CN113698391B - 4-aminopyrimidine or 2-aminotriazine compound and preparation method thereof - Google Patents
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Abstract
The present disclosure relates to 4-aminopyrimidine or 2-aminotriazine compounds and methods for preparing the same. In particular, the present disclosure provides a compound of formula I or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer or tautomer thereof, wherein R 1 ～R 4 X is as defined herein. The compounds of formula I are useful as cyclin-dependent kinase inhibitors for the prophylaxis and/or treatment of diseases which are associated therewith, such as cell proliferative diseases, cancer or immunological diseases.
Description
Technical Field
The disclosure belongs to the field of medicines and relates to a 4-aminopyrimidine or 2-aminotriazine compound.
Background
Cyclin-dependent kinases (CDKs) are important cellular enzymes that play an important role in regulating eukaryotic cell division and proliferation. Cyclin-dependent kinase catalytic units are known as cyclin-mediated subunit activation. At least 16 mammalian cyclin have been identified (Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312). Cyclin B/CDK1, cyclin a/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6 and possibly other heterodynes are important mediators of cell cycle progression. Other functions of cyclin/CDK heterodynes include transcriptional regulation, DNA repair, differentiation, and apoptosis (Annu.Rev.cell.Dev.biol. (1997) 13:261-291).
In recent years, the greatest progress in the field of breast cancer treatment has undoubtedly been the use of CDK4/6 alone or in combination with endocrine therapy in the treatment of hormone receptor positive advanced breast cancers such as palbociclib, ribociclib and bomaciclib in combination with aromatase inhibitors has been approved for the treatment of Hormone Receptor (HR) -positive, human epidermal growth factor receptor 2 (HER 2) -negative advanced or metastatic breast cancer in postmenopausal women, and palbociclib and bomaciclib (abemaciclib) have been approved in combination with fulvestrant for the treatment of Hormone Receptor (HR) -positive, human epidermal growth factor receptor 2 (HER 2) -negative advanced or metastatic breast cancer (Nature Reviews 13:417-430, J Clin Oncol 2017,35,2875-2884) in postmenopausal women after disease progression following endocrine therapy. Although CDK4/6 inhibitors show significant clinical efficacy in estrogen receptor ER positive metastatic breast cancer, as with other kinases, their effect may be limited over time by the development of primary or acquired resistance.
Overexpression of CDK2 is associated with abnormal regulation of the cell cycle. Cyclin E/CDK2 complexes play an important role in regulating G1/S conversion, histone biosynthesis and centrosome replication. Progressive phosphorylation of Rb by cyclin D/Cdk4/6 and cyclin E/Cdk2 releases the G1 transcription factor E2F and facilitates S phase entry. Activation of cyclin a/CDK2 during early S-phase promotes phosphorylation of endogenous substrates, which allows DNA replication and inactivation of E2F to complete S-phase. (Nat. Rev. Drug. Discov.2015;14 (2): 130-146).
In recent years, various companies respectively identify and discover a series of inhibitors for selectively inhibiting CDK2, which are used for treating diseases such as cancers, such as Seliciclib, dinaciclib, but in order to achieve better cancer treatment effect, market demands are better met, and new generation of high-efficiency low-toxicity selective CDK2 inhibitors still need to be developed.
Disclosure of Invention
The present disclosure provides compounds of formula I,
wherein R is 1 Selected from hydrogen, alkyl (e.g. C 1-6 Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), cycloalkyl groups (e.g., C 3-12 Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (e.g., 3-to 12-membered heterocycloalkyl, including but not limited to pyrrolyl), said alkyl, cycloalkyl or heterocyclyl optionally substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, alkyl optionally substituted with A, cycloalkyl optionally substituted with A, heterocyclyl optionally substituted with A, alkoxy optionally substituted with A, alkenyl optionally substituted with A, alkynyl optionally substituted with A, aryl optionally substituted with A, heteroaryl optionally substituted with A, SR ', SOR', SO 2 R'、SO 2 NR '(R "), COOR' or CONR '(R'),
R 2 selected from cycloalkyl groups (e.g. C 3-12 Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (e.g., 3-to 12-membered heterocycloalkyl, including but not limited to pyrrolyl) containing 1-4 heteroatoms independently selected from N, O or S, and which cycloalkyl or heterocyclyl is optionally substituted with one or more groups selected from halo, hydroxy, oxo, nitro, cyano, alkyl optionally substituted with A, cycloalkyl optionally substituted with A, heterocyclyl optionally substituted with A, alkoxy optionally substituted with A, alkenyl optionally substituted with A, alkynyl optionally substituted with A, aryl optionally substituted with A, heteroaryl optionally substituted with A, SR ', SOR', SO 2 R'、SO 2 NR '(R "), COOR' or CONR '(R');
R 3 selected from 9-12 membered aryl (e.g., 6-12 membered aryl including but not limited to phenyl, naphthyl) or heteroaryl (e.g., 5-A 12 membered heteroaryl, a 5-7 membered heterocycloaromatic ring, including but not limited to pyridine, piperidine, containing 1-4 heteroatoms independently selected from N, O or S, and the aryl or heteroaryl group is optionally substituted with one or more heteroatoms selected from halogen, hydroxy, nitro, cyano, alkyl optionally substituted with A, alkoxy optionally substituted with A, cycloalkyl optionally substituted with A, heterocyclyl optionally substituted with A, alkenyl optionally substituted with A, alkynyl optionally substituted with A, aryl optionally substituted with A, heteroaryl optionally substituted with A, SR ', SOR', SO 2 R'、SO 2 NR '(R "), COOR' or CONR '(R');
x is selected from N or CR 5 ；
R 4 Or R is 5 Each independently selected from hydrogen, halogen (e.g., fluorine, chlorine, bromine), hydroxy, nitro, cyano, alkyl (e.g., C) 1-6 Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C 1-6 Alkoxy groups including, but not limited to, methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl groups (e.g., C 3-12 Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (e.g., 3-to 12-membered heterocycloalkyl, including but not limited to pyrrolyl), aryl (e.g., 6-12-membered aryl, including but not limited to phenyl, naphthyl), heteroaryl (e.g., 5-12-membered heteroaryl, 5-7-membered heterocyclobenzene, 5-6-membered heteroaryl, including but not limited to pyridine, piperidine), SR ', SOR', SO 2 R'、SO 2 NR ' (R "), NR ' (R), COOR ' or CONR ' (R '), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, alkyl optionally substituted with A, cycloalkyl optionally substituted with A, heterocyclyl optionally substituted with A, alkoxy optionally substituted with A, alkenyl optionally substituted with A, alkynyl optionally substituted with A, aryl optionally substituted with A, heteroaryl optionally substituted with A, SR ', SOR ', SO 2 R'、SO 2 NR ' (R "), COR ', COOR ', or CONR ' (R ');
