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

Abstract

The present disclosure provides a compound containing a 6-(pyrimidin-4-yl)quinoline structure, its use for selectively inhibiting the activity of CDK4, and a pharmaceutical composition containing the compound for the treatment of various diseases including cancer.

Description

Technical Field

[0001] The present disclosure provides a compound comprising a 6-(pyrimidin-4-yl)quinoline structure, its use for selectively inhibiting the activity of cyclin-dependent kinase 4 (CDK4), and a pharmaceutical composition comprising the compound for the treatment of various diseases including cancer.

Background Art

[0002] Human kinases are a large group of enzymes that add phosphate groups (PO 4 3- ) to other molecules in the human body [1. FASEB J. 1995 May; 9(8): 576-96. 2. Enzyme Res. 2011; 2011: 794089.]. There are genes encoding more than 500 kinases present in the human genome and its 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.]. Dysregulation of kinases has been identified in many diseases, including cancer, autoimmunity, neuropathy, diabetes, and cardiovascular diseases. For example, mutant kinases can become constitutively active and thus cause various cellular abnormalities, leading to cancer initiation or proliferation. The use of small molecule inhibitors to inhibit kinase activity has proven to be a successful method 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.].

[0003] The protein kinase family occupies a large part of the kinase superfamily. Regarding protein targets, protein kinases can phosphorylate amino acids, including serine, threonine, tyrosine, and histidine. [7.Science.2002 Dec 6;298(5600):1912-34.] Protein kinases play a major role in the cell activation process through the reversible phosphorylation and dephosphorylation of proteins by the antagonism of kinases and phosphatases. Since the phosphorylated and non-phosphorylated states of target proteins can have different levels of activity, they are important components of cell signaling. [8.Biochimie.2014 Dec;107 Pt B:167-87.9.Clin Transl Oncol.2006 Mar;8(3):153-60.] Different protein kinases, including EGFR, BTK, ALK, JAK, PI3K, and CDK, have been proven to be good targets for anti-cancer drug development.

[0004] An over-activated cell cycle is a common feature of human cancers [10. Nat Rev Cancer. 2009 Mar;9(3):153-66.]. On the other hand, cyclin is one of the most important core cell cycle regulators. In humans, four basic cyclin types have been found, including G1 cyclin, G1 / S cyclin, S cyclin, and M cyclin. To advance the cell cycle, cyclin must activate or inactivate many target proteins inside the cell. And these cyclins drive cell cycle events mainly by partnering with a family of enzymes called cyclin-dependent kinases (CDKs). The CDK kinase itself is inactive, but its binding to cyclin activates it, making the CDK / cyclin complex a functional holoenzyme that can modify target proteins [11. Orphanet J Rare Dis. 2020 Aug 6;15(1):203. 12. J Mol Biol. 1999 Apr 16;287(5):821-8.]. There are 26 serine / threonine protein kinases that form the CDK and CDK-like branches of the CMGC subfamily of the human kinome, 21 of which are classified as CDKs. Among all currently identified CDKs, CDK1, CDK2, CDK4, and CDK6 are regarded as direct modulators of the cell cycle mainly by phosphorylating and inactivating the retinoblastoma protein and releasing the E2F transcription factor, and the E2F downstream pathway is important in regulating the initiation of DNA replication. And CDK4 / 6 is essential for early G1 onset and G1 / S transition. [13. Cell Death Differ. 1998 Feb;5(2):132-40. 14. Oncogene. 2016 Sep 15;35(37):4829-35.]

[0005] The CDK4 / 6-related pathway is generally dysregulated in many different cancer types such as breast cancer, lung cancer, and pancreatic cancer. And there are four approved CDK4 / 6 inhibitors, including palbociclib, ribociclib, abemaciclib, and trilaciclib, which are approved by the FDA or CDE to be used either as monotherapy or in combination with endocrine therapy for the treatment of HR+, Her2-breast cancer. This approach shows good efficacy in the clinic, while hematotoxicities such as neutropenia and leukopenia can limit the clinical application of CDK4 / 6 dual inhibitors. And new data show that inhibition of CDK6 / cyclin D3 can cause the hematotoxicity observed clinically [15.Cell.2004 Aug 20;118(4):493-504.16.Haematologica.2021 Oct 1;106(10):2624-2632.]. On the other hand, CDK4 / cyclin D1 is an oncogenic driver in different 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, alleviated hematological toxicity, and expanded clinical utilization in many cancers including but not limited to breast cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, liver cancer, and endometrial cancer.

Summary of the Invention

Problems to be Solved by the Invention

[0006] Therefore, there remains a great need to develop selective CDK4 inhibitors. Here, the inventors of the present invention have found selective CDK4 inhibitor compounds with high CDK4 selectivity that may lead to better efficacy, improved toxicity profiles, and the potential to overcome resistance mechanisms, among other things, over all other kinases including CDK6.

Means for Solving the Problems

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

[0008] Aspect 1. A compound of formula (I):

Chemical formula

Chemical formula

[0009] Aspect 2. The compound is selected from formula (IIa), (IIb), (IIc), (IId), or (IIe),

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0010] Embodiment 3. CyA is a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, and the ring contains, as ring members (plural possible), independently, 0, 1, or 2 heteroatoms (plural possible) selected from nitrogen, oxygen, or optionally oxidized sulfur, and the ring is optionally substituted with 0, 1, 2, 3, 4, or 5 R 10 and the ring is a saturated or unsaturated ring, preferably, CyA is a 3-, 4-, 5-, 6-, 7-, or 8-membered saturated ring, and the ring contains, as ring members (plural possible), independently, 0, 1, or 2 heteroatoms (plural possible) selected from nitrogen, oxygen, or optionally oxidized sulfur, and the ring is optionally substituted with 0, 1, 2, or 3 R 10 and more preferably, CyA is a 5-, 6-, or 7-membered saturated ring, and the ring contains, as ring members (plural possible), independently, 1 or 2 heteroatoms (plural possible) selected from nitrogen or oxygen, and the ring is optionally substituted with 0, 1, 2, or 3 R 10 and Even more preferably, CyA is a ring selected from tetrahydrofuranyl or tetrahydropyranyl, and the ring is optionally substituted with 0, 1, 2, or 3 R 10 in any one of the preceding embodiments.

[0011] Embodiment 4. The ring CyA is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0012] Embodiment 5. R 10 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, heterocyclyl, phenyl, heteroaryl, -CN, -OR 10a , -COR 10a , -CO 2 R 10a , -CONR 10a R 10b , -NR 10a R 10b , -NR 10a COR 10b , -NR 10a CO 2 R 10bor -NR 10a CONR 10b R 10c selected from, each of the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, the -C 2-8 alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl is optionally substituted with at least one substituent R 10d ; R 10a R 10b and R 10c are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl selected from, each of the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, the -C 2-8 alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl is optionally substituted with at least one substituent R 10f ; R 10d and R 10f are each independently hydrogen, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, halheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said -haloC 1-8 alkyl, said methoxy, said ethoxy, said propoxy, said butoxy, said pentoxy, said hexoxy, said heptoxy, said octoxy, said -C 2-8 alkenyl, said -C 2-8 alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, said halocycloalkyl, said heterocyclyl, said halheterocyclyl, said phenyl, said haloaryl, said heteroaryl, or said haloheteroaryl, each of which 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, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, halheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, optionally substituted with Preferably, R 10 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, heterocyclyl, phenyl, heteroaryl, -CN, -OH, or -NH 2 selected from More preferably, R10 The compound according to any one of the preceding aspects, wherein it is -OH.

[0013] Aspect 6.

Chem.

Chem.

[0014] Aspect 7. 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, -CN, -OR 1a , -COR 1a , -CO 2 R 1a , -CONR 1a R 1b , -NR 1a R 1b , -NR 1a COR 1b , -NR 1a CO 2 R 1b , or -NR 1a CONR 1b R 1c and each of the said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said -C 2-8 alkenyl, said -C 2-8 alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, said haloalkyl, or said heterocyclyl is optionally substituted with at least one substituent R 1d , R 1a , R 1b , and R1c is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl is optionally substituted with at least one substituent R 1f optionally substituted with R 1d and R 1f are independently selected from hydrogen, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, halheterocyclyl, phenyl, haloaryl, heteroaryl, or halheteroaryl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 alkyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptoxy, the octoxy, the -C 2-8 alkenyl, the -C 2-8Each of alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, said halocycloalkyl, said heterocyclyl, said halheterocyclyl, said phenyl, said haloaryl, said heteroaryl, or said haloheteroaryl has at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, halheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, optionally substituted with 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, More preferably, R 1 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, In another embodiment, R 1 is

Chemical formula

[0015] Aspect 8. R 2 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR 2a 、-SO 2 R 2a 、-SO 2 NR 2a R 2b 、-COR 2a 、-CO 2 R 2a 、-CONR 2a R 2b 、-NR 2a R 2b 、-NR 2a COR 2b 、-NR 2a CO 2 R 2b 、-NR 2a CONR 2b R 2c 、または-NR 2a SO 2 R 2b and is such that each of said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said -C 2-8 alkenyl, said -C 2-8 alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, said heterocyclyl, said phenyl, or said heteroaryl is optionally substituted with at least one substituent R 2d and R 2a 、R 2b 、and R 2c are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said -C 2-8 alkenyl, said -C 2-8 alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, said heterocyclyl, said phenyl, or said heteroaryl, each of which is optionally substituted with at least one substituent R 2f or, (R 2a and R 2b ), (R 2b and R 2c ), or (R 2a and R 2c ) together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, said ring containing, as ring member(s), independently, 0, 1, or 2 heteroatom(s) (plural) selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring being optionally substituted with at least one substituent R 2f and, R 2d and R 2f 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, oxo, -CN, -OR 2g , -SO 2 R 2g , -SO 2 NR 2g R 2h , -COR 2g , -CO 2 R 2g , -CONR 2g R2h 、 -NO 2 、 -NR 2g R 2h 、 -NR 2g COR 2h 、 -NR 2g CO 2 R 2h 、 -NR 2g CONR 2h R 2i 、 or -NR 2g SO 2 R 2h selected from, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl is optionally substituted with at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, halheterocyclyl, phenyl, haloaryl, heteroaryl, or halheteroaryl, or when adjacent or geminal, (two Rs 2d ) or (two Rs 2f) together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, the ring containing, as ring member(s), independently, 0, 1, or 2 heteroatom(s) selected from nitrogen, oxygen, or optionally oxidized sulfur, the ring being optionally substituted with at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, halheterocyclyl, phenyl, haloaryl, heteroaryl, or halheteroaryl, R 2g 、R 2h 、and R 2i are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and each of said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said -C 2-8 alkenyl, said -C 2-8 alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, said heterocyclyl, said phenyl, or said heteroaryl is optionally substituted with at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, and the compound according to any one of the preceding aspects, optionally substituted.

