53) to (56) and (58) to (59) above; R 3i2 is as defined in paragraphs (57), (58) and (59) above; n is as defined in paragraphs (60)-(62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0385] In an embodiment of the compound of formula (III), X is as defined in paragraph (22) above; R 3i1 is as defined in paragraph (56) above; R 3i2 is as defined in paragraph (57) above; n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0386] In a particular group of compounds of formula (III), X is as defined in paragraph (20), (21) or (22) above, and R 1a is as defined in paragraphs (23) to (42) above; R 3i1 is as defined in paragraph (56) above; R 3i2 is as defined in paragraph (57) above; n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0387] In a particular group of compounds of formula (III), X is as defined in paragraph (22) above, and R 1a is as defined in paragraphs (30) to (35) or (36) to (42) above; R 3i1 is as defined in paragraph (56) above; R 3i2 is as defined in paragraph (57) above; n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0388] In a particular group of compounds of the invention, Y is as defined in paragraph (64), i.e., the compounds have the structural formula (IV) (a subdefinition of formula (1)) shown below: [ka] wherein X, n, and Z each have any of the meanings defined herein. or a pharmaceutically acceptable salt thereof.

[0389] In an embodiment of the compound of formula (IV), X is as defined in paragraphs (11) to (22) above; n is as defined in paragraphs (60)-(62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0390] In an embodiment of the compound of formula (IV), X is as defined in paragraph (22) above; n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0391] In a particular group of compounds of formula (IV), X is as defined in paragraph (20), (21) or (22) above, and R 1a is as defined in paragraphs (23) to (42) above; n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0392] In a particular group of compounds of formula (IV), X is as defined in paragraph (22) above, and R 1a is as defined in paragraphs (30) to (35) or (36) to (42) above; n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0393] In a particular group of compounds of the invention, Y is as defined in paragraph (74), i.e., the compounds have the structural formula (V) (a subdefinition of formula (1)) shown below: [ka] [In the formula, X, R 3j1 , R 3j2 , n and Z each have any of the meanings defined herein. or a pharmaceutically acceptable salt thereof.

[0394] In an embodiment of the compound of Formula (V), X is as defined in paragraphs (11) to (22) above; R 3j1 is as defined in paragraphs (53) to (56) and (58) to (59) above; R 3j2 is as defined in paragraphs (57), (58) and (59) above; n is as defined in paragraphs (60)-(62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0395] In an embodiment of the compound of Formula (V), X is as defined in paragraph (22) above; R 3j1 is as defined in paragraph (56) above; R 3j2 is as defined in paragraph (57) above; n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0396] In a particular group of compounds of formula (V), X is as defined in paragraph (20), (21) or (22) above, and R 1a is as defined in paragraphs (23) to (42) above; R 3j1 is as defined in paragraph (56) above; R 3j2 is as defined in paragraph (57) above; n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0397] In a particular group of compounds of formula (V), X is as defined in paragraph (22) above, and R 1a is as defined in paragraphs (30) to (35) or (36) to (42) above; R 3j1 is as defined in paragraph (56) above; R 3j2 is as defined in paragraph (57) above; n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0398] In a particular group of compounds of the invention, X is as defined in paragraph (15), i.e., the compounds have the structural formula (VI) (a subdefinition of formula (I)) shown below: [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , R 2d , Y and Z each have any of the meanings defined herein. or a pharmaceutically acceptable salt thereof.

[0399] In an embodiment of the compound of Formula (VI), Q1 is as defined in any of paragraphs (1) to (4); R 1a is as defined in paragraphs (23) to (42) above; R 1b is as defined in paragraphs (43)-(44) above; R 2a , R 2b and R 2d is as defined in paragraphs (47) to (52) above; Y is as defined in any of paragraphs (63) to (89) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0400] In an embodiment of the compound of Formula (VI), Q1 is as defined in either paragraph (3) or (4); R 1a is as defined in paragraphs (30) to (35) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (51) or (52); Y is as defined in paragraph (86), (87), (88) or (89) above; and Z is as defined in any of paragraphs (186) to (193) above.

[0401] In an embodiment of the compound of Formula (VI), Q1 is as defined in either paragraph (3) or (4); R 1a is as defined in paragraphs (38) to (42) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (51) or (52); Y is as defined in paragraph (86), (87), (88) or (89) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0402] In an embodiment of the compound of Formula (VI), Q1 is as defined in paragraph (3) or (4); R 1a is as defined in paragraphs (38) to (42) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (51) or (52); Y is as defined in any of paragraphs (85) to (89) above; and Z is as defined in any of paragraphs (189) to (193) above.

[0403] In a particular group of compounds of formula (VI), Q1 is as defined in paragraph (4); R 1a is as defined in paragraph (32) or (35) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (52); Y is as defined in paragraph (89) above; Z is as defined in any of paragraphs (193) above.

[0404] In a particular group of compounds of formula (XI) Q1 is as defined in paragraph (4); R 1a is as defined in paragraph (40a), (41a), (41b), (41c) or (42) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (52); Y is as defined in paragraph (89) above; and Z is as defined in paragraph (193) above.

[0405] In a particular group of compounds of the present invention, X is as defined in paragraph (15) and Y is as defined in paragraph (63), i.e., the compounds have structural formula (VII) (a subdefinition of formula (I)) as shown below: [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , R 2d , R 3a1 , R 3a2 , n and Z each have any of the meanings defined herein. or a pharmaceutically acceptable salt thereof.

[0406] In an embodiment of the compound of formula (VII), Q1 is as defined in any of paragraphs (1) to (4); R 1a is as defined in paragraphs (23) to (42) above; R 1b is as defined in paragraphs (43)-(44) above; R 2a , R 2b and R 2dis as defined in paragraphs (47) to (52) above; R 3a1 is as defined in paragraphs (53) to (56) and (58) to (59) above; R 3a2 is as defined in paragraphs (57), (58) and (59) above; n is as defined in paragraphs (60), (61) and (62) above; Z is as defined in any of paragraphs (136) to (193) above.

[0407] In an embodiment of the compound of formula (VII), Q1 is as defined in either paragraph (3) or (4); R 1a is as defined in paragraphs (30) to (35) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (51) or (52); R 3a1 is as defined in paragraph (56) above; R 3a2 is as defined in paragraph (57) above; n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (186) to (191) above.

[0408] In an embodiment of the compound of formula (VII), Q1 is as defined in either paragraph (3) or (4); R 1a is as defined in paragraphs (38) to (42) above; R 1b is as defined in paragraph (44) above; R 2a , R2b and R 2d is as defined in paragraph (51) or (52); R 3a1 is as defined in paragraph (56) above; R 3a2 is as defined in paragraph (57) above; n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0409] In an embodiment of the compound of formula (VII), Q1 is as defined in either paragraph (3) or (4); R 1a is as defined in paragraphs (38) to (42) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (51) or (52); R 3a1 is as defined in paragraph (56) above; R 3a2 is as defined in paragraph (57) above; n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (186) to (191) above.

[0410] In an embodiment of the compound of formula (VII), Q1 is as defined in either paragraph (3) or (4); R 1a is as defined in paragraph (32) or (35) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R2d is as defined in paragraph (51) or (52); R 3a1 is as defined in paragraph (56) above; R 3a2 is as defined in paragraph (57) above; n is as defined in paragraph (62) above; and Z is as defined in any of paragraphs (186) to (191) above.

[0411] In an embodiment of the compound of formula (VII), Q1 is as defined in either paragraph (3) or (4); R 1a is as defined in paragraphs (38) to (42) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (51) or (52); R 3a1 is as defined in paragraph (56) above; R 3a2 is as defined in paragraph (57) above; n is as defined in paragraph (62) above; and Z is as defined in paragraph (193) above.

[0412] In a particular group of compounds of the present invention, X is as defined in paragraph (15) and Z is as defined in paragraph (146), i.e., the compounds have the structural formula (VIII) (a subdefinition of formula (I)) shown below: [ka] [In the formula, X, R 1a , R 1b , R 2a , R 2b , R 2d, Y, A5, A6, R Z1 and R Z2 each of which has any of the meanings defined herein. or a pharmaceutically acceptable salt thereof.

[0413] In an embodiment of the compound of Formula (VIII), Q1 is as defined in any of paragraphs (1) to (4); R 1a is as defined in paragraphs (23) to (42) above; R 1b is as defined in paragraphs (43)-(44) above; R 2a , R 2b and R 2d is as defined in paragraphs (47) to (52) above; Y is as defined in any of paragraphs (63) to (89) above; R Z1 is as defined in paragraphs (99) to (102) above; R Z2 is as defined in paragraphs (103) to (105) above; A5 is CR 16 and R 16 is as defined in paragraphs (121) to (124) above; and A6 is CR 17 and R 17 is as defined in paragraphs (125) to (131) above.

[0414] In an embodiment of the compound of Formula (VIII), Q1 is as defined in paragraph (3) or (4); R 1a is as defined in paragraphs (30) to (35) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2dis as defined in paragraph (51) or (52); Y is as defined in any of paragraphs (85) to (89) above; and R Z1 is as defined in paragraphs (101)-(102) above; R Z2 is as defined in paragraphs (104)-(105) above; A5 is CR 16 and R 16 is as defined in paragraphs (123)-(124) above; and A6 is CR 17 and R 17 is as defined in paragraphs (128) to (131) above.

[0415] In an embodiment of the compound of Formula (VIII), Q1 is as defined in paragraph (3) or (4); R 1a is as defined in paragraphs (38) to (42) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (51) or (52); Y is as defined in any of paragraphs (85) to (89) above; and R Z1 is as defined in paragraphs (101)-(102) above; R Z2 is as defined in paragraphs (104)-(105) above; A5 is CR 16 and R 16 is as defined in paragraphs (123)-(124) above; and A6 is CR 17 and R 17 is as defined in paragraphs (128) to (131) above.

[0416] In a particular group of compounds of formula (VIII), Q1 is as defined in paragraph (4); R 1a is as defined in paragraph (40a), (41a), (41b), (41c) or (42) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in any of paragraphs (52); Y is as defined in paragraph (87), (88) or (89) above; R Z1 is as defined in paragraph (102) above; R Z2 is as defined in paragraph (105) above; A5 is CR 16 and R 16 is as defined in paragraph (124) above; and A6 is CR 17 and R 17 is as defined in paragraphs (130)-(131) above.

[0417] In a particular group of compounds of formula (VIII), Q1 is as defined in paragraph (4); R 1a is as defined in paragraph (32) or (35) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (52); Y is as defined in any of paragraphs (87), (88) or (89) above; R Z1 is as defined in paragraph (102) above; R Z2 is as defined in paragraph (105) above; A5 is CR 16 and R 16 is as defined in paragraph (124) above; and A6 is CR 17 and R 17 is as defined in paragraphs (130)-(131) above.

[0418] In a particular group of compounds of the present invention, X is as defined in paragraph (14), (15) or (16) and Z is as defined in paragraph (142), i.e., the compounds have the structural formula (IX) or (X) (a subdefinition of formula (I)) shown below: [ka] or [ka] [In the formula, R 1a , R 1b , R 2a , R 2b , R 2d , Q1, Y, A1, A2, R 4、 Each of R5 and R6 has any of the meanings defined herein. or a pharmaceutically acceptable salt thereof.

[0419] In an embodiment of the compound of Formula (IX), Q1 is as defined in any of paragraphs (1) to (4); R 1a is as defined in paragraphs (23) to (42) above; R 1b is as defined in paragraphs (43)-(44) above; R 2a , R 2b and R 2d is as defined in paragraphs (47) to (52) above; Y is as defined in any of paragraphs (63) to (89) above; A1 is CR 12 and R 12 is as defined in paragraphs (112), (113) or (114) to (117) above; A2 is CR 13 and R 13 is as defined in paragraphs (112), (113) or (118) to (120) above; R4 is as defined in paragraph (90) or (91) above; R5 is as defined in paragraph (90) or (91) above; and R6 is as defined in paragraph (90) or (91) above.

[0420] In an embodiment of the compound of Formula (IX), Q1 is as defined in paragraph (3) or (4); R 1a is as defined in paragraphs (30) to (35) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (51) or (52); Y is as defined in any of paragraphs (85) to (89) above; A1 is CR 12 and R 12 is as defined in paragraphs (114) to (117) above; A2 is CR 13 and R 13 is as defined in paragraph (120) above; R4 is as defined in paragraph (91) above; R5 is as defined in paragraph (91) above; and R6 is as defined in paragraph (91) above.

[0421] In an embodiment of the compound of Formula (IX), Q1 is as defined in paragraph (3) or (4); R 1a is as defined in paragraphs (38) to (42) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (51) or (52); Y is as defined in any of paragraphs (85) to (89) above; A1 is CR 12 and R 12 is as defined in paragraphs (114) to (117) above; A2 is CR 13 and R 13 is as defined in paragraph (120) above; R4 is as defined in paragraph (91) above; R5 is as defined in paragraph (91) above; and R6 is as defined in paragraph (91) above.

[0422] In an embodiment of the compound of Formula (IX), Q1 is as defined in paragraph (4); R 1a is as defined in paragraph (40a), (41a), (41b), (41c) or (42) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (52); Y is as defined in either paragraph (88) or (89) above; A1 is CR 12 and R 12is as defined in paragraphs (116) to (117) above; A2 is CR 13 and R 13 is as defined in paragraph (120) above; R4 is as defined in paragraph (91) above; R5 is as defined in paragraph (91) above; and R6 is as defined in paragraph (91) above.

[0423] In an embodiment of the compound of Formula (IX), Q1 is as defined in paragraph (4); R 1a is as defined in paragraph (32) or (35) above; R 1b is as defined in paragraph (44) above; R 2a and R 2d is as defined in paragraph (52); Y is as defined in either paragraph (88) or (89) above; A1 is CR 12 and R 12 is as defined in paragraphs (116) to (117) above; A2 is CR 13 and R 13 is as defined in paragraph (120) above; R4 is as defined in paragraph (91) above; R5 is as defined in paragraph (91) above; and R6 is as defined in paragraph (91) above.

[0424] In an embodiment of the compound of Formula (X), Q1 is as defined in any of paragraphs (1) to (4); R 1a is as defined in paragraphs (23) to (42) above; R 1bis as defined in paragraphs (43)-(44) above; R 2a and R 2d is as defined in paragraphs (47) to (52) above; Y is as defined in any of paragraphs (63) to (89) above; A1 is CR 12 and R 12 is as defined in paragraphs (112), (113) or (114) to (117) above; A2 is CR 13 and R 13 is as defined in paragraphs (112), (113) or (118) to (120) above; R4 is as defined in paragraph (90) or (91) above; R5 is as defined in paragraph (90) or (91) above; and R6 is as defined in paragraph (90) or (91) above.

[0425] In an embodiment of the compound of Formula (X), Q1 is as defined in paragraph (3) or (4); R 1a is as defined in paragraphs (38) to (42) above; R 1b is as defined in paragraph (44) above; R 2a and R 2d is as defined in paragraph (51) or (52); Y is as defined in any of paragraphs (85) to (89) above; A1 is CR 12 and R 12 is as defined in paragraphs (114) to (117) above; A2 is CR 13 and R 13 is as defined in paragraph (120) above; R4 is as defined in paragraph (91) above; R5 is as defined in paragraph (91) above; and R6 is as defined in paragraph (91) above.

[0426] In an embodiment of the compound of Formula (X), Q1 is as defined in paragraph (4); R 1a is as defined in paragraph (40a), (41a), (41b), (41c) or (42) above; R 1b is as defined in paragraph (44) above; R 2a and R 2d is as defined in paragraph (52); Y is as defined in either paragraph (88) or (89) above; A1 is CR 12 and R 12 is as defined in paragraphs (116) to (117) above; A2 is CR 13 and R 13 is as defined in paragraph (120) above; R4 is as defined in paragraph (91) above; R5 is as defined in paragraph (91) above; and R6 is as defined in paragraph (91) above.

[0427] In an embodiment of the compound of Formula (X), Q1 is as defined in paragraph (4); R 1a is as defined in paragraph (32) or (35) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (52); Y is as defined in either paragraph (88) or (89) above; A1 is CR 12 and R 12 is as defined in paragraphs (116) to (117) above; A2 is CR 13 and R 13 is as defined in paragraph (120) above; R4 is as defined in paragraph (91) above; R5 is as defined in paragraph (91) above; and R6 is as defined in paragraph (91) above.

[0428] In a particular group of compounds of the present invention, X is as defined in paragraph (15) and Z is as defined in paragraph (147), i.e., the compounds have structural formula (XI) (a subdefinition of formula (I)) as shown below: [ka] [In the formula, X, R 1a , R 1b , R 2a , R 2b , R 2d , Y, A5, A6, R Z1 , R Z2 and R Zi1b each of which has any of the meanings defined herein. or a pharmaceutically acceptable salt thereof.

[0429] In an embodiment of the compound of formula (XI), Q1 is as defined in any of paragraphs (1) to (4); R 1a is as defined in paragraphs (23) to (42) above; R 1b is as defined in paragraphs (43)-(44) above; R 2a , R 2b and R 2dis as defined in paragraphs (47) to (52) above; Y is as defined in any of paragraphs (63) to (89) above; and A5 is CR 16 and R 16 is as defined in paragraphs (121) to (124) above; A6 is CR 17 and R 17 is as defined in paragraphs (125) to (131) above; R Z1 is as defined in paragraphs (99) to (102) above; R Z2 is as defined in paragraphs (103) to (105) above; and R Zi1b is as defined in paragraphs (103) to (105) above;

[0430] In an embodiment of the compound of formula (XI), Q1 is as defined in paragraph (3) or (4); R 1a is as defined in paragraphs (38) to (42) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (51) or (52); Y is as defined in any of paragraphs (85) to (89) above; and A5 is CR 16 and R 16 is as defined in paragraphs (123)-(124) above; A6 is CR 17 and R 17 is as defined in paragraphs (128) to (131) above; R Z1 is as defined in paragraphs (101)-(102) above; RZ2 is as defined in paragraphs (104)-(105) above; and R Zi1b is as defined in paragraphs (104)-(105) above.

