Novel compounds

Abstract

To provide compounds and their use in treating or preventing various proliferative diseases, and related compositions, methods and intermediate compounds.SOLUTION: There is provided a compound such as (R)-2-cyclobutoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to compounds and their use in treating or preventing various proliferative disorders, as well as related compositions, methods and intermediate compounds. [Background technology]

[0002] Inflammation, autoimmunity, fibrosis and even cancer share a number of underlying disease mechanisms, particularly abnormal cell proliferation and in some circumstances shared pathology. Autoimmunity is best expressed as adhesive recognition of self-antigens leading to tissue destruction by lymphocytes of the T-cell and B-cell lineages, with rheumatoid arthritis (RA) being a classic example. Inflammation also encompasses these mechanisms, but is primarily induced by innate immunity through metabolic imbalance or repeated injury and irritation, an example being non-alcoholic steatohepatitis (NASH) (initiated and sustained by accumulation of lipids in the liver and potentially microfauna from the gastrointestinal system). All these mechanisms can also lead to organ sclerosis, scarring and fibrosis through fibroblast activation and proliferation, but in some instances fibrosis can occur without obvious evidence of inflammation or autoimmunity: an example is idiopathic pulmonary fibrosis (IPF). These exemplary diseases highlight that our current knowledge of the mechanisms proceeding in immune system pathology is inadequate and as a result clinical unmet need for patients remains high. In the case of cancer, our understanding of disease progression has progressed significantly with many genetic mutations identified that lead to the loss of cell cycle control and uncontrolled proliferation, which are key features of neoplastic disease. However, clinical unmet needs in cancer remain high due to the number and diversity of mutations present that make targeted therapy difficult.

[0003] In many of these diseases, compounds that target excessive cell proliferation primarily through metabolic processes are the mainstay of therapeutic intervention. Exemplary drugs include methotrexate (MTX) and fluorouracil (5-FU), which are used to treat both cancer and autoimmune diseases, e.g., RA, through suppressing proliferation of cancer cells and, in the case of autoimmunity, T and B cells. MTX and 5-FU target enzymes on the one-carbon (1C) metabolic pathway, which involves redox balance and the transfer of a single carbon unit between molecules used for the biosynthesis of methyl donors, purines, and thymidylate. 1C metabolism is significantly upregulated in rapidly dividing cells, including lymphocytes and many cancer cells. (Ducker and Rabinowitz, 2017; Yang and Vousden, 2016). Although they have been in clinical use for decades for the treatment of cancer and autoimmune diseases (Grem JL.2000; Chan ESL.& Cronstein BN.2010) and have demonstrated significant disease-modifying efficacy, side effects such as anemia, vomiting, diarrhea, paralysis, lethargy and joint pain limit the effectiveness of these drugs.MTX is a powerful inhibitor of the 1C cycle that acts as an inhibitor of dihydrofolate reductase (DHRF), blocking the conversion of folate to tetrahydrofolate.This brings efficacy, but at the cost of a number of side effects previously described.

[0004] Targeting 1C metabolism in a more specific, disease-relevant context is likely to maintain therapeutic benefit but reduce the side effect burden associated with current 1C-targeted drugs (Cuthbertson CR.et al.,2021). Since the inception of MTX and 5-FU, our understanding of the enzymes involved in 1C metabolism has improved significantly, and it is recognized that more selective and focused modulation of 1C metabolism could result in more effective therapies with improved risk-benefit profiles. Enzymes of interest for selective targeting of 1C targeting include cytosolic methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2).

[0005] In the cytoplasm, the trifunctional enzyme MTHFD1 converts 5,10-methylenetetrahydrofolate (5,10me-tetrahydrofolate) to formate. The MTHFD1 dehydrogenase / cyclohydrolase domain (D / Cd) first converts 5,10me-tetrahydrofolate to 10-formyltetrahydrofolate via NADP-mediated oxidation. In a second ATP-induced reaction, the MTHFD1 synthetase domain (Sd) converts 10-formyltetrahydrofolate to formate (Kurniawan H. et al., 2021).

[0006] In mitochondria, dehydrogenase and cyclohydrolase functions are carried out by MTHFD2 with a preference for nicotinamide adenine dinucleotide (NAD)-mediated oxidation.

[0007] While MTHFD1 cytosolic 1C metabolism is generally required for homeostatic functions, mitochondrial MTHFD2 flux supports highly proliferative cells and disease progression in some inflammatory conditions, autoimmune diseases, and cancer. MTHFD2 expression is increased in diseases where rapid cell division is also present, especially in inflammation and cancer; other key enzymes in the mitochondrial 1C pathway are also increased (Eich ML.et al.,2019; Adewale F.et al.,2017; Lee D.et al.,2017; Nilsson R.et al.,2014). Thus, the use of inhibitors of MTHFD2 that selectively target the 1C pathway in disease-inducing cells could lead to new therapies with improved safety profiles compared to MTX and 5-FU.

[0008] RNA-seq analysis from immune cells in peripheral blood showed that MTHFD2 is consistently overexpressed across multiple inflammatory conditions, including ulcerative colitis, Crohn's disease, celiac disease, systemic lupus erythematosus (SLE), psoriatic arthritis, multiple sclerosis (MS), Sjögren's syndrome, and RA (Aune TM. et al., 2017). Furthermore, activated CD4 + T cells show a significant increase in MTHFD2 mRNA after activation, with protein expression peaking at 48 hours. + The T cell subsets Th17 and Th1 had the highest expression of MTHFD2.

[0009] [ka] Moreover, treatment with the MTHFD2 inhibitor DS18561882 (disclosed as Example 5 in US2019 / 0284198 by Daiichi Sankyo and referred to herein as "Reference Example 1") increased CD4 + It significantly reduced the number of Th1 and Th17 cells differentiated in vitro from T cells and the expression of the respective Th1 and Th17 cytokines. IFNg and IL-17 were also significantly reduced (Kawai J., 2019). DS18561882 treatment also increased immunosuppressive Treg cells, suggesting that inhibition of MTHFD2 may also deviate immune responses from pro-inflammatory to anti-inflammatory effects. Further evaluation in vivo demonstrated that DS18561882 was able to reduce ear swelling in a murine keyhole limpet hemocyanin (KLH) contact sensitization model (Sugiura A. et al., 2022). However, as shown herein below, Reference Example 1 has activity against certain receptors that are not involved in the 1C pathway. This may ultimately result in off-target effects, which may limit the development of such molecules into pharmaceuticals.

[0010] Further validation for therapeutic targeting MTHFD2 in the context of autoimmune disease was demonstrated in a murine experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). Disease was induced and mice were treated with oral dual MTHFD1 D / Cd and MTHDF2 inhibitor LY345899 on days 4-26 (Gustafsson R. et al., 2017); treatment resulted in significantly reduced disease severity and cumulative clinical scores compared to vehicle, as well as reduced immune cell infiltration into the spinal cord. Given these observations, it is possible that dual MTHFD1 D / Cd and MTHFD2 inhibitors may be more effective in a given indication than inhibitors targeting MTHFD2 alone. Dual MTHFD1 D / Cd and MTHFD2 inhibitors may present a different risk-benefit profile and result in a new therapy with an improved safety profile compared to MTX and 5-FU.

[0011] Both DS18561882 and LY345899 were well tolerated at the therapeutic doses used [Sugiura A.et al.,2022]. Further validation of MTHFD2 as a suitable target in inflammation was demonstrated in a murine model of heart transplantation. T cell-specific ablation of MTHFD2 in the host protected the allografted heart from vascular occlusion and fibrosis and significantly increased the survival of transplanted mice [Li Y.et al.,2023].

[0012] There remains a need to identify and develop new compounds that possess improved properties compared to existing MTHFD2 inhibitors (e.g., that are more suitable drug candidates). The inventors have now developed compounds that are not only potent MTHFD2 and MTHFD1 D / Cd inhibitors, or selective MTHFD2 inhibitors for MTHFD1 D / Cd, but also avoid the problem of off-target effects compared to other compounds in the prior art. Summary of the Invention

[0013] The present invention relates to compounds of formula (I): [ka] (In the formula, R 1 is C 1-4 Alkyl or C 3-5 is cycloalkyl; R 2 is C 1-4 is alkyl; or R 1 and R 2 are connected to form a 5- to 7-membered heterocycloalkyl; R 3 is C 1-3 selected from the group consisting of alkyl and halo; R 4 is C 1-3 Alkyl, halo, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, NR 4a R 4b and 4- to 7-membered heterocycloalkyl; R 4a H and C 1-3 selected from the group consisting of alkyl; R 4b H and C 1-3 selected from the group consisting of alkyl; m is 0, 1 or 2; n is 0, 1 or 2; R 5 , R 6 and R 7 is defined as follows: (a)R 6 teeth, [ka] and R 7 is non-existent; R 5 H, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, O-C 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl; R 8 is C 3-6 Cycloalkyl, NR 8b R 8c and 4-10 membered heterocycloalkyl, C 3-6 Cycloalkyl and 4- to 10-membered heterocycloalkyl may each be selected from the group consisting of one or more R 8a and optionally replaced by R 8a is C 1-3 Alkyl, C substituted by OH 1-3 Alkyl, OC 1-2 Alkyl-substituted C 1-2 Alkyl, C 1-3 Alkoxy, halo and C 1-3 haloalkyl; R 8b , H, C 1-3 Alkyl and C 3-6 cycloalkyl; R 8c , H, C 1-3 Alkyl and C 3-6cycloalkyl; or: (b)R 7 teeth, [ka] is: (i)R 6 is H and R 5 H, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, O-C 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl; or (ii)R 5 is H and R 6 H, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 6bR 6c and 4- to 7-membered heterocycloalkyl, O-C 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 6a is optionally replaced by; R 6a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 6a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 6b H and C 1-3 selected from the group consisting of alkyl; R 6c is C 1-3 Alkyl and C 3-6 cycloalkyl; or (iii)R 5 and R 6 are connected to form a 4- to 8-membered heterocyclic ring; R 8 is C 3-6 Cycloalkyl, NR 8b R 8c and 4-10 membered heterocycloalkyl, C 3-6 Cycloalkyl and 4- to 10-membered heterocycloalkyl may each be selected from the group consisting of one or more R 8a and optionally replaced by R 8a is C 1-3 Alkyl, C substituted by OH 1-3 Alkyl, OC 1-2 Alkyl-substituted C 1-2 Alkyl, C 1-3 Alkoxy, halo and C 1-3 haloalkyl; R 8b , H, C 1-3 Alkyl and C 3-6 cycloalkyl; R 8c , H, C 1-3 Alkyl and C 3-6cycloalkyl; or a pharma- ceutically acceptable salt and / or solvate thereof.

[0014] In one embodiment, the present invention also provides a compound of formula (I): [ka] (In the formula, R 1 is C 1-4 Alkyl or C 3-5 is cycloalkyl; R 2 is C 1-4 is alkyl; or R 1 and R 2 are connected to form a 5- to 7-membered heterocycloalkyl; R 3 is C 1-3 selected from the group consisting of alkyl and halo; R 4 is C 1-3 Alkyl, halo, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, NR 4a R 4b and 4- to 7-membered heterocycloalkyl; R 4a H and C 1-3 selected from the group consisting of alkyl; R 4b H and C 1-3 selected from the group consisting of alkyl; m is 0, 1 or 2; n is 0, 1 or 2; R 5 , R 6 and R 7 is defined as follows: (a)R 6 teeth, [ka] and R 7is non-existent; R 5 H, halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, O-C 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl; R 8 is C 3-6 Cycloalkyl, NR 8b R 8c and 4-8 membered heterocycloalkyl, C 3-6 Cycloalkyl and 4- to 8-membered heterocycloalkyl may each be represented by one or more R 8a and optionally replaced by R 8a is C 1-3 Alkyl, halo and C 1-3 haloalkyl; R 8b , H, C 1-3 Alkyl and C 3-6 cycloalkyl; R 8c , H, C 1-3 Alkyl and C 3-6cycloalkyl; or: (b)R 7 teeth, [ka] is: (i)R 6 is H and R 5 H, halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, O-C 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl; or (ii)R 5 is H and R 6 H, halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 6b R 6cand 4- to 7-membered heterocycloalkyl, O-C 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 6a is optionally replaced by; R 6a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 6a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 6b H and C 1-3 selected from the group consisting of alkyl; R 6c is C 1-3 Alkyl and C 3-6 cycloalkyl; or (iii)R 5 and R 6 are connected to form a 4- to 8-membered heterocyclic ring; R 8 is C 3-6 Cycloalkyl, NR 8b R 8c and 4-8 membered heterocycloalkyl, C 3-6 Cycloalkyl and 4- to 8-membered heterocycloalkyl may each be represented by one or more R 8a is optionally replaced by: R 8a is C 1-3 Alkyl, halo and C 1-3 haloalkyl; R 8b , H, C 1-3 Alkyl and C 3-6 cycloalkyl; R 8c , H, C 1-3 Alkyl and C 3-6 cycloalkyl; or a pharma- ceutically acceptable salt and / or solvate thereof.

[0015] In one embodiment, the present invention also provides a compound of formula (I): [ka] (In the formula, R 1 is C 1-4 Alkyl or C 3-5 is cycloalkyl; R 2 is C 1-4 is alkyl; or R 1 and R 2 are connected to form a 5- to 7-membered heterocycloalkyl; R 3 is C 1-3 selected from the group consisting of alkyl and halo; R 4 is C 1-3 Alkyl, halo, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 selected from the group consisting of haloalkoxy and 4- to 7-membered heterocycloalkyl; R 6 teeth, [ka] and R 7 is non-existent; or R 7 teeth, [ka] and; R 6 but [ka] and R 7 If is non-existent: R 5 H, halo, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR5b R 5c and 4- to 7-membered heterocycloalkyl, O-C 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl; R 8 is C 3-6 Cycloalkyl, N(C 1-3 Alkyl) 2 and 4-8 membered heterocycloalkyl, C 3-6 Cycloalkyl and 4- to 8-membered heterocycloalkyl may each be represented by one or more R 8a and optionally substituted by R 8a is C 1-3 Alkyl, halo and C 1-3 haloalkyl; or: R 7 but [ka] If: R 6 is H and R 5 H, halo, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5cand 4- to 7-membered heterocycloalkyl, O-C 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl; or R 5 is H and R 6 H, halo, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 6b R 6c and 4- to 7-membered heterocycloalkyl, O-C 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 6a is optionally replaced by; R 6a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 6a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 6b H and C 1-3 selected from the group consisting of alkyl; R 6c is C 1-3 Alkyl and C 3-6 cycloalkyl; or R 5 and R 6 are connected to form a 4- to 8-membered heterocyclic ring; R 8 is C 3-6 Cycloalkyl, N(C 1-3 Alkyl) 2 and 4-8 membered heterocycloalkyl, C 3-6 Cycloalkyl and 4- to 8-membered heterocycloalkyl may each be represented by one or more R 8a and optionally substituted by R 8a is C 1-3 Alkyl, halo and C 1-3 haloalkyl; m is 0, 1 or 2; n is 0, 1 or 2); or a pharma- ceutically acceptable salt and / or solvate thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Compounds of formula (I) The embodiments and preferences given herein for the compounds of formula (I) apply equally to the pharmaceutical compositions, compounds for use or their pharma- ceutically acceptable salts and / or solvates, pharmaceutical compositions for use, uses and methods of the invention, as well as to intermediates used in the synthesis of compounds of formula (I). They also apply equally well to compounds of formula (IA), (IB), (IC), (IC-1) and (ID), where appropriate.

[0017] The term "alkyl" (e.g., C 1-4 Alkyl or C 1-3As used herein, "alkyl" refers to a straight-chain or branched, fully saturated hydrocarbon group having the specified number of carbon atoms. The term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. The term "alkyl" also includes "alkylene," which is a difunctional straight-chain or branched, fully saturated hydrocarbon group having the specified number of carbon atoms. Exemplary "alkylene" groups include methylene, ethylene, n-propylene, and n-butylene.

[0018] The term "halo" as used herein refers to fluoro, chloro, bromo and iodo. Particular examples of halo are fluorine and chlorine, especially fluorine.

[0019] The term "alkoxy" (e.g., C 1-3 Alkoxy, as used herein, refers to an alkyl group as defined above, singly bonded through an oxygen atom (e.g., C 1-3 The term includes methoxy, ethoxy, 1-propoxy and 2-propoxy.

[0020] The term "haloalkyl" (e.g., C 1-3 Haloalkyl, as used herein, refers to a straight or branched fully saturated hydrocarbon chain containing the specified number of carbon atoms and at least one halogen atom, e.g., fluoro or chloro, especially fluoro. An example of a haloalkyl is CF 3 It is.

[0021] The term "haloalkoxy" (e.g., C 1-3 Haloalkoxy, as used herein, refers to a haloalkyl group, as defined above, single bonded through an oxygen atom (e.g., C 1-3 Examples of haloalkoxy groups include OCF 3 , O.C.H.F. 2 and OCH 2 CF 3 Includes:

[0022] The term "cycloalkyl" (e.g., C 3-6 Cycloalkyl, C 3-5 Cycloalkyl or OC 3-10 Cycloalkyl, as used herein, refers to a fully saturated cyclic hydrocarbon group having the specified number of carbon atoms. The term includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl, as well as bridged and fused systems, such as bicyclo[1.1.1]pentyl, bicyclo[3.1.0]hexyl, and 2-adamantanyl: [ka]

[0023] The term "heterocycloalkyl" (e.g., 4-10 membered heterocycloalkyl, 4-8 membered heterocycloalkyl, 4-7 membered heterocycloalkyl or 5-7 membered heterocycloalkyl) as used herein refers to a non-aromatic cyclic group having a specified number of ring atoms, at least one of which is a heteroatom selected from N, O, S and B, e.g., N or O, e.g., N. The term "heterocycloalkyl" is interchangeable with "heterocyclic ring". A heterocyclic group can typically be substituted by one or more (e.g., one or two) oxo groups. Suitably, thietanyl is substituted by one or two oxo groups. The term includes oxetanyl, thietanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl and oxepanyl, as well as bridged, fused and spirocyclic ring systems such as 5,8-dioxaspiro[3.4]octanyl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo(2.2.1)heptyl, 7-azanorbornanyl and 5-azaspiro[2.5]octyl: [ka]

[0024] Further examples of fused ring systems include: [ka]

[0025] Further examples of bridged ring systems include: [ka]

[0026] Further examples of spiro ring systems include: [ka]

[0027] The most preferred heterocycloalkyl groups contain one N atom and no other heteroatoms, or one N atom and one O atom.

[0028] Such groups may be attached to the compounds of formula (I) through an NH atom (in which case the H atom is replaced by a group attached to the heterocycloalkyl group) or through an available carbon atom (meaning that the carbon atom must have at least one C-H bond and the H is replaced by a group attached to the heterocycloalkyl group).

[0029] In some preferred compounds of formula (I), R 1 is C 1-4 In other suitable compounds of formula (I), R 1 is C 3-5 Cycloalkyl, for example, cyclopropyl.

[0030] Most preferably, R 1 is methyl or cyclopropyl.

[0031] In some preferred compounds of formula (I), R 2 is C 1-4Alkyl, for example methyl.

[0032] Alternatively, in some preferred compounds of formula (I), R 1 and R 2 are connected to form a 5- to 7-membered heterocycloalkyl, for example a 6-membered heterocycloalkyl.

[0033] In such compounds of formula (I), the following structures may be formed: [ka] where r is 1, 2 or 3, most preferably 2.

[0034] In some preferred compounds of formula (I), R 3 is C 1-3 In other suitable compounds of formula (I), R 3 is halo, for example chloro.

[0035] Most preferably, R 3 is methyl or chloro.

[0036] In some preferred compounds of formula (I), when m is 1 or 2, R 3 is attached at the following positions: [ka] (In the formula, [ka] represents the point of attachment to the remainder of the compound of formula (I).

[0037] In some preferred compounds of formula (I), m is 0. In other preferred compounds of formula (I), m is 1. In other preferred compounds of formula (I), m is 2.

[0038] Most preferably, m is 1 or 2.

[0039] In some preferred compounds of formula (I), R 3 is methyl and m is 2. In some preferred compounds of formula (I), R 3 is selected from methyl and halo (eg, chloro) and m is 2, e.g., one occurrence is methyl and the other occurrence is methyl or halo (eg, chloro).

[0040] In some preferred compounds of formula (I), R 1 is C 1-4 alkyl, e.g., methyl; R 2 is C 1-4 alkyl, e.g., methyl; R 3 is C 1-4 Alkyl, for example methyl.

[0041] In some preferred compounds of formula (I), R 4 is C 1-3 In other suitable compounds of formula (I), R 4 is halo, e.g., fluoro, or chloro, e.g., fluoro. In other suitable compounds of formula (I), R 4 is C 1-3 haloalkyl, for example trifluoromethyl. In other suitable compounds of formula (I), R 4 is C 1-3 In other suitable compounds of formula (I), R 4 is C 1-3 In other preferred compounds of formula (I), R 4 is 4-7 membered heterocycloalkyl, e.g., pyrrolidinyl. In other suitable compounds of formula (I), R 4 is NR 4a R 4b It is.

[0042] In some preferred compounds of formula (I), R 4a is H. In other suitable compounds of formula (I), R 4a is C 1-3 Alkyl, for example methyl.

[0043] In some preferred compounds of formula (I), R 4b is H. In other more preferred compounds of formula (I), R 4b is C 1-3 It is alkyl, for example, methyl.

[0044] Most preferably, R 4 is fluoro.

[0045] In some preferred compounds of formula (I), R 1 is C 1-4 alkyl, e.g., methyl; R 2 is C 1-4 alkyl, e.g., methyl; R 3 is C 1-4 alkyl, e.g., methyl; R 4 is halo, for example fluoro.

[0046] In some compounds of formula (I), R 4 is a 4-7 membered heterocycloalkyl group, which is attached via a nitrogen atom, i.e. [ka] (In the formula, [ka] is a 4- to 7-membered heterocycloalkyl group, [ka] indicates the connection to the remainder of the compound of formula (I).

[0047] For example, if the 4-7 membered heterocycloalkyl group is pyrrolidinyl, the pyrrolidinyl group is attached through the nitrogen atom, e.g., 1-pyrrolidinyl: [ka] (In the formula, [ka] indicates the connection to the remainder of the compound of formula (I).

[0048] In some preferred compounds of formula (I), n is 0. In other preferred compounds of formula (I), n is 1. In other preferred compounds of formula (I), n is 2.

[0049] Most preferably, n is 0 or 1.

[0050] In some preferred compounds of formula (I), when n is 1, R 4 is attached to the phenyl ring at the following position: [ka]

[0051] In other preferred compounds of formula (I), when n is 1, R 4 is attached to the phenyl ring at the following position: [ka]

[0052] As noted above, in some preferred compounds of formula (I), R 7 has the following structure: [ka] where all other variables are defined above are absent so as to form

[0053] In such preferred compounds, R 4 may be present at any unsubstituted position on the phenyl ring. By "unsubstituted position" is meant any position where a C-H bond is present. The substituent R 4 is replaced by an H atom, so that CR 4 Form a bond.

[0054] Thus, in some preferred compounds of formula (I), R 7 The absence of 7 In other preferred compounds of formula (I), R 7 If is non-existent, R 4 is expressed as follows: 7 It can be located at:

[0055] Therefore, R 7 In some preferred compounds of formula (I) where R is absent, when n is 1, 4 is attached to the phenyl ring at the following position: [ka]

[0056] R 7 In some preferred compounds of formula (I) where R is absent, when n is 1, 4 is attached to the phenyl ring at the following position: [ka]

[0057] R 7 In some preferred compounds of formula (I) where R is absent, when n is 1, 4 is attached to the phenyl ring at the following position: [ka]

[0058] In some preferred compounds of formula (I), when n is 2, R 4 is attached to the phenyl ring at the following positions, and both R 4 are identical: [ka]

[0059] In some preferred compounds of formula (I), when n is 2, R 4 is attached to the phenyl ring at the following positions, and both R 4 are non-identical: [ka]

[0060] Option (a) In some compounds of formula (I), R 6 teeth, [ka] and 7 is non-existent.

[0061] In such compounds, R 5 H, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, O-C 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl.

[0062] In some such compounds, R 5 H, halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, O-C 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl.

[0063] In some such compounds, R 5 H, halo, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, O-C 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C 1-3alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl.

[0064] In some preferred compounds of formula (I), R 5 is H. In other suitable compounds of formula (I), R 5 is halo, e.g., chloro. In other suitable compounds of formula (I), R 5 is C 1-3 In other preferred compounds of formula (I), R 5 is C 1-3 Alkoxy, for example methoxy or ethoxy, for example methoxy. In other suitable compounds of formula (I), R 5 is C 1-3 In other preferred compounds of formula (I), R 5 , SC 1-3 In other preferred compounds of formula (I), R 5 , SC 1-3 In other preferred compounds of formula (I), R 5 is O.C. 3-10 Cycloalkyl, for example, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, bicyclo[3.1.0]hexyloxy, and 2-adamantanyloxy. In other suitable compounds of formula (I), R 5 is 4-7 membered heterocycloalkyl, such as pyrrolidinyl, piperidinyl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo(2.2.1)heptyl and 7-azanorbornanyl. In other suitable compounds of formula (I), R 5 is NR 5b R 5c It is.

[0065] Most preferably, R 5 is C 1-3 Alkoxy, for example methoxy or ethoxy, for example methoxy, or OC 3-10 Cycloalkyl, for example, cyclobutyloxy or cyclopentyloxy.

[0066] In some compounds of formula (I), R 5 is a 4-7 membered heterocycloalkyl group, which is attached via a nitrogen atom, i.e. [ka] (In the formula, [ka] is a 4- to 7-membered heterocycloalkyl group, [ka] indicates the connection to the remainder of the compound of formula (I).

[0067] For example, if the 4-7 membered heterocycloalkyl group is pyrrolidinyl, the pyrrolidinyl group is attached through the nitrogen atom, e.g., 1-pyrrolidinyl: [ka] (In the formula, [ka] indicates the connection to the remainder of the compound of formula (I).

[0068] In some such preferred compounds of formula (I), R 5 O.C. 3-10 If it is cycloalkyl, it is O-C. 3-10 Cycloalkyl is unsubstituted. In other preferred compounds of formula (I), R 5In other preferred compounds of formula (I), when R is a 4- to 7-membered heterocycloalkyl, the 4- to 7-membered heterocycloalkyl is unsubstituted. 5 O.C. 3-10 If it is cycloalkyl, it is O-C. 3-10 Cycloalkyl can have one or more (e.g., one, two or three, e.g., one) R 5a In other preferred compounds of formula (I), R 5 When R is a 4- to 7-membered heterocycloalkyl, the 4- to 7-membered heterocycloalkyl may have one or more (e.g., 1, 2 or 3, e.g., 1) R 5a has been replaced by

[0069] In some such preferred compounds of formula (I), R 5a is halo, e.g., fluoro. In other suitable compounds of formula (I), R 5a is C 1-3 Alkyl, for example methyl.

[0070] Some such preferred compounds of formula (I), R 5 is one R 5a In other suitable compounds of formula (I), R 5 There are two R 5a In other suitable compounds of formula (I), R 5 The three R's 5a In other preferred compounds of formula (I), R 5 There are two R 5a groups, which are attached to the same carbon atom and connected by C 3-6 Cycloalkyl rings, e.g., C 3 It forms a cycloalkyl ring.

[0071] In some such preferred compounds of formula (I), R 5b is H. In other suitable compounds of formula (I), R 5b is C 1-3 Alkyl, for example methyl.

[0072] In some such preferred compounds of formula (I), R 5c is C 1-3 In other suitable compounds of formula (I), R 5c is C 3-6 Cycloalkyl, for example, cyclopropyl.

[0073] Most preferably, R 5b and R 5c are both methyl. Most preferably, R 5 is NR 5b R 5c and R 5b and R 5c Both are methyl.

[0074] Option (b) In some alternative compounds of formula (I), R 7 teeth, [ka] It is.

[0075] Option (b)(i) In some such compounds, R 6 is H and R 5 H, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, O-C 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C 1-3alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl.

[0076] In some such compounds, R 6 is H and R 5 H, halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, O-C 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl.

[0077] For example, R 6 is H and R 5 H, halo, C 1-3 Alkoxy, C1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, O-C 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl.

[0078] In some such preferred compounds of formula (I), R 5 is H. In other suitable compounds of formula (I), R 5 In other preferred compounds of formula (I), R 5 is C 1-3 Alkyl, for example, methyl or ethyl.

[0079] In some other suitable compounds of formula (I), R 5 is C 1-3 In other preferred compounds of formula (I), R 5 is C 1-3 In some other preferred compounds of formula (I), R 5 , SC 1-3 In other preferred compounds of formula (I), R 5 , SC 1-3 In other preferred compounds of formula (I), R 5 is O.C.3-10 In other suitable compounds of formula (I), R 5 is 4-7 membered heterocycloalkyl. In some other suitable compounds of formula (I), R 5 is NR 5b R 5c It is.

[0080] In some such compounds of formula (I), R 5 is a 4-7 membered heterocycloalkyl group, which is attached via a nitrogen atom, i.e. [ka] (In the formula, [ka] is a 4- to 7-membered heterocycloalkyl group, [ka] indicates the connection to the remainder of the compound of formula (I).

[0081] For example, if the 4-7 membered heterocycloalkyl group is pyrrolidinyl, the pyrrolidinyl group is attached through the nitrogen atom, e.g., 1-pyrrolidinyl: [ka] (In the formula, [ka] indicates the connection to the remainder of the compound of formula (I).

[0082] In some such preferred compounds of formula (I), R 5 O.C. 3-10 If it is cycloalkyl, it is O-C. 3-10 Cycloalkyl is unsubstituted. In other preferred compounds of formula (I), R 5In other preferred compounds of formula (I), when R is a 4- to 7-membered heterocycloalkyl, the 4- to 7-membered heterocycloalkyl is unsubstituted. 5 O.C. 3-10 If it is cycloalkyl, it is O-C. 3-10 Cycloalkyl can have one or more (e.g., one, two or three, e.g., one) R 5a In other preferred compounds of formula (I), R 5 When R is a 4- to 7-membered heterocycloalkyl, the 4- to 7-membered heterocycloalkyl may have one or more (e.g., 1, 2 or 3, e.g., 1) R 5a has been replaced by

[0083] In some such preferred compounds of formula (I), R 5a In other preferred compounds of formula (I), R 5a is C 1-3 It is an alkyl.

[0084] In some preferred compounds of formula (I), R 5 There are two R 5a groups, which are attached to the same carbon atom and connected by C 3-6 It forms a cycloalkyl or 4- to 7-membered heterocycloalkyl ring.

[0085] In some such preferred compounds of formula (I), R 5b is H. In other suitable compounds of formula (I), R 5b is C 1-3 It is an alkyl.

