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CN112625026B - Quinoline derivatives of TAM family kinase inhibitors - Google Patents

Quinoline derivatives of TAM family kinase inhibitors Download PDF

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CN112625026B
CN112625026B CN202011005183.8A CN202011005183A CN112625026B CN 112625026 B CN112625026 B CN 112625026B CN 202011005183 A CN202011005183 A CN 202011005183A CN 112625026 B CN112625026 B CN 112625026B
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CN112625026A (en
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吴永谦
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Yaojie Ankang Nanjing Technology Co ltd
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Abstract

The invention provides a novel quinoline derivative inhibitor, in particular to a quinoline derivative of a TAM family kinase inhibitor, which has a structure shown in the following general formula (I).

Description

Quinoline derivatives of TAM family kinase inhibitors
Technical Field
The invention belongs to the field of medicines, and particularly relates to a TAM family kinase inhibitor compound represented by a general formula (I), pharmaceutically acceptable salts, esters, stereoisomers and tautomers thereof, and a pharmaceutical composition, a pharmaceutical preparation and application thereof. The compound can selectively inhibit the TAM family of tyrosine kinases, and can be used for treating and/or preventing diseases mediated by abnormal expression of the TAM family kinases/receptors and/or ligands thereof
Background
The TAM family includes 3 members of Axl, Mer, Tyro-3, which contains the extracellular domain, the transmembrane domain, and the conserved intracellular kinase domain. Wherein the extracellular domain consists of two immunoglobulin-like domains connecting two type III fibronectin repeat units. The conserved amino acid sequence KW (I/L) A (I/L) ES of the intracellular kinase domain is a unique structural feature of the TAM family. This family has 1 common ligand, growth inhibitory specific protein 6(Gas6), which binds to all TAM receptors, but differs in strength. Besides TAM family, there are vitamin K dependent protein S (ProS), short crude-like protein Tubby, recombinant human short crude-like protein 1(Tulp1), galactose lectin-3 (galectin-3) and other related receptors (Wuyangjun, J.Xinyao, 2016; Lemna, J.practical diagnosis and treatment, 2016).
Among them, Axl (named UFO, Ark, Tyro-7, JTK1, respectively), Mer (named c-Mer, Mertk, Eyk, Nyk, Tyro-12, respectively), Tyro-3 (named Sky, Byk, Rse, Dtk, etc.), galectin-3, Gas6, and ProS are abnormally expressed in various solid tumors such as lung cancer, stomach cancer, and liver cancer, and various hematological tumors such as AML, ALL, and CML, and have strong correlation with poor prognosis of disease, disease progression, tumor metastasis, and tumor resistance (Douglas K, Nature reviews, 2014). Particularly, Axl, a tyrosine kinase, has been shown to be one of the causes of EGFR inhibitor resistance in NSCLC and is closely related to the metastasis of various solid tumors. The drug developed with this as a target also demonstrated the effect of inhibiting Axl in delaying drug resistance and tumor metastasis of EGFR inhibitors (T. Jimbo, Annals of Oncology, 2017; Sacha J. Holland, American Association for Cancer Research, 2010). At the same time, Axl, Mer, Tryo-3 and TAM ligands also play a significant role in the direction of immune tumors. Inhibition of the TAM family and its ligands can reverse the immunosuppressive environment of tumors, enhance the ability of the immune system to kill tumor cells, by promoting the polarization of macrophages to M1-type macrophages, increasing the activation and function of effector T cells, enhancing the anti-tumor activity of NK cells, and the like (yemsrat T. akalu, Immunological Reviews, 2017; Greg Lemke, Nature Reviews Immunology, 2008). Therefore, the development of the inhibitor can have strong inhibition and treatment effects on various solid and blood tumors induced by the family, such as lung cancer, liver cancer, breast cancer, brain glioma, melanoma, AML, ALL, CML and the like.
In addition to the above-mentioned tumor diseases, TAM family receptors and ligands can regulate various physiological functions such as vascular smooth muscle homeostasis, platelet aggregation, thrombus stabilization, erythropoiesis, oligodendrocyte survival, osteoclast function, apoptotic cell phagocytosis, inflammation, innate immunity, and the like. Therefore, the TAM family inhibitor can also be used for treating endometriosis, vascular diseases/injuries, psoriasis, visual defects/pathological changes (caused by macular degeneration, diabetes, premature birth and the like), kidney diseases, rheumatoid arthritis, osteoporosis and other related diseases caused by the disturbance of TAM family signal pathways.
Disclosure of Invention
The present invention provides a novel inhibitor compound and a pharmaceutically acceptable salt, ester, stereoisomer, and tautomer thereof (hereinafter, also referred to as the present compound). The compounds of the invention have inhibitory effects on TAM family kinases. The compounds of the present invention are useful for the treatment and/or prevention of diseases mediated by aberrant expression of TAM family kinase receptors and/or their ligands. The compound reverses the immunosuppression in a tumor microenvironment by inhibiting TAM family kinase, inhibits the growth, migration and/or drug resistance of tumors, and exerts the tumor immune effect and the anti-tumor curative effect. In particular, the method of manufacturing a semiconductor device,
the technical scheme adopted by the invention is as follows:
a compound represented by the general formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof:
Figure BDA0002695632730000021
wherein W is selected from hydrogen or C optionally substituted by a substituent 1-6 An alkyl group;
r represents a group represented by the following general formula (b):
Figure BDA0002695632730000022
in the group
Figure BDA0002695632730000023
Represents an optional double bond moiety in the ring structure;
Figure BDA0002695632730000024
moiety and M 3 Group attachment;
X 1 、X 2 、X 3 are each independently selected from CR a 、C＝O、NR b O, and wherein at least one is C ═ O;
X 4 、X 5 each is independently selected from C or N;
M 3 selected from H, methyl, or optionally substituted by one or more R 0 Substituted C 2-8 Alkenyl radical, C 2-8 Alkynyl radical, R 0 Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NR b R c 、-C(O)R d 、-C(O)NR b R c 、-OC(O)NR b R c 、-NR b C(O)OR d 、-NR b C(O)R d 、-SO 2 -NR b R c 、-SO 2 R d 、-NR b SO 2 R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, -C 1-6 alkyl-R', -C 1-6 alkoxy-R ', -O-R ', -C (O) -R ', -SO 2 -R’、-NR b C (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Cy 2 selected from optionally substituted one or more R 2 Substituted 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl, R 2 Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NR b R c 、-C(O)R d 、-C(O)NR b R c 、-OC(O)NR b R c 、-NR b C(O)OR d 、-NR b C(O)R d 、-SO 2 -NR b R c 、-SO 2 R d 、-NR b SO 2 R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl radicalCyano group C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, -C 1-6 alkyl-R', -C 1-6 alkoxy-R ', -O-R ', -C (O) -R ', -SO 2 -R’、-NR b C (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Cy 3 selected from optionally substituted by one or more R 3 Substituted 3-12 membered cycloalkyl, 3-14 membered heterocyclyl, 5-10 membered heteroaryl, R 3 Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NR b R c 、-C(O)R d 、-C(O)NR b R c 、-OC(O)NR b R c 、-NR b C(O)OR d 、-NR b C(O)R d 、-SO 2 -NR b R c 、-SO 2 R d 、-NR b SO 2 R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, -C 1-6 alkyl-R', -C 1-6 alkoxy-R ', -O-R ', -C (O) -R ', -SO 2 -R’、-NR b C (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl; when X is present 1 Or X 2 Represents NR b When is, Cy 3 May also be optionally substituted by more than one R 3 A substituted 6-14 membered aromatic group;
Cy 4 selected from optionally substituted one or more R 4 Substituted 3-14 membered heterocyclic group, 5-14 membered heteroAryl radical, R 4 Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NR b R c 、-C(O)R d 、-C(O)NR b R c 、-OC(O)NR b R c 、-NR b C(O)OR d 、-NR b C(O)R d 、-SO 2 -NR b R c 、-SO 2 R d 、-NR b SO 2 R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, -C 1-6 alkyl-R', -C 1-6 alkoxy-R ', -O-R ', -C (O) -R ', -SO 2 -R’、-NR b C (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl, or two R 4 May form a 5-6 membered cyclic group with the atom to which it is attached;
l is selected from-NR b -、-O-、-S-、-(CR a R a ) m -, m is an integer from 1 to 3;
R a is absent or, at each occurrence, is independently selected from hydrogen, cyano, hydroxy, halogen atom, carboxy, nitro, -NR e R f 、-C(O)R g 、-C(O)NR e R f 、-OC(O)NR e R f 、-NR e C(O)OR g 、-NR e C(O)R g 、-SO 2 -NR e R f 、-SO 2 R g 、-NR e SO 2 R g 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, -C 1-6 alkyl-R', -C 1-6 alkoxy-R ', -O-R ', -C (O) -R ', -SO 2 -R’、-NR e C (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
R b 、R c is absent, or at each occurrence, is independently selected from hydrogen, hydroxy, -C (O) R g 、-C(O)NR e R f 、-SO 2 -NR e R f 、-SO 2 R g 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl, -C 1-6 alkyl-R ', -C (O) -R', -SO 2 -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
R d is absent or, at each occurrence, is independently selected from hydrogen, -NR e R f 、-NR e C(O)OR g 、-NR e C(O)R g 、-NR e SO 2 R g 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy, -C 1-6 alkyl-R', -C 1-6 alkoxy-R ', -O-R', -NR e C (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
R e 、R f absent or, at each occurrence, independently selected from hydrogen, hydroxy, carboxy, cyano, nitro, halogen atoms, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl, -C 1-6 alkyl-R ', -C (O) -R', -SO 2 -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
R g is absent or, at each occurrence, is independently selected from hydrogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy, -C 1-6 alkyl-R ', -C (O) -R', -SO 2 -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
r' is 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl.
In another preferred embodiment, the compound represented by the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein W is selected from hydrogen or C 1-6 An alkyl group;
X 1 、X 2 、X 3 are each independently selected from CR a 、C＝O、NR b And wherein at least one is C ═ O;
X 4 、X 5 each is independently selected from C or N;
M 3 selected from H, methyl, or optionally substituted by one or more R 0 Substituted C 2-8 Alkenyl radical, C 2-8 Alkynyl radical, R 0 Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NR b R c 、-C(O)R d 、-C(O)NR b R c 、-OC(O)NR b R c 、-NR b C(O)OR d 、-NR b C(O)R d 、-SO 2 -NR b R c 、-SO 2 R d 、-NR b SO 2 R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, -C 1-6 alkyl-R', -C 1-6 alkoxy-R ', -O-R ', -C (O) -R ', -SO 2 -R’、-NR b C (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Cy 2 selected from optionally substituted one or more R 2 Substituted 6-14 membered aryl, 5-10 membered heteroaryl, R 2 Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NR b R c 、-C(O)R d 、-C(O)NR b R c 、-OC(O)NR b R c 、-NR b C(O)OR d 、-NR b C(O)R d 、-SO 2 -NR b R c 、-SO 2 R d 、-NR b SO 2 R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, -C 1-6 alkyl-R', -C 1-6 alkoxy-R ', -O-R ', -C (O) -R ', -SO 2 -R’、-NR b C (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Cy 3 selected from optionally substituted one or more R 3 Substituted by3-8 membered cycloalkyl, 5-10 membered heteroaryl, R 3 Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NR b R c 、-C(O)R d 、-C(O)NR b R c 、-OC(O)NR b R c 、-NR b C(O)OR d 、-NR b C(O)R d 、-SO 2 -NR b R c 、-SO 2 R d 、-NR b SO 2 R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, -C 1-6 alkyl-R', -C 1-6 alkoxy-R ', -O-R ', -C (O) -R ', -SO 2 -R’、-NR b C (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl; when X is 1 Or X 2 Represents NR b When is, Cy 3 May also be optionally substituted by more than one R 3 A substituted 6-14 membered aromatic group;
Cy 4 selected from optionally substituted one or more R 4 Substituted 9-10 membered heteroaryl, R 4 Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NR b R c 、-C(O)R d 、-C(O)NR b R c 、-OC(O)NR b R c 、-NR b C(O)OR d 、-NR b C(O)R d 、-SO 2 -NR b R c 、-SO 2 R d 、-NR b SO 2 R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 An alkyl group,C 1-6 Alkoxy radical C 1-6 Alkoxy radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, -C 1-6 alkyl-R', -C 1-6 alkoxy-R ', -O-R ', -C (O) -R ', -SO 2 -R’、-NR b C (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl, or two R 4 May form a 5-6 membered cyclic group with the attached atom;
l is selected from-NR b -、-O-、-S-；
R a Is absent or, at each occurrence, is independently selected from hydrogen, cyano, hydroxyl, a halogen atom, carboxyl, nitro, -NR e R f 、-C(O)R g 、-C(O)NR e R f 、-OC(O)NR e R f 、-NR e C(O)OR g 、-NR e C(O)R g 、-SO 2 -NR e R f 、-SO 2 R g 、-NR e SO 2 R g 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, -C 1-6 alkyl-R', -C 1-6 alkoxy-R ', -O-R ', -C (O) -R ', -SO 2 -R’、-NR e C (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
R b 、R c is absent, or, at each occurrence, is independently selected from hydrogen, hydroxy, -C (O) R g 、-C(O)NR e R f 、-SO 2 -NR e R f 、-SO 2 R g 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl, -C 1-6 alkyl-R ', -C (O) -R', -SO 2 -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
R d is absent or, at each occurrence, is independently selected from hydrogen, -NR e R f 、-NR e C(O)OR g 、-NR e C(O)R g 、-NR e SO 2 R g 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy, -C 1-6 alkyl-R', -C 1-6 alkoxy-R ', -O-R', -NR e C (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
R e 、R f absent or, at each occurrence, independently selected from hydrogen, hydroxy, carboxy, cyano, nitro, halogen atoms, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkyl, -C 1-6 alkyl-R ', -C (O) -R', -SO 2 -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
R g absent or, at each occurrence, independently selected from hydrogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, cyano C 1-6 Alkyl, amino C 1-6 Alkyl radical, C 1-6 Alkylamino radical C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy, -C 1-6 alkyl-R ', -C (O) -R', -SO 2 -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
r' is 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
preferably, X 1 Is N, X 2 Is CR a ，X 3 Is C ═ O;
preferably, X 1 Is CR a ，X 2 Is N, X 3 Is C ═ O;
preferably, X 1 Is CR a ，X 2 Is CR a ，X 3 Is C ═ O.