[0016] Aspect 9. 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]decanyl, oxa-azaspiro[4.5]decanyl, azabicyclo[3.3.1]nonanyl, piperidinyl, piperazinyl, oxa-azaspiro[2.5]octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, phenyl, oxo, -CN, -OR 2a , -COR 2a , -CO 2 R 2a , -CONR 2a R 2b , -NR 2a R 2b , -NR 2a COR 2band each of 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]decanyl, oxa-azaspiro[4.5]decanyl, azabicyclo[3.3.1]nonanyl, piperidinyl, piperazinyl, oxa-azaspiro[2.5]octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, or phenyl is optionally substituted with at least one substituent R 2d is optionally substituted with R 2a and R 2b are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8Selected from 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]decanyl, oxa-azaspiro[4.5]decanyl, azabicyclo[3.3.1]nonanyl, piperidinyl, piperazinyl, oxa-azaspiro[2.5]octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, or phenyl, said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said -C 2-8 alkenyl, said -C 2-8Alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, said pyrrolidinyl, said morpholinyl, said thiomorpholinyl, said tetrahydrofuranyl, said tetrahydropyranyl, said oxazepanyl, said oxetanyl, said azetidinyl, said oxa-azaspiro[4.4]nonanyl, said hexahydro-1H-furo[3,4-c]pyrrolyl, said octahydropyrrolo[3,4-c]pyrrolyl, said diazaspiro[4.5]decanyl, said oxa-azaspiro[4.5]decanyl, said azabicyclo[3.3.1]nonanyl, said piperidinyl, said piperazinyl, said oxa-azaspiro[2.5]octanyl, said oxa-azabicyclo[3.1.1]heptanyl, said oxa-azabicyclo[2.2.1]heptanyl, said diazaspiro[5.5]undecanyl, said oxa-azabicyclo[3.3.1]nonanyl, said azabicyclo[3.2.1]octanyl, said azabicyclo[2.1.1]hexanyl, said pyridinyl, said pyrimidinyl, said pyrazolyl, said oxa-azabicyclo[3.2.1]octanyl, or each of said phenyl is optionally substituted with at least one substituent R 2f is optionally substituted with, or (R 2a and R 2b ), (R 2b and R 2c ), or (R 2a and R 2c ) together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, said ring containing, as ring member(s), independently, 0, 1, or 2 heteroatom(s) (plural) selected from nitrogen or oxygen, said ring being optionally substituted with at least one substituent R 2f and R 2d and R 2f 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, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazepanyl, oxetanyl, azetidinyl, oxa-azaspiro[4.4]nonanyl, hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decanyl, oxa-azaspiro[4.5]decanyl, azabicyclo[3.3.1]nonanyl, piperidinyl, piperazinyl, oxa-azaspiro[2.5]octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, phenyl, oxo, -CN, -OR 2g , -SO 2 R 2g , -COR 2g , -CO 2 R 2g , -CONR 2g R 2h , -NO 2 , -NR 2g R 2h , or -NR 2g COR 2h selected from, the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, the -C 2-8Each of alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, said pyrrolidinyl, said morpholinyl, said thiomorpholinyl, said tetrahydrofuranyl, said tetrahydropyranyl, said oxazepanyl, said oxetanyl, said azetidinyl, said oxa-azaspiro[4.4]nonanyl, said hexahydro-1H-furo[3,4-c]pyrrolyl, said octahydropyrrolo[3,4-c]pyrrolyl, said diazaspiro[4.5]decanyl, said oxa-azaspiro[4.5]decanyl, said azabicyclo[3.3.1]nonanyl, said piperidinyl, said piperazinyl, said oxa-azaspiro[2.5]octanyl, said oxa-azabicyclo[3.1.1]heptanyl, said oxa-azabicyclo[2.2.1]heptanyl, said diazaspiro[5.5]undecanyl, said oxa-azabicyclo[3.3.1]nonanyl, said azabicyclo[3.2.1]octanyl, said azabicyclo[2.1.1]hexanyl, said pyridinyl, said pyrimidinyl, said pyrazolyl, said oxa-azabicyclo[3.2.1]octanyl, or said phenyl is optionally substituted with at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, halheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, optionally substituted, or when adjacent or geminal, (two Rs 2d ) or (two Rs 2f) together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, said ring containing, as ring member(s), independently, 0, 1 or 2 heteroatom(s) selected from nitrogen, oxygen or optionally oxidized sulfur, said ring being substituted with at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, halheterocyclyl, phenyl, haloaryl, heteroaryl or haloheteroaryl, optionally substituted with R 2g 、R 2h 、and R 2i are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl or heteroaryl, and each of said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said -C 2-8 alkenyl, said -C 2-8 alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, said heterocyclyl, said phenyl or said heteroaryl is 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, pentoxy, hexoxy, heptoxy, octoxy, -C2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, and the compound according to any one of the preceding aspects, optionally substituted.

[0017] Aspect 10. 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]decanyl, oxa-azaspiro[4.5]decanyl, azabicyclo[3.3.1]nonanyl, piperidinyl, piperazinyl, oxa-azaspiro[2.5]octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, phenyl, -OR 2a , -NR 2a R 2b , or -NR 2a COR 2band each of said methyl, said ethyl, said propyl, said butyl, said pyrrolidinyl, said morpholinyl, said thiomorpholinyl, said tetrahydrofuranyl, said tetrahydropyranyl, said oxazepanyl, said oxetanyl, said azetidinyl, said oxa-azaspiro[4.4]nonanyl, said hexahydro-1H-furo[3,4-c]pyrrolyl, said octahydropyrrolo[3,4-c]pyrrolyl, said diazaspiro[4.5]decanyl, said oxa-azaspiro[4.5]decanyl, said azabicyclo[3.3.1]nonanyl, said piperidinyl, said piperazinyl, said oxa-azaspiro[2.5]octanyl, said oxa-azabicyclo[3.1.1]heptanyl, said oxa-azabicyclo[2.2.1]heptanyl, said diazaspiro[5.5]undecanyl, said oxa-azabicyclo[3.3.1]nonanyl, said azabicyclo[3.2.1]octanyl, said azabicyclo[2.1.1]hexanyl, said pyridinyl, said pyrimidinyl, said pyrazolyl, said oxa-azabicyclo[3.2.1]octanyl, or said phenyl is optionally substituted by at least one substituent R 2d optionally substituted with R 2a and R 2bis, independently of each other, hydrogen, methyl, ethyl, propyl (n-propyl or iso-propyl), butyl (n-butyl, sec-butyl, iso-butyl, or tert-butyl), pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazepanyl, oxetanyl, azetidinyl, oxa-azaspiro[4.4]nonanyl, hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decanyl, oxa-azaspiro[4.5]decanyl, azabicyclo[3.3.1]nonanyl, piperidinyl, piperazinyl, oxa-azaspiro[2.5]octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, or phenyl, and the methyl, the ethyl, the propyl, the butyl, the pentyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the pyrrolidinyl, the morpholinyl, the thiomorpholinyl, the tetrahydrofuranyl, the tetrahydropyranyl, the oxazepanyl, the oxetanyl, the azetidinyl, the oxa-azaspiro[4.4]nonanyl, the hexahydro-1H-furo[3,4-c]pyrrolyl, the octahydropyrrolo[3,4-c]pyrrolyl, the diazaspiro[4.5]decanyl, the oxa-azaspiro[4.5]decanyl, the azabicyclo[3.3.1]nonanyl, the piperidinyl, the piperazinyl, the oxa-azaspiro[2.5]octanyl, the oxa-azabicyclo[3.1.1]heptanyl, the oxa-azabicyclo[2.2.1]heptanyl, the diazaspiro[5.5]undecanyl, the oxa-azabicyclo[3.3.1]nonanyl, the azabicyclo[3.2.1]octanyl, the azabicyclo[2.1.1) Each of the hexanyl, the pyridinyl, the pyrimidinyl, the pyrazolyl, the oxa-azabicyclo[3.2.1]octanyl, or the phenyl is optionally substituted with at least one substituent R. 2f or (R 2a and R 2b ), (R 2b and R 2c ), or (R 2a and R 2c ) together with the atom(s) to which they are attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, the ring containing, as ring member(s), independently, 0, 1, or 2 heteroatom(s) (if any) selected from nitrogen or oxygen, the ring being optionally substituted with at least one substituent R 2f , R 2d and R 2f are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, -CF 3 , -CF 2 H, -CFH 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CH 2 OH, -CH(CH 3 )OH, -C(CH 3 ) 2 OH, -CH 2 CH 2OH, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazepanyl, oxetanyl, azetidinyl, oxa-aspir[4.4]nonanyl, hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]decanyl, oxa-azaspiro[4.5]decanyl, azabicyclo[3.3.1]nonanyl, peridinyl, piperazinyl, oxa-azabicyclo[2.5]octanyl, oxa-azabicyclo[3.1.1]heptanyl, oxa-azabicyclo[2.2.1]heptanyl, diazaspiro[5.5]undecanyl, oxa-azabicyclo[3.3.1]nonanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.1.1]hexanyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, phenyl, oxo, -CN, -OH, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy, -SO 2 Me, -SO 2 Et, -SO 2 C 3 H 7 , -COMe, -COEt, -COC 3 H 7 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHC 2 H 5 , -NHC 3 H 7 , -NHC 4 H 9 , -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , -CONHC 2 H 5 , -CONHC 3 H 7 , -CONHC 4 H 9 A compound according to any one of the preceding aspects, selected from

[0018] Aspect 11.R 2 is -H, -Me, -OMe, -OH, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH(CH 3 ) 2 , -NHC(CH 3 ) 3 , -NHCOCH 3 ,

Chem.

Chem.

[0019] Aspect 12.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, and each of said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said -C 2-8 alkenyl, said -C 2-8 alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, said heterocyclyl, said phenyl, or said heteroaryl is optionally substituted with at least one substituent R 3c , or R 3A and R 3Bwhich, together with the atoms to which they are attached, form an acyl (-C(=O)-), or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, said ring containing, as ring member(s), independently, 0, 1, or 2 heteroatom(s) (s) selected from nitrogen, oxygen, or optionally oxidized sulfur, said ring being a monocyclic, spiro, fused, or bridged ring, said ring being optionally substituted with at least one substituent R 3c and being optionally substituted with R 3c each independently being 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 -, -SO 2 R 3d -, -SO 2 NR 3d R 3e -, -COR 3d -, -CO 2 R 3d -, -CONR 3d R 3e -, -NO 2 -, -NR 3d R 3e -, -NR 3d COR 3e -, -NR 3d CO 2 R 3e -, -NR 3d CONR 3e R 3f -, or -NR 3d SO 2 R 3e selected from, said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said -C 2-8 alkenyl, said -C 2-8Each of the alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl is substituted with at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, halheterocyclyl, phenyl, haloaryl, heteroaryl, or halheteroaryl, R 3d 、R 3e 、and R 3f are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, selected from the methyl, the ethyl, the propyl, the butyl, the pentyl, the hexyl, the heptyl, the octyl, the -C 2-8 alkenyl, the -C 2-8 alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or the heteroaryl is 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, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8Optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, halheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, 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 R 3A and R 3B together with the atom to which they are attached form an acyl (-C(=O)-), or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, and the ring contains, as ring members (plural possible), independently 0, 1, or 2 heteroatoms (plural possible) selected from nitrogen, oxygen, or optionally oxidized sulfur, the ring is a monocyclic, spiro, fused, or bridged ring, and the ring is optionally substituted with at least one substituent R 3c and R 3c are each independently 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 , -CO 2 R 3d , -CONR 3d R 3e , -NO 2 , -NR 3d R 3e , -NR 3d COR 3e , or -SO 2 R 3dselected from, each of said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, said heterocyclyl being 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, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, hal heterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, R 3d and R 3e are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, each of said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, or said cyclooctyl being 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, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, hal heterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, More preferably, R 3A and R 3Beach independently is hydrogen, methyl, ethyl, propyl, butyl, pentyl, or R 3A and R 3B together with the atom to which they are attached form an acyl (-C(=O)-), or a 3-, 4-, 5-, 6-, 7-, or 8-membered ring, the ring containing, as ring member(s), independently, 0, 1, or 2 heteroatom(s) (s) selected from nitrogen, oxygen, or oxidized sulfur, the ring being a monocyclic, spiro, fused, or bridged ring, the ring being optionally substituted with at least one substituent selected from -F, methyl, ethyl, propyl, butyl, -CF 3 , oxo, or -CN, a compound according to any one of the preceding aspects.

[0020] Aspect 13.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0021] Aspect 14.

Chemical formula

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[0022] Aspect 15.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, wherein each of said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said -C 2-8 alkenyl, said -C 2-8 alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, or said heterocyclyl is optionally substituted with at least one substituent R 4a and R 4a is, independently of each other, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR 4b -SO 2 R 4b -SO 2 NR 4b R 4c -COR 4b, -CO 2 R 4b , -CONR 4b R 4c , -NO 2 , -NR 4b R 4c , -NR 4b COR 4c , -NR 4b CO 2 R 4c , -NR 4b CONR 4c R 4d , or -NR 4b SO 2 R 4c selected from, where each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C 1-8 alkyl, -haloC 1-8 alkyl, -C 1-8 alkoxy, -haloC 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, halheterocyclyl, aryl, haloaryl, heteroaryl, or halheteroaryl, R 4b , R 4c , and R 4d are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said -C 2-8 alkenyl, said -C 2-8 alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, said heterocyclyl, said phenyl, or said heteroaryl, each of which is halogen, hydroxy, -C 1-8 alkyl, -haloC 1-8 alkyl, -C 1-8 alkoxy, -haloC 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 Optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, hal heterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, 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, More preferably, R 4 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl(

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Chem.

Chem.