[0086] In some such preferred compounds of formula (I), R 5c is C 1-3 In other preferred compounds of formula (I), R 5c is C 3-6 It is cycloalkyl.

[0087] Option (b)(ii) Alternatively, in some such compounds, R5 is H and R 6 H, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 6b R 6c and 4- to 7-membered heterocycloalkyl, O-C 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 6a is optionally replaced by; R 6a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 6b H and C 1-3 selected from the group consisting of alkyl; R 6c is C 1-3 Alkyl and C 3-6 cycloalkyl.

[0088] In some such compounds, R 5 is H and R 6 H, halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 6b R 6c and 4- to 7-membered heterocycloalkyl, O-C 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 6a is optionally replaced by; R 6a Halo and C1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 6b H and C 1-3 selected from the group consisting of alkyl; R 6c is C 1-3 Alkyl and C 3-6 cycloalkyl.

[0089] For example, R 5 is H and R 6 H, halo, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 6b R 6c and 4- to 7-membered heterocycloalkyl, 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 6a is optionally replaced by; R 6a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 6a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 6b H and C 1-3 selected from the group consisting of alkyl; R 6c is C 1-3 Alkyl and C 3-6 cycloalkyl.

[0090] In some preferred compounds of formula (I), R 6 is H. In other suitable compounds of formula (I), R 6 In other preferred compounds of formula (I), R6 is C 1-3 In other preferred compounds of formula (I), R 6 is C 1-3 In other preferred compounds of formula (I), R 6 is C 1-3 In other preferred compounds of formula (I), R 6 , SC 1-3 In other preferred compounds of formula (I), R 6 , SC 1-3 In other preferred compounds of formula (I), R 6 is O.C. 3-10 In other suitable compounds of formula (I), R 6 is 4-7 membered heterocycloalkyl. In other preferred compounds of formula (I), R 6 is NR 6b R 6c It is.

[0091] In some compounds of formula (I), R 6 is a 4-7 membered heterocycloalkyl group, which is attached via a nitrogen atom, i.e. [ka] (In the formula, [ka] is a 4- to 7-membered heterocycloalkyl group, [ka] indicates the connection to the remainder of the compound of formula (I).

[0092] For example, if the 4-7 membered heterocycloalkyl group is pyrrolidinyl, the pyrrolidinyl group is attached through the nitrogen atom, e.g., 1-pyrrolidinyl: [ka] (In the formula, [ka] indicates the connection to the remainder of the compound of formula (I).

[0093] In some preferred compounds of formula (I), R 6 O.C. 3-10 If it is cycloalkyl, it is O-C. 3-10 Cycloalkyl is unsubstituted. In other preferred compounds of formula (I), R 6 In other preferred compounds of formula (I), when R is a 4- to 7-membered heterocycloalkyl, the 4- to 7-membered heterocycloalkyl is unsubstituted. 6 O.C. 3-10 If it is cycloalkyl, it is O-C. 3-10 Cycloalkyl can have one or more (e.g., one, two or three, e.g., one) R 6a In other preferred compounds of formula (I), R 6 When R is a 4- to 7-membered heterocycloalkyl, the 4- to 7-membered heterocycloalkyl may have one or more (e.g., 1, 2 or 3, e.g., 1) R 6a has been replaced by

[0094] In some preferred compounds of formula (I), R 6a In other preferred compounds of formula (I), R 6a is C 1-3 It is an alkyl.

[0095] In some preferred compounds of formula (I), R 6 There are two R 6a groups, which are attached to the same carbon atom and connected by C 3-6 It forms a cycloalkyl or 4- to 7-membered heterocycloalkyl ring.

[0096] In some preferred compounds of formula (I), R 6b is H. In other suitable compounds of formula (I), R 6b is C 1-3 It is an alkyl.

[0097] In some preferred compounds of formula (I), R 6c is C 1-3 In other preferred compounds of formula (I), R 6c is C 3-6 It is cycloalkyl.

[0098] Option (b)(iii) Alternatively, in some such compounds, R 5 and R 6 are connected to form a 4-8 membered heterocyclic ring, for example, a 5,8-dioxaspiro[3.4]octanyl ring.

[0099] R 8 base In some preferred compounds of formula (I), R 8 is C 3-6 In other suitable compounds of formula (I), R 8 is 4 to 10 (e.g., 4 to 8) membered heterocycloalkyl, such as pyrrolidinyl (e.g., pyrrolidin-1-yl), piperidinyl (e.g., piperidin-1-yl), 7-azanorbornanyl, 3-azabicyclo[3.1.0]hexyl (e.g., 3-azabicyclo[3.1.0]hexan-3-yl), 6-azaspiro[2.5]octyl (e.g., 6-azaspiro[2.5]octan-6-yl) and 3-oxa-6-azabicyclo[3.2.1]octyl (e.g., 3-oxa-8-azabicyclo[3.2.1]octan-8-yl), preferably pyrrolidinyl (e.g., pyrrolidin-1-yl). Further examples include 7-azabicyclo[2.2.1]heptan-7-yl, (3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl, octahydro-2H-isoindol-2-yl, 2-azaspiro[3.3]heptan-2-yl, (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl), 2-azabicyclo[2.2.1]heptan-2-yl, and 8-azabicyclo[3.2.1]octan-8-yl.

[0100] In other suitable compounds of formula (I), R 8 is NR 8b R 8c It is.

[0101] In some preferred compounds of formula (I), R 8b is H. In other suitable compounds of formula (I), R 8b is C 1-3 In other suitable compounds of formula (I), R 8b is C 3-6 Cycloalkyl is, for example, cyclopropyl or cyclopentyl.

[0102] In some preferred compounds of formula (I), R 8c is H. In other suitable compounds of formula (I), R 8c is C 1-3 In other suitable compounds of formula (I), R 8c is C 3-6 Cycloalkyl is, for example, cyclopropyl or cyclopentyl.

[0103] For example, R 8 is N(C 1-3 Alkyl) 2 , e.g., N(CH 3 ) 2 or N(CH 3 )(CH(CH 3 ) 2 ). Alternatively, R 8 is N(cyclopropyl) 2 , NMe (cyclopropyl) or NMe (cyclopentyl).

[0104] In some compounds of formula (I), R 8 is a 4-8 membered heterocycloalkyl group, which is attached via a nitrogen atom, i.e. [ka] (In the formula, [ka] is a 4-10 (e.g., 4-8) membered heterocycloalkyl group; [ka] indicates the connection to the remainder of the compound of formula (I).

[0105] For example, when the 4-10 (e.g., 4-8) membered heterocycloalkyl group is pyrrolidinyl, the pyrrolidinyl group is attached through the nitrogen atom, such as 1-pyrrolidinyl: [ka] (In the formula, [ka] indicates the connection to the remainder of the compound of formula (I).

[0106] R 8 Examples of substituted heterocycloalkyl groups which may be present include (3-CF 3 )-Pyrrolidine-1-yl, (2-CH 2 OMe)-pyrrolidine-1-yl, (2-CH 2 OCH 2 Me)-pyrrolidine-1-yl, (4-CF 3 )-piperidin-1-yl, (3-OMe)-piperidin-1-yl, (3-OMe)-pyrrolidin-1-yl, (2-CF 3 )-pyrrolidine-1-yl, (4-OMe)-piperidin-1-yl, (3-diF)-piperidin-1-yl, (3-diF)-pyrrolidin-1-yl, (3-diMe)-pyrrolidin-1-yl, (2,5-diMe)-pyrrolidin-1-yl, (4-F)-piperidin-1-yl, and (3-F)-pyrrolidin-1-yl.

[0107] In some preferred compounds of formula (I), R 8 C 3-6 If it is cycloalkyl, C 3-6Cycloalkyl is unsubstituted. In other preferred compounds of formula (I), R 8 In other suitable compounds of formula (I), when R is a 4-10 (e.g., 4-8) membered heterocycloalkyl, the 4-10 (e.g., 4-8) membered heterocycloalkyl is unsubstituted. 8 C 3-6 If it is cycloalkyl, C 3-6 Cycloalkyl can have one or more (e.g., one, two or three, e.g., one) R 8a For example, R 8 In other preferred compounds of formula (I), R 8 When R is a 4-10 (e.g., 4-8) membered heterocycloalkyl, the 4-10 (e.g., 4-8) membered heterocycloalkyl may have one or more (e.g., 1, 2 or 3, e.g., 1 or 2, e.g., 1) R 8a has been replaced by

[0108] In some preferred compounds of formula (I), R 8a is C 1-3 In other suitable compounds of formula (I), R 8a is C replaced by OH 1-3 Alkyl, e.g., -CH 2 In other suitable compounds of formula (I), R 8a is O.C. 1-2 Alkyl-substituted C 1-2 Alkyl, e.g., -CH 2 OMe or CH 2 OCH 2 In other preferred compounds of formula (I), R 8a is C 1-3 In other suitable compounds of formula (I), R 8a is halo, e.g., F. In other suitable compounds of formula (I), R 8a is C 1-3 Haloalkyl, e.g., CF 3 It is.

[0109] In some preferred compounds of formula (I), R 8 There are two R 8a It is substituted by a group, for example, two methyl groups.

[0110] In some preferred compounds of formula (I), R 1 and R 2 is methyl, m is 1 or 2, R 3 is selected from methyl and halo (e.g., chloro), e.g., methyl; n is 1; R 4 is fluoro and R 5 is O.C. 3-10 Cycloalkyl, for example, cyclobutyloxy; R 6 teeth, [ka] and R 7 is non-existent, and R 8 is 4-8 membered heterocycloalkyl, for example 1-pyrrolidinyl. In such compounds of formula (I), suitably R 4 is R 5 and is attached ortho to, i.e., a compound of formula (IA) as defined below: [ka] (In the formula, R 1 and R 2 is methyl, m is 1 or 2, R 3 is selected from methyl and halo (e.g., chloro), (e.g., m is 1 or 2, and R 3 is methyl), R 4 is fluoro and R 5 is O.C. 3-10 Cycloalkyl, for example, cyclobutyloxy; R 6 teeth, [ka] and R 7 is absent, i.e., hydrogen, and R 8is 4-10 (e.g., 4-8) membered heterocycloalkyl, e.g., 1-pyrrolidinyl. When m is 2, for example, R 3 is methyl and the other occurrence is methyl or halo (eg, chloro).

[0111] In other suitable compounds of formula (I), R 1 and R 2 is methyl, m is 1 or 2, R 3 is methyl, n is 1, and R 4 is fluoro and R 5 is C 1-3 Alkoxy, such as methoxy and ethoxy, or NR 5b R 5c and R 5b and R 5c are each independently 1-3 alkyl, e.g., methyl; R 6 teeth, [ka] and R 7 is non-existent, and R 8 is one R 8a 4-8 membered heterocycloalkyl or C 3-6 cycloalkyl, R 8a is C 1-3 In such preferred compounds of formula (I), R 5 C 1-3 When R is alkoxy, e.g., methoxy or ethoxy, it is preferred that 4 is R 5 and is attached ortho to, i.e., a compound of formula (IB) as defined below: [ka] (In the formula, R 1 and R 2 is methyl, m is 1 or 2, R 3 is selected from methyl and halo (e.g., chloro), (e.g., m is 1 or 2, and R3 is methyl), n is 1, and R 4 is fluoro and R 5 is C 1-3 Alkoxy, such as methoxy and ethoxy, or NR 5b R 5c and R 5b and R 5c are each independently 1-3 alkyl, e.g., methyl; R 6 is -C(=O)NHSO 2 and R 8 and R 8 is one R 8a or C 3-6 cycloalkyl, R 8a is C 1-3 is alkyl, R 5 is C 1-3 When m is 2, for example, R 3 is methyl and the other occurrence is methyl or halo (eg, chloro).

[0112] In other such preferred compounds of formula (I), R 5 is methoxy, ethoxy, cyclopropyloxy or NR 5b R 5c (For example, R 5 NR 5b R 5c (For example, NMe 2 )), preferably R 4 is R 5 and is linked para to, i.e., a compound of formula (IC) as defined below: [ka] (In the formula, R 1 , R 2 , R 3 , m, R 4 and R 6 is as defined elsewhere herein, and R 5is methoxy, ethoxy, cyclopropyloxy or NR 5b R 5c (For example, NMe 2 )is)is.

[0113] In the compound of formula (IC), preferably: R 1 is methyl, R 2 is methyl, m is 1 or 2, most preferably 2, R 3 is selected from methyl and halo (e.g., chloro); R 4 is fluoro and R 5 is methoxy, ethoxy, cyclopropyloxy or NR 5b R 5c and R 5b and R 5c are methyl, and R 6 is -C(=O)NHSO 2 R 8 and R 8 is R 8 is a 4-10 (e.g., 4-8) membered heterocycloalkyl having one nitrogen atom, and R 8 The group is connected to the remainder of the molecule through the nitrogen atom. When m is 2, for example, R 3 is methyl and the other occurrence is methyl or halo (eg, chloro).

[0114] Some suitable compounds of formula (IC) are compounds of formula (IC-1) [ka] (In the formula, R 50 is methoxy, ethoxy, cyclopropyloxy or NMe 2 and R 6 is -C(=O)NHSO 2 R 8 and R 8 is a 4-10 (e.g., 4-8) membered heterocycloalkyl containing one nitrogen atom, R 8The 4- to 10- (e.g., 4- to 8-) membered heterocycloalkyl group is attached to the remainder of the molecule through the nitrogen atom, and the 4- to 10- (e.g., 4- to 8-) membered heterocycloalkyl group is selected from one or two R 8a R 30 and R 31 are independently selected from methyl and halo (e.g., chloro), e.g., R 30 is methyl, R 31 is methyl or halo (e.g., chloro). Suitably, in the compound of formula (IC-1), R 8 is a 4-10 (e.g., 4-8) membered heterocycloalkyl group containing one nitrogen atom and no other heteroatoms. For example, in the compound of formula (IC-1), the 4-10 (e.g., 4-8) membered heterocycloalkyl group is R 8a In one embodiment, R 50 is methoxy. In one embodiment, R 50 is ethoxy. In one embodiment, R 50 is cyclopropyloxy. In one embodiment, R 50 is NMe 2 It is.

[0115] The present invention also relates to a compound of formula (ID): [ka] (In the formula, R 11 is C 1-4 Alkyl or C 3-5 is cycloalkyl; R 21 is C 1-4 is alkyl; or R 11 and R 21 are connected to form a 5- to 7-membered heterocycloalkyl; R 32 , R 33 and R 34 , H, C 1-3 independently selected from the group consisting of alkyl and halo, where R 32 , R 33 and R 34at least one of is H; R 41 and R 42 , H, C 1-3 Alkyl, halo, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, NR 4a R 4b and 4 to 7 membered heterocycloalkyl; R 4a H and C 1-3 selected from the group consisting of alkyl; R 4b H and C 1-3 selected from the group consisting of alkyl; However, R 41 , R 42 and R 71 at least one of is H; R 51 , R 61 and R 71 is -C(=O)NHSO 2 R 8 , H, Halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl; or R 51 and R 61 are connected to form a 4- to 8-membered heterocyclic ring; However, R 51 , R 61 and R 71 One or only one of the following is -C(=O)NHSO 2 R 8 and R 8 is C 3-6 Cycloalkyl, NR 8b R 8c and 4-8 membered heterocycloalkyl, C 3-6 Cycloalkyl and 4- to 8-membered heterocycloalkyl may each be represented by one or more R 8a and optionally replaced by R 8a is C 1-3 Alkyl, halo and C 1-3 haloalkyl; R 8b , H, C 1-3 Alkyl and C 3-6 cycloalkyl; R 8c , H, C 1-3 Alkyl and C 3-6 cycloalkyl; or a pharma- ceutically acceptable salt and / or solvate thereof.

[0116] The compounds of formula (ID) are utilized in accordance with the present invention as provided for the compounds of formula (I).

[0117] In the compound of formula (ID), for example, R 61 is -C(=O)NHSO 2 R 8 It is.

[0118] In the compound of formula (ID), for example, R71 H, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, NR 5b R 5c and 4- to 7-membered heterocycloalkyl.

[0119] In the compound of formula (ID), for example, R 41 , R 42 and R 71 is independently selected from H and halo (e.g., F or Cl). In one embodiment, R 41 is H and R 42 is H and R 71 is H. In one embodiment, R 41 is halo, e.g., Cl or F, and R 42 is H and R 71 is H. In one embodiment, R 41 is H and R 42 is halo, e.g., Cl or F (especially F), and R 71 is H. In one embodiment, R 41 is H and R 42 is H and R 71 is halo, for example Cl or F. In the compound of formula (ID), suitably R 33 is H. In the compound of formula (ID), for example, R 32 and R 34 are independently selected from methyl and halo (e.g., chloro), e.g., R 34 is methyl, R 32 is methyl or halo (eg, chloro).

[0120] In compounds of formula (I), (IA), (IB), (IC) and (IC-1), and correspondingly for compounds of formula (ID), preferably the stereochemistry around the piperazine ring is as follows: [ka]

[0121] Suitably, the compound of formula (I) is selected from the group consisting of any one of Examples 1 to 180, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0122] Suitably, the compound of formula (I) is selected from the group consisting of any one of Examples 1 to 270, such as 181 to 270, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0123] Suitably, the compound of formula (I) is selected from the group consisting of any one of Examples 1 to 331, such as 271 to 331, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0124] Suitably, the compound of formula (I) is (R)-2-(cyclopentyloxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-3-Fluoro-2-isopropoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(cyclopentyloxy)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(cyclopentyloxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-3-fluoro-2-methoxy-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-ethoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; and 2-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; or a pharma- ceutically acceptable salt and / or solvate thereof.

[0125] Suitably, the compound of formula (I) is (R)-2-(cyclopentyloxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-3-Fluoro-2-isopropoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(cyclopentyloxy)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(cyclopentyloxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-3-fluoro-2-methoxy-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-ethoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; and (R)-2-Cyclopropoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; or a pharma- ceutically acceptable salt and / or solvate thereof.

[0126] Suitably, the compound of formula (I) is (R)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(dimethylamino)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(Dimethylamino)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-5-chloro-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-5-chloro-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-3-Fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-2-(pyrrolidin-1-yl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-chloro-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; and 2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-chloro-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; or a pharma- ceutically acceptable salt and / or solvate thereof.

[0127] Suitably, the compound of formula (I) is (R)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(dimethylamino)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(Dimethylamino)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-5-chloro-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-5-chloro-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-3-Fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-2-(pyrrolidin-1-yl)benzamide; 2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-chloro-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-chloro-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-ethoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-Fluoro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-Fluoro-2-(methoxy-d 3 )-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-ethoxy-4-(10-ethyl-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(dimethylamino)-4-(10-ethyl-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-N-(N-cyclopropyl-N-methylsulfamoyl)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxy-5-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-N-(N,N-dimethylsulfamoyl)-5-fluorobenzamide; and (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-2-methoxy-N-(pyrrolidin-1-ylsulfonyl)benzamide; or any one of its pharma- ceutically acceptable salts and / or solvates.

[0128] Suitably, the compound of formula (I) is (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; N-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-2-methoxybenzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-cyclopropoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-N-((2-azaspiro[3.3]heptan-2-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide or any one of its pharma- ceutically acceptable salts and / or solvates.

[0129] The present invention relates to all mixtures of stereoisomeric forms, including racemic mixtures (e.g., -CH to the piperazine ring). 2 OR 2 Provided herein are each of the foregoing exemplary compounds (i.e., Examples 1-331) and pharma- ceutically acceptable salts and / or solvates thereof in the (S) form instead of the (R) form shown above, where reference is made to a stereocenter involving the bonding site.

[0130] Compounds of formula (I) may be synthesized as shown in the following schemes and in the Examples section. For each scheme, the variables are as defined above unless otherwise stated.

[0131] Scheme 1: Synthesis of compounds of formula (I) [ka]

[0132] Compounds of formula (I) can be prepared by coupling an amine intermediate (II) with a carboxylic acid (III) using coupling agents (e.g., EDCI and HOBt) in the presence of an organic base (e.g., TEA) in a solvent (e.g., DCM).

[0133] Compounds of formula (II) and formula (III) can be synthesized, for example, as shown in the Examples section below, or according to the following schemes.

[0134] Scheme 2: Synthesis of compounds of formula (II) [ka] (In the scheme, R 1 , R 2 , R 3 and m are defined elsewhere herein, and PG is a nitrogen protecting group.) Compounds of formula (V) can be prepared according to the literature (e.g., the Daiichi Sankyo patent applications disclosed above).

[0135] Step 1: A compound of formula (V) is reacted with a compound of formula (VI) under palladium catalyzed reaction conditions to form a compound of formula (IV).

[0136] Step 2: The nitrogen protecting group is removed under standard deprotection conditions known to those skilled in the art to give a compound of formula (II). For example, when PG is Boc, this group can be removed under acidic conditions such as HCl in 1,4-dioxane, among other known methods such as those described herein.

[0137] Scheme 3: Synthesis of compounds of formula (VI) [ka] (In the scheme, R 2 is defined elsewhere herein, and -CH(R')(R'') is R 1 Corresponding to PG and PG 1 is the orthogonal nitrogen protecting group).

[0138] Step 1: The compound of formula (XII) is reacted with PG 1 -X, where X is a leaving group, for example halo, for example chloro, to give a compound of formula (XI).

[0139] Step 2: Compounds of formula (XI) can be prepared by reacting alkyl halides R 2 -X 1 (In the formula, X 1is reacted with a leaving group, such as bromo, iodo or tosyl, to give a compound of formula (X).

[0140] Step 3: PG is removed from the compound of formula (X) under standard deprotection conditions known to those skilled in the art to give the compound of formula (IX). For example, when PG is Boc, this group can be removed under acidic conditions such as TFA in DCM, among other known methods such as those described herein.

[0141] Step 4: Compounds of formula (IX) can be prepared using standard reductive amination conditions (e.g., NaBH(OAc) in acetonitrile and water). 3 ) to give a compound of formula (VII). -CH(R')(R'') is R 1 Thus, R' and R'' are independently H or C 1-3 Alkyl or connected to C 3-5 A cycloalkyl ring may be formed.

[0142] Process 5:PG 1 can be removed from a compound of formula (VII) under standard deprotection conditions known to one skilled in the art to give a compound of formula (VI). For example, PG 1 When is Cbz, this group can be cleaved by, among other known methods, e.g., Pd / C in MeOH, H 2 can be removed under hydrogenation conditions such as

[0143] Scheme 4: Alternative synthesis of compounds of formula (VI) [ka] (In the scheme, R Q is R 1 and R 2 where PG is a nitrogen protecting group and X is a leaving group, e.g., bromo, iodo, or tosyl. This route can be carried out by reacting R 1 R 2 may be used if it is the same as

[0144] Step 1: The compound of formula (XIV) is Q -X(where R Q =R 1 =R 2 ) under basic conditions, such as NaH / THF or N-methyl-2-pyrrolidone, to give a compound of formula (VIII).

[0145] Step 2: The nitrogen protecting group is removed under standard deprotection conditions known to those skilled in the art to give a compound of formula (VI). For example, when PG is Boc, this group can be removed under acidic conditions such as HCl in 1,4-dioxane or EtOAc, among other known methods such as those described herein.

[0146] Scheme 5: R 5 is OR''' and R 7 Process A for preparing a compound of formula (III) when is absent [ka] (In the scheme, R 4 , n and R 8 is defined elsewhere herein, and R''' is C 1-3 Alkyl, C 1-3 Haloalkyl or C 3-10 cycloalkyl, Alk is C 1-4 alkyl, LG is a leaving group, for example, halo, such as bromo, and X is halo or OH.

[0147] Step 1: Compounds of formula (XX) can be prepared by the addition of a base, e.g., Cs in DMA. 2 CO 3 In the presence of S N 2 under reaction conditions (X is halo, e.g., chloro or bromo) or in a solvent, e.g., THF, DIAD, PPh 3 with R'''-X under Mitsunobu reaction conditions (X is OH) in the presence of to give compounds of formula (XIX).

[0148] Step 2: The alkyl ester in the compound of formula (XIX) can be prepared by reaction under basic conditions (e.g., MeOH / H 2 Hydrolysis under LiOH in O gives the carboxylic acid of formula (XVIII).

[0149] Step 3: The compound of formula (XVIII) is carbonylated under palladium catalyzed conditions, e.g., Pd catalyst, base, e.g., TEA, CO, alcohol, e.g., EtOH, and DMA, to give the compound of formula (XVII).

[0150] Step 4: The compound of formula (XVII) is coupled with a compound of formula (XVI) under standard coupling conditions (e.g., EDCI, DMAP and DCM, or other conditions disclosed herein) to give a compound of formula (XV).

[0151] Step 5: For example, basic conditions, such as MeOH / H 2 Hydrolysis of the alkyl ester in the compound of formula (XV) under LiOH in O provides the compound of formula (III).

[0152] For Method A, it is also possible to swap steps 3 and 4.

[0153] Scheme 6: R 5 Alternative synthesis of compounds of formula (XVIII) where is OR''' [ka] (In the scheme, R 4 and n are defined elsewhere herein, and R''' is C 1-3 Alkyl, C 1-3 Haloalkyl or C 3-10 cycloalkyl and LG is a leaving group, for example, halo, for example bromo.

[0154] Compounds of formula (XXI) are reacted with R'''-OH under basic conditions (eg, NaH in DMF) to give compounds of formula (XVIII).

[0155] Scheme 7: R 5 is OR''' and R 8 is linked by N, for example, N(C 1-3 Alkyl) 2 or N-linked 4-8 membered heterocycloalkyl, R 7 is absent, [ka] (In the scheme, R 4 and n are defined elsewhere herein, and R''' is C 1-3 Alkyl, C 1-3 Haloalkyl or C 3-10 cycloalkyl, Alk is C 1-4 alkyl, LG is a leaving group, for example, halo, such as bromo, and X is halo or OH.

[0156] Step 1: Compounds of formula (XXIII) can be prepared by the addition of a base, e.g., Cs in DMA. 2 CO 3 In the presence of S N 2 under reaction conditions (X is halo, e.g., chloro or bromo) or in a solvent, e.g., THF, DIAD, PPh 3 with R'''-X under Mitsunobu reaction conditions (X is OH) in the presence of to give compounds of formula (XXII).

[0157] Step 2: Compounds of formula (XXII) can be prepared by palladium catalysis (e.g., Hellman's palladacycle, [(tBu) 3 PH]BF 4 , Mo(CO) 6 , DBU and 1,4-dioxane) to give a compound of formula (XV).

[0158] Compounds of formula (XV) can be converted to compounds of formula (III) using the methods disclosed herein.

[0159] It is possible to hydrolyze the alkyl ester in the compound of formula (XXII) before carrying out step 2. This route also allows the preparation of a compound of formula (I), 5 is H and R 6 is -OR''' and R 7 teeth, [ka] The compound of formula (III) may be used to synthesize a compound of formula (III) which is a precursor to

[0160] Scheme 8: Compounds of formula (III) 4 is fluoro and R 5 is OR''', and R 7 is non-existent, and R 8 represents an N-linked group, e.g., N(C 1-3 Alkyl) 2 or N-linked 4-8 membered heterocycloalkyl [ka] (In the scheme, R 4 and n are defined elsewhere herein, and R''' is C 1-3 Alkyl, C 1-3 Haloalkyl or C 3-10 cycloalkyl, Alk is C 1-4 alkyl, LG is a leaving group, for example, halo, such as bromo, and X is halo or OH.

[0161] Step 1: Compound of formula (XXVI) can be prepared by the addition of a base, e.g., Cs in DMA. 2 CO 3 In the presence of S N 2 under reaction conditions (X is halo, e.g., chloro or bromo) or in a solvent, e.g., THF, DIAD, PPh 3 with R'''-X under Mitsunobu reaction conditions (X is OH) in the presence of to give compounds of formula (XXV).

[0162] Step 2: Compounds of formula (XXV) can be prepared by the addition of a strong base such as LDA, CO in THF. 2 to give compounds of formula (XXIV).

[0163] Step 3: Compounds of formula (XXIV) can be prepared by palladium catalysis (e.g., Hellman's palladacycle, [(tBu) 3 PH]BF 4 , Mo(CO) 6 , DBU and 1,4-dioxane) to give a compound of formula (III).

[0164] Scheme 9: R 5 is linked through N, for example, NR 5b R 5c or N-linked 4- to 7-membered heterocycloalkyl, R 7 Process D for preparing compounds of formula (III) when is absent [ka] (In the scheme, R 4 , R 8 , n is defined elsewhere herein, and R 5 represents an N-linked group, e.g., NR 5b R 5c or an N-linked 4- to 7-membered heterocycloalkyl, Alk being C 1-4 alkyl, LG is a leaving group, for example, halo, such as bromo, and X is halo or OH.

[0165] Step 1: Compounds of formula (XXXI) can be prepared by basic conditions, e.g., K 2 CO 3 and R under KI 5 -H to give a compound of formula (XXX).

[0166] Step 2: The alkyl ester in the compound of formula (XXX) can be prepared by, for example, reaction under basic conditions, for example, LiOH, MeOH / THF / H 2Hydrolysis under O gives the compound of formula (XXIX).

[0167] Step 3: The compound of formula (XXIX) is coupled with the compound of formula (XVI) under conditions such as HATU, DIPEA, NaH in DMF, or other conditions disclosed herein to give the compound of formula (XXVIII).

[0168] Step 4: The compound of formula (XXVIII) can be carbonylated under palladium catalyzed reaction conditions (e.g., Pd catalyst, KOAc, CO and an alcohol such as EtOH) to give the compound of formula (XXVII).

[0169] Step 5: The alkyl ester in the compound of formula (XXVIII) can be prepared by, for example, reaction under basic conditions, for example, LiOH, MeOH / THF / H 2 Hydrolysis under O gives the compound of formula (III).

[0170] Scheme 10: R 5 NR 5b R 5c and R 5b and R 5c Alternative synthesis of (XXX) when is the same [ka] (In the scheme, R 4 and n are defined elsewhere herein; R S =R 5b =R 5c and Alk is C 1-4 LG is a leaving group, for example, halo, for example, bromo, and X is halo, for example, chloro or bromo.

[0171] Compounds of formula (XXXII) can be prepared by reacting R S -X to give a compound of formula (XXX).

[0172] Scheme 11: R 5is linked through N, for example, NR 5b R 5c or N-linked 4- to 7-membered heterocycloalkyl, R 7 Process E for preparing compounds of formula (III) when is absent [ka] (In the scheme, R 4 , R 8 , n is defined elsewhere herein, and R 5 represents an N-linked group, e.g., NR 5b R 5c or an N-linked 4- to 7-membered heterocycloalkyl, Alk being C 1-4 alkyl and LG is a leaving group, for example, halo, for example bromo).

[0173] Step 1: A compound of formula (XXXV) is coupled with a compound of formula (XVI) under coupling conditions such as HATU, DIPEA, NaH in DMF, or other conditions disclosed herein to provide a compound of formula (XXXIV).

