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CN-121986096-A - Substituted 6- (pyrimidin-4-yl) quinoline compounds as cyclin dependent kinase inhibitors

CN121986096ACN 121986096 ACN121986096 ACN 121986096ACN-121986096-A

Abstract

The present disclosure provides compounds containing a 6- (pyrimidin-4-yl) quinoline structure, their use for selectively inhibiting CDK4 activity, and pharmaceutical compositions comprising the compounds as treatment for various diseases, including cancer.

Inventors

  • LI JING
  • XU WENQING
  • WANG ZHIWEI

Assignees

  • 百济神州(苏州)生物科技有限公司

Dates

Publication Date
20260505
Application Date
20241010
Priority Date
20231011

Claims (20)

  1. 1. A compound of formula (I): (I) Or an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof, or a prodrug thereof, Wherein: R 1 is H, halogen, -C 1-8 alkyl, cycloalkyl, haloalkyl, heterocyclyl, -C 1-8 alkoxy, or-CN; R 2 is hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo 、-CN、-OR 2a 、-SO 2 R 2a 、-SO 2 NR 2a R 2b 、-COR 2a 、-CO 2 R 2a 、-CONR 2a R 2b 、-NR 2a R 2b 、-NR 2a COR 2b 、-NR 2a CO 2 R 2b 、-NR 2a CONR 2b R 2c , or-NR 2a SO 2 R 2b , wherein each of the-C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent R 2d ; 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 the-C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or 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 atoms to which they are attached form a 3 to 12 membered ring comprising 0,1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, said ring optionally being substituted with at least one substituent R 2f ; R 2d and R 2f are each independently selected from hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo 、-CN、-OR 2g 、-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 , wherein each of said-C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, oxo, -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, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl, or (Two R 2d ) or (two R 2f ) together with the atoms to which they are attached form a 3 to 12 membered ring comprising 0,1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, said ring optionally being substituted with at least one substituent selected from the group consisting of halogen, hydroxy, oxo, -C 1-8 alkyl, -halogenated C 1-8 alkyl, -C 1-8 alkoxy, -halogenated C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halogenated cycloalkyl, heterocyclyl, halogenated heterocyclyl, aryl, halogenated aryl, heteroaryl or halogenated heteroaryl; R 2g 、R 2h and R 2i are each independently selected from hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the-C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, 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, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 3A and R 3B are each independently hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl or-CN, wherein each of the-C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with at least one substituent R 3c , or R 3A and R 3B together with the atoms to which they are attached form an acyl (-C (=o) -) or a3 to 12 membered ring comprising 0,1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, said ring optionally being substituted with at least one substituent R 3c ; Wherein each of said-C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, 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, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 3d 、R 3e and R 3f are each independently selected from hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each of the-C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclyl, aryl, 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, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; R 4 is hydrogen, halogen, -C 1-8 alkyl, cycloalkyl or