In another preferred embodiment, in the compound represented by the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein, X 1 、X 2 、X 3 Are each independently selected from CR a 、C＝O、NR b And at least one of which is C ═ O;
X 4 selected from C or N, X 5 Is selected from C;
M 3 selected from H, methyl, or optionally substituted by one or more R 0 Substituted C 2-8 Alkenyl radical, C 2-8 Alkynyl, R 0 Each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro and-NR b R c 、-C(O)R d 、-C(O)NR b R c 、-NR b C(O)R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 An alkoxy group;
Cy 2 selected from optionally substituted by one or more R 2 Substituted phenyl, 5-6 membered heteroaryl, R 2 Each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NR b R c 、-C(O)R d 、-C(O)NR b R c 、-NR b C(O)R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 An alkoxy group;
Cy 3 selected from optionally substituted one or more R 3 Substituted 5-6 membered heteroaryl, 3-6 membered cycloalkyl, R 3 Each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NR b R c 、-C(O)R d 、-C(O)NR b R c 、-NR b C(O)R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 An alkoxy group;
Cy 4 selected from optionally substituted one or more R 4 Substituted 9-10 membered heteroaryl, R 4 Each independently selected from hydrogen, hydroxyl, halogen atom, nitro, -NR b R c 、-C(O)R d 、-C(O)NR b R c 、-NR b C(O)R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy, 3-14 membered heterocyclyl, or, two R 4 May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-NR b -、-O-、-S-；
R a Is absent or, at each occurrence, is independently selected from hydrogen, C 1-6 Alkyl, halo C 1-6 An alkyl group;
R b 、R c is absent or, at each occurrence, is independently selected from hydrogen, C 1-6 An alkyl group;
R d is absent or, at each occurrence, is independently selected from hydrogen, C 1-6 An alkyl group;
preferably, X 1 Is N, X 2 Is CR a ，X 3 Is C ═ O;
preferably, the first and second electrodes are formed of a metal,X 1 is CR a ，X 2 Is N, X 3 Is C ═ O;
preferably, X 1 Is CR a ，X 2 Is CR a ，X 3 Is C ═ O;
preferably, Cy is 3 Is composed of
Figure BDA0002695632730000051
Y 2 、Y 3 、Y 6 、Y 7 Each independently selected from C or N, and at least one is N.
In another preferred embodiment, in the compound represented by the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
X 1 、X 2 、X 3 are each independently selected from CR a 、C＝O、NR b And at least one of which is C ═ O;
X 4 selected from C or N, X 5 Is selected from C;
Cy 2 selected from optionally substituted by one or more R 2 Substituted phenyl, 5-6 membered heteroaryl;
Cy 3 denotes an optionally substituted one or more R 3 Substituted by
Figure BDA0002695632730000052
Y 2 、Y 3 、Y 6 And Y 7 Each independently selected from CH or N, and at least one is N;
Cy 4 selected from optionally substituted one or more R 4 Substituted by
Figure BDA0002695632730000053
Y 4 And Y 5 Independently selected from CH or N, and at least one is N, ring B is phenyl or 5-6 membered heteroaryl;
M 3 selected from H, methyl, or optionally substituted by one or more R 0 Substituted C 2-5 Alkenyl radical, C 2-5 Alkynyl radical, R 0 Each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl and nitro、-NR b R c 、-C(O)R d 、-C(O)NR b R c 、-NR b C(O)R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 An alkoxy group;
R 2 each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NR b R c 、-C(O)R d 、-C(O)NR b R c 、-NR b C(O)R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 An alkoxy group;
R 3 each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NR b R c 、-C(O)R d 、-C(O)NR b R c 、-NR b C(O)R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 An alkoxy group;
R 4 each independently selected from hydrogen, hydroxyl, halogen atom, nitro, -NR b R c 、-C(O)R d 、-C(O)NR b R c 、-NR b C(O)R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy, 3-14 member heterocyclyl, or, two R 4 May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-NR b -、-O-、-S-；
R a Is absent or, at each occurrence, is independently selected from hydrogen, C 1-6 Alkyl, halo C 1-6 An alkyl group;
R b 、R c is absent or, at each occurrence, is independently selected from hydrogen, C 1-6 An alkyl group;
R d is absent or, at each occurrence, is independently selected from hydrogen, C 1-6 An alkyl group;
preferably, X 1 Is N, X 2 Is CR a ，X 3 Is C ═ O;
preferably, X 1 Is CR a ，X 2 Is N, X 3 Is C ═ O;
preferably, X 1 Is CR a ，X 2 Is CR a ，X 3 Is C ═ O;
in another preferred embodiment, in the compound represented by formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein, X 1 、X 2 Are each independently selected from CR a Or NR b ，X 3 Is C ═ O;
X 4 selected from C or N, X 5 Is selected from C;
Cy 2 selected from optionally substituted one or more R 2 A substituted phenyl group;
Cy 3 denotes an optionally substituted one or more R 3 Substituted by
Figure BDA0002695632730000061
Y 2 、Y 3 、Y 6 And Y 7 Each independently selected from CH or N, and at least one is N;
Cy 4 selected from optionally substituted one or more R 4 Substituted by
Figure BDA0002695632730000062
M 3 Selected from H, methyl, or optionally substituted by one or more R 0 Substituted C 2-5 Alkenyl radical, R 0 Each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NR b R c 、-C(O)R d 、-C(O)NR b R c 、-NR b C(O)R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 An alkoxy group;
R 2 each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro and-NR b R c 、-C(O)R d 、-C(O)NR b R c 、-NR b C(O)R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 An alkoxy group;
R 3 each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NR b R c 、-C(O)R d 、-C(O)NR b R c 、-NR b C(O)R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 An alkoxy group;
R 4 each independently selected from hydrogen, hydroxyl, halogen atom, nitro, -NR b R c 、-C(O)R d 、-C(O)NR b R c 、-NR b C(O)R d 、C 1-6 Alkyl, hydroxy C 1-6 Alkyl, amino C 1-6 Alkyl, halo C 1-6 Alkyl radical, C 1-6 Alkoxy, halo C 1-6 Alkoxy radical, C 1-6 Alkoxy radical C 1-6 Alkyl radical, C 1-6 Alkoxy radical C 1-6 Alkoxy, 3-14 membered heterocyclyl, or, two R 4 May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-NR b -、-O-、-S-；
R a Is absent or, at each occurrence, is independently selected from hydrogen, C 1-6 Alkyl, halo C 1-6 An alkyl group;
R b 、R c is absent or, at each occurrence, is independently selected from hydrogen, C 1-6 An alkyl group;
R d is absent or, at each occurrence, is independently selected from hydrogen, C 1-6 An alkyl group;
in another preferred embodiment, in the compound represented by formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein W is selected from hydrogen;
X 1 、X 2 are each independently selected from CR a Or NR b ，X 3 Is C ═ O;
X 4 selected from C, X 5 Is selected from C;
M 3 selected from H, methyl, or optionally substituted with one or more R 0 Substituted allyl, R 0 Each independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, C 1-4 An alkyl group;
Cy 2 selected from optionally substituted one or more R 2 Substituted
Figure BDA0002695632730000071
R 2 Each independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, C 1-4 An alkyl group;
Cy 3 selected from optionally substituted one or more R 3 Substituted
Figure BDA0002695632730000072
R 3 Each independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, C 1-4 An alkyl group;
Cy 4 selected from optionally substituted one or more R 4 Substituted by
Figure BDA0002695632730000073
Figure BDA0002695632730000074
R 4 Each independently selected from hydrogen, hydroxyl, halogen atom, C 1-4 Alkyl, halo C 1-4 Alkyl radical, C 1-4 Alkoxy, halo C 1-4 Alkoxy, 3-to 14-membered heterocyclic group,
l is-O-;
R a is absent or, at each occurrence, is independently selected from hydrogen, C 1-6 Alkyl, halo C 1-6 An alkyl group;
R b is absent or, at each occurrence, is independently selected from hydrogen, C 1-6 An alkyl group;
in another preferred embodiment, in the compound represented by formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein W is selected from hydrogen;
X 1 、X 2 selected from the group consisting of CR a Or NR b ，X 3 Is C ═ O;
X 4 selected from C, X 5 Is selected from C;
M 3 each independently selected from H, methyl, allyl;
Cy 2 selected from optionally substituted one or more R 2 Substituted by
Figure BDA0002695632730000075
R 2 Each independently selected from hydrogen, fluorine, chlorine, C 1-4 An alkyl group;
Cy 3 selected from optionally substituted one or more R 3 Substituted by
Figure BDA0002695632730000076
R 3 Each independently selected from hydrogen, fluorine, chlorine, C 1-4 An alkyl group;
Cy 4 selected from optionally substituted by one or more R 4 Substituted
Figure BDA0002695632730000077
R 4 Each independently selected from hydrogen, halogen atom, C 1-4 Alkyl radical, C 1-4 Alkoxy, or, two R 4 May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is-O-;
R a is absent, or present at each occurrenceEach independently selected from hydrogen, C 1-4 Alkyl, halo C 1-6 An alkyl group;
R b is absent or, at each occurrence, is independently selected from hydrogen, C 1-4 An alkyl group.
In another preferred embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, wherein the compound is:
Figure BDA0002695632730000081
Figure BDA0002695632730000091
Figure BDA0002695632730000101
Figure BDA0002695632730000111
Figure BDA0002695632730000121
the invention also provides a pharmaceutical composition which comprises at least one of the compounds shown in the formula (I) and pharmaceutically acceptable salts, esters, stereoisomers and tautomers thereof.
The invention also provides a pharmaceutical composition comprising the compound shown in the formula (I) or pharmaceutically acceptable salt, ester, stereoisomer and tautomer thereof, which can optionally contain one or more pharmaceutical carriers.
The invention also provides a pharmaceutically acceptable dosage form comprising a compound of formula (I) as described above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, optionally with one or more pharmaceutically acceptable carriers.
In one embodiment of the present invention, the aforementioned pharmaceutical composition or dosage form may further comprise one or more second active therapeutic agents.
In one embodiment of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) as described above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, which may optionally contain at least one second active therapeutic agent.
