Novel quinoline derivative inhibitor
阅读说明：本技术 一种新型的喹啉衍生物抑制剂 (Novel quinoline derivative inhibitor ) 是由 吴永谦 万中晖 于 2019-08-23 设计创作，主要内容包括：本发明提供一种新型的喹啉衍生物抑制剂,其具有下述通式(I)所示的结构,本发明的化合物可选择性抑制酪氨酸激酶TAM家族/和CSF1R激酶,可用于TAM家族激酶/和CSF1R激酶受体和/或其配体异常表达所介导的疾病治疗和/或预防,进而,本发明的化合物可以用于治疗和/或预防由NTRK引发的相关疾病,更具体而言,可以用于治疗和/或预防由NTRK突变产生的耐药型的相关疾病。<Image he="404" wi="700" file="DDA0002177777710000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention provides a novel quinoline derivative inhibitor which has a structure shown in the following general formula (I), can selectively inhibit tyrosine kinase TAM family and CSF1R kinase, and can be used for TAM family kinase and/or CSF1R kinase receptor and/or ligand abnormity table thereofTo the treatment and/or prevention of mediated diseases, the compounds of the present invention may be used for the treatment and/or prevention of related diseases caused by NTRK, and more specifically, may be used for the treatment and/or prevention of related diseases caused by drug-resistant forms of NTRK mutations.)
1. A compound represented by the general formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof:
wherein W is selected from hydrogen or C1-6An alkyl group;
r represents a group represented by the following general formula (a), (b) or (c):
in formula (a), ring A is selected from phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl;
q is independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6Alkoxy radicalThe radicals-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
q is an integer of 0 to 4;
in the formulae (a) and (b),
in the formula (c), the compound represented by the formula (c),
X1、X2、X3are each independently selected from CRa、C＝O、NRbO, and wherein at least one is C ═ O;
X4、X5each is independently selected from C or N;
M1、M2are respectively and independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro and-NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', or, M1And M2May form a 3-8 membered cycloalkyl group with the atom to which it is attached; or
Cy2selected from optionally substituted one or more R2Substituted 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl, R2Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Cy3selected from optionally substituted one or more R3Substituted 3-12 membered cycloalkyl, 3-14 membered heterocyclyl, 5-10 membered heteroaryl, R3Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl radicalHydroxy group C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (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 present1Or X2Represents NRbWhen is, Cy3May also be optionally substituted by more than one R3A substituted 6-14 membered aromatic group;
Cy4selected from optionally substituted one or more R4Substituted 3-14 membered heterocyclyl, 5-14 membered heteroaryl, R4Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl, or two R4May form a 5-6 membered cyclic group with the attached atom;
l is selectedfrom-NRb-、-O-、-S-、-(CRaRa)m-, m is an integer from 1 to 3;
Rais absent or, at each occurrence, is independently selected from hydrogen, cyano, hydroxy, halogen atom, carboxy, nitro, -NReRf、-C(O)Rg、-C(O)NReRf、-OC(O)NReRf、-NReC(O)ORg、-NReC(O)Rg、-SO2-NReRf、-SO2Rg、-NReSO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NReC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rb、Rcis absent, or, at each occurrence, is independently selected from hydrogen, hydroxy, -C (O) Rg、-C(O)NReRf、-SO2-NReRf、-SO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, -C1-6alkyl-R ', -C (O) -R', -SO2-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rdis absent or, at each occurrence, is independently selected from hydrogen, -NReRf、-NReC(O)ORg、-NReC(O)Rg、-NReSO2Rf、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R', -NReC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Re、Rfabsent or, at each occurrence, independently selected from hydrogen, hydroxy, carboxy, cyano, nitro, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, -C1-6alkyl-R ', -C (O) -R', -SO2-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rgis absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, -C1-6alkyl-R ', -C (O) -R', -SO2-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;
n is an integer of 0 to 4;
in the groups of formulae (b) and (c)
with the proviso that, in the groups of the formulae (a) and (c),
with the proviso that, in the group of formula (b), X1And X3Selected from C ═ O, X4When selected from N, as Cy2R of the substituent(s)2Does not represent a halogen atom.
2. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, having a structure represented by the following general formula (II),
wherein W is selected from hydrogen or C1-6An alkyl group;
X1、X2、X3are each independently selected from CRa、C＝O、NRbAnd wherein at least one is C ═ O;
X4、X5each is independently selected from C or N;
M1、M2are respectively and independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro and-NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radicals, or, M1And M2May form a 3-8 membered cycloalkyl group with the atom to which it is attached; or
Cy2selected from optionally substituted one or more R2Substituted 6-14 membered aryl, 5-10 membered heteroaryl, R2Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Cy3selected from optionally substituted one or more R3Substituted 3-8 membered cycloalkyl, 5-10 membered heteroaryl, R3Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (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 present1Or X2Represents NRbWhen is, Cy3May also be optionally substituted by more than one R3A substituted 6-14 membered aromatic group;
Cy4selected from optionally substituted one or more R4Substituted 9-10 membered heteroaryl, R4Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl, or two R4Can be combined withThe atoms to which they are attached form a 5-6 membered cyclic group;
l is selected from-NRb-、-O-、-S-；
RaIs absent or, at each occurrence, is independently selected from hydrogen, cyano, hydroxy, halogen atom, carboxy, nitro, -NReRf、-C(O)Rg、-C(O)NReRf、-OC(O)NReRf、-NReC(O)ORg、-NReC(O)Rg、-SO2-NReRf、-SO2Rg、-NReSO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NReC (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rb、Rcis absent, or, at each occurrence, is independently selected from hydrogen, hydroxy, -C (O) Rg、-C(O)NReRf、-SO2-NReRf、-SO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, -C1-6alkyl-R ', -C (O) -R', -SO2-R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rdis absent or, at each occurrence, is independently selected from hydrogen, -NReRf、-NReC(O)ORg、-NReC(O)Rg、-NReSO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R', -NReC (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Re、Rfabsent or, at each occurrence, independently selected from hydrogen, hydroxy, carboxy, cyano, nitro, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, -C1-6alkyl-R ', -C (O) -R', -SO2-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rgis absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, -C1-6alkyl-R ', -C (O) -R', -SO2-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;
n is an integer of 0 to 3;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is C ═ O, X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is CRa；
Preferably, X1Is CRa，X2Is C ═ O, X3Is CRa；
provided that X is1And X3Selected from C ═ O, X4When selected from N, as Cy2R of the substituent(s)2Does not represent a halogen atom.
