Substituted 6-(pyrimidin-4-yl) quinoline compounds as cyclin dependent kinase inhibitors

Abstract

The present disclosure provides compounds containing a 6-(pyrimidin-4-yl) quinoline structure, their use for selective inhibition of CDK4 activity, and pharmaceutical compositions comprising these compounds that can treat various diseases, including cancer.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202380036165.1 (application date: April 28, 2023, invention name: Substituted 6-(pyrimidin-4-yl)quinoline compounds as cyclin-dependent kinase inhibitors). Technical Field

[0002] The present disclosure provides compounds containing a 6-(pyrimidin-4-yl)quinoline structure, their use for selectively inhibiting cyclin-dependent kinase 4 (CDK4) activity, and pharmaceutical compositions containing these compounds for treating various diseases including cancer. Background Art

[0003] Human kinases are a large class of kinases that convert phosphate groups (PO4 3- ) are enzymes that are added to other molecules in the human body [1. FASEB J. 1995 May;9(8):576-96. 2. Enzyme Res. 2011;2011:794089.]. There are more than 500 genes encoding kinases 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.]. Kinase dysregulation has been identified in many diseases, including cancer, autoimmunity, neurological disorders, diabetes, and cardiovascular disease. For example, mutated kinases can become constitutively active, causing a variety of cellular abnormalities that can lead to the development or progression of cancer. Inhibiting kinase activity using small molecule inhibitors has been shown to be a successful approach for treating cancer and other diseases [5.Expert Rev Anticancer Ther. 2018 Dec;18(12):1249-1270.]. To date, more than 70 kinase inhibitors have been approved as drugs by the FDA, EMA, or CDE [6.Nat Rev Drug Discov. 2018 May;17(5):353-377.].

[0004] The protein kinase family accounts for the majority of the kinase superfamily. For protein targets, protein kinases can phosphorylate amino acids including serine, threonine, tyrosine, and histidine [7. Science. [Science] December 6, 2002; 298(5600): 1912-34.]. Protein kinases play a major role in cell activation. Through the antagonistic effects of kinases and phosphatases, the reversible phosphorylation and dephosphorylation of proteins are important components of cell signaling because the phosphorylated and non-phosphorylated states of target proteins can have different activity levels [8. Biochimie. [Biochemistry] December 2014; 107 PtB: 167-87. 9. Clin Transl Oncol. [Clinical and Translational Oncology] March 2006; 8(3): 153-60.]. Different protein kinases, including EGFR, BTK, ALK, JAK, PI3K, and CDK, have been shown to be good targets for cancer drug development.

[0005] Over-activated cell cycle is a common feature of human cancer [10. Nat Rev Cancer. 2009 Mar;9(3):153-66.]. Cyclins are one of the most important core cell cycle regulators. Four basic types of cyclins have been found in humans, including G1 cyclins, G1 / S cyclins, S cyclins, and M cyclins. In order to drive the cell cycle forward, cyclins must activate or inactivate many target proteins within the cell. Moreover, these cyclins mainly drive cell cycle events by cooperating with a family of enzymes called cyclin-dependent kinases (CDKs). The CDK kinases themselves are inactive, but binding to cyclins activates them, making the CDK / cyclin complex a functional holoenzyme and allowing it to 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 branches of the CMGC subfamily of the human kinase group; of these, 21 are classified as CDKs. Of all the CDKs identified to date, CDK1, CDK2, CDK4, and CDK6 are considered direct regulators of the cell cycle, primarily by phosphorylating and inactivating the retinoblastoma protein and releasing the E2F transcription factor, whose downstream pathway is crucial in regulating the initiation of DNA replication. Moreover, CDK4 / 6 is very important for early G1 initiation and G1 / S transition [13. Cell Death Differ. [Cell Death and Differentiation] 1998 February; 5(2): 132-40. 14. Oncogene. [Oncogene] 2016 September 15; 35(37): 4829-35.].

[0006] The CDK4 / 6-related pathway is often dysregulated in many different cancer types, such as breast cancer, lung cancer, and pancreatic cancer. In addition, there are four approved CDK4 / 6 inhibitors, including palbociclib, ribociclib, abemaciclib, and trilaciclib, which have been approved by the FDA or CDE as a single agent or in combination with endocrine therapy to treat HR+, Her2- breast cancer. This approach has shown good efficacy in the clinic, but hematopoietic toxicity such as neutropenia and leukopenia may limit the clinical application of CDK4 / 6 dual inhibitors. Furthermore, emerging data suggest that inhibition of CDK6 / cyclin D3 may contribute to the hematologic toxicities observed clinically [15. Cell. 2004 Aug 20;118(4):493-504. 16. Haematologica. 2021 Oct 1;106(10):2624-2632.], whereas CDK4 / cyclin D1 is an oncogenic driver in diverse cancers [17. Nat Commun. 2019 Dec 20;10(1):5817. 18. 18. Cancer Cell. 2006 Jan;9(1):23-32.]. The development of selective CDK4 inhibitors may show improved efficacy, reduced hematologic toxicity, and expanded clinical applications in many cancers, including but not limited to breast, lung, pancreatic, prostate, bone, liver, and endometrial cancers.

[0007] Therefore, there remains a great need to develop selective CDK4 inhibitors.Herein, the inventors of the present invention have discovered that selective CDK4 inhibitor compounds have high CDK4 selectivity over all other kinases (including CDK6), which may lead to better efficacy, improved toxicity profiles and the potential to overcome resistance mechanisms, etc. Summary of the Invention

[0008] One object of the present invention is to provide compounds and derivatives that act as CDK4 inhibitors, as well as methods for their preparation and use.

[0009] Aspect 1. A compound having formula (I):

[0010]

[0011] 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,

[0012] in:

[0013] Cyclic CyA is a 3- to 8-membered ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members; the ring is optionally substituted with at least one substituent R 10 replace;

[0014] n is 0, 1, 2, 3, 4, or 5;

[0015] m is 0 or 1; the condition is that when m=0, the The part as a whole is replaced by H;

[0016] 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 ; wherein said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted with at least one substituent R 1d replace;

[0017] R 1a 、R 1b and R 1c are each independently selected from hydrogen, -C 1-8 Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted with at least one substituent R 1f replace;

[0018] R 1d and R 1f are independently selected from hydrogen, halogen, hydroxyl, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -C2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl, wherein the -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0019] R 2 It is 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 ; wherein said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted with at least one substituent R 2d replace;

[0020] R 2a 、R 2b and R2c are each independently selected from hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted with at least one substituent R 2f replace; or

[0021] (R 2a and R 2b )、(R 2b and R 2c ) or (R 2a and R 2c ) together with the atom or atoms to which they are attached form a 3 to 12 membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 2f replace;

[0022] R 2d and R 2f are each independently selected from 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 ; wherein said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, oxo, -C1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; or

[0023] (Two R 2d ) or (two R 2f ) together with the atom or atoms to which they are attached form a 3 to 12 membered ring comprising, as one or more ring members, 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur, said ring being optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, oxo, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0024] R 2g 、R 2h and R 2i are each independently selected from hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0025] R 3A and R 3B are independently hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or -CN; wherein the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted with at least one substituent R 3c replace; or

[0026] R 3A and R 3B Together with the atoms to which they are attached, they form an acyl group (-C(=O)-) or a 3 to 12 membered ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, the ring optionally substituted with at least one substituent R 3c replace;

[0027] Each R 3c are independently selected from 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 、-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 ; wherein said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0028] R 3d 、R 3e and R 3f are each independently selected from hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0029] R 4 It is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl or heterocyclyl; wherein the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl or heterocyclyl groups is optionally substituted with at least one substituent R 4a replace;

[0030] Each R 4a are independently selected from 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 CONR4c R 4d or –NR 4b SO2R 4c ; wherein said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0031] R 4b 、R 4c and R 4d are each independently selected from hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0032] R 5 、R 6 、R 7 、R 8 and R 9 are each independently selected from 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 ; wherein said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted with at least one substituent R 5d replace;

[0033] R 5a 、R 5b and R 5c are each independently selected from hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted with at least one substituent R 5f replace;

[0034] R 5d and R 5f are independently selected from hydrogen, halogen, hydroxyl, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl, wherein the -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0035] R 10 Selected from 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 ; wherein said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted with at least one substituent R 10d replace;

[0036] R 10a 、R 10b and R 10c are each independently selected from hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted with at least one substituent R 10f replace;

[0037] R 10d and R 10f are independently selected from hydrogen, halogen, hydroxyl, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl, wherein the -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0038] R 11 Selected from H, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl; wherein the -C 1-8 Alkyl, -C 2-8 Alkenyl or -C 2-8 Each of the alkynyl groups is optionally substituted with at least one substituent R 11a replace;

[0039] R 11a Selected from hydrogen, halogen, hydroxyl, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl, wherein the -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl.

[0040] Aspect 2. The compound according to Aspect 1, wherein the compound is selected from Formula (IIa), (IIb), (IIc), (IId) or (IIe):

[0041]

[0042] where 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;

[0043] Preferably, the compound is selected from formula (IIf), (IIg), (IIh) or (IIi):

[0044]

[0045] where 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;

[0046] More preferably, the compound is selected from formula (IIj), (IIk), (IIl) or (IIm):

[0047]

[0048] where 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;

[0049] Even more preferably, the compound is selected from formula (IIn), (IIo), (IIp) or (IIq):

[0050]

[0051] where R 1 、R 2 、R 3A 、R 3B 、R 5 、R 6 、R 7 、R 8 、R 10 , m and n are each as defined in aspect 1.

[0052] Aspect 3. A compound according to any of the preceding aspects, wherein ring CyA is a 3-, 4-, 5-, 6-, 7- or 8-membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members; said ring is optionally substituted with 0, 1, 2, 3, 4 or 5 R 10 substituted; the ring is a saturated or unsaturated ring;

[0053] Preferably, CyA is a 3-, 4-, 5-, 6-, 7- or 8-membered saturated ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members; said ring is optionally substituted with 0, 1, 2 or 3 R 10 replace;

[0054] More preferably, CyA is a 5-, 6- or 7-membered saturated ring comprising 1 or 2 heteroatoms independently selected from nitrogen or oxygen as one or more ring members; the ring is optionally substituted with 0, 1, 2 or 3 R 10 replace;

[0055] Even more preferably, CyA is a ring selected from tetrahydrofuranyl or tetrahydropyranyl; said ring is optionally substituted with 0, 1, 2 or 3 R 10 replace.

[0056] Aspect 4. The compound according to any one of the preceding aspects, wherein ring CyA is

[0057] Preferably, CyA is

[0058] More preferably, CyA is

[0059] Even more preferably, CyA is

[0060] Aspect 5. The compound according to any one of the preceding aspects, wherein R 10Selected 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 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 wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl groups is optionally substituted with at least one substituent R 10d replace;

[0061] R 10a 、R 10b and R 10c Each is independently selected from 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, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl groups is optionally substituted with at least one substituent R 10f replace;

[0062] R 10d and R 10f Each is independently selected from hydrogen, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halogenated C 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl or haloheteroaryl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halogenated C 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl groups is optionally substituted with at least one of -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl substitution;

[0063] Preferably, R 10 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, -OH or -NH2;

[0064] More preferably, R 10 It is -OH.

[0065] Aspect 6. The compound according to any one of the preceding aspects, wherein the Partly

[0066] Aspect 7. The compound according to any one of the preceding aspects, wherein R 1 is 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, heterocyclic, -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 wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, haloalkyl or heterocyclyl groups is optionally substituted with at least one substituent R 1d replace;

[0067] 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, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl or heteroaryl is optionally substituted with at least one substituent R 1f replace;

[0068] R 1d and R 1f Each is independently selected from hydrogen, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halogenated C 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl or haloheteroaryl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halogenated C 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl groups is optionally substituted with at least one of -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl substitution;

[0069] Preferably, R 1 is 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, or -CN;

[0070] More preferably, R 1 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;

[0071] In another embodiment, R 1 yes

[0072] Aspect 8. The compound according to any one of the preceding aspects, wherein 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 wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl groups is optionally substituted with at least one substituent R 2d replace;

[0073] R 2a 、R 2b and R 2c Each is independently selected from 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, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl groups is optionally substituted with at least one substituent R 2f replace; or

[0074] (R 2a and R 2b )、(R 2b and R 2c ) or (R 2a and R 2c ) together with the atom or atoms to which they are attached form a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent R 2f replace;

[0075] R 2d and R 2f Each is independently selected from 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 、-COR 2g 、-CO2R 2g 、-CONR 2g R 2h 、-NO2、-NR 2g R 2h 、-NR 2g COR2h 、-NR 2g CO2R 2h 、-NR 2g CONR 2h R 2i , or –NR 2g SO2R 2h wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl groups is optionally substituted with at least one of -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; or

[0076] When adjacent or co-located, (two R 2d ) or (two R 2f ) together with the atom or atoms to which they are attached form a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally being substituted with at least one of -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl substitution;

[0077] R 2g 、R 2h and R 2i Each is independently selected from 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, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl radicals is optionally substituted with at least one of -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 The alkyl radicals may be substituted with alkyl, ...

[0078] Aspect 9. The compound according to any one of the preceding aspects, wherein R 2 is 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]decyl, oxa-azaspiro[4 .5]decyl, azabicyclo[3.3.1]nonyl, piperidinyl, piperazinyl, oxa-azaspiro[2.5]octyl, oxa-azabicyclo[3.1.1]heptyl, oxa-azabicyclo[2.2.1]heptyl, diazaspiro[5.5]undecyl, oxa-azabicyclo[3.3.1]nonyl, azabicyclo[3.2.1]octyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octyl, phenyl, oxo, -CN, -OR 2a 、-COR 2a 、-CO2R 2a 、-CONR 2a R 2b 、-NR 2a R 2b 、-NR 2a COR 2bwherein the 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]decyl, oxa-azaspiro[4.5]decyl, nitrogen Each of heterobicyclo[3.3.1]nonyl, piperidinyl, piperazinyl, oxa-azaspiro[2.5]octanyl, oxa-azabicyclo[3.1.1]heptyl, oxa-azabicyclo[2.2.1]heptyl, diazaspiro[5.5]undecyl, oxa-azabicyclo[3.3.1]nonyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl or phenyl is optionally substituted by at least one substituent R 2d replace;

[0079] R 2a and R 2b Each is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, 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]decyl, oxa-azaspiro[4.5]decyl, azabicyclo[3.3.1]nonanyl, piperidinyl, piperazinyl , oxa-azaspiro[2.5]octyl, oxa-azabicyclo[3.1.1]heptyl, oxa-azabicyclo[2.2.1]heptyl, diazaspiro[5.5]undecyl, oxa-azabicyclo[3.3.1]nonyl, azabicyclo[3.2.1]octyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octyl or phenyl, wherein the 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]decyl, oxa-azaspiro[4.5]decyl, azabicyclo[3.3.1]nonanyl , piperidinyl, piperazinyl, oxa-azaspiro[2.5]octanyl, oxa-azabicyclo[3.1.1]heptyl, oxa-azabicyclo[2.2.1]heptyl, diazaspiro[5.5]undecyl, 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 is optionally substituted with at least one substituent R 2f replace; or

[0080] (R 2a and R 2b )、(R 2b and R 2c ) or (R 2a and R 2c ) together with the atom or atoms to which they are attached form a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen or oxygen as one or more ring members, said ring optionally substituted with at least one substituent R 2f replace;

[0081] R 2d and R 2f Each is independently selected from 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 alkyl, piperidinyl, piperazinyl, oxa-azaspiro[2.5]octyl, oxa-azabicyclo[3.1.1]heptyl, oxa-azabicyclo[2.2.1]heptyl, diazaspiro[5.5]undecyl, oxa-azabicyclo[3.3.1]nonyl, azabicyclo[3.2.1]octyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octyl, 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 wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 alkynyl, 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]decyl, oxa-azaspiro[4.5]decyl, azabicyclo[3.3.1]nonanyl, piperidinyl, piperazinyl, oxa-azaspiro[2.5]octanyl, Each of oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecyl, 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 is optionally substituted with at least one -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl; or

[0082] When adjacent or co-located, (two R 2d ) or (two R 2f ) together with the atom or atoms to which they are attached form a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally being substituted with at least one of -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl substitution;

[0083] R 2g 、R 2h and R 2i Each is independently selected from 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, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl radicals is optionally substituted with at least one of -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 The alkyl radicals may be substituted with alkyl, ...

[0084] Aspect 10. The compound according to any one of the preceding aspects, wherein R 2 is 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]decyl, oxa-azaspiro[4.5]decyl, azabicyclo[3.3.1]nonanyl , piperidinyl, piperazinyl, oxa-azaspiro[2.5]octyl, oxa-azabicyclo[3.1.1]heptyl, oxa-azabicyclo[2.2.1]heptyl, diazaspiro[5.5]undecyl, oxa-azabicyclo[3.3.1]nonyl, azabicyclo[3.2.1]octyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octyl, phenyl, -OR 2a 、-NR 2a R 2b or -NR 2a COR 2b wherein the 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]decyl, oxa-azaspiro[4.5]decyl, azabicyclo[3.3.1]nonanyl, piperidinyl, Each of piperazinyl, oxa-azaspiro[2.5]octanyl, oxa-azabicyclo[3.1.1]heptyl, oxa-azabicyclo[2.2.1]heptyl, diazaspiro[5.5]undecyl, 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 is optionally substituted with at least one substituent R 2d replace;

[0085] R 2a and R 2bEach is independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl 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]decane 1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]hexanyl, 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]undecyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1 ] octyl or phenyl, wherein the methyl, ethyl, propyl, 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]decyl, oxa-azaspiro[4.5]decyl, azabicyclo[3 .3.1]nonyl, piperidinyl, piperazinyl, oxa-azaspiro[2.5]octyl, oxa-azabicyclo[3.1.1]heptyl, oxa-azabicyclo[2.2.1]heptyl, diazaspiro[5.5]undecyl, oxa-azabicyclo[3.3.1]nonyl, azabicyclo[3.2.1]octyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octyl or phenyl are each optionally substituted with at least one substituent R 2f replace; or

[0086] (R 2a and R 2b )、(R 2b and R 2c ) or (R 2a and R 2c ) together with the atom or atoms to which they are attached form a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen or oxygen as one or more ring members, said ring optionally substituted with at least one substituent R 2f replace;

[0087] R 2d and R2f Each is independently selected from 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, tetrahydropyranyl , oxazepanyl, oxetanyl, azetidinyl, oxa-azaspiro[4.4]nonanyl, hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decyl, oxa-azaspiro[4.5]decyl, azabicyclo[3.3.1]nonanyl, piperidinyl, piperazinyl, oxa-azaspiro[2.5]octyl, oxa-azabicyclo[3.1.1 ]heptyl, oxa-azabicyclo[2.2.1]heptyl, diazaspiro[5.5]undecyl, oxa-azabicyclo[3.3.1]nonyl, azabicyclo[3.2.1]octyl, azabicyclo[2.1.1]hexanyl, pyridyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octyl, phenyl, oxo, -CN, -OH, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, Heptyloxy, octyloxy, -SO2Me, -SO2Et, -SO2C3H7, -COMe, -COEt, -COC3H7, -NH2, -NHCH3, -N(CH3)2, -NHC2H5, -NHC3H7, -NHC4H9, -CONH2, -CONHCH3, -CON(CH3)2, -CONHC2H5, -CONHC3H7, -CONHC4H9.

[0088] Aspect 11. The compound according to any one of the preceding aspects, wherein R 2 Is -H, -Me, -OMe, -OH, -NH2, -NHCH3, -N(CH3)2, -NHCH(CH3)2, -NHC(CH3)3, -NHCOCH3,

[0089] Aspect 12. The compound according to any one of the preceding aspects, wherein R 3A and R 3B are each independently 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, heterocyclyl, phenyl, heteroaryl or -CN; wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl groups is optionally substituted with at least one substituent R 3c replace; or

[0090] R 3A and R 3B Together with the atoms to which they are attached, they form an acyl group (-C(=O)-) or a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, the ring being monocyclic, spirocyclic, fused or bridged, the ring optionally substituted with at least one substituent R 3c replace;

[0091] Each R 3c independently selected from 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 、-SO2R 3d 、-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 wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl radicals is optionally substituted with at least one of -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 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl substitution;

[0092] R 3d 、R 3e and R 3f Each is independently selected from 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, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl radicals is optionally substituted with at least one of -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl substitution;

[0093] Preferably, R 3A and R 3B are each independently 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; or

[0094] R 3A and R 3BTogether with the atoms to which they are attached, they form an acyl group (-C(=O)-) or a 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, the ring being monocyclic, spirocyclic, fused or bridged, the ring optionally substituted with at least one substituent R 3c replace;

[0095] Each R 3c independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, oxo, -CN, -OR 3d 、-COR 3d 、-CO2R 3d 、-CONR 3d R 3e 、-NO2、-NR 3d R 3e 、-NR 3d COR 3e or-SO2R 3d wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and heterocyclyl groups is optionally substituted with at least one -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halogenated C 1-8 substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halogenated cycloalkyl, heterocyclyl, halogenated heterocyclyl, phenyl, halogenated aryl, heteroaryl, or halogenated heteroaryl;

[0096] R 3d and R 3e each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl is optionally substituted with 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, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl substitution;

[0097] More preferably, R 3A and R 3B are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl; or

[0098] R 3A and R 3B Together with the atoms to which they are attached, they form an acyl group (-C(=O)-) or a 3-, 4-, 5-, 6-, 7- or 8-membered ring, said ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or oxidized sulfur as one or more ring members, said ring being a monocyclic, spirocyclic, fused or bridged ring, said ring being optionally substituted with at least one substituent selected from hydrogen, -F, methyl, ethyl, propyl, butyl, -CF3, oxo or -CN.

[0099] Aspect 13. The compound according to any one of the preceding aspects, wherein the Partly

[0100] in* 3 is attached to Part of the location, and ** 3 is attached to the the location of the part;

[0101] Preferably, the Partly

[0102] Aspect 14. The compound according to any one of the preceding aspects, wherein the Part of it is -Me, -Et,

[0103] Aspect 15. The compound according to any one of the preceding aspects, wherein R 4 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 or heterocyclic; wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or heterocyclyl groups is optionally substituted with at least one substituent R4a replace;

[0104] Each R 4a independently selected from 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 wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0105] R 4b 、R 4c and R 4d Each is independently selected from 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, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0106] Preferably, R 4 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 or heterocyclyl;

[0107] More preferably, R 4 Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl Isobutyl tert-butyl

[0108] Aspect 16. The compound according to any one of the preceding aspects, wherein R 5 、R 6 、R 7 、R 8 and R 9 Each is 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 、-CO2R 5a 、-CONR 5a R 5b 、-NR 5a R 5b 、-NR 5a COR 5b 、-NR 5a CO2R 5b or -NR 5a CONR 5b R 5cwherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl groups is optionally substituted with at least one substituent R 5d replace;

[0109] R 5a 、R 5b and R 5c Each is independently selected from 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, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl groups is optionally substituted with at least one substituent R 5f replace;

[0110] R 5d and R 5f Each is independently selected from hydrogen, -F, -Cl, -Br, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halogenated C 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl or haloheteroaryl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halogenated C 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0111] Preferably, R 5 、R 6 、R 7 、R 8 and R 9 Each is 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 、-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 ;

[0112] R 5a 、R 5b and R 5c Each is independently selected from 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;

[0113] More preferably, R 5 、R 6 、R 7 、R 8 and R 9 Each is 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, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -CN.

[0114] Aspect 17. The compound according to any one of the preceding aspects, wherein R 5 、R6 and R 7 Each is independently selected from H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl; and / or

[0115] R 8 is selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -CN; and / or

[0116] R 9 Selected from H;

[0117] Preferably, R 5 、R 6 and R 7 Each independently selected from H, -F, -Cl, methyl, ethyl, propyl, butyl; and / or

[0118] R 8 is selected from -F, -Cl, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, -CN; and / or

[0119] R 9 Selected from H.

[0120] Aspect 18. The compound according to any one of the preceding aspects, wherein R 11 Selected from H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl or -C 2-8 wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl or -C 2-8 Each of the alkynyl groups is optionally substituted with at least one substituent R 11a replace;

[0121] R 11a Selected from hydrogen, halogen, hydroxyl, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl, wherein the -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C2-8 Each of the alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl;

[0122] Preferably, R 11 Selected from H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl or -C 2-8 Alkynyl;

[0123] More preferably, R 11 Selected from H, methyl, ethyl, propyl, butyl;

[0124] Even more preferably, R 11 It’s H.

[0125] Aspect 19. The compound according to any one of the preceding aspects, wherein the compound is selected from

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139] Aspect 20. A pharmaceutical composition comprising the compound according to any one of aspects 1 to 19 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, and a pharmaceutically acceptable excipient.

[0140] Aspect 21. A method of reducing CDK4 activity by inhibition, comprising administering to a subject a compound according to any one of aspects 1-19 or a pharmaceutically acceptable salt thereof, including the compound of formula (I) or a specific compound exemplified herein.

[0141] Aspect 22. The method according to 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.

[0142] Aspect 23. Use of a compound according to any one of aspects 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.

[0143] 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.

[0144] Aspect 25. A method of treating a disease or disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of Aspects 1-19, or a pharmaceutically acceptable salt thereof, as a CDK4 kinase inhibitor, wherein the disease or disorder is associated with inhibition of CDK4.

[0145] Aspect 26. The method according to 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

[0146] The following terms have the indicated meanings throughout this specification:

[0147] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0148] The following terms have the indicated meanings throughout this specification:

[0149] As used herein, including the appended claims, singular forms of words such as "a," "an," and "the" include their corresponding plural referents unless the context clearly dictates otherwise.

[0150] Unless the context clearly indicates otherwise, the term "or" means and is used interchangeably with the term "and / or."

[0151] The term "alkyl" includes hydrocarbon groups selected from linear and branched saturated hydrocarbon groups containing from 1 to 18, such as from 1 to 12, further such as from 1 to 10, further such as from 1 to 8, or from 1 to 6, or from 1 to 4 carbon atoms. 1-6 Examples of alkyl groups 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 sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-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.

[0152] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0153] The term "butyl" includes 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or sec-butyl ("s-Bu"), 1,1-dimethylethyl or tert-butyl ("t-Bu").

[0154] 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.

[0155] 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.

[0156] The term "alkylene" refers to a divalent alkyl group formed by removing two hydrogen atoms from an alkane. Alkylene includes, but is not limited to, methylene, ethylene, propylene, and the like.

[0157] The term "halogen" includes fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).

