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

Abstract

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

Description

Technical Field

[0001] The present disclosure provides compounds containing a 6-(pyrimidin-4-yl)quinoline structure, their use for selectively inhibiting cyclin-dependent kinase 4 (CDK4) activity, and pharmaceutical compositions comprising these compounds that are useful for treating various diseases including cancer. Background Art

[0002] Human kinases are a large class of enzymes that add a phosphate group (PO 4 3- ) to other molecules in the human body [1. FASEB J. [Journal of the Federation of American Societies for Experimental Biology] May 1995; 9(8):576-96. 2. Enzyme Res. [Enzyme Research] 2011; 2011:794089.]. There are more than 500 genes encoding kinases present in the human genome and their substrates, including proteins, lipids, and nucleic acids [3. Cell Signal. [Cell Signaling] September 2004; 16(9):983-9. 4. Cell. [Cell] August 10, 2017; 170(4):605-635.]. Kinase dysregulation has been identified in many diseases, including cancer, autoimmunity, neurological disorders, diabetes, and cardiovascular diseases. For example, mutant kinases can become constitutively active, causing a variety of cellular abnormalities that can lead to the occurrence or development of cancer. Inhibiting kinase activity using small molecule inhibitors has proven to be a successful approach for treating cancer and other diseases [5. Expert Rev Anticancer Ther. [Expert Review of Anticancer Therapy] December 2018; 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. [Nature Reviews Drug Discovery] May 2018; 17(5):353-377.].

[0003] 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. 6 December 2002; 298(5600):1912-34.]. Protein kinases play a major role in cell activation, and through the antagonistic action of kinases and phosphatases, the reversible phosphorylation and dephosphorylation of proteins are important components of cell signaling because the phosphorylated and non-phosphorylated states of target proteins can have different activity levels [8. Biochimie. December 2014; 107PtB:167-87. 9. Clin Transl Oncol. March 2006; 8(3):153-60.]. Different protein kinases, including EGFR, BTK, ALK, JAK, PI3K, and CDK, have been shown to be good targets for cancer drug development.

[0004] Overactivated cell cycle is a common feature of human cancers [10. Nat Rev Cancer. [Nature Reviews Cancer] March 2009; 9(3): 153-66.]. And cyclins are one of the most important core cell cycle regulators. Four basic cyclin types have been found in humans, including G1 cyclins, G1 / S cyclins, S cyclins, and M cyclins. To drive the cell cycle forward, cyclins must activate or inactivate many target proteins within the cell. Also, these cyclins mainly drive cell cycle events by cooperating with an enzyme family called cyclin-dependent kinases (Cdks). Cdk kinases themselves are inactive, but binding to cyclins can activate them, making the CDK / cyclin complex a functional holoenzyme and allowing it to modify target proteins [11. Orphanet J Rare Dis. [Journal of Orphan Diseases] August 6, 2020; 15(1): 203. 12. J Mol Biol. [Journal of Molecular Biology] April 16, 1999; 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; among them, 21 are classified as CDKs. Among all the CDKs identified so far, CDK1, CDK2, CDK4, and CDK6 are considered direct regulators of the cell cycle, mainly by phosphorylating and inactivating the RB protein and releasing the E2F transcription factor, and the E2F downstream pathway is crucial in regulating the initiation of DNA replication. Also, CDK4 / 6 is very important for the early G1 initiation and G1 / S transition [13. Cell Death Differ. [Cell Death and Differentiation] February 1998; 5(2): 132-40. 14. Oncogene. [Oncogene] September 15, 2016; 35(37): 4829-35.].

[0005] The CDK4 / 6-related pathway is typically dysregulated in many different cancer types, such as breast cancer, lung cancer, and pancreatic cancer. Moreover, there are 4 approved CDK4 / 6 inhibitors, including palbociclib, ribociclib, abemaciclib, and trilaciclib, which have been approved by the FDA or CDE as single agents or in combination with endocrine therapy to treat HR+, Her2-breast cancer. This approach has shown good efficacy clinically, but CDK4 / 6 inhibitors more or less cause hematological toxicity, such as neutropenia and leukopenia, which greatly limits the clinical application of CDK4 / 6 inhibitors. Furthermore, emerging data suggest that inhibiting CDK6 / cyclin D3 may lead to the hematological toxicity observed clinically [15. Cell. August 20, 2004; 118(4):493-504. 16. Haematologica. October 1, 2021; 106(10):2624-2632.], while CDK4 / cyclin D1 is an oncogenic driver in different cancers [17. Nat Commun. December 20, 2019; 10(1):5817. 18. 18. Cancer Cell. January 2006; 9(1):23-32.]. Developing CDK4-selective inhibitors may bring many advantages, including improving efficacy, reducing hematological toxicity, and expanding clinical application in many cancers, including but not limited to breast cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, liver cancer, and endometrial cancer.

[0006] Since the protein structures of CDK4 and CDK4 have very high homology, there is still a great need to develop CDK4-selective inhibitors. Most of the previously reported compounds are CDK4 / 6 dual inhibitors. Here, we report compounds with high CDK4 selectivity compared to all other kinases, including CDK6, which may lead to better efficacy, improved toxicity profiles, and the potential to overcome resistance mechanisms, etc. Summary of the Invention

[0007] An object of the present invention is to provide compounds and derivatives that act as CDK4 inhibitors, their preparation methods, and uses.

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

[0009]

[0010] or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analogue, or its prodrug,

[0011] Wherein:

[0012] Ring CyA is a 3- to 8-membered ring, said ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members; said ring is optionally substituted by at least one substituent R 10 substituted;

[0013] n is 0, 1, 2, 3, 4 or 5;

[0014] m is 0 or 1; provided that when m = 0, this moiety is replaced as a whole by H;

[0015] R 1 is H, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, haloalkyl, heterocyclic group, 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 ; wherein each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted by at least one substituent R 1d substituted;

[0016] R 1a 、R 1b and R 1c are each independently selected from hydrogen, -C 1-8 alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, wherein each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted by at least one substituent R 1f substituted;

[0017] R 1d and R 1fEach independently selected from hydrogen, halogen, hydroxy, -C 1-8 alkyl, -halo-C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic, halocyclic, aryl, haloaryl, heteroaryl or haloheteroaryl, wherein each of said -C 1-8 alkyl, -halo-C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic, halocyclic, aryl, haloaryl, heteroaryl or haloheteroaryl is optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo-C 1-8 alkyl, -C 1-8 alkoxy, -halo-C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic, halocyclic, aryl, haloaryl, heteroaryl or haloheteroaryl;

[0018] R 2 is hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic, 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 said -C 1-8 alkyl, -C2-8 An alkenyl group, -C 2-8 An alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group is each optionally substituted with at least one substituent R 2d ;

[0019] 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, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group is each optionally substituted with at least one substituent R 2f ; or

[0020] (R 2a and R 2b ), (R 2b and R 2c ), or (R 2a and R 2c ) together with one or more atoms to which they are attached form a 3- to 12-membered ring, the ring containing 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members, the ring being optionally substituted with at least one substituent R 2f ;

[0021] R 2d and R 2f are each independently selected from hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, 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 , -NR2g CONR 2h R 2i 、 or –NR 2g SO 2 R 2h ; wherein said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, 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 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; or

[0022] (two R 2d ) or (two R 2f ) together with one or more atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, 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 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl;

[0023] 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, heterocyclic group, aryl or heteroaryl, wherein said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -halo C 1-8an alkoxy group, -C 2-8 an alkenyl group, -C 2-8 an alkynyl group, a cycloalkyl group, a halocycloalkyl group, a heterocyclic group, a halopyrimidine group, an aryl group, a haloaryl group, a heteroaryl group or a haloheteroaryl group;

[0024] R 3A and R 3B are each independently hydrogen, a halogen, -C 1-8 an alkyl group, -C 2-8 an alkenyl group, -C 2-8 an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group or -CN; wherein each of said -C 1-8 an alkyl group, -C 2-8 an alkenyl group, -C 2-8 an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group is optionally substituted with at least one substituent R 3c ; or

[0025] R 3A and R 3B together with the atoms to which they are attached form an acyl group (-C(=O)-) or a 3- to 12-membered ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring being optionally substituted with at least one substituent R 3c ;

[0026] each R 3c is independently selected from hydrogen, a halogen, -C 1-8 an alkyl group, -C 2-8 an alkenyl group, -C 2-8 an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, 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 R3e ; wherein said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by at least one substituent selected from the group consisting of: 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 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl;

[0027] 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, heterocyclic group, aryl or heteroaryl, wherein said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by at least one substituent selected from the group consisting of: 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 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl;

[0028] R 4 is hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, oxo, -CN, -OR 401b , -SO 2 R 401b , -SO 2 NR 401b R 401c , -COR 401b , -CO 2 R 401b , -CONR 401b R 401c , -NO 2 , -NR401b R 4c 、-NR 401b COR 401c 、-NR 401b CO 2 R 401c 、-NR 401b CONR 401c R 401d or –NR 401b SO 2 R 401c ; wherein said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted with at least one substituent R 4a replace;

[0029] R 401b , R 401c and R 401d are each independently selected from hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl;

[0030] Each R 4a are independently selected from hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -OR 4b 、-SO 2 R 4b 、-SO 2 NR 4b R 4c 、-COR 4b , -CO 2 R 4b 、-CONR 4b R4c 、-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 ; wherein said -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted with at least one substituent selected from the group consisting of halogen, hydroxy, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl;

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

[0032] Preferably, R 4 It is hydrogen, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8Alkynyl, cycloalkyl or heterocyclic group; wherein said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl or heterocyclic group is each optionally substituted with at least one substituent R 4a ;

[0033] Each R 4a is independently selected from hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, oxo, -CN, -OR 4b , -SO 2 R 4b , -SO 2 , -SO 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 ; wherein said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -halo C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl;

[0034] R 4b , R 4c and R 4d are each independently selected from hydrogen, -C 1-8 alkyl, -C 2-8Alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, wherein said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -halo C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl;

[0035] R 5 、R 6 、R 7 、R 8 and R 9 are each independently selected from H, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, 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 ; wherein said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted by at least one substituent R 5d ;

[0036] R 5a 、R 5b and R 5c are each independently selected from hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, wherein said -C1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted with at least one substituent R 5f Substituted;

[0037] R 5d And R 5f Are each independently selected from hydrogen, halogen, hydroxy, -C 1-8 Alkyl, -haloalkyl C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, haloalkylcycloalkyl, heterocyclic group, haloheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl, wherein the -C 1-8 Alkyl, -haloalkyl C 1-8 Alkyl, -C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, haloalkylcycloalkyl, heterocyclic group, haloheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl is each optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 Alkyl, -haloalkyl C 1-8 Alkyl, -C 1-8 Alkoxy, -haloalkyl C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, haloalkylcycloalkyl, heterocyclic group, haloheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl;

[0038] R 10 Is selected from H, halogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclic group, 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 ; wherein the -C1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, each of which is optionally substituted by at least one substituent R 10d substituted;

[0039] R 10a , R 10b and R 10c are each independently selected from hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, wherein the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, each of which is optionally substituted by at least one substituent R 10f substituted;

[0040] R 10d and R 10f are each independently selected from hydrogen, halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl, wherein the -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl, each of which is optionally substituted by at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -halo C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl;

[0041] R 11 is selected from H, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl; wherein the -C 1-8 alkyl, -C2-8 An alkenyl group or -C 2-8 each of the alkynyl groups is optionally substituted with at least one substituent R 11a ;

[0042] R 11a is selected from hydrogen, halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl, wherein each of the -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl is optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -halo C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl.

