Substituted 7-(pyrimidin-4-yl)quinolin-4(1H)-one compounds as cyclin-dependent kinase inhibitors

Abstract

Provided are compounds comprising the 7-(pyrimidin-4-yl)quinolin-4(1H)-one structure of formula (I), their use for selectively inhibiting the activity of CDK4, and pharmaceutical compositions comprising the compounds as treatments for various diseases, including cancer. [Formula 1] JPEG2025515483000386.jpg58165

Description

[Technical Field]

[0001] The present disclosure provides compounds comprising a 7-(pyrimidin-4-yl)quinolin-4(1H)-one structure, their use for selectively inhibiting the activity of cyclin-dependent kinase 4 (CDK4), and pharmaceutical compositions comprising the compounds as treatments for various diseases, including cancer. [Background technology]

[0002] Human kinases are the molecules that attach phosphate groups (PO4 3- ) are a large group of enzymes that add ATP to proteins [1. FASEBJ. 1995 May;9(8):576-96. 2. Enzyme Res. 2011;2011:794089.]. There are over 500 genes encoding kinases present in the human genome and their substrates, including proteins, lipids, and nucleic acids [3. Cell Signal. 2004 Sep;16(9):983-9. 4. Cell. 2017 Aug 10;170(4):605-635.]. Misregulation of kinases has been identified in many diseases, including cancer, autoimmunity, neuropathies, diabetes, and cardiovascular disease. For example, mutant kinases can become constitutively active and thus cause a variety of cellular abnormalities, potentially leading to the initiation or progression of cancer. The use of small molecule inhibitors to inhibit kinase activity has proven to be a successful method for treating cancer and other diseases. To date, over 70 kinase inhibitors have been approved as drugs by the FDA, EMA, or CDE. Nat Rev Drug Discov. 2018 May;17(5):353-377.

[0003] The protein kinase family accounts for the majority of the kinase superfamily. Regarding protein targets, protein kinases can phosphorylate amino acids, including serine, threonine, tyrosine, and histidine. [7. Science. 2002 Dec 6;298(5600):1912-34.] Protein kinases play a key role in the cell activation process through the reversible phosphorylation and dephosphorylation of proteins by the antagonism of kinases and phosphatases. Protein kinases are important components of cell signaling because the phosphorylated and unphosphorylated states of target proteins can have different levels of activity. [8. Biochimie. 2014 Dec;107 Pt B:167-87. 9. Clin Transl Oncol. 2006 Mar;8(3):153-60.] Different protein kinases, including EGFR, BTK, ALK, JAK, PI3K, and CDK, have proven to be good targets for anticancer drug development.

[0004] An overactive cell cycle is a common feature of human cancer [10. Nat Rev Cancer. 2009 Mar;9(3):153-66.]. Meanwhile, cyclins are one of the most important core cell cycle regulators. In humans, four basic cyclin types have been found, including G1 cyclins, G1 / S cyclins, S cyclins, and M cyclins. To advance the cell cycle, cyclins must activate or inactivate many target proteins inside the cell. These cyclins then drive cell cycle events primarily by partnering with a family of enzymes called cyclin-dependent kinases (CDKs). Although CDKs themselves are inactive, binding to cyclins activates them, converting the CDK / cyclin complex into a functional holoenzyme that can modify target proteins [11. Orphanet J Rare Dis. 2020 Aug 6;15(1):203. 12. J Mol Biol. 1999 Apr 16;287(5):821-8.]. There are 26 serine / threonine protein kinases that form the CDK and CDK-like branch of the CMGC subfamily of the human kinome, and 21 of these are classified as CDKs. Among all currently identified CDKs, CDK1, CDK2, CDK4, and CDK6 are considered direct modulators of the cell cycle, primarily by phosphorylating and inactivating retinoblastoma proteins and releasing E2F transcription factors. The E2F downstream pathway is important in regulating the initiation of DNA replication. CDK4 / 6 are essential for early G1 initiation and the G1 / S transition. [13.Cell Death Differ.1998 Feb;5(2):132-40.14.Oncogene.2016 Sep 15;35(37):4829-35.]

[0005] The CDK4 / 6-related pathway is commonly dysregulated in many different cancer types, including breast, lung, and pancreatic cancer. Four CDK4 / 6 inhibitors, including palbociclib, ribociclib, abemaciclib, and trilaciclib, have been approved by the FDA or CDE for use as either monotherapy or in combination with endocrine therapy to treat HR+, Her2- breast cancer. While this approach has shown good efficacy in the clinic, hematopoietic toxicities such as neutropenia and leukopenia have also been observed, which may limit the clinical application of CDK4 / 6 dual inhibitors. Emerging data indicate that CDK6 / cyclin D3 inhibition can cause clinically observed hematologic toxicity [15. Cell. 2004 Aug 20;118(4):493-504. 16. Haematologica. 2021 Oct 1;106(10):2624-2632.], while CDK4 / cyclin D1 is an oncogenic driver in various cancers [17. Nat Commun. 2019 Dec 20;10(1):5817. 18. Cancer Cell. 2006 Jan;9(1):23-32.]. The development of selective CDK4 inhibitors may demonstrate clinical benefits, including improved efficacy, reduced hematologic toxicity, and expanded use in many cancers, including, but not limited to, breast, lung, pancreatic, prostate, bone, liver, and endometrial cancers.

[0006] Therefore, there remains a great need to develop selective CDK4 inhibitors. Now, the inventors of the present invention have discovered selective CDK4 inhibitor compounds that may lead to better efficacy, improved toxicity profiles, and the potential to overcome resistance mechanisms, etc. Summary of the Invention [Problem to be solved by the invention]

[0007] One object of the present invention is to provide compounds and derivatives that function to act as CDK4 inhibitors, as well as methods for their preparation and use. [Means for solving the problem]

[0008] Aspect 1. A compound of formula (I): [ka] or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, or a prodrug thereof, During the ceremony, The ring CyA is a 3-8 membered ring containing, as ring member(s), 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and the ring contains at least one substituent R 10 optionally substituted with n is 0, 1, 2, 3, 4, or 5; m is 0 or 1, but when m=0, then as a whole [ka] provided that the part is replaced by H, R 1 H, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, haloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR 1a , -COR 1a , -CO2R 1a , -CONR 1a R 1b , -NR 1a R 1b , -NR 1a COR 1b , -NR 1a CO2R 1b , or -NR 1a CONR 1b R 1c and the -C 1-8 Alkyl, the -C 2-8 Alkenyl, the -C 2-8Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may be selected from the group consisting of at least one substituent R 1d optionally substituted with R 1a , R 1b , and R 1c are each independently hydrogen, -C 1-8 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and 1-8 Alkyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may be selected from the group consisting of at least one substituent R 1f optionally substituted with R 1d and R 1f are each independently hydrogen, halogen, hydroxy, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; 1-8 Alkyl, haloC 1-8 Alkyl, the -C 1-8 Alkoxy, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, the halocycloalkyl, the heterocyclyl, the haloheterocyclyl, the aryl, the haloaryl, the heteroaryl, or the haloheteroaryl may be selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -haloC 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 2 But hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR 2a , -SO2R 2a , -SO2NR 2a R 2b , -COR 2a , -CO2R 2a , -CONR 2a R 2b , -NR 2a R 2b , -NR 2a COR 2b , -NR 2a CO2R 2b , -NR 2a CONR 2b R 2c , or -NR 2a SO2R 2b and the -C 1-8 Alkyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may be selected from the group consisting of at least one substituent R 2d optionally substituted with R 2a , R 2b , and R 2c are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 1-8 Alkyl, the -C 2-8 Alkenyl, the -C 2-8Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may be selected from the group consisting of at least one substituent R 2f or (R 2a and R 2b ), (R 2b and R 2c ), or (R 2a and R 2c ), together with the atom(s) to which they are attached, form a 3- to 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and which ring contains at least one substituent R 2f optionally substituted with R 2d and R 2f are each independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR 2g , -SO2R 2g , -SO2NR 2g R 2h , -COR 2g , -CO2R 2g , -CONR 2g R 2h , -NO2, -NR 2g R 2h , -NR 2g COR 2h , -NR 2g CO2R 2h , -NR 2g CONR 2h R 2i , or -NR 2g SO2R 2h Selected from the -C 1-8 Alkyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may be selected from the group consisting of halogen, hydroxy, oxo, -C 1-8Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -haloC 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; (2 R 2d ) and / or (two R 2f ), together with the atom(s) to which they are attached, form a 3- to 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and which ring is not selected from halogen, hydroxy, oxo, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C(O)C 1-8 Alkyl, -C 1-8 Alkoxy, -haloC 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 2g , R 2h , and R 2i are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the —C 1-8 Alkyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may be selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -C(O)C 1-8Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -haloC 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 3A and R 3B are each independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or -CN, and the -C 1-8 Alkyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may be selected from the group consisting of at least one substituent R 3c or R 3A and R 3B together with the atom to which they are attached form an oxo group (—C(═O)—) or a 3- to 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and which ring contains at least one substituent R 3c optionally substituted with R 3c are each independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR 3d , -SO2R 3d , -SO2NR 3d R 3e , -COR 3d , -CO2R 3d , -CONR3d R 3e , -NO2, -NR 3d R 3e , -NR 3d COR 3e , -NR 3d CO2R 3e , -NR 3d CONR 3e R 3f , or -NR 3d SO2R 3e Selected from the -C 1-8 Alkyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may be selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -haloC 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 3d , R 3e , and R 3f are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the —C 1-8 Alkyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may be selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -haloC 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 4 But hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, or heterocyclyl, and the -C 1-8 Alkyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, or the heterocyclyl may contain at least one substituent R 4a optionally substituted with R 4a are each independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR 4b , -SO2R 4b , -SO2NR 4b R 4c , -COR 4b , -CO2R 4b , -CONR 4b R 4c , -NO2, -NR 4b R 4c , -NR 4b COR 4c , -NR 4b CO2R 4c , -NR 4b CONR 4c R 4d , or -NR 4b SO2R 4c Selected from the -C 1-8 Alkyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may be selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C1-8 Alkoxy, -haloC 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 4b , R 4c , and R 4d are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the —C 1-8 Alkyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may be selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -haloC 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 5 , R 6 , R 7 , R 8 , and R 9 are each independently H, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR 5a , -COR 5a , -CO2R 5a , -CONR 5a R 5b , -NR5a R 5b , -NR 5a COR 5b , -NR 5a CO2R 5b , or -NR 5a CONR 5b R 5c Selected from the -C 1-8 Alkyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may be selected from the group consisting of at least one substituent R 5d optionally substituted with R 5a , R 5b , and R 5c are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the —C 1-8 Alkyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may be selected from the group consisting of at least one substituent R 5f optionally substituted with R 5d and R 5f are each independently hydrogen, halogen, hydroxy, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; 1-8 Alkyl, haloC 1-8 Alkyl, the -C 1-8 Alkoxy, the -C 2-8 Alkenyl, the -C 2-8Each of the alkynyl, the cycloalkyl, the halocycloalkyl, the heterocyclyl, the haloheterocyclyl, the aryl, the haloaryl, the heteroaryl, or the haloheteroaryl may be selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -haloC 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 10 H, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR 10a , -COR 10a , -CO2R 10a , -CONR 10a R 10b , -NR 10a R 10b , -NR 10a COR 10b , -NR 10a CO2R 10b , or -NR 10a CONR 10b R 10c Selected from the -C 1-8 Alkyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may be selected from the group consisting of at least one substituent R 10d optionally substituted with R 10a , R 10b , and R 10c are each independently hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the —C 1-8 Alkyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl may be selected from the group consisting of at least one substituent R 10f optionally substituted with R 10d and R 10f are each independently hydrogen, halogen, hydroxy, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; 1-8 Alkyl, haloC 1-8 Alkyl, the -C 1-8 Alkoxy, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, the halocycloalkyl, the heterocyclyl, the haloheterocyclyl, the aryl, the haloaryl, the heteroaryl, or the haloheteroaryl may be selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -haloC 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 11 But, H, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, wherein -C 1-8Alkyl, the -C 2-8 alkenyl, or the -C 2-8 Each alkynyl is selected from the group consisting of at least one substituent R 11a optionally substituted with R 11a However, hydrogen, halogen, hydroxy, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; 1-8 Alkyl, haloC 1-8 Alkyl, the -C 1-8 Alkoxy, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, the halocycloalkyl, the heterocyclyl, the haloheterocyclyl, the aryl, the haloaryl, the heteroaryl, or the haloheteroaryl may be selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -haloC 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 A compound, or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, or a prodrug thereof, optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl.

[0009] Embodiment 2. The compound is selected from formula (IIa), (IIb), (IIc), (IId), or (IIe): [ka] In the formula, R 1 , R 2 , R 3A , R 3B , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m, and n are each as defined in Aspect 1; Preferably, the compound is selected from formula (IIf), (IIg), (IIh), or (IIi), [ka] In the formula, R 1 , R 2 , R 3A , R 3B , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and n are each as defined in Aspect 1; More preferably, the compound is selected from formula (IIj), (IIk), (IIl), or (IIm): [ka] In the formula, R 1 , R 2 , R 3A , R 3B , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and n are each as defined in Aspect 1; Even more preferably, the compound is selected from formula (IIn), (IIo), (IIp), or (IIq), [ka] In the formula, R 1 , R 2 , R3A , R 3B , R 5 , R 6 , R 7 , R 8 , R 10 2. The compound according to embodiment 1, wherein m and n are each as defined in embodiment 1.

[0010] Embodiment 3. The ring CyA is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, which ring contains, as ring member(s), 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and which ring contains 0, 1, 2, 3, 4, or 5 R 10 wherein the ring is a saturated or unsaturated ring; Preferably, CyA is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated ring, which contains, as ring member(s), 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and which ring contains 0, 1, 2, or 3 R 10 optionally substituted with More preferably, CyA is a 5-, 6-, or 7-membered saturated ring, which ring contains, as ring member(s), 1 or 2 heteroatom(s) independently selected from nitrogen or oxygen, and which ring contains 0, 1, 2, or 3 R 10 optionally substituted with Even more preferably, CyA is a ring selected from tetrahydrofuranyl or tetrahydropyranyl, and the ring contains 0, 1, 2, or 3 R 10 The compound of any one of the preceding aspects, optionally substituted with

[0011] Embodiment 4. The ring CyA is [ka] and Preferably, CyA is [ka] and More preferably, CyA is [ka] and Even more preferably, CyA is [ka]

[0023] The compound of any one of the preceding aspects, wherein

[0012] Aspect 5.R 10 -H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, -CN, -OR 10a , -COR 10a , -CO2R 10a , -CONR 10a R 10b , -NR 10a R 10b , -NR 10a COR 10b , -NR 10a CO2R 10b , or -NR 10a CONR 10b R 10c the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl is selected from the group consisting of at least one substituent R 10d optionally substituted with R 10a , R 10b , and R 10ceach independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl is selected from the group consisting of at least one substituent R 10f optionally substituted with R 10d and R 10f each independently represents hydrogen, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; and 1-8 Alkyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptoxy, the octoxy, the -C 2-8 Alkenyl, the -C 2-8Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the halocycloalkyl, the heterocyclyl, the haloheterocyclyl, the phenyl, the haloaryl, the heteroaryl, or the haloheteroaryl may be selected from the group consisting of at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; Preferably, R 10 -H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, -CN, -OH, or -NH; More preferably, R 10 The compound of any one of the preceding embodiments, wherein is —OH.

[0013] Aspect 6. [ka] The part is, [ka]

[0023] The compound of any one of the preceding aspects, wherein

[0014] Aspect 7.R 1-H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, haloalkyl, heterocyclyl, -CN, -OR 1a , -COR 1a , -CO2R 1a , -CONR 1a R 1b , -NR 1a R 1b , -NR 1a COR 1b , -NR 1a CO2R 1b , or -NR 1a CONR 1b R 1c and the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the haloalkyl, or the heterocyclyl is selected from the group consisting of at least one substituent R 1d optionally substituted with R 1a , R 1b , and R 1c are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl is selected from the group consisting of at least one substituent R 1f optionally substituted with R 1d and R 1f each independently represents hydrogen, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; and 1-8 Alkyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptoxy, the octoxy, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the halocycloalkyl, the heterocyclyl, the haloheterocyclyl, the phenyl, the haloaryl, the heteroaryl, or the haloheteroaryl may be selected from the group consisting of at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; Preferably, R 1-H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -OR 1a , -COR 1a and the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, or the cyclooctyl is optionally substituted with at least one substituent selected from hydrogen, -F, -Cl, -Br, -I, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; R 1a is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl; More preferably, R 1 is H, -F, -Cl, -Br, -I, C 1-8 Alkoxy-C 1-8 alkyl-, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, haloalkyl, heterocyclyl, or -C(O)C 1-8 is alkyl, Even more preferably, R 1

[0023] The compound of any one of the preceding aspects, wherein is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -C(O)CH3, -C(CH3)2OH, -OMe, -F, -Cl, cyclopropyl, or cyclobutyl.

[0015] Aspect 8.R 2 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR 2a , -SO2R 2a , -SO2NR 2a R 2b , -COR 2a , -CO2R 2a , -CONR 2a R 2b , -NR 2a R 2b , -NR 2a COR 2b , -NR 2a CO2R 2b , -NR 2a CONR 2b R 2c , or -NR 2a SO2R 2b and the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl is selected from the group consisting of at least one substituent R 2d optionally substituted with R 2a , R 2b , and R 2ceach independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl is selected from the group consisting of at least one substituent R 2f or (R 2a and R 2b ), (R 2b and R 2c ), or (R 2a and R 2c ), together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and which ring contains at least one substituent R 2f optionally substituted with R 2d and R 2f each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR 2g , -SO2R 2g , -SO2NR 2g R 2h , -COR2g , -CO2R 2g , -CONR 2g R 2h , -NO2, -NR 2g R 2h , -NR 2g COR 2h , -NR 2g CO2R 2h , -NR 2g CONR 2h R 2i , or -NR 2g SO2R 2h the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may contain at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; When they are adjacent or geminal, (two R 2d ) and / or (two R 2f), together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and which ring contains at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH2CH2CH3, -C(O)-CH2(CH3)2, -C(O)-CH2CH2CH2CH3, -C(O)-CH(CH3)CH2CH3, -C(O)-CH2CH(CH3)CH3, -C(O)-C(CH3)3, -C 2-8 Alkenyl, -C 2-8 optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; R 2g , R 2h , and R 2i each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 Alkenyl, the -C 2-8Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH2CH2CH3, -C(O)-CH2(CH3)2, -C(O)-CH2CH2CH2CH3, -C(O)-CH(CH3)CH2CH3, -C(O)-CH2CH(CH3)CH3, -C(O)-C(CH3)3, -C 2-8 Alkenyl, -C 2-8 The compound of any one of the preceding aspects optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl.

[0016] Aspect 9.R 2is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazepanyl, oxetanyl, azetidinyl, oxa-azaspiro[4.4]nonanyl, hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decanyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decanyl, octahydropyrrolo[4.5]decanyl, octahydropyrrolo[4.5]pyrrol ... oxa-azaspiro[4.5]decanyl, azabicyclo[3.3.1]nonanyl, piperidinyl, piperazinyl, oxa-azaspiro[2.5]octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, phenyl, oxo, -CN, -OR 2a , -COR 2a , -CO2R 2a , -CONR 2a R 2b , -NR 2a R 2b , or -NR 2a COR 2band the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the pyrrolidinyl, the morpholinyl, the thiomorpholinyl, the tetrahydrofuranyl, the tetrahydropyranyl, the oxazepanyl, the oxetanyl, the azetidinyl, the oxa-azaspiro[4.4]nonanyl, the hexahydro-1H-furo[3,4-c]pyrrolyl, the octahydropyrrolo[3,4-c]pyrrolyl, the diazaspiro[4.5]decanyl, the the oxa-azaspiro[4.5]decanyl, the azabicyclo[3.3.1]nonanyl, the piperidinyl, the piperazinyl, the oxa-azaspiro[2.5]octanyl, the oxa-azabicyclo[3.1.1]heptanyl, the oxa-azabicyclo[2.2.1]heptanyl, the diazaspiro[5.5]undecanyl, the oxa-azabicyclo[3.3.1]nonanyl, the azabicyclo[3.2.1]octanyl, the azabicyclo[2.1.1]hexanyl, the pyridinyl, the pyrimidinyl, the pyrazolyl, the oxa-azabicyclo[3.2.1]octanyl, or the phenyl is selected from the group consisting of phenyl, oxa-azabicyclo[4.5]decanyl, aza-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, phenyl, oxa-azabicyclo[3.2.1]octanyl, and phenyl. 2d optionally substituted with R 2a and R 2b each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazepanyl, oxetanyl, azetidinyl, oxa-azaspiro[4.4]nonanyl, hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decanyl, oxa-azaspiro[4.5]decanyl, azabicyclo[3.3.1]nonanyl, piperidinyl, piperazinyl, oxa - selected from azaspiro[2.5]octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, or phenyl; 2-8 Alkenyl, the -C 2-8Alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the pyrrolidinyl, the morpholinyl, the thiomorpholinyl, the tetrahydrofuranyl, the tetrahydropyranyl, the oxazepanyl, the oxetanyl, the azetidinyl, the oxa-azaspiro[4.4]nonanyl, the hexahydro-1H-furo[3,4-c]pyrrolyl, the octahydropyrrolo[3,4-c]pyrrolyl, the diazaspiro[4.5]decanyl, the oxa-azaspiro[4.5]decanyl, the azabicyclo each of the oxa-azabicyclo[3.3.1]nonanyl, the piperidinyl, the piperazinyl, the oxa-azaspiro[2.5]octanyl, the oxa-azabicyclo[3.1.1]heptanyl, the oxa-azabicyclo[2.2.1]heptanyl, the diazaspiro[5.5]undecanyl, the oxa-azabicyclo[3.3.1]nonanyl, the azabicyclo[3.2.1]octanyl, the azabicyclo[2.1.1]hexanyl, the pyridinyl, the pyrimidinyl, the pyrazolyl, the oxa-azabicyclo[3.2.1]octanyl, or the phenyl is selected from the group consisting of phenyl, ... 2f or (R 2a and R 2b ), (R 2b and R 2c ), or (R 2a and R 2c ), together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 heteroatom(s) independently selected from nitrogen or oxygen, and which ring contains at least one substituent R 2f optionally substituted with R 2d and R 2f each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazepanyl, oxetanyl, azetidinyl, oxa-azaspiro[4.4]nonanyl, hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decanyl, oxa-azaspiro[4.5]decanyl, azabicyclo[ 3.3.1]nonanyl, piperidinyl, piperazinyl, oxa-azaspiro[2.5]octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, phenyl, oxo, -CN, -OR 2g , -SO2R 2g , -COR 2g , -CO2R 2g , -CONR 2g R 2h , -NO2, -NR 2g R 2h , or -NR 2g COR 2h the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 Alkenyl, the -C 2-8alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the pyrrolidinyl, the morpholinyl, the thiomorpholinyl, the tetrahydrofuranyl, the tetrahydropyranyl, the oxazepanyl, the oxetanyl, the azetidinyl, the oxa-azaspiro[4.4]nonanyl, the hexahydro-1H-furo[3,4-c]pyrrolyl, the octahydropyrrolo[3,4-c]pyrrolyl, the diazaspiro[4.5]decanyl, the oxa-azaspiro[4.5]decanyl, the azabicyclo[3.3.1]nonanyl, the piperidinyl, the piperazinyl, the each of the oxa-azaspiro[2.5]octanyl, the oxa-azabicyclo[3.1.1]heptanyl, the oxa-azabicyclo[2.2.1]heptanyl, the diazaspiro[5.5]undecanyl, the oxa-azabicyclo[3.3.1]nonanyl, the azabicyclo[3.2.1]octanyl, the azabicyclo[2.1.1]hexanyl, the pyridinyl, the pyrimidinyl, the pyrazolyl, the oxa-azabicyclo[3.2.1]octanyl, or the phenyl is selected from the group consisting of at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; When they are adjacent or geminal, (two R 2d ) and / or (two R 2f), together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and which ring contains at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH2CH2CH3, -C(O)-CH2(CH3)2, -C(O)-CH2CH2CH2CH3, -C(O)-CH(CH3)CH2CH3, -C(O)-CH2CH(CH3)CH3, -C(O)-C(CH3)3, -C 2-8 Alkenyl, -C 2-8 optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; R 2g , R 2h , and R 2i each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 Alkenyl, the -C 2-8Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C(O)-CH3, -C(O)-CH2CH3, -C(O)-CH2CH2CH3, -C(O)-CH2(CH3)2, -C(O)-CH2CH2CH2CH3, -C(O)-CH(CH3)CH2CH3, -C(O)-CH2CH(CH3)CH3, -C(O)-C(CH3)3, -C 2-8 Alkenyl, -C 2-8 The compound of any one of the preceding aspects optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl.

[0017] Aspect 10.R 2is hydrogen, methyl, ethyl, propyl, butyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazepanyl, oxetanyl, azetidinyl, oxa-azaspiro[4.4]nonanyl, hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decanyl, oxa-azaspiro[4.5]decanyl, azabicyclo[3.3.1]nonanyl, pyrrolidin ...tetrahydropyranyl, oxazepanyl, oxetanyl, azetidinyl, oxa-azaspiro[4.4]nonanyl, hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decanyl, oxa-azaspiro[4.5]decanyl, azabicyclo[3.3.1]nonanyl, pyrrolidinyl, tetrahydropyranyl, tetrahydropyranyl, tetrahydropyranyl, tetrahydropyranyl, tetrahydropyranyl, tetrahydropyranyl, tetrahydropy Peridinyl, piperazinyl, oxa-azaspiro[2.5]octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, phenyl, -OR 2a , -NR 2a R 2b , or -NR 2a COR 2b and the methyl, the ethyl, the propyl, the butyl, the pyrrolidinyl, the morpholinyl, the thiomorpholinyl, the tetrahydrofuranyl, the tetrahydropyranyl, the oxazepanyl, the oxetanyl, the azetidinyl, the oxa-azaspiro[4.4]nonanyl, the hexahydro-1H-furo[3,4-c]pyrrolyl, the octahydropyrrolo[3,4-c]pyrrolyl, the diazaspiro[4.5]decanyl, the oxa-azaspiro[4.5]decanyl, the azabicyclo[3.3.1]nonanyl, the piperi and each of the oxa-azabicyclo[3.1.1]hexanyl, the pyridinyl, the pyrimidinyl, the pyrazolyl, the oxa-azabicyclo[3.2.1]octanyl, or the phenyl is selected from the group consisting of oxa-azabicyclo[3.3.1]hexanyl, oxa-azabicyclo[3.2 ... 2doptionally substituted with R 2a and R 2beach independently represents hydrogen, methyl, ethyl, propyl (n-propyl or iso-propyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazepanyl, oxetanyl, azetidinyl, oxa-azaspiro[4.4]nonanyl, hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4 -c]pyrrolyl, diazaspiro[4.5]decanyl, oxa-azaspiro[4.5]decanyl, azabicyclo[3.3.1]nonanyl, piperidinyl, piperazinyl, oxa-azaspiro[2.5]octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa- azabicyclo[3.2.1]octanyl, or phenyl, and the methyl, the ethyl, the propyl, the butyl, the pentyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the pyrrolidinyl, the morpholinyl, the thiomorpholinyl, the tetrahydrofuranyl, the tetrahydropyranyl, the oxazepanyl, the oxetanyl, the azetidinyl, the oxa-azaspiro[4.4]nonanyl, the hexahydro-1H-furo[3,4-c]pyrrolyl, the octahydro pyrrolo[3,4-c]pyrrolyl, the diazaspiro[4.5]decanyl, the oxa-azaspiro[4.5]decanyl, the azabicyclo[3.3.1]nonanyl, the piperidinyl, the piperazinyl, the oxa-azaspiro[2.5]octanyl, the oxa-azabicyclo[3.1.1]heptanyl, the oxa-azabicyclo[2.2.1]heptanyl, the diazaspiro[5.5]undecanyl, the oxa-azabicyclo[3.3.1]nonanyl, the azabicyclo[3.2.1]octanyl, the azabicyclo[2.1.1]hexanyl, the pyridinyl, the pyrimidinyl, the pyrazolyl, the oxa-azabicyclo[3.2.1]octanyl, or the phenyl is selected from the group consisting of at least one substituent R. 2f or (R 2a and R 2b ), (R 2b and R 2c ), or (R 2a and R 2c ), together with the atom(s) to which they are attached, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 heteroatom(s) independently selected from nitrogen or oxygen, and which ring contains at least one substituent R 2f optionally substituted with R 2d and R 2feach independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, -CF3, -CF2H, -CFH2, -CH2CF3, -CF2CH3, -CH2OH, -CH(CH3)OH, -C(CH3)2OH, -CH2CH2OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyridine ... Ranyl, oxazepanyl, oxetanyl, azetidinyl, oxa-aspiro[4.4]nonanyl, hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decanyl, oxa-azaspiro[4.5]decanyl, azabicyclo[3.3.1]nonanyl, peridinyl, piperazinyl, oxa-azabicyclo[2.5]octanyl, oxa-azabicyclo[3.1.1] Heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, phenyl, oxo, -CN, -OH, methoxy, ethoxy, propoxy, butoxy, pentoxy , hexoxy, heptoxy, octoxy, -SO2Me, -SO2Et, -SO2C3H7, -COMe, -COEt, -COC3H7, -NH2, -NHCH3, -N(CH3)2, -NHC2H5, -NHC3H7, -NHC4H9, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CONHC3H7, or -CONHC4H9.

[0018] Aspect 11.R 2 is -H, -Me, -OMe, -OH, -NH2, -NHCH3, -N(CH3)2, -NHCH(CH3)2, -NHC(CH3)3, -NHCOCH3, [ka] [ka]

[0023] The compound of any one of the preceding aspects, wherein

[0019] Aspect 12.R 3A and R 3B each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, or -CN, and the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl is selected from the group consisting of at least one substituent R 3c optionally replaced by R 3A and R 3B together with the atom to which they are attached form an oxo group (—C(═O)—) or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and which ring contains at least one substituent R 3c optionally substituted with R 3c each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR 3d , -SO2R3d , -SO2NR 3d R 3e , -COR 3d , -CO2R 3d , -CONR 3d R 3e , -NO2, -NR 3d R 3e , -NR 3d COR 3e , -NR 3d CO2R 3e , -NR 3d CONR 3e R 3f , or -NR 3d SO2R 3e the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; R 3d , R 3e , and R 3f each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may contain at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; Preferably, R 3A and R 3B each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, or -CN; R 3A and R 3B together with the atom to which they are attached form an oxo group (—C(═O)—) or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, which ring contains, as ring member(s), 0, 1, or 2 heteroatom(s) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and preferably R3A and R 3B together with the atom to which they are attached form an oxo group (-C(=O)-), More preferably, R 3A and R 3B are each independently hydrogen, methyl, ethyl, propyl, butyl, or pentyl; R 3A and R 3B

[0039] The compound of any one of the preceding embodiments, wherein, together with the atom to which they are attached, form an oxo group (-C(=O)-), or a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, which ring contains 0, 1, or 2 heteroatom(s) independently selected from nitrogen or oxygen.