3. The compound of claim 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein, X1、X2、X3Are each independently selected from CRa、C＝O、NRbAnd wherein at least one is C ═ O;
X4selected from C or N, X5Is selected from C;
M1、M2are respectively and independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitryl and-NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, orThen, M1And M2May form a 3-8 membered cycloalkyl group with the atom to which it is attached; or
Cy2selected from optionally substituted one or more R2Substituted phenyl, 5-6 membered heteroaryl, R2Each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
Cy3selected from optionally substituted one or more R3Substituted 5-6 membered heteroaryl, 3-6 membered cycloalkyl, R3Each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
Cy4selected from optionally substituted one or more R4Substituted 9-10 membered heteroaryl, R4Each independently selected from hydrogen, hydroxyl, halogen atom, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, 3-14 membered heterocyclyl, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-NRb-、-O-、-S-；
RaIs absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, halo C1-6An alkyl group;
Rb、Rcis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
Rdis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
n is an integer of 0 to 2;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is CRa；
Preferably, X1Is CRa，X2Is C ═ O, X3Is CRa；
Preferably, Cy is3Is composed of
4. The compound of claim 3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
X1、X2、X3are each independently selected from CRa、C＝O、NRbAnd wherein at least one is C ═ O;
X4is selected from the group consisting of C or N,X5is selected from C;
Cy2selected from optionally substituted one or more R2Substituted phenyl, 5-6 membered heteroaryl;
Cy3denotes an optionally substituted one or more R3Substituted by
Y2、Y3、Y6And Y7Each independently selected from CH or N, and at least one is N;
Cy4selected from optionally substituted one or more R4Substituted by
M1、M2each independently selected from: hydrogen, hydroxy, halogen atoms, carboxy, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, or, M1And M2May form a 3-6 membered cycloalkyl group with the atom to which it is attached; or
R2each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R3each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R4each independently selected from hydrogen, hydroxyl, halogen atom, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, 3-14 membered heterocyclyl, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-NRb-、-O-、-S-；
RaIs absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, halo C1-6An alkyl group;
Rb、Rcis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
Rdis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
n is an integer of 0 to 2;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is CRa；
Preferably, X1Is CRa，X2Is C ═ O, X3Is CRa。
5. The compound of claim 4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, having the structure of formula (III),
wherein, X1、X2、X3Are each independently selected from CRa、C＝O、NRbAnd wherein at least one is C ═ O;
Cy2selected from phenyl, 5-6 membered heteroaryl;
Y2and Y3Each independently selected from CH or N, and at least one is N;
Cy4is selected from
M1、M2each independently selected from: hydrogen, hydroxy, halogen atoms, carboxy, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, or, M1And M2May form a 3-6 membered cycloalkyl group with the atom to which it is attached; or
R2each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group; preferably, the halogen atom is a fluorine atom;
R3each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R4each independently selected from hydrogen, hydroxyl, halogen atom, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, 3-14 membered heterocyclyl, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-NRb-、-O-、-S-；
RaIs absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, halo C1-6An alkyl group;
Rb、Rcis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
Rdis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
n is an integer of 0 to 2;
t2、t3、t4each independently selected from an integer of 1 to 5;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O.
6. The compound of claim 4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, having a structure according to formula (IV),
wherein, X1、X2、X3Are each independently selected from CRa、C＝O、NRbAnd wherein at least one is C ═ O;
Cy2selected from phenyl, 5-6 membered heteroaryl;
Y6and Y7Each independently selected from CH or N, and at least one is N;
Cy4is selected from
M1、M2each independently selected from: hydrogen, hydroxy, halogen atoms, carboxy, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, or, M1And M2May form a 3-6 membered cycloalkyl group with the atom to which it is attached; or
R2each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group; preferably, the halogen atom is a fluorine atom;
R3each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R4each independently selected from hydrogen, hydroxyl, halogen atom, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, 3-14 membered heterocyclyl, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-NRb-、-O-、-S-；
RaIs absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, halo C1-6An alkyl group;
Rb、Rcis absent, or is present at each timeAt each occurrence, independently selected from hydrogen, C1-6An alkyl group;
Rdis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
n is an integer of 0 to 2;
t2、t3、t4each independently selected from an integer of 1 to 5;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O.
7. The compound of claim 4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein R represents a group represented by the following formula,
X1、X2、X3are each independently selected from CRa、C＝O、NRbAnd wherein at least one is C ═ O;
Cy2selected from optionally substituted one or more R2Substituted phenyl, 5-6 membered heteroaryl;
Cy3denotes an optionally substituted one or more R3Substituted by
Y2、Y3、Y6And Y7Each independently selected from CH or N, and at least one is N;
Cy4selected from optionally substituted one or more R4Substituted by
M1、M2each independently selected from: hydrogen, hydroxy, halogen atoms, carboxy, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, or, M1And M2May form a 3-6 membered cycloalkyl group with the atom to which it is attached; or
R2each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R3each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R4each independently selected from hydrogen, hydroxyl, halogen atom, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, 3-14 membered heterocyclyl, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-NRb-、-O-、-S-；
RaIs absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, halo C1-6An alkyl group;
Rb、Rcis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
Rdis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
n is an integer of 0 to 2;
provided that X is1And X3When selected from C ═ O, as Cy2R of the substituent(s)2Does not represent a halogen atom;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is CRa；
Preferably, X1Is CRa，X2Is C ═ O, X3Is CRa。
8. The compound of claim 7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein, X1、X2Are each independently selected from CRaOr NRb，X3Is C ═ O;
Cy2selected from optionally substituted one or more R2Substituted phenyl;
Cy3denotes an optionally substituted one or more R3Substituted by
Y2And Y3Independently selected from CH or N, and at least one is N, Y6And Y7Each is independently selected from CH or N;
Cy4selected from optionally substituted one or more R4Substituted by
M1、M2Are respectively and independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitryl and-NRbRc、C1-6Alkyl, or, M1And M2May form a 3-6 membered cycloalkyl group with the atom to which it is attached; orMoieties may be formed as hydrogen atoms;
R2each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R3each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R4each independently selected from hydrogen, hydroxyl, halogen atom, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, 3-14 membered heterocyclyl, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-NRb-、-O-、-S-；
RaIs absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, halo C1-6An alkyl group;
Rb、Rcis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
Rdis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
n is an integer of 0 to 1;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O.
9. A compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein W is selected from hydrogen;
X1、X2are each independently selected from CRaOr NRb，X3Is C ═ O;
X4selected from CH or N;
M1、M2each independently selected from: hydrogen, hydroxy, halogen atom, nitro, C1-4Alkyl, or, M1And M2May form a 3-6 membered cycloalkyl group with the atom to which it is attached; orMoieties may be formed as hydrogen atoms;
Cy2selected from optionally substituted one or more R2Substituted by
Cy3selected from optionally substituted one or more R3Substituted by
Cy4selected from optionally substituted one or more R4Substituted by
R4Each independently selected from hydrogen, hydroxyl, halogen atom, C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, 3-14 membered heterocyclyl, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is-O-;
Rais absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, halo C1-6An alkyl group;
Rbis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
n is an integer of 0 to 1;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O.
10. The compound of claim 9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein W is selected from hydrogen;
X1、X2selected from the group consisting of CRaOr NRb，X3Is C ═ O;
X4is selected from C;
M1、M2each independently selected from hydrogen, hydroxy, C1-4Alkyl, or, M1And M2May form a 3-6 membered cycloalkyl group with the atom to which it is attached; or
Cy2selected from optionally substituted one or more R2Substituted by
Cy3selected from optionally substituted one or more R3Substituted by
Cy4selected from optionally substituted one or more R4Substituted by
l is-O-;
Rais absent or, at each occurrence, is independently selected from hydrogen, C1-4Alkyl, halo C1-6An alkyl group;
Rbis absent or, at each occurrence, is independently selected from hydrogen, C1-4An alkyl group;
n is an integer of 0 to 1;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O.
11. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, which is a compound selected from the following structures:
12. a pharmaceutical composition of a compound of any one of claims 1-11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof.
13. The pharmaceutical composition of claim 12, further comprising one or more second therapeutically active agents that are antimetabolites, growth factor inhibitors, inhibitors of the filamentation class, antitumor hormones, alkylating agents, metals, topoisomerase inhibitors, hormonal drugs, immunomodulators, tumor suppressor genes, cancer vaccines, immune checkpoints, or antibodies or small molecule drugs associated with tumor immunotherapy.
14. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof and pharmaceutical composition according to claim 12, for the preparation of a medicament for the treatment and/or prevention of diseases associated with abnormal signalling pathways, caused by abnormal expression of TAM family receptors and/or their ligands, including tumors, endometriosis, vascular diseases/injuries, psoriasis, visual defects/lesions, kidney diseases, rheumatoid arthritis, osteoporosis.
15. Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof and a pharmaceutical composition according to claim 12 for the manufacture of a medicament for the treatment and/or prophylaxis of disorders associated with abnormal signalling pathways resulting from abnormal expression of the TAM family kinase/CSF 1R kinase receptor and/or its ligand, including tumours, endometriosis, vascular disease/damage, psoriasis, visual deficits/pathologies, renal diseases, rheumatoid arthritis, osteoporosis.
16. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof and pharmaceutical composition according to claim 12, for the manufacture of a medicament for the treatment and/or prevention of a related disease caused by NTRK, preferably for the treatment or prevention of a related disease caused by a drug-resistant form resulting from a mutation in NTRK.
17. A process for the preparation of a compound of the general formula (I), wherein
Adding the formula (I-a) into a solvent, adding a peptide coupling reagent and alkali, and reacting with the formula (I-b) to obtain a compound shown in the formula (I); alternatively, the first and second electrodes may be,
adding the formula (I-a) and the formula (I-b) into alkali, dropwise adding a coupling reagent, reacting to obtain a compound shown in the formula (I),
wherein M is1、M2、R、n、W、Cy3L and Cy4As defined in claims 1-10.
18. The method of claim 17, wherein the step of selecting the target,
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 or a mixture of methylamine, ethylamine, propylamine, N-diisopropylethylamine, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline and quinoline;
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.
19. The preparation intermediate of the compound of the general formula (I) has a structure shown as the following formula (I-a) or formula (I-c):
wherein R is1Is C1-6An alkyl group, a carboxyl group,
X1、X2、X3、X4、X5、M1、M2、R、Cy2n andas defined in claims 1-10.
Technical Field
The invention belongs to the field of medicines, and particularly relates to a TAM family kinase/CSF 1R 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 tyrosine kinase TAM family and/or CSF1R kinase, and can be used for treating and/or preventing diseases mediated by abnormal expression of TAM family kinase and/or CSF1R kinase receptor and/or ligand thereof. Furthermore, the compounds of the present invention may be used for the treatment and/or prevention of related diseases caused by NTRK, more specifically, for the treatment and/or prevention of related diseases caused by drug-resistant forms of NTRK mutations.
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 and thick like protein Tubby, recombinant human short and thick like protein 1(Tulp1), galactose agglutinin-3 (galectin-3) and other related receptors (Wuyangjun, J.Xin.Med., 2016; Lemna, J.practical diagnosis and treatment of China, 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 by taking the protein as a target also proves that the effect of inhibiting Axl on delaying the drug resistance and tumor metastasis of an EGFR inhibitor (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.
Colony Stimulating Factor 1 receptors (CSF1R, Colony Stimulating Factor 1Receptor), otherwise known as c-FMS, FIM2, MCSF and CD115, are single-chain transmembrane glycoproteins consisting of 972 amino acid residues, which belong to the type III Receptor Tyrosine Kinase (RTK) family with FLT-3, PDGFR and KIT. CSF1R is expressed only on the surface of monocytes, such as macrophages. The CSF1R ligands reported so far include colony stimulating factor 1(CSF1, male collagen-stimulating factor, also known as M-CSF) and Interleukin-34 (IL-34, Interleukin-34). CSF1 affects various cellular functions of monocyte by combining with CSF1R, IL-34 can firmly bind CSF1R to promote survival, proliferation and differentiation of monocyte. They constitute the CSF1/IL-34/CSF1R pathway.
In the CSF1/CSF1R pathway, CSF1 and CSF1R form a signal axis to promote the growth of macrophages in the body and regulate the normal development and homeostasis of tissues and organs, and the imbalance of the homeostasis of the body can cause various diseases such as inflammation, immune system diseases, tumors and the like. Although macrophages have the potential to kill tumor cells, macrophages in tumor tissue infiltration areas (TAMs) exert more immunosuppressive effects. Especially myeloid-derived suppressor cells (MDSCs), can promote macrophages to selectively ignore the existence of tumor cells by highly expressing CSF1R, thereby further promoting the development and metastasis of tumors. Increased CSF1/CSF1R expression has been found in a variety of tumors including breast, ovarian, colorectal, prostate, lung, and hodgkin lymphoma (O' Brien J, Am J Pathol, 2010). Overexpressed CSF1/CSF1R was associated with tumor malignancy aggressiveness and poor prognosis. The CSF1R high expression can be detected in fibroblasts and epithelial cells induced by CSF1, and finally tumors are formed in nude mice, which shows that the CSF1/CSF1R axis promotes the proliferation and survival of tumor cells and plays an important role in the generation and development of tumors. Furthermore, CSF1R plays a role in osteolytic bone destruction in bone metastasis (Ohno, mol. Therefore, the CSF1/IL-34/CSF1R signal channel is inhibited, the immunosuppression effect of the tumor can be relieved, the activity of an immune system is improved, and the development and the metastasis of the tumor are inhibited; meanwhile, CSF1R inhibitors have been reported to significantly reduce tumor volume, such as glioblastoma, and reduce tumor invasiveness and proliferation (Pyonteck Stephanie M, Nature Medicine, 2013). Taken together, inhibition of the CFS1R pathway has become one of the major therapeutic targets for cancer.
Both TAM and CSF1R inhibitors can improve the immunosuppressive environment of tumors, enhance the ability of the immune system to kill tumor cells, but based on the complexity of tumor pathogenesis, if both targets can be targeted simultaneously, they can exert their dual effects on tumor immunotherapy. At present, the CSF1R inhibitor is more clinically combined with PD-1, and no inhibitor which simultaneously targets TAM/CSF 1R is on the market.
The NTRK genes include NTRK1, NTRK2, and NTRK3, which are responsible for the synthesis of Tropomyosin-receptor-kinase (TRK) family proteins, TRKA, TRKB, and TRKC, respectively. Gene expression studies have shown that the NTRK gene is expressed primarily in the nervous system, with it being expressed both during embryonic development and in adults. When activated by signal induction, TRK is able to autophosphorylate and activate downstream signaling pathways to perform various physiological functions. Downstream signal molecules of TRK include SHC, FRS2, PLC gamma, MAPK, PI3K, PKC and the like, most of the signal molecules are closely related to functions of energy exchange, survival, proliferation and the like of cells, and if TRK is dysfunctional, physiological functions of the cells can be out of control, and even become cancer cells. Thus, when a chromosomal variation undergoes NTRK gene fusion, the TRK fusion protein will be in a persistently active state, triggering a permanent cascade of downstream signaling pathways, driving the spread and growth of TRK-fused tumors (Yekaterina b. khotskaya, Pharmacology & Therapeutics, 2017).