each R 'or R' is independently selected from hydrogen, hydroxy, alkyl (e.g., C 1-6 Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C 1-6 Alkoxy groups including, but not limited to, methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl groups (e.g., C 3-12 Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (e.g., 3 to 12 membered heterocycloalkyl, including but not limited to pyrrolyl), aryl, or heteroaryl, optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, cyano, alkyl optionally substituted with a, alkoxy optionally substituted with a, cycloalkyl optionally substituted with a, heterocyclyl optionally substituted with a, aryl optionally substituted with a, heteroaryl optionally substituted with a;
a is selected from halogen (such as fluorine, chlorine, bromine), hydroxy, oxo, nitro, cyano C 1-6 Alkyl (including but not limited to methyl, ethyl, propyl or isopropyl), C 1-6 Alkoxy (including but not limited to methoxy, ethoxy, propoxy or isopropoxy), C 3-7 Cycloalkyl (including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, SR 16 、SOR 16 、SO 2 R 16 、SO 2 NR 16 (R 17 )、NR 16 (R 17 )、COR 16 、COOR 16 Or CONR 16 (R 17 ) The alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are optionally substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, SR 16 、SOR 16 、SO 2 R 16 、SO 2 NR 16 (R 17 )、NR 16 (R 17 )、COR 16 、COOR 16 Or CONR 16 (R 17 )；
Each R 16 Or R is 17 Independently selected from hydrogen, hydroxy, alkyl (e.g. C 1-6 Alkyl groups including, but not limited to, methyl, ethyl, propyl orIsopropyl), alkoxy (e.g. C 1-6 Alkoxy groups including, but not limited to, methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl groups (e.g., C 3-12 Cycloalkyl, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl (e.g., 3-to 12-membered heterocycloalkyl, including but not limited to pyrrolyl), aryl (e.g., 6-to 12-membered aryl, including but not limited to phenyl, naphthyl), heteroaryl (e.g., 5-to 12-membered heteroaryl, 5-to 7-membered heterocyclobenzene, 5-to 6-membered heteroaryl, including but not limited to pyridine, piperidine), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl.
In some embodiments, a 3-12 membered heterocyclyl in the present disclosure may be a 3-5 membered heterocyclyl, a 5-7 membered heterocyclyl, a 9-12 membered heterocyclyl, a 6-10 membered heterocyclyl, and the heterocyclyl contains 1-4 heteroatoms selected independently from N, O or S, or contains 2-3 heteroatoms selected independently from N, O or S.
In some embodiments, C in the present disclosure 3-7 Cycloalkyl groups may be C 3-7 Cycloalkyl, C 5-7 Cycloalkyl, C 6-7 Cycloalkyl groups.
In some embodiments, a 6-12 membered aryl group in the present disclosure may be a 5-7 membered aryl group, a 6-10 membered aryl group, a 9-12 membered aryl group, a 6-8 membered aryl group.
In some embodiments, a 3-12 membered heteroaryl in the present disclosure may be a 3-5 membered heteroaryl, a 5-7 membered heteroaryl, a 9-12 membered heteroaryl, a 6-10 membered heteroaryl, and the heteroaryl contains 1-4 heteroatoms independently selected from N, O or S, or contains 2-3 heteroatoms independently selected from N, O or S.
In some embodiments, a compound R of formula I 1 Or R is 2 Forms together with the adjacent atoms a 3-to 12-membered, preferably 3-to 8-membered, carbocyclic, heterocyclic ring which is optionally substituted by a ring selected from halogen, hydroxy, oxo, nitro, cyano, alkyl optionally substituted by A, alkoxy optionally substituted by A, optionally substituted by A Alkyl, heterocyclyl optionally substituted with a, aryl optionally substituted with a, heteroaryl optionally substituted with a, SR ', SOR', SO 2 R'、SO 2 One or more substituents of NR '(R "), COOR' or CONR '(R') are substituted.
In some embodiments, the compound of formula I is selected from:
wherein each R 6 Independently selected from hydrogen, halogen (e.g., fluorine, chlorine, bromine), hydroxy, nitro, oxo, cyano, alkyl (e.g., C) 1-6 Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C 1-6 Alkoxy groups including, but not limited to, methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl groups (e.g., C 3-12 Cycloalkyl groups including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl groups (e.g., 3-to 12-membered heterocycloalkyl groups including, but not limited to, pyrrolyl), aryl, heteroaryl, SR ', SOR', SO 2 R'、SO 2 NR ' (R), COOR ' or CONR ' (R "), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with one or more substituents selected from halogen, hydroxy, oxo, nitro, cyano;
n is selected from 0, 1, 2, 3 or 4;
t is selected from 1, 2, 3 or 4;
s is selected from 0, 1, 2, 3 or 4;
y is selected from NR 7 O or CR 8 R 9 ；
R 7 Selected from hydrogen, alkyl (e.g. C 1-6 Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C 1-6 Alkoxy groups including, but not limited to, methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl groups (e.g., C 3-12 Cycloalkyl groups including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl groups (e.g., 3-to 12-membered heterocycloalkyl groups including, but not limited to, pyrrolyl), aryl, heteroaryl, SR ', SOR', SO 2 R'、SO 2 NR '(R), COR', COOR 'or CONR' (R "), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally being substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO 2 R'、SO 2 NR ' (R "), COR ', COOR ', or CONR ' (R ');
R 8 or R is 9 Each independently selected from hydrogen, alkyl (e.g. C 1-6 Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups (e.g., C 1-6 Alkoxy groups including, but not limited to, methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl groups (e.g., C 3-12 Cycloalkyl groups including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl), heterocyclyl groups (e.g., 3-to 12-membered heterocycloalkyl groups including, but not limited to, pyrrolyl), aryl, heteroaryl, SR ', SOR', SO 2 R'、SO 2 NR '(R), COR', COOR 'or CONR' (R "), said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally being substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO 2 R'、SO 2 NR ' (R "), COR ', COOR ' or CONR ' (R '),
alternatively, R 8 Or R is 9 Forms together with the adjacent atoms a 3-to 12-membered, preferably 3-to 8-membered, carbocyclic, heterocyclic ring, which is optionally substituted with a member selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, SR ', SOR', SO 2 R'、SO 2 NR ' (R "), COR ', COOR ', or CONR ' (R ');
R 1 、R 3 、R 4 x, R ', R' are as defined for the compounds of formula I above.