[0043] Aspect 2. The compound according to Aspect 1, wherein the compound is selected from formula (IIa), (IIb), (IIc), (IId), (IIe) or (IIaa):

[0044]

[0045] wherein R 1 , R 2 , R 3A , R 3B , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , m and n are each as defined in Aspect 1;

[0046] Preferably, the compound is selected from formula (IIf), (IIg), (IIh), (IIi), (IIab) or (IIac):

[0047]

[0048] wherein R 1 、R 2 、R 3A 、R 3B 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 and n are each as defined in aspect 1; more preferably, the compound is selected from formula (IIj), (IIk), (IIl) or (IIm):

[0049]

[0050]

[0051] wherein R 1 、R 2 、R 3A 、R 3B 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 and n are each as defined in aspect 1; even more preferably, the compound is selected from formula (IIn), (IIo), (IIp) or (IIq):

[0052]

[0053] wherein R 1 、R 2 、R 3A 、R 3B 、R 5 、R 6 、R 7 、R 8 、R 10 、m and n are each as defined in aspect 1.

[0054] Aspect 3. A compound according to any one of the preceding aspects, wherein ring CyA is a 3-, 4-, 5-, 6-, 7- or 8-membered ring, the ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members; the ring is optionally substituted with 0, 1, 2, 3, 4 or 5 R 10 substituents; the ring is a saturated or unsaturated ring;

[0055] Preferably, CyA is a 3-, 4-, 5-, 6-, 7- or 8-membered saturated ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members; the ring is optionally substituted with 0, 1, 2 or 3 R 10 substituents;

[0056] More preferably, CyA is a 5-, 6- or 7-membered saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen or oxygen as one or more ring members; the ring is optionally substituted with 0, 1, 2 or 3 R 10 substituents;

[0057] Even more preferably, CyA is a ring selected from tetrahydrofuranyl or tetrahydropyranyl; the ring is optionally substituted with 0, 1, 2 or 3 R 10 substituents; or

[0058] Even more preferably, CyA is a ring selected from piperidinyl; the ring is optionally substituted with 0, 1, 2 or 3 R 10 substituents.

[0059] Aspect 4. A compound according to any one of the preceding aspects, wherein the ring CyA is

[0060] Preferably, CyA is

[0061] More preferably, CyA is

[0062] Even more preferably, CyA is

[0063] Aspect 5. A compound according to any one of the preceding aspects, wherein R 10 is selected from -H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, 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 10aCONR 10b R 10c ; wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted by at least one substituent R 10d ;

[0064] R 10a , R 10b and R 10c 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, heterocyclic group, phenyl or heteroaryl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted by at least one substituent R 10f ;

[0065] R 10d and R 10f are each independently selected from hydrogen, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, phenyl, haloaryl, heteroaryl or haloheteroaryl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, phenyl, haloaryl, heteroaryl or haloheteroaryl is optionally substituted by 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, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C2-8 Alkenyl, -C 2-8 is substituted by alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halogenated cycloalkyl, heterocyclic group, halogenated heterocyclic group, phenyl, halogenated aryl, heteroaryl or halogenated heteroaryl;

[0066] Preferably, R 10 is selected from -H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl, heteroaryl, -CN, -OH, -NH 2 , -COOMe, -COOEt, -COOCH 2 CH 2 CH 3 , -COOCH(CH 3 ) 2 , -COOCH 2 CH 2 CH 2 CH 3 , -COOCH(CH 3 )CH 2 CH 3 , -COOCH 2 CH(CH 3 ) 2 or -COOC(CH 3 ) 3 ;

[0067] More preferably, R 10 is -OH, -COOMe, -COOEt, -COOCH 2 CH 2 CH 3 , -COOCH(CH 3 ) 2 , -COOCH 2 CH 2 CH 2 CH 3 , -COOCH(CH 3 )CH 2 CH 3 , -COOCH 2 CH(CH 3 ) 2 or -COOC(CH 3 ) 3 .

[0068] Aspect 6. A compound according to any one of the preceding aspects, wherein the Part is

[0069] Aspect 7. A compound according to any one of the foregoing aspects, wherein R 1 is H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, haloalkyl, heterocyclic group, -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 ; wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, haloalkyl or heterocyclic group is optionally substituted by at least one substituent R 1d ;

[0070] R 1a , R 1b and R 1c are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted by at least one substituent R 1f ;

[0071] R 1d and R 1f are each independently selected from hydrogen, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halosubstituted heterocyclic group, phenyl, haloaryl, heteroaryl or halosubstituted heteroaryl, wherein said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halosubstituted heterocyclic group, phenyl, haloaryl, heteroaryl or halosubstituted heteroaryl is each optionally substituted with at least one substituent -F, -Cl, -Br, -I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halosubstituted heterocyclic group, phenyl, haloaryl, heteroaryl or halosubstituted heteroaryl;

[0072] 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, heterocyclic group or -CN;

[0073] More preferably, R 1 is H, methyl, ethyl, n - propyl, isopropyl, n - butyl, sec - butyl, isobutyl or tert - butyl.

[0074] Aspect 8. The compound according to any one of the foregoing aspects, wherein R 2 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl, heteroaryl, oxo, -CN, -OR 2a , -SO 2 R 2a , -SO 2 NR 2a R 2b , -COR 2a , -CO 2 R2a 、 -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 said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted by at least one substituent R 2d ;

[0075] 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, heterocyclic group, phenyl or heteroaryl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted by at least one substituent R 2f ; or

[0076] (R 2a and R 2b ), (R 2b and R 2c ) or (R 2a and R 2c ) together with one or more atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, said ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, and said ring is optionally substituted by at least one substituent R 2f ;

[0077] R 2d and R 2fare 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 the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl radicals is optionally substituted with at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -haloC 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl or haloheteroaryl; or

[0078] When adjacent or co-located, (two R 2d ) or (two R 2fTogether with one or more atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, said ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally being substituted by at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halopyrrolyl, phenyl, haloaryl, heteroaryl or haloheteroaryl substituted;

[0079] 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, heterocyclic group, phenyl or heteroaryl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted by 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, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halopyrrolyl, phenyl, haloaryl, heteroaryl or haloheteroaryl substituted.

[0080] Aspect 9. The compound according to any one of the preceding aspects, wherein R 2is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxaazepanyl, 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 2b ; wherein each of said 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]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 substituted;

[0081] R 2a and R 2bEach independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxaazepanyl, 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, pyridyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl or phenyl, wherein each of said 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]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, pyridyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl or phenyl is optionally substituted by at least one substituent R 2f ; or

[0082] (R 2a and R 2b ), (R 2b and R 2c ), or (R 2a and R 2c)Together with one or more atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, said ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen or oxygen as one or more ring members, said ring being optionally substituted by at least one substituent R 2f substituted;

[0083] 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]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, pyridyl, 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 ; wherein said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8Each of 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 is optionally substituted by at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halosubstituted heterocyclic group, phenyl, haloaryl, heteroaryl or halosubstituted heteroaryl; or

[0084] When adjacent or geminal, (two R 2d ) or (two R 2f ) together with one or more atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, the ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, the ring optionally being substituted by at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halosubstituted heterocyclic group, phenyl, haloaryl, heteroaryl or halosubstituted heteroaryl;

[0085] R 2g 、R 2h and R 2i are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl, wherein said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is each optionally substituted by 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, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halocyclic group, phenyl, haloaryl, heteroaryl or haloheteroaryl substituted.

[0086] Aspect 10. The compound according to any one of the foregoing aspects, wherein R 2 is hydrogen, methyl, ethyl, propyl, butyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazepanyl, oxetanyl, azetidinyl, oxa-azaspiro[4.4]nonanyl, hexahydro-1H-furo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-c]pyrrolyl, diazaspiro[4.5]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, pyridyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl, phenyl, -OR 2a , -NR 2a R 2b or -NR 2a COR 2b; wherein each of the methyl, ethyl, propyl, butyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazepanyl, oxetanyl, azetidinyl, oxa - azaspiro[4.4]nonanyl, hexahydro - 1H - furo[3,4 - c]pyrrolyl, octahydropyrrolo[3,4 - c]pyrrolyl, diazaspiro[4.5]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 by at least one substituent R 2d substituted;

[0087] R 2a and R 2bEach independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxaazepanyl, 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, pyridyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl or phenyl, wherein each of said methyl, ethyl, propyl, 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]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, pyridyl, pyrimidinyl, pyrazolyl, oxa-azabicyclo[3.2.1]octanyl or phenyl is optionally substituted with at least one substituent R 2f substituted; or

[0088] (R 2a and R 2b ), (R 2b and R 2c ) or (R 2a and R 2c ) together with one or more atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, said ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen or oxygen as one or more ring members, said ring being optionally substituted with at least one substituent R 2f substituted;

[0089] R 2d and R2f 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]nonanyl, hexahydro - 1H - furano[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, pyridyl, pyrimidinyl, pyrazolyl, oxa - azabicyclo[3.2.1]octanyl, phenyl, oxo, -CN, -OH, methoxy, ethoxy, propoxy, butoxy, pentyloxy, 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 。

[0090] Aspect 11. A compound as described in any one of the foregoing aspects, 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 ,

[0091]

[0092] Aspect 12. A compound as described in any one of the foregoing aspects, wherein R 3A and R 3B are each independently hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl, heteroaryl or -CN; wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted with at least one substituent R 3c ; or

[0093] R 3A and R 3B together with the atoms to which they are attached form an acyl group (-C(=O)-) or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, said ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring being a monocyclic, spiro, fused or bridged ring, said ring being optionally substituted with at least one substituent R 3c ;

[0094] Each R 3care 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 the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, or heteroaryl radicals is optionally substituted with at least one -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, halocycloalkyl, heterocyclyl, haloheterocyclyl, phenyl, haloaryl, heteroaryl or haloheteroaryl substituted;

[0095] 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 2-8Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl, wherein said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is each 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, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl;

[0096] 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, heterocyclic group, phenyl, heteroaryl or -CN; or

[0097] R 3A and R 3B together with the atoms to which they are attached form an acyl group (-C(=O)-) or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, said ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring being a monocyclic, spiro, fused or bridged ring, said ring being optionally substituted with at least one substituent R 3c substituted;

[0098] Each R 3c is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, oxo, -CN, -OR 3d , -COR 3d , -CO 2 R 3d , -CONR 3d R 3e , -NO 2 , -NR 3d R 3e , -NR 3dCOR 3e or -SO 2 R 3d ; wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group is optionally substituted by at least one substituent -F, -Cl, -Br, -I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, phenyl, haloaryl, heteroaryl or haloheteroaryl;

[0099] 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 said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl is optionally substituted by at least one substituent -F, -Cl, -Br, -I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl;

[0100] More preferably, R 3A and R 3B are each independently hydrogen, methyl, ethyl, propyl, butyl, pentyl; or

[0101] R 3A and R 3B together with the atoms to which they are attached form an acyl group (-C(=O)-) or a 3-, 4-, 5-, 6-, 7- or 8-membered ring, said ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or oxidized sulfur as one or more ring members, said ring being a monocyclic, spiro, fused or bridged ring, said ring being optionally substituted by at least one substituent selected from hydrogen, -F, methyl, ethyl, propyl, butyl, -CF 3 , oxo or -CN.