NTRK gene fusion can occur anywhere in the body and is found in a variety of solid tumors in adults and children, including breast analog secreting carcinomas (MASCs), colon carcinomas, lung carcinomas, pancreatic carcinomas, thyroid carcinomas, and various sarcomas. NTRK fusion occurs with low frequency, not enough 5%, in common cancer types such as colon and lung cancer; however, there is a very high mutation rate in some rare cancer types, such as congenital renal tumor, infantile sarcoma, salivary gland cancer, and secretory breast cancer, and the frequency of individual cancer types is more than 90% (journal of clinical medicine, vol. 15, 12 th in 2017). Therefore, the development of the NTRK inhibitor has great clinical value.
Although the first generation of NTRK inhibitors such as larotectonib, entrectonib, etc. for NTRK gene fusion are available at present, TKI (tyrosine kinase inhibitor) therapy targeting NTRK also faces the problem of acquired resistance. TRKs which have been found in some patients treated with TRK inhibitors to date have mutations at kinase sites, such as NTRK1-LMNA-G667C, NTRK1-LMNA-V573M, etc., which result in secondary resistance in cancer cells, including colon cancer, MASC, etc. (Mariangla Russo, American Association for cancer research, 2015; A.Drilon, antibodies of Oncology, 2016). These emerging mutations can render the first generation NTRK inhibitors entrecteinb and larotecteinb unable to bind kinases, thereby rendering the drug ineffective. Thus, acquired resistance to first-generation NTRK inhibitor therapy is a continuing challenge, and second-generation NTRK inhibitors are urgently needed to address some of the resistance issues.
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. In addition, the compound of the invention can also target CSF1R kinase and has an inhibitory effect on CSF1R kinase. 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. In addition, the compounds of the present invention are useful for the treatment and/or prevention of diseases mediated by aberrant expression of TAM family kinase/CSF 1R kinase receptors and/or their ligands. The compound reverses immunosuppression in a tumor microenvironment by inhibiting TAM family kinase/CSF 1R kinase, inhibits growth, migration and/or drug resistance expression of tumors, and exerts tumor immune effect and anti-tumor curative effect. In addition, the compound can treat and/or prevent related diseases caused by NTRK, especially related diseases caused by NTRK mutation and drug-resistant type.
Specifically, 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:
wherein W is selected from hydrogen or C1-6An alkyl group;
r represents a group represented by the following general formula (a), (b) or (c):
in formula (a), ring A is selected from phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl;
q is independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
q is an integer of 0 to 4;
in the formulae (a) and (b),
in the formula (c), the compound represented by the formula (c),
X1、X2、X3are each independently selected from CRa、C＝O、NRbO, and wherein at least one is C ═ O;
X4、X5each is independently selected from C or N;
M1、M2are respectively and independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro and-NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', or, M1And M2May form a 3-8 membered cycloalkyl group with the atom to which it is attached; or
Cy2selected from optionally substituted one or more R2Substituted 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl, R2Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Cy3selected from optionally substituted one or more R3Substituted 3-12 membered cycloalkyl, 3-14 membered heterocyclyl, 5-10 membered heteroaryl, R3Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical、C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (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 present1Or X2Represents NRbWhen is, Cy3May also be optionally substituted by more than one R3A substituted 6-14 membered aromatic group;
Cy4selected from optionally substituted one or more R4Substituted 3-14 membered heterocyclyl, 5-14 membered heteroaryl, R4Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl, or two R4May form a 5-6 membered cyclic group with the attached atom;
l is selected from-NRb-、-O-、-S-、-(CRaRa)m-, m is selected fromAn integer from 1 to 3;
Rais absent or, at each occurrence, is independently selected from hydrogen, cyano, hydroxy, halogen atom, carboxy, nitro, -NReRf、-C(O)Rg、-C(O)NReRf、-OC(O)NReRf、-NReC(O)ORg、-NReC(O)Rg、-SO2-NReRf、-SO2Rg、-NReSO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NReC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rb、Rcis absent, or, at each occurrence, is independently selected from hydrogen, hydroxy, -C (O) Rg、-C(O)NReRf、-SO2-NReRf、-SO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, -C1-6alkyl-R ', -C (O) -R', -SO2-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rdis absent or, at each occurrence, is independently selected from hydrogen, -NReRf、-NReC(O)ORg、-NReC(O)Rg、-NReSO2Rf、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R', -NReC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Re、Rfabsent or, at each occurrence, independently selected from hydrogen, hydroxy, carboxy, cyano, nitro, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rgis absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, 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;
n is an integer of 0 to 4,
in the groups of formulae (b) and (c)
with the proviso that, in the groups of the formulae (a) and (c),
with the proviso that, in the group of formula (b), X1And X3Selected from C ═ O, X4When selected from N, as Cy2R of the substituent(s)2Does not represent a halogen atom.
In another embodiment, in the compound of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein W is selected from hydrogen or C1-6An alkyl group;
r represents a group represented by the following formula (a), (b-1), (b-2) or (c):
in formula (a), ring A is selected from phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl;
q is independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
q is an integer of 0 to 4;
in the formulae (a), (b-1), (b-2),moiety through a linking group to M1And M2Group attachment;
in the formula (c), the compound represented by the formula (c),
X1、X2、X3are each independently selected from CRa、C＝O、NRbO, and wherein at least one is C ═ O;
M1、M2are respectively and independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro and-NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R'; or M1And M2May form a 3-8 membered cycloalkyl group with the atom to which it is attached; or
Cy2selected from optionally substituted one or more R2Substituted 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl, R2Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Cy3selected from optionally substituted one or more R3Substituted 3-12 membered cycloalkyl, 3-14 membered heterocyclyl, 5-10 membered heteroaryl, R3Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (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 present1Or X2Represents NRbWhen is, Cy3May also be optionally substituted by more than one R3A substituted 6-14 membered aromatic group;
Cy4selected from optionally substituted one or more R4Substituted 3-14 membered heterocyclyl, 5-14 membered heteroaryl, R4Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl, or two R4May form a 5-6 membered cyclic group with the attached atom;
l is selected from-NRb-、-O-、-S-、-(CRaRa)m-, m is an integer from 1 to 3;
Raat each occurrence, is independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NReRf、-C(O)Rg、-C(O)NReRf、-OC(O)NReRf、-NReC(O)ORg、-NReC(O)Rg、-SO2-NReRf、-SO2Rg、-NReSO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NReC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rb、Rcat each occurrence, each is independently selected from hydrogen, hydroxy, -C (O) Rg、-C(O)NReRf、-SO2-NReRf、-SO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, -C1-6alkyl-R ', -C (O) -R', -SO2-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rdat each occurrence, each is independently selected from hydrogen, -NReRf、-NReC(O)ORg、-NReC(O)Rg、-NReSO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R', -NReC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Re、Rfabsent or, at each occurrence, independently selected from hydrogen, hydroxy, carboxy, cyano, nitro, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rgis absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, 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;
n is an integer of 0 to 4,
in the group represented by the formula (b), the formula (b-1) or the formula (b-2)
with the proviso that, in the groups of the formulae (a) and (c),part of it is not formed as a hydrogen atom,
in the group of formula (b), X1And X3Selected from C ═ O, X4When selected from N, as Cy2R of the substituent(s)2Does not represent a halogen atom, and does not represent,
in the group represented by the formula (b-1), X1And X3When selected from C ═ O, as Cy2R of the substituent(s)2Does not represent a halogen atom.