[0174] Step 2: Compounds of formula (XXXIV) can be prepared by basic conditions, e.g., K 2 CO 3 and R under K (or other conditions disclosed herein). 5 -H to give a compound of formula (XXXIII).

[0175] Step 3: The compound of formula (XXXIII) can be carbonylated under palladium catalyzed reaction conditions (e.g., Pd catalyst, KOAc, CO and an alcohol such as EtOH) to give the compound of formula (XXVII).

[0176] Step 4: The alkyl ester in the compound of formula (XXVII) can be prepared by, for example, reaction under basic conditions, for example, LiOH, MeOH / THF / H 2 Hydrolysis under O gives the compound of formula (III).

[0177] Scheme 12: R 5 is linked through N, for example, NR 5b R 5c or N-linked 4- to 7-membered heterocycloalkyl, R 7 Process F for preparing compounds of formula (III) when is absent [ka] (In the scheme, R 4 , R 8 , n is defined elsewhere herein, and R 5 represents an N-linked group, e.g., NR 5b R 5c or an N-linked 4- to 7-membered heterocycloalkyl, Alk being C 1-4 (It is alkyl).

[0178] Step 1: A compound of formula (XXXVII) is coupled with a compound of formula (XVI) under coupling conditions such as HATU, DIPEA, NaH in DMF, or other conditions disclosed herein to provide a compound of formula (XXXVI).

[0179] Step 2: Compounds of formula (XXXVI) can be prepared by reacting R 5 -H to give a compound of formula (XXVII). The compound of formula (XXVII) may be converted to a compound of formula (III) as described herein.

[0180] Compounds of formula (III) and related intermediates, 7 (wherein is not absent) can be prepared by adaptation of Schemes 5, 7, 8, 9, 11 and 12, which are within the knowledge of one skilled in the art.

[0181] Scheme 13: R 7 Alternative synthesis of compounds of formula (I) in which [ka] (In the scheme, R1 , R 2 , R 3 , R 4 , R 5 , R 8 , n and m are defined elsewhere herein, and Alk is C 1-4 alkyl and LG is a leaving group, for example, halo, for example bromo).

[0182] Step 1: A compound of formula (XXIV) can be carbonylated under palladium catalyzed reaction conditions (e.g., Pd catalyst, TEA, CO, an alcohol such as EtOH and DMA) to give a compound of formula (XXXX).

[0183] Step 2: A compound of formula (XXXX) is coupled with a compound of formula (II) under standard coupling conditions (e.g., EDCI, HOBt, DIPEA and DCM, or other conditions disclosed herein) to give a compound of formula (XXXIX).

[0184] Step 3: The alkyl ester in the compound of formula (XXXIX) can be prepared by, for example, reaction under basic conditions, for example, LiOH, MeOH / THF / H 2 Hydrolysis under O gives the compound of formula (XXXVIII).

[0185] Step 4: The compound of formula (XXXVIII) is coupled with a compound of formula (XVI) under standard coupling conditions (e.g., EDCI, DMAP and DCM, or other conditions disclosed herein) to give a compound of formula (I).

[0186] Alternatively, steps 5 and 6 can be used to convert compounds of formulae (XXIV)-(XXXIX). Step 5 is a coupling reaction like step 2 in Scheme 13, and step 6 is a carbonylation like step 1 in Scheme 13.

[0187] A compound of formula (I) 7 (wherein is not absent) can be prepared by adaptation of Scheme 13, which is within the knowledge of one skilled in the art.

[0188] The present invention provides novel intermediates as an aspect of the invention.

[0189] Thus, the present invention relates to a compound of formula (II): [ka] or its salts and / or solvates (In the formula, R 1 , R 2 , R 3 and m is as defined elsewhere herein.

[0190] The present invention also relates to a compound of formula (III): [ka] or its salts and / or solvates (In the formula, R 4 , R 5 , R 6 , R 7 and n is as defined elsewhere herein. In particular, R 5 represents an O-linked group, e.g., C 1-3 Alkoxy, C 1-3 Haloalkoxy or OC 3-10 Cycloalkyl, or N-linked groups such as NR 5b R 5c Or it can be an N-linked 4- to 7-membered heterocycloalkyl.

[0191] In some preferred compounds of formula (III), the compound of formula (III) has the following structure: [ka] or its salts and / or solvates (In the formula, R 4 , R 5 , R 6 and n is as defined elsewhere herein. In particular, R 5represents an O-linked group, e.g., C 1-3 Alkoxy, C 1-3 Haloalkoxy or OC 3-10 Cycloalkyl, or N-linked groups such as NR 5b R 5c Or it can be an N-linked 4- to 7-membered heterocycloalkyl.

[0192] The present invention also relates to a compound of formula (XXXVIII): [ka] or its salts and / or solvates (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , n and m are defined elsewhere herein.

[0193] The present invention also relates to a compound of formula (XXXIX): [ka] or its salts and / or solvates (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , n and m are defined elsewhere herein, and Alk is C 1-4 wherein the aryl group is an alkyl group.

[0194] The present invention also relates to a compound of formula (XXXXI): [ka] or its salts and / or solvates (In the formula, R 1 , R 2 , R 3 , R 4 , R 5, n and m are defined elsewhere herein, and LG provides a leaving group, for example, halo, for example bromo.

[0195] It will be understood that the salt of the compound of formula (I) for use in therapy should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include salts of the compounds of the present invention that contain a basic group, for example, an amino group, formed with acid addition salts, preferably inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid. Also included are salts formed with organic acids, such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid and 1,5-naphthalenedisulfonic acid. Other salts, such as oxalates or formates, may be used, for example, in the isolation of the compound of formula (I), and are included within the scope of the present invention, as are base addition salts, such as sodium, potassium, calcium, aluminum, zinc, magnesium and other metal salts.

[0196] Pharmaceutically acceptable salts may also be formed with organic bases, such as basic amines, such as ammonia, meglumine, tromethamine, piperazine, arginine, choline, diethylamine, benzathine or lysine.

[0197] In some embodiments, compounds of formula (I) are provided in the form of a salt, e.g., a pharma- ceutically acceptable salt. Alternatively, compounds of formula (I) are provided. When a compound contains a basic group and a free acid, it may be zwitterionic.

[0198] Suitably the compound of formula (I) is not in the form of a salt, for example not in the form of a pharma- ceutically acceptable salt.

[0199] Suitably, when the compound of formula (I) is in the form of a salt, the pharma- ceutically acceptable salt is a base addition salt, for example a carboxylate salt formed with a Group 1 metal (e.g. sodium or potassium salt), a Group 2 metal (e.g. magnesium or calcium salt) or an ammonium salt of a basic amine (e.g. NH 4 + salts), for example, sodium salts.

[0200] The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and if crystalline, may be optionally solvated, for example as a hydrate. The present invention includes within its scope stoichiometric solvates (e.g., hydrates) and compounds containing variable amounts of solvent (e.g., water). Suitably, the compounds of formula (I) are not solvates.

[0201] The present invention extends to pharma- ceutically acceptable derivatives thereof, such as pharma- ceutically acceptable prodrugs of compounds of formula (I). Exemplary prodrugs of compounds of formula (I) that contain a carboxylic acid include esters thereof, such as C 1-6 Alkyl, e.g., C 1-4 Alkyl ester) derivatives are included. Thus, in one embodiment, the compounds of formula (I) are provided as pharma- ceutically acceptable prodrugs. In another embodiment, the compounds of formula (I) are not provided as pharma-ceutically acceptable prodrugs.

[0202] It should be understood that the present invention encompasses all isomers of the compounds of formula (I), including all geometric, tautomeric and optical forms, and mixtures thereof (e.g., racemic mixtures). In particular, the invention extends to all tautomeric forms of the compounds of formula (I). When additional chiral centers are present in the compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

[0203] The present invention also includes all isotopic forms of the compounds provided herein, whether (i) in which all atoms of a given atomic number have a mass number (or mixture of mass numbers) that is predominant in nature (referred to as "natural isotopic forms"), or (ii) in which one or more atoms are replaced by atoms having the same atomic number but a mass number different from the mass number of the atom that is predominant in nature (referred to as "non-natural variant isotopic forms" herein). It is understood that atoms may naturally exist as a mixture of mass numbers. The term "non-natural variant isotopic forms" also includes embodiments in which the proportion of atoms of a given atomic number that have mass numbers that are less commonly found in nature (referred to as "uncommon isotopes" herein) is increased compared to that occurring in nature, for example, to a level of >20%, >50%, >75%, >90%, >95% or >99% depending on the number of atoms of that atomic number (the latter embodiment is referred to as "isotopically enriched variants of"). The term "non-natural variant isotopic form" also includes embodiments in which the proportion of uncommon isotopes is reduced relative to those occurring in nature. Isotopic forms can include radioactive forms (i.e., those that incorporate a radioactive isotope) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.

[0204] Thus, non-natural variant isotopic forms of a compound may contain one or more artificial or uncommon isotopes, such as deuterium ( 2 H or D), carbon-11 ( 11 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-15( 15 N), oxygen-15( 15 O), oxygen-17( 17 O), oxygen-18( 18 O), phosphorus-32( 32 P), sulfur-35( 35 S), Chlorine-36( 36 Cl), Chlorine-37( 37 Cl), Fluorine-18( 18F) Iodine-123( 123 I), iodine-125( 125 I) at one or more atoms, or may contain an increased proportion of said isotopes as compared to the proportion predominant in nature at one or more atoms.

[0205] Non-natural variant isotopic forms containing radioactive isotopes may be used, for example, for drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Non-natural variant isotope forms incorporating deuterium, i.e., 2H or D, may offer certain therapeutic advantages due to higher metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. Additionally, positron emitting isotopes, e.g., 11 C. 18 F, 15 O and 13 Non-natural variant isotopic forms can be prepared which incorporate N and may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0206] In certain embodiments, the compound of formula (I) is provided in a natural isotopic form. In certain embodiments, the compound of formula (I) is provided in a non-natural variant isotopic form. In a specific embodiment, the non-natural variant isotopic form is deuterium (i.e., 2 In some embodiments, the atom of the compound of formula (I) is in an isotopic form that is not radioactive. In some embodiments, the atom of the compound of formula (I) is in an isotopic form that is radioactive. Preferably, the radioisotope is a stable isotope. Preferably, the non-natural variant isotopic form is a pharma- ceutically acceptable form.

[0207] In one embodiment, compounds of formula (I) are provided in which a single atom of the compound exists in a non-natural variant isotopic form. In another embodiment, compounds of formula (I) are provided in which two or more atoms exist in a non-natural variant isotopic form.

[0208] Non-natural isotopically variant forms can usually be prepared by conventional techniques known to those skilled in the art or by processes described herein, for example, processes similar to those described in the accompanying examples for preparing natural isotopically variant forms. Thus, non-natural isotopically variant forms can be prepared using appropriate isotopically variant (or labeling) reagents instead of the conventional reagents used in the examples. Since the compounds of formula (I) are intended for use in pharmaceutical compositions, it will be readily understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more preferably at least 75% pure and preferably at least 85%, particularly at least 98% pure (% being weight on a weight basis). Non-pure preparations of the compounds can be used to prepare purer forms for use in pharmaceutical compositions.

[0209] Treatment indications Targeting MTHFD2 and optionally additionally MTHFD1 D / Cd with specific inhibitors offers a novel and attractive approach to control 1C pathways in autoimmunity, inflammation and cancer with the potential for an improved safety profile compared to clinically validated drugs such as MTX that more broadly block 1C metabolism. Selectively inhibiting MTHFD2 represents a particularly attractive option for autoimmunity with the potential to very specifically target activated lymphocytes that orchestrate inflammation and tissue damage.

[0210] Compounds of formula (I) are utilized in therapy, particularly to treat or prevent proliferative diseases, such as inflammatory, autoimmune or fibrotic diseases, and cancer. Biological Example 1 shows that compounds of the present invention have inhibitory activity against MTHFD2. Certain examples show comparable inhibitory activity against MTHFD2 and MTHFD1 D / Cd, and therefore certain compounds of formula (I) are expected to have utility in treating diseases in which targeting both MTHFD2 and MTHFD1 D / Cd may be beneficial. By comparable activity, this means that the selectivity for targeting MTHFD2 over targeting MTHFD1 D / Cd is less than 3-fold (e.g., as shown by the ratio values ​​in Table 1), i.e., the IC for MTHFD1 D / Cd is 1.0-1.0 times higher than that of MTHFD1 D / Cd. 50 However, the IC for MTHFD2 50 Certain other examples are selective (e.g., 3-30 fold selective or >30 fold selective) for MTHFD2 over MTHFD1 D / Cd (e.g., as indicated by the ratio values ​​in Table 1, i.e., IC for MTHFD1 D / Cd). 50 Values ​​are IC for MTHFD2 50 values), and therefore certain compounds of formula (I) are expected to have utility in treating diseases in which targeting MTHFD2 over MTHFD1 D / Cd may be beneficial. Certain other examples are selective (e.g., 30-600 fold) for MTHFD2 over MTHFD1 D / Cd (e.g., as shown by the ratio values ​​in Table 1, i.e., IC for MTHFD1 D / Cd). 50 Values ​​are IC for MTHFD2 50 30-fold higher than the value of MTHFD1 D / Cd), and therefore certain compounds of formula (I) are expected to have utility in treating diseases in which targeting MTHFD2 over MTHFD1 D / Cd may be beneficial.

[0211] References to targeting MTHFD1 throughout are interchangeable with targeting MTHFD1 D / Cd. Biological Example 2 shows that certain examples, unlike Reference Example 1, do not have off-target effects on α4β2 nicotinic receptors, as shown in Table 2. Therefore, it is expected that compounds of formula (I) are more suitable for drug development compared to Reference Example 1.

[0212] Thus, in a further aspect, the present invention provides a compound of formula (I) or a pharma-ceutically acceptable salt and / or solvate thereof as defined herein for use as a medicament.

[0213] In a further aspect, the present invention provides a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in treating or preventing a disease selected from the group consisting of inflammatory, autoimmune or fibrotic diseases, and cancer.

[0214] In a further aspect, the present invention provides a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in treating a disease selected from the group consisting of inflammatory, autoimmune or fibrotic diseases, and cancer.

[0215] In a further aspect, the present invention provides a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in preventing a disease selected from the group consisting of inflammatory, autoimmune or fibrotic diseases, and cancer.

[0216] In a further aspect, the present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein in the manufacture of a medicament for the treatment or prevention of a disease selected from the group consisting of inflammatory, autoimmune or fibrotic diseases, and cancer.

[0217] In a further aspect, the present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt and / or solvate thereof as defined herein in the manufacture of a medicament for the treatment of a disease selected from the group consisting of inflammatory, autoimmune or fibrotic diseases, and cancer.

[0218] In a further aspect, the present invention provides the use of a compound of formula (I) as defined herein, or a pharma- ceutically acceptable salt and / or solvate thereof, in the manufacture of a medicament for the prevention of a disease selected from the group consisting of inflammatory, autoimmune or fibrotic diseases, and cancer.

[0219] In a further aspect, the present invention provides a method of treating or preventing a disease selected from the group consisting of inflammatory, autoimmune or fibrotic diseases, and cancer, comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0220] In a further aspect, the present invention provides a method of treating a disease selected from the group consisting of inflammatory, autoimmune or fibrotic diseases, and cancer, comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0221] In a further aspect, the present invention provides a method of preventing a disease selected from the group consisting of inflammatory, autoimmune or fibrotic diseases, and cancer, comprising administering a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof.

[0222] In any one of the above embodiments, the disease is an inflammatory, autoimmune or fibrotic disease. Alternatively, the disease is cancer.

[0223] Suitably, compounds of formula (I) exhibiting comparable inhibitory activity against MTHFD2 and MTHFD1 D / Cd are for use in treating or preventing inflammatory, autoimmune or fibrotic diseases.

[0224] Suitably, compounds of formula (I) exhibiting comparable inhibitory activity against MTHFD2 and MTHFD1 D / Cd are for use in treating or preventing cancer.

[0225] Suitably, compounds of formula (I) that are selective (e.g., 3-30 fold selective or >30 fold selective) for MTHFD2 over MTHFD1 D / Cd are for use in treating or preventing inflammatory, autoimmune or fibrotic diseases.

[0226] Suitably, compounds of formula (I) that are selective (e.g., 3-30 fold selective or >30 fold selective) for MTHFD2 over MTHFD1 D / Cd are for use in treating or preventing cancer.

[0227] Suitably, the inflammatory, autoimmune or fibrotic disease is selected from the group consisting of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, psoriasis, myasthenia gravis (MG), Crohn's disease, multiple sclerosis, sarcoidosis, ulcerative colitis, celiac disease, systemic lupus erythematosus (SLE), Sjogren's syndrome, asthma, atopic dermatitis, vitiligo, systemic sclerosis (SSC), graft versus host disease (GvHD), type 1 diabetes, hidradenitis suppurativa, idiopathic pulmonary fibrosis (IPF), interstitial lung disease (ILD) and non-alcoholic steatohepatitis (NASH).

[0228] The following diseases can be treated using methotrexate, which targets enzymes on the one-carbon (1C) metabolic pathway and has known utility in treating autoimmune diseases, as described in the introduction (Kozminski P. et al., 2020; Kerschbaumer A. et al., 2019; Ferrara G. et al., 2018; Gotterer L. et al., 2016; Diaz-Manera J. et al., 2012; Chantam W. 2010; Smolen JS. et al., 2010; Mahr AD. et al., 2007; Baughman RP. et al. 1999). Since the compounds of the present invention are expected to act in a similar but superior manner to methotrexate, it is expected that the compounds of formula (I) will have utility in treating the diseases listed below.

[0229] Thus, preferably, the inflammatory, autoimmune or fibrotic disease is selected from the group consisting of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, psoriasis, myasthenia gravis (MG), Crohn's disease, multiple sclerosis and sarcoidosis.

[0230] The following diseases are associated with overexpression of MTHFD2 (Aune TM. et al., 2017; Sugiura A. et al., 2022), and therefore, inhibition of MTHFD2 using compounds of formula (I) represents a strategy for treating the diseases listed below.

[0231] Suitably, the inflammatory, autoimmune or fibrotic disease is selected from the group consisting of ulcerative colitis, celiac disease, systemic lupus erythematosus (SLE) and Sjogren's syndrome.

[0232] The following diseases are related to T cell differentiation as described in the introduction and show strong association with CD4 +The T cell subsets Th17 and Th1 had the highest expression of MTHFD2 (Sun L. et al., 2023; Witte K. et al., 2023; Gaydosik AM. et al., 2021; Karl F. et al., 2021; Raphael I. et al., 2020; Sabat R. et al., 2019). The known MTHFD2 inhibitor DS18561882 inhibited CD4 + It significantly reduced the number of Th1 and Th17 cells differentiated in vitro from T cells and the expression of Th1 and Th17 cytokines, respectively. Thus, inhibiting MTHFD2 with compounds of formula (I), which are superior to DS18561882 as shown in the Biological Examples section, represents a strategy for treating the diseases listed below.

[0233] Preferably, the inflammatory, autoimmune or fibrotic disease is selected from the group consisting of asthma, atopic dermatitis, vitiligo, systemic sclerosis (SSC), graft-versus-host disease (GvHD), type 1 diabetes and hidradenitis suppurativa.

[0234] The following diseases are associated with fibrosis, which shares many underlying disease mechanisms with inflammation and autoimmunity (Yanjie G. et al., 2023; Hamanaka RB., et al., 2022; Hiroshi F. et al., 2021). Thus, the compounds of formula (I) are expected to have utility in treating the following diseases:

[0235] Suitably, the inflammatory, autoimmune or fibrotic disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), interstitial lung disease (ILD) and non-alcoholic steatohepatitis (NASH).

[0236] The following diseases may be treated using methotrexate, which targets enzymes in the one-carbon (1C) metabolic pathway as described in the introduction and has known utility in treating cancer, particularly those listed below (Gong F. et al., 2019; De Wilde V. et al., 2016; Bergner N. et al., 2012; Zhu JJ. et al., 2009; Abrao R. et al., 2008; Fahey JB. 2007; Meyers PA. et al., 2005; Batchelor TT. et al., 2003; Khan RB. et al., 2002; Krailo M. et al., 1987; Rizzoli V. et al., 1985; Canello GP., et al., 1981; Nilsson R. et al., 2014). Since the compounds of the present invention are expected to act in a manner similar to but superior to methotrexate, it is expected that the compounds of formula (I) will have utility in treating the diseases listed below. Furthermore, MTHFD2 knockdown in tumor cell lines is known to be associated with anti-proliferative effects (Zhu Z., et al., 2020). Therefore, inhibitors of MTHFD2, such as the compounds of formula (I), are expected to have utility in treating cancer.

[0237] Suitably, the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), primary central nervous system lymphoma (PCNSL), lymphoma, mycosis fungoides, refractory non-Hodgkin's lymphoma (NHL), head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), bladder cancer, lymphoma, breast cancer, osteosarcoma, gestational trophoblastic neoplasia (GTN), acute myeloid leukemia (AML), hepatocellular carcinoma, renal cell carcinoma, colorectal cancer, lung cancer, glioma, ovarian cancer, melanoma, and solid tumors, such as cervical, uterine, testicular, gastric, prostate and pancreatic tumors.

[0238] Preferably, the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), primary central nervous system lymphoma (PCNSL), lymphoma, mycosis fungoides, refractory non-Hodgkin's lymphoma (NHL) and acute myeloid leukemia (AML).

[0239] References providing associations between diseases and MTHFD2 and / or MTHFD1(D / Cd) are provided in the references section and above.

[0240] Administration The compound of formula (I) is usually administered as a pharmaceutical composition.Thus, in one embodiment, a pharmaceutical composition is provided that comprises a compound of formula (I) and one or more pharma-ceutically acceptable diluents or carriers.The present invention also provides a pharmaceutical composition that comprises a compound of formula (I) as defined herein or a pharma-ceutically acceptable salt and / or solvate thereof for use as a medicament.

[0241] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in treating or preventing a disease selected from the group consisting of an inflammatory disease, an autoimmune disease and cancer.

[0242] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in treating a disease selected from the group consisting of an inflammatory disease, an autoimmune disease and cancer.

[0243] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined herein or a pharma- ceutically acceptable salt and / or solvate thereof for use in preventing a disease selected from the group consisting of an inflammatory disease, an autoimmune disease and cancer.

[0244] The compounds of formula (I) may be administered by any convenient way, for example by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration, and the pharmaceutical compositions adapted accordingly.

[0245] The compounds of formula (I) may be administered locally to a target organ, for example, to the eye, lung, nose or skin.Thus, the present invention provides pharmaceutical compositions comprising a compound of formula (I), optionally in combination with one or more topically acceptable diluents or carriers.

[0246] Compounds of formula (I) that are active when given orally may be formulated as liquids or solids, for example, as syrups, suspensions, emulsions, tablets, capsules or lozenges.

[0247] Liquid formulations may generally consist of a suspension or solution of the compound of formula (I) in a suitable liquid carrier(s).Preferably, the carrier is non-aqueous, for example, polyethylene glycol or oil.The formulation may also contain a suspending agent, a preservative, a flavoring agent and / or a coloring agent.

[0248] A composition in the form of a tablet may be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose, and cellulose.

[0249] A composition in the form of a capsule may be prepared using conventional encapsulation procedures, for example, pellets containing the active ingredient may be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension may be prepared using any suitable pharmaceutical carrier(s), for example, aqueous gums, celluloses, silicates or oils, and the dispersion or suspension then filled into a soft gelatin capsule.

[0250] A typical parenteral composition consists of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, such as polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. Alternatively, the solution can be lyophilized and then reconstituted with a suitable solvent just prior to administration.

[0251] Compositions for nasal administration can be conveniently formulated as aerosols, drops, gels and powders. Aerosol formulations typically contain a solution or fine suspension of a compound of formula (I) in a pharma-ceutically acceptable aqueous or non-aqueous solvent, and are usually provided in single or multiple doses in sterile form in a sealed container that can take the form of a cartridge or refill for use with a nebulizer device. Alternatively, the sealed container can be a disposable dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser fitted with a metering valve. When the dosage form comprises an aerosol dispenser, it will contain a propellant that can be a compressed gas, such as air, or an organic propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). The aerosol dosage form can take the form of a pump-atomizer.

[0252] Topical administration to the lung can be achieved by use of an aerosol formulation, which typically contains the active ingredient suspended or dissolved in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or hydrofluorocarbon (HFC).

[0253] Local administration to the lungs can also be achieved by the use of non-pressurized formulations, such as aqueous solutions or suspensions. These can be administered by means of a nebulizer, which can be hand-held, portable, or for home or hospital use (i.e., non-portable). The formulation can include excipients, such as water, buffers, tonicity adjusters, pH adjusters, surfactants, and cosolvents.

[0254] Topical administration to the lung may also be achieved by use of a dry powder formulation, which will typically contain a locally acceptable diluent such as lactose, glucose or mannitol, preferably lactose.

[0255] The compound of the present invention can also be administered rectally in the form of suppository or enema, including, for example, aqueous or oily solution, as well as suspension and emulsion and foam.Such compositions are prepared according to standard procedures well known to those skilled in the art.For example, suppository can be prepared by mixing active ingredient with conventional suppository base, for example, cocoa butter or other glycerides.In this case, drug is mixed with suitable non-irritating excipient that is solid at normal temperature but liquid at rectal temperature, and therefore can melt in rectum and release drug.Such materials are cocoa butter and polyethylene glycol.

[0256] Typically, for compositions intended to be administered topically to the eye in the form of eye drops or eye ointment, the total amount of the compounds of the invention will be from about 0.0001 to less than 4.0% (w / w).

[0257] Preferably, for topical ocular administration, compositions administered in accordance with the present invention will be formulated as solutions, suspensions, emulsions and other dosage forms.

[0258] The composition administered according to the present invention may include various other components, including but not limited to tonicity agents, buffers, surfactants, stabilizing polymers, preservatives, cosolvents and viscosity building agents.Suitable pharmaceutical compositions of the present invention include the compounds of the present invention formulated with tonicity agents and buffers.Pharmaceutical compositions of the present invention may further include optional surfactants and / or emollients and / or stabilizing polymers.

[0259] Various tonicity agents may be used to adjust the tonicity of the composition, preferably to that of natural tears for ophthalmic compositions. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, simple sugars such as dextrose, fructose, galactose, and / or simple polyols such as the sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, and hydrogenated starch hydrolysates may be added to the composition to approximately physiological tonicity. Such amount of tonicity agent will vary depending on the particular agent added. Usually, however, the composition will have a tonicity agent in an amount sufficient such that the final composition has an osmolality acceptable for the eye (usually about 150-450 mOsm, preferably 250-350 mOsm, most preferably about 290 mOsm). Usually, the tonicity agents of the present invention will be present in the range of 2-4% w / w. Preferred tonicity agents of the present invention include simple sugars or sugar alcohols such as D-mannitol.

[0260] An appropriate buffer system (e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid) may be added to the composition to prevent pH changes under storage conditions. The specific concentration will vary depending on the agent used. However, preferably, the buffer will be selected to maintain a target pH within the range of pH 5-8, more preferably a target pH of pH 5-7.

[0261] Surfactants may be optionally used to deliver higher concentrations of the compounds of the present invention. Surfactants function to solubilize compounds and stabilize colloidal dispersions, such as micellar solutions, microemulsions, emulsions and suspensions. Examples of surfactants that may be optionally used include polysorbates, poloxamers, polyoxyl 40 stearate, polyoxyl castor oil, tyloxapol, Triton, and sorbitan monolaurate. Preferred surfactants used in the present invention have a hydrophilic / lipophilic / balance "HLB" in the range of 12.4 to 13.2 and are acceptable for ophthalmic use, such as Triton™ X-114 and tyloxapol.

[0262] An additional agent that may be added to the ophthalmic composition of the compounds of the present invention is a demulcent, which acts as a stabilizing polymer. The stabilizing polymer should be an ionic / charged example in preference to topical ocular applications, more specifically a polymer that carries a negative charge on its surface that may exhibit a zeta potential (-) of 10-50 mV for physical stability, and is capable of creating a dispersion in water (i.e., is water-soluble). The preferred stabilizing polymer of the present invention would be a polyelectrolyte, or polyelectrolyte(s), from the family of crosslinked polyacrylates, such as Carbomer and Pemulen®, specifically Carbomer 974p (polyacrylic acid) (0.1-0.5% w / w).

[0263] Other compounds may also be added to the ophthalmic composition of the compound of the present invention to increase the viscosity of the carrier. Examples of viscosity enhancers include, but are not limited to, polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextran, various polymers of the cellulose family; vinyl polymers; and acrylic acid polymers.

[0264] Topical ophthalmic products are typically packaged in multi-dose form. Thus, a preservative is required to prevent microbial contamination during use. Suitable preservatives include benzalkonium chloride, chlorobutanol, benzodecinium bromide, methylparaben, propylparaben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art. Such preservatives are typically used at levels of 0.001-1.0% w / v. The unit dose compositions of the present invention are sterile, but will typically not be preserved. As such, such compositions will usually not contain preservatives.

[0265] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, where the compound of formula (I) is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

[0266] Compositions suitable for transdermal administration include ointments, gels, and patches.

[0267] The composition may contain 0.1% to 100% by weight, for example 10 to 60% by weight, of the compound of formula (I), depending on the method of administration. The composition may contain 0% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration. The composition may contain 0.05 mg to 1000 mg, for example 1.0 mg to 500 mg, for example 1.0 mg to 50 mg, for example about 10 mg, of the compound of formula (I), depending on the method of administration. The composition may contain 50 mg to 1000 mg, for example 100 mg to 400 mg, of the carrier, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual manner depending on the severity of the disorder, the weight of the affected person, and other similar factors. However, as a general guideline, suitable unit doses may be from 0.05 to 1000 mg, more preferably from 1.0 to 500 mg, for example from 1.0 mg to 50 mg, for example about 10 mg, and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for a number of weeks or months.

[0268] In some embodiments of the present invention, the compound of formula (I) is used in combination with additional therapeutic agents or drugs.When the compound of formula (I) is used in combination with other therapeutic agents, the compounds can be administered by any convenient route, either sequentially or simultaneously.Alternatively, the compounds can be administered separately.

[0269] Compounds of formula (I) may exhibit, or be expected to have, one or more of the following desirable properties: ·Inhibitory activity against MTHFD1 and MTHFD2; ·Selective inhibitory activity against MTHFD2 over MTHFD1; · No off-target effects, e.g., on α4β2 nicotinic receptors; Improved suitability as a potential drug candidate; Improved oral systemic bioavailability; · Good tolerability, for example by limiting the side effects exhibited by other medicines that broadly target 1C metabolism, e.g. MTX; ·Low toxicity at relevant therapeutic doses; · Notable anti-inflammatory profile; Disease-modifying effects.