In some embodiments, R in the compound of formula I 3 Selected from the group consisting of 5-7 membered heterocycloaromatic rings, 5-7 membered heterocycloaromatic rings containing 1-4 heteroatoms independently selected from N, O or S.
In some embodiments, R in the compound of formula I 3 Selected from:
In some embodiments, R in the compounds of the present disclosure 10 Or R is 11 Selected from hydrogen.
In some embodiments, R in the compounds of the present disclosure 12 Selected from fluorine, chlorine, C optionally substituted by one or more A 1-6 Alkyl, C optionally substituted by one or more A 1-6 Alkoxy, C optionally substituted by one or more A 3-4 Cycloalkyl or 3-7 membered heterocycloalkyl optionally substituted with one or more a, said a being selected from fluoro; the R is 12 Fluorine is preferred.
In some embodiments, R in the compounds of the present disclosure 14 Or R is 15 Selected from C optionally substituted by one or more A 1-6 Alkyl or C optionally substituted by one or more A 1-6 Alkoxy, C optionally substituted by one or more A 3-4 Cycloalkyl or 3-7 membered heterocycloalkyl optionally substituted with one or more a, said a being selected from halogen; the R is 14 Methyl, ethyl, propyl or isopropyl are preferred.
In some embodiments, R in the compounds of the present disclosure 6 Selected from hydrogen, halogen, hydroxy, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, 6-12 membered aryl or 5-12 membered heteroaryl.
In other embodiments, R in the compound of formula I 3 Selected from the group consisting of
Wherein R is 10 -R 14 As defined above.
In some embodiments, R in the compound of formula I 3 Selected from the group consisting of
Wherein B is selected from CR 10 Or NR (NR) 10 ；
C is selected from CR 11 Or NR (NR) 11 ；
D is selected from CR 12 Or NR (NR) 12 ；
E is selected from CR 13 Or NR (NR) 13 ；
F is selected from CR 14 Or NR (NR) 14 ；
R 10 -R 14 Independently selected from hydrogen, halogen (e.g., fluorine, chlorine, bromine), hydroxy, nitro, cyano, alkyl optionally substituted with A (e.g., C 1-6 Alkyl groups including, but not limited to, methyl, ethyl, propyl, or isopropyl), anyOptionally substituted alkoxy (e.g. C) with A 1-6 Alkoxy groups including, but not limited to, methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl optionally substituted with A (e.g., C 3-12 Cycloalkyl including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl), heterocycloalkyl optionally substituted with a (e.g., 3-to 12-membered heterocycloalkyl including, but not limited to, pyrrolyl), alkenyl optionally substituted with a, alkynyl optionally substituted with a, aryl optionally substituted with a, heteroaryl optionally substituted with a, SR ', SOR', SO 2 R'、SO 2 NR ' (R "), COR ', COOR ', or CONR ' (R '); a is selected from halogen (such as fluorine, chlorine, bromine), hydroxy, oxo, nitro, cyano.
In other embodiments, the compound of formula I is selected from:
wherein B is selected from CR 10 Or NR (NR) 10 The method comprises the steps of carrying out a first treatment on the surface of the C is selected from CR 11 Or NR (NR) 11 The method comprises the steps of carrying out a first treatment on the surface of the D is selected from CR 12 Or NR (NR) 12 The method comprises the steps of carrying out a first treatment on the surface of the E is selected from CR 13 Or NR (NR) 13 The method comprises the steps of carrying out a first treatment on the surface of the F is selected from CR 14 Or NR (NR) 14 ；
When E is CR 13 When F is NR 14 ；
When E is NR 13 When F is NR 14 Or CR (CR) 14 ；
Wherein R is 10 -R 14 Independently selected from hydrogen, halogen (e.g., fluorine, chlorine, bromine), hydroxy, nitro, cyano, alkyl optionally substituted with A (e.g., C 1-6 Alkyl groups including, but not limited to, methyl, ethyl, propyl or isopropyl), alkoxy groups optionally substituted with A (e.g., C 1-6 Alkoxy groups including, but not limited to, methoxy, ethoxy, propoxy or isopropoxy), cycloalkyl optionally substituted with A (e.g., C 3-12 Cycloalkyl including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl), heterocycloalkyl optionally substituted with a (e.g., 3 to 12 membered heterocycloalkyl including, but not limited to, pyrrolyl), alkenyl optionally substituted with a, alkynyl optionally substituted with a, aryl optionally substituted with a A substituted heteroaryl, SR ', SOR', SO 2 R'、SO 2 NR ' (R "), COR ', COOR ', or CONR ' (R '); a is selected from halogen (such as fluorine, chlorine, bromine), hydroxy, oxo, nitro, cyano;
R 1 、R 4 、R 6 s, t, n, X, Y are as defined for the compounds of formula II above.