[0431] In an embodiment of the compound of formula (XI), Q1 is as defined in paragraph (3) or (4); R 1a is as defined in paragraphs (30) to (35) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (51) or (52); Y is as defined in any of paragraphs (85) to (89) above; and A5 is CR 16 and R 16 is as defined in paragraphs (123)-(124) above; A6 is CR 17 and R 17 is as defined in paragraphs (128) to (131) above; R Z1 is as defined in paragraphs (101)-(102) above; R Z2 is as defined in paragraphs (104)-(105) above; and R Zi1b is as defined in paragraphs (104)-(105) above.

[0432] In a particular group of compounds of formula (XI) Q1 is as defined in paragraph (4); R 1a is as defined in paragraph (40a), (41a), (41b), (41c) or (42) above; R 1bis as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (52); Y is as defined in any of paragraphs (87), (88) or (89) above; A5 is CR 16 and R 16 is as defined in paragraph (124) above; A6 is CR 17 and R 17 is as defined in paragraphs (130)-(131) above; and R Z1 is as defined in paragraph (102) above; R Z2 is as defined in paragraph (105) above; and R Zi1b is as defined in paragraph (105) above.

[0433] In a particular group of compounds of formula (XI) Q1 is as defined in paragraph (4); R 1a is as defined in paragraph (32) or (35) above; R 1b is as defined in paragraph (44) above; R 2a , R 2b and R 2d is as defined in paragraph (52); Y is as defined in any of paragraphs (87), (88) or (89) above; A5 is CR 16 and R 16 is as defined in paragraph (124) above; A6 is CR 17 and R 17 is as defined in paragraphs (130)-(131) above; and R Z1is as defined in paragraph (102) above; R Z2 is as defined in paragraph (105) above; and R Zi1b is as defined in paragraph (105) above.

[0434] In a particular group of compounds of the present invention, X is as defined in paragraph (16), i.e., the compounds have the structural formula (XII) (a subdefinition of formula (I)) shown below: [ka] [In the formula, X, R 1a , R 1b , R 2a , R 2d , Y and Z each have any of the meanings defined herein. or a pharmaceutically acceptable salt thereof.

[0435] In an embodiment of the compound of Formula (XII), Q1 is as defined in any of paragraphs (1) to (4); R 1a is as defined in paragraphs (23) to (42) above; R 1b is as defined in paragraphs (43)-(44) above; R 2a and R 2d is as defined in paragraphs (47) to (52) above; Y is as defined in any of paragraphs (63) to (89) above; and Z is as defined in any of paragraphs (136) to (193) above.

[0436] In an embodiment of the compound of Formula (XII), Q1 is as defined in paragraph (3) or (4); R 1a is as defined in paragraphs (30) to (35) above; R1b is as defined in paragraph (44) above; R 2a and R 2d is as defined in paragraph (51) or (52); Y is as defined in any of paragraphs (85) to (89) above; and Z is as defined in any of paragraphs (189) to (193) above.

[0437] In an embodiment of the compound of Formula (XII), Q1 is as defined in paragraph (3) or (4); R 1a is as defined in paragraphs (38) to (42) above; R 1b is as defined in paragraph (44) above; R 2a and R 2d is as defined in paragraph (51) or (52); Y is as defined in any of paragraphs (85) to (89) above; and Z is as defined in any of paragraphs (189) to (193) above.

[0438] In a particular group of compounds of formula (XII), Q1 is as defined in paragraph (4); R 1a is as defined in paragraph (32) or (35) above; R 1b is as defined in paragraph (44) above; R 2a and R 2d is as defined in paragraph (52); Y is as defined in paragraph (89) above; Z is as defined in any of paragraphs (193) above.

[0439] In a particular group of compounds of formula (XII), Q1 is as defined in paragraph (4); R 1a is as defined in paragraph (40a), (41a), (41b), (41c) or (42) above; R 1b is as defined in paragraph (44) above; R 2a and R 2d is as defined in paragraph (52); Y is as defined in paragraph (89) above; and Z is as defined in paragraph (193) above.

[0440] In a particular group of compounds of the invention, Z is as defined in paragraph (155), i.e. the compounds have the structural formula (XIII) (a subdefinition of formula (I)) shown below: [ka]

[0441] In an embodiment of the compound of Formula (XII), X is as defined in paragraphs (11) to (22) above; Y is as defined in any of paragraphs (63) to (89) above; and R8, R9, R 10 and R 11 is as defined in paragraphs (94) to (98) above.

[0442] In an embodiment of the compound of Formula (XIII), X is as defined in paragraph (14), (15), (16) or (22) above; Y is as defined in any of paragraphs (85) to (89) above; R8, R9, R 10 and R 11 is as defined in paragraphs (94) to (98) above.

[0443] In an embodiment of the compound of Formula (XIII), X is as defined in paragraph (14), (15), (16) or (22) above; Y is as defined in any of paragraphs (86), (87), (88) or (89); R8, R9, R 10 and R 11 is as defined in paragraphs (95a) to (97) above.

[0444] In a particular group of compounds of formula (XIII), X is as defined in paragraph (14), (15), (16) or (22) above; Y is as defined in either paragraph (88) or (89);

[0445] In a particular group of compounds of formula (XIII), X is as defined in paragraph (22) above; Y is as defined in paragraph (89); R8, R9, R 10 and R 11 is as defined in paragraph (96), (97) or (97a).

[0446] Particular compounds of the present invention include any of the compounds exemplified in this application or a pharmaceutically acceptable salt thereof, particularly any 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-azabicyclo[2.1.1]hexan-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-(3-azabicyclo[3.1.1]heptanean-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-piperidylmethyl)-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(4-fluoro-1-piperidyl)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-oxo-N-[[2-[[[rac-(1S,2S,4S)-7-oxabicyclo[2.2.1]heptan-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-[[[rac-(1S,2R,4S)-7-oxabicyclo[2.2.1]heptan-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]pentanylamino)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]heptanean-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]octan-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-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; 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-[(oxetan-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]pentanylmethylamino)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)-deuterio-methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-indazole-4-carboxamide; N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[3,2-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-(1H-indol-6-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-(1H-indol-2-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-(indolizin-2-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]methyl}-1H-indol-2-yl)methyl]cyclopropanamine; (1R,2S)-2-[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamino]cyclopentanol; N-[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methyl]cyclopentanamine; N-(cyclopropylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine; 1-[[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamino]methyl]cyclobutanol; N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine; N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-b]pyridin-2-yl]methanamine; N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine; N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine; 2-[1-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]triazol-4-yl]pyrido[1,2-a]pyrimidin-4-one; N-(cyclobutylmethyl)-1-[6-[[4-(6-methoxyimidazo[1,5-a]pyridin-8-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine; N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)imidazol-1-yl]methyl]-1H-indol-2-yl]methanamine; N-(cyclobutylmethyl)-1-[6-[[3-(1H-indazol-4-yl)-1,2,4-oxadiazol-5-yl]methyl]-1H-indol-2-yl]methanamine; N-[[2-(2-azaspiro[3.3]heptanean-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]hexan-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-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-1,3-benzodiazol-6-yl)methyl]-4-oxo-4H-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]hexan-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]hexan-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-methylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-fluoroazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(azetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({2-azaspiro[3.4]octan-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-hydroxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3,3-dimethylazetidin-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)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[3-(difluoromethyl)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-methoxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[3-(tert-butoxy)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-oxo-N-[(2-{[3-(trifluoromethyl)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-ethoxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({2-azaspiro[3.5]nonan-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(2-methylazetidin-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]heptanean-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]heptanean-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-cyclobutylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-cyclopropylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-tert-butylazetidin-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-trimethylbutan-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-diethylazetidin-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]octan-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-({octahydrocyclopenta[c]pyrrol-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({5-azaspiro[2.4]heptanean-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]hexan-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]octan-6-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({2-azaspiro[4.4]nonan-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]hexan-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-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; N-({2-[(tert-butylamino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-(1-{[2-({2-azaspiro[3.3]heptanean-2-yl}methyl)-1H-indol-6-yl]methyl}-1H-1,2,3-triazol-4-yl)-1H-indazole; N-{[2-(2-{2-azaspiro[3.3]heptanean-2-yl}ethyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; ({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; N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-7-carboxamide; 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; 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; N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-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-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 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; N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-c].ylidene-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; (cyclobutylmethyl)({6-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-imidazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine; (cyclobutylmethyl)({6-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine; N-[(2-{[(2,2-dimethylpropyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; (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; N-[[2-(2-azabicyclo[2.2.1]heptanean-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methyl]-1-[6-[(4-imidazo[1,5-a]pyridin-8-yltriazol-1-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine; (cyclobutylmethyl)[(6-{[1-(1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine; [(3,3-difluorocyclobutyl)methyl][(6-{[1-(1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine; (cyclobutylmethyl)[(6-{[1-(isoquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine; (cyclobutylmethyl)({6-[(1-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-4-yl)methyl]-1H-indol-2-yl}methyl)amine; 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-pyridinecarbonitrile; 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-pyridinecarbonitrile; 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-pyridinecarbonitrile; 3-{1-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarbonitrile; 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-pyridinecarbonitrile; 3-[1-({2-[(4,4-dimethyl-1-piperidyl)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile; N-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 3-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-5-fluoropicolinonitrile; 1-Cyclobutyl-N-((6-((4-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine; 5-chloro-3-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)picolinonitrile; 2-((6-Azaspiro[3.4]octan-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.

[0447] Further compounds of the invention, or pharmaceutically acceptable salts thereof, include any of the following: 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-pyridinecarbonitrile; 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-pyridinecarbonitrile; 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-pyridinecarbonitrile; 3-{1-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarbonitrile; 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-pyridinecarbonitrile; and 3-[1-({2-[(4,4-dimethyl-1-piperidyl)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile.

[0448] Particular compounds of the present invention include any of the compounds exemplified in this application or a pharmaceutically acceptable salt thereof, particularly any of the following: 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-[(4,4-dimethyl-1-piperidyl)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; N-(cyclobutylmethyl)-1-[6-[[4-(1H-pyrazolo[4,3-c]pyridin-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine; N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine; N-(cyclobutylmethyl)-1-[6-[[4-(1H-pyrrolo[2,3-b]pyridin-5-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine; 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]pentanylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; 1-[[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamino]methyl]cyclobutanol; N-[[2-[[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-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-[(3,3-difluorocyclobutyl)methyl]-1-[6-[[1-(1H-indazol-4-yl)triazol-4-yl]methyl]-1H-indol-2-yl]methanamine; N-[[2-[(oxetan-2-ylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-indazole-4-carboxamide; N-[[2-[[(1-fluorocyclobutyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(cyclobutylmethylamino)methyl]-3H-benzimidazol-5-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-(cyclobutylmethyl)-1-[6-[[1-(4-isoquinolyl)triazol-4-yl]methyl]-1H-indol-2-yl]methanamine; 4-oxo-N-[[2-[(prop-2-ynylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(2,2-dimethylpropylamino)methyl]-1H-indol-6-yl]methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; N-[[2-[(cyclopropylmethylamino)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.

[0449] The various functional groups and substituents comprising the compound of formula (I) are generally selected so that the molecular weight of the compound of formula (I) does not exceed 1000. More typically, the molecular weight of the compound is 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.

[0450] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts of compounds of the present invention that are sufficiently basic, for example, acid addition salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of compounds of the present invention that are sufficiently acidic are alkali metal salts, for example, sodium or potassium salts, alkaline earth metal salts, for example, calcium or magnesium salts, ammonium salts or salts with organic bases that provide a pharmaceutically acceptable cation, for example, salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0451] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and those that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of the asymmetric center and are designated as dextrorotatory or levorotatory (i.e., (+)- or (-)-isomers, respectively) according to the Cahn-Prelog R- and S-sequencing rules or even by the direction in which the molecule rotates the plane of polarized light. Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0452] The compounds of the present invention may have one or more asymmetric centers; such compounds can therefore be prepared as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise specified, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and racemic or other mixtures. Methods for determining stereochemistry and separating stereoisomers, for example, by synthesis from optically active starting materials or by resolution of racemates, are well known in the art (see Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present invention may have geometric isomeric centers (E- and Z-isomers). It is understood that the present invention includes all optical, diastereomeric, and geometric isomers and mixtures thereof that have antiproliferative activity.

[0453] The present invention also includes compounds of the invention as defined herein that contain one or more isotopic substitutions. For example, H is 1 H, 2 H(D) and 3H(T) may be in any isotopic form; 12 C. 13 C and 14 and O may be any isotopic form, including C; 16 O and 18 It may be in any isotopic form, including O;

[0454] It is also understood that the compounds of formula (I) (and compounds of formulas (II), (III), and (IV)) can exist in solvated as well as unsolvated forms, such as, for example, hydrated forms. It is understood that the present invention encompasses all such solvated forms that possess antiproliferative activity.

[0455] It is understood that certain compounds of formula (I) (and compounds of formulas (II), (III) and (IV)) may exhibit polymorphism, and the invention encompasses all such forms which possess antiproliferative activity.

[0456] Compounds of formula (I) (and compounds of formulae (II), (III), and (IV)) can exist in a number of different tautomeric forms, and references to compounds of formula (I) include all such forms. For the avoidance of doubt, where a compound may exist in one of several tautomeric forms and only one is specifically described or shown, all others are nevertheless intended to be encompassed by formula (I). Examples of tautomeric forms include keto, enol, and enolate forms, for example, as in the following tautomeric pairs: keto / enol (described below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acinitro. [ka]

[0457] Compounds of formula (I) containing an amine functional group may also form N-oxides. The description of compounds of formula (I) containing an amine functional group herein also includes N-oxides. When a compound contains several amine functional groups, one or more of the nitrogen atoms may be oxidized to form an N-oxide. Specific examples of N-oxides are the N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides may be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), as described, for example, in Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 101-104. More specifically, N-oxides can be prepared by the method of LW Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0458] The compounds of formula (I) may be administered in the form of prodrugs, which are broken down in the human or animal body to release the compounds of the present invention. Prodrugs may be used to alter the physical and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs may be formed when the compounds of the present invention contain a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include in vivo cleavable ester derivatives that may be formed at a carboxy or hydroxy group in the compounds of formula (I) and in vivo cleavable amide derivatives that may be formed at a carboxy or amino group in the compounds of formula (I).

[0459] The present invention therefore includes compounds of formula I as defined above when made available by organic synthesis and when made available in the human or animal body by way of cleavage of a prodrug thereof. The present invention therefore includes compounds of formula (I) prepared by organic synthetic means and also such compounds produced in the human or animal body by way of metabolism of a precursor compound, i.e., compounds of formula (I) can be synthetically produced compounds or metabolically produced compounds.

[0460] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) are those that, based on sound medical judgment, are suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity.

[0461] Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology , Vol. 42 , p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b)Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c)A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews , 8 , 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences , 77 , 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull. , 32 , 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACS Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0462] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) having a carboxy group are, for example, in vivo cleavable esters thereof. In vivo cleavable esters of compounds of formula (I) containing a carboxy group are, for example, pharmaceutically acceptable esters that are cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include C 1-6 Alkyl esters, such as methyl, ethyl and tert-butyl, C 1-6 Alkoxymethyl esters, such as methoxymethyl esters, C 1-6 Alkanoyloxymethyl esters, such as pivaloyloxymethyl esters, 3-phthalidyl esters, C 3-8 Cycloalkylcarbonyloxy-C 1-6 Alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl ester, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester and C 1-6 Alkoxycarbonyloxy-C 1-6 Alkyl esters include, for example, methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters.

[0463] Suitable pharmaceutically acceptable prodrugs of a compound of formula (I) having a hydroxy group are, for example, in vivo cleavable esters or ethers thereof. An in vivo cleavable ester or ether of a compound of formula (I) containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether that is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups of a hydroxy group include inorganic esters, such as phosphate esters (including phosphoramido cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups of a hydroxy group include C1-10 Alkanoyl groups, such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C 1-10 Alkoxycarbonyl groups, such as ethoxycarbonyl, N,N-(C 1-6 ) 2 carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of ring substituents for the phenylacetyl and benzoyl groups are aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1-4 Suitable pharmaceutically acceptable ether-forming groups of a hydroxy group include α-acyloxyalkyl groups, for example acetoxymethyl and pivaloyloxymethyl groups.

[0464] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) having a carboxy group include, for example, in vivo cleavable amides thereof, e.g. amines, e.g. ammonia, C 1-4 Alkylamines, such as methylamine (C 1-4 alkyl)2amines, 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 Amides formed with alkylamines, such as benzylamine, and amino acids, such as glycine or its esters.

[0465] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) having an amino group include, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example, C 1-10 Alkanoyl groups include acetyl, benzoyl, phenylacetyl, and substituted benzoyl and amides formed with phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups are aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-4 alkyl)piperazin-1-ylmethyl.

[0466] The in vivo effects of compounds of formula (I) may be exerted in part by one or more metabolites formed in the human or animal body following administration of a compound of formula (I). As noted above, the in vivo effects of compounds of formula (I) may also be exerted by metabolism of a precursor compound (prodrug).

[0467] While the present invention may relate to any compound or particular group of compounds as otherwise defined herein in terms of any, preferred or suitable property or particular embodiment, the present invention also relates to any compound or particular group of compounds that is specifically excluded from that any, preferred or suitable property or particular embodiment.

[0468] Preferably, the present invention excludes any individual compound that does not have biological activity as defined herein.