[0023] Aspect 16.R 5 , R 6 , R 7 , R 8 , and R 9 are each independently H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, -CN, -OR 5a , -COR 5a , -CO 2 R 5a , -CONR 5a R 5b , -NR 5a R 5b , -NR 5a COR 5b , -NR 5a CO 2 R 5b , or -NR 5a CONR 5b R 5c and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl is optionally substituted with at least one substituent R 5d . R 5a , R 5b , and R 5c are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said -C 2-8 alkenyl, said -C 2-8 alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, said heterocyclyl, said phenyl, or said heteroaryl, each of which is optionally substituted with at least one substituent R 5f and is optionally substituted with R 5d and R 5f are each independently hydrogen, -F, -Cl, -Br, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, halheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said -haloC 1-8 alkyl, said methoxy, said ethoxy, said propoxy, said butoxy, said pentoxy, said hexoxy, said heptoxy, said octoxy, said -C 2-8 alkenyl, said -C 2-8 alkynyl, said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl, said cycloheptyl, said cyclooctyl, said halocycloalkyl, said heterocyclyl, said halheterocyclyl, said phenyl, said haloaryl, said heteroaryl, or said haloheteroaryl, each of which is halogen, hydroxy, -C 1-8 alkyl, -haloC1-8 Alkyl, -C 1-8 Alkoxy, -haloC 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, halheterocyclyl, aryl, haloaryl, heteroaryl, or halheteroaryl, Preferably, R 5 , R 6 , R 7 , R 8 , and R 9 are each independently H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, -CN, -OR 5a , -COR 5a , -CO 2 R 5a , -CONR 5a R 5b , -NR 5a R 5b , -NR 5a COR 5b , -NR 5a CO 2 R 5b , or -NR 5a CONR 5b R 5c selected from, R 5a , R 5b , and R 5c are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl selected from, More preferably, R5 , R 6 , R 7 , R 8 , and R 9 and R are each independently 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, pentoxy, hexoxy, heptoxy, octoxy, -CN, a compound according to any one of the preceding aspects.

[0024] Aspect 17. R 5 , R 6 , and R 7 are each independently selected from H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and / or 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, pentoxy, hexoxy, heptoxy, octoxy, -CN, and / or R 9 is selected from H, Preferably, R 5 , R 6 , and R 7 are each independently selected from H, -F, -Cl, methyl, ethyl, propyl, butyl, and / or R 8 is selected from -F, -Cl, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, -CN, and / or R 9 is selected from H, a compound according to any one of the preceding aspects.

[0025] Aspect 18.R 11 is H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, or -C 2-8 alkynyl, each of said methyl, said ethyl, said propyl, said butyl, said pentyl, said hexyl, said heptyl, said octyl, said -C 2-8 alkenyl, or said -C 2-8 alkynyl is optionally substituted with at least one substituent R 11a and R 11a is hydrogen, halogen, hydroxy, -C 1-8 alkyl, -haloC 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, each of said -C 1-8 alkyl, said -haloC 1-8 alkyl, said -C 1-8 alkoxy, said -C 2-8 alkenyl, said -C 2-8 alkynyl, said cycloalkyl, said halocycloalkyl, said heterocyclyl, said haloheterocyclyl, said aryl, said haloaryl, said heteroaryl, or said haloheteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C 1-8 alkyl, -haloC 1-8 alkyl, -C 1-8 alkoxy, -haloC 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkynyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl and is optionally substituted with at least one substituent selected from the group consisting of Preferably, R 11is selected from H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, or -C 2-8 alkynyl, and more preferably, R 11 is selected from H, methyl, ethyl, propyl, butyl, and even more preferably, R 11 is H, a compound according to any one of the preceding aspects.

[0026] Aspect 19. A compound according to any one of the preceding aspects, wherein the compound is selected from the following. [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula]

[0027] 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, together with a pharmaceutically acceptable excipient.

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

[0029] 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.

[0030] 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 regulation.

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

[0032] 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 to 19, or a pharmaceutically acceptable salt thereof, as a CDK4 kinase inhibitor, wherein the disease or disorder is related to the inhibition of CDK4.

[0033] 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.

Mode for Carrying Out the Invention

[0034] The following terms have the meanings indicated throughout this specification:

[0035] Unless otherwise defined elsewhere in this specification, all other technical and scientific terms used herein shall have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0036] The following terms shall have the meanings set forth throughout this specification:

[0037] As used herein, including in the appended claims, singular words such as "a," "an," and "the" shall include their corresponding plural references unless the context clearly indicates otherwise.

[0038] The term "or" shall mean "and / or" and be used interchangeably, unless the context clearly dictates otherwise.

[0039] The term "alkyl" includes hydrocarbon groups selected from straight-chain and branched-chain saturated hydrocarbon groups containing 1 to 18 carbon atoms, such as 1 to 12 carbon atoms, more particularly 1 to 10 carbon atoms, even more particularly 1 to 8 carbon atoms, or 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Examples of alkyl groups containing 1 to 6 carbon atoms (i.e., C 1-6 alkyl) include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0040] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0041] The term "butyl" includes 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu").

[0042] 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.

[0043] 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.

[0044] The term "alkylene" includes a divalent alkyl group formed by removing two hydrogens from an alkane. Alkylene includes, but is not limited to, methylene, ethylene, propylene, etc.

[0045] The term "halogen" includes fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0046] The term "alkenyl" includes a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C=C double bond and 2 to 18 carbon atoms, for example, 2 to 8 carbon atoms, and further for example, 2 to 6 carbon atoms, etc. An alkenyl group, for example, C 2-6Examples of alkenyl include, but are not limited to, ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1,3-dienyl groups.

[0047] The term "alkenylene" means a divalent alkyl group obtained by removing two hydrogens from an alkane. Examples of alkenylene include, but are not limited to, vinylidene, butenylene, and the like.

[0048] The term "alkynyl" includes a hydrocarbon group selected from linear and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 18 carbon atoms, for example, 2 to 8 carbon atoms, and further for example, 2 to 6 carbon atoms. An alkynyl group, for example, C 2-6 Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, and 3-butynyl groups.

[0049] The term "alkynylene" means a divalent alkynyl group obtained by removing two hydrogens from an alkyne. Examples of alkynylene include, but are not limited to, ethynylene, and the like.

[0050] The term "cycloalkyl" includes a hydrocarbon group selected from saturated cyclic hydrocarbon groups including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups including fused, bridged, or spirocycloalkyl.

[0051] For example, a cycloalkyl group may contain 3 to 12 carbon atoms, such as 3 to 10 carbon atoms, more specifically 3 to 8 carbon atoms, still more specifically 3 to 6 carbon atoms, 3 to 5 carbon atoms, or 3 to 4 carbon atoms. Further, for example, the cycloalkyl group may be selected from monocyclic groups containing 3 to 12 carbon atoms, such as 3 to 10 carbon atoms, further 3 to 8 carbon atoms, and 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, saturated monocyclic cycloalkyl groups, such as C 3-8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embodiment, the cycloalkyl is a monocyclic ring containing 3 to 6 carbon atoms, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl (C 3-6 abbreviated as cycloalkyl). Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as a bridged bicyclic ring selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. Further examples of bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5,6] and [6,6] ring systems.

[0052] The term "spirocycloalkyl" includes a cyclic structure formed by at least two rings sharing one atom and containing carbon atoms.

[0053] The term "fused cycloalkyl" is saturated and includes bicyclic cycloalkyl groups as defined herein formed by two or more rings sharing two adjacent atoms.

[0054] The term "bridged cycloalkyl" includes a cyclic structure formed by two rings that contain carbon atoms and share two atoms that are not adjacent to each other. The term "7- to 10-membered bridged cycloalkyl" includes a cyclic structure formed by two rings that contain 7 to 12 carbon atoms and share two atoms that are not adjacent to each other.

[0055] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl include bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and benzo 3- to 8-membered cycloalkyl, benzo C 4-6 cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetralyl, 1,4-dihydronaphthyl, etc., but are not limited thereto. Preferred embodiments are 8- to 9-membered fused rings, referring to a cyclic structure containing 8 to 9 ring atoms among the above examples.

[0056] The term "aryl", used alone or in combination with other terms, includes groups selected from the following: - 5- and 6-membered carbocyclic aromatic rings, e.g., phenyl, - bicyclic ring systems such as 7- to 12-membered bicyclic ring systems where at least one ring is carbocyclic and aromatic, e.g., naphthyl and indanyl, and - tricyclic ring systems such as 10- to 15-membered tricyclic ring systems where at least one ring is carbocyclic and aromatic, e.g., fluorenyl.

[0057] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure of this specification. In some embodiments, monocyclic or bicyclic aromatic hydrocarbon rings have 5 to 10 ring-forming carbon atoms (i.e., C 5-10is aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthracenyl, phenanthrenyl, etc. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphth-1-yl or naphth-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0058] Specifically, the term "bicyclic fused aryl" includes a bicyclic aryl ring as defined herein. A typical bicyclic fused aryl is naphthalene.

[0059] The term "heteroaryl" includes a group selected from the following: - at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), for example, containing 1 to 4, or in some embodiments 1 to 3, or in some embodiments 1 to 2 heteroatoms, with the remaining ring atoms being carbon, a 5-, 6-, or 7-membered aromatic monocyclic ring, - at least one heteroatom selected from N, O, and S, for example, containing 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, with the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom being present in the aromatic ring, a 7- to 12-membered bicyclic ring, and - at least one heteroatom selected from N, O, and S, for example, containing 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms, with the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom being present in the aromatic ring, an 11- to 14-membered tricyclic ring.

[0060] When the total number of S atoms and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. In some embodiments, the total number of S atoms and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S atoms and O atoms in the aromatic heterocyclic ring does not exceed 1. When the heteroaryl group contains more than one heteroatomic ring member, these heteroatoms can be the same or different. The nitrogen atom in the ring(s) of the heteroaryl group can be oxidized to form an N-oxide.

[0061] Specifically, the term "bicyclic fused heteroaryl" as defined herein includes 7- to 12-membered, preferably 7- to 10-membered, more preferably 9- or 10-membered fused bicyclic heteroaryl rings. Typically, the bicyclic fused heteroaryl is bicyclic 5-membered / 5-membered, 5-membered / 6-membered, 6-membered / 6-membered, or 6-membered / 7-membered. The group can be attached to the remainder of the molecule through any of the rings.

[0062] The terms "heterocyclyl", "heterocycle", or "heterocyclic" are interchangeable and include non-aromatic heterocyclyl groups containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro rings, i.e., including monocyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, and fused heterocyclic groups.

[0063] The term "at least one substituent" disclosed herein includes, as long as the valence theory is satisfied, for example, 1 to 4 substituents such as 1 to 3, or further 1 or 2. For example, the "at least one substituent F" disclosed herein includes, for example, 1 to 4 substituents F such as 1 to 3, or further 1 or 2.

[0064] The term "divalent" refers to a linking group that can form a covalent bond with two other moieties. For example, a "divalent cycloalkyl group" refers to a cycloalkyl group obtained by removing two hydrogens from the corresponding cycloalkane to form a linking group. The terms "divalent aryl group", "divalent heterocyclyl group", or "divalent heteroaryl group" should be understood similarly.

[0065] The compounds disclosed herein may contain chiral 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 possess two or more chiral centers, they may additionally exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. It is intended that all such possible stereoisomers be included, such as substantially pure resolved enantiomers, racemic mixtures thereof, and mixtures of diastereomers. It is intended that all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts be included. Unless otherwise specified, a reference to one isomer applies to any of the possible isomers. When the isomeric composition is not specified, all possible isomers are always included.

[0066] When the compounds disclosed herein contain an olefinic double bond, unless otherwise specified, it is intended that such double bonds include both E and Z geometric isomers.

[0067] When the compounds disclosed herein contain a disubstituted cyclic ring system, the substituents found in such ring systems may adopt cis and trans configurations. The cis configuration means that both substituents are found on the upper side of the arrangement of the two substituents on the carbon, while trans means that they are on opposite sides. For example, the disubstituted cyclic ring system can be a cyclohexyl or cyclobutyl ring.

[0068] It may be advantageous to separate the reaction products from each other and / or from the starting materials. The desired product of each step or series of steps is separated (hereinafter, separated) to the desired degree of homogeneity by techniques common in the art. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods, such as, for example, reverse 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, and small scale thin layer and flash techniques. One of ordinary skill in the art can select and apply the technique most likely to achieve the desired separation.

[0069] “Diastereomer” refers to stereoisomers of a compound that have two or more chiral centers but are not mirror images of each other. A mixture of diastereomers can be separated into its individual diastereomers based on their physical and chemical differences by methods well known to one of ordinary skill in the art, such as chromatography and / or fractional recrystallization. Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride) to convert the enantiomer mixture to a diastereomer mixture, separating the diastereomers, and converting the individual diastereoisomers to the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated by use of a chiral HPLC column.

[0070] A single stereoisomer, e.g., a substantially pure enantiomer, can be obtained by resolution of a racemic mixture using methods such as formation of diastereomers using an optically active resolving agent (Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, C. H., et al. “Chromatographic resolution of enantiomers: Selective review.” J. Chromatogr., 113(3)(1975): pp. 283 - 302). The racemic mixture of the chiral compounds of the present invention can be separated and isolated by any suitable method including (1) formation of ionic diastereomeric salts with a chiral compound and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with a chiral derivatizing reagent, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) direct separation of substantially pure or enriched stereoisomers under chiral conditions. See Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.