In another preferred embodiment, in the compound represented by the above formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein W is selected from hydrogen or C1-6An alkyl group;
r represents a group represented by the following formula (a), (b-1) or (b-2):
in formula (a), ring A is selected from phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl;
q is independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radicalBase, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
q is an integer of 0 to 4;
in the formulae (a), (b-1), (b-2),
M1、M2are respectively and independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro and-NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', or, M1And M2May form a 3-8 membered cycloalkyl group with the atom to which it is attached; or
Cy2selected from optionally substituted one or more R2Substituted 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-10 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl, R2Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Cy3selected from optionally substituted one or more R3Substituted 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl, R3Each independently selected from hydrogen, cyano, hydroxy, halogen, carboxy, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radicalRadical, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (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 present1Or X2Represents NRbWhen is, Cy3May also be optionally substituted by more than one R3A substituted 6-14 membered aromatic group;
Cy4selected from optionally substituted one or more R4Substituted 3-10 membered heterocyclyl, 5-10 membered heteroaryl, R4Each independently selected from hydrogen, cyano, hydroxy, halogen, carboxy, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl, or two R4May form a 5-6 membered cyclic group with the attached atom;
l is selected from-NRb-、-O-、-S-；
RaIs absent or, at each occurrence, is independently selected from hydrogen, cyano, hydroxy, halogen atom, carboxy, nitro、-NReRf、-C(O)Re、-C(O)NReRf、-OC(O)NReRf、-NReC(O)ORf、-NReC(O)Rf、-SO2-NReRf、-SO2Rg、-NReSO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NReC (O) -R', 3-8 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rb、Rcis absent, or, at each occurrence, is independently selected from hydrogen, hydroxy, -C (O) Rg、-C(O)NReRf、-SO2-NReRf、-SO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, -C1-6alkyl-R ', -C (O) -R', -SO2-R', 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rdis absent or, at each occurrence, is independently selected from hydrogen, -NReRf、-NReC(O)ORg、-NReC(O)Rg、-NReSO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, aryl, heteroaryl, and heteroaryl,Halogen substituted C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R', -NReC (O) -R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Re、Rfabsent or, at each occurrence, independently selected from hydrogen, hydroxy, carboxy, cyano, nitro, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, -C1-6alkyl-R ', -C (O) -R', -SO2-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rgis absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, -C1-6alkyl-R ', -C (O) -R', -SO2-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, 3-10 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
n is an integer of 0 to 4,
in the groups represented by the formulae (b-1) and (b-2)
with the proviso that, in the group of formula (b-1), X1And X3When selected from C ═ O, as Cy2R of the substituent(s)2Does not represent a halogen atom, and does not represent,
in the group of formula (a),
In another preferred embodiment, the compound represented by the formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof has a structure represented by the general formula (II),
wherein W is selected from hydrogen or C1-6An alkyl group;
X1、X2、X3are each independently selected from CRa、C＝O、NRbAnd wherein at least one is C ═ O;
X4、X5each is independently selected from C or N;
M1、M2are respectively and independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro and-NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radicals, or, M1And M2May form a 3-8 membered cycloalkyl group with the atom to which it is attached; or
Cy2selected from optionally substituted one or more R2Substituted 6-14 membered aryl, 5-10 membered heteroaryl, R2Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Cy3selected from optionally substituted one or more R3Substituted 3-8 membered cycloalkyl, 5-10 membered heteroaryl, R3Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (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 present1Or X2Represents NRbWhen is, Cy3May also be optionally substituted by more than one R3A substituted 6-14 membered aromatic group;
Cy4selected from optionally substituted one or more R4Substituted 9-10 membered heteroaryl, R4Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl, or two R4May form a 5-6 membered cyclic group with the attached atom;
l is selected from-NRb-、-O-、-S-；
RaIs absent or, at each occurrence, is independently selected from hydrogen, cyano, hydroxy, halogen atom, carboxy, nitro, -NReRf、-C(O)Rg、-C(O)NReRf、-OC(O)NReRf、-NReC(O)ORg、-NReC(O)Rg、-SO2-NReRf、-SO2Rg、-NReSO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NReC (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rb、Rcis absent, or, at each occurrence, is independently selected from hydrogen, hydroxy, -C (O) Rg、-C(O)NReRf、-SO2-NReRf、-SO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, -C1-6alkyl-R ', -C (O) -R', -SO2-R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rdis absent or, at each occurrence, is independently selected from hydrogen, -NReRf、-NReC(O)ORf、-NReC(O)Rg、-NReSO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R', -NReC (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Re、Rfabsent or, at each occurrence, independently selected from hydrogen, hydroxy, carboxy, cyano, nitro, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, -C1-6alkyl-R ', -C (O) -R', -SO2-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rgis absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, -C1-6alkyl-R ', -C (O) -R', -SO2-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;
n is an integer of 0 to 3;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is C ═O；
Preferably, X1Is CRa，X2Is C ═ O, X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is CRa；
Preferably, X1Is CRa，X2Is C ═ O, X3Is CRa，
provided that X is1And X3Selected from C ═ O, X4When selected from N, as Cy2R of the substituent(s)2Does not represent a halogen atom.
In another preferred embodiment, the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof has a structure represented by formula (II),
wherein W is selected from hydrogen or C1-6An alkyl group;
X1、X2、X3are each independently selected from CRa、C＝O、NRbAnd wherein at least one is C ═ O;
M1、M2are respectively and independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro and-NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radicals, or, M1And M2May form a 3-8 membered cycloalkyl group with the atom to which it is attached; or
Cy2selected from optionally substituted one or more R2Substituted 6-14 membered aryl, 5-10 membered heteroaryl, R2Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Cy3selected from optionally substituted one or more R3Substituted 3-8 membered cycloalkyl, 5-10 membered heteroaryl, R3Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (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 present1Or X2Represents NRbWhen is, Cy3May also be optionally substituted by more than one R3A substituted 6-14 membered aromatic group;
Cy4selected from optionally substituted one or more R4Substituted 9-10 membered heteroaryl, R4Each independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)ORd、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2Rd、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenylA 3-14 membered heterocyclyl, a 6-14 membered aryl, a 5-10 membered heteroaryl, or two R4May form a 5-6 membered cyclic group with the attached atom;
l is selected from-NRb-、-O-、-S-；
RaAt each occurrence, is independently selected from hydrogen, cyano, hydroxyl, halogen atom, carboxyl, nitro, -NReRf、-C(O)Rg、-C(O)NReRf、-OC(O)NReRf、-NReC(O)ORg、-NReC(O)Rg、-SO2-NReRf、-SO2Rg、-NReSO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy radical, C2-8Alkenyl radical, C2-8Alkynyl, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NReC (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rb、Rcat each occurrence, each is independently selected from hydrogen, hydroxy, -C (O) Rg、-C(O)NReRf、-SO2-NReRf、-SO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, -C1-6alkyl-R ', -C (O) -R', -SO2-R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rdat each occurrence, independently selectedFrom hydrogen, -NReRf、-NReC(O)ORg、-NReC(O)Rg、-NReSO2Rg、C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, -C1-6alkyl-R', -C1-6alkoxy-R ', -O-R', -NReC (O) -R', 3-8 membered cycloalkyl, 3-8 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Re、Rfabsent or, at each occurrence, independently selected from hydrogen, hydroxy, carboxy, cyano, nitro, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, -C1-6alkyl-R ', -C (O) -R', -SO2-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
Rgis absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, hydroxy C1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, -C1-6alkyl-R ', -C (O) -R', -SO2-R', 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-14 membered heterocyclyl, 6-14 membered aryl, 5-10 membered heteroaryl;
n is an integer of 0 to 3;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is C ═ O, X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is CRa；
Preferably, X1Is CRa，X2Is C ═ O, X3Is CRa，
provided that X is1And X3Selected from C ═ O, X4When selected from N, as Cy2R of the substituent(s)2Does not represent a halogen atom.