heterocyclyl, wherein each of said-C 1-8 alkyl, cycloalkyl or heterocyclyl is optionally substituted with at least one substituent selected from halogen, cycloalkyl, halocycloalkyl, heterocyclyl, -C 1-8 alkoxy, -haloC 1-8 alkoxy, oxo, -CN, -OH or-NH 2 ; R 5 、R 6 、R 7 、R 8 and R 9 are each independently selected from H, halogen, -C 1-8 alkyl, -halogenated C 1-8 alkyl, -C 1-8 alkoxy, -halogenated C 1-8 alkoxy, cycloalkyl, halogenated cycloalkyl or-CN; R 10 is selected from-OR 10a OR-NR 10a R 10b ; R 10a and R 10b are each independently selected from hydrogen, -C 1-8 alkyl, halogenated C 1-8 alkyl, cycloalkyl or halogenated cycloalkyl; R 11 is selected from H, -C 1-8 alkyl, -halogenated C 1-8 alkyl, cycloalkyl or halogenated cycloalkyl.
  2. 2. The compound of claim 1, wherein the compound is selected from formula (IIa): (IIa) Wherein R 1 、R 2 、R 3A 、R 3B 、R 5 、R 6 、R 7 、R 8 、R 9 and R 10 are each as defined in claim 1; preferably, the compound is selected from formula (IIb): (IIb) Wherein R 2 、R 3A 、R 3B 、R 6 and R 8 are each as defined in claim 1.
  3. 3. The compound of any one of the preceding claims, wherein R 10 is selected from-OR 10a ; R 10a is independently selected from hydrogen, -C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 cycloalkyl or C 3-6 halogenated cycloalkyl; Preferably, R 10 is selected from-OH, methoxy, ethoxy, propoxy or butoxy; More preferably, R 10 is-OH.
  4. 4. The compound of any one of the preceding claims, wherein R 1 is H, halo, -C 1-4 alkyl, C 3-6 cycloalkyl, -C 1-4 haloalkyl, C 3-6 heterocyclyl, -C 1-4 alkoxy, or-CN; Preferably, R 1 is H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -C 1-4 haloalkyl, C 3-6 heterocyclyl, -CN, methoxy, ethoxy, propoxy or butoxy; More preferably, R 1 is H, -F, -Cl, -Br, -I, methyl, ethyl, cyclopropyl, cyclobutyl, methoxy or ethoxy; even more preferably, R 1 is H, -F, -Cl, or-Br; even more preferably, R 1 is H.
  5. 5. The compound of any one of the preceding claims, wherein R 2 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo 、-CN、-OR 2a 、-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 , wherein 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 2d ; R 2a 、R 2b and R 2c are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, wherein 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 2f , or (R 2a and R 2b )、(R 2b and R 2c ) or (R 2a and R 2c ) together with the atoms to which they are attached form a 3,4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring comprising 0,1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, said ring optionally substituted with at least one substituent R 2f ; R 2d and R 2f are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo 、-CN、-OR 2g 、-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 ; wherein 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 groups 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, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl or haloheteroaryl groups, or When adjacent or co-located, (two R 2d ) or (two R 2f ) together with the atoms to which they are attached form a 3,4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring containing 0,1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, said ring optionally being substituted with at least one substituent-F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halogenated C 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, haloheterocyclyl, phenyl, haloaryl, heteroaryl or haloheteroaryl; R 2g 、R 2h and R 2i are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, wherein 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, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halo cycloalkyl, heterocyclyl, halo, heteroaryl, or heteroaryl.