[0071] Some of the compounds disclosed herein may exist with different hydrogen - bonding patterns, called tautomers. For example, a compound containing a carbonyl - CH 2 C(O)- group (keto form) can undergo tautomerism to form a hydroxyl - CH = C(OH)- group (enol form). Where applicable, both the keto and enol forms, as well as mixtures thereof, are intended to be included.

[0072] A “prodrug” refers to a derivative of an active agent that requires conversion in the body to release the active drug. In certain embodiments, the conversion is enzymatic. A prodrug is often, but not necessarily, pharmacologically inactive until it is converted to the active drug.

[0073] The term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and that correspond to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base functional group with a suitable organic acid, or by reacting an acidic group with a suitable base. This term also includes salts of stereoisomers (such as enantiomers and / or diastereomers), tautomers, and prodrugs of the compounds of the present invention.

[0074] In addition, when 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, when the product is a free base, addition salts such as pharmaceutically acceptable addition salts can be generated 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 basic compounds. Those skilled in the art will recognize the various synthetic methods that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0075] As used herein, the terms "administer", "administering", "treating", and "treatment", when applied to an animal, human, subject, cell, tissue, organ, or biological fluid, mean the contact of an exogenous pharmaceutical, therapeutic, diagnostic, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of cells includes contact of the reagent with the cells, as well as contact of the fluid with the reagent in which the cells are in contact. The terms "administer" and "treatment" also mean, for example, in vitro and ex vivo treatment of cells by a reagent, diagnostic, 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.

[0076] The terms "effective amount" or "therapeutically effective amount" refer to the amount of an active ingredient, such as a compound, that is sufficient to have an impact on the treatment of a disease, disorder, or symptom thereof when administered to a subject for treating at least one of the clinical manifestations of the disease, or the disease or disorder. The "therapeutically effective amount" can vary depending on the compound, the disease, the disorder, and / or the symptoms of the disease or disorder, the severity of the disease, the disorder, and / or the symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. The appropriate amount in any given case can be apparent to those skilled in the art or can be determined by conventional experimentation. In some embodiments, the "therapeutically effective amount" is the amount of at least one compound and / or at least one stereoisomer, tautomer, or prodrug thereof, and / or at least one pharmaceutically acceptable salt thereof, disclosed herein that is effective to "treat" a disease or disorder in a subject as defined herein. In the case of combination therapy, the term "therapeutically effective amount" refers to the total amount of the combination subject matter for the effective treatment of a disease, disorder, or condition.

[0077] The term "disease" refers to any disease, discomfort, illness, symptom, or indication and can be interchangeable with the terms "disorder" or "condition".

[0078] Throughout this specification and the following claims, unless the context requires otherwise, the term "comprise", and variations such as "comprises" and "comprising", are intended to specify the presence of the stated features but not to preclude the presence or addition of one or more other features. As used herein, the term "comprising" can be replaced by the terms "containing", "including", or in some cases "having".

[0079] Throughout this specification and the following claims, "C" n-mThe term "」" indicates a range including the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 , C 1-6 and the like.

[0080] Unless otherwise defined elsewhere in this specification, all other technical and scientific terms used in this specification have the meanings commonly understood by those of ordinary skill in the technical field to which the present invention pertains.

Examples

[0081] General synthesis The compounds and their salts disclosed herein can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes. The reactions for preparing the compounds disclosed herein can be carried out in a suitable solvent that can be readily selected by those of ordinary skill in the field of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials, intermediates, or products at the temperature at which the reaction is carried out, for example, a temperature that can vary from the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of solvents.

[0082] The selection of appropriate protecting groups can be readily determined by those of ordinary skill in the art.

[0083] The reaction can be monitored according to any suitable method known in the art, such as NMR, UV, HPLC, LC-MS, and TLC. The compounds can be purified by various methods including HPLC and normal-phase silica chromatography.

[0084] Chiral analysis HPLC was used for the retention time analysis of various chiral examples, and the conditions were divided into the following methods according to the column, mobile phase, and solvent ratio used.

[0085] Scheme I

Chemical formula

[0086] Scheme II

Chemical Structure

[0087] Example 1: 6-(5-Fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropyl-N-methylquinoline-3-carboxamide

Chemical Structure

Chemical Structure

[0088] Step 2: Ethyl 4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate

Chemical formula

[0089] Step 3: Ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate

Chem.

[0090] Step 4: Ethyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate

Chem.

[0091] Step 5: 6-(5-Fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carboxylic acid

Chemical formula

[0092] Step 6: 6-(5-Fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropyl-N-methylquinoline-3-carboxamide A 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 hours 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 1H-NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.74 (s, 1H), 8.60 (d, J = 4.3 Hz, 1H), 8.51 (d, J = 3.5 Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 4.97 (d, J = 4.9 Hz, 1H), 4.00 - 3.79 (m, 3H), 3.72 (dd, J = 14.2, 7.0 Hz, 1H), 3.55 (s, 1H), 3.38 - 3.36 (m, 1H), 3.06 (t, J = 10.4 Hz, 1H), 2.84 (d, J = 4.3 Hz, 3H), 2.03 (s, 1H), 1.55 - 1.49 (m, 7H). LC-MS (M+H) + = 440.3.

[0093] 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

Chem.

[0094] Example 3: (3S,4R)-4-((5-Fluoro-4-(3-(hydroxymethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chem.

[0095] Example 4: (3S,4R)-4-((5-chloro-4-(4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chemical formula

Chemical formula

[0096] Step 2: 6-Chloro-4-(prop-1-en-2-yl)quinoline

Chemical formula

[0097] Step 3: 6-Chloro-4-isopropylquinoline

Chemical formula

[0098] Step 4: 4-Isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Chem.

[0099] Step 5: 6-(2,5-Dichloropyrimidin-4-yl)-4-isopropylquinoline

Chem.

[0100] Step 6: (3S,4R)-4-((5-Chloro-4-(4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol 6-(2,5-Dichloropyrimidin-4-yl)-4-isopropylquinoline (500 mg, 1.57 mmol) and N,N-diisopropylethylamine (609 mg, 4.71 mmol) were dissolved in acetonitrile (20 mL). (3S,4R)-4-Aminotetrahydro-2H-pyran-3-ol hydrochloride (362 mg, 2.36 mmol) was added, and the mixture was stirred at 80 °C for 36 hours and then cooled to room temperature. After removing the solvent under vacuum, water (20 mL) was added. The aqueous layer was extracted with ethyl acetate (40 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 (40 mg, 6.4%). 1 1H-NMR (400 MHz, DMSO-d6) δ 8.92 (d, J=4.5 Hz, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 8.14 (d, J=8.2 Hz, 1H), 8.09 (s, 1H), 7.56 (s, 1H), 7.51 (d, J=4.4 Hz, 1H), 4.95 (d, J=5.3 Hz, 1H), 3.91 - 3.72 (m, 4H), 3.51 (s, 1H), 3.33 - 3.26 (m, 1H), 3.03 (t, J=10.1 Hz, 1H), 1.97 (s, 1H), 1.61 - 1.41 (m, 1H), 1.38 (d, J=6.7 Hz, 6H). LC-MS (M+H) + =399.0.

[0101] Example 5: (3S,4R)-4-((5-Chloro-4-(4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chemical formula

Chemical formula

[0102] Step 2: 6-Chloro-2-methyl-4-(prop-1-en-2-yl)quinoline

Chemical formula

[0103] Step 3: 6-Chloro-4-isopropyl-2-methylquinoline

Chemical formula

[0104] Step 4: 4-Isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Chemical formula

[0105] Step 5: 6-(2,5-Dichloropyrimidin-4-yl)-4-isopropyl-2-methylquinoline

Chemical formula

[0106] Step 6: (3S,4R)-4-((5-chloro-4-(4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol 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 days 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, 30×150 mm, 5 um; mobile phase, acetonitrile in water (containing 10 mmol / L of NH 4 HCO 3 and 0.1% of NH 4 OH), 31% - 61% gradient in 9 min; detector, UV254 nm. The title compound (10 mg, 12%) was obtained. 1H-NMR (300 MHz, DMSO-d6) δ 8.55 (broad singlet, 1H), 8.46 (singlet, 1H), 8.07 - 8.01 (multiplet, 2H), 7.56 - 7.48 (multiplet, 1H), 7.41 (singlet, 1H), 4.95 (doublet, J = 5.3 Hz, 1H), 3.94 - 3.65 (multiplet, 4H), 3.57 - 3.47 (multiplet, 1H), 3.39 - 3.29 (multiplet, 1H), 3.11 - 2.98 (multiplet, 1H), 2.68 (singlet, 3H), 2.04 - 1.93 (multiplet, 1H), 1.61 - 1.43 (multiplet, 1H), 1.38 (doublet, J = 6.7 Hz, 6H). LC-MS (M+H) + =413.1.

[0107] Example 6: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chemical formula

Chemical formula

[0108] Step 2: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol A 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 an atmosphere of hydrogen. 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 1H-NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.71 (s, 1H), 8.44 (d, J = 2.9 Hz, 1H), 8.19 (d, J = 9.0 Hz, 1H), 8.06 (d, J = 8.7 Hz, 1H), 7.21 (d, J = 7.5 Hz, 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 = 10.4 Hz, 1H), 2.48 (s, 3H), 1.98 (s, 1H), 1.50 - 1.48 (m, 7H). LC-MS (M+H) + = 397.3.

[0109] Example 7: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-2,3-dimethylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chemical formula

Chemical formula

[0110] Step 2: 4-Bromo-6-chloro-2,3-dimethylquinoline

Chemical formula

[0111] Step 3: 6-Chloro-4-isopropyl-2,3-dimethylquinoline

Chemical formula

[0112] Step 4: 4-Isopropyl-2,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Chemical Structure

[0113] Step 5: 6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-isopropyl-2,3-dimethylquinoline

Chemical Structure

[0114] Step 6: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-2,3-dimethylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol The title compound (60 mg, 61%) was prepared from 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyl-2,3-dimethylquinoline and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol in the same manner as in Step 4 of Example 1. 1 H-NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.48 (s, 1H), 8.19 (d, J=8.1 Hz, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 4.97 (d, J=5.2 Hz, 1H), 3.86 - 3.85 (m, 4H), 3.55 (s, 1H), 3.39 - 3.33 (m, 1H), 3.06 (t, J=10.4 Hz, 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.

[0115] Example 8: (3S,4R)-4-((5-Fluoro-4-(4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chem.

Chem.

[0116] Step 2: 6-Chloro-4-(prop-1-en-2-yl)quinoline

Chemical formula

[0117] Step 3: 6-Chloro-4-isopropylquinoline

Chemical formula

[0118] Step 4: 4-Isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Chemical formula

[0119] Step 5: 6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinoline

Chemical Structure

[0120] Step 6: (3S,4R)-4-((5-Fluoro-4-(4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol The title compound (150 mg, 23%) was prepared from 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinoline and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride in the same manner as in Step 4 of Example 1. 11H-NMR (400 MHz, DMSO-d6) δ 8.92 (d, J = 4.5 Hz, 1H), 8.86 (s, 1H), 8.50 (d, J = 3.6 Hz, 1H), 8.31 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 9.3 Hz, 1H), 7.52 (d, J = 4.4 Hz, 1H), 7.29 (d, J = 7.3 Hz, 1H), 4.96 (s, 1H), 3.97 - 3.71 (m, 4H), 3.65 - 3.45 (m, 1H), 3.38 (m, 1H), 3.07 (t, J = 10.4 Hz, 1H), 2.13 - 1.93 (m, 1H), 1.56 - 1.39 (m, 1H), 1.40 (d, J = 6.6 Hz, 6H). LC-MS (M+H) + = 383.0.

[0121] Example 9: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-5-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chemical Structure

Chemical Structure

[0122] Step 2: 6-Chloro-4-hydroxy-5-methylquinoline-2-carboxylic acid

Chemical Structure

[0123] Step 3: 6-Chloro-5-methylquinolin-4-ol

Chemical Structure

[0124] Step 4: 4,6-Dichloro-5-methylquinoline

Chemical Structure

[0125] Step 5: 6-Chloro-5-methyl-4-(prop-1-en-2-yl)quinoline

Chemical Structure

[0126] Step 6: 6-Chloro-4-isopropyl-5-methylquinoline

Chem.

[0127] Step 7: 4-Isopropyl-5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline

Chem.

[0128] Step 8: 6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-isopropyl-5-methylquinoline

Chem.