[0469] manufacturing The compounds of the present invention may be prepared by any suitable technique known in the art. Specific methods for preparing these compounds are further described in the accompanying Examples.

[0470] With respect to the description of the synthetic methods described herein and any referenced synthetic methods used to prepare starting materials, it is understood that all proposed reaction conditions, including the choice of solvents, reaction atmospheres, reaction temperatures, experimental times, and work-up procedures, can be selected by one of ordinary skill in the art.

[0471] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions employed.

[0472] It will be understood that during the synthesis of the compounds of the invention or of particular starting materials in the processes defined herein, it may be desirable to protect certain substituents to prevent undesired reactions. The skilled chemist will recognize when such protection is necessary and how such protecting groups can be placed and subsequently removed.

[0473] For examples of protecting groups, see one of the many relevant general textbooks, for example 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons). Protecting groups can be removed by any conventional method described in the literature or known by a skilled chemist to be suitable for removing the protecting group in question, such method being chosen so as to effect removal of the protecting group with minimal interference with groups elsewhere in the molecule.

[0474] Thus, when reactants contain groups such as amino, carboxy or hydroxy, it may be desirable to protect these groups in some of the reactions mentioned herein.

[0475] By way of example, suitable protecting groups for amino or alkylamino groups include, for example, acyl groups, such as alkanoyl groups, e.g., acetyl; alkoxycarbonyl groups, e.g., methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl; arylmethoxycarbonyl groups, e.g., benzyloxycarbonyl; or aroyl groups, e.g., benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, acyl groups, e.g., alkanoyl or alkoxycarbonyl groups, or aroyl groups, can be removed by hydrolysis with a suitable base, e.g., an alkali metal hydroxide, e.g., lithium hydroxide or sodium hydroxide. Alternatively, acyl groups, e.g., tert-butoxycarbonyl groups, can be removed by treatment with a suitable acid, e.g., hydrochloric acid, sulfuric acid, or phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups, e.g., benzyloxycarbonyl groups, can be removed by hydrogenation over a catalyst such as palladium on carbon or treatment with a Lewis acid, e.g., boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0476] Suitable protecting groups for hydroxy groups include, for example, acyl groups, such as alkanoyl groups, e.g., acetyl; aroyl groups, e.g., benzoyl; or arylmethyl groups, e.g., benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, acyl groups, e.g., alkanoyl or aroyl groups, can be removed by hydrolysis with a suitable base, such as an alkali metal hydroxide, e.g., lithium, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups, e.g., benzyl groups, can be removed by hydrogenation over a catalyst, e.g., palladium on carbon.

[0477] Suitable protecting groups for carboxy groups are, for example, an esterifying group, such as a methyl or ethyl group, which may be removed by hydrolysis with a base such as sodium hydroxide, for example, a t-butyl group which may be removed by treatment with an acid, for example an organic acid such as trifluoroacetic acid, and a benzyl group, for example, which may be removed by hydrogenation over a catalyst such as palladium on carbon.

[0478] Resins may also be used as protecting groups.

[0479] The method used to synthesize the compounds of formula I will vary depending on the nature of the variables. Suitable methods for preparation are further described in the accompanying examples.

[0480] Once a compound of formula I has been synthesized by any of the methods defined herein, the method then proceeds to: (i) removal of any protecting groups present; (ii) converting a compound of formula I into another compound of formula I; (iii) the formation of a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) Formation of a prodrug thereof The method may further comprise the additional step of:

[0481] The resulting compound of formula I can be isolated and purified using techniques well known in the art.

[0482] biological activity The pharmacological effects of compounds of the present invention may be measured using the METTL3 enzyme and cellular assays described in the accompanying Examples section.

[0483] Although the pharmacological properties of compounds of formula I vary with structural variation, as would be expected, compounds of the present invention were found to be active in the METTL3 assay.

[0484] Generally, compounds of the present invention have an IC of 10 μM or less in the METTL3 enzyme assay described herein. 50 and preferred compounds of the present invention exhibit an IC50 and most preferred compounds of the present invention exhibit an IC 50 Shows.

[0485] In the METTL3 cell assay described in the Examples section, compounds of formula (I) suitably exhibit activity of 10 μM, with preferred compounds of the invention exhibiting IC values ​​of 5 μM or less. 50 and most preferred compounds show an activity of 2 μM or less.

[0486] Pharmaceutical Composition According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the invention as hereinbefore defined, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0487] Compositions of the invention may be in a form 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), administration by inhalation (e.g., as a fine powder or liquid aerosol), administration by insufflation (e.g., as a fine powder) or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration or as a suppository for rectal administration).

[0488] The compositions of the invention may be obtained in a conventional manner using conventional pharmaceutical additives well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0489] An effective amount of a compound of the invention for use in therapy is an amount sufficient to treat or prevent the proliferative conditions and / or autoimmune diseases described herein, slow the progression of and / or reduce the symptoms associated with the conditions and / or diseases.

[0490] The amount of active ingredient combined with one or more additives to produce a single dosage form will necessarily vary depending on the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain 0.5 mg to 0.5 g of active agent (more preferably 0.5 to 100 mg, e.g., 1 to 30 mg), mixed with an appropriate and convenient amount of additive, which may vary, for example, from about 5 to about 98 percent by weight of the total composition.

[0491] The dose of the compounds of formula (I) for therapeutic or prophylactic purposes will vary essentially with the nature and severity of the condition, the age and sex of the animal or patient and the route of administration, in accordance with well-known principles of medicine.

[0492] When using the compounds of the present invention for therapeutic or prophylactic purposes, they are generally administered so that a daily dose ranging, for example, from 0.1 mg / kg to 75 mg / kg of body weight is administered, and if necessary, in divided doses. When parenteral routes are used, lower doses are generally administered. Thus, for example, for intravenous or intraperitoneal administration, a dose ranging, for example, from 0.1 mg / kg to 30 mg / kg of body weight is generally used. Similarly, for administration by inhalation, a dose ranging, for example, from 0.05 mg / kg to 25 mg / kg of body weight is used. Oral administration, particularly in tablet form, may also be appropriate. Generally, a unit dosage form contains about 0.5 mg to 0.5 g of the compound of the present invention.

[0493] Therapeutic Uses and Applications The present invention provides compounds that function as inhibitors of METTL3 activity.

[0494] Thus, the present invention provides a method for inhibiting METTL3 activity in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0495] The present invention also provides a method of treating a disease or disorder associated with METTL3 activity in a patient in need thereof, 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. Preferably, the disease or disorder associated with METTL3 activity is cancer, such as lung cancer, kidney cancer, solid organ cancer, pancreatic cancer or leukemia, type 2 diabetes, a neuropsychiatric-related behavioral disorder, an infection (e.g., a viral infection), or a depressive disorder.

[0496] The present invention provides a method for inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0497] The present invention provides a method for treating a proliferative disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0498] The present invention provides a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition. Preferably, the cancer is lung cancer, kidney cancer, solid organ cancer, pancreatic cancer or leukemia, preferably AML leukemia or chronic myeloid leukemia.

[0499] The present invention provides a method for treating leukemia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0500] The present invention provides a method for treating AML leukemia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0501] The present invention provides a method for treating an autoimmune disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Preferably, the autoimmune disease is colitis, multiple sclerosis, rheumatoid arthritis, lupus, cirrhosis, or dermatitis.

[0502] The present invention provides a method for treating a neurological-related disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0503] The present invention provides a method for treating an infectious disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0504] In another aspect, the present invention provides a method for treating a viral infection, comprising administering to a subject in need thereof an effective amount of a therapeutically effective compound or pharmaceutically acceptable salt thereof as defined herein, or a pharmaceutical composition as defined herein. Preferably, the viral infection is an RNA virus infection. Preferably, the viral infection is human papillomavirus (HPV) or hepatitis.

[0505] The present invention provides a method for treating an inflammatory disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0506] METTL3 inhibitors may also be useful as therapeutic agents for treating diseases associated with reactivation of the silenced X chromosome (Patil et al., Nature, 2016 Sep 15;537(7620):369-373). That is, they may be effective therapeutic agents for treating Rett syndrome.

[0507] The present invention further provides a method for treating a disease associated with reactivation of a silenced X chromosome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0508] The present invention further provides a method for treating Rett Syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition.

[0509] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in therapy.

[0510] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of a proliferative condition.

[0511] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating cancer. In certain embodiments, the cancer is a human cancer. Preferably, the cancer is lung cancer, kidney cancer, solid organ cancer, pancreatic cancer, or leukemia, preferably AML leukemia or chronic myeloid leukemia.

[0512] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of leukemia.

[0513] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of AML leukemia.

[0514] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in inhibiting METTL3 activity.

[0515] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of an autoimmune disease, preferably wherein the autoimmune disease is colitis, multiple sclerosis, rheumatoid arthritis, lupus, cirrhosis, or dermatitis.

[0516] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of a neurological-related disease.

[0517] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of infectious disease.

[0518] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the treatment of inflammatory diseases.

[0519] In another aspect, the present invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in treating a viral infection. Preferably, the viral infection is an RNA viral infection. Preferably, the viral infection is human papillomavirus (HPV) or hepatitis.

[0520] The present invention provides a compound as defined herein or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder associated with METTL3 activity. Preferably, the disease or disorder associated with METTL3 activity is cancer, such as lung cancer, kidney cancer, solid organ cancer, pancreatic cancer or leukemia, type 2 diabetes, a neuropsychiatric-related behavioral disorder or a depressive disorder.

[0521] The present invention provides a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in treating a disease associated with reactivation of a silenced X chromosome.

[0522] The present invention provides a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein, for use in the treatment of Rett Syndrome.

[0523] The invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a proliferative condition.

[0524] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. Preferably, the medicament is for use in the treatment of human cancer. Preferably, the cancer is lung cancer, kidney cancer, solid organ cancer, pancreatic cancer, or leukemia, preferably AML leukemia or chronic myeloid leukemia.

[0525] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of leukemia.

[0526] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of AML leukemia.

[0527] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an autoimmune disease, preferably the autoimmune disease is colitis, multiple sclerosis, rheumatoid arthritis, lupus, cirrhosis or dermatitis.

[0528] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neurological-related disorder.

[0529] The invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an inflammatory disease.

[0530] In another aspect, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating a viral infection. Preferably, the viral infection is an RNA viral infection. Preferably, the viral infection is human papillomavirus (HPV) or hepatitis.

[0531] The invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an infectious disease.

[0532] The invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the inhibition of METTL3 activity.

[0533] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with METTL3 activity. Preferably, the disease or disorder associated with METTL3 activity is cancer, such as lung cancer, kidney cancer, solid organ cancer, pancreatic cancer or leukemia, type 2 diabetes, a neuropsychiatric-related behavioral disorder or a depressive disorder.

[0534] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with reactivation of a silenced X chromosome.

[0535] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of Rett Syndrome.

[0536] The term "proliferative disorder" is used interchangeably herein and refers to unwanted or uncontrolled cell proliferation of unwanted, excessive, or abnormal cells, such as neoplastic or hyperplastic growth, whether in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, premalignant and malignant cell proliferation, including, but not limited to, malignant neoplasms and tumors, cancer, leukemia, psoriasis, bone disease, fibroproliferative disorders (e.g., of connective tissue), and atherosclerosis. Cells of any type can be treated, including, but not limited to, lung, colon, breast, ovary, prostate, liver, pancreas, brain, and skin.

[0537] The antiproliferative effects of the compounds of the present invention have particular application in the treatment of human cancers (by inhibiting METTL3 activity).

[0538] The anti-cancer effect may occur through one or more mechanisms, including, but not limited to, cell proliferation control, inhibition of angiogenesis (new blood vessel formation), inhibition of metastasis (spread of a tumor from its origin), invasion (spread of tumor cells into nearby normal structures), or promotion of apoptosis (programmed cell death).

[0539] In certain embodiments of the invention, the proliferative condition to be treated is cancer.

[0540] Route of administration The compounds of the present invention or pharmaceutical compositions containing these compounds may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (ie, at the site of desired action).

[0541] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by patches, plasters, etc.); transmucosal (including, e.g., by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., via the oral or nasal cavity, e.g., by aerosol, e.g., by inhalation or insufflation therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, by injection, including, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intrathecal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; and implantation of a depot or reservoir, e.g., subcutaneously or intramuscularly.

[0542] Combination therapy The antiproliferative treatment as defined above may be applied as the sole treatment or may include, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of antitumor agents: (i) Other antiproliferative / antineoplastic drugs and their combinations used in medical oncology, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide, and nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates, such as fluoropyrimidines, e.g., 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumor antibiotics (e.g., anthracyclines, Cyclins such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin; mitotic inhibitors (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids such as taxol and taxotere, and polokinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, and camptothecin); (ii) cytostatics, such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and idoxifene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or agonists (e.g., goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and 5α-reductase inhibitors, such as finasteride; (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}thiazole-5-carboxamide (dasatinib, BMS-354825); J. Med. Chem. , 2004, 47 , 6658-6661) and bosutinib (SKI-606) and metalloproteinase inhibitors, such as marimastat, urokinase plasminogen activator receptor function inhibitors or antibodies against heparanase]; (iv) Growth factor function inhibitors: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., the anti-erbB2 antibody trastuzumab [Herceptin TM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225], and 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, e.g., N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774), and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors, e.g., lapatinib; hepatocyte growth factor family inhibitors; insulin growth factor family inhibitors; platelet-derived growth factor family inhibitors, e.g., imatinib and / or nilotinib (AMN107); serine / threonine kinase inhibitors (e.g., Ras / Raf signaling inhibitors, e.g., farnesyltransferase inhibitors, e.g., 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, including CDK2 and / or CDK4 inhibitors; (v) Antiangiogenic agents, such as those that inhibit the effects of vascular endothelial growth factor [e.g., anti-vascular endothelial growth factor antibody bevacizumab (Avastin)] TM) and, for example, VEGF receptor tyrosine kinase inhibitors, such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 in WO00 / 47212), compounds such as those disclosed in International Patent Applications WO97 / 22596, WO97 / 30035, WO97 / 32856 and WO98 / 13354 and compounds acting by other mechanisms (e.g. linomide, integrin αvβ3 function inhibitors and angiostatin)]; (vi) vascular damaging agents, such as combretastatin A4 and compounds disclosed in International Patent Applications WO99 / 02166, WO00 / 40529, WO00 / 41669, WO01 / 92224, WO02 / 04434 and WO02 / 08213; (vii) endothelin receptor antagonists, such as zibotentan (ZD4054) or atrasentan; (viii) antisense therapy, e.g., directed against the targets listed above, e.g., ISIS 2503, anti-ras antisense; (ix) gene therapy approaches, including, for example, approaches that replace abnormal genes, such as abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) approaches, such as those that use cytosine deaminase, thymidine kinase, or bacterial nitroreductase enzymes, and approaches that increase patient tolerance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; (x) immunotherapy methods, including, for example, ex vivo and in vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines, e.g., interleukin 2, interleukin 4, or granulocyte-macrophage colony-stimulating factor, approaches to reduce T-cell anergy, approaches using transfected immune cells, e.g., cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines, and approaches using anti-idiotypic antibodies; and (xi) Agents for treating AML leukemia, including, for example, cytarabine, FLT3 inhibitors, BCL2 inhibitors (e.g., venetoclax), or IDH1 / 2 inhibitors.

[0543] In certain embodiments, the antiproliferative treatment as defined herein above may comprise, in addition to the compounds of the present invention, conventional surgery or radiotherapy or chemotherapy.

[0544] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range noted above and the other pharmaceutically active agent within its approved dosage range.

[0545] According to this aspect of the invention there is provided a combination for use in the treatment of cancer (e.g. cancers involving solid tumours) comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt thereof, and another anti-tumour agent.

[0546] According to this aspect of the invention there is provided a combination for use in the treatment of a proliferative condition such as cancer (e.g. cancers including solid tumours), comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt thereof, and any of the anti-tumour agents listed above.

[0547] In a further aspect of the invention there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer, optionally in combination with another anti-tumour agent selected from one of the above-listed agents.

[0548] It is understood herein that when the term "combination" is used, this refers to simultaneous, separate, or sequential administration. In some embodiments of the invention, "combination" refers to simultaneous administration. In other embodiments of the invention, "combination" refers to separate administration. In a further embodiment of the invention, "combination" refers to sequential administration. When administration is sequential or separate, the delay in administration of the second component should not be such that the beneficial effect of the combination is lost.

[0549] According to a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in combination with an anti-tumour agent (optionally selected from one of those listed above), together with a pharmaceutically acceptable diluent or carrier.

[0550] In another embodiment, the invention relates to a therapeutic combination comprising a compound as defined herein and another agent used in the treatment of AML leukemia, such as cytarabine, an FLT3 inhibitor, a BCL2 inhibitor, or an IDH1 / 2 inhibitor. Preferably, the agent used in the treatment of AML leukemia is a BCL2 inhibitor, such as venetoclax. [Example]

[0551] The following abbreviations are used in the examples: AIBN - Azobisisobutyronitrile DBU - 1,8-diazabicyclo[5.4.0]undec-7-ene DCE - dichloroethane DCM - dichloromethane DIBAL - Diisobutylaluminum hydride DIPEA - N-Ethyl-N-isopropyl-propan-2-amine DMAP - 4-dimethylaminopyridine DMF - dimethylformamide DMSO - Dimethyl Sulfoxide DPPA - diphenylphosphoryl azide HATU - [Dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethyl-ammonium; hexafluorophosphate HPLC - High Performance Liquid Chromatography IPA - Isopropanol LCMS - Liquid Chromatography Mass Spectrometry NBS - N-Bromosuccinimide NMP - N-methyl-2-pyrrolidone Phase Separation Cartridge - Telos Phase Separator 6mL RBF - Round Bottom Flask RM - reaction mixture RT - retention time STAB - Sodium triacetoxyborohydride T3P - Propylphosphonic Anhydride TBAF - Tetra-n-butylammonium fluoride TEA - Triethylamine TFA - Trifluoroacetic acid TFAA - Trifluoroacetic Anhydride THF - tetrahydrofuran

[0552] In the examples the following methods are used: LCMS Method A refers to a low pH separation using a mobile phase consisting of 0.1% formic acid in an aqueous gradient of 5 to 100% MeCN over 1.2 minutes at a flow rate of 1.2 mL / min. The stationary phase consisted of Kinetex Core-Shell C18, 2.1 mm x 50 mm, 5 μm. Experiments were performed at 40 °C.