  6. 6. The compound of any one of the preceding claims, wherein R 2 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxaazepanyl, oxetanyl, azetidinyl, oxa-azaspiro [4.4] nonanyl, hexahydro-1H-furo [3,4-c ] pyrrolyl, octahydropyrrolo [3,4-c ] pyrrolyl, diazaspiro [4.5] decane, oxa-azaspiro [4.5] decane, azabicyclo [3.3.1] nonanyl, piperidinyl, piperazinyl, oxa-azaspiro [2.5] octanyl, oxa-azabicyclo [3.1.1] heptanyl oxa-azabicyclo [2.2.1] heptyl, diazaspiro [5.5] undecyl, oxa-azabicyclo [3.3.1] nonyl, azabicyclo [3.2.1] octyl, azabicyclo [2.1.1] hexyl, pyridyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo [3.2.1] octyl, phenyl, oxo 、-CN、-OR 2a 、-COR 2a 、-CO 2 R 2a 、-CONR 2a R 2b 、-NR 2a R 2b 、-NR 2a COR 2b ; wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxaazepanyl, oxetanyl, azetidinyl, oxa-azaspiro [4.4] nonyl, hexahydro-1H-furo [3,4-c ] pyrrolyl, octahydropyrrolo [3,4-c ] pyrrolyl, diazaspiro [4.5] decyl, oxa-azaspiro [4.5] decyl, azabicyclo [3.3.1] nonyl, piperidinyl, piperazinyl, oxa-azaspiro [2.5] octyl, oxa-azabicyclo [3.1.1] heptyl, oxa-azabicyclo [2.2.1] heptyl, diazaspiro [5.5] undecyl, oxa-azabicyclo [3.3.1] nonyl, azabicyclo [3.2.1] octyl, azabicyclo [2.1.1] hexyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo [3.2.1] octyl, or phenyl, each of which is optionally substituted with at least one substituent R 2d ; R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxaazepanyl, oxetanyl, azetidinyl, oxa-azaspiro [4.4] nonanyl, hexahydro-1H-furo [3,4-c ] pyrrolyl, octahydropyrrolo [3,4-c ] pyrrolyl, diazaspiro [4.5] decane, oxa-azaspiro [4.5] decane, azabicyclo [3.3.1] nonanyl, piperidinyl, piperazinyl, oxa-azaspiro [2.5] octanyl, oxa-azabicyclo [3.1.1] heptanyl, Oxa-azabicyclo [2.2.1] heptyl, diazaspiro [5.5] undecyl, oxa-azabicyclo [3.3.1] nonyl, azabicyclo [3.2.1] octyl, azabicyclo [2.1.1] hexyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo [3.2.1] octyl or phenyl, wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxaazepanyl, oxetanyl, azetidinyl, oxa-azaspiro [4.4] nonanyl, hexahydro-1H-furo [3,4-c ] pyrrolyl, octahydropyrrolo [3,4-c ] pyrrolyl, diazaspiro [4.5] decane, oxa-azaspiro [4.5] decane, azabicyclo [3.3.1] nonanyl, piperidinyl, piperazinyl, oxa-azaspiro [2.5] octanyl, oxa-azabicyclo [3.1.1] heptanyl, oxa-azabicyclo [2.2.1] heptyl, diazaspiro [5.5] undecyl, oxa-azabicyclo [3.3.1] nonyl, azabicyclo [3.2.1] octyl, azabicyclo [2.1.1] hexyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo [3.2.1] octyl, or phenyl each 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 atoms to which they are attached form a 3,4,5, 6, 7, 8, 9,10, 11 or 12 membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen or oxygen as ring members, said ring optionally substituted with at least one substituent R 2f ; R 2d and R 2f are each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxaazepanyl, oxetanyl, azetidinyl, oxa-azaspiro [4.4] nonanyl, hexahydro-1H-furo [3,4-c ] pyrrolyl, octahydropyrrolo [3,4-c ] pyrrolyl, diazaspiro [4.5] decane, oxa-azaspiro [4.5] decane, azabicyclo [3.3.1] nonanyl, piperidinyl, piperazinyl, oxa-azaspiro [2.5] octanyl, oxa-azabicyclo [3.1.1] heptanyl, Oxa-azabicyclo [2.2.1] heptyl, diazaspiro [5.5] undecyl, oxa-azabicyclo [3.3.1] nonyl, azabicyclo [3.2.1] octyl, azabicyclo [2.1.1] hexyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo [3.2.1] octyl, 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 , wherein the methyl group, Ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxaazepanyl, oxetanyl, azetidinyl, oxa-azaspiro [4.4] nonanyl, hexahydro-1H-furo [3,4-c ] pyrrolyl, octahydropyrrolo [3,4-c ] pyrrolyl, diazaspiro [4.5] decyl, oxa-azaspiro [4.5] decyl, azabicyclo [3.3.1] nonyl, piperidinyl, piperazinyl, oxa-azaspiro [2.5] octyl, oxa-azabicyclo [3.1.1] heptyl, oxa-azabicyclo [2.2.1] heptyl, diazaspiro [5.5] undecyl, oxa-azabicyclo [3.3.1] nonyl, azabicyclo [3.2.1] octyl, azabicyclo [2.1.1] hexyl, pyridinyl, Each of pyrimidinyl, pyrazolyl, oxa-azabicyclo [3.2.1] octanyl or phenyl optionally substituted with at least one substituent-F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl butyl, pentyl, hexyl, heptyl, octyl, -halogenated C 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, haloheterocyclyl, phenyl, haloaryl, heteroaryl or haloheteroaryl substitution, or When adjacent or co-located, (two R 2d ) or (two R 2f ) together with the atoms to which they are attached form a 3,4, 5, 6, 7, 8, 9, 10, 11 or 12 membered ring containing 0,1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, said ring optionally being substituted with at least one substituent-F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halogenated C 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, haloheterocyclyl, phenyl, haloaryl, heteroaryl or haloheteroaryl; R 2g 、R 2h and R 2i are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, wherein 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, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halo cycloalkyl, heterocyclyl, halo, heteroaryl, or heteroaryl.
  7. 7. The compound of any one of the preceding claims, wherein R 2 is hydrogen, methyl, ethyl, propyl, butyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxaazepanyl, oxetanyl, azetidinyl, oxa-azaspiro [4.4] nonanyl, hexahydro-1H-furo [3,4-c ] pyrrolyl, octahydropyrrolo [3,4-c ] pyrrolyl, diazaspiro [4.5] decane, oxa-azaspiro [4.5] decane, azabicyclo [3.3.1] nonanyl, piperidinyl, piperazinyl, oxa-azaspiro [2.5] octanyl, oxa-azabicyclo [3.1.1] heptanyl, oxa-azabicyclo [2.2.1] heptanyl, diazaspiro [5.5] undecyl, oxa-azabicyclo [3.3.1] nonanyl, oxa [2.5] octanyl, oxa-azabicyclo [3.3.1] nonanyl, oxa-azabicyclo [2.5] octanyl, oxa-1.1 ] octanyl, oxa-azabicyclo [3.1.1] octanyl, oxa-1, OR-bicyclo [2.1.1] octanyl; wherein the methyl, ethyl, propyl, butyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxaazepanyl, oxetanyl, azetidinyl, oxa-azaspiro [4.4] nonanyl, hexahydro-1H-furo [3,4-c ] pyrrolyl, octahydropyrrolo [3,4-c ] pyrrolyl, diazaspiro [4.5] decane, oxa-azaspiro [4.5] decane, azabicyclo [3.3.1] nonanyl, piperidinyl, piperazinyl, oxa-azaspiro [2.5] octanyl, each of oxa-azabicyclo [3.1.1] heptyl, oxa-azabicyclo [2.2.1] heptyl, diazaspiro [5.5] undecyl, oxa-azabicyclo [3.3.1] nonyl, azabicyclo [3.2.1] octyl, azabicyclo [2.1.1] hexyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo [3.2.1] octyl, or phenyl is optionally substituted with at least one substituent R 2d ; R 2a and R 2b are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxaazepanyl, oxetanyl, azetidinyl, oxa-azaspiro [4.4] nonanyl, hexahydro-1H-furo [3,4-c ] pyrrolyl, octahydropyrrolo [3,4-c ] pyrrolyl, diazaspiro [4.5] decane, oxa-azaspiro [4.5] decane, 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.oxaundecyl, oxa [3.1.1] octanyl, oxa-1.1 ] bicycloalkyl, oxa [ 3.5 ] octanyl, oxa-1.1 ] bicycloalkyl, wherein the methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazepanyl, oxetanyl, azetidinyl, oxa-azaspiro [4.4] nonanyl, hexahydro-1H-furo [3,4-c ] pyrrolyl, octahydropyrrolo [3,4-c ] pyrrolyl, diazaspiro [4.5] decane, oxa-azaspiro [4.5] decane, each of the azabicyclo [3.3.1] nonylalkyl, piperidinyl, piperazinyl, oxa-azaspiro [2.5] octyl, oxa-azabicyclo [3.1.1] heptyl, oxa-azabicyclo [2.2.1] heptyl, diazaspiro [5.5] undecyl, oxa-azabicyclo [3.3.1] nonylalkyl, azabicyclo [3.2.1] octyl, azabicyclo [2.1.1] hexyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo [3.2.1] octyl or phenyl being optionally substituted by 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 atoms to which they are attached form a 3,4,5, 6, 7, 8, 9,10, 11 or 12 membered ring comprising 0, 1 or 2 heteroatoms independently selected