In some embodiments, B in the compound of formula III is selected from CR 10 The method comprises the steps of carrying out a first treatment on the surface of the C is selected from CR 11 The method comprises the steps of carrying out a first treatment on the surface of the D is selected from CR 12 The method comprises the steps of carrying out a first treatment on the surface of the E is selected from CR 13 The method comprises the steps of carrying out a first treatment on the surface of the F is selected from NR 14 。
In some embodiments, B in the compound of formula III is selected from CR 10 The method comprises the steps of carrying out a first treatment on the surface of the C is selected from CR 11 The method comprises the steps of carrying out a first treatment on the surface of the D is selected from CR 12 The method comprises the steps of carrying out a first treatment on the surface of the E is selected from NR 13 The method comprises the steps of carrying out a first treatment on the surface of the F is selected from CR 14 。
In some embodiments, B in the compound of formula III is selected from CR 10 The method comprises the steps of carrying out a first treatment on the surface of the C is selected from CR 11 The method comprises the steps of carrying out a first treatment on the surface of the D is selected from NR 12 The method comprises the steps of carrying out a first treatment on the surface of the E is selected from CR 13 The method comprises the steps of carrying out a first treatment on the surface of the F is selected from NR 14 。
In some embodiments, B in the compound of formula III is selected from CR 10 The method comprises the steps of carrying out a first treatment on the surface of the C is selected from CR 11 The method comprises the steps of carrying out a first treatment on the surface of the D is selected from NR 12 The method comprises the steps of carrying out a first treatment on the surface of the E is selected from NR 13 The method comprises the steps of carrying out a first treatment on the surface of the F is selected from CR 14 。
In some embodiments, the compound of formula I wherein X is selected from N; r is R 4 Selected from hydrogen, halogen, hydroxy, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, preferably hydrogen, fluorine, chlorine, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, more preferably hydrogen.
In some embodiments, X in the compound of formula I is selected from CR 5 ；R 4 Or R is 5 Each independently selected from hydrogen, halogen, hydroxy, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, 6-12 membered aryl or 5-12 membered heteroaryl, preferably hydrogen, fluorine, chlorine, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl groups, more preferablyHydrogen.
In some embodiments, R 'or R' in the compounds of formula I are independently selected from hydrogen, hydroxy, C 1-6 An alkyl group, a 6-12 membered aryl group or a 5-12 membered heteroaryl group, said alkyl, aryl or heteroaryl group optionally being substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano.
In some embodiments, A in the compound of formula I is selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally being substituted with one or more groups selected from halogen, hydroxy, oxo, nitro, cyano.
In another aspect, the compound of formula I is selected from:
wherein B, C, D, E, F is as defined for the compound of formula III; r is R 4 、R 6 N, X, Y are as defined for the compounds of formula II above.
In some embodiments, Y in the compounds of formulas II-IV is selected from NR 7 Or O; further R 7 Preferably hydrogen, C 1-6 Alkyl, SO 2 R'、SO 2 NR '(R "), COR', COOR ', or CONR' (R '), R' are as defined for the compounds of formula I.
In some embodiments, R in the compounds of formulas II-IV 7 Selected from SO 2 R ', COR' or COOR ', R' is selected from methyl, ethyl and propyl.
In other embodiments, Y in the compounds of formulas II-IV is selected from CR 8 R 9 ，R 8 Or R is 9 Each independently selected from hydrogen, C 1-6 Alkyl, SO 2 R'、SO 2 NR '(R "), COR', COOR ', or CONR' (R '), R' are as defined for the compounds of formula I.
In the case of the use of the present invention in the case of a further embodiment,r in the compounds of the formulae II to IV 8 Or R is 9 Each independently selected from hydrogen, COR ', COOR ', R ' selected from methyl, ethyl, propyl.
In another aspect, the compound of formula I is selected from:
wherein R is 4 、R 6 N, X, Y are as defined for the compounds of formula II above; r is R 10 -R 14 As defined in the compounds of formula III above.
In some embodiments, R in the compounds of formulas III-IV 10 Or R is 11 Selected from hydrogen, halogen, hydroxy, nitro, cyano, C 1-6 Alkyl (e.g. C 1-6 Alkyl groups including, but not limited to, methyl, ethyl, propyl, or isopropyl).
In some embodiments, R in the compounds of formulas III-IV 12 Selected from fluorine, chlorine, C optionally substituted by one or more A 1-6 Alkyl, C optionally substituted by one or more A 1-6 Alkoxy, C optionally substituted by one or more A 3-4 Cycloalkyl or 3-7 membered heterocycloalkyl optionally substituted with one or more a, said a being selected from fluoro; the R is 12 Fluorine is preferred.
In some embodiments, R in the compounds of formulas III-IV 14 Selected from C optionally substituted by one or more A 1-6 Alkyl or C optionally substituted by one or more A 1-6 Alkoxy, C optionally substituted by one or more A 3-4 Cycloalkyl or 3-7 membered heterocycloalkyl optionally substituted with one or more a, said a being selected from halogen; the R is 14 Preferably methyl, ethyl, propyl, isopropyl, 2-hydroxyethyl or 2-hydroxypropyl.
In some embodiments, R in the compounds of formulas III-IV 6 Selected from hydrogen, halogen, hydroxy, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl, 6-12 membered aryl or 5-A 12 membered heteroaryl.
Typical compounds of formula I include, but are not limited to:
In some embodiments, the compound of formula I is selected from:
Comprising the step of reacting a compound of formula IC with a compound of formula ID to form a compound of formula I,
wherein LG (glass fiber reinforced plastic) 1 Or LG (light emitting diode) 2 Selected from leaving groups, preferably halogen, sulfonate, boric acid, borate.
In some embodiments, the reaction is carried out under catalyst conditions, the catalyst selected from metallic palladium, metallic nickel.
In some embodiments, the catalyst is selected from palladium on carbon, raney nickel, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1 '-bis (diphenylphosphino) ferrocene ] palladium dichloride, 1' - [1,1 '-bis (di-tert-butylphosphino) ferrocene ] palladium dichloride, tris (dibenzylideneacetone) dipalladium or 2-dicyclohexylphosphine-2', 6 '-dimethoxybiphenyl, preferably [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl.