[0553] LCMS method B refers to a high pH separation using a mobile phase consisting of 2 mM ammonium bicarbonate buffered to pH 10 in a gradient of 5 to 100% MeCN in water over 2.1 minutes at a flow rate of 1.0 mL / min. The stationary phase consisted of Phenomenex Gemini-NX C18, 2.0 x 50 mm, 3 μm. The run was performed at 40 °C.

[0554] LCMS method C refers to a high pH separation using a mobile phase consisting of 2 mM ammonium bicarbonate buffered to pH 10 in an aqueous gradient of 5 to 100% MeCN over 5.8 minutes at a flow rate of 0.6 mL / min. The stationary phase consisted of a Waters UPLC® BEH™ C18, 2.1 x 100 mm, 1.7 μm. Experiments were performed at 40°C.

[0555] LCMS method D refers to a high pH separation using a mobile phase consisting of 2 mM ammonium bicarbonate buffered to pH 10 in an aqueous gradient of 5 to 100% MeCN over 5.9 minutes at a flow rate of 0.6 mL / min. The stationary phase consisted of Phenomenex Gemini-NX C18, 2.0 x 100 mm, 3 μm. The run was performed at 40 °C.

[0556] LCMS method E refers to a low pH separation using a mobile phase consisting of 0.1% formic acid in an aqueous gradient of 5 to 100% MeCN over 5.3 minutes at a flow rate of 0.6 mL / min. The stationary phase consisted of Phenomenex Kinetix-XB C18, 2.1 mm x 100 mm, 1.7 μm. The run was performed at 40 °C.

[0557] LCMS method F refers to a high pH separation using a mobile phase consisting of 2 mM ammonium bicarbonate buffered to pH 10 in an aqueous gradient of 5 to 100% MeCN over 0.75 minutes at a flow rate of 1.0 mL / min. The stationary phase consisted of a Waters UPLC® BEH™ C18, 2.1 x 100 mm, 1.7 μm. Experiments were performed at 40°C.

[0558] Method G refers to a low pH separation using a mobile phase consisting of 0.1% formic acid (pH = 2.70) in a gradient of 3 to 100% 0.1% formic acid:acetonitrile (10:90) solution over 3.00 minutes at a flow rate of 0.8 mL / min. The stationary phase consisted of a C18, 50*2.1 mm, 1.6 μm column. The experiment was performed at 35°C.

[0559] Method H refers to a high pH separation using a mobile phase consisting of 5 mM ammonium bicarbonate (pH 7.35) in a gradient of aqueous MeCN over 3.0 minutes at a flow rate of 0.5 mL / min. The stationary phase consisted of C18, 50*2.1 mm, 2.5 μm. The run was performed at 35°C.

[0560] Method I refers to a high pH separation using a mobile phase consisting of 5 mM ammonium bicarbonate (pH 7.35) in a gradient of aqueous MeCN over 3.0 minutes at a flow rate of 0.5 mL / min. The stationary phase consisted of C18, 50*2.1 mm, 2.5 μm. The experiment was performed at 35°C.

[0561] Method J refers to a high pH separation using a mobile phase consisting of 2 mM ammonium bicarbonate buffered to pH 10 in a gradient of 1 to 100% MeCN over 1.35 minutes at a flow rate of 1 mL / min. The stationary phase consisted of a Waters UPLC® BEH™ C18 2.1 x 30 mm, 1.7 μm. Experiments were performed at 40°C.

[0562] Method K refers to a low pH separation using a mobile phase consisting of 0.1% formic acid in water in a gradient of 5-100% 0.1% formic acid in water:0.1% formic acid in acetonitrile over 5.4 minutes at a flow rate of 0.6 mL / min. The stationary phase consisted of Phenomenex Kinetex Core-Shell C8 50 x 2.1 mm, 2.6 μm (protected by a "security guard" column). Experiments were performed at 40 °C.

[0563] Method L refers to a low pH separation using a mobile phase consisting of 0.1% formic acid in water in a gradient of 5-100% 0.1% formic acid in water:0.1% formic acid in acetonitrile over 1.1 minutes at a flow rate of 0.9 mL / min. The stationary phase consisted of a Waters UPLC® BEH™ C18 2.1 x 50 mm, 1.7 μm. Experiments were performed at 40°C.

[0564] Method M refers to a low pH separation using a mobile phase consisting of 0.1% formic acid in water in a gradient of 5-100% 0.1% formic acid in water:0.1% formic acid in acetonitrile over 2.25 minutes at a flow rate of 1.2 mL / min. The stationary phase consisted of Phenomenex Kinetex Core-Shell C8 50 x 2.1 mm, 2.6 μm. Experiments were performed at 40°C.

[0565] LC04_ABF3 refers to a high pH separation using a mobile phase consisting of 5 mM ammonium bicarbonate buffered to pH 10 in a gradient of 50 to 100% acetonitrile in water over 2.70 minutes at a flow rate of 1.0 mL / min. The stationary phase consisted of a Waters UPLC® C18 4.6 x 50 mm, 3.5 μm. The experiment was performed at 30°C.

[0566] LC04_ABR2 refers to a high pH analysis using a mobile phase consisting of 5 mM ammonium bicarbonate buffered to pH 10 in a gradient of 10 to 100% acetonitrile in water over 9.0 minutes at a flow rate of 1.0 mL / min. The stationary phase was a Waters UPLC® BEH TM It consisted of a C18 4.6 x 150 mm, 3.5 μm. The experiment was carried out at 30°C.

[0567] LC03_ABR2 refers to a high pH separation using a mobile phase consisting of 5 mM ammonium bicarbonate buffered to pH 10 in a gradient of 3 to 100% acetonitrile in water over 3.0 minutes at a flow rate of 0.5 mL / min. The stationary phase was a Waters UPLC® BEH TM It consisted of C18 2.1 x 50 mm, 2.5 μm. The experiment was carried out at 30°C.

[0568] UC02_FAR1 refers to a low pH separation using a mobile phase consisting of 0.1% aqueous formic acid (pH=2.70) in a gradient of 3-100% aqueous 0.1% formic acid:acetonitrile (10:90) over 3.00 minutes at a flow rate of 0.8 mL / min. The stationary phase was a Waters UPLC® BEH TMIt consisted of C18 2.1 x 50 mm, 2.5 μm. The experiment was carried out at 30°C.

[0569] In the examples, the following preparative HPLC method is used: Preparative method A refers to a low pH purification using a mobile phase consisting of 0.1% formic acid in a gradient of 10 to 95% MeCN in water over 14.4 minutes at a flow rate of 40 mL / min. The stationary phase consisted of a Waters Sunfire C18, 30 x 100 mm, 10 μm.

[0570] Preparative method B refers to a high pH purification using a mobile phase consisting of 0.2% ammonium hydroxide in an aqueous gradient of 30 to 95% MeCN over 10 minutes at a flow rate of 40 mL / min. The stationary phase consisted of Waters XBridge™ C18 OBD™, 30 x 100 mm, 10 μm.

[0571] Intermediate 1: 4-Oxopyrido[1,2-a]pyrimidine-2-carboxylic acid [ka] Methyl 4-oxopyrido[1,2-a]pyrimidine-2-carboxylate [Tetrahedron (2014), 70(17), 2761-2765] (3.94 g, 19.3 mmol) was dissolved in hydrogen chloride solution (8 M, 7.5 mL) at room temperature (the addition was exothermic), and the mixture was heated to reflux for 2 hours. The mixture was cooled to room temperature, and the precipitate was collected by filtration and dried under reduced pressure to give the title compound (3.00 g, 81%) as a white solid. Method A: LC-MS (electrospray): m / z=191.1 (M+H) + , RT=0.32 minutes

[0572] 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 [ka] Step 1: 2-(4,4-dimethylpiperidine-1-carbonyl)-1H-indole-6-carbonitrile [ka] 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), and the mixture was stirred at ambient temperature for 5 minutes. 4,4-Dimethylpiperidine hydrochloride (292 mg, 1.95 mmol) was then added, and the mixture was stirred at ambient temperature for 1 hour. The mixture was extracted with EtOAc and HO, the layers were separated, and the mixture was extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine, dried over MgSO, and concentrated. Purification by basic reverse-phase HPLC afforded the title compound (100 mg, 20%) as a yellow solid. Method A: LC-MS (electrospray): m / z = 281.95 (M+H) + , RT=1.20 minutes

[0573] Step 2: [2-[(4,4-dimethyl-1-piperidyl)methyl]-1H-indol-6-yl]methanamine [ka] Lithium aluminum hydride (2 M in THF, 0.22 mL, 0.44 mmol) was added to a solution of 2-(4,4-dimethylpiperidine-1-carbonyl)-1H-indole-6-carbonitrile (100 mg, 0.355 mmol) in anhydrous THF (2 mL) at 0 °C. The mixture was stirred at 0 °C, then warmed to room temperature and stirred for 1 h. Additional lithium aluminum hydride (2 M in THF, 0.22 mL, 0.44 mmol) was added, and the mixture was stirred at ambient temperature for 67 h. The reaction was cooled to 0 °C and treated dropwise with HO (2 mL), NaOH (1 M, 2 mL), and HO (6 mL). The mixture was stirred for 10 min, filtered, and the filter cake was washed with THF. The filtrate was concentrated and purified by acidic reverse-phase chromatography to give the title compound (86 mg, 89%) as a yellow solid. Method A: LC-MS (electrospray): m / z=272.1 (M+H) + , RT=0.31 min

[0574] 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 [ka] 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 minutes. [2-[(4,4-dimethyl-1-piperidyl)methyl]-1H-indol-6-yl]methanamine (48 mg, 0.18 mmol) was then added, and the mixture was stirred at ambient temperature for 1 hour. An additional 45 mg of HATU was added, and stirring was continued for 2 hours. The mixture was partitioned between EtOAc and HO. The layers were separated, and the mixture was extracted with EtOAc (3 × 10 mL). The organic layer was washed with brine, dried over MgSO, and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Method B) to give the title compound (4.0 mg, 5.1%) as a white solid. Method B: LC-MS (electrospray): m / z=444.3 (M+H) + , RT=4.59 minutes

[0575] Example 2: N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] Step 1: 3-amino-4-(3,3-diethoxyprop-1-yn-1-yl)benzonitrile [ka] 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) was added Pd(PPh)Cl (230 mg, 0.328 mmol) and triphenylphosphine (172 mg, 0.656 mmol) at ambient temperature. The solution was degassed by bubbling nitrogen through the solution for 20 minutes. Copper(I) iodide (125 mg, 0.66 mmol) and 3,3-diethoxyprop-1-yne (5.04 g, 39.3 mmol) were then added sequentially, and the reaction was stirred under a nitrogen atmosphere for 18 hours. The precipitate (triethylamine hydrochloride) was filtered off and washed with EtOAc (approximately 20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Biotage KP-Sil 100 g, eluting with 0-50% EtOAc in heptane). The product-containing fractions were combined and concentrated under reduced pressure to give the title compound (8.19 g, quantitative) as an orange oil. Method B: LC-MS (electrospray): m / z=262.3 (M+H) + , RT=1.65 minutes

[0576] Step 2: 2-(diethoxymethyl)-1H-indole-6-carbonitrile [ka] To a stirred solution of 3-amino-4-(3,3-diethoxyprop-1-ynyl)benzonitrile (8.00 g, 31.1 mmol) in NMP (99 mL) was added potassium tert-butoxide (6.98 g, 62.2 mmol) at 0 °C (the color of the solution changed from orange to dark red). After warming to RT, the solution was stirred at ambient temperature for 16 h. Saturated aqueous ammonium chloride solution (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 more with water (2 × 200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a brown oil. The original aqueous layer was re-extracted 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 reduced pressure to give an orange oil. The crude material was purified by SiO2 chromatography [Biotage KP-Sil 100 g, eluting with 0-50% EtOAc in heptane]. Product-containing fractions were combined and concentrated under reduced pressure. The residue (yellow solid) was recrystallized from EtOAc / heptane to give the title compound (5.86 g, 24.0 mmol, 77%) as a colorless crystalline solid. Method B: LC-MS (electrospray): m / z=262.3 (M+H) + , RT=1.69 minutes

[0577] Step 3: [2-(diethoxymethyl)-1H-indol-6-yl]methanamine [ka] To a degassed solution of 2-(diethoxymethyl)-1H-indole-6-carbonitrile (5.8 g, 24 mmol) in ethanol (70 mL) was added ammonia in MeOH (7 M, 20 mL, 0.14 mmol), and the reaction was degassed and refilled with nitrogen three times. Raney nickel (estimated 50%, approximately 5.4 g, 0.1 mmol) was added, and the reaction was degassed and refilled with nitrogen three times. The flask was evacuated one final time, placed under a hydrogen atmosphere, and stirred at ambient temperature for 3 hours. Additional Raney nickel (approximately 2.7 g) was added, and the reaction was evacuated, placed under a hydrogen atmosphere, and stirred at ambient temperature for 16 hours. The catalyst was removed by filtration (through diatomaceous earth) 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 solidified upon standing. Method C: LC-MS (electrospray): m / z = 247.3 (M−H) - , RT=2.74 minutes

[0578] Step 4: N-[(2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] To a stirring 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) was added HATU (910 mg, 2.39 mmol). A color change from colorless to green was observed, and a suspension formed. After stirring at ambient temperature for an additional 30 minutes, a solution of [2-(diethoxymethyl)-1H-indol-6-yl]methanamine (500 mg, 1.99 mmol) in DMF (5 mL) was added dropwise to the reaction. A color change from green to red was observed, and the reaction became homogeneous and was allowed to stir at ambient temperature overnight. The mixture was partitioned between EtOAc (100 mL) and saturated NaHCO solution (50 mL). The organic layer was separated, washed with water (80 mL) and brine (20 mL), dried (NaSO), filtered, and concentrated under reduced pressure to give a viscous red oil. 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. The THF was removed under reduced pressure, and water (10 mL) was added to the resulting mixture to precipitate more solids. The brown solid was collected with water (2 × 5 mL), filtered, washed with ether (3 × 5 mL), and dried under reduced pressure to give the title compound (520 mg, 75%) as a brown solid. Method C: LC-MS (electrospray): m / z=347.2 (M+H) + , RT=2.37 minutes

[0579] Step 5: N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] A pressure vial was charged with 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-cyclobutylmethanamine (0.13 mL, 1.0 mmol) at ambient temperature. The vial was sealed, and the mixture was stirred at 65°C for 2 h. After cooling to RT, sodium triacetoxyborohydride (340 mg, 1.85 mmol) was added, and the mixture was heated at 65°C for 2 h. The mixture was partitioned between EtOAc (40 mL) and saturated sodium bicarbonate solution (30 mL). The organic layer was separated, washed with brine (20 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The residue (pale yellow oil) was purified by reverse-phase chromatography (basic method, SNAP ULTRA 30 g cartridge, eluting with MeCN + 0.1% NH / HO + 0.1% NH, 10-90%). Fractions containing the desired product were lyophilized overnight to afford the title compound (85 mg, 38%) as an off-white solid. Method C: LC-MS (electrospray): m / z=416.4 (M+H) + , RT=3.14 minutes

[0580] Example 6: N-[[2-[[(1-methylcyclopropyl)methylamino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] (1-Methylcyclopropyl)methanamine 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 DCE (7 mL) in a pressure vial, and the RM was stirred at 60 °C for 3 h. (1-Methylcyclopropyl)methanamine hydrochloride (70 mg, 0.577 mmol) was added along with N-ethyl-N-isopropyl-propan-2-amine (0.30 mL, 1.73 mmol), and the reaction was stirred at 60 °C for 1 h. The mixture was cooled to room temperature and added dropwise over 5 min to a solution of NaBH (11 mg, 0.289 mmol) in ethanol (2.5 mL). The mixture was stirred at ambient temperature overnight. A solution of NaBH4 (11 mg, 0.289 mmol) in ethanol (2.5 mL) was added dropwise and the reaction was stirred at ambient temperature for an additional 1 h. The mixture was quenched with water (30 mL), extracted with DCM (3 x 40 mL), passed through a Telos phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method B) and the product-containing fractions were combined, concentrated under reduced pressure and lyophilized overnight to give the title compound (70 mg, 59%) as a pale yellow solid. Method C: LC-MS (electrospray): m / z=416.5 (M+H) + , RT=3.16 minutes

[0581] The compounds in Table 1 were prepared in the same manner as in Examples 2 and 3 using commercially available amines or the intermediates listed. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16]

[0582] Example 42: 4-Oxo-N-[[2-[(2,2,2-trifluoroethylamino)methyl]-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide [ka] 2,2,2-Trifluoroethanamine (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 Example 2, Step 4 (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, treated with additional 2,2,2-trifluoroethanamine (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 NaBH (18 mg, 0.476 mmol) in ethanol (2 mL). The mixture was stirred at ambient temperature overnight. To the mixture was added NaBH4 (18 mg, 0.476 mmol) and stirred at ambient temperature for 1 hour 15 minutes. The mixture was quenched with water (30 mL) and extracted with DCM (3 x 40 mL). The combined organic layers were passed through an Isolute phase separator and concentrated under reduced pressure. The crude material was purified by preparative HPLC (Method B) to give the title compound (40.2 mg, 59%) as an off-white solid. Method C: LC-MS (electrospray): m / z=430.3 (M+H) + , RT=2.94 minutes