[0158] The term "alkenyl" includes hydrocarbon groups selected from straight and branched hydrocarbon groups containing at least one C=C double bond and from 2 to 18, such as from 2 to 8, further such as from 2 to 6 carbon atoms. 2-6 Examples of alkenyl groups 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.

[0159] The term "alkenylene" refers to a divalent alkenyl group formed by removing two hydrogen atoms from an alkene. Alkenylene groups include, but are not limited to, vinylene, butenylene, and the like.

[0160] The term "alkynyl" includes hydrocarbon groups selected from straight and branched hydrocarbon groups containing at least one C≡C triple bond and from 2 to 18, such as from 2 to 8, further such as from 2 to 6 carbon atoms. 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0161] The term "alkynylene" refers to a divalent alkynyl group formed by removing two hydrogen atoms from an alkyne. Alkenylene groups include, but are not limited to, ethynylene and the like.

[0162] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (eg, bicyclic and tricyclic) groups (including fused, bridged or spirocyclic alkyl groups).

[0163] For example, cycloalkyl group can comprise from 3 to 12, for example from 3 to 10, further for example 3 to 8, further for example 3 to 6, 3 to 5 or 3 to 4 carbon atoms.Even further for example, cycloalkyl group can be selected from and comprise from 3 to 12, for example from 3 to 10, further for example 3 to 8, 3 to 6 carbon atom monocyclic group.The example of monocyclic cycloalkyl group comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl group.Especially, saturated monocyclic cycloalkyl group (for example C 3-8Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embodiment, a cycloalkyl group is a monocyclic ring (abbreviated as C 3-6 Examples of bicyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups having from 7 to 12 ring atoms, fused bicyclic ring arrangements (selected from [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems) or bridged bicyclic ring arrangements (selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane). Additional examples of bicyclic cycloalkyl groups include those having bicyclic ring arrangements (selected from [5,6] and [6,6] ring systems).

[0164] The term "spirocycloalkyl" includes cyclic structures containing carbon atoms and formed by at least two rings that share one atom.

[0165] The term "fused cycloalkyl" includes bicyclic cycloalkyl groups as defined herein which are saturated and formed by two or more rings which share two adjacent atoms.

[0166] The term "bridged cycloalkyl" includes cyclic structures containing carbon atoms and formed by two rings that share two atoms that are not adjacent to each other. The term "7- to 10-membered bridged cycloalkyl" includes cyclic structures containing 7 to 12 carbon atoms and formed by two rings that share two atoms that are not adjacent to each other.

[0167] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl groups include, but are not limited to, 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 Cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, etc. Preferred embodiments are 8- to 9-membered fused rings, which refer to cyclic structures containing 8 to 9 ring atoms within the above examples.

[0168] The term "aryl" used alone or in combination with other terms includes groups selected from:

[0169] - 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0170] - bicyclic ring systems (eg 7- to 12-membered bicyclic ring systems) in which at least one ring is carbocyclic and aromatic, such as naphthyl and indanyl; and,

[0171] - a tricyclic ring system (eg a 10- to 15-membered tricyclic ring system) in which at least one ring is carbocyclic and aromatic, such as fluorenyl.

[0172] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring carbon atoms (i.e., C 5-10 Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphthalene-1-yl, naphthalene-2-yl, anthracenyl, phenanthrenyl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalene-1-yl or naphthalene-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0173] Specifically, the term "bicyclic fused aryl" includes bicyclic aryl rings as defined herein. A typical bicyclic fused aryl is naphthalene.

[0174] The term "heteroaryl" includes groups selected from:

[0175] - a 5-, 6-, or 7-membered aromatic monocyclic ring containing at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, or in some embodiments, from 1 to 2 heteroatoms) selected from nitrogen (N), sulfur (S), and oxygen (O), the remaining ring atoms being carbon;

[0176] - a 7- to 12-membered bicyclic ring containing at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, or in other embodiments, 1 or 2 heteroatoms) selected from N, O, and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring; and - an 11- to 14-membered tricyclic ring containing at least one heteroatom (e.g., from 1 to 4, or in some embodiments, from 1 to 3, or in other embodiments, 1 or 2 heteroatoms) selected from N, O, and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.

[0177] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in a heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle does not exceed 1. When a heteroaryl group contains more than one heteroatom ring member, those heteroatoms may be the same or different. Nitrogen atoms in one or more rings of a heteroaryl group may be oxidized to form N-oxides.

[0178] Specifically, the term "bicyclic fused heteroaryl" includes 7 to 12 membered, preferably 7 to 10 membered, more preferably 9 or 10 membered fused bicyclic heteroaryl rings as defined herein. Typically, the bicyclic fused heteroaryl is a 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered bicyclic ring. The group can be attached to the rest of the molecule through either ring.

[0179] "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, the remaining ring members being carbon, including monocyclic, fused, bridged, and spirocyclic rings, i.e., heterocyclyl, bridged, spiroheterocyclyl, and fused heterocyclic groups.

[0180] The term "at least one substituent" disclosed herein includes, for example, from 1 to 4, for example, from 1 to 3, and further, for example, 1 or 2 substituents, provided that the valence theory is satisfied. For example, "at least one substituent F" disclosed herein includes from 1 to 4, for example, from 1 to 3, and further, for example, 1 or 2 substituents F.

[0181] The term "divalent" refers to a linking group that is capable of forming a covalent bond with two other moieties. For example, a "divalent cycloalkyl group" refers to a cycloalkyl group obtained by removing two hydrogen atoms from a corresponding cycloalkane to form a linking group. The terms "divalent aryl group," "divalent heterocyclyl group," or "divalent heteroaryl group" should be understood in a similar manner.

[0182] The compounds disclosed herein may contain asymmetric centers and therefore may exist as enantiomers. "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other. When the compounds disclosed herein have two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader category of stereoisomers. It is intended to include all such possible stereoisomers, such as substantially pure resolved enantiomers, their racemic mixtures, and mixtures of diastereomers. It is intended to include stereoisomers of all compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specifically stated, reference to an isomer is applicable to any possible isomer. Whenever the composition of an isomer is not specified, all possible isomers are included.

[0183] When compounds disclosed herein contain olefinic double bonds, unless specified otherwise, such double bonds are intended to include both E and Z geometric isomers.

[0184] When the compounds disclosed herein contain a disubstituted ring system, the substituents found on such ring systems can be in both cis and trans forms. Cis formation means that both substituents are located on the upper side of the carbon 2 substituent positions, while trans formation means that they are located on opposite sides. For example, the disubstituted ring system can be a cyclohexyl ring or a cyclobutyl ring.

[0185] It can be advantageous to separate the reaction products from each other and / or from the starting materials. By the common techniques of the art, the desired product of each step or series of steps is separated and / or purified (hereinafter referred to as separation) to the desired uniformity. 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 analysis; simulated moving bed ("SMB") and preparative thin or thick layer chromatography, as well as small-scale thin layer and flash chromatography techniques. Those skilled in the art can select and apply the technology most likely to achieve the desired separation.

[0186] "Diastereoisomers" refer to stereoisomers of compounds that have two or more chiral centers but are not mirror images of each other. Diastereoisomer mixtures can be separated into their individual diastereomers according to their physicochemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated as follows: by reacting an enantiomeric mixture with an appropriate optically active compound (e.g., a chiral auxiliary, such as a chiral alcohol or Mosher's acid chloride), converting the enantiomeric mixture into a diastereomeric mixture, separating these diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into the corresponding pure enantiomers. Enantiomers can also be separated by using a chiral HPLC column.

[0187] Single stereoisomers (e.g., substantially pure enantiomers) can be obtained by resolution of the racemic mixture using, for example, an optically active resolving agent to form diastereomers (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH et al. "Chromatographic resolution of enantiomers: Selective review." J. Chromatogr., 113(3) (1975): 283-302). Racemic mixtures of the chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods; (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of these diastereomers and conversion to pure stereoisomers; and (3) separation of substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., ed., Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0188] Some of the compounds disclosed herein may have different points of attachment of hydrogen, known as tautomers. For example, a compound comprising a carbonyl -CH2C(O)- group (keto form) may undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Where applicable, both the individual keto and enol forms, as well as mixtures thereof, are also intended to be included.

[0189] "Prodrug" refers to a derivative of an active agent that requires a transformation in vivo to release the active agent. In some embodiments, the transformation is an enzymatic transformation. A prodrug is often (although not necessarily) pharmacologically inactive until converted to an active agent.

[0190] "Pharmaceutically acceptable salts" refers to those salts which are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and which are commensurate with a reasonable benefit / risk ratio, within the scope of sound medical judgment. 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 separately by reacting an acidic group with a suitable base. The term also includes salts of stereoisomers (e.g., enantiomers and / or diastereomers), tautomers, and prodrugs of the compounds of the invention.

[0191] In addition, if the compounds disclosed herein are obtained as acid addition salts, 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 that various synthetic methods can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

[0192] The terms "administration," "administering," and "treating," "treatment," as used herein, when applied to an animal, a human, a laboratory subject, a cell, a tissue, an organ, or a biological fluid, mean contacting an exogenous agent, therapeutic agent, diagnostic agent, or composition with an animal, a human, a subject, a cell, a tissue, an organ, or a biological fluid. Treatment of cells encompasses contact of an agent with a cell and contact of an agent with a fluid, wherein the fluid is in contact with the cell. The terms "administering" and "treating" also mean, for example, in vitro and ex vivo treatment of a cell by an agent, a diagnostic agent, a binding compound, or 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.

[0193] The term "effective amount" or "therapeutically effective amount" refers to the amount of an active ingredient (e.g., 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 the treatment of such disease, disorder, or symptom. The term "therapeutically effective amount" may vary with the compound, the disease, disorder, and / or the symptoms of the disease or disorder, the severity of the disease, disorder, and / or the symptoms of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. The appropriate amount in any given case will be apparent to those skilled in the art or may 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, as defined herein, that is effective to "treat" the disease or disorder of the subject. In the case of combination therapy, the term "therapeutically effective amount" refers to the total amount of the combination subject used to effectively treat the disease, disorder, or condition.

[0194] The term "disease" refers to any illness, ailment, condition, symptom, or indication, and is interchangeable with the terms "disorder" or "condition."

[0195] Throughout this specification and the appended claims, unless the context requires otherwise, the term "comprise" and variations such as "comprises and comprising" are intended to specify the presence of the following features, but do not preclude the presence or addition of one or more other features. When used herein, the term "comprise" may be replaced by the terms "containing," "including," or sometimes "having."

[0196] Throughout this specification and the appended claims, the term “C n-m " indicates a range including endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 、C 1-6 wait.

[0197] Unless specifically defined elsewhere in this document, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0198] Examples

[0199] Universal synthesis

[0200] Compound disclosed herein (including its salt) can be prepared using known organic synthesis techniques and can be synthesized according to any of the numerous possible synthetic pathways. The reaction for preparing the compound disclosed herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. Suitable solvents can be substantially free from reaction with starting material, intermediate or product at a temperature (e.g., ranging from the boiling temperature of the solvent) for reacting. A given reaction can be carried out in a mixture of a solvent or a plurality of solvents.

[0201] The selection of appropriate protecting groups can be readily determined by one skilled in the art.

[0202] The reaction can be monitored according to any suitable method known in the art (e.g., NMR, UV, HPLC, LC-MS, and TLC).The compound can be purified by a variety of methods including HPLC and normal phase silica gel chromatography.

[0203] Chiral analytical HPLC was used for retention time analysis of different chiral samples, and the conditions were divided into the following methods based on the column, mobile phase, and solvent ratio used.

[0204] Plan I

[0205]

[0206] For example, compounds of formula (I), (II), (III), or (IV) can be formed as shown in Scheme 1. Compound (i) can be reacted with a halogenated pyrimidine under palladium-catalyzed reaction conditions or base-mediated coupling conditions to obtain compound (ii), which can be coupled with an amine to obtain compound (iii), which can be reduced and halogenated to obtain compound (iv), which can be used for coupling to obtain compound (v).

[0207] Option II

[0208]

[0209] For example, compounds of formula (I), (II), (AIII), (III), (AIV), or (IV) can be formed as shown in Scheme II. Compound (i) can be reacted with a halogenated pyrimidine under palladium-catalyzed reaction conditions to provide compound (ii), which can be coupled with an amine to provide compound (iii).

[0210] Example 1: 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropyl-N-methylquinoline-3-carboxamide

[0211]

[0212] Step 1: Ethyl 6-chloro-4-isopropylquinoline-3-carboxylate

[0213]

[0214] To an isopropylmagnesium bromide solution (15 mL, 1 M, 15 mmol) was added a solution of zinc chloride in tetrahydrofuran (21.4 mL, 0.7 M, 15 mmol) under nitrogen, and the mixture was stirred at 50°C for 2 h. A solution of ethyl 4,6-dichloroquinoline-3-carboxylate (2 g, 7.5 mmol) in dimethylformamide (10 mL), copper (I) iodide (143 mg, 0.75 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (275 mg, 0.375 mmol) was added, and the resulting mixture was stirred at 50°C for 2 h and then cooled to room temperature. The reaction was quenched with methanol (10 mL), and the solvent was evaporated. The residue was suspended in ethyl acetate and water and then filtered. The filtrate was washed with water and brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate in petroleum ether (16%, v / v) to give the title compound (1.5 g, 71%). LC-MS (M+H) + =278.2.

[0215] Step 2: Ethyl 4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline- 3-formate

[0216]

[0217] A mixture of ethyl 6-chloro-4-isopropylquinoline-3-carboxylate (1.3 g, 4. mmol), bis(pinacolato)diboron (1.4 g, 5.6 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (172 mg, 0.24 mmol) and potassium acetate (921 mg, 9.4 mmol) in 1,4-dioxane (40 mL) was stirred at 80°C overnight under nitrogen and then cooled to room temperature. The mixture was filtered and the filtrate was evaporated to give the crude product, which was used in the next step without further purification. LC-MS (M+H) + =370.3.

[0218] Step 3: Ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate

[0219]

[0220] A mixture of ethyl 4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate, 2,4-dichloro-5-fluoropyrimidine (785 mg, 4.7 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (176 mg, 0.24 mmol) and K2CO3 (1.3 g, 9.4 mmol) in 1,4-dioxane (40 mL) and water (5 mL) was stirred at 80 ° C. under nitrogen overnight and then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (eluted with methanol (3%, v / v) in dichloromethane) to give the title compound (790 mg, 45% over two steps). LC-MS (M+H) + =374.1.

[0221] Step 4: Ethyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidine-4-yl 4-Isopropylquinoline-3-carboxylate

[0222]

[0223] A reaction mixture of ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate (790 mg, 2.11 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol (390 mg, 2.53 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (89 mg, 0.11 mmol) and cesium carbonate (2.1 g, 6.33 mmol) in 1,4-dioxane (30 mL) was stirred overnight at 100° C. under nitrogen. The mixture was cooled to room temperature and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with methanol (6%, v / v) in dichloromethane to give the title compound (780 mg, 81%). LC-MS (M+H) + =455.8.

[0224] Step 5: 6-(5-Fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4- Isopropylquinoline-3-carboxylic acid

[0225]

[0226] To a solution of ethyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate (150 mg, 0.33 mmol) in tetrahydrofuran (15 mL) was added aqueous lithium hydroxide monohydrate solution (30 mg, 0.66 mmol), and the mixture was stirred at 55° C. overnight and then cooled to room temperature. The mixture was acidified to pH = 6 with 1N HCl. The precipitate was filtered and dried to give the product (130 mg, 92%). LC-MS (M+H) + =427.3

[0227] Step 6: 6-(5-Fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4- Isopropyl-N-methylquinoline-3-carboxamide

[0228] The reaction mixture of 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carboxylic acid (100 mg, 0.24 mmol), methylamine hydrochloride (30 mg, 0.47 mmol), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (91 mg, 0.24 mmol), N,N-diisopropylethylamine (61 mg, 0.47 mmol) and dimethylformamide (5 mL) was stirred at 50 ° C for 3 h and then cooled to room temperature. Water was added and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC (eluent: water (0.1% formic acid) / acetonitrile (0.1% formic acid)) to give the product (45 mg, 43%). 1 H-NMR (400MHz, DMSO-d6) δ9.08(s,1H),8.74(s,1H),8.60(d,J=4.3Hz,1H),8.51(d,J=3 .5Hz,1H),8.35(d,J=8.8Hz,1H),8.19(d,J=8.8Hz,1H),7.28(d,J=7.7Hz,1H),4.97(d, J=4.9Hz,1H),4.00–3.79(m,3H),3.72(dd,J=14.2,7.0Hz,1H),3.55(s,1H),3.38–3.36 (m,1H),3.06(t,J=10.4Hz,1H),2.84(d,J=4.3Hz,3H),2.03(s,1H),1.55–1.49(m,7H). LC-MS(M+H) + =440.3.

[0229] Example 2: (3S,4R)-4-((5-fluoro-4-(3-(2-hydroxypropan-2-yl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0230]

[0231] To a solution of ethyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate (50 mg, 0.11 mmol) in tetrahydrofuran (10 mL) was added 3 M methylmagnesium bromide in tetrahydrofuran (0.1 mL, 0.33 mmol) at -78 ° C under nitrogen, and the mixture was stirred at room temperature for 4 h. The reaction was quenched with water and the mixture was evaporated. The residue was purified by preparative HPLC (eluent: water (0.1% formic acid) / acetonitrile (0.1% formic acid)) to give the product (6 mg, 12%). 1 H-NMR (400MHz, DMSO-d6) δ9.19 (s, 1H), 9.08 (s, 1H), 8.49 (d, J = 3.8Hz, 1H), 8.25 (t,J=9.2Hz,1H),8.11(d,J=8.8Hz,1H),7.24(d,J=7.9Hz,1H),5.43(s,1H),4.97 (d,J=4.7Hz,1H),4.74–4.54(m,1H),3.99–3.77(m,3H),3.54(s,1H),3.39–3.36( m,1H),3.05(t,J=10.4Hz,1H),2.1-1.93(m,1H),1.70(s,6H),1.65–1.40(m,7H). LC-MS (M+H) + =441.3.

[0232] Example 3: (3S,4R)-4-((5-fluoro-4-(3-(hydroxymethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0233]

[0234] To a solution of ethyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate (50 mg, 0.11 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (13 mg, 0.33 mmol) at 0 ° C under nitrogen and stirred at room temperature for 3 h. The reaction was quenched with methanol and the solvent was evaporated. The residue was purified by preparative HPLC (eluent: water (0.1% formic acid) / acetonitrile (0.1% formic acid)) to give the product (6 mg, 12%). 1 H-NMR (400MHz, DMSO-d6) δ9.10(s,1H),8.90(s,1H),8.50(d,J=3.7Hz,1H),8.28(d,J=8.8Hz,1H),8.14(d,J=8.8Hz,1H),7.26(d,J=7.8Hz,1H),5.39 (s,1H),4.97(s,1H),4.78(s,2H),4.01–3.77(m,4H),3.55(s,1H),3.39-3 .36(m,1H),3.06(t,J=10.4Hz,1H),2.06–1.99(m,1H),1.59–1.47(m,7H). LC-MS(M+H) + =413.3.

[0235] Example 4: (3S,4R)-4-((5-chloro-4-(4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0236]

[0237] Step 1: 6-Chloroquinolin-4-yl trifluoromethanesulfonate

[0238]

[0239] 6-Chloroquinolin-4-ol (3 g, 16.7 mmol) and N,N-diisopropylethylamine (2.59 g, 20.1 mmol) were dissolved in dichloromethane (30 mL). Trifluoromethanesulfonic anhydride (5.66 g, 20.1 mmol) was added dropwise at 0 ° C, and the reaction solution was stirred at 0 ° C for 2 h and then water (20 mL) was added. The aqueous layer was extracted with dichloromethane (50 mL X 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography to give the title compound (4.1 g, 79%). LC-MS (M+H) + =312.0.

[0240] Step 2: 6-chloro-4-(prop-1-en-2-yl)quinoline

[0241]

[0242] The title compound (700 mg, 26%) was prepared in a similar manner to Example 1, Step 3, from 6-chloroquinolin-4-yl trifluoromethanesulfonate and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane. LC-MS (M+H) + =204.0.

[0243] Step 3: 6-Chloro-4-isopropylquinoline

[0244]

[0245] A mixture of 6-chloro-4-(prop-1-en-2-yl)quinoline (610 mg, 2.995 mmol) in methanol (10 mL) and PtO2 (30.5 mg) was stirred under a hydrogen atmosphere for 2.5 h. The mixture was filtered and the filtrate was concentrated under vacuum. The crude residue (616 mg) was used in the next step without further purification. LC-MS (M+H) + =206.0.

[0246] Step 4: 4-Isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

[0247]

[0248] The title compound (1.01 g, 100%) was prepared in a similar manner to Example 1, Step 2, from 6-chloro-4-isopropylquinoline and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane). LC-MS (M+H) + =298.0.

[0249] Step 5: 6-(2,5-dichloropyrimidin-4-yl)-4-isopropylquinoline

[0250]

[0251] The title compound (500 mg, 46%) was prepared in a similar manner to Example 1, Step 3, from 2,4,5-trichloropyrimidine and 4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline. LC-MS (M+H) + =318.0.

[0252] Step 6: (3S,4R)-4-((5-chloro-4-(4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyridine furan-3-ol

[0253] 6-(2,5-dichloropyrimidin-4-yl)-4-isopropylquinoline (500mg, 1.57mmol) and N,N-diisopropylethylamine (609mg, 4.71mmol) were dissolved in acetonitrile (20mL). (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (362mg, 2.36mmol) was added, and the mixture was stirred at 80°C for 36h and then cooled to room temperature. The solvent was removed under vacuum and water (20mL) was added. The aqueous layer was extracted with ethyl acetate (40mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel to obtain the title product (40mg, 6.4%). 1 H-NMR(400MHz,DMSO-d6)δ8.92(d,J=4.5Hz,1H),8.60(s,1H),8.47(s,1H) ,8.14(d,J=8.2Hz,1H),8.09(s,1H),7.56(s,1H),7.51(d,J=4.4Hz,1H),4. 95(d,J=5.3Hz,1H),3.91–3.72(m,4H),3.51(s,1H),3.33–3.26(m,1H),3.0 3(t,J=10.1Hz,1H),1.97(s,1H),1.61–1.41(m,1H),1.38(d,J=6.7Hz,6H). LC-MS(M+H) + =399.0.

[0254] Example 5: (3S,4R)-4-((5-chloro-4-(4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0255]

[0256] Step 1: 6-Chloro-2-methylquinolin-4-yl trifluoromethanesulfonate

[0257]

[0258] Under nitrogen atmosphere at 0 DEG C to 6- chloro-2-methylquinoline-4-ol (800mg, 4.13mmol) and pyridine (653mg, 8.26mmol) in dichloromethane (20mL) solution, add trifluoromethanesulfonic anhydride (1.75g, 6.20mmol). The resulting mixture is stirred at room temperature for 12h and then quenched by adding water (30mL). The resulting mixture is extracted with dichloromethane (20mL × 3). The combined organic phases are washed with brine, dried over sodium sulfate, filtered and concentrated. The residue is purified by flash chromatography on silica gel (eluted with ethyl acetate (0-20% gradient, v / v) in petroleum ether) to obtain the title compound (700mg, 52%). LC-MS (M+H) + =325.9.

[0259] Step 2: 6-Chloro-2-methyl-4-(prop-1-en-2-yl)quinoline

[0260]

[0261] To a solution of 6-chloro-2-methylquinolin-4-yl trifluoromethanesulfonate (650 mg, 1.99 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-ene-2-yl)-1,3,2-dioxaborolane (302 mg, 1.79 mmol) in tetrahydrofuran (10 mL) and water (2 mL) was added potassium carbonate (552 mg, 3.99 mmol) and tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.10 mmol). The resulting mixture was stirred at 70 ° C for 3 h under a nitrogen atmosphere, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluted with ethyl acetate (0-25% gradient, v / v) in petroleum ether) to give the title compound (368 mg, 84%). LC-MS (M+H) + =218.0.

[0262] Step 3: 6-Chloro-4-isopropyl-2-methylquinoline

[0263]

[0264] To a solution of 6-chloro-2-methyl-4-(prop-1-en-2-yl)quinoline (342 mg, 1.57 mmol) in methanol (10 mL) was added 5% Rh / C (324 mg, 0.16 mmol). The resulting mixture was stirred at room temperature for 12 h under a hydrogen atmosphere. The mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column (eluted with acetonitrile in water (0-25% in 10 min, v / v, both eluents containing 0.1% trifluoroacetic acid) to give the title compound (285 mg, 82%). LC-MS (M+H)+ =220.1.

[0265] Step 4: 4-Isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinol phenotype

[0266]

[0267] To a solution of 6-chloro-4-isopropyl-2-methylquinoline (238 mg, 1.08 mmol) and bis(pinacol)diboron (411 mg, 1.62 mmol) in 1,4-dioxane (10 mL) was added potassium acetate (160 mg, 1.62 mmol) and dichlorobis(tricyclohexylphosphine)palladium(II) (80 mg, 0.108 mmol). The resulting mixture was stirred at 100 ° C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluted with methanol (0-25% gradient, v / v) in dichloromethane) to give the title compound (144 mg, 42%). LC-MS (M+H) + =312.1.

[0268] Step 5: 6-(2,5-dichloropyrimidin-4-yl)-4-isopropyl-2-methylquinoline

[0269]

[0270] To a solution of 2,4,5-trichloropyrimidine (80 mg, 0.44 mmol) and 4-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (163 mg, 0.52 mmol) in dioxane (5 mL) and water (1 mL) was added potassium carbonate (90 mg, 0.65 mmol) and tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.044 mmol). The resulting mixture was stirred at 100 ° C. for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a C18 column (eluted with acetonitrile (0-35% in 15 min, v / v) in water containing 0.1% trifluoroacetic acid) to give the title compound (80 mg, 55%). LC-MS (M+H) + =332.0.

[0271] Step 6: (3S,4R)-4-((5-chloro-4-(4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrakis Hydrogen-2H-pyran-3-ol

[0272] A solution of 6-(2,5-dichloropyrimidin-4-yl)-4-isopropyl-2-methylquinoline (70 mg, 0.21 mmol), (3S,4R)-4-aminooxan-3-ol hydrochloride (65 mg, 0.42 mmol), and N,N-diisopropylethylamine (0.11 mL, 0.63 mmol) in DMSO (4 mL) was stirred at 90° C. for 2 d under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 30 x 150 mm, 5 μm; mobile phase, acetonitrile in water (with 10 mmol / L NH4HCO3 and 0.1% NH4OH), gradient from 31% to 61% over 9 min; detector, UV 254 nm. The title compound (10 mg, 12%) was obtained. 1 H-NMR(300MHz,DMSO-d6)δ8.55(brs,1H),8.46(s,1H),8.07-8.01(m,2H),7.56-7.48(m,1H),7.41(s,1H),4.95(d,J=5.3Hz,1H),3.94-3.65 (m,4H),3.57-3.47(m,1H),3.39-3.29(m,1H),3.11-2.98(m,1H),2.68(s,3H),2.04-1.93(m,1H),1.61-1.43(m,1H),1.38(d,J=6.7Hz,6H). LC-MS(M+H) + =413.1.