In one embodiment of the invention, the second active therapeutic agent is at least one selected from the group consisting of: antimetabolites, growth factor inhibitors, inhibitors of the filamentation class, antitumor hormones, alkylating agents, metalloplatins, topoisomerase inhibitors, hormonal drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immune checkpoints or antibodies related to tumor immunotherapy, small molecule drugs and cell therapy agents.
In one embodiment of the present invention, the pharmaceutical composition or dosage form may be administered to a patient or subject in need of prophylaxis and/or treatment by any suitable administration means known in the art, for example, by oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal, and epidural), transdermal, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary, and intranasal administration.
In one embodiment of the present invention, the pharmaceutical composition or dosage form can be prepared into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; can also be made into oral liquid preparation, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, the pharmaceutical composition may be formulated as an injection, a sterile powder for injection, or a concentrated solution for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding suitable additives according to the properties of the medicine. For rectal administration, the pharmaceutical composition may be formulated as a suppository or the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalant or a spray.
In one embodiment of the present invention, there is provided a compound represented by the above formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, pharmaceutical composition thereof, and a use of the above dosage form for preparing a medicament for treating and/or preventing a disease mediated by abnormal expression of TAM family kinase receptors and/or ligands thereof, including at least one of the following diseases: tumor, tumor immunity, endometriosis, vascular disease/injury, psoriasis, visual defect/lesion (due to macular degeneration, diabetes, premature birth, etc.), kidney disease, rheumatoid arthritis, osteoporosis, and related diseases.
In one embodiment of the present invention, the tumor includes sarcoma, lymphoma and cancer, and specifically may be respiratory system cancer, mesothelioma, nervous system tumor, skin malignancy, bone cancer, squamous cell carcinoma, breast cancer, head and neck cancer, urinary and reproductive system cancer, biliary tract system cancer, sarcoma, digestive system cancer, leukemia, lymphoma, myelodysplastic syndrome, carcinoma in situ, and cytoma.
In one embodiment of the present invention, the tumor includes sarcoma, lymphoma and cancer, and specifically may be lung cancer, thyroid cancer, oral cancer, pharyngeal cancer, peritoneal cancer, glioma, neurofibromatosis, skin cancer, melanoma, multiple myeloma, squamous lung cancer, esophageal squamous cancer, ductal breast cancer, brain cancer, ovarian cancer, uterine cancer, endometrial cancer, prostate cancer, testicular cancer, bladder cancer, kidney cancer, renal pelvis cancer, bile duct cancer, gallbladder cancer, osteosarcoma, liposarcoma, ewing's sarcoma, liver cancer, stomach cancer, esophageal cancer, large intestine cancer, pancreatic cancer, cardia cancer, gastrointestinal stromal tumor, large intestine villous adenoma, acute leukemia, chronic leukemia, non-hodgkin's malignant lymphoma (NHL), T/NK cell lymphoma, Hodgkin's Lymphoma (HL), myelodysplasia syndrome, carcinoma in situ, and cytoma.
Effects of the invention
The compounds of the invention have inhibitory effects on TAM family kinases. The compounds of the present invention are useful for the treatment and/or prevention of diseases mediated by the aberrant expression of TAM family kinase receptors and/or their ligands. The compound of the invention reverses immunosuppression in tumor microenvironment through targeted inhibition of TAM family kinase, inhibits growth, migration and/or drug resistance of tumor, and exerts tumor immune effect and anti-tumor curative effect.
Furthermore, the compound of the present invention has a long half-life in vivo, excellent metabolic stability in vivo and excellent drug-forming properties, and therefore, the compound of the present invention can improve the therapeutic effect of a drug, reduce the burden of administration on a patient, and improve the compliance of the patient.
Detailed Description
Embodiments of the present invention will be described in more detail below with reference to specific embodiments, but those skilled in the art will appreciate that the specific embodiments described below are merely illustrative of the present invention and should not be construed as limiting the scope of the present invention. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Unless otherwise specified, the embodiments of the present invention may be combined in any manner, and the resulting changes, modifications, and alterations of the technical solutions are also included in the scope of the present invention, and do not exceed the scope of the present invention.
In the context of the present invention, unless otherwise explicitly defined, or the meaning is beyond the understanding of those skilled in the art, hydrocarbons or hydrocarbon-derived groups of 3 or more carbon atoms (such as propyl, propoxy, butyl, butane, butene, butenyl, hexane, and the like) all have the same meaning when not preceded by the word "n". For example, propyl is generally understood to be n-propyl, and butyl is generally understood to be n-butyl, unless otherwise specified.
All publications, patent applications, patents, and other references mentioned in this specification are herein incorporated by reference in their entirety. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present specification, including definitions, will control.
In the context of this specification, anything or things not mentioned is directly applicable to the art-known technology without any change except where explicitly stated. Moreover, any embodiment described herein may be freely combined with one or more other embodiments described herein, and the technical solutions or concepts resulting therefrom are considered part of the original disclosure or original disclosure of the invention, and should not be considered as new matters not disclosed or contemplated herein, unless a person skilled in the art would consider such a combination to be clearly unreasonable.
In the present invention, "C a-b The expression "radicals" (a and b denote integers of 1 or more, a < b) denotes the presence of a-b carbon atoms in the "radical", e.g. C 1-4 Alkyl, i.e. alkyl having 1-4 carbon atoms, C 1-4 Alkoxy, i.e. alkoxy having 1 to 4 carbon atoms, C 3-10 Cycloalkyl, i.e. a cycloalkyl group having 3 to 10 carbon atoms, C 1-4 Alkoxy radical C 1-4 The alkyl group means a group in which an alkoxy group having 1 to 4 carbon atoms is bonded to an alkyl group having 1 to 4 carbon atoms.
In the present invention, "group" and "group" represent a monovalent group or a divalent or more group in accordance with the valence as required, and for example, "cycloalkyl group (also expressed as cycloalkyl group)" includes a monovalent group obtained by removing one hydrogen atom therefrom, and also includes a divalent or more group obtained by removing two or more hydrogen atoms from the same carbon atom or two or more different carbon atoms therein. "cycloalkyl" is naturally a monovalent group when it is a terminal group, and is a divalent or higher group when it is a linking group in the structure. In the present invention, a monovalent or divalent or higher group generally means a monovalent group or a divalent group, but the group may be higher in valence (for example, trivalent, tetravalent, pentavalent, hexavalent, etc.) as required. The person skilled in the art can unambiguously determine the number of valences represented by the "radical" and "radical". The group "derived by removing one or more hydrogen atoms" as used herein means a monovalent group obtained by removing one hydrogen atom, a divalent group obtained by removing two hydrogen atoms, a trivalent group obtained by removing three hydrogen atoms, a tetravalent group obtained by removing four hydrogen atoms, and the like, and the number of hydrogen atoms to be removed can be determined according to the valency (for example, 1,2,3, 4, and the like) of the group.
The "halogen atom" as referred to herein means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom. Preferably a fluorine atom, a chlorine atom, or a bromine atom.
As used herein, "halo" means that any carbon atom in a substituent has one or more hydrogens of the same or different halogen atoms replaced. The "halogen atom" is as defined above.
"C" according to the invention 1-6 Alkyl "refers to a straight or branched chain alkyl group derived from an alkane moiety containing 1 to 6 carbon atoms by the removal of one or more hydrogen atoms, including straight chain C 1-6 Alkyl and branched C 1-6 An alkyl group. In fact, C is well known to those skilled in the art 1-6 The alkyl group having a branch (branch C) 1-6 Alkyl) having at least 3 carbon atoms. As "C 1-6 Examples of the "alkyl group" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, and 1-methyl-2-methylpropyl. Said "C 1-4 Alkyl "refers to the above examples containing 1 to 4 carbon atoms.
The "hydroxy group C" of the present invention 1-6 Alkyl group and cyano group C 1-6 Alkyl group and amino group C 1-6 Alkyl group "," C 1-6 Alkylamino radical C 1-6 Alkyl group "," halogeno C 1-6 Alkyl group "," C 1-6 Alkoxy radical C 1-6 Alkyl radical "isRefers to more than one hydroxyl, cyano, amino, C 1-6 Alkylamino, halogen, C 1-6 Alkoxy is independently substituted for C 1-6 Hydrogen atoms on alkyl groups.
“C 1-6 Alkylamino groups "," (C) 1-6 Alkyl radical) 2 Amino group and C 1-6 Alkylaminocarbonyl group and C 1-6 Alkylcarbonyl group and C 1-6 Alkylcarbonyloxy group and C 1-6 Alkylsulfonylamino group "," C 1-6 Alkylsulfonyl group "," C 1-6 Alkylthio "and the like include" C 1-6 The radical of alkyl "denotes C 1-6 Alkyl is independently linked to-NH-, -CO-O-, -NH-CO-, -SO 2 NH-、-SO 2 -, -S-, etc. corresponding groups are linked to form a group. For example, the above-mentioned "C" may be mentioned 1-6 The radicals listed under alkyl are each independently substituted with-NH-, -CO-O-, -NH-CO-, -SO 2 NH-、-SO 2 -, -S-, etc. corresponding groups are linked to form a group.
"C" according to the invention 2-8 The alkenyl group "means a straight-chain or branched alkenyl group derived by removing one or more hydrogen atoms from an olefin moiety having 2 to 8 carbon atoms and containing at least one carbon-carbon double bond, and examples thereof include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1, 3-butan-1-yl, 1-penten-3-yl, 2-penten-1-yl, 3-penten-2-yl, 1, 3-pentadien-1-yl, 1, 4-pentadien-3-yl, 1-hexen-3-yl, and 1, 4-hexadien-1-yl. Preferably, "C" is 2-8 Alkenyl "contains one carbon-carbon double bond.
"C" according to the invention 2-8 The alkynyl group "means a straight-chain or branched alkynyl group derived by removing one or more hydrogen atoms from an alkynyl group of 2 to 8 carbon atoms having at least one carbon-carbon triple bond, and examples thereof include ethynyl, propynyl, 2-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl, 4-methyl-2-pentyn-1-yl, 2-hexyn-2-yl, 3-hexyn-1-yl and 3-hexyn-2-yl. Preferably, "C" is 2-8 Alkynyl "contains a carbon-carbon triple bond.
The invention is as described"C" of 1-6 Alkoxy "means" C "as defined hereinbefore 1-6 Alkyl "radicals attached to the parent moiety through an oxygen atom, i.e." C 1-6 Examples of the alkyl-O- "group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentoxy, and n-hexoxy. Said "C 1-4 Alkoxy "refers to the above examples containing 1 to 4 carbon atoms, i.e." C 1-4 An alkyl-O- "group.
The "halo C" of the present invention 1-6 Alkoxy group "," C 1-6 Alkoxy radical C 1-6 Alkoxy group "," C 1-6 Alkyl radical C 1-6 Alkoxy "etc. contain" C 1-6 The radical of alkoxy "means more than one halogen atom, C 1-6 Alkoxy radical, C 1-6 Alkyl and the like corresponding groups each independently substituted for C 1-6 A group formed by more than one hydrogen atom on an alkoxy group.
The "condensed ring" in the present invention refers to a polycyclic structure formed by connecting two or more cyclic structures in a parallel, spiro or bridged manner. The fused ring refers to a fused ring structure formed by two or more ring structures sharing two adjacent ring atoms with each other (i.e., sharing a bond). The bridged ring refers to a condensed ring structure formed by two or more than two ring structures sharing two non-adjacent ring atoms. The spiro ring refers to a fused ring structure formed by two or more cyclic structures sharing one ring atom with each other.
The "cycloalkyl group" or "cycloalkyl group" (hereinafter, collectively referred to as "cycloalkyl group") in the present invention means a monovalent group or (if necessary) divalent or more group derived from a cycloalkane derivative, and the cycloalkane includes a monocyclic cycloalkane or a fused ring cycloalkane. It is, for example, "3-12 membered cycloalkyl", i.e. may have 3,4,5, 6,7,8, 9, 10, 11 or 12 ring-forming carbon atoms. Unless otherwise specified, a certain cycloalkyl group includes all monocyclic, fused rings (including fused rings in the form of a parallel, spiro, or bridge) which may be formed. The cycloalkyl group may be a 3-to 12-membered monovalent group or (as required) a divalent or more group, and may be a 3-to 10-membered monovalent group or (as required) a divalent or more group, a 3-to 8-membered monovalent group or (as required) a divalent or more group, a 3-to 6-membered monovalent group or (as required) a divalent or more group, a 4-to 6-membered monovalent group or (as required) a divalent or more group, a 5-to 7-membered monovalent group or (as required) a divalent or more group.