In another preferred embodiment, in the compound represented by the above formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein, X1、X2、X3Are each independently selected from CRa、C＝O、NRbAnd wherein at least one is C ═ O;
X4selected from C or N, X5Is selected from C;
M1、M2are respectively and independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitryl and-NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, or, M1And M2Can form a 3-8 membered cycloalkyl with the atom to which it is attachedA group; or
Cy2selected from optionally substituted one or more R2Substituted phenyl, 5-6 membered heteroaryl, R2Each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
Cy3selected from optionally substituted one or more R3Substituted 5-6 membered heteroaryl, 3-6 membered cycloalkyl, R3Each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
Cy4selected from optionally substituted one or more R4Substituted 9-10 membered heteroaryl, R4Each independently selected from hydrogen, hydroxyl, halogen atom, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, 3-14 membered heterocyclyl, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-NRb-、-O-、-S-；
RaAbsent, or at each occurrence,each independently selected from hydrogen and C1-6Alkyl, halo C1-6An alkyl group;
Rb、Rcis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
Rdis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
n is an integer of 0 to 2;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is CRa；
Preferably, X1Is CRa，X2Is C ═ O, X3Is CRa；
Preferably, Cy is3Is composed of
In another preferred embodiment, in the compound represented by the above formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
X1、X2、X3are each independently selected from CRa、C＝O、NRbAnd wherein at least one is C ═ O;
X4selected from C or N, X5Is selected from C;
Cy2is selected from optionally one toPlural R2Substituted phenyl, 5-6 membered heteroaryl;
Cy3denotes an optionally substituted one or more R3Substituted by
Y2、Y3、Y6And Y7Each independently selected from CH or N, and at least one is N;
Cy4selected from optionally substituted one or more R4Substituted by
M1、M2each independently selected from: hydrogen, hydroxy, halogen atoms, carboxy, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, or, M1And M2May form a 3-6 membered cycloalkyl group with the atom to which it is attached; or
R2each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R3each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl radicalHalogen substituted C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R4each independently selected from hydrogen, hydroxyl, halogen atom, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, 3-14 membered heterocyclyl, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-NRb-、-O-、-S-；
RaIs absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, halo C1-6An alkyl group;
Rb、Rcis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
Rdis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
n is an integer of 0 to 2;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is CRa；
Preferably, X1Is CRa，X2Is C ═ O, X3Is CRa。
In another preferred embodiment, the compound represented by the formula (I) or the formula (II) or the pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof has the structure represented by the general formula (III),
wherein, X1、X2、X3Are each independently selected from CRa、C＝O、NRbAnd wherein at least one is C ═ O;
Cy2selected from phenyl, 5-6 membered heteroaryl;
Y2and Y3Independently selected from CH or N, and at least one is N;
Cy4is selected fromY4And Y5Independently selected from CH or N, and at least one is N, ring B is phenyl or 5-6 membered heteroaryl;
M1、M2are respectively and independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitryl and-NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, or, M1And M2May form a 3-6 membered cycloalkyl group with the atom to which it is attached; or
R2each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R3each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R4each independently selected from hydrogen, hydroxyl, halogen atom, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, 3-14 membered heterocyclyl, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-NRb-、-O-、-S-；
RaIs absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, halo C1-6An alkyl group;
Rb、Rcis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
Rdis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
n is an integer of 0 to 2;
t2、t3、t4each independently selected from an integer of 1 to 5;
provided that X is1And X3Selected from C ═ O, asCy2R of the substituent(s)2Does not represent a halogen atom;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is CRa；
Preferably, X1Is CRa，X2Is C ═ O, X3Is CRa。
In another preferred embodiment, the compound represented by the formula (I) or the formula (II) or the pharmaceutically acceptable salt, ester, stereoisomer or tautomer thereof has a structure represented by the general formula (IV),
wherein, X1、X2、X3Are each independently selected from CRa、C＝O、NRbAnd wherein at least one is C ═ O;
Cy2selected from phenyl, 5-6 membered heteroaryl;
Y6and Y7Each independently selected from CH or N, and at least one is N;
Cy4is selected from
M1、M2each independently selected from: hydrogen, hydroxyl, halogen atom, carboxyl, nitro,-NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, or, M1And M2May form a 3-6 membered cycloalkyl group with the atom to which it is attached; orMoieties may be formed as hydrogen atoms;
R2each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R3each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R4each independently selected from hydrogen, hydroxyl, halogen atom, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, 3-14 membered heterocyclyl, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-NRb-、-O-、-S-；
RaIs absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, halo C1-6An alkyl group;
Rb、Rcis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
Rdis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
n is an integer of 0 to 2;
t2、t3、t4each independently selected from an integer of 1 to 5;
provided that X is1And X3When selected from C ═ O, as Cy2R of the substituent(s)2Does not represent a halogen atom;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is CRa；
Preferably, X1Is CRa，X2Is C ═ O, X3Is CRa。
In another preferred embodiment, in the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein R represents a group represented by the following formula,
X1、X2、X3are each independently selected from CRa、C＝O、NRbAnd wherein at least one is C ═ O;
Cy2selected from optionally substituted one or more R2Substituted phenyl, 5-6 membered heteroaryl;
Cy3denotes an optionally substituted one or more R3Substituted by
Y2、Y3、Y6And Y7Each independently selected from CH or N, and at least one is N;
Cy4selected from optionally substituted one or more R4Substituted by
M1、M2each independently selected from: hydrogen, hydroxy, halogen atoms, carboxy, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, or, M1And M2May form a 3-6 membered cycloalkyl group with the atom to which it is attached; or
R2each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R3each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R4each independently selected from hydrogen, hydroxyl, halogen atom, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, 3-14 membered heterocyclyl, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-NRb-、-O-、-S-；
RaIs absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, halo C1-6An alkyl group;
Rb、Rcis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
Rdis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
n is an integer of 0 to 2;
t2、t3、t4each independently selected from an integer of 1 to 5;
provided that X is1And X3When selected from C ═ O, as Cy2R of the substituent(s)2Does not represent a halogen atom;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is CRa；
Preferably, X1Is CRa，X2Is C ═ O, X3Is CRa。
In another preferred embodiment, in the compound represented by formula (I) or formula (II) or formula (III) or formula (IV) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein, X1、X2Are each independently selected from CRaOr NRb，X3Is C ═ O;
Cy2selected from optionally substituted one or more R2Substituted phenyl;
Cy3denotes an optionally substituted one or more R3Substituted by
Y2And Y3Independently selected from CH or N, and at least one is N, Y6And Y7Each is independently selected from CH or N;
Cy4selected from optionally substituted one or more R4Substituted by
M1、M2Are respectively and independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitryl and-NRbRc、C1-6Alkyl, or, M1And M2May form a 3-6 membered cycloalkyl group with the atom to which it is attached; or
R2each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R3each independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
R4each independently selected from hydrogen, hydroxyl, halogen atom, nitro, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, 3-14 membered heterocyclyl, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-NRb-、-O-、-S-；
RaIs absent or is present inAt each occurrence, each is independently selected from hydrogen, C1-6Alkyl, halo C1-6An alkyl group;
Rb、Rcis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
Rdis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
n is an integer of 0 to 1;
t2、t3、t4each independently selected from integers of 1 to 3;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O.