Also provided in the present disclosure is a pharmaceutical composition comprising at least one therapeutically effective amount of a compound of formula I, II, III, IV, IV-1 or IV-2, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer or tautomer thereof, as described above, and a pharmaceutically acceptable excipient.
In some embodiments, the pharmaceutical composition is in a unit dose of 0.001mg to 1000mg.
In certain embodiments, the pharmaceutical composition comprises 0.01 to 99.99% of a compound of formula I, II, III, IV, IV-1 or IV-2 described previously or a pharmaceutically acceptable salt thereof or a stereoisomer, rotamer or tautomer thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical compositions comprise 0.1-99.9% of a compound of formula I, II, III, IV, IV-1 or IV-2 described above or a pharmaceutically acceptable salt thereof or a stereoisomer, rotamer or tautomer thereof. In certain embodiments, the pharmaceutical compositions comprise 0.5% to 99.5% of a compound of formula I, II, III, IV, IV-1 or IV-2 described above or a pharmaceutically acceptable salt thereof or a stereoisomer, rotamer or tautomer thereof. In certain embodiments, the pharmaceutical compositions comprise 1% to 99% of a compound of formula I, II, III, IV, IV-1 or IV-2 described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer or tautomer thereof. In certain embodiments, the pharmaceutical compositions comprise 2% to 98% of a compound of formula I, II, III, IV, IV-1 or IV-2 described above, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer or tautomer thereof.
In certain embodiments, the pharmaceutical composition contains 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2% to 98% of a pharmaceutically acceptable excipient.
The present disclosure also provides a method of preventing and/or treating a patient suffering from a protein-dependent kinase-associated disease, preferably a cell proliferative disease, cancer or an immune disease, comprising administering to the patient a therapeutically effective amount of a compound as shown in the foregoing formula I, II, III, IV, IV-1 or IV-2 or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer or tautomer thereof, or a pharmaceutical composition as described above. The present disclosure also provides the use of a compound of formula I, II, III, IV, IV-1 or IV-2 as hereinbefore described, or a pharmaceutically acceptable salt thereof, or a stereoisomer, rotamer or tautomer thereof, or a pharmaceutical composition as hereinbefore described, in the manufacture of a medicament for the prevention and/or treatment of a protein dependent kinase related disease, preferably a cell proliferative disease, cancer or an immune disease.
In another aspect, pharmaceutically acceptable salts of the compounds described in this disclosure are selected from inorganic salts or organic salts.
The compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-) -and (+) -pairs of enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present disclosure. The asymmetric carbon atom containing compounds of the present disclosure may be isolated in optically active pure or racemic forms. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.
Optically active (R) -and (S) -isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it may be prepared by asymmetric synthesis or derivatization with chiral auxiliary wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric resolution is carried out by conventional methods well known in the art, and then the pure enantiomer is recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amine).
In the chemical structure of the compounds of the present disclosure, the bond
Indicating the unspecified configuration, i.e.the bond +.>
Can be +.>
Or->
Or at the same time contain->
And->
Two configurations. Key with a key
Indicating unspecified configurations including cis (E) or trans (Z) configurations.
The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton transfer, such as keto-enol and imine-enamine, lactam-lactam isomerization. Examples of lactam-lactam balances are between a and B as shown below.
All compounds in the present disclosure may be drawn as form a or form B. All tautomeric forms are within the scope of the disclosure. The naming of the compounds does not exclude any tautomers.
The present disclosure also includes some isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the replacement of one or more atoms by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as, respectively 2 H、 3 H、 11 C、 13 C、 14 C、 13 N、 15 N、 15 O、 17 O、 18 O、 31 P、 32 P、 35 S、 18 F、 123 I、 125 I and 36 cl, and the like.
Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium (i.e., at least 10% deuterium incorporation) having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). The natural abundance of a compound in an example can be at least 1000 times greater than the abundance of deuterium, at least 2000 times greater than the abundance of deuterium, at least 3000 times greater than the abundance of deuterium, at least 4000 times greater than the abundance of deuterium, at least 5000 times greater than the abundance of deuterium, at least 6000 times greater than the abundance of deuterium, or higher than the abundance of deuterium. The present disclosure also includes various deuterated forms of the compounds of formula (I). Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art are able to refer to the relevant literature for the synthesis of deuterated forms of the compounds of formula (I). Commercially available deuterated starting materials may be used in preparing the deuterated form of the compound of formula (I) or they may be synthesized using conventional techniques with deuterated reagents including, but not limited to, deuterated boranes, trideuteroborane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.
Term interpretation:
"pharmaceutically acceptable excipients" include, but are not limited to, any auxiliary agent, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifying agent that has been approved by the U.S. food and drug administration for use in humans or livestock animals.
"alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups having 1 to 12 carbon atoms are preferred, and alkyl groups having 1 to 6 carbon atoms are more preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, and various branched isomers thereof, and the like. The alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any useful point of attachment, preferably one or more groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-12 membered heterocyclyl, and the like.
"alkenyl" includes branched and straight chain olefins having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups. For example "C 2-6 Alkenyl "means alkenyl having 2, 3, 4, 5 or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylbut-2-enyl, 3-methylbut-1-enyl, 1-pentenyl, 3-pentenyl and 4-hexenyl. Alkenyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any useful point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-12 membered heterocyclyl, and the like.
"alkynyl" includes branched and straight chain alkynyl groups having 2 to 12 carbon atoms or olefins containing aliphatic hydrocarbon groups, or if specified, means that particular number of carbon atoms. Such as ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl, and 1-methylpent-2-ynyl. Alkynyl groups may be substituted or unsubstituted and when substituted, substituents may be substituted at any useful point of attachment, preferably one or more of the following groups, independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-12 membered heterocyclyl, and the like.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably oneOr a plurality of groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-12 membered heterocyclyl, and the like.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups. Non-limiting examples of "heterocyclyl" include:
The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:
The heterocyclic groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-12 membered heterocyclyl, and the like.
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 12 membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-12 membered heterocyclic group, etc., preferably phenyl.