[0020] Aspect 13. [ka] The part is, [ka] and In the formula, * 3 but, [ka] ** indicates the position where the molecule is attached to the 3 but, [ka] refers to the position where the molecule is attached to the moiety, In another embodiment, [ka] The part is, [ka] and In the formula, * 3 but, [ka] ** indicates the position where the molecule is attached to the 3 but, [ka]

[0023] The compound of any one of the preceding embodiments, wherein the moiety is linked to

[0021] Aspect 14. [ka] The parts are -Me, -Et, [ka] [ka] [ka] and In another embodiment, [ka] The part is, [ka]

[0023] The compound of any one of the preceding aspects, wherein

[0022] Aspect 15.R 4 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or heterocyclyl, and the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 Alkenyl, the -C 2-8Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, or the heterocyclyl is selected from the group consisting of at least one substituent R 4a optionally substituted with R 4a each independently represents hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR 4b , -SO2R 4b , -SO2NR 4b R 4c , -COR 4b , -CO2R 4b , -CONR 4b R 4c , -NO2, -NR 4b R 4c , -NR 4b COR 4c , -NR 4b CO2R 4c , -NR 4b CONR 4c R 4d , or -NR 4b SO2R 4c the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may be selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -haloC 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 4b , R 4c , and R 4d each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl may be selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -haloC 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; Preferably, R 4 is hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or heterocyclyl; More preferably, R 4The compound of any one of the preceding embodiments, wherein is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0023] Aspect 16.R 5 , R 6 , R 7 , R 8 , and R 9 each independently represents H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, -CN, -OR 5a , -COR 5a , -CO2R 5a , -CONR 5a R 5b , -NR 5a R 5b , -NR 5a COR 5b , -NR 5a CO2R 5b , or -NR 5a CONR 5b R 5c and the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl is selected from the group consisting of at least one substituent R 5d optionally substituted with R 5a , R 5b , and R 5c each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8Alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl is selected from the group consisting of at least one substituent R 5f optionally substituted with R 5d and R 5f each independently represents hydrogen, -F, -Cl, -Br, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 Alkenyl, -C 2-8 selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; and 1-8 Alkyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptoxy, the octoxy, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the halocycloalkyl, the heterocyclyl, the haloheterocyclyl, the phenyl, the haloaryl, the heteroaryl, or the haloheteroaryl may be selected from the group consisting of halogen, hydroxy, -C1-8 Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -haloC 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; Preferably, R 5 , R 6 , R 7 , R 8 , and R 9 each independently represents H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, -CN, -OR 5a , -COR 5a , -CO2R 5a , -CONR 5a R 5b , -NR 5a R 5b , -NR 5a COR 5b , -NR 5a CO2R 5b , or -NR 5a CONR 5b R 5c is selected from R 5a , R 5b , and R 5c each independently represents hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl; More preferably, R 5 , R6 , R 7 , R 8 , and R 9 each independently represents H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 The compound of any one of the preceding embodiments, wherein the aryl is selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl.

[0024] Aspect 17.R 5 , R 6 , and R 7 are each independently selected from H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl; and / or R 8 is selected from -F, -Cl, -Br, or -I, and / or R 9 is selected from H, Preferably, R 5 , R 6 , and R 7 are each independently selected from H, —F, —Cl, methyl, ethyl, propyl, or butyl; and / or R 8 is selected from -F or -Cl, and / or R 9 is selected from H.

[0025] Aspect 18.R 11 H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, or -C 2-8 alkynyl, selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C 2-8 alkenyl, or the -C 2-8Each alkynyl is selected from the group consisting of at least one substituent R 11a optionally substituted with R 11a However, hydrogen, halogen, hydroxy, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; 1-8 Alkyl, haloC 1-8 Alkyl, the -C 1-8 Alkoxy, the -C 2-8 Alkenyl, the -C 2-8 Each of the alkynyl, the cycloalkyl, the halocycloalkyl, the heterocyclyl, the haloheterocyclyl, the aryl, the haloaryl, the heteroaryl, or the haloheteroaryl may be selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -haloC 1-8 Alkyl, -C 1-8 Alkoxy, -haloC 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkynyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; Preferably, R 11 H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, or -C 2-8 alkynyl, More preferably, R 11 is selected from H, methyl, ethyl, propyl, or butyl; Even more preferably, R 11 The compound of any one of the preceding embodiments, wherein is H.

[0026] Embodiment 19. The compound of any one of the preceding embodiments, wherein the compound is selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0027] Embodiment 20. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 19, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, together with a pharmaceutically acceptable excipient.

[0028] Embodiment 21. A method of decreasing CDK4 activity by inhibition, comprising administering to an individual a compound according to any one of embodiments 1-19, or a pharmaceutically acceptable salt thereof, including a compound of formula (I) or the specific compounds exemplified herein.

[0029] Aspect 22. The method of aspect 21, wherein the disease is selected from cancer, preferably breast cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, liver cancer, and endometrial cancer.

[0030] Embodiment 23. Use of a compound according to any one of embodiments 1 to 19, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, in the preparation of a medicament for treating a disease that can be affected by CDK4 modulation.

[0031] Aspect 24. The use according to Aspect 23, wherein the disease is cancer, preferably breast cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, liver cancer, and endometrial cancer.

[0032] Embodiment 25. A method of treating a disease or disorder in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to any one of embodiments 1 to 19, or a pharmaceutically acceptable salt thereof, as a CKD4 kinase inhibitor, wherein the disease or disorder is associated with inhibition of CDK4.

[0033] Aspect 26. The method of aspect 25, wherein the disease is selected from cancer, preferably breast cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, liver cancer, and endometrial cancer. DETAILED DESCRIPTION OF THE INVENTION

[0034] The following terms have the meanings indicated throughout this specification: Unless otherwise defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs.

[0035] The following terms have the meanings indicated throughout this specification: As used in this specification, including the appended claims, singular words such as "a," "an," and "the" include their corresponding plural references unless the context clearly dictates otherwise.

[0036] The term "or" means, and is used interchangeably with, the term "and / or," unless context clearly dictates otherwise.

[0037] The term "alkyl" includes hydrocarbon groups selected from linear and branched saturated hydrocarbon groups containing 1 to 18, for example, 1 to 12, further 1 to 10, further 1 to 8, or 1 to 6, or 1 to 4 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C 1-6Examples of alkyl include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0038] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0039] The term "butyl" includes 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), and 1,1-dimethylethyl or t-butyl ("t-Bu").

[0040] The term "pentyl" includes 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl.

[0041] The term "hexyl" includes 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0042] The term "alkylene" includes divalent alkyl groups formed by removing two hydrogens from an alkane. Alkylene includes, but is not limited to, methylene, ethylene, propylene, and the like.

[0043] The term "halogen" includes fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0044] The term "alkenyl" includes hydrocarbon groups selected from straight-chain and branched-chain hydrocarbon groups containing at least one C=C double bond and 2 to 18, such as 2 to 8, further such as 2 to 6, carbon atoms. Alkenyl groups, such as C 2-6 Examples of alkenyl include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.

[0045] The term "alkenylene" refers to a divalent alkyl group formed by removing two hydrogens from an alkane. Alkenylene includes, but is not limited to, vinylidene, butenylene, and the like.

[0046] The term "alkynyl" includes hydrocarbon groups selected from straight and branched chain hydrocarbon groups containing at least one C≡C triple bond and 2 to 18, for example, 2 to 8, further for example, 2 to 6, carbon atoms. Alkynyl groups, for example, C 2-6 Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0047] The term "alkynylene" refers to a divalent alkynyl group formed by removing two hydrogens from an alkyne. Alkenylene includes, but is not limited to, ethynylene, and the like.

[0048] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or spirocycloalkyls.

[0049] For example, the cycloalkyl group can contain 3 to 12, e.g., 3 to 10, further e.g., 3 to 8, further e.g., 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Further, for example, the cycloalkyl group can be selected from monocyclic groups containing 3 to 12, e.g., 3 to 10, further e.g., 3 to 8, 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, saturated monocyclic cycloalkyl groups, e.g., C 3-8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In preferred embodiments, cycloalkyl is a monocyclic ring containing 3 to 6 carbon atoms (C), including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3-6 (Abbreviated as cycloalkyl). Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.

[0050] The term "spirocycloalkyl" includes cyclic structures containing carbon atoms and formed by at least two rings that share one atom.

[0051] The term "fused cycloalkyl" includes bicyclic cycloalkyl groups, as defined herein, that are saturated and formed by two or more rings sharing two adjacent atoms.

[0052] The term "bridged cycloalkyl" includes a cyclic structure containing carbon atoms and formed by two rings that share two non-adjacent atoms. The term "7-10 membered bridged cycloalkyl" includes a cyclic structure containing 7-12 carbon atoms and formed by two rings that share two non-adjacent atoms.

[0053] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and benzo 3- to 8-membered cycloalkyl, benzo C 4-6 These include, but are not limited to, cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8-9 membered fused rings, referring to ring structures containing 8-9 ring atoms within the above examples.

[0054] The term "aryl" used alone or in combination with other terms, 5- and 6-membered carbocyclic aromatic rings, for example phenyl, bicyclic ring systems, such as 7-12 membered bicyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example naphthyl and indanyl, and - Tricyclic ring systems, such as 10-15 membered tricyclic ring systems, in which at least one ring is carbocyclic and aromatic, for example fluorenyl.

[0055] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 (aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0056] Specifically, the term "bicyclic fused aryl" includes bicyclic aryl rings as defined herein. An exemplary bicyclic fused aryl is naphthalene.

[0057] The term "heteroaryl" includes groups selected from: a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), for example, 1 to 4, or in some embodiments 1 to 3, and in some embodiments 1 to 2 heteroatoms, with the remaining ring atoms being carbon; - a 7-12 membered bicyclic ring containing at least one heteroatom selected from N, O, and S, for example, 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being in the aromatic ring; and - An 11-14 membered tricyclic ring containing at least one heteroatom selected from N, O, and S, for example, 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, the remaining ring atoms being carbon, and at least one ring being aromatic, with at least one heteroatom being in the aromatic ring.

[0058] When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. When a heteroaryl group contains more than one heteroatom ring member, these heteroatoms can be the same or different. Nitrogen atoms in the ring(s) of a heteroaryl group can be oxidized to form an N-oxide.

[0059] Specifically, the term "bicyclic fused heteroaryl" includes 7- to 12-membered, preferably 7- to 10-membered, and more preferably 9- or 10-membered fused bicyclic heteroaryl rings as defined herein. Typically, bicyclic fused heteroaryls are 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclics. Groups can be attached to the remainder of the molecule through either ring.

[0060] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and include non-aromatic heterocyclyl groups containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, and including monocyclic, fused, bridged, and spirocyclic groups, i.e., monocyclic, heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclic groups.

[0061] The term "at least one substituent" as disclosed herein includes 1 to 4 substituents, such as 1 to 3, further 1 or 2, as long as valence theory is satisfied. For example, "at least one substituent F" as disclosed herein includes 1 to 4 substituents F, such as 1 to 3, further 1 or 2.

[0062] The term "divalent" refers to a linking group that can form a covalent bond with two other moieties. For example, a "divalent cycloalkyl group" refers to a cycloalkyl group obtained by removing two hydrogens from the corresponding cycloalkane to form the linking group. The terms "divalent aryl group," "divalent heterocyclyl group," or "divalent heteroaryl group" should be understood similarly.

[0063] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. When the compounds disclosed herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. All such possible stereoisomers are intended to be included, including substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. All stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts are intended to be included. Unless otherwise specified, a reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is not specified, all possible isomers are included.

[0064] When compounds disclosed herein contain olefinic double bonds, unless otherwise specified, it is intended that such double bond include both E and Z geometric isomers.

[0065] When the compounds disclosed herein comprise a disubstituted cyclic ring system, the substituents found in such ring system can adopt cis and trans configuration.Cis configuration means that both substituents are found on the upper side of the arrangement of the two substituents on carbon, while trans means that they are on the opposite side.For example, the disubstituted cyclic ring system can be a cyclohexyl or cyclobutyl ring.

[0066] It may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter "separated") to the desired degree of homogeneity by techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods, including, for example, reverse-phase and normal-phase, size exclusion, ion exchange, high-, medium-, and low-pressure liquid chromatography methods and apparatus, small-scale analytical, simulated moving bed ("SMB"), and preparative thin- or thick-layer chromatography, as well as small-scale thin-layer and flash techniques. One skilled in the art can select and apply the techniques most likely to achieve the desired separation.

[0067] "Diastereomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers based on their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by use of a chiral HPLC column.

[0068] Single stereoisomers, e.g., substantially pure enantiomers, can be obtained by resolution of racemic mixtures using methods such as the formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C.H., et al., "Chromatographic resolution of enantiomers: Selective review," J. Chromatogr., 113(3)(1975): pp. 283-302). Racemic mixtures of chiral compounds of the present invention can be separated and isolated by any suitable method, including (1) the formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) the formation of diastereomeric compounds with chiral derivatizing agents, separation of diastereomers, and conversion to pure stereoisomers, and (3) the direct separation of substantially pure or enriched stereoisomers under chiral conditions. See Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0069] Some of the compounds disclosed herein may exist with different points of hydrogen attachment, called tautomers. For example, compounds containing a carbonyl -CHC(O)- group (keto form) may undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Where applicable, both the keto and enol forms, as well as mixtures thereof, are intended to be included.

[0070] "Prodrug" refers to a derivative of an active drug that requires conversion within the body to release the active drug. In certain embodiments, the conversion is enzymatic. Prodrugs are often, but not necessarily, pharmacologically inactive until converted to an active drug.

[0071] "Pharmaceutically acceptable salt" refers to a salt that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and that corresponds to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting a free base functional group with a suitable organic acid, or an acidic group with a suitable base. The term also includes salts of stereoisomers (such as enantiomers and / or diastereomers), tautomers, and prodrugs of the compounds of the invention.

[0072] In addition, when a compound disclosed herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0073] The terms "administration," "administering," "treating," and "treatment," as used herein, when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, refer to the contact of an exogenous pharmaceutical, therapeutic, diagnostic, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of a cell encompasses contact of a reagent with a cell, as well as contact of a reagent with a fluid where the fluid contacts the cell. The terms "administration" and "treatment" also refer to in vitro and ex vivo treatment, e.g., of a cell with a reagent, diagnostic, binding compound, or with another cell. The term "subject," as used herein, includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0074] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient, such as a compound, that, when administered to a subject to treat a disease or at least one clinical symptom of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or condition. A "therapeutically effective amount" may vary depending on the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. The appropriate amount in any given case will be apparent to one of ordinary skill in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound disclosed herein and / or at least one stereoisomer, tautomer, or prodrug thereof, and / or at least one pharmaceutically acceptable salt thereof that is effective to "treat" a disease or disorder in a subject, as defined herein. In the case of a combination therapy, the term "therapeutically effective amount" refers to the total amount of the combined components for effective treatment of a disease, disorder, or condition.

[0075] The term "disease" refers to any disease, ailment, disorder, symptom, or indication, and may be used interchangeably with the term "disorder" or "condition."

[0076] Throughout this specification and the claims that follow, unless the context otherwise requires, the word "comprise," as well as variations such as "comprises" and "comprising," are intended to specify the presence of the subsequent feature but do not exclude the presence or addition of one or more other features. As used herein, the word "comprising" can be replaced with the words "containing," "including," or, in some cases, "having."

[0077] Throughout this specification and the claims that follow, "C n-mThe term "" denotes a range inclusive of the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 , C 1-6 Examples include:

[0078] Unless otherwise defined elsewhere herein, all other technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention belongs. [Example]

[0079] General Synthesis The compounds disclosed herein and their salts can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.The reactions for preparing the compounds disclosed herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.A suitable solvent can be substantially non-reactive with the starting material, intermediate, or product at the temperature at which the reaction is carried out, for example, at a temperature that can vary from the boiling temperature of the solvent.A given reaction can be carried out in one solvent or a mixture of solvents.

[0080] The selection of an appropriate protecting group can be readily determined by one of ordinary skill in the art.

[0081] Reactions can be monitored according to any suitable method known in the art, such as NMR, UV, HPLC, LC-MS, and TLC. Compounds can be purified by a variety of methods, including HPLC and normal phase silica chromatography.

[0082] Chiral analytical HPLC was used for retention time analysis of various chiral examples, and the conditions were divided into the following methods according to the column, mobile phase, and solvent ratio used:

[0083] Scheme I [ka] For example, compounds of formula (I), (II), (III), or (IV) can be formed as shown in Scheme I. Compound (i) can be reacted with a halogenated pyrimidine under palladium-catalyzed reaction conditions or base-mediated coupling conditions to give compound (ii), which can be coupled with an amine to give compound (iii), and halogenation of compound (iii) gives compound (iv), which can be used in coupling to give compound (v).

[0084] Abbreviation [Table 1]

[0085] Example 1: 5-chloro-7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] Step 1: 4-Bromo-2-chloro-6-fluorobenzoyl chloride [ka] 4-Bromo-2-chloro-6-fluorobenzoic acid (6 g, 23.7 mmol) was dissolved in dry dichloromethane (60 mL) before the addition of dimethylformamide (0.5 mL). Oxalyl dichloride (3 mL, 35.5 mmol) was added dropwise at 0 °C, and the reaction solution was stirred at room temperature for 1.5 hours. The solvent was removed under reduced pressure. The crude title compound (6.44 g, 100%) was obtained without further purification.

[0086] Step 2: (Z)-2-(4-bromo-2-chloro-6-fluorobenzoyl)-3-(isopropylamino)acrylate ethyl ester [ka] To a solution of 4-bromo-2-chloro-6-fluorobenzoyl chloride (6.44 g, 23.7 mmol) and ethyl (E)-3-(dimethylamino)acrylate (5.1 g, 35.5 mol) in toluene (100 mL), triethylamine (4.9 mL, 35.5 mmol) was added, and the solution was refluxed overnight. After the reaction solution was cooled to room temperature, triethylamine (8 g, 79.2 mmol) and propan-2-amine hydrochloride (4.54 g, 47.5 mmol) were added. The resulting mixture was heated to 50 °C and stirred at 50 °C for 2 hours before cooling to room temperature. Water (20 mL) was added, and the aqueous layer was extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, decanted, and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (7 g, 100%). LC-MS (M+H) + =392.0.

[0087] Step 3: Ethyl 7-bromo-5-chloro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylate [ka] Ethyl (Z)-2-(4-bromo-2-chloro-6-fluorobenzoyl)-3-(isopropylamino)acrylate (7 g, 17.83 mmol) and potassium carbonate (3.7 g, 26.74 mmol) were dissolved in dimethylformamide (100 mL), and the reaction mixture was stirred at 60° C. for 14 hours before cooling to room temperature. The solvent was removed under reduced pressure before the addition of water (20 mL). The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (2.66 g, 40%). LC-MS (M+H) + =372.0.

[0088] Step 4: 7-Bromo-5-chloro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid [ka] To ethyl 7-bromo-5-chloro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (359 mg, 0.964 mmol) in ethanol (20 mL) was added 6N HCl (20 mL), and the resulting mixture was heated to reflux for 14 hours before cooling to room temperature. The mixture was filtered, and the crude product (290 mg, 87%) was used in the next step without further purification. LC-MS (M+H) + =344.0.

[0089] Step 5: 7-Bromo-5-chloro-1-isopropylquinolin-4(1H)-one [ka] A solution of 7-bromo-5-chloro-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (290 mg, 0.84 mmol) was dissolved in diphenyl ether (5 mL) and stirred at 260° C. for 14 hours before being cooled to room temperature and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (244 mg, 96%). LC-MS (M+H) + =300.0.

[0090] Step 6: 5-chloro-1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one [ka] A mixture of 7-bromo-5-chloro-1-isopropylquinolin-4(1H)-one (244 mg, 0.812 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (268 mg, 1.06 mmol), potassium acetate (119.5 mg, 1.22 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (59.4 mg, 0.0812 mmol) in 1,4-dioxane (10 mL) was stirred at 95 °C under nitrogen for 14 h before being cooled to room temperature and concentrated. Water (20 mL) was added, and the aqueous mixture was extracted with ethyl acetate (40 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (282.2 mg, 100%). LC-MS (M+H) + =348.0.

[0091] Step 7: 5-chloro-7-(2,5-dichloropyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] A mixture of 2,4,5-trichloropyrimidine (148.9 mg, 0.812 mmol), 5-chloro-1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one (282.2 mg, 0.812 mmol), sodium carbonate (258 mg, 2.436 mmol), and tetrakis(triphenylphosphine)palladium(0) (94 mg, 0.0812 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 90 °C under N for 1.5 h before cooling to room temperature. The solvent was removed under reduced pressure. Water (20 mL) was added, and the aqueous layer was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (207 mg, 69%). LC-MS (M+H) +=368.0.

[0092] Step 8: 5-chloro-7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] A mixture of 5-chloro-7-(2,5-dichloropyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one (207 mg, 0.56 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (129 mg, 0.84 mmol), and N,N-diisopropylethylamine (217.9 mg, 1.69 mmol) in acetonitrile (10 mL) was heated to reflux for 2 days before being cooled to room temperature and concentrated. Water (5 mL) was added, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (40 mg, 16%). 1 H-NMR (400 MHz, DMSO-d6) δ 8.48 (s, 1H), 8.14 (s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.63 (s, 2H), 6.15 (d, J = 8.0 Hz, 1H), 5.05 - 4.95 (m, 1H), 4.93 (d, J = 5.3 Hz, 1H), 3.91 - 3.74 (m, 3H), 3.50 (s, 1H), 3.31 - 3.25 (m, 1H), 3.04 (d, J = 9.6 Hz, 1H), 1.95 (s, 1H), 1.46 (d, J = 6.2 Hz, 7H).LC-MS(M+H) + =449.0.

[0093] Example 2: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] Step 1: 7-Bromo-1-isopropyl-3-methylquinolin-4(1H)-one [ka] To a solution of 7-bromo-3-methylquinolin-4(1H)-one (300 mg, 1.26 mmol) in dimethylformamide (5 mL) was added potassium carbonate (1.043 g, 7.56 mmol) and 2-iodopropane (1.071 g, 6.30 mmol). The resulting mixture was heated to 80° C. and stirred at 80° C. for 14 hours before being cooled to room temperature and concentrated. Water (5 mL) was added and the aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (40 mg, 11%). LC-MS (M+H) + =280.0.

[0094] Step 2: 1-Isopropyl-3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one [ka] The title compound (42 mg, 89.9%) was prepared from 7-bromo-1-isopropyl-3-methylquinolin-4(1H)-one and bis(pinacolato)diboron in a manner similar to that in Step 6 of Example 1. LC-MS (M+H) + =328.0.

[0095] Step 3: 7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (26 mg, 61%) was prepared from 1-isopropyl-3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one and 2,4-dichloro-5-fluoropyrimidine in a manner similar to that described in Step 7 of Example 1. LC-MS (M+H) + =332.0.

[0096] Step 4: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] A mixture of 7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one (26 mg, 0.0784 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (24 mg, 0.0157 mmol), tris(dibenzylideneacetone)dipalladium(0) (7.2 mg, 0.00784 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9.07 mg, 0.0157 mmol), and cesium carbonate (76.6 mg, 0.235 mmol) in 1,4-dioxane (5 mL) was stirred at 100° C. under nitrogen for 14 hours before cooling to room temperature. The solvent was removed under reduced pressure. Water (5 mL) was added, and the aqueous layer was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel to give the title compound (5 mg, 61%). 1H-NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 3.4 Hz, 1H), 8.40 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 7.4 Hz, 1H), 5.11 - 4.99 (m, 1H), 4.94 (d, J = 5.2 Hz, 1H), 3.89 - 3.75 (m, 3H), 3.54 (s, 1H), 3.36 (d, J = 11.4 Hz, 1H), 3.06 (t, J = 10.3 Hz, 1H), 2.05 (s, 3H), 2.08 - 1.90 (m, 1H), 1.52 (d, J = 6.5 Hz, 6H), 1.58 - 1.45 (m, 1H).LC-MS(M+H) + =413.0.

[0097] Example 3: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] Step 1: (Z)-2-(4-bromo-2-fluorobenzoyl)-3-(dimethylamino)ethyl acrylate [ka] To a solution of ethyl (2E)-3-(dimethylamino)prop-2-enoate (1.2 mL, 8.36 mmol) and N,N-diisopropylethylamine (3.06 mL, 17.6 mmol) in toluene (10.0 mL) was added 4-bromo-2-fluorobenzoyl chloride (1.14 mL, 8.36 mmol). The resulting mixture was stirred at 90° C. under a nitrogen atmosphere for 3 hours. The solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (0% to 50% gradient, v / v) to give the title compound (2.5 g, 86%). LC-MS (M+H) + =343.9.

[0098] Step 2: Ethyl 7-bromo-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylate [ka] To a solution of (Z)-2-(4-bromo-2-fluorobenzoyl)-3-(dimethylamino)ethyl acrylate (1.5 g, 4.36 mmol) in toluene (20 mL) was added isopropylamine (335 mg, 5.67 mmol). The resulting mixture was stirred at 110° C. for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was dissolved in dimethylformamide (20.0 mL), followed by the addition of potassium carbonate (1.51 g, 10.9 mmol) at room temperature. The resulting mixture was stirred at 100° C. for 12 hours under a nitrogen atmosphere. The reaction was cooled to room temperature and quenched by the addition of water (60 mL). The resulting mixture was extracted with dichloromethane (30 mL×3). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (0% to 30% gradient) to give the title compound (1.1 g, 74%). LC-MS (M+H) + =337.9.

[0099] Step 3: 7-Bromo-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid [ka] The title compound (930 mg, 92%) was prepared from ethyl 7-bromo-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylate in a manner similar to Step 4 of Example 1. LC-MS (M+H) + =310.0.

[0100] Step 4: 7-Bromo-1-isopropylquinolin-4(1H)-one [ka] The title compound (550 mg, 72%) was prepared from 7-bromo-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid in a manner similar to Step 5 of Example 1. LC-MS (M+H) + =265.9.

[0101] Step 5: 1-Isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one [ka] The title compound (500 mg, 84%) was prepared from 7-bromo-1-isopropylquinolin-4(1H)-one and bis(pinacolato)diboron in a manner similar to that described in Step 6 of Example 1. LC-MS (M+H) + =314.1.

[0102] Step 6: 7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (273 mg, 71%) was prepared from 1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one in a manner similar to that described in Step 7 of Example 1. LC-MS (M+H) + =318.0.

[0103] Step 7: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (35 mg, 15%) was prepared from 7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (3S,4R)-4-aminooxan-3-ol hydrochloride in a manner similar to that in Step 8 of Example 1. 1 H-NMR (300 MHz, DMSO-d6) δ 8.57-8.40 (m, 2H), 8.34 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 7.9 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 6.18 (d, J = 7.9 Hz, 1H), 5.12-4.84 (m, 2H), 3.91-3.78 (m, 3H), 3.58-3.52 (m, 1H), 3.42-3.32 (m, 1H), 3.13-3.00 (m, 1H), 2.08-1.98 (m, 1H), 1.52 (d, J = 6.6 Hz, 6H), 1.58 - 1.45 (m, 1H).LC-MS(M+H) + =399.1.

[0104] Example 4: 3-acetyl-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] Step 1: 3-acetyl-7-bromo-1-isopropylquinolin-4(1H)-one [ka] To a solution of ethyl 7-bromo-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (2.6 g, 7.7 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise a 3 M solution of methylmagnesium bromide in ethyl ether (3.1 mL, 9.3 mmol) at 0 °C. The resulting solution was stirred at room temperature for 4 h before being quenched with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was purified on silica gel by Combiflash eluting with ethyl acetate in petroleum ether (33%, v / v) to give the title compound (0.47 g, 20%). LC-MS (M+H) + =308.1,310.1.

[0105] Step 2: 3-acetyl-1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one [ka] The title compound (110 mg, 30%) was prepared from 3-acetyl-7-bromo-1-isopropylquinolin-4(1H)-one and bis(pinacolato)diboron in a manner similar to Step 6 of Example 1. LC-MS (M+H) + =356.0.

[0106] Step 3: 3-acetyl-7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (70 mg, 65%) was prepared from 3-acetyl-1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =360.1.

[0107] Step 4: 3-acetyl-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (5 mg, 6%) was prepared from 3-acetyl-7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride in a manner similar to Step 4 of Example 2. 1 H-NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.54 (d, J = 3.3 Hz, 1H), 8.49 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.2 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 5.23 - 5.05 (m, 1H), 4.95 (d, J = 5.3 Hz, 1H), 3.90 - 3.73 (m, 3H), 3.54 (s, 1H), 3.37 (s, 1H),3.06 (t, J = 10.4 Hz, 1H), 2.65 (s, 3H), 2.01 (s, 1H), 1.58 (d, J = 6.5 Hz, 6H), 1.61 - 1.41 (m, 1H).LC-MS(M+H) + =441.1.

[0108] Example 5: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3-(2-hydroxypropan-2-yl)-1-isopropylquinolin-4(1H)-one [ka] Step 1: 7-Bromo-3-(2-hydroxypropan-2-yl)-1-isopropylquinolin-4(1H)-one [ka] To a solution of ethyl 7-bromo-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (2.6 g, 7.7 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise a solution of 3 M methylmagnesium bromide solution in ethyl ether (3.1 mL, 9.3 mmol) at 0 °C. The resulting solution was then stirred at room temperature for 4 hours. The reaction was quenched with water (50 mL), and the aqueous layer was extracted with ethyl acetate (100 mL × 3). The combined organic phases were dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was purified on silica gel by Combiflash eluting with ethyl acetate in petroleum ether (33%, v / v) to give the title compound (0.65 g, 28%). LC-MS (M+H) + =324.1,326.1.

[0109] Step 2: 3-(2-hydroxypropan-2-yl)-1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one [ka] The title compound (110 mg, 34%) was prepared from 7-bromo-3-(2-hydroxypropan-2-yl)-1-isopropylquinolin-4(1H)-one and bis(pinacolato)diboron in a manner similar to Step 6 of Example 1. LC-MS (M+H) + =372.1.

[0110] Step 3: 7-(2-chloro-5-fluoropyrimidin-4-yl)-3-(2-hydroxypropan-2-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (110 mg, 34%) was prepared from 3-(2-hydroxypropan-2-yl)-1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one and 2,4-dichloro-5-fluoropyrimidine in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =376.1.

[0111] Step 4: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3-(2-hydroxypropan-2-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (7 mg, 7%) was prepared from 7-(2-chloro-5-fluoropyrimidin-4-yl)-3-(2-hydroxypropan-2-yl)-1-isopropylquinolin-4(1H)-one and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride in a manner similar to Step 4 of Example 2. 1H-NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 3.3 Hz, 1H), 8.42 (s, 1H), 8.38 (d, J = 8.5 Hz, 1H), 8.23 ​​(s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 5.44 (s, 1H), 5.14 - 5.02 (m, 1H), 4.95 (d, J = 5.2 Hz, 1H), 3.90 - 3.71 (m, 3H), 3.53 (s, 1H), 3.40 - 3.25 (m, 1H), 3.06 (t, J = 10.4 Hz, 1H), 2.01 (s, 1H), 1.63 - 1.43 (m, 13H).LC-MS(M+H) + =457.1.

[0112] Example 6: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-methylquinolin-4(1H)-one [ka] Step 1: (E)-1-(4-bromo-2-fluorophenyl)-3-(dimethylamino)but-2-en-1-one [ka] A mixture of 1-(4-bromo-2-fluorophenyl)ethanone (7 g, 32.25 mmol) in (1,1-dimethoxyethyl)dimethylamine (14.00 g, 105 mmol) was stirred at 120° C. under a nitrogen atmosphere for 1 hour before being cooled to room temperature. The solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (0% to 10% gradient, v / v) to give the title compound (7.2 g, 78%). LC-MS (M+H) + =286.0.

[0113] Step 2: (E)-1-(4-bromo-2-fluorophenyl)-3-(isopropylamino)but-2-en-1-one [ka] A mixture of (E)-1-(4-bromo-2-fluorophenyl)-3-(dimethylamino)but-2-en-1-one (7.2 g, 25.16 mmol) and isopropylamine (1.93 g, 32.71 mmol) in toluene (60 mL) was stirred at 110° C. under a nitrogen atmosphere for 14 hours before being cooled to room temperature. The solvent was removed under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (0% to 25% gradient, v / v) to give the title compound (5.6 g, 74%). LC-MS (M+H) + =300.0.

[0114] Step 3: 7-Bromo-1-isopropyl-2-methylquinolin-4(1H)-one [ka] A mixture of (E)-1-(4-bromo-2-fluorophenyl)-3-(isopropylamino)but-2-en-1-one (5.6 g, 18.66 mmol) and cesium carbonate (12.16 g, 37.31 mmol) in dimethylformamide (60 mL) was stirred at 100° C. under a nitrogen atmosphere for 14 hours before being cooled to room temperature. The reaction was then quenched by the addition of water (50 mL). The resulting solution was extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (0% to 20% gradient, v / v) to give the title compound (4 g, 76%). LC-MS (M+H) + =279.9.