In another preferred embodiment, in the compound represented by formula (I) or formula (II) or formula (III) or formula (IV) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein M is1、M2Are respectively and independently selected from hydrogen, hydroxyl, halogen atom, carboxyl, nitryl and-NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)Rd、C1-6Alkyl, or, M1And M2May form a 3-6 membered cycloalkyl group with the atom to which it is attached; orMoieties may be formed as hydrogen atoms;
Cy2selected from optionally substituted one or more R2Substituted phenyl, pyridyl, R2Each independently selected from hydrogen, hydroxyl, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
Cy3selected from optionally substituted one or more R3Substituted 5-6 membered nitrogen containing heteroaryl, R3Each independently selected from hydrogen, hydroxyl, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group;
Cy4selected from optionally substituted one or more R4Substituted by
R4each independently selected from hydrogen, hydroxyl, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkoxy, 3-14 membered heterocyclyl, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-O-;
Rbis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
Rdis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
n is an integer of 0 to 2;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O;
preferably, X1Is C ═ O, X2Is CRa，X3Is CRa；
Preferably, X1Is CRa，X2Is C ═ O, X3Is CRa。
In another preferred embodiment, in the compound represented by formula (I) or formula (II) or formula (III) or formula (IV) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein W is selected from hydrogen;
X1、X2are each independently selected from CRaOr NRb，X3Is C ═ O;
X4selected from C or N;
M1、M2are respectively and independently selected from hydrogen, hydroxyl, halogen atom, nitro and C1-4Alkyl, or, M1And M2May form a 3-6 membered cycloalkyl group with the atom to which it is attached; or
Cy2selected from optionally substituted one or more R2Substituted by
Cy3selected from optionally substituted one or more R3Substituted byR3Each independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, C1-4An alkyl group;
Cy4selected from optionally substituted one or more R4Substituted by
R4Each independently selected from hydrogen, hydroxyl, halogen atom, C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkoxy, 3-14 membered heterocyclyl, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is-O-;
Rais absent or, at each occurrence, is independently selected from hydrogen, C1-6Alkyl, halo C1-6An alkyl group;
Rbis absent or, at each occurrence, is independently selected from hydrogen, C1-6An alkyl group;
n is an integer of 0 to 1;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O.
In another preferred embodiment, in the compound represented by formula (I) or formula (II) or formula (III) or formula (IV) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
wherein W is selected from hydrogen;
X1、X2selected from the group consisting of CRaOr NRb，X3Is C ═ O;
X4is selected from C;
M1、M2each independently selected from hydrogen, hydroxy, C1-4Alkyl, or, M1And M2May form a 3-6 membered cycloalkyl group with the atom to which it is attached; or
Cy2selected from optionally substituted one or more R2Substituted by
Cy3selected from optionally substituted one or more R3Substituted by
Cy4selected from optionally substituted one or more R4Substituted by
l is-O-;
Rais absent or, at each occurrence, is independently selected from hydrogen, C1-4Alkyl, halo C1-6An alkyl group;
Rbis absent or, at each occurrence, is independently selected from hydrogen, C1-4An alkyl group;
n is an integer of 0 to 1;
preferably, X1Is N, X2Is CRa，X3Is C ═ O;
preferably, X1Is CRa，X2Is N, X3Is C ═ O;
preferably, X1Is CRa，X2Is CRa，X3Is C ═ O.
In another preferred embodiment, in the compound represented by formula (I) or formula (II) or formula (III) or formula (IV) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
X1、X3are each independently selected from CRa、C＝O、NRbAnd both are not C ═ O at the same time; x2Is CRaOr NRb。
In another preferred embodiment, the compound of formula (I) or formula (II) or formula (III) or formula (IV) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof,
Cy3selected from optionally substituted one or more R3Substituted 5-6 membered heteroaryl.
More specifically, the present invention provides the following technical solutions.