The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 6 to 12 membered, more preferably 5 or 6 membered. For example. Non-limiting examples of which include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, 
Etc.
The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
heteroaryl group canOptionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-12 membered heterocyclyl, and the like.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from halogen, hydroxy, oxo, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-12 membered heterocyclyl, and the like.
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to-NH 2 。
The term "cyano" refers to-CN.
The term "nitro" refers to-NO 2 。
The term "oxo" refers to an =o substituent.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
Detailed Description
The present disclosure is further described below in connection with the examples, which are not intended to limit the scope of the present disclosure.
Experimental methods for which specific conditions are not noted in the examples of the present disclosure are generally performed according to conventional conditions or according to conditions suggested by the manufacturer of the raw materials or goods. The reagents of specific origin are not noted and are commercially available conventional reagents.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 -6 Units of (ppm) are given. NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard is Tetramethylsilane (TMS).
MS was measured using Shimadzu 2010Mass Spectrometer or Agilent 6110A MSD mass spectrometer.
HPLC was performed using a Shimadzu LC-20A systems, shimadzu LC-2010HT series or Agilent 1200LC high pressure liquid chromatograph (Ultimate XB-C18.0 x 150mm column or Xtime C18.1 x 30mm column).
Chiral HPLC analysis was performed using a chiral HPLC analysis of 3um, chiral pak AD-3X 4.6mm I.D.,3um, chiral pak AS-3 150X 4.6mm I.D.,3um, chiral pak AS-3X 4.6mm I.D.,3um, chiral pak OD-3X 4.6mm I.D.,3um, chiral Cel OJ-H150X 4.6mm I.D.,5um, chiral Cel OJ-3X 4.6mm I.D.,3um column;
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
Column chromatography generally uses 100-200 mesh, 200-300 mesh or 300-400 mesh of yellow sea silica gel as a carrier.
Chiral preparative columns used DAICEL CHIRALPAK IC (250 mm. Times.30 mm,10 um) or Phenomnex-Amylose-1 (250 mm. Times.30 mm,5 um).
The CombiFlash flash rapid prep instrument used CombiFlash Rf150 (teldyne ISCO).
Average inhibition rate of kinase and IC 50 The values were measured using a NovoStar microplate reader (BMG, germany).
Known starting materials of the present disclosure may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, shaog chemical technology (Accela ChemBio Inc), dary chemicals, and the like.
The examples are not particularly described, and the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.
An argon or nitrogen atmosphere means that the reactor flask is connected to a balloon of argon or nitrogen of about 1L volume.
The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.
The pressure hydrogenation reaction uses a Parr 3916 model EKX hydrogenometer and a clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.
The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.
The microwave reaction used was a CEM Discover-S908860 type microwave reactor.
The examples are not specifically described, and the solution refers to an aqueous solution.
The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.
The reaction progress in the examples was monitored by Thin Layer Chromatography (TLC),
the volume ratio of the solvent is adjusted according to the polarity of the compound, and small amount of alkaline or acidic reagents such as triethylamine and acetic acid can be added for adjustment.
Example 1
6- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) -N- (1- (methylsulfonyl) piperidin-4-yl) pyrimidin-4-amine
First step
6-chloro-N- (1- (methylsulfonyl) piperidin-4-yl) pyrimidin-4-amine 1c
2, 4-dichloropyrimidine 1a (0.2 g,1.3 mmol) and 1- (methylsulfonyl) piperidin-4-amine 1b (0.26 g,1.5 mmol) were dissolved in 5mL DMSO, N-diisopropylethylamine (0.52 g,4.0 mmol) was added, the reaction was reacted at 90℃until the reaction was essentially complete, 10mL of ice-water mixture was added, filtered, the ice-water washed, and the resulting solid was concentrated to dryness under reduced pressure to give the title compound 1c (0.35 g, yield: 90%).
MS(ESI)m/z 291.1[M+H] +
1 H NMR(400MHz,CDCl 3 )δ＝8.37(s,1H),6.37(d,J＝0.8Hz,1H),5.05(s,1H),4.04-3.88(m,1H),3.87-3.77(m,2H),2.90(dt,J＝2.4,12.4Hz,2H),2.83(s,3H),2.21-2.12(m,2H),1.65-1.58(m,2H)。
Second step
5-bromo-2-chloro-N- (2, 2-dimethoxyethyl) -6-methylpyridin-4-amine 1
To a mixed solution of 0.9mL of 1, 4-dioxane and 0.3mL of water, compound 1c (50 mg,0.17 mmol), 4-fluoro-1-isopropyl-2-methyl-6- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-benzo [ d ] imidazole 1d (80 mg,0.26 mmol), sodium carbonate (73 mg,0.69 mmol), and palladium tetraphenylphosphine (40 mg,0.034 mmol) were added under nitrogen atmosphere. The reaction was allowed to proceed to substantially completion under a nitrogen atmosphere at 100 ℃. The reaction solution was cooled to room temperature, filtered, washed with a mixed solution of dichloromethane and methanol, the filtrate was collected, concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with dichloromethane and methanol to give the title compound 1 (23 mg, yield: 30%).
MS(ESI)m/z 447.2[M+H]+
1 H NMR(400MHz,CDCl 3 )δ＝8.67(s,1H),8.09(d,J＝1.2Hz,1H),7.42(dd,J＝0.8,11.2Hz,1H),6.70(d,J＝1.2Hz,1H),4.92(br d,J＝6.8Hz,1H),4.81-4.67(m,1H),4.08(br s,1H),3.84(br d,J＝12.4Hz,2H),2.99-2.89(m,2H),2.84(s,3H),2.68(s,3H),2.27-2.19(m,2H),1.69(d,J＝6.8Hz,6H),1.65(br s,2H)。
Example 2
4- (4-fluoro-1-isopropyl-2-methyl-1H-benzo [ d ] imidazol-6-yl) -N- (1- (methylsulfonyl) piperidin-4-yl) -1,3, 5-triazin-2-amine see example 1, where the aforementioned compound 2 was prepared by substituting compound 2, 4-dichloro-1, 3, 5-triazine for compound 2, 4-dichloropyrimidine.