[0115] Step 4: 1-Isopropyl-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one [ka] The title compound (200 mg, 34%) was prepared from 7-bromo-1-isopropyl-2-methylquinolin-4(1H)-one in a manner similar to that in Step 6 of Example 1. LC-MS (M+H) + =328.2.

[0116] Step 5: 7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-2-methylquinolin-4(1H)-one [ka] The title compound (50 mg, 25%) was prepared from 1-isopropyl-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one and 2,4-dichloro-5-fluoropyrimidine in a manner similar to that described in Step 7 of Example 1. LC-MS (M+H) + =332.0.

[0117] Step 6: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-methylquinolin-4(1H)-one [ka] The title compound (12 mg, 10%) was prepared from 7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-2-methylquinolin-4(1H)-one and (3S,4R)-4-aminooxan-3-ol hydrochloride in a manner similar to Step 4 of Example 2. 1H-NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 8.51 (d, J = 3.8 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 7.9 Hz, 1H), 6.12 (s, 1H), 5.17-5.04 (m, 1H), 4.97 (d, J = 5.3 Hz, 1H), 3.98-3.77 (m, 3H), 3.62-3.46 (m, 1H), 3.40-3.27 (m, 1H), 3.11-2.98 (m, 1H), 2.56 (s, 3H), 2.11-1.97 (m, 1H), 1.76-1.59 (m, 6H), 1.57-1.48 (m, 1H).LC-MS(M+H) + =413.2.

[0118] Example 7: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] Step 1: 1-(4-bromo-2-(isopropylamino)phenyl)ethan-1-one [ka] To a solution of 1-(4-bromo-2-fluorophenyl)ethanone (6 g, 27.645 mmol) and isopropylamine (2.45 g, 41.47 mmol) in dimethylacetamide (20 mL) was added potassium carbonate (5.73 g, 41.47 mmol). The resulting mixture was stirred at 130° C. under a nitrogen atmosphere for 3 hours. The reaction was then quenched by the addition of water (200 mL). The resulting solution was extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with dichloromethane in petroleum ether (0% to 50% gradient, v / v) to give the title compound (5.6 g, 79%). LC-MS (M+H) + =256.0.

[0119] Step 2: Ethyl 2-((2-acetyl-5-bromophenyl)(isopropyl)amino)-2-oxoacetate [ka] To a solution of 1-(4-bromo-2-(isopropylamino)phenyl)ethan-1-one (5.6 g, 22.1 mmol) in tetrahydrofuran (100 mL) was added dropwise ethyl chloroglyoxylate (4.82 g, 35.3 mmol) and triethylamine (6.14 mL, 44.16 mmol) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 1 h and at 40° C. for an additional 1 h under a nitrogen atmosphere before being cooled to room temperature. The mixture was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (0% to 50% gradient, v / v) to give the title compound (6.86 g, 87%). LC-MS (M+H) + =355.9.

[0120] Step 3: Ethyl 7-bromo-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylate [ka] To a solution of ethyl 2-((2-acetyl-5-bromophenyl)(isopropyl)amino)-2-oxoacetate (6.86 g, 19.3 mmol) in ethanol (100.0 mL) was added potassium carbonate (7.99 g, 57.8 mmol). The resulting mixture was stirred at 55° C. under a nitrogen atmosphere for 3 hours before being cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate (100 mL×3). The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (0% to 100% gradient, v / v) to give the title compound (3.8 g, 58%). LC-MS (M+H) + =337.9.

[0121] Step 4: 7-Bromo-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid [ka] The title compound (110 mg, 41%) was prepared from ethyl 7-bromo-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylate in a manner similar to Step 4 of Example 1. LC-MS (M+H) + =310.0.

[0122] Step 5: 7-Bromo-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] To a mixture of 7-bromo-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (110 mg, 0.36 mmol), N,N-diisopropylethylamine (138 mg, 1.06 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (203 mg, 0.53 mmol) in dimethylformamide (2 mL) was added methylamine (0.43 mL, 0.430 mmol, 1 M in tetrahydrofuran) dropwise at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 14 hours before being quenched by the addition of water (10 mL). The resulting solution was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with dichloromethane in petroleum ether (0% to 50% gradient, v / v) to give the title compound (85 mg, 74%). LC-MS (M+H) + =322.9.

[0123] Step 6: (1-Isopropyl-2-(methylcarbamoyl)-4-oxo-1,4-dihydroquinolin-7-yl)boronic acid [ka] The title compound (45 mg, 48%) was prepared from 7-bromo-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide in a manner similar to that in Step 6 of Example 1. LC-MS (M+H) + =289.2.

[0124] Step 7: 7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] The title compound (30 mg, 46%) was prepared from (1-isopropyl-2-(methylcarbamoyl)-4-oxo-1,4-dihydroquinolin-7-yl)boronic acid and 2,4-dichloro-5-fluoropyrimidine in a manner similar to that in Step 7 of Example 1. LC-MS (M+H) + =375.1.

[0125] Step 8: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] The title compound (1 mg, 4%) was prepared from 7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide and (3S,4R)-4-aminooxan-3-ol hydrochloride in a manner similar to that described in Step 4 of Example 2. 1 H-NMR (300 MHz, DMSO-d6) δ 9.03 (s, 1H), 8.53 (d, J = 3.8 Hz, 1H), 8.32 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 7.9 Hz, 1H), 6.08 (s, 1H), 4.97 (d, J = 5.1 Hz, 1H), 4.79-4.64 (m, 1H), 3.90-3.79 (m, 3H), 3.61-3.45 (m, 1H), 3.29 (s, 1H), 3.10-2.97 (m, 1H), 2.82 (d, J = 4.6 Hz, 3H), 2.06-1.96 (m, 1H), 1.76-1.67 (m, 6H), 1.56-1.44 (m, 1H).LC-MS(M+H) + =456.2.

[0126] Example 8: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methoxyquinolin-4(1H)-one [ka] Step 1: 7-Bromo-1-isopropyl-4-oxo-1,4-dihydroquinolin-3-yl acetate [ka] To a solution of 3-acetyl-7-bromo-1-isopropylquinolin-4(1H)-one (440 mg, 1.42 mmol) in anhydrous dichloromethane (30 mL) was slowly added 3-chloroperoxybenzoic acid (246 mg, 1.42 mmol) at 0 °C. The resulting solution was stirred at room temperature for 16 hours. The reaction was quenched with water (20 mL), and the aqueous layer was extracted with dichloromethane (30 mL × 3). The combined organic phases were dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was purified on silica gel by Combiflash eluting with ethyl acetate in petroleum ether (33%, v / v) to give the title compound (350 mg, 76%). LC-MS (M+H) + =324.1,326.1.

[0127] Step 2: 7-Bromo-3-hydroxy-1-isopropylquinolin-4(1H)-one [ka] A mixture of 7-bromo-1-isopropyl-4-oxo-1,4-dihydroquinolin-3-yl acetate (350 mg, 1.08 mmol) and potassium carbonate (298 mg, 2.16 mmol) in ethanol (20 mL) was stirred at 60° C. for 1 h before cooling to room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified on silica gel by Combiflash eluting with ethyl acetate in petroleum ether (50%, v / v) to give the title compound (240 mg, 79%). LC-MS (M+H) +=282.1,284.1.

[0128] Step 3: 7-Bromo-1-isopropyl-3-methoxyquinolin-4(1H)-one [ka] A mixture of 7-bromo-3-hydroxy-1-isopropylquinolin-4(1H)-one (120 mg, 0.43 mmol), iodomethane (121 mg, 0.85 mmol), and potassium carbonate (117 mg, 0.85 mmol) in dimethylformamide (10 mL) was stirred at room temperature for 1 hour. Water (20 mL) was added, and the aqueous layer was extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel by Combiflash eluting with ethyl acetate in petroleum ether (50%, v / v) to give the title compound (110 mg, 87%). LC-MS (M+H) + =296.1,298.1.

[0129] Step 4: 1-Isopropyl-3-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one [ka] The title compound (91 mg, 71%) was prepared from 7-bromo-1-isopropyl-3-methoxyquinolin-4(1H)-one and bis(pinacolato)diboron in a manner similar to Step 6 of Example 1. LC-MS (M+H) + =344.1.

[0130] Step 5: 7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-3-methoxyquinolin-4(1H)-one [ka] The title compound (60 mg, 50%) was prepared from 1-isopropyl-3-methoxy-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one and 2,4-dichloro-5-fluoropyrimidine in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =348.1.

[0131] Step 5: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methoxyquinolin-4(1H)-one [ka] The title compound (12 mg, 16%) was prepared from 7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-3-methoxyquinolin-4(1H)-one and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride in a manner similar to that described in Step 4 of Example 2. 1 H-NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 3.2 Hz, 1H), 8.43 (s, 1H), 8.39 (d, J = 8.5 Hz, 1H), 8.00 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 5.19 - 5.03 (m, 1H), 4.95 (d, J = 5.1 Hz, 1H), 3.83 (s, 3H), 3.92 - 3.72 (m, 3H), 3.54 (s, 1H), 3.37 - 3.35 (m, 1H), 3.06 (t, J = 10.4 Hz, 1H), 2.00 (brs, 1H), 1.53 (t, J = 10.8 Hz, 7H).LC-MS(M+H) + =429.1.

[0132] Example 9: 3-Cyclopropyl-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] Step 1: 3-bromo-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] To a mixture of 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one (100 mg, 0.25 mmol) in acetic acid (1 mL) was added N-bromosuccinimide (45 mg, 0.25 mmol). The mixture was stirred at room temperature for 14 hours before being diluted with saturated aqueous sodium bicarbonate solution (10 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC eluting with methanol in dichloromethane (5%, v / v) to give the title compound (100 mg, 83%). LC-MS (M+H) + =477.3,479.1.

[0133] Step 2: 3-Cyclopropyl-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] To a mixture of 3-bromo-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one (8 mg, 0.02 mmol) and cyclopropylboronic acid (10 mg, 0.11 mmol) in toluene (5 mL) and water (1 mL) was added tribasic potassium phosphate (30 mg, 0.14 mmol) and dichlorobis(tricyclohexylphosphine)palladium(II) (10 mg, 0.01 mmol). The mixture was stirred at 100° C. for 2 hours. The mixture was cooled to room temperature and diluted with water (10 ml). The aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC eluting with methanol in dichloromethane (5%, v / v) to give the title compound (4 mg, 45%). 1 H-NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 3.2 Hz, 1H), 8.46 - 8.31 (m, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.32 (d, J = 7.5 Hz, 1H), 5.08 - 4.98 (m, 1H), 4.96 (d, J = 4.9 Hz, 1H), 3.88 - 3.75 (m, 3H), 3.59 - 3.48 (m, 1H), 3.39 - 3.29 (m, 1H), 3.10 - 3.03 (m, 1H), 2.08 - 1.91 (m, 2H), 1.57 - 1.45 (m, 7H), 0.84 - 0.71 (m, 4H).LC-MS(M+H) + =439.5.

[0134] Example 10: 1-Cyclopentyl-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4(1H)-one [ka] Step 1: (E)-1-(4-bromo-2-fluorophenyl)-3-(cyclopentylamino)but-2-en-1-one [ka] To a solution of (E)-1-(4-bromo-2-fluorophenyl)-3-(dimethylamino)but-2-en-1-one (1.5 g, 5.3 mmol) in toluene (20 mL) was added cyclopentanamine (536 mg, 6.3 mmol). The reaction mixture was stirred at 120° C. for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product (1.5 g, 88%) was used in the next step without further purification. LC-MS (M+H) + =326.1

[0135] Step 2: 7-Bromo-1-cyclopentyl-2-methylquinolin-4(1H)-one [ka] To a solution of (E)-1-(4-bromo-2-fluorophenyl)-3-(cyclopentylamino)but-2-en-1-one (1.5 g, 4.6 mmol) in dimethylformamide (15 mL) was added cesium carbonate (3.0 g, 9.2 mmol). The mixture was stirred at 100° C. overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel by Combiflash eluting with ethyl acetate in petroleum ether (50%, v / v) to give the title compound (1.1 g, 76%). LC-MS (M+H) + =306.1.

[0136] Step 3: 1-Cyclopentyl-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one [ka] The title compound (358 mg, 100%) was prepared from 7-bromo-1-cyclopentyl-2-methylquinolin-4(1H)-one and bis(pinacolato)diboron in a manner similar to Step 6 of Example 1. LC-MS (M+H) + =354.0.

[0137] Step 4: 7-(2-chloro-5-fluoropyrimidin-4-yl)-1-cyclopentyl-2-methylquinolin-4(1H)-one [ka] The title compound (362.3 mg, 100%) was prepared from 2,4-dichloro-5-fluoropyrimidine and 1-cyclopentyl-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =358.0.

[0138] Step 5: 1:1-Cyclopentyl-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-methylquinolin-4(1H)-one [ka] The title compound (65 mg, 22%) was prepared from 7-(2-chloro-5-fluoropyrimidin-4-yl)-1-cyclopentyl-2-methylquinolin-4(1H)-one and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride in a manner similar to that described in Step 4 of Example 2. 1H-NMR (400 MHz, DMSO-d6) δ 8.51 (d, J = 3.1 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.19 (s, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 6.14 (s, 1H), 5.25 - 5.12 (m, 1H), 4.95 (d, J = 5.0 Hz, 1H), 3.83 (d, J = 5.1 Hz, 3H), 3.59 - 3.45 (m, 1H), 3.35 (s, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.58 LC-MS(M+H) + =439.0.

[0139] Example 11: 7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-methylquinolin-4(1H)-one [ka] Step 1: 7-(2,5-dichloropyrimidin-4-yl)-1-isopropyl-2-methylquinolin-4(1H)-one [ka] The title compound (313 mg, 99%) was prepared from 2,4,5-trichloropyrimidine and 1-isopropyl-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =348.

[0140] Step 2: 7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-methylquinolin-4(1H)-one [ka] The title compound (19 mg, 29%) was prepared from 7-(2,5-dichloropyrimidin-4-yl)-1-isopropyl-2-methylquinolin-4(1H)-one and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol in a manner similar to that described in Step 8 of Example 1. 1 H-NMR (400 MHz, DMSO-d6) δ:8.46 (s, 1H), 8.41 - 8.08 (m, 2H), 7.78-7.55 (m, 2H), 6.11 (s, 1H), 5.15 - 5.01 (m, 1H), 4.96 (d, J = 3.8 Hz, 1H), 3.94 - 3.74 (m, 3H), 3.60 - 3.44 (m, 1H), 3.30-3.23 (m, 1H), 3.10 - 2.92 (m, 1H), 2.55 (s, 3H), 2.02-1.90 (d, J = 9.9 Hz, 1H), 1.67 (d, J = 6.8 Hz, 6H), 1.56-1.48 (m, 1H).LC-MS(M+H) + =429.

[0141] Example 12: 3-chloro-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (30 mg, 69%) was prepared from 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and N-chlorosuccinimide in a manner similar to Step 1 of Example 9. 1H-NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.52 (d, J = 3.2 Hz, 1H), 8.48 (brs, 1H), 8.40 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 5.17 - 5.06 (m, 1H), 4.95 (d, J = 5.3 Hz, 1H), 3.89 - 3.76 (m, 3H), 3.59 - 3.48 (m, 1H), 3.39 - 3.30 (m, 1H), 3.10 - 3.01 (m, 1H), 2.07 - 1.96 (m, 1H), 1.60 - 1.44 (m, 7H).LC-MS(M+H) + =433.5.

[0142] Example 13: 7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-(morpholine-4-carbonyl)quinolin-4(1H)-one [ka] Step 1: Ethyl 1-isopropyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydroquinoline-2-carboxylate [ka] The title compound (4 g, 92%) was prepared from ethyl 7-bromo-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylate and bis(pinacolato)diboron in a manner similar to that described in Step 6 of Example 1. LC-MS (M+H) + =386.1.

[0143] Step 2: Ethyl 7-(2,5-dichloropyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylate [ka] The title compound (1.5 g, 51%) was prepared from ethyl 1-isopropyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydroquinoline-2-carboxylate and 2,4,5-trichloropyrimidine in a manner similar to that described in Step 7 of Example 1. LC-MS (M+H) + =406.0.

[0144] Step 3: Ethyl 7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylate [ka] The title compound (900 mg, 50%) was prepared from ethyl 7-(2,5-dichloropyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylate and (3S,4R)-4-aminooxan-3-ol hydrochloride in a manner similar to that described in Step 4 of Example 2. LC-MS (M+H) + =487.1.

[0145] Step 4: 7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid [ka] The title compound (800 mg, 95%) was prepared from ethyl 7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylate in a manner similar to that in Step 4 of Example 1. LC-MS (M+H) + =459.1.

[0146] Step 5: 7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-(morpholine-4-carbonyl)quinolin-4(1H)-one [ka] The title compound (30 mg, 51%) was prepared from 7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid and morpholine in a manner similar to that described in Step 5 of Example 7. 1 H-NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.37 - 8.17 (m, 2H), 7.92 - 7.64 (m, 1H), 7.58 (d, J = 7.7 Hz, 1H), 6.11 (s, 1H), 4.96 (d, J = 4.5 Hz, 1H), 4.69 - 4.57 (m, 1H), 3.95 - 3.56 (m, 8H), 3.48 - 3.40 (m, 4H), 3.31 - 3.18 (m, 1H), 3.07 - 2.94 (m, 1H), 2.01 - 1.90 (m, 1H), 1.80 - 1.62 (m, 6H), 1.58 - 1.45 (m, 1H).LC-MS(M+H) + =528.5.

[0147] Example 14: 7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] Step 1: 7-(2,5-dichloropyrimidin-4-yl)-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] The title compound (80 mg, 38%) was prepared from (1-isopropyl-2-(methylcarbamoyl)-4-oxo-1,4-dihydroquinolin-7-yl)boronic acid and 2,4,5-trichloropyrimidine in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =391.1.

[0148] Step 2: 7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] The title compound (6 mg, 6%) was prepared from 7-(2,5-dichloropyrimidin-4-yl)-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride in a manner similar to that described in Step 8 of Example 1. 1 H-NMR (400 MHz, DMSO-d6) δ 9.02 (s, 1H), 8.47 (s, 1H), 8.31 - 8.28 (m, 2H), 7.83 (brs, 1H), 7.57 (d, J = 7.5 Hz, 1H), 6.08 (s, 1H), 4.95 (d, J = 5.1 Hz, 1H), 4.82 - 4.62 (m, 1H), 3.82 (d, J = 5.5 Hz, 3H), 3.51 (s, 1H), 3.32 - 3.23 (m, 1H), 3.01 (s, 1H), 2.81 (d, J = 4.5 Hz, 3H), 1.94 (s, 1H), 1.67 (d, J = 6.9 Hz, 6H), 1.52 (s, 1H).LC-MS(M+H) + =472.1.

[0149] Example 15: 3-chloro-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-methylquinolin-4(1H)-one [ka] The title compound (12 mg, 28%) was prepared from 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-methylquinolin-4(1H)-one and N-chlorosuccinimide in a manner similar to Step 1 of Example 9. 1 H-NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.53 (d, J = 3.8 Hz, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.03-7.94 (m, 1H), 7.32 (d, J = 7.9 Hz, 1H), 5.28-5.12 (m, 1H), 4.96 (d, J = 5.2 Hz, 1H), 3.91-3.80 (m, 3H), 3.62-3.48 (m, 1H), 3.39-3.26 (m, 1H), 3.11-2.98 (m, 1H), 2.81 (s, 3H), 2.07-1.97 (m, 1H), 1.78-1.69 (m, 6H), 1.63-1.48 (m, 1H).LC-MS(M+H) + =447.2.

[0150] Example 16: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2,3-dimethylquinolin-4(1H)-one [ka] Step 1: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3-iodo-1-isopropyl-2-methylquinolin-4(1H)-one [ka] A mixture of 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-methylquinolin-4(1H)-one (143 mg, 0.345 mmol), iodine (88 mg, 0.345 mmol), and ammonium cerium(IV) nitrate (17 mg, 0.031 mmol) in acetonitrile (4 mL) was stirred at 70° C. under a nitrogen atmosphere for 2 hours before being cooled to room temperature. The solvent was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with methanol in ethyl acetate (0% to 25% gradient) to give the title compound (105 mg, 56%). LC-MS (M+H) + =539.0.

[0151] Step 2: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2,3-dimethylquinolin-4(1H)-one [ka] To a mixture of 7-(5-fluoro-2-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3-iodo-1-isopropyl-2-methylquinolin-4(1H)-one (86 mg, 0.159 mmol) and tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.016 mmol) in dimethylformamide (4 mL) was added 1 M trimethylaluminum solution in tetrahydrofuran (3.18 mL, 3.18 mmol) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 3 hours before being cooled to 0° C. and quenched by the addition of water (5 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with methanol in ethyl acetate (0% to 25% gradient, v / v). The residue was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase, acetonitrile in water (containing 10 mmol / L NH4HCO3 and 0.1% NH3.H2O), 20% to 50% gradient in 9 min; detector, UV 254 nm. The title compound (33 mg, 48%) was obtained. 1 H-NMR (300 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.51-8.45 (m, 1H), 8.34-8.25 (m, 1H), 7.91-7.82 (m, 1H), 7.31-7.22 (m, 1H), 5.15-5.09 (m, 1H), 4.99-4.91 (m, 1H), 3.87-3.81 (m, 3H), 3.55-3.49 (m, 1H), 3.35-3.29 (m, 1H), 3.09-2.96 (m, 1H), 2.49 (s, 3H), 2.08 (s, 3H), 2.02-1.96 (m, 1H), 1.71-1.65 (m, 6H), 1.56-1.46 (m, 1H).LC-MS(M+H) + =427.1.

[0152] Example 17: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(hydroxymethyl)-1-isopropylquinolin-4(1H)-one [ka] Step 1: 7-Bromo-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carbaldehyde [ka] A mixture of 7-bromo-1-isopropyl-2-methylquinolin-4(1H)-one (2.65 g, 9.46 mmol) and selenium dioxide (2.10 g, 18.9 mmol) in 1,4-dioxane (30 mL) was stirred at 100° C. under a nitrogen atmosphere for 16 hours before being cooled to room temperature. The resulting mixture was then quenched by the addition of saturated aqueous sodium bicarbonate solution (30 mL). The organic layer was extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (0% to 50% gradient, v / v) to give the title compound (1.2 g, 43%). LC-MS (M+H+CH4OH) + =325.9.

[0153] Step 2: 7-Bromo-2-(hydroxymethyl)-1-isopropylquinolin-4(1H)-one [ka] To a solution of 7-bromo-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carbaldehyde (900 mg, 3.06 mmol) in dichloromethane (10 mL) and methanol (20 mL) was added sodium borohydride (174 mg, 4.6 mmol) at 0° C. The mixture was stirred at 25° C. for 0.5 h before being concentrated. Saturated aqueous ammonium chloride solution (20 mL) was added. The aqueous layer was extracted with dichloromethane (30 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude title compound (900 mg) without further purification before the next step. LC-MS (M+H) + =296.

[0154] Step 3: 2-(hydroxymethyl)-1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one [ka] The title compound (3.5 g, 100%) was prepared from 7-bromo-2-(hydroxymethyl)-1-isopropylquinolin-4(1H)-one and bis(pinacolato)diboron in a manner similar to Step 6 of Example 1. LC-MS (M+H) + =344.1.

[0155] Step 4: 7-(2-chloro-5-fluoropyrimidin-4-yl)-2-(hydroxymethyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (3 g, 86%) was prepared from 2-(hydroxymethyl)-1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one and 2,4-dichloro-5-fluoropyrimidine in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =348.1.

[0156] Step 5: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(hydroxymethyl)-1-isopropylquinolin-4(1H)-one [ka] Under nitrogen, a mixture of 7-(2-chloro-5-fluoropyrimidin-4-yl)-2-(hydroxymethyl)-1-isopropylquinolin-4(1H)-one (0.5 g, 1.44 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol (0.51 g, 4.32 mmol), and N,N-diisopropylethylamine (0.19 g, 1.44 mmol) in dimethylacetamide (15 mL) was stirred at 120 °C overnight before being cooled to room temperature and quenched with water (30 mL). The aqueous layer was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel by Combiflash eluting with methanol in dichloromethane (5% gradient, v / v) to give the title compound (0.6 g, 97%) as an off-white solid. 1 H-NMR (400 MHz, DMSO-d6) δ 8.70 (brs, 1H), 8.51 (s, 1H), 8.31 (d, J = 8.6 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 6.28 (s, 1H), 5.86 (brs, 1H), 5.15 - 5.05 (m, 1H), 5.05 - 4.90 (m, 1H), 4.62 (s, 2H), 3.95 - 3.80 (m, 3H), 3.54 (s, 1H), 3.45 - 3.25 (m, 1H), 3.03 (t, J = 10.4 Hz, 1H), 2.07 - 1.97 (m, 1H), 1.76 - 1.68 (m, 6H), 1.57 - 1.45 (m, 1H).LC-MS(M+H) + =429.2.

[0157] Example 18: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-(((R)-2-methylmorpholino)methyl)quinolin-4(1H)-one [ka] Step 1: 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] To 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(hydroxymethyl)-1-isopropylquinolin-4(1H)-one (0.6 g, 1.4 mmol) in anhydrous dichloromethane (30 mL) was added thionyl chloride (0.34 g, 2.8 mmol) dropwise at 0° C. The resulting solution was then stirred at 0° C. for 1 hour. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (20 mL) and the aqueous phase was extracted with dichloromethane (30 mL×3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel by Combiflash eluting with methanol in dichloromethane (5% gradient, v / v) to give the title compound (0.47 g, 80%). LC-MS (M+H) + =447.1

[0158] Step 2: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-(((R)-2-methylmorpholino)methyl)quinolin-4(1H)-one [ka] Under nitrogen, a mixture of 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one (25 mg, 0.056 mmol), (R)-2-methylmorpholine (11 mg, 0.112 mmol), and diisopropylethylamine (22 mg, 0.168 mmol) in dimethylformamide (30 mL) was cooled to room temperature and stirred at 50° C. overnight before adding water (10 mL). The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC to give the title compound (14 mg, 49%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.52 (s, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.18 (s, 1H), 5.45 - 5.29 (m, 1H), 4.98 (s, 1H), 3.85 - 3.83 (m, 3H), 3.78 - 3.76 (m, 1H), 3.69 - 3.58 (m, 2H), 3.51 - 3.45 (m, 3H), 3.33 - 3.28 (m, 1H), 3.04 (t, J = 10.3 Hz, 1H), 2.75 (d, J = 10.8 Hz, 1H), 2.69 (d, J = 11.1 Hz, 1H), 2.16 (t, J = 10.7 Hz, 1H), 2.01 (d, J = 10.8 Hz, 1H), 1.86 (t, J = 10.3 Hz, 1H), 1.74 (s, 6H), 1.53 (d, J = 11.4 Hz, 1H), 1.04 (d, J = 5.8 Hz, 3H).LC-MS(M+H) + =513.1.

[0159] Example 19: 5-fluoro-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] Step 1: 1-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)ethan-1-one [ka] The title compound (700 mg, 100%) was prepared from 1-(4-bromo-2,6-difluorophenyl)ethan-1-one in a manner similar to Step 1 of Example 7. LC-MS (M+H) + =274.1,276.1.

[0160] Step 2: Ethyl 2-((2-acetyl-5-bromo-3-fluorophenyl)(isopropyl)amino)-2-oxoacetate [ka] The title compound (360 mg, 38%) was prepared from 1-(4-bromo-2-fluoro-6-(isopropylamino)phenyl)ethan-1-one in a manner similar to Step 2 of Example 7. LC-MS (M+H)+ = 374.1, 376.1.

[0161] Step 3: 7-Bromo-5-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylate methyl ester [ka] The title compound (200 mg, 51%) was prepared from ethyl 2-((2-acetyl-5-bromo-3-fluorophenyl)(isopropyl)amino)-2-oxoacetate in a manner similar to Step 3 of Example 7. LC-MS (M+H) + =342.1,344.1.

[0162] Step 4: Methyl 5-fluoro-1-isopropyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydroquinoline-2-carboxylate [ka] The title compound (226 mg, 100%) was prepared from methyl 7-bromo-5-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylate and bis(pinacolato)diboron in a manner similar to Step 6 of Example 1. LC-MS (M+H) + =390.1.

[0163] Step 5: Methyl 7-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylate [ka] The title compound (160 mg, 73%) was prepared from methyl 5-fluoro-1-isopropyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydroquinoline-2-carboxylate and 2,4-dichloro-5-fluoropyrimidine in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =394.1.

[0164] Step 6: methyl 5-fluoro-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylate [ka] The title compound (100 mg, 53%) was prepared from methyl 7-(2-chloro-5-fluoropyrimidin-4-yl)-5-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylate in a manner similar to Step 4 of Example 2. LC-MS (M+H) + =475.1.

[0165] Step 7: 5-fluoro-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid [ka] The title compound (80 mg, 87%) was prepared from methyl 5-fluoro-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylate in a manner similar to Step 4 of Example 1. LC-MS (M+H) + =461.1.

[0166] Step 8: 5-fluoro-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] The title compound (10 mg, 12%) was prepared from 5-fluoro-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid in a manner similar to that described in Step 5 of Example 7. 1H-NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 4.6 Hz, 1H), 8.55 (d, J = 3.6 Hz, 1H), 8.42 (s, 1H), 7.63 (d, J = 12.7 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 6.03 (s, 1H), 4.96 (d, J = 5.0 Hz, 1H), 4.74 - 4.62 (m, 1H), 3.96 - 3.76 (m, 3H), 3.52 (s, 1H), 3.35 - 3.20 (m, 1H), 3.06 - 3.01 (m, 1H), 2.80 (d, J = 4.5 Hz, 3H), 1.97 (s, 1H), 1.76 - 1.61 (m, 6H), 1.53 - 1.50 (m, 1H).LC-MS(M+H) + =474.2.

[0167] Example 20: 2-((dimethylamino)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (12 mg, 19%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and dimethylamine in a manner similar to Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.51 (d, J = 3.8 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.17 (s, 1H), 5.48-5.33 (m, 1H), 4.97 (d, J = 5.2 Hz, 1H), 3.90-3.79 (m, 3H), 3.57-3.47 (m, 3H), 3.38-3.28 (m, 1H), 3.10-2.97 (m, 1H), 2.25 (s, 6H), 2.06-1.96 (m, 1H)), 1.76-1.65 (m, 6H), 1.58-1.47 (m, 1H).LC-MS(M+H) + =456.2.

[0168] Example 21: 7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-N-(2-cyanoethyl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] The title compound (17 mg, 17%) was prepared from 7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid and 3-aminopropanenitrile in a manner similar to that in Step 5 of Example 7. 1H-NMR (400 MHz, DMSO-d6) δ 9.47 (t, J = 5.8 Hz, 1H), 8.48 (s, 1H), 8.35-8.21 (m, 2H), 7.88-7.54 (m, 2H), 6.13 (s, 1H), 4.96 (d, J = 5.3 Hz, 1H), 4.87-4.72 (m, 1H), 3.88-3.76 (m, 3H), 3.61-3.46 (m, 3H), 3.34-3.19 (m, 1H), 3.01 (s, 1H), 2.84 (t, J = 6.3 Hz, 2H), 2.01-1.90 (m, 1H), 1.73-1.64 (m, 6H), 1.57-1.46 (m, 1H).LC-MS(M+H) + =511.1.

[0169] Example 22: 7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-N-(2-hydroxy-2-methylpropyl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] The title compound (7 mg, 7%) was prepared from 7-(5-chloro-2-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid and 1-amino-2-methylpropan-2-ol in a manner similar to that described in Step 5 of Example 7. 1H-NMR (400 MHz, DMSO-d6) δ 9.02-8.95 (m, 1H), 8.47 (s, 1H), 8.40-8.13 (m, 2H), 7.93-7.40 (m, 2H), 6.10 (s, 1H), 4.99-4.93 (m, 1H), 4.85-4.73 (m, 1H), 4.60 (s, 1H), 3.86-3.76 (m, 3H), 3.54-3.49 (m, 1H), 3.28-3.23 (m, 3H), 3.04-2.99 (m, 1H), 1.96 (s, 1H), 1.72-1.66 (m, 6H), 1.56-1.48 (m, 1H), 1.16 (s, 6H).LC-MS(M+H) + =530.2.