[0273] Example 6: (3S,4R)-4-((5-fluoro-4-(4-isopropyl-3-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0274]

[0275] Step 1: (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino 1-H-pyran-3-ol

[0276]

[0277] To a solution of (3S,4R)-4-((5-fluoro-4-(3-(hydroxymethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (80 mg, 0.19 mmol) in dichloromethane (5 mL) was added thionyl chloride (46 mg, 0.39 mmol) at 0°C, and the mixture was stirred for 1 h and then quenched with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to give 85 mg of crude product, which was used in the next step without further purification. LC-MS (M+H) + =431.2.

[0278] Step 2: (3S,4R)-4-((5-fluoro-4-(4-isopropyl-3-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrakis Hydrogen-2H-pyran-3-ol

[0279] The reaction mixture of (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (85 mg, 0.19 mmol) and 5% Pd / C (15 mg) in methanol (5 mL) was stirred at room temperature for 14 h under a hydrogen atmosphere. The mixture was filtered and evaporated. The residue was purified by preparative HPLC (eluent: water (0.1% formic acid) / acetonitrile (0.1% formic acid)) to give the product (4 mg, 0.5%). 1 H-NMR (400MHz, DMSO-d6) δ8.99(s,1H),8.71(s,1H),8.44(d,J=2.9Hz,1H),8.19(d,J=9.0Hz,1H),8.06(d,J=8.7Hz,1H),7.21(d,J=7.5Hz, 1H), 4.92 (s, 1H), 3.92–3.68 (m, 4H), 3.50 (s, 1H), 3.34–3.31 (m, 1H), 3.01 (t, J = 10.4Hz, 1H), 2.48 (s, 3H), 1.98 (s, 1H), 1.50–1.48 (m, 7H). LC-MS(M+H) + =397.3.

[0280] Example 7: (3S,4R)-4-((5-fluoro-4-(4-isopropyl-2,3-dimethylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0281]

[0282] Step 1: 6-Chloro-2,3-dimethylquinolin-4-ol

[0283]

[0284] A reaction mixture of 4-chloroaniline (6 g, 46.9 mmol), ethyl 2-methyl-3-oxobutanoate (13.5 g, 93.8 mmol) in polyphosphoric acid (20 mL) was stirred at 175° C. for 4 h and then cooled to room temperature. Water was added and the resulting precipitate was filtered and dried to give the title compound (8.1 g, 82%). LC-MS (M+H) + =208.0.

[0285] Step 2: 4-Bromo-6-chloro-2,3-dimethylquinoline

[0286]

[0287] To a solution of 6-chloro-2,3-dimethylquinolin-4-ol (2.1 g, 10 mmol) in dimethylformamide (20 mL) was added phosphorus tribromide (3.3 g, 12.1 mmol), and the reaction solution was stirred at room temperature overnight. The reaction was quenched with water and the precipitate was filtered. The crude product was purified by flash chromatography on silica gel (eluted with ethyl acetate (33%, v / v) in petroleum ether) to give the title compound (2 g, 73%). LC-MS (M+H) + =270.0, 272.0.

[0288] Step 3: 6-chloro-4-isopropyl-2,3-dimethylquinoline

[0289]

[0290] To a 1M solution of isopropylmagnesium bromide in tetrahydrofuran (3.7 mL, 3.7 mmol) was added a 0.7M solution of zinc chloride in tetrahydrofuran (5.3 mL, 3.7 mmol) under nitrogen, and the mixture was stirred at 50°C for 2 h. A solution of 4-bromo-6-chloro-2,3-dimethylquinoline (500 mg, 1.85 mmol) in dimethylformamide (10 mL), copper (I) iodide (36 mg, 0.37 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (139 mg, 0.19 mmol) were added, and the mixture was stirred at 50°C for 2 h and then cooled to room temperature. The reaction was quenched with methanol (10 mL), and the solvent was evaporated, followed by addition of ethyl acetate and water. The resulting precipitate was filtered. The filtrate was washed with water and brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate in petroleum ether (0-16% gradient, v / v) to give the title compound (200 mg, 43%). 1H-NMR (400MHz, DMSO-d6) δ8.16(d,J=8.6Hz,1H),7.86(s,1H),7.39(d,J=8.6Hz,1H),6.08(s,1H),5.05(s,1H),2.52(s,3H),1.62(d,J=6.9Hz,7H). LC-MS(M+H) + =234.0.

[0291] Step 4: 4-isopropyl-2,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- quinoline

[0292]

[0293] A reaction mixture of 6-chloro-4-isopropyl-2,3-dimethylquinoline (200 mg, 0.85 mmol), bis(pinacolato)diboron (326 mg, 1.28 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (63 mg, 0.085 mmol) and potassium acetate (167 mg, 1.7 mmol) in 1,4-dioxane (10 mL) was stirred at 80°C overnight under nitrogen. The mixture was filtered and the filtrate was evaporated to give the crude product, which was used in the next step without further purification. LC-MS (M+H) + =244.1 for the corresponding boronic acid.

[0294] Step 5: 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyl-2,3-dimethylquinoline

[0295]

[0296] A mixture of 4-isopropyl-2,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (crude), 2,4-dichloro-5-fluoropyrimidine (284 mg, 1.7 mmol), dichlorobis(tricyclohexylphosphine)palladium(II) (62 mg, 0.085 mmol) and potassium carbonate (235 mg, 1.7 mmol) in 1,4-dioxane (20 mL) and water (3 mL) was stirred at 70 ° C under nitrogen for 2 h, then cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (eluted with methanol in dichloromethane (0-3% gradient, v / v) to give the title compound (80 mg, 28% over two steps). LC-MS (M+H) + =330.1.

[0297] Step 6: (3S,4R)-4-((5-fluoro-4-(4-isopropyl-2,3-dimethylquinolin-6-yl)pyrimidin-2-yl)amino 1-H-pyran-3-ol

[0298] The title compound (60 mg, 61%) was prepared in a manner similar to Example 1, Step 4, from 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyl-2,3-dimethylquinoline and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol. 1 H-NMR (400MHz, DMSO-d6) δ9.01(s,1H),8.48(s,1H),8.19(d,J=8.1Hz,1H),8.00(d,J=8.7Hz,1H),7.23(d,J=7.5Hz,1H),4.97(d,J=5.2Hz,1H ),3.86–3.85(m,4H),3.55(s,1H),3.39–3.33(m,1H),3.06(t,J=10.4H z,1H),2.67(s,3H),2.46(s,3H),2.14–1.94(m,1H),1.64–1.44(m,7H). LC-MS(M+H) + =411.1.

[0299] Example 8: (3S,4R)-4-((5-fluoro-4-(4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0300]

[0301] Step 1: 6-Chloroquinolin-4-yl trifluoromethanesulfonate

[0302]

[0303] 6-Chloroquinolin-4-ol (3 g, 16.71 mmol) and N,N-diisopropylethylamine (2.59 g, 20.05 mmol) were dissolved in dichloromethane (30 mL). Trifluoromethanesulfonic anhydride (5.66 g, 20.05 mmol) was added dropwise at 0°C, and the reaction solution was stirred at 0°C for 2 h and then water (20 mL) was added. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound (4.1 g, 79%). LC-MS (M+H) + =312.0.

[0304] Step 2: 6-chloro-4-(prop-1-en-2-yl)quinoline

[0305]

[0306] The title compound (700 mg, 26%) was prepared in a similar manner to Example 1, Step 3, from 6-chloroquinolin-4-yl trifluoromethanesulfonate and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane. LC-MS (M+H) + =204.0.

[0307] Step 3: 6-Chloro-4-isopropylquinoline

[0308]

[0309] The title compound (616 mg, 100%) was prepared from 6-chloro-4-(prop-1-en-2-yl)quinoline in a manner similar to that described in Example 4, Step 3. LC-MS (M+H) + =206.0.

[0310] Step 4: 4-Isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

[0311]

[0312] The title compound (1.0 g, 100%) was prepared from 6-chloro-4-isopropylquinoline in a similar manner to Example 1, Step 2. LC-MS (M+H) + =298.0.

[0313] Step 5: 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinoline

[0314]

[0315] The title compound (526 mg, 97%) was prepared in a similar manner to Example 1, Step 3, from 2,4-dichloro-5-fluoropyrimidine and 4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline. LC-MS (M+H) + =302.0.

[0316] Step 6: (3S,4R)-4-((5-fluoro-4-(4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0317] The title compound (150 mg, 23%) was prepared in a manner similar to Example 1, Step 4, from 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinoline and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride. 1H-NMR (400MHz, DMSO-d6) δ8.92(d,J=4.5Hz,1H),8.86(s,1H),8.50(d,J=3.6Hz,1 H),8.31(d,J=8.7Hz,1H),8.17(d,J=9.3Hz,1H),7.52(d,J=4.4Hz,1H),7.29(d,J =7.3Hz,1H),4.96(s,1H),3.97–3.71(m,4H),3.65–3.45(m,1H),3.38(m,1H),3.0 7(t,J=10.4Hz,1H),2.13–1.93(m,1H),1.56–1.39(m,1H),1.40(d,J=6.6Hz,6H). LC-MS (M+H) + =383.0.

[0318] Example 9: (3S,4R)-4-((5-fluoro-4-(4-isopropyl-5-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0319]

[0320] Step 1: Methyl 6-chloro-4-hydroxy-5-methylquinoline-2-carboxylate

[0321]

[0322] To a solution of 4-chloro-3-methylaniline (8 g, 56.5 mmol) in methanol (110 mL) was added dimethylbut-2-ynedioate (8.11 g, 57.1 mmol) dropwise at 0°C, and the resulting solution was stirred at room temperature for 1 h. The solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel to give the title compound (4.24 g, 30%). LC-MS (M+H) + =252.0.

[0323] Step 2: 6-Chloro-4-hydroxy-5-methylquinoline-2-carboxylic acid

[0324]

[0325] The title compound (3.3 g, 82.5%) was prepared from methyl 6-chloro-4-hydroxy-5-methylquinoline-2-carboxylate in a similar manner to Example 1, Step 5. LC-MS (M+H) + =238.0.

[0326] Step 3: 6-Chloro-5-methylquinolin-4-ol

[0327]

[0328] A solution of 6-chloro-4-hydroxy-5-methylquinoline-2-carboxylic acid (3.3 g, 13.9 mmol) in diphenyl ether (30 mL) was stirred at 260° C. for 1 h, then cooled to room temperature and purified by silica gel flash chromatography to give the title compound (2.35 g, 87%). LC-MS (M+H) + =194.0.

[0329] Step 4: 4,6-Dichloro-5-methylquinoline

[0330]

[0331] 6-Chloro-5-methylquinolin-4-ol (553 mg, 2.86 mmol) was dissolved in phosphorus oxychloride (15 mL), and the solution was refluxed for 3 h, then cooled to room temperature and concentrated in vacuo. Ethyl acetate (20 mL) was added and saturated sodium bicarbonate solution was added until pH = 8. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound (491 mg, 81%). LC-MS (M+H) + =212.0.

[0332] Step 5: 6-Chloro-5-methyl-4-(prop-1-en-2-yl)quinoline

[0333]

[0334] The title compound (191 mg, 51%) was prepared from 4,6-dichloro-5-methylquinoline and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane in a manner similar to that described in Example 1, Step 3. LC-MS (M+H) + =218.0.

[0335] Step 6: 6-Chloro-4-isopropyl-5-methylquinoline

[0336]

[0337] The title compound (193 mg, 100%) was prepared from 6-chloro-5-methyl-4-(prop-1-en-2-yl)quinoline in a manner similar to that described in Example 4, Step 3. LC-MS (M+H) + =220.0.

[0338] Step 7: 4-Isopropyl-5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

[0339]

[0340] The title compound (302 mg, 100%) was prepared from 6-chloro-4-isopropyl-5-methylquinoline in a similar manner to Example 1, Step 2. LC-MS (M+H) + =312.0.

[0341] Step 8: 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyl-5-methylquinoline

[0342]

[0343] The title compound (72 mg, 24%) was prepared from 4-isopropyl-5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline in a manner similar to that described in Example 1, Step 3. LC-MS (M+H) + =316.0.

[0344] Step 9: (3S,4R)-4-((5-fluoro-4-(4-isopropyl-5-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0345] The title compound (25 mg, 28%) was prepared in a manner similar to Example 1, Step 4, from 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyl-5-methylquinoline. 1 H-NMR (400MHz, DMSO-d6) δ8.84(d,J=4.5Hz,1H),8.47(s,1H),7.96(d,J=8.6Hz,1H),7.6 4(d,J=8.6Hz,1H),7.62(d,J=4.5Hz,1H),7.30(d,J=7.6Hz,1H),4.94(d,J=5.1Hz,1H),4 .22–4.02(m,1H),3.85–3.70(m,3H),3.58–3.42(m,1H),3.32–3.22(m,1H),3.03(t,J=10 .3Hz,1H),2.71(s,3H),1.98(d,J=11.5Hz,1H),1.55–1.35(m,1H),1.34(d,J=6.4Hz,6H). LC-MS(M+H) + =397.0.

[0346] Example 10: (3S,4R)-4-((5-fluoro-4-(4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0347]

[0348] Step 1: 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyl-2-methylquinoline

[0349]

[0350] The title compound (180 mg, 69%) was prepared in a similar manner to that in Step 3 of Example 1 from 4-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline and 2,4-dichloro-5-fluoropyrimidine. LC-MS (M+H) + =316.1.

[0351] Step 2: (3S,4R)-4-((5-fluoro-4-(4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrakis Hydrogen-2H-pyran-3-ol

[0352] The title compound (25 mg, 11%) was prepared in a similar manner to that in Example 1, Step 4, from 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyl-2-methylquinoline and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol. 1 H-NMR (400MHz, DMSO-d6) δ8.80(s,1H),8.48(d,J=3.6Hz,1H),8.26(d,J=8.2Hz,1H ),8.05(d,J=8.8Hz,1H),7.42(s,1H),7.25(d,J=7.5Hz,1H),4.96(s,1H),3.90–3.7 9(m,3H),3.74(dt,J=14.0,7.0Hz,1H),3.54(s,1H),3.39–3.33(m,1H),3.07(t,J= 10.3Hz,1H),2.68(s,3H),2.12–1.92(m,1H),1.55–1.47(m,1H),1.42–1.35(m,6H). LC-MS(M+H) + =397.3.

[0353] Example 11: (3S,4R)-4-((4-(3-((dimethylamino)methyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0354]

[0355] To a solution of (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (25 mg, 0.058 mmol) in dimethylformamide (2 mL) was added dimethylamine hydrochloride (9.5 mg, 0.116 mmol) and N,N-diisopropylethylamine (22.4 mg, 0.174 mmol) at 25 ° C. The mixture was stirred at 25 ° C for 5 h and then diluted with ethyl acetate (20 mL). The organic solution was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluted with methanol (5%, v / v) in dichloromethane) to give the title compound (7.4 mg, 29%). 1 H-NMR(400MHz,DMSO-d6)δ:9.12(s,1H),8.78(s,1H),8.50(s,1H),8.34-8.25( m,1H),8.18-8.10(m,1H),7.26(d,J=7.9Hz,1H),4.52-4.94(m,1H),4.04-3.90( m,1H),3.92-3.80(m,3H),3.66-3.61(m,2H),3.57-3.50(m,1H),3.42-3.35(m, 1H), 3.05 (t, J = 10.3Hz, 1H), 2.20 (s, 6H), 2.09-2.01 (m, 1H), 1.62-1.49 (m, 7H). LC-MS (M+H) + =440.1.

[0356] Example 12: 1-((6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)pyrrolidin-2-one

[0357]

[0358] Step 1: (6-chloro-4-isopropylquinolin-3-yl)methanol

[0359]

[0360] Ethyl 6-chloro-4-isopropylquinoline-3-carboxylate (2.45 g, 8.82 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). A solution of diisobutylaluminum hydride in tetrahydrofuran (11.8 mL, 1.5 M, 17.64 mmol) was added dropwise at 0 ° C., and the reaction solution was stirred at room temperature overnight. Saturated NH4Cl solution (30 mL) was added, and the aqueous layer was extracted with ethyl acetate (100 mL X 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound (1.73 g, 56%). LC-MS (M+H) + =236.0.

[0361] Step 2: (6-Chloro-4-isopropylquinolin-3-yl)methyl methanesulfonate

[0362]

[0363] (6-Chloro-4-isopropylquinolin-3-yl)methanol (868 mg, 3.68 mmol) and methanesulfonic anhydride (770 mg, 4.42 mmol) were dissolved in anhydrous dichloromethane (10 mL) at 0 ° C. N, N-diisopropylethylamine (571.2 mg, 4.42 mmol) was added at 0 ° C and the reaction solution was stirred at 0 ° C for 30 min, and then stirred at room temperature for 2 h. Saturated aqueous sodium bicarbonate solution (10 mL) was added, and the aqueous layer was extracted with ethyl acetate (30 mL X 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound (736 mg, 63.4%). LC-MS (M+H) + =314.0.

[0364] Step 3: 1-((6-chloro-4-isopropylquinolin-3-yl)methyl)pyrrolidin-2-one

[0365]

[0366] To a solution of pyrrolidin-2-one (81.4 mg, 0.96 mmol) in anhydrous dimethylformamide (3 mL) was added sodium hydride (5 mg, 60%, 1.28 mmol) at 0°C under a nitrogen atmosphere, and the reaction mixture was stirred at 0°C for 30 min. (6-chloro-4-isopropylquinolin-3-yl)methyl methanesulfonate (200 mg, 0.64 mmol) was added, and the mixture was stirred at room temperature overnight and then water (20 mL) was added. The aqueous layer was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound (96 mg, 50%). LC-MS (M+H) + =303.0.

[0367] Step 4: 1-((4-Isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)methyl)pyrrolidin-2-one

[0368]

[0369] The title compound (152 mg, 100%) was prepared in a similar manner to that in Example 1, Step 2, from 1-((6-chloro-4-isopropylquinolin-3-yl)methyl)pyrrolidin-2-one. LC-MS (M+H) + =395.0.

[0370] Step 5: 1-((6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)pyrrolidin-2-one

[0371]

[0372] The title compound (126 mg, 100%) was prepared in a manner similar to that in Example 1, Step 3, from 1-((4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)methyl)pyrrolidin-2-one. LC-MS (M+H) + =399.0.

[0373] Step 6: 1-((6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)pyrrolidin-2-one

[0374] The title compound (46 mg, 30%) was prepared in a similar manner to that in Example 1, Step 4, from 1-((6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)pyrrolidin-2-one.1 H-NMR (400MHz, DMSO-d6) δ9.12(s,1H),8.82(s,1H),8.50(d,J=3.7Hz,1H),8.31(d,J=8.8Hz ,1H),8.16(d,J=8.8Hz,1H),7.28(d,J=7.8Hz,1H),4.97(d,J=5.2Hz,1H),4.68(s,2H),4.01– 3.68(m,4H),3.67–3.47(m,1H),3.37(d,J=11.9Hz,1H),3.15(t,J=6.9Hz,2H),3.05(t,J=10. 4Hz, 1H), 2.30 (t, J = 8.0Hz, 2H), 2.13–1.93 (m, 1H), 1.96–1.82 (m, 2H), 1.53 (t, J = 6.3Hz, 7H). LC-MS(M+H) + =480.0.

[0375] Example 13: 4-((6-(5-Fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)morpholin-3-one

[0376]

[0377] Step 1: 4-((6-chloro-4-isopropylquinolin-3-yl)methyl)morpholin-3-one

[0378]

[0379] The title compound (152 mg, 100%) was prepared from (6-chloro-4-isopropylquinolin-3-yl)methyl methanesulfonate in a similar manner to that in Example 12, Step 3. LC-MS (M+H) + =319.0.

[0380] Step 2: 4-((4-Isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)methyl)morpholin-3-one

[0381]

[0382] The title compound (205 mg, 100%) was prepared in a similar manner to that in Example 1, Step 2, from 4-((6-chloro-4-isopropylquinolin-3-yl)methyl)morpholin-3-one. LC-MS (M+H) + =411.0.

[0383] Step 3: 4-((6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)morpholin-3-one

[0384]

[0385] The title compound (120 mg, 100%) was prepared in a manner similar to that in Example 1, Step 3, from 4-((4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)methyl)morpholin-3-one. LC-MS (M+H) + =415.15.

[0386] Step 4: 4-((6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)morpholin-3-one

[0387] The title compound was prepared in a similar manner to that in Example 1, Step 4, from 4-((6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)morpholin-3-one (25 mg, 10%). 1 H-NMR (400MHz, DMSO-d6) δ9.13(s,1H),8.82(s,1H),8.50(d,J=3.7Hz,1H),8.31(d,J=8 .5Hz,1H),8.16(d,J=8.7Hz,1H),7.28(d,J=7.6Hz,1H),4.97(d,J=5.2Hz,1H),4.92(s, 2H),4.14(s,2H),3.93–3.81(m,3H),3.89–3.69(m,3H),3.60–3.48(m,1H),3.37(d,J=1 1.3Hz, 1H), 3.17 (s, 2H), 3.05 (t, J = 10.3Hz, 1H), 2.12–1.92 (s, 1H), 1.64–1.44 (m, 7H). LC-MS(M+H) + =496.0.

[0388] Example 14: (3S,4R)-4-((4-(3-((6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)methyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0389]

[0390] The title compound (20 mg, 35%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and 6-oxa-3-azabicyclo[3.1.1]heptane. 1 H-NMR (400MHz, DMSO-d6) δ9.13(s,1H),8.86(s,1H),8.50(d,J=3.8Hz,1H),8.29(d,J=8.9Hz,1H),8.14(d,J=8.8Hz,1H),7.26 (d,J=7.8Hz,1H),4.97(d,J=5.3Hz,1H),4.42(d,J=6.0Hz,2H),4.04(dd,J=14.4,7.0Hz,1H),3.97(s,2H),3.85(dd,J=10.6,5. 1Hz,3H),3.61–3.48(m,1H),3.37(d,J=11.4Hz,1H),3.05(t,J=10.4Hz,1H),2.92(d,J=11.1Hz,2H),2.84(q,J=6.6Hz,1H),2.7 5(d,J=11.2Hz,2H),2.20(d,J=7.6Hz,1H),2.13–1.93(s,1H),1.65–1.45(m,1H),1.55(d,J=9.0Hz,3H),1.53(d,J=9.0Hz,3H). LC-MS(M+H) + =494.0.

[0391] Example 15: (3S,4R)-4-((5-fluoro-4-(3-(hydroxymethyl)-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0392]

[0393] Step 1: Ethyl 6-chloro-2-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate

[0394]

[0395] To a solution of ethyl 3-oxobutanoate (7.9 g, 60.6 mmol) in dimethylacetamide (50 mL) was added sodium hydride (2.83 g, 60%, 70.7 mmol) followed by 6-chloro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (10 g, 50.5 mmol) under nitrogen. The mixture was stirred at 120°C for 1 h and then cooled to room temperature. The mixture was concentrated in vacuo and water was added. The formed precipitate was filtered and dried to give the product (9 g, 67%). LC-MS (M+H) + =265.9.

[0396] Step 2: Ethyl 4-bromo-6-chloro-2-methylquinoline-3-carboxylate

[0397]

[0398] To a solution of ethyl 6-chloro-2-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (1 g, 3.76 mmol) in dimethylformamide (20 mL) was added phosphorus tribromide (1.32 g, 4.89 mmol) at 0°C. The solution was stirred at room temperature overnight, and then saturated aqueous sodium bicarbonate solution was added. The formed precipitate was filtered and dried to give the crude product (900 mg, 73%). LC-MS (M+H) + =328.0, 330.0.

[0399] Step 3: Ethyl 6-chloro-4-isopropyl-2-methylquinoline-3-carboxylate

[0400]

[0401] The title compound (520 mg, 65%) was prepared in a similar manner to that in Example 1, Step 1, from ethyl 4-bromo-6-chloro-2-methylquinoline-3-carboxylate. LC-MS (M+H) + =292.1.

[0402] Step 4: ethyl 4-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- quinoline-3-carboxylate

[0403]

[0404] The title compound was prepared from ethyl 6-chloro-4-isopropyl-2-methylquinoline-3-carboxylate in a similar manner to Example 1, Step 2. LC-MS (M+H) + =384.1.

[0405] Step 5: Ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyl-2-methylquinoline-3-carboxylate

[0406]

[0407] The title compound (170 mg, 24% over two steps) was prepared in a manner similar to that described in Example 1, Step 3, from ethyl 4-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate. LC-MS (M+H) + =388.2.

[0408] Step 6: Ethyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidine-4-yl 4-Isopropyl-2-methylquinoline-3-carboxylate

[0409]

[0410] The title compound (120 mg, 58%) was prepared in a similar manner to Example 1, Step 4, from ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyl-2-methylquinoline-3-carboxylate. LC-MS (M+H) + =469.3.

[0411] Step 7: (3S,4R)-4-((5-fluoro-4-(3-(hydroxymethyl)-4-isopropyl-2-methylquinolin-6-yl)pyrimidine- 2-amino)tetrahydro-2H-pyran-3-ol

[0412] The title compound was prepared in a similar manner to Example 3 from ethyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropyl-2-methylquinoline-3-carboxylate (2 mg, 5%). 1 H-NMR(400MHz,DMSO-d6)δ9.07(s,1H),8.48(d,J=3.8Hz,1H),8.24(d,J=8.9Hz,1H), 8.02(d,J=8.8Hz,1H),7.24(d,J=7.8Hz,1H),5.18(s,1H),4.97(d,J=5.4Hz,1H),4.7 4(d,J=4.0Hz,2H),4.11–3.94(m,1H),3.94–3.75(m,3H),3.59–3.49(m,1H),3.39–3. 25(m,1H),3.05(t,J=10.4Hz,1H),2.79(s,3H),2.03–1.99(m,1H),1.70–1.40(m,7H). LC-MS(M+H) + =427.3.