from nitrogen or oxygen as ring members, said ring optionally substituted with at least one substituent R 2f ; R 2d and R 2f are each independently selected from 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 2 OH、 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxaazepanyl, oxetanyl, azetidinyl, oxa-azaspiro [4.4] nonyl, hexahydro-1H-furo [3,4-c ] pyrrolyl, octahydropyrrolo [3,4-c ] pyrrolyl, diazaspiro [4.5] decyl, oxa-azaspiro [4.5] decyl azabicyclo [3.3.1] nonylalkyl, piperidinyl, piperazinyl, oxa-azaspiro [2.5] octyl, oxa-azabicyclo [3.1.1] heptyl, oxa-azabicyclo [2.2.1] heptyl, diazaspiro [5.5] undecyl, oxa-azabicyclo [3.3.1] nonylalkyl, azabicyclo [3.2.1] octyl, azabicyclo [2.1.1] hexyl, pyridinyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo [3.2.1] octyl, 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 .
  8. 8. The compound of any one of the preceding claims, wherein 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 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
  9. 9. The compound of any of the preceding claims, wherein R 3A and R 3B are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, or-CN, wherein 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 3c , or R 3A and R 3B 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 comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, said ring being a monocyclic, spiro, fused or bridged ring, said ring being optionally substituted with at least one substituent R 3c ; R 3c is each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, oxo 、-CN、-OR 3d 、-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 , wherein 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, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halogenated C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halogenated cycloalkyl, heterocyclyl, halo, phenyl, heteroaryl, or heteroaryl; R 3d 、R 3e and R 3f are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl, wherein 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, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, heteroaryl, haloaryl, heteroaryl, or heteroaryl; 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 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 comprising 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, said ring being a monocyclic, spiro, fused or bridged ring, said ring being optionally substituted with at least one substituent R 3c ; R 3c is each independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, oxo 、-CN、-OR 3d 、-COR 3d 、-CO 2 R 3d 、-CONR 3d R 3e 、-NO 2 、-NR 3d R 3e 、-NR 3d COR 3e , or-SO 2 R 3d , wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl is optionally substituted with at least one substituent-F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, heptoxy, octoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, 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, wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl is optionally substituted with at least one substituent-F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halogenated C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl, or haloheteroaryl; More preferably, R 3A and R 3B are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl, or R 3A and R 3B together with the atoms to which they are attached form an acyl (-C (=o) -) or a3, 4,5, 6, 7 or 8 membered ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or oxidized sulphur as ring members, said ring being a monocyclic, spiro, fused or bridged ring, said ring being optionally substituted with at least one substituent selected from hydrogen, -F, methyl, ethyl, propyl, butyl, -CF 3 , oxo or-CN.