Specifically, the monocyclic cycloalkyl group (monovalent or divalent or more) may be a 3-12-membered cycloalkyl group, a 3-10-membered cycloalkyl group, a 3-8-membered cycloalkyl group, a 3-6-membered cycloalkyl group, a 4-6-membered cycloalkyl group, a 5-6-membered cycloalkyl group or a 5-7-membered cycloalkyl group. Examples include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentane-1, 3-diyl, cyclohexane-1, 4-diyl, cycloheptane-1, 4-diyl, etc.
The fused ring cycloalkyl group (monovalent or divalent or more) includes a fused ring cycloalkyl group, a bridged cycloalkyl group, and a spiro cycloalkyl group.
The (monovalent or divalent or more) acyclic cycloalkyl group may be a 6-11-membered acyclic cycloalkyl group, a 7-10-membered acyclic cycloalkyl group, and representative examples thereof include, but are not limited to, monovalent groups derived from bicyclo [3.1.1] heptane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, bicyclo [3.3.1] nonane, and bicyclo [4.2.1] nonane, or divalent or more groups.
The bridged cycloalkyl group (monovalent or divalent or more) may be a monovalent group obtained by removing one hydrogen atom from a 6-12-membered bridged ring or a 7-11-membered bridged ring, or a divalent or more group obtained by removing two or more hydrogen atoms from the same carbon atom or different carbon atoms as required.
Examples of such bridge rings include, but are not limited to:
Figure BDA0002695632730000161
the spirocyclic cycloalkyl group (monovalent or divalent or more) may be a monovalent group obtained by removing one hydrogen atom from a 7-12 membered spirocyclic ring or a 7-11 membered spirocyclic ring, or a divalent or more group obtained by removing two or more hydrogen atoms from the same carbon atom or different carbon atoms as requiredA group of (1). Examples of spiro rings include, but are not limited to:
Figure BDA0002695632730000162
Figure BDA0002695632730000163
the "cycloalkenyl group" in the present invention means a group having at least one double bond in the group of the above cycloalkyl group. It may, for example, be a "3-12 membered cycloalkenyl", i.e. may have 3,4,5, 6,7,8, 9, 10, 11 or 12 ring-forming carbon atoms. Unless otherwise specified, a certain cycloalkenyl group includes all monocyclic, fused-ring (including fused in a parallel, spiro, bridged) forms that may be formed. Cycloalkenyl can be 3-12 membered cycloalkenyl, 3-8 membered cycloalkenyl, 4-6 membered cycloalkenyl, 7-11 membered spirocycloalkenyl, 7-11 membered cycloalkenyl, 6-11 membered bridged cycloalkenyl, and the like. Examples of cycloalkenyl groups include cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, 1, 4-cyclohexadien-1-yl, cycloheptenyl, 1, 4-cycloheptadien-1-yl, cyclooctenyl, 1, 5-cyclooctadien-1-yl and the like, but are not limited thereto.
The "heterocyclic ring" of the present invention includes a non-aromatic cyclic hydrocarbon containing at least one (may be 1 to 5, 1 to 4, 1 to 3, 1 to 2 or 1) hetero atom selected from O, S, N as a ring-constituting atom in the ring. It may be a heterocyclic ring having 3,4,5, 6,7,8, 9, 10, 11, 12, 13, 14 ring-forming atoms. Optionally having at least one double bond in the ring. The heterocyclic ring of the present invention may be a monocyclic ring system or a fused ring system (fused in the form of a parallel, spiro or bridge). Examples of the heterocyclic ring include monocyclic heterocyclic rings such as pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, dihydropyridine, dihydropyridazine, dioxane, oxathiolane, cyclopentane sulfide, tetrahydrofuran, tetrahydropyran, thiazolidine, and tetrahydroisothiazole; fused heterocycles of indoline, isoindoline, benzopyran, benzodioxan, tetrahydroquinoline, benzo [ d ] oxazol-2 (3H) -one, tetrahydrobenzothiophene and the like. Further, there may be mentioned heterocyclic rings obtained by substituting at least one ring carbon atom in the 7-12 membered spirocyclic ring, the 7-11 membered spirocyclic ring, the 6-12 membered bridged ring and the 7-11 membered bridged ring with a heteroatom selected from O, S, N, preferably 1 to 4 heteroatoms. Further, there may be mentioned 6-to 12-membered fused ring group, 7-to 10-membered fused ring group, 6-to 12-membered saturated fused ring group, 6-to 12-membered spiroheterocycle, 7-to 11-membered spiroheterocycle, 6-to 12-membered saturated spiroheterocycle, 7-to 11-membered saturated spiroheterocycle, 6-to 12-membered bridged heterocycle, 7-to 11-membered bridged heterocycle, 6-to 12-membered saturated bridged heterocycle, and 7-to 8-membered saturated bridged heterocycle, which are described below in the present invention.
The "heterocyclic group" or "heterocyclic group" (hereinafter, generally referred to as "heterocyclic group") in the present invention means a monovalent or divalent or higher group derived from the above "heterocyclic ring". The "heterocyclic group" according to the present invention may be a non-aromatic monovalent or divalent or more cyclic group in which at least one ring carbon atom of the above cycloalkyl or cycloalkenyl group is replaced with at least one hetero atom selected from O, S, N, preferably 1 to 4 hetero atoms. The heterocyclic group also includes a case where a carbon atom or a sulfur atom is substituted with oxygen or nitrogen, for example, a carbon atom or a sulfur atom is substituted with C (═ O), S (═ O) 2 And S (═ O) (═ N).
Specifically, the "heterocyclic group" may be a heterocyclic group having 3,4,5, 6,7,8, 9, 10, 11, 12, 13, 14 ring-forming atoms. It may be a 3-14-membered heterocyclic group, a 3-10-membered heterocyclic group, a 4-10-membered heterocyclic group, a 3-8-membered heterocyclic group, a 4-6-membered heterocyclic group, a 3-12-membered heterocyclic group, a 4-12-membered heterocyclic group including a mono-heterocyclic group or a fused heterocyclic group.
Further, "heterocyclic group" means a monovalent or (as necessary) divalent or more monocyclic heterocyclic group, a monovalent or (as necessary) divalent or more bicyclic heterocyclic group system, or a monovalent or (as necessary) divalent or more polycyclic heterocyclic group system (also referred to as condensed ring system), and includes a saturated, partially saturated heterocyclic group, but does not include an aromatic ring. All monocyclic, fused ring (including fused in the form of a parallel, spiro, bridge), saturated, partially saturated situations are included, where possible, unless otherwise specified. It may be, for example, "3-14 membered heterocyclyl".
One or (if necessary) two or moreThe monoheterocyclic group may be a 3-14-membered heterocyclic group, a 3-12-membered heterocyclic group, a 3-10-membered heterocyclic group, a 4-10-membered heterocyclic group, a 3-8-membered saturated heterocyclic group, a 4-8-membered heterocyclic group, a 3-6-membered heterocyclic group, a 4-7-membered heterocyclic group, a 5-6-membered oxygen-containing heterocyclic group, a 3-8-membered nitrogen-containing heterocyclic group, a 5-6-membered saturated heterocyclic group, etc. Further, it may be a 3-to 14-membered oxygen-containing heterocyclic group, a 3-to 14-membered nitrogen-containing heterocyclic group, a 3-to 12-membered oxygen-containing heterocyclic group, a 3-to 12-membered sulfur-containing heterocyclic group, a 3-to 12-membered sulfone group (S (O)) 2 ) Heterocyclic group, 3-to 12-membered sulfoxide group-containing (S (O) -containing heterocyclic group, etc. Examples of "heterocyclyl" include, but are not limited to, aziridinyl, oxacyclopropane, thietane, azetidinyl, oxetanyl, thietane, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, 1, 2-oxazolidinyl, 1, 3-oxazolidinyl, 1, 2-thiazolidinyl, 1, 3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1, 4-dioxanyl, 1, 4-oxathianyl; 4, 5-dihydroisoxazolyl, 4, 5-dihydrooxazolyl, 2, 3-dihydrooxazolyl, 3, 4-dihydro-2H-pyrrolyl, 2, 3-dihydro-1H-pyrrolyl, 2, 5-dihydro-1H-imidazolyl, 4, 5-dihydro-1H-pyrazolyl, 4, 5-dihydro-3H-pyrazolyl, 4, 5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4, 5-tetrahydropyridinyl, 1, 2-isoxazolyl, 1, 4-isoxazolyl or 6H-1, 3-oxazinyl, and the like.
Monovalent or (as desired) divalent or higher fused heterocyclic rings include heterocyclic, spiro heterocyclic, bridged heterocyclic, which may be saturated, partially saturated or unsaturated, but are not aromatic. The fused heterocyclic group may be a heterocyclic group obtained by fusing the above-mentioned heterocyclic group to 6-14-membered aryl (e.g., benzene ring), 3-12-membered cycloalkyl, 3-12-membered alkenylene, 3-14-membered heterocyclic group or 3-14-membered heteroaryl, 5-6-membered monocyclic cycloalkyl, 5-6-membered monocyclic cycloalkenyl, 5-6-membered monocyclic heterocyclic group or 5-6-membered monocyclic heteroaryl.
The heterocyclic group may be 6-12 membered fused ring group, 7-10 membered fused ring group, 6-12 membered saturated fused ring group, representative examples include but are not limited to: 3-azabicyclo [3.1.0] hexanyl, 3, 6-diazabicyclo [3.2.0] heptanyl, 3, 8-diazabicyclo [4.2.0] octanyl, 3, 7-diazabicyclo [4.2.0] octanyl, octahydropyrrolo [3,4-c ] pyrrolyl, octahydropyrrolo [3,4-b ] [1,4] oxazinyl, octahydro-1H-pyrrolo [3,4-c ] pyridyl, 2, 3-dihydrobenzofuran-2-yl, 2, 3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin 3-yl, 2, 3-dihydrobenzothien-2 yl, octahydro-1H-indolyl, heptahydrobenzo [3,4-c ] pyrrolyl, octahydropyrrolo [3,4-c ] pyrrolyl, 2, 3-dihydrobenzofuran-2-yl, 3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-yl, 2, octahydro-1H-indolyl, heptanyl, 3-1-yl, and mixtures thereof, Octahydrobenzofuranyl, octahydrocyclopenta [ c ] pyrrole, hexahydrocyclopenta [ c ] furan, 2-dioxohexahydrocyclopenta [ c ] thiophene, 2-imino-2 oxo-octahydrocyclopenta [ c ] thiophene.
The spiroheterocyclic group may be a monovalent group obtained by removing a hydrogen atom from a 6-12-membered spiroheterocyclic ring, a 7-11-membered spiroheterocyclic ring, a 6-12-membered saturated spiroheterocyclic ring, a 7-membered saturated spiroheterocyclic ring, or a divalent or more group obtained by removing a hydrogen atom from the same carbon atom or different carbon atoms, respectively, as required, and examples of spiroheterocyclic groups include, but are not limited to:
Figure BDA0002695632730000171
the bridged heterocyclic group may be a monovalent group obtained by removing a hydrogen atom from a 6-12-membered bridged heterocyclic ring, a 7-11-membered bridged heterocyclic ring, a 6-12-membered saturated bridged heterocyclic ring, a 7-8-membered saturated bridged heterocyclic ring, or a divalent or more groups obtained by removing a hydrogen atom from the same carbon atom or different carbon atoms, respectively, as required, and examples of the bridged heterocyclic group include, but are not limited to:
Figure BDA0002695632730000172
the "aromatic ring" in the present invention means a carbocyclic hydrocarbon having aromaticity. A monovalent group derived from an aromatic carbocyclic hydrocarbon including a 6-to 14-membered aromatic ring, a 6-to 10-membered aromatic ring, a 6-to 8-membered monocyclic aromatic hydrocarbon and an 8-to 14-membered fused ring aromatic hydrocarbon, or a divalent or more group obtained as necessary. 6-8 membered monocyclic aryl is for example phenyl. Examples of the 8-to 14-membered fused ring aryl group include naphthyl, phenanthryl, anthryl and the like. When the group is a divalent group, phenylene, naphthylene and the like are exemplified.