[0270] The present invention can be described by the following items: Item 1. Compound of formula (I): [ka] (In the formula, R 1 is C 1-4 Alkyl or C 3-5 is cycloalkyl; R 2 is C 1-4 is alkyl; or R 1 and R 2 are connected to form a 5- to 7-membered heterocycloalkyl; R 3 is C 1-3selected from the group consisting of alkyl and halo; R 4 is C 1-3 Alkyl, halo, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, NR 4a R 4b and 4- to 7-membered heterocycloalkyl; R 4a H and C 1-3 selected from the group consisting of alkyl; R 4b H and C 1-3 selected from the group consisting of alkyl; m is 0, 1 or 2; n is 0, 1 or 2; R 5 , R 6 and R 7 is defined as follows: (a)R 6 teeth, [ka] and R 7 is non-existent; R 5 H, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a Optionally substituted by (e.g., R 5 H, halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a optionally replaced by ); R 5a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl; R 8 is C 3-6 Cycloalkyl, NR 8b R 8c and 4-10 (e.g., 4-8) membered heterocycloalkyl, 3-6 Cycloalkyl and 4-10 (e.g., 4-8) membered heterocycloalkyl can each be selected from one or more R 8a and optionally replaced by R 8a is C 1-3 Alkyl, C substituted by OH 1-3 Alkyl, OC 1-2 Alkyl-substituted C 1-2 Alkyl, C 1-3 Alkoxy, halo and C 1-3 haloalkyl (e.g., R 8a is C 1-3 Alkyl, halo and C 1-3 haloalkyl); R 8b , H, C 1-3 Alkyl and C 3-6 cycloalkyl; R 8c , H, C 1-3 Alkyl and C 3-6 cycloalkyl; or: (b)R 7 teeth, [ka] is: (i)R 6 is H and R 5 H, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a Optionally substituted by (e.g., R 5 H, halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a optionally replaced by ); R 5a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5bH and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl; or (ii)R 5 is H and R 6 H, halo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 6b R 6c and 4- to 7-membered heterocycloalkyl, 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 6a Optionally substituted by (e.g., R 6 H, halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 6b R 6c and 4- to 7-membered heterocycloalkyl, 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 6a optionally replaced by ); R 6a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 6a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 6b H and C 1-3 selected from the group consisting of alkyl; R 6c is C1-3 Alkyl and C 3-6 cycloalkyl; or (iii)R 5 and R 6 are connected to form a 4- to 8-membered heterocyclic ring; R 8 is C 3-6 Cycloalkyl, NR 8b R 8c and 4-10 (e.g., 4-8) membered heterocycloalkyl, 3-6 Cycloalkyl and 4-10 (e.g., 4-8) membered heterocycloalkyl can each be selected from one or more R 8a and optionally replaced by R 8a is C 1-3 Alkyl, C substituted by OH 1-3 Alkyl, OC 1-2 Alkyl-substituted C 1-2 Alkyl, C 1-3 Alkoxy, halo and C 1-3 haloalkyl (e.g., R 8a is C 1-3 Alkyl, halo and C 1-3 haloalkyl); R 8b , H, C 1-3 Alkyl and C 3-6 cycloalkyl; R 8c , H, C 1-3 Alkyl and C 3-6 cycloalkyl; or a pharma- ceutically acceptable salt and / or solvate thereof.

[0271] Item 2. The compound of formula (I) according to item 1: [ka] (In the formula, R 1 is C 1-4 Alkyl or C 3-5is cycloalkyl; R 2 is C 1-4 is alkyl; or R 1 and R 2 are connected to form a 5- to 7-membered heterocycloalkyl; R 3 is C 1-3 selected from the group consisting of alkyl and halo; R 4 is C 1-3 Alkyl, halo, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 selected from the group consisting of haloalkoxy and 4- to 7-membered heterocycloalkyl; R 6 teeth, [ka] and R 7 is non-existent; or R 7 teeth, [ka] and; R 6 but [ka] and R 7 If is non-existent: R 5 H, halo, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl; R 8 is C 3-6 Cycloalkyl, N(C 1-3 Alkyl) 2 and 4-8 membered heterocycloalkyl, 3-6 Cycloalkyl and 4- to 8-membered heterocycloalkyl may each be represented by one or more R 8a and optionally substituted by R 8a is C 1-3 Alkyl, halo and C 1-3 haloalkyl; or: R 7 but [ka] If: R 6 is H and R 5 H, halo, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C 1-3alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl; or R 5 is H and R 6 H, halo, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 6b R 6c and 4- to 7-membered heterocycloalkyl, 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 6a is optionally replaced by; R 6a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 6a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 6b H and C 1-3 selected from the group consisting of alkyl; R 6c is C 1-3 Alkyl and C 3-6 cycloalkyl; or R 5 and R 6 are connected to form a 4- to 8-membered heterocyclic ring; R 8 is C 3-6 Cycloalkyl, N(C 1-3 Alkyl)2 and 4-8 membered heterocycloalkyl, 3-6 Cycloalkyl and 4- to 8-membered heterocycloalkyl may each be represented by one or more R 8a and optionally substituted by R 8a is C 1-3 Alkyl, halo and C 1-3 haloalkyl; m is 0, 1 or 2; n is 0, 1 or 2); or a pharma- ceutically acceptable salt and / or solvate thereof.

[0272] Item 3.R 1 is C 1-4 3. The compound according to item 1 or 2, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl.

[0273] Item 4.R 1 is methyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0274] Item 5.R 1 is C 3-5 3. The compound according to item 1 or 2, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is cycloalkyl.

[0275] Item 6.R 1 is cyclopropyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0276] Item 7.R 2 7. The compound according to any one of items 1 to 6, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is methyl.

[0277] Item 8.R 1 and R 2 is connected to form a 5- to 7-membered heterocycloalkyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0278] Item 9.R 1 and R 2 is connected to form a 6-membered heterocycloalkyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0279] Item 10.R 3 is C 1-3 10. The compound according to any one of items 1 to 9, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl.

[0280] Item 11.R 3 is methyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0281] Item 12.R 3 10. The compound according to any one of items 1 to 9, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein: is halo.

[0282] Item 13.R 3 is chloro, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0283] Item 14. The compound according to any one of items 1 to 9, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein m=0.

[0284] Item 15. The compound according to any one of items 1 to 13, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein m=1.

[0285] Item 16. The compound according to any one of items 1 to 13, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein m=2.

[0286] Item 17.R 4 is C 1-3 17. The compound according to any one of items 1 to 16, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl.

[0287] Item 18.R 4 18. The compound according to item 17, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is methyl.

[0288] Item 19.R 4 17. The compound according to any one of items 1 to 16, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein: is halo.

[0289] Item 20.R 4 is selected from the group consisting of chloro and fluoro, e.g. fluoro, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0290] Item 21.R 4 is C 1-3 17. The compound according to any one of items 1 to 16, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein: R is haloalkyl.

[0291] Item 22.R 4 22. The compound according to item 21, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein:

[0292] Item 23.R 4 is C 1-3 17. The compound according to any one of items 1 to 16, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkoxy.

[0293] Item 24.R 4 24. The compound according to item 23, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is methoxy.

[0294] Item 25.R 4 is C 1-3 17. The compound according to any one of items 1 to 16, or a pharma- ceutically acceptable salt and / or solvate thereof, which is haloalkoxy.

[0295] Item 26.R 4is 4-7 membered heterocycloalkyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0296] Item 27.R 4 27. The compound according to item 26, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein:

[0297] Item 28.R 4 is NR 4a R 4b 17. The compound according to any one of items 1 to 16, wherein:

[0298] Item 29.R 4a is H, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0299] Item 30.R 4a is C 1-3 29. The compound according to item 28, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl, for example methyl.

[0300] Item 31.R 4b is H, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0301] Item 32.R 4b is C 1-3 29. The compound according to item 28, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl, for example methyl.

[0302] Item 33. The compound according to any one of items 1 to 16, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein n is 0.

[0303] Item 34. The compound according to any one of items 1 to 32, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein n is 1.

[0304] Item 35. The compound according to any one of items 1 to 32, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein n is 2.

[0305] Item 36. R 6 teeth, [ka] and R 7 is non-existent, 36. The compound according to any one of items 1 to 35, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0306] Item 37.R 5 is H, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0307] Item 38.R 5 is halo, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0308] Item 39.R 5 39. The compound according to item 38, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is chloro.

[0309] Item 40.R 5 is C 1-3 37. The compound according to item 36, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl, for example methyl or ethyl.

[0310] Item 41.R 5 is C 1-3 37. The compound according to item 36, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein alkoxy, for example methoxy, or ethoxy, for example methoxy.

[0311] Item 42.R 5 is C 1-337. The compound according to item 36, or a pharma- ceutically acceptable salt and / or solvate thereof, which is haloalkoxy.

[0312] Item 43.R 5 , SC 1-3 37. The compound according to item 36, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is an alkyl group.

[0313] Item 44.R 5 , SC 1-3 37. The compound according to item 36, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein: R is haloalkyl.

[0314] Item 45.R 5 is O.C. 3-10 37. The compound according to item 36, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is cycloalkyl.

[0315] Item 46.R 5 46. ​​The compound according to item 45, wherein is selected from the group consisting of cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, bicyclo[3.1.0]hexyloxy and 2-adamantanyloxy, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0316] Item 47.R 5 is 4-7 membered heterocycloalkyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0317] Item 48.R 5 48. The compound according to item 47, wherein is selected from the group consisting of pyrrolidinyl, piperidinyl, 3-azabicyclo[3.1.0]hexyl, 2-azabicyclo(2.2.1)heptyl and 7-azanorbornanyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0318] Item 49.R 5 is unsubstituted, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0319] Item 50.R 5 is one or more (e.g., 1, 2 or 3, e.g., 1) R 5a 49. The compound according to any one of items 45 to 48, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein

[0320] Item 51.R 5a is halo, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0321] Item 52.R 5a 52. The compound according to item 51, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is fluoro.

[0322] Item 53.R 5a is C 1-3 51. The compound according to item 50, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl.

[0323] Item 54.R 5a 54. The compound according to item 53, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is methyl.

[0324] Item 55.R 5 is substituted by one methyl group, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0325] Item 56.R 5 is a methyl group and a fluoro group. 5a 51. The compound according to item 50, or a pharma- ceutically acceptable salt and / or solvate thereof, substituted by a group.

[0326] Item 57. Two R's bonded to the same carbon atom 5a The group is connected to C 3-6 Cycloalkyl rings, e.g., C 351. The compound according to item 50, or a pharma- ceutically acceptable salt and / or solvate thereof, which forms a cycloalkyl ring.

[0327] Item 58.R 5 is NR 5b R 5c 37. The compound according to item 36, wherein:

[0328] Item 59.R 5b is H, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0329] Item 60.R 5b is C 1-3 59. The compound according to item 58, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl.

[0330] Item 61.R 5b 61. The compound according to item 60, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is methyl.

[0331] Item 62.R 5c is C 1-3 62. The compound according to any one of items 58 to 61, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl.

[0332] Item 63.R 5c 63. The compound according to item 62, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein is selected from the group consisting of methyl and isopropyl.

[0333] Item 64.R 5c is C 3-6 62. The compound according to any one of items 58 to 61, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is cycloalkyl.

[0334] Item 65.R 8 is C 3-665. The compound according to any one of items 1 to 64, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is cycloalkyl.

[0335] Item 66.R 8 66. The compound according to item 65, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is cyclopropyl.

[0336] Item 67.R 8 is 4-10 (e.g., 4-8) membered heterocycloalkyl; or a pharma- ceutically acceptable salt and / or solvate thereof.

[0337] Item 68.R 8are pyrrolidinyl (e.g., pyrrolidin-1-yl), piperidinyl (e.g., piperidin-1-yl), 7-azanorbornanyl, 3-azabicyclo[3.1.0]hexyl (e.g., 3-azabicyclo[3.1.0]hexan-3-yl), 6-azaspiro[2.5]octyl (e.g., 6-azaspiro[2.5]octan-6-yl) and 3-oxa-6-azabicyclo[3.2. 1]Octyl (e.g., 3-oxa-8-azabicyclo[3.2.1]octan-8-yl), 7-azabicyclo[2.2.1]heptan-7-yl, (3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl, octahydro-2H-isoindol-2-yl, 2-azaspiro[3.3]heptan-2-yl, (1S,4S)-2-oxa-5-azabicyclo [2.2.1]heptan-5-yl), 2-azabicyclo[2.2.1]heptan-2-yl), and 8-azabicyclo[3.2.1]octan-8-yl, for example pyrrolidinyl (e.g. pyrrolidin-1-yl), piperidinyl (e.g. piperidin-1-yl), 7-azanorbornanyl, 3-azabicyclo[3.1.0]hexyl (e.g. 3-azabicyclo[3.1.0]hexyl), 68. The compound according to item 67, or a pharma- ceutically acceptable salt and / or solvate thereof, selected from the group consisting of 6-azaspiro[2.5]octyl (e.g., 6-azaspiro[2.5]octan-6-yl) and 3-oxa-6-azabicyclo[3.2.1]octyl (e.g., 3-oxa-8-azabicyclo[3.2.1]octan-8-yl).

[0338] Item 69.R 8 is unsubstituted, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0339] Item 70.R 8 is one or more (e.g., 1, 2 or 3, e.g., 1) R 8a 69. The compound according to any one of items 65 to 68, or a pharma- ceutically acceptable salt and / or solvate thereof, substituted by a group.

[0340] Item 71.R 8a is C 1-3 71. The compound according to item 70, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl.

[0341] Item 72.R 8a 72. The compound according to item 71, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is methyl.

[0342] Item 73.R 8a 71. The compound according to item 70, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein: is halo.

[0343] Item 74.R 8a is C 1-3 71. The compound according to item 70, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein: R is haloalkyl.

[0344] Item 75.R 8 71. The compound according to item 70, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein: is substituted by two methyl groups.

[0345] Item 76.R 8 is N(C 1-3 Alkyl) 2 65. The compound according to any one of items 1 to 64, wherein:

[0346] Item 77.R 8 is N(CH 3 ) 2 and N(CH 3 )(CH(CH 3 ) 2 77. The compound according to item 76, selected from the group consisting of:

[0347] Item 78.R 8 is NR 8b R 8c65. The compound according to any one of items 1 to 64, wherein:

[0348] Item 79.R 8b is H, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0349] Item 80.R 8b is C 1-3 79. The compound according to item 78, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl, for example methyl.

[0350] Item 81.R 8b is C 3-6 79. The compound according to item 78, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is cycloalkyl, for example cyclopropyl or cyclopentyl.

[0351] Item 82.R 8c is H, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0352] Item 83.R 8c is C 1-3 79. The compound according to item 78, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl, for example methyl.

[0353] Item 84.R 8c is C 3-6 79. The compound according to item 78, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is cycloalkyl, for example cyclopropyl or cyclopentyl.

[0354] Item 85. R 7 teeth, [ka] That is, 44. A compound according to any one of items 1 to 43, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0355] Item 86. R 6 is H and R 5 H, halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl, 86. The compound according to item 85, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0356] Item 87. R 6 is H and R 5 H, halo, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, 3-10Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl, 86. The compound according to item 85, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0357] Item 88.R 5 88. The compound according to item 86 or 87, wherein is H, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0358] Item 89.R 5 88. The compound according to item 86 or 87, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein: is halo.

[0359] Item 90.R 5 is C 1-3 88. The compound according to item 86 or 87, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein alkyl is, for example, methyl or ethyl.

[0360] Item 91.R 5 is C 1-3 88. The compound according to item 86 or 87, or a pharma- ceutically acceptable salt and / or solvate thereof, which is alkoxy.

[0361] Item 92.R 5 is C 1-388. The compound according to item 86 or 87, or a pharma- ceutically acceptable salt and / or solvate thereof, which is haloalkoxy.

[0362] Item 93.R 5 , SC 1-3 88. The compound according to item 86 or 87, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl.

[0363] Item 94.R 5 , SC 1-3 88. The compound according to item 86 or 87, or a pharma- ceutically acceptable salt and / or solvate thereof, which is haloalkyl.

[0364] Item 95.R 5 is O.C. 3-10 88. The compound according to item 86 or 87, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is cycloalkyl.

[0365] Item 96.R 5 96. The compound according to item 95, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein:

[0366] Item 97.R 5 88. The compound according to item 86 or 87, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein: is 4-7 membered heterocycloalkyl.

[0367] Item 98.R 5 97. The compound according to any one of items 95 to 96, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein: is unsubstituted.

[0368] Item 99.R 5 is one or more (e.g., 1, 2 or 3, e.g., 1) R 5a 98. The compound according to any one of items 95 to 97, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein

[0369] Item 100.R 5a99. The compound according to item 99, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein:

[0370] Item 101.R 5a is C 1-3 99. The compound according to item 99, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl.

[0371] Item 102. Two R's bonded to the same carbon atom 5a The group is connected to C 3-6 99. The compound according to item 99, or a pharma- ceutically acceptable salt and / or solvate thereof, which forms a cycloalkyl or 4- to 7-membered heterocycloalkyl ring.

[0372] Item 103.R 5 is NR 5b R 5c 88. The compound according to item 86 or 87, wherein:

[0373] Item 104.R 5b is H, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0374] Item 105.R 5b is C 1-3 104. The compound according to item 103, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl.

[0375] Item 106.R 5c is C 1-3 106. The compound according to any one of items 103 to 105, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl.

[0376] Item 107.R 5c is C 3-6 106. The compound according to any one of items 103 to 105, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is cycloalkyl.

[0377] Item 108. R 5 is H and R 6 H, halo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 5b R 5c and 4- to 7-membered heterocycloalkyl, 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 5a is optionally replaced by; R 5a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 5a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 5b H and C 1-3 selected from the group consisting of alkyl; R 5c is C 1-3 Alkyl and C 3-6 cycloalkyl, 86. The compound according to item 85, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0378] Item 109. R 5 is H and R 6 H, halo, C 1-3 Alkoxy, C 1-3 Haloalkoxy, SC 1-3 Alkyl, SC 1-3 Haloalkyl, OC 3-10 Cycloalkyl, NR 6b R 6c and 4- to 7-membered heterocycloalkyl, 3-10 Cycloalkyl and 4- to 7-membered heterocycloalkyl may each be selected from the group consisting of one or more R 6a is optionally replaced by; R 6a Halo and C 1-3 alkyl, or two R bonded to the same carbon atom 6a The group is connected to C 3-6 forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R 6b H and C 1-3 selected from the group consisting of alkyl; R 6c is C 1-3 Alkyl and C 3-6 cycloalkyl, 86. The compound according to item 85, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0379] Item 110.R 6 is H, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0380] Item 111.R 6 is halo, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0381] Item 112.R 6 is C 1-3 108. The compound according to item 107, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl, for example methyl or ethyl.

[0382] Item 113.R 6 is C 1-3 101. The compound according to item 108 or 109, or a pharma- ceutically acceptable salt and / or solvate thereof, which is alkoxy.

[0383] Item 114.R 6 is C 1-3 101. The compound according to item 108 or 109, or a pharma- ceutically acceptable salt and / or solvate thereof, which is haloalkoxy.

[0384] Item 115.R6 , SC 1-3 101. The compound according to item 108 or 109, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl.

[0385] Item 116.R 6 , SC 1-3 101. The compound according to item 108 or 109, or a pharma- ceutically acceptable salt and / or solvate thereof, which is haloalkyl.

[0386] Item 117.R 6 is O.C. 3-10 101. The compound according to item 108 or 109, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is cycloalkyl.

[0387] Item 118.R 6 is cyclobutyloxy, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0388] Item 119.R 6 is 4-7 membered heterocycloalkyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0389] Item 120.R 6 is pyrrolidinyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0390] Item 121.R 6 is unsubstituted, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0391] Item 122.R 6 is one or more (e.g., 1, 2 or 3, e.g., 1) R 6a 121. The compound according to any one of items 117 to 120, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein

[0392] Item 123.R 6a is halo, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0393] Item 124.R 6a is C 1-3 123. The compound according to item 122, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl.

[0394] Item 125. Two R's bonded to the same carbon atom 6a The group is connected to C 3-6 123. The compound according to item 122, or a pharma- ceutically acceptable salt and / or solvate thereof, which forms a cycloalkyl or 4- to 7-membered heterocycloalkyl ring.

[0395] Item 126.R 6 is NR 6b R 6c 101. The compound according to item 108 or 109, wherein:

[0396] Item 127.R 6b is H, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0397] Item 128.R 6b is C 1-3 127. The compound according to item 126, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl.

[0398] Item 129.R 6c is C 1-3 129. The compound according to any one of items 126 to 128, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl.

[0399] Item 130.R 6c is C 3-6 129. The compound according to any one of items 126 to 128, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is cycloalkyl.

[0400] Item 131.R 5 and R 6 are connected to form a 4- to 8-membered heterocyclic ring, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0401] Item 132.R 5 and R 6 are connected to form an 8-membered heterocyclic ring, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0402] Item 133.R 5 and R 6 is connected to form a 5,8-dioxaspiro[3.4]octanyl ring, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0403] Item 134.R 8 is C 3-6 The compound according to any one of items 1 to 35 and 85 to 133, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is cycloalkyl.

[0404] Item 135.R 8 is 4-8 membered heterocycloalkyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0405] Item 136.R 8 is pyrrolidinyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0406] Item 137.R 8 137. The compound according to any one of items 134 to 136, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein: is unsubstituted.

[0407] Item 138.R 8 is one or more (e.g., 1, 2 or 3, e.g., 1) R 8a137. The compound according to any one of items 134 to 136, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein

[0408] Item 139.R 8a is C 1-3 139. The compound according to item 138, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl.

[0409] Item 140.R 8a is halo, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0410] Item 141.R 8a is C 1-3 139. The compound according to item 138, or a pharma- ceutically acceptable salt and / or solvate thereof, which is haloalkyl.

[0411] Item 142.R 8 is N(C 1-3 Alkyl) 2 or a pharma- ceutically acceptable salt and / or solvate thereof, wherein

[0412] Item 143.R 8 is NR 8b R 8c The compound according to any one of 1 to 35 and 85 to 133, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0413] Item 144.R 8b is H, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0414] Item 145.R 8b is C 1-3 144. The compound according to item 143, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl, for example methyl.

[0415] Item 146.R 8bis C 3-6 144. The compound according to item 143, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is cycloalkyl, for example cyclopropyl or cyclopentyl.

[0416] Item 147.R 8c is H, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0417] Item 148.R 8c is C 1-3 144. The compound according to item 143, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is alkyl, for example methyl.

[0418] Item 149.R 8c is C 3-6 144. The compound according to item 143, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein R is cycloalkyl, for example cyclopropyl or cyclopentyl.

[0419] Item 150.R 4 is a 4-7 membered heterocycloalkyl and is attached via a nitrogen atom, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0420] Item 151.R 5 is a 4-7 membered heterocycloalkyl and is attached via a nitrogen atom, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0421] Item 152.R 6 is a 4-7 membered heterocycloalkyl and is attached via a nitrogen atom, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0422] Item 153.R 8is a 4-8 membered heterocycloalkyl and is attached via a nitrogen atom, or a pharma- ceutically acceptable salt and / or solvate thereof.

[0423] Item 154. (R)-2-Cyclobutoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-Cyclobutoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(cyclopentyloxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(cyclopentyloxy)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(cyclopentyloxy)-3-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-Cyclobutoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(cyclopentyloxy)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(cyclopentyloxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-cyclobutoxy-N-((1-methylcyclopropyl)sulfonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(cyclopentyloxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-cyclobutoxy-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-2-(pyrrolidin-1-yl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)benzamide; (R)-2-Cyclobutoxy-4-(8-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)benzamide; (R)-2-Cyclobutoxy-4-(8-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(N,N-dimethylsulfamoyl)-6-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(cyclopentyloxy)-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; 2-(3-Azabicyclo[3.1.0]hexan-3-yl)-N-(N,N-dimethylsulfamoyl)-6-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(N,N-dimethylsulfamoyl)-6-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(cyclopentyloxy)-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)benzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-cyclobutoxy-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)benzamide; (R)-N-(N-isopropyl-N-methylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-chloro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; 2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-chloro-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(3-Azabicyclo[3.1.0]hexan-3-yl)-6-chloro-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(cyclobutyl(methyl)amino)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(cyclobutyl(methyl)amino)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-chloro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(cyclopentyloxy)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(cyclopentyloxy)-N-(N,N-dimethylsulfamoyl)-3-fluorobenzamide; (R)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-2-(pyrrolidin-1-yl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; 2-(3-Azabicyclo[3.1.0]hexan-3-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-Cyclobutoxy-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-Cyclobutoxy-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-cyclobutoxy-N-(N,N-dimethylsulfamoyl)-3-fluorobenzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-cyclobutoxy-3-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(cyclobutyl(methyl)amino)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(cyclopentyloxy)-3-fluoro-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(cyclopentyloxy)-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-4-(7-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-fluoro-N-((1-methylcyclopropyl)sulfonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-4-(7-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(N,N-dimethylsulfamoyl)-3-fluorobenzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-4-(7-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-4-(7-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)benzamide; 2-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-3-Fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-2-(pyrrolidin-1-yl)benzamide; (R)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(3,3-difluoropiperidin-1-yl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(3,3-difluoropiperidin-1-yl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(3,3-difluoropiperidin-1-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(3,3-difluoropiperidin-1-yl)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-chloro-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(3,3-difluoropyrrolidin-1-yl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(3,3-difluoropyrrolidin-1-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(cyclopropyl(methyl)amino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(cyclopropyl(methyl)amino)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-((4,4-difluorocyclohexyl)oxy)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-((4,4-difluorocyclohexyl)oxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(3,3-dimethylpyrrolidin-1-yl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(3,3-dimethylpyrrolidin-1-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(azetidin-1-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-((adamantan-2-yl)oxy)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(azetidin-1-yl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(3,3-difluoropyrrolidin-1-yl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-Cyclobutoxy-N-(N,N-dimethylsulfamoyl)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-((adamantan-2-yl)oxy)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-3-Fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-((4,4-difluorocyclohexyl)oxy)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-((adamantan-2-yl)oxy)-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(cyclopentyloxy)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-6-(trifluoromethyl)benzamide; N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-((R)-2-methylpyrrolidin-1-yl)benzamide; N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-((S)-2-methylpyrrolidin-1-yl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-6-(trifluoromethyl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-chloro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methyl-6-(pyrrolidin-1-yl)benzamide; (R)-2-(cyclopentyloxy)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-6-(trifluoromethyl)benzamide; 2-(bicyclo[3.1.0]hexan-3-yloxy)-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(bicyclo[3.1.0]hexan-3-yloxy)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(cyclopentyloxy)-N-(N,N-dimethylsulfamoyl)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(cyclopentyloxy)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-6-(trifluoromethyl)benzamide; 2-(bicyclo[3.1.0]hexan-3-yloxy)-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(bicyclo[3.1.0]hexan-3-yloxy)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(2-azabicyclo[2.2.1]heptan-2-yl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(2-azabicyclo[2.2.1]heptan-2-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(cyclopentyloxy)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-6-(trifluoromethyl)benzamide; 2-(3-Azabicyclo[3.1.0]hexan-3-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-6-(trifluoromethyl)benzamide; (R)-N-(N,N-dimethylsulfamoyl)-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-6-(pyrrolidin-1-yl)benzamide; (R)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(5-azaspiro[2.5]octan-5-yl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-((S)-2-methylpyrrolidin-1-yl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-2-((R)-2-methylpyrrolidin-1-yl)benzamide; 4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-((R)-2-methylpyrrolidin-1-yl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-2-((S)-2-methylpyrrolidin-1-yl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(cyclopentyloxy)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-6-(pyrrolidin-1-yl)benzamide; (R)-2-(cyclopentyloxy)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-6-(trifluoromethyl)benzamide; (R)-2-(cyclopentyloxy)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-6-(trifluoromethyl)benzamide; (R)-2-Cyclobutoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-6-(trifluoromethyl)benzamide; (S)-2-Cyclobutoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-Cyclobutoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-6-(trifluoromethyl)benzamide; (R)-2-Cyclobutoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-6-(trifluoromethyl)benzamide; (R)-N-(N,N-dimethylsulfamoyl)-3-fluoro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-3-Fluoro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(Dimethylamino)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(dimethylamino)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(dimethylamino)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(dimethylamino)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-methyl-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-2-(pyrrolidin-1-yl)benzamide; (R)-2-Cyclobutoxy-4-(8-(3-(ethoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-N-(N,N-dimethylsulfamoyl)-2-ethoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide;(R)-2-ethoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-N-(N,N-dimethylsulfamoyl)-3-fluoro-2-isopropoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-3-Fluoro-2-isopropoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-chloro-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-chloro-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-5-(trifluoromethyl)benzamide; (R)-2-(cyclopentyloxy)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-6-(trifluoromethyl)benzamide; (R)-2-Methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-6-(trifluoromethyl)benzamide; (R)—N-((6-azaspiro[2.5]octan-6-yl)sulfonyl)-3-fluoro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-3-fluoro-2-methoxy-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-3-fluoro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-3-fluoro-2-methoxy-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-5-(trifluoromethyl)benzamide; (R)-2-ethoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-6-(trifluoromethyl)benzamide; (R)-2-isopropoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-6-(trifluoromethyl)benzamide; (R)-2-Cyclobutoxy-5-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-3-Cyclobutoxy-5-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-6-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)spiro[benzo[d][1,3]dioxole-2,1'-cyclobutane]-4-carboxamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-Cyclobutoxy-4-fluoro-5-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-3-Cyclobutoxy-4-fluoro-5-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-Cyclobutoxy-N-(((2R,5R)-2,5-dimethylpyrrolidin-1-yl)sulfonyl)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-Cyclobutoxy-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-Cyclobutoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-methyl-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-4-Fluoro-5-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)spiro[benzo[d][1,3]dioxole-2,1'-cyclobutane]-7-carboxamide; (R)-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-5-(trifluoromethyl)benzamide; (R)-3-Fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-2-(trifluoromethoxy)benzamide; (R)-2-chloro-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-4-(8-(4-isopropyl-3-(methoxymethyl)piperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(difluoromethoxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-Cyclobutoxy-4-(8-(4-ethyl-3-(methoxymethyl)piperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-Cyclobutoxy-4-(8-(4-cyclopropyl-3-(methoxymethyl)piperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (S)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; and (S)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; or a pharma- ceutically acceptable salt and / or solvate thereof.