[0413] Example 16: 1-((6-(5-Fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)azetidin-3-ol

[0414]

[0415] The title compound (6.9 mg, 25%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and azetidin-3-ol. 1 H-NMR (400MHz, DMSO-d6) δ: 9.09 (s, 1H), 8.81 (s, 1H), 8.49 (d, J = 5.2Hz, 1H), 8.33-8. 24(m,1H),8.18-8.10(m,1H),7.26(d,J=7.9Hz,1H),5.34(d,J=8.4Hz,1H),4.97(d,J= 6.8Hz,1H),4.24-4.16(m,1H),4.00-3.79(m,7H),3.60-3.45(m,3H),3.42-3.35(m,1H) ),3.03(t,J=10.3Hz,1H),2.86(t,J=6.5Hz,1H),2.09-1.95(m,1H)1.61-1.49(m,7H). LC-MS(M+H) + =468.1.

[0416] Example 17: (3S,4R)-4-((5-fluoro-4-(4-isopropyl-3-(morpholinomethyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0417]

[0418] The title compound (9.1 mg, 15%) was prepared in a manner similar to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and morpholine. 1H-NMR(400MHz,DMSO-d6)δ:9.13(s,1H),8.78(s,1H),8.52-8.48(m,1H),8.33-8.24( m,1H),8.18-8.10(m,1H),7.26(d,J=7.9Hz,1H),5.00-4.95(m,1H),4.04-4.00(m,1H) ,3.92-3.81(m,3H),3.76-3.71(m,2H),3.60-3.50(m,5H),3.42-3.35(m,1H),3.05(t ,J=10.3Hz,1H),2.40(s,3H),2.45–2.30(m,1H),2.09-2.00(m,1H)1.62-1.50(m,7H). LC-MS(M+H) + =482.1.

[0419] Example 17 can also be obtained by the following steps:

[0420] Step 1: Ethyl 6-chloro-4-isopropylquinoline-3-carboxylate

[0421]

[0422] To an isopropylmagnesium bromide solution (15 mL, 1 M, 15 mmol) was added a tetrahydrofuran solution of zinc chloride (21.4 mL, 0.7 M, 15 mmol) under nitrogen, and the mixture was stirred at 50 ° C for 2 h. A solution of ethyl 4,6-dichloroquinoline-3-carboxylate (2 g, 7.5 mmol) in dimethylformamide (10 mL), copper (I) iodide (143 mg, 0.75 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (275 mg, 0.375 mmol) were added, and the resulting mixture was stirred at 50 ° C for 2 h and then cooled to room temperature. The reaction was quenched with methanol (10 mL), and the solvent was evaporated. The residue was suspended in ethyl acetate and water and then filtered. The filtrate was washed with water and brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate in petroleum ether (16%, v / v) to give the title compound (1.5 g, 71%). LC-MS (M+H) + =278.2.

[0423] Step 2: Ethyl 4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline- 3-formate

[0424]

[0425] A mixture of ethyl 6-chloro-4-isopropylquinoline-3-carboxylate (1.3 g, 4. mmol), bis(pinacolato)diboron (1.4 g, 5.6 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (172 mg, 0.24 mmol) and potassium acetate (921 mg, 9.4 mmol) in 1,4-dioxane (40 mL) was stirred at 80°C overnight under nitrogen and then cooled to room temperature. The mixture was filtered and the filtrate was evaporated to give the crude product, which was used in the next step without further purification. LC-MS (M+H) + =370.3.

[0426] Step 3: Ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate

[0427]

[0428] A mixture of ethyl 4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate, 2,4-dichloro-5-fluoropyrimidine (785 mg, 4.7 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (176 mg, 0.24 mmol) and K2CO3 (1.3 g, 9.4 mmol) in 1,4-dioxane (40 mL) and water (5 mL) was stirred at 80 ° C. under nitrogen overnight and then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (eluted with methanol (3%, v / v) in dichloromethane) to give the title compound (790 mg, 45% over two steps). LC-MS (M+H) + =374.1.

[0429] Step 4: Ethyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidine-4-yl 4-Isopropylquinoline-3-carboxylate

[0430]

[0431] A reaction mixture of ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate (790 mg, 2.11 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol (390 mg, 2.53 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (89 mg, 0.11 mmol) and cesium carbonate (2.1 g, 6.33 mmol) in 1,4-dioxane (30 mL) was stirred overnight at 100° C. under nitrogen. The mixture was cooled to room temperature and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with methanol (6%, v / v) in dichloromethane to give the title compound (780 mg, 81%). LC-MS (M+H) + =455.8.

[0432] Step 5: (3S,4R)-4-((5-fluoro-4-(3-(hydroxymethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino 1-H-pyran-3-ol

[0433]

[0434] To a solution of ethyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate (50 mg, 0.11 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (13 mg, 0.33 mmol) at 0°C under nitrogen and stirred at room temperature for 3 h. The reaction was quenched with methanol and the solvent was evaporated. The residue was purified by preparative HPLC (eluent: water (0.1% formic acid) / acetonitrile (0.1% formic acid)) to give the product (6 mg, 12%). LC-MS (M+H) + =413.3.

[0435] Step 6: (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino 1-H-pyran-3-ol

[0436]

[0437] To a solution of (3S,4R)-4-((5-fluoro-4-(3-(hydroxymethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (80 mg, 0.19 mmol) in dichloromethane (5 mL) was added thionyl chloride (46 mg, 0.39 mmol) at 0°C, and the mixture was stirred for 1 h and then quenched with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with dichloromethane (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to give 85 mg of crude product, which was used in the next step without further purification. LC-MS (M+H) + =431.2.

[0438] Step 7: (3S,4R)-4-((5-fluoro-4-(4-isopropyl-3-(morpholinomethyl)quinolin-6-yl)pyrimidin-2-yl) amino)tetrahydro-2H-pyran-3-ol

[0439]

[0440] To a solution of (3S, 4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (59 mg, 0.14 mmol) in dimethylformamide (2 mL) was added morpholine (24 mg, 0.27 mmol) and N,N-diisopropylethylamine (35 mg, 0.27 mmol) at 25 ° C. The mixture was stirred at 25 ° C for 5 h and then diluted with ethyl acetate (20 mL). The organic solution was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluted with methanol (5%, v / v) in dichloromethane) to give the title compound (9.1 mg, 15%). 1 H-NMR(400MHz,DMSO-d6)δ:9.13(s,1H),8.78(s,1H),8.52-8.48(m,1H),8.33-8.24( m,1H),8.18-8.10(m,1H),7.26(d,J=7.9Hz,1H),5.00-4.95(m,1H),4.04-4.00(m,1H) ,3.92-3.81(m,3H),3.76-3.71(m,2H),3.60-3.50(m,5H),3.42-3.35(m,1H),3.05(t ,J=10.3Hz,1H),2.40(s,3H),2.45–2.30(m,1H),2.09-2.00(m,1H)1.62-1.50(m,7H). LC-MS(M+H) + =482.1.

[0441] Example 18: (3S,4R)-4-((5-fluoro-4-(3-(((S)-3-fluoropyrrolidin-1-yl)methyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0442]

[0443] The title compound (8.1 mg, 18%) was prepared in a manner similar to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (S)-3-fluoropyrrolidine. 1 H-NMR(400MHz,DMSO-d6)δ:9.12(s,1H),8.83(s,1H),8.52-8.48(m,1H),8.33-8.24(m,1H),8.18 -8.10(m,1H),7.26(d,J=7.9Hz,1H),5.30-5.10(m,1H),5.00-4.94(m,1H),4.04-3.98(m,1H),3. 92-3.80(m,5H),3.58-3.50(m,1H),3.42-3.36(m,1H),3.03(t,J=10.3Hz,1H),2.85-2.73(m,2H) ,2.71-2.60(m,1H),2.40-2.31(m,1H),2.23-2.00(m,2H),1.93-1.78(m,1H),1.60-1.49(m,7H). LC-MS(M+H) + =484.1.

[0444] Example 19: (3S,4R)-4-((4-(3-((cyclobutylamino)methyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0445]

[0446] The title compound (20 mg, 37%) was prepared in a manner similar to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and cyclobutanamine. 1H-NMR(400MHz,DMSO-d6)δ9.10(brs,1H),8.83(s,1H),8.50(d,J=3.9Hz,1H),8 .32-8.23(m,1H),8.13(d,J=8.8Hz,1H),7.25(d,J=7.8Hz,1H),4.97(d,J=5.3Hz ,1H),4.06-3.77(m,6H),3.63-3.49(m,1H),3.43-3.35(m,1H),3.26-3.13(m,1 H),3.13-3.00(m,1H),2.19-2.00(m,3H),1.82-1.69(m,3H),1.67-1.48(m,9H). LC-MS (M+H) + =466.1.

[0447] Example 20: (3S,4R)-4-((4-(3-(((3,3-difluorocyclobutyl)amino)methyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0448]

[0449] The title compound (15 mg, 34%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and 3,3-difluorocyclobutane-1-amine. 1 H-NMR(300MHz,DMSO-d6)δ9.11(brs,1H),8.84(s,1H),8.50(d,J=3.9Hz,1H),8.28(d ,J=8.8Hz,1H),8.13(d,J=8.8Hz,1H),7.26(d,J=7.7Hz,1H),4.97(d,J=5.3Hz,1H),4 .06–3.78(m,6H),3.59-3.53(m,1H),3.43-3.35(m,1H),3.23-3.17(m,1H),3.13-3.0 0(m,1H),2.79-2.73(m,3H),2.44-2.30(m,2H),2.11-2.01(m,1H),1.68-1.47(m,7H). LC-MS(M+H) + =502.2.

[0450] Example 21: (3S,4R)-4-((5-fluoro-4-(4-isopropyl-3-(((tetrahydrofuran-3-yl)amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0451]

[0452] The title compound (18 mg, 44%) was prepared in a manner similar to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and tetrahydrofuran-3-amine. 1 H-NMR(300MHz,DMSO-d6)δ9.11(brs,1H),8.86(s,1H),8.50(d,J=3.9Hz,1H),8.32- 8.22(m,1H),8.13(d,J=8.9Hz,1H),7.26(d,J=7.8Hz,1H),4.98(d,J=5.2Hz,1H),4.0 3-3.81(m,6H),3.80-3.63(m,3H),3.62-3.44(m,2H),3.42-3.35(m,2H),3.13-3.00 (m,1H),2.36-2.30(m,1H),2.10-1.89(m,2H),1.83-1.67(m,1H),1.64-1.47(m,7H). LC-MS(M+H) + =482.1.

[0453] Example 22: (3S,4R)-4-((5-fluoro-4-(4-isopropyl-3-((isopropylamino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0454]

[0455] The title compound (10 mg, 12%) was prepared in a manner similar to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and isopropylamine. 1H-NMR(300MHz,DMSO-d6)δ9.10(brs,1H),8.85(s,1H),8.49(d,J=3.9Hz,1H),8 .32-8.22(m,1H),8.12(d,J=8.8Hz,1H),7.26(d,J=7.7Hz,1H),4.98(d,J=5.2Hz ,1H),4.05-3.80(m,6H),3.63-3.48(m,1H),3.43-3.34(m,1H),3.13-3.00(m,1 H),2.86-2.72(m,1H),2.11-2.01(m,1H),1.64-1.48(m,7H),1.10-1.02(m,6H). LC-MS (M+H) + =454.3.

[0456] Example 23: (3S,4R)-4-((5-fluoro-4-(3-(((R)-3-fluoropyrrolidin-1-yl)methyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0457]

[0458] The title compound (9.2 mg, 19%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (R)-3-fluoropyrrolidine. 1 H-NMR(400MHz,DMSO-d6)δ:9.12(s,1H),8.83(s,1H),8.52-8.48(m,1H),8.33-8.24(m,1H),8.18 -8.10(m,1H),7.26(d,J=7.9Hz,1H),5.30-5.10(m,1H),5.00-4.94(m,1H),4.04-3.98(m,1H),3. 92-3.80(m,5H),3.58-3.50(m,1H),3.42-3.36(m,1H),3.03(t,J=10.3Hz,1H),2.85-2.73(m,2H) ,2.71-2.60(m,1H),2.40-2.31(m,1H),2.23-2.00(m,2H),1.93-1.78(m,1H),1.60-1.49(m,7H). LC-MS(M+H) + =484.1.

[0459] Example 24: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-(((((R)-tetrahydrofuran-2-yl)methyl)amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0460]

[0461] The title compound (14 mg, 19%) was prepared in a manner similar to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (R)-(tetrahydrofuran-2-yl)methanamine. 1 H-NMR(400MHz,DMSO-d6)δ:9.11(s,1H),8.84(s,1H),8.52-8.48(m,1H),8.33-8.24( m,1H),8.18-8.10(m,1H),7.26(d,J=7.9Hz,1H),4.97(s,1H),4.00-3.81(m,7H),3.76 -3.69(m,1H),3.63-3.50(m,2H),3.40-3.33(m,2H),3.05(t,J=10.3Hz,1H),2.64-2.5 9(m,2H),2.10-2.00(m,1H),1.93-1.84(m,1H),1.83-1.75(m,2H),1.62-1.51(m,8H). LC-MS(M+H) + =496.1.

[0462] Example 25: (3S,4R)-4-((4-(3-((cyclopropylamino)methyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0463]

[0464] The title compound (20 mg, 48%) was prepared in a manner similar to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and cyclopropylamine. 1H-NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 8.84 (s, 1H), 8.49 (d, J = 3.1Hz, 1H), 8. 26(d,J=8.6Hz,1H),8.12(d,J=8.8Hz,1H),7.26(d,J=7.6Hz,1H),4.97(s,1H) ,4.08–3.75(m,6H),3.65–3.45(m,1H),3.39–3.33(m,2H),3.05(t,J=10.4Hz, 1H), 2.20–1.93 (m, 2H), 1.65–1.42 (m, 7H), 0.38 (d, J = 5.5Hz, 2H), 0.23 (s, 2H). LC-MS(M+H) + =452.1.

[0465] Example 26: (3S,4R)-4-((4-(3-((cyclopentylamino)methyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0466]

[0467] The title compound (20 mg, 45%) was prepared in a manner similar to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and cyclopentylamine. 1 H-NMR (400MHz, DMSO-d6) δ9.10(s,1H),8.84(s,1H),8.50(s,1H),8.27(d,J=8.5Hz,1H),8.12(d,J=8.8Hz,1H),7.26(d,J=7.4Hz,1H),4 .97(s,1H),3.99–3.86(m,6H),3.55(s,1H),3.36(t,J=11.3Hz,2H),3.14–2.99(m,2H),2.04(s,1H),1.80–1.55(m,10H),1.54–1.42(m). LC-MS(M+H) + =480.1.

[0468] Example 27: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-(((((R)-tetrahydrofuran-3-yl)methyl)amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0469]

[0470] The title compound (10 mg, 16%) was prepared in a manner similar to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (R)-(tetrahydrofuran-3-yl)methanamine. 1 H-NMR (400MHz, DMSO-d6) δ9.12(s,1H),8.84(s,1H),8.52-8.48(m,1H),8.33-8.24(m,1H),8.18-8.10(m,1H),7.26(d,J=7.9Hz,1H),4.98(br s,1H),4.00-3.80(m,6H),3.80-3.65(m,2H),3.59-3.46(m,2H),3.42-3.36(m,3H),3.03(t,J=10.3H z,1H),2.65-2.57(m,2H),2.40-2.30(m,1H),2.10-2.00(m,1H)2.00-1.88(m,1H),1.62-1.50(m,8H). LC-MS(M+H) + =496.2.

[0471] Example 28: (3S,4R)-4-((4-(3-((cyclohexylamino)methyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0472]

[0473] The title compound (8 mg, 35%) was prepared in a manner similar to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and cyclohexylamine. 1H-NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.85(s,1H),8.49(s,1H),8.27(d,J=8.7Hz,1H), 8.12(d,J=8.8Hz,1H),7.26(d,J=7.4Hz,1H),4.97(s,1H),3.96(s,3H),3.86(s,3H),3.6 5–3.45(m,1H),3.45–3.25(m,1H),3.05(t,J=10.5Hz,1H),2.49–2.41(m,2H),2.14–1.94 (m,1H),1.89(d,J=10.6Hz,2H),1.77–1.57(m,2H),1.66–1.46(m,8H),1.30–1.06(m,5H). LC-MS(M+H) + =494.0.

[0474] Example 29: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-(((tetrahydro-2H-pyran-4-yl)amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0475]

[0476] The title compound (16 mg, 70%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and tetrahydro-2H-pyran-4-amine. 1 H-NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.86(s,1H),8.50(s,1H),8.27(d,J=8.3Hz,1H) ,8.12(d,J=8.7Hz,1H),7.26(d,J=7.4Hz,1H),4.97(s,1H),3.98(s,3H),3.84(d,J=10.0 Hz,5H),3.64–3.44(m,1H),3.46–3.19(m,4H),3.05(t,J=10.6Hz,1H),2.75–2.55(m,1H ),2.13–1.93(m,1H),1.84(d,J=12.3Hz,2H),1.68–1.44(m,7H),1.32(d,J=10.1Hz,2H). LC-MS(M+H) + =496.0.

[0477] Example 30: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-((((R)-tetrahydro-2H-pyran-3-yl)amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0478]

[0479] The title compound (16 mg, 70%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (R)-tetrahydrofuran-3-amine. 1 H-NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.85(s,1H),8.50(s,1H),8.27(d,J=8.9Hz,1H), 8.12(d,J=8.8Hz,1H),7.26(d,J=7.6Hz,1H),4.97(d,J=4.9Hz,1H),4.06–3.92(m,3H),3. 91–3.71(m,4H),3.69(d,J=11.4Hz,1H),3.64–3.44(m,1H),3.48–3.17(m,2H),3.06(t,J= 10.0Hz,2H),2.66–2.46(m,2H),2.09–1.89(m,2H),1.71–1.37(m,9H),1.40–1.20(m,1H). LC-MS(M+H) + =496.0.

[0480] Example 31: (3S,4R)-4-((5-fluoro-4-(4-isopropyl-3-(methoxymethyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0481]

[0482] To a solution of (3S,4R)-4-((5-fluoro-4-(4-isopropyl-3-(methoxymethyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (20 mg, 0.046 mmol) in dimethylformamide (1 mL) was added sodium methoxide (5 mg, 0.092 mmol, 2 equivalents) at room temperature. The mixture was stirred at 80 ° C for 16 h, then cooled to room temperature and water (10 mL) was added. The aqueous layer was extracted with ethyl acetate (30 mL). The organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluted with methanol (5%, v / v) in dichloromethane) to give the title compound (17 mg, 80%). 1 H-NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.87(s,1H),8.50(d,J=3.0Hz,1H),8 .30(d,J=8.8Hz,1H),8.15(d,J=8.7Hz,1H),7.27(d,J=7.8Hz,1H),4.97(s,1 H),4.70(s,2H),4.00–3.75(m,J=4.6Hz,4H),3.54(s,1H),3.36(s,3H),3.46 –3.26(m,1H),3.05(t,J=10.6Hz,1H),2.12–1.93(m,1H),1.65–1.45(m,7H). LC-MS(M+H) + =427.1.

[0483] Example 32: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-((((S)-tetrahydrofuran-3-yl)amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0484]

[0485] The title compound (8.5 mg, 15%) was prepared in a manner similar to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (S)-tetrahydrofuran-3-amine. 1H-NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.85(s,1H),8.52-8.48(m,1H),8.3 3-8.24(m,1H),8.18-8.10(m,1H),7.26(d,J=7.9Hz,1H),4.98(s,1H),4.00 -3.80(m,6H),3.80-3.65(m,3H),3.59-3.46(m,2H),3.42-3.36(m,3H),3.0 3(t,J=10.3Hz,1H),2.00-1.93(m,2H)1.80-1.70(m,1H),1.61-1.50(m,7H). LC-MS(M+H) + =482.1.

[0486] Example 33: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-(((((S)-tetrahydrofuran-3-yl)methyl)amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0487]

[0488] The title compound (9.5 mg, 16%) was prepared in a manner similar to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (S)-(tetrahydrofuran-3-yl)methanamine. 1 H-NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.84(s,1H),8.52-8.48(m,1H),8.33-8.24(m ,1H),8.18-8.10(m,1H),7.26(d,J=7.9Hz,1H),4.97(s,1H),4.00-3.80(m,6H),3.80- 3.65(m,2H),3.59-3.46(m,2H),3.42-3.36(m,3H),3.03(t,J=10.3Hz,1H),2.65-2.5 7(m,2H),2.40-2.30(m,1H),2.10-2.00(m,1H),2.00-1.88(m,1H),1.62-1.50(m,8H). LC-MS(M+H) + =496.1.

[0489] Example 34: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-(((((S)-tetrahydrofuran-2-yl)methyl)amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0490]

[0491] The title compound (6 mg, 12%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (S)-(tetrahydrofuran-2-yl)methanamine. 1 H-NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.84(s,1H),8.52-8.48(m,1H),8.33-8.24(m ,1H),8.18-8.10(m,1H),7.26(d,J=7.9Hz,1H),4.98(s,1H),4.00-3.81(m,7H),3.76- 3.69(m,1H),3.63-3.50(m,2H),3.40-3.33(m,2H),3.05(t,J=10.3Hz,1H),2.64-2.5 9(m,2H),2.10-2.00(m,1H),1.93-1.84(m,1H),1.83-1.75(m,2H),1.62-1.51(m,8H). LC-MS(M+H) + =496.1.

[0492] Example 35: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-((((R)-tetrahydrofuran-3-yl)amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0493]

[0494] The title compound (11.5 mg, 18%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (R)-tetrahydrofuran-3-amine. 1H-NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.85(s,1H),8.52-8.48(m,1H),8.3 3-8.24(m,1H),8.18-8.10(m,1H),7.26(d,J=7.9Hz,1H),4.98(s,1H),4.00- 3.80(m,6H),3.80-3.65(m,3H),3.59-3.46(m,2H),3.42-3.36(m,3H),3.03 (t,J=10.3Hz,1H),2.00-1.93(m,2H),1.80-1.70(m,1H),1.61-1.50(m,7H). LC-MS(M+H) + =482.1.

[0495] Example 36: (3S,4R)-4-((4-(3-((7-oxa-4-azaspiro[2.5]octan-4-yl)methyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0496]

[0497] The title compound (4 mg, 17%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and 7-oxa-4-azaspiro[2.5]octane hydrochloride. 1 H-NMR (400MHz, DMSO-d6) δ9.17–9.04(m,1H),8.79(s,1H),8.50(s,1H),8.27(d,J=8. 6Hz,1H),8.12(d,J=8.8Hz,1H),7.26(d,J=8.5Hz,1H),4.97(s,1H),4.13–4.01(m,2H ),3.97–3.79(m,4H),3.68(s,2H),3.52(s,3H),3.31–3.29(m,1H),3.10–3.00(m,1H) ,2.75–2.59(m,2H),2.10–1.99(m,1H),1.60–1.45(m,7H),0.69(s,2H),0.50(s,2H). LC-MS(M+H) + =508.1.

[0498] Example 37: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-((((S)-tetrahydro-2H-pyran-3-yl)amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0499]

[0500] The title compound (12 mg, 41%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (S)-tetrahydro-2H-pyran-3-amine. 1 H-NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.85(s,1H),8.50(s,1H),8.27(d,J=8.4Hz,1H) ,8.12(d,J=9.3Hz,1H),7.26(d,J=7.4Hz,1H),4.98(s,1H),4.05–3.91(m,3H),3.86(d,J =8.1Hz, 4H), 3.69 (d, J = 11.4Hz, 1H), 3.55 (s, 1H), 3.36 (t, J = 11.2Hz, 2H), 3.27 (t, J = 10. 9Hz, 2H), 3.06 (t, J = 9.8Hz, 2H), 2.00 (s, 2H), 1.71–1.39 (m, 9H), 1.30 (d, J = 10.4Hz, 1H). LC-MS(M+H) + =496.0.

[0501] Example 38: (3S,4R)-4-((4-(3-(aminomethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0502]

[0503] Step 1: (3S,4R)-4-((4-(3-(azidomethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl) amino)tetrahydro-2H-pyran-3-ol

[0504]

[0505] A solution of (3S,4R)-4-({5-fluoro-4-[3-(hydroxymethyl)-4-isopropylquinolin-6-yl]pyrimidin-2-yl}amino)oxan-3-ol (190 mg, 0.46 mmol) and diphenylphosphoryl azide (255 mg, 0.92 mmol) in dimethylformamide (2 mL) was stirred at 50 ° C. for 5 h under a nitrogen atmosphere. The solution was concentrated under reduced pressure and the residue was purified by flash chromatography (eluting with MeOH in dichloromethane (0% to 20% gradient, v / v)) to give the title compound (66 mg, 32%). LC-MS (M+H) + =438.2.

[0506] Step 2: (3S,4R)-4-((4-(3-(aminomethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino 1-H-pyran-3-ol

[0507] A solution of (3S,4R)-4-((4-(3-(azidomethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (66 mg, 0.15 mmol) and triphenylphosphine (79 mg, 0.30 mmol) in tetrahydrofuran / water (11 mL, 10 / 1, v / v) was stirred at 50° C. for 3 h under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with MeOH in dichloromethane (0% to 20% gradient)) followed by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 30 x 150 mm, 5 μm; mobile phase, acetonitrile in water (with 10 mmol / L NH4HCO3 and 0.1% NH4OH), gradient from 17% to 47% in 9 min; detector, UV 254 nm. The title compound (14 mg, 24%) was obtained. 1 H-NMR (400MHz, DMSO-d6) δ9.10(s,1H),8.90(s,1H),8.49(d,J=3.9Hz,1H),8.26(d,J=8.8Hz,1H),8.12(d,J=8.8Hz,1H),7.26(d,J=7.8Hz, 1H),5.01-4.95(m,1H),4.04-3.80(m,6H),3.60-3.50(m,1H),3.42-3 .34(m,1H),3.11-3.01(m,1H),2.10-1.85(m,3H),1.65-1.46(m,7H). LC-MS(M+H) + =412.1.

[0508] Example 39 and Example 40: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-((((S)-tetrahydrofuran-3-yl)amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-((((R)-tetrahydrofuran-3-yl)amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0509]

[0510] The title compound was prepared in a manner analogous to Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and racemic tetrahydrofuran-3-amine. Example 39 and Example 40 were separated by chiral HPLC to give (3S,4R)-4-((5-fluoro-4-(4-isopropyl-3-((((S)-tetrahydrofuran-3-yl)amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (3S,4R)-4-((5-fluoro-4-(4-isopropyl-3-((((R)-tetrahydrofuran-3-yl)amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol. Analytical chiral HPLC conditions: CHIRALPAK ID-3, 0.46 x 5 cm, 3.0 um. Mobile phase: (hexane: dichloromethane = 3:1, v / v, methanol solution containing 0.5% 2M NH 3 ): EtOH, 20 mL / min within 13 min.