[0102] Aspect 13. A compound according to any of the preceding aspects, wherein the moiety is

[0103]

[0104] wherein * 3 refers to the position attached to the part, and ** 3 refers to the position attached to this part;

[0105] Preferably, the part is

[0106]

[0107] Aspect 14. A compound according to any one of the foregoing aspects, wherein the part is -Me, -Et,

[0108]

[0109]

[0110]

[0111] Aspect 15. A compound according to any one of the foregoing aspects, wherein R 4 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, aryl, heteroaryl, oxo, -CN, -OR 401b , -SO 2 R 401b , -SO 2 NR 401b R 401c , -COR 401b , -CO 2 R 401b , -CONR 401b R 401c , -NO 2 , -NR 401b R 4c , -NR 401b COR 401c , -NR 401b CO 2 R 401c , -NR 401b CONR 401c R401d or -NR 401b SO 2 R 401c ; wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, aryl or heteroaryl is optionally substituted with at least one substituent R 4a ;

[0112] R 401b , R 401c and R 401d 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, heterocyclic group, phenyl or heteroaryl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of: 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 alkynyl, cycloalkyl, halo cycloalkyl, heterocyclic group, halo heterocyclic group, aryl, halo aryl, heteroaryl or halo heteroaryl;

[0113] Each R 4a is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, 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 ; wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -halo C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl;

[0114] R 4b , R 4c and R 4d 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, heterocyclic group, phenyl or heteroaryl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -halo C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl;

[0115] Preferably, R 4is 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, heterocyclic group, -COOMe, -COOEt, -COOC 3 H 7 , -COOCH(CH 3 ) 2 , -COOCH 2 CH 2 CH 2 CH 3 , -COOCH(CH 3 )CH 2 CH 3 , -COOCH 2 CH(CH 3 ) 2 , -COOC(CH 3 ) 3 , -CH 2 OH, -CH(CH 3 )OH, -C(CH 3 ) 2 , -CH 2 NH 2 , -CH(CH 3 )NH 2 or -C(CH 3 ) 2 NH 2 ;

[0116] More preferably, R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl isobutyl tert-butyl , -COOMe, -COOEt, -COOCH 2 CH 2 CH 3 , -COOCH(CH 3 ) 2 , -COOCH 2 CH 2 CH 2 CH 3 , -COOCH(CH 3 )CH 2 CH 3 , -COOCH 2 CH(CH 3 ) 2 , -COOC(CH 3 )3 , -CH 2 OH, -CH(CH 3 )OH, -C(CH 3 ) 2 OH, -CH 2 NH 2 , -CH(CH 3 )NH 2 or -C(CH 3 ) 2 NH 2 .

[0117] Aspect 16. A compound as described in any one of the foregoing aspects, wherein R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, 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 ; wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted by at least one substituent R 5d ;

[0118] R 5a , R 5b and R 5c are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl, wherein said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is each optionally substituted with at least one substituent R 5f Substituted;

[0119] R 5d And R 5f Are each independently selected from hydrogen, -F, -Cl, -Br, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halocyclic group, phenyl, haloaryl, heteroaryl or haloheteroaryl, wherein said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 Alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halocyclic group, phenyl, haloaryl, heteroaryl or haloheteroaryl is each optionally substituted with at least one substituent selected from the group consisting of: 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 Alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl;

[0120] Preferably, R 5 、R 6 、R 7 、R 8 And R 9 Are each independently selected from H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8Alkynyl, 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 ;

[0121] R 5a , R 5b and R 5c 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;

[0122] More preferably, R 5 , R 6 , R 7 , R 8 and R 9 Each is independently selected from H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl, heteroaryl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -CN.

[0123] Aspect 17. A compound as described in any one of the preceding aspects, wherein 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

[0124] R 8Selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -CN; and / or

[0125] R 9 Selected from H;

[0126] Preferably, R 5 、R 6 and R 7 are each independently selected from H, -F, -Cl, methyl, ethyl, propyl, butyl; and / or

[0127] R 8 is selected from -F, -Cl, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, -CN; and / or

[0128] R 9 is selected from H.

[0129] Aspect 18. The compound according to any one of the foregoing aspects, wherein R 11 is selected from H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl or -C 2-8 alkynyl; wherein each of the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl or -C 2-8 alkynyl is optionally substituted by at least one substituent R 11a ;

[0130] R 11a is selected from hydrogen, halogen, hydroxyl, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl, wherein each of the -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl is optionally substituted by at least one substituent selected from the group consisting of: halogen, hydroxyl, -C 1-8 alkyl, -halo C1-8 alkyl, -C 1-8 alkoxy, -halo-C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halosubstituted heterocyclic group, aryl, haloaryl, heteroaryl or halosubstituted heteroaryl;

[0131] Preferably, R 11 is selected from H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl or -C 2-8 alkynyl;

[0132] More preferably, R 11 is selected from H, methyl, ethyl, propyl, butyl;

[0133] Even more preferably, R 11 is H.

[0134] Aspect 19. A compound as described in any of the preceding aspects, wherein m = 0 and the moiety is replaced as a whole by H.

[0135] Aspect 20. A compound as described in any of the preceding aspects, wherein the compound is selected from

[0136]

[0137] Aspect 21. A pharmaceutical composition comprising a compound as described in any of Aspects 1 - 20 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof, and a pharmaceutically acceptable excipient.

[0138] Aspect 22. A method of inhibiting CDK4 activity by reducing, the method comprising administering to an individual a compound as described in any of Aspects 1 - 19 or a pharmaceutically acceptable salt thereof, including the compound of formula (I) or the specific compounds exemplified herein.

[0139] Aspect 23. The method as described in Aspect 22, wherein the disease is selected from cancer, preferably breast cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, liver cancer and endometrial cancer.

[0140] Aspect 24. Use of a compound as described in any of Aspects 1 - 20 or a pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug thereof in the manufacture of a medicament for treating a disease that can be affected by CDK4 regulation.

[0141] Aspect 25. The use as described in aspect 24, wherein the disease is cancer, preferably breast cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, liver cancer and endometrial cancer.

[0142] Aspect 26. A method for treating a disease or disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of aspects 1-20 as a CDK4 kinase inhibitor, wherein the disease or disorder is related to the inhibition of CDK4.

[0143] Aspect 27. The method as described in aspect 26, wherein the disease is selected from cancer, preferably breast cancer, lung cancer, pancreatic cancer, prostate cancer, bone cancer, liver cancer and endometrial cancer. Detailed embodiments

[0144] The following terms have the indicated meanings throughout the specification:

[0145] Unless otherwise specifically defined elsewhere in this document, all other technical and scientific terms used in this invention have the meanings commonly understood by those of ordinary skill in the art to which this invention belongs.

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

[0147] As used herein, including in the appended claims, unless the context clearly indicates otherwise, singular forms of words such as "a / an" and "the" include their corresponding plural referents.

[0148] Unless the context clearly indicates otherwise, the term "or" means the term "and / or" and can be used interchangeably with the term "and / or".

[0149] The term "alkyl" includes hydrocarbon groups selected from straight-chain and branched-chain saturated hydrocarbon groups, the hydrocarbon groups containing from 1 to 18, for example from 1 to 12, further for example from 1 to 10, still further for example from 1 to 8, or from 1 to 6, or from 1 to 4 carbon atoms. An alkyl group containing from 1 to 6 carbon atoms (i.e., C 1-6Examples of (alkyl) include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or sec-butyl (“s-Bu”), 1,1-dimethylethyl or tert-butyl (“t-Bu”), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups.

[0150] The term “propyl” includes 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”).

[0151] The term “butyl” includes 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or sec-butyl (“s-Bu”), 1,1-dimethylethyl or tert-butyl (“t-Bu”).

[0152] 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.

[0153] 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.

[0154] The term “alkylene” refers to a divalent alkyl group obtained by removing two hydrogens from an alkane. Alkylene includes, but is not limited to, methylene, ethylene, propylene, etc.

[0155] The term “halogen” includes fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0156] The term “alkenyl” includes hydrocarbon groups selected from straight-chain and branched-chain hydrocarbon groups that contain at least one C═C double bond and from 2 to 18, such as from 2 to 8, and further such as from 2 to 6 carbon atoms. Alkenyl groups (e.g., C 2-6Examples of (alkenyl) include, but are not limited to: ethenyl (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 hex-1,3-dienyl groups.

[0157] The term "alkenylene" refers to a divalent alkenyl group obtained by removing two hydrogens from an alkene. Alkenylene includes, but is not limited to, vinylene, butenylene, etc.

[0158] The term "alkynyl" includes hydrocarbon groups selected from straight-chain and branched-chain hydrocarbon groups, which contain at least one C≡C triple bond and from 2 to 18, for example from 2 to 8, further for example from 2 to 6 carbon atoms. Alkynyl groups (e.g., 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.

[0159] The term "alkynylene" refers to a divalent alkynyl group obtained by removing two hydrogens from an alkyne. Alkenylene includes, but is not limited to, ethynylene, etc.

[0160] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, which contain monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups (including fused, bridged, or spirocycloalkyl).

[0161] For example, a cycloalkyl group may contain from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms. Even further for example, a cycloalkyl group may be selected from monocyclic groups containing from 3 to 12, such as from 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups. In particular, examples of saturated monocyclic cycloalkyl groups (e.g., C 3-8 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In a preferred embodiment, the cycloalkyl is a monocyclic (abbreviated as C 3-6cycloalkyl), including but not limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms, having a fused bicyclic arrangement (selected from [4,4], [4,5], [5,5], [5,6] and [6,6] ring systems) or having a bridged bicyclic arrangement (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 having a bicyclic arrangement (selected from [5,6] and [6,6] ring systems).

[0162] The term "spirocycloalkyl" includes a cyclic structure containing carbon atoms and formed by at least two rings sharing one atom.

[0163] The term "fused cycloalkyl" includes bicyclic cycloalkyl groups as defined herein, which are saturated and formed by two or more rings sharing two adjacent atoms.

[0164] The term "bridged cycloalkyl" includes a cyclic structure containing carbon atoms and formed by two rings sharing two non-adjacent atoms with each other. The term "7- to 10-membered bridged cycloalkyl" includes a cyclic structure containing 7 to 12 carbon atoms and formed by two rings sharing two non-adjacent atoms with each other.

[0165] Examples of fused cycloalkyl, fused cycloalkenyl or fused cycloalkynyl include but are not limited to bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, decalin, and benzo 3- to 8-membered cycloalkyl, benzo C 4-6 cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthalenyl, 1,4-dihydronaphthalenyl, etc. A preferred embodiment is an 8- to 9-membered fused ring, which refers to a ring structure containing 8 to 9 ring atoms in the above examples.