[0424] Item 155. N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(cyclopentyloxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-3-chloro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-3-chloro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-10-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(cyclopentyloxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-10-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((6-azaspiro[2.5]octan-6-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((6-azaspiro[2.5]octan-6-yl)sulfonyl)-5-chloro-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(isopropoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-5-chloro-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(azetidin-1-yl)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-amino-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-ethoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(piperidin-1-ylsulfonyl)benzamide; (R)-2-ethoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(piperidin-1-ylsulfonyl)benzamide; (R)-N-(N-cyclopentyl-N-methylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(cyclobutyl(methyl)amino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(methylamino)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-ethoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-2-(azetidin-1-yl)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-3-Fluoro-N-((4-fluoropiperidin-1-yl)sulfonyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-3-Fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-propoxy-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-3-Fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-2-(2,2,2-trifluoroethoxy)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-2-cyclopropoxy-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-4-(7-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxy-3-fluorobenzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxy-3-fluorobenzamide N-(((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((octahydro-2H-isoindol-2-yl)sulfonyl)benzamide; (R)-2-Cyclopropoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-cyclopropoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-2-ethoxy-4-(7-ethyl-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-fluorobenzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-ethoxy-4-(7-ethyl-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-fluorobenzamide; (R)-N-(N,N-dicyclopropylsulfamoyl)-2-ethoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((3,3-dimethylpyrrolidin-1-yl)sulfonyl)-2-ethoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-ethoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-2-ethoxy-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-N-((2-azaspiro[3.3]heptan-2-yl)sulfonyl)-2-ethoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2-ethoxy-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-3-Fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-2-(3,3,3-trifluoropropoxy)benzamide; (R)-3-ethoxy-2-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-Fluoro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-fluoro-2-(methoxy-d3)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-ethoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-ethoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-2-ethoxy-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((2-azabicyclo[2.2.1]heptan-2-yl)sulfonyl)-2-ethoxy-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-N-(N,N-dicyclopropylsulfamoyl)-2-ethoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-ethoxy-3-fluoro-N-(((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-N-((2-azaspiro[3.3]heptan-2-yl)sulfonyl)-2-ethoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2-ethoxy-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.2.1]octan-3-yl)sulfonyl)-2-ethoxy-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2-ethoxy-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.2.1]octan-3-yl)sulfonyl)-2-ethoxy-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-N-(N-cyclopentyl-N-methylsulfamoyl)-3-fluoro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-3-Fluoro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(piperidin-1-ylsulfonyl)benzamide; (R)-3-Fluoro-N-((4-fluoropiperidin-1-yl)sulfonyl)-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methylbenzamide; (R)-5-(dimethylamino)-2-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-ethyl-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-ethoxy-4-(10-ethyl-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(dimethylamino)-4-(10-ethyl-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-2-(methoxy-d3)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-5-fluoro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-5-fluoro-2-methoxy-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-5-fluoro-2-(methoxy-d3)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-5-fluoro-2-(methoxy-d3)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-3-fluoro-2-(methoxy-d3)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((2-azaspiro[3.3]heptan-2-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(Dimethylamino)-5-fluoro-N-(((S)-3-fluoropyrrolidin-1-yl)sulfonyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-N-(N-cyclopropyl-N-methylsulfamoyl)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxy-3-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxy-5-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-N-(N,N-dimethylsulfamoyl)-5-fluorobenzamide; 2-ethoxy-5-fluoro-N-(((R)-3-fluoropyrrolidin-1-yl)sulfonyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-2-methoxy-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-Cyclopropoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-2-cyclopropoxy-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-Fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-Fluoro-5-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; N-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)sulfonyl)-2-ethoxy-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-Ethoxy-5-fluoro-N-(((S)-3-fluoropyrrolidin-1-yl)sulfonyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-N-(N-cyclopropyl-N-methylsulfamoyl)-2-ethoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; and (R)-2-Fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-methyl-N-(pyrrolidin-1-ylsulfonyl)benzamide; or any one of its pharma- ceutically acceptable salts and / or solvates thereof.

[0425] Item 156. (R)—N-((2-oxa-5-azaspiro[3.5]nonan-5-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; (R)—N-((2-oxa-6-azaspiro[3.5]nonan-6-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; R)-N-((2-oxa-6-azaspiro[3.4]octan-6-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; (R)—N-((5-azaspiro[2.4]heptan-5-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(piperidin-1-ylsulfonyl)benzamide; (R)-N-(N,N-dicyclopropylsulfamoyl)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(N,N-dicyclopropylsulfamoyl)-2-(dimethylamino)-5-fluorobenzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(((R)-2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)benzamide; (R)-N-((2-azaspiro[3.3]heptan-2-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methoxybenzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methoxybenzamide; 2-(Dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(((S)-3-methoxypiperidin-1-yl)sulfonyl)benzamide; (R)—N-((2-oxa-6-azaspiro[3.3]heptan-6-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methoxy-N-(((S)-2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)benzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(((S)-3-methoxypyrrolidin-1-yl)sulfonyl)benzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(((R)-3-methoxypyrrolidin-1-yl)sulfonyl)benzamide; 2-(Dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(((R)-3-methoxypiperidin-1-yl)sulfonyl)benzamide; 2-(Dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(((R)-2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)benzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methoxy-N-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)benzamide; (R)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((4-methoxypiperidin-1-yl)sulfonyl)benzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)benzamide; (R)-5-chloro-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-N-(N,N-dimethylsulfamoyl)benzamide; 2-(Dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(((S)-2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)benzamide; N-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)sulfonyl)-4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(((S)-2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)benzamide; (R)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(N,N-dicyclopropylsulfamoyl)-5-fluoro-2-methoxybenzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(N-cyclopropyl-N-methylsulfamoyl)-2-ethoxy-5-fluorobenzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxy-5-fluoro-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-N-((2-azaspiro[3.3]heptan-2-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxy-5-fluorobenzamide; N-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)sulfonyl)-4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxy-5-fluorobenzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(((S)-3-fluoropyrrolidin-1-yl)sulfonyl)benzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(((R)-3-fluoropyrrolidin-1-yl)sulfonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(10-fluoro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-5-fluoro-4-(10-fluoro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methoxybenzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-cyclopropoxy-N-(N,N-dimethylsulfamoyl)-5-fluorobenzamide; N-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-cyclopropoxy-5-fluorobenzamide; (R)-2-(dimethylamino)-5-fluoro-4-(10-fluoro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-fluoro-4-(10-fluoro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methoxy-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-fluoro-5-methyl-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(Dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)benzamide; 2-(Dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(((S)-2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)benzamide; N-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(Dimethylamino)-5-fluoro-N-(((R)-3-fluoropyrrolidin-1-yl)sulfonyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxy-5-fluorobenzamide; (R)—N-((2-azaspiro[3.3]heptan-2-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-fluoro-5-methoxy-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxybenzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methoxybenzamide; N-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(N-cyclopropyl-N-methylsulfamoyl)-2-(dimethylamino)-5-fluorobenzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-2-methoxybenzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-2-methoxybenzamide; (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-2-(methoxy-d3)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-2-(methoxy-d3)benzamide; (R)-5-chloro-2-(methoxy-d3)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-chloro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-chloro-2-ethoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; and (R)-N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-cyclopropoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; or any one of its pharma- ceutically acceptable salts and / or solvates thereof.

[0426] Item 157. A pharma- ceutically acceptable salt according to any one of items 1 to 156.

[0427] Item 158. A pharma- ceutically acceptable solvate according to any one of items 1 to 156.

[0428] Item 159. The compound according to any one of items 1 to 156.

[0429] Item 160. A pharmaceutical composition comprising a compound according to any one of items 1 to 159 or a pharma- ceutically acceptable salt and / or solvate thereof and one or more pharma- ceutically acceptable diluents or carriers.

[0430] Item 161. A compound according to any one of items 1 to 159 or a pharma- ceutically acceptable salt and / or solvate thereof or a pharmaceutical composition according to item 133 for use as a medicament.

[0431] Item 162. A compound according to any one of items 1 to 159 or a pharma- ceutically acceptable salt and / or solvate thereof or a pharmaceutical composition according to item 158 for use in treating or preventing a disease selected from the group consisting of inflammatory, autoimmune or fibrotic diseases, and cancer.

[0432] Item 163. Use of a compound according to any one of items 1 to 159 or a salt and / or solvate thereof or a pharmaceutical composition according to item 160 in the manufacture of a medicament for treating or preventing a disease selected from inflammatory, autoimmune and fibrotic diseases, and cancer.

[0433] Item 164. A method for treating or preventing a disease selected from inflammatory, autoimmune and fibrotic diseases, and cancer, comprising administering a compound according to any one of items 1 to 159 or a salt and / or solvate thereof or a pharmaceutical composition according to item 160.

[0434] Item 165. The compound for use, composition for use, use or method according to any one of Items 162 to 164, wherein the inflammatory, autoimmune or fibrotic disease is selected from the group consisting of rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, psoriasis, myasthenia gravis (MG), Crohn's disease, multiple sclerosis, sarcoidosis, ulcerative colitis, celiac disease, systemic lupus erythematosus (SLE), Sjogren's syndrome, asthma, atopic dermatitis, vitiligo, systemic sclerosis (SSC), graft versus host disease (GvHD), type 1 diabetes, hidradenitis suppurativa, idiopathic pulmonary fibrosis (IPF), interstitial lung disease (ILD) and non-alcoholic steatohepatitis (NASH).

[0435] Item 166. The compound for use, composition for use, use or method according to any one of items 162 to 164, wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), primary central nervous system lymphoma (PCNSL), lymphoma, mycosis fungoides, refractory non-Hodgkin's lymphoma (NHL), head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), bladder cancer, lymphoma, breast cancer, osteosarcoma, gestational trophoblastic neoplasia (GTN), acute myeloid leukemia (AML), hepatocellular carcinoma, renal cell carcinoma, colorectal cancer, lung cancer, glioma, ovarian cancer, melanoma, and solid tumors, such as cervical, uterine, testicular, gastric, prostate and pancreatic tumors.

[0436] Item 167. The compound for use, composition for use, use or method according to item 166, wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), primary central nervous system lymphoma (PCNSL), lymphoma, mycosis fungoides, refractory non-Hodgkin's lymphoma (NHL) and acute myeloid leukemia (AML).

[0437] Item 168. A process for preparing a compound of formula (I), or a salt thereof, for example a pharma- ceutical acceptable salt, comprising reacting a compound of formula (II): [ka] or its salts and / or solvates (In the formula, R 1 , R 2 , R 3 and m is as defined in any one of items 1 to 156, Compounds of formula (III): [ka] or its salts and / or solvates (In the formula, R 4 , R 5 , R 6 , R 7 and n is as defined in any one of items 1 to 156.

[0438] Item 169. A compound of formula (I) or a salt thereof, for example a pharma- ceutical acceptable salt (wherein R 7 is absent), comprising the step of preparing a compound of formula (XXXVIII): [ka] or its salts and / or solvates (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 8, n and m are as defined in any one of items 1 to 156, Compound of formula (XVI): [ka] or its salts and / or solvates (In the formula, R 8 is as defined in any one of items 1 to 156).

[0439] Item 170. Compound of formula (II): [ka] or its salts and / or solvates (In the formula, R 1 , R 2 , R 3 and m is as defined in any one of items 1 to 156).

[0440] Item 171. Compound of formula (III): [ka] or its salts and / or solvates (In the formula, R 4 , R 5 , R 6 , R 7 and n is as defined in any one of items 1 to 156, for example, R 5 represents an O-linked group, e.g., C 1-3 Alkoxy, C 1-3 Haloalkoxy or OC 3-10 Cycloalkyl, or N-linked groups such as NR 5b R 5c or an N-linked 4- to 7-membered heterocycloalkyl.

[0441] Item 172. Compound of formula (XXXVIII): [ka] or its salts and / or solvates (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , n and m are defined in any one of items 1 to 156).

[0442] Item 173. Compound of formula (XXXIX): [ka] or its salts and / or solvates (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , n and m are defined in any one of items 1 to 156; and Alk is C 1-4 (It is alkyl).

[0443] Item 174. Compound of formula (XXXXI): [ka] or its salts and / or solvates (In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , n and m are defined in any one of items 1 to 156, and LG is a leaving group, for example, halo, for example bromo).

[0444] [Table 1-1] [Table 1-2] [Table 1-3] EXAMPLES

[0445] Analyzer Thin-layer chromatography (TLC) was performed on silica gel plates (GF254, glass, silica gel size: 400-600 mesh). Spots were visualized by UV light (214 and 254 nm) or staining reagents (iodine, KMnO 4 All evaporations were performed in vacuo using a rotary evaporator.

[0446] Purification by column and flash chromatography was performed using silica gel (200-300 mesh). Solvent systems are reported as mixtures by volume. NMR spectra were recorded at room temperature on a Bruker 400 MHz Avance III spectrometer equipped with a BBFO 5 mm probe, a Bruker 500 MHz Avance III HD spectrometer equipped with a Bruker 5 mm SmartProbe™, or a Jeol ECS400. 1 H chemical shifts are reported in δ values ​​(ppm) using deuterated solvents as internal standards. Data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, br=broad, m=multiplet), coupling constant (Hz), integration.

[0447] [Table 2-1] [Table 2-2] [Table 2-3]

[0448] Commercially available substances All starting materials are commercially available unless otherwise stated.

[0449] Synthesis of intermediates Intermediate 1: (R)-2-(methoxymethyl)-1-methylpiperazine [ka] Process 1 Benzyl chloroformate (47.4 g, 277 mmol) was added dropwise to a solution of (R)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate (50.0 g, 231 mmol) and TEA (56.0 g, 555 mmol) in DCM (1.1 L) at 0° C. The mixture was stirred at room temperature for 3 h. Ice water (800 mL) was added and the mixture was extracted with DCM (3×1 L). The organic layers were combined, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20-50% EtOAc / petroleum ether) to provide (R)-4-benzyl 1-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (72.0 g, 205 mmol) as a colorless oil. LCMS (System 1, Method F) Rt = 1.59 min, m / z 251.0 (M-100+H). + , 295(M-56+H) + (ES + ). 1 H NMR (400 MHz, CDCl 3 ) δ: 7.38-7.29 (m, 5H), 5.15 (br s, 2H), 4.17-4.08 (m, 2H), 4.00 (s, 1H), 3.86-3.83 (m, 1H), 3.57 (m, 2H), 2.99 (m, 3H), 1.48-1.41 (s, 9H).

[0450] Process 2 Sodium hydride (60% dispersion in mineral oil, 16.4 g, 411 mmol) was added portionwise to a solution of (R)-4-benzyl 1-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (72.0 g, 205 mmol) in THF (822 mL) at −10° C. The mixture was stirred at this temperature for 30 min, iodomethane (64.2 g, 452 mmol) was added, and the reaction was stirred for 2 h at −10° C. The mixture was diluted with NH 4 The mixture was poured into saturated aqueous Cl (500 mL) and extracted with MTBE (3x800 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20-30% MTBE / petroleum ether) to provide (R)-4-benzyl 1-tert-butyl 2-(methoxymethyl)piperazine-1,4-dicarboxylate (41.0 g, 113 mmol) as a pale yellow oil. LCMS (System 1, Method F) Rt = 1.77 min, m / z 309.0 (M-56+H). + (ES + ). 1 H NMR (400 MHz, CDCl 3 ) δ: 7.35-7.27 (m, 5H), 5.19-5.09 (m, 2H), 4.19-3.85 (m, 4H), 3.39-3.26 (m, 5H), 3.04-2.94 (m, 3H), 1.49-1.29 (s, 9H).

[0451] Process 3 To a solution of (R)-4-benzyl 1-tert-butyl 2-(methoxymethyl)piperazine-1,4-dicarboxylate (41.0 g, 113 mmol) in DCM (500 mL) was added TFA (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 h. TFA was evaporated and the residue was dissolved in DCM (500 mL) and NaHCO 3 The combined organic layers were washed with brine, dried (Na 2 SO 4), filtered and concentrated under reduced pressure to provide (R)-benzyl 3-(methoxymethyl)piperazine-1-carboxylate (29.0 g, 110 mmol) as a yellow oil. LCMS (System 1, Method F) Rt = 1.33 min, m / z 265.2 (M+H) + (ES + ).

[0452] Process 4 To a solution of (R)-benzyl 3-(methoxymethyl)piperazine-1-carboxylate (29.0 g, 110 mmol) in ACN (400 mL) and water (133 mL) was added aqueous formaldehyde (37%, 27.8 g, 340 mmol) and the mixture was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (46.5 g, 219 mmol) was added at 0° C. and the mixture was stirred at room temperature overnight. The pH of the mixture was adjusted with NaHCO 3 A saturated aqueous solution of ACN was added to give 8, the ACN was evaporated under reduced pressure and the resulting aqueous solution was extracted with DCM (3×400 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1-5% MeOH / DCM) to provide (R)-benzyl 3-(methoxymethyl)-4-methylpiperazine-1-carboxylate (27.0 g, 97 mmol) as a yellow oil. LCMS (System 1, Method F) Rt = 1.45 min, m / z 279.2 (M+H). + (ES + ).

[0453] Process 5 Pd / C (10%, 2.70 g) was added to a solution of (R)-benzyl 3-(methoxymethyl)-4-methylpiperazine-1-carboxylate (27.0 g, 97.0 mmol) in MeOH (750 mL), and the mixture was heated at room temperature overnight under H 2 The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to provide (R)-2-(methoxymethyl)-1-methylpiperazine (14 g, 97.0 mmol) as a yellow oil. 1H NMR (400 MHz, DMSO-d 6 ) δ: 3.44 (dd, J = 10.0, 5.6 Hz, 1H), 3.45-3.41 (m, 4H), 2.96-2.85 (m, 2H), 2.72-2.63 (m, 2H), 2.48-2.42 (m, 1H), 2.18-2.09 (m, 5H).

[0454] Alternative Procedure: Process 1 Five batches were run in parallel: 4 x 1.49 kg and 1.0 kg.

[0455] To a solution of tert-butyl (R)-3-(hydroxymethyl)piperazine-1-carboxylate (1.49 kg, 6.89 mol, 1.0 eq) in THF (14.9 L) was added NaH (303 g, 7.58 mol, 60%, 1.1 eq) portionwise at 20 °C. The mixture was stirred at 20 °C for 0.5 h. Methyl iodide (1.08 kg, 7.58 mol, 472 mL, 1.1 eq) was added dropwise to the mixture at 20-30 °C. The mixture was stirred at 20 °C for 0.5 h. Further NaH (386 g, 9.65 mol, 60%, 1.4 eq) was added slowly to the mixture at 20 °C and the mixture was stirred at 20-30 °C for 0.5 h. Additional methyl iodide (1.37 kg, 9.65 mol, 600 mL, 1.4 eq) was added dropwise to the mixture at 20° C. The resulting mixture was stirred at 20° C. for 12 h. The reaction mixture was diluted with saturated aqueous NH 4 The mixture was quenched at 0° C. by the addition of Cl (1.49 L) and further saturated aqueous NH 4 The mixture was diluted with Cl (13.41 L) and then extracted with EtOAc (14.9 L, 7.45 L). The combined organic layers were washed with brine (14.9 L) and Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue. The material from the five batches was combined. Compound tert-butyl (R)-3-(methoxymethyl)-4-methylpiperazine-1-carboxylate (5.80 kg, 23.7 mol, 86.1% yield) was obtained as a yellow oil.

[0456] Process 2 Three batches were run in parallel.

[0457] To a solution of tert-butyl (R)-3-(methoxymethyl)-4-methylpiperazine-1-carboxylate (1.93 kg, 7.90 mol, 1.0 eq) in EtOAc (3.86 L) was added HCl / EtOAc (4 M, 15.4 L, 7.82 eq) at 20° C. and the mixture was stirred at 20° C. for 3 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The material from the three batches was combined. (R)-2-(methoxymethyl)-1-methylpiperazine hydrochloride (5.44 kg) was obtained as a yellow solid.

[0458] Process 3 Two batches were run in parallel.

[0459] A solution of (R)-2-(methoxymethyl)-1-methylpiperazine hydrochloride (2.72 kg, 15.1 mol, 1.0 eq) in MeOH (13.6 L) was added to the 2 CO 3 (2.29 kg, 16.6 mol, 1.1 eq) was added at 10-20°C. The mixture was stirred at 20-30°C for 3 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure at 35°C to give a residue. The residue was dissolved in DCM (13.6 L), stirred at 20-30°C for 0.5 h, the solid was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was dissolved in DCM (10 L) and stirred at 20-30°C for 0.5 h, the solid was filtered and the filtrate was concentrated under reduced pressure to give a residue. 2 SO 4 was added and the suspension was stirred at 20-30 °C for 0.5 h, filtered, and the filtrate was concentrated under reduced pressure to give the product. The material from the three batches was combined. (R)-2-(methoxymethyl)-1-methylpiperazine hydrochloride (2.90 kg, 20.1 mol) was obtained as a brown oil.

[0460] Intermediate 2: tert-Butyl 7-methyl-5-oxo-8-(((trifluoromethyl)sulfonyl)oxy)-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate [ka] Process 1 A mixture of 2-methylbenzene-1,3-diol (25.0 g, 202 mmol) and ethyl 4-oxopiperidine-3-carboxylate hydrochloride (41.7 g, 202 mmol) in sulfuric acid (64%, 200 mL) was stirred at room temperature overnight. The reaction was quenched by adding ice water (300 mL) and the mixture was stirred at room temperature for 2 h. The precipitate was collected by filtration, washed with water and hexanes, and dried under reduced pressure to provide 8-hydroxy-7-methyl-1,2,3,4-tetrahydro-5H-chromeno[3,4-c]pyridin-5-one hemisulfate (46.0 g, 164 mmol) as an off-white solid. LCMS (System 2, Method B) Rt 0.38 min, m / z 232.2 (M+H) + (ES + ).

[0461] Process 2 Aqueous sodium hydroxide 1M (115 mL, 115 mmol) was added to a mixture of 8-hydroxy-7-methyl-1,2,3,4-tetrahydro-5H-chromeno[3,4-c]pyridin-5-one hemisulfate (30.0 g, 107 mmol) in DCM (500 mL) and the reaction was stirred at room temperature for 30 min. Then NaHCO 3 Saturated aqueous solution (200 mL) and di-tert-butyl dicarbonate (25.7 g, 118 mmol) were added and the reaction was stirred at room temperature overnight. The organic solvent was evaporated and the resulting precipitate was collected by filtration, washed with water, hexane and dried to provide tert-butyl 7-chloro-8-hydroxy-5-oxo-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (25.0 g, 75.5 mmol) as an off-white solid. LCMS (System 2, Method B) Rt=1.74 min, m / z 354.0 (M+Na). + (ES + ).

[0462] Process 3 To a mixture of tert-butyl 7-chloro-8-hydroxy-5-oxo-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (25.0 g, 75.5 mmol) in DCM (400 mL) was added pyridine (11.9 g, 151 mmol), the mixture was cooled to 0° C., and trifluoromethanesulfonic anhydride (21.3 g, 75.5 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred for 1 h. Water (300 mL) was added, the organic phase was separated, washed with aqueous HCl 0.1 N (50 mL) and brine (200 mL), dried (Na 2 SO 4 ) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-2% MeOH / DCM) to provide tert-butyl 7-methyl-5-oxo-8-(((trifluoromethyl)sulfonyl)oxy)-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (30.0 g, 64.8 mmol) as a pale yellow solid. LCMS: (System 2, Method B). Rt=2.14 min, m / z 486.1 (M+Na). + (ES + ).

[0463] Alternative Procedure: Process 1 2 x 500g batches were run in parallel.

[0464] Ethyl 4-oxopiperidine-3-carboxylate hydrochloride (920 g, 4.43 mol, 1.1 eq) was added to a solution of 2-methylbenzene-1,3-diol (500 g, 4.03 mol, 1.0 eq) in sulfuric acid (5.0 L, 75%) at 20° C., and the reaction mixture was stirred at 30° C. for 12 h. The reaction mixture was added to ice water (20 L). The precipitate was collected by filtration and washed with water (5.0 L) and hexane (3.0 L). The filter cake was dried under reduced pressure. The crude product was used in the next step without further purification. The material from the two batches was combined. 8-Hydroxy-7-methyl-1,2,3,4-tetrahydro-5H-chromeno[3,4-c]pyridin-5-one hemisulfate (3.50 kg, crude) was obtained as a white solid.

[0465] Process 2 To a suspension of 8-hydroxy-7-methyl-1,2,3,4-tetrahydro-5H-chromeno[3,4-c]pyridin-5-one hemisulfate (3.15 kg, 6.42 mol, 1.0 eq) in THF (19 L) was added NaOH (1.0 M, 3.71 L) and the mixture was stirred at 25 °C for 0.5 h. 3 Saturated aqueous solution (165 mL) and di-tert-butyl dicarbonate (1.40 kg, 6.42 mol, 1.0 eq) were added to the mixture. The reaction mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure at 35° C. to remove THF, and the residue was filtered and washed with water (2.0 L) and hexane (4.0 L). The crude product was triturated with n-hexane / acetone 1 / 1 (4.0 L) at 20° C. for 12 h. tert-Butyl 7-chloro-8-hydroxy-5-oxo-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (2.14 kg, 5.76 mol, 89.7% yield) was obtained as a white solid.

[0466] Process 3 Seven batches were run in parallel: 5×330 g batches, a 290 g batch and a 200 g batch.

[0467] To a solution of tert-butyl 7-chloro-8-hydroxy-5-oxo-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (330 g, 996 mmol, 1.0 eq) in DCM (1.65 L) was added pyridine (197 g, 2.49 mol, 201 mL, 2.5 eq) at -10 to 0 °C, then trifluoromethanesulfonic anhydride (421 g, 1.49 mol, 246 mL, 1.5 eq) was added dropwise to the mixture at the same temperature. The mixture was stirred at -10 to 0 °C for 0.5 h until the reaction was complete by HPLC. The reaction mixture was quenched at -10 to 0 °C by adding water (1.65 L), then the organic phase was separated, washed with HCl (0.1 M, 0.9 L) and brine (1.65 L) and diluted with anhydrous NaCl. 2 SO 4 The crude product was triturated with n-heptane (5.0 L) at 20° C. for 1 h. The solid was filtered and the filter cake was dried at 35° C. to give tert-butyl 7-methyl-5-oxo-8-(((trifluoromethyl)sulfonyl)oxy)-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (2.64 kg, 99.0% purity, 88.2% yield) as a pale yellow solid.

[0468] Intermediate 3: tert-Butyl 7,10-dimethyl-5-oxo-8-(((trifluoromethyl)sulfonyl)oxy)-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate [ka] Prepared by a method similar to tert-butyl 7-methyl-5-oxo-8-(((trifluoromethyl)sulfonyl)oxy)-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (Intermediate 2) starting from 2,5-dimethylbenzene-1,3-diol (10.0 g, 73 mmol). Yield: 9.3 g, 19.5 mmol. White solid. LCMS: (System 1, Method A) Rt=2.47 min, m / z 422.2 (M-56+H). + (ES + ).

[0469] Alternative Procedure: Process 1 Three batches were run in parallel: 50.0 g and 2 x 225 g.

[0470] H 2 SO 4 A mixture of 2,5-dimethylbenzene-1,3-diol (225 g, 1.63 mol, 1.0 eq), ethyl 4-oxopiperidine-3-carboxylate hydrochloride (371 g, 1.79 mol, 1.1 eq, HCl) in hexane (75%, 2250 mL) was degassed and purged with nitrogen three times, then the mixture was stirred at 30 °C for 96 h under nitrogen atmosphere. The three batches were combined and poured into ice water (6750 mL) at 0-10 °C, the solid was collected by filtration and washed with water (2 × 120 mL). The filter cake was dried under reduced pressure. The crude product was used in the next step without further purification. 8-Hydroxy-7,10-dimethyl-1,2,3,4-tetrahydro-5H-chromeno[3,4-c]pyridin-5-one hemisulfate (1.27 kg, crude) was obtained as a white solid.

[0471] Process 2 8-Hydroxy-7,10-dimethyl-1,2,3,4-tetrahydro-5H-chromeno[3,4-c]pyridin-5-one hemisulfate (1.15 kg, 3.58 mol, 1.0 eq), tert-butyl carbonate (687 g, 3.15 mol, 723 mL, 0.88 eq), NaHCO in THF (16.5 L). 3A mixture of (1.14 M, 890 mL, 0.28 eq) and NaOH (1.0 M, 4.30 L, 1.2 eq) was degassed and purged with nitrogen three times, then the mixture was stirred at 15-25 °C for 12 h under nitrogen atmosphere. The solids were filtered and the filtrate was concentrated under reduced pressure to give a residue. The crude product was purified by recrystallization from 1000 mL of 1 / 1 acetone / n-hexane. tert-Butyl 8-hydroxy-7,10-dimethyl-5-oxo-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (489 g, 1.42 mol, 39.5% yield) was obtained as a white solid.

[0472] Process 3 Two 239.5g batches were run in parallel.

[0473] To a mixture of tert-butyl 8-hydroxy-7,10-dimethyl-5-oxo-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (239.5 g, 693 mmol, 1.0 eq) in DCM (2.40 L) was added pyridine (137 g, 1.73 mol, 140 mL, 2.5 eq) at -10 to 0 °C, followed by trifluoromethanesulfonic anhydride (293 g, 1.04 mol, 172 mL, 1.5 eq) at -10 to 0 °C. The mixture was stirred at -10 to 0 °C for 0.5 h. The mixture was quenched at -10 to 0 °C by the addition of water (1.12 L) and the organic phase was separated and extracted with DCM (718 mL). The combined organic phase was washed with HCl (1.0 M, 3×718 mL) and brine (1.12 L) and then with anhydrous Na 2 SO 4 The crude product was triturated with n-heptane (1.5 L) at 25° C. for 1 h, filtered, and concentrated under reduced pressure to give a residue. The two batches were combined for further purification. The crude product was triturated with n-heptane (1.5 L) at 25° C. for 1 h, filtered, and concentrated under reduced pressure to give tert-butyl 7,10-dimethyl-5-oxo-8-(((trifluoromethyl)sulfonyl)oxy)-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (459 g, 959 mmol, 69.2% yield, 99.8% purity) as a light yellow solid.

[0474] Intermediate 4: tert-Butyl 7-chloro-5-oxo-8-(((trifluoromethyl)sulfonyl)oxy)-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate [ka] Prepared by a method similar to tert-butyl 7-methyl-5-oxo-8-(((trifluoromethyl)sulfonyl)oxy)-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (Intermediate 2) starting from 2-chlorobenzene-1,3-diol (20.0 g, 139 mmol). Yield: 31.0 g, mmol. Light yellow solid. LCMS: (System 1, Method F) Rt=1.97 min, m / z 428.0 (M-56+H). + (ES + ).

[0475] Intermediate 5: (R)-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-1,2,3,4-tetrahydro-5H-chromeno[3,4-c]pyridin-5-one [ka] Process 1 (R)-2-(methoxymethyl)-1-methylpiperazine (Intermediate 1, 3.73 g, 25.9 mmol), tert-butyl 7-methyl-5-oxo-8-(((trifluoromethyl)sulfonyl)oxy)-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (Intermediate 2, 8.0 g, 17.3 mmol), Cs 2 CO 3A mixture of (11.2 g, 34.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.58 g, 1.73 mmol) and BINAP (2.16 g, 3.46 mmol) was stirred at 100 °C for 16 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature, EtOAc was added, the mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (20-80% EtOAc / petroleum ether, then 1-5% MeOH / DCM) to provide (R)-tert-butyl 8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-4,5-dihydro-1H-chromeno[3,4-c]pyridine-3(2H)-carboxylate (7.8 g, 17.0 mmol) as a yellow solid. LCMS: (System 1, Method A). Rt=2.19min, 458.2(M+H) + (ES + ).