[0583] Example 70: N-[[2-[[cyclobutylmethyl(methyl)amino]methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] 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) was added N-ethyl-N-isopropyl-propan-2-amine (0.25 mL, 1.44 mmol) and methyl iodide (30 μL, 0.481 mmol) at ambient temperature, 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 product-containing fractions 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. Method C: LC-MS (electrospray): m / z=430.4 (M+H) + , RT=3.62 minutes

[0584] Example 43: N-[(2-{[N-(cyclobutylmethyl)acetamido]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] 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-propan-2-amine (0.18 mL, 1.05 mmol) in DCM (5 mL) was added acetic anhydride (36 μL, 0.385 mmol) 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. Method E: LC-MS (electrospray): m / z=458.2 (M+H) + , RT=3.01 minutes

[0585] Example 44: 4-oxo-N-{[2-(piperidin-2-yl)-1H-indol-6-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] Step 1: tert-butyl 2-[2-(2-amino-4-cyano-phenyl)ethynyl]piperidine-1-carboxylate [ka] 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), bis(triphenylphosphine)palladium(II) chloride (30 mg, 0.0430 mmol) and triphenylphosphine (23 mg, 0.0861 mmol) were added at room temperature. The solution was degassed by bubbling nitrogen through it for 15 minutes. Copper(I) iodide (16 mg, 0.0861 mmol) and tert-butyl 2-ethynylpiperidine-1-carboxylate (0.99 g, 4.73 mmol) were then added sequentially, and the reaction was stirred under a nitrogen atmosphere for 4 hours. The precipitate (triethylamine hydroiodide) was collected by filtration and washed with EtOAc (approximately 20 mL). The combined filtrates were concentrated under reduced pressure, and the residue was purified by SiO2 chromatography (eluting with 0-50% EtOAc in heptane). The product-containing fractions were combined and concentrated under reduced pressure. The orange solid was triturated with heptane. The resulting solid was collected by filtration, washed with heptane (approximately 25 mL), and dried in a vacuum oven at 45 °C for 2 h to afford the title compound (1.03 g, 70%) as a white solid. Method C: LC-MS (electrospray): m / z = 651.5 (2M+H) + , RT = 4.21 min

[0586] Step 2: tert-butyl 2-(6-cyano-1H-indol-2-yl)piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl 2-[2-(2-amino-4-cyano-phenyl)ethynyl]piperidine-1-carboxylate (1.00 g, 3.07 mmol) in anhydrous NMP (12 mL) was added potassium 2-methylpropan-2-olide (0.69 g, 6.15 mmol) at 0 °C (the solution color changed from colorless to orange within seconds). After warming to room temperature under a nitrogen atmosphere for 16 h, 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 (NaSO), filtered, and concentrated under reduced pressure. The residue (brown solid) was purified by SiO chromatography (eluting with 0–50% EtOAc in heptane). The product-containing fractions were combined and concentrated under reduced pressure. The residue (an orange solid) was triturated 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. Method C: LC-MS (electrospray): m / z=326.3 (M+H) + , RT=4.19 minutes

[0587] Step 3: tert-butyl 2-[6-(aminomethyl)-1H-indol-2-yl]piperidine-1-carboxylate [ka] The title compound (785 mg, 83%) was prepared from tert-butyl 2-(6-cyano-1H-indol-2-yl)piperidine-1-carboxylate using the chemistry described in Example 2, Step 3. Method E: LC-MS (electrospray): m / z=330.2 (M+H) + , RT=2.22 minutes

[0588] Step 4: tert-butyl 2-{6-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)methyl]-1H-indol-2-yl}piperidine-1-carboxylate [ka] To a solution of 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (135 mg, 0.711 mmol) (Intermediate 1), N-ethyl-N-isopropyl-propan-2-amine (0.11 mL, 0.647 mmol), and tert-butyl 2-[6-(aminomethyl)-1H-indol-2-yl]piperidine-1-carboxylate (213 mg, 0.647 mmol) in anhydrous DMF (4 mL) was added HATU (246 mg, 0.647 mmol), and the mixture was stirred at ambient temperature for 2 h. 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 (NaSO), filtered, and concentrated to dryness under reduced pressure. The residue was purified by SiO chromatography (eluting with 0–100% EtOAc in heptane). Product-containing fractions were combined and concentrated under reduced pressure to give the title compound (313 mg, 92%) as a yellow oil. Method C: LC-MS (electrospray): m / z=502.4 (M+H) + , RT=3.89 minutes

[0589] Step 5: 4-oxo-N-{[2-(piperidin-2-yl)-1H-indol-6-yl]methyl}-4H-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] A solution of tert-butyl 2-{6-[({4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl}formamido)methyl]-1H-indol-2-yl}piperidine-1-carboxylate (96%, 313 mg, 0.599 mmol) in 4 M HCl (4.5 mL) in dioxane was stirred at 40° C. for 2 h [the solution turned dark red and gas evolution ceased]. The mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was dissolved in MeOH (3 mL) and subjected to preparative HPLC (Method B). Product-containing fractions were combined and concentrated to dryness under reduced pressure. 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. Method C: LC-MS (electrospray): m / z=402.5 (M+H) + , RT=2.77 minutes

[0590] Example 45: N-[(2-{[(cyclobutylmethyl)amino]methyl}-3-fluoro-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] Step 1: N-[(3-fluoro-2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] To a solution of N-[(2-formyl-1H-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide (95%, 530 mg, 1.45 mmol) in anhydrous NMP (10 mL) was added 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (515 mg, 1.45 mmol) 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 (NaSO), and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method B). Product-containing fractions were combined and concentrated to dryness to give the title compound (97 mg, 15%) as a beige solid. Method C: LC-MS (electrospray): m / z=365.3 (M+H) + , RT=2.60 minutes

[0591] Step 2: N-[(2-{[(cyclobutylmethyl)amino]methyl}-3-fluoro-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] The title compound (40 mg, 43.5%) was prepared in the same manner as in Example 2, Step 5. Method C: LC-MS (electrospray): m / z=434.4 (M+H) + , RT=3.29 minutes

[0592] Example 46: N-[(2-{[(cyclobutylmethyl)amino]methyl}-1-methyl-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] Step 1: 2-(diethoxymethyl)-1-methyl-1H-indole-6-carbonitrile [ka] To a slurry of sodium hydride (60%, 266 mg, 6.65 mmol) in DMF (1 mL) at 0 °C was added a solution of 2-(diethoxymethyl)-1H-indole-6-carbonitrile (650 mg, 2.66 mmol) in DMF (1 mL). The reaction was allowed to warm to room temperature for 10 minutes and then re-cooled to 0 °C. Methyl iodide (0.33 mL, 5.32 mmol) was added dropwise to the slurry and the reaction was stirred at 0 °C for 5 minutes and then warmed to room temperature. The reaction was stirred for 1 hour. The mixture was cooled to 0 °C and quenched by the dropwise addition of water (3 mL). 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, washed with brine (5 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product as a yellow oil. The crude material was purified by SiO.sub.2 chromatography [0-50% EtOAc / heptane] to afford the title compound (624 mg, 90%) as a white solid. Method B: LC-MS (electrospray): m / z=259.1 (M+H) + , RT=0.68 min

[0593] Step 2: 1-[2-(diethoxymethyl)-1-methyl-1H-indol-6-yl]methanamine [ka] The title compound (570 mg, 90%) was prepared in the same manner as in Example 2, Step 3. Method B: LC-MS (electrospray): m / z=263.3 (M+H) + , RT=1.75 minutes

[0594] Step 3: N-[(2-formyl-1-methyl-indol-6-yl)methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] T3P (50%, 1.6 mL, 2.61 mmol) was added to a mixture of 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (454 mg, 2.39 mmol) (Intermediate 1), [2-(diethoxymethyl)-1-methyl-indol-6-yl]methanamine (570 mg, 2.17 mmol), and DIPEA (1.9 mL, 10.9 mmol) in DMF (10 mL), and the mixture was stirred at ambient temperature overnight. The mixture was further 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 h. The mixture was extracted with DCM and HO, the layers were separated, and the mixture was extracted with DCM (3 × 10 mL). The organic layer was passed through a Telos phase separator and concentrated. The crude material was purified by SiO.sub.2 chromatography [0-100% EtOAc / heptane] to afford the title compound (369 mg, 46%) as an off-white solid. Method A: LC-MS (electrospray): m / z=361.1 (M+H) + , RT=1.06 minutes

[0595] Step 4: N-[(2-{[(cyclobutylmethyl)amino]methyl}-1-methyl-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] 1-Cyclobutylmethanamine (87 mg, 1.02 mmol) was added to a solution of N-[(2-formyl-1-methyl-indol-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-Cyclobutylmethanamine (87 mg, 1.02 mmol) was added, and the mixture was stirred at ambient temperature for 1 hour. The mixture was then heated at 40°C for 2 hours. Additional 1-cyclobutylmethanamine (87 mg, 1.02 mmol) was added, and the mixture was stirred at ambient temperature overnight. NaBH4 (58 mg, 1.53 mmol) was added, 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 reduced pressure. The residue was partitioned between saturated NaHCO3 (aq) (10 mL) and DCM (10 mL) and the phases were separated. The aqueous phase was extracted with DCM (2 x 10 mL) and the combined organic phases were passed through a Telos phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC (Method B) to give the title compound (119 mg, 54.3%) as a pale yellow solid. Method C: LC-MS (electrospray): m / z=430.6 (M+H) + , RT=3.42 minutes

[0596] Example 47: N-[[2-[(cyclobutylmethylamino)-deuterio-methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] Step 1: 6-cyano-1H-indole-2-carboxylic acid [ka] To a suspension of methyl 6-cyano-1H-indole-2-carboxylate (1.00 g, 5.00 mmol) in MeOH (15 mL) was added 1 M sodium hydroxide (7.5 mL, 7.49 mmol) at ambient temperature. The mixture was stirred at 40 °C for 2 hours. After cooling to room temperature, the reaction was acidified with 2 M HCl (5 mL) and water (20 mL) was added. The resulting precipitate was collected by vacuum filtration, washed with water (50 mL), and dried in a vacuum oven at 45 °C overnight to give the title compound (926 mg, 95%) as a pale yellow solid. Method A: LC-MS (electrospray): m / z = 185.2 (M−H) − , RT = 0.98 min

[0597] Step 2: 6-cyano-N-(cyclobutylmethyl)-1H-indole-2-carboxamide [ka] To a solution of 6-cyano-1H-indole-2-carboxylic acid (97%, 626 mg, 3.26 mmol) in DMF (5 mL) was added di(imidazol-1-yl)methanone (529 mg, 3.26 mmol) at ambient temperature. The mixture was stirred at 70°C (considerable gas evolution) for 1 hour. The mixture was cooled to room temperature, and 1-cyclobutylmethanamine (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. To the filtrate was added water (50 mL) and diethyl ether (50 mL) with stirring. The resulting precipitate was collected by vacuum filtration, washed with water (20 mL) and diethyl ether (20 mL), and dried in a vacuum oven at 45°C overnight to give the title compound (550 mg, 63%) as an off-white solid. Method A: LC-MS (electrospray): m / z = 253.9 (M+H) + , RT=1.14 minutes

[0598] Step 3: 6-(aminomethyl)-N-(cyclobutylmethyl)-1H-indole-2-carboxamide [ka] The title compound (487 mg, 94%) was prepared in the same manner as in Example 2, Step 3. Method C: LC-MS (electrospray): m / z=258.1 (M+H) + , RT=2.56 minutes

[0599] Step 4: 1-[6-(aminomethyl)-1H-indol-2-yl]-N-(cyclobutylmethyl)-1,1-deuterio-methanamine [ka] Chilled (ice bath) lithium tetrahydride ( 2 To a suspension of (H4) aluminate (1-) (221 mg, 5.83 mmol) in anhydrous 1,4-dioxane (5 mL), 6-(aminomethyl)-N-(cyclobutylmethyl)-1H-indole-2-carboxamide (150 mg, 0.583 mmol) was added in one portion. The ice bath was removed, and the mixture was stirred at reflux for 3 h (heating block temperature 110 °C). The mixture was cooled to 0 °C (ice bath) and quenched by the dropwise addition of a mixture of THF (10 mL) and water (1 mL), followed by 2 M NaOH (0.2 mL). The mixture was stirred for 30 min at ambient temperature. The solids were removed by filtration (diatomaceous earth) 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 resulting 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. Method C: LC-MS (electrospray): m / z=246.2 (M+H) + , RT=2.96 minutes

[0600] Step 5: N-[[2-[(cyclobutylmethylamino)-deuterio-methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] To a solution of 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (78 mg, 0.408 mmol) (Intermediate 1), 1-[6-(aminomethyl)-1H-indol-2-yl]-N-(cyclobutylmethyl)-1,1-deuterio-methanamine (86%, 116 mg, 0.408 mmol), and DIPEA (0.21 mL, 1.22 mmol) in DMF (3 mL) was added HATU (170 mg, 0.448 mmol). The reaction was stirred at ambient temperature overnight. The mixture was partitioned between EtOAc (600 mL) and saturated NaHCO solution (20 mL). The organic layer was separated, washed with brine (10 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by open access preparative HPLC method A. The product-containing fractions were combined and concentrated under reduced pressure (water bath temperature 45°C, pressure 100 mbar) until most of the acetonitrile was removed. The clear solution was basified with saturated aqueous sodium carbonate solution and extracted with 3:1 chloroform / 2-propanol (3 x 40 mL). The combined extracts were washed with brine (40 mL), dried (Na2SO4), filtered, and concentrated to dryness under reduced pressure. The residue was triturated with acetonitrile. The solid was collected by vacuum filtration, washed with acetonitrile (10 mL), and dried in a vacuum oven at 45°C overnight to give the title compound (63 mg 36%) as a white solid. Method C: LC-MS (electrospray): m / z=418.5 (M+H) + , RT=3.14 minutes

[0601] Example 48: N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-indazole-4-carboxamide [ka] A pressure vial was charged with 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-cyclobutylmethanamine (0.091 mL, 0.745 mmol) at ambient temperature. The vial was sealed, and the mixture was stirred at 65°C for 2 hours. After cooling to room temperature, sodium triacetoxyboranide (184 mg, 0.866 mmol) was added, and the mixture was heated at 65°C for 2 hours. The mixture was partitioned between EtOAc (40 mL) and saturated sodium bicarbonate solution (30 mL). The organic layer was separated, washed with brine (20 mL), dried (NaSO), filtered, and concentrated under reduced pressure. The orange residue was purified by basic reverse-phase chromatography (SNAP Ultra 30 g cartridge, MeCN+0.1% NH3 / H2O+0.1% NH3 10-90%). Fractions containing pure product were concentrated under reduced pressure to give a beige residue. The crude material was redissolved in MeOH (1 mL), and DCM (4 mL) and 4 M HCl in dioxane (1 mL) were added. The reaction was stirred at ambient temperature for 5 h. The solvent was removed under reduced pressure, and the crude pink solid was purified using a 2 g-SCX cartridge eluting first with MeOH (10 mL) and then with 2 M ammonia solution in MeOH (10 mL). The second filtrate was concentrated under reduced pressure to give the desired product as an off-white solid. The compound was lyophilized overnight to give the title compound (78 mg, 53%) as an off-white powder. Method C: LC-MS (electrospray): m / z=388.3 (M+H) + , RT=2.96 minutes

[0602] Intermediate 2: tert-butyl N-(cyclobutylmethyl)-N-prop-2-ynyl-carbamate [ka] To a solution of tert-butyl prop-2-yn-1-ylcarbamate (3.00 g, 19.3 mmol) in anhydrous DMF (30 mL) was added sodium hydride (60%, 852 mg, 21.3 mmol) at 0 °C. The mixture was stirred for 10 minutes, after which (bromomethyl)cyclobutane (2.4 mL, 21.3 mmol) was added. The resulting mixture was then stirred at ambient temperature overnight. The mixture was diluted with water (50 mL) and extracted with diethyl ether (3 × 50 mL). The combined organic extracts were washed with water (80 mL) and brine (30 mL), dried over MgSO, filtered, and concentrated under reduced pressure. The crude material was purified by SiO chromatography [50 g Sfar silica D cartridge; 0–20% EtOAc in heptane, 12 CV]. The product-containing fractions were combined and concentrated under reduced pressure to give the title compound (3.12 g, 13.3 mmol, 69%) as a colorless oil.