[0170] Example 23: 3-chloro-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] The title compound (22 mg, 55%) was prepared from 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide and N-chlorosuccinimide in a manner similar to that described in Step 1 of Example 9. 1H-NMR (300 MHz, DMSO-d6) δ 9.22-9.14 (m, 1H), 8.72 (s, 1H), 8.54 (d, J = 3.8 Hz, 1H), 8.42 (d, J = 8.5 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 4.97 (d, J = 5.2 Hz, 1H), 4.81-4.68 (m, 1H), 3.90-3.79 (m, 3H), 3.61-3.45 (m, 1H), 3.38-3.26 (m, 1H), 3.09-2.97 (m, 1H), 2.87 (d, LC-MS(M+H) + =490.1.

[0171] Example 24: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-N,3-dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] Step 1: 1-(4-bromo-2-(isopropylamino)phenyl)propan-1-one [ka] The title compound (934 mg, 79%) was prepared from 1-(4-bromo-2-fluorophenyl)propan-1-one and isopropylamine in a manner similar to that in Step 1 of Example 7. LC-MS (M+H) + =270.0.

[0172] Step 2: Ethyl 2-((5-bromo-2-propionylphenyl)(isopropyl)amino)-2-oxoacetate [ka] The title compound (976 mg, 76%) was prepared from 1-(4-bromo-2-(isopropylamino)phenyl)propan-1-one and ethyl 2-chloro-2-oxoacetate in a manner similar to that in Step 2 of Example 7. LC-MS (M+H) + =370.0.

[0173] Step 3: Ethyl 7-bromo-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate [ka] The title compound (946 mg, 83%) was prepared from ethyl 2-((5-bromo-2-propionylphenyl)(isopropyl)amino)-2-oxoacetate in a manner similar to that in Step 3 of Example 7. LC-MS (M+H) + =352.0.

[0174] Step 4: Ethyl 1-isopropyl-3-methyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydroquinoline-2-carboxylate [ka] The title compound (646 mg, 63%) was prepared from ethyl 7-bromo-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate and bis(pinacolato)diboron in a manner similar to that described in Step 6 of Example 1. LC-MS (M+H) + =400.2.

[0175] Step 5: Ethyl 7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate [ka] The title compound (450 mg, 60%) was prepared from ethyl 1-isopropyl-3-methyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydroquinoline-2-carboxylate and 2,4-dichloro-5-fluoropyrimidine in a manner similar to that described in Step 7 of Example 1. LC-MS (M+H) + =404.2.

[0176] Step 6: Ethyl 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate [ka] The title compound (190 mg, 71%) was prepared from ethyl 7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate and (3S,4R)-4-aminooxan-3-ol hydrochloride in a manner similar to that described in Step 4 of Example 2. LC-MS (M+H) + =485.1.

[0177] Step 7: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid [ka] The title compound (95 mg, 50%) was prepared from ethyl 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate in a manner similar to that described in Step 4 of Example 1. LC-MS (M+H) + =457.2.

[0178] Step 8: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-N,3-dimethyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] The title compound (17 mg, 18%) was prepared from 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid and methylamine in a manner similar to that described in Step 5 of Example 7. 1 H-NMR (400 MHz, DMSO-d6) δ 9.06-8.98 (m, 1H), 8.67 (s, 1H), 8.52 (d, J = 3.7 Hz, 1H), 8.37 (d, J = 8.5 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 5.06-4.96 (m, 1H), 4.74-4.62 (m, 1H), 3.89-3.79 (m, 3H), 3.57-3.50 (m, 1H), 3.35-3.28 (m, 1H), 3.09-2.99 (m, 1H), 2.86 (d, J = LC-MS(M+H) + =470.3.

[0179] Example 25: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-(morpholinomethyl)quinolin-4(1H)-one [ka] The title compound (12 mg, 20%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and morpholine in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ:8.74 (s, 1H), 8.51 (d, J = 3.6 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 6.18 (s, 1H), 5.41-5.34 (m, 1H), 4.97 (d, J = 5.0 Hz, 1H), 3.94 - 3.77 (m, 3H), 3.65 (s, 2H), 3.62 - 3.46 (m, 5H), 3.36-3.31 (m, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.46 (s, 4H), 2.01 (d, J = 12.1 Hz, 1H), 1.74 (t, J = 6.5 Hz, 6H), 1.56-1.48 (m, 1H).LC-MS(M+H) + =498.

[0180] Example 26: 7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-(morpholinomethyl)quinolin-4(1H)-one [ka] Step 1: 7-Bromo-2-(hydroxymethyl)-1-isopropylquinolin-4(1H)-one [ka] To a solution of 7-bromo-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carbaldehyde (900 mg, 3.06 mmol) in dichloromethane (10 mL) and methanol (20 mL) was added sodium borohydride (174 mg, 4.6 mmol) at 0° C. The mixture was stirred at 25° C. for 0.5 h before being concentrated. Saturated aqueous ammonium chloride solution (20 mL) was added. The aqueous layer was extracted with dichloromethane (30 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give the crude title compound (900 mg) without further purification before the next step. LC-MS (M+H) + =296.

[0181] Step 2: 7-Bromo-2-(chloromethyl)-1-isopropylquinolin-4(1H)-one [ka] To a solution of 7-bromo-2-(hydroxymethyl)-1-isopropylquinolin-4(1H)-one (900 mg, 3.06 mmol) in dichloromethane (20 mL) was added thionyl chloride (728 mg, 6.12 mmol) at 0° C. The mixture was stirred under nitrogen atmosphere at 25° C. for 0.5 h. The solvent was removed under reduced pressure to give the crude title compound (900 mg). LC-MS (M+H) + =314.

[0182] Step 3: 7-Bromo-1-isopropyl-2-(morpholinomethyl)quinolin-4(1H)-one [ka] To a mixture of morpholine (83 mg, 0.952 mmol), potassium carbonate (132 mg, 0.952 mmol), and potassium iodide (53 mg, 0.317 mmol) in acetonitrile (3 mL) was added 7-bromo-2-(chloromethyl)-1-isopropylquinolin-4(1H)-one (100 mg, 0.317 mmol). The mixture was stirred at 25° C. under a nitrogen atmosphere for 3 hours. Water (10 mL) was added, and the aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with water (10 mL) and brine (10 mL), then dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel by Combiflash eluting with methanol in dichloromethane (5%, v / v) to give the title compound (120 mg, 99%). LC-MS (M+H) + =365.

[0183] Step 4: 1-Isopropyl-2-(morpholinomethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one [ka] The title compound (136 mg, 91%) was prepared from 7-bromo-1-isopropyl-2-(morpholinomethyl)quinolin-4(1H)-one and bis(pinacolato)diboron in a manner similar to Step 6 of Example 1. LC-MS (M+H) + =413.

[0184] Step 5: 7-(2,5-Dichloropyrimidin-4-yl)-1-isopropyl-2-(morpholinomethyl)quinolin-4(1H)-one [ka] The title compound (122 mg, 85%) was prepared from 2,4,5-trichloropyrimidine (73 mg, 0.396 mmol, 1.2 equiv.) and 1-isopropyl-2-(morpholinomethyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =433.

[0185] Step 6: 7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-(morpholinomethyl)quinolin-4(1H)-one [ka] The title compound (16.2 mg, 11%) was prepared from 7-(2,5-dichloropyrimidin-4-yl)-1-isopropyl-2-(morpholinomethyl)quinolin-4(1H)-one and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride in a manner similar to that described in Step 8 of Example 1. 1 H-NMR (400 MHz, DMSO-d6) δ:8.47 (s, 1H), 8.38-8.24 (m, 2H), 7.80-7.64 (m, 1H), 7.55 (d, J = 8.1 Hz, 1H), 6.18 (s, 1H), 5.39-5.32 (m, 1H), 4.95 (d, J = 5.1 Hz, 1H), 3.93 - 3.75 (m, 3H), 3.65 (s, 2H), 3.58 (s, 4H), 3.51-3.47 (m, 1H), 3.33 - 3.17 (m, 1H), 3.10 - 2.87 (m, 1H), 2.46 (s, 4H), 2.07 - 1.88 (m, 1H), 1.71 (d, J = 6.8 Hz, 6H), 1.58 - 1.40 (m, 1H).LC-MS(M+H) + =514.

[0186] Example 27: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((S)-3-fluoropyrrolidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (65 mg, 25%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (S)-3-fluoropyrrolidine hydrochloride in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.51 (d, J = 3.6 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.23 (s, 1H), 5.42 - 5.33 (m, 1H), 5.30 -5.16 (m, 1H), 4.96 (d, J = 4.7 Hz, 1H), 3.97 - 3.82 (m, 3H), 3.80 - 3.76 (m, 2H), 3.53 (s, 1H), 3.35 - 3.30 (m, 1H), 3.06 - 3.01 (m, 1H), 2.96 - 2.81 (m, 2H), 2.77 - 2.58 (m, 1H), 2.42 - 2.38 (m, 1H), 2.30 - 2.08 (m, 1H), 1.96 - 1.93 (m, 2H), 1.71 (t, J = 6.4 Hz, 6H), 1.63 - 1.41 (m, 1H).LC-MS(M+H) + =500.1.

[0187] Example 28: 2-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (6 mg, 11%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 8-oxa-3-azabicyclo[3.2.1]octane in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ:8.75 (s, 1H), 8.52 (d, J = 3.6 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 6.14 (s, 1H), 5.52 - 5.32 (m, 1H), 4.97 (d, J = 4.4 Hz, 1H), 4.25 (s, 2H), 4.02 - 3.78 (m, 3H), 3.53 (s, 3H), 3.36-3.31 (m, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.64 (d, J = 10.8 Hz, 2H), 2.33 (d, J = 10.6 Hz, 2H), 2.01 (d, J = 12.4 Hz, 1H), 1.90 - 1.65 (m, 10H), 1.62 - 1.44 (m, 1H).LC-MS(M+H) + =524.

[0188] Example 29: 2-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (9.6 mg, 12%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 3-oxa-8-azabicyclo[3.2.1]octane in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ:8.76 (s, 1H), 8.52 (d, J = 3.6 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.19 (s, 1H), 5.62 (dt, J = 14.1, 7.2 Hz, 1H), 4.97 (d, J = 4.5 Hz, 1H), 4.04 - 3.72 (m, 3H), 3.64 - 3.47 (m, 5H), 3.44 (d, J = 10.1Hz, 2H), 3.36-3.31 (m, 1H), 3.13 (s, 2H), 3.04 (t, J = 10.5 Hz, 1H), 1.97 (d, J = 23.6 Hz, 3H), 1.78 (t, J = 6.1 Hz, 8H), 1.58-1.48 (m, 1H).LC-MS(M+H) + =524.

[0189] Example 30: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-((3-hydroxyazetidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (20 mg, 62%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and azetidin-3-ol hydrochloride in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.50 - 8.36 (m, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 6.14 (s, 1H), 5.34 (d, J = 6.2 Hz, 1H), 5.30 - 5.13 (m, 1H), 4.92 (d, J = 5.1 Hz, 1H), 4.19 (dd, J = 12.1, 6.0 Hz, 1H), 3.93 - 3.74 (m, 3H), 3.68 (s, 2H), 3.53 - 3.50 (m, 3H), 3.34 - 3.18 (m, 1H), 2.99 (t, J = 10.4 Hz, 1H), 2.87 (t, J = 6.4 Hz, 2H), 1.96 (d, J = 12.7 Hz, 1H), 1.65 (t, J = 6.0 Hz, 6H), 1.47 (dd, J = 21.1, 11.3 Hz, 1H).LC-MS(M+H) + =484.1.

[0190] Example 31: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((3S,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (22 mg, 32%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (3R,4S)-4-fluoropyrrolidin-3-ol hydrochloride in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.51 (d, J = 3.5 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.23 (s, 1H), 5.27 (dt, J = 13.9, 6.8 Hz, 1H), 5.14 (s, 1H), 4.96 - 4.2 (m, 2H), 4.11 (d, J = 19.8 Hz, 1H), 3.86 - 3.77 (m, 5H), 3.53 (s, 1H), 3.35 - 3.30 (m, 1H), 3.19 - 2.98 (m, 2H), 2.91 (t, J = 7.9 Hz, 1H), 2.78 (dd, J = 28.7, 11.7 Hz, 1H), 2.55 (t, J = 8.3 Hz, 1H), 2.01 (d, J = 12.3 Hz, 1H), 1.70 (t, J = 6.3 Hz, 6H), 1.56 - 1.48 (m, 1H).LC-MS(M+H) + =516.3.

[0191] Example 32: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((3S,4S)-3-fluoro-4-hydroxypyrrolidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (37 mg, 55%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (3S,4S)-4-fluoropyrrolidin-3-ol hydrochloride in a manner similar to that in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.51 (d, J = 3.3 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.22 (s, 1H), 5.38 - 5.30 (m, 2H), 4.96 (d, J = 4.9 Hz, 1H), 4.84 (d, J = 55.7 Hz, 1H), 4.18 (d, J = 23.3 Hz, 1H), 3.97 - 3.78 (m, 4H), 3.72 (d, J = 13.6 Hz, 1H), 3.53 (s, 1H), 3.33 - 3.29 (m, 1H), 3.21 - 3.10 (m, 1H), 3.03 (t, J = 10.4 Hz, 1H), 2.96 - 2.69 (m, 2H), 2.28 (dd, J = 9.0, 5.6 Hz, 1H), 2.01 (d, J = 13.9 Hz, 1H), 1.70 (s, 6H), 1.53 - 1.52 (m, 1H).LC-MS(M+H) + =516.3.

[0192] Example 33: 2-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (14 mg, 14%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ:8.71 (s, 1H), 8.51 (d, J = 3.6 Hz, 1H), 8.30 (d, J = 8.5 Hz,1H), 7.93 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 6.25 (s, 1H), 5.41 (dt, J = 14.0, 6.9 Hz, 1H), 4.98 (s, 1H), 4.39 (s, 1H), 3.98 - 3.76 (m, 6H), 3.68-3.48 (m, 3H), 3.33 (t, J = 11.4 Hz, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.81 (d, J = 9.7 Hz, 1H), 2.55 (d, J = 7.2 Hz,1H), 2.06-1.96 (m, 1H), 1.83 (d, J = 9.5 Hz, 1H), 1.72 (d, J = 6.8 Hz, 6H), 1.62 (d, J = 9.4 Hz, 1H), 1.58-1.45 (m, 1H).LC-MS(M+H) + =510.

[0193] Example 34: 2-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (13 mg, 13%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ:8.71 (s, 1H), 8.51 (d, J = 3.6 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 6.25 (s, 1H), 5.41 (dt, J = 13.8, 6.8 Hz, 1H), 4.98 (s, 1H), 4.39 (s, 1H), 4.02 - 3.77 (m, 6H), 3.62 - 3.46 (m, 3H), 3.33 (t, J = 11.4 Hz, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.81 (d, J = 9.6 Hz, 1H), 2.55 (d, J = 9.1 Hz, 1H), 2.01 (d, J = 12.8 Hz, 1H), 1.83 (d, J = 9.5 Hz, 1H), 1.78 - 1.65 (m, 6H), 1.62 (d, J = 9.4 Hz, 1H), 1.59-1.45 (m, 1H).LC-MS(M+H) + =510.

[0194] Example 35: 2-(aminomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (5 mg, 46%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and ammonia in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ:8.69 (s, 1H), 8.51 (d, J = 3.6 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 6.30 (s, 1H), 5.26 (dt, J = 14.2, 7.0 Hz, 1H), 4.95 (s, 1H), 3.97 - 3.77 (m, 5H), 3.58-3.48 (m, 1H), 3.32 (t, J = 11.5 Hz, 1H), 3.03 (t, J = 10.4 Hz, 1H), 2.01 (d, J = 13.9 Hz, 1H), 1.72 (t, J = 5.8 Hz, 6H), 1.59-1.44 (m, 1H).LC-MS(M+H) + =428.

[0195] Example 36: 5-chloro-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] Step 1: 1-(4-bromo-2-chloro-6-(isopropylamino)phenyl)ethan-1-one [ka] The title compound (200 mg, 85%) was prepared from 1-(4-bromo-2-chloro-6-fluorophenyl)ethan-1-one in a manner similar to Step 1 of Example 7. LC-MS (M+H) +=290.0,292.0.

[0196] Step 2: Ethyl 2-((2-acetyl-5-bromo-3-chlorophenyl)(isopropyl)amino)-2-oxoacetate [ka] The title compound (200 mg, 88%) was prepared from 1-(4-bromo-2-chloro-6-(isopropylamino)phenyl)ethan-1-one in a manner similar to Step 2 of Example 7. LC-MS (M+H) + =390.0,392.0.

[0197] Step 3: 7-Bromo-5-chloro-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylate methyl ester [ka] The title compound (150 mg, 92%) was prepared from ethyl 2-((2-acetyl-5-bromo-3-chlorophenyl)(isopropyl)amino)-2-oxoacetate in a manner similar to Step 3 of Example 7. LC-MS (M+H) + =358.0,360.0.

[0198] Step 4: 7-Bromo-5-chloro-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid [ka] The title compound (120 mg, 78%) was prepared from methyl 7-bromo-5-chloro-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylate in a manner similar to Step 4 of Example 1. LC-MS (M+H) + =344.0,346.0.

[0199] Step 5: 7-Bromo-5-chloro-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] The title compound (100 mg, 81%) was prepared from 7-bromo-5-chloro-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid and methylamine in a manner similar to that described in Step 5 of Example 7. LC-MS (M+H) + =357.0,359.0.

[0200] Step 6: 5-chloro-1-isopropyl-N-methyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydroquinoline-2-carboxamide [ka] The title compound (100 mg, 88%) was prepared from 7-bromo-5-chloro-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide and bis(pinacolato)diboron in a manner similar to Step 6 of Example 1. LC-MS (M+H) + =405.1.

[0201] Step 7: 5-chloro-7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] The title compound (60 mg, 59%) was prepared from 5-chloro-1-isopropyl-N-methyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydroquinoline-2-carboxamide and 2,4-dichloro-5-fluoropyrimidine in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =409.1.

[0202] Step 8: 5-chloro-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide [ka] The title compound (5 mg, 8%) was prepared from 5-chloro-7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-N-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride in a manner similar to Step 4 of Example 2. 1 H-NMR (400 MHz, DMSO-d6) δ 9.02 (d, J = 4.6 Hz, 1H), 8.55 (d, J = 3.2 Hz, 2H), 7.92 (s, 1H), 7.40 (d, J = 8.1 Hz, 1H), 6.09 (s, 1H), 4.96 (d, J = 4.7 Hz, 1H), 4.75 - 4.57 (m, 1H), 3.95 - 3.77 (m, 3H), 3.52 (s, 1H), 3.31 - 3.26 (m, 1H), 3.03 (t, J = 10.6 Hz, 1H), 2.80 (d, J = 4.4 Hz, 3H), 1.97 (s, 1H), 1.68 (d, J = 3.6 Hz, 6H), 1.54 - 1.51 (m, 1H).LC-MS(M+H) + =490.1.

[0203] Example 37: 1-((7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)piperidine-4-carbonitrile [ka] Step 1: 7-Bromo-2-(1,3-dioxolan-2-yl)-1-isopropylquinolin-4(1H)-one [ka] A mixture of 7-bromo-1-isopropyl-4-oxoquinoline-2-carbaldehyde (1.0 g, 3.40 mmol) and ethylene glycol (740 mg, 11.900 mmol) in toluene (10 mL) was stirred at 135° C. under a nitrogen atmosphere for 12 hours before being cooled to room temperature and quenched by the addition of water (20 mL). The aqueous solution was extracted with ethyl acetate (20 mL×3). The combined organic phases were washed with brine, dried over sodium sulfate, and filtered. The solvent was concentrated under reduced pressure to give the title compound (550 mg, 47%). LC-MS (M+H) + =337.9.

[0204] Step 2: 2-(1,3-dioxolan-2-yl)-1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one [ka] The title compound (380 mg, 60%) was prepared from 7-bromo-2-(1,3-dioxolan-2-yl)-1-isopropylquinolin-4(1H)-one and bis(pinacolato)diboron in a manner similar to that described in Step 6 of Example 1. LC-MS (M+H) + =386.1.

[0205] Step 3: 7-(2-chloro-5-fluoropyrimidin-4-yl)-2-(1,3-dioxolan-2-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (210 mg, 54%) was prepared from 2-(1,3-dioxolan-2-yl)-1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one and 2,4-dichloro-5-fluoropyrimidine in a manner similar to that described in Step 7 of Example 1. LC-MS (M+H) + =390.0.

[0206] Step 4: 2-(1,3-dioxolan-2-yl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (120 mg, 47%) was prepared from 7-(2-chloro-5-fluoropyrimidin-4-yl)-2-(1,3-dioxolan-2-yl)-1-isopropylquinolin-4(1H)-one and (3S,4R)-4-aminooxan-3-ol hydrochloride in a manner similar to that described in Step 4 of Example 2. LC-MS (M+H) + =471.1.

[0207] Step 5: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carbaldehyde [ka] A mixture of 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-2-carbaldehyde (120 mg, 0.270 mmol) and iron(III) p-toluenesulfonate (2.90 g, 5.100 mmol) in water (5 mL) was stirred at 100° C. under a nitrogen atmosphere for 16 hours before being cooled to room temperature and quenched by the addition of water (10 mL). The resulting aqueous layer was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with methanol in dichloromethane (0% to 15% gradient, v / v) to give the title compound (46 mg, 42%). LC-MS (M+H+CH4OH) + =459.1.

[0208] Step 6: 1-((7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)piperidine-4-carbonitrile To a mixture of 7-(5-fluoro-2-{[(3S,4R)-3-hydroxyoxan-4-yl]amino}pyrimidin-4-yl)-1-isopropyl-4-oxoquinoline-2-carbaldehyde (15 mg, 0.036 mmol) in dichloromethane (2 mL) was added piperidine-4-carbonitrile (14 mg, 0.129 mmol) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. To the above mixture was added sodium triacetoxyborohydride (11 mg, 0.054 mmol) in small portions at room temperature. The resulting mixture was stirred at room temperature for an additional 16 hours before being concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase, acetonitrile in water (containing 10 mmol / L NH4HCO3 and 0.1% NH3.H2O), 22% to 50% gradient in 8 min; detector, UV 254 nm. The title compound (12 mg, 19%) was obtained. 1 H-NMR (300 MHz, DMSO-d6) δ 8.75 (brs, 1H), 8.52 (d, J = 3.8 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.98-7.91 (m, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.19 (s, 1H), 5.37-5.26 (m, 1H), 4.99 (d, J = 5.2 Hz, 1H), 3.93-3.80 (m, 3H), 3.65 (s, 2H), 3.60-3.49 (m, 1H), 3.39-3.28 (m, 1H), 3.10-3.00 (m, 1H), 2.94-2.89 (m, 1H), 2.66-2.61 (m, 2H), 2.41-2.36 (m, 2H), 2.06-1.98 (m, 1H), 1.90-1.84 (m, 2H), 1.77-1.66 (m, 8H), 1.60-1.46 (m, 1H).LC-MS(M+H) + =521.3.

[0209] Example 38: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-((4-hydroxy-4-methylpiperidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (7 mg, 19%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 4-methylpiperidin-4-ol in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ 8.74 (brs, 1H), 8.52 (d, J = 3.8 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.97-7.91 (m, 1H), 7.33 (d, J = 7.9 Hz, 1H), 6.17 (s, 1H), 5.44-5.32 (m, 1H), 4.98 (d, J = 5.3 Hz, 1H), 4.19 (s, 1H), 3.90-3.81 (m, 3H), 3.62 (s, 2H), 3.60-3.48 (m, 1H), 3.39-3.28 (m, 1H), 3.09-2.99 (m, 1H), 2.48-2.44 (m, 4H), 2.06-1.98 (m, 1H), 1.77-1.68 (m, 6H), 1.57-1.40 (m, 5H), 1.11 (s, 3H).LC-MS(M+H) + =526.3.

[0210] Example 39: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-((4-hydroxypiperidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (15 mg, 45%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and piperidin-4-ol in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (300 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.50 (d, J = 3.8 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 7.97-7.88 (m, 1H), 7.29 (d, J = 7.9 Hz, 1H), 6.14 (s, 1H), 5.42-5.27 (m, 1H), 4.95 (d, J = 5.2 Hz, 1H), 4.58 (d, J = 4.1 Hz, 1H), 3.90-3.78 (m, 3H), 3.64-3.45 (m, 4H), 3.39-3.25 (m, 1H), 3.09-2.96 (m, 1H), 2.72 (d, J = 10.9 Hz, 2H), 2.20-2.08 (m, 2H), 2.06-1.95 (m, 1H), 1.72 (s, 8H), 1.57-1.33 (m, 3H).LC-MS(M+H) + =512.3.

[0211] Example 40: 3-Cyclopropyl-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-methylquinolin-4(1H)-one [ka] Step 1: 3-bromo-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-methylquinolin-4(1H)-one [ka] The title compound (1.2 g, 84%) was prepared from 7-(5-fluoro-2-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-methylquinolin-4(1H)-one (1.2 g, 2.9 mmol) in a manner similar to that in Step 1 of Example 9. LC-MS (M+H) + =491.1,493.1.

[0212] Step 2: 3-Cyclopropyl-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-methylquinolin-4(1H)-one [ka] The title compound (20 mg, 46%) was prepared from 3-bromo-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-methylquinolin-4(1H)-one and cyclopropylboronic acid in a manner similar to that described in Step 7 of Example 1. 1 H-NMR (400 MHz, DMSO-d6) δ 8.59 (brs, 1H), 8.50 (d, J = 3.6 Hz, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.3 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 5.18 - 5.08 (m, 1H), 4.97 (d, J = 4.6 Hz, 1H), 3.94 - 3.78 (m, 3H), 3.58 - 3.48 (m, 1H), 3.37 - 3.27 (m, 1H), 3.03 (t, J = 10.5 Hz, 1H), 2.74 (s, 3H), 2.06 - 1.96 (m, 1H), 1.73 - 1.65 (m, 6H), 1.57 - 1.44 (m, 2H), 0.96 - 0.89 (m, 2H), 0.55 - 0.48 (m, 2H).LC-MS(M+H) + =453.2.

[0213] Example 41: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-(((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)quinolin-4(1H)-one [ka] The title compound (12 mg, 41%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (3aR,6aS)-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.52 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 6.19 (s, 1H), 5.62 - 5.30 (m, 1H), 4.97 (d, J = 3.9 Hz, 1H), 4.00 - 3.77 (m, 5H), 3.69 (s, 2H), 3.53 (s, 1H), 3.33 (s, 5H), 3.04 (t, J = 10.5 Hz, 1H), 2.73 (s, 2H), 2.56 (d, J = 9.0 Hz, 2H), 2.01 (d, J = 11.5 Hz, 1H), 1.72 (t, J = 6.4 Hz, 6H), 1.52 (d, J = 12.1 Hz, 1H).LC-MS(M+H) + =524.0.

[0214] Example 42: 2-((3,3-dimethylpyrrolidin-1-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (9 mg, 32%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 3,3-dimethylpyrrolidine in a manner similar to that in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.52 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 6.18 (s, 1H), 5.62 - 5.35 (m, 1H), 4.97 (s, 1H), 3.84 (d, J = 10.8 Hz, 3H), 3.70 (s, 2H), 3.53 (s, 1H), 3.43 - 3.30 (m, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.64 (s, 2H), 2.34 (s, 2H), 2.01 (d, J = 11.1 Hz, 1H), 1.73 (t, J = 6.1 Hz, 6H), 1.65 - 1.45 (m, 3H), 1.06 (s, 6H).LC-MS(M+H) + =510.0.

[0215] Example 43: 2-((2-Azabicyclo[2.1.1]hexan-2-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (6 mg, 22%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 2-azabicyclo[2.1.1]hexane in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.52 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 6.26 (s, 1H), 5.57 (s, 1H), 4.97 (s, 1H), 3.85 (s, 5H), 3.53 (s, 1H), 3.43 (d, J = 5.3 Hz, 1H), 3.34 (s, 1H), 3.04 (s, 1H), 2.74 (s, 1H), 2.66 (s, 2H), 2.00 (s, 1H), 1.71 (d, J = 14.9 Hz, 8H), 1.52 (d, J = 11.7 Hz, 1H), 1.45 (s, 2H).LC-MS(M+H) + =494.0.

[0216] Example 44: 2-((1-oxa-8-azaspiro[4.5]decan-8-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (7 mg, 22%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 1-oxa-8-azaspiro[4.5]decane in a manner similar to that described in Step 2 of Example 18.1 H-NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.58 (s, 1H), 8.37 (d, J = 7.9 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 6.23 (s, 1H), 5.44 (s, 1H), 5.04 (s, 1H), 3.92 (s, 3H), 3.76 (s, 2H), 3.68 (s, 2H), 3.65 - 3.45 (m, 3H), 3.10 (t, J = 10.1 Hz, 1H), 2.50 (s, 2H), 2.06 (s, 1H), 1.90 (s, 3H), 1.79 (s, 6H), 1.71 (s, 2H), 1.62 (s, 5H).LC-MS(M+H) + =552.0.

[0217] Example 45: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((3R,4S)-3-fluoro-4-hydroxypyrrolidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (12 mg, 41%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (3S,4R)-4-fluoropyrrolidin-3-ol hydrochloride in a manner similar to that in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.52 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 7.3 Hz, 1H), 6.23 (s, 1H), 5.38 - 5.20 (m, 1H), 5.14 (d, J = 5.8 Hz, 1H), 4.96 (s, 1H), 4.89 (d, J = 57.1 Hz, 1H), 4.13 - 4.09 (m, 1H), 3.85 - 3.77 (m, 5H), 3.53 (s, 1H), 3.30 (s, 1H), 3.16 - 3.01 (m, 2H), 2.91 (t, J = 8.3 Hz, 1H), 2.78 (dd, J = 28.5, 11.3 Hz, 1H), 2.57 - 2.55 (m, 1H), 1.99 (s, 1H), 1.70 (s, 6H), 1.54 - 1.51 (m, 1H).LC-MS(M+H) + =516.1.

[0218] Example 46: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((3R,4R)-3-fluoro-4-hydroxypyrrolidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (15 mg, 52%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (3R,4R)-4-fluoropyrrolidin-3-ol hydrochloride in a manner similar to that in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.52 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.22 (s, 1H), 5.39 - 5.30 (m, 2H), 4.96 (d, J = 4.5 Hz, 1H), 4.84 (d, J = 54.3 Hz, 1H), 4.18 (d, J = 25.1 Hz, 1H), 3.85 - 3.71 (m, 5H), 3.53 (s, 1H), 3.29 (s, 1H), 3.20 - 3.11 (m, 1H), 3.03 (t, J = 10.3 Hz, 1H), 2.93 - 2.77 (m, 2H), 2.28 (s, 1H), 2.00 (s, 1H), 1.70 (t, J = 7.9 Hz, 6H), 1.53 - 1.52 (m, 1H).LC-MS(M+H) + =516.1.

[0219] Example 47: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-((isopropylamino)methyl)quinolin-4(1H)-one [ka] The title compound (10 mg, 38%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and propan-2-amine in a manner similar to that in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.52 (s, 1H), 8.30 (d, J = 8.5 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.24 (s, 1H), 5.56 - 5.35 (m, 1H), 4.97 (s, 1H), 3.82 (s, 5H), 3.54 (s, 1H), 3.32 - 3.22 (m, 2H), 3.04 (t, J = 10.3 Hz, 1H), 2.78 (t, J = 6.1 Hz, 1H), 2.01 (d, J = 10.3 Hz, 1H), 1.72 (s, 6H), 1.54 - 1.51 (m, 1H), 1.05 (d, J = 6.0 Hz, 6H).LC-MS(M+H) + =470.1.