[0166] The term "aryl", used alone or in combination with other terms, includes groups selected from:

[0167] - 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0168] - bicyclic systems (such as 7- to 12-membered bicyclic systems), wherein at least one ring is carbocyclic and aromatic, such as naphthyl and indanyl; and,

[0169] - tricyclic systems (such as 10- to 15-membered tricyclic systems), wherein at least one ring is carbocyclic and aromatic, such as fluorenyl.

[0170] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, the monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C 5-10 aryl). Examples of the monocyclic or bicyclic aromatic hydrocarbon ring include, but are not limited to, phenyl, naphthalen-1-yl, naphthalen-2-yl, anthryl, phenanthryl, and the like. In some embodiments, the aromatic hydrocarbon ring is a naphthalene ring (naphthalen-1-yl or naphthalen-2-yl) or a phenyl ring. In some embodiments, the aromatic hydrocarbon ring is a phenyl ring.

[0171] In particular, the term "bicyclic fused aryl" includes the bicyclic aryl ring as defined herein. A typical bicyclic fused aryl is naphthalene.

[0172] The term "heteroaryl" includes groups selected from:

[0173] - a 5-, 6- or 7-membered aromatic monocyclic ring containing at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O) (e.g., from 1 to 4, or in some embodiments from 1 to 3, or in some embodiments from 1 to 2 heteroatoms), wherein the remaining ring atoms are carbon;

[0174] - a 7- to 12-membered bicyclic ring containing at least one heteroatom selected from N, O, and S (e.g., from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2 heteroatoms), wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0175] - an 11- to 14-membered tricyclic ring containing at least one heteroatom selected from N, O, and S (e.g., from 1 to 4, or in some embodiments from 1 to 3, or in other embodiments 1 or 2 heteroatoms), wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0176] When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed 1. When the heteroaryl group contains more than one heteroatom ring member, these heteroatoms can be the same or different. One or more nitrogen atoms in the heteroaryl group can be oxidized to form N-oxides.

[0177] In particular, the term "bicyclic fused heteroaryl" includes a 7- to 12-membered, preferably 7- to 10-membered, more preferably 9- or 10-membered fused bicyclic heteroaryl ring as defined herein. Typically, the bicyclic fused heteroaryl is a 5 / 5, 5 / 6, 6 / 6, or 6 / 7 bicyclic ring. The group can be attached to the remainder of the molecule through either ring.

[0178] The terms "heterocyclic group", "heterocycle", or "heterocyclic" are interchangeable and include non-aromatic heterocyclic groups (which contain one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, where the remaining ring members are carbon), including monocyclic, fused, bridged, and spiro rings, i.e., containing monocyclic heterocyclic groups, bridged heterocyclic groups, spiro heterocyclic groups, and fused heterocyclic groups.

[0179] The term "at least one substituent" as disclosed herein includes, for example, from 1 to 4, such as from 1 to 3, and further such as 1 or 2 substituents, provided that the valence theory is satisfied. For example, "at least one substituent F" as disclosed herein includes from 1 to 4, such as from 1 to 3, and further such as 1 or 2 substituents F.

[0180] The term "divalent" refers to a linking group capable of forming covalent bonds 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 heterocyclic group", or "divalent heteroaryl group" should be understood in a similar manner.

[0181] The compounds disclosed herein may contain asymmetric centers and can thus exist as enantiomers. "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of each other. When the compounds disclosed herein have two or more asymmetric centers, they can additionally exist as diastereomers. Enantiomers and diastereomers belong to the broader category of stereoisomers. It is intended to include all possible stereoisomers, such as substantially pure resolved enantiomers, their racemic mixtures, and mixtures of diastereomers. It is intended to include all stereoisomers of the compounds and / or their pharmaceutically acceptable salts disclosed herein. Unless otherwise specifically stated, a reference to an isomer applies to any possible isomer. Whenever the composition of an isomer is not specified, all possible isomers are included.

[0182] When the compounds disclosed herein contain an olefinic double bond, such double bonds are intended to include E and Z geometric isomers unless otherwise stated.

[0183] When the compounds disclosed herein contain a disubstituted ring system, the substituents found on such a ring system can adopt cis and trans forms. The cis form means that both substituents are on the upper side of the 2 substituent positions on carbon, while the trans means that they are on opposite sides. For example, the disubstituted ring system can be a cyclohexyl ring or a cyclobutyl ring.

[0184] It may be advantageous to separate the reaction products from each other and / or from the starting materials. By ordinary skill in the art, the desired product of each step or series of steps is separated and / or purified (hereinafter referred to as separation) to the desired degree of homogeneity. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve many methods, including, 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 techniques of small scale thin layer and flash chromatography. One of ordinary skill in the art can select and apply the technique most likely to achieve the desired separation.

[0185] “Diastereomers” refer to stereoisomers of a compound having two or more chiral centers that are not mirror images of each other. A mixture of diastereomers can be separated into its individual diastereomers by methods known to those skilled in the art, such as chromatography and / or fractional crystallization, based on their physicochemical differences. Enantiomers can be separated as follows: the enantiomer mixture is converted into a mixture of diastereomers by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), the diastereomers are separated, and the individual diastereomers are converted (e.g., hydrolyzed) into the corresponding pure enantiomers. Enantiomers can also be separated by using a chiral HPLC column.

[0186] A single stereoisomer (e.g., a substantially pure enantiomer) can be obtained by resolving a racemic mixture using methods such as forming diastereomers with 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 mixtures of the chiral compounds of the present invention can be separated and resolved by any suitable method, including: (1) forming an ionic diastereomeric salt with the chiral compound and separating by fractional crystallization or other methods; (2) forming diastereomeric compounds with a chiral derivatizing reagent, separating these diastereomers and converting to the pure stereoisomers; and (3) directly separating 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.

[0187] Some of the compounds disclosed herein can have different attachment points for hydrogen, called tautomers. For example, a compound including a carbonyl - CH 2 C(O)- group (keto form) can undergo tautomerization to form a hydroxy - CH=C(OH)- group (enol form). Where applicable, it is also intended to include both the individual keto and enol forms and mixtures thereof.

[0188] A "prodrug" refers to a derivative of an active agent that requires conversion in vivo to release the active agent. In some embodiments, the conversion is an enzymatic conversion. Prodrugs are often (although not necessarily) pharmacologically inactive until converted to the active agent.

[0189] "Pharmaceutically acceptable salts" refers to those salts that are suitable, within the scope of reasonable medical judgment, for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and that are commensurate with 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. The term also includes salts of stereoisomers (e.g., enantiomers and / or diastereomers), tautomers, and prodrugs of the compounds of the invention.

[0190] In addition, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, the addition salt (such as a pharmaceutically acceptable addition salt) can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts without undue experimentation.

[0191] As used herein, the terms "administration" and "treating", when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, mean the contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition with the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of cells encompasses the contact of a reagent with the cells and the contact of a reagent with a fluid that contacts the cells. The terms "administration" and "treating" also mean, for example, in vitro and ex vivo treatment of cells by a reagent, diagnostic agent, binding compound, or another cell. As used herein, the term "subject" includes any living organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0192] The term "effective amount" or "therapeutically effective amount" means an amount of an active ingredient (e.g., a compound) sufficient to effect treatment of a disease, or at least one clinical symptom of a disease or disorder, when administered to a subject for treating the disease, disorder or symptom. The term "therapeutically effective amount" can vary with the compound, the disease, the disorder, and / or the symptom of the disease or disorder, the severity of the disease, disorder, and / or symptom of the disease or disorder, the age of the subject to be treated, and / or the weight of the subject to be treated. The appropriate amount in any given case will be apparent to those skilled in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount of at least one compound and / or at least one of its stereoisomers, tautomers or prodrugs, and / or at least one of its pharmaceutically acceptable salts as defined herein that effectively "treats" a disease or disorder of a subject. In the case of combination therapies, the term "therapeutically effective amount" refers to the total amount of the combination components used to effectively treat a disease, disorder or condition.

[0193] The term "disease" refers to any disease, discomfort, affliction, symptom or indication and may be used interchangeably with the term "disorder" or "condition".

[0194] Throughout this specification and the appended claims, unless the context otherwise requires, the term "comprise" and variations such as "comprises" and "comprising" are intended to specify the presence of the stated features, but do not preclude the presence or addition of one or more other features. When used herein, the term "comprise" may be replaced with the terms "containing", "including", or sometimes "having".

[0195] Throughout this specification and the appended claims, the term "C n-m " indicates a range that includes the endpoints, where n and m are integers and indicate the number of carbons. Examples include C 1-8 、C 1-6 etc.

[0196] Unless otherwise specifically defined elsewhere in this document, all other technical and scientific terms used in this invention have the meanings commonly understood by one of ordinary skill in the art to which this invention belongs.

[0197] General Synthesis

[0198] The compounds (including their salts) disclosed herein can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes. The reactions for preparing the compounds disclosed herein can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents can react essentially not at all with the starting materials, intermediates, or products at the temperature at which the reaction is carried out (e.g., a temperature ranging from the boiling temperature of the solvent). A given reaction can be carried out in one solvent or a mixture of solvents.

[0199] The selection of appropriate protecting groups can be readily determined by those skilled in the art.

[0200] The reaction can be monitored according to any suitable method known in the art (e.g., NMR, UV, HPLC, LC-MS, and TLC). The compounds can be purified by a variety of methods including HPLC and normal-phase silica gel chromatography.

[0201] Chiral analytical HPLC is used for the retention time analysis of different chiral examples, and the conditions are classified into the following methods according to the column, mobile phase, and solvent ratio used.

[0202] Scheme I

[0203]

[0204] For example, compounds having formula (I), (II), (III), or (IV) can be formed as shown in Scheme I. Compound (i) can react with a halogenated pyrimidine under palladium-catalyzed reaction conditions or base-mediated coupling conditions to give compound (ii), compound (ii) can be coupled with an amine to give compound (iii), compound (iii) is reduced and halogenated to give compound (iv), and compound (iv) can be used for coupling to give compound (v).

[0205] Scheme II

[0206]

[0207] For example, compounds having formula (I), (II), (AIII), (III), (AIV), or (IV) can be formed as shown in Scheme II. Compound (i) can react with a halogenated pyrimidine under

[0208] palladium-catalyzed reaction conditions to give compound (ii), and compound (ii) can be coupled with an amine to give compound (iii).

[0209] Examples

[0210] Example A1: Methyl 8-fluoro-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)quinoline-4-carboxylate

[0211]

[0212] Step 1: 5-(((4-chloro-2-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0213]

[0214] At 85 °C under a nitrogen atmosphere, a mixture of 4-chloro-2-fluoroaniline (50 g, 343.50 mmol) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (65.0 g, 349.16 mmol) in isopropanol (500 mL) was stirred for 4 h and then cooled to room temperature. The precipitated solid was collected by filtration and washed with isopropanol (2 x 20 mL), giving the title compound (95 g, 92%). LC-MS (M+H) + = 299.9.

[0215] Step 2: 6-chloro-8-fluoroquinolin-4-ol

[0216]

[0217] At 265 °C under a nitrogen atmosphere, a mixture of 5-(((4-chloro-2-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (36 g, 120.128 mmol) in phenoxybenzene (240 mL) was stirred for 1.5 h and then cooled to room temperature. The resulting mixture was diluted with petroleum ether (240 mL) and filtered. The precipitated solid was washed with petroleum ether (2 x 20 mL). The residue was diluted with ethyl acetate (60 mL). The precipitated solid was collected by filtration and washed with ethyl acetate (1 x 10 mL), giving the title compound (6.1 g, 25%). LC-MS (M+H) + = 197.9.