[0476] Process 2 To a solution of (R)-tert-butyl 8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-4,5-dihydro-1H-chromeno[3,4-c]pyridine-3(2H)-carboxylate (7.8 g, 17.0 mmol) in MeOH (100 mL) was added a 4 M solution of HCl in 1,4-dioxane (100 mL). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was diluted with water (50 mL) and washed with DCM (2×20 mL). The pH of the aqueous layer was adjusted to 100% by addition of NaHCO 3 The pH was adjusted to 7-8 by adding saturated aqueous NaCl and washing with DCM (20 mL). 2 CO 3 The pH was adjusted to 10-11 with saturated aqueous solution and extracted with DCM (3 × 30 mL). The combined organic layers were dried (Na 2 SO 4), filtered and concentrated under reduced pressure to provide (R)-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-1,2,3,4-tetrahydro-5H-chromeno[3,4-c]pyridin-5-one (3.5 g, 9.8 mmol) as a yellow solid. LCMS: (System 1, Method A). Rt=1.48 min, 358.4 (M+H) + (ES + ). 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.49 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 3.59-3.53 (m, 3H), 3.36-3.30 (m, 2H), 3.26 (s, 3H), 3.13-3.10 (m, 1H), 3.03-3.00 (m, 3H), 2.84-2.81 (m, 2H), 2.79-2.73 (m, 2H), 2.62-2.57 (m, 1H), 2.41-2.38 (m, 2H), 2.29-2.26 (m, 6H).

[0477] Intermediate 6: (R)-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-1,2,3,4-tetrahydro-5H-chromeno[3,4-c]pyridin-5-one [ka] Prepared by a method similar to that of Intermediate 5 starting from (R)-2-(methoxymethyl)-1-methylpiperazine (Intermediate 1, 3.6 g, 25.2 mmol) and tert-butyl 7,10-dimethyl-5-oxo-8-(((trifluoromethyl)sulfonyl)oxy)-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (Intermediate 3, 8.0 g, 16.8 mmol). Yield: 4.4 g, 11.8 mmol. Yellow solid. LCMS: (System 1, Method F) Rt=1.34 min, m / z 372.0 (M+H). + (ES + ). 1 H NMR (400 MHz, DMSO-d 6) δ: 6.80 (s, 1H), 3.58-3.53 (m, 3H), 3.34-3.30 (m, 2H), 3.26 (s, 3H), 3.11-3.08 (m, 1H), 3.01-2.94 (m, 3H), 2.90-2.88 (m, 2H), 2.82-2.77 (m, 2H), 2.65 (s, 3H), 2.61-2.56 (m, 1H), 2.39-2.35 (m, 2H), 2.28 (s, 3H), 2.20 (s, 3H)

[0478] Specific steps: Process 1 A solution of tert-butyl 7,10-dimethyl-5-oxo-8-(trifluoromethylsulfonyloxy)-4,5-dihydro-1H-chromeno[3,4-c]pyridine-3(2H)-carboxylate (40.0 g, 83.9 mmol) in toluene (850 mL) was subjected to Cs 2 CO 3 (54.7g, 167.7mmol), Pd 2 (dba) 3 (7.7 g, 8.39 mmol), BINAP (10.4 g, 16.77 mmol) and (R)-2-(methoxymethyl)-1-methylpiperazine (15.7 g, 109.0 mmol) were added. The reaction mixture was stirred at 100 °C overnight under nitrogen atmosphere. The reaction mixture was cooled to room temperature, ethyl acetate was added and the resulting solid was filtered off. The filtrate was concentrated under reduced pressure at 45 °C and purified by silica gel column chromatography (20-80% EtOAc / petroleum ether, then 1-5% MeOH / DCM) to give (R)-tert-butyl 8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-4,5-dihydro-1H-chromeno[3,4-c]pyridine-3(2H)-carboxylate (30.0 g, 92.4% purity, 76% yield) as a yellow solid. LCMS: (System 1, Method A) Rt=2.14 min, m / z 472.2 (M+H) + (ES + ).

[0479] Process 2 To a solution of (R)-tert-butyl 8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-4,5-dihydro-1H-chromeno[3,4-c]pyridine-3(2H)-carboxylate (30.0 g, 63.7 mmol) in dioxane (120 mL) was added HCl in dioxane (4 M, 120 mL). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure at 45° C. Water was added (200 mL) and the aqueous phase was washed with DCM (2×80 mL). The DMC layer was discarded. The pH was adjusted to 100 with NaHCO 3 The pH was adjusted to 7-8 with sodium hydroxide and the aqueous phase was washed with DCM (80 mL). The DCM layer was discarded. The pH was adjusted to 7-8 with sodium hydroxide. 2 CO 3 The acid was adjusted to 10-11 with 10 mL of sodium hydroxide, and the aqueous phase was extracted with DCM (3 x 120 mL). 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure at 35° C. to give (R)-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-3,4-dihydro-1H-chromeno[3,4-c]pyridin-5(2H)-one (21.0 g, >95% purity, 89% yield) as a yellow solid.

[0480] Intermediate 7: (R)-7-Chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-5H-chromeno[3,4-c]pyridin-5-one [ka] Prepared by a method similar to that of Intermediate 5 starting from (R)-2-(methoxymethyl)-1-methylpiperazine (Intermediate 1, 671 mg, 4.7 mmol) and tert-butyl 7-chloro-5-oxo-8-(((trifluoromethyl)sulfonyl)oxy)-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (Intermediate 4, 1.5 g, 3.1 mmol). Yield: 330 mg, 0.87 mmol. Yellow solid. LCMS: (System 1, Method F) Rt=1.31 min, m / z 377.2 (M+H). + (ES+ ). 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.61 (d, J = 8.8 Hz, 1H), 7.13 (d, J = 8.4 Hz, 1H), 3.60-3.55 (m, 3H), 3.44-3.32 (m, 4H), 3.26 (s, 3H), 3.01 (br s, 2H), 2.94-2.82 (m, 2H), 2.74 (br s, 2H), 2.68-2.63 (m, 1H), 2.41-2.36 (m, 2H), 2.28 (s, 3H).

[0481] Intermediate 8: (R)-8-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-7-methyl-1,2,3,4-tetrahydro-5H-chromeno[3,4-c]pyridin-5-one [ka] Prepared by a method similar to that of Intermediate 5 starting from (R)-Octahydropyrazino[2,1-c][1,4]oxazine (936 mg, 5.89 mmol) and tert-butyl 7-methyl-5-oxo-8-(((trifluoromethyl)sulfonyl)oxy)-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (Intermediate 2, 2.1 g, 5.54 mmol). Yield: 900 mg, 2.53 mmol. Yellow solid. LCMS: (System 2, Method F) Rt=1.23 min, m / z 355.9 (M+H). + (ES + ).

[0482] Intermediate 9: (R)-8-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-7,10-dimethyl-1,2,3,4-tetrahydro-5H-chromeno[3,4-c]pyridin-5-one [ka] Prepared by a method similar to that of Intermediate 5 starting from (R)-Octahydropyrazino[2,1-c][1,4]oxazine (233 mg, 1.63 mmol) and tert-butyl 7,10-dimethyl-5-oxo-8-(((trifluoromethyl)sulfonyl)oxy)-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate (Intermediate 3, 600 mg, 1.26 mmol). Yield: 31.0 g, mmol. Light yellow solid. LCMS: (System 1, Method F) Rt=1.97 min, m / z 428.0 (M-56+H). + (ES + ).

[0483] Intermediate 10: 3-Cyclobutoxy-4-((pyrrolidin-1-ylsulfonyl)carbamoyl)benzoic acid [ka] Process 1 4-Bromo-2-hydroxybenzoate (3.0 g, 13.0 mmol), bromocyclobutane (3.5 g, 26.0 mmol) and Cs in DMA (30 mL) 2 CO 3 (8.5 g, 26.0 mmol) was stirred at 80° C. overnight. The reaction was cooled to room temperature, diluted with water (150 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ) and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (1-10% EtOAc / petroleum ether) to provide methyl 4-bromo-2-cyclobutoxybenzoate (3.0 g, 10.6 mmol) as a colorless oil. LCMS: (System 2, Method B) Rt = 2.02 min, m / z 285.0 (M+H) + (ES + ).

[0484] Process 2 Methyl 4-bromo-2-cyclobutoxybenzoate (3.0 g, 10.5 mmol) and LiOH H in MeOH (20 mL) and water (10 mL). 2A mixture of 2-bromo-2-cyclobutoxybenzoic acid (1.3 g, 31.6 mmol) was stirred at room temperature overnight. The organic solvent was removed under reduced pressure, then the pH of the mixture was adjusted to pH=3 by adding aqueous HCl 1N, the precipitate was collected by filtration, washed with water and hexanes, and dried under reduced pressure to provide 4-bromo-2-cyclobutoxybenzoic acid (2.50 g, 9.30 mmol) as an off-white solid. LCMS: (System 1, Method A) Rt=1.25 min, m / z 271.2 (M+H). + (ES + ).

[0485] Process 3 A mixture of 4-bromo-2-cyclobutoxybenzoic acid (1.4 g, 5.16 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.8 g, 1.04 mmol) and triethylamine (2.6 g, 25.7 mmol) in DMA (8 mL) and EtOH (30 mL) was stirred at 90° C. overnight under CO atmosphere. The reaction was cooled to room temperature, diluted with water (80 mL) and washed with EtOAc (3×40 mL). The pH of the aqueous layer was then adjusted to pH=3 by adding aqueous HCl 1N, which was extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ) and concentrated under reduced pressure to provide 2-cyclobutoxy-4-(ethoxycarbonyl)benzoic acid (1.1 g, 4.16 mmol) as a brown solid, which was used in the next step without further purification. LCMS: (System 1, Method A) Rt=1.27 min, m / z 265.3 (M+H). + (ES + ).

[0486] Process 4 A mixture of 2-cyclobutoxy-4-(ethoxycarbonyl)benzoic acid (600 mg, 2.27 mmol), EDCI (871 mg, 4.54 mmol), pyrrolidine-1-sulfonamide (512 mg, 3.41 mmol) and DMAP (549 mg, 4.49 mmol) in DCM (20 mL) was stirred at room temperature overnight. The reaction was diluted with water (20 mL) and the mixture was extracted with DCM (3×20 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1-50% EtOAc / petroleum ether) to provide ethyl 3-cyclobutoxy-4-(pyrrolidin-1-ylsulfonylcarbamoyl)benzoate (880 mg, 2.22 mmol) as a colorless oil. LCMS: (System 1, Method A) Rt=1.65 min, m / z 397.3 (M+H) + (ES + ).

[0487] Process 5 Ethyl 3-cyclobutoxy-4-(pyrrolidin-1-ylsulfonylcarbamoyl)benzoate (400 mg, 1.0 mmol) and LiOH H in MeOH (10 mL) and water (5 mL). 2 A mixture of 2,4-dimethylformamide (127 mg, 3.03 mmol) and 1,4-dichloroform (1,2-dichloroform) was stirred at room temperature overnight. The organic solvent was removed under reduced pressure, the pH of the resulting aqueous solution was adjusted to pH=3 by adding 1N aqueous HCl, and the resulting solution was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ) and concentrated under reduced pressure to provide 3-cyclobutoxy-4-(pyrrolidin-1-ylsulfonylcarbamoyl)benzoic acid (330 mg, 0.90 mmol) as a white solid. LCMS: (System 1, Method A) Rt = 1.13 min, m / z 369.2 (M+H) + (ES + ).

[0488] Intermediate 11: 3-Cyclobutoxy-4-(1-methylcyclopropylsulfonylcarbamoyl)benzoic acid [ka] Prepared by a similar method to intermediate 10 starting from 4-bromo-2-hydroxybenzoate (3.0 g, 13.0 mmol) and bromocyclobutane (3.5 g, 26.0 mmol) except step 4 was performed with 1-methylcyclopropane-1-sulfonamide instead of pyrrolidine-1-sulfonamide. Yield: 310 mg, 0.88 mmol. White solid. LCMS: (System 1, Method A) Rt=0.95 min, m / z 354.2 (M+H). + (ES + ).

[0489] Intermediate 12: 3-(cyclopentyloxy)-4-(((1-methylcyclopropyl)sulfonyl)carbamoyl)benzoic acid [ka] Prepared by a similar method to intermediate 10 starting from 4-bromo-2-hydroxybenzoate (5.0 g, 21.6 mmol) and bromocyclopentane (12.9 g, 86.6 mmol) except step 4 was performed using 1-methylcyclopropane-1-sulfonamide instead of pyrrolidine-1-sulfonamide. Yield: 1.0 g, 2.72 mmol. White solid. LCMS: (System 1, Method A) Rt=1.07 min, m / z 366.0 (MH). - (ES - ).

[0490] Intermediate 13: 3-Cyclobutoxy-2-fluoro-4-((pyrrolidin-1-ylsulfonyl)carbamoyl)benzoic acid [ka] Process 1 2-Bromo-6-fluorophenol (2.0 g, 10.5 mmol), bromocyclobutane (2.8 g, 20.9 mmol) and Cs in DMA (50 mL) 2 CO 3A mixture of (10.2 g, 31.4 mmol) was stirred at room temperature overnight. The mixture was diluted with water (150 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1-10% EtOAc / petroleum ether) to give 1-bromo-2-cyclobutoxy-3-fluorobenzene (2.2 g, 8.98 mmol) as a pale yellow oil. 1 H NMR (400 MHz, CD 3 OD) δ: 7.35 (dd, J = 8.0, 1.2 Hz, 1H), 7.14-7.10 (m, 1H), 7.00-6.94 (m, 1H), 4.70-4.63 (m, 1H), 2.32-2.20 (m, 4H), 1.81-1.72 (m, 1H), 1.58-1.49 (m, 1H).

[0491] Process 2 To a solution of 1-bromo-2-cyclobutoxy-3-fluorobenzene (2.20 g, 8.98 mmol) in THF (70 mL) was added LDA 2M (5.4 mL, 10.8 mmol) slowly at -70 °C and stirred for 1 h, then dry ice (10 g) was added slowly and the mixture was stirred at room temperature overnight. The reaction was cooled to NH 4 The mixture was quenched with saturated aqueous Cl (100 mL) and partitioned with EtOAc (3×60 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to provide 4-bromo-3-cyclobutoxy-2-fluorobenzoic acid (1.6 g, 5.53 mmol) as a white solid. LCMS: (System 1, Method A) Rt = 1.36 min, m / z 287.0 (MH). - (ES - ).

[0492] Process 3 A mixture of 4-bromo-3-cyclobutoxy-2-fluorobenzoic acid (650 mg, 2.25 mmol), pyrrolidine-1-sulfonamide (1.01 g, 6.75 mmol), trans-bis(acetato)bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(II) (Hellman's palladacycle, 216 mg, 0.23 mmol), tri-tert-butylphosphonium tetrafluoroborate (133 mg, 0.46 mmol), molybdenum hexacarbonyl (891 mg, 3.38 mmol) and DBU (1.03 g, 6.75 mmol) in 1,4-dioxane (20 mL) was stirred at 140° C. for 15 min under microwave irradiation. The mixture was concentrated under reduced pressure and the residue was purified by HCl / HCl (HCl 3 , 100 ng / ml). 2 CO 3 The mixture was taken up in aqueous 2M (40 mL) and washed with EtOAc (3×40 mL). The pH of the aqueous layer was adjusted to pH=4 by adding aqueous HCl 1N, and then it was extracted with EtOAc (3×40 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1-5% MeOH / DCM) to provide 3-cyclobutoxy-2-fluoro-4-((pyrrolidin-1-ylsulfonyl)carbamoyl)benzoic acid (200 mg, 0.52 mmol) as a colorless oil. LCMS: (System 1, Method A) Rt=0.99 min, m / z 385.0 (MH). - (ES - ).

[0493] Intermediate 14: 3-(cyclopentyloxy)-2-fluoro-4-((pyrrolidin-1-ylsulfonyl)carbamoyl)benzoic acid [ka] Prepared by a method similar to intermediate 13 starting from 2-bromo-6-fluorophenol (50.0 g, 263 mmol) and bromocyclopentane (78.0 g, 526 mmol). Yield: 32.0 g, 79.9 mmol. White solid. LCMS: (System 1, Method A) Rt=1.11 min, m / z (MH).- (ES - ).

[0494] Intermediate 15: 3-(cyclopentyloxy)-4-((N,N-dimethylsulfamoyl)carbamoyl)-2-fluorobenzoic acid [ka] Prepared by a similar method to Intermediate 14, except step 3 was performed using N,N-dimethylsulfamide instead of pyrrolidine-1-sulfonamide. Yield: 410 mg, 1.10 mmol. Pale yellow solid. LCMS: (System 1, Method A) Rt=0.96 min, m / z 373.0 (MH). - (ES - ).

[0495] Intermediate 16: 3-(cyclopentyloxy)-2-fluoro-4-(((1-methylcyclopropyl)sulfonyl)carbamoyl)benzoic acid [ka] Prepared by a similar method to intermediate 14, except step 3 was performed using 1-methylcyclopropane-1-sulfonamide instead of pyrrolidine-1-sulfonamide. Yield: 440 mg, 1.14 mmol. Pale yellow solid. LCMS: (System 1, Method A) Rt=1.01 min, m / z 384.2 (MH). - (ES).

[0496] Intermediate 17: 3-(cyclopentyloxy)-2-fluoro-4-(N-isopropyl-N-methylsulfamoylcarbamoyl)benzoic acid [ka] Prepared by a similar method to Intermediate 14, except step 3 was performed using N-methyl-N-isopropylsulfamoylamide instead of pyrrolidine-1-sulfonamide. Yield: 220 mg, 0.55 mmol. White solid. LCMS: (System 1, Method F) Rt=0.99 min, m / z 401.0 (MH). - (ES - ).

[0497] Intermediate 18: 3-Cyclobutoxy-2-fluoro-4-((N-isopropyl-N-methylsulfamoyl)carbamoyl)benzoic acid [ka] Prepared by a similar method to intermediate 13, except step 3 was performed using N-methyl-N-isopropylsulfamoylamide instead of pyrrolidine-1-sulfonamide. Yield: 240 mg, 0.62 mmol. White solid. LCMS: (System 1, Method F) Rt=0.94 min, m / z 387.0 (MH). - (ES - ).

[0498] Intermediate 19: 3-Cyclobutoxy-2-fluoro-4-(1-methylcyclopropylsulfonylcarbamoyl)benzoic acid [ka] Prepared by a similar method to intermediate 13, except step 3 was performed using 1-methylcyclopropane-1-sulfonamide instead of pyrrolidine-1-sulfonamide. Yield: 500 mg, 1.35 mmol. White solid. LCMS: (System 1, Method A) Rt=0.85 min, m / z 370.0 (MH). - (ES - ).

[0499] Intermediate 20: 3-Cyclobutoxy-4-(N,N-dimethylsulfamoylcarbamoyl)-2-fluorobenzoic acid [ka] Prepared by a similar method to intermediate 13, except step 3 was performed using N,N-dimethylsulfamide instead of pyrrolidine-1-sulfonamide. Yield: 670 mg, 1.86 mmol. White solid. LCMS: (System 2, Method B) Rt=1.61 min, m / z 361.1 (MH). - (ES - ).

[0500] Intermediate 21: (1R,3r,5S)-3-(2-bromo-6-fluorophenoxy)bicyclo[3.1.0]hexane [ka] Process 1 DIAD (6.8 g, 33.7 mmol) was dissolved in THF (150 mL) and 2-bromo-6-fluorophenol (3.2 g, 16.8 mmol), PPh 3 (8.8 g, 33.7 mmol) and cyclopent-3-en-1-ol (2.1 g, 25.3 mmol) were added at 0° C. and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1% EtOAc / petroleum ether) to provide 1-bromo-2-(cyclopent-3-en-1-yloxy)-3-fluorobenzene (2.1 g, 8.17 mmol) as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.47-7.45 (m, 1H), 7.35-7.30 (m, 1H), 7.10-7.05 (m, 1H), 5.77 (s, 2H), 5.06-5.03 (m, 1H), 2.67-2.50 (m, 4H).

[0501] Process 2 A solution of diethylzinc 1M (24.6 mL, 24.6 mmol) in heptane in DCM (80 mL) was slowly added to a solution of chloroiodomethane (11.6 g, 65.6 mmol) in DCM (20 mL) at 0° C. and the mixture was stirred at this temperature for 1 h. Then a solution of 1-bromo-2-(cyclopent-3-en-1-yloxy)-3-fluorobenzene (2.1 g, 8.2 mmol) in DCM (10 mL) was added and the mixture was allowed to come to room temperature and stirred overnight. The reaction was cooled to 30° C. with NH 4 It was quenched by adding aqueous Cl (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1% EtOAc / petroleum ether) to give (1R,3r,5S)-3-(2-bromo-6-fluorophenoxy)bicyclo[3.1.0]hexane (1.7 g, 6.27 mmol) as a pale yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 7.46-7.43 (m, 1H), 7.33-7.27 (m, 1H), 7.08-7.02 (m, 1H), 4.81-4.78 (m, 1H), 2.18-2.11 (m, 2H), 2.05-2.01 (m, 2H), 1.36-1.30 (m, 2H), 0.86-0.83 (m, 1H), 0.54-0.50 (m, 1H).

[0502] Intermediate 22: 3-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-2-fluoro-4-((pyrrolidin-1-ylsulfonyl)carbamoyl)benzoic acid [ka] Prepared in a similar manner to intermediate 13 (steps 2 and 3 only) starting from (1R,3r,5S)-3-(2-bromo-6-fluorophenoxy)bicyclo[3.1.0]hexane (intermediate 21, 1.2 g, 3.8 mmol) in step 2. Yield: 370 mg, 0.90 mmol. Pale yellow solid. LCMS: (system 1, method A) Rt=1.10 min, m / z 410.9 (MH). - (ES - ).

[0503] Intermediate 23: 3-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-4-((N,N-dimethylsulfamoyl)carbamoyl)-2-fluorobenzoic acid [ka] Prepared by a similar method to intermediate 22, except step 3 was performed using N,N-dimethylsulfamide instead of pyrrolidine-1-sulfonamide. Yield: 600 mg, 1.55 mmol. Yellow solid. LCMS: (System 1, Method F) Rt=0.83 min, m / z 385.4 (MH). - (ES - ).

[0504] Intermediate 24: 3-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-2-fluoro-4-((N-isopropyl-N-methylsulfamoyl)carbamoyl)benzoic acid [ka] Prepared by a similar method to intermediate 22, except step 3 was performed using N-methyl-N-isopropylsulfamoylamide instead of pyrrolidine-1-sulfonamide. Yield: 356 mg, 0.86 mmol. Pale yellow solid. LCMS: (System 1, Method A) Rt=1.21 min, m / z 412.8 (MH). - (ES - ).

[0505] Intermediate 25: 3-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-2-fluoro-4-(((1-methylcyclopropyl)sulfonyl)carbamoyl)benzoic acid [ka] Prepared by a similar method to intermediate 22, except step 3 was performed using 1-methylcyclopropane-1-sulfonamide instead of pyrrolidine-1-sulfonamide. Yield: 364 mg, 0.92 mmol. Pale yellow solid. LCMS: (System 1, Method A) Rt=1.06 min, m / z 395.9 (MH). - (ES - ).

[0506] Intermediate 26: (1R,3s,5S)-3-(2-bromo-6-fluorophenoxy)bicyclo[3.1.0]hexane [ka] DIAD (6.4 g, 31.6 mmol) was dissolved in THF (50 mL) with 2-bromo-6-fluorophenol (2.0 g, 10.5 mmol), (1R,3r,5S)-bicyclo[3.1.0]hexan-3-ol (1.0 g, 10.5 mmol) and PPh 3 (8.3 g, 31.6 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1-10% EtOAc / petroleum ether) to give (1R,3s,5S)-3-(2-bromo-6-fluorophenoxy)bicyclo[3.1.0]hexane (1.9 g, 7.0 mmol) as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ: 7.46-7.43 (m, 1H), 7.33-7.28 (m, 1H), 7.10-7.04 (m, 1H), 4.43-4.35 (m, 1H), 2.17-2.13 (m, 2H), 2.03-1.98 (m, 2H), 1.34-1.30 (m, 2H), 0.37-0.32 (m, 1H), 0.07-0.04 (m, 1H).

[0507] Intermediate 27: 1-Bromo-2-((4,4-difluorocyclohexyl)oxy)-3-fluorobenzene [ka] Prepared by a method similar to intermediate 26 starting from 2-bromo-6-fluorophenol (500 mg, 2.62 mmol) and 4,4-difluorocyclohexanol (535 mg, 3.93 mmol). Yield: 650 mg, 2.1 mmol. White solid. LCMS: (System 3, Method I). Rt=2.14 min.

[0508] Intermediate 28: 2-(2-bromo-6-fluorophenoxy)adamantane [ka] Prepared by a method similar to intermediate 26 starting from 2-bromo-6-fluorophenol (1.0 g, 5.24 mmol) and 2-adamantanol (1.2 g, 7.85 mmol). Yield: 700 mg, 2.2 mmol. White solid. LCMS: (System 3, Method I). Rt=2.21 min.

[0509] Intermediate 29: 3-((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yloxy)-2-fluoro-4-(pyrrolidin-1-ylsulfonylcarbamoyl)benzoic acid [ka] Prepared by a method similar to intermediate 13 (steps 2 and 3 only) starting from (1R,3s,5S)-3-(2-bromo-6-fluorophenoxy)bicyclo[3.1.0]hexane (intermediate 26, 1.9 g, 16.7 mmol) in step 2. Yield: 250 mg, 0.61 mmol. Pale yellow solid. LCMS: (System 1, Method F) Rt=0.91 min, m / z 411.0 (MH). - (ES - ).

[0510] Intermediate 30: 3-((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yloxy)-2-fluoro-4-(pyrrolidin-1-ylsulfonylcarbamoyl)benzoic acid [ka] Prepared by a similar method to intermediate 29, except step 3 was performed using N,N-dimethylsulfamide instead of pyrrolidine-1-sulfonamide. Yield: 230 mg, 0.60 mmol. White solid. LCMS: (System 1, Method A) Rt=1.01 min, m / z 384.8 (MH). - (ES - )

[0511] Intermediate 31: 3-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-2-fluoro-4-(((1-methylcyclopropyl)sulfonyl)carbamoyl)benzoic acid [ka] Prepared by a similar method to intermediate 29, except step 3 was performed using 1-methylcyclopropane-1-sulfonamide instead of pyrrolidine-1-sulfonamide. Yield: 240 mg, 0.60 mmol. White solid. LCMS: (System 1, Method F) Rt=0.85 min, m / z 396.0 (MH). - (ES - )

[0512] Intermediate 32: 3-(4,4-difluorocyclohexoxy)-4-(dimethylsulfamoylcarbamoyl)-2-fluoro-benzoic acid [ka] Prepared by a similar method to intermediate 13 (steps 2 and 3 only) starting from 1-bromo-2-((4,4-difluorocyclohexyl)oxy)-3-fluorobenzene (intermediate 27, 650 mg, 2.10 mmol) in step 2. Step 3 was carried out using N,N-dimethylsulfamide instead of pyrrolidine-1-sulfonamide. Yield: 190 mg, 0.45 mmol. White solid. LCMS: (System 3, Method I) Rt=0.80 min, m / z 423.2 (MH). - (ES - )

[0513] Intermediate 33: 3-(4,4-difluorocyclohexoxy)-2-fluoro-4-[(1-methylcyclopropyl)sulfonylcarbamoyl]benzoic acid [ka] Prepared by a similar method to intermediate 32, except step 3 was performed using 1-methylcyclopropane-1-sulfonamide instead of pyrrolidine-1-sulfonamide. Yield: 165 mg, 0.38 mmol. Yellow solid. LCMS: (System 3, Method I) Rt=0.98 min, m / z 434.3 (MH). - (ES - )

[0514] Intermediate 34: 3-((adamantan-2-yl)oxy)-2-fluoro-4-((pyrrolidin-1-ylsulfonyl)carbamoyl)benzoic acid [ka] Prepared in a similar manner to intermediate 13 (steps 2 and 3 only) starting from 2-(2-bromo-6-fluorophenoxy)adamantane (intermediate 28, 700 mg, 2.15 mmol) in step 2. Yield: 16 mg, 0.03 mmol. Yellow solid. LCMS: (System 3, Method I) Rt=1.19 min, m / z 467.2 (M+H). + (ES + )

[0515] Intermediate 35: 3-((adamantan-2-yl)oxy)-4-((N,N-dimethylsulfamoyl)carbamoyl)-2-fluorobenzoic acid [ka] Prepared by a similar method to Intermediate 34, except step 3 was performed using N,N-dimethylsulfamide instead of pyrrolidine-1-sulfonamide. Yield: 27 mg, 0.06 mmol. White solid. LCMS: (System 3, Method J) Rt=1.84 min, m / z 439.0 (MH). - (ES - )

[0516] Intermediate 36: 5-Cyclobutoxy-4-((N,N-dimethylsulfamoyl)carbamoyl)-2-fluorobenzoic acid [ka] Process 1 DIAD (1.3 mL, 6.42 mmol) was dissolved in THF (25 mL) and methyl 4-bromo-5-fluoro-2-hydroxybenzoate (800 mg, 3.21 mmol), PPh 3 A mixture of 1,2-dichlorophenyl ether (1685 mg, 6.42 mmol) and cyclobutanol (0.38 mL, 4.82 mmol) was added at 0° C. and the mixture was stirred at room temperature overnight. The reaction was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1-10% EtOAc / iso-hexane) to give methyl 4-bromo-2-cyclobutoxy-5-fluorobenzoate (619 mg, 2.04 mmol) as a pale yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.57 (d, J = 8.7 Hz, 1H), 6.97 (d, J = 5.5 Hz, 1H), 4.64 (p, J = 7.1 Hz, 1H), 3.88 (s, 3H), 2.51-2.43 (m, 2H), 2.29-2.19 (m, 2H), 1.93-1.84 (m, 1H), 1.75-1.64 (m, 1H).