Scheme 1. compounds represented by general formula (I) or pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof:
wherein W is selected from hydrogen or C optionally substituted by a substituent1-6An alkyl group;
r represents a group represented by the following general formula (a '), (b ') or (c '):
in the formula (a'), the ring A part represents a 6-to 10-membered aromatic ring having a structure selected from NRb5-6 membered heteroaromatic ring with 1-3 heteroatoms in O and S or with a heteroatom selected from NRb5-6 membered heterocycle of 1-4 heteroatoms in O and S; preferably, the ring a moiety represents a benzene ring, a naphthalene ring, a furan ring, a thiophene ring, a pyrrole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, a pyrazole ring, a thiazole ring, an imidazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a pyran ring, a thiopyran ring, a pyrrolidine ring, a pyrroline ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a piperidine ring or a tetrahydropyran ring;
q is independently selected from hydrogen atom, cyano, hydroxyl, sulfhydryl, halogen atom, carboxyl, nitro and-NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6Alkoxy, C optionally substituted by substituents2-8Alkenyl, C optionally substituted by substituents2-8Alkynyl, -C optionally substituted by substituents1-6alkyl-R', -C optionally substituted with a substituent1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl optionally substituted by a substituent, 3-12 membered cycloalkenyl optionally substituted by a substituent, 3-14 membered heterocyclyl optionally substituted by a substituent, 6-14 membered aryl optionally substituted by a substituent, 5-10 membered heteroaryl optionally substituted by a substituent;
in the formula (a'), in the presence of a catalyst,
in the formula (a'), X6、X7Each independently selected from CRaRaC ═ O and NRbAnd wherein at least one is C ═ O;
in the formula (b'), in the presence of a catalyst,moiety through a linking group with
in the formula (c'),
X1、X2、X3each independently selected from CRaRaC ═ O and NRbAnd wherein at least one is C ═ O;
X4、X5each independently selected from CRaOr N;
M1、M2each independently selected from a hydrogen atom, C optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6Alkoxy, C optionally substituted by substituents2-8Alkenyl, C optionally substituted by substituents2-8Alkynyl, -C optionally substituted by substituents1-6alkyl-R', -C optionally substituted with a substituent1-6alkoxy-R', or, M1And M2May form, together with the atoms to which they are attached, a 3-8 membered cycloalkyl group optionally substituted by a substituent, or
Cy2selected from optionally substituted by more than one R2Substituted 3-12 membered cycloalkyl, optionally substituted with more than one R2Substituted 3-12 membered cycloalkenyl, optionally substituted with more than one R2Substituted 3-14 membered heterocyclyl, optionally substituted with more than one R2Substituted 6-14 membered aryl and optionally substituted with more than one R2Substituted 5-10 membered heteroaryl, R2Each independently selected from hydrogen atom, cyano group, hydroxyl group, mercapto group, halogen atom, carboxyl group, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6Alkoxy, C optionally substituted by substituents2-8Alkenyl, C optionally substituted by substituents2-8Alkynyl, -C optionally substituted by substituents1-6alkyl-R', -C optionally substituted with a substituent1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl optionally substituted by a substituent, 3-12 membered cycloalkenyl optionally substituted by a substituent, 3-14 membered heterocyclyl optionally substituted by a substituent, 6-14 membered aryl optionally substituted by a substituent, 5-10 membered heteroaryl optionally substituted by a substituent;
Cy3selected from optionally substituted by more than one R3Substituted 3-12 membered cycloalkyl group, optionally substituted with more than one R3A substituted 3-to 14-membered heterocyclic group, optionally substituted with more than one R3Substituted 5-to 10-membered heteroaromatic radical, R3Each independently selected from hydrogen atom, cyano group, hydroxyl group, mercapto group, halogen atom, carboxyl group, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6Alkoxy, C optionally substituted by substituents2-8Alkenyl, C optionally substituted by substituents2-8Alkynyl, -C optionally substituted by substituents1-6alkyl-R', -C optionally substituted with a substituent1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl optionally substituted by a substituent, 3-12 membered cycloalkenyl optionally substituted by a substituent, 3-14 membered heterocyclyl optionally substituted by a substituent, 6-14 membered aryl optionally substituted by a substituent, 5-10 membered heteroaryl optionally substituted by a substituent; when X is present1Or X2Represents NRbWhen is, Cy3May also be optionally substituted by more than one R3A substituted 6-14 membered aromatic group;
Cy4selected from optionally substituted by more than one R4Substituted 3-12 membered cycloalkyl, optionally substituted with more than one R4Substituted 3-14 membered heterocyclyl, optionally substituted with more than one R4Substituted 5-14 membered heteroaryl and optionally substituted with one or moreUpper R4Substituted 6-14 membered aryl, R4Each independently selected from hydrogen atom, cyano group, hydroxyl group, mercapto group, halogen atom, carboxyl group, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6Alkoxy, C optionally substituted by substituents2-8Alkenyl, C optionally substituted by substituents2-8Alkynyl, -C optionally substituted by substituents1-6alkyl-R', -C optionally substituted with a substituent1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl optionally substituted by a substituent, 3-12 membered cycloalkenyl optionally substituted by a substituent, 3-14 membered heterocyclyl optionally substituted by a substituent, 6-14 membered aryl optionally substituted by a substituent, 5-10 membered heteroaryl optionally substituted by a substituent, or two R4May form a 5-14 membered cyclic group with the atom to which it is attached;
l is selected from-NRb-, -O-, -S-and- (CR)aRa)m-, m is an integer from 1 to 3;
Rais absent or, at each occurrence, is independently selected from the group consisting of a hydrogen atom, cyano group, hydroxyl group, mercapto group, halogen atom, carboxyl group, nitro group, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6Alkoxy, C optionally substituted by substituents2-8Alkenyl, C optionally substituted by substituents2-8Alkynyl, -C optionally substituted by substituents1-6alkyl-R', -C optionally substituted with a substituent1-6Alkoxy radicalThe radicals-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl optionally substituted by a substituent, 3-12 membered cycloalkenyl optionally substituted by a substituent, 3-14 membered heterocyclyl optionally substituted by a substituent, 6-14 membered aryl optionally substituted by a substituent, 5-10 membered heteroaryl optionally substituted by a substituent;
Rb、Rceach being absent or, at each occurrence, independently selected from the group consisting of a hydrogen atom, a hydroxyl group, C optionally substituted with a substituent1-6Alkyl, -C optionally substituted by substituents1-6alkyl-R ', -C (O) -R', -SO2-R', 3-12 membered cycloalkyl optionally substituted by a substituent, 3-12 membered cycloalkenyl optionally substituted by a substituent, 3-14 membered heterocyclyl optionally substituted by a substituent, 6-14 membered aryl optionally substituted by a substituent, 5-10 membered heteroaryl optionally substituted by a substituent;
Rdis absent or, at each occurrence, is independently selected from hydroxy, halogen atom, amino, -amino (C optionally substituted by a substituent)1-6Alkyl radical)1-2C optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6Alkoxy, -C optionally substituted by substituents1-6alkyl-R', -C optionally substituted with a substituent1-6alkoxy-R ', -O-R', 3-12 membered cycloalkyl optionally substituted by a substituent, 3-12 membered cycloalkenyl optionally substituted by a substituent, 3-14 membered heterocyclyl optionally substituted by a substituent, 6-14 membered aryl optionally substituted by a substituent, 5-10 membered heteroaryl optionally substituted by a substituent;
r' is each independently selected from the group consisting of 3-12 membered cycloalkyl optionally substituted by a substituent, 3-12 membered cycloalkenyl optionally substituted by a substituent, 3-14 membered heterocyclyl optionally substituted by a substituent, 6-14 membered aryl optionally substituted by a substituent, and 5-10 membered heteroaryl optionally substituted by a substituent;
q is an integer of 0 to 4;
n is an integer of 0 to 4
The substituents in said "optionally substituted with substituents" are each independently selected from: hydroxy, mercapto, amino, carboxylCyano groups, nitro groups, halogen atoms, C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkyl radical C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkoxy radical, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino group, C1-6Alkylaminocarbonyl, (C)1-6Alkyl radical)2Aminocarbonyl group, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkylcarbonylamino, C1-6Alkylsulfonylamino, halo C1-6Alkyl, halo C1-6Alkoxy radical, C1-6Alkylsulfonyl radical, C1-6Alkylthio, 3-12 membered cycloalkyl, 6-14 membered aryl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, and oxo;
in the groups of the formulae (a '), (b ') and (c ')
with the proviso that, in the groups of the formulae (a ') and (c'),
with the proviso that, in the group of formula (b'), X1And X3Selected from C ═ O, X4When selected from N, as Cy2R of the substituent(s)2Does not represent a halogen atom.
Scheme 2. the compounds of scheme 1 or pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof, wherein,
M1、M2each independently selected from a hydrogen atom, C optionally substituted by a substituent1-6Alkyl and C optionally substituted by substituents2-8Alkenyl radicals, or, M1And M2May form, together with the atoms to which they are attached, a 3-8 membered cycloalkyl group optionally substituted by a substituent, or
in formula (a'), ring A moiety represents a 6-to 10-membered aromatic ring; preferably, the ring