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

[0219]

[0220] At 0 °C under a nitrogen atmosphere, phosphorus tribromide (22.8 g, 84.23 mmol) was added dropwise to a solution of 6-chloro-8-fluoroquinolin-4-ol (8.1 g, 40.99 mmol) in N,N-dimethylformamide (130 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 h and then quenched by the addition of water (200 mL). The mixture was basified to pH 8 with saturated sodium bicarbonate solution. The precipitated solid was collected by filtration and washed with water (2 x 25 mL). The crude solid was purified by flash chromatography (eluting with ethyl acetate in petroleum ether (0 - 15% gradient, v / v)) to give the title compound (6 g, 56%). LC-MS (M+H) + = 259.8.

[0221] Step 4: Methyl 6-chloro-8-fluoroquinoline-4-carboxylate

[0222]

[0223] In a pressure vessel, triethylamine (234 mg, 2.304 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride - dichloromethane (1:1) (188 mg, 0.23 mmol) were added to a solution of 4-bromo-6-chloro-8-fluoroquinoline (200 mg, 0.768 mmol) in 8 mL of methanol. The mixture was pressurized with carbon monoxide to 40 atm at 80 °C for 12 h and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (eluting with ethyl acetate in petroleum ether (0 - 20% gradient, v / v)) to give the title compound (150 mg, 87%). LC-MS (M+H) + = 239.9.

[0224] Step 5: (8-fluoro-4-(methoxycarbonyl)quinolin-6-yl)boronic acid

[0225]

[0226] To a solution of methyl 6-chloro-8-fluoroquinoline-4-carboxylate (90 mg, 0.376 mmol) and bis(pinacolato)diboron (190 mg, 0.748 mmol) in 1,4-dioxane (3 mL) was added potassium acetate (110 mg, 1.12 mmol) and dichlorobis(tricyclohexylphosphine)palladium(II) (35 mg, 0.047 mmol). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure and diluted with ethyl acetate (10 mL). The resulting mixture was filtered and the cake was washed with ethyl acetate (2 x 5 mL). The filtrates were combined and concentrated under reduced pressure to give the title compound (90 mg, crude). The crude product was used directly in the next step without further purification. LC-MS (M+H) + = 250.1.

[0227] Step 6: Methyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoroquinoline-4-carboxylate

[0228]

[0229] To a solution of (8-fluoro-4-(methoxycarbonyl)quinolin-6-yl)boronic acid (90 mg, crude) and 2,4-dichloro-5-fluoropyrimidine (50 mg, 0.299 mmol) in 1,4-dioxane (6 mL) and water (0.6 mL) was added potassium phosphate (120 mg, 0.565 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (25 mg, 0.034 mmol). After stirring at 100 °C under a nitrogen atmosphere for 3 h, the resulting mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with ethyl acetate in petroleum ether (0 - 40% gradient, v / v)) to give the title compound (67 mg, 51%, over 2 steps). LC-MS (M+H) + = 335.9.

[0230] Step 7: 8-fluoro-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4- yl)quinoline-4-carboxylate methyl ester

[0231]

[0232] At 100 °C under a nitrogen atmosphere, a mixture of methyl 6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoroquinoline-4-carboxylate (60 mg, 0.179 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloropalladium(II) (2-methylpyridine) (15 mg, 0.018 mmol), cesium carbonate (174 mg, 0.537 mmol), and (3S,4R)-4-aminooxolan-3-ol hydrochloride (55 mg, 0.358 mmol) in 1,4-dioxane (3 mL) was stirred for 3 h and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC under the following conditions: column, XBridge Shield RP18 OBD column, 30 x 150 mm, 5 μm; mobile phase, acetonitrile in water (with 10 mmol / L ammonium bicarbonate and 0.1% ammonium hydroxide), 23% to 53% gradient in 8 min; detector, UV 254 nm. The title compound was obtained (22 mg, 29%). 1 H NMR (300 MHz, DMSO-d6) δ 9.25 (s, 1H), 9.20 (d, J = 3.8 Hz, 1H), 8.53 (d, J = 3.8 Hz, 1H), 8.27 - 8.17 (m, 1H), 8.13 (d, J = 4.4 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 4.97 (d, J = 4.8 Hz, 1H), 4.02 (s, 3H), 3.91 - 3.80 (m, 3H), 3.61 - 3.35 (m, 2H), 3.10 (t, J = 10.3 Hz, 1H), 2.11 - 2.00 (m, 1H), 1.61 - 1.42 (m, 1H). LC-MS (M+H) + = 417.0.

[0233] Example A2: (3S,4R)-4-((5-Fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0234]

[0235] Step 1: 2-(6-chloro-8-fluoroquinolin-4-yl)propan-2-ol

[0236]

[0237] At 0 °C under a nitrogen atmosphere, methylmagnesium iodide (1 M in diethyl ether, 15.6 mL, 15.6 mmol) was added dropwise to a mixture of methyl 6-chloro-8-fluoroquinoline-4-carboxylate (750 mg, 3.13 mmol) in tetrahydrofuran (20 mL). The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 4 h, and then saturated ammonium chloride solution (20 mL) was added at 0 °C. The resulting solution was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (eluting with ethyl acetate in petroleum ether (0 - 50% gradient, v / v)) to give the title compound (425 mg, 56%). LC-MS (M+H) + = 240.0.

[0238] Step 2: (8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)boronic acid

[0239]

[0240] The title compound (375 mg, crude) was prepared from 2-(6-chloro-8-fluoroquinolin-4-yl)propan-2-ol in a similar manner to Step 5 of Example A1. The crude product was used directly in the next step without further purification. LC-MS (M+H) + = 250.0.

[0241] Step 3: 2-(6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-4-yl)propan-2-ol

[0242]

[0243] The title compound (400 mg, 67%, 2 steps) was prepared from (8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)boronic acid and 2,4-dichloro-5-fluoropyrimidine in a similar manner to Step 6 of Example A1. LC-MS (M+H) + = 335.9.

[0244] Step 4: (3S,4R)-4-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl) amino)tetrahydro-2H-pyran-3-ol

[0245]

[0246] The title compound (11 mg, 11%) was prepared from 2-(6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-4-yl)propan-2-ol and (3S,4R)-4-aminooxolan-3-ol hydrochloride in a similar manner to Step 7 of Example A1. 11H NMR (300 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.96 (d, J = 4.6 Hz, 1H), 8.51 (d, J = 3.8 Hz, 1H), 8.12 - 8.02 (m, 1H), 7.72 (d, J = 4.6 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 5.73 (s, 1H), 4.96 (d, J = 5.3 Hz, 1H), 3.88 - 3.77 (m, 3H), 3.58 - 3.35 (m, 2H), 3.07 (t, J = 10.4 Hz, 1H), 2.08 - 1.99 (m, 1H), 1.74 (s, 6H), 1.54 - 1.43 (m, 1H). LC-MS (M+H) + = 417.2

[0247] Example A3: (3S,4R)-4-((5-Fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)pyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0248]

[0249] Step 1: 5-chloro-7-fluoroindoline-2,3-dione

[0250]

[0251] At 0 °C under a nitrogen atmosphere, trichloro-1,3,5-triazinane-2,4,6-trione (665 mg, 2.861 mmol) was added portionwise to a solution of 7-fluoro-1H-indole-2,3-dione (950 mg, 5.753 mmol) in sulfuric acid (5 mL) and trifluoroacetic acid (5 mL). The resulting mixture was then stirred at room temperature under a nitrogen atmosphere for 4 h and then quenched at 0 °C by the addition of water (25 mL). The precipitated solid was collected by filtration and washed with water (2 x 5 mL) to give the title compound (800 mg, 69%). LC-MS (M+H) + = 200.1

[0252] Step 2: 6-chloro-8-fluoro-2-methylquinoline-4-carboxylic acid

[0253]

[0254] At room temperature under a nitrogen atmosphere, potassium hydroxide (472 mg, 8.40 mmol) was added portionwise to a stirred solution of 5-chloro-7-fluoroindoline-2,3-dione (600 mg, 3.00 mmol) and acetone (620 μL, 8.40 mmol) in ethanol (3.5 mL) and water (1.2 mL). The reaction mixture was irradiated with microwave at 100 °C for 20 min. The resulting mixture was concentrated under reduced pressure and then diluted with water (15 mL). The resulting mixture was washed with dichloromethane (20 mL). The aqueous layer was acidified to pH 3 with 2N HCl solution and then extracted with ethyl acetate (2 x 15 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product (580 mg) was used directly in the next step without further purification. LC-MS (M+H) + = 239.9

[0255] Step 3: Methyl 6-chloro-8-fluoro-2-methylquinoline-4-carboxylate

[0256]

[0257] At room temperature under a nitrogen atmosphere, sulfuric acid (0.2 mL) was added dropwise to a solution of 6-chloro-8-fluoro-2-methylquinoline-4-carboxylic acid (580 mg, 2.835 mmol) in methanol (30 mL). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h, then cooled to room temperature and concentrated under reduced pressure. The resulting mixture was diluted with water (15 mL) and extracted with ethyl acetate (2 x 15 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (eluting with ethyl acetate in petroleum ether (0% to 30% gradient, v / v)), yielding the title compound (184 mg, 24% yield, over 2 steps). LC-MS (M+H) + = 253.9

[0258] Step 4: 2-(6-chloro-8-fluoro-2-methylquinolin-4-yl)propan-2-ol

[0259]

[0260] The title compound (153 mg, 83%) was prepared in a manner similar to Step 1 of Example A2 from methyl 6-chloro-8-fluoro-2-methylquinoline-4-carboxylate. LC-MS (M+H)+ = 254.0

[0261] Step 5: (8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)boronic acid

[0262]

[0263] The title compound (70 mg, crude) was prepared from 2-(6-chloro-8-fluoro-2-methylquinolin-4-yl)propan-2-ol in a similar manner to Step 5 of Example A1. The crude product was used directly in the next step without further purification. LC-MS (M+H) + = 264.0

[0264] Step 6: 2-(6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinolin-4-yl)propan-2-ol

[0265]

[0266] The title compound (10 mg, 9%, 2 steps) was prepared from (8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)boronic acid and 2,4-dichloro-5-fluoropyrimidine in a similar manner to Step 6 of Example A1. LC-MS (M+H) + = 350.0

[0267] Step 7: (3S,4R)-4-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)-2-methylquinolin-6-yl)pyrim idin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0268]

[0269] The title compound (4 mg, 38%) was prepared from 2-(6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoro-2-methylquinolin-4-yl)propan-2-ol and (3S,4R)-4-aminooxolan-3-ol hydrochloride in a similar manner to Step 7 of Example A1. 1 1H NMR (300 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.49 (d, J = 3.9 Hz, 1H), 8.09 - 7.99 (m, 1H), 7.61 (s, 1H), 7.25 (d, J = 7.6 Hz, 1H), 5.67 (s, 1H), 4.97 (d, J = 5.3 Hz, 1H), 3.89 - 3.79 (m, 3H), 3.57 - 3.40 (m, 2H), 3.14 - 3.01 (m, 1H), 2.72 (s, 3H), 2.12 - 1.95 (m, 1H), 1.73 (s, 6H), 1.58 - 1.42 (m, 1H). LC-MS (M+H) + = 431.1

[0270] Example A4: tert-Butyl 4-((5-fluoro-4-(8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate

[0271]

[0272] A mixture of 2-(6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-4-yl)propan-2-ol (200 mg, 0.6 mmol), (SP-4-1)-[1,3-bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloropalladium(II) (2-methylpyridine) (51 mg, 0.059 mmol), caesium carbonate (582 mg, 1.79 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (239 mg, 1.19 mmol) in 1,4-dioxane (15 mL) was stirred at 100 °C under a nitrogen atmosphere for 3 h and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with 16% ethyl acetate (v / v) in petroleum ether) and further purified by preparative HPLC under the following conditions: column, XBridge ShieldRP18 OBD column, 30 x 150 mm, 5 µm; mobile phase, acetonitrile in water (with 10 mmol / L ammonium bicarbonate and 0.05% ammonium hydroxide), 25% to 55% gradient in 8 min; detector, UV 254 nm. The title compound was obtained as a white solid (110 mg, 41%). 1 H NMR (300 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.96 (d, J = 4.6 Hz, 1H), 8.52 (d, J = 3.8 Hz, 1H), 8.12 - 8.02 (m, 1H), 7.71 (d, J = 4.7 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 5.71 (s, 1H), 3.99 - 3.89 (m, 3H), 2.98 - 2.78 (m, 2H), 1.98 - 1.82 (m, 2H), 1.73 (s, 6H), 1.50 - 1.30 (m, 11H). LC-MS (M+H) + = 500.1.