[0129] Step 9: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-5-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol The title compound (25 mg, 28%) was prepared from 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyl-5-methylquinoline in the same manner as in Step 4 of Example 1. 1 H-NMR (400 MHz, DMSO-d6) δ8.84 (d, J=4.5 Hz, 1H), 8.47 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.64 (d, J=8.6 Hz, 1H), 7.62 (d, J=4.5 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 4.94 (d, J=5.1 Hz, 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=10.3 Hz, 1H), 2.71 (s, 3H), 1.98 (d, J=11.5 Hz, 1H), 1.55 - 1.35 (m, 1H), 1.34 (d, J=6.4 Hz, 6H).LC-MS(M+H) + =397.0.

[0130] Example 10: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chemical formula

Chemical formula

[0131] Step 2: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol The title compound (25 mg, 11%) was prepared from 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyl-2-methylquinoline and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol in the same manner as in Step 4 of Example 1. 1 1H-NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.48 (d, J = 3.6 Hz, 1H), 8.26 (d, J = 8.2 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.42 (s, 1H), 7.25 (d, J = 7.5 Hz, 1H), 4.96 (s, 1H), 3.90 - 3.79 (m, 3H), 3.74 (dt, J = 14.0, 7.0 Hz, 1H), 3.54 (s, 1H), 3.39 - 3.33 (m, 1H), 3.07 (t, J = 10.3 Hz, 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.

[0132] Example 11: (3S,4R)-4-((4-(3-((Dimethylamino)methyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chemical formula

[0133] 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

Chemical formula

Chem.

[0134] Step 2: (6-Chloro-4-isopropylquinolin-3-yl)methyl methanesulfonate

Chem.

[0135] Step 3: 1-((6-Chloro-4-isopropylquinolin-3-yl)methyl)pyrrolidin-2-one

Chem.

[0136] Step 4: 1-((4-Isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)methyl)pyrrolidin-2-one

Chem.

[0137] Step 5: 1-((6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)pyrrolidin-2-one

Chem.

[0138] 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 The title compound (46 mg, 30%) was prepared from 1-((6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)pyrrolidin-2-one in the same manner as in Step 4 of Example 1. 1 H-NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.82 (s, 1H), 8.50 (d, J = 3.7 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.16 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 4.97 (d, J = 5.2 Hz, 1H), 4.68 (s, 2H), 4.01 - 3.68 (m, 4H), 3.67 - 3.47 (m, 1H), 3.37 (d, J = 11.9 Hz, 1H), 3.15 (t, J = 6.9 Hz, 2H), 3.05 (t, J = 10.4 Hz, 1H), 2.30 (t, J = 8.0 Hz, 2H), 2.13 - 1.93 (m, 1H), 1.96 - 1.82 (m, 2H), 1.53 (t, J = 6.3 Hz, 7H). LC-MS (M+H) + =480.0.

[0139] 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 [Chemistry] Step 1: 4-((6-Chloro-4-isopropylquinolin-3-yl)methyl)morpholin-3-one [Chemistry] The title compound (152 mg, 100%) was prepared from (6-chloro-4-isopropylquinolin-3-yl)methyl methanesulfonate in the same manner as in Step 3 of Example 12. LC-MS (M+H) + = 319.0.

[0140] Step 2: 4-((4-Isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)methyl)morpholin-3-one [Chemistry] The title compound (205 mg, 100%) was prepared from 4-((6-chloro-4-isopropylquinolin-3-yl)methyl)morpholin-3-one in the same manner as in Step 2 of Example 1. LC-MS (M+H) + = 411.0.

[0141] Step 3: 4-((6-(2-Chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)morpholin-3-one [Chemistry] The title compound (120 mg, 100%) was prepared from 4-((4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)methyl)morpholin-3-one in the same manner as in Step 3 of Example 1. LC-MS (M+H) + = 415.15.

[0142] 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 The title compound (25 mg, 10%) was prepared from 4-((6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinolin-3-yl)methyl)morpholin-3-one in the same manner as in Step 4 of Example 1. 1 H-NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.82 (s, 1H), 8.50 (d, J = 3.7 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 4.97 (d, J = 5.2 Hz, 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 = 11.3 Hz, 1H), 3.17 (s, 2H), 3.05 (t, J = 10.3 Hz, 1H), 2.12 - 1.92 (s, 1H), 1.64 - 1.44 (m, 7H). LC-MS(M + H) + = 496.0.

[0143] 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 [Chemical formula] The title compound (20 mg, 35%) was prepared 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 in the same manner as in Step 1 of Example 11. 1 H-NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.86 (s, 1H), 8.50 (d, J=3.8 Hz, 1H), 8.29 (d, J=8.9 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 4.97 (d, J=5.3 Hz, 1H), 4.42 (d, J=6.0 Hz, 2H), 4.04 (dd, J=14.4, 7.0 Hz, 1H), 3.97 (s, 2H), 3.85 (dd, J=10.6, 5.1 Hz, 3H), 3.61 - 3.48 (m, 1H), 3.37 (d, J=11.4 Hz, 1H), 3.05 (t, J=10.4 Hz, 1H), 2.92 (d, J=11.1 Hz, 2H), 2.84 (q, J=6.6 Hz, 1H), 2.75 (d, J=11.2 Hz, 2H), 2.20 (d, J=7.6 Hz, 1H), 2.13 - 1.93 (s, 1H), 1.65 - 1.45 (m, 1H), 1.55 (d, J=9.0 Hz, 3H), 1.53 (d, J=9.0 Hz, 3H).LC-MS(M+H) + =494.0.

[0144] 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

Chem.

[0145] Step 2: Ethyl 4-bromo-6-chloro-2-methylquinoline-3-carboxylate [Chemical formula] Phosphorus tribromide (1.32 g, 4.89 mmol) was added 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) at 0 °C. The solution was stirred at room temperature overnight, and then a saturated aqueous solution of sodium bicarbonate was added. The formed precipitate was filtered and dried to obtain the crude product (900 mg, 73%). LC-MS (M+H) + = 328.0, 330.0.

[0146] Step 3: Ethyl 6-chloro-4-isopropyl-2-methylquinoline-3-carboxylate [Chemical formula] The title compound (520 mg, 65%) was prepared from ethyl 4-bromo-6-chloro-2-methylquinoline-3-carboxylate in the same manner as in Step 1 of Example 1. LC-MS (M+H) + = 292.1.

[0147] Step 4: Ethyl 4-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate

Chem.

[0148] Step 5: Ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropyl-2-methylquinoline-3-carboxylate

Chem.

[0149] Step 6: Ethyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropyl-2-methylquinoline-3-carboxylate

Chem.

[0150] Step 7: (3S,4R)-4-((5-Fluoro-4-(3-(hydroxymethyl)-4-isopropyl-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol The title compound (2 mg, 5%) was prepared from ethyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropyl-2-methylquinoline-3-carboxylate in the same manner as in Example 3. 1 H-NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.48 (d, J = 3.8 Hz, 1H), 8.24 (d, J = 8.9 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 5.18 (s, 1H), 4.97 (d, J = 5.4 Hz, 1H), 4.74 (d, J = 4.0 Hz, 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 = 10.4 Hz, 1H), 2.79 (s, 3H), 2.03 - 1.99 (m, 1H), 1.70 - 1.40 (m, 7H). LC-MS(M + H) + = 427.3.

[0151] 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

Chemical Structure

[0152] Example 17: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-(morpholinomethyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chemical formula

[0153] Example 17 can also be obtained by the following steps: Step 1: Ethyl 6-chloro-4-isopropylquinoline-3-carboxylate [Chemical formula] Under nitrogen, a solution of magnesium isopropyl bromide (15 mL, 1 M, 15 mmol) was added to a solution of zinc chloride in tetrahydrofuran (21.4 mL, 0.7 M, 15 mmol), 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)palladium(II) dichloride (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 before filtration. The filtrate was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by combiflash eluting with ethyl acetate in petroleum ether (16%, v / v) on silica gel to give the title compound (1.5 g, 71%). LC-MS (M+H) + =278.2.

[0154] Step 2: Ethyl 4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate

Chem.

[0155] Step 3: Ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate

Chem.

[0156] Step 4: Ethyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate

Chem.

[0157] Step 5: (3S,4R)-4-((5-Fluoro-4-(3-(hydroxymethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chem.

[0158] Step 6: (3S,4R)-4-((4-(3-(Chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chem.

[0159] Step 7: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-(morpholinomethyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chem.

[0160] 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 [Chemical formula] The title compound (8.1 mg, 18%) was prepared 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 in the same manner as in Step 1 of Example 11. 1 H-NMR (400 MHz, 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 = 7.9 Hz, 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 = 10.3 Hz, 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.

[0161] Example 19: (3S,4R)-4-((4-(3-((cyclobutylamino)methyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chemical Structure

[0162] 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

Chemical formula

[0163] 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

Chemical Structure

[0164] 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

Chemical Structure

[0165] 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

Chem.

[0166] 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

Chemical Structure

[0167] Example 25: (3S,4R)-4-((4-(3-((Cyclopropylamino)methyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol [Chemical Structure Diagram] The title compound (20 mg, 48%) was prepared from (3S,4R)-4-((4-(3-(chloromethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and cyclopropanamine in the same manner as in Step 1 of Example 11. 1H-NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.84 (s, 1H), 8.49 (d, J=3.1 Hz, 1H), 8.26 (d, J=8.6 Hz, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.26 (d, J=7.6 Hz, 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=10.4 Hz, 1H), 2.20 - 1.93 (m, 2H), 1.65 - 1.42 (m, 7H), 0.38 (d, J=5.5 Hz, 2H), 0.23 (s, 2H). LC-MS(M+H) + =452.1.

[0168] Example 26: (3S,4R)-4-((4-(3-((Cyclopentylamino)methyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chemical formula

[0169] 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

Chemical formula

[0170] Example 28: (3S,4R)-4-((4-(3-((Cyclohexylamino)methyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chemical formula

[0171] 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

Chemical Structure

[0172] 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

Chemical formula

[0173] Example 31: (3S,4R)-4-((5-Fluoro-4-(4-isopropyl-3-(methoxymethyl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol [Chemical formula] 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 equiv) 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 combiflash eluting with methanol in dichloromethane (5%, v / v) on silica gel to give the title compound (17 mg, 80%). 1H-NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.87 (s, 1H), 8.50 (d, J = 3.0 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 4.97 (s, 1H), 4.70 (s, 2H), 4.00 - 3.75 (m, J = 4.6 Hz, 4H), 3.54 (s, 1H), 3.36 (s, 3H), 3.46 - 3.26 (m, 1H), 3.05 (t, J = 10.6 Hz, 1H), 2.12 - 1.93 (m, 1H), 1.65 - 1.45 (m, 7H). LC-MS(M + H) + = 427.1.

[0174] 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

Chemical formula

[0175] 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

Chemical formula

[0176] 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

Chemical formula

[0177] 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

Chem.

[0178] 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

Chem.

[0179] 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

Chemical Structure

[0180] Example 38: (3S,4R)-4-((4-(3-(Aminomethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chemical formula

Chemical formula

[0181] Step 2: (3S,4R)-4-((4-(3-(aminomethyl)-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol 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% - 20% gradient), and then by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 30×150 mm, 5 um; mobile phase, acetonitrile in water (containing 10 mmol / L of NH 4 HCO 3 and 0.1% of NH 4 OH), 17% - 47% gradient in 9 min; detector, UV254 nm. The title compound (14 mg, 24%) was obtained. 1H-NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.90 (s, 1H), 8.49 (d, J = 3.9 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 7.8 Hz, 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.

[0182] 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

Chemical formula

[0183] Example 39 (5 mg, 10%) 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (brs, 1H), 8.86 (s, 1H), 8.50 (d, J = 3.9 Hz, 1H), 8.31 - 8.24 (m, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 4.98 (d, J = 5.3 Hz, 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.

[0184] Example 40: (2 mg, 3%) 1H NMR (400 MHz, DMSO-d6) δ 9.12 (brs, 1H), 8.86 (s, 1H), 8.50 (d, J = 3.8 Hz, 1H), 8.31 - 8.24 (m, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 4.99 (d, J = 5.3 Hz, 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.

[0185] Examples 41 and 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 [Chemical formula] Step 1: 6-(5-Fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carbaldehyde [Chemical formula] 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 ethyl acetate (6 mL × 4). The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography eluting with methanol in dichloromethane (0% - 10% gradient, v / v) to give the title compound (748 mg, 95%). LC-MS (M+H) + =411.2.