[0517] Process 2 A mixture of methyl 4-bromo-2-cyclobutoxy-5-fluorobenzoate (619 mg, 2.04 mmol) and aqueous LiOH 2N (2.0 mL, 4.00 mmol) in MeOH (2 mL) was stirred at room temperature overnight. The organic solvent was removed under reduced pressure and then the pH of the mixture was adjusted to 3 by adding 1N aqueous HCl. The precipitate was collected by filtration, washed with water and hexanes, and dried under reduced pressure to provide 4-bromo-2-cyclobutoxy-5-fluorobenzoic acid (424 mg, 1.47 mmol) as an off-white solid. LCMS: (System 3, Method I) Rt=1.24 min, m / z 287.0 (MH). - (ES - )

[0518] Process 3 A mixture of 4-bromo-2-cyclobutoxy-5-fluorobenzoic acid (212 mg, 0.73 mmol), EDCI (290 mg, 1.51 mmol), pyrrolidine-1-sulfonamide (276 mg, 2.23 mmol) and DMAP (185 mg, 1.51 mmol) in DCM (4 mL) was stirred at room temperature overnight. The reaction was diluted with water (15 mL) and the mixture was extracted with DCM (3×15 mL). The combined organic layers were dried (Na 2 SO 4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (20-100% EtOAc / iso-hexane) to provide 4-bromo-2-cyclobutoxy-N-(N,N-dimethylsulfamoyl)-5-fluorobenzamide (175 mg, 0.43 mmol) as a white solid. LCMS: (System 3, Method I) Rt=1.43 min, m / z 393.1 (MH). - (ES - ).

[0519] Process 4 A mixture of 4-bromo-2-cyclobutoxy-N-(N,N-dimethylsulfamoyl)-5-fluorobenzamide (175 mg, 0.43 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (16 mg, 0.02 mmol) and triethylamine (216 mg, 2.14 mmol) in DMF (3.5 mL) and EtOH (2 mL) was stirred at 100° C. overnight under a CO atmosphere. The reaction was cooled to room temperature, diluted with water (20 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (20-80% EtOAc / iso-hexane then 1%-10% MeOH / DCM) to provide ethyl 5-cyclobutoxy-4-((N,N-dimethylsulfamoyl)carbamoyl)-2-fluorobenzoate (102 mg, 0.25 mmol) as a brown solid. LCMS: (System 3, Method I) Rt=1.36 min, m / z 387.2 (MH). - (ES - ).

[0520] Process 5 LiOH H 2HO (1.2 mL, 2.46 mmol) was added to a solution of ethyl 5-(cyclobutoxy)-2-fluoro-4-(pyrrolidin-1-ylsulfonylcarbamoyl)benzoate (102 mg, 0.25 mmol) in MeOH (3.0 mL) and the reaction was stirred at room temperature for 1 h. The organic solvent was removed under reduced pressure and the crude product was obtained as C 18 The residue was purified by column chromatography at rt (0-100% ACN / 0.1% FA in water) to provide 5-cyclobutoxy-4-((N,N-dimethylsulfamoyl)carbamoyl)-2-fluorobenzoic acid (41 mg, 0.11 mmol) as an off-white solid. LCMS: (System 3, Method J) Rt = 1.64 min, m / z 359.2 (M-H). - (ES - ).

[0521] Intermediate 37: (S)-2-(methoxymethyl)-1-methylpiperazine [ka] Process 1 Sodium hydride (60% dispersion in mineral oil, 2.3 g, 57.8 mmol) was added in portions to a solution of tert-butyl (S)-3-(hydroxymethyl)piperazine-1-carboxylate (5.0 g, 23.1 mmol) in THF (50 mL) at 0° C. for 1 h. Iodomethane (8.2 g, 57.8 mmol) was then added dropwise at 0° C. and the mixture was stirred at room temperature for 12 h. The reaction was cooled to 0° C. with NH 4 The mixture was quenched at 0° C. by the addition of saturated aqueous Cl (30 mL) and the resulting aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to provide tert-butyl (S)-3-(methoxymethyl)-4-methylpiperazine-1-carboxylate (6.2 g, 25.4 mmol) as a white solid, which was used in the next step without further purification. 1 H NMR (400 MHz, CDCl 3) δ 3.87-3.84 (m, 2H), 3.52-3.41 (m, 2H), 3.31 (s, 3H), 3.06-2.67 (m, 3H), 2.34 (s, 3H), 2.22-2.01 (m, 2H), 1.44 (s, 9H).

[0522] Process 2 A mixture of tert-butyl (S)-3-(methoxymethyl)-4-methylpiperazine-1-carboxylate (5.7 g, 23.1 mmol, 1.0 eq) in EtOAc (25 mL) and HCl 4N solution in EtOAc (25 mL) was stirred at room temperature for 12 h. The mixture was concentrated under reduced pressure to provide (S)-2-(methoxymethyl)-1-methylpiperazine hydrochloride (3.00 g, 16.60 mmol) as a brown solid, which was used in the next step without further purification. LCMS: (System 3, Method J) Rt=0.33 min, m / z 145.1 (M+H). + (ES + )

[0523] Process 3 (S)-2-(methoxymethyl)-1-methylpiperazine hydrochloride (1.50 g, 8.30 mmol) and K in MeOH (7.50 mL) 2 CO 3 A mixture of (1.26 g, 9.13 mmol, 1.1 eq) was stirred at room temperature for 1 h. The reaction was partitioned between water (10 mL) and DCM (3×10 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to provide (S)-2-(methoxymethyl)-1-methylpiperazine (1.1 g, 7.63 mmol) as a black solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 3.44-3.48 (m, 1H), 3.30-3.35 (m, 1H), 3.24 (s, 3H), 3.10-3.14 (m, 2H), 2.78-2.85 (m, 2H), 2.63-2.69 (m, 1H), 2.39-2.46 (m, 2H), 2.22 (s, 3H),

[0524] Intermediate 38: 3-(bicyclo[3.1.0]hexan-3-yloxy)-4-((N,N-dimethylsulfamoyl)carbamoyl)benzoic acid [ka] Process 1 DIAD (15.9 g, 77.9 mmol) was dissolved in THF (300 mL) and methyl 4-bromo-3-hydroxybenzoate (6.0 g, 26.0 mmol), cyclopent-3-enol (6.6 g, 78.0 mmol) and PPh 3 (20.4 g, 77.9 mmol) was added to the mixture and the mixture was stirred at room temperature overnight. Water (300 mL) was added and the mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine and dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1-10% EtOAc / petroleum ether) to provide methyl 4-bromo-3-(cyclopent-3-en-1-yloxy)benzoate (6.0 g, 20.2 mmol) as a brown solid. LCMS: (System 2, Method C) Rt=0.86 min, m / z 297.1 2 (M+H) + (ES + ).

[0525] Process 2 Chloroiodomethane (23.6 g, 133 mmol) was added dropwise to a solution of diethylzinc 1 M in heptane (67.5 mL) in DCM (75 mL) at 0° C., the mixture was stirred at this temperature for 30 min, and then a solution of methyl 4-bromo-3-(cyclopent-3-en-1-yloxy)benzoate (6.0 g, 20.2 mmol) in DCM (75 mL) was added. The mixture was stirred at room temperature overnight. The reaction was cooled to 30° C. with NH 4 The mixture was quenched with saturated aqueous Cl (200 mL) and extracted with DCM (3×200 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1-10% EtOAc / petroleum ether) to provide methyl 3-(bicyclo[3.1.0]hexan-3-yloxy)-4-bromobenzoate (4.5 g, 14.5 mmol) as a colorless oil. LCMS: (System 2, Method C) Rt = 0.92 min, m / z 311.2 (M+H) + (ES + ).

[0526] Process 3 A mixture of methyl 3-(bicyclo[3.1.0]hexan-3-yloxy)-4-bromobenzoate (2.0 g, 6.45 mmol), tri-tert-butylphosphonium tetrafluoroborate (377 mg, 1.3 mmol), trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II) (Hellman's palladacycle, 610 mg, 0.65 mmol), molybdenum hexacarbonyl (2.6 g, 9.67 mmol), DBU (2.9 g, 19.35 mmol) and methanesulfonamide (2.4 g, 19.4 mmol) in 1,4-dioxane (50 mL) was stirred overnight at 100° C. The reaction mixture was cooled to room temperature, diluted with DCM / water (5:1, 120 mL) and filtered through Celite. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel (0-5% MeOH / DCM) to provide methyl 3-(bicyclo[3.1.0]hexan-3-yloxy)-4-((N,N-dimethylsulfamoyl)carbamoyl)benzoate (1.3 g, 3.40 mmol) as a pale yellow solid. LCMS: (System 2, Method F) Rt = 1.31 min, m / z 383.2 (M+H). + (ES + ).

[0527] Process 4 A mixture of 3-(bicyclo[3.1.0]hexan-3-yloxy)-4-((N,N-dimethylsulfamoyl)carbamoyl)benzoate (1.0 g, 2.62 mmol) in MeOH (20 mL) and water (5 mL) was dissolved in LiOH H 22H2O (660 mg, 15.7 mmol) was added and the mixture was then stirred at room temperature overnight. The organic solvent was removed under reduced pressure and the pH of the mixture was then adjusted to about 5 by adding 1N aqueous HCl and extracted with EtOAc (3 x 20 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to provide 3-(bicyclo[3.1.0]hexan-3-yloxy)-4-((N,N-dimethylsulfamoyl)carbamoyl)benzoic acid (849 mg, 2.30 mmol) as a white solid, which was used in the next step without further purification. LCMS: (System 1, Method A) Rt = 1.14 min, m / z 366.8 (MH). - (ES - ).

[0528] Intermediate 39: 3-(bicyclo[3.1.0]hexan-3-yloxy)-4-((pyrrolidin-1-ylsulfonyl)carbamoyl)benzoic acid [ka] Prepared by a similar method to intermediate 38 starting from 4-bromo-3-hydroxybenzoate (6.0 g, 26.0 mmol) except step 3 was performed with pyrrolidine-1-sulfonamide instead of N,N-dimethylsulfamide. Yield: 1.3 g, 3.30 mmol. Pale yellow solid. LCMS: (System 2, Method F) Rt=1.31 min, m / z 409.2 (M+H). + (ES + ).

[0529] Intermediate 40: 3-((4,4-difluorocyclohexyl)oxy)-4-((pyrrolidin-1-ylsulfonyl)carbamoyl)benzoic acid [ka] Process 1 DIAD (963 mg, 4.76 mmol) was dissolved in methyl 4-bromo-3-hydroxybenzoate (500 mg, 2.38 mmol), 4,4-difluorocyclohexanol (487 mg, 3.57 mmol) and PPh in THF (12 mL). 3 (1.25 g, 4.76 mmol) was added to a mixture of 1,2-dichlorophenyl ether (1.25 g, 4.76 mmol) and the mixture was stirred at room temperature overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1-10% EtOAc / petroleum ether) to provide methyl 4-bromo-3-((4,4-difluorocyclohexyl)oxy)benzoate (810 mg, 2.32 mmol) as a pale yellow solid. LCMS: (System 3, Method I) Rt=2.07 min.

[0530] Process 2 A solution of 2 M LiOH (3.5 mL, 7.0 mmol) was added to a solution of methyl 4-bromo-3-((4,4-difluorocyclohexyl)oxy)benzoate (810 mg, 2.32 mmol) in MeOH (3.5 mL). The reaction mixture was stirred at 40 °C overnight. The reaction mixture was cooled to room temperature and the pH was adjusted to 3 with aqueous HCl 1N, followed by extraction with EtOAc (2 × 30 mL). The combined organic layers were dried (MgSO 4 ), filtered and concentrated under reduced pressure to provide 4-bromo-3-(4,4-difluorocyclohexoxy)benzoic acid (530 mg, 1.58 mmol) as a pale yellow solid. LCMS: (System 3, Method I) Rt = 1.38 min, m / z 334.9 (MH). - (ES - ).

[0531] Process 3 A mixture of DBU (0.39 mL, 2.64 mmol), 4-bromo-3-(4,4-difluorocyclohexoxy)benzoic acid (295 mg, 0.88 mmol), molybdenum hexacarbonyl (594 mg, 1.32 mmol), pyrrolidine-1-sulfonamide (397 mg, 2.64 mmol), trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II) (Hellman palladacycle, 83 mg, 0.09 mmol) and tri-tert-butylphosphonium tetrafluoroborate (51 mg, 0.18 mmol) in 1,4-dioxane (4.7 mL) was stirred at 140° C. for 30 min under microwave irradiation. The mixture was dissolved in MeOH (20 mL) and concentrated under reduced pressure. The residue was purified by HPLC using HPLC. 2 CO 3 The mixture was diluted with aqueous 2M (30 mL) and washed with EtOAc (3×30 mL). The resulting aqueous layer was acidified to pH 1-2 by adding aqueous HCl 2N and extracted with EtOAc (3×30 mL). The combined organic layers were dried (MgSO 4 ), filtered and concentrated under reduced pressure to provide 3-(4,4-difluorocyclohexoxy)-4-(pyrrolidin-1-ylsulfonylcarbamoyl)benzoic acid (33 mg, 0.08 mmol) as a white solid, which was used in the next step without further purification. LCMS: (System 3, Method I) Rt=1.71 min, m / z 431.2 (MH). - (ES - ).

[0532] Intermediate 41: 3-((adamantan-2-yl)oxy)-4-((pyrrolidin-1-ylsulfonyl)carbamoyl)benzoic acid [ka] Process 1 DIAD (2.1 mL, 10.5 mmol) was dissolved in methyl 4-bromo-3-hydroxybenzoate (1.2 g, 5.24 mmol), adamantan-2-ol (1.2 g, 7.85 mmol) and PPh in THF (25 mL). 3(2.7 g, 10.5 mmol) was added to a mixture of 1,2-dichlorophenyl ether (1.0 g, 10.5 mmol) and the mixture was stirred at room temperature overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine and dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1-10% EtOAc / petroleum ether) to provide methyl 3-((adamantan-2-yl)oxy)-4-bromobenzoate (49 mg, 0.12 mmol) as a pale yellow solid. LCMS: (System 3, Method I) Rt=1.21 min, m / z 421.1 (MH). - (ES - ).

[0533] Process 2 A mixture of DBU (0.31 mL, 0.68 mmol), methyl 3-((adamantan-2-yl)oxy)-4-bromobenzoate (249 mg, 0.68 mmol), molybdenum hexacarbonyl (459 mg, 1.02 mmol), N,N-dimethylsulfamide (253 mg, 2.04 mmol), trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II) (Hellman palladacycle, 128 mg, 0.14 mmol), tri-tert-butylphosphonium tetrafluoroborate (79 mg, 0.27 mmol) in 1,4-dioxane (4.5 mL) was stirred under microwave irradiation at 140° C. for 30 min. The mixture was dissolved in MeOH (20 mL) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (10-90% EtOAc / iso-hexane) to provide methyl 3-((adamantan-2-yl)oxy)-4-((N,N-dimethylsulfamoyl)carbamoyl)benzoate (124 mg, 0.28 mmol) as a yellow solid. LCMS: (System 3, Method I) Rt = 1.62 min, m / z 435.1 (MH). - (ES - ).

[0534] Process 3 A mixture of methyl 3-((adamantan-2-yl)oxy)-4-((N,N-dimethylsulfamoyl)carbamoyl)benzoate (124 mg, 0.284 mmol) and aqueous LiOH 2 M (0.43 mL, 0.85) in THF (0.4 mL) and MeOH (0.4 mL) was stirred at 40 °C overnight. The mixture was acidified to pH 1-2 by adding aqueous HCl 2 N (10 mL) and extracted with EtOAc (2 × 30 mL). The combined organic layers were then dried (MgSO 4 ), filtered and concentrated under reduced pressure to provide 3-(2-adamantyloxy)-4-(dimethylsulfamoylcarbamoyl)benzoic acid (49 mg, 0.12 mmol) as a pale yellow solid, which was used in the next step without further purification. LCMS: (System 3, Method I) Rt=1.21 min, m / z 421.1 (MH). - (ES - ).

[0535] Intermediate 42: 4-(ethoxycarbonyl)-2-fluoro-6-(trifluoromethyl)benzoic acid [ka] Process 1 N-Bromosuccinimide (24.8 g, 140 mmol) was added portionwise to a solution of 3-fluoro-5-(trifluoromethyl)aniline (25.0 g, 140 mmol) in ACN (500 mL) at 0° C., then the reaction was stirred for 2 h at 0° C. The reaction was concentrated under reduced pressure and the crude product was purified by column chromatography on silica gel (10% DCM / petroleum ether) to provide 4-bromo-3-fluoro-5-(trifluoromethyl)aniline (25.0 g, 96.9) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ: 6.81-6.80 (m, 1H), 6.59 (dd, J = 9.8, 2.6 Hz, 1H), 4.00 (br s, 2H).

[0536] Process 2 NaNO in water (125 mL)2 A solution of (7.4 g, 107 mmol) was added to a solution of 4-bromo-3-fluoro-5-(trifluoromethyl)aniline (25.0 g, 96.9 mmol) in concentrated aqueous HCl (250 mL) at 0° C., and the mixture was stirred at 0° C. for 1 h. NaI (16.0 g, 107 mmol) was then added in portions, and the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was cooled to 0° C. and cooled to 0° C. 2 S 2 O 3 It was quenched with saturated aqueous solution (500 mL) and extracted with EtOAc (3×500 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (10% DCM / petroleum ether) to provide 2-bromo-1-fluoro-5-iodo-3-(trifluoromethyl)benzene (21.8 g, 59.1 mmol) as a brown solid. 1 H NMR (400 MHz, CDCl 3 ) δ: 7.81 (s, 1H), 7.65 (dd, J = 7.2, 1.6 Hz, 1H).

[0537] Process 3 A mixture of 2-bromo-1-fluoro-5-iodo-3-(trifluoromethyl)benzene (21.8 g, 59.1 mmol), TEA (29.9 g, 295 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.7 g, 11.8 mmol) in EtOH (600 mL) was stirred at 80° C. overnight under CO atmosphere. The reaction mixture was brought to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (4% DCM / petroleum ether) to provide ethyl 4-bromo-3-fluoro-5-(trifluoromethyl)benzoate (13.1 g, 41.6 mmol) as a brown solid. 1 H NMR (400 MHz, CDCl 3) δ: 8.17 (s, 1H), 7.95 (dd, J = 8.2, 2.2 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H).

[0538] Process 4 Ethyl 4-bromo-3-fluoro-5-(trifluoromethyl)benzoate (8.0 g, 25.4 mmol), potassium vinyltrifluoroborate (10.2 g, 76.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.9 g, 2.5 mmol), and K in 1,4-dioxane (200 mL) and water (50 mL). 2 CO 3 A mixture of (7.0 g, 50.8 mmol) was stirred at 100° C. overnight under nitrogen atmosphere. The reaction was brought to room temperature and partitioned between water (300 mL) and EtOAc (3×300 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (10% DCM / petroleum ether) to give ethyl 3-fluoro-5-(trifluoromethyl)-4-vinylbenzoate (5.0 g, 19.2 mmol) as a brown oil. 1 H NMR (400 MHz, CDCl 3 ) δ: 8.07 (s, 1H), 7.86 (d, J = 10.8 Hz, 1H), 6.76-6.68 (m, 1H), 5.93 (d, J = 17.6 Hz, 1H), 5.75-5.71 (m, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H).

[0539] Process 5 A solution of ethyl 3-fluoro-5-(trifluoromethyl)-4-vinylbenzoate (5.0 g, 19.2 mmol) in acetone (150 mL) and water (150 mL) was treated with anhydrous potassium osmate(VI) (1.4 g, 3.8 mmol), followed by NaIO4 (16.41 g, 76.74 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. 2 S 2 O 3 It was quenched with saturated aqueous solution and extracted with EtOAc (3×200 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. t Dissolve in BuOH (75 mL) and water (75 mL) and add NaH 2 PO·2H 2 O (6.9 g, 57.6 mmol), followed by NaClO 2 (5.2 g, 57.6 mmol) and 2-methylbut-2-ene (15 mL) were added. The reaction mixture was stirred at room temperature overnight. Then, t BuOH was removed under reduced pressure and the pH of the mixture was adjusted to about 3 with 1N aqueous HCl. The aqueous solution was extracted with DCM (3×100 mL) and the combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to provide 4-(ethoxycarbonyl)-2-fluoro-6-(trifluoromethyl)benzoic acid (2.5 g, 8.92 mmol) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ: 14.67 (br s, 1H), 8.16 (d, J = 9.2 Hz, 1H), 8.08 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H).

[0540] Intermediate 43: 3-(Cyclopentyloxy)-4-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5-(trifluoromethyl)benzoic acid [ka] Process 1 A mixture of 4-(ethoxycarbonyl)-2-fluoro-6-(trifluoromethyl)benzoic acid (Intermediate 42, 1.6 g, 5.7 mmol), HATU (2.6 g, 6.9 mmol) and DIPEA (3.0 g, 22.8 mmol) in DMF (50 mL) was stirred at room temperature for 1.5 h. After this time, 1-methylcyclopropane-1-sulfonamide (2.3 g, 17.1 mmol) was added, followed by sodium hydride (60% in mineral oil, 914 mg, 22.8 mmol). The reaction was stirred at room temperature overnight and then NH 4 The mixture was poured into saturated aqueous Cl (150 mL). Aqueous 1N HCl (20 mL) was added and the mixture was extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1-10% EtOAc / petroleum ether) to provide ethyl 3-fluoro-4-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5-(trifluoromethyl)benzoate (1.5 g, 3.8 mmol) as a brown oil. LCMS: (System 1, Method A) Rt = 1.81 min, m / z 398.0 (M+H) + (ES + ).

[0541] Process 2 Ethyl 3-fluoro-4-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5-(trifluoromethyl)benzoate (500 mg, 1.26 mmol), LiOH H in THF (16 mL), MeOH (4 mL) and water (4 mL). 2A mixture of 207 mg, 5.04 mmol) and 1H 2 O (207 mg, 5.04 mmol) was stirred at room temperature overnight. The organic solvent was removed under reduced pressure and then the pH of the mixture was adjusted to about 3 by adding aqueous HCl 1N. The precipitate was collected by filtration, washed with water then hexane and dried to provide 3-fluoro-4-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5-(trifluoromethyl)benzoic acid (400 mg, 1.08 mmol) as a brown solid. LCMS: (System 1, Method A) Rt=0.61 min, m / z 387.0 (M+NH 4 ) + (ES + ).

[0542] Process 3 Sodium hydride (60% in mineral oil, 867 mg, 21.7 mmol) was added in portions to a solution of 3-fluoro-4-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5-(trifluoromethyl)benzoic acid (400.0 mg, 1.08 mmol) in DMSO (15 mL). Cyclopentanol (932 mg, 10.84 mmol) was then added and the mixture was stirred at 100° C. for 30 min. The reaction mixture was brought to room temperature and NH 4 The aqueous solution was poured into saturated aqueous Cl (45 mL). The pH of the solution was adjusted to about 8 by adding 1N aqueous HCl. The aqueous solution was extracted with EtOAc (3×60 mL) and the combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure to provide 3-(cyclopentyloxy)-4-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-5-(trifluoromethyl)benzoic acid (275 mg, 0.63) as a brown solid. LCMS: (System 1, Method A) Rt = 1.08 min, m / z 453.0 (M+NH 4 ) + (ES + ).

[0543] Intermediate 44: 3-(cyclopentyloxy)-4-((pyrrolidin-1-ylsulfonyl)carbamoyl)-5-(trifluoromethyl)benzoic acid [ka] Prepared in a similar manner to Intermediate 43 starting from 4-(ethoxycarbonyl)-2-fluoro-6-(trifluoromethyl)benzoic acid (Intermediate 42, 1.6 g, 5.7 mmol) except step 1 was performed using pyrrolidine-1-sulfonamide instead of 1-methylcyclopropane-1-sulfonamide. Yield: 255 mg, 0.57 mmol. Brown solid. LCMS: (System 1, Method G) Rt=0.45 min, m / z 451.1 (M+H). + (ES + ).

[0544] Intermediate 45: 3-(cyclopentyloxy)-4-((N,N-dimethylsulfamoyl)carbamoyl)-5-(trifluoromethyl)benzoic acid [ka] Prepared in a similar manner to Intermediate 43 starting from 4-(ethoxycarbonyl)-2-fluoro-6-(trifluoromethyl)benzoic acid (Intermediate 42, 1.6 g, 5.7 mmol) except step 1 was performed using N,N-dimethylsulfamide instead of 1-methylcyclopropane-1-sulfonamide. Yield: 400 mg, 0.94 mmol. Brown solid. LCMS: (System 1, Method A) Rt=1.00 min, m / z 422.8 (MH). - (ES - ).

[0545] Intermediate 46: 4-(((1-methylcyclopropyl)sulfonyl)carbamoyl)-3-(pyrrolidin-1-yl)benzoic acid [ka] Process 1 Methyl 4-bromo-2-fluorobenzoate (5.0 g, 21.6 mmol) in DMSO (100 mL), K 2 CO 3A mixture of (8.9 g, 64.7 mmol), KI (1.8 g, 10.8 mmol) and pyrrolidine (2.3 g, 32.3 mmol) was stirred at 100° C. overnight. The reaction was brought to room temperature and partitioned between water (200 mL) and EtOAc (3×200 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (35% DCM / petroleum ether) to provide methyl 4-bromo-2-(pyrrolidin-1-yl)benzoate (5.0 g, 17.7 mmol) as a white solid. LCMS: (System 1, Method F) Rt=1.88 min, m / z 283.8 (MH). - (ES - ).

[0546] Process 2 Methyl 4-bromo-2-(pyrrolidin-1-yl)benzoate (5.0 g, 17.7 mmol) and LiOH H in THF (60 mL), MeOH (15 mL) and water (15 mL). 2 A mixture of 2.9 g, 70.7 mmol) and 1H 2 O (2.9 g, 70.7 mmol) was stirred at 65° C. overnight. The reaction was cooled to room temperature and the organic solvent was removed under reduced pressure. The pH of the resulting aqueous solution was set to about 3 by adding aqueous HCl 1N. The precipitate was collected by filtration, washed with water and hexanes, and dried under reduced pressure to provide 4-bromo-2-(pyrrolidin-1-yl)benzoic acid (4.0 g, 14.8 mmol) as a white solid. LCMS: (System 1, Method F) Rt=1.09 min, m / z 269.8 (M+H) + (ES + ).

[0547] Process 3 A mixture of 4-bromo-2-(pyrrolidin-1-yl)benzoic acid (1.1 g, 4.09 mmol), HATU (1.86 g, 4.91 mmol) and DIPEA (2.11 g, 16.36 mmol) in DMF (20 mL) was stirred at room temperature for 1 h, then 1-methylcyclopropane-1-sulfonamide (1.7 g, 12.3 mmol) and sodium hydride (60% dispersion in mineral oil, 655 mg, 16.4 mmol) were added and the reaction was stirred at room temperature overnight. The pH of the crude mixture was adjusted to about 4 by adding aqueous HCl 1N and the mixture was extracted with EtOAc (3×25 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (1-10% MeOH / DCM) to provide 4-bromo-N-(1-methylcyclopropylsulfonyl)-2-(pyrrolidin-1-yl)benzamide (700 mg, 1.81 mmol) as a white solid. LCMS: (System 1, Method F) Rt=1.24 min, m / z 387.3 (M+H). + (ES + ).

[0548] Process 4 A mixture of 4-bromo-N-(1-methylcyclopropylsulfonyl)-2-(pyrrolidin-1-yl)benzamide (700 mg, 1.81 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (265 mg, 0.36 mmol) and potassium acetate (532 mg, 5.43 mmol) in EtOH (15 mL) was stirred at 90° C. overnight under CO atmosphere. The mixture was dissolved in MeOH (20 mL) and concentrated under reduced pressure. The residue was purified by HPLC. 2 CO 3 The resulting aqueous layer was acidified to pH 2-3 by adding 1N aqueous HCl and extracted with EtOAc (3×15 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4), filtered and concentrated under reduced pressure to provide ethyl 4-(1-methylcyclopropylsulfonylcarbamoyl)-3-(pyrrolidin-1-yl)benzoate (600 mg, 1.58 mmol) as a yellow oil. LCMS: (System 1, Method A) Rt = 1.42 min, m / z 381.4 (M+H) + (ES + ).

[0549] Process 5 Ethyl 4-(1-methylcyclopropylsulfonylcarbamoyl)-3-(pyrrolidin-1-yl)benzoate (600 mg, 1.58 mmol) and LiOH H in THF (12 mL), MeOH (3 mL) and water (3 mL). 2 A mixture of 2-(1-methylcyclopropylsulfonylcarbamoyl)-3-(pyrrolidin-1-yl)benzoic acid (500 mg, 1.42 mmol) was stirred at room temperature overnight. The organic solvent was removed under reduced pressure. The pH of the resulting aqueous solution was set to about 3 by adding aqueous HCl 1N. The precipitate was collected by filtration, washed with water and hexanes, and dried under reduced pressure to provide 4-(1-methylcyclopropylsulfonylcarbamoyl)-3-(pyrrolidin-1-yl)benzoic acid (500 mg, 1.42 mmol) as a yellow solid. LCMS: (System 1, Method A) Rt=0.73 min, m / z 353.0 (M+H). + (ES + ).

[0550] Intermediate 47: 4-((N,N-dimethylsulfamoyl)carbamoyl)-3-(pyrrolidin-1-yl)benzoic acid [ka] Prepared by a similar method to inter...