[0273] Example A5: 2-(8-Fluoro-6-(5-fluoro-2-(piperidin-4-ylamino)pyrimidin-4-yl)quinolin-4-yl)propan-2-ol

[0274]

[0275] A mixture of tert-butyl 4-({5-fluoro-4-[8-fluoro-4-(2-hydroxypropan-2-yl)quinolin-6-yl]pyrimidin-2-yl}amino)piperidine-1-carboxylate (100 mg, 0.200 mmol) and trifluoroacetic acid (5 mL) in dichloromethane (5 mL) was stirred at room temperature for 2 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions: column, XBridgeShield RP18 OBD column, 30 x 150 mm, 5 μm; mobile phase, acetonitrile in water (with 10 mmol / L ammonium bicarbonate and 0.1% ammonium hydroxide), 18% to 48% gradient in 9 min; detector, UV 254 nm. The title compound was obtained (23 mg, 29%). 1 H NMR (300 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.96 (d, J = 4.6 Hz, 1H), 8.49 (d, J = 3.8 Hz, 1H), 8.12 - 8.01 (m, 1H), 7.72 (d, J = 4.6 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 5.82 - 5.65 (m, 1H), 3.94 - 3.64 (m, 1H), 3.02 - 2.92 (m, 2H), 2.61 - 2.51 (m, 2H), 1.93 - 1.83 (m, 2H), 1.74 (s, 6H), 1.49 - 1.32 (m, 2H). LC-MS (M+H) + = 400.1.

[0276] Examples A6 and A7: (3S,4R)-4-((4-(4-((S)-1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (3S,4R)-4-((4-(4-((R)-1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[0277]

[0278] Step 1: 6-chloro-8-fluoroquinoline-4-carboxylic acid

[0279]

[0280] At room temperature, lithium hydroxide monohydrate (2.72 g, 64.92 mmol) in water (15 mL) was added dropwise to a mixture of 6-chloro-8-fluoroquinoline-4-carboxylic acid methyl ester (5.2 g, 21.64 mmol) in tetrahydrofuran (40 mL). The resulting mixture was stirred at room temperature for 14 h and then concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL) and extracted with dichloromethane (30 mL). The aqueous layer was acidified to pH 3 with 2N HCl solution and extracted with ethyl acetate (2 x 60 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product (3.95 g, 81%) was used directly in the next step without further purification. LC-MS (M+H) + = 226.0.

[0281] Step 2: 6-chloro-8-fluoro-N-methoxy-N-methylquinoline-4-carboxamide

[0282]

[0283] At room temperature under a nitrogen atmosphere, diisopropylethylamine (180 mg, 1.397 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (725 mg, 4.651 mmol) were added in portions to a mixture of 6-chloro-8-fluoroquinoline-4-carboxylic acid (350 mg, 1.550 mmol) and N,O-dimethylhydroxylamine hydrochloride (360 mg, 3.721 mmol) in acetonitrile (10 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 h and then concentrated under reduced pressure. The resulting mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 2). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with ethyl acetate in petroleum ether (0 - 30% gradient, v / v)) to give the title compound (300 mg, 71%). LC-MS (M+H) + = 269.0.

[0284] Step 3: 1-(6-chloro-8-fluoroquinolin-4-yl)ethan-1-one

[0285]

[0286] At 0 °C under a nitrogen atmosphere, methylmagnesium bromide (3 M in diethyl ether, 0.560 mL, 1.67 mmol) was added dropwise to a solution of 6-chloro-8-fluoro-N-methoxy-N-methylquinoline-4-carboxamide (300 mg, 1.115 mmol) in tetrahydrofuran (15.00 mL). The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 3 h and then quenched by the addition of saturated ammonium chloride (20 mL). The resulting mixture was extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography (eluting with ethyl acetate in petroleum ether (0 - 25% gradient, v / v)) to give the title compound (150 mg, 60%). LC-MS (M+H) + = 224.0

[0287] Step 4: (S,Z)-N-(1-(6-chloro-8-fluoroquinolin-4-yl)ethylidene)-2-methylpropane-2-sulfinamide

[0288]

[0289] At room temperature under a nitrogen atmosphere, titanium(IV) ethoxide (408 mg, 1.787 mmol) was added dropwise to a mixture of 1-(6-chloro-8-fluoroquinolin-4-yl)ethanone (200 mg, 0.893 mmol) and (S)-2-methylpropane-2-sulfinamide (140 mg, 1.160 mmol) in tetrahydrofuran (10 mL). The resulting mixture was stirred at 70 °C under a nitrogen atmosphere for 16 h. When the reaction was cooled to room temperature, the resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (15 mL) and extracted with ethyl acetate (25 mL x 2). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with ethyl acetate in petroleum ether (0 - 20% gradient, v / v)) to give the title compound (275 mg, 94%). LC-MS (M+H) + = 327.0

[0290] Step 5: (S)-N-(1-(6-chloro-8-fluoroquinolin-4-yl)ethyl)-2-methylpropane-2-sulfinamide

[0291]

[0292] At 0 °C, sodium borohydride (95 mg, 2.511 mmol) was added portionwise to a stirred solution of (S,Z)-N-(1-(6-chloro-8-fluoroquinolin-4-yl)ethylidene)-2-methylpropane-2-sulfinamide (275 mg, 0.841 mmol) in methanol (8 mL). The resulting mixture was stirred at room temperature for 4 h and then quenched by the addition of ice water (20 mL). The resulting mixture was extracted with ethyl acetate (2 x 20 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. Na 2 SO 4 . The residue was purified by flash chromatography (eluting with methanol in dichloromethane (0% to 20% gradient, v / v)) to afford the title compound (230 mg, 83%). LC-MS (M+H) + = 329.0.

[0293] Step 6: (4-(1-(((S)-tert-butylsulfinyl)amino)ethyl)-8-fluoroquinolin-6-yl)boronic acid

[0294]

[0295] The title compound (288 mg, crude) was prepared from (S)-N-(1-(6-chloro-8-fluoroquinolin-4-yl)ethyl)-2-methylpropane-2-sulfinamide in a manner similar to Step 5 of Example A1. The crude product was used directly in the next step without further purification. LC-MS (M+H) + = 339.0.

[0296] Step 7: (S)-N-(1-(6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-4-yl)ethyl)-2-methylprop ane-2-sulfinamide

[0297]

[0298] The title compound (230 mg, 73%, 2 steps) was prepared from (4-(1-(((S)-tert-butylsulfinyl)amino)ethyl)-8-fluoroquinolin-6-yl)boronic acid and 2,4-dichloro-5-fluoropyrimidine in a manner similar to Step 6 of Example A1. LC-MS (M+Na) + = 447.0.

[0299] Step 8: (S)-N-(1-(8-fluoro-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino ((4-(4-(1-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)quinolin-4-yl)ethyl)-2-methylpropane-2-sulfinamide

[0300]

[0301] The title compound (175 mg, 63%) was prepared from (S)-N-(1-(6-(2-chloro-5-fluoropyrimidin-4-yl)-8-fluoroquinolin-4-yl)ethyl)-2-methylpropane-2-sulfinamide and (3S,4R)-4-aminooxolan-3-ol hydrochloride in a manner similar to Step 7 of Example A1. LC-MS (M+Na) + = 528.2

[0302] Step 9: (3S,4R)-4-((4-(4-(1-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino tetrahydro-2H-pyran-3-ol

[0303]

[0304] At room temperature under a nitrogen atmosphere, a solution of (S)-N-(1-(8-fluoro-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)quinolin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (175 mg, 0.346 mmol) in methanol (1.5 mL) was added dropwise with a hydrochloride in methanol (4 M, 0.50 mL, 2.00 mmol). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h and then concentrated under reduced pressure. The resulting mixture was diluted with saturated sodium bicarbonate solution (15 mL). The resulting solution was extracted with ethyl acetate (2 x 15 mL). The organic phases were combined, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC under the following conditions: column, XBridgeShield RP18 OBD column, 30 x 150 mm, 5 um; mobile phase, acetonitrile in water (with 10 mmol / L ammonium bicarbonate and 0.1% ammonium hydroxide), 15% to 45% gradient in 8 min; detector, UV 254 nm. The title compound (80 mg, 57%) was obtained. LC-MS (M+H) + = 402.1

[0305] Step 10: (3S,4R)-4-((4-(4-((S)-1-Aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoropyrimidin-2- yl)amino)tetrahydro-2H-pyran-3-ol and (3S,4R)-4-((4-(4-((R)-1-Aminoethyl)-8-fluoroquinolin-6-yl)- 5-fluoropyrimidin-2-yl)

[0306] amino)tetrahydro-2H-pyran-3-ol

[0307]

[0308] Separate Example A7 and Example A8 on chiral HPLC to obtain (3S,4R)-4-((4-(4-((S)-1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol and (3S,4R)-4-((4-(4-((R)-1-aminoethyl)-8-fluoroquinolin-6-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol. Analytical chiral HPLC conditions: CHIRALPAK IG, 2 x 25 cm, 5.0 um. Mobile phase: (hexane:dichloromethane = 3:1, containing 0.5% of 2M ammonia in methanol): isopropanol, 20 mL / min within 26 min.

[0309] Example A7 (50 mg, 62%): 1 H NMR (400 MHz, DMSO-d6) δ 9.04 - 8.98 (m, 1H), 8.72 (s, 1H), 8.55 - 8.49 (m, 1H), 8.14 - 8.06 (m, 1H), 7.90 (d, J = 4.6, 1H), 7.33 (d, J = 7.8 Hz, 1H), 4.99 - 4.93 (m, 1H), 4.88 - 4.78 (m, 1H), 3.91 - 3.78 (m, 3H), 3.57 - 3.50 (m, 1H), 3.43 - 3.35 (m, 1H), 3.08 (t, J = 10.4 Hz, 1H), 2.38 - 2.12 (br, 2H), 2.06 - 1.92 (m, 1H), 1.59 - 1.46 (m, 1H), 1.43 (d, J = 6.6 Hz, 3H). LC-MS (M+H) + = 402.2. Chiral HPLC: tR = 3.949 min.