[0220] Example 48: 2-((cyclopropylamino)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (10 mg, 38%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and cyclopropanamine in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.51 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.24 (s, 1H), 5.42 - 5.20 (m, 1H), 4.97 (s, 1H), 3.98 - 3.73 (m, 5H), 3.53 (s, 1H), 3.31 - 3.24 (m, 1H), 3.03 (t, J = 10.3 Hz, 1H), 2.17 (s, 1H), 1.99 (s, 1H), 1.69 (t, J = 6.0 Hz, 6H), 1.54 - 1.51 (m, 1H), 0.39 (d, J = 5.4 Hz, 2H), 0.25 (s, 2H).LC-MS(M+H) + =468.1.

[0221] Example 49: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((R)-3-fluoropyrrolidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (65 mg, 25%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (R)-3-fluoropyrrolidine hydrochloride in a manner similar to Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.51 (d, J = 3.6 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.23 (s, 1H), 5.42 - 5.33 (m, 1H), 5.30 -5.16 (m, 1H), 4.96 (d, J = 4.7 Hz, 1H), 3.97 - 3.82 (m, 3H), 3.80 - 3.76 (m, 2H), 3.53 (s, 1H), 3.35 - 3.30 (m, 1H), 3.06 - 3.01 (m, 1H), 2.96 - 2.81 (m, 2H), 2.77 - 2.58 (m, 1H), 2.42 - 2.38 (m, 1H), 2.30 - 2.08 (m, 1H), 1.96 - 1.93 (m, 2H), 1.71 (t, J = 6.4 Hz, 6H), 1.63 - 1.41 (m, 1H).LC-MS(M+H) + =500.1.

[0222] Example 50: N-((7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)acetamide [ka] Step 1: 2-(aminomethyl)-7-bromo-1-isopropylquinolin-4(1H)-one [ka] A mixture of 7-bromo-2-(chloromethyl)-1-isopropylquinolin-4(1H)-one (200 mg, 0.634 mmol) and ammonia (10 mL, 7N in methanol) was stirred in a sealed tube at 40° C. for 18 hours before being cooled to room temperature. The solvent was removed under reduced pressure and the residue was suspended in dichloromethane (20 mL) before being filtered. The filtrate was concentrated in vacuo to give the title compound (190 mg, 99%). LC-MS (M+H) + =295.

[0223] Step 2: tert-Butyl ((7-bromo-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)carbamate [ka] A solution of 2-(aminomethyl)-7-bromo-1-isopropylquinolin-4(1H)-one (190 mg, 0.644 mmol), di-tert-butyl dicarbonate (327 mg, 0.966 mmol), and triethylamine (194 mg, 1.92 mmol) in dichloromethane (15 mL) was stirred at 25° C. for 18 hours. The solvent was removed under reduced pressure. The residue was purified on silica gel by Combiflash eluting with methanol in dichloromethane (5% gradient, v / v) to give the title compound (190 mg, 75%). LC-MS (M+H) + =395.

[0224] Step 3: tert-butyl ((1-isopropyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydroquinolin-2-yl)methyl)carbamate [ka] The title compound (213 mg, 100%) was prepared from tert-butyl ((7-bromo-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)carbamate and bis(pinacolato)diboron in a manner similar to Step 6 of Example 1. LC-MS (M+H) +=443.

[0225] Step 4: tert-Butyl ((7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)carbamate [ka] The title compound (190 mg, 88%) was prepared from tert-butyl ((1-isopropyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydroquinolin-2-yl)methyl)carbamate and 2,4-dichloro-5-fluoropyrimidine in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =447.0.

[0226] Step 5: 2-(aminomethyl)-7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] A solution of tert-butyl ((7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)carbamate (190 mg, 0.55 mmol) in trifluoroacetic acid (2 mL) and dichloromethane (6 mL) was stirred at 25° C. for 3 hours. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (10 mL) and saturated aqueous sodium bicarbonate solution (2 mL) was added. The aqueous layer was extracted with dichloromethane (10 mL×2). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel by Combiflash eluting with methanol in dichloromethane (10%, v / v) to give the title compound (120 mg, 89%). LC-MS (M+H) + =347.

[0227] Step 6: N-((7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)acetamide [ka] To a solution of 2-(aminomethyl)-7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one (112 mg, 0.346 mmol) in tetrahydrofuran (5 mL) was added pyridine (55 mg, 0.69 mmol), followed by acetic anhydride (53 mg, 0.52 mmol). The reaction was stirred at 25° C. for 1 hour. The solvent was removed under reduced pressure. A saturated aqueous solution of sodium bicarbonate (2 mL) was added, and the aqueous solution was extracted with dichloromethane (10 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel by Combiflash eluting with methanol in dichloromethane (10%, v / v) to give the title compound (112 mg, 83%). LC-MS (M+H) + =389.

[0228] Step 7: N-((7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)acetamide [ka] The title compound (23 mg, 32%) was prepared from N-((7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)acetamide and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol in a manner similar to that described in Step 8 of Example 1. 1H-NMR (400 MHz, DMSO-d6) δ:8.69 (s, 1H), 8.57 (s, 1H), 8.52 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 6.19 (s, 1H), 5.04 - 4.84 (m, 2H), 4.48 (s, 2H), 3.97-3.77 (m, 3H), 3.53 (s, 1H), 3.30 (s, 1H), 3.04 (t, J = 10.2 Hz, 1H), 2.01 (d, J = 13.3 Hz, 1H), 1.94 (s, 3H), 1.70 (s, 6H), 1.52 (q, J = 12.9 Hz, 1H).LC-MS(M+H) + =470.

[0229] Example 51 and Example 52: (R)-7-((7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)-2-methyl-2,7-diazaspiro[4.5]decan-1-one and (S)-7-((7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)-2-methyl-2,7-diazaspiro[4.5]decan-1-one [ka] The mixture of Example 51 and Example 52 was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and racemic 2-methyl-2,7-diazaspiro[4.5]decan-1-one in a manner similar to that of Step 2 of Example 18. Examples 51 and 52 were separated by chiral preparative HPLC using 50% mobile phase A and 50% mobile phase B. Chiral HPLC conditions: Cellulose-C column, 20.0 mm x 250 mm, 5 um. Mobile phase A: hexane, mobile phase B: ethanol containing 0.2% 2M NH3 in methanol, 18 mL / min in 13 min.

[0230] Example 51 (12 mg, 60%). RT=6.5 min. 1 H-NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.52 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 6.15 (s, 1H), 5.41 (m, 1H), 4.97 (s, 1H), 3.86 (m, 3H), 3.66 - 3.63 (m, 1H), 3.51 - 3.48 (m, 2H), 3.32 - 3.29 (m, 1H), 3.23 (m, 2H), 3.04 (m, 1H), 2.81 (m, 1H), 2.70 (s, 3H), 2.63 - 2.60 (m, 1H), 2.17 - 2.14 (m, 1H), 2.12 - 1.93 (m, 3H), 1.90 (brs, 1H), 1.73 (s, 6H), 1.64 - 1.34 (m, 5H).LC-MS(M+H) + =579.1.

[0231] Example 52 (12 mg, 60%). RT=10.5 min. 1H-NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.52 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 6.16 (s, 1H), 5.41 (m, 1H), 4.97 (s, 1H), 3.84 (m, 3H), 3.66- 3.63 (m, 1H), 3.51 - 3.47 (m, 2H), 3.30 (s, 1H), 3.24 (m, 2H), 3.04 (t, J = 10.7 Hz, 1H), 2.83 (d, J = 10.0 Hz, 1H), 2.70 (s, 3H), 2.62 (d, J = 10.7 Hz, 1H), 2.16 (d, J = 10.9 Hz, 1H), 2.10 - 1.84 (m, 4H), 1.73 (t, J = 6.6 Hz, 6H), 1.66 - 1.33 (m, 5H).LC-MS(M+H) + =579.1.

[0232] Example 53: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-(((S)-3-methylmorpholino)methyl)quinolin-4(1H)-one [ka] The title compound (12 mg, 33%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (3S)-3-methylmorpholine in a manner similar to that described in Step 2 of Example 18. 1H-NMR (300 MHz, DMSO-d6) δ 8.73 (brs, 1H), 8.52 (d, J = 3.8 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.22 (s, 1H), 5.48 (s, 1H), 4.97 (d, J = 5.1 Hz, 1H), 4.32-4.22 (m, 1H), 3.99-3.79 (m, 3H), 3.72-3.59 (m, 2H), 3.55-3.44 (m, 2H), 3.38-3.34 (m, 1H), 3.27-3.17 (m, 2H), 3.11-2.98 (m, 1H), 2.67-2.51 (m, 2H), 2.29-2.23 (m, 1H), 2.07-1.96 (m, 1H), 1.79-1.69 (m, 6H), 1.58-1.47 (m, 1H), 1.08 (d, J = 6.2 Hz, 3H).LC-MS(M+H) + =512.2.

[0233] Example 54: 2-((4,4-difluoropiperidin-1-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (14 mg, 35%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 4,4-difluoropiperidine in a manner similar to that in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.76 (brs, 1H), 8.52 (d, J = 3.8 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.98-7.91 (m, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.20 (s, 1H), 5.39-5.28 (m, 1H), 4.98 (d, J = 5.2 Hz, 1H), 3.97-3.81 (m, 3H), 3.72 (s, 2H), 3.60-3.48 (m, 1H), 3.39-3.28 (m, 1H), 3.09-2.99 (m, 1H), 2.63-2.58 (m, 4H), 2.03-1.93 (m, 5H), 1.78-1.70 (m, 6H), 1.60-1.45 (m, 1H).LC-MS(M+H) + =532.3.

[0234] Example 55: 2-ethyl-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] Step 1: N-(2-acetyl-5-bromophenyl)-N-isopropylpropionamide [ka] To a solution of 1-(4-bromo-2-(isopropylamino)phenyl)ethan-1-one (2.4 g, 9.392 mmol) in tetrahydrofuran (40.0 mL) was added potassium bis(trimethylsilyl)amide (18.78 mL, 18.78 mmol, 1 M in tetrahydrofuran) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 30 minutes under a nitrogen atmosphere. To the above mixture was added propanoyl chloride (1.30 g, 14.09 mmol) at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 5 hours before being quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (0% to 25% gradient, v / v) to give the title compound (1.0 g, 34%). LC-MS (M+H) + =312.0.

[0235] Step 2: 7-Bromo-2-ethyl-1-isopropylquinolin-4(1H)-one [ka] The title compound (166 mg, 17%) was prepared from N-(2-acetyl-5-bromophenyl)-N-isopropylpropionamide in a manner similar to that in Step 3 of Example 7. LC-MS (M+H) + =294.1.

[0236] Step 3: 2-Ethyl-1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one [ka] The title compound (100 mg, 51%) was prepared from 7-bromo-2-ethyl-1-isopropylquinolin-4(1H)-one in a manner similar to that in Step 6 of Example 1. For the corresponding boronic acid, LC-MS (M+H)+ =260.1.

[0237] Step 4: 2-chloro-5-fluoro-4-((4-methoxybenzyl)oxy)pyrimidine [ka] To a solution of sodium hydride (925 mg, 23.13 mmol, 60%) in tetrahydrofuran (30 mL) was added (4-methoxyphenyl)methanol (2350 mg, 17.018 mmol) in tetrahydrofuran (12.0 mL) dropwise at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 30 minutes under a nitrogen atmosphere. To the above mixture was added 2,4-dichloro-5-fluoropyrimidine (2375 mg, 14.23 mmol) in tetrahydrofuran (12 mL) dropwise over 20 minutes at 0° C. The resulting mixture was stirred at 0° C. under a nitrogen atmosphere for an additional 2 hours before being quenched by the addition of saturated aqueous ammonium chloride solution (30 mL). The resulting solution was extracted with ethyl acetate (40 mL×2). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (0% to 10% gradient, v / v) to give the title compound (3300 mg, 86%). LC-MS (M+H) + =269.2.

[0238] Step 5: (3S,4R)-4-((5-fluoro-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol [ka] The title compound (1900 mg, 73%) was prepared from 2-chloro-5-fluoro-4-((4-methoxybenzyl)oxy)pyrimidine and (3S,4R)-4-aminooxan-3-ol hydrochloride in a manner similar to that in Step 4 of Example 2. LC-MS (M+H) + =350.1.

[0239] Step 6: (3S,4R)-4-((5-fluoro-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate [ka] To a solution of (3S,4R)-4-((5-fluoro-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (1900 mg, 5.43 mmol) and triethylamine (4400 mg, 43.47 mmol) in dichloromethane (40 mL) was added dropwise acetic anhydride (3325 mg, 32.57 mmol) at 0° C. under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours before being quenched by the addition of saturated aqueous sodium bicarbonate solution (30 mL). The resulting mixture was extracted with dichloromethane (40 mL×2). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate in dichloromethane (0% to 25% gradient, v / v) to give the title compound (1950 mg, 91%). LC-MS (M+H) + =392.0.

[0240] Step 7: (3S,4R)-4-((5-fluoro-4-hydroxypyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate [ka] To a solution of (3S,4R)-4-((5-fluoro-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate (1950 mg, 4.98 mmol) in methanol (30 mL) was added Pd / C (945 mg, 0.888 mmol, 10%) under a nitrogen atmosphere. The mixture was hydrogenated under 1 atmosphere of hydrogen at room temperature for 6 hours. The reaction was filtered through a celite pad and concentrated under reduced pressure to give the title compound (1200 mg, 88%). LC-MS (M+H) + =272.0.

[0241] Step 8: (3S,4R)-4-((4-chloro-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate [ka] To a solution of (3S,4R)-4-((5-fluoro-4-hydroxypyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate (1200 mg, 4.42 mmol) and N,N-diethylaniline (1985 mg, 13.31 mmol) in 1,2-dichloroethane (25 mL) was added phosphoryl chloride (2055 mg, 13.42 mmol) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 3 hours before being cooled to room temperature and concentrated. The residue was purified by flash chromatography eluting with ethyl acetate in petroleum ether (0% to 30% gradient) to give the title compound (820 mg, 63%). LC-MS (M+H) + =290.0.

[0242] Step 9: (3S,4R)-4-((4-(2-ethyl-1-isopropyl-4-oxo-1,4-dihydroquinolin-7-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate [ka] The title compound (75 mg, 66%) was prepared from (3S,4R)-4-((4-chloro-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate and 2-ethyl-1-isopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one in a manner similar to that described in Step 7 of Example 1. LC-MS (M+H) + =469.3.

[0243] Step 10: 2-Ethyl-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] A solution of (3S,4R)-4-((4-(2-ethyl-1-isopropyl-4-oxo-1,4-dihydroquinolin-7-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate (75 mg, 0.16 mmol) and hydrogen chloride in methanol (3.0 mL, 4 M) was stirred at 60 °C under a nitrogen atmosphere for 2 hours before being cooled to room temperature and concentrated. The residue was purified by preparative HPLC under the following conditions: Column, XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase, acetonitrile in water (containing 10 mmol / L NH4HCO3 and 0.1% NH3.HO), 20% to 48% gradient in 9 min; Detector, UV 254 nm. The title compound (39 mg, 57%) was obtained. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (brs, 1H), 8.51 (d, J = 3.8 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.98-7.88 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.11 (s, 1H), 5.18-5.03 (m, 1H), 4.97 (d, J = 5.2 Hz, 1H), 3.91-3.80 (m, 3H), 3.62-3.46 (m, 1H), 3.40-3.26 (m, 1H), 3.11- 2.98 (m, 1H), 2.93-2.79 (m, 2H), 2.07-1.97 (m, 1H), 1.78-1.63 (m, 6H), 1.63-1.43 (m, 1H), 1.29 (t, J = 7.4 Hz, 3H).LC-MS(M+H) + =427.1.

[0244] Example 56: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((S)-3-hydroxypiperidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (16 mg, 47%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (3S)-piperidin-3-ol hydrochloride in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.74 (brs, 1H), 8.52 (d, J = 3.8 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.17 (s, 1H), 5.40-5.28 (m, 1H), 4.98 (d, J = 5.2 Hz, 1H), 4.65 (d, J = 4.5 Hz, 1H), 3.99-3.80 (m, 3H), 3.73-3.65 (m, 1H), 3.60-3.42 (m, 3H), 3.38-3.28 (m, 1H), 3.09-2.99 (m, 1H), 2.89-2.81 (m, 1H), 2.75-2.67 (m, 1H), 2.03-1.93 (m, 2H), 1.89-1.77 (m, 2H), 1.75-1.61 (m, 7H), 1.60-1.36 (m, 2H), 1.17-1.04 (m, 1H).LC-MS(M+H) + =512.2.

[0245] Example 57: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((R)-3-hydroxypiperidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (11 mg, 32%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (3R)-piperidin-3-ol hydrochloride in a manner similar to that in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.74 (brs, 1H), 8.52 (d, J = 3.8 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.17 (s, 1H), 5.40-5.28 (m, 1H), 4.98 (d, J = 5.2 Hz, 1H), 4.65 (d, J = 4.6 Hz, 1H), 3.92-3.80 (m, 3H), 3.73-3.65 (m, 1H), 3.60-3.41 (m, 3H), 3.39-3.28 (m, 1H), 3.09-2.99 (m, 1H), 2.89-2.81 (m, 1H), 2.74 -2.67 (m, 1H), 2.03-1.94 (m, 2H), 1.89-1.76 (m, 2H), 1.76- 1.61 (m, 7H), 1.57-1.34 (m, 2H), 1.17-1.04 (m, 1H).LC-MS(M+H) + =512.3.

[0246] Example 58: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methyl-2-(morpholinomethyl)quinolin-4(1H)-one [ka] Step 1: 2-(Bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] To a mixture of 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2,3-dimethylquinolin-4(1H)-one (640 mg, 1.5 mmol) and N-bromosuccinimide (218 mg, 1.2 mmol) in carbon tetrachloride (25 mL) was added azobisisobutyronitrile (46 mg, 0.3 mmol). The mixture was stirred at 70° C. for 2 hours before being cooled to room temperature and concentrated. The residue was purified on silica gel by Combiflash eluting with methanol in dichloromethane (3%, v / v) to give the title compound (300 mg, 39%). LC-MS (M+H) + =505.1,507.1.

[0247] Step 2: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methyl-2-(morpholinomethyl)quinolin-4(1H)-one [ka] The title compound (20 mg, 39%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and morpholine in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.74 (brs, 1H), 8.51 (s, 1H), 8.34 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 5.53 - 5.43 (m, 1H), 4.97 (s, 1H), 3.92 - 2.72 (m, 5H), 3.67 - 3.47 (m, 5H), 3.38 - 3.28 (m, 1H), 3.04 (t, J = 10.6 Hz, 1H), 2.60 - 2.48 (m, 4H), 2.18 (s, 3H), 2.05 - 1.95 (m, 1H), 1.80 - 1.70 (m, 6H), 1.58 - 1.48 (m, 1H).LC-MS(M+H) + =512.1.

[0248] Example 59: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-((((R)-tetrahydro-2H-pyran-3-yl)amino)methyl)quinolin-4(1H)-one [ka] The title compound (8 mg, 30%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (R)-tetrahydro-2H-pyran-3-amine in a manner similar to that in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.70 (brs, 1H), 8.51 (d, J = 3.0 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 6.25 (s, 1H), 5.43 - 5.33 (m, 1H), 4.98 (s, 1H), 3.95 - 3.80 (m, 6H), 3.72 - 3.65 (m, 1H), 3.58 - 3.48 (m, 1H), 3.35 - 3.25 (m, 2H), 3.10 - 3.00 (m, LC-MS(M+H) + =512.1.

[0249] Example 60: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-((((S)-tetrahydro-2H-pyran-3-yl)amino)methyl)quinolin-4(1H)-one [ka] The title compound (6 mg, 23%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (S)-tetrahydro-2H-pyran-3-amine in a manner similar to that in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.70 (brs, 1H), 8.51 (d, J = 3.0 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 9.1 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 6.25 (s, 1H), 5.43 - 5.33 (m, 1H), 4.98 (s, 1H), 3.95 - 3.80 (m, 6H), 3.72 - 3.65 (m, 1H), 3.58 - 3.48 (m, 1H), 3.35 - 3.25 (m, 2H), 3.10 - 3.00 (m, LC-MS(M+H) + =512.1.

[0250] Example 61: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((S)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (6 mg, 26%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (S)-3-methylpyrrolidin-3-ol in a manner similar to that in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.52 (d, J = 3.0 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 6.20 (s, 1H), 5.41 (t, 1H), 4.97 (s, 1H), 4.59 (s, 1H), 3.86 - 3.80 (m, 3H), 3.72 (dd, J = 35.3, 13.4 Hz, 2H), 3.53 - 3.41 (m, 1H), 3.31 - 3.27 (m, 1H), 3.04 (t, J = 10.8 Hz, 1H), 2.71-2.61 (m, 2H), 2.66 - 2.45 (m, 2H), 2.00 (d, 1H), 1.76 - 1.60 (m, 8H), 1.53 - 1.48 (m, 1H), 1.26 (s, 3H).LC-MS(M+H) + =512.1.

[0251] Example 62: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-(((S)-2-methylmorpholino)methyl)quinolin-4(1H)-one [ka] The title compound (13 mg, 45%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (S)-2-methylmorpholine in a manner similar to Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.52 (d, J = 3.0 Hz, 1H), 8.30 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 6.18 (s, 1H), 5.47 - 5.30 (m, 1H), 4.98 (s, 1H), 3.96 - 3.76 (m, 3H), 3.78 - 3.76 (m, 1H), 3.69 - 3.58 (m, 2H), 3.57 - 3.42 (m, 3H), 3.41-3.26 (m, 1H), 3.04 (t, J = 10.5 Hz, 1H), 2.76 (d, J = 11.1 Hz, 1H), 2.69 (d, J = 10.6 Hz, 1H), 2.16 (t, J = 10.8 Hz, 1H), 2.01 (d, J = 11.1 Hz, 1H), 1.86 (t, J = 10.2 Hz, 1H), 1.75 - 1.72 (m, 6H), 1.54 - 1.51 (m, 1H), 1.05 (d, J = 5.8 Hz, 3H).LC-MS(M+H) + =513.1.

[0252] Example 63: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-((((1r,3R)-3-fluorocyclobutyl)amino)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (12 mg, 43%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (1r,3r)-3-fluorocyclobutan-1-amine in a manner similar to Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.52 (d, J = 3.0 Hz, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 6.23 (s, 1H), 5.37 - 5.33 (m, 1H), 5.28 - 5.14 (m, 1H), 4.98 (s, 1H), 3.86 - 3.64 (m, 5H), 3.54 - 3.46 (m, 2H), 3.40 - 3.20 (m, 1H), 3.04 (t, J = 10.1 Hz, 1H), 2.31 - 2.28 (m, 2H), 2.22 - 2.18 (m, 2H), 2.02 (d, J = 11.9 Hz, 1H), 1.75 - 1.72 (m, 6H), 1.54 - 1.51 (m, 1H).LC-MS(M+H) + =500.1.

[0253] Example 64: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-((((1s,3S)-3-fluorocyclobutyl)amino)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (12 mg, 43%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (1s,3s)-3-fluorocyclobutan-1-amine in a manner similar to Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.51 (d, J = 3.0 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 6.21 (s, 1H), 5.35 (s, 1H), 4.97 (s, 1H), 4.84 - 4.70 (m, 1H), 3.95 - 3.75 (m, 5H), 3.63 - 3.43 (m, 2H), 3.32 - 3.25 (m, 1H), 3.03 (t, J = 10.2 Hz, 1H), 2.74 (s, 1H), 2.42 - 2.12 (m, 4H), 2.10 - 1.90 (m, 1H), 1.75 - 1.72 (m, 6H), 1.53 - 1.51 (m, 1H).LC-MS(M+H) + =500.1.

[0254] Example 65: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-((((R)-tetrahydrofuran-3-yl)amino)methyl)quinolin-4(1H)-one [ka] The title compound (14 mg, 50%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (R)-tetrahydrofuran-3-amine in a manner similar to Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.51 (d, J = 3.0 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 6.26 (s, 1H), 5.45 - 5.31 (m, 1H), 4.97 (s, 1H), 3.89 - 3.83 (m, 5H), 3.82 - 3.69 (m, 3H), 3.68 - 3.66 (m, 1H), 3.54 (brs, 1H), 3.48 - 3.46 (m, 1H), 3.30 - 3.28 (m, 2H), 3.06 - 3.01 (m, 1H), 2.02 - 2.00 (m, 2H), 1.72 (brs, 7H), 1.54 - 1.51 (m, 1H).LC-MS(M+H) + =498.1.

[0255] Example 66: 2-((cyclopentylamino)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (14 mg, 50%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and cyclopentanamine in a manner similar to Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.51 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 6.23 (s, 1H), 5.47 - 5.36 (m, 1H), 4.97 (s, 1H), 3.94 - 3.71 (m, 5H), 3.64 - 3.44 (m, 2H), 3.15 - 2.92 (m, 3H), 2.03 - 2.00 (m, 1H), 1.72 (brs, 8H), 1.74 - 1.54 (m, 2H), 1.59 - 1.39 (m, 3H), 1.49 - 1.29 (m, 2H).LC-MS(M+H) + =496.1.

[0256] Example 67: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-((((S)-tetrahydrofuran-3-yl)amino)methyl)quinolin-4(1H)-one [ka] The title compound (13 mg, 46%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (S)-tetrahydrofuran-3-amine in a manner similar to Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.52 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 6.26 (s, 1H), 5.48 - 5.28 (m, 1H), 4.97 (s, 1H), 3.85 - 3.83 (m, 5H), 3.79 - 3.60 (m, 3H), 3.54 (brs, 1H), 3.48 - 3.46 (m, 1H), 3.33 - 3.24 (m, 3H), 3.06 - 3.01 (m, 1H), 2.05 - 1.85 (m, 2H), 1.72 (brs, 7H), 1.54 - 1.51 (m, 1H).LC-MS(M+H) + =498.1.

[0257] Example 68: 2-((3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (8 mg, 30%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and

[0258] Prepared from 3-oxa-6-azabicyclo[3.1.1]heptane hydrochloride. 1H-NMR (400 MHz, DMSO-d6) δ:8.72 (s, 1H), 8.51 (s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 7.0 Hz, 1H), 6.27 (s, 1H), 5.35 (s, 1H), 4.98 (s, 1H), 4.21 (d, J = 9.9 Hz, 2H), 4.09-3.75 (m, 5H), 3.68 (d, J = 10.3 Hz, 2H), 3.60-3.45 (m, 3H), 3.39 (s, 1H), 3.04 (t, J = 10.3 Hz, 1H), 2.69 - 2.49 (m, 1H), 2.01 (d, J = 10.0 Hz, 1H), 1.74 (brs, 7H), 1.60 - 1.41 (m, 1H).LC-MS(M+H) + =510.

[0259] Example 69: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((S)-3-fluoropiperidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (10.6 mg, 37%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (S)-3-fluoropiperidine hydrochloride in a manner similar to Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ:8.74 (s, 1H), 8.52 (s, 1H), 8.31 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 6.18 (s, 1H), 5.39 - 5.22 (m, 1H), 4.97 (d, J = 4.4 Hz, 1H), 4.67 (d, J = 49.3 Hz, 1H), 3.97-3.79 (m, 3H), 3.74-3.60 (m, 2H), 3.59-3.46 (m, 1H), 3.31 - 3.27 (m, 1H), 3.04 (t, J = 10.1 Hz, 1H), 2.81 - 2.65 (m, 1H), 2.62-2.54 (m, 1H), 2.43 (s, 2H), 2.01 (d, J = 11.5 Hz, 1H), 1.88-1.61 (m, 8H), 1.66-1.41 (m, 3H).LC-MS(M+H) + =514.

[0260] Example 70: 2-((3,3-difluoropiperidin-1-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (8.3 mg, 28%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 3,3-difluoropiperidine hydrochloride in a manner similar to Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ:8.74 (s, 1H), 8.52 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 6.19 (s, 1H), 5.36 - 5.19 (m, 1H), 4.97 (d, J = 4.4 Hz, 1H), 3.98-3.80 (m, 3H), 3.74 (s, 2H), 3.63 - 3.43 (m, 1H), 3.30 (s, 1H), 3.04 (t, J = 10.3 Hz, 1H), 2.77 (t, LC-MS(M+H) + =532.

[0261] Example 71: 2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (1 mg, 5%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and (3R,5R)-3,5-dimethylmorpholine hydrochloride in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.74 (brs, 1H), 8.51 (d, J = 2.7 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 5.67 - 5.51 (m, 1H), 4.99 (s, 1H), 4.22 - 4.15 (m, 1H), 3.96 - 3.80 (m, 4H), 3.66 - 3.49 (m, 3H), 3.48 - 3.28 (m, 3H), 3.04 (t, J = 10.4 Hz, 1H), 2.86 - 2.76 (m, 2H), 2.24 (s, 3H), 2.06 - 1.96 (m, 1H), 1.82 - 1.69 (m, 6H), 1.59 - 1.46 (m, 1H), 1.05 - 0.98 (m, 6H).LC-MS(M+H) + =540.1.

[0262] Example 72: 2-(((3R,5S)-3,5-dimethylmorpholino)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (20 mg, 20%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and (3R,5S)-3,5-dimethylmorpholine hydrochloride in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.73 (brs, 1H), 8.51 (s, 1H), 8.32 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 5.78 - 5.63 (m, 1H), 4.97 (s, 1H), 4.02 (s, 2H), 3.96 - 3.79 (m, 3H), 3.64 (d, J = 11.1 Hz, 2H), 3.58 - 3.49 (m, 1H), 3.39 - 3.30 (m, 1H), 3.21 (t, J = 9.9 Hz, 2H), 3.05 (t, J = 10.3 Hz, 1H), 2.66 - 2.57 (m, 2H), 2.25 (s, 3H), 2.09 - 1.95 (m, 1H), 1.79 - 1.71 (m, 6H), 1.60 - 1.45 (m, 1H), 0.98 - 0.92 (m, 6H).LC-MS(M+H) + =540.1.

[0263] Example 73: 2-((7-oxa-4-azaspiro[2.5]octan-4-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (4 mg, 14%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 7-oxa-4-azaspiro[2.5]octane in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.51 (s, 1H), 8.29 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 6.27 (s, 1H), 5.31 - 5.11 (m, 1H), 4.97 (s, 1H), 3.98 (s, 2H), 3.95 - 3.75 (m, 3H), 3.67 (s, 2H), 3.59 - 3.39 (m, 3H), 3.45 - 3.25 (m, 1H), 3.05 (t, J = 10.3 Hz, LC-MS(M+H) + =524.0.

[0264] Example 74: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-((3-fluoroazetidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (8.4 mg, 40%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 3-fluoroazetidine hydrochloride in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.51 (s, 1H), 8.29 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 6.23 (s, 1H), 5.44 - 5.12 (m, 2H), 4.97 (s, 1H), 3.97 - 3.76 (m, 5H), 3.75 - 3.61 (m, 2H), 3.53 (s, 1H), 3.39 - 2.19 (m, 2H), 3.03 (t, J = 10.0 Hz, 1H), 2.14 - 1.93 (m, J = 13.9 Hz, 1H), 1.71 (s, 7H), 1.58 - 1.36 (m, 1H).LC-MS(M+H) + =486.1.

[0265] Example 75: 2-((tert-butylamino)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (17 mg, 55%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and tert-butylamine in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.51 (d, J = 2.9 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.24 (s, 1H), 5.53 - 5.30 (m, 1H), 4.97 (s, 1H), 3.99 - 3.80 (m, 3H), 3.75 (s, 2H), 3.54 - 3.53 (m, 1H), 3.32 (t, J = 10.6 Hz, 2H), 3.04 (t, J = 10.4 Hz, 1H), 2.02 (d, J = 11.3 Hz, 1H), 1.73 (t, J = 6.3 Hz, 6H), 1.54 - 1.51 (m, 1H), 1.13 (s, 9H).LC-MS(M+H) + =484.1.

[0266] Example 76: 2-((cyclobutylamino)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (15 mg, 45%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and cyclobutylamine in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.51 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 6.20 (s, 1H), 5.51 - 5.27 (m, 1H), 4.97 (s, 1H), 3.95 - 3.75 (m, 3H), 3.75 (s, 2H), 3.54 (s, 1H), 3.36 - 3.30 (m, 2H), 3.25 - 3.13 (m, 1H), 3.04 (t, J = 10.2 Hz, 1H), 2.12 - 2.00 (m, 3H), 1.82 - 1.42 (m, 11H).LC-MS(M+H) + =482.1.

[0267] Example 77: 2-(((3,3-difluorocyclobutyl)amino)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (27 mg, 46%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 3,3-difluorocyclobutan-1-amine in a manner similar to that in Step 2 of Example 18.

[0268] 1H-NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.51 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.25 (s, 1H), 5.41 - 5.24 (m, 1H), 4.97 (s, 1H), 3.86 - 3.80 (m, 5H), 3.54 (s, 1H), 3.30 - 3.21 (m, 2H), 3.04 (t, J = 10.4 Hz, 1H), 2.94 (s, 1H), 2.77 (s, 2H), 2.49 - 2.29 (m, 2H), 2.01 (d, J = 12.3 Hz, 1H), 1.72 (s, 6H), 1.53 - 1.51 (m, 1H).LC-MS(M+H) + =518.1.

[0269] Example 78: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-(((1-methyl-1H-pyrazol-4-yl)amino)methyl)quinolin-4(1H)-one [ka] The title compound (22 mg, 41%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 1-methyl-1H-pyrazol-4-amine in a manner similar to that in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.52 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.15 (s, 1H), 7.03 (s, 1H), 6.31 (s, 1H), 5.21 - 5.15 (m, 2H), 4.97 (s, 1H), 4.23 (d, J = 3.8 Hz, 2H), 3.85 - 3.83 (m, 3H), 3.68 (s, 3H), 3.53 (s, 1H), 3.33 - 3.30 (m, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.01 (d, J = 11.3 Hz, 1H), 1.73 (s, 6H), 1.54 - 1.51 (m, 1H).LC-MS(M+H) + =508.1.

[0270] Example 79: 2-((1,4-oxazepan-4-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (15 mg, 52%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 1,4-oxazepane in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.52 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 6.18 (s, 1H), 5.50 - 5.30 (m, 1H), 4.97 (s, 1H), 3.86 (s, 3H), 3.77 (s, 2H), 3.70 (s, 2H), 3.63 (s, 2H), 3.53 (s, 1H), 3.44 - 2.24 (m, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.71 (s, 4H), 2.10 - 1.90 (m, 1H), 1.84 (s, 2H), 1.74 (s, 6H), 1.52 (d, J = 11.7 Hz, 1H).LC-MS(M+H) + =512.0.

[0271] Example 80: 2-((3,3-difluoropyrrolidin-1-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (6 mg, 26%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 3,3-difluoropyrrolidine hydrochloride in a manner similar to that in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.52 (s, 1H), 8.31 (d, J = 8.9 Hz, 1H), 7.94 (d, J = 8.3 Hz, 1H), 7.32 (d, J = 7.2 Hz, 1H), 6.23 (s, 1H), 5.38 - 5.24 (m, 1H), 5.02 - 4.92 (m, 1H), 3.99 - 3.76 (m, 5H), 3.53 (s, 1H), 3.29 (d, J = 11.6 Hz, 1H), 3.11 - 2.93 (m, 3H), 2.85 - 2.70 (m, 2H), 2.37 - 2.21 (m, 2H), 2.09 - 1.96 (m, 1H), 1.71 (s, 6H), 1.57 - 1.46 (m, 1H).LC-MS(M+H) + =518.1.

[0272] Example 81: 2-((3-oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (9 mg, 22%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 3-oxa-8-azaspiro[3.2.1]octane hydrochloride in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.74 (brs, 1H), 8.50 (d, J = 3.8 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 6.17 (s, 1H), 5.69-5.53 (m, 1H), 4.95 (d, J = 5.1 Hz, 1H), 3.90-3.79 (m, 3H), 3.59-3.32 (m, 8H), 3.15-2.94 (m, 3H), 2.03-1.95 (m, 3H), 1.82-1.72 (m, 8H), 1.56-1.46 (m, 1H).LC-MS(M+H) + =524.3.

[0273] Example 82: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-(((R)-3-methylmorpholino)methyl)quinolin-4(1H)-one [ka] The title compound (17 mg, 51%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (3R)-3-methylmorpholine in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.73 (brs, 1H), 8.52 (d, J = 3.8 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.25-6.15 (m, 1H), 5.53-5.42 (m, 1H), 4.97 (d, J = 5.0 Hz, 1H), 4.32-4.22 (m, 1H), 3.90-3.80 (m, 3H), 3.72-3.60 (m, 2H), 3.60-3.44 (m, 2H), 3.33-3.17 (m, 3H), 3.11-2.98 (m, 1H), 2.80-2.64 (m, 1H), 2.63-2.53 (m, 1H), 2.34-2.19 (m, 1H), 2.07-1.96 (m, 1H), 1.92-1.67 (m, 6H), 1.61-1.47 (m, 1H), 1.12-1.00 (m, 3H).LC-MS(M+H) + =512.3.

[0274] Example 83: 2-((1,1-dioxidethiomorpholino)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (14 mg, 41%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and thiomorpholine 1,1-dioxide hydrochloride in a manner similar to that in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.76 (brs, 1H), 8.52 (d, J = 3.8 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.24 (s, 1H), 5.34-5.22 (m, 1H), 4.99 (s, 1H), 4.01-3.76 (m, 5H), 3.57-3.49 (m, 1H), 3.38-3.29 (m, 1H), 3.18-3.11 (m, 4H), 3.09-2.97 (m, 5H), 2.05-1.98 (m, 1H), 1.78-1.70 (m, 6H), 1.60-1.46 (m, 1H).LC-MS(M+H) + =546.2.

[0275] Example 84 and Example 85: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((3R,4R)-4-fluoro-3-hydroxypiperidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one and 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((3S,4S)-4-fluoro-3-hydroxypiperidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compounds Example 84 and Example 85 were prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and trans-4-fluoro-3-piperidinol in a manner similar to that in Step 2 of Example 18. The two isomeric products were separated on chiral HPLC to give 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((3R,4R)-4-fluoro-3-hydroxypiperidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one and 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((3S,4S)-4-fluoro-3-hydroxypiperidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one. Analytical chiral HPLC conditions: CHIRALPAK ID-3, 0.46 x 5 cm, 3.0 um. Mobile phase: (hexane:chloromethane = 3:1) ((0.5% 2M NH3 in methanol)):ethanol, 20 mL / min in 13 min.

[0276] Example 84: (5 mg, 10%) 1H-NMR (300 MHz, DMSO-d6) δ 8.74 (brs, 1H), 8.52 (d, J = 3.8 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.18 (s, 1H), 5.37-5.26 (m, 1H), 5.21 (d, J = 4.7 Hz, 1H), 4.97 (d, J = 5.1 Hz, 1H), 4.39-4.15 (m, 1H), 3.91-3.80 (m, 3H), 3.74-3.48 (m, 4H), 3.38 (s, 1H), 3.11-2.98 (m, 1H), 2.93-2.76 (m, 2H), 2.23-2.10 (m, 1H), 2.07-1.94 (m, 3H), 1.78-1.43 (m, 8H).LC-MS(M+H) + =530.3.Kura HPLC:RT=2.851 points.

[0277] Example 85: (2mg, 3%) 1 H-NMR (300 MHz, DMSO-d6) δ 8.74 (brs, 1H), 8.55-8.49 (m, 1H), 8.36-8.27 (m, 1H), 7.98-7.92 (m, 1H), 7.34-7.28 (m, 1H), 6.18 (s, 1H), 5.35-5.16 (m, 2H), 5.00-4.94 (m, 1H), 4.39-4.11 (m, 1H), 3.89-3.83 (m, 3H), 3.76-3.40 (m, 4H), 3.33-3.28 (m, 1H), 3.08-3.02 (m, 1H), 2.88-2.82 (m, 2H), 2.20-2.14 (m, 1H), 2.08-1.97 (m, 3H), 1.79-1.48 (m, 8H).LC-MS(M+H) + =530.3.Kura HPLC:RT=3.729 points.

[0278] Example 86: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (7 mg, 20%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (S)-pyrrolidin-3-ol in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.52 (d, J = 3.7 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.97-7.90 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.21 (s, 1H), 5.44-5.31 (m, 1H), 4.98 (d, J = 5.1 Hz, 1H), 4.73 (d, J = 4.0 Hz, 1H), 4.26-4.19 (m, 1H), 3.97-3.74 (m, 4H), 3.73-3.65 (m, 1H), 3.60-3.48 (m, 1H), 3.38-3.27 (m, 1H), 3.09-2.99 (m, 1H), 2.80-2.66 (m, 2H), 2.51-2.45 (m, 1H), 2.45-2.37 (m, 1H), 2.07-1.94 (m, 2H), 1.76-1.67 (m, 6H), 1.59-1.49 (m, 2H).LC-MS(M+H) + =498.3.

[0279] Example 87: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (16 mg, 43%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (R)-pyrrolidin-3-ol in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ 8.73 (brs, 1H), 8.52 (d, J = 3.8 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.97-7.90 (m, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.21 (s, 1H), 5.44-5.33 (m, 1H), 4.97 (d, J = 5.2 Hz, 1H), 4.73 (d, J = 4.0 Hz, 1H), 4.25-4.20 (m, 1H), 3.89-3.75 (m, 4H), 3.73-3.65 (m, 1H), 3.59-3.48 (m, 1H), 3.31-3.28 (m, 1H), 3.09-2.99 (m, 1H), 2.80-2.63 (m, 2H), 2.51-2.37 (m, 2H), 2.10-1.94 (m, 2H), 1.74-1.68 (m, 6H), 1.63-1.46 (m, 2H).LC-MS(M+H) + =498.3.

[0280] Example 88: (R)-1-((7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)piperidine-3-carbonitrile [ka] The title compound (18 mg, 45%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (3R)-piperidine-3-carbonitrile hydrochloride in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ 8.75 (brs, 1H), 8.52 (d, J = 3.8 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.98-7.91 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.18 (s, 1H), 5.43-5.32 (m, 1H), 4.98 (d, J = 5.2 Hz, 1H), 4.00-3.78 (m, 3H), 3.72 (d, J = 13.8 Hz, 1H), 3.64-3.47 (m, 2H), 3.35-3.27 (m, 1H), 3.11-2.99 (m, 2H), 2.82-2.77 (m, 1H), 2.61-2.57 (m, 2H), 2.38-2.23 (m, 1H), 2.05-1.97 (m, 1H), 1.82-1.66 (m, 9H), 1.61-1.45 (m, 2H).LC-MS(M+H) + =521.3.

[0281] Example 89: (S)-1-((7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)piperidine-3-carbonitrile [ka] The title compound (19 mg, 48%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (3S)-piperidine-3-carbonitrile hydrochloride in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ 8.75 (brs, 1H), 8.52 (d, J = 3.8 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.98-7.91 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 6.18 (s, 1H), 5.43-5.31 (m, 1H), 4.98 (d, J = 5.2 Hz, 1H), 4.00-3.79 (m, 3H), 3.76-3.68 (m, 1H), 3.64-3.48 (m, 2H), 3.35-3.30 (m, 1H), 3.10-2.95 (m, 2H), 2.82-2.77 (m, 1H), 2.61-2.57 (m, 2H), 2.37-2.26 (m, 1H), 2.05-1.97 (m, 1H), 1.79-1.65 (m, 9H), 1.60-1.45 (m, 2H).LC-MS(M+H) + =521.3.

[0282] Example 90: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((1R,3R,5S)-3-hydroxy-9-azabicyclo[3.3.1]nonan-9-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (17 mg, 22%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (1R,3r,5S)-9-azabicyclo[3.3.1]nonan-3-ol hydrochloride in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (300 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.50 (d, J = 3.8 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 7.97-7.87 (m, 1H), 7.36-7.25 (m, 1H), 6.19 (s, 1H), 5.44-5.28 (m, 1H), 4.99-4.93 (m, 1H), 4.53-4.47 (m, 1H), 4.01-3.78 (m, 4H), 3.56-3.50 (m, 1H), 3.40-3.26 (m, 3H), 3.10-2.93 (m, 3H), 2.40-2.34 (m, 1H), 2.30-2.14 (m, 2H), 2.06-1.95 (m, 1H), 1.94-1.81 (m, 2H), 1.79-1.66 (m, 6H), 1.61-1.36 (m, 2H), 1.33-1.21 (m, 2H), 1.19-1.09 (m, 2H).LC-MS(M+H) + =552.4.

[0283] Example 91: 2-((1-oxa-7-azaspiro[4.4]nonan-7-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (2.2 mg, 9%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 1-oxa-7-azaspiro[4.4]nonane in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.52 (s, 1H), 8.30 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 6.28 - 6.15 (m, 1H), 5.49 - 5.29 (m, 1H), 5.04 - 4.89 (m, 1H), 3.96 - 3.74 (m, 4H), 3.73 - 3.60 (m, J = 13.1 Hz, 3H), 3.53 (s, 1H), 3.44 - 3.24 (m, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.74 - 2.61 (m, J = 7.8 Hz, 2H), 2.58 (s, 2H), 2.08 - 1.96 (m, 1H), 1.93 - 1.77 (m, 6H), 1.75 - 1.66 (m, 6H), 1.62 - 1.44 (m, 1H).LC-MS(M+H) + =538.1.

[0284] Example 92: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((R)-3-fluoropyrrolidin-1-yl)methyl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (30 mg, 58%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and (R)-3-fluoropyrrolidine in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ 8.73 (brs, 1H), 8.51 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.56 - 5.43 (m, 1H), 5.3 - 5.11 (m, 1H), 4.97 (d, J = 5.1 Hz, 1H), 3.97 (s, 2H), 3.93 - 3.79 (m, 3H), 3.58 - 3.48 (m, 1H), 3.37 - 3.28 (s, 1H), 3.03 (t, J = 10.5 Hz, 1H), 2.97 - 2.86 (m, 2H), 2.83 - 2.65 (m, 1H), 2.51 - 2.41 (m, 1H), 2.22 - 2.10 (m, 4H), 2.06 - 1.79 (m, 2H), 1.77 - 1.67 (m, 6H), 1.58 - 1.48 (m, 1H).LC-MS(M+H) + =514.1.

[0285] Example 93: 2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (20 mg, 90%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (3S,5S)-3,5-dimethylmorpholine hydrochloride in a manner similar to that described in Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ 8.74 (brs, 1H), 8.52 (d, J = 3.7 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 6.32 (s, 1H), 5.69 - 5.56 (m, 1H), 4.97 (s, 1H), 4.29 - 4.22 (m, 1H), 3.97 - 3.78 (m, 3H), 3.65 - 3.58 (m, 2H), 3.58 - 3.49 (m, 1H), 3.47 - 3.40 (m, 1H), 3.38 - 3.26 (m, 3H), 3.04 (t, J = 10.2 Hz, 1H), 2.81 - 2.71 (m, 2H), 2.06 - 1.96 (m, 1H), 1.80 - 1.68 (m, 6H), 1.59 - 1.46 (m, 1H), 1.08 - 1.02 (m, 6H).LC-MS(M+H) + =526.1.

[0286] Example 94: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-((phenylamino)methyl)quinolin-4(1H)-one [ka] The title compound (14 mg, 50%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and aniline in a manner similar to Step 2 of Example 18. 1 H-NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.52 (s, 1H), 8.29 (d, J = 8.6 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 7.11 (t, J = 7.3 Hz, 2H), 6.65 (d, J = 8.0 Hz, 2H), 6.59 (s, 1H), 6.38 (s, 1H), 6.30 (s, 1H), 5.22 - 5.02 (m, 1H), 4.97 (s, 1H), 4.46 (s, 2H), 3.95 - 3.75 (m, 3H), 3.53 (s, 1H), 3.31 - 3.29 (m, 1H),3.03 (t, J = 10.6 Hz, 1H), 2.00 (s, 1H), 1.75 (s, 6H), 1.54 (s, 1H).LC-MS(M+H) + =504.1.

[0287] Example 95: 2-(((3-chlorophenyl)amino)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (14 mg, 50%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 3-chloroaniline in a manner similar to Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.52 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 7.3 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 9.0 Hz, 2H), 6.62 (d, J = 7.8 Hz, 2H), 6.28 (s, 1H), 5.16 - 4.96 (m, 1H), 4.97 (s, 1H), 4.51 (s, 2H), 3.96 - 3.76 (m, 3H), 3.54 (s, 1H), 3.31 - 3.27 (m, 1H), 3.04 (t, J = 10.3 Hz, 1H), 2.00 (s, 1H), 1.74 (s, 6H), 1.54 - 1.51 (m, 1H).LC-MS(M+H) + =538.1.

[0288] Example 96: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((4-fluorophenyl)amino)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (13 mg, 45%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 4-fluoroaniline in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.70 (brs, 1H), 8.52 (s, 1H), 8.29 (d, J = 8.2 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 6.96 (t, J = 7.9 Hz, 2H), 6.65 (s, 2H), 6.33 (s, 1H), 6.29 (s, 1H), 5.20 - 5.00 (m, 1H), 4.97 (s, 1H), 4.45 (s, 2H), 3.95 - 3.75 (m, 3H), 3.54 (s, 1H), 3.29 (s, 1H), 3.03 (t, J = 10.0 Hz, 1H), 2.09 - 1.89 (m, 1H), 1.74 (s, 6H), 1.54 - 1.51 (m, 1H).LC-MS(M+H) + =522.1.

[0289] Example 97: 2-((4,4-dimethylpiperidin-1-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (13 mg, 45%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 4,4-dimethylpiperidine in a manner similar to Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.52 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 6.17 (s, 1H), 5.36 (s, 1H), 4.97 (s, 1H), 3.96 - 3.76 (m, 3H), 3.63 (s, 2H), 3.54 (s, 1H), 3.34-3.28 (m, 1H), 3.04 (t, J = 10.2 Hz, 1H), 2.43 (s, 4H), 2.00 (s, 1H), 1.71 (d, J = 6.5 Hz, 6H), 1.54 - 1.51 (m, 1H), 1.34 (s, 4H), 0.91 (s, 6H).LC-MS(M+H) + =524.1.

[0290] Example 98: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((R)-3-fluoropiperidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (13 mg, 45%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (R)-3-fluoropiperidine hydrochloride in a manner similar to Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ:8.74 (s, 1H), 8.51 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 6.18 (s, 1H), 5.39-5.25 (m, 1H), 4.96 (s, 1H), 4.67 (d, J = 48.5 Hz, 1H), 4.09 - 3.73 (m, 3H), 3.73 - 3.60 (m, 2H), 3.59-3.49 (m, 1H), 3.31(s, 1H), 3.03 (t, J = 10.1 Hz, 1H), 2.81-2.64 (m, 1H), 2.62-2.54 (m, 1H), 2.42 (s, 2H), 2.01 (d, J = 10.7 Hz, 1H), 1.88 - 1.67 (m, 8H), 1.67 - 1.36 (m, 3H).LC-MS(M+H) + =514.

[0291] Example 99: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-((4-fluoropiperidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (12 mg, 42%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 4-fluoropiperidine in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ:8.74 (s, 1H), 8.52 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 6.17 (s, 1H), 5.41-5.29 (m, 1H), 4.97 (s, 1H), 4.72 (d, J = 48.9 Hz, 1H), 3.98-3.77 (m, 3H), 3.64 (s, 2H), 3.60-3.49 (m, 1H), 3.35 (s, 1H), 3.04 (t, J = 10.2 Hz, 1H), 2.70-2.55 (m, 2H), 2.47-2.35 (m, 2H), 2.01 (d, J = 12.4 Hz, 1H), 1.95-1.79 (m, 2H), 1.73 (s, 8H), 1.60 - 1.39 (m, 1H).LC-MS(M+H) + =514.

[0292] Example 100: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-(pyrrolidin-1-ylmethyl)quinolin-4(1H)-one [ka] The title compound (6.2 mg, 26%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and pyrrolidine in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.51 (s, 1H), 8.30 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.31 (d, J = 7.4 Hz, 1H), 6.20 (s, 1H), 5.55 - 5.30 (m, 1H), 4.97 (s, 1H), 4.05 - 3.80 (m, 3H), 3.75 (s, 2H), 3.53 (s, 1H), 3.34 - 3.30 (m, 5H), 3.04 (t, J = 10.4 Hz, 1H), 2.08 - 1.95 (m, 1H), 1.80 - 1.65 (m, 10H), 1.60 - 1.44 (m, 1H).LC-MS(M+H) + =482.1.

[0293] Example 101: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-(((4-methoxyphenyl)amino)methyl)quinolin-4(1H)-one [ka] The title compound (12 mg, 40%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and 4-methoxyaniline in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.52 (s, 1H), 8.29 (d, J = 8.7 Hz, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 6.74 (d, J = 8.1 Hz, 2H), 6.61 (d, J = 7.3 Hz, 2H), 6.30 (s, 1H), 6.00 (s, 1H), 5.13 (s, 1H), 4.97 (s, 1H), 4.41 (s, 2H), 3.92 - 3.72 (m, 3H), 3.63 (s, 3H), 3.53 (s, 1H), 3.35 - 3.15 (m, 1H), 3.06 - 3.03 (m, 1H), 2.00 (brs, 1H), 1.74 (brs, 6H), 1.54 - 1.51(m, 1H).LC-MS(M+H) + =534.1.

[0294] Example 102: 2-((8-oxa-3-azabicyclo[3.2.1]octan-3-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (17 mg, 40%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and 8-oxa-3-azabicyclo[3.2.1]octane in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.73 (brs, 1H), 8.51 (d, J = 3.8 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 7.96-7.86 (m, 1H), 7.29 (d, J = 8.0 Hz, 1H), 5.65-5.49 (m, 1H), 4.96 (d, J = 5.2 Hz, 1H), 4.28-4.22 (m, 2H), 4.01-3.79 (m, 3H), 3.70 (s, 2H), 3.62-3.47 (m, 1H), 3.42-3.32 (m, 1H), 3.12-2.99 (m, LC-MS(M+H) + =538.2.

[0295] Example 103: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-((4-hydroxy-4-methylpiperidin-1-yl)methyl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (13 mg, 30%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and 4-methylpiperidin-4-ol in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.72 (brs, 1H), 8.51 (d, J = 3.8 Hz, 1H), 8.34 (d, J = 8.5 Hz, 1H), 7.95-7.86 (m, 1H), 7.28 (d, J = 7.9 Hz, 1H), 5.58-5.43 (m, 1H), 4.96 (d, J = 5.2 Hz, 1H), 4.18 (s, 1H), 4.00-3.73 (m, 5H), 3.62-3.47 (m, 1H), 3.42-3.27 (m, 1H), 3.11-2.98 (m, 1H), 2.65-2.52 (m, 4H), 2.18 (s, 3H), 2.11-1.98 (m, 1H), 1.79-1.68 (m, 6H), 1.63-1.38 (m, 5H), 1.11 (s, 3H).LC-MS(M+H) + =540.2.

[0296] Example 104 and Example 105: (R)-7-((7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)-2,7-diazaspiro[4.5]decan-1-one and (S)-7-((7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)-2,7-diazaspiro[4.5]decan-1-one [ka] A mixture of Example 104 and Example 105 was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and racemic 2,7-diazaspiro[4.5]decan-1-one in a manner similar to that of Step 2 of Example 18. Example 104 and Example 105 were separated by chiral preparative HPLC using 70% mobile phase A and 30% mobile phase B. Chiral HPLC conditions: Cellulose-C column, 20.0 mm x 250 mm, 5 um. Mobile phase A: hexane, mobile phase B: ethanol containing 0.2% 2M NH3 in methanol, 18 mL / min in 15 min.

[0297] Example 104 (25 mg, 69%). RT=9.5 min. 1 H-NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.52 (s, 1H), 8.31 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.59 (s, 1H), 7.32 (d, J = 7.7 Hz, 1H), 6.16 (s, 1H), 5.53 - 5.34 (m, 1H), 4.97 (d, J = 4.5 Hz, 1H), 3.96 - 3.76 (m, 3H), 3.70 - 3.66 (m, 1H), 3.53 (brs, 1H), 3.49 - 3.46 (m, 1H), 3.31 (brs, 1H), 3.13 (s, 2H), 3.07 - 3.01 (m, 1H), 2.82 (d, J = 9.7 Hz, 1H), 2.64 (d, J = 11.1 Hz, 1H), 2.15 (d, J = 11.1 Hz, 1H), 2.18 - 2.02 (m, 2H), 1.95 - 1.93 (m, 2H), 1.84 - 1.64 (m, 6H), 1.74 -1.51 (m, 3H), 1.43 (s, 2H).LC-MS(M+H) + =565.1.

[0298] Example 105 (24 mg, 68%). RT=11 min. 1 H-NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.52 (s, 1H), 8.31 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 7.32 (d, J = 7.8 Hz, 1H), 6.16 (s, 1H), 5.44 - 5.40 (m, 1H), 4.98 (s, 1H), 3.95 - 3.75 (m, 3H), 3.70 - 3.67 (m, 1H), 3.54 (brs, 1H), 3.48 - 3.45 (m, 1H), 3.30 (s, 1H), 3.14 (s, 2H), 3.04 (t, J = 10.1 Hz, 1H), 2.82 (d, J = 9.8 Hz, 1H), 2.64 (d, J = 10.8 Hz, 1H), 2.17 - 2.15 (m, 1H), 2.07 - 1.80 (m, 4H), 1.74 (t, J = 7.4 Hz, 6H), 1.65 - 1.47 (m, 3H), 1.43 (brs, 2H).LC-MS(M+H) + =565.1.

[0299] Example 106: 2-(((3R,5R)-3,5-dimethylmorpholino)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (10 mg, 50%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (3R,5R)-3,5-dimethylmorpholine hydrochloride in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.74 (brs, 1H), 8.52 (d, J = 3.7 Hz, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 6.32 (s, 1H), 5.69 - 5.56 (m, 1H), 4.97 (s, 1H), 4.29 - 4.22 (m, 1H), 3.97 - 3.78 (m, 3H), 3.65 - 3.58 (m, 2H), 3.58 - 3.49 (m, 1H), 3.47 - 3.40 (m, 1H), 3.38 - 3.26 (m, 3H), 3.04 (t, J = 10.2 Hz, 1H), 2.81 - 2.71 (m, 2H), 2.06 - 1.96 (m, 1H), 1.80 - 1.68 (m, 6H), 1.59 - 1.46 (m, 1H), 1.08 - 1.02 (m, 6H).LC-MS(M+H) + =526.1.

[0300] Example 107: 2-(((3R,5S)-3,5-dimethylmorpholino)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (10 mg, 50%) was prepared from 2-(chloromethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropylquinolin-4(1H)-one and (3R,5S)-3,5-dimethylmorpholine hydrochloride in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.67 (brs, 1H), 8.52 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 6.72 (s, 1H), 5.22 - 5.12 (m, 1H), 4.98 (s, 1H), 3.95 - 3.80 (m, 5H), 3.75 - 3.65 (m, 2H), 3.59 - 3.49 (m, 1H), 3.38 - 3.28 (m, 1H), 3.27 - 3.17 (m, 2H), 3.04 (t, J = 10.0 Hz, 1H), 2.73 - 2.63 (s, 2H), 2.06 - 1.96 (m, 1H), 1.76 - 1.69 (m, 6H), 1.58 - 1.46 (m, 1H), 0.90 - 0.84 (m, 6H).LC-MS(M+H) + =526.1.

[0301] Example 108: 2-((dimethylamino)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (15 mg, 82%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and dimethylamine in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.72 (brs, 1H), 8.51 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 5.60 - 5.48 (m, 1H), 4.97 (s, 1H), 3.95 - 3.80 (m, 3H), 3.70 (s, 2H), 3.60 - 3.50 (m, 1H), 3.38 - 3.28 (m, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.29 (s, 6H), 2.18 (s, 3H), 2.06 - 1.97 (m, 1H), 1.75 - 1.68 (m, 6H), 1.58 - 1.46 (m, 1H).LC-MS(M+H) + =470.1.

[0302] Example 109: 2-((cyclopropylamino)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (15 mg, 80%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and cyclopropanamine in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.66 (brs, 1H), 8.50 (s, 1H), 8.32 (d, J = 8.7 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 5.51 - 5.39 (s, 1H), 4.97 (s, 1H), 3.97 - 3.80 (m, 5H), 3.58 - 3.48 (m, 1H), 3.38 - 3.28 (m, 1H), 3.04 (t, J = 10.3 Hz, 1H), 2.30 - 2.22 (m, 1H), 2.20 (s, 3H), 2.05 - 1.96 (m, 1H), 1.75 - 1.65 (m, 6H), 1.58 - 1.45 (m, 1H), 0.48 - 0.40 (m, 2H), 0.34 - 0.26 (m, 2H).LC-MS(M+H) + =482.1.

[0303] Example 110: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-((isopropylamino)methyl)-3-methylquinolin-4(1H)-one [ka] The title compound (15 mg, 79%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and propan-2-amine in a manner similar to that in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.67 (brs, 1H), 8.51 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 9.1 Hz, 1H), 5.62 - 5.50 (m, 1H), 4.98 (s, 1H), 3.94 - 3.80 (m, 5H), 3.59 - 3.49 (m, 1H), 3.38 - 3.29 (m, 1H), 3.04 (t, J = 10.7 Hz, 1H), 2.93 - 2.83 (m, 1H), 2.17 (s, 3H), 2.05 - 1.96 (m, 1H), 1.77 - 1.67 (s, 6H), 1.60 - 1.38 (m, 2H), 1.10 (brs, 6H).LC-MS(M+H) + =484.1.

[0304] Example 111: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-((((1r,3R)-3-fluorocyclobutyl)amino)methyl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (13 mg, 65%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and (1r,3r)-3-fluorocyclobutan-1-amine in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.68 (brs, 1H), 8.51 (d, J = 2.1 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 5.56 - 5.46 (m, 1H), 5.35 - 5.12 (m, 1H), 4.97 (d, J = 3.8 Hz, 1H), 3.95 - 3.73 (m, 5H), 3.58 - 3.48 (m, 2H), 3.38 - 3.29 (m, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.80 - 2.70 (m, 1H), 2.42 - 2.13 (m, 4H), 2.16 (s, 3H), 2.06 - 1.96 (m, 1H), 1.78 - 1.69 (m, 6H), 1.59 - 1.46 (m, 1H).LC-MS(M+H) + =514.1.

[0305] Example 112: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methyl-2-((((R)-tetrahydrofuran-3-yl)amino)methyl)quinolin-4(1H)-one [ka] The title compound (10 mg, 50%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and (R)-tetrahydrofuran-3-amine in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.68 (brs, 1H), 8.51 (s, 1H), 8.32 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.62 - 5.46 (m, 1H), 4.97 (d, J = 4.6 Hz, 1H), 3.95 - 3.76 (m, 7H), 3.75 - 3.67 (m, 1H), 3.58 - 3.50 (m, 2H), 3.48 - 3.41 (m, 1H), 3.37 - 3.29 (m, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.18 (s, 3H), 2.06 - 1.96 (m, 2H), 1.85 - 1.65 (m, 7H), 1.60 - 1.45 (m, 1H).LC-MS(M+H) + =512.1.

[0306] Example 113: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methyl-2-((((S)-tetrahydrofuran-3-yl)amino)methyl)quinolin-4(1H)-one [ka] The title compound (10 mg, 50%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and (S)-tetrahydrofuran-3-amine in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.68 (brs, 1H), 8.51 (s, 1H), 8.32 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 5.62 - 5.46 (m, 1H), 4.97 (d, J = 4.6 Hz, 1H), 3.95 - 3.76 (m, 7H), 3.75 - 3.67 (m, 1H), 3.58 - 3.50 (m, 2H), 3.48 - 3.41 (m, 1H), 3.37 - 3.29 (m, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.18 (s, 3H), 2.06 - 1.96 (m, 2H), 1.85 - 1.65 (m, 7H), 1.60 - 1.45 (m, 1H).LC-MS(M+H) + =512.1.

[0307] Example 114: 6-Fluoro-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((R)-3-fluoropyrrolidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] Step 1: (E)-1-(4-bromo-2,5-difluorophenyl)-3-(dimethylamino)but-2-en-1-one [ka] The title compound (730 mg, 51%) was prepared from 1-(4-bromo-2,5-difluorophenyl)ethan-1-one and 1,1-dimethoxy-N,N-dimethylethan-1-amine in a manner similar to that in Step 1 of Example 6. LC-MS (M+H) + =303.9.

[0308] Step 2: (E)-1-(4-bromo-2,5-difluorophenyl)-3-(isopropylamino)but-2-en-1-one [ka] The title compound (600 mg, 77%) was prepared from (E)-1-(4-bromo-2,5-difluorophenyl)-3-(dimethylamino)but-2-en-1-one and propan-2-amine in a manner similar to that in Step 2 of Example 6. LC-MS (M+H) + =317.9.

[0309] Step 3: 7-Bromo-6-fluoro-1-isopropyl-2-methylquinolin-4(1H)-one [ka] The title compound (450 mg, 80%) was prepared from (E)-1-(4-bromo-2,5-difluorophenyl)-3-(isopropylamino)but-2-en-1-one in a manner similar to that in Step 3 of Example 6. LC-MS (M+H) + =297.9.

[0310] Step 4: 6-Fluoro-1-isopropyl-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one [ka] The title compound (300 mg, 75%) was prepared from 7-bromo-6-fluoro-1-isopropyl-2-methylquinolin-4(1H)-one and bis(pinacolato)diboron in a manner similar to that described in Step 6 of Example 1. The corresponding boronic acid was analyzed by LC-MS (M+H). + =264.1.

[0311] Step 5: (3S,4R)-4-((5-fluoro-4-(6-fluoro-1-isopropyl-2-methyl-4-oxo-1,4-dihydroquinolin-7-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate [ka] The title compound (200 mg, 31%) was prepared from 6-fluoro-1-isopropyl-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4(1H)-one and (3S,4R)-4-((4-chloro-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate in a manner similar to that described in Step 7 of Example 1. LC-MS (M+H) + =473.2.

[0312] Step 6: (3S,4R)-4-((5-fluoro-4-(6-fluoro-2-formyl-1-isopropyl-4-oxo-1,4-dihydroquinolin-7-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate [ka] The title compound (56 mg, 27%) was prepared from (3S,4R)-4-((5-fluoro-4-(6-fluoro-1-isopropyl-2-methyl-4-oxo-1,4-dihydroquinolin-7-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate in a manner similar to that in Step 1 of Example 17. LC-MS (M+H) + =487.1.

[0313] Step 7: (3S,4R)-4-((5-fluoro-4-(6-fluoro-2-(((R)-3-fluoropyrrolidin-1-yl)methyl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-7-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate [ka] The title compound (57 mg, 88%) was prepared from (3S,4R)-4-((5-fluoro-4-(6-fluoro-2-formyl-1-isopropyl-4-oxo-1,4-dihydroquinolin-7-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate and (R)-3-fluoropyrrolidine in a manner similar to that described in Step 6 of Example 37. LC-MS (M+H) + =560.3.

[0314] Step 8: 6-fluoro-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((R)-3-fluoropyrrolidin-1-yl)methyl)-1-isopropylquinolin-4(1H)-one [ka] The title compound (12 mg, 23%) was prepared from (3S,4R)-4-((5-fluoro-4-(6-fluoro-2-(((R)-3-fluoropyrrolidin-1-yl)methyl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-7-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate in a manner similar to that in Step 10 of Example 55. 1H-NMR (400 MHz, DMSO-d6) δ 8.52 (d, J = 2.3 Hz, 1H), 8.28 (brs, 1H), 7.97 (d, J = 10.1 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 6.24 (s, 1H), 5.41-5.26 (m, 2H), 4.96 (d, J = 5.2 Hz, 1H), 3.87-3.74 (m, 5H), 3.58-3.46 (m, 1H), 3.32-3.21 (m, 1H), 3.04-2.95 (m, 1H), 2.92-2.81 (m, 2H), 2.76-2.60 (m, 1H), 2.45-2.35 (m, 1H), 2.27-2.08 (m, 1H), 2.04-1.80 (m, 2H), 1.70-1.60 (m, 6H), 1.58-1.43 (m, 1H).LC-MS(M+H) + =518.3.

[0315] Example 115: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-((4-hydroxypiperidin-1-yl)methyl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (22 mg, 55%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and piperidin-4-ol in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.73 (brs, 1H), 8.51 (d, J = 3.8 Hz, 1H), 8.34 (d, J = 8.5 Hz, 1H), 7.95-7.86 (m, 1H), 7.29 (d, J = 7.9 Hz, 1H), 5.56-5.40 (m, 1H), 4.96 (d, J = 5.2 Hz, 1H), 4.59 (d, J = 4.1 Hz, 1H), 3.97-3.80 (m, 3H), 3.77 (s, 2H), 3.63-3.46 (m, 2H), 3.41-3.27 (m, 1H), 3.11-2.98 (m, 1H), 2.81-2.71 (m, 2H), 2.31-2.19 (m, 2H), 2.17 (s, 3H), 2.08-1.98 (m, 1H), 1.79-1.69 (m, 8H), 1.65-1.45 (m, 1H), 1.43-1.34 (m, 2H).LC-MS(M+H) + =526.2.

[0316] Example 116: 2-((3,3-difluoropiperidin-1-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (8 mg, 37%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and 3,3-difluoropiperidine in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.74 (brs, 1H), 8.51 (d, J = 2.9 Hz, 1H), 8.35 (d, J = 8.6 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 5.46 - 5.33 (m, 1H), 4.97 (d, J = 4.5 Hz, 1H), 3.95 - 3.80 (m, 5H), 3.58 - 3.48 (m, 1H), 3.38 - 3.28 (m, 1H), 3.03 (t, J = 10.4 Hz, 1H), 2.89 - 2.79 (m, 2H), 2.58 - 2.50 (m, 2H), 2.18 (s, 3H), 2.05 - 1.84 (m, 3H), 1.77 - 1.60 (m, 8H), 1.58 - 1.46 (m, 1H).LC-MS(M+H) + =546.1.

[0317] Example 117: 2-((7-oxa-4-azaspiro[2.5]octan-4-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (3 mg, 14%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and 7-oxa-4-azaspiro[2.5]octane in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.71 (brs, 1H), 8.51 (d, J = 3.1 Hz, 1H), 8.33 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 5.36 - 5.23 (m, 1H), 4.97 (s, 1H), 4.05 (s, 2H), 3.96 - 3.79 (m, 3H), 3.69 - 3.63 (m, 2H), 3.58 - 3.49 (m, 3H), 3.39 - 3.29 (m, 1H), 3.04 (t, J = 10.3 Hz, 1H), 2.81 - 2.75 (m, 2H), 2.21 (s, 3H), 2.06 - 1.96 (m, 1H), 1.75 - 1.64 (m, 6H), 1.59 - 1.44 (m, 1H), 0.77 - 0.70 (m, 2H), 0.53 - 0.46 (m, 2H).LC-MS(M+H) + =538.1.

[0318] Example 118: 2-(((3S,5S)-3,5-dimethylmorpholino)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (1 mg, 5%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and (3S,5S)-3,5-dimethylmorpholine hydrochloride in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.74 (brs, 1H), 8.51 (d, J = 2.7 Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 5.67 - 5.51 (m, 1H), 4.99 (s, 1H), 4.22 - 4.15 (m, 1H), 3.96 - 3.80 (m, 5H), 3.66 - 3.49 (m, 4H), 3.38 - 3.28 (m, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.86 - 2.76 (m, 2H), 2.24 (s, 3H), 2.06 - 1.96 (m, 1H), 1.82 - 1.69 (m, 6H), 1.59 - 1.46 (m, 1H), 1.05 - 0.98 (m, 6H).LC-MS(M+H) + =540.1.

[0319] Example 119: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(hydroxymethyl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (10 mg, 56%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and water in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.67 (brs, 1H), 8.51 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 5.79 (brs, 1H), 5.45 - 5.25 (m, 1H), 4.98 (brs, 1H), 4.71 (s, 2H), 3.95 - 3.80 (m, 3H), 3.57 - 3.50 (m, 1H), 3.38 - 3.28 (m, 1H), 3.04 (t, J = 10.1 Hz, 1H), 2.18 (s, 3H), 2.07 - 1.97 (m, 1H), 1.78 - 1.70 (m, 6H), 1.60 - 1.45 (m, 1H).LC-MS(M+H) + =443.1.

[0320] Example 120: 2-(aminomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (10 mg, 56%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and ammonia in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.66 (brs, 1H), 8.52 (s, 1H), 8.32 (d, J = 8.6 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 6.86 (brs, 2H), 532 - 5.20 (m, 1H), 5.01 (d, J = 4.6 Hz, 1H), 4.12 (s, 2H), 3.95 - 3.80 (m, 3H), 3.60 - 3.50 (m, 1H), 3.38 - 3.28 (m, 1H), 3.04 (t, J = 10.2 Hz, 1H), 2.18 (s, 3H), 2.06 - 1.96 (m, 1H), 1.78 - 1.70 m, 6H), 1.59 - 1.46 (m, 1H).LC-MS(M+H) + =442.1.

[0321] Embodiment 121: 2-((4,4-difluoropiperidin-1-yl)methyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (1.5 mg, 7%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and 4,4-difluoropiperidine hydrochloride in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.51 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 5.56 - 5.40 (m, 1H), 4.97 (s, 1H), 4.02 - 3.76 (m, 5H), 3.54 (s, 1H), 3.04 (t, J = 10.3 Hz, 1H), 2.65 (s, 4H), 2.54 (s, 1H), 2.17 (s, 3H), 2.10 - 1.89 (m, 5H), 1.75 (t, J = 7.1 Hz, 6H), 1.64 - 1.44 (m, J = 11.9 Hz, 1H).LC-MS(M+H) + =546.1.

[0322] Example 122: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((R)-3-hydroxypiperidin-1-yl)methyl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (5.1 mg, 23%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and (R)-piperidin-3-ol hydrochloride in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.51 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 5.47 (d, J = 7.1 Hz, 1H), 4.97 (d, J = 4.7 Hz, 1H), 4.64 (d, J = 3.7 Hz, 1H), 4.02 - 3.72 (m, 5H), 3.59 - 3.49 (m, 1H), 3.43 (s, 1H), 3.35 (s, 1H), 3.32 - 3.28 (m, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.91 - 2.82 (m, 1H), 2.71 (s, 1H), 2.17 (s, 3H), 2.15 - 1.90 (m, J = 35.7, 23.0 Hz, 3H), 1.87 - 1.57 (m, 1H), 1.77 - 1.70 (m, 6H), 1.59 - 1.47 (m, J = 10.9 Hz, 1H), 1.45 - 1.31 (m, 1H), 1.19 - 1.04 (m, J = 11.1 Hz, 1H).LC-MS(M+H) + =526.1.

[0323] Example 123: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((S)-3-hydroxypiperidin-1-yl)methyl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (5 mg, 23%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and (S)-piperidin-3-ol hydrochloride in a manner similar to that described in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.51 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 5.57 - 5.37 (m, 1H), 4.97 (d, J = 4.7 Hz, 1H), 4.64 (d, J = 3.7 Hz, 1H), 4.02 - 3.72 (m, 5H), 3.59 - 3.49 (m, 1H), 3.43 (s, 1H), 3.35 (s, 1H), 3.32 - 3.28 (m, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.91 - 2.82 (m, 1H), 2.71 (s, 1H), 2.17 (s, 3H), 2.15 - 1.90 (m, J = 35.7, 23.0 Hz, 3H), 1.87 - 1.57 (m, LC-MS(M+H) + =526.1.

[0324] Example 124: 7-((7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)methyl)-2,7-diazaspiro[4.5]decan-1-one [ka] The title compound (4 mg, 20%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and 2,7-diazaspiro[4.5]decan-1-one in a manner similar to that described in Step 2 of Example 18.1 H-NMR (400 MHz, DMSO-d6) δ 8.72 (brs, 1H), 8.51 (s, 1H), 8.34 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 5.65 - 5.51 (m, 1H), 4.97 (d, J = 4.7 Hz, 1H), 3.95 - 3.75 (m, 3H), 3.74 (s, 2H), 3.59 - 3.49 (m, 1H), 3.38 - 3.29 (m, 1H), 3.17 - 3.09 (m, 2H), 3.04 (t, J = 10.4 Hz, 1H), 2.82 (d, J = 10.2 Hz, 1H), 2.69 - 2.60 (m, 1H), 2.34 - 2.26 (m, 1H), 2.16 (s, 3H), 2.14 - 1.88 (m, 4H), 1.78 - 1.70 m, 6H), 1.65 - 1.38 (m, 5H).LC-MS(M+H) + =579.2.

[0325] Example 125: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-2-(((S)-3-hydroxy-3-methylpyrrolidin-1-yl)methyl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] The title compound (6.9 mg, 27%) was prepared from 2-(bromomethyl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one and (S)-3-methylpyrrolidin-3-ol in a manner similar to that in Step 2 of Example 18. 1H-NMR (400 MHz, DMSO-d6) δ:8.72 (s, 1H), 8.51 (s, 1H), 8.33 (d, J = 7.9 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 5.61 - 5.50 (m, 1H), 5.00 - 4.93 (m, 1H), 4.58 (s, 1H), 3.96 - 3.80 (m, 5H), 3.58 - 3.49 (m, 1H), 3.40 - 3.34 (m, 1 H), 3.04 (t, J = 10.3 Hz, 1H), 2.76 - 2.69 (m, 2H), 2.64 - 2.58 (m, 1H), 2.57 - 2.53 (m, 1H), 2.19 (s, 3H), 2.06 - 1.97 (m, 1H) 1.80 - 1.66 (m, 8H), 1.59 - 1.46 (m, 1H), 1.25 (s, 3H).LC-MS(M+H) + =526.1.

[0326] Example 386: 2-(azetidin-2-yl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] Step 1: tert-butyl 2-(3-(4-chloro-2-fluorophenyl)-3-oxoprop-1-yn-1-yl)azetidine-1-carboxylate [ka] To a solution of 4-chloro-2-fluorobenzoyl chloride (7 g, 36.3 mmol), copper(I) iodide (345 mg, 1.81 mmol), and bis(triphenylphosphine)palladium(II) dichloride (2.55 g, 3.63 mmol) in tetrahydrofuran (70 mL), triethylamine (4.77 g, 47.2 mmol, 6.56 mL) and tert-butyl 2-ethynylazetidine-1-carboxylate (6.57 g, 36.3 mmol) were added dropwise at 25 °C under a nitrogen atmosphere. The resulting mixture was stirred at 25 °C for 12 hours before the addition of water (70 mL). The mixture was extracted with dichloromethane (100 mL × 3). The combined organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate in petroleum ether (16%, v / v) to give the title compound (7.2 g, 59%). LC-MS (M+H) + =238.1(M-99).

[0327] Step 2: tert-Butyl 2-(3-(4-chloro-2-fluorophenyl)-1-(isopropylamino)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate [ka] To a solution of tert-butyl 2-(3-(4-chloro-2-fluorophenyl)-3-oxoprop-1-yn-1-yl)azetidine-1-carboxylate (3 g, 8.88 mmol) in tetrahydrofuran (30 mL) and ethanol (30 mL) was added propan-2-amine (788 mg, 13.3 mmol) at 25° C., and the reaction solution was stirred for 8 hours before being concentrated. The residue was purified on silica gel by column chromatography eluting with ethyl acetate in petroleum ether (0-100% gradient, v / v) to give the title compound (2.5 g, 71%). LC-MS (M+H) + =397.2.

[0328] Step 3: tert-Butyl 2-(7-chloro-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)azetidine-1-carboxylate [ka] To a solution of tert-butyl 2-(3-(4-chloro-2-fluorophenyl)-1-(isopropylamino)-3-oxoprop-1-en-1-yl)azetidine-1-carboxylate (5 g, 12.60 mmol) in dimethylacetamide (50 mL) was added potassium carbonate (2.61 g, 18.9 mmol) under a nitrogen atmosphere at 25° C. for 0.5 h. The mixture was stirred at 130° C. for 48 h before being cooled to room temperature and concentrated. The residue was purified on silica gel by column chromatography eluting with ethyl acetate in petroleum ether (0-2% gradient, v / v) to give the title compound (2.1 g, 44%). LC-MS (M+H) + =377.2.

[0329] Step 4: tert-Butyl 2-(7-chloro-3-iodo-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)azetidine-1-carboxylate [ka] The title compound (0.8 g, 40%) was prepared from tert-butyl 2-(7-chloro-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)azetidine-1-carboxylate and iodine in a manner similar to Step 1 of Example 16. LC-MS (M+H) + =503.1.

[0330] Step 5: tert-Butyl 2-(7-chloro-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)azetidine-1-carboxylate [ka] The title compound (0.52 g, 82%) was prepared from tert-butyl 2-(7-chloro-3-iodo-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)azetidine-1-carboxylate in a manner similar to Step 2 of Example 9. LC-MS (M+H) + =391.1.

[0331] Step 6: tert-Butyl 2-(1-isopropyl-3-methyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydroquinolin-2-yl)azetidine-1-carboxylate [ka] The title compound (0.5 g, 90%) was prepared from tert-butyl 2-(7-chloro-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)azetidine-1-carboxylate and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane in a manner similar to Step 6 of Example 1. LC-MS (M+H) + =483.4.

[0332] Step 7: tert-Butyl 2-(7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)azetidine-1-carboxylate [ka] The title compound (0.5 g, 90%) was prepared from tert-butyl 2-(1-isopropyl-3-methyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydroquinolin-2-yl)azetidine-1-carboxylate and 2,4-dichloro-5-fluoro-pyrimidine in a manner similar to Step 7 of Example 1. LC-MS (M+H) + =487.2.

[0333] Step 8: tert-Butyl 2-(7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)azetidine-1-carboxylate [ka] The title compound (0.15 g, 64%) was prepared from tert-butyl 2-(7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)azetidine-1-carboxylate and (3S,4R)-4-aminotetrahydropyran-3-ol in a manner similar to that described in Step 8 of Example 1. LC-MS (M+H) + =568.3.

[0334] Step 9: 2-(Azetidin-2-yl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one [ka] To a solution of tert-butyl 2-(7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)azetidine-1-carboxylate (150 mg, 264 μmol) in dichloromethane (3 mL) was added zinc bromide (297 mg, 1.32 mmol), and the reaction mixture was stirred at 25 °C for 12 h before being concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini NX-C18, 75 × 30 mm, 5 μm; mobile phase: acetonitrile in water (containing 10 mM NH4HCO3), 10% to 50% gradient in 8.0 min); detector, UV 254 nm. The title compound (25 mg, 92%) was obtained. 1H NMR (400 MHz, DMSO-d6) δ = 8.65 (br d, J = 1.2 Hz, 1H), 8.50 (d, J = 3.6 Hz, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 5.42 (t, J = 7.8 Hz, 1H), 5.19 - 5.28 (m, 1H), 4.95 (d, J = 5.2 Hz, 1H), 3.84 (d, J = 5.2, 10.8 Hz, 4H), 3.49 - 3.63 (m, 2H), 3.12 (t, J = 6.4 Hz, 1H), 3.03 (t, J = 10.4 Hz, 1H), 2.70 - 2.79 (m, 1H), 2.06 (s, 3H), 2.02 (d, J = 7.2 Hz, 1H), 1.77 (t, J = 6.4 Hz, 3H), 1.66 - 1.74 (m, 1H), 1.51 - 1.59 (m, 4H), 1.45 - 1.51 (m, 1H).LC-MS(M+H) + =468.3.

[0335] Example 387: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methyl-2-(1-methylazetidin-2-yl)quinolin-4(1H)-one [ka] To a solution of 2-(azetidin-2-yl)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylquinolin-4(1H)-one (30 mg, 64.17 μmol) in methanol (1 mL) was added formaldehyde solution (52.1 mg, 642 μmol, 47.8 μL, 37%) and sodium cyanoborohydride (8.06 mg, 128 μmol). The reaction mixture was stirred at 25° C. for 1 hour before being quenched by the addition of water (3 mL). The mixture was extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm, 10 μm; mobile phase: acetonitrile in water (containing 10 mM NH4HCO3), 20% to 70% gradient in 8.0 min); detector, UV 254 nm. The title compound (11 mg, 35.6%) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ = 8.69 (br s, 1H), 8.50 (d, J = 3.6 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 6.36 - 6.43 (m, 1H), 4.96 (d, J = 5.4 Hz, 1H), 4.62 (t, J = 8.8 Hz, 1H), 3.83 -3.87 (m, 3H), 3.47 - 3.59 (m, 2H), 3.04 (t, J = 10.4Hz, 1H), 2.94 - 2.96 (m, 1H), 2.48 (s, 1H), 2.34 - 2.40 (m, 1H), 2.32 (s, 3H), 2.26 (s, 3H), 2.02 (d, J = 12.0 Hz, 1H), 1.69 - 1.75 (m, 6H), 1.61 - 1.69 (m, 1H), 1.46 - 1.58 (m, 1H).LC-MS(M+H) + =482.3.

[0336] Example 388: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-(pyrrolidin-2-yl)quinolin-4(1H)-one [ka] Step 1: tert-butyl 2-(3-(4-chloro-2-fluorophenyl)-3-oxoprop-1-yn-1-yl)pyrrolidine-1-carboxylate [ka] The title compound (1.3 g, 76%) was prepared from 4-chloro-2-fluorobenzoyl chloride and tert-butyl 2-ethynylpyrrolidine-1-carboxylate in a manner similar to that in Step 1 of Example 386. LC-MS (M+H) + =352.1.

[0337] Step 2: tert-Butyl 2-(7-chloro-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate [ka] To a solution of tert-butyl 2-(3-(4-chloro-2-fluorophenyl)-3-oxoprop-1-yn-1-yl)pyrrolidine-1-carboxylate (0.9 g, 2.7 mmol) in dimethylacetamide (10 mL) was added isopropylamine (240 mg, 4.06 mmol) and potassium carbonate (572 mg, 4.14 mmol) in small portions at room temperature. The resulting mixture was stirred at 130° C. under a nitrogen atmosphere for 5 hours before being cooled to room temperature. Water (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel by Combiflash eluting with ethyl acetate in petroleum ether (0-60%, v / v) to give the title compound (180 mg, 17%). LC-MS (M+H) +=391.1.

[0338] Step 3: tert-Butyl 2-(1-isopropyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate [ka] The title compound (170 mg, crude for next step) was prepared from tert-butyl 2-(7-chloro-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate in a manner similar to that in Step 6 of Example 1. LC-MS (M+H) + =483.3.

[0339] Step 4: tert-Butyl 2-(7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate [ka] The title compound (50 mg, 23%) was prepared from tert-butyl 2-(1-isopropyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate and 2,4-dichloro-5-fluoropyrimidine in a manner similar to that described in Step 7 of Example 1. LC-MS (M+H) + =487.2.

[0340] Step 5: tert-Butyl 2-(7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate [ka] The title compound (31 mg, 68%) was prepared from tert-butyl 2-(7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate and (3S,4R)-4-aminooxan-3-ol hydrochloride in a manner similar to that in Step 8 of Example 1. LC-MS (M+H) + =568.3.

[0341] Step 6: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-2-(pyrrolidin-2-yl)quinolin-4(1H)-one [ka] The title compound (7 mg, 27%) was prepared from tert-butyl 2-(7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate in a manner similar to that in Step 9 of Example 386. 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.51 (d, J = 3.8 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 5.32-5.20 (m, 1H), 4.97 (d, J = 5.2 Hz, 1H), 4.45-4.37 (m, 1H), 3.90-3.81 (m, 3H), 3.60-3.48 (m, 1H), 3.37 -3.32 (m, 1H), 3.09-2.95 (m, 3H), 2.45-2.30 (m, 2H), 2.05-1.98 (m, 1H), 1.83-1.69 (m, 8H), 1.68-1.46 (m, 2H).LC-MS(M+H) + =468.1.

[0342] Example 389: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methyl-2-(pyrrolidin-2-yl)quinolin-4(1H)-one [ka] Step 1: tert-Butyl 2-(7-chloro-3-iodo-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate [ka] The title compound (43 mg, 23%) was prepared from tert-butyl 2-(7-chloro-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate in a manner similar to that in Step 1 of Example 16. LC-MS (M+H) + =517.1.

[0343] Step 2: tert-Butyl 2-(7-chloro-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate [ka] The title compound (32 mg, 94%) was prepared from tert-butyl 2-(7-chloro-3-iodo-1-isopropyl-4-oxo-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate in a manner similar to that in Step 2 of Example 9. LC-MS (M+H) + =405.1.

[0344] Step 3: tert-butyl 2-(1-isopropyl-3-methyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate [ka] The title compound (50 mg, crude used in the next step) was prepared from tert-butyl 2-(7-chloro-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate in a manner similar to that in Step 6 of Example 1. LC-MS (M+H) + =497.4.

[0345] Step 4: tert-Butyl 2-(7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate [ka] The title compound (14 mg, 35%) was prepared from tert-butyl 2-(1-isopropyl-3-methyl-4-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate and 2,4-dichloro-5-fluoropyrimidine in a manner similar to that described in Step 7 of Example 1. LC-MS (M+H) + =501.2.

[0346] Step 5: tert-butyl 2-(7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate [ka] The title compound (10 mg, 57%) was prepared from tert-butyl 2-(7-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate and (3S,4R)-4-aminooxan-3-ol hydrochloride in a manner similar to that in Step 8 of Example 1. LC-MS (M+H)+ =582.4.

[0347] Step 6: 7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methyl-2-(pyrrolidin-2-yl)quinolin-4(1H)-one [ka] The title compound (1 mg, 11%) was prepared from tert-butyl 2-(7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methyl-4-oxo-1,4-dihydroquinolin-2-yl)pyrrolidine-1-carboxylate in a manner similar to that in Step 9 of Example 386. 1 H NMR (400 MHz, DMSO-d6) δ 8.73-8.68 (m, 1H), 8.50 (d, J = 3.8 Hz, 1H), 8.34-8.27 (m, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 5.71-5.59 (m, 1H), 4.96 (d, J = 5.2 Hz, 1H), 4.79-4.70 (m, 1H), 3.89-3.81 (m, 3H), 3.60-3.49 (m, 1H), 3.33-3.28 (m, 2H), 3.09-2.92 (m, 3H), 2.57-2.52 (m, 1H), 2.36-2.25 (m, 2H), 2.20 (s, 3H), 2.00 (s, 1H), 1.78-1.70 (m, 3H), 1.69-1.61 (m, 3H), 1.58-1.44 (m, 1H).LC-MS(M+H) + =482.1.

[0348] Biological assays The compounds disclosed herein were tested for inhibition of CDK4 / cyclin D1 or CDK6 / cyclin D3 kinase in an assay based on time-resolved fluorescence resonance energy transfer (TR-FRET) technology. The assay was performed in a 384-well low-volume black plate in a reaction mixture containing CDK4 / cyclin D1 or CDK6 / cyclin D3, 1 mM ATP, 0.15 μM Rb(Ser780)-biotin substrate, and 0-10 μM compound in a buffer containing 50 mM HEPES, 0.01% BSA, 0.1 mM orthovanadate, 50 mM MgCl2, 1 mM DTT, and 0.005% Tween-20 at pH 7.0. The kinase was incubated with the compound for 60 minutes at room temperature, and the reaction was initiated by the addition of ATP and Rb(Ser780)-biotin substrate. After 120 min of incubation at room temperature, an equal volume of stop / detection solution was added according to the manufacturer's instructions (Cisbio Bioassays). The stop / detection solution contained streptavidin-XL665 and anti-pRb (Ser780) mAb-Eu cryptate in detection buffer (Cisbio Bioassays). The plate was incubated for 60 min at room temperature, and the TR-FRET signal (ex 337 nm, em 665 nm / 620 nm) was recorded using a PHERAstar FSX plate reader (BMG Labtech). The percent inhibition of CDK4 / cyclin D1 or CDK6 / cyclin D3 kinase activity in the presence of increasing concentrations of compound was calculated based on the ratio of fluorescence at 665 nm to 620 nm. The IC50 of each compound was derived by fitting the data to a four-parameter logistic equation using Dotmatics. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

Claims

1. Compound of formula (I): 【Chemistry 1】 or its N-oxide, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its deuterated analog, or its prodrug, During the ceremony, The ring CyA is a 3- to 8-membered ring, and the ring contains, as ring members (or more), 0, 1, or 2 heteroatoms (or more) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and the ring has at least one substituent R １０ It is optionally replaced by, n is 0, 1, 2, 3, 4, or 5, m is 0 or 1, however, when m = 0, the whole 【Chemistry 2】 The condition is that the part is replaced by H, R １ where R is H, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, cycloalkyl, haloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR １ａ , -COR １ａ , -CO ２ R １ａ , -CONR １ａ R １ｂ , -NR １ａ R １ｂ , -NR １ａ COR １ｂ , -NR １ａ CO ２ R １ｂ , or -NR １ａ CONR １ｂ R １ｃ and each of said -C １－８ alkyl, said -C ２－８ alkenyl, said -C ２－８ alkynyl, said cycloalkyl, said heterocyclyl, said aryl, or said heteroaryl is optionally substituted with at least one substituent R １ｄ . R １ａ , R １ｂ , and R １ｃ However, each independently, hydrogen, -C １－８ Selected from alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C １－８ Alkyl, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has at least one substituent R １ｆ It is optionally replaced by, R １ｄ and R １ｆ However, each independently, hydrogen, halogen, hydroxyl, and -C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, and the -C １－８ Alkyl, the above-mentioned -halo C １－８ Alkyl, the above-C １－８ Alkoxy, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl is a halogen, hydroxy, -C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -halo C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, R ２ is hydrogen, halogen, -C １－８ alkyl, -C ２－８ alkenyl, -C ２－８ alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR ２ａ , -SO ２ R ２ａ , -SO ２ NR ２ａ R ２ｂ , -COR ２ａ , -CO ２ R ２ａ , -CONR ２ａ R ２ｂ , -NR ２ａ R ２ｂ , -NR ２ａ COR ２ｂ , -NR ２ａ CO ２ R ２ｂ , -NR ２ａ CONR ２ｂ R ２ｃ , or -NR ２ａ SO ２ R ２ｂ and each of the -C １－８ alkyl, the -C ２－８ alkenyl, the -C ２－８ alkynyl, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl is optionally substituted with at least one substituent R ２ｄ , R ２ａ , R ２ｂ , and R ２ｃ are each independently hydrogen, -C[[ID=7​​​​​​​​​​​​​ (R ２ａ and R ２ｂ ), (R ２ｂ and R ２ｃ ), or (R ２ａ and R ２ｃ ) together with the atom(s) to which they are attached form a 3- to 12-membered ring, said ring containing, as ring member(s), independently, 0, 1, or 2 heteroatom(s) (s) selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring being optionally substituted with at least one substituent R ２ｆ . R ２ｄ and R ２ｆ However, each independently, hydrogen, halogen, and -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR ２ｇ , -SO ２ R ２ｇ , -SO ２ NR ２ｇ R ２ｈ , -COR ２ｇ , -CO ２ R ２ｇ , -CONR ２ｇ R ２ｈ , -NO ２ , -NR ２ｇ R ２ｈ , -NR ２ｇ COR ２ｈ , -NR ２ｇ CO ２ R ２ｈ , -NR ２ｇ CONR ２ｈ R ２ｉ , or -NR ２ｇ SO ２ R ２ｈ Selected from, the above-C １－８ Alkyl, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is a halogen, hydroxy, oxo, or -C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -halo C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ They are optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, or (2 R ２ｄ ) and / or (two R ２ｆ ) together with the atoms (or more) to which they are bonded, form a 3- to 12-membered ring, wherein the ring contains, as ring members (or more), 0, 1, or 2 heteroatoms (or more) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and the ring contains halogen, hydroxyl, oxo, -C １－８ Alkyl, -halo C １－８ Alkyl, -C(O)C １－８ Alkyl, -C １－８ Alkoxy, -halo C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, R ２ｇ , R ２ｈ , and R ２ｉ However, each independently, hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C １－８ Alkyl, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is a halogen, hydroxyl, -C １－８ Alkyl, -C(O)C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -halo C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, R ３Ａ and R ３Ｂ However, each independently, hydrogen, halogen, and -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or -CN, the -C １－８ Alkyl, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has at least one substituent R ３ｃ It is optionally replaced by, R ３Ａ and R ３Ｂ However, together with the atoms to which they are bonded, they form an oxo group (-C(=O)-) or a 3- to 12-membered ring, and the ring contains, as ring members (multiple), 0, 1, or 2 heteroatoms (multiple) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and the ring has at least one substituent R ３ｃ It is optionally replaced by, R ３ｃ However, each independently, hydrogen, halogen, and -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR ３ｄ , -SO ２ R ３ｄ , -SO ２ NR ３ｄ R ３ｅ , -COR ３ｄ , -CO ２ R ３ｄ , -CONR ３ｄ R ３ｅ , -NO ２ , -NR ３ｄ R ３ｅ , -NR ３ｄ COR ３ｅ , -NR ３ｄ CO ２ R ３ｅ , -NR ３ｄ CONR ３ｅ R ３ｆ , or -NR ３ｄ SO ２ R ３ｅ Selected from, the above-C １－８ Alkyl, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is a halogen, hydroxyl, -C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -halo C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, R ３ｄ , R ３ｅ , and R ３ｆ However, each independently, hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C １－８ Alkyl, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is a halogen, hydroxyl, -C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -halo C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, R ４ However, hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, or heterocyclyl, and the -C １－８ Alkyl, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, or heterocyclyl has at least one substituent R ４ａ It is optionally replaced by, R ４ａ However, each independently, hydrogen, halogen, and -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR ４ｂ , -SO ２ R ４ｂ , -SO ２ NR ４ｂ R ４ｃ , -COR ４ｂ , -CO ２ R ４ｂ , -CONR ４ｂ R ４ｃ , -NO ２ , -NR ４ｂ R ４ｃ , -NR ４ｂ COR ４ｃ , -NR ４ｂ CO ２ R ４ｃ , -NR ４ｂ CONR ４ｃ R ４ｄ , or -NR ４ｂ SO ２ R ４ｃ Selected from, the above-C １－８ Alkyl, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is a halogen, hydroxyl, -C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -halo C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, R ４ｂ , R ４ｃ , and R ４ｄ However, each independently, hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C １－８ Alkyl, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is a halogen, hydroxyl, -C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -halo C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, R ５ , R ６ , R ７ , R ８ , and R ９ However, each is independent of H, halogen, and -C. １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR ５ａ , -COR ５ａ , -CO ２ R ５ａ , -CONR ５ａ R ５ｂ , -NR ５ａ R ５ｂ , -NR ５ａ COR ５ｂ , -NR ５ａ CO ２ R ５ｂ , or -NR ５ａ CONR ５ｂ R ５ｃ Selected from, the above-C １－８ Alkyl, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has at least one substituent R ５ｄ It is optionally replaced by, R ５ａ , R ５ｂ , and R ５ｃ However, each independently, hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C １－８ Alkyl, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has at least one substituent R ５ｆ It is optionally replaced by, R ５ｄ and R ５ｆ However, each independently, hydrogen, halogen, hydroxyl, and -C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, and the -C １－８ Alkyl, the above-mentioned -halo C １－８ Alkyl, the above-C １－８ Alkoxy, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl is a halogen, hydroxy, -C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -halo C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, R １０ However, H, halogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -CN, -OR １０ａ , -COR １０ａ , -CO ２ R １０ａ , -CONR １０ａ R １０ｂ , -NR １０ａ R １０ｂ , -NR １０ａ COR １０ｂ , -NR １０ａ CO ２ R １０ｂ , or -NR １０ａ CONR １０ｂ R １０ｃ Selected from, the above-C １－８ Alkyl, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has at least one substituent R １０ｄ It is optionally replaced by, R １０ａ , R １０ｂ , and R １０ｃ However, each independently, hydrogen, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, the -C １－８ Alkyl, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl has at least one substituent R １０ｆ It is optionally replaced by, R １０ｄ and R １０ｆ However, each independently, hydrogen, halogen, hydroxyl, and -C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, and the -C １－８ Alkyl, the above-mentioned -halo C １－８ Alkyl, the above-C １－８ Alkoxy, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl is a halogen, hydroxy, -C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -halo C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, R １１ However, H, -C １－８ Alkyl, -C ２－８ Alkenyl, -C ２－８ Selected from alkynyl, and the -C １－８ Alkyl, the above-C ２－８ Alkenyl, or the aforementioned -C ２－８ Each alkynyl has at least one substituent R １１ａ It is optionally replaced by, R １１ａ However, hydrogen, halogen, hydroxyl, -C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, and the -C １－８ Alkyl, the above-mentioned -halo C １－８ Alkyl, the above-C １－８ Alkoxy, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl is a halogen, hydroxy, -C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -halo C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ The compound, its N-oxide, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its deuterated analog, or its prodrug, which is optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl.

2. The compound is selected from formulas (IIa), (IIb), (IIc), (IId), or (IIe), 【Transformation 3】 In the formula, R １ , R ２ , R ３Ａ , R ３Ｂ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , R １１ m and n are as defined in claim 1, Preferably, the compound is selected from formula (IIf), (IIg), (IIh), or (III), 【Chemistry 4】 In the formula, R １ , R ２ , R ３Ａ , R ３Ｂ , R ４ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , and n are as defined in claim 1, More preferably, the compound is selected from formula (IIj), (IIk), (IIl), or (IIm), 【Transformation 5】 In the formula, R １ , R ２ , R ３Ａ , R ３Ｂ , R ５ , R ６ , R ７ , R ８ , R ９ , R １０ , and n are as defined in claim 1, More preferably, the compound is selected from formula (IIn), (IIo), (IIp), or (IIq), 【Transformation 6】 In the formula, R １ , R ２ , R ３Ａ , R ３Ｂ , R ５ , R ６ , R ７ , R ８ , R １０ The compound according to claim 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, or its stereoisomer, or its tautomer, or its deuterated analog, or its prodrug, wherein m and n are as defined in claim 1, respectively.

3. The ring CyA is a 3, 4, 5, 6, 7, or 8-membered ring, and the ring contains, as ring members, 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and the ring contains 0, 1, 2, 3, 4, or 5 R １０ The ring is optionally substituted, and the ring is either saturated or unsaturated. Preferably, CyA is a 3, 4, 5, 6, 7, or 8-membered saturated ring, and the ring contains, as ring members, 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur, and the ring contains 0, 1, 2, or 3 R １０ It is optionally replaced by, More preferably, CyA is a 5, 6, or 7-membered saturated ring, wherein the ring contains, as ring members, one or two heteroatoms independently selected from nitrogen or oxygen, and the ring has 0, 1, 2, or 3 R １０ It is optionally replaced by, More preferably, CyA is a ring selected from tetrahydrofuranyl or tetrahydropyranyl, wherein the ring has 0, 1, 2, or 3 R １０ A compound according to claim 1, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, its tautomer, its deuterated analog, or its prodrug, which is optionally substituted by the compound.

4. The circumference CyA is 【Transformation 7】 And, Preferably, CyA is 【Transformation 8】 And, More preferably, CyA 【Chemistry 9】 And, More preferably, CyA is 【Chemistry 10】 The compound according to claim 1, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, its tautomer, its deuterated analog, or its prodrug.

5. R １０ However, -H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, -CN, -OR １０ａ , -COR １０ａ , -CO ２ R １０ａ , -CONR １０ａ R １０ｂ , -NR １０ａ R １０ｂ , -NR １０ａ COR １０ｂ , -NR １０ａ CO ２ R １０ｂ , or -NR １０ａ CONR １０ｂ R １０ｃ Selected from, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl has at least one substituent R １０ｄ It is optionally replaced by, R １０ａ , R １０ｂ , and R １０ｃ However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are present. ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl has at least one substituent R １０ｆ It is optionally replaced by, R １０ｄ and R １０ｆ However, each is independent of hydrogen, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -haloC. １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ alkyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptoxy, the octoxy, the -C ２－８ Alkenyl, the above-C ２－８ Alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the halocycloalkyl, the heterocyclyl, the haloheterocyclyl, the phenyl, the haloaryl, the heteroaryl, or each of the haloheteroaryl has at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, Preferably, R １０ However, -H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, -CN, -OH, or -NH ２ Selected from, More specifically, R １０ The compound according to claim 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, or its stereoisomer, or its tautomer, or its deuterated analog, or its prodrug, wherein the compound is -OH. 【Request Item 6】 【Chemistry 11】 The part, 【Chemistry 12】 The compound according to claim 1, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, its tautomer, its deuterated analog, or its prodrug.

7. R １ However, H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, haloalkyl, heterocyclyl, -CN, -OR １ａ , -COR １ａ , -CO ２ R １ａ , -CONR １ａ R １ｂ , -NR １ａ R １ｂ , -NR １ａ COR １ｂ , -NR １ａ CO ２ R １ｂ , or -NR １ａ CONR １ｂ R １ｃ The methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are all present. ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, haloalkyl, or heterocyclyl has at least one substituent R １ｄ It is optionally replaced by, R １ａ , R １ｂ , and R １ｃ Each of these is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl has at least one substituent R １ｆ It is optionally replaced by, R １ｄ and R １ｆ However, each is independent of hydrogen, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -haloC. １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ alkyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptoxy, the octoxy, the -C ２－８ Alkenyl, the above-C ２－８ Alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the halocycloalkyl, the heterocyclyl, the haloheterocyclyl, the phenyl, the haloaryl, the heteroaryl, or each of the haloheteroaryl has at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, Preferably, R １ However, H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -OR １ａ , -COR １ａ The methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are all present. ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl is optionally substituted with at least one substituent selected from hydrogen, -F, -Cl, -Br, -I, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl. R １ａ However, it is selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl. More specifically, R １ is H, -F, -Cl, -Br, -I, C １－８ Alkoxy-C １－８ Alkyl-, Methoxy, Ethoxy, Propoxy, Butoxy, Pentoxy, Hexoxy, Heptoxy, Octoxy, Methyl, Ethyl, Propyl, Butyl, Pentyl, Hexyl, Heptyl, Octyl, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl, Cyclooctyl, Haloalkyl, Heterocyclyl, or -C(O)C １－８ It is alkyl, More specifically, R １ However, H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, -C(O)CH ３ , -C(CH ３ ) ２ The compound according to claim 1, wherein the compound is OH, -OMe, -F, -Cl, cyclopropyl, or cyclobutyl, or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analog, or its prodrug.

8. R ２ However, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR ２ａ , -SO ２ R ２ａ , -SO ２ NR ２ａ R ２ｂ , -COR ２ａ , -CO ２ R ２ａ , -CONR ２ａ R ２ｂ , -NR ２ａ R ２ｂ , -NR ２ａ COR ２ｂ , -NR ２ａ CO ２ R ２ｂ , -NR ２ａ CONR ２ｂ R ２ｃ , or -NR ２ａ SO ２ R ２ｂ The methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are all present. ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl has at least one substituent R ２ｄ It is optionally replaced by, R ２ａ , R ２ｂ , and R ２ｃ However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are present. ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl has at least one substituent R ２ｆ It is optionally replaced by, (R ２ａ and R ２ｂ ), (R ２ｂ and R ２ｃ ), or (R ２ａ and R ２ｃ ) together with the atom(s) to which they are bonded, form a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered ring, wherein the ring(s) independently contain 0, 1, or 2 heteroatoms (multiple) selected from nitrogen, oxygen, or optionally oxidized sulfur, and the ring(s) contain at least one substituent R ２ｆ It is optionally replaced by, R ２ｄ and R ２ｆ However, each is independent of hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR ２ｇ , -SO ２ R ２ｇ , -SO ２ NR ２ｇ R ２ｈ , -COR ２ｇ , -CO ２ R ２ｇ , -CONR ２ｇ R ２ｈ , -NO ２ , -NR ２ｇ R ２ｈ , -NR ２ｇ COR ２ｈ , -NR ２ｇ CO ２ R ２ｈ , -NR ２ｇ CONR ２ｈ R ２ｉ , or -NR ２ｇ SO ２ R ２ｈ Selected from, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl is at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ They are optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, or When adjacent or geminal, (two R ２ｄ ) and / or (two R ２ｆ ) together with the atom(s) to which they are bonded, form a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered ring, wherein the ring(s) independently contain 0, 1, or 2 heteroatoms (multiple) selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the ring(s) contain at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, R ２ｇ , R ２ｈ , and R ２ｉ However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are present. ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl molecules has at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ The compound according to claim 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, or a prodrug thereof, optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl.

9. R ２ However, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranil, tetrahydropyranil, oxazepanil, oxetanil, azetidinil, oxa-azaspiro[4.4]nonanil, hexahydro-1H-fl[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decanil, o Xer-azabicyclo[4.5]decanyl, azabicyclo[3.3.1]nonanyl, piperidinyl, piperazinyl, oxa-azabicyclo[2.5]octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, phenyl, oxo, -CN, -OR ２ａ , -COR ２ａ , -CO ２ R ２ａ , -CONR ２ａ R ２ｂ , -NR ２ａ R ２ｂ , -NR ２ａ COR ２ｂ The following are the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranil, tetrahydropyranil, oxazepanil, oxetanil, azetidinil, oxa-azaspiro[4.4]nonanil, hexahydro-1H-fl[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decanil, and Each of the following has at least one substituent R: xer-azaspiro[4.5]decanyl, azabicyclo[3.3.1]nonanyl, piperidinyl, piperazinyl, oxa-azaspiro[2.5]octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, or phenyl ２ｄ It is optionally replaced by, R ２ａ and R ２ｂ However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are present. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranil, tetrahydropyranil, oxazepanil, oxetanil, azetidinil, oxazaspiro[4.4]nonanil, hexahydro-1H-fl[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decanil, oxazaspiro[4.5]decanil, azabicyclo[3.3.1]nonanil, piperidinil, piperazinil, oxa - Selected from azaspiro[2.5]octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, or phenyl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C ２－８ Alkenyl, the above-C ２－８ Alkinyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the pyrrolidinyl, the morpholinyl, the thiomorpholinyl, the tetrahydrofuranil, the tetrahydropyranil, the oxazepanil, the oxetanil, the azetidinil, the oxa-azaspiro[4.4]nonanil, the hexahydro-1H-fl[3,4-c]pyrrolyl, the octahydropyrrolo[3,4-c]pyrrolyl, the diazaspiro[4.5]decanil, the oxa-azaspiro[4.5]decanil, the azabicyclo [3.3.1]nonanyl, piperidinyl, piperazinyl, oxazaspiro[2.5]octanyl, oxazabicyclo[3.1.1]heptanyl, oxazabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxazabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxazabicyclo[3.2.1]octanyl, or phenyl each have at least one substituent R ２ｆ It is optionally replaced by, (R ２ａ and R ２ｂ ), (R ２ｂ and R ２ｃ ), or (R ２ａ and R ２ｃ ) together with the atom(s) to which they are bonded, form a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered ring, wherein the ring(s) independently contain 0, 1, or 2 heteroatoms selected from nitrogen or oxygen as ring members, and the ring(s) contain at least one substituent R ２ｆ It is optionally replaced by, R ２ｄ and R ２ｆ However, each is independent of hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranil, tetrahydropyranil, oxazepanil, oxetanil, azetidinil, oxazaspiro[4.4]nonanil, hexahydro-1H-fl[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decanil, oxazaspiro[4.5]decanil, azabicyclo[ 3.3.1] Nonanyl, piperidinyl, piperazinyl, oxazaspiro[2.5]octanyl, oxazabicyclo[3.1.1]heptanyl, oxazabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxazabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxazabicyclo[3.2.1]octanyl, phenyl, oxo, -CN, -OR ２ｇ , -SO ２ R ２ｇ , -COR ２ｇ , -CO ２ R ２ｇ , -CONR ２ｇ R ２ｈ , -NO ２ , -NR ２ｇ R ２ｈ , or -NR ２ｇ COR ２ｈ Selected from, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C ２－８ Alkenyl, the above-C ２－８ Alkinyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the pyrrolidinyl, the morpholinyl, the thiomorpholinyl, the tetrahydrofuranil, the tetrahydropyranil, the oxazepanil, the oxetanil, the azetidinil, the oxa-azaspiro[4.4]nonanil, the hexahydro-1H-fl[3,4-c]pyrrolyl, the octahydropyrrolo[3,4-c]pyrrolyl, the diazaspiro[4.5]decanil, the oxa-azaspiro[4.5]decanil, the azabicyclo[3.3.1]nonanil, the piperidinil, the piperazinil, the Each of the following substituents may be: oxa-azabicyclo[2.5]octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, or phenyl, each of which may have at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, or -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ They are optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, or When adjacent or geminal, (two R ２ｄ ) and / or (two R ２ｆ ) together with the atom(s) to which they are bonded, form a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered ring, wherein the ring(s) independently contain 0, 1, or 2 heteroatoms (multiple) selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, and the ring(s) contain at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, R ２ｇ , R ２ｈ , and R ２ｉ However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are present. ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl molecules has at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ The compound according to claim 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, or a prodrug thereof, optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl.

10. R ２ However, hydrogen, methyl, ethyl, propyl, butyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranil, tetrahydropyranil, oxazepanil, oxetanil, azetidinil, oxa-azaspiro[4.4]nonanil, hexahydro-1H-fl[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decanil, oxa-azaspiro[4.5]decanil, azabicyclo[3.3.1]nonanil, pi Peridinyl, piperazinyl, oxazaspiro[2.5]octanyl, oxazabicyclo[3.1.1]heptanyl, oxazabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxazabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxazabicyclo[3.2.1]octanyl, phenyl, -OR ２ａ , -NR ２ａ R ２ｂ , or -NR ２ａ COR ２ｂ The following are the methyl, ethyl, propyl, butyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranil, tetrahydropyranil, oxazepanil, oxetanil, azetidinil, oxa-azaspiro[4.4]nonanil, hexahydro-1H-fl[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decanil, oxa-azaspiro[4.5]decanil, azabicyclo[3.3.1]nonanil, and piperi Each of the dinyl, piperazinyl, oxa-azabicyclo[2.5]octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, or phenyl has at least one substituent R ２ｄ It is optionally replaced by, R ２ａ and R ２ｂ However, each independently, hydrogen, methyl, ethyl, propyl (n-propyl or iso-propyl), butyl (n-butyl, sec-butyl, isobutyl, or tert-butyl), pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranil, tetrahydropyranil, oxazepanil, oxetanil, azetidi Nyl, oxazaspiro[4.4]nonanil, hexahydro-1H-fl[3,4-c]pyrrolyl, octahydropyrrollo[3,4-c]pyrrolyl, diazaspiro[4.5]decanil, oxazaspiro[4.5]decanil, azabicyclo[3.3.1]nonanil, piperidinil, piperazinil, oxazaspiro[2.5]octanil, oxazabicyclo[3.1.1]heptanil, oxaza Selected from bicyclo[2.2.1]heptanil, diazaspiro[5.5]undecanil, oxa-azabicyclo[3.3.1]nonanil, azabicyclo[3.2.1]octanil, azabicyclo[2.1.1]hexanil, pyridinil, pyrimidinil, pyrazolyl, oxa-azabicyclo[3.2.1]octanil, or phenyl, and the methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinil, morpholinil, thiomorpholinil, tetrahydrofuranil, tetrahydropyranil, oxazepanil, oxetanil, azetidinil, oxa-azabicyclo[4.4]nonanil, hexahydro-1H-fl[3,4-c]pyrrolyl, octahydropyrrolo[3,Each of the following is a substituent R: 4-c]pyrrolyl, the diazaspiro[4.5]decanyl, the oxa-azabicyclo[4.5]decanyl, the azabicyclo[3.3.1]nonanyl, the piperidinyl, the piperazinyl, the oxa-azabicyclo[2.5]octanyl, the oxa-azabicyclo[3.1.1]heptanyl, the oxa-azabicyclo[2.2.1]heptanyl, the diazaspiro[5.5]undecanyl, the oxa-azabicyclo[3.3.1]nonanyl, the azabicyclo[3.2.1]octanyl, the azabicyclo[2.1.1]hexanyl, the pyridinyl, the pyrimidinyl, the pyrazolyl, the oxa-azabicyclo[3.2.1]octanyl, or the phenyl ２ｆ It is optionally replaced by, (R ２ａ and R ２ｂ ), (R ２ｂ and R ２ｃ ), or (R ２ａ and R ２ｃ ) together with the atom(s) to which they are bonded, form a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered ring, wherein the ring(s) independently contain 0, 1, or 2 heteroatoms selected from nitrogen or oxygen as ring members, and the ring(s) contain at least one substituent R ２ｆ It is optionally replaced by, R ２ｄ and R ２ｆ However, each independently, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, -CF ３ , -CF ２ H, -CFH ２ ien-CH ２ CF ３ , -CF ２ CH ３ ien-CH ２ OH, -CH(CH ３ )OH, -C(CH ３ ) ２ OH, -CH ２ CH ２ OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, morpholinil, thiomorpholinil, tetrahydrofuranil, tetrahydropyranil, oxazepanil, oxetanil, azetidinil, oxa-aspiro[4.4]nonanil, hexahydro-1H-fl[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decanil, oxa-azabicyclo[4.5]decanil, azabicyclo[3.3.1]nonanil, peridinil, piperazinil, oxa-azabicyclo[ 2.5] Octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, phenyl, oxo, -CN, -OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -SO ２ Me, -SO ２ Et, -SO ２ C ３ H ７ , -COMe, -COEt, -COC ３ H ７ , -NH ２ , - NHCH ３ , -N(CH ３ ) ２ , - NHC ２ H ５ , - NHC ３ H ７ , - NHC ４ H ９ , -CONH ２ , -CONHCH ３ , -CON(CH ３ ) ２ , -CONHC ２ H ５ , -CONHC ３ H ７ , -CONHC ４ H ９ A compound selected from claim 1, its N-oxide, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its deuterated analog, or its prodrug.

11. ( ２ The ２ 、!\H ３ 、!(C) ３ ) ２ 、!\\\H ３ ) ２ 、!\CCH ３ ) ３ 、!\CH ３ 、 【Chemistry 13-1】 【Chemistry 13-2】 The compound according to claim 1, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, its tautomer, its deuterated analog, or its prodrug.

12. R ３Ａ and R ３Ｂ However, each is independent of hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, or -CN, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are all compounds. ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl has at least one substituent R ３ｃ It is either optionally replaced, or R ３Ａ and R ３Ｂ However, together with the atoms to which they are bonded, they form an oxo group (-C(=O)-) or a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered ring, wherein the ring(s) independently contain 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur, and the ring(s) contain at least one substituent R ３ｃ It is optionally replaced by, R ３ｃ However, each is independent of hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR ３ｄ , -SO ２ R ３ｄ , -SO ２ NR ３ｄ R ３ｅ , -COR ３ｄ , -CO ２ R ３ｄ , -CONR ３ｄ R ３ｅ , -NO ２ , -NR ３ｄ R ３ｅ , -NR ３ｄ COR ３ｅ , -NR ３ｄ CO ２ R ３ｅ , -NR ３ｄ CONR ３ｅ R ３ｆ , or -NR ３ｄ SO ２ R ３ｅ Selected from, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl molecules has at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, R ３ｄ , R ３ｅ , and R ３ｆ However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are present. ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl molecules has at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, Preferably, R ３Ａ and R ３Ｂ However, each is independent of hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, or -CN, or R ３Ａ and R ３Ｂ However, together with the atoms to which they are bonded, they form an oxo group (-C(=O)-) or a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered ring, and the ring contains, as ring members (multiple), 0, 1, or 2 heteroatoms (multiple) independently selected from nitrogen, oxygen, or optionally oxidized sulfur, preferably R ３Ａ and R ３Ｂ However, together with the atoms to which they are bonded, they form an oxo group (-C(=O)-), More specifically, R ３Ａ and R ３Ｂ However, each is independently hydrogen, methyl, ethyl, propyl, butyl, or pentyl, or R ３Ａ and R ３Ｂ The compound according to claim 1, or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analog, or its prodrug, wherein, together with the atoms to which they are bonded, they form an oxo group (-C(=O)-), or a 3, 4, 5, 6, 7, or 8-membered ring, and the ring independently comprises 0, 1, or 2 heteroatoms selected from nitrogen or oxygen, or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analog, or its prodrug. 【Request Item 13】 【Chemistry 14】 The part, 【Chemistry 15】 And, During the ceremony, * ３ but, 【Chemistry 16】 This refers to the position where it is joined to the part, ** ３ but, 【Chemistry 17】 The compound according to claim 1, its N-oxide, its pharmaceutically acceptable salt, its stereoisomer, its tautomer, its deuterated analog, or its prodrug, referring to a position where it is bonded to a portion. 【Request Item 14】 【Chemistry 18】 The parts are -Me, -Et, 【Chemistry 19-1】 【Chemistry 19-2】 【Chemistry 19-3】 The compound according to claim 1, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, its tautomer, its deuterated analog, or its prodrug.

15. R ４ However, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or heterocyclyl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or heterocyclyl has at least one substituent R ４ａ It is optionally replaced by, R ４ａ is, independently of each other, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR ４ｂ , -SO ２ R ４ｂ , -SO ２ NR ４ｂ R ４ｃ , -COR ４ｂ , -CO ２ R ４ｂ , -CONR ４ｂ R ４ｃ , -NO ２ , -NR ４ｂ R ４ｃ , -NR ４ｂ COR ４ｃ ]>, -NR ４ｂ CO ２ R ４ｃ , -NR ４ｂ CONR ４ｃ R ４ｄ , or -NR ４ｂ SO ２ R ４ｃ selected from, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl is halogen, hydroxy, -C １－８ alkyl, -haloC １－８ alkyl, -C １－８ alkoxy, -haloC １－８ alkoxy, -C ２－８ alkenyl, -C ２－８ Optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, R ４ｂ 、 R ４ｃ 、 and R ４ｄ are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and each of said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said -C ２－８ alkenyl, said -C ２－８ alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, said heterocyclyl, said phenyl, or said heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C １－８ alkyl, -haloC １－８ [[ID=z18]]alkyl, -C １－８ alkoxy, -haloC １－８ alkoxy, -C ２－８ alkenyl, -C ２－８ alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, halheterocyclyl, aryl, haloaryl, heteroaryl, or halheteroaryl. Preferably, R ４ However, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or heterocyclyl, More specifically, R ４ The compound according to claim 1, wherein the compound is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analog, or its prodrug.

16. R ５ , R ６ , R ７ , R ８ , and R ９ However, each is independent of H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, -CN, -OR ５ａ , -COR ５ａ , -CO ２ R ５ａ , -CONR ５ａ R ５ｂ , -NR ５ａ R ５ｂ , -NR ５ａ COR ５ｂ , -NR ５ａ CO ２ R ５ｂ , or -NR ５ａ CONR ５ｂ R ５ｃ The methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are all present. ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl has at least one substituent R ５ｄ It is optionally replaced by, R ５ａ , R ５ｂ , and R ５ｃ However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are present. ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl has at least one substituent R ５ｆ It is optionally replaced by, R ５ｄ and R ５ｆ However, each is independent of hydrogen, -F, -Cl, -Br, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -haloC. １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ alkyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptoxy, the octoxy, the -C ２－８ Alkenyl, the above-C ２－８ Alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the halocycloalkyl, the heterocyclyl, the haloheterocyclyl, the phenyl, the haloaryl, the heteroaryl, or the haloheteroaryl each of these is a halogen, hydroxyl, -C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -halo C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, Preferably, R ５ R ６ R ７ R ８ and R ９ are each independently selected from H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, -CN, -OR ５ａ -COR ５ａ -CO ２ R ５ａ -CONR ５ａ R ５ｂ -NR ５ａ R ５ｂ -NR ５ａ COR ５ｂ -NR ５ａ CO ２ R ５ｂ or -NR ５ａ CONR ５ｂ R ５ｃ and are selected from R ５ａ , R ５ｂ , and R ５ｃ However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are present. ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, More specifically, R ５ , R ６ , R ７ , R ８ , and R ９ However, each is independent of H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ A compound according to claim 1, selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analog, or its prodrug.

17. R ５ , R ６ , and R ７ Each is independently selected from H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl, and / or R ８ However, it is selected from -F, -Cl, -Br, or -I, and / or R ９ However, selected from H, preferably R ５ , R ６ , and R ７ However, each is independently selected from H, -F, -Cl, methyl, ethyl, propyl, or butyl, and / or R ８ However, it is selected from -F or -Cl, and / or R ９ The compound according to claim 1, selected from H, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, its tautomer, its deuterated analog, or its prodrug.

18. R １１ However, H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, or -C ２－８ Selected from alkynyl, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C ２－８ Alkenyl, or the aforementioned -C ２－８ Each alkynyl has at least one substituent R １１ａ It is optionally replaced by, R １１ａ However, hydrogen, halogen, hydroxyl, -C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, and the -C １－８ Alkyl, the above-mentioned -halo C １－８ Alkyl, the above-C １－８ Alkoxy, the above-C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl is a halogen, hydroxy, -C １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -halo C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkynyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, Preferably, R １１ However, H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, or -C ２－８ Selected from Alkinir, More specifically, R １１ However, it is selected from H, methyl, ethyl, propyl, or butyl, More specifically, R １１ The compound according to claim 1, or its N-oxide, or a pharmaceutically acceptable salt thereof, or its stereoisomer, or its tautomer, or its deuterated analog, or its prodrug, wherein H is present.

19. The compound described above is selected from the following: the compound according to claim 1, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, its tautomer, its deuterated analog, or its prodrug. 【Chemistry 20-1】 【Chemistry 20-2】 【Chemistry 20-3】 【Chemistry 20-4】 【Chemistry 20-5】 【Chemistry 20-6】 【Chemistry 20-7】 【Chemistry 20-8】 【Chemistry 20-9】 【Chemistry 20-10】 【Chemistry 20-11】 【Chemistry 20-12】 【Chemistry 20-13】 【Chemistry 20-14】 【Chemistry 20-15】 【Chemistry 20-16】 【Chemistry 20-17】 【Chemistry 20-18】 【Chemistry 20-19】 【Chemistry 20-20】 【Chemistry 20-21】 [Chemistry 20-22]

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, its N-oxide, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a deuterated analog thereof, or a prodrug thereof, together with a pharmaceutically acceptable excipient.

21. A composition for reducing CDK4 activity by inhibition, wherein the composition comprises a compound according to any one of claims 1 to 19, its N-oxide, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a deuterated analog thereof, or a prodrug thereof, and comprises a compound of formula (I) or a specific compound as exemplified herein.

22. The composition according to claim 21, wherein the disease is selected from cancer, preferably breast cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, liver cancer, and endometrial cancer.

23. Use of a compound according to any one of claims 1 to 19, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, its tautomer, its deuterated analog, or its prodrug in the preparation of a drug for treating a disease that may be affected by CDK4 modulation.

24. The use according to claim 23, wherein the disease is cancer, preferably breast cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, liver cancer, and endometrial cancer.

25. A composition for treating a disease or disorder in a patient, wherein the composition comprises a compound according to any one of claims 1 to 19, its N-oxide, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a deuterated analog thereof, or a prodrug thereof, characterized in that the composition is administered as a CKD4 kinase inhibitor, wherein the disease or disorder is related to the inhibition of CDK4.

26. The composition according to claim 25, wherein the disease is selected from cancer, preferably breast cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, liver cancer, and endometrial cancer.

27. ​​A composition for treating a disease that may be affected by CDK4 modulation, wherein the composition comprises a compound according to any one of claims 1 to 19, its N-oxide, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, a deuterated analog thereof, or a prodrug thereof.

28. The composition according to claim 27, wherein the disease is cancer, preferably breast cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, liver cancer, and endometrial cancer.

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