[0603] Intermediate 3: tert-Butyl 6-(azidomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate [ka] Step 1: Methyl 5-amino-6-bromo-pyridine-3-carboxylate [ka] NBS (6434 mg, 36.1 mmol) was added to a solution of methyl 5-aminopyridine-3-carboxylate (5000 mg, 32.9 mmol) in anhydrous DMF (50 mL), and the mixture was stirred at room temperature over the weekend. The mixture was diluted with water (250 mL) and extracted with EtOAc (250 mL). The combined organic layers were washed with water (250 mL) and brine (250 mL), dried over magnesium sulfate, and evaporated to dryness. The crude material was purified by SiO2 chromatography (Biotage; 100 g Sfar Duo; 0-100% EtOAc in heptane) to afford the title compound (2850 mg, 25%) as a yellow solid. Method A: LC-MS (electrospray): m / z=231 / 233 (M+H) + , RT=0.95 minutes

[0604] Step 2: Methyl 6-bromo-5-[(2,2,2-trifluoroacetyl)amino]pyridine-3-carboxylate [ka] TFAA (4.5 mL, 32.2 mmol) was added to a solution of methyl 5-amino-6-bromo-pyridine-3-carboxylate (70%, 3540 mg, 10.7 mmol) in DCM (30 mL), and the RM was stirred at ambient temperature for 3 h. The RM was evaporated to dryness to give the methyl (5250 mg, 99%) as an orange oil. Method A: LC-MS (electrospray): m / z=327 / 329 (M+H) + , RT=1.10 minutes

[0605] Step 3: Methyl 2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-1H-pyrrolo[3,2-b]pyridine-6-carboxylate [ka] A solution of methyl 6-bromo-5-[(2,2,2-trifluoroacetyl)amino]pyridine-3-carboxylate (66%, 5250 mg, 10.6 mmol) in anhydrous 1,4-dioxane (11 mL) was added to a suspension of tert-butyl N-(cyclobutylmethyl)-N-prop-2-ynylcarbamate (95%, 2490 mg, 10.6 mmol) (Intermediate 2), CuI (304 mg, 1.59 mmol), potassium phosphate (4562 mg, 21.2 mmol), and triphenylphosphane (834 mg, 3.18 mmol) in anhydrous 1,4-dioxane (55 mL). The resulting suspension was degassed with nitrogen for 10 minutes and then stirred at 110 °C for 2 hours. The mixture was cooled and concentrated under reduced pressure. The residue was partitioned between water (30 mL) and EtOAc (30 mL). The organic phase was collected, and the aqueous phase was extracted with EtOAc (2 × 30 mL). The combined organic phases were dried over magnesium sulfate and concentrated to give the crude material as a brown oil. The crude material was purified by SiO2 chromatography (Biotage Isolera 4; 100 g Sfar Duo; 10-60% EtOAc in heptane) and then further purified by SiO2 chromatography (Biotage Isolera 4; 55 g Sfar Amino D; 10-50% EtOAc in heptane) to give the title compound (1180 mg, 30%) as a white solid. Method A: LC-MS (electrospray): m / z = 374.2 (M+H) + , RT=1.07 minutes

[0606] Step 4: 1-tert-butyl 6-methyl 2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]pyrrolo[3,2-b]pyridine-1,6-dicarboxylate [ka] Boc anhydride (947 mg, 4.34 mmol) was added to an ice-cold solution of methyl 2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-1H-pyrrolo[3,2-b]pyridine-6-carboxylate (1350 mg, 3.61 mmol) in DCM (28.602 mL), followed by DMAP (44 mg, 0.361 mmol). The mixture was warmed to room temperature and stirred for 30 min. Water (50 mL) was added, and the mixture was extracted with DCM (3 × 50 mL). The combined organic layers were dried over magnesium sulfate, evaporated to dryness, and purified by SiO2 chromatography (55 g Sfar Amino D; 0–50% EtOAc in heptane) to afford the title compound (1630 mg, 95%) as a colorless oil. Method B: LC-MS (electrospray): m / z=474.3 (M+H) + , RT=2.28 minutes

[0607] Step 5: tert-butyl 2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-(hydroxymethyl)pyrrolo[3,2-b]pyridine-1-carboxylate [ka] 1M DIBAL in DCM (14 mL, 13.5 mmol) was added to a solution of 1-tert-butyl 6-methyl 2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]pyrrolo[3,2-b]pyridine-1,6-dicarboxylate (1600 mg, 3.38 mmol) in anhydrous DCM (32 mL) at −78° C. The mixture was stirred at this temperature for 2 hours. The reaction was quenched with water (10 mL) at −78° C. The mixture was stirred for 10 minutes and then warmed to room temperature. Water (50 mL) was added, and the mixture was extracted with DCM (3×50 mL). The combined organic phases were dried over magnesium sulfate, evaporated to dryness, and purified by SiO2 chromatography (Biotage Isolera 4; 55 g Sfar Amino D; 0-100% EtOAc in heptane) to afford the title compound (1160 mg, 74%) as a colorless oil. Method A: LC-MS (electrospray): m / z=446.3 (M+H) + , RT=1.25 minutes

[0608] Step 6: tert-butyl 6-(azidomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate [ka] DPPA (241 μL, 1.12 mmol) was added to an ice-cold solution of tert-butyl 2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-(hydroxymethyl)pyrrolo[3,2-b]pyridine-1-carboxylate (250 mg, 0.561 mmol) and DBU (167 μL, 1.12 mmol) in anhydrous DMF (3.125 mL). The mixture was stirred at ambient temperature for 24 h, and an additional amount of DPPA (241 μL, 1.12 mmol) was added, and the mixture was stirred at ambient temperature for 18 h and then heated at 40° C. for 2 h. The mixture was diluted with water (25 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (25 mL), dried over magnesium sulfate, and evaporated to dryness. The crude material was purified by SiO.sub.2 chromatography (Biotage Isolera 4; 28 g Sfar Amino D; 0-100% EtOAc in heptane) to afford the title compound (140 mg, 0.24, 44%) as a colorless oil. Method A: LC-MS (electrospray): m / z=471.3 (M+H) + , RT=1.53 minutes

[0609] Example 49: N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[3,2-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] Step 1: tert-butyl 6-(aminomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate [ka] Triphenylphosphane (524 mg, 2.00 mmol) was added to an ice-cold solution of tert-butyl 6-(azidomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate (94%, 500 mg, 0.999 mmol) (Intermediate 3) in THF (5 mL) and water (0.5 mL). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was evaporated to dryness and purified by basic reverse-phase chromatography to afford (55 mg, 12%) as a colorless oil. Method B: LC-MS (electrospray): m / z=445.3 (M+H) + , RT=1.89 minutes

[0610] Step 2: tert-butyl 2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate [ka] A mixture of tert-butyl 6-(aminomethyl)-2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate (55 mg, 0.124 mmol), 4-oxopyrido[1,2-a]pyrimidine-2-carboxylic acid (24 mg, 0.124 mmol) (Intermediate 1), DIPEA (65 μL, 0.371 mmol), and HATU (52 mg, 0.136 mmol) in DMF (1 mL) was stirred at ambient temperature over the weekend. The mixture was partitioned between saturated aqueous NaHCO (15 mL) and EtOAc (15 mL). The organic phase was collected, dried over magnesium sulfate, and evaporated to dryness. The crude material was purified by SiO.sub.2 chromatography (11 g Sfar Amino D; 0-100% EtOAc in heptane) to afford the title compound (51 mg, 57%) as a yellow oil. Method B: LC-MS (electrospray): m / z = 617.4 (M+H) + , RT=1.91 minutes

[0611] Step 3: N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[3,2-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] 4 M HCl in dioxane (0.17 mL, 0.697 mmol) was added to a solution of tert-butyl 2-[[tert-butoxycarbonyl(cyclobutylmethyl)amino]methyl]-6-[[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]methyl]pyrrolo[3,2-b]pyridine-1-carboxylate (86%, 50 mg, 0.0697 mmol) in DCM (0.5 mL) and MeOH (0.5 mL). The mixture was stirred at 40° C. for 2 h and then at room temperature overnight. The mixture was evaporated to dryness and purified by preparative HPLC (Method B) to give the title compound (15 mg, 50%) as a white powder. Method C: LC-MS (electrospray): m / z=417.3 (M+H) + , RT=2.32 minutes

[0612] Intermediate 12: tert-butyl N-[[6-(aminomethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-N-(cyclobutylmethyl)carbamate [ka] Step 1: tert-butyl N-[3-(2-amino-6-chloro-3-pyridyl)prop-2-ynyl]-N-(cyclobutylmethyl)carbamate [ka] To a solution of 6-chloro-3-iodopyridin-2-amine (0.96 g, 3.77 mmol) in anhydrous THF (5 mL) and triethylamine (9.0 mL, 64.6 mmol) was added palladium(2+) chloride-triphenylphosphane (1:2:2) (26 mg, 0.0377 mmol) and triphenylphosphane (20 mg, 0.0755 mmol) at ambient temperature. The solution was degassed by bubbling nitrogen through the solution for 15 minutes. Copper(1+) iodide (14 mg, 0.0755 mmol) and tert-butyl N-(cyclobutylmethyl)-N-prop-2-ynylcarbamate (1.01 g, 4.53 mmol) (Intermediate 2) were then added sequentially, and the reaction was stirred under a nitrogen atmosphere for 4 hours. 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 Si0 chromatography (BIOTAGE Sfar silica D-Duo 60 μm cartridge, 12 CV of 0-50% EtOAc in heptane). Product-containing fractions were combined and concentrated under reduced pressure to give the title compound (1.31 g, 92%) as an orange oil that solidified upon standing to give a brown solid. Method C: LC-MS (electrospray): m / z=350.3 (M+H) + , RT=4.54 minutes

[0613] Step 2: tert-butyl N-[(6-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl]-N-(cyclobutylmethyl)carbamate [ka] To a stirred solution of tert-butyl N-[3-(2-amino-6-chloro-3-pyridyl)prop-2-ynyl]-N-(cyclobutylmethyl)carbamate (93%, 1.41 g, 3.74 mmol) in anhydrous NMP (15 mL) was added potassium 2-methylpropan-2-olide (0.84 g, 7.49 mmol) at 0 °C (the color of the solution changed from orange to black within a few seconds). After warming to room temperature, the solution was stirred at ambient temperature for 16 h under a nitrogen atmosphere. Saturated aqueous ammonium chloride solution (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 (NaSO), filtered, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography (BIOTAGE Sfar silica D - Duo 60 μm cartridge, 50 g, 12 CV of 0-50% EtOAc in heptane). Product-containing fractions were combined and concentrated under reduced pressure. The residue (an orange solid) was triturated 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 h to give the title compound (650 mg, 47%) as a white solid. Method C: LC-MS (electrospray): m / z = 350.3 / 352.3 (M+H) + , RT=4.60 minutes

[0614] Step 3: tert-butyl N-[(6-cyano-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl]-N-(cyclobutylmethyl)carbamate [ka] To a degassed suspension of tert-butyl N-[(6-chloro-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl]-N-(cyclobutylmethyl)carbamate (585 mg, 1.67 mmol) and zinc dicyanide (216 mg, 1.84 mmol) in NMP-anhydrous (7 mL) in a pressure vial was added tBuXPhos Pd G3 (33 mg, 0.0418 mmol) at ambient temperature. The vial was sealed, and the reaction was stirred at 120 °C for 2 h. After cooling to room temperature, the mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic extracts were washed with water (50 mL), saturated NaHCO3 (aqueous) solution (20 mL), and brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica chromatography (BIOTAGE Sfar silica D-Duo 60 μm cartridge, 25 g, 12 CV of 0–100% EtOAc in heptane). The product-containing fraction (fraction 3) was concentrated under reduced pressure to give the title compound (475 mg, 79%) as a white solid. Method C: LC-MS (electrospray): m / z=341.4 (M+H) + , RT=4.22 minutes

[0615] Step 4: tert-butyl N-[[6-(aminomethyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]-N-(cyclobutylmethyl)carbamate [ka] To a degassed suspension of tert-butyl N-[(6-cyano-1H-pyrrolo[2,3-b]pyridin-2-yl)methyl]-N-(cyclobutylmethyl)carbamate (475 mg, 1.40 mmol) in ethanol (20 mL) was added 7 M ammonia in MeOH (5.0 mL, 35.0 mmol) and Raney nickel (164 mg, 2.79 mmol) at ambient temperature. The mixture was degassed again and stirred under a hydrogen atmosphere for 16 hours. The catalyst was removed by filtration (Celite) and washed with ethanol (approximately 20 mL). The filtrate was concentrated to dryness under reduced pressure to give the title compound (480 mg, 95%) as a greenish oil. Method C: LC-MS (electrospray): m / z=345.4 (M+H) + , RT=3.58 minutes

[0616] Example 71: N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] Step 1: N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] The title compound (345 mg, 64%) was prepared in the same manner as the precursor to Example 42 using Intermediate 12. Method C: LC-MS (electrospray): m / z=517.4 (M+H) + , RT=3.92 minutes

[0617] Step 2: N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] To a solution of tert-butyl N-(cyclobutylmethyl)-N-[[6-[[(4-oxopyrido[1,2-a]pyrimidine-2-carbonyl)amino]methyl]-1H-pyrrolo[2,3-b]pyridin-2-yl]methyl]carbamate (90%, 730 mg, 1.27 mmol) in DCM (5 mL) was added TFA (5 mL) at ambient temperature. The mixture was stirred at ambient temperature until gas evolution ceased (approximately 1 h). The mixture was concentrated to dryness under reduced pressure. The residue was dissolved in MeOH (6 mL) and purified by open access preparative HPLC method B. The product-containing fractions were combined and concentrated to dryness under reduced pressure. The residue (colorless oil) was triturated with acetonitrile (5 mL). The resulting solid was collected by vacuum filtration, washed with acetonitrile (2 mL) and heptane (5 mL), and dried in a vacuum oven at 45° C. overnight to give the title compound (345 mg, 64%). Method C: LC-MS (electrospray): m / z=417.4 (M+H) + , RT=2.85 minutes

[0618] Example 72: N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-1,3-benzodiazol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide [ka] Step 1: tert-butyl N-[(5-cyano-1H-benzimidazol-2-yl)methyl]carbamate [ka] To a suspension of 3,4-diaminobenzonitrile (98%, 0.50 g, 3.68 mmol) and N-(tert-butoxycarbonyl)glycine (0.71 g, 4.05 mmol) in DCE (10 mL) was added a solution of N-ethyl-N-isopropyl-propan-2-amine (3.2 mL, 18.4 mmol) and T3P (50%, 4.4 mL, 7.36 mmol) in EtOAc at ambient temperature. The mixture was stirred in a pressure vial for 24 h at 100 °C. After cooling to room temperature, the mixture was poured into saturated aqueous NaHCO3 solution (25 mL). The organic layer was separated, and the water was extracted with DCE (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by SiO2 chromatography [SNAP cartridge KP-Sil 25 g; 0-100% EtOAc in heptane, 12 CV]. Product-c...