[0310] Example A8 (4 mg, 5%): 1 H NMR (400 MHz, DMSO-d6) δ 9.04 - 8.98 (m, 1H), 8.74 (s, 1H), 8.55 - 8.49 (m, 1H), 8.14 - 8.06 (m, 1H), 7.94 - 7.88 (m, 1H), 7.33 (d, J = 7.8 Hz, 1H), 5.00 - 4.95 (m, 1H), 4.88 - 4.79 (m, 1H), 3.90 - 3.79 (m, 3H), 3.57 - 3.49 (m, 1H), 3.43 - 3.35 (m, 1H), 3.09 (t, J = 10.3 Hz, 1H), 2.40 - 2.10 (m, 2H), 2.04 - 1.90 (m, 1H), 1.59 - 1.46 (m, 1H), 1.42 (d, J = 6.7, 3H). LC-MS (M+H) += 402.2. Chiral HPLC: tR = 5.594 min.

[0311] Biological assay

[0312] In an assay based on the time-resolved fluorescence resonance energy transfer (TR-FRET) method, the inhibition of the compounds disclosed herein against CDK4 / cyclin D1 or CDK6 / cyclin D3 kinases was tested. The assay was carried out in a 384-well small-volume black plate in a reaction mixture in buffer, which reaction mixture contained CDK4 / cyclin D1 or CDK6 / cyclin D3, 1 mM ATP, 0.15 μM Rb(Ser780)-biotin substrate, and 0 - 10 μM compound, and the buffer contained 50 mM HEPES pH 7.0, 0.02% NaN3, 0.01% BSA, 0.1 mM orthovanadate, 50 mM MgCl2, 1 mM DTT, and 0.005% Tween-20. The kinase was incubated with the compound at room temperature for 60 minutes, and the reaction was initiated by adding ATP and Rb(Ser780)-biotin substrate. After reacting at room temperature for 120 minutes, an equal volume of termination / detection solution was added according to the instructions of the manufacturer (Xinsi Bioassay Co., Ltd.). The termination / detection solution contained streptavidin-XL665 and anti-pRb(Ser780) mAb-Eu cryptate in detection buffer (Xinsi Bioassay Co., Ltd.). The plate was incubated at room temperature for 60 minutes, and the TR-FRET signal (ex 337 nm, em 665 nm / 620 nm) was recorded on a PHERAstar FSX microplate reader (BMG Labtech Co., Ltd.). Based on the fluorescence ratio at 665 nm to that at 620 nm, the percentage of inhibition of CDK4 / cyclin D1 or CDK6 / cyclin D3 kinase activity was calculated at increasing compound concentrations. The data was fitted to a four-parameter logistic equation by Dotmatics to derive the IC50 of each compound.

[0313] Table 1. Enzymatic activity IC50 (nM) of the compounds disclosed herein

[0314] Example number CDK4D1 IC50 (nM) CDK6D3 IC50 (nM) A1 122 688 A2 12 84 A3 33 249 A4 171 1700 A5 83 220 A6 32 760 A7 97 2378

Claims

1. A compound having the formula (I): or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analogue, or its prodrug, wherein: The ring CyA is a 3- to 8-membered ring, said ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members; said ring is optionally substituted by at least one substituent R 10 substituted; n is 0, 1, 2, 3, 4 or 5; m is 0 or 1; provided that when m = 0, the portion as a whole is replaced by H; R 1 is H, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, haloalkyl, heterocyclic group, 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 ; wherein each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted by at least one substituent R 1d ; R 1a 、R 1b and R 1c each independently is selected from hydrogen, -C 1-8 alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, wherein each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted with at least one substituent R 1f ; R 1d and R 1f each independently selected from hydrogen, halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl, wherein each of said -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl is optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -halo C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; R 2 is hydrogen, a halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, 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 said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, 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 the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted with at least one substituent R 2f replace; or (R 2a and R 2b ), (R 2b and R 2c ), or (R 2a and R 2c ), together with one or more atoms to which they are attached, form a 3- to 12-membered ring, the ring containing 0, 1, or 2 heteroatoms independently selected from nitrogen, oxygen, or optionally oxidized sulfur as one or more ring members, the ring optionally being substituted by at least one substituent R 2f ; R 2d and R 2f each independently selected from hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, 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 ; provided that each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, 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 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; or (Two Rs 2d ) or (two Rs 2f ) together with one or more atoms to which they are attached form a 3- to 12-membered ring, said ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring being 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, heterocyclic, halheterocyclic, aryl, haloaryl, heteroaryl or haloheteroaryl; 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, heterocyclic group, aryl or heteroaryl, wherein each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted by at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo-C 1-8 alkyl, -C 1-8 alkoxy, -halo-C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halheterocyclic group, aryl, haloaryl, heteroaryl or halheteroaryl; R 3A and R 3B each independently is hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl or -CN; wherein said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted with at least one substituent R 3c ; or R 3A and R 3B together with the atom(s) to which they are attached form an acyl group (—C(═O)—) or a 3- to 12-membered ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, the ring being optionally substituted with at least one substituent R 3c substituted; Each R 3c is independently selected from hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, 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 ; wherein each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo-C 1-8 alkyl, -C 1-8 alkoxy, -halo-C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, 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, heterocyclic group, aryl or heteroaryl, wherein each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo-C 1-8 alkyl, -C 1-8 alkoxy, -halo-C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; R 4 is hydrogen, a halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, oxo, -CN, -OR 401b 、-SO 2 R 401b 、-SO 2 NR 401b R 401c 、-COR 401b 、-CO 2 R 401b 、-CONR 401b R 401c 、-NO 2 、-NR 401b R 4c 、-NR 401b COR 401c 、-NR 401b CO 2 R 401c 、-NR 401b CONR 401c R 401d or –NR 401b SO 2 R 401c ; wherein each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted by at least one substituent R 4a ; R 401b 、R 401c and R 401d are each independently selected from hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, wherein each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -halo C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; Each R 4a is independently selected from hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, 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 ; wherein each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -halo C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; R 4b 、 R 4c and R 4d are each independently selected from hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, wherein each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo-C 1-8 alkyl, -C 1-8 alkoxy, -halo-C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; Preferably, R 4 is hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl or heterocyclic group; wherein each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl or heterocyclic group is optionally substituted by at least one substituent R 4a ; Each R 4a is independently selected from hydrogen, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, 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 ; wherein each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -halo C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; R 4b 、 R 4c and R 4d each independently selected from hydrogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, wherein said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is each optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo-C 1-8 alkyl, -C 1-8 alkoxy, -halo-C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; R 5 、R 6 、R 7 、R 8 and R 9 are each independently selected from H, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, 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 ; wherein each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted by at least one substituent R 5d ; R 5a , R 5b and R 5c are each independently selected from hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted with at least one substituent R 5f replace; R 5d and R 5f each independently selected from hydrogen, halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl, wherein each of said -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl is optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -halo C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; R 10 Selected from H, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, 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 ; wherein each of said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally substituted by at least one substituent R 10d ; R 10a , R 10b and R 10c are each independently selected from hydrogen, -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups is optionally substituted with at least one substituent R 10f replace; R 10d and R 10f each independently selected from hydrogen, halogen, hydroxy, -C 1-8 alkyl, -halo-C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl, wherein each of said -C 1-8 alkyl, -halo-C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl is optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo-C 1-8 alkyl, -C 1-8 alkoxy, -halo-C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; R 11 selected from H, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl; wherein said -C 1-8 alkyl, -C 2-8 alkenyl or -C 2-8 alkynyl is each optionally substituted with at least one substituent R 11a substituted; R 11a selected from hydrogen, halogen, hydroxy, -C 1-8 alkyl, -halo-C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl, wherein each of said -C 1-8 alkyl, -halo-C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl is optionally substituted by at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo-C 1-8 alkyl, -C 1-8 alkoxy, -halo-C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl.

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

3. A compound according to any one of the preceding claims, wherein ring CyA is a 3-, 4-, 5-, 6-, 7- or 8-membered ring, the ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members; the ring is optionally substituted with 0, 1, 2, 3, 4 or 5 R 10 substituents; the ring is a saturated or unsaturated ring; Preferably, CyA is a 3-, 4-, 5-, 6-, 7- or 8-membered saturated ring, said ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members; said ring is optionally substituted with 0, 1, 2 or 3 R 10 substituents; More preferably, CyA is a 5-, 6- or 7-membered saturated ring containing 1 or 2 heteroatoms independently selected from nitrogen or oxygen as one or more ring members; the ring is optionally substituted with 0, 1, 2 or 3 R 10 substituents; Even more preferably, CyA is a ring selected from tetrahydrofuranyl or tetrahydropyranyl; said ring is optionally substituted with 0, 1, 2 or 3 R 10 substituents; or Even more preferably, CyA is a ring selected from piperidinyl; the ring is optionally substituted with 0, 1, 2 or 3 Rs 10 substituted.

4. A compound according to any one of the preceding claims, wherein ring CyA is Preferably, CyA is More preferably, CyA is Even more preferably, CyA is 5. A compound according to any one of the preceding claims, wherein R 10 is selected from -H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, 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 ; wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted with at least one substituent R 10d ; R 10a , R 10b and R 10c 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 the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl or heteroaryl groups is optionally substituted with at least one substituent R 10f replace; R 10d and R 10f each independently selected from hydrogen, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, phenyl, haloaryl, heteroaryl or haloheteroaryl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, phenyl, haloaryl, heteroaryl or haloheteroaryl is optionally substituted by 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, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, phenyl, haloaryl, heteroaryl or haloheteroaryl; Preferably, R 10 is selected from -H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl, heteroaryl, -CN, -OH, -NH 2 , -COOMe, -COOEt, -COOCH 2 CH 2 CH 3 , -COOCH(CH 3 ) 2 , -COOCH 2 CH 2 CH 2 CH 3 , -COOCH(CH 3 )CH 2 CH 3 , -COOCH 2 CH(CH 3 ) 2 or -COOC(CH 3 ) 3 ; More preferably, R 10 is -OH, -COOMe, -COOEt, -COOCH 2 CH 2 CH 3 、-COOCH(CH 3 ) 2 、-COOCH 2 CH 2 CH 2 CH 3 、-COOCH(CH 3 )CH 2 CH 3 、-COOCH 2 CH(CH 3 ) 2 or -COOC(CH 3 ) 3 .