The "aryl group" or "aromatic group" (hereinafter, collectively referred to as "aryl group") as used herein means a group containing a monovalent group derived from an aromatic carbocyclic hydrocarbon or, if necessary, a divalent or more group. It includes 6-14 membered aryl, 6-10 membered aryl. 6-14 membered aryl is for example phenyl, naphthyl, phenanthryl, anthracyl. 6-10 membered aryl groups such as phenyl, naphthyl. When it is a divalent group, phenylene, naphthylene and the like are exemplified.
The "heteroaromatic ring" according to the present invention means a cyclic hydrocarbon having aromaticity having at least one ring-forming atom (which may be 1 to 5, 1 to 4, 1 to 3, 1 to 2 or 1 hetero atom) selected from O, S, N. It may be a 5,6,7,8, 9, 10, 11, 12, 13 or 14 membered aromatic cyclic group, preferably having 1 to 3 heteroatoms. In addition, the heteroaromatic rings of the present invention may be monocyclic or fused (fused in the form of a parallel, spiro or bridge). Specific examples thereof include monocyclic heteroaromatic rings such as pyrrole, pyrazine, pyrazole, indole, tetrazole, furan, thiophene, pyridine, imidazole, triazole, tetrazole, triazine, pyridazine, pyrimidine, pyrazine, isoxazole, thiazole, isothiazole, thiadiazole, oxazole, and oxadiazole; also, there may be mentioned fused heteroaromatic rings such as isoindole, indazole, indolizine, isoindoline, quinoline, isoquinoline, cinnoline, 2, 3-naphthyridine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, benzimidazoline and the like.
The "heteroaryl" or "heteroaryl group" (hereinafter, generically referred to as "heteroaryl") in the present invention means a monovalent or more group derived from the above-mentioned "heteroaryl ring". The "heteroaryl" in the present invention may have 5,6,7,8, 9, 10, 11, 12 ring-forming atoms containing at least one heteroatom selected from O, S, NAn aromatic cyclic hydrocarbon group of 13 or 14. That is, there may be 5-14 membered heteroaryl, 5-10 membered heteroaryl, 5-6 membered heteroaryl. The heteroaryl group may have 1,2,3, 4 or 5 heteroatoms as ring-forming atoms. The heteroaryl group also includes a case where a carbon atom or a sulfur atom is substituted with oxo or nitrogen, and examples thereof include a case where a carbon atom or a sulfur atom is substituted with C (═ O), S (═ O) 2 And S (═ O) (═ N) substitution. Heteroaryl includes both mono-and fused heteroaryl, where not specifically indicated, a single heteroaryl includes all monocyclic, fused, fully aromatic, partially aromatic situations where possible. The monoheteroaryl group may be a 5-7 membered heteroaryl group, a 5-6 membered heteroaryl group, and examples thereof include, but are not limited to, furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl and triazinyl. In some examples, fused heteroaryl refers to a group formed by fusing a monocyclic heteroaryl ring to a phenyl, cycloalkenyl, heteroaryl, cycloalkyl, heterocyclyl group, the fused heteroaryl group can be an 8-12 membered fused heteroaryl, a 9-10 membered fused heteroaryl, examples include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzooxadiazolyl, benzothiadiazolyl, benzothiazolyl, cinnolinyl, 5, 6-dihydroquinolin-2-yl, 5, 6-dihydroisoquinolin-1-yl, furopyridinyl, indazolyl, indolyl, isoindolyl, isoquinolyl, naphthyridinyl, purinyl, quinolinyl, 5,6,7, 8-tetrahydroquinolin-2-yl, 5,6,7, 8-tetrahydroquinolinyl, 5,6,7, 8-tetrahydroquinolin-4-yl, 5,6,7, 8-tetrahydroisoquinolin-1-yl, thienopyridinyl, 4,5,6, 7-tetrahydrobenzo [ c ]][1,2,5]Oxadiazolyl and 6, 7-dihydrobenzo [ c ]][1,2,5]Oxadiazol-4 (5H) onyl. The heteroaryl group may also be a divalent group derived from the above groups.
The "5 to 14-membered cyclic group" in the present invention means a group having 5,6,7,8, 9, 10, 11, 12, 13, 14 ring-forming atoms, which may be the case where the above-mentioned cycloalkyl group, cycloalkenyl group, heterocyclic group, aryl group, heteroaryl group in the present invention have 5 to 14 ring-forming atoms. Specifically, it may be a 5-to 10-membered cyclic group or a 5-to 6-membered cyclic group. In addition, the invention isThe "5-6 membered cyclic group" refers to a chemically feasible cyclic structure of 5-6 ring atoms, which may be optionally selected from C, N, O, S, C (═ O), S (═ O) 2 The cyclic structure formed by S (═ O) (═ N) may be a monocyclic ring, a condensed polycyclic ring, a saturated ring, a partially saturated ring, or an aromatic ring. Examples include, but are not limited to, groups derived from pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran, dihydropyridine, dihydropyridazine, dioxane, oxathiolane, sulfurized cyclopentane, tetrahydrofuran, tetrahydropyran, thiazolidine, tetrahydroisothiazole, pyrrole, pyrazine, pyrazole, indole, tetrazole, furan, thiophene, pyridine, imidazole, triazole, tetrazole, triazine, pyridazine, pyrimidine, pyrazine, isoxazole, thiazole, isothiazole, thiadiazole, oxazole, oxadiazole, benzene, and the like. Preferably, it is a 5-6 membered oxygen containing cyclic group, i.e., a cyclic group having at least one O with the number of ring atoms of 5 or 6.
The term "one or more" or "one to more" as used herein means that the number of the substituents may be 1 to 6, preferably 1 to 5, more preferably 1 to 3, still more preferably 1 to 2, and still more preferably 1, of all the positions of the substituted group which may be chemically substituted.
In the "optionally substituted with a substituent" according to the present invention, the number of the substituent may be 0 (i.e., unsubstituted), or 1 to the number of all chemically substitutable positions of the group to be substituted, preferably 1 to 6, more preferably 1 to 5, more preferably 1 to 4, more preferably 1 to 3, more preferably 1 to 2 or 1.
The "ester" of the present invention means a pharmaceutically acceptable ester formed by the compound of the present invention, more specifically, an ester of formate, acetate, propionate, butyrate, acrylate, ethylsuccinate, etc. of the compound of the present invention, but is not limited thereto.
The "pharmaceutically acceptable salt" of the present invention refers to a pharmaceutically acceptable acid or base addition salt or a solvate thereof. Such pharmaceutically acceptable salts include salts of acids such as: hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid,Sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanoic acids (such as acetic acid, HOOC- (CH) 2 ) n -COOH (wherein n is 0 to 4)), and the like. Salts of bases: sodium, potassium, calcium, ammonium salts and the like. The person skilled in the art is aware of a number of non-toxic pharmaceutically acceptable addition salts.
The hydrogen atom, fluorine atom, carbon atom, nitrogen atom, oxygen atom, sulfur atom and the like in the present invention also include their respective radioactive isotopes or stable isotopes.
The 'tumor' comprises sarcoma, lymphoma and cancer, and can be respiratory system cancer, mesothelioma, nervous system tumor, skin malignant tumor, bone cancer, squamous cell carcinoma, breast cancer, head and neck cancer, cancer of urinary and reproductive systems, cancer of biliary tract system, sarcoma, cancer of digestive system, leukemia, lymphoma, myelodysplastic syndrome, carcinoma in situ, and cytoma; further specific examples are lung cancer, thyroid cancer, oral cancer, pharyngeal cancer, peritoneal cancer, glioma, neurofibromatosis, skin cancer, melanoma, multiple myeloma, squamous lung cancer, squamous esophageal cancer, ductal breast cancer, brain cancer, ovarian cancer, corpus uteri cancer, endometrial cancer, prostate cancer, testicular cancer, bladder cancer, kidney cancer, renal pelvis cancer, bile duct cancer, gallbladder cancer, osteosarcoma, liposarcoma, ewing sarcoma, liver cancer, stomach cancer, esophageal cancer, large intestine cancer, pancreatic cancer, cardiac carcinoma, gastrointestinal stromal tumors, villous adenoma of the large intestine, acute leukemia, chronic leukemia, non-hodgkin's malignant lymphoma (NHL), T/NK cell lymphoma, Hodgkin's Lymphoma (HL), myelodysplastic syndrome, carcinoma in situ, and cell tumor.
"stereoisomers" of the compounds of formula (I) according to the invention mean that when asymmetric atoms are present in the compounds of formula (I), enantiomers are produced; when the compound has a carbon-carbon double bond or a cyclic structure, cis-trans isomers are generated, and all enantiomers, diastereomers, racemic isomers, cis-trans isomers, geometric isomers, epimers and mixtures thereof of the compound of formula (I) are included in the scope of the present invention. The definition of the compounds of the present invention includes all possible stereoisomers and mixtures thereof. In particular including racemic forms and isolated optical isomers having the indicated activity. The racemic forms can be resolved by physical methods, for example fractional crystallization, separation or crystallization of diastereomeric derivatives or separation by chiral column chromatography. The individual optical isomers can be obtained from the racemates by conventional methods (e.g., salt formation with an optically active acid followed by crystallization).
"tautomer" of a compound of formula (I) according to the invention means that an isomer of a functional group which is produced when an atom in the compound of formula (I) moves rapidly in two positions is called tautomer; when the hydrogen in the alpha position of the carbonyl-containing functional group is on the alpha carbon, keto tautomers are produced; when the hydrogen in the alpha position of the carbonyl-containing functional group is on the oxygen of the carbonyl, alcoholic tautomers are produced.
The pharmaceutical composition comprises at least one of a compound shown as a formula (I) and pharmaceutically acceptable salts, esters, stereoisomers and tautomers thereof.
The pharmaceutical composition comprises a compound shown as a formula (I), or pharmaceutically acceptable salt, ester, stereoisomer, tautomer and optional one or more pharmaceutical carriers thereof.
The pharmaceutical compositions of the present invention may be administered to a patient or subject in need of prophylaxis and/or treatment by any suitable mode of administration known in the art, for example, by oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal modes of administration and the like.
The pharmaceutical composition can be prepared into conventional solid preparations, such as tablets, capsules, pills, granules and the like; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When formulated for oral administration, one or more substances selected from suitable excipients, diluents, sweeteners, solubilizers, lubricants, binders, tablet disintegrating agents, stabilizers, preservatives, and encapsulating materials may be added. For parenteral administration, the pharmaceutical compositions may be formulated as injections, sterile powders for injection and concentrated solutions for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding appropriate additives according to the properties of the medicine. For rectal administration, the pharmaceutical composition may be formulated as suppositories and the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalant or a spray. In the present invention, suitable solid carriers include, but are not limited to, for example, cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin, tragacanth, acacia, sodium alginate, p-hydroxybenzoate, methyl cellulose, sodium carboxymethyl cellulose, low-melting waxes, cocoa butter, and the like. Suitable liquid carriers include, but are not limited to, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, glycerides, and mixtures thereof.
Methods of preparing the pharmaceutical compositions of the present invention are generally known. The pharmaceutical compositions of the present invention may be prepared in a manner known per se, including conventional mixing, granulating, tabletting, coating, dissolving or lyophilizing processes.
The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage forms can be packaged in packages containing discrete quantities of preparation, such as packeted tablets, capsules, or powders in vials or ampoules.
The dose of the drug to be administered depends on various factors including the age, weight and condition of the patient and the route of administration. The precise dose to be administered is determined at the discretion of the attendant physician. Typical dosages for administering the active compound may be, for example, from about 0.01 to about 100mg per day, from about 0.05 to about 75mg per day, from about 0.1 to about 50mg per day, or from about 5 to about 10mg per day. The desired dosage will also depend on the particular compound employed, the severity of the disease, the route of administration, the weight and health of the patient and the judgment of the treating physician.
A process for the preparation of a compound of formula (I),
Figure BDA0002695632730000201
adding the formula (I-a) into a solvent, adding a peptide coupling reagent, alkali and the formula (I-b), stirring to react completely, and separating to obtain the formula (I); or,
adding the formula (I-a) and the formula (I-b) into alkali, dripping a coupling reagent, stirring to react completely, separating to obtain the formula (I),
wherein M is 3 、R、W、Cy 3 L and Cy 4 As defined above.