MS(ESI)m/z 462.2[M+H] +
Example 3
(3R, 4R) -4- ((4- (4-fluoro-2- ((R) -1-hydroxyethyl) -1-isopropyl-1H-benzo [ d ] imidazol-6-yl) -1,3, 5-triazin-2-yl) amino) -1- (methylsulfonyl) piperidin-3-ol
First step
(3R, 4R) -4- ((4-chloro-1, 3, 5-triazin-2-yl) amino) -1- (methylsulfonyl) piperidin-3-ol 3b
The compounds methyl 2, 4-dichloro-1, 3, 5-triazine (93 mg,0.62 mmol) and N, N-diisopropylethylamine (107 mg,0.82 mmol) were dissolved in 3mL of N, N-dimethylformamide. The compound (3R, 4R) -4-amino-1- (methylsulfonyl) piperidin-3-ol 3a (synthesized by reference to patent WO2019207463A1, 80mg,0.41 mmol) was added in portions to the reaction solution at room temperature and the reaction was essentially complete at room temperature until TLC. 20mL of water was added, extracted with ethyl acetate (20 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, concentrated under reduced pressure, and the residue was purified by C-18 reverse phase chromatography to give the title compound 3b (28 mg, yield: 22%).
MS(ESI)m/z 308.2[M+H] +
Second step
(3R, 4R) -4- ((4- (4-fluoro-2- ((R) -1-hydroxyethyl) -1-isopropyl-1H-benzo [ d ] imidazol-6-yl) -1,3, 5-triazin-2-yl) amino) -1- (methylsulfonyl) piperidin-3-ol 3
The compound (R) -1- (6-bromo-4-fluoro-1-isopropyl-1H-benzo [ d ] imidazol-2-yl) ethan-1-ol 3c (synthesized with reference to patent WO2019207463A1, 15.3mg,0.05 mmol), pinacol biborate (20.8 mg,0.08 mmol), potassium acetate (10 mg,0.1 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (7.0 mg,0.01 mmol) were dissolved in 2mL of 1, 4-dioxane under nitrogen. The reaction was essentially complete at 100℃until TLC detection. The reaction solution was cooled to room temperature, and 1,3,5, 7-tetramethyl-6-phenyl-2, 4, 8-trioxa-6-phosphoryl adamantane (3.0 mg,0.01 mmol), potassium carbonate (14 mg,0.1 mmol), compound 3b (12 mg,0.04 mmol), tris (dibenzylideneacetone) dipalladium (9 mg,0.01 mmol) and 0.5mL water were added to react at 80℃for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was collected, and the residue was purified by C-18 reverse phase chromatography to give the title compound 3 (4.2 mg, yield: 22%).
MS(ESI)m/z 494.4[M+H] +
1 H NMR(400MHz,DMSO_d6)δ＝8.63(d,J＝20.0Hz,1H),8.52(d,J＝11.6Hz,1H),8.15(br d,J＝8.4Hz,1H),7.95(dd,J＝12.4,15.2Hz,1H),5.79(d,J＝6.4Hz,1H),5.31(d,J＝4.4Hz,1H),5.25-5.16(m,1H),5.14-5.06(m,1H),4.05-3.86(m,1H),3.75-3.65(m,1H),3.65-3.61(m,1H),3.57-3.49(m,1H),2.92(d,J＝9.2Hz,3H),2.90-2.81(m,1H),2.74-2.60(m,1H),2.13-1.95(m,1H),1.64-1.60(m,9H),1.60-1.50(m,1H).
Biological evaluation
The present disclosure is explained in further detail below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.
Test example 1, compounds of the present disclosure for cyclin-dependent kinase activity assays
1. Experimental materials
2. Mobility shift assay measurement of kinase Activity
In vitro CDK (CDK 1, CDK2, CDK4, CDK6, CDK7, CDK 9) kinase activity was tested by the method of Mobility Shift Assay. In the experiment, the test compounds were tested for inhibition of CDK activity at an initial concentration of 300nM, 3-fold dilution, 10 total concentrations, and the multiplex assay. Compound Staurosporine was used as a standard control.
A1-fold kinase buffer (CDK 2) (50mM HEPES,pH 7.5,0.0015% Brij-35), a 1-fold kinase buffer (CDK 4) (20mM HEPES,pH 7.5,0.01% Triton X-100) and a stop solution (100mM HEPES,pH 7.5,0.015% Brij-35,0.2% Coating Reagent #3,50mM EDTA) were prepared. Adding a proper amount of kinase into a 1-time kinase buffer solution to prepare a 2.5-time enzyme solution; compound dilutions (1-fold kinase buffer, 10% dmso) were prepared at the corresponding 5-fold compound concentrations tested; appropriate amounts of FAM-labeled polypeptide and ATP were added to 1-fold kinase buffer to prepare a 2.5-fold substrate solution. Adding 5 mu l of 5-fold compound diluent and 10 mu l of 2.5-fold enzyme solution into a reaction well of a 384-well reaction plate, uniformly mixing, and incubating for 10 minutes at room temperature; then 10. Mu.l of 2.5-fold substrate solution was added to 384-well plates and centrifuged at 1000rpm for 1 minute; the reaction plate was incubated at 28℃for 60 minutes (Biochemical incubator model: SPX-100B-Z); 30 μl of stop solution was added to 384-well reaction plates to stop the reaction, and the mixture was centrifuged at 1000rpm for 1 minute; finally, the conversion data were read on Caliper EZ Reader II (excitation wavelength: 400nm, emission wavelengths: 445nm and 520 nm).