  10. 10. The compound of any one of the preceding claims, wherein the Is divided into Wherein the method comprises the steps of Refers to being connected to The position of the part, and Refers to being connected to the The position of the portion; Preferably, the said Is divided into 。
  11. 11. The compound of any one of the preceding claims, wherein the Part is-Me, -Et, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 Or (b) 。
  12. 12. The compound of any one of the preceding claims, wherein R 4 is hydrogen, halogen, -C 1-4 alkyl, -C 3-6 cycloalkyl, or heterocyclyl, wherein each of the-C 1-4 alkyl, -C 3-6 cycloalkyl, or heterocyclyl is optionally substituted with at least one substituent selected from halogen, cycloalkyl, halocycloalkyl, heterocyclyl, -C 1-8 alkoxy, -haloC 1-8 alkoxy, oxo, -CN, -OH, or-NH 2 ; Preferably, R 4 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or heterocyclyl, wherein each of the methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or heterocyclyl is optionally substituted with at least one substituent-F, -Cl, -Br, -I, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, heterocyclyl, -C 1-4 alkoxy, -haloC 1-4 alkoxy, oxo, -CN, -OH, or-NH 2 ; More preferably, R 4 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; Even more preferably, R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl ) Isobutyl radical ) Tertiary butyl radical ); Even more preferably, R 4 is isopropyl.
  13. 13. The compound of any one of the preceding claims, wherein R 5 、R 6 、R 7 、R 8 and R 9 are each independently selected from H, halogen, -C 1-4 alkyl, -halogenated C 1-4 alkyl, -C 1-4 alkoxy, -halogenated C 1-4 alkoxy, cycloalkyl, halogenated cycloalkyl, or-CN; Preferably, R 5 、R 6 、R 7 、R 8 and R 9 are each independently selected from H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy or-CN; More preferably, R 5 、R 6 and R 7 are each independently selected from H, -F, -Cl, -Br, -I, methyl, ethyl, propyl or butyl, and/or R 8 is selected from-F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethoxy, propoxy, butoxy or-CN, and/or R 9 is selected from H; Even more 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; Even more preferably, R 5 is selected from H, and R 6 is selected from H, -F or-Cl, and R 7 are each independently selected from H, and R 8 is selected from-F or-Cl, and R 9 is selected from H.
  14. 14. The compound of any one of the preceding claims, wherein R 11 is selected from H, -C 1-4 alkyl, -halogenated C 1-4 alkyl, C 3-6 cycloalkyl, or C 3-6 halogenated cycloalkyl; Preferably, R 11 is selected from H, methyl, ethyl, propyl, butyl, -halogenated C 1-4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; More preferably, R 11 is selected from H, methyl, ethyl, propyl, butyl; Even more preferably, R 11 is H.
  15. 15. The compound of any one of the preceding claims, wherein the compound is selected from the group consisting of 。
  16. 16. A pharmaceutical composition comprising a compound of any one of claims 1-15, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, and a pharmaceutically acceptable excipient.
  17. 17. A method of reducing CDK4 activity by inhibition, comprising administering to a subject a compound according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, comprising the compound of formula (I) or a specific compound exemplified herein.
  18. 18. The method of claim 17, wherein the disease is selected from cancer, preferably breast cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, liver cancer and endometrial cancer.
  19. 19. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or prodrug thereof, in the manufacture of a medicament for the treatment of a disease that is likely to be affected by CDK4 modulation.
  20. 20. The use according to claim 19, wherein the disease is cancer, preferably breast cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, liver cancer and endometrial cancer.