The solvent is selected from: one of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, toluene, benzene, xylene, trimethylbenzene, cyclohexane, hexane, dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, diethyl ether, dioxane, 1, 2-dimethoxyethane, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, acetonitrile, methanol, ethanol, isopropanol, t-butanol, water, and a mixture thereof;
the base is selected from: one of methylamine, ethylamine, propylamine, N-diisopropylethylamine, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline and mixtures thereof;
the peptide coupling reagent is selected from: one of 2- (7-azobenzotriazol) -tetramethyluronium Hexafluorophosphate (HATU), benzotriazol-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU), 2- (1H-benzo [ d ] [1,2,3] trisazo-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate (TBTU), and a mixture thereof;
the coupling reagent is selected from: phosphorus oxychloride, Dicyclohexylcarbodiimide (DCC), N' -carbonyldiimidazole, isobutyl chloroformate, 1-N-propylphosphoric anhydride, and the like, and mixtures thereof.
In the synthesis of the compound of the present invention, the reaction solvent may be any solvent commonly used in the art, including but not limited to ethers, alkanes, halogenated alkanes, aromatic hydrocarbons, alcohols, etc. Specific examples thereof include N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, aromatic hydrocarbons (e.g., toluene, benzene, xylene, trimethylbenzene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1, 2-dichloroethane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, 1, 2-dimethoxyethane, etc.), esters (e.g., methyl acetate, ethyl acetate, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), alcohols (e.g., methanol, ethanol, isopropanol, t-butanol, etc.), water and a mixed solvent thereof.
Bases used in the synthesis of the compounds of the invention may be bases commonly used in the art, including organic and inorganic bases. Examples of the organic base include methylamine, ethylamine, propylamine, N-diisopropylethylamine, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, and quinoline; examples of the inorganic base include hydroxides, carbonates, and bicarbonates of alkali metals (for example, lithium, sodium, potassium, and cesium); hydroxides, carbonates, bicarbonates of alkaline earth metals (magnesium, calcium, strontium, barium); sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, etc.
The acid used in the synthesis of the compounds of the present invention may be an acid commonly used in the art, including organic and inorganic acids. Examples of the organic acid include formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, and ethanesulfonic acid; examples of the inorganic acid include hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, and hydroiodic acid.
The reducing agent used in the synthesis of the compound of the present invention may be any reducing agent commonly used in the art, including, but not limited to, triphenylphosphine, tri-n-butylphosphine, sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, iron powder, zinc powder, stannous chloride, sodium dithionite, hydrogen, etc.
The oxidizing agent used in the synthesis of the compound of the present invention may be an oxidizing agent commonly used in the art, including, but not limited to, copper chloride, manganese dioxide, permanganate, dichromate, peracetic acid, perbenzoic acid, and the like.
In the synthesis of the compound of the present invention, the catalyst used may be a catalyst commonly used in the art, including, but not limited to, copper acetate, copper chloride, palladium carbon, ferric chloride, palladium acetate, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride, and the like.
Examples
The present invention can be better understood from the following examples and experimental examples. And those skilled in the art will readily appreciate that the description of the embodiments is illustrative only and should not be taken as limiting the invention as defined by the following claims.
The reaction conditions are not specified in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
In the present invention, unless otherwise specified, wherein: (i) temperatures are expressed in degrees Celsius (. degree. C.) and, unless otherwise noted, operation is carried out in ambient temperature conditions; (ii) the progress of the reaction is followed by Thin Layer Chromatography (TLC) or LC-MS; (iii) the final product has a clear proton NMR spectrum ( 1 H-NMR) data and Mass Spectrometry (MS) data. The abbreviations and english expressions used in the present invention have the following meanings.
DCM: methylene dichloride
-Boc: tert-butyloxycarbonyl radical
TEA: triethylamine
TBSCl: tert-butyldimethylsilyl chloride
TBS-: tert-butyl dimethyl silicon base
DMSO (dimethylsulfoxide): dimethyl sulfoxide
NaHMDS: hexamethyldisilazane sodium diazoxide
TBAF: tetrabutylammonium fluoride
MsCl: methanesulfonyl chloride
TFA: trifluoroacetic acid (trifluoroacetic acid)
DMF: n, N-dimethylformamide
Pd 2 (dba) 3 : tris (dibenzylideneacetone) dipalladium
conc. HCl: concentrated hydrochloric acid
NBS: n-bromosuccinimide
AIBN: azobisisobutyronitrile
THF: tetrahydrofuran (THF)
TMSCN: trimethylnitrile silane
CPBA: meta-chloroperoxybenzoic acid
TMSI: trimethylsilylimidazole
BHT: dibutylhydroxytoluene
Pd(PPh 3 ) 2 Cl 2 : bis (triphenylphosphine) palladium dichloride
EA: ethyl acetate
EtOH: ethanol
MTBE: methyl tertiary butyl ether
PE: petroleum ether
HATU: 2- (7-azobenzotriazol) -tetramethylurea hexafluorophosphate
reflux: reflux of
pyridine, pyridine
tolumene toluene
PBu 3: tributyl phosphine
1, 4-dioxane: 1,4-dioxane
DMF-DMA: n, N-dimethylformamide dimethyl acetal
DIPEA/DIEA: n, N-diisopropylethylamine
And (4) DEC: dichloroethane
Pd(dppf)Cl 2 ·CH 2 Cl 2 : [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex
DMAP: 4-dimethylaminopyridine
SEMCl: (2- (chloromethoxy) ethyl) trimethylsilane
rt: at room temperature
Example 1: synthesis of N- (5- ((6, 7-dimethoxyquinolin-4-yl) oxy) pyridin-2-yl) -5- (4-fluorophenyl) -1-methyl-4-oxo-1, 4-dihydropyridazine-3-carboxamide (Compound 1)
Figure BDA0002695632730000221
Step 1: synthesis of N- (5- ((6, 7-dimethoxyquinolin-4-yl) oxy) pyridin-2-yl) -5- (4-fluorophenyl) -1-methyl-4-oxo-1, 4-dihydropyridazine-3-carboxamide
Figure BDA0002695632730000231
5- (4-fluorophenyl) -1-methyl-4-oxo-1, 4-dihydropyridazine-3-carboxylic acid (1200066-02) (260.0mg,1.047mmol,1.0eq) was added to pyridine (7mL), 5- ((6, 7-dimethoxyquinolin-4-yl) oxy) pyridin-2-amine (311.4mg,1.047mmol,1.0eq) was added, phosphorus oxychloride (0.5mL) was added dropwise with stirring, stirring was carried out for 15min, the reaction was monitored by TLC for completion, ethyl acetate (150mL) and water (200mL) were added, the organic phase was separated, dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin layer chromatography (DCM: MeOH ═ 13:1) to give the product (300.0mg, yield: 54.3%).
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):13.13(s,1H),8.90(s,1H),8.43-8.51(m,1H),8.41-8.42(m,2H),7.87-7.96(m,3H),7.54(s,1H),7.42(s,1H),7.33-7.37(m,2H),6.57-6.58(m,1H),4.14(s,3H),3.95-3.96(d,6H).
Molecular formula C 28 H 22 FN 5 O 5 Molecular weight 527.51LC-MS (Pos, M/z) ═ 528.32[ M + H ]] + .
Example 2: n- (5- ((6, 7-Dimethoxyquinolin-4-yl) oxy) pyridin-2-yl) -5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridazine-3-carboxamide (Compound 2)
Figure BDA0002695632730000232
Step 1: synthesis of methyl 5- (4-fluorophenyl) -4-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 4-dihydropyridazine-3-carboxylate
Figure BDA0002695632730000233
Methyl 5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridazine-3-carboxylate (607.0mg,2.445mmol,1.0eq) was added to N, N-dimethylformamide (DMF: 5mL), anhydrous potassium carbonate (675.9mg,4.891mmol,2.0eq) and (2- (chloromethoxy) ethyl) trimethylsilane (815.4mg,4.891mmol,2.0eq) were added, and the mixture was stirred at 50 ℃ for 5 hours. TLC to monitor the reaction completion, concentrating under reduced pressure to remove DMF, adding ethyl acetate (100mL) and water (100mL), separating, washing the organic phase with saturated sodium chloride solution (100mL), drying over anhydrous sodium sulfate, suction filtering, concentrating the filtrate under reduced pressure, and subjecting the crude product to silica gel column chromatography (PE: EA: 8: 1-4: 1) to obtain the product (420.0mg, yield: 45.4%).
Step 2: synthesis of 5- (4-fluorophenyl) -4-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 4-dihydropyridazine-3-carboxylic acid
Figure BDA0002695632730000234
Methyl 5- (4-fluorophenyl) -4-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 4-dihydropyridazine-3-carboxylate (420.0mg,1.109mmol,1.0eq) was added to methanol (4mL), an aqueous solution (1.0mL) of lithium hydroxide monohydrate (139.6mg,3.329mmol,3.0eq) was added, stirring was carried out at room temperature for 2 hours, the reaction was monitored by TLC for completion, methanol was removed by concentration under reduced pressure, the system pH was adjusted to 4 with a saturated aqueous citric acid solution, extraction was carried out with Dichloromethane (DCM), the organic phase was dried over anhydrous sodium sulfate, suction filtration was carried out, and the filtrate was concentrated to give a product (336.5mg, yield: 83.1%).
And step 3: synthesis of N- (5- ((6, 7-dimethoxyquinolin-4-yl) oxy) pyridin-2-yl) -5- (4-fluorophenyl) -4-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 4-dihydropyridazine-3-carboxamide
Figure BDA0002695632730000241
5- (4-fluorophenyl) -4-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 4-dihydropyridazine-3-carboxylic acid (336.5mg,0.923mmol,1.0eq) was added to acetonitrile (5mL), N-diisopropylethylamine (DIPEA:357.7mg,2.769mmol,3.0eq) and 2- (7-azobenzotriazol) -tetramethylurea hexafluorophosphate (HATU:526.4mg,1.384mmol,1.5eq) were added in this order under ice-cooling, 5- ((6, 7-dimethoxyquinolin-4-yl) oxy) pyridin-2-amine (274.4mg,0.923mmol,1.0eq) was added after stirring for 3 hours, gradually warmed to room temperature and stirred for 15 hours, TLC was monitored for reaction completion, ethyl acetate (EA: 50mL) and water (50mL) were added, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the crude product was purified by silica gel column chromatography (DCM: MeOH: 100:1 to 80:1) to give the product (280.0mg, yield: 47.1%).
And 4, step 4: synthesis of N- (5- ((6, 7-dimethoxyquinolin-4-yl) oxy) pyridin-2-yl) -5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridazine-3-carboxamide
Figure BDA0002695632730000242
N- (5- ((6, 7-dimethoxyquinolin-4-yl) oxy) pyridin-2-yl) -5- (4-fluorophenyl) -4-oxo-1- ((2- (trimethylsilyl) ethoxy) methyl) -1, 4-dihydropyridazine-3-carboxamide (280.0mg,0.434mmol,1.0eq) was added to isopropanol (3.5mL), carbon tetrabromide (144.2mg,0.434mmol,1.0eq) was added, stirring was carried out at 80 ℃ for 5 hours, the reaction was monitored by TLC for completion, the system was cooled to room temperature and then filtered, and the filter cake was dried to give the product (96.0mg, yield: 43.6%).
1 HNMR(400MHz,DMSO-d 6 )δ(ppm):14.46(s,1H),13.18(s,1H),8.87-8.89(m,1H),8.83(s,1H),8.51-8.55(m,2H),8.02-8.05(m,1H),7.93-7.96(m,2H),7.81(s,1H),7.57(s,1H),7.31-7.35(t,2H),7.09-7.11(d,1H),4.05-4.07(d,6H).
Molecular formula C 27 H 20 FN 5 O 5 Molecular weight 513.49LC-MS (Pos, M/z) ═ 514.33[ M + H ]] + .