Claims

1. A compound of formula (I) as shown below or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 where: X is: 【Chemistry 2】 is selected from where: Q １ is NH, N-C １－４ selected from alkyl, O, or S; Q ２ａ is N or CR ２ａ Selected from: Q ２ｂ is N or CR ２ｂ Selected from: Q ２ｃ is N or CR ２ｃ Selected from: Q ２ｄ is N or CR ２ｄ Selected from: Q ３ is N or CR １ｂ Selected from: Q ４ is N or CR １ｘ selected from; and Q １ , Q ２ａ , Q ２ｂ , Q ２ｃ , Q ２ｄ , Q ３ and Q ４ not more than three are nitrogen; R １ａ teeth: (i) each optionally containing halo, cyano, hydroxy, C ３－６ Cycloalkyl, 3- to 6-membered heterocyclyl C １－４ Alkoxy, C １－４ C optionally substituted with haloalkoxy, aryl or heteroaryl １－４ Alkyl or C １－４ alkoxy; or Formula (ii): -(CR １ｃ R １ｄ ) ｐ -NR １ｅ R １ｆ is selected from the group where: p is an integer selected from 0, 1, 2, or 3; R １ｃ and R １ｄ Independently: (i) hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C １－４ Alkoxy, Halo, C １－４ Haloalkoxy, C ３－６ Cycloalkyl, —O—C ３－６ Cycloalkyl, NR １ｃａ R １ｄａ or -S(O) ０－２ R １ｃａ R １ｄａ C substituted with one or more substituents selected from １－６ alkyl, where R １ｃａ and R １ｄａ is H or C １－２ alkyl; and C ３－６ Cycloalkyl and —O—C ３－６ Cycloalkyl optionally further substituted with halo, cyano or hydroxy. (iii) C ３－４ cycloalkyl or 3- to 5-membered heterocyclyl, each of which is optionally C １－４ Alkyl, C １－４ Haloalkyl, cyano, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, NR １ｃａ R １ｄａ or -S(O) ０－２ R １ｃａ R １ｄａ where R １ｃａ and R １ｄａ is H or C １－２ those which are alkyl; (iv) or R １ｃ and R １ｄ are bonded to each other so as to form, together with the carbon atoms to which they are attached, a 3- to 6-membered cycloalkyl or heterocyclic ring or spirocyclic ring system, each of which optionally is C １－２ Alkyl, C １－２ Haloalkyl, cyano, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, NR １ｃａ R １ｄａ or -S(O) ０－２ R １ｃａ R １ｄａ wherein R １ｃａ and R １ｄａ is H or C １－２ those which are alkyl; Selected from: R １ｅ and R １ｆ are each independently: (i) hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, NR １ｅａ R １ｆａ or -S(O) ０－２ R １ｅａ R １ｆａ C substituted with one or more substituents selected from １－６ alkyl optionally cyano, oxo, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, NR １ｅａ R １ｆａ or -S(O) ０－２ R １ｅａ R １ｆａ C substituted with one or more substituents selected from １－６ alkyl, where R １ｅａ and R １ｆａ is H or C １－２ those which are alkyl; Formula (iii): -(CR １ｇ R １ｈ ) ｑ -T １ is a group wherein q is 0, 1, 2, 3, 4, 5 or 6; R １ｇ and R １ｈ Independently: a) hydrogen; b) optionally cyano, hydroxy, C １－４ Alkoxy, Halo, C １－４ Haloalkoxy, —O—C ３－６ Cycloalkyl, NR １ｇａ R １ｈａ or -S(O) ０－２ R １ｇａ R １ｈａ C substituted with one or more substituents selected from １－６ alkyl, where R １ｇａ and R １ｈａ is H or C １－２ alkyl; and —O—C ３－６ cycloalkyl optionally substituted with halo, cyano or hydroxy; 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 of which is optionally C １－２ Alkyl, cyano, C １－２ Haloalkyl, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, NR １ｇａ R １ｈａ or -S(O) ０－２ R １ｇａ R １ｈａ wherein R １ｇａ and R １ｈａ is H or C １－２ alkyl; or d) R １ｇ and R １ｈ are optionally bonded to each other so as to form, together with the carbon atoms to which they are attached, a 3- to 6-membered cycloalkyl or heterocyclic ring, which is optionally C １－２ Alkyl, cyano, C １－２ Haloalkyl, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, NR １ｇａ R １ｈａ or -S(O) ０－２ R １ｇａ R １ｈａ wherein R １ｇａ and R １ｈａ is H or C １－２ Alkyl selected from; and T １ is hydrogen, halo, C １－４ Alkyl, C １－４ Haloalkyl, cyano, hydroxy, NR １ｔ R ２ｔ or -S(O) ０－２ R １ｔ R ２ｔ (where R １ｔ and R ２ｔ is H or C １－４ alkyl, C ３－８ Cycloalkyl, C ２－３ Alkenyl, C ２－３ Alkynyl, aryl, heterocyclyl, monocyclic or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C ３－８ Cycloalkyl, bridged bicyclic C ５－１２ cycloalkyl or bridged heterocyclic ring systems, each of which is optionally C １－２ Alkyl, C １－２ Haloalkyl, cyano, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, C ３－６ Cycloalkyl, NR ３ｔ R ４ｔ or -S(O) ０－２ R ３ｔ R ４ｔ wherein R ３ｔ and R ４ｔ is H or C １－２ those which are alkyl; (iv) or R １ｅ and R １ｆ are bonded to each other so as to form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic ring, which optionally includes C １－４ Alkyl, C １－４ Haloalkyl, C ３－６ Cycloalkyl, cyano, hydroxy, C １－４ Alkoxy, Halo, C １－４ Haloalkoxy, NR １ｉ R １ｊ or -S(O) ０－２ R １ｉ R １ｊ wherein R １ｉ and R １ｊ is H or C １－４ alkyl and / or R １ｅ and R １ｆ The monocyclic or bicyclic heterocyclic ring formed by ３－６ spiro-fused to a cycloalkyl or heterocyclic ring, which in turn is optionally C １－４ Alkyl, C １－４ Haloalkyl, C ３－６ Cycloalkyl, cyano, hydroxy, C １－４ Alkoxy, Halo, C １－４ Haloalkoxy, NR １ｉ R １ｊ or -S(O) ０－２ R １ｉ R １ｊ wherein R １ｉ and R １ｊ is H or C １－４ alkyl; wherein alkyl, alkoxy or C ３－６ Any of the cycloalkyls may optionally be cyano, hydroxy, halo, NR １ｋ R １ｌ or -S(O) ０－２ R １ｋ R １ｌ and further substituted with one or more substituents selected from, wherein R １ｋ and R １ｌ is H or C １－４ Alkyl Selected from: R １ｂ is hydrogen, cyano, halo or C １－３ alkyl; R １ｘ is hydrogen, cyano, halo or C １－３ alkyl; R ２ａ , R ２ｂ , R ２ｃ and R ２ｄ are independently hydrogen, cyano, halo, or a group of the formula: -L ２ａ -L ２ｂ -Q ２ wherein: L ２ａ is absent or possibly C １－２ C substituted with alkyl or oxo １－３ alkylene; L ２ｂ is not present or O, S, SO, SO ２ , 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) ２ N(R ｎ ) or N(R ｎ )SO ２ where R ｎ and R ｏ are each independently hydrogen or C １－２ alkyl; and Q ２ is hydrogen, cyano, C １－６ Alkyl, C ３－６ cycloalkyl, aryl, heterocyclyl, or heteroaryl, each of which is optionally halo, trifluoromethyl, trifluoromethoxy, amino, cyano, hydroxy, amino, carboxy, carbamoyl, sulfamoyl, C １－４ Alkyl, NR ｐ R ｑ , OR ｐ , C(O)R ｐ , C(O)OR ｐ , O.C.(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; SO ２ N(R ｐ )R ｑ , N(R ｒ )SO ２ R ｐ or (CH ２ ) ｚ NR ｐ R ｑ wherein z is substituted with one or more substituents selected from 1, 2, or 3, and wherein R ｐ and R ｑ are each independently hydrogen or C １－４ Alkyl is selected from: Y is: 【Transformation 3】 is selected from where: 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 are independently hydrogen (including deuterium), C １－６ Alkyl, C ３－４ cycloalkyl, hydroxy, and halo; and C １ - ６ Alkyl or C ３－４ cycloalkyl optionally substituted with one or more substituents selected from halo, amino, cyano, and hydroxy; 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 is hydrogen or halo; However, 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 where n=1 or n=2 and cannot be halo when the carbon atom to which they are attached is attached to an oxygen or nitrogen atom; or R ３ａ１ and R ３ａ２ , R ３ｂ１ and R ３ｂ２ , R ３ｃ１ and R ３ｃ２ , R ３ｄ１ and R ３ｄ２ , R ３ｅ１ and R ３ｅ２ , R ３ｆ１ and R ３ｆ２ , R ３ｇ１ and R ３ｇ２ , R ３ｈ１ and R ３ｈ２ , R ３ｉ１ and R ３ｉ２ , R ３ｊ１ and R ３ｊ２ , R ３ｋ１ and R ３ｋ２ , R ３ｌ１ and R ３ｌ２ , R ３ｍ１ and R ３ｍ２ , R ３ｎ１ and R ３ｎ２ , R ３ｏ１ and R ３ｏ２ , R ３ｐ１ and R ３ｐ２ , R ３ｑ１ and R ３ｑ２ or R ３ｒ１ and R ３ｒ２ or R ３ｓ１ and R ３ｓ２ together with the carbon atoms to which they are attached form a spiro-fused C ３－４ may be joined together to form a cycloalkyl, which is optionally substituted with one or more substituents selected from halo, methyl, amino, cyano, and hydroxy; n is 0, 1 or 2; Z is: 【Chemistry 4】 【Transformation 5】 【Transformation 6】 is selected from where: R ４ is hydrogen, halo, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ selected from haloalkoxy (e.g., hydrogen, halo, cyano, and methyl); R ５ is hydrogen, halo, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ selected from haloalkoxy (e.g., hydrogen, halo, cyano, and methyl); R ６ is hydrogen, halo, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ selected from haloalkoxy (e.g., hydrogen, halo, cyano, and methyl); R ８ , R ９ , R １０ and R １１ are independently hydrogen, NH ２ , Halo, Cyano, C １－４ Alkoxy, C １－４ Haloalkoxy, C １－６ Alkyl, —CH ２ OCH ３ , -CH ２ SO ２ CH ３ , -SO ２ CH ３ , -NHC(O)CH ３ and —C(O)NR ｖ１ R ｖ２ where R ｖ１ and R ｖ２ are independently selected from hydrogen and methyl; or R ９ and R １０ may be linked together to form a fused 5- or 6-membered saturated or unsaturated ring system together with the atoms to which they are attached, or R １０ and R １１ may be linked to each other so as to form, together with the atoms to which they are attached, a fused 5- or 6-membered saturated or unsaturated ring system, or wherein any of the fused 5- or 6-membered saturated or unsaturated ring systems optionally includes C １－２ Alkyl, cyano, C １－２ Haloalkyl, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, NR １ｉａ R １ｊａ or -S(O) ０－２ R １ｉａ R １ｊａ wherein R １ｉａ and R １ｊａ is H or C １－２ is alkyl; R ７ and R １１Ｎ are independently hydrogen, NH ２ , halo, cyano and C １－６ alkyl; R Ｚ１ and R Ｚ１ａ is hydrogen, C １－４ Alkyl, cyano, halo, C １－４ Haloalkyl, C １－４ Haloalkoxy, C １－４ Alkoxy, C ３－６ Cycloalkyl and —O—C ３－６ cycloalkyl, wherein C ３－６ Cycloalkyl and —O—C ３－６ cycloalkyl optionally substituted with one or more of halo, methyl, or methoxy; R Ｚ２ and R Ｚ２ａ is hydrogen, C １－４ Alkyl, cyano, halo, NH ２ and C １－４ alkoxy; R Ｚ３ａ is hydrogen, C １－４ Alkyl, cyano, halo, NH ２ and C １－４ alkoxy; R Ｚｉ１ｂ is hydrogen, C １－４ Alkyl, cyano, halo, NH ２ and C １－４ alkoxy; R Ｚｉ２ｅ is hydrogen, C １－４ Alkyl, cyano, halo, NH ２ and C １－４ alkoxy; R Ｙ５Ｎ and R Ｚ２Ｎ is hydrogen or C １－４ selected from alkyl; R Ｚ９ is hydrogen, halo, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ haloalkoxy; R Ｚ１０ is hydrogen, halo, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ haloalkoxy; R Ｚ１１ is hydrogen, halo, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ haloalkoxy; R Ｚ１２ is hydrogen, halo, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ haloalkoxy; R Ｚ１３ is hydrogen, halo, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ haloalkoxy; R Ｚ１４ is hydrogen, halo, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ haloalkoxy; R Ｚ１５ is hydrogen, halo, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ haloalkoxy; R Ｚ１６ is hydrogen, halo, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ haloalkoxy; A １ is CR １２ and N; A ２ is CR １３ and N; A ５ is CR １６ and N; A ６ is CR １７ and N; A ７ is CR １８ and N; A ８ is CR １９ R ２０ and N.R. ２１ Selected from: A ９ is CR ２２ R ２３ and N.R. ２４ Selected from: A １１ is CR ２８ R ２９ and N.R. ３０ Selected from: R １２ is hydrogen, halo, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy (e.g., hydrogen, halo, cyano, and C １－４ alkyl); R １３ is hydrogen, halo, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ haloalkoxy (e.g., hydrogen, halo, cyano, methoxy, and methyl); R １６ and R １８ is hydrogen, halo, cyano, C １－４ Alkyl, C １－４ Alkoxy, C １－４ Haloalkyl, C １－４ Haloalkoxy, C ３－４ Cycloalkyl, 3- to 4-membered heterocyclyl and C ３－４ cycloalkoxy; R １７ is hydrogen, halo, cyano, C １－４ 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-membered or heteroaryl, C ３－６ Cycloalkyl, —O—C ３－６ Cycloalkyl, heterocyclyl, -O-heterocyclyl(carbon bond), -(OCH ２ CH ２ ) ｍ -OCH ３ (where m is an integer from 1 to 6), NR ｑ R ｒ where R ｑ and R ｒ are each independently hydrogen, C １－５ Alkyl, C ３－６ cycloalkyl, 3- to 6-membered carbon-bonded heterocyclyl, or R ｑ and R ｒ are linked to each other so as to form, together with the nitrogen atom to which they are attached, a 3- to 6-membered heterocyclic ring; １－５ Alkyl, C １－４ Alkoxy, C ２－４ Alkenyl, C ２－４ alkynyl, phenyl, 5- or 6-membered or heteroaryl, C ３－６ Cycloalkyl, —O—C ３－６ Any of cycloalkyl, heterocyclyl, or —O-heterocyclyl(carbon bond) may optionally be C １－２ Alkyl, cyano, C １－２ Haloalkyl, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, NR １ｅａ R １ｆａ or -S(O) ０－２ R １ｅａ R １ｆａ is further substituted with one or more substituents selected from, wherein R １ｅａ and R １ｆａ is H or C １－２ is alkyl; R １９ and R ２０ is hydrogen, halo, cyano and C １－４ alkyl; R ２２ and R ２３ is hydrogen, halo, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ haloalkoxy (e.g., selected from hydrogen, halo, cyano, and methyl); R ２８ and R ２９ is selected from hydrogen, halo, methoxy and methyl; R ２１ , R ２４ and R ３０ is hydrogen or C １－４ It is alkyl.

2. X is: 【Transformation 7】 where Q is selected from １ , R １ａ , R １ｂ , R １ｘ , R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ 2. The compound of claim 1, wherein:

3. X is: 【Transformation 8】 wherein Q is selected from １ , R １ａ , R １ｂ , R ２ａ , R ２ｂ and R ２ｄ 3. The compound of claim 1 or claim 2, wherein:

4. Q １ is NH or N-C １－４ 4. The compound of claim 1, wherein the aryl group is aryl, ...

5. X is: 【Chemistry 9】 【Chemistry 10】 Selected from: Here, R １ａ 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein:

6. R １ａ but: (i) optionally halo, cyano, hydroxy, C ３－６ Cycloalkyl, 3- to 6-membered heterocyclyl, C １－４ Alkoxy, C １－４ C substituted with haloalkoxy, aryl or heteroaryl １－４ alkyl; or Formula (ii): -(CR １ｃ R １ｄ ) ｐ -NR １ｅ R １ｆ wherein: p is an integer selected from 1 or 2; R １ｃ and R １ｄ independently: (i) hydrogen (including deuterium); (ii) optionally C １－３ C substituted with one or more substituents selected from alkyl １－３ alkyl, where R １ｃａ and R １ｄａ is H or C １－２ alkyl; and —O—C ３－６ cycloalkyl optionally substituted with halo, cyano or hydroxy; (iii) or R １ｃ and R １ｄ are linked to each other so as to form, together with the carbon atoms to which they are attached, a 3- to 5-membered cycloalkyl or heterocyclic or spirocyclic ring system, each of which optionally is C １－２ Alkyl, C １－２ Haloalkyl, cyano, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, NR １ｃａ R １ｄａ or -S(O) ０－２ R １ｃａ R １ｄａ wherein R １ｃａ and R １ｄａ is H or C １－２ Alkyl is selected from R １ｅ and R １ｆ are each independently: (i) hydrogen (including deuterium); (ii) optionally cyano, oxo, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, NR １ｅａ R １ｆａ or -S(O) ０－２ R １ｅａ R １ｆａ C substituted with one or more substituents selected from １－６ alkyl optionally cyano, oxo, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, NR １ｅａ R １ｆａ or -S(O) ０－２ R １ｅａ R １ｆａ C substituted with one or more substituents selected from １－６ alkyl, where R １ｅａ and R １ｆａ is H or C １－２ those which are alkyl; Formula (iii): -(CR １ｇ R １ｈ ) ｑ -T １ is a group wherein q is 0, 1, 2 or 3; R １ｇ and R １ｈ independently: a) hydrogen (including deuterium); or b) In some cases, C １－３ C substituted with one or more substituents selected from alkyl １－３ alkyl, where —O—C ３－４ cycloalkyl optionally substituted with halo, cyano, or hydroxy; NR １ｃａ R １ｄａ or -S(O) ０－２ R １ｃａ R １ｄａ , where R １ｃａ and R １ｄａ is H or C １－２ NR is alkyl １ｇａ R １ｈａ or -S(O) ０－２ R １ｇａ R １ｈａ , where R １ｇａ and R １ｈａ is H or C １－２ alkyl; or c) or R １ｇ and R １ｈ are optionally linked to each other so as to form, together with the carbon atoms to which they are attached, a 3- to 6-membered cycloalkyl or heterocyclic ring, which is optionally C １－２ Alkyl, C １－２ Haloalkyl, cyano, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, NR １ｇａ R １ｈａ or -S(O) ０－２ R １ｇａ R １ｈａ wherein R １ｇａ and R １ｈａ is H or C １－２ Alkyl Selected from: And T １ is hydrogen, halo, C １－４ Alkyl, C １－４ Haloalkyl, cyano, hydroxy, NR １ｔ R ２ｔ or -S(O) ０－２ R １ｔ R ２ｔ (where R １ｔ and R ２ｔ is H or C １－４ alkyl, C ３－８ Cycloalkyl, C ２－３ Alkenyl, C ２－３ Alkynyl, aryl, heterocyclyl, monocyclic or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C ３－８ Cycloalkyl, bridged bicyclic C ５－１２ cycloalkyl or bridged heterocyclic ring systems, each of which is optionally C １－２ Alkyl, C １－２ Haloalkyl, cyano, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, C ３－６ Cycloalkyl, NR ３ｔ R ４ｔ or -S(O) ０－２ R ３ｔ R ４ｔ wherein R ３ｔ and R ４ｔ is H or C １－２ those which are alkyl; (iv) or R １ｅ and R １ｆ are bonded to each other so as to form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic ring, which optionally includes C １－４ Alkyl, C １－４ Haloalkyl, C ３－６ Cycloalkyl, cyano, hydroxy, C １－４ Alkoxy, Halo, C １－４ Haloalkoxy, NR １ｉ R １ｊ or -S(O) ０－２ R １ｉ R １ｊ wherein R １ｉ and R １ｊ is H or C １－４ alkyl and / or R １ｅ and R １ｆ The monocyclic or bicyclic heterocyclic ring formed by ３－６ spiro-fused to a cycloalkyl or heterocyclic ring, which is optionally C １－４ Alkyl, C １－４ Haloalkyl, C ３－６ Cycloalkyl, cyano, hydroxy, C １－４ Alkoxy, Halo, C １－４ Haloalkoxy, NR １ｉ R １ｊ or -S(O) ０－２ R １ｉ R １ｊ wherein R １ｉ and R １ｊ is H or C １－４ alkyl; wherein alkyl, alkoxy or C ３－６ Any of the cycloalkyls may optionally be cyano, hydroxy, halo, NR １ｋ R １ｌ or -S(O) ０－２ R １ｋ R １ｌ and further substituted with one or more substituents selected from, wherein R １ｋ and R １ｌ is H or C １－４ Alkyl 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