6. A compound according to any one of the preceding claims, wherein the moiety is 7. A compound according to any one of the preceding claims, wherein R 1 is H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, haloalkyl, heterocyclic group, -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 ; wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, haloalkyl or heterocyclic group is optionally substituted by at least one substituent R 1d ; R 1a 、R 1b and R 1c each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted by at least one substituent R 1f substituted; R 1d and R 1f are each independently selected from hydrogen, -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halosubstituted heterocyclic group, phenyl, haloaryl, heteroaryl or halosubstituted heteroaryl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halosubstituted heterocyclic group, phenyl, haloaryl, heteroaryl or halosubstituted heteroaryl is optionally substituted by 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, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halosubstituted heterocyclic group, phenyl, haloaryl, heteroaryl or halosubstituted heteroaryl; Preferably, R 1 is H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, haloalkyl, heterocyclic group or -CN; More preferably, R 1 is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

8. The compound according to 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, heterocyclic group, 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, heterocyclic group, phenyl or heteroaryl is optionally substituted by 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 the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl or heteroaryl groups is optionally substituted with at least one substituent R 2f replace; or (R 2a and R 2b ), (R 2b and R 2c ), or (R 2a and R 2c ), together with one or more atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, said ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring being optionally substituted by 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, heterocyclic group, 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 said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted by at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halocyclic group, phenyl, haloaryl, heteroaryl or haloheteroaryl; or When adjacent or geminal, (two Rs 2d ) or (two Rs 2f ) together with one or more atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, the ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, the ring optionally being substituted by 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, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halopycocyclic group, phenyl, haloaryl, heteroaryl or halopycocyclic group; R 2g 、 R 2h and R 2i are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted by at least one substituent -F, -Cl, -Br, -I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halocyclic group, phenyl, haloaryl, heteroaryl or haloheteroaryl.

9. A compound according to 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, oxa - azepanyl, 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, pyridyl, 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 ; wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxa - azepanyl, 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, pyridyl, pyrimidinyl, pyrazolyl, oxa - azabicyclo[3.2.1]octanyl or phenyl is optionally substituted by at least one substituent R 2d substituted; R 2a and R 2b 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, 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]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, wherein each of said 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]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 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 one or more atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, said ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen or oxygen as one or more ring members, said ring being optionally substituted by 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, tetrahydrofuryl, tetrahydropyranyl, oxaazepanyl, 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, pyridyl, 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 ; wherein the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 Each of alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuryl, 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 -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 is substituted with alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halocyclic group, phenyl, haloaryl, heteroaryl or haloheteroaryl; or When adjacent or geminal, (two R 2d ) or (two R 2f ) together with one or more atoms to which they are attached form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring, said ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, said ring optionally being substituted by at least one substituent -F, -Cl, -Br, -I, hydroxy, oxo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halopyrrolyl, phenyl, haloaryl, heteroaryl or halopyrrolyl; R 2g 、 R 2h and R 2i are each independently selected from hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted by at least one substituent -F, -Cl, -Br, -I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo-C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halocyclic group, phenyl, haloaryl, heteroaryl or haloheteroaryl.

10. The compound according to any one of the preceding claims, wherein R 2 is hydrogen, methyl, ethyl, propyl, butyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxazepanyl, oxetanyl, azetidinyl, oxa - azaspiro[4.4]nonanyl, hexahydro - 1H - furo[3,4 - c]pyrrolyl, octahydropyrrolo[3,4 - c]pyrrolyl, diazaspiro[4.5]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 2b ; wherein each of said 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 or phenyl is optionally substituted by at least one substituent R 2d ; R 2a and R 2b are each independently selected from hydrogen, methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl, isobutyl or tert-butyl), pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, oxaazepanyl, 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, wherein each of said methyl, ethyl, propyl, 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]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 2f ; or (R 2a and R 2b ), (R 2b and R 2c ), or (R 2a and R 2c ), together with one or more atoms to which they are attached, form a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered ring, said ring containing 0, 1, or 2 heteroatoms independently selected from nitrogen or oxygen as one or more of the 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, -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]nonanyl, hexahydro - 1H - furano[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, -OH, methoxy, ethoxy, propoxy, butoxy, pentyloxy, 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 .

11. A compound according to 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 , 12. A compound according to any one 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 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl, heteroaryl or -CN; wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, 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 group (-C(=O)-) or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring which contains 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, the ring being monocyclic, spirocyclic, fused or bridged, and the ring being optionally substituted by at least one substituent R 3c substituted; Each R 3c is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, 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 said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted by at least one substituent -F, -Cl, -Br, -I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halocyclic group, phenyl, haloaryl, heteroaryl or haloheteroaryl; 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, heterocyclic group, phenyl or heteroaryl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted by at least one substituent -F, -Cl, -Br, -I, hydroxyl, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halocyclic group, 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, heterocyclic group, phenyl, heteroaryl or -CN; or R 3A and R 3B together with the atoms to which they are attached form an acyl group (-C(=O)-) or a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or optionally oxidized sulfur as one or more ring members, the ring being monocyclic, spiro, fused or bridged, the ring being optionally substituted by at least one substituent R 3c substituted; Each R 3c is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, 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 said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group is optionally substituted by 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, pentyloxy, hexyloxy, heptyloxy, octyloxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halosubstituted heterocyclic group, phenyl, haloaryl, heteroaryl or halosubstituted heteroaryl; 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 said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl is optionally substituted with at least one substituent -F, -Cl, -Br, -I, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, halosubstituted heterocyclic group, aryl, haloaryl, heteroaryl or halosubstituted heteroaryl; 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 group (-C(=O)-) or a 3-, 4-, 5-, 6-, 7- or 8-membered ring, said ring containing 0, 1 or 2 heteroatoms independently selected from nitrogen, oxygen or oxidized sulfur as one or more ring members, said ring being monocyclic, spirocyclic, fused or bridged, and said ring being optionally substituted with at least one substituent selected from hydrogen, -F, methyl, ethyl, propyl, butyl, -CF 3 , oxo or -CN.

13. A compound according to any one of the preceding claims, wherein the moiety is wherein * 3 refers to the position attached to part, and ** 3 refers to the position attached to this part; Preferably, the part is 14. The compound according to any one of the preceding claims, wherein the moiety is -Me, -Et, 15. A compound as claimed in any one of the preceding claims, wherein R 4 is hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, aryl, heteroaryl, oxo, -CN, -OR 401b , -SO 2 R 401b , -SO 2 NR 401b R 401c , -COR 401b , -CO 2 R 401b , -CONR 401b R 401c , -NO 2 , -NR 401b R 4c , -NR 401b COR 401c , -NR 401b CO 2 R 401c , -NR 401b CONR 401c R 401d or –NR 401b SO 2 R 401c ; wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, aryl or heteroaryl is optionally substituted by at least one substituent R 4a ; R 401b , R 401c and R 401d 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 the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of 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, hydroxyl, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl; Each R 4a is independently selected from hydrogen, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, 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 ; wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -halo C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; R 4b , R 4c and R 4d 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 the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of 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, hydroxyl, -C 1-8 Alkyl, -halogenated C 1-8 Alkyl, -C 1-8 Alkoxy, -halogenated C 1-8 Alkoxy, -C 2-8 Alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, haloheterocyclyl, aryl, haloaryl, heteroaryl or haloheteroaryl; 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, heterocyclic group, -COOMe, -COOEt, -COOC 3 H 7 , -COOCH(CH 3 ) 2 , -COOCH 2 CH 2 CH 2 CH 3 , -COOCH(CH 3 )CH 2 CH 3 , -COOCH 2 CH(CH 3 ) 2 , -COOC(CH 3 ) 3 , -CH 2 OH, -CH(CH 3 )OH, -C(CH 3 ) 2 OH, -CH 2 NH 2 , -CH(CH 3 )NH 2 or -C(CH 3 ) 2 NH 2 ; More preferably, R 4 Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl Isobutyl Tert-butyl -COOMe, -COOEt, -COOCH 2 CH 2 CH 3 、-COOCH(CH 3 ) 2 、-COOCH 2 CH 2 CH 2 CH 3 、-COOCH(CH 3 )CH 2 CH 3 、-COOCH 2 CH(CH 3 ) 2 、-COOC(CH 3 ) 3 、-CH 2 OH, -CH(CH 3 )OH, -C(CH 3 ) 2 OH, -CH 2 NH 2 、-CH(CH 3 )NH 2 or -C(CH 3 ) 2 NH 2 .

16. A compound as claimed in any one of the preceding claims, wherein R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, 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 ; wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 ynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl or heteroaryl is optionally substituted by at least one substituent R 5d ; R 5a , R 5b and R 5c 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 the methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 Alkenyl, -C 2-8 Each of the alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclyl, phenyl or heteroaryl groups is optionally substituted with at least one substituent R 5f replace; R 5d and R 5f each independently selected from hydrogen, -F, -Cl, -Br, hydroxy, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, phenyl, haloaryl, heteroaryl or haloheteroaryl, wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -halo C 1-8 alkyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, phenyl, haloaryl, heteroaryl or haloheteroaryl is optionally substituted with at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo C 1-8 alkyl, -C 1-8 alkoxy, -halo C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, haloheterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; Preferably, R 5 、R 6 、R 7 、R 8 and R 9 are each independently selected from H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 enyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, 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 ; R 5a , R 5b and R 5c 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; More preferably, R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from H, -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl, -C 2-8 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, heterocyclic group, phenyl, heteroaryl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -CN.

17. A compound according to any one of the preceding claims, wherein 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 selected from -F, -Cl, -Br, -I, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, -CN; and / or R 9 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 selected from -F, -Cl, methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, butoxy, -CN; and / or R 9 Selected from H.

18. A compound according to any one of the preceding claims, wherein R 11 is selected from H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl or -C 2-8 alkynyl; wherein each of said methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl or -C 2-8 alkynyl is optionally substituted by at least one substituent R 11a ; R 11a selected from hydrogen, halogen, hydroxy, -C 1-8 alkyl, -halo-C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halosubstituted heterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl, wherein each of said -C 1-8 alkyl, -halo-C 1-8 alkyl, -C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halosubstituted heterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl is optionally substituted by at least one substituent selected from the group consisting of: halogen, hydroxy, -C 1-8 alkyl, -halo-C 1-8 alkyl, -C 1-8 alkoxy, -halo-C 1-8 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, cycloalkyl, halocycloalkyl, heterocyclic group, halosubstituted heterocyclic group, aryl, haloaryl, heteroaryl or haloheteroaryl; Preferably, R 11 is selected from H, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, -C 2-8 alkenyl or -C 2-8 alkynyl; More preferably, R 11 is selected from H, methyl, ethyl, propyl, butyl; Even more preferably, R 11 is H.

19. A compound according to any one of the preceding claims, wherein m = 0 and the moiety is replaced in its entirety by H.

20. The compound according to any one of the preceding claims, wherein the compound is selected from 21. A pharmaceutical composition comprising the compound according to any one of claims 1-20 or its pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug, and a pharmaceutically acceptable excipient.

22. A method of inhibiting the reduction of CDK4 activity, the method comprising administering to an individual the compound according to any one of claims 1-19 or its pharmaceutically acceptable salt, including the compound having the formula (I) or the specific compounds exemplified herein.

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

24. Use of the compound according to any one of claims 1-20 or its pharmaceutically acceptable salt, stereoisomer, tautomer or prodrug in the manufacture of a medicament for the treatment of a disease that can be affected by the modulation of CDK4.

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

26. A method of treating a disease or disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1-20 or its pharmaceutically acceptable salt as a CDK4 kinase inhibitor, wherein the disease or disorder is related to the inhibition of CDK4.

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

Images