Description

Substituted 6- (pyrimidin-4-yl) quinoline compounds as cyclin dependent kinase inhibitors Technical Field The present disclosure provides compounds containing a 6- (pyrimidin-4-yl) quinoline structure, their use for selectively inhibiting cyclin dependent kinase 4 (CDK 4) activity, and pharmaceutical compositions containing the compounds as treatment for various diseases, including cancer. Background Human kinases are a broad class of enzymes that add phosphate groups (PO 43-) to other molecules in the human body [1. FASEB J. 1995; 9 (8): 576-96.2. Enzyme Res. 2011; 2011: 794089 ]. There are over 500 kinase-encoding genes in the human genome, as well as their substrates, including proteins, lipids and nucleic acids [ 3.cell Signal 2004, 9 months; 16 (9): 983-9.4. Cell 2017, 8, 10 days; 170 (4): 605-635 ]. Kinase disorders are identified in a number of diseases including cancer, autoimmune, neurological disorders, diabetes and cardiovascular diseases. For example, mutated kinases can become continuously active and thus cause various cellular abnormalities, leading to initiation or growth of cancer. The use of small molecule inhibitors to inhibit kinase activity has proven to be a successful approach to the treatment of cancer and other diseases [5. Expert REV ANTICANCER th er. Month 12 2018; 18 (12): 1249-1270 ]. Up to now, more than 70 kinase inhibitors have been approved by the FDA, EMA or CDE as drugs [6. Nat Rev Drug discovery 5 month 2018; 17 (5): 353-377 ]. The protein kinase family accounts for the majority of the kinase superfamily. For protein targets, protein kinases can phosphorylate amino acids including serine, threonine, tyrosine, and histidine. [ 7.science 12, 6; 298 (5600): 1912-34 ] protein kinase plays a major role in cell activation by antagonism of kinases and phosphatases, via reversible phosphorylation and dephosphorylation of proteins, an important component of cell signaling, because the phosphorylated and non-phosphorylated states of target proteins can have different activity levels. [ 8.Biochimie.2014, 12.107 Pt B167-87.9. CLIN TRANSL Oncol.2006, 8 (3): 153-60 ] different protein kinases including EGFR, BTK, ALK, JAK, PI K and CDK have proven to be good targets for cancer drug development. The overactivated cell cycle is a common feature of human cancers [10. Nat Rev cancer 2009, 3 months; 9 (3): 153-66 ]. Cyclin is one of the most important core cell cycle regulatory factors. Four basic cyclin types are found in humans, including G1 cyclin, G1/S cyclin, S cyclin and M cyclin. In order to drive the cell cycle forward, cyclin must activate or inactivate many target proteins within the cell. And these cyclin proteins drive the cell cycle event mainly by cooperating with a family of enzymes called cyclin-dependent kinases (cdks). Cdk kinase is inactive itself but binding to cyclin activates it, rendering the Cdk/cyclin complex a functional holoenzyme and allowing it to modify the target protein [11. Orphanet J Rare dis 2020, 8/6; 15 (1): 203.12. J Mol biol 1999, 4/16; 287 (5): 821-8 ]. There are 26 serine/threonine protein kinases forming the CDKs and CDK-like branches of the CMGC subfamily of the human kinase group, 21 of which are classified as CDKs. Of all the CDKs currently identified, CDK1, CDK2, CDK4 and CDK6 are thought to directly regulate the cell cycle, primarily by phosphorylating and inactivating RB proteins and releasing E2F transcription factors, whereas the E2F downstream pathway plays a key role in regulating initiation of DNA replication. And CDK4/6 is critical for G1 early initiation and G1/S conversion. [13. CELL DEATH Differ.1998, 2 nd, 5 (2): 132-40.14. Oncogene.2016, 9 th, 15 th, 35 (37): 4829-35 ] CDK 4/6-related pathways are commonly deregulated in many different cancer types (such as breast, lung and pancreatic cancers). And there are 4 approved CDK4/6 inhibitors including palbociclib (palbociclib), rebabociclib (ribociclib), abbe-cili (abemaciclib) and fraxil (trilaciclib), all of which have been approved by the FDA or CDE for use as single agents for the treatment of hr+, her 2-breast cancer or in combination with endocrine therapy. This approach shows good efficacy clinically, but CDK4/6 inhibitors more or less lead to hematopoietic toxicity such as neutropenia and leukopenia, greatly limiting the clinical use of CDK4/6 inhibitors. And the emerging data indicate that inhibition of CDK 6/cyclin D3 may cause clinically observed hematological toxicity [ 15.cell. 8.20. 2004; 118 (4): 493-504.16. Haemato logica. 2021, 10. 1; 106 (10): 2624-2632.] whereas CDK 4/cyclin D1 is an oncogenic driver in different cancers [17. Nat Commun. 2019, 12. 20; 10 (1): 5817.18.18. Cancer cell. 2006; 9 (1): 23-32.]. Development of CDK4 selective inhibitors may be advantageous, including increased efficacy, reduced hematological toxicity, and expanded clinical use in many cancers including, but not limited to, breast, lung, pancreatic, prostate, bone, liver, and endometrial cancers