7. R １ａ is the formula: -(CR １ｃ R １ｄ ) ｐ -NR １ｅ R １ｆ is a group where p is an integer selected from 1 or 2; R １ｃ and R １ｄ independently: (i) hydrogen (including deuterium) or (ii) optionally cyano, oxo, hydroxy, C １－３ Alkoxy, Halo, C １－３ Haloalkoxy, —O—C ３－４ Cycloalkyl or NH ２ C substituted with one or more substituents selected from １－３ Alkyl where —O—C ３－６ cycloalkyl optionally substituted with halo, cyano, or hydroxy; (iii) or R １ｃ and R １ｄ are bonded to each other so as to form, together with the carbon atoms to which they are attached, a 3- to 5-membered cycloalkyl or heterocyclic ring or spirocyclic ring system, each of which optionally is C １－２ Alkyl, C １－２ Haloalkyl, cyano, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, NR １ｃａ R １ｄａ or -S(O) ０－２ R １ｃａ R １ｄａ wherein R １ｃａ and R １ｄａ is H or C １－２ Alkyl Selected from: R １ｅ and R １ｆ are each independently: (i) hydrogen (including deuterium); (ii) optionally cyano, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy and NH ２ C substituted with one or more substituents selected from １－６ Alkyl Formula (iii): -(CR １ｇ R １ｈ ) ｑ -T １ is a group wherein q is 0, 1, 2 or 3; R １ｇ and R １ｈ independently: a) hydrogen (including deuterium); b) optionally cyano, hydroxy, C １－４ Alkoxy, Halo, C １－４ Haloalkoxy, —O—C ３－６ Cycloalkyl, NR １ｃａ R １ｄａ or -S(O) ０－２ R １ｃａ R １ｄａ C substituted with one or more substituents selected from １－６ alkyl, where R １ｃａ and R １ｄａ is H or C １－２ NR is alkyl １ｇａ R １ｈａ or -S(O) ０－２ R １ｇａ R １ｈａ , where R １ｇａ and R １ｈａ is H or C １－２ alkyl; and —O—C ３－６ cycloalkyl optionally substituted with halo, cyano, or hydroxy; or c) or R １ｇ and R １ｈ are optionally linked to each other so as to form, together with the carbon atoms to which they are attached, a 3- to 6-membered cycloalkyl or heterocyclic ring, which is optionally C １－２ Alkyl, C １－２ Haloalkyl, cyano, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, NR １ｇａ R １ｈａ or -S(O) ０－２ R １ｇａ R １ｈａ wherein R １ｇａ and R １ｈａ is H or C １－２ Alkyl Selected from: And T １ is hydrogen, halo, C １－４ Alkyl, C １－４ Haloalkyl, cyano, hydroxy, NR １ｔ R ２ｔ or -S(O) ０－２ R １ｔ R ２ｔ (where R １ｔ and R ２ｔ is H or C １－４ alkyl, C ３－８ Cycloalkyl, C ２－３ Alkenyl, C ２－３ Alkynyl, aryl, heterocyclyl, monocyclic or bicyclic heteroaryl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C ３－８ Cycloalkyl, bridged bicyclic C ５－１２ cycloalkyl or bridged heterocyclic ring systems, each of which is optionally C １－２ Alkyl, C １－２ Haloalkyl, cyano, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, C ３－６ Cycloalkyl, NR ３ｔ R ４ｔ or -S(O) ０－２ R ３ｔ R ４ｔ wherein R ３ｔ and R ４ｔ is H or C １－２ those which are alkyl; (iv) or R １ｅ and R １ｆ are bonded to each other so as to form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic ring, which optionally includes C １－４ Alkyl, C １－４ Haloalkyl, C ３－６ Cycloalkyl, cyano, hydroxy, C １－４ Alkoxy, Halo, C １－４ Haloalkoxy, NR １ｉ R １ｊ or -S(O) ０－２ R １ｉ R １ｊ wherein R １ｉ and R １ｊ is H or C １－４ alkyl and / or R １ｅ and R １ｆ The monocyclic or bicyclic heterocyclic ring formed by ３－６ spiro-fused to a cycloalkyl or heterocyclic ring, which in turn optionally １－４ Alkyl, C １－４ Haloalkyl, C ３－６ Cycloalkyl, cyano, hydroxy, C １－４ Alkoxy, Halo, C １－４ Haloalkoxy, NR １ｉ R １ｊ or -S(O) ０－２ R １ｉ R １ｊ wherein R １ｉ and R １ｊ is H or C １－４ Alkyl 7. The compound of claim 1, wherein the compound is selected from the group consisting of:

8. R １ａ is the formula: -(CR １ｃ R １ｄ ) ｐ -NR １ｅ R １ｆ is a group wherein R １ｃ and R １ｄ are independently hydrogen (including deuterium) or C １－２ alkyl; R １ｅ is hydrogen (including deuterium) or C １－２ alkyl; and R １ｆ is the formula: -(CR １ｇ R １ｈ ) ｑ -T １ Based on this, q is 1; R １ｇ and R １ｈ are independently hydrogen (including deuterium) or C １－２ alkyl; And T １ is C ３－４ Cycloalkyl, heterocyclyl, spirocyclic carbocyclic or heterocyclic ring systems, bridged C ３－８ Cycloalkyl, bridged bicyclic C ５－１２ cycloalkyl or bridged heterocyclic ring systems, each of which is optionally C １－２ Alkyl, C １－２ Haloalkyl, cyano, hydroxy, C １－２ Alkoxy, Halo, C １－２ haloalkoxy or C ３－６ cycloalkyl) is the basis of 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein any alkyl or alkoxy is optionally further substituted with one or more substituents selected from cyano, hydroxy, or halo.

9. R １ａ is the formula: -(CR １ｃ R １ｄ ) ｐ -NR １ｅ R １ｆ is a group wherein p is 1; R １ｃ and R １ｄ are independently hydrogen (including deuterium) or C １－２ alkyl; and R １ｅ and R １ｆ are bonded to each other so as to form, together with the nitrogen atom to which they are attached, a monocyclic or bicyclic heterocyclic ring, which optionally includes C １－２ Alkyl, C １－２ Haloalkyl, C ３－６ Cycloalkyl, cyano, hydroxy, C １－２ Alkoxy, halo or C １－２ haloalkoxy and / or R １ｅ and R １ｆ The monocyclic or bicyclic heterocyclic ring formed by ３－６ spiro-fused to a cycloalkyl or heterocyclic ring, which in turn optionally １－２ Alkyl, C １－２ Haloalkyl, cyano, hydroxy, C １－２ Alkoxy, halo or C １－２ The compound of any one of claims 1 to 8, which is substituted with one or more substituents selected from haloalkoxy.

10. R １ａ but 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 The compound of any one of claims 1 to 7, selected from:

11. R １ｂ is hydrogen, halo or C １－２ 11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein:

12. R ２ａ , R ２ｂ , R ２ｃ and R ２ｄ are independently hydrogen, cyano, halo, or C １－３ 12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein:

13. Y: [Chemistry 18] 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, selected from:

14. Z is: 【Chemistry 19】 【Chemistry 20】 Selected from: Here, A １ , A ２ , A ５ , A ６、 A ７ , A ８ , A ９ , A １１ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ , R １１Ｎ , R １２ , R １３ , R １９ , R ２２ , R Ｚ１、 R Ｚ２、 R Ｚ２Ｎ , 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 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein:

15. (i) R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , 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 is independently selected from hydrogen, methyl, cyano, or halo; and R Ｙ５Ｎ , R Ｚ２Ｎ and R １１Ｎ is selected from methyl or hydrogen; (ii) R Ｚ１ and R Ｚ１ａ is hydrogen, C １－４ Alkyl, cyano, halo, C １－４ Haloalkyl, C １－４ Haloalkoxy, C １－４ Alkoxy, C ３－６ Cycloalkyl and —O—C ３－６ cycloalkyl; (iii) R １２ , R １３ , R １６ , R １８ , R １９ , R ２０ , R ２１ , R ２２ , R ２３ , R ２４ and R ３０ is independently selected from hydrogen, halo, cyano, and methyl; (iv) R １７ is hydrogen, halo, cyano, C １－４ 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-membered or heteroaryl, C ３－６ Cycloalkyl, —O—C ３－６ Cycloalkyl, heterocyclyl, -(OCH ２ CH ２ ) ｍ -OCH ３ (wherein m is an integer from 1 to 6), NR ｑ R ｒ where R ｑ and R ｒ are each independently hydrogen, C １－４ Alkyl or R ｑ and R ｒ are linked to each other so as to form a 3- to 6-membered heterocyclic ring together with the nitrogen atom to which they are attached; １－４ Alkyl, C ２－４ Alkenyl, C ２－４ alkynyl, phenyl, 5- or 6-membered or heteroaryl, C ３－６ Cycloalkyl, —O—C ３－６ Cycloalkyl, heterocyclyl or —O-heterocyclyl(carbon bond) optionally represents C １－２ Alkyl, cyano, C １－２ Haloalkyl, hydroxy, C １－２ Alkoxy, Halo, C １－２ Haloalkoxy, NR １ｅａ R １ｆａ or -S(O) ０－２ R １ｅａ R １ｆａ is further substituted with one or more substituents selected from, wherein R １ｅａ and R １ｆａ is H or C １－２ is alkyl; (v) R ２１ , R ２４ and R ３０ are independently selected from hydrogen or methyl; (vi) R ２８ and R ２９ is selected from hydrogen or halo, methoxy and methyl; 15. The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

16. R １７ is hydrogen, halo, cyano, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ Alkoxy, C １－４ Haloalkoxy, C ２－４ Alkenyl, C ２－４ Alkynyl, C ３－６ Cycloalkyl, —O—C ３－４ Cycloalkyl, heterocyclyl, -(OCH ２ CH ２ ) ｍ -OCH ３ (wherein m is 1, 2 or 3), NR ｑ R ｒ where R ｑ and R ｒ are each independently hydrogen or C １－２ is alkyl; Here, any C １－４ Alkyl, C ２－４ Alkenyl, C ２－４ The alkynyl or ring system is optionally C １－２ Alkyl, C １－２ Haloalkyl, cyano, hydroxy, C １－２ Alkoxy, halo and C １－２ 16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, substituted with one or more substituents selected from haloalkoxy.

17. Z is: 【Chemistry 21】 is selected from, where A １ , A ２ , A ５ , A ６、 A ７ , A ８ , A ９ , A １１ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , 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 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein:

18. X is 【Chemistry 22】 and Y: 【Chemistry 23】 selected from; and Z is: 【Chemistry 24】 is selected from where: (i) R １ａ , R １ｂ、 R ２ａ , R ２ｂ and R ２ｄ is as defined in any of claims 1 to 17; (ii) R ３ａ１ , R ３ａ２、 R ３ｂ１ , R ３ｂ２ , R ３ｉ１ , R ３ｉ２ , R ３ｊ１、 R ３ｊ２ and n is as defined in any of claims 1 to 17; and (iii) A １ , A ２ , A ５ , A ６ , A ７ , R ４ , R ５、 R ６ , R ８ , R ９ , 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 is as defined in any of claims 1 to 17, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

19. X is 【Chemistry 25】 and Y is 【Chemistry 26】 and and Z is 【Chemistry 27】 and (i) where R １ａ , R １ｂ、 R ２ａ , R ２ｂ and R ２ｄ is as defined in any of claims 1 to 18; (ii) n, R ３ａ１ and R ３ａ２ is as defined in any of claims 1 to 18; and (iii) A １ , A ２ , R ４ , R ５ and R ６ is as defined in any of claims 1 to 18, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

20. A compound or a pharmaceutically acceptable salt thereof selected from 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-azabicyclo[2.1.1]hexan-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-(3-azabicyclo[3.1.1]heptanean-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-piperidylmethyl)-1H-indol-6-yl]methyl]pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(4-fluoro-1-piperidyl)methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-oxo-N-[[2-[[[rac-(1S,2S,4S)-7-oxabicyclo[2.2.1]heptan-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-[[[rac-(1S,2R,4S)-7-oxabicyclo[2.2.1]heptan-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]pentanylamino)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]heptanean-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]octan-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-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; 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-[(oxetan-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]pentanylmethylamino)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)-deuterio-methyl]-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]-1H-indazole-4-carboxamide; N-[[2-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[3,2-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-(1H-indol-6-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-(1H-indol-2-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-(indolizin-2-ylmethyl)-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(6-{[4-(1H-indazol-4-yl)-1H-1,2,3-triazol-1-yl]methyl}-1H-indol-2-yl)methyl]cyclopropanamine; (1R,2S)-2-[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamino]cyclopentanol; N-[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methyl]cyclopentanamine; N-(cyclopropylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine; 1-[[[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methylamino]methyl]cyclobutanol; N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine; N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-b]pyridin-2-yl]methanamine; N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine; N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)triazol-1-yl]methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine; 2-[1-[[2-[(cyclobutylmethylamino)methyl]-1H-indol-6-yl]methyl]triazol-4-yl]pyrido[1,2-a]pyrimidin-4-one; N-(cyclobutylmethyl)-1-[6-[[4-(6-methoxyimidazo[1,5-a]pyridin-8-yl)triazol-1-yl]methyl]-1H-indol-2-yl]methanamine; N-(cyclobutylmethyl)-1-[6-[[4-(1H-indazol-4-yl)imidazol-1-yl]methyl]-1H-indol-2-yl]methanamine; N-(cyclobutylmethyl)-1-[6-[[3-(1H-indazol-4-yl)-1,2,4-oxadiazol-5-yl]methyl]-1H-indol-2-yl]methanamine; N-[[2-(2-azaspiro[3.3]heptanean-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]hexan-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-[(cyclobutylmethylamino)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-1,3-benzodiazol-6-yl)methyl]-4-oxo-4H-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]hexan-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]hexan-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-methylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-fluoroazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(azetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({2-azaspiro[3.4]octan-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-hydroxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3,3-dimethylazetidin-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)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[3-(difluoromethyl)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-methoxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[3-(tert-butoxy)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-oxo-N-[(2-{[3-(trifluoromethyl)azetidin-1-yl]methyl}-1H-indol-6-yl)methyl]-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-ethoxyazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({2-azaspiro[3.5]nonan-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(2-methylazetidin-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]heptanean-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]heptanean-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-cyclobutylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-cyclopropylazetidin-1-yl)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-({2-[(3-tert-butylazetidin-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-trimethylbutan-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-diethylazetidin-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]octan-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-({octahydrocyclopenta[c]pyrrol-2-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({5-azaspiro[2.4]heptanean-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]hexan-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]octan-6-yl}methyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-{[2-({2-azaspiro[4.4]nonan-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]hexan-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-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; N-({2-[(tert-butylamino)methyl]-1H-indol-6-yl}methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 4-(1-{[2-({2-azaspiro[3.3]heptanean-2-yl}methyl)-1H-indol-6-yl]methyl}-1H-1,2,3-triazol-4-yl)-1H-indazole; N-{[2-(2-{2-azaspiro[3.3]heptanean-2-yl}ethyl)-1H-indol-6-yl]methyl}-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; ({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; N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-indol-6-yl)methyl]-5-oxo-5H-[1,3]thiazolo[3,2-a]pyrimidine-7-carboxamide; 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; 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; N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-pyrrolo[3,2-b]pyridin-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-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 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; N-[(2-{[({3-fluorobicyclo[1.1.1]pentan-1-yl}methyl)amino]methyl}-1H-pyrrolo[3,2-c].ylidene-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; (cyclobutylmethyl)({6-[(4-{1H-pyrrolo[2,3-b]pyridin-5-yl}-1H-imidazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine; (cyclobutylmethyl)({6-[(4-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-1-yl)methyl]-1H-indol-2-yl}methyl)amine; N-[(2-{[(2,2-dimethylpropyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; N-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxamide; (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; N-[[2-(2-azabicyclo[2.2.1]heptanean-2-ylmethyl)-1H-indol-6-yl]methyl]-4-oxo-pyrido[1,2-a]pyrimidine-2-carboxamide; N-[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methyl]-1-[6-[(4-imidazo[1,5-a]pyridin-8-yltriazol-1-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-2-yl]methanamine; (cyclobutylmethyl)[(6-{[1-(1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine; [(3,3-difluorocyclobutyl)methyl][(6-{[1-(1H-indazol-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine; (cyclobutylmethyl)[(6-{[1-(isoquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methyl}-1H-indol-2-yl)methyl]amine; (cyclobutylmethyl)({6-[(1-{imidazo[1,5-a]pyridin-8-yl}-1H-1,2,3-triazol-4-yl)methyl]-1H-indol-2-yl}methyl)amine; 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-pyridinecarbonitrile; 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-pyridinecarbonitrile; 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-pyridinecarbonitrile; 3-{1-[(2-{[(cyclobutylmethyl)amino]methyl}-1H-indol-6-yl)methyl]-1H-1,2,3-triazol-4-yl}-5-methoxy-2-pyridinecarbonitrile; 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-pyridinecarbonitrile; 3-[1-({2-[(4,4-dimethyl-1-piperidyl)methyl]-1H-indol-6-yl}methyl)-1H-1,2,3-triazol-4-yl]-5-methoxy-2-pyridinecarbonitrile; N-((2-((6-azaspiro[3.4]octan-6-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxamide; 3-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)-5-fluoropicolinonitrile; 1-cyclobutyl-N-((6-((4-(5-methoxypyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)-1H-indol-2-yl)methyl)methanamine; 5-chloro-3-(1-((2-(((cyclobutylmethyl)amino)methyl)-1H-indol-6-yl)methyl)-1H-1,2,3-triazol-4-yl)picolinonitrile; and 2-((6-Azaspiro[3.4]octan-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.

21. 21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable additives.

22. A compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 21, for use in therapy.

23. 22. A compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 21 for use in the treatment of a proliferative condition.

24. A compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 21, for use in treating cancer.

25. A compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 21, for use in treating leukemia.

26. A compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 21, for use in treating an autoimmune disease, a neurological disease, an inflammatory disease, an infectious disease, or a disease associated with reactivation of a silenced X chromosome.

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