Example 3: synthesis of 1-allyl-N- (5- ((6, 7-dimethoxyquinolin-4-yl) oxy) pyridin-2-yl) -5-p-fluorophenyl-4-oxo-1, 4-dihydropyridazine-3-carboxamide (Compound 45)
Figure BDA0002695632730000251
Step 1: synthesis of 1-allyl-5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridazine-3-carboxylic acid
Figure BDA0002695632730000252
Ethyl 5-p-fluorophenyl-4-oxo-1, 4-dihydropyridazine-3-carboxylate (2.010g,7.66mmol,1.0eq), cyclopropylboronic acid (1.975g,22.99mmol,3.0eq), copper acetate (2.784g,15.33mmol,2.0eq), triethylamine (3.878g,38.32mmol,5.0eq) and pyridine (4.850g,61.32mmol,8.0eq) were added to N, N-Dimethylformamide (DMF) (40mL) and the reaction was stirred under oxygen conditions at 50 ℃ overnight. TLC (thin layer chromatography) for monitoring the reaction completion, concentrating under reduced pressure, adding dichloromethane for dissolution, washing with 1mol/L hydrochloric acid (20mL), adding 10% sodium hydroxide aqueous solution into an organic phase for back extraction, extracting an aqueous phase with dichloromethane (10mL × 4), filtering the aqueous phase, adjusting the pH value of a filtrate to 3-4 with 1mol/L hydrochloric acid to precipitate a light brown solid, filtering, dissolving a filter cake with dichloromethane, drying with anhydrous sodium sulfate, performing suction filtration, concentrating the filtrate under reduced pressure, and purifying a crude product by silica gel column chromatography (DCM: MeOH ═ 20:1) to obtain a product (0.54g, yield: 25.7%).
Step 2: synthesis of 1-allyl-N- (5- ((6, 7-dimethoxyquinolin-4-yl) oxy) pyridin-2-yl) -5-p-fluorophenyl-4-oxo-1, 4-dihydropyridazine-3-carboxamide
Figure BDA0002695632730000253
1-allyl-5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridazine-3-carboxylic acid (180.0mg,0.66mmol,1.1eq) was dissolved in N, N-dimethylformamide (DMF:2mL), 2- (7-azobenzotriazol) -tetramethylurea hexafluorophosphate (HATU:340.3mg,0.90mmol,1.5eq) and N, N-diisopropylethylamine (DIPEA:231.4mg,1.79mmol,3.0eq) were added, stirring was carried out for 10min, 5- ((6, 7-dimethoxyquinolin-4-yl) oxy) pyridin-2-amine (177.4mg,0.60mmol,1.0eq.) was added, and reaction was stirred at room temperature for 1 h. TLC the reaction was monitored to completion, concentrated under reduced pressure, and the crude product was dissolved in ethyl acetate (10mL), washed successively with saturated aqueous sodium bicarbonate (5mL), saturated aqueous ammonium chloride (5mL), water (5mL × 4) and saturated brine (5mL), dried over anhydrous sodium sulfate, filtered under suction, and the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin layer chromatography (DCM: MeOH ═ 15:1) to give the product (204mg, yield: 74.2%).
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):12.99(s,1H),8.92(s,1H),8.51-8.50(d,1H),8.42-8.40(t,2H),7.96-7.88(m,3H),7.55(s,1H),7.42(s,1H),7.37-7.33(t,2H),6.59-6.58(d,1H),6.21-6.11(m,1H),5.40-5.36(t,2H),5.00-4.99(d,2H),3.96-3.95(d,6H).
Molecular formula C 30 H 24 FN 5 O 5 Molecular weight 553.55LC-MS (Pos, M/z) ═ 554.33[ M + H ]] + .
Example 4: synthesis of 1-allyl-N- (5- ((6, 7-dimethoxyquinolin-4-yl) oxy) pyrimidin-2-yl) -5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxamide (Compound 46)
Figure BDA0002695632730000261
Step 1: synthesis of 1-allyl-N- (5- ((6, 7-dimethoxyquinolin-4-yl) oxy) pyrimidin-2-yl) -5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridine-3-carboxamide
Figure BDA0002695632730000262
1-allyl-5- (4-fluorophenyl) -4-oxo-1, 4-dihydropyridazine-3-carboxylic acid (245.0mg,0.89mmol,1.0eq) and 5- ((6, 7-dimethoxyquinolin-4-yl) oxy) pyrimidin-2-amine (266.4mg,0.89mmol,1.0eq) were added to pyridine (3mL), phosphorus oxychloride (0.2mL) was added dropwise, stirring was performed for 30 minutes, the reaction was monitored by TLC for completion, concentration was performed under reduced pressure, ethyl acetate (20mL) and water (10mL) were added, liquid was separated, the organic phase was dried over anhydrous sodium sulfate, filtration and concentration was performed, and the crude product was purified by preparative thin layer chromatography (dichloromethane: methanol 15:1) to give a product (132.0mg, yield: 26.6%).
1 H NMR(400MHz,DMSO-d 6 )δ(ppm):12.86(s,1H),8.88(s,1H),8.79(s,2H),8.49-8.50(m,1H),7.90-7.93(m,2H),7.54(s,1H),7.42(s,1H),7.31-7.35(m,2H),6.67-6.68(m,1H),6.09-6.19(m,1H),5.32-5.36(m,2H),4.96-4.96(m,2H),3.95-3.96(s,6H).
Molecular formula C 29 H 23 FN 6 O 5 Molecular weight 554.54LC-MS (Pos, M/z) ═ 555.29[ M + H ]] + .
The present invention can be better understood from the following experimental examples. And those skilled in the art will readily appreciate that the description of the embodiments is illustrative only and should not be taken as limiting the invention as defined by the following claims.
Experimental example 1 evaluation of hepatic microsome stability of mouse and dog as a Compound of the present invention
Test article: the structures and preparations of the compounds 45 and 46 of the present invention are shown above.
Figure BDA0002695632730000263
The incubation system comprises the following components:
preparing a test substance:
an appropriate amount of the compound was weighed out accurately and dissolved in DMSO to prepare a 5.0mM stock solution. 5.0mM stock solution was diluted to 1.0mM with DMSO, and finally diluted to 100M of the test substance working solution with water, and was used (DMSO content in the reaction system was 0.1%).
The test steps are as follows:
(1) the liver microsomes (20mg protein/mL) are taken out from a refrigerator at the temperature of-80 ℃, put on a water bath constant temperature oscillator at the temperature of 37 ℃ for pre-incubation for 3min, and melted for standby.
(2) According to the proportion of the experimental incubation system, a mixed solution of the incubation system (without the compound and the beta-NADPH) is prepared and placed on a water bath constant temperature oscillator at 37 ℃ for pre-incubation for 2 min.
(3) Control group (without β -NADPH): and (3) respectively adding 30 mu L of water and 30 mu L of compound working solution (10 mu M) into 240 mu L of the mixed solution of the incubation system in the step (2), vortexing for 30s, uniformly mixing, reacting for the total volume of 300 mu L, and performing sample recovery. And putting the mixture into a water bath constant temperature oscillator at 37 ℃ for incubation, and starting timing, wherein sampling time points are 0min and 60 min.
(4) Sample set: and (3) adding 70 mu L of beta-NADPH solution (10mM) and 70 mu L of compound working solution (10 mu M) into 560 mu L of the mixed solution in the step (2), reacting for total volume of 700 mu L, vortexing for 30s, mixing uniformly, and performing pore renaturation. Putting into a 37 ℃ water bath constant temperature oscillator for incubation, and starting timing, wherein the sampling time points are 0min,5min,10min,20min,30min and 60min after timing.
(5) After vortexing for 3min, centrifuge at 4000rpm for 10 min.
(6) Taking 50 mu L of supernatant, adding 150 mu L of water, mixing uniformly by vortex, and analyzing by LC/MS/MS sample injection.
And (3) data analysis:
half-life (t) was calculated using the following first order kinetic equation 1/2 ) And clearance (Cl):
C t ＝C 0 *e –kt
t 1/2 ＝ln2/k＝0.693/k
Clint＝V d *k
V d 1/protein content in liver microsomes
Note: k is the slope of the log of the remaining amount of compound plotted against time, V d Is the apparent distribution volume.
The test results are shown in table 1 below:
TABLE 1 stability of mouse and canine liver microsomes with the compounds of the invention
Figure BDA0002695632730000271
And (4) test conclusion: the experimental results in table 1 show that the compound of the present invention has low clearance rate and good stability of liver microsome. Experimental example 2 evaluation of rat PK by the Compound of the present invention
Compound 45 for experiments was dissolved in 5% DMSO + 10% (30% solutol) + 85% saline to prepare a solution, which was administered to SD rats at 5.0mg/kg by intragastric administration at the time of blood collection: 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h, 30h and 48 h.
Compound 45 for experiments was prepared as a solution dissolved in 5% DMSO + 10% (30% solutol) + 85% saline, and the solution of compound was administered to SD rats as a bolus injection at a dose of 1mg/kg, and the blood collection time points were: 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h, 30h and 48 h.
Compound 46 for experiment was dissolved in 5% DMSO + 20% (30% solutol) + 75% saline to prepare a solution, and the solution of compound was administered to SD rats at 5.0mg/kg by intragastric administration at the following blood sampling time points: 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h, 30h and 48 h.
Compound 46 for experiments was prepared as a solution dissolved in 5% DMSO + 20% (30% solutol) + 75% saline, and the solution of compound was administered to SD rats as a bolus intravenous injection at a dose of 1mg/kg, at the time points of blood collection: 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h, 30h and 48 h.
Inserting jugular vein into animal before administration, collecting about 300 μ L of blood via jugular vein after administration, and placing the blood into a container containing EDTA-K 2 In an anticoagulation tube. The blood sample was centrifuged at 8000rpm at 4 ℃ for 6min to obtain a plasma sample, which was prepared within 30min after blood collection. Plasma was stored in a-80 ℃ freezer prior to testing.
The sample analysis method comprises the following steps:
1) taking out the sample to be tested from a refrigerator at the temperature of minus 80 ℃, naturally melting at room temperature, and then whirling for 5 min;
2) precisely sucking 20 mu L of plasma sample into a 1.5mL centrifuge tube;
3) adding 200 μ L of internal standard working solution (methanol solution of tolbutamide) with concentration of 100ng/mL, and mixing;
4) after vortexing for 5min, centrifuging at 12000rpm for 5 min;
5) precisely sucking 50 mu L of supernatant into a 96-well plate in which 150 mu L/well of water is added in advance;
6) vortex and mix for 5min for LC-MS/MS assay analysis.
The data processing method comprises the following steps:
the test substance concentration was outputted using Analyst 1.6.3 from AB. Calculating parameters such as mean value, standard deviation, coefficient of variation and the like by Microsoft Excel (analysis 1.6.3 is directly output without calculation), and calculating PK parameter by adopting Pharsight Phoenix 6.1 software NCA (T) max Median).
The results are shown in table 2 below:
TABLE 2 PK parameters of compounds in SD rats (IV: 1mg/kg, PO: 5mg/kg, n ═ 3)
Figure BDA0002695632730000281
Note: t is t z1/2 : terminal elimination half-life, Cl _obs : clearance rate, V z_ o bs : apparent volume of distribution, T max : peak time of blood concentration, AUC last : area under the drug-time curve is 0-48 h, F%: absolute bioavailability.
The experimental results in table 2 show that the compound of the present invention has good pharmacokinetic properties and good drug-forming properties.
Experimental example 3 enzymatic Activity test of the Compound of the present invention
Test article: the structure and preparation of the compound of the invention are shown in the specification.
The test method comprises the following steps:
(1) preparation of stock solutions of the Compounds
Compounds were dissolved in 100% DMSO to prepare stock solutions with a maximum concentration of 500 μ M.
(2) Preparation of Compound working solutions
Compound stock solutions were diluted to compound final concentrations of 500. mu.M, 150. mu.M, 50. mu.M, 15. mu.M, 5. mu.M, 1.5. mu.M, 0.5. mu.M, 0.15. mu.M, 0.05. mu.M as compound working solutions (50X).
(3) Preparation of different enzyme reaction solutions
a)Axl(h)
Axl (h) enzyme was dissolved in 8mM MOPS (pH 7.0), 0.2mM EDTA, 250. mu. M KKSRGDYMTMQIG to prepare an enzyme solution at a final concentration of 1.7 nM. 10mM magnesium acetate, 10. mu.M [ gamma- 33 P]ATP makes up Mg-ATP mixed liquor activates enzymatic reaction.
b)Mer(h)
Mer (h) the enzyme was dissolved in 8mM MOPS (pH 7.0), 0.2mM EDTA, 30mM NaCl, 250. mu. M GGMEDIYFEFMGGKKK to prepare an enzyme solution having a final concentration of 3.1 nM. 10mM magnesium acetate, 10. mu.M [ gamma- 33 P]ATP constitutes a Mg/ATP mixture, activating the enzymatic reaction.
c)Tyro-3(h)
Tyro3(h) enzyme dissolved in 8mM MOPS (pH 7.0), 0.2mM EDTA, 1mM MnCl 2 250 μ M KVEKIGEGTYGVVYK, the enzyme solution was prepared to a final concentration of 38 nM. 10mM magnesium acetate, 10. mu.M [ gamma- 33 P]ATP constitutes a Mg/ATP mixture, activating the enzymatic reaction.