Claims

1. Compounds of formula (I): 【Chemistry 1】 (In the formula, R １ is C １－４ Alkyl or C ３－５ is cycloalkyl; R ２ is C １－４ is alkyl; or R １ and R ２ are connected to form a 5- to 7-membered heterocycloalkyl; R ３ is C １－３ selected from the group consisting of alkyl and halo; R ４ is C １－３ Alkyl, halo, C １－３ Haloalkyl, C １－３ Alkoxy, C １－３ Haloalkoxy, NR ４ａ R ４ｂ and 4- to 7-membered heterocycloalkyl; R ４ａ is H and C １－３ selected from the group consisting of alkyl; R ４ｂ is H and C １－３ selected from the group consisting of alkyl; m is 0, 1 or 2; n is 0, 1 or 2; R ５ , R ６ and R ７ is defined as follows: (a) R ６ teeth, 【Chemistry 2】 and R ７ is non-existent; R ５ H, halo, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, C １－３ Haloalkoxy, SC １－３ Alkyl, SC １－３ Haloalkyl, O.C. ３－１０ Cycloalkyl, NR ５ｂ R ５ｃ and 4- to 7-membered heterocycloalkyl, ３－１０ Cycloalkyl and 4- to 7-membered heterocycloalkyl are each independently selected from one or more R ５ａ is optionally substituted by R ５ａ Halo and C １－３ alkyl, or two R ５ａ The group is connected to C ３－６ forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R ５ｂ is H and C １－３ selected from the group consisting of alkyl; R ５ｃ is C １－３ Alkyl and C ３－６ cycloalkyl; R ８ is C ３－６ Cycloalkyl, NR ８ｂ R ８ｃ and 4- to 10-membered heterocycloalkyl, ３－６ Cycloalkyl and 4- to 10-membered heterocycloalkyl are each independently selected from one or more R ８ａ and optionally replaced by R ８ａ is C １－３ Alkyl, C substituted by OH １－３ Alkyl, O.C. １－２ C substituted with alkyl １－２ Alkyl, C １－３ Alkoxy, halo and C １－３ haloalkyl; R ８ｂ is H, C １－３ Alkyl and C ３－６ cycloalkyl; R ８ｃ is H, C １－３ Alkyl and C ３－６ cycloalkyl; or: (b) R ７ teeth, 【Chemistry 3】 is: (i) R ６ is H, R ５ H, halo, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, C １－３ Haloalkoxy, SC １－３ Alkyl, SC １－３ Haloalkyl, O.C. ３－１０ Cycloalkyl, NR ５ｂ R ５ｃ and 4- to 7-membered heterocycloalkyl, ３－１０ Cycloalkyl and 4- to 7-membered heterocycloalkyl are each independently selected from one or more R ５ａ is optionally substituted by R ５ａ Halo and C １－３ alkyl, or two R ５ａ The group is connected to C ３－６ forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R ５ｂ is H and C １－３ selected from the group consisting of alkyl; R ５ｃ is C １－３ Alkyl and C ３－６ cycloalkyl; or (ii) R ５ is H, R ６ H, halo, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkoxy, C １－３ Haloalkoxy, SC １－３ Alkyl, SC １－３ Haloalkyl, O.C. ３－１０ Cycloalkyl, NR ６ｂ R ６ｃ and 4- to 7-membered heterocycloalkyl, ３－１０ Cycloalkyl and 4- to 7-membered heterocycloalkyl are each independently selected from one or more R ６ａ is optionally substituted by R ６ａ Halo and C １－３ alkyl, or two R ６ａ The group is connected to C ３－６ forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R ６ｂ is H and C １－３ selected from the group consisting of alkyl; R ６ｃ is C １－３ Alkyl and C ３－６ cycloalkyl; or (iii) R ５ and R ６ are connected to form a 4- to 8-membered heterocyclic ring; R ８ is C ３－６ Cycloalkyl, NR ８ｂ R ８ｃ and 4- to 10-membered heterocycloalkyl, ３－６ Cycloalkyl and 4- to 10-membered heterocycloalkyl are each independently selected from one or more R ８ａ and optionally replaced by R ８ａ is C １－３ Alkyl, C substituted by OH １－３ Alkyl, O.C. １－２ C substituted with alkyl １－２ Alkyl, C １－３ Alkoxy, halo and C １－３ haloalkyl; R ８ｂ is H, C １－３ Alkyl and C ３－６ cycloalkyl; R ８ｃ is H, C １－３ Alkyl and C ３－６ cycloalkyl); or a pharma- ceutically acceptable salt and / or solvate thereof.

2. The compound of formula (I) according to claim 1: 【Chemistry 4】 (In the formula, R １ is C １－４ Alkyl or C ３－５ is cycloalkyl; R ２ is C １－４ is alkyl; or R １ and R ２ are connected to form a 5- to 7-membered heterocycloalkyl; R ３ is C １－３ selected from the group consisting of alkyl and halo; R ４ is C １－３ Alkyl, halo, C １－３ Haloalkyl, C １－３ Alkoxy, C １－３ Haloalkoxy, NR ４ａ R ４ｂ and 4- to 7-membered heterocycloalkyl; R ４ａ is H and C １－３ selected from the group consisting of alkyl; R ４ｂ is H and C １－３ selected from the group consisting of alkyl; m is 0, 1 or 2; n is 0, 1 or 2; R ５ , R ６ and R ７ is defined as follows: (a) R ６ teeth, 【Chemistry 5】 and R ７ is non-existent; R ５ H, halo, C １－３ Alkyl, C １－３ Alkoxy, C １－３ Haloalkoxy, SC １－３ Alkyl, SC １－３ Haloalkyl, O.C. ３－１０ Cycloalkyl, NR ５ｂ R ５ｃ and 4- to 7-membered heterocycloalkyl, ３－１０ Cycloalkyl and 4- to 7-membered heterocycloalkyl are each independently selected from one or more R ５ａ is optionally substituted by R ５ａ Halo and C １－３ alkyl, or two R ５ａ The group is connected to C ３－６ forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R ５ｂ is H and C １－３ selected from the group consisting of alkyl; R ５ｃ is C １－３ Alkyl and C ３－６ cycloalkyl; R ８ is C ３－６ Cycloalkyl, NR ８ｂ R ８ｃ and 4- to 8-membered heterocycloalkyl, ３－６ Cycloalkyl and 4- to 8-membered heterocycloalkyl are each independently selected from one or more R ８ａ and optionally replaced by R ８ａ is C １－３ Alkyl, halo and C １－３ haloalkyl; R ８ｂ is H, C １－３ Alkyl and C ３－６ cycloalkyl; R ８ｃ is H, C １－３ Alkyl and C ３－６ cycloalkyl; or: (b) R ７ teeth, 【Chemistry 6】 is: (i) R ６ is H, R ５ H, halo, C １－３ Alkyl, C １－３ Alkoxy, C １－３ Haloalkoxy, SC １－３ Alkyl, SC １－３ Haloalkyl, O.C. ３－１０ Cycloalkyl, NR ５ｂ R ５ｃ and 4- to 7-membered heterocycloalkyl, ３－１０ Cycloalkyl and 4- to 7-membered heterocycloalkyl are each independently selected from one or more R ５ａ is optionally substituted by R ５ａ Halo and C １－３ alkyl, or two R ５ａ The group is connected to C ３－６ forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R ５ｂ is H and C １－３ selected from the group consisting of alkyl; R ５ｃ is C １－３ Alkyl and C ３－６ cycloalkyl; or (ii) R ５ is H, R ６ H, halo, C １－３ Alkyl, C １－３ Alkoxy, C １－３ Haloalkoxy, SC １－３ Alkyl, SC １－３ Haloalkyl, O.C. ３－１０ Cycloalkyl, NR ６ｂ R ６ｃ and 4- to 7-membered heterocycloalkyl, ３－１０ Cycloalkyl and 4- to 7-membered heterocycloalkyl are each independently selected from one or more R ６ａ is optionally substituted by R ６ａ Halo and C １－３ alkyl, or two R ６ａ The group is connected to C ３－６ forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R ６ｂ is H and C １－３ selected from the group consisting of alkyl; R ６ｃ is C １－３ Alkyl and C ３－６ cycloalkyl; or (iii) R ５ and R ６ are connected to form a 4- to 8-membered heterocyclic ring; R ８ is C ３－６ Cycloalkyl, NR ８ｂ R ８ｃ and 4- to 8-membered heterocycloalkyl, ３－６ Cycloalkyl and 4- to 8-membered heterocycloalkyl are each independently selected from one or more R ８ａ is optionally replaced by: R ８ａ is C １－３ Alkyl, halo and C １－３ haloalkyl; R ８ｂ is H, C １－３ Alkyl and C ３－６ cycloalkyl; R ８ｃ is H, C １－３ Alkyl and C ３－６ cycloalkyl); or a pharma- ceutically acceptable salt and / or solvate thereof.

3. The compound of formula (I) according to claim 1: 【Chemistry 7】 (In the formula, R １ is C １－４ Alkyl or C ３－５ is cycloalkyl; R ２ is C １－４ is alkyl; or R １ and R ２ are connected to form a 5- to 7-membered heterocycloalkyl; R ３ is C １－３ selected from the group consisting of alkyl and halo; R ４ is C １－３ Alkyl, halo, C １－３ Haloalkyl, C １－３ Alkoxy, C １－３ selected from the group consisting of haloalkoxy and 4- to 7-membered heterocycloalkyl; R ６ teeth, 【Chemistry 8】 and R ７ is non-existent; or R ７ teeth, 【Chemistry 9】 and R ６ but 【Chemistry 10】 and R ７ If is non-existent: R ５ H, halo, C １－３ Alkoxy, C １－３ Haloalkoxy, SC １－３ Alkyl, SC １－３ Haloalkyl, O.C. ３－１０ Cycloalkyl, NR ５ｂ R ５ｃ and 4- to 7-membered heterocycloalkyl, ３－１０ Cycloalkyl and 4- to 7-membered heterocycloalkyl are each independently selected from one or more R ５ａ is optionally substituted by R ５ａ Halo and C １－３ alkyl, or two R ５ａ The group is connected to C ３－６ forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R ５ｂ is H and C １－３ selected from the group consisting of alkyl; R ５ｃ is C １－３ Alkyl and C ３－６ cycloalkyl; R ８ is C ３－６ Cycloalkyl, N(C １－３ Alkyl) ２ and 4- to 8-membered heterocycloalkyl, ３－６ Cycloalkyl and 4- to 8-membered heterocycloalkyl are each independently selected from one or more R ８ａ and R ８ａ is C １－３ Alkyl, halo and C １－３ haloalkyl; or: R ７ but 【Chemistry 11】 If: R ６ is H, R ５ H, halo, C １－３ Alkoxy, C １－３ Haloalkoxy, SC １－３ Alkyl, SC １－３ Haloalkyl, O.C. ３－１０ Cycloalkyl, NR ５ｂ R ５ｃ and 4- to 7-membered heterocycloalkyl, ３－１０ Cycloalkyl and 4- to 7-membered heterocycloalkyl are each independently selected from one or more R ５ａ is optionally substituted by R ５ａ Halo and C １－３ alkyl, or two R ５ａ The group is connected to C ３－６ forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R ５ｂ is H and C １－３ selected from the group consisting of alkyl; R ５ｃ is C １－３ Alkyl and C ３－６ cycloalkyl; or R ５ is H, R ６ H, halo, C １－３ Alkoxy, C １－３ Haloalkoxy, SC １－３ Alkyl, SC １－３ Haloalkyl, O.C. ３－１０ Cycloalkyl, NR ６ｂ R ６ｃ and 4- to 7-membered heterocycloalkyl, ３－１０ Cycloalkyl and 4- to 7-membered heterocycloalkyl are each independently selected from one or more R ６ａ is optionally substituted by R ６ａ Halo and C １－３ alkyl, or two R ６ａ The group is connected to C ３－６ forming a cycloalkyl or 4- to 7-membered heterocycloalkyl ring; R ６ｂ is H and C １－３ selected from the group consisting of alkyl; R ６ｃ is C １－３ Alkyl and C ３－６ cycloalkyl; or R ５ and R ６ are connected to form a 4- to 7-membered heterocyclic ring; R ８ is C ３－６ Cycloalkyl, N(C １－３ Alkyl) ２ and 4- to 8-membered heterocycloalkyl, ３－６ Cycloalkyl and 4- to 8-membered heterocycloalkyl are each independently selected from one or more R ８ａ and R ８ａ is C １－３ Alkyl, halo and C １－３ haloalkyl; m is 0, 1 or 2; n is 0, 1 or 2; or a pharma- ceutically acceptable salt and / or solvate thereof.

4. R １ is methyl, R ２ The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein is methyl.

5. m is 2; R ３ is methyl, or m is 1, R ３ The compound according to any one of claims 1 to 4, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein:

6. n is 1, R ４ The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein is selected from the group consisting of chloro and fluoro.

7. R ６ teeth, 【Chemistry 12】 and R ７ The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein is absent.

8. R ５ is C １－３ Alkoxy, for example, methoxy or ethoxy, or OC ３－１０ 8. The compound of claim 7, or a pharma- ceutically acceptable salt and / or solvate thereof, wherein: R is cycloalkyl, e.g., cyclobutyloxy or cyclopentyloxy.

9. Compound of formula (IC): 【Chemistry 13】 (In the formula, R １ , R ２ , R ３ , m and R ４ is as defined in any one of claims 1 to 6, and R ６ is as defined in claim 7, and R ５ is methoxy, ethoxy, cyclopropyloxy or NR ５ｂ R ５ｃ and R ５ｂ and R ５ｃ is as defined in claim 1, or a pharma- ceutically acceptable salt and / or solvate thereof.

10. R ５ is N.R. ５ｂ R ５ｃ and R ５ｂ and R ５ｃ and R are each methyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

11. R ８ is C ３－６ cycloalkyl, for example cyclopropyl; R ８ is one R ８ａ substituted by a group such as methyl, or R ８ is 4-8 membered heterocycloalkyl, such as, for example, pyrrolidinyl, 7-azanorbornanyl, 3-azabicyclo[3.1.0]hexyl, 6-azaspiro[2.5]octyl or 3-oxa-6-azabicyclo[3.2.1]octyl, or a pharma- ceutically acceptable salt and / or solvate thereof.

12. R ８ is pyrrolidinyl, e.g., pyrrolidin-1-yl, or a pharma- ceutically acceptable salt and / or solvate thereof.

13. (R)-2-cyclobutoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-cyclobutoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(cyclopentyloxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(cyclopentyloxy)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(cyclopentyloxy)-3-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-cyclobutoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(cyclopentyloxy)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(cyclopentyloxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-cyclobutoxy-N-((1-methylcyclopropyl)sulfonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(cyclopentyloxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-cyclobutoxy-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-2-(pyrrolidin-1-yl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)—N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)benzamide; (R)-2-cyclobutoxy-4-(8-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)—N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)benzamide; (R)-2-cyclobutoxy-4-(8-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(N,N-dimethylsulfamoyl)-6-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(cyclopentyloxy)-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-cyclobutoxy-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(N,N-dimethylsulfamoyl)-6-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(N,N-dimethylsulfamoyl)-6-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(cyclopentyloxy)-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)benzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-cyclobutoxy-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)benzamide; (R)—N-(N-isopropyl-N-methylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-chloro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-chloro-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-chloro-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(cyclobutyl(methyl)amino)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(cyclobutyl(methyl)amino)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-chloro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(cyclopentyloxy)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(cyclopentyloxy)-N-(N,N-dimethylsulfamoyl)-3-fluorobenzamide; (R)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-2-(pyrrolidin-1-yl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-cyclobutoxy-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-cyclobutoxy-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-cyclobutoxy-N-(N,N-dimethylsulfamoyl)-3-fluorobenzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-cyclobutoxy-3-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(cyclobutyl(methyl)amino)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-cyclobutoxy-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(cyclopentyloxy)-3-fluoro-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(cyclopentyloxy)-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-4-(7-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-fluoro-N-((1-methylcyclopropyl)sulfonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-4-(7-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(N,N-dimethylsulfamoyl)-3-fluorobenzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-4-(7-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(((1R,3r,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-4-(7-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-fluoro-N-(N-isopropyl-N-methylsulfamoyl)benzamide; 2-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(((1R,3s,5S)-bicyclo[3.1.0]hexan-3-yl)oxy)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-2-(pyrrolidin-1-yl)benzamide; (R)—N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(3,3-difluoropiperidin-1-yl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(3,3-difluoropiperidin-1-yl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(3,3-difluoropiperidin-1-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(3,3-difluoropiperidin-1-yl)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-6-chloro-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(3,3-difluoropyrrolidin-1-yl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(3,3-difluoropyrrolidin-1-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(cyclopropyl(methyl)amino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(cyclopropyl(methyl)amino)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-((4,4-difluorocyclohexyl)oxy)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-((4,4-difluorocyclohexyl)oxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(3,3-dimethylpyrrolidin-1-yl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(3,3-dimethylpyrrolidin-1-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(azetidin-1-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-((adamantan-2-yl)oxy)-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(azetidin-1-yl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(3,3-difluoropyrrolidin-1-yl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-cyclobutoxy-N-(N,N-dimethylsulfamoyl)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-((adamantan-2-yl)oxy)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-((4,4-difluorocyclohexyl)oxy)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-((adamantan-2-yl)oxy)-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(cyclopentyloxy)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-6-(trifluoromethyl)benzamide; N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-((R)-2-methylpyrrolidin-1-yl)benzamide; N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-((S)-2-methylpyrrolidin-1-yl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-6-(trifluoromethyl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-6-chloro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)—N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methyl-6-(pyrrolidin-1-yl)benzamide; (R)-2-(cyclopentyloxy)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-6-(trifluoromethyl)benzamide; 2-(bicyclo[3.1.0]hexan-3-yloxy)-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(bicyclo[3.1.0]hexan-3-yloxy)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(cyclopentyloxy)-N-(N,N-dimethylsulfamoyl)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(cyclopentyloxy)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-6-(trifluoromethyl)benzamide; 2-(bicyclo[3.1.0]hexan-3-yloxy)-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(bicyclo[3.1.0]hexan-3-yloxy)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(2-azabicyclo[2.2.1]heptan-2-yl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(2-azabicyclo[2.2.1]heptan-2-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(cyclopentyloxy)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-6-(trifluoromethyl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(N,N-dimethylsulfamoyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-6-(trifluoromethyl)benzamide; (R)—N-(N,N-dimethylsulfamoyl)-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-6-(pyrrolidin-1-yl)benzamide; (R)—N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(5-azaspiro[2.5]octan-5-yl)benzamide; (R)-2-(7-azabicyclo[2.2.1]heptan-7-yl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-((S)-2-methylpyrrolidin-1-yl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-2-((R)-2-methylpyrrolidin-1-yl)benzamide; 4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-((R)-2-methylpyrrolidin-1-yl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-2-((S)-2-methylpyrrolidin-1-yl)benzamide; 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(cyclopentyloxy)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-6-(pyrrolidin-1-yl)benzamide; (R)-2-(cyclopentyloxy)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-6-(trifluoromethyl)benzamide; (R)-2-(cyclopentyloxy)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-6-(trifluoromethyl)benzamide; (R)-2-cyclobutoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-6-(trifluoromethyl)benzamide; (S)-2-cyclobutoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-cyclobutoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-6-(trifluoromethyl)benzamide; (R)-2-cyclobutoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-6-(trifluoromethyl)benzamide; (R)—N-(N,N-dimethylsulfamoyl)-3-fluoro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-3-fluoro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(dimethylamino)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(dimethylamino)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(dimethylamino)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(dimethylamino)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-methyl-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(pyrrolidin-1-yl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-2-(pyrrolidin-1-yl)benzamide; (R)-2-cyclobutoxy-4-(8-(3-(ethoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-N-(N,N-dimethylsulfamoyl)-2-ethoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-ethoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)—N-(N,N-dimethylsulfamoyl)-3-fluoro-2-isopropoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-3-fluoro-2-isopropoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-chloro-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-chloro-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-5-(trifluoromethyl)benzamide; (R)-2-(cyclopentyloxy)-N-(N,N-dimethylsulfamoyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-6-(trifluoromethyl)benzamide; (R)-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-6-(trifluoromethyl)benzamide; (R)—N-((6-azaspiro[2.5]octan-6-yl)sulfonyl)-3-fluoro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-3-fluoro-2-methoxy-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-3-fluoro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-3-fluoro-2-methoxy-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-5-(trifluoromethyl)benzamide; (R)-2-ethoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-6-(trifluoromethyl)benzamide; (R)-2-isopropoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-6-(trifluoromethyl)benzamide; (R)-2-cyclobutoxy-5-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-3-cyclobutoxy-5-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-6-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)spiro[benzo[d][1,3]dioxole-2,1′-cyclobutane]-4-carboxamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-cyclobutoxy-4-fluoro-5-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-3-cyclobutoxy-4-fluoro-5-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-cyclobutoxy-N-(((2R,5R)-2,5-dimethylpyrrolidin-1-yl)sulfonyl)-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-cyclobutoxy-N-(N,N-dimethylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-cyclobutoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-methyl-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)-4-fluoro-5-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)spiro[benzo[d][1,3]dioxole-2,1′-cyclobutane]-7-carboxamide; (R)-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((1-methylcyclopropyl)sulfonyl)-5-(trifluoromethyl)benzamide; (R)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-2-(trifluoromethoxy)benzamide; (R)-2-chloro-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-cyclobutoxy-3-fluoro-4-(8-(4-isopropyl-3-(methoxymethyl)piperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(difluoromethoxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-cyclobutoxy-4-(8-(4-ethyl-3-(methoxymethyl)piperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-cyclobutoxy-4-(8-(4-cyclopropyl-3-(methoxymethyl)piperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (S)-2-Cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (S)-2-cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(cyclopentyloxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-3-chloro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-3-chloro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-cyclobutoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-10-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(cyclopentyloxy)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-10-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((6-azaspiro[2.5]octan-6-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((6-azaspiro[2.5]octan-6-yl)sulfonyl)-5-chloro-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-cyclobutoxy-3-fluoro-4-(8-(3-(isopropoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-5-chloro-2-(dimethylamino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(azetidin-1-yl)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-amino-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-ethoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(piperidin-1-ylsulfonyl)benzamide; (R)-2-ethoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(piperidin-1-ylsulfonyl)benzamide; (R)—N-(N-cyclopentyl-N-methylsulfamoyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-(cyclobutyl(methyl)amino)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(methylamino)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-ethoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-2-(azetidin-1-yl)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-3-fluoro-N-((4-fluoropiperidin-1-yl)sulfonyl)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-propoxy-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-2-(2,2,2-trifluoroethoxy)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-2-cyclopropoxy-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-4-(7-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxy-3-fluorobenzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-4-(7-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxy-3-fluorobenzamide; N-(((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((octahydro-2H-isoindol-2-yl)sulfonyl)benzamide; (R)-2-cyclopropoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-cyclopropoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-2-ethoxy-4-(7-ethyl-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-fluorobenzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-ethoxy-4-(7-ethyl-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-3-fluorobenzamide; (R)—N-(N,N-dicyclopropylsulfamoyl)-2-ethoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((3,3-dimethylpyrrolidin-1-yl)sulfonyl)-2-ethoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-ethoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-2-ethoxy-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((2-azaspiro[3.3]heptan-2-yl)sulfonyl)-2-ethoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2-ethoxy-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)-2-(3,3,3-trifluoropropoxy)benzamide; (R)-3-ethoxy-2-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-fluoro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-fluoro-2-(methoxy-d3)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-ethoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-ethoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-2-ethoxy-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((2-azabicyclo[2.2.1]heptan-2-yl)sulfonyl)-2-ethoxy-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-(N,N-dicyclopropylsulfamoyl)-2-ethoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-ethoxy-3-fluoro-N-(((3aR,6aS)-hexahydrocyclopenta[c]pyrrol-2(1H)-yl)sulfonyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((2-azaspiro[3.3]heptan-2-yl)sulfonyl)-2-ethoxy-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2-ethoxy-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.2.1]octan-3-yl)sulfonyl)-2-ethoxy-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2-ethoxy-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.2.1]octan-3-yl)sulfonyl)-2-ethoxy-3-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-(N-cyclopentyl-N-methylsulfamoyl)-3-fluoro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-3-fluoro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(piperidin-1-ylsulfonyl)benzamide; (R)-3-fluoro-N-((4-fluoropiperidin-1-yl)sulfonyl)-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methylbenzamide; (R)-5-(dimethylamino)-2-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-ethyl-3-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-ethoxy-4-(10-ethyl-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-(dimethylamino)-4-(10-ethyl-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-2-(methoxy-d3)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-5-fluoro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-5-fluoro-2-methoxy-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-5-fluoro-2-(methoxy-d3)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-5-fluoro-2-(methoxy-d3)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-3-fluoro-2-(methoxy-d3)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((2-azaspiro[3.3]heptan-2-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(dimethylamino)-5-fluoro-N-(((S)-3-fluoropyrrolidin-1-yl)sulfonyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-(N-cyclopropyl-N-methylsulfamoyl)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxy-3-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxy-5-fluoro-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-N-(N,N-dimethylsulfamoyl)-5-fluorobenzamide; 2-ethoxy-5-fluoro-N-(((R)-3-fluoropyrrolidin-1-yl)sulfonyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-2-methoxy-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-cyclopropoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-2-cyclopropoxy-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-2-fluoro-5-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; N-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)sulfonyl)-2-ethoxy-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-ethoxy-5-fluoro-N-(((S)-3-fluoropyrrolidin-1-yl)sulfonyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-(N-cyclopropyl-N-methylsulfamoyl)-2-ethoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-2-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-methyl-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)—N-((2-oxa-5-azaspiro[3.5]nonan-5-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; (R)—N-((2-oxa-6-azaspiro[3.5]nonan-6-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; R)—N-((2-oxa-6-azaspiro[3.4]octan-6-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; (R)—N-((5-azaspiro[2.4]heptan-5-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(piperidin-1-ylsulfonyl)benzamide; (R)—N-(N,N-dicyclopropylsulfamoyl)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(N,N-dicyclopropylsulfamoyl)-2-(dimethylamino)-5-fluorobenzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(((R)-2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)benzamide; (R)—N-((2-azaspiro[3.3]heptan-2-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methoxybenzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methoxybenzamide; 2-(dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(((S)-3-methoxypiperidin-1-yl)sulfonyl)benzamide; (R)—N-((2-oxa-6-azaspiro[3.3]heptan-6-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methoxy-N-(((S)-2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)benzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(((S)-3-methoxypyrrolidin-1-yl)sulfonyl)benzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(((R)-3-methoxypyrrolidin-1-yl)sulfonyl)benzamide; 2-(dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(((R)-3-methoxypiperidin-1-yl)sulfonyl)benzamide; 2-(dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(((R)-2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)benzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methoxy-N-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)benzamide; (R)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((4-methoxypiperidin-1-yl)sulfonyl)benzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)benzamide; (R)-5-chloro-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-N-(N,N-dimethylsulfamoyl)benzamide; 2-(dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(((S)-2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)benzamide; N-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)sulfonyl)-4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(((S)-2-(trifluoromethyl)pyrrolidin-1-yl)sulfonyl)benzamide; (R)-2-(dimethylamino)-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-((4-(trifluoromethyl)piperidin-1-yl)sulfonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(N,N-dicyclopropylsulfamoyl)-5-fluoro-2-methoxybenzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(N-cyclopropyl-N-methylsulfamoyl)-2-ethoxy-5-fluorobenzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxy-5-fluoro-N-((1-methylcyclopropyl)sulfonyl)benzamide; (R)—N-((2-azaspiro[3.3]heptan-2-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxy-5-fluorobenzamide; N-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)sulfonyl)-4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxy-5-fluorobenzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(((S)-3-fluoropyrrolidin-1-yl)sulfonyl)benzamide; 4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluoro-N-(((R)-3-fluoropyrrolidin-1-yl)sulfonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(10-fluoro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-5-fluoro-4-(10-fluoro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methoxybenzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-cyclopropoxy-N-(N,N-dimethylsulfamoyl)-5-fluorobenzamide; N-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-cyclopropoxy-5-fluorobenzamide; (R)-2-(dimethylamino)-5-fluoro-4-(10-fluoro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-fluoro-4-(10-fluoro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methoxy-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-fluoro-5-methyl-N-(pyrrolidin-1-ylsulfonyl)benzamide; 2-(dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(((R)-2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)benzamide; 2-(dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(((S)-2-(methoxymethyl)pyrrolidin-1-yl)sulfonyl)benzamide; N-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; 2-(dimethylamino)-5-fluoro-N-(((R)-3-fluoropyrrolidin-1-yl)sulfonyl)-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-2-(dimethylamino)-5-fluoro-4-(8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxy-5-fluorobenzamide; (R)—N-((2-azaspiro[3.3]heptan-2-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-fluoro-5-methoxy-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-ethoxybenzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-methoxybenzamide; N-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)sulfonyl)-4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-2-(dimethylamino)-5-fluorobenzamide; (R)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(N-cyclopropyl-N-methylsulfamoyl)-2-(dimethylamino)-5-fluorobenzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-2-methoxybenzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-2-methoxybenzamide; (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-4-(10-chloro-8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-2-(methoxy-d3)benzamide; N-((3-azabicyclo[3.1.0]hexan-3-yl)sulfonyl)-4-(10-chloro-8-((R)-3-(methoxymethyl)-4-methylpiperazin-1-yl)-7-methyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-5-fluoro-2-(methoxy-d3)benzamide; (R)-5-chloro-2-(methoxy-d3)-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-chloro-2-methoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; (R)-5-chloro-2-ethoxy-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)-N-(pyrrolidin-1-ylsulfonyl)benzamide; and (R)—N-((7-azabicyclo[2.2.1]heptan-7-yl)sulfonyl)-2-cyclopropoxy-5-fluoro-4-(8-(3-(methoxymethyl)-4-methylpiperazin-1-yl)-7,10-dimethyl-5-oxo-1,3,4,5-tetrahydro-2H-chromeno[3,4-c]pyridine-3-carbonyl)benzamide; or any one of its pharma- ceutically acceptable salts and / or solvates.

2. The compound of claim 1, selected from the list consisting of:

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharma- ceutically acceptable salt and / or solvate thereof and one or more pharma- ceutically acceptable diluents or carriers.

15. A compound according to any one of claims 1 to 13 or a pharma- ceutically acceptable salt and / or solvate thereof or a pharmaceutical composition according to claim 14 for use as a medicament.

16. A compound according to any one of claims 1 to 13 or a pharma- ceutically acceptable salt and / or solvate thereof or a pharmaceutical composition according to claim 14 for use in treating or preventing a disease selected from inflammatory, autoimmune and fibrotic diseases, and cancer.

17. A method for treating or preventing a disease selected from inflammatory, autoimmune and fibrotic diseases, and cancer, said method comprising administering a compound according to any one of claims 1 to 13 or a salt and / or solvate thereof or a pharmaceutical composition according to claim 14.

18. Compounds of formula (I) 【Chemistry 14】 or salts and / or solvates thereof, for example pharma- ceutically acceptable salts and / or solvates thereof, １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , m and n are defined in any one of claims 1 to 13, (a) A compound of formula (II): 【Chemistry 15】 or a salt thereof, e.g., a pharma- ceutically acceptable salt, Compound of formula (III): 【Chemistry 16】 or a salt thereof, e.g., a pharma- ceutically acceptable salt. (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , m and n are defined in any one of claims 1 to 13. Coupling with; or (b) a compound of formula (I), ７ is absent) with a compound of formula (XXXVIII): 【Chemistry 17】 or a salt and / or solvate thereof (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ８ , n and m are defined in any one of claims 1 to 13, Compound of formula (XVI): 【Chemistry 18】 or a salt and / or solvate thereof (In the formula, R ８ is defined in any one of claims 1 to 13) and preparing the compound by a process comprising coupling the compound with The process comprising:

19. Compound of formula (II): 【Chemistry 19】 or a salt thereof, e.g., a pharma- ceutically acceptable salt. (In the formula, R １ , R ２ , R ３ and m are as defined in any one of claims 1 to 13).

20. Compound of formula (III): 【Chemistry 20】 or a salt thereof, e.g., a pharma- ceutically acceptable salt. (In the formula, R ４ , R ５ , R ６ , R ７ , R ８ and n are as defined in any one of claims 1 to 13).

21. Compound of formula (XXXVIII): 【Chemistry 21】 or a salt and / or solvate thereof (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , n and m are as defined in any one of claims 1 to 13).

22. Compound of formula (XXXIX): 【Chemical 22】 or a salt and / or solvate thereof (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , n and m are as defined in any one of claims 1 to 13, and Alk is C １－４ (alkyl).

23. Compound of formula (XXXXI): 【Chemistry 23】 or a salt and / or solvate thereof (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , n and m are as defined in any one of claims 1 to 13, and LG is a leaving group, for example halo, for example bromo).

Images