[0186] Step 2: (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 A solution of methylmagnesium bromide (1.50 mL, 3 M solution in diethyl ether, 4.50 mmol) in tetrahydrofuran (15 mL) was added dropwise with 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 hours under a nitrogen atmosphere and then quenched by the addition of saturated aqueous ammonium chloride (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with methanol in dichloromethane (0% - 20% gradient, v / v). The residue was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; mobile phase, acetonitrile in water (containing 10 mmol / L NH 4 HCO 3 and 0.1% NH 3 .H 2 O), 20% - 50% gradient in 9 minutes; detector, UV254 nm. The mixture obtained as a result of Example 59 and Example 60 was separated by chiral separation on chiral HPLC. Column: CHIRALPAK OD-H 4.6*150mm 5μm. Mobile phase: hexane:EtOH (containing 0.1% diethylamine) = 9:1, 1 mL / min in 18 minutes.

[0187] Example 41 (2.8 mg, 31%): RT = 6.355 minutes. 1H-NMR (400 MHz, CD 3OD) 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.

[0188] Example 42 (3.2 mg, 36%): RT = 9.244 min. 1H-NMR (400 MHz, CD 3 OD) 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, 1H), 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.

[0189] 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 [Chemical formula] The title compound (7.9 mg, 26.5%) was prepared in the same manner as in Step 1 of Example 11 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 (400 MHz, DMSO-d6) δ 9.11 (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=7.9 Hz, 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, 1 H), 3.40 - 3.34 (m, 1 H), 3.05 (t, J=10.3 Hz, 1H), 2.10 - 2.00 (m, 1H), 1.62 - 1.50 (m, 7H).LC-MS(M+H) + =492.1.

[0190] 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

Chem.

[0191] 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

Chemical Structure

[0192] 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

Chemical Structure

[0193] 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

Chemical formula

Chemical formula

[0194] Step 2: 6-Chloro-4-isopropyl-N-methoxy-N-methylquinoline-3-carboxamide

Chem.

[0195] Step 3: 1-(6-Chloro-4-isopropylquinolin-3-yl)ethan-1-one

Chem.

[0196] Step 4: 1-(6-Chloro-4-isopropylquinolin-3-yl)ethan-1-ol

Chem.

[0197] Step 5: 6-Chloro-3-(1-chloroethyl)-4-isopropylquinoline

Chem.

[0198] Step 6: 6-Chloro-3-(1-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropylquinoline

Chemical Structure

[0199] 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

Chemical Structure

[0200] Step 8: 6-(2-Chloro-5-fluoropyrimidin-4-yl)-3-(1-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropylquinoline [Chemical formula] The title compound (80 mg, 68% in two steps) was prepared from 3-(1-((R)-3-fluoropyrrolidin-1-yl)ethyl)-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline in the same manner as in Step 3 of Example 1. LC-MS (M+H) + =417.3

[0201] Step 9: (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 The 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 in the same manner as in Step 4 of Example 1. Example 47 and Example 48 were separated by chiral HPLC to obtain (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, 0.46×5 cm, 3.0 μm. Mobile phase: (hexane:dichloromethane = 1:1)((0.5% 2M NH3-MeOH)):EtOH, 20 mL / min for 11.5 minutes.

[0202] Example 47 (10 mg, 27%) 1 1H-NMR (400 MHz, DMSO-d6) δ 9.13 - 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: tR = 2.127 minutes.

[0203] Example 47 (11 mg, 29%)1 H-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: tR = 2.760 min.

[0204] 1 H-NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 9.01 (s, 1H), 8.50 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.12 (d, J = 9.3 Hz, 1H), 7.27 (d, J = 6.9 Hz, 1H), 5.21 (dd, J = 55.7, 16.8 Hz, 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 = 27.6 Hz, 2H), 2.44 - 1.78 (m, 4H), 1.58 - 1.51 (m, 7H), 1.44 (s, 3H). LC-MS(M + H) + = 498.1.

[0205] 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

Chem.

[0206] Example 50: (3S,4R)-4-((5-Fluoro-4-(3-(1-hydroxycyclopentyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chem.

Chem.

[0207] Step 2: 1-(4-Isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)cyclopentan-1-ol

Chemical Structure

[0208] This compound can also be obtained by the following steps:

[0209] 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)palladium(II) dichloride (223 mg, 0.31 mmol), and potassium acetate (1.32 g, 13.5 mmol) in 1,4-dioxane (50 mL) was stirred under nitrogen at 80 °C overnight 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. For the corresponding boronic acid, LC-MS (M+H) + = 300.3.

[0210] Step 3: 1-(6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinolin-3-yl)cyclopentan-1-ol

Chemical formula

[0211] This compound can also be obtained by the following steps:

[0212] 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)palladium(II) dichloride (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 under nitrogen at 80 °C 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 combiflash eluting with methanol (3%, v / v) in dichloromethane on silica gel to afford the title compound (80 mg, 86%). LC-MS (M+H) + =386.2.

[0213] Step 4: (3S,4R)-4-((5-Fluoro-4-(3-(1-hydroxycyclopentyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol The title compound (5 mg, 61%) was prepared 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 in the same manner as in Step 4 of Example 1. 1H-NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 9.03 (s, 1H), 8.50 (s, 1H), 8.27 (d, J=8.7 Hz, 1H), 8.11 (d, J=9.1 Hz, 1H), 7.25 (d, J=7.8 Hz, 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=10.1 Hz, 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.

[0214] This compound can also be obtained by the following steps:

[0215] 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]dichlorido(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 at 100 °C overnight under nitrogen. The mixture was cooled to room temperature and the solvent was evaporated. The residue was purified on silica gel by combiflash eluting with methanol in dichloromethane (6%, v / v) to give the title compound (5 mg, 61%). 1H-NMR (400 MHz, DMSO-d6) δ 9.20 (s, 1H), 9.03 (s, 1H), 8.50 (s, 1H), 8.27 (d, J = 8.7 Hz, 1H), 8.11 (d, J = 9.1 Hz, 1H), 7.25 (d, J = 7.8 Hz, 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 = 10.1 Hz, 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.

[0216] 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

Chem.

Chem.

[0217] Step 2: Ethyl 6-chloro-8-fluoro-4-hydroxyquinoline-3-carboxylate

Chem.

[0218] Step 3: Ethyl 4-bromo-6-chloro-8-fluoroquinoline-3-carboxylate

Chem.

[0219] Step 4: Ethyl 6-chloro-8-fluoro-4-isopropylquinoline-3-carboxylate

Chemical formula

[0220] Step 5: Ethyl 8-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate

Chem.

[0221] Step 6: Ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropylquinoline-3-carboxylate

Chem.

[0222] Step 7: Ethyl 8-fluoro-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate

Chem.

[0223] Step 8: (3S,4R)-4-((5-Fluoro-4-(8-fluoro-3-(hydroxymethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol The title compound (56 mg, 26%) was prepared from ethyl 8-fluoro-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate in the same manner as in Example 3. 1 H-NMR (400 MHz, DMSO-d6) δ 8.96 (s, 1H), 8.93 (s, 1H), 8.52 (d, J = 2.7 Hz, 1H), 8.07 (d, J = 11.6 Hz, 1H), 7.32 (d, J = 7.7 Hz, 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 = 10.4 Hz, 1H), 2.02 (s, 1H), 1.63 - 1.42 (m, 7H). LC-MS (M+H) + =431.1.

[0224] 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 [Chemistry] Step 1: (3S,4R)-4-((4-(3-(Chloromethyl)-8-fluoro-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol [Chemistry] 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. The reaction solution was stirred for 1 hour and then diluted with dichloromethane. This solution was washed with saturated aqueous sodium bicarbonate, water, and brine, dried over sodium sulfate, filtered, and evaporated to give the crude title compound (40 mg). LC-MS (M+H) + = 449.3.

[0225] Step 2: (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 The title compound (17 mg, 72%) was prepared 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-difluorocyclobutan-1-amine hydrochloride in the same manner as in Step 1 of Example 11. 1H-NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.90 (s, 1H), 8.52 (s, 1H), 8.07 (d, J=11.5 Hz, 1H), 7.32 (d, J=7.7 Hz, 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=10.1 Hz, 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.

[0226] 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

Chemical Structure

[0227] Example 53 can also be obtained by the following steps: Step 1: Diethyl 2-(((4-chloro-2-fluorophenyl)amino)methylene)malonate

Chemical Structure

[0228] Step 2: Ethyl 6-chloro-8-fluoro-4-hydroxyquinoline-3-carboxylate

Chem.

[0229] Step 3: Ethyl 4-bromo-6-chloro-8-fluoroquinoline-3-carboxylate

Chem.

[0230] Step 4: Ethyl 6-chloro-8-fluoro-4-isopropylquinoline-3-carboxylate

Chem.

[0231] Step 5: Ethyl 8-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate [Chemical formula] A mixture of ethyl 6-chloro-8-fluoro-4-isopropylquinoline-3-carboxylate (532 mg, 1.8 mmol), bis(pinacolato)diboron (635 mg, 2.5 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (72 mg, 0.1 mmol), and potassium acetate (459 mg, 4.7 mmol) in 1,4-dioxane (18 mL) was stirred under nitrogen at 80 °C overnight 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. For the corresponding boronic acid, LC-MS (M+H) + = 306.1

[0232] Step 6: Ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-4-isopropylquinoline-3-carboxylate [Chemical formula] 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)palladium(II) dichloride (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 under nitrogen at 80 °C 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 combiflash eluting with methanol (3%, v / v) in dichloromethane on silica gel to afford the title compound (420 mg, 45%). LC-MS (M+H) + =392.2.

[0233] Step 7: Ethyl 8-fluoro-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate

Chemical Structure

[0234] Step 8: (3S,4R)-4-((5-Fluoro-4-(8-fluoro-3-(hydroxymethyl)-4-isopropylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chem.

[0235] Step 9: (3S,4R)-4-((4-(3-(Chloromethyl)-8-fluoro-4-isopropylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chem.

[0236] 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

Chem.

[0237] 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

Chemical Structure

[0238] 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

Chemical formula

Chem.

[0239] Step 2: (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 A mixture of Example 55 and Example 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 the same manner as in Step 2 of Example 38. Example 55 and Example 56 were separated by chiral HPLC to obtain (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, 0.46×5 cm, 3.0 um. Mobile phase: (hexane:dichloromethane = 1:1, 0.5% 2M NH3 -containing MeOH): EtOH, 20 mL / min for 22.5 minutes.

[0240] Example 55 (5 mg, 17%): 1 H-NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 9.08 (brs, 1H), 8.49 (d, J = 3.9 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 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 = 6.5 Hz, 3H). LC-MS(M + H) + = 426.1. Chiral HPLC: RT = 3.148 minutes.

[0241] Example 56 (5 mg, 17%) 1 H-NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 9.08 (brs, 1H), 8.49 (d, J = 3.9 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 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 = 6.6 Hz, 3H). LC-MS(M + H) + = 426.1. Chiral HPLC: RT = 5.669 minutes.

[0242] 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

Chemical formula

[0243] The title compound (16 mg, 44%) was prepared 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 in the same manner as in Step 1 of Example 11. 1 H-NMR (300 MHz, DMSO-d6) δ 9.12 (brs, 1H), 8.76 (s, 1H), 8.50 (d, J = 3.9 Hz, 1H), 8.33 - 8.25 (m, 1H), 8.14 (d, J = 8.9 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 4.99 (d, J = 5.3 Hz, 1H), 4.59 (d, J = 4.6 Hz, 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.

[0244] 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

Chemical formula

[0245] 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

Chemical formula

[0246] 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

Chem.

[0247] 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

Chemical Structure

[0248] 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

Chemical Structure

[0249] 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

Chemical Structure

Chemical Structure

[0250] Step 2: 2-(6-chloro-8-fluoro-4-isopropylquinolin-3-yl)propan-2-ol

Chemical Structure

[0251] Step 3: 2-(8-Fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-2-ol

Chem.

[0252] Step 4: 2-Chloro-5-fluoro-4-((4-methoxybenzyl)oxy)pyrimidine

Chem.

[0253] Step 5: (3S,4R)-4-((5-Fluoro-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

Chem.

[0254] Step 6: (3S,4R)-4-((5-Fluoro-4-((4-methoxybenzyl)oxy)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate

Chem.

[0255] Step 7: (3S,4R)-4-((5-Fluoro-4-hydroxypyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate

Chem.

[0256] Step 8: (3S,4R)-4-((4-Chloro-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate

Chem.

[0257] Step 9: (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 The title compound (11 mg, 20%) was prepared in the same manner as 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-3-yl)propan-2-ol and (3S,4R)-4-((4-chloro-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl. 1H NMR (400 MHz, d-DMSO) δ 9.14 (s, 1H), 9.02 (s, 1H), 8.52 (s, 1H), 8.05 (d, J = 11.7 Hz, 1H), 7.31 (d, J = 7.7 Hz, 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 = 10.1 Hz, 1H), 2.02 (s, 1H), 1.70 (s, 6H), 1.64 - 1.43 (m, 7H). LC-MS(M + H)+ = 459.1.