(4) Enzymatic reaction
The compound working solution was added to the 384-well plate to a final concentration of 10000nM, 3000nM, 1000nM, 300nM, 100nM, 30nM, 10nM, 3nM, 1nM, respectively, and the different enzyme reaction solutions prepared under the above conditions were added to the compound working solution, and after incubation at room temperature for 40min, the test was terminated by adding 0.5% phosphoric acid solution. 10 μ L of the reaction solution was dropped on a P30 filter paper, washed 4 times with 0.425% phosphoric acid solution, washed once with methanol, and then placed in a scintillation counter for detection. Results were grey scale analyzed using Image J software and IC calculated using GraphPad5.0 software 50 The value is obtained.
The test results are shown in table 3 below:
TABLE 3 inhibitory Activity of the Compounds of the invention on different kinases-IC 50 (nM)
Figure BDA0002695632730000291
Means not determined
As can be seen from the experimental results shown in Table 3, the compounds of the present invention have good inhibitory activity against Axl (h), Mer (h) and Tyro3(h), and thus the compounds of the present invention are useful for the prevention and/or treatment of diseases mediated by Axl (h), Mer (h) and Tyro-3 (h).
EXAMPLE 4 cellular Axl inhibitory Activity of Compounds of the invention
H1299 is a non-small cell lung cancer cell.
Test article: the structures of the compounds of the present invention are shown above.
Testing an instrument: protein electrophoresis apparatus (Bio Rad), Membrane rotation apparatus (Bio Rad), Exposure apparatus (Tanon), CO 2 Cell culture incubator (manufactured by Thermo).
The test method comprises the following steps:
h1299 cells were seeded in 6-well plates (containing 10% FBS 1640 medium, 5X 10 cells per well) 5 Cells), 37 ℃, 5% CO 2 After 18h adherent culture, starving the cells overnight, and adding compounds at different concentrations of 1.1nM, 3.3nM, 10nM and 30nM, wherein the DMSO content is 1 ‰. Negative control wells were media containing 1% DMSO. 37 ℃ and 5% CO 2 After 60min incubation, hGAS6 (R) was added per well&D, final concentration 200ng/mL), and after further incubation for 60min, total cell protein was extracted for Western Blot (Western Blot) and IC was calculated using GraphPad5.0 software 50 Value, the inhibitory activity of the compounds on pAxl cells was examined.
The test results are shown in table 4 below:
TABLE 4 inhibitory Activity of the Compounds of the invention on pAxl cells
Compound (I) IC 50 (nM)
Compound 1 1.1
Compound 2 <3.3
Compound 45 <1.1
Compound 46 <1.1
The experimental results in table 4 show that the compound of the present invention has a significant inhibitory effect on pAxl of H1299 cells, which indicates that the compound of the present invention can effectively inhibit Axl activity at a cellular level, and is a good Axl inhibitor.
Experimental example 5 cell pMer inhibitory Activity test of the Compound of the present invention
H1299 is a non-small cell lung cancer cell.
Test article: the structure of the compound of the present invention is as described above.
Testing an instrument: protein electrophoresis apparatus (Bio Rad), Membrane rotation apparatus (Bio Rad), Exposure apparatus (Tanon), CO 2 Cell culture incubator (manufactured by Thermo).
The test method comprises the following steps:
h1299 cells were seeded in 6-well plates (containing 10% FBS 1640 medium, 5X 10 cells per well) 5 Cells), 37 ℃, 5% CO 2 After 18h adherent culture, starving the cells overnight, and adding different concentrations of compounds, wherein the final concentration of the compounds is 0.37, 1.1nM, 3.3nM and 10nM, and the final DMSO content is 1 ‰. The negative control wells were media containing 1% DMSO. 37 ℃ and 5% CO 2 After 60min incubation, Human MerMab (R) was added per well&D, final concentration of 200ng/mL), continuously incubating for 60min, extracting total cell protein, performing protein immunoblotting (Western Blot) experiment, performing grey-scale analysis on the result by using Image J software, and calculating IC by using GraphPad5.0 software 50 Value, the inhibitory activity of the compounds on cell pMer was examined.
The test results are shown in table 5 below:
TABLE 5 inhibitory Activity of Compounds of the invention against cellular pMer
Compound (I) IC 50 (nM)
Compound 1 <0.37
Compound 2 <0.37
Compound 45 <0.37
Compound 46 <0.37
The experimental results in table 5 show that the compound of the present invention has significant inhibitory effect on the pMer of H1299 cells, which indicates that the compound of the present invention can effectively inhibit the Mer activity at the cellular level, and is a good Mer inhibitor.
Industrial applicability
The present invention provides a novel TAM family kinase inhibitor compound which has excellent kinase inhibitory activity and is useful for the prophylaxis and/or treatment of diseases mediated by abnormal expression of TAM family kinase receptors and/or their ligands. Further, the compounds of the present invention may inhibit tumor growth, migration, and/or resistance expression caused by TAM family kinases. Furthermore, the compounds of the present invention have a long half-life in vivo and excellent metabolic stability in vivo, and therefore, the compounds of the present invention can improve the therapeutic effects of drugs, reduce the burden of patients on taking drugs, and improve the compliance of patients.

Claims (9)

1. A compound represented by the general formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof:
Figure FDA0003656570280000011
wherein W is selected from hydrogen or C 1-6 An alkyl group;
r represents a group represented by the following general formula (b):
Figure FDA0003656570280000012
in the group
Figure FDA0003656570280000013
A double bond moiety represented in a ring structure;
Figure FDA0003656570280000014
moiety and M 3 Group attachment;
X 1 is CR a ，X 2 Is NR b (ii) a Or alternatively
X 1 Is NR b ，X 2 Is CR a ；X 3 Is C ═ O;
X 4 、X 5 are each independently selected from C;
M 3 selected from H, methyl, or optionally substituted with one or more R 0 Substituted C 2-8 Alkenyl radical, R 0 Each independently selected from hydrogen, hydroxyl, halogen atom, C 1-6 An alkyl group;
Cy 2 selected from optionally substituted one or more R 2 Substituted phenyl radicals, R 2 Each independently selected from hydrogen, hydroxyl, halogen atom, C 1-6 An alkyl group;
Cy 3 denotes an optionally substituted one or more R 3 Substituted
Figure FDA0003656570280000015
Y 2 、Y 3 、Y 6 And Y 7 Each independently selected from CH or N, and at least one is N, R 3 Each independentlySelected from hydrogen, hydroxy, halogen atoms, C 1-6 An alkyl group;
Cy 4 selected from optionally substituted one or more R 4 Substituted by
Figure FDA0003656570280000016
R 4 Each independently selected from hydrogen, hydroxyl, halogen atom, NR b R c 、C 1-6 Alkyl radical, C 1-6 An alkoxy group;
l is selected from-O-;
R a is absent or, at each occurrence, is independently selected from hydrogen, hydroxy, halogen atom, C 1-6 An alkyl group;
R b 、R c is absent or, at each occurrence, is independently selected from hydrogen, hydroxy, C 1-6 An alkyl group.
2. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof,
wherein,
X 1 is CR a ，X 2 Is NR b (ii) a Or
X 1 Is NR b ，X 2 Is CR a ；X 3 Is C ═ O;
X 4 selected from C, X 5 Is selected from C;
Cy 2 selected from optionally substituted by one or more R 2 Substituted phenyl;
Cy 3 denotes an optionally substituted one or more R 3 Substituted
Figure FDA0003656570280000021
Y 2 、Y 3 、Y 6 And Y 7 Each independently selected from CH or N, and at least one is N;
Cy 4 is one to more than one R 4 Substituted by
Figure FDA0003656570280000022
M 3 Selected from H, methyl, or optionally substituted with one or more R 0 Substituted C 2-8 Alkenyl radical, R 0 Each independently selected from hydrogen, hydroxyl, halogen atom, C 1-6 An alkyl group;
R 2 each independently selected from hydrogen, hydroxyl, halogen atom, C 1-6 An alkyl group;
R 3 each independently selected from hydrogen, hydroxyl, halogen atom, C 1-6 An alkyl group;
R 4 each independently selected from hydrogen, hydroxyl, halogen atom, -NR b R c 、C 1-6 Alkyl radical, C 1-6 An alkoxy group;
l is selected from-O-;
R a is absent or, at each occurrence, is independently selected from hydrogen, C 1-6 An alkyl group;
R b 、R c is absent or, at each occurrence, is independently selected from hydrogen, C 1-6 An alkyl group.
3. A compound of claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof,
wherein W is selected from hydrogen;
X 1 is CR a ，X 2 Is NR b (ii) a Or
X 1 Is NR b ，X 2 Is CR a ；X 3 Is C ═ O;
X 4 selected from C, X 5 Is selected from C;
M 3 selected from H, methyl, or optionally substituted by one or more R 0 Substituted allyl, R 0 Each independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, C 1-4 An alkyl group;
Cy 2 selected from optionally substituted by one or more R 2 Substituted
Figure FDA0003656570280000023
R 2 Each independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, C 1-4 An alkyl group;
Cy 3 selected from optionally substituted one or more R 3 Substituted by
Figure FDA0003656570280000031
R 3 Each independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, C 1-4 An alkyl group;
Cy 4 selected from optionally substituted one or more R 4 Substituted
Figure FDA0003656570280000032
R 4 Each independently selected from hydrogen, hydroxyl, halogen atom, C 1-4 Alkyl radical, C 1-4 An alkoxy group;
l is-O-;
R a is absent or, at each occurrence, is independently selected from hydrogen, C 1-6 An alkyl group;
R b is absent or, at each occurrence, is independently selected from hydrogen, C 1-6 An alkyl group.
4. The compound of claim 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof,
wherein W is selected from hydrogen;
X 1 is CR a ，X 2 Is NR b (ii) a Or alternatively
X 1 Is NR b ，X 2 Is CR a ，X 3 Is C ═ O;
X 4 selected from C, X 5 Is selected from C;
M 3 each independently selected from H, methyl, allyl;
Cy 2 selected from optionally substituted one or more R 2 Substituted by
Figure FDA0003656570280000033
R 2 Each independently selected from hydrogen, fluorine, chlorine, C 1-4 An alkyl group;
Cy 3 selected from optionally substituted one or more R 3 Substituted by
Figure FDA0003656570280000034
R 3 Each independently selected from hydrogen, fluorine, chlorine, C 1-4 An alkyl group;
Cy 4 selected from optionally substituted one or more R 4 Substituted by
Figure FDA0003656570280000035
R 4 Each independently selected from hydrogen, halogen atom, C 1-4 Alkyl radical, C 1-4 An alkoxy group;
l is-O-;
R a is absent or, at each occurrence, is independently selected from hydrogen, C 1-4 Alkyl, halo C 1-6 An alkyl group;
R b is absent or, at each occurrence, is independently selected from hydrogen, C 1-4 An alkyl group.
5. The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, which is a compound selected from the following structures:
Figure FDA0003656570280000041
Figure FDA0003656570280000051
Figure FDA0003656570280000061
Figure FDA0003656570280000071
6. a pharmaceutical composition of a compound of any one of claims 1-5 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof.
7. The pharmaceutical composition of claim 6, further comprising one or more second active therapeutic agents that are antimetabolites, growth factor inhibitors, mitotic inhibitors, alkylating agents, metalloplatins, topoisomerase inhibitors, hormonal agents, immunomodulators, tumor suppressor genes, cancer vaccines or immune checkpoints.
8. The pharmaceutical composition of claim 7, further comprising one or more second active therapeutic agents that are anti-tumor hormones or antibodies or small molecule drugs associated with tumor immunotherapy.
9. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof and pharmaceutical composition according to claim 6, for the preparation of a medicament for the treatment and/or prevention of disorders related to abnormal signaling pathways, caused by abnormal expression of receptors of the TAM family and/or their ligands, including at least one of the following disorders: tumors, endometriosis, vascular disease/injury, psoriasis, visual defects/lesions, kidney disease, rheumatoid arthritis, osteoporosis.
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