IC50 values for compounds were fit using XLFIT excel add-in version 5.4.0.8. Fitting formula:
Y＝Bottom+(Top-Bottom)/(1+(IC50/X)^HillSlope)。
the CDK (CDK 1, CDK2, CDK4, CDK6, CDK7, CDK 9) kinase biochemical inhibitory activity of the compounds of the present disclosure is determined by the assays described above, IC measured 50 The values are shown in Table 1 (CDK 2, CDK 4)
TABLE 1
Test example 2, compounds of the present disclosure for cyclin-dependent kinase Activity assays
1. Experimental material and instrument
2. Experimental procedure
Compound dilutions were transferred into each well of the assay plate using Echo 550 (784075, greiner). Sealing the measuring plate, centrifuging the measuring plate at 1000g for 1 minute; 2 Xenzyme was prepared in 1 Xkinase buffer (prepared from 1 volume of 5 Xkinase buffer and 4 volumes of distilled water and 50uM DTT), 2.5. Mu.l of 2 Xenzyme was added to 384 well assay plates, and the plates were centrifuged at 1000g for 30s and left at room temperature for 10 min. A2 x substrate and ATP mixture was prepared in 1x kinase buffer and the reaction was started by adding 2.5. Mu.l of the 2x substrate and ATP mixture. The plates were centrifuged at 1000g for 30 seconds, the assay plates were sealed and reacted at room temperature for 1 hour. Add 4. Mu.l ADP-Glo reagent, incubate at room temperature for 40 minutes, add 8. Mu.l kinase detection reagent, incubate at room temperature for 40 minutes.
Each well was read on an Envision 2104 plate reader.
Percent inhibition was calculated as follows:
percent inhibition = 100- (cmpd signal-ave_pc signal)/(ave_vc signal-ave_pc signal) ×100.
Calculation of IC using GraphPad 8.0 by fitting the percent inhibition values and the logarithm of compound concentration to a nonlinear regression (dose response-variable slope) 50 。
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
X: logarithm of inhibitor concentration; y: % inhibition.
Measured IC 50 The values are shown in Table 3.
TABLE 3 Table 3
| Numbering device | CDK1/B | CDK2/A2 | CDK2/E2 | CDK4/D3 | CDK6/D3 |
| Palbociclib | / | / | / | 6.50 | 7.2 |
| Compound 1 | / | / | / | / | / |
| Compound 2 | 7.2 | 1.1 | 16.0 | 10.3 | / |
| Compound 3 | >300 | / | >300 | 7.45 | 58.8 |
Note that: /indicate undetected
Claims (16)
1. A compound of formula I or a pharmaceutically acceptable salt thereof,
it is that
The compound shown or a pharmaceutically acceptable salt thereof,
wherein X is selected from N; the R is 4 Selected from hydrogen, halogen, hydroxy, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl;
or X is selected from CR 5 The method comprises the steps of carrying out a first treatment on the surface of the The R is 4 Or R is 5 Each independently selected from hydrogen, halogen, hydroxy, nitro, cyanoRadical, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl;
wherein Y is selected from NR 7 Or O, R 7 Selected from SO 2 R ', COR' or COOR ', R' is selected from methyl, ethyl and propyl;
the R is 10 Or R is 11 Selected from hydrogen, halogen, hydroxy, nitro, cyano, C 1-6 An alkyl group;
the R is 12 Selected from fluorine, chlorine, C optionally substituted by one or more fluorine 1-6 Alkyl, C optionally substituted by one or more fluoro 1-6 Alkoxy, C optionally substituted with one or more fluoro 3-4 Cycloalkyl or 3-7 membered heterocycloalkyl optionally substituted with one or more fluoro;
the R is 13 Selected from C optionally substituted by one or more halogen or hydroxy groups 1-6 Alkyl, C optionally substituted by one or more halogen or hydroxy groups 1-6 Alkoxy, C optionally substituted by one or more halogen or hydroxy groups 3-4 Cycloalkyl or 3-7 membered heterocycloalkyl optionally substituted with one or more halo or hydroxy;
the R is 14 Selected from C optionally substituted by one or more hydroxy groups 1-6 Alkyl or C optionally substituted by one or more hydroxy groups 1-6 Alkoxy, C optionally substituted with one or more hydroxy groups 3-4 Cycloalkyl or 3-7 membered heterocycloalkyl optionally substituted with one or more hydroxy;
the R is 6 Selected from hydrogen, halogen, hydroxy, nitro, oxo, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl, 3-7 membered heterocyclyl.
2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is selected from N; r is R 4 Selected from hydrogen, fluorine, chlorine, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl groups.
3. A compound of formula I according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R 4 Is hydrogen.
4. The compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein X is selected from CR 5 ；R 4 Or R is 5 Each independently selected from hydrogen, fluorine, chlorine, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-7 Cycloalkyl groups.
5. A compound of formula I or a pharmaceutically acceptable salt thereof according to claim 4, R 4 Or R is 5 Each independently selected from hydrogen.
6. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 12 Is fluorine.
7. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 13 Selected from methyl, ethyl, propyl, isopropyl, cyclopropyl or 2-hydroxyethyl.
8. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 14 Selected from methyl, ethyl, propyl, isopropyl, 2-hydroxyethyl or 2-hydroxypropyl.
9. The compound of claim 1, selected from the group consisting of:
pharmaceutically acceptable salts thereof.
10. The compound of claim 1, selected from the group consisting of:
11. a process for preparing a compound of formula I according to any one of claims 1 to 10,
comprising the step of reacting a compound of formula IC with a compound of formula ID to form a compound of formula I,
wherein R is 1 -R 4 X is as defined in claim 1, LG 1 Or LG (light emitting diode) 2 Selected from leaving groups selected from halogen, sulfonate, boric acid, borate.
12. The process of claim 11, wherein the reaction is carried out under catalytic conditions, and the catalyst is selected from metallic palladium and metallic nickel.
13. The process of claim 12, wherein the catalyst is selected from palladium on carbon, raney nickel, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, 1' - [1,1' -bis (di-tert-butylphosphino) ferrocene ] palladium dichloride, tris (dibenzylideneacetone) dipalladium, or 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl.
14. The process of claim 13, the catalyst being selected from the group consisting of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride and 2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl.
15. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
16. Use of a compound according to any one of claims 1-10 or a pharmaceutical composition according to claim 15 in the manufacture of a medicament for the prevention and/or treatment of a protein dependent kinase related disease selected from a cell proliferative disease, cancer or an immune disease.
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