[0258] 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

Chemical formula

[0259] 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

Chemical Structure

[0260] 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

Chemical formula

Chemical formula

[0261] Step 2: Ethyl 7-chloro-4-hydroxy-6-methoxyquinoline-3-carboxylate

Chem.

[0262] Step 3: Ethyl 4,7-dichloro-6-methoxyquinoline-3-carboxylate

Chem.

[0263] Step 4: Ethyl 7-chloro-4-isopropyl-6-methoxyquinoline-3-carboxylate

Chem.

[0264] Step 5: Ethyl 7-chloro-6-hydroxy-4-isopropylquinoline-3-carboxylate

Chemical Structure

[0265] Step 6: Ethyl 7-chloro-4-isopropyl-6-(((trifluoromethyl)sulfonyl)oxy)quinoline-3-carboxylate

Chem.

[0266] Step 7: Ethyl 7-chloro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate

Chem.

[0267] Step 8: Ethyl 7-chloro-6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate

Chem.

[0268] Step 9: Ethyl 7-chloro-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate

Chemical formula

[0269] 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 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 with methyllithium (0.6 mL, 0.96 mmol, 1.6 M in tetrahydrofuran) at -40 °C. Then, the reaction mixture was stirred at 0 °C for 2 hours 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 eluting with ethyl acetate in petroleum ether (50%, v / v) to give the title compound, and the title compound (12 mg, 13%) was obtained. 1 1H-NMR (400 MHz, 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.

[0270] 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

Chemical formula

Chemical formula

[0271] Step 2: Ethyl 6-chloro-7-fluoro-4-hydroxyquinoline-3-carboxylate

Chemical Structure

[0272] Step 3: Ethyl 4,6-dichloro-7-fluoroquinoline-3-carboxylate and ethyl 4,6-dichloro-5-fluoroquinoline-3-carboxylate

Chemical Structure

[0273] Step 4: Ethyl 6-chloro-7-fluoro-4-isopropylquinoline-3-carboxylate

Chemical Structure

[0274] Step 5: Ethyl 7-fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-3-carboxylate

Chem.

[0275] Step 6: Ethyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-7-fluoro-4-isopropylquinoline-3-carboxylate

Chem.

[0276] Step 7: Ethyl 7-fluoro-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-3-carboxylate

Chem.

[0277] Step 8: (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 The title compound (9 mg, 5%) was prepared 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 in the same manner as in Step 10 of Example 70. 1H-NMR (400 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.74 (s, 1H), 8.51 (s, 1H), 7.87 (d, J = 11.1 Hz, 1H), 7.36 (d, J = 7.3 Hz, 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.

[0278] 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

Chemical formula

Chemical formula

[0279] Step 2: (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 The title compound (17 mg, 40%) was prepared 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 in the same manner as in Step 6 of Example 4. 1H-NMR (400 MHz, DMSO-d 6 ) δ: 9.13 (s, 1H), 8.71 (br, 1H), 8.48 (s, 1H), 7.93 (br, 1H), 7.57 (d, J = 8.0 Hz, 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 = 8.0 Hz, 6H), 1.60 - 1.45 (m, 1H). LC-MS (M+H) + =475.1.

[0280] Example 117 can be obtained by the following procedure: Step 1: Diethyl 2-(((4-chloro-2-fluorophenyl)amino)methylene)malonate

Chemical Structure

[0281] Step 2: Ethyl 6-chloro-8-fluoro-4-hydroxyquinoline-3-carboxylate

Chemical formula

[0282] Step 3: Ethyl 4-bromo-6-chloro-8-fluoroquinoline-3-carboxylate

Chemical formula

[0283] Step 4: 2-(4-Bromo-6-chloro-8-fluoroquinolin-3-yl)propan-2-ol

Chemical formula

[0284] Step 5: 2-(6-Chloro-8-fluoro-4-isopropylquinolin-3-yl)propan-2-ol

Chemical formula

[0285] Step 6: 2-(8-Fluoro-4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-3-yl)propan-2-ol

Chemical formula

[0286] Step 7: 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-isopropylquinolin-3-yl)propan-2-ol

Chemical formula

[0287] Step 8: (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

Chem.

[0288] 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

Chem.

[0289] Step 2: Ethyl 6-chloro-4-hydroxy-8-iodo-5-methylquinoline-3-carboxylate [Chemical formula] 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 hours. Diphenyl ether (60 mL) was added, and the resulting mixture was heated to 260 °C for 3 hours, then cooled to 60 °C, ethyl acetate (100 mL) was added, and the resulting slurry was stirred at room temperature for 2 hours. The title compound (10.5 g, 50%) was obtained by filtration. LC-MS (M+H) + = 392.0.

[0290] Step 3: Ethyl 6-chloro-4-hydroxy-5-methylquinoline-3-carboxylate [Chemical formula] 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 subsequently water (50 mL) was added. The precipitate was filtered and washed with water and ethyl acetate to afford the title compound (1.224 g, 100%). LC-MS (M+H) + =266.0.

[0291] Step 4: Ethyl 4,6-dichloro-5-methylquinoline-3-carboxylate

Chemical formula

[0292] Step 5: Ethyl 6-chloro-4-isopropyl-5-methylquinoline-3-carboxylate

Chemical formula

[0293] Step 6: 6-Chloro-4-isopropyl-5-methylquinoline-3-carboxylic acid [Chemical formula] To a solution of ethyl 6-chloro-4-isopropyl-5-methylquinoline-3-carboxylate (200 mg, 0.686 mmol) in methanol (3 mL) was added a 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 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 combiflash on silica gel to give the title compound (180 mg, 99.6%). LC-MS (M+H) + =264.0.

[0294] Step 7: (6-Chloro-4-isopropyl-5-methylquinolin-3-yl)(1H-imidazol-1-yl)methanone [Chemical formula] To a solution of 6-chloro-4-isopropyl-5-methylquinoline-3-carboxylic acid (60 mg, 0.228 mmol) in tetrahydrofuran, carbonyldiimidazole (73.81 mg, 0.455 mmol) was added, and the reaction mixture was stirred at room temperature overnight. 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 on silica gel by combiflash to give the title compound (71.4 mg, 100%). LC-MS (M+H) + = 314.0.

[0295] Step 8: (6-Chloro-4-isopropyl-5-methylquinolin-3-yl)methanol [Chemical formula] 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, lithium aluminum hydride (9.5 mg, 0.250 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 1 hour 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 minutes. Then, ethyl acetate was added. The mixture was stirred at room temperature for an additional 1 hour and then filtered. The filtrate was concentrated, and the residue was purified on silica gel by combiflash to give the title compound (25.6 mg, 45%). LC-MS (M+H) + = 250.0.

[0296] Step 9: 3-(((tert-Butyldimethylsilyl)oxy)methyl)-6-chloro-4-isopropyl-5-methylquinoline [Chemical formula] 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 with tert-butyldimethylsilyl chloride (166.6 mg, 1.105 mmol) at 0 °C. After the reaction solution was stirred at room temperature overnight, water was added. The aqueous layer was extracted three times with dichloromethane. The combined layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by combiflash on silica gel to give the title compound (212 mg, 79%). LC-MS (M+H) + = 364.0.

[0297]

Chemical Structure

[0298] Step 11: (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

Chemical Structure

[0299] Step 12: (3S,4R)-4-((5-Fluoro-4-(3-(hydroxymethyl)-4-isopropyl-5-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol 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). The reaction solution was stirred at room temperature for 2 hours, then water (5 mL) was added. 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 preparative HPLC to give the title compound (46 mg, 56%). 1 1H-NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.48 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 7.29 (d, J = 7.5 Hz, 1H), 5.45 (t, J = 5.4 Hz, 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 = 10.3 Hz, 1H), 2.64 (s, 3H), 1.98 (d, J = 10.8 Hz, 1H), 1.55 - 1.35 (m, 1H), 1.43 (d, J = 6.4 Hz, 6H). LC-MS(M + H)+ = 427.0.

[0300] Example 145: (3S,4R)-4-((4-(3-(Aminomethyl)-4-isopropyl-5-methylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol [Chemical Formula] Step 1: (3S,4R)-4-((4-(3-(Chloromethyl)-4-isopropyl-5-methylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol [Chemical Formula] 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 hours. Saturated sodium bicarbonate solution was added until pH = 8, and 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 title compound (364 mg, 100%) was obtained. LC-MS (M+H) + = 445.0.

[0301] Step 2: (3S,4R)-4-((4-(3-(Aminomethyl)-4-isopropyl-5-methylquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol In a sealed tube, (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 a solution of 7N ammonia in methanol (5 mL) were stirred 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 (400 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.47 (d, J = 1.7 Hz, 1H), 8.26 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 7.7 Hz, 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 = 11.2 Hz, 1H), 3.04 (t, J = 10.4 Hz, 1H), 2.62 (s, 3H), 1.98 (d, J = 10.6 Hz, 1H), 1.57 - 1.31 (m, 1H), 1.44 (d, J = 8.0 Hz, 3H), 1.44 (d, J = 8.0 Hz, 3H). LC-MS(M + H) + =426.0.

[0302] 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

Chemical Structure

Chemical Structure

[0303] Step 2: Methyl 6-chloro-4-oxo-1,4-dihydroquinoline-2-carboxylate [Chemical formula] 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 hour and then cooled to room temperature. The mixture was diluted with water (300 mL) at 0 °C and stirred for 1 hour. 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.

[0304] Step 3: Methyl 4,6-dichloroquinoline-2-carboxylate [Chemical formula] 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 hours. The mixture was cooled to room temperature and poured into ice water (200 mL). The mixture was then stirred for 1 hour and filtered. The precipitate was dried under vacuum to give the title compound (2.4 g, 74%). LC-MS (M+H) + = 256.1.

[0305] Step 4: Methyl 6-chloro-4-(prop-1-en-2-yl)quinoline-2-carboxylate [Chemical formula] The title compound (1.5 g, 73%) was prepared from methyl 4,6-dichloroquinoline-2-carboxylate (2.0 g, 7.8 mmol) and potassium isopropenyltrifluoroborate in the same manner as in Step 3 of Example 1. LC-MS (M+H) + = 262.2.

[0306] Step 5: Methyl 4-(prop-1-en-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-carboxylate [Chemical formula] The title compound (1.2 g, 59%) was prepared from 6-chloro-4-(prop-1-en-2-yl)quinoline-2-carboxylate methyl and 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) in the same manner as in Step 2 of Example 1. LC-MS (M+H) + = 354.2.

[0307] Step 6: Methyl 4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-carboxylate [Chemical formula] 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 palladium 10% on carbon powder (100 mg). The mixture was stirred overnight under a hydrogen atmosphere (1 atm). The mixture was filtered and concentrated to give the title compound (900 mg, 90%). LC-MS (M+H) + = 356.2.

[0308] Step 7: Methyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinoline-2-carboxylate [Chemical formula] The title compound (500 mg, 52%) was prepared 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 in the same manner as in Step 3 of Example 1. LC-MS (M+H) + = 360.1.

[0309] Step 8: Methyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinoline-2-carboxylate [Chemical formula] The title compound (200 mg, 32%) was prepared from methyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinoline-2-carboxylate and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol in the same manner as in Step 4 of Example 1. LC-MS (M+H) + = 441.2.

[0310] 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 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 with 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 hour. 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%). 1H-NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.49 (d, J=3.7 Hz, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.10 (d, J=8.8 Hz, 1H), 7.87 (s, 1H), 7.28 (d, J=7.4 Hz, 1H), 5.49 (s, 1H), 4.97 (d, J=5.2 Hz, 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.

[0311] 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

Chemical formula

Chemical formula

[0312] Step 2: Methyl 6-chloro-4-oxo-1,4-dihydroquinazoline-2-carboxylate

Chem.

[0313] Step 3: Methyl 4,6-dichloroquinazoline-2-carboxylate

Chem.

[0314] Step 4: Methyl 6-chloro-4-(prop-1-en-2-yl)quinazoline-2-carboxylate

Chem.

[0315] Step 5: Methyl 4-(prop-1-en-2-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline-2-carboxylate

Chem.

[0316] Step 6: Methyl 4-isopropyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline-2-carboxylate

Chem.

[0317] Step 7: Methyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinazoline-2-carboxylate

Chem.

[0318] Step 8: Methyl 6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-isopropylquinazoline-2-carboxylate [Chemical formula] The title compound (350 mg, 46%) was prepared from methyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-isopropylquinazoline-2-carboxylate and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol in the same manner as in Step 4 of Example 1. LC-MS (M+H) + = 442.2.