[0511] Example 39 (5 mg, 10%) 1 H NMR(400MHz,DMSO-d6)δ9.11(brs,1H),8.86(s,1H),8.50(d,J=3.9Hz,1H),8.31-8.24(m ,1H),8.13(d,J=8.8Hz,1H),7.27(d,J=7.8Hz,1H),4.98(d,J=5.3Hz,1H),4.04-3.80(m, 6H),3.78-3.65(m,3H),3.61-3.44(m,2H),3.41-3.36(m,1H),3.34-3.26(m,1H),3.13-3 .00(m,1H),2.40-2.22(m,1H),2.09-1.91(m,2H),1.81-1.69(m,1H),1.62-1.42(m,7H). LC-MS(M+H) +=482.3. Chiral HPLC: RT=2.083 min.

[0512] Example 40: (2mg, 3%) 1H NMR(400MHz,DMSO-d6)δ9.12(brs,1H),8.86(s,1H),8.50(d,J=3.8Hz,1H),8.31-8.24(m ,1H),8.13(d,J=8.8Hz,1H),7.28(d,J=7.8Hz,1H),4.99(d,J=5.3Hz,1H),4.02-3.81(m, 6H),3.80-3.63(m,3H),3.60-3.44(m,2H),3.42-3.37(m,1H),3.35-3.32(m,1H),3.11-3 .01(m,1H),2.37-2.32(m,1H),2.09-1.88(m,2H),1.81-1.69(m,1H),1.62-1.45(m,7H). LC-MS(M+H) + =482.3. Chiral HPLC: RT=2.674 min.

[0513] Example 41 and Example 42: (3S,4R)-4-((5-fluoro-4-(3-((S)-1-hydroxyethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (3S,4R)-4-((5-fluoro-4-(3-((R)-1-hydroxyethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0514]

[0515] Step 1: 6-(5-Fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4- Isopropylquinoline-3-carboxaldehyde

[0516]

[0517] A mixture of (3S,4R)-4-({5-fluoro-4-[3-(hydroxymethyl)-4-isopropylquinolin-6-yl]pyrimidin-2-yl}amino)oxan-3-ol (790 mg, 1.92 mmol) and manganese dioxide (8.33 g, 95.85 mmol) in dichloromethane (20 mL) was stirred at 40 ° C for 4 h and then cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with dichloromethane (6 mL × 4). The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography (eluted with methanol in dichloromethane (0% to 10% gradient, v / v) to produce the title compound (748 mg, 95%). LC-MS (M+H) + =411.2.

[0518] Step 2: (3S,4R)-4-((5-fluoro-4-(3-((S)-1-hydroxyethyl)-4-isopropylquinolin-6-yl)pyrimidine- 2-yl)amino)tetrahydro-2H-pyran-3-ol and (3S,4R)-4-((5-fluoro-4-(3-((R)-1-hydroxyethyl)-4-isopropyl (quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0519] To a solution of methylmagnesium bromide (1.50 mL, 3M solution in diethyl ether, 4.50 mmol) in tetrahydrofuran (15 mL) was added dropwise 6-(5-fluoro-2-(((3S, 4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carbaldehyde (360 mg, 0.877 mmol) in tetrahydrofuran (2 mL) at -10 ° C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h under a nitrogen atmosphere and then quenched at room temperature by adding saturated aqueous ammonium chloride (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL × 2). 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 methanol in dichloromethane (0% to 20% gradient, v / v)). The residue was purified by preparative HPLC under the following conditions: XBridge Shield RP18 OBD column, 30 x 150 mm, 5 μm; mobile phase: acetonitrile in water (containing 10 mmol / L NH₄HCO₃ and 0.1% NH₃.H₂O), gradient from 20% to 50% over 9 minutes; detector: UV 254 nm. The resulting mixture of Example 59 and Example 60 was separated by chiral separation on chiral HPLC. Column: CHIRALPAK OD-H 4.6 x 150 mm, 5 μm. Mobile phase: hexane:EtOH (containing 0.1% diethylamine) = 9:1, 1 mL / min over 18 minutes.

[0520] Example 41 (2.8 mg, 31%): RT=6.355 min. 1H-NMR(400MHz,CD3OD)δ:9.22(s,1H),9.08(s,1H),8.42-8.37(m,1H),8.37-8.33(m,1H),8.13-8.08(m,1H),5.49(s,1H),4.10- 3.90(m,4H),3.70-3.60(m,1H),3.57-3.47(m,1H),3.28-3.20(m,1H),2.25-2.16(m,1H),1.71-1.52(m,11H),1.37-1.26(m,2H). LC-MS(M+H) + =427.1.

[0521] Example 42 (3.2 mg, 36%): RT = 9.244 min. 1H-NMR(400MHz,CD3OD)δ:9.22(s,1H),9.08(s,1H),8.42-8.37(m,1H),8.37-8.33(m,1H),8.13-8.08(m,1H),5.48(s,1 H),4.08-3.90(m,4H),3.70-3.60(m,1H),3.57-3.47(m,1H),3.28-3.20(m,1H),2.25-2.16(m,1H),1.72-1.26(m,13H). LC-MS(M+H) + =427.2.

[0522] Example 43: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-(((1-methyl-1H-pyrazol-4-yl)amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0523]

[0524] The title compound (7.9 mg, 26.5%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and 1-methyl-1H-pyrazol-4-amine. 1 H-NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.88(s,1H),8.50(s,1H),8.31-8.25(m ,1H),8.16-8.11(m,1H),7.26(d,J=7.9Hz,1H),7.13(s,1H),7.00(s,1H),4.99- 4.90(m,2H),4.27(s,2H),3.94-3.80(m,4H),3.69(s,3H),3.60-3.50(m,1H),3 .40-3.34(m,1H),3.05(t,J=10.3Hz,1H),2.10-2.00(m,1H),1.62-1.50(m,7H). LC-MS (M+H) + =492.1.

[0525] Example 44: (3S,4R)-4-((4-(3-((1,4-oxazepan-4-yl)methyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0526]

[0527] The title compound (6.2 mg, 27%) was prepared in a manner similar to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and 1,4-oxazepane hydrochloride. 1 H-NMR (400MHz, DMSO-d6) δ9.12(s,1H),8.79(s,1H),8.50(s,1H),8.28(d,J=8.8Hz,1H),8.13(d,J= 8.5Hz,1H),7.27(d,J=7.5Hz,1H),5.10–4.87(m,1H),4.13–3.97(m,1H),3.94–3.79(m,5H),3.74–3. 65(m,2H),3.65–3.49(m,3H),3.43–3.35(m,J=12.2Hz,1H),3.06(t,J=10.3Hz,1H),2.74–2.59(m,4 H), 2.13–1.98 (m, 1H), 1.89–1.76 (m, 2H), 1.66–1.57 (m, J = 6.3Hz, 6H), 1.57–1.44 (m, J = 11.9Hz, 1H). LC-MS(M+H) + =496.1.

[0528] Example 45: (3S,4R)-4-((5-fluoro-4-(4-isopropyl-3-((pyrimidin-2-ylamino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0529]

[0530] The title compound (1.08 mg, 3.67%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and pyrimidin-2-amine. 1H-NMR (400MHz, DMSO-d6) δ9.10(s,1H),8.91(s,1H),8.49(s,1H),8.37–8.17(m,3H),8.12(d,J=8.8Hz,1H),7.81(s,1H),7.26(d,J=7.2Hz,1H),6.6 0(s,1H),4.97(s,1H),4.73(s,2H),3.90(d,J=39.7Hz,4H),3.54(s,1H), 3.38(s,1H),3.05(t,J=10.6Hz,1H),2.03(s,1H),1.53(d,J=24.2Hz,7H). LC-MS(M+H) + =490.0.

[0531] Example 46: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-(((4-methoxyphenyl)amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0532]

[0533] The title compound (18 mg, 50%) was prepared in a manner similar to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and 4-methoxyaniline. 1 H-NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.89(s,1H),8.50(s,1H),8.28(d,J=8.2Hz,1 H),8.13(d,J=8.8Hz,1H),7.27(d,J=7.6Hz,1H),6.73(d,J=8.0Hz,2H),6.62(d,J=7. 9Hz,2H),5.72(s,1H),4.98(s,1H),4.43(s,2H),3.96–3.76(m,4H),3.63(s,3H),3.5 4(s,1H),3.47–3.27(m,1H),3.05(t,J=10.3Hz,1H),2.03(s,1H),1.68–1.43(m,4H). LC-MS(M+H) + =518.0.

[0534] Example 47 and Example 48: (3S,4R)-4-((5-Fluoro-4-(3-((S)-1-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (3S,4R)-4-((5-Fluoro-4-(3-((R)-1-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0535]

[0536] Step 1: 6-Chloro-4-isopropylquinoline-3-carboxylic acid

[0537]

[0538] The title compound (390 mg, 82%) was prepared in a similar manner to Example 1, Step 5, from ethyl 6-chloro-4-isopropylquinoline-3-carboxylate. 1 H-NMR(400MHz,DMSO-d6)δ13.75(s,1H),8.89(s,1H),8.39(s,1H),8.09(d,J =8.8Hz,1H),7.86(d,J=8.8Hz,1H),4.06–3.84(m,1H),1.48(d,J=6.9Hz,6H). LC-MS(M+H) + =250.1.

[0539] Step 2: 6-Chloro-4-isopropyl-N-methoxy-N-methylquinoline-3-carboxamide

[0540]

[0541] By 6-chloro-4-isopropylquinoline-3-formic acid (390mg, 1.56mmol), N, O-dimethylhydroxylamine hydrochloride (183mg, 1.87mmol), (benzotriazole-1-yloxy) tripyrrolidinylphosphonium hexafluorophosphate (811mg, 1.56mmol) and N, N-diisopropylethylamine (402mg, 3.12mmol) mixture in dimethylformamide (20mL) stirred at room temperature overnight and then add water.Mixture is extracted with ethyl acetate (40mL × 3).The organic layer merged is washed with water and salt water, dried over sodium sulfate, filtered and concentrated.Resistates is passed through silica gel flash chromatography (being eluted with ethyl acetate (50%, v / v) in petroleum ether) purifying, obtain title compound (340mg, 74%). 1H-NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.34(s,1H),8.09(d,J=8.9Hz,1H),7.83 (d,J=8.5Hz,1H),3.66(s,1H),3.49(s,3H),3.35(s,3H),1.41(d,J=6.6Hz,6H). LC-MS(M+H) + =293.1.

[0542] Step 3: 1-(6-chloro-4-isopropylquinolin-3-yl)ethan-1-one

[0543]

[0544] To a solution of 6-chloro-4-isopropyl-N-methoxy-N-methylquinoline-3-carboxamide (340 mg, 1.16 mmol) in tetrahydrofuran (10 mL) was added 1.6 M methyllithium (0.9 mL, 1.4 mmol) in diethyl ether at 0 ° C under nitrogen. The reaction solution was stirred for 2 h and then quenched with saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (eluted with ethyl acetate (50%, v / v) in petroleum ether) to give the title compound (150 mg, 51%). LC-MS (M+H) + =248.1.

[0545] Step 4: 1-(6-chloro-4-isopropylquinolin-3-yl)ethan-1-ol

[0546]

[0547] To a solution of 1-(6-chloro-4-isopropylquinolin-3-yl)ethan-1-one (150 mg, 0.6 mmol) in ethanol (5 mL) was added sodium borohydride (46 mg, 1.2 mmol) at 0°C, and the resulting mixture was stirred for 1 h and then quenched with 1N HCl. The resulting precipitate (130 mg, crude) was filtered and used in the next step without further purification. LC-MS (M+H) + =250.1.

[0548] Step 5: 6-chloro-3-(1-chloroethyl)-4-isopropylquinoline

[0549]

[0550] To a solution of 1-(6-chloro-4-isopropylquinolin-3-yl)ethan-1-ol (130 mg, crude product) in dichloromethane (10 mL) was added thionyl chloride (0.2 mL) at 0°C, and the reaction solution was stirred for 1 h and then diluted with dichloromethane. The solution was washed with a saturated aqueous sodium bicarbonate solution. The mixture was washed with water and brine, dried over sodium sulfate, filtered and evaporated to give a crude product (130 mg, crude product). LC-MS (M+H) + =268.0.

[0551] Step 6: 6-chloro-3-(1-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropylquinoline

[0552]

[0553] The reaction mixture of 6-chloro-3-(1-chloroethyl)-4-isopropylquinoline (130 mg, 0.49 mmol), (R)-3-fluoropyrrolidine hydrochloride (123 mg, 0.97 mmol) and N,N-diisopropylethylamine (125 mg, 0.97 mmol) in dimethylformamide (5 mL) was stirred at 100 ° C overnight and then cooled to room temperature. The solvent was evaporated and the residue was purified by silica gel flash chromatography (eluted with ethyl acetate in petroleum ether (67%, v / v)) to give the title compound (90 mg, 57%). LC-MS (M+H) + =321.2.

[0554] Step 7: 3-(1-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)quinoline

[0555]

[0556] The title compound was prepared in a similar manner to Example 1, Step 2, from 6-chloro-3-(1-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropylquinoline. LC-MS (M+H) + =413.4.

[0557] Step 8: 6-(2-chloro-5-fluoropyrimidin-4-yl)-3-(1-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropyl Quinoline

[0558]

[0559] The title compound (80 mg, 68% over two steps) was prepared in a manner similar to that described in Example 1, Step 3, from 3-(1-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline. LC-MS (M+H) + =417.3

[0560] Step 9: (3S,4R)-4-((5-fluoro-4-(3-((S)-1-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropyl (quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (3S,4R)-4-((5-fluoro-4-(3-((R)-1- ((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0561] In a manner similar to Example 1, Step 4, a mixture of Example 47 and Example 48 was prepared from 6-(2-chloro-5-fluoropyrimidin-4-yl)-3-(1-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropylquinoline. Example 47 and Example 48 were separated on chiral-HPLC to give (3S,4R)-4-((5-fluoro-4-(3-((S)-1-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (3S,4R)-4-((5-fluoro-4-(3-((R)-1-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol. Analytical chiral HPLC conditions: CHIRALPAK ID-3, 0.46 x 5 cm, 3.0 um. Mobile phase: (hexane:dichloromethane=1:1)((0.5% 2M NH 3 -MeOH)):EtOH, 20 mL / min in 11.5 min.

[0562] Example 47 (10 mg, 27%) 1 H-NMR (400MHz, DMSO-d6) δ9.13-8.87(m,2H),8.52-8.48(m,1H),8.30-8.25(m,1H),8.16-8. 09(m,1H),7.30-7.24(m,1H),5.32-5.09(m,1H),5.00-4.96(m,1H),4.16-4.12(m,1H),3.88- 3.84 (m, 4H), 3.76-3.45 (m, 2H), 3.07-3.03 (m, 1H), 2.97-2.92 (m, 1H), 2.62-2.57 (m, 2H), 2.46-2.37 (m, 2H), 2.16-2.04 (m, 2H), 1.89-1.84 (m, 1H), 1.60-1.55 (m, 6H), 1.45-1.41 (m, 3H). LC-MS (M+H) = 498.2. Chiral HPLC: t = 2.127 min.

[0563] Example 47 (11 mg, 29%) 1H-NMR (400 MHz, DMSO-d6) δ 9.17-9.12 (m, 2H), 8.67-8.10 (m, 3H), 7.45-7.18 (m, 1H), 5.42-4.90 (m, 2H), 4.40-3.49 (m, 7H), 3.07-3.03 (m, 2H), 2.76-2.47 (m, 3H), 2.38-2.14 (m, 2H), 2.08-2.03 (m, 2H), 1.73-1.52 (m, 6H), 1.48-1.43 (m, 3H). LC-MS (M+H) = 498.2. Chiral HPLC: t = 2.760 min.

[0564] 1 H-NMR(400MHz,DMSO-d6)δ9.11(s,1H),9.01(s,1H),8.50(s,1H),8.27(d,J=8.2Hz ,1H),8.12(d,J=9.3Hz,1H),7.27(d,J=6.9Hz,1H),5.21(dd,J=55.7,16.8Hz,1H), 4.98(s,1H),4.16(s,1H),3.86(s,4H),3.54(s,1H),3.38–3.33(m,1H),3.03–2.92 (m,2H),2.62(d,J=27.6Hz,2H),2.44–1.78(m,4H),1.58–1.51(m,7H),1.44(s,3H). LC-MS(M+H) + =498.1.

[0565] Example 49: (3S,4R)-4-((4-(3-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0566]

[0567] The title compound (11 mg, 41%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride. 1H-NMR(300MHz,DMSO-d6)δ9.10(brs,1H),8.84(s,1H),8.48(d,J=3.9Hz,1H),8.26( d,J=9.1Hz,1H),8.11(d,J=8.8Hz,1H),7.24(d,J=7.8Hz,1H),4.95(d,J=5.2Hz,1H) ,4.36(s,1H),4.12-3.77(m,7H),3.61-3.46(m,2H),3.44-3.31(m,3H),3.11-2.98( m,1H),2.77-2.68(m,1H),2.09-1.99(m,1H),1.86-1.77(m,1H),1.63-1.41(m,8H). LC-MS(M+H) + =494.3.

[0568] Example 50: (3S,4R)-4-((5-fluoro-4-(3-(1-hydroxycyclopentyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0569]

[0570] Step 1: 1-(6-chloro-4-isopropylquinolin-3-yl)cyclopentan-1-ol

[0571]

[0572] The reaction mixture of 1,4-dibromobutane (500mg, 2.31mmol), magnesium (556mg, 23.1mmol) and iodine (10mg) in tetrahydrofuran (3mL) is heated to 50 DEG C for 5min, then stirred at room temperature for 1h, then ethyl 6-chloro-4-isopropylquinoline-3-formate (200mg, 0.72mmol) is added. The resulting mixture is stirred at 50 DEG C for 6h and then cooled to room temperature. The reaction is quenched with saturated aqueous ammonium chloride solution, and the water layer is extracted with ethyl acetate. The combined organic layer is washed with brine, dried over sodium sulfate, filtered and evaporated. The residue is purified by column chromatography (using methanol (3%, v / v) in dichloromethane) to obtain the title compound (70mg, 33%). 1H-NMR (400MHz, DMSO-d6) δ8.97(s,1H),8.31(s,1H),8.02(d,J=8.9Hz,1H),7.71(d,J=8.8Hz,1H),5.20 (s,1H),4.55–4.41(m,1H),2.18(s,2H),2.09(s,2H),1.89(s,2H),1.72(s,2H),1.52(d,J=7.1Hz,6H). LC-MS(M+H) + =290.2.

[0573] Step 2: 1-(4-Isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-yl) 1-Hydroxycyclopentan-1-ol

[0574]

[0575] The title compound (1.8 g, 91%) was prepared in a similar manner to Example 1, Step 2, from 1-(6-chloro-4-isopropylquinolin-3-yl)cyclopentan-1-ol and bis(pinacolato)diboron. LC-MS (M+H) + =300.3 for the corresponding boronic acid.

[0576] The compound can also be obtained by the following steps:

[0577] A mixture of 1-(6-chloro-4-isopropylquinolin-3-yl)cyclopentan-1-ol (1.5 g, 5.19 mmol), bis(pinacolato)diboron (1.84 g, 7.3 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (223 mg, 0.31 mmol) and potassium acetate (1.32 g, 13.5 mmol) in 1,4-dioxane (50 mL) was stirred at 80°C overnight under nitrogen and then cooled to room temperature. The mixture was filtered and the filtrate was evaporated to give the crude product (1.8 g, 91%), which was used in the next step without further purification. LC-MS (M+H) + =300.3 for the corresponding boronic acid.

[0578] Step 3: 1-(6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinolin-3-yl)cyclopentan-1-ol

[0579]

[0580] The title compound (80 mg, 86%) was prepared in a similar manner to Example 1, Step 3, from 1-(6-chloro-4-isopropylquinolin-3-yl)cyclopentan-1-ol and 2,4-dichloro-5-fluoropyrimidine. LC-MS (M+H) + =386.2.

[0581] The compound can also be obtained by the following steps:

[0582] A mixture of 1-(6-chloro-4-isopropylquinolin-3-yl)cyclopentan-1-ol (92 mg, 0.24 mmol), 2,4-dichloro-5-fluoropyrimidine (40 mg, 0.24 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (8.3 mg, 0.012 mmol) and potassium carbonate (65 mg, 0.48 mmol) in 1,4-dioxane (2 mL) and water (0.25 mL) was stirred at 80 ° C. under nitrogen overnight and then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (eluted with methanol (3%, v / v) in dichloromethane) to give the title compound (80 mg, 86%). LC-MS (M+H) + =386.2.

[0583] Step 4: (3S,4R)-4-((5-fluoro-4-(3-(1-hydroxycyclopentyl)-4-isopropylquinolin-6-yl)pyrimidine-2-yl) 1-[4-(2-amino-3-methyl)tetrahydro-2H-pyran-3-ol]

[0584] The title compound (5 mg, 61%) was prepared in a manner similar to Example 1, Step 4, from 1-(6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinolin-3-yl)cyclopentan-1-ol and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride. 1 H-NMR (400MHz, DMSO-d6) δ9.20 (s, 1H), 9.03 (s, 1H), 8.50 (s, 1H), 8.27 (d, J = 8. 7Hz,1H),8.11(d,J=9.1Hz,1H),7.25(d,J=7.8Hz,1H),5.21(s,1H),4.98(s,1H) ,4.63–4.44(m,1H),3.90–3.83(m,3H),3.54(s,1H),3.38–3.36(m,1H),3.05(t, J=10.1Hz,1H),2.30–1.99(m,5H),1.91(s,2H),1.74(s,2H),1.65–1.43(m,7H). LC-MS (M+H) + =467.1.

[0585] The compound can also be obtained by the following steps:

[0586] A reaction mixture of 1-(6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinolin-3-yl)cyclopentan-1-ol (6.6 mg, 0.018 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (5.5 mg, 0.035 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (1.6 mg, 0.002 mmol) and cesium carbonate (18 mg, 0.054 mmol) in 1,4-dioxane (0.4 mL) was stirred overnight at 100° C. under nitrogen. The mixture was cooled to room temperature, and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with methanol (6%, v / v) in dichloromethane to give the title compound (5 mg, 61%). 1 H-NMR (400MHz, DMSO-d6) δ9.20 (s, 1H), 9.03 (s, 1H), 8.50 (s, 1H), 8.27 (d, J = 8. 7Hz,1H),8.11(d,J=9.1Hz,1H),7.25(d,J=7.8Hz,1H),5.21(s,1H),4.98(s,1H) ,4.63–4.44(m,1H),3.90–3.83(m,3H),3.54(s,1H),3.38–3.36(m,1H),3.05(t, J=10.1Hz,1H),2.30–1.99(m,5H),1.91(s,2H),1.74(s,2H),1.65–1.43(m,7H). LC-MS (M+H) + =467.1.

[0587] Example 51: (3S,4R)-4-((5-fluoro-4-(8-fluoro-3-(hydroxymethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0588]

[0589] Step 1: Diethyl 2-(((4-chloro-2-fluorophenyl)amino)methylene)malonate

[0590]

[0591] A solution of 4-chloro-2-fluoroaniline (25 g, 171.2 mmol) and diethyl 2-(ethoxymethylene) malonate (55 g) was stirred at 110° C. for 4 h. After cooling to room temperature, the reaction mixture was treated with petroleum ether (600 mL). The precipitate was filtered and dried to give the title compound (43.9 g, 81%). 1H-NMR (400MHz, DMSO-d6) δ10.87(d,J=13.3Hz,1H),8.44(d,J=13.4Hz,1H),7.72-7.67(m,1H),7.60(d, J=10.9Hz,1H),7.33(d,J=8.7Hz,1H),4.22(q,J=6.9Hz,2H),4.14(q,J=6.9Hz,2H),1.33–1.19(m,6H). LC-MS(M+H) + =316.2.

[0592] Step 2: Ethyl 6-chloro-8-fluoro-4-hydroxyquinoline-3-carboxylate

[0593]

[0594] The reaction mixture of diethyl 2-(((4-chloro-2-fluorophenyl)amino)methylene)malonate (34.6 g, 109.5 mmol) and diphenyl ether (50 mL) was stirred at 260 ° C for 9 h. After cooling to room temperature, the mixture was treated with petroleum ether (600 mL). The precipitate was filtered and dried to give the title product (43.9 g, 81%). 1 H-NMR (400MHz, DMSO-d6) δ12.65 (s, 1H), 8.39 (s, 1H), 7.91 (d, J = 9.8Hz, 2H), 4.23 (q, J = 6.8Hz, 2H), 1.28 (t, J = 7.0Hz, 3H). LC-MS(M+H) + =270.1.

[0595] Step 3: Ethyl 4-bromo-6-chloro-8-fluoroquinoline-3-carboxylate

[0596]

[0597] To a solution of ethyl 6-chloro-8-fluoro-4-hydroxyquinoline-3-formate (5.5g, 20.4mmol) in dimethylformamide (80mL) was added phosphorus tribromide (11g, 40.8mmol), and the mixture was stirred at 80°C for 4h. The mixture was cooled to room temperature and poured into ice water. The precipitate was filtered and dissolved in ethyl acetate. The mixture was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluted with ethyl acetate (16%, v / v) in petroleum ether) to obtain the title compound (5.2g, 76%). 1H-NMR (400MHz, DMSO-d6) δ9.09 (s, 1H), 8.15 (s, 1H), 8.10 (d, J = 10.0Hz, 1H), 4.46 (q, J = 7.0Hz, 2H), 1.39 (t, J = 7.0Hz, 3H). LC-MS(M+H) + =332.0, 334.0.

[0598] Step 4: Ethyl 6-chloro-8-fluoro-4-isopropylquinoline-3-carboxylate

[0599]

[0600] The title compound (950 mg, 86%) was prepared in a manner similar to Example 1, Step 1, from ethyl 4-bromo-6-chloro-8-fluoroquinoline-3-carboxylate. 1 H-NMR (400MHz, DMSO-d6) δ8.92(s,1H),8.25(s,1H),7.93(d,J=10.0Hz,1H),4.42 (q,J=7.0Hz,2H),4.04–3.82(m,1H),1.44(d,J=6.9Hz,6H),1.37(t,J=7.0Hz,3H). LC-MS(M+H) + =296.1.

[0601] Step 5: 8-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl Quinoline-3-carboxylate

[0602]

[0603] The title compound (0.7 g, 100%) was prepared in a similar manner to Example 1, Step 2, from ethyl 6-chloro-8-fluoro-4-isopropylquinoline-3-carboxylate and bis(pinacolato)diboron. LC-MS (M+H) + =306.1 for the corresponding boronic acid.

[0604] Step 6: Ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropylquinoline-3-carboxylate

[0605]

[0606] The title compound (420 mg, 45%) was prepared in a manner similar to Example 1, Step 3, from ethyl 8-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate and 2,4-dichloro-5-fluoropyrimidine. 1H-NMR(400MHz,DMSO-d6)δ9.08(d,J=14.4Hz,2H),8.90(s,1H),8.18(d,J=11.1Hz,1H), 4.44(q,J=6.3Hz,2H), 4.04–3.86(m,1H), 1.54(d,J=6.9Hz,6H), 1.38(t,J=6.9Hz,3H). LC-MS(M+H) + =392.2.

[0607] Step 7: Ethyl 8-fluoro-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidine- 4-Isopropylquinoline-3-carboxylate

[0608]

[0609] The title compound (300 mg, 59%) was prepared in a similar manner to Example 1, Step 4, from ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropylquinoline-3-carboxylate and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride. LC-MS (M+H) + =473.3.

[0610] Step 8: (3S,4R)-4-((5-fluoro-4-(8-fluoro-3-(hydroxymethyl)-4-isopropylquinolin-6-yl)pyrimidine-2-yl) 1-[4-(2-amino-3-methyl)tetrahydro-2H-pyran-3-ol]

[0611] The title compound was prepared in a similar manner to Example 3 from ethyl 8-fluoro-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate (56 mg, 26%). 1 H-NMR (400MHz, DMSO-d6) δ8.96(s,1H),8.93(s,1H),8.52(d,J=2.7Hz,1H),8.07(d,J=11.6Hz,1H),7.32(d,J=7.7Hz,1H),5.48(s,1H) ,4.97(s,1H),4.81(s,2H),4.02–3.73(m,4H),3.54(s,1H),3.39–3.36(m,1H),3.07(t,J=10.4Hz,1H),2.02(s,1H),1.63–1.42(m,7H). LC-MS(M+H) + =431.1.

[0612] Example 52: (3S,4R)-4-((4-(3-(((3,3-difluorocyclobutyl)amino)methyl)-8-fluoro-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0613]

[0614] Step 1: (3S,4R)-4-((4-(3-(chloromethyl)-8-fluoro-4-isopropylquinolin-6-yl)-5-fluoropyrimidine-2-yl) 1-[4-(2-amino-3-methyl)tetrahydro-2H-pyran-3-ol]

[0615]

[0616] To a solution of (3S,4R)-4-((5-fluoro-4-(8-fluoro-3-(hydroxymethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (40 mg, 0.093 mmol) in dichloromethane (10 mL) was added thionyl chloride (0.1 mL) at 0°C, and the reaction solution was stirred for 1 hour and then diluted with dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, filtered, and evaporated to give the crude title compound (40 mg). LC-MS (M+H) + =449.3.

[0617] Step 2: (3S,4R)-4-((4-(3-(((3,3-difluorocyclobutyl)amino)methyl)-8-fluoro-4-isopropylquinol (6-(2-((1,2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-[(2-((- ...

[0618] The title compound (17 mg, 72%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-8-fluoro-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and 3,3-difluorocyclobutane-1-amine hydrochloride. 1 H-NMR (400MHz, DMSO-d6) δ8.95(s,1H),8.90(s,1H),8.52(s,1H),8.07(d,J=11.5Hz,1H),7.32(d,J=7.7Hz,1H),4.97(s,1H),4.06–3.76(m ,6H),3.54(s,1H),3.39–3.36(m,1H),3.19(s,1H),3.06(t,J=10.1Hz ,1H),2.77(s,2H),2.41–2.37(m,2H),2.02(s,1H),1.57–1.51(m,7H). LC-MS(M+H) + =520.1.

[0619] Example 53: (3S,4R)-4-((5-Fluoro-4-(8-fluoro-4-isopropyl-3-((((R)-tetrahydro-2H-pyran-3-yl)amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0620]

[0621] The title compound (14 mg, 61%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-8-fluoro-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (R)-tetrahydro-2H-pyran-3-amine hydrochloride. 1 H-NMR (400MHz, DMSO-d6) δ8.95(s,1H),8.91(s,1H),8.52(s,1H),8.06(d,J=11.6Hz,1H),7.32(d,J=7.5Hz,1H),4.97(s,1H),4.10–3.77(m,7H),3. 69(d,J=11.0Hz,1H),3.54(s,1H),3.39–3.24(m,3H),3.06(t,J=10.1Hz,2 H),2.56(s,1H),2.01-1.97(m,2H),1.75–1.38(m,9H),1.38–1.17(m,1H). LC-MS(M+H) + =514.1.

[0622] Example 53 can also be obtained by the following steps:

[0623] Step 1: Diethyl 2-(((4-chloro-2-fluorophenyl)amino)methylene)malonate

[0624]

[0625] A solution of 4-chloro-2-fluoroaniline (25 g, 171.2 mmol) and diethyl 2-(ethoxymethylene) malonate (55 g) was stirred at 110° C. for 4 h. After cooling to room temperature, the reaction mixture was treated with petroleum ether (600 mL). The precipitate was filtered and dried to give the title compound (43.9 g, 81%). 1 H-NMR (400MHz, DMSO-d6) δ10.87(d,J=13.3Hz,1H),8.44(d,J=13.4Hz,1H),7.72-7.67(m,1H),7.60(d, J=10.9Hz,1H),7.33(d,J=8.7Hz,1H),4.22(q,J=6.9Hz,2H),4.14(q,J=6.9Hz,2H),1.33–1.19(m,6H). LC-MS(M+H) + =316.2.

[0626] Step 2: Ethyl 6-chloro-8-fluoro-4-hydroxyquinoline-3-carboxylate

[0627]

[0628] The reaction mixture of diethyl 2-(((4-chloro-2-fluorophenyl)amino)methylene)malonate (34.6 g, 109.5 mmol) and diphenyl ether (50 mL) was stirred at 260 ° C for 9 h. After cooling to room temperature, the mixture was treated with petroleum ether (600 mL). The precipitate was filtered and dried to give the title product (43.9 g, 81%). 1 H-NMR (400MHz, DMSO-d6) δ12.65 (s, 1H), 8.39 (s, 1H), 7.91 (d, J = 9.8Hz, 2H), 4.23 (q, J = 6.8Hz, 2H), 1.28 (t, J = 7.0Hz, 3H). LC-MS(M+H) + =270.1.

[0629] Step 3: Ethyl 4-bromo-6-chloro-8-fluoroquinoline-3-carboxylate

[0630]

[0631] To a solution of ethyl 6-chloro-8-fluoro-4-hydroxyquinoline-3-formate (5.5g, 20.4mmol) in dimethylformamide (80mL) was added phosphorus tribromide (11g, 40.8mmol), and the mixture was stirred at 80°C for 4h. The mixture was cooled to room temperature and poured into ice water. The precipitate was filtered and dissolved in ethyl acetate. The mixture was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluted with ethyl acetate (16%, v / v) in petroleum ether) to obtain the title compound (5.2g, 76%). 1 H-NMR (400MHz, DMSO-d6) δ9.09 (s, 1H), 8.15 (s, 1H), 8.10 (d, J = 10.0Hz, 1H), 4.46 (q, J = 7.0Hz, 2H), 1.39 (t, J = 7.0Hz, 3H). LC-MS(M+H) + =332.0, 334.0.

[0632] Step 4: Ethyl 6-chloro-8-fluoro-4-isopropylquinoline-3-carboxylate

[0633]

[0634] To an isopropylmagnesium bromide solution (7.5 mL, 1 M, 7.5 mmol) under nitrogen was added a solution of zinc chloride in tetrahydrofuran (10.7 mL, 0.7 M, 7.5 mmol), and the mixture was stirred at 50°C for 2 h. A solution of ethyl 4-bromo-6-chloro-8-fluoroquinoline-3-carboxylate (1.24 g, 3.74 mmol) in dimethylformamide (5 mL), copper (I) iodide (71 mg, 0.37 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium (II) (139 mg, 0.19 mmol) were added, and the resulting mixture was stirred at 50°C for 2 h and then cooled to room temperature. The reaction was quenched with methanol (5 mL), and the solvent was evaporated. The residue was suspended in ethyl acetate and water and then filtered. The filtrate was washed with water and brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate (16%, v / v) in petroleum ether to give the title compound (0.95 mg, 86%). 1 H-NMR (400MHz, DMSO-d6) δ8.92(s,1H),8.25(s,1H),7.93(d,J=10.0Hz,1H),4.42 (q,J=7.0Hz,2H),4.04–3.82(m,1H),1.44(d,J=6.9Hz,6H),1.37(t,J=7.0Hz,3H). LC-MS(M+H) + =296.1.

[0635] Step 5: 8-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl Quinoline-3-carboxylate

[0636]

[0637] A mixture of ethyl 6-chloro-8-fluoro-4-isopropylquinoline-3-carboxylate (532 mg, 1.8 mmol), bis(pinacol)diboron (635 mg, 2.5 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (72 mg, 0.1 mmol) and potassium acetate (459 mg, 4.7 mmol) in 1,4-dioxane (18 mL) was stirred at 80°C overnight under nitrogen and then cooled to room temperature. The mixture was filtered and the filtrate was evaporated to give the product (0.7 g, 100%), which was used in the next step without further purification. LC-MS (M+H) + =306.1 for the corresponding boronic acid.

[0638] Step 6: Ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropylquinoline-3-carboxylate

[0639]

[0640] A mixture of ethyl 8-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate (921 mg, 2.38 mmol), 2,4-dichloro-5-fluoropyrimidine (478 mg, 2.86 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (103 mg, 0.14 mmol) and potassium carbonate (0.86 g, 6.2 mmol) in 1,4-dioxane (20 mL) and water (2.5 mL) was stirred at 80 ° C. under nitrogen overnight and then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (eluted with methanol (3%, v / v) in dichloromethane) to give the title compound (420 mg, 45%). LC-MS (M+H) + =392.2.

[0641] Step 7: Ethyl 8-fluoro-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidine- 4-Isopropylquinoline-3-carboxylate

[0642]

[0643] A reaction mixture of ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropylquinoline-3-carboxylate (423 mg, 1.08 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (198 mg, 1.29 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (44 mg, 0.054 mmol) and cesium carbonate (1.1 g, 3.24 mmol) in 1,4-dioxane (15 mL) was stirred overnight at 100° C. under nitrogen. The mixture was cooled to room temperature, and the solvent was evaporated. The residue was purified by flash chromatography on silica gel eluting with methanol (6%, v / v) in dichloromethane to give the title compound (300 mg, 59%). LC-MS (M+H) + =473.3.

[0644] Step 8: (3S,4R)-4-((5-fluoro-4-(8-fluoro-3-(hydroxymethyl)-4-isopropylquinolin-6-yl)pyrimidine-2-yl) 1-[4-(2-amino-3-methyl)tetrahydro-2H-pyran-3-ol]

[0645]

[0646] To a solution of ethyl 8-fluoro-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate (236 mg, 0.5 mmol) in tetrahydrofuran (50 mL) was added lithium aluminum hydride (57 mg, 1.5 mmol) at 0 ° C under nitrogen and stirred at room temperature for 3 h. The reaction was quenched with methanol and the solvent was evaporated. The residue was purified by preparative HPLC (eluent: water (0.1% formic acid) / acetonitrile (0.1% formic acid)) to give the product (56 mg, 26%). 1 H-NMR (400MHz, DMSO-d6) δ8.96(s,1H),8.93(s,1H),8.52(d,J=2.7Hz,1H),8.07(d,J=11.6Hz,1H),7.32(d,J=7.7Hz,1H),5.48(s,1H) ,4.97(s,1H),4.81(s,2H),4.02–3.73(m,4H),3.54(s,1H),3.39–3.36(m,1H),3.07(t,J=10.4Hz,1H),2.02(s,1H),1.63–1.42(m,7H). LC-MS(M+H) + =431.1.

[0647] Step 9: (3S,4R)-4-((4-(3-(chloromethyl)-8-fluoro-4-isopropylquinolin-6-yl)-5-fluoropyrimidine-2-yl) 1-[4-(2-amino-3-methyl)tetrahydro-2H-pyran-3-ol]

[0648]

[0649] To a solution of (3S,4R)-4-((5-fluoro-4-(8-fluoro-3-(hydroxymethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (40 mg, 0.093 mmol) in dichloromethane (10 mL) was added thionyl chloride (0.1 mL) at 0°C, and the reaction solution was stirred for 1 hour and then diluted with dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate solution, water, and brine, dried over sodium sulfate, filtered, and evaporated to give the crude title compound (40 mg). LC-MS (M+H) + =449.3.

[0650] Step 10: (3S,4R)-4-((5-fluoro-4-(8-fluoro-4-isopropyl-3-((((R)-tetrahydro-2H-pyran-3-yl) (amino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0651]

[0652] To a solution of (3S,4R)-4-((4-(3-(chloromethyl)-8-fluoro-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (20 mg, 0.045 mmol) in dimethylformamide (1.5 mL) was added (R)-tetrahydro-2H-pyran-3-amine hydrochloride (12 mg, 0.089 mmol) and N,N-diisopropylethylamine (17 mg, 0.13 mmol) at 25 ° C. The mixture was stirred at 25 ° C for 5 h and then diluted with ethyl acetate (15 mL). The organic solution was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluted with methanol (5%, v / v) in dichloromethane) to give the title compound (14 mg, 61%). 1 H-NMR (400MHz, DMSO-d6) δ8.95(s,1H),8.91(s,1H),8.52(s,1H),8.06(d,J=11.6Hz,1H),7.32(d,J=7.5Hz,1H),4.97(s,1H),4.10–3.77(m,7H),3. 69(d,J=11.0Hz,1H),3.54(s,1H),3.39–3.24(m,3H),3.06(t,J=10.1Hz,2 H),2.56(s,1H),2.01-1.97(m,2H),1.75–1.38(m,9H),1.38–1.17(m,1H). LC-MS(M+H) + =514.1.

[0653] Example 54: (3R,4R)-4-Fluoro-1-((6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)pyrrolidin-3-ol

[0654]

[0655] The title compound (11.5 mg, 16.5%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (3R,4R)-4-fluoropyrrolidin-3-ol. 1H-NMR(400MHz,DMSO-d6)δ9.11(s,1H),8.82(s,1H),8.52-8.48(m,1H),8.31-8.25(m,1H),8.1 7-8.12(m,1H),7.26(d,J=7.9Hz,1H),5.37-5.32(m,1H),4.99-4.95(m,1H),4.90-4.72(m,1H), 4.22-4.09(m,1H),4.02-3.95(m,1H),3.94-3.78(m,5H),3.60-3.50(m,1H),3.40-3.35(m,1H) ,3.12-3.00(m,2H),2.84-2.68(m,2H),2.24-2.18(m,1H),2.10-2.00(m,1H)1.61-1.48(m,7H). LC-MS(M+H) + =500.1.

[0656] Example 55 and Example 56: (3S,4R)-4-((4-(3-((S)-1-aminoethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (3S,4R)-4-((4-(3-((R)-1-aminoethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0657]

[0658] Step 1: (3S,4R)-4-((4-(3-(1-azidoethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidine-2-yl) 1-[4-(2-amino-3-methyl)tetrahydro-2H-pyran-3-ol]

[0659]

[0660] The title compound (71 mg, 37%) was prepared in a manner similar to that in Step 1 of Example 38 from (3S,4R)-4-((5-fluoro-4-(3-(1-hydroxyethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol. LC-MS (M+H) + =452.2.

[0661] Step 2: (3S,4R)-4-((4-(3-((S)-1-aminoethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidine- 2-yl)amino)tetrahydro-2H-pyran-3-ol and (3S,4R)-4-((4-(3-((R)-1-aminoethyl)-4-isopropylquinolin- 6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0662] A mixture of Examples 55 and 56 was prepared from (3S,4R)-4-((4-(3-(1-azidoethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol in a manner similar to that in Example 38, Step 2. Examples 55 and 56 were separated on chiral-HPLC to give (3S,4R)-4-((4-(3-((S)-1-aminoethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (3S,4R)-4-((4-(3-((R)-1-aminoethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol. Analytical chiral HPLC conditions: CHIRALPAK ID-3, 0.46 x 5 cm, 3.0 μm. Mobile phase: (hexane:dichloromethane = 1:1, containing 0.5% 2M NH 3 -MeOH):EtOH, 20 mL / min over 22.5 min.

[0663] Example 55 (5 mg, 17%): 1 H-NMR (400MHz, DMSO-d6) δ9.17 (s, 1H), 9.08 (brs, 1H), 8.49 (d, J = 3.9Hz, 1H), 8. 25(d,J=8.8Hz,1H),8.11(d,J=8.8Hz,1H),7.24(d,J=7.8Hz,1H),5.00-4.94(m, 1H),4.71-4.61(m,1H),4.03-3.80(m,4H),3.60-3.49(m,1H),3.41-3.32(m,1H) ,3.11-3.01(m,1H),2.10-2.01(m,1H),1.61-1.45(m,7H),1.38(d,J=6.5Hz,3H). LC-MS (M+H) + =426.1. Chiral HPLC: RT=3.148 min.

[0664] Example 56 (5 mg, 17%) 1H-NMR (400MHz, DMSO-d6) δ9.18 (s, 1H), 9.08 (brs, 1H), 8.49 (d, J = 3.9Hz, 1H), 8. 25(d,J=8.8Hz,1H),8.11(d,J=8.8Hz,1H),7.24(d,J=7.8Hz,1H),4.99-4.95(m, 1H),4.71-4.61(m,1H),4.06-3.75(m,4H),3.57-3.49(m,1H),3.42-3.31(m,1H) ,3.11-3.01(m,1H),2.09-2.01(m,1H),1.60-1.44(m,7H),1.38(d,J=6.6Hz,3H). LC-MS (M+H) + =426.1. Chiral HPLC: RT=5.669 min.

[0665] Example 57: (S)-1-((6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)piperidin-3-ol

[0666]

[0667] The title compound (16 mg, 44%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (3S)-piperidin-3-ol hydrochloride. 1H-NMR (300MHz, DMSO-d6) δ9.12(brs,1H),8.76(s,1H),8.50(d,J=3.9Hz,1H),8.33-8.25(m,1H),8.14(d,J=8.9Hz,1H) ,7.27(d,J=7.8Hz,1H),4.99(d,J=5.3Hz,1H),4.59(d,J=4.6Hz,1H),4.04-3.92(m,1H),3.90-3.81(m,3H),3.80-3.72 (m,1H),3.68-3.61(m,1H),3.61-3.50(m,1H),3.43-3.35(m,2H),3.11-3.01(m,1H),2.79-2.71(m,1H),2.69-2.61(m, 1H),2.10-2.02(m,1H),2.00-1.90(m,1H),1.84-1.74(m,2H),1.65–1.45(m,8H),1.41-1.33(m,1H),1.16-1.02(m,1H). LC-MS(M+H) + =496.3.

[0668] Example 58: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-(((R)-3-methylmorpholino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0669]

[0670] The title compound (8 mg, 24%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (R)-3-methylmorpholine. 1H-NMR(300MHz,DMSO-d6)δ9.12(brs,1H),8.80(s,1H),8.50(d,J=3.9Hz,1H),8.34-8.24(m,1H),8 .14(d,J=8.8Hz,1H),7.75–7.45(m,1H),7.27(d,J=7.8Hz,1H),5.03-4.94(m,1H),4.35-4.24(m,1H ),4.14-3.98(m,1H),3.93-3.81(m,3H),3.70-3.48(m,3H),3.44-3.28(m,2H),3.23-3.00(m,2H), 2.51-2.45(m,1H),2.42-2.32(m,1H),2.22-2.00(m,2H),1.65-1.49(m,7H),1.11(d,J=6.2Hz,3H). LC-MS(M+H) + =496.4.

[0671] Example 59: (3S,4R)-4-((5-fluoro-4-(4-isopropyl-3-((pyridin-2-ylamino)methyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0672]

[0673] The title compound (6.8 mg, 24%) was prepared in a manner similar to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and pyridin-2-amine. 1 H-NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.60(s,1H),8.52(s,1H),8.48(s,1H),8.39-8 .34(m,1H),8.23-8.18(m,1H),7.77-7.70(m,1H),7.69-7.64(m,1H),7.38-7.32(m,1H ),7.17-7.11(m,1H),6.70-6.64(m,1H),5.62(s,2H),3.92-3.80(m,2H),3.60-3.54(m ,2H),3.39-3.31(m,2H),3.05(t,J=10.3Hz,1H),2.11-2.00(m,1H),1.60-1.48(m,7H). LC-MS(M+H) + =489.2.

[0674] Example 60: (1R,3R,5S)-9-((6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)-9-azabicyclo[3.3.1]nonan-3-ol

[0675]

[0676] The title compound (9 mg, 32%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (1R,3r,5S)-9-azabicyclo[3.3.1]nonan-3-ol hydrochloride. 1 H-NMR(300MHz,DMSO-d6)δ9.10(brs,1H),8.77(s,1H),8.48(d,J=3.9Hz,1H),8.30-8.21(m,1H),8.11(d ,J=8.8Hz,1H),7.24(d,J=7.8Hz,1H),4.95(d,J=5.2Hz,1H),4.42(d,J=4.5Hz,1H),4.07-3.91(m,4H),3 .90-3.78(m,3H),3.61-3.46(m,1H),3.42-3.32(m,1H),3.11-2.98(m,1H),2.93-2.84(m,2H),2.40-2.0 9(m,3H),2.09-1.83(m,3H),1.62-1.52(m,6H),1.51-1.35(m,2H),1.31-1.17(m,2H),1.14-1.04(m,2H). LC-MS(M+H) + =536.4.

[0677] Example 61: (S)-1-((6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)piperidine-3-carbonitrile

[0678]

[0679] The title compound (12 mg, 38%) was prepared in a manner similar to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (S)-piperidine-3-carbonitrile. 1H-NMR(300MHz,DMSO-d6)δ9.13(brs,1H),8.80-8.74(m,1H),8.55-8.45(m,1H ),8.34-8.23(m,1H),8.20-8.09(m,1H),7.31-7.23(m,1H),4.99-4.93(m,1H) ,4.10-3.66(m,6H),3.58-3.52(m,1H),3.43-3.33(m,2H),3.07-3.01(m,2H), 2.76-2.70(m,1H),2.29-2.19(m,1H),2.07-2.01(m,1H),1.81-1.41(m,12H). LC-MS (M+H) + =505.4.

[0680] Example 62: (R)-1-((6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)piperidine-3-carbonitrile

[0681]

[0682] The title compound (13 mg, 37%) was prepared in a manner similar to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (R)-piperidine-3-carbonitrile. 1 H-NMR(300MHz,DMSO-d6)δ9.14(brs,1H),8.80-8.74(m,1H),8.53-8.46(m,1H),8.29 (d,J=8.8Hz,1H),8.14(d,J=8.6Hz,1H),7.26(d,J=7.6Hz,1H),5.02-4.94(m,1H),4. 04-3.80(m,4H),3.77-3.65(m,2H),3.60-3.54(m,1H),3.45-3.36(m,2H),3.13-2.99 (m,2H),2.78-2.68(m,1H),2.28-2.22(m,1H),2.11-2.00(m,1H),1.82-1.42(m,12H). LC-MS(M+H) + =505.4.

[0683] Example 67: (3S,4R)-4-((5-fluoro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0684]

[0685] Step 1: 2-(4-bromo-6-chloro-8-fluoroquinolin-3-yl)propan-2-ol

[0686]

[0687] To a solution of ethyl 4-bromo-6-chloro-8-fluoroquinoline-3-carboxylate (333 mg, 1 mmol) in tetrahydrofuran (8 mL) was added methylmagnesium bromide (3 mL, 3 mmol, 1 M in tetrahydrofuran) at -78 ° C under nitrogen, and the mixture was slowly warmed to 0 ° C over 2 h and then quenched by saturated aqueous ammonium chloride solution. The aqueous layer was extracted 3 times 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 (eluted with ethyl acetate (33%, v / v) in petroleum ether) to give the title compound (240 mg, 75%). LC-MS (M+H) = 318.0, 320.0.

[0688] Step 2: 2-(6-chloro-8-fluoro-4-isopropylquinolin-3-yl)propan-2-ol

[0689]

[0690] To an isopropylmagnesium bromide solution (3 mL, 1 M in tetrahydrofuran, 3 mmol) under nitrogen was added zinc chloride (3 mL, 1 M in tetrahydrofuran, 3 mmol), and the mixture was stirred at 50°C for 2 h. 2-(4-bromo-6-chloro-8-fluoroquinolin-3-yl)propan-2-ol (240 mg, 0.75 mmol), CuI (14 mg, 0.075 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (28 mg, 0.038 mmol) in N,N-dimethylformamide (10 mL) were then added. The reaction mixture was stirred at 50°C for 2 h and then cooled to room temperature. The reaction was quenched with methanol (10 mL), and the solvent was concentrated. The residue was diluted with ethyl acetate, and the organic solution was washed with water and saturated aqueous ammonium chloride. The aqueous phase was extracted three times with ethyl acetate. The organic layers were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography eluting with ethyl acetate in petroleum ether (50%, v / v) to give the title compound (75 mg, 35%). LC-MS (M+H)+ = 282.2.

[0691] Step 3: 2-(8-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinol (3-Methyl-1-piperidin-2-yl)propan-2-ol

[0692]

[0693] The title compound (99 mg, 100%) was prepared from 2-(6-chloro-8-fluoro-4-isopropylquinolin-3-yl)propan-2-ol and bis(pinacolato)diboron in a manner analogous to Example 1, Step 2. LC-MS (M+H)+ = 292.2 for the corresponding boronic acid.

[0694] Step 4: 2-Chloro-5-fluoro-4-((4-methoxybenzyl)oxy)pyrimidine

[0695]

[0696] To a solution of sodium hydride (925 mg, 23.13 mmol, 60%) in tetrahydrofuran (30 mL) at 0 ° C under a nitrogen atmosphere was added dropwise (4- methoxyphenyl) methanol (2350 mg, 17.018 mmol) in tetrahydrofuran (12.0 mL). The resulting mixture was stirred at 0 ° C for 30 min under a nitrogen atmosphere. 2,4- dichloro-5-fluoropyrimidine (2375 mg, 14.23 mmol) in tetrahydrofuran (12 mL) was added dropwise at 0 ° C over 20 min to the above mixture. The resulting mixture was stirred at 0 ° C for another 2 h under a nitrogen atmosphere and then quenched by adding a 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.

[0697] Step 5: (3S,4R)-4-((5-fluoro-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)amino)tetrahydro-2H- Pyran-3-ol

[0698]

[0699] The title compound (1900 mg, 73%) was prepared in a similar manner to that in Step 4 of Example 1 from 2-chloro-5-fluoro-4-((4-methoxybenzyl)oxy)pyrimidine and (3S,4R)-4-aminooxan-3-ol hydrochloride. LC-MS (M+H) + =350.1.

[0700] Step 6: (3S,4R)-4-((5-fluoro-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)amino)tetrahydro-2H- Pyran-3-yl acetate

[0701]

[0702] 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 acetic anhydride (3325 mg, 32.57 mmol) dropwise at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 16 h under a nitrogen atmosphere and then quenched by the addition of saturated aqueous sodium bicarbonate solution (30 mL). The resulting mixture was extracted with dichloromethane (40 mL x 2). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (eluted 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.

[0703] Step 7: (3S,4R)-4-((5-fluoro-4-hydroxypyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate

[0704]

[0705] 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 10% Pd / C (945 mg, 0.888 mmol) under a nitrogen atmosphere. The mixture was hydrogenated under a hydrogen atmosphere at room temperature for 6 h. The reaction was filtered through a pad of celite and concentrated under reduced pressure to give the title compound (1200 mg, 88%). LC-MS (M+H) + =272.0.

[0706] Step 8: (3S,4R)-4-((4-chloro-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate

[0707]

[0708] 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 dropwise phosphorus oxychloride (2055 mg, 13.42 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 ° C for 3 h under a nitrogen atmosphere, then cooled to room temperature and concentrated. The residue was purified by flash chromatography (eluted with ethyl acetate in petroleum ether (0% to 30% gradient)) to produce the title compound (820 mg, 63%). LC-MS (M+H) +=290.0.

[0709] Step 9: (3S,4R)-4-((5-fluoro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)-4-isopropylquinolin-6-yl)pyrimidine (2-pyridin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0710] The title compound (11 mg, 20%) was prepared in a manner analogous to Example 1, Step 3, from 2-(8-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-2-ol and (3S,4R)-4-((4-chloro-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate. 1H NMR (400MHz, d-DMSO) δ9.14(s,1H),9.02(s,1H),8.52(s,1H),8.05(d,J=11.7Hz,1H),7.31(d,J=7.7Hz,1H),5.51(s,1H),4.97(s,1H),4. 81–4.55(m,1H),3.95–3.75(m,3H),3.54(s,1H),3.40–3.30(m,1H),3.06(t,J=10.1Hz,1H),2.02(s,1H),1.70(s,6H),1.64–1.43(m,7H). LC-MS(M+H)+=459.1.

[0711] Example 68: (3S,4R)-4-((4-(3-(((3R,5S)-3,5-dimethylmorpholino)methyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0712]

[0713] The title compound (5.3 mg, 18%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (3R,5S)-3,5-dimethylmorpholine hydrochloride. 1H-NMR(400MHz,DMSO-d6)δ:9.31(s,1H),9.07(s,1H),8.49(s,1H),8.29-8.21(m,1H),8.1 5-8.08(m,1H),7.30-7.20(m,1H),5.03-4.91(m,1H),4.05-3.97(m,2H),3.80-3.97(m,4H ),3.75-3.65(m,2H),3.60-3.50(m,1H),3.40-3.35(m,1H),3.27-3.18(m,2H),3.05(t,J= 10.3Hz,1H),2.71-2.60(m,2H),2.10-1.95(m,1H),1.62-1.50(m,7H),0.86-0.78(m,6H). LC-MS(M+H) + =510.1.

[0714] Example 69: (3S,4R)-4-((4-(3-(((3R,5R)-3,5-dimethylmorpholino)methyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0715]

[0716] The title compound (5.6 mg, 19%) was prepared in a manner analogous to that in Example 11, Step 1, from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (3R,5R)-3,5-dimethylmorpholine hydrochloride. 1 H-NMR(400MHz,DMSO-d6)δ:9.12(s,1H),8.89(s,1H),8.50(s,1H),8.31-8.24(m,1H),8.1 5-8.10(m,1H),7.30-7.22(m,1H),5.00-4.94(m,1H),4.30-4.21(m,1H),4.20-4.10(m,1H ),3.95-3.80(m,3H),3.63-3.50(m,4H),3.40-3.35(m,1H),3.28-3.19(m,2H),3.05(t,J= 10.3Hz,1H),2.71-2.60(m,2H),2.10-1.95(m,1H),1.62-1.50(m,7H),1.07-1.00(m,6H). LC-MS(M+H) + =510.1.

[0717] Example 70: (3S,4R)-4-((4-(7-chloro-3-(2-hydroxypropan-2-yl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0718]

[0719] Step 1: Diethyl 2-(((3-chloro-4-methoxyphenyl)amino)methylene)malonate

[0720]

[0721] To 3-chloro-4-methoxyaniline (8.0 g, 50.76 mmol) was added diethyl 2-(ethoxymethylene) malonate (16.4 g, 76.14 mmol). The reaction mixture was stirred at 110° C. for 3 h and then cooled to 60° C. The mixture was poured into petroleum ether (500 mL) and the precipitate was filtered to give the title compound (14.1 g, 85%). LC-MS (M+H) = 328.1

[0722] Step 2: Ethyl 7-chloro-4-hydroxy-6-methoxyquinoline-3-carboxylate

[0723]

[0724] A mixture of diethyl 2-(((3-chloro-4-methoxyphenyl)amino)methylene)malonate (10.0 g, 30.57 mmol) and diphenyl ether (50 mL) was stirred at 260° C. for 2 h and then cooled to 60° C. The mixture was poured into petroleum ether (500 mL) and the precipitate was filtered to give the title compound (7.0 g, 82%). LC-MS (M+H) + =282.1.

[0725] Step 3: Ethyl 4,7-dichloro-6-methoxyquinoline-3-carboxylate

[0726]

[0727] To a solution of ethyl 7-chloro-4-hydroxy-6-methoxyquinoline-3-carboxylate (5.0 g, 17.73 mmol) in dichloromethane (50 mL) and N,N-dimethylformamide (0.4 mL) was added oxalyl chloride (2.7 g, 17.73 mmol). The reaction mixture was stirred at 40 ° C for 3 h, then cooled to room temperature and diluted with ethyl acetate (50 mL). The organic solution was washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate (50%, v / v) in petroleum ether) to give the title compound (3.9 g, 76%). LC-MS (M+H) + =300.1

[0728] Step 4: Ethyl 7-chloro-4-isopropyl-6-methoxyquinoline-3-carboxylate

[0729]

[0730] Zinc chloride (14.3 mL, 10.0 mmol, 0.7 M in tetrahydrofuran) was added to isopropylmagnesium bromide (4.0 mL, 10.0 mmol, 2.5 M in tetrahydrofuran). The reaction mixture was stirred at 50 ° C for 1 hour and then cooled to room temperature. Ethyl 4,7-dichloro-6-methoxyquinoline-3-carboxylate (2.0 g, 6.67 mmol), CuI (128 mg, 0.67 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (248 mg, 0.34 mmol) were added to the mixture. The reaction mixture was then stirred at 50 ° C for 3 hours, then cooled to room temperature and diluted with ethyl acetate (50 mL). The mixture was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate (50%, v / v) in petroleum ether) to give the title compound (1.4 g, 69%). LC-MS (M+H) + =308.3.

[0731] Step 5: Ethyl 7-chloro-6-hydroxy-4-isopropylquinoline-3-carboxylate

[0732]

[0733] To a solution of ethyl 7-chloro-4-isopropyl-6-methoxyquinoline-3-carboxylate (1.1 g, 3.57 mmol) in dichloromethane (10 mL) was added BBr (17.8 mL, 17.85 mmol, 1 M in dichloromethane) at 0°C. The reaction mixture was then stirred at 0°C for 2 h and then diluted with ethyl acetate (30 mL). The mixture was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate (50%, v / v) in petroleum ether) to give the title compound (750 mg, 72%). LC-MS (M+H) = 294.3.

[0734] Step 6: Ethyl 7-chloro-4-isopropyl-6-(((trifluoromethyl)sulfonyl)oxy)quinoline-3-carboxylate

[0735]

[0736] To a solution of ethyl 7-chloro-6-hydroxy-4-isopropylquinoline-3-carboxylate (720 mg, 2.46 mmol) in dichloromethane (10 mL) was added triethylamine (596 mg, 5.90 mmol) and trifluoromethanesulfonic anhydride (1.39 g, 4.92 mmol) at 0 ° C. The reaction mixture was stirred for 2 h at 0 ° C. and then diluted with ethyl acetate (30 mL). The mixture was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate (50%, v / v) in petroleum ether) to obtain the title compound, giving the title compound (889 mg, 85%). LC-MS (M+H) = 426.4.

[0737] Step 7: 7-chloro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl Quinoline-3-carboxylate

[0738]

[0739] The title compound (508 mg, 92%) was prepared from ethyl 7-chloro-4-isopropyl-6-(((trifluoromethyl)sulfonyl)oxy)quinoline-3-carboxylate and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) in a manner analogous to Example 1, Step 2. LC-MS (M+H) = 404.4.

[0740] Step 8: Ethyl 7-chloro-6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate

[0741]

[0742] The title compound (396 mg, 76%) was prepared from ethyl 7-chloro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate and 2,4-dichloro-5-fluoropyrimidine in a manner analogous to Example 1, Step 3. LC-MS (M+H) = 408.1.

[0743] Step 9: Ethyl 7-chloro-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidine- 4-Isopropylquinoline-3-carboxylate

[0744]

[0745] The title compound (221 mg, 72%) was prepared from ethyl 7-chloro-6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride in a manner similar to that described in Example 4, Step 6. LC-MS (M+H) = 489.3.

[0746] Step 10: (3S,4R)-4-((4-(7-chloro-3-(2-hydroxypropan-2-yl)-4-isopropylquinolin-6-yl)-5-fluoroPyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0747] To a solution of ethyl 7-chloro-6-(5-fluoro-2-(((3S, 4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate (100 mg, 0.20 mmol) in tetrahydrofuran (4 mL) was added methyllithium (0.6 mL, 0.96 mmol, 1.6 M in tetrahydrofuran) at -40 ° C. The reaction mixture was then stirred at 0 ° C for 2 h and then diluted with ethyl acetate (30 mL). The mixture was washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with ethyl acetate (50%, v / v) in petroleum ether) to give the title compound (12 mg, 13%). 1 H-NMR(400MHz,DMSO-d6)δ:9.10(s,1H),8.53(s,1H),8.50(s,1H),8.20(s,1H),7.40-7.34(m,1H),5.47(s,1H),4.99-4.95(m,1H),4.65-4 .55(m,1H),3.85-3.74(m,3H),3.56-3.45(m,1H),3.38-3.28(m,1H), 3.05-2.95(m,1H),2.09-1.96(m,1H),1.68(s,6H),1.58-1.45(m,7H). LC-MS(M+H) + =475.3.

[0748] Example 116: (3S,4R)-4-((5-fluoro-4-(7-fluoro-3-(2-hydroxypropan-2-yl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0749]

[0750] Step 1: Diethyl 2-(((4-chloro-3-fluorophenyl)amino)methylene)malonate

[0751]

[0752] The title compound (26.4 g, 81%) was prepared from 4-chloro-3-fluoroaniline and diethyl 2-(ethoxymethylene)malonate in a manner analogous to Example 51, Step 1. LC-MS (M+H)+ = 316.2.

[0753] Step 2: Ethyl 6-chloro-7-fluoro-4-hydroxyquinoline-3-carboxylate

[0754]

[0755] A mixture of the title compound and ethyl 6-chloro-5-fluoro-4-hydroxyquinoline-3-carboxylate (9.5 g, 43%) was prepared from diethyl 2-(((4-chloro-3-fluorophenyl)amino)methylene)malonate in a manner analogous to Example 51, Step 2. LC-MS (M+H) = 270.1.

[0756] Step 3: Ethyl 4,6-dichloro-7-fluoroquinoline-3-carboxylate and ethyl 4,6-dichloro-5-fluoroquinoline-3-carboxylate

[0757]

[0758] The title compound (5.5 g, 84%) was prepared from a mixture of ethyl 6-chloro-7-fluoro-4-hydroxyquinoline-3-carboxylate and ethyl 6-chloro-5-fluoro-4-hydroxyquinoline-3-carboxylate in a manner similar to that described in Example 51, Step 3. LC-MS (M+H)+ = 288.1.

[0759] Step 4: Ethyl 6-chloro-7-fluoro-4-isopropylquinoline-3-carboxylate

[0760]

[0761] The title compound (2.2 g, 66%) was prepared from ethyl 4,6-dichloro-7-fluoroquinoline-3-carboxylate in a manner analogous to Example 1, Step 1. LC-MS (M+H)+ = 296.3.

[0762] Step 5: 7-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl Quinoline-3-carboxylate

[0763]

[0764] The title compound (1.9 g, crude, used in the next step) was prepared from ethyl 6-chloro-7-fluoro-4-isopropylquinoline-3-carboxylate in a manner similar to Example 1, Step 2. LC-MS (M+H)+ = 306.3 for the corresponding boronic acid.

[0765] Step 6: Ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-7-fluoro-4-isopropylquinoline-3-carboxylate

[0766]

[0767] The title compound (1.5 g, 52% over 2 steps) was prepared from ethyl 7-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate and 2,4-dichloro-5-fluoropyrimidine in a manner analogous to Example 1, Step 3. LC-MS (M+H) = 392.1.

[0768] Step 7: Ethyl 7-fluoro-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidine- 4-Isopropylquinoline-3-carboxylate

[0769]

[0770] The title compound (1.1 g, 61%) was prepared from ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-7-fluoro-4-isopropylquinoline-3-carboxylate and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol in a manner analogous to Example 4, Step 6. LC-MS (M+H) = 473.4.

[0771] Step 8: (3S,4R)-4-((5-fluoro-4-(7-fluoro-3-(2-hydroxypropan-2-yl)-4-isopropylquinolin-6-yl)pyrimidine (2-pyridin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0772] The title compound (9 mg, 5%) was prepared in a manner analogous to Example 70, Step 10, from ethyl 7-fluoro-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate and methyllithium. 1H-NMR (400MHz, DMSO-d6) δ9.09(s,1H),8.74(s,1H),8.51(s,1H),7.87(d,J=11.1Hz,1H),7.36(d,J=7.3Hz,1H),5.45(s,1H),4.96(s,1H ),4.76–4.47(m,1H),3.95–3.75(m,3H),3.54(s,1H),3.27–3.18(m,1H),3.01–3.00(m,1H),2.02(s,1H),1.69(s,6H),1.56–1.49(m,7H). LC-MS(M+H)+=459.5.

[0773] Example 117: (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0774]

[0775] Step 1: 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-isopropylquinolin-3-yl)propan-2-ol

[0776]

[0777] The title compound (50 mg, 48%) was prepared in a manner similar to that described in Example 1, Step 3, from 2-(8-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-2-ol and 2,4,5-trichloropyrimidine. LC-MS (M+H) + =394.1.

[0778] Step 2: (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)-4-isopropylquinolin-6-yl)pyrimidine (2-pyridin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0779] The title compound (17 mg, 40%) was prepared in a manner similar to Example 4, Step 6, from 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-isopropylquinolin-3-yl)propan-2-ol and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol. 1H-NMR(400MHz,DMSO-d6)δ:9.13(s,1H),8.71(br,1H),8.48(s,1H),7.93( br,1H),7.57(d,J=8.0Hz,1H),5.50(s.1H),4.96(s,1H),4.75-4.55(m,1H) ,3.95-3.80(m,3H),3.55-3.45(m,1H),3.25–3.35(m,1H),3.10-2.95(m,1H ), 2.05-1.90 (m, 1H), 1.70 (s, 6H), 1.56 (d, J = 8.0Hz, 6H), 1.60-1.45 (m, 1H). LC-MS(M+H) + =475.1.

[0780] Example 117 can be obtained by the following procedure:

[0781] Step 1: Diethyl 2-(((4-chloro-2-fluorophenyl)amino)methylene)malonate

[0782]

[0783] A solution of 4-chloro-2-fluoroaniline (25 g, 171.2 mmol) and diethyl 2-(ethoxymethylene) malonate (55 g) was stirred at 110° C. for 4 h. After cooling to room temperature, the reaction mixture was treated with petroleum ether (600 mL). The precipitate was filtered and dried to give the title compound (43.9 g, 81%). 1 H-NMR (400MHz, DMSO-d6) δ10.87(d,J=13.3Hz,1H),8.44(d,J=13.4Hz,1H),7.72-7.67(m,1H),7.60(d, J=10.9Hz,1H),7.33(d,J=8.7Hz,1H),4.22(q,J=6.9Hz,2H),4.14(q,J=6.9Hz,2H),1.33–1.19(m,6H). LC-MS(M+H) + =316.2.

[0784] Step 2: Ethyl 6-chloro-8-fluoro-4-hydroxyquinoline-3-carboxylate

[0785]

[0786] The reaction mixture of diethyl 2-(((4-chloro-2-fluorophenyl)amino)methylene)malonate (34.6 g, 109.5 mmol) and diphenyl ether (50 mL) was stirred at 260 ° C for 9 h. After cooling to room temperature, the mixture was treated with petroleum ether (600 mL). The precipitate was filtered and dried to give the title product (43.9 g, 81%). 1 H-NMR (400MHz, DMSO-d6) δ12.65 (s, 1H), 8.39 (s, 1H), 7.91 (d, J = 9.8Hz, 2H), 4.23 (q, J = 6.8Hz, 2H), 1.28 (t, J = 7.0Hz, 3H). LC-MS(M+H) + =270.1.

[0787] Step 3: Ethyl 4-bromo-6-chloro-8-fluoroquinoline-3-carboxylate

[0788]

[0789] To a solution of ethyl 6-chloro-8-fluoro-4-hydroxyquinoline-3-formate (5.5g, 20.4mmol) in dimethylformamide (80mL) was added phosphorus tribromide (11g, 40.8mmol), and the mixture was stirred at 80°C for 4h. The mixture was cooled to room temperature and poured into ice water. The precipitate was filtered and dissolved in ethyl acetate. The mixture was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (eluted with ethyl acetate (16%, v / v) in petroleum ether) to obtain the title compound (5.2g, 76%). 1 H-NMR (400MHz, DMSO-d6) δ9.09 (s, 1H), 8.15 (s, 1H), 8.10 (d, J = 10.0Hz, 1H), 4.46 (q, J = 7.0Hz, 2H), 1.39 (t, J = 7.0Hz, 3H). LC-MS(M+H) + =332.0, 334.0.

[0790] Step 4: 2-(4-bromo-6-chloro-8-fluoroquinolin-3-yl)propan-2-ol

[0791]

[0792] To a solution of ethyl 4-bromo-6-chloro-8-fluoroquinoline-3-carboxylate (333 mg, 1 mmol) in tetrahydrofuran (8 mL) was added methylmagnesium bromide (3 mL, 3 mmol, 1 M in tetrahydrofuran) at -78 ° C under nitrogen, and the mixture was slowly warmed to 0 ° C over 2 h and then quenched by saturated aqueous ammonium chloride solution. The aqueous layer was extracted 3 times 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 (eluted with ethyl acetate (33%, v / v) in petroleum ether) to give the title compound (240 mg, 75%). LC-MS (M+H) = 318.0, 320.0.

[0793] Step 5: 2-(6-chloro-8-fluoro-4-isopropylquinolin-3-yl)propan-2-ol

[0794]

[0795] To an isopropylmagnesium bromide solution (3 mL, 1 M in tetrahydrofuran, 3 mmol) under nitrogen was added zinc chloride (3 mL, 1 M in tetrahydrofuran, 3 mmol), and the mixture was stirred at 50°C for 2 h. 2-(4-bromo-6-chloro-8-fluoroquinolin-3-yl)propan-2-ol (240 mg, 0.75 mmol), CuI (14 mg, 0.075 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (28 mg, 0.038 mmol) in N,N-dimethylformamide (10 mL) were then added. The reaction mixture was stirred at 50°C for 2 h and then cooled to room temperature. The reaction was quenched with methanol (10 mL), and the solvent was concentrated. The residue was diluted with ethyl acetate, and the organic solution was washed with water and saturated aqueous ammonium chloride. The aqueous phase was extracted three times with ethyl acetate. The organic layers were combined, washed with water and brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by column chromatography eluting with ethyl acetate in petroleum ether (50%, v / v) to give the title compound (75 mg, 35%). LC-MS (M+H)+ = 282.2.

[0796] Step 6: 2-(8-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinol (3-Methyl-1-piperidin-2-yl)propan-2-ol

[0797]

[0798] A mixture of 2-(6-chloro-8-fluoro-4-isopropylquinolin-3-yl)propan-2-ol (75 mg, 0.265 mmol) and bis(pinacolato)diboron (94 mg, 0.37 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (9 mg, 0.013 mmol) and potassium acetate (39 mg, 0.4 mmol) in 1,4-dioxane (2.5 mL) was stirred at 80° C. under nitrogen overnight and then cooled to room temperature. The mixture was filtered and the filtrate was evaporated to give the title compound (99 mg, 100%). LC-MS (M+H) = 292.2 for the corresponding boronic acid.

[0799] Step 7: 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-isopropylquinolin-3-yl)propan-2-ol

[0800]

[0801] A mixture of 2-(8-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-2-ol (99 mg, 0.264 mmol), 2,4,5-trichloropyrimidine (97 mg, 0.53 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (19 mg, 0.026 mmol) and potassium carbonate (0.14 g, 1 mmol) in 1,4-dioxane (4 mL) and water (0.5 mL) was stirred at 80 ° C. under nitrogen overnight and then cooled to room temperature. The mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica gel (eluted with methanol (3%, v / v) in dichloromethane) to give the title compound (50 mg, 48%). LC-MS (M+H) + =394.1.

[0802] Step 8: (3S,4R)-4-((5-chloro-4-(8-fluoro-3-(2-hydroxypropan-2-yl)-4-isopropylquinolin-6-yl)pyrimidine (2-pyridin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0803]

[0804] 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-isopropylquinolin-3-yl)propan-2-ol (35 mg, 0.089 mmol) and N,N-diisopropylethylamine (35 mg, 0.27 mmol) were dissolved in acetonitrile (1 mL). (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol (20 mg, 0.17 mmol) was added, and the mixture was stirred at 80 ° C for 36 h and then cooled to room temperature. The solvent was removed under vacuum and water (2 mL) was added. The aqueous layer was extracted with ethyl acetate (3 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography on silica gel to give the title product (17 mg, 40%). 1H-NMR(400MHz,DMSO-d6)δ:9.13(s,1H),8.71(br,1H),8.48(s,1H),7.93( br,1H),7.57(d,J=8.0Hz,1H),5.50(s.1H),4.96(s,1H),4.75-4.55(m,1H) ,3.95-3.80(m,3H),3.55-3.45(m,1H),3.25–3.35(m,1H),3.10-2.95(m,1H ), 2.05-1.90 (m, 1H), 1.70 (s, 6H), 1.56 (d, J = 8.0Hz, 6H), 1.60-1.45 (m, 1H). LC-MS(M+H) + =475.1.

[0805] Example 120: (3S,4R)-4-((5-fluoro-4-(3-(hydroxymethyl)-4-isopropyl-5-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0806]

[0807] Step 1: 4-Chloro-2-iodo-5-methylaniline

[0808]

[0809] 4-Chloro-3-methylaniline (12.7 g, 89.69 mmol) was dissolved in acetic acid (150 mL). N-iodosuccinimide (20.2 g, 89.69 mmol) was added at 0 ° C, and the reaction solution was stirred at room temperature for 14 h. Acetic acid was removed by reduced pressure, and then water (50 mL) and ethyl acetate (200 mL) were added. Saturated sodium bicarbonate aqueous solution was added until pH = 8. The aqueous layer was separated from the organic layer and then extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound (23.35 g, 97%). LC-MS (M+H) + =268.0.

[0810] Step 2: Ethyl 6-chloro-4-hydroxy-8-iodo-5-methylquinoline-3-carboxylate

[0811]

[0812] A mixture of 4-chloro-2-iodo-5-methylaniline (14.35 g, 53.65 mmol) and diethyl 2-(ethoxymethylene) malonate (12.2 g, 56.33 mmol) was stirred at 120° C. for 4 h. Diphenyl ether (60 mL) was added, and the resulting mixture was heated to 260° C. for 3 h, then cooled to 60° C., ethyl acetate (100 mL) was added, and the resulting slurry was stirred at room temperature for 2 h. The title compound (10.5 g, 50%) was obtained by filtration. LC-MS (M+H) + =392.0.

[0813] Step 3: Ethyl 6-chloro-4-hydroxy-5-methylquinoline-3-carboxylate

[0814]

[0815] A solution of ethyl 6-chloro-4-hydroxy-8-iodo-5-methylquinoline-3-carboxylate (1.76 g, 4.49 mmol), sodium formate (1.53 g, 22.47 mmol) and tetrakis(triphenylphosphine)palladium(0) (259.7 mg, 0.2247 mmol) in N,N-dimethylformamide (20 mL) was stirred at 120 ° C. for 1 h under a nitrogen atmosphere, then cooled to room temperature, and then water (50 mL) was added. The precipitate was filtered and washed with water and ethyl acetate to give the title compound (1.224 g, 100%). LC-MS (M+H) + =266.0.

[0816] Step 4: Ethyl 4,6-dichloro-5-methylquinoline-3-carboxylate

[0817]

[0818] Ethyl 6-chloro-4-hydroxy-5-methylquinoline-3-carboxylate (1.224 g, 4.61 mmol) was dissolved in anhydrous dichloromethane (20 mL) and N,N-dimethylformamide (0.1 mL). Oxalyl chloride (643.2 mg, 5.07 mmol) was added dropwise at 35 ° C, and the reaction solution was stirred at 40 ° C overnight and then cooled to 0 ° C. Saturated sodium bicarbonate solution was added until pH = 8, and the aqueous layer was separated from the organic layer. The aqueous layer was extracted 3 times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound (1.31 g, 100%). LC-MS (M+H) + =284.0.

[0819] Step 5: Ethyl 6-chloro-4-isopropyl-5-methylquinoline-3-carboxylate

[0820]

[0821] Zinc chloride in tetrahydrofuran (1N, 6.92 mL, 6.92 mmol) was added to a solution of isopropylmagnesium chloride in tetrahydrofuran (6.92 mL, 1N, 6.92 mmol) at 0°C, and the reaction mixture was heated to 50°C for 1 hour under nitrogen, then cooled to 0°C. Ethyl 4,6-dichloro-5-methylquinoline-3-carboxylate (1.31 g, 4.61 mmol), CuI (87.8 mg, 0.461 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (168.7 mg, 0.231 mmol) were added, and the resulting mixture was heated to 50°C for 2 hours under nitrogen, then cooled to 0°C. Saturated ammonium chloride solution (20 mL) was added, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound (1.35 g, 100%). LC-MS (M+H) + =292.0.

[0822] Step 6: 6-Chloro-4-isopropyl-5-methylquinoline-3-carboxylic acid

[0823]

[0824] To a solution of ethyl 6-chloro-4-isopropyl-5-methylquinoline-3-carboxylate (200 mg, 0.686 mmol) in methanol (3 mL) was added potassium hydroxide solution (2N, 1.02 mL, 2.04 mmol). The resulting mixture was stirred at 60 ° C overnight, then cooled to room temperature and concentrated. Water (2 mL) was added and 2N HCl solution was added until pH = 6. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound (180 mg, 99.6%). LC-MS (M+H) + =264.0.

[0825] Step 7: (6-Chloro-4-isopropyl-5-methylquinolin-3-yl)(1H-imidazol-1-yl)methanone

[0826]

[0827] To a solution of 6-chloro-4-isopropyl-5-methylquinoline-3-carboxylic acid (60 mg, 0.228 mmol) in tetrahydrofuran was added carbonyldiimidazole (73.81 mg, 0.455 mmol), and the reaction mixture was stirred at room temperature overnight, and then water was added at 0°C. The aqueous layer was extracted three times with ethyl acetate. The combined layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound (71.4 mg, 100%). LC-MS (M+H) + =314.0.

[0828] Step 8: (6-Chloro-4-isopropyl-5-methylquinolin-3-yl)methanol

[0829]

[0830] To a solution of (6-chloro-4-isopropyl-5-methylquinolin-3-yl)(1H-imidazol-1-yl)methanone (71.4 mg, 0.228 mmol) in tetrahydrofuran was added lithium aluminum hydride (9.5 mg, 0.250 mmol) at 0°C, and the reaction mixture was stirred at 0°C for 1 h and then at room temperature overnight. Sodium sulfate decahydrate was added to the reaction mixture at 0°C, and the mixture was stirred for 30 min and then ethyl acetate was added. The mixture was stirred at room temperature for another 1 h and then filtered. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel to give the title compound (25.6 mg, 45%). LC-MS (M+H) + =250.0.

[0831] Step 9: 3-(((tert-Butyldimethylsilyl)oxy)methyl)-6-chloro-4-isopropyl-5-methylquinoline

[0832]

[0833] To a solution of (6-chloro-4-isopropyl-5-methylquinolin-3-yl)methanol (184 mg, 0.737 mmol) and 1H-imidazole (88.53 mg, 1.474 mmol) in dichloromethane was added tert-butyldimethylsilyl chloride (166.6 mg, 1.105 mmol) at 0° C., and the reaction solution was stirred at room temperature overnight, and then water was added. The aqueous layer was extracted 3 times with dichloromethane. The combined layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound (212 mg, 79%). LC-MS (M+H) + =364.0.

[0834] Step 10: 3-(((tert-Butyldimethylsilyl)oxy)methyl)-6-(2-chloro-5-fluoropyrimidin-4-yl)-4- Isopropyl-5-methylquinoline

[0835]

[0836] A mixture of 3-(((tert-butyldimethylsilyl)oxy)methyl)-6-chloro-4-isopropyl-5-methylquinoline (212 mg, 0.583 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (295.8 mg, 1.165 mmol), potassium acetate (171.5 mg, 1.75 mmol) and dichlorobis(tricyclohexylphosphine)palladium (43 mg, 0.0583 mmol) in anhydrous 1,4-dioxane (10 mL) was stirred at 110° C. under nitrogen overnight and then cooled to room temperature. Potassium carbonate (241 mg, 1.75 mmol), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (42.6 mg, 0.0582 mmol) and 2,4-dichloro-5-fluoropyrimidine (291.8 mg, 1.75 mmol) in water (3 mL) were added, and the mixture was heated to 70 ° C. for 2 h, then cooled to room temperature and concentrated. Water (2 mL) was added, and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound (88 mg, 32.8%). LC-MS (M+H) + =460.0.

[0837] Step 11: (3S,4R)-4-((4-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-isopropyl- 5-(5-Methylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0838]

[0839] The title compound (103 mg, 100%) was prepared in a manner similar to that described in Example 1, Step 4, from 3-(((tert-butyldimethylsilyl)oxy)methyl)-6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyl-5-methylquinoline and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride. LC-MS (M+H) + =541.2.

[0840] Step 12: (3S,4R)-4-((5-fluoro-4-(3-(hydroxymethyl)-4-isopropyl-5-methylquinolin-6-yl)pyrimidine (2-pyridin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0841] To a solution of (3S,4R)-4-((4-(3-(((tert-butyldimethylsilyl)oxy)methyl)-4-isopropyl-5-methylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (103.43 mg, 0.191 mmol) in tetrahydrofuran (1 mL) was added tetrabutylammonium fluoride in tetrahydrofuran (1 N, 0.57 mL, 0.57 mmol), and the reaction solution was stirred at room temperature for 2 h, then water (5 mL) was added. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC to give the title compound (46 mg, 56%). 1 H-NMR (400MHz, DMSO-d6) δ8.90(s,1H),8.48(s,1H),7.87(d,J=8.5Hz,1H),7.60(d,J =8.6Hz,1H),7.29(d,J=7.5Hz,1H),5.45(t,J=5.4Hz,1H),4.94(s,1H),4.90(s,2H),4 .10–3.95(m,1H),3.85–3.70(m,3H),3.55–3.40(m,1H),3.30(s,1H),3.04(t,J=10.3H z,1H),2.64(s,3H),1.98(d,J=10.8Hz,1H),1.55–1.35(m,1H),1.43(d,J=6.4Hz,6H). LC-MS(M+H)+=427.0.

[0842] Example 145: (3S,4R)-4-((4-(3-(aminomethyl)-4-isopropyl-5-methylquinolin-6-yl)-5-fluoropyrimidine (2-pyridin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0843]

[0844] Step 1: (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropyl-5-methylquinolin-6-yl)-5-fluoropyrimidine-2-yl) 1-[4-(2-amino-3-methyl)tetrahydro-2H-pyran-3-ol]

[0845]

[0846] To (3S,4R)-4-((5-fluoro-4-(3-(hydroxymethyl)-4-isopropyl-5-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (349 mg, 0.818 mmol) in dichloromethane (20 mL) was added thionyl chloride (116.8 mg, 0.982 mmol) at 0°C, and the reaction mixture was stirred at room temperature for 3 h. Saturated sodium bicarbonate solution was added until pH = 8, and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The title compound (364 mg, 100%) was obtained. LC-MS (M+H) + =445.0.

[0847] Step 2: (3S,4R)-4-((4-(3-(aminomethyl)-4-isopropyl-5-methylquinolin-6-yl)-5-fluoropyrimidine- 2-amino)tetrahydro-2H-pyran-3-ol

[0848] A solution of (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropyl-5-methylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (24 mg, 0.054 mmol) and 7N ammonia in methanol (5 mL) was stirred in a sealed tube at 50 °C overnight, then cooled to room temperature and concentrated. The residue was purified by preparative HPLC to give the title compound (6 mg, 25%). 1 H-NMR(400MHz,DMSO-d6)δ8.92(s,1H),8.47(d,J=1.7Hz,1H),8.26(s,1H),7.8 7(d,J=8.5Hz,1H),7.60(d,J=8.5Hz,1H),7.30(d,J=7.7Hz,1H),5.75-4.25(br s,2H),4.19(s,2H),4.05–3.90(m,1H),3.85–3.70(m,3H),3.55–3.45(m,1H),3.32(t,J=11.2Hz,1H),3.04(t,J=1 0.4Hz,1H),2.62(s,3H),1.98(d,J=10.6Hz,1H),1.57–1.31(m,1H),1.44(d,J=8.0Hz,3H),1.44(d,J=8.0Hz,3H). LC-MS(M+H) + =426.0.

[0849] Example 206: (3S,4R)-4-((5-Fluoro-4-(2-(2-hydroxypropan-2-yl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0850]

[0851] Step 1: Dimethyl 2-((4-chlorophenyl)amino)fumarate

[0852]

[0853] To a solution of 4-chloroaniline (3.0 g, 23.5 mmol) in ethanol (40 mL) was added dimethylbut-2-ynedioate (3.4 g, 23.5 mmol). The mixture was stirred at room temperature for 15 h and then concentrated under vacuum. The title compound (6.5 g, crude product) was obtained. LC-MS (M+H) + =270.1.

[0854] Step 2: Methyl 6-chloro-4-oxo-1,4-dihydroquinoline-2-carboxylate

[0855]

[0856] A mixture of dimethyl 2-((4-chlorophenyl)amino)fumarate (5.5 g, 20 mmol) and polyphosphoric acid (30 mL) was stirred at 100°C for 1 h and then cooled to room temperature. The mixture was diluted with water (300 mL) at 0°C and stirred for 1 h. The precipitate was collected by filtration and dried under vacuum to give the title compound (3.0 g, 63%). LC-MS (M+H) + =238.1.

[0857] Step 3: Methyl 4,6-dichloroquinoline-2-carboxylate

[0858]

[0859] A mixture of methyl 6-chloro-4-oxo-1,4-dihydroquinoline-2-carboxylate (3.0 g, 12.6 mmol) and phosphorus oxychloride (30 mL) was stirred at 100 ° C for 8 h. The mixture was cooled to room temperature and poured into ice water (200 mL). The mixture was then stirred for 1 h and then filtered. The precipitate was dried under vacuum to give the title compound (2.4 g, 74%). LC-MS (M+H) + =256.1.

[0860] Step 4: Methyl 6-chloro-4-(prop-1-en-2-yl)quinoline-2-carboxylate

[0861]

[0862] The title compound (1.5 g, 73%) was prepared in a similar manner to Example 1, Step 3, from methyl 4,6-dichloroquinoline-2-carboxylate (2.0 g, 7.8 mmol) and potassium isopropenyltrifluoroborate. LC-MS (M+H) +=262.2.

[0863] Step 5: Methyl 4-(prop-1-en-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-carboxylate

[0864]

[0865] The title compound (1.2 g, 59%) was prepared in a manner similar to that described in Example 1, Step 2, from methyl 6-chloro-4-(prop-1-en-2-yl)quinoline-2-carboxylate and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane). LC-MS (M+H) + =354.2.

[0866] Step 6: Methyl 4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-carboxylate

[0867]

[0868] To a solution of methyl 4-(prop-1-en-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-carboxylate (1.0 g, 3.8 mmol) in methanol (30 mL) was added 10% palladium on carbon (100 mg). The mixture was stirred under a hydrogen atmosphere (1 atm) overnight. The mixture was filtered and concentrated to give the title compound (900 mg, 90%). LC-MS (M+H) + =356.2.

[0869] Step 7: Methyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinoline-2-carboxylate

[0870]

[0871] The title compound (500 mg, 52%) was prepared in a similar manner to Example 1, Step 3, from methyl 4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-carboxylate and 2,4-dichloro-5-fluoropyrimidine. LC-MS (M+H) + =360.1.

[0872] Step 8: Methyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-2-carboxylate

[0873]

[0874] The title compound (200 mg, 32%) was prepared in a similar manner to Example 1, Step 4, from methyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinoline-2-carboxylate and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol. LC-MS (M+H) + =441.2.

[0875] Step 9: (3S,4R)-4-((5-fluoro-4-(2-(2-hydroxypropan-2-yl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0876] To a solution of methyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-2-carboxylate (100 mg, 0.23 mmol) in tetrahydrofuran (5 mL) was added dropwise a solution of methylmagnesium iodide (3 M in tetrahydrofuran, 0.4 mL, 1.2 mmol) at -78 ° C. The mixture was stirred at -78 ° C for 1 h. The mixture was diluted with water (10 ml) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by TLC (eluting with methanol (5%, v / v) in dichloromethane) to give the title compound (10 mg, 10%). 1 H-NMR (400MHz, DMSO-d6) δ8.84(s,1H),8.49(d,J=3.7Hz,1H),8.28(d,J=8.8Hz,1 H),8.10(d,J=8.8Hz,1H),7.87(s,1H),7.28(d,J=7.4Hz,1H),5.49(s,1H),4.97( d,J=5.2Hz,1H),3.92–3.73(m,4H),3.59–3.49(m,1H),3.41–3.30(m,1H),3.11–3 .02(m,1H),2.10–1.98(m,1H),1.55(s,6H),1.62–1.46(m,1H),1.45–1.38(m,6H). LC-MS(M+H) + =441.6.

[0877] Example 207: (3S,4R)-4-((5-Fluoro-4-(2-(2-hydroxypropan-2-yl)-4-isopropylquinazolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0878]

[0879] Step 1: Ethyl 2-((2-carbamoyl-4-chlorophenyl)amino)-2-oxoacetate

[0880]

[0881] To a solution of 2-amino-5-chlorobenzamide (10 g, 58.6 mmol) and triethylamine (18 g, 178 mmol) in tetrahydrofuran (170 mL) was added dropwise a solution of ethyl 2-chloro-2-oxoacetate (10 g, 73.3 mmol) in tetrahydrofuran (30 mL) at 0°C. The mixture was stirred at 0°C for 1 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (3×300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to give the title compound (15 g, 93%). LC-MS (M+H) + =271.2.

[0882] Step 2: Methyl 6-chloro-4-oxo-1,4-dihydroquinazoline-2-carboxylate

[0883]

[0884] To a solution of ethyl 2-((2-carbamoyl-4-chlorophenyl)amino)-2-oxoacetate (15 g, 55 mmol) in methanol (500 mL) was added sodium ethoxide (15 g, 221 mmol). The mixture was stirred at room temperature for 15 h, and then the solvent was removed under vacuum. The residue was treated with hydrochloride solution (1 M, 500 mL), and the mixture was stirred at room temperature for 30 min. The precipitate was collected by filtration, washed with water (200 mL) and dried under vacuum at 50 ° C for 2 h to give the title compound (10 g, 72%). LC-MS (M+H) + =239.2.

[0885] Step 3: Methyl 4,6-dichloroquinazoline-2-carboxylate

[0886]

[0887] The title compound (500 mg, 46%) was prepared in a similar manner to Example 206, Step 3, from methyl 6-chloro-4-oxo-1,4-dihydroquinazoline-2-carboxylate. LC-MS (M+H) + =257.2.

[0888] Step 4: Methyl 6-chloro-4-(prop-1-en-2-yl)quinazoline-2-carboxylate

[0889]

[0890] The title compound (2.0 g, 46%) was prepared in a similar manner to Example 1, Step 3, from methyl 4,6-dichloroquinazoline-2-carboxylate and potassium isopropenyl trifluoroborate, potassium salt. LC-MS (M+H) + =263.2.

[0891] Step 5: Methyl 4-(prop-1-en-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline-2-carboxylate

[0892]

[0893] The title compound (1.2 g, 59%) was prepared in a manner similar to that described in Example 1, Step 2, from methyl 6-chloro-4-(prop-1-en-2-yl)quinazoline-2-carboxylate and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane). LC-MS (M+H) + =355.2.

[0894] Step 6: Methyl 4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline-2-carboxylate

[0895]

[0896] The title compound (1.0 g, 90%) was prepared from methyl 4-(prop-1-en-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline-2-carboxylate in a manner similar to that described in Example 206, Step 6. LC-MS (M+H) + =357.2.

[0897] Step 7: Methyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinazoline-2-carboxylate

[0898]

[0899] The title compound (600 mg, 59%) was prepared in a similar manner to Example 1, Step 3, from methyl 4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline-2-carboxylate and 2,4-dichloro-5-fluoropyrimidine. LC-MS (M+H) + =361.2.

[0900] Step 8: Methyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinazoline-2-carboxylate

[0901]

[0902] The title compound (350 mg, 46%) was prepared in a similar manner to Example 1, Step 4, from methyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinazoline-2-carboxylate and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol. LC-MS (M+H) + =442.2.

[0903] Step 9: (3S,4R)-4-((5-fluoro-4-(2-(2-hydroxypropan-2-yl)-4-isopropylquinazolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0904] The title compound (10 mg, 10%) was prepared in a manner analogous to Example 206, Step 9, from methyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinazoline-2-carboxylate and methylmagnesium iodide. 1 H-NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.57–8.46(m,2H),8.15(d,J=8.8Hz,1 H),7.34(d,J=7.6Hz,1H),5.16(s,1H),4.96(d,J=5.2Hz,1H),4.10–4.00(m,1H ),3.89–3.79(m,3H),3.58–3.48(m,1H),3.36(t,J=10.3Hz,1H),3.07(t,J=10 .3Hz,1H),2.02(s,1H),1.60(s,6H),1.64–1.45(m,1H),1.41(d,J=6.7Hz,6H). LC-MS(M+H) + =442.5.

[0905] Example 208: (3S,4R)-4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0906]

[0907] Step 1: Dimethyl 2-((4-chloro-2-fluorophenyl)amino)fumarate

[0908]

[0909] The title compound (10.5 g, 52%) was prepared in a similar manner to Example 206, Step 1, from 4-chloro-2-fluoroaniline and dimethylacetylene dicarboxylate. LC-MS (M+H) + =288.0.

[0910] Step 2: Methyl 6-chloro-8-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylate

[0911]

[0912] The title compound (3.5 g, 87%) was prepared in a similar manner to Example 206, Step 2, from dimethyl 2-((4-chloro-2-fluorophenyl)amino)fumarate. LC-MS (M+H) + =256.2.

[0913] Step 3: Methyl 4-bromo-6-chloro-8-fluoroquinoline-2-carboxylate

[0914]

[0915] The title compound (2.38 g, 63%) was prepared in a similar manner to Example 206, Step 3, from methyl 6-chloro-8-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylate and phosphorus tribromide. LC-MS (M+H) + =318.0.

[0916] Step 4: Methyl 6-chloro-8-fluoro-4-isopropylquinoline-2-carboxylate

[0917]

[0918] The title compound (270 mg, 30%) was prepared in a similar manner to that in Example 1, Step 1, from methyl 4-bromo-6-chloro-8-fluoroquinoline-2-carboxylate. LC-MS (M+H) + =282.2.

[0919] Step 5: 2-(6-chloro-8-fluoro-4-isopropylquinolin-2-yl)propan-2-ol

[0920]

[0921] The title compound (45 mg, 26%) was prepared from methyl 6-chloro-8-fluoro-4-isopropylquinoline-2-carboxylate in a manner similar to that in Example 70, Step 10. LC-MS (M+H) + =282.0.

[0922] Step 6: 2-(8-Fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-yl)propan-2-ol

[0923]

[0924] The title compound (60 mg, 90%) was prepared from 2-(6-chloro-8-fluoro-4-isopropylquinolin-2-yl)propan-2-ol in a similar manner to that in Example 1, Step 2. LC-MS (M+H) + =374.1.

[0925] Step 7: 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-isopropylquinolin-2-yl)propan-2-ol

[0926]

[0927] The title compound (27 mg, 42%) was prepared in a manner similar to that in Step 3 of Example 1 from 2-(8-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-yl)propan-2-ol and 2,4,5-trichloropyrimidine. LC-MS (M+H) + =394.0.

[0928] Step 8: (3S,4R)-4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0929] The title compound (16 mg, 44%) was prepared in a manner similar to Example 4, Step 6, from 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-isopropylquinolin-2-yl)propan-2-ol and (3S,4R)-4-aminooxan-3-ol hydrochloride. 1 H-NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.50-8.37(m,1H),7.96(s,1H),7. 98-7.84(m,1H),7.60-7.56(m,1H),5.52(s,1H),4.94(d,J=5.4Hz,1H),3. 89-3.68(m,4H),3.53-3.49(m,1H),3.38-3.32(m,1H),3.09-2.99(m,1H), 1.99-1.95(m,1H),1.56(s,6H),1.58-1.48(m,1H),1.39(d,J=6.7Hz,6H). LC-MS(M+H)+ =475.1.

[0930] Example 209: (3S,4R)-4-((5-Fluoro-4-(2-(2-hydroxypropan-2-yl)-4-isopropylquinazolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0931]

[0932] Step 1: 2-Amino-5-chloro-3-fluorobenzamide

[0933]

[0934] The title compound (1.85 g, 81%) was prepared in a similar manner to Example 1, Step 6, from 2-amino-5-chloro-3-fluorobenzoic acid and ammonium chloride. LC-MS (M+H) + =189.0.

[0935] Step 2: Ethyl 6-chloro-8-fluoro-4-hydroxyquinazoline-2-carboxylate

[0936]

[0937] To a solution of 2-amino-5-chloro-3-fluorobenzamide (1.57g, 8.38mmol) and diisopropylethylamine (1.72g, 12.64mmol) in tetrahydrofuran (30mL) was added dropwise ethyl chloroglyoxylate (1.275g, 9.32mmol) at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3h and then quenched by adding saturated sodium bicarbonate (30mL) at room temperature. The resulting mixture was stirred for 1h, and the organic layer was separated from the aqueous layer. The aqueous layer was extracted with ethyl acetate (80mL x 2). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluted with ethyl acetate (0% to 30% gradient, v / v) in petroleum ether) to produce the title compound (850mg, 37%). LC-MS (M+H) + =270.9.

[0938] Step 3: Ethyl 4-bromo-6-chloro-8-fluoroquinazoline-2-carboxylate

[0939]

[0940] The title compound (0.6 g, 67%) was prepared in a similar manner to Example 206, Step 3, from ethyl 6-chloro-8-fluoro-4-hydroxyquinazoline-2-carboxylate and phosphorus oxybromide. LC-MS (M+H) + =332.9.

[0941] Step 4: Ethyl 6-chloro-8-fluoro-4-isopropylquinazoline-2-carboxylate

[0942]

[0943] The title compound (120 mg, 22%) was prepared in a similar manner to Example 1, Step 1, from ethyl 4-bromo-6-chloro-8-fluoroquinazoline-2-carboxylate. LC-MS (M+H) + =297.1.

[0944] Step 5: 2-(6-chloro-8-fluoro-4-isopropylquinazolin-2-yl)propan-2-ol

[0945]

[0946] The title compound (70 mg, 61%) was prepared from ethyl 6-chloro-8-fluoro-4-isopropylquinazoline-2-carboxylate in a manner similar to that in Example 70, Step 10. LC-MS (M+H) + =283.0.

[0947] Step 6: 2-(8-Fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)propan-2-ol

[0948]

[0949] The title compound (100 mg, crude, used in the next step) was prepared in a similar manner to that in Example 1, Step 2, from 2-(6-chloro-8-fluoro-4-isopropylquinazolin-2-yl)propan-2-ol. LC-MS (M+H) + =375.2

[0950] Step 7: 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-isopropylquinazolin-2-yl)propan-2-ol

[0951]

[0952] The title compound (40 mg, 41% over 2 steps) was prepared in a manner similar to that in Step 3 of Example 1 from 2-(8-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-yl)propan-2-ol and 2,4,5-trichloropyrimidine. LC-MS (M+H) + =395.0

[0953] Step 8: (3S,4R)-4-((5-chloro-4-(8-fluoro-2-(2-hydroxypropan-2-yl)-4-isopropylquinazolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0954] The title compound (28 mg, 41%) was prepared in a manner similar to that in Example 4, Step 6, from 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-isopropylquinazolin-2-yl)propan-2-ol and (3S,4R)-4-aminooxan-3-ol hydrochloride. 1 H-NMR(400MHz,DMSO-d6)δ8.41(s,1H),7.95-7.90(m,1H),7.88-7.81(m,1H),7.53-7.47(m,1H),5.19(s,1H),4.91(d,J=5.5Hz,1H),3.89-3.7 5(m,3H),3.53-3.41(m,1H),3.39-3.28(m,1H),3.10-3.00(m,1H),2.97 -2.85(m,1H),1.96-1.89(m,1H),1.55-1.39(m,7H),1.19-1.13(m,6H). LC-MS(M+H) + =476.2.

[0955] Biological assays

[0956] In an assay based on time-resolved fluorescence resonance energy transfer (TR-FRET) methods, compounds disclosed herein were tested for inhibition of CDK4 / cyclin D1 or CDK6 / cyclin D3 kinases. The assay was performed in a 384-well small-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 pH 7.0, 0.02% NaN3, 0.01% BSA, 0.1 mM orthovanadate, 50 mM MgCl2, 1 mM DTT, and 0.005% Tween-20. The kinases were incubated with the compounds at room temperature for 60 minutes, and the reaction was initiated by adding ATP and Rb (Ser780) -biotin substrate. After 120 minutes of reaction 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 at room temperature for 60 minutes, and TR-FRET signals (ex337 nm, em665 nm / 620 nm) were recorded on a PHERAstar FSX microplate reader (BMG Labtech). The percent inhibition of CDK4 / cyclin D1 or CDK6 / cyclin D3 kinase activity was calculated based on the fluorescence ratio at 665 nm to 620 nm at increasing compound concentrations. The data were fitted to a four-parameter logistic equation using Dotmatics to derive the IC50 for each compound.

[0957] Table 1. Enzyme activity IC50 (nM) of the compounds disclosed herein

[0958]

[0959]

[0960]

[0961]

Claims

1. A compound having formula (I): 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, in: Partly R 1 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl or Part of it is -Me, -Et, R 4 It is methyl, ethyl, n-propyl, isopropyl, n-butyl, R 5 、R 6 、R 7 、R 8 and R 9 Each is 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, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -CN; and R 11 Selected from H, methyl, ethyl, propyl, butyl.

2. A compound or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analog, or its prodrug, wherein the compound is selected from 3. A pharmaceutical composition comprising the compound according to claim 1 or 2, or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analog, or its prodrug, and a pharmaceutically acceptable excipient.

4. Use of the compound according to claim 1 or 2, or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analog, or its prodrug in the preparation of a medicament for reducing CDK4 activity by inhibition.

5. Use of a compound according to claim 1 or 2, 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, in the preparation of a medicament for treating a disease or disorder in a patient, wherein the disease or disorder is associated with inhibition of CDK4.

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