[0319] 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 The title compound (10 mg, 10%) was prepared 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 in the same manner as in Step 9 of Example 206. 1 H-NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.57 - 8.46 (m, 2H), 8.15 (d, J = 8.8 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 5.16 (s, 1H), 4.96 (d, J = 5.2 Hz, 1H), 4.10 - 4.00 (m, 1H), 3.89 - 3.79 (m, 3H), 3.58 - 3.48 (m, 1H), 3.36 (t, J = 10.3 Hz, 1H), 3.07 (t, J = 10.3 Hz, 1H), 2.02 (s, 1H), 1.60 (s, 6H), 1.64 - 1.45 (m, 1H), 1.41 (d, J = 6.7 Hz, 6H). LC-MS (M+H)+ =442.5.

[0320] 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

Chemical Structure

Chemical Structure

[0321] Step 2: Methyl 6-chloro-8-fluoro-4-oxo-1,4-dihydroquinoline-2-carboxylate

Chemical Structure

[0322] Step 3: Methyl 4-bromo-6-chloro-8-fluoroquinoline-2-carboxylate

Chemical Structure

[0323] Step 4: Methyl 6-chloro-8-fluoro-4-isopropylquinoline-2-carboxylate

Chem.

[0324] Step 5: 2-(6-Chloro-8-fluoro-4-isopropylquinolin-2-yl)propan-2-ol

Chem.

[0325] 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

Chem.

[0326] Step 7: 2-(6-(2,5-Dichloropyrimidin-4-yl)-8-fluoro-4-isopropylquinolin-2-yl)propan-2-ol

Chem.

[0327] 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 The title compound (16 mg, 44%) was prepared 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 in the same manner as in Step 6 of Example 4. 1 1H-NMR (400 MHz, DMSO-d6) δ 8.48 (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 = 5.4 Hz, 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 = 6.7 Hz, 6H). LC-MS (M+H) + =475.1.

[0328] 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

Chem.

Chemical formula

[0329] Step 2: Ethyl 6-chloro-8-fluoro-4-hydroxyquinazoline-2-carboxylate

Chemical formula

[0330] Step 3: Ethyl 4-bromo-6-chloro-8-fluoroquinazoline-2-carboxylate

Chemical formula

[0331] Step 4: Ethyl 6-chloro-8-fluoro-4-isopropylquinazoline-2-carboxylate

Chemical Structure

[0332] Step 5: 2-(6-Chloro-8-fluoro-4-isopropylquinazolin-2-yl)propan-2-ol

Chemical Structure

[0333] 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

Chemical Structure

[0334] Step 7: 2-(6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-isopropylquinazolin-2-yl)propan-2-ol

Chem.

[0335] 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 The title compound (28 mg, 41%) was prepared 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 in the same manner as in Step 6 of Example 4. 1 H-NMR (400 MHz, DMSO-d6) δ 8.41 (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=5.5 Hz, 1H), 3.89-3.75 (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.

[0336] Biological assay The compounds disclosed herein were tested for inhibition of CDK4 / cyclin D1 or CDK6 / cyclin D3 kinases in an assay based on the time-resolved fluorescence resonance energy transfer (TR-FRET) method. The assay was performed in a 384-well low-volume black plate in a reaction mixture containing 0-10 μM of the compound in a buffer containing CDK4 / cyclin D1 or CDK6 / cyclin D3, 1 mM ATP, 0.15 μM Rb(Ser780)-biotin substrate, and 50 mM HEPES, 0.02% NaN3, 0.01% BSA, 0.1 mM orthovanadate, 50 mM MgCl2, 1 mM DTT, and 0.005% Tween-20 at pH 7.0. The kinase was incubated with the compound at room temperature for 60 minutes, and the reaction was initiated by the addition of ATP and the Rb(Ser780)-biotin substrate. After reacting at room temperature for 120 minutes, 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 the detection buffer (Cisbio Bioassays). The plate was incubated at room temperature for 60 minutes, and the TR-FRET signal (ex337 nm, em665 nm / 620 nm) was recorded with a PHERAstar FSX plate reader (BMG Labtech). The inhibition rate of CDK4 / cyclin D1 or CDK6 / cyclin D3 kinase activity in the presence of increasing concentrations of the compound was calculated based on the ratio of fluorescence at 665 nm and 620 nm. The IC50 of each compound was derived by fitting the data to a four-parameter logistic equation by Dotmatics. [Table 1-1] [Table 1-2]

Claims

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

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

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

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

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

7. R １ However, H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, haloalkyl, heterocyclyl, -CN, -OR １ａ , -COR １ａ , -CO ２ R １ａ , -CONR １ａ R １ｂ , -NR １ａ R １ｂ , -NR １ａ COR １ｂ , -NR １ａ CO ２ R １ｂ , or -NR １ａ CONR １ｂ R １ｃ The methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are all present. ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, haloalkyl, or heterocyclyl has at least one substituent R １ｄ It is optionally replaced by, R １ａ , R １ｂ , and R １ｃ Each of these is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl has at least one substituent R １ｆ It is optionally replaced by, R １ｄ and R １ｆ However, each is independent of hydrogen, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -haloC. １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ alkyl, the methoxy, the ethoxy, the propoxy, the butoxy, the pentoxy, the hexoxy, the heptoxy, the octoxy, the -C ２－８ Alkenyl, the above-C ２－８ Alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the halocycloalkyl, the heterocyclyl, the haloheterocyclyl, the phenyl, the haloaryl, the heteroaryl, or each of the haloheteroaryl has at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, Preferably, R １ However, H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, haloalkyl, heterocyclyl, or -CN, More specifically, R １ However, it is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl, Preferably, R １ However, H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, or 【Chemistry 13】 The compound according to claim 1, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, its tautomer, its deuterated analog, or its prodrug.

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

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

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

11. ( ２ The ２ 、!\H ３ 、!(C) ３ ) ２ 、!\\HHH ３ ) ２ 、!\CCH ３ ) ３ 、!\CH ３ 、 【Chemistry 14-1】 【Chemistry 14-2】 The compound according to claim 1, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, its tautomer, its deuterated analog, or its prodrug.

12. R ３Ａ and R ３Ｂ However, each is independent of hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, or -CN, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are all compounds. ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl has at least one substituent R ３ｃ It is either optionally replaced by, R ３Ａ and R ３Ｂ However, together with the atoms to which they are bonded, they form an acyl (-C(=O)-) or a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered ring, wherein the ring(s) independently contain 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members(s), and the ring is a monoring, spiroring, fused ring, or bridging ring, and the ring has at least one substituent R ３ｃ It is optionally replaced by, R ３ｃ However, each is independent of hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR ３ｄ , -SO ２ R ３ｄ , -SO ２ NR ３ｄ R ３ｅ , -COR ３ｄ , -CO ２ R ３ｄ , -CONR ３ｄ R ３ｅ , -NO ２ , -NR ３ｄ R ３ｅ , -NR ３ｄ COR ３ｅ , -NR ３ｄ CO ２ R ３ｅ , -NR ３ｄ CONR ３ｅ R ３ｆ , or -NR ３ｄ SO ２ R ３ｅ Selected from, the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl molecules has at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, -C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, R ３ｄ , R ３ｅ , and R ３ｆ However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are present. ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl molecules has at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, Preferably, R ３Ａ and R ３Ｂ However, each is independent of hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C. ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, or -CN, or R ３Ａ and R ３Ｂ However, together with the atoms to which they are bonded, they form an acyl (-C(=O)-) or a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered ring, wherein the ring(s) independently contain 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members(s), and the ring is a monoring, spiroring, fused ring, or bridging ring, and the ring has at least one substituent R ３ｃ It is optionally replaced by, R ３ｃ However, each independently, 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 , -CO ２ R ３ｄ , -CONR ３ｄ R ３ｅ , -NO ２ , -NR ３ｄ R ３ｅ , -NR ３ｄ COR ３ｅ , or -SO ２ R ３ｄ Selected from, each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and heterocyclyl has at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Optionally substituted with alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl, or haloheteroaryl, R ３ｄ and R ３ｅ Each of these is independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl has at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC １－８ Alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, More specifically, R ３Ａ and R ３Ｂ However, each is independently hydrogen, methyl, ethyl, propyl, butyl, or pentyl. R ３Ａ and R ３Ｂ However, together with the atoms to which they are bonded, they form an acyl (-C(=O)-) or a 3, 4, 5, 6, 7, or 8-membered ring, wherein the ring(s) independently contain 0, 1, or 2 heteroatoms selected from nitrogen, oxygen, or oxidized sulfur as ring members(s), and the ring(s) are monorings, spirorings, fused rings, or bridging rings, and the ring(s) are -F, methyl, ethyl, propyl, butyl, or -CF ３ The compound according to claim 1, or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analog, or its prodrug, which is optionally substituted with at least one substituent selected from oxo or -CN. 【Request Item 13】 【Chemistry 15】 The part, 【Chemistry 16】 And, During the ceremony, * ３ but, 【Chemistry 17】 This refers to the position where it is joined to the part, ** ３ but, [Chemistry 18] It refers to the position where it is joined to a part. Preferably, 【Chemistry 19】 The part, 【Chemistry 20】 The compound according to claim 1, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, its tautomer, its deuterated analog, or its prodrug. 【Request Item 14】 【Chemistry 21】 The parts are -Me, -Et, 【Chemistry 22-1】 【Chemistry 22-2】 【Chemistry 22-3】 The compound according to claim 1, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, its tautomer, its deuterated analog, or its prodrug.

15. R ４ However, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or heterocyclyl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C ２－８ Alkenyl, the above-C ２－８ Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or heterocyclyl has at least one substituent R ４ａ It is optionally replaced by, R ４ａ is, independently of each other, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ alkenyl, -C ２－８ alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo, -CN, -OR ４ｂ , -SO ２ R ４ｂ , -SO ２ NR ４ｂ R ４ｃ , -COR ４ｂ , -CO ２ R ４ｂ , -CONR ４ｂ R ４ｃ , -NO ２ , -NR ４ｂ R ４ｃ , -NR ４ｂ COR ４ｃ , -NR ４ｂ CO ２ R ４ｃ , -NR ４ｂ CONR ４ｃ R ４ｄ , or -NR ４ｂ SO ２ R ４ｃ ２－８ ２－８ alkenyl, the -C １－８ alkynyl, the cyclopropyl, the cyclobutyl, the cyclopentyl, the cyclohexyl, the cycloheptyl, the cyclooctyl, the heterocyclyl, the phenyl, or each of the heteroaryl is halogen, hydroxy, -C １－８ alkyl, -haloC １－８ alkyl, -C １－８ alkoxy, -haloC １－８ alkoxy, -C ２－８ alkenyl, -C ２－８ Optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, R ４ｂ , R ４ｃ , and R ４ｄ However, each independently, hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and -C are present. ２－８ Alkenyl, -C ２－８ Selected from alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, and the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, the above-C ２－８ Each of the following is a halogen, hydroxyl, -C: alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl. １－８ Alkyl, -halo C １－８ Alkyl, -C １－８ Alkoxy, -halo C １－８ Alkoxy, -C ２－８ Alkenyl, -C ２－８ Optionally substituted with at least one substituent selected from the group consisting of alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, Preferably, R ４ However, hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C ２－８ Alkenyl, -C ２－８ Alkinyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or heterocyclyl, More specifically, R ４ However, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl ( 【Chemistry 23】 ), isobutyl ( 【Chemistry 24】 ), tert-butyl ( 【Chemistry 25】 The compound according to claim 1, or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analog, or its prodrug.

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

17. R ５ , R ６ , and R ７ Each is independently selected from H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and / or R ８ -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, -CN, and / or R ９ However, it was selected from H, Preferably, R ５ , R ６ , and R ７ However, each is independently selected from H, -F, -Cl, methyl, ethyl, propyl, and butyl, and / or R ８ but selected from -F, -Cl, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, -CN, and / or R ９ The compound according to claim 1, selected from H, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, its tautomer, its deuterated analog, or its prodrug.

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

19. The compound described above is selected from the following: the compound according to claim 1, its N-oxide, a pharmaceutically acceptable salt thereof, its stereoisomer, its tautomer, its deuterated analog, or its prodrug. 【Chemistry 26-1】 【Chemistry 26-2】 【Chemistry 26-3】 【Chemistry 26-4】 【Chemistry 26-5】 【Chemistry 26-6】 【Chemistry 26-7】 【Chemistry 26-8】 【Chemistry 26-9】 【Chemistry 26-10】 【Chemistry 26-11】 【Chemistry 26-12】 【Chemistry 26-13】 [Chemistry 26-14]

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

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

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

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

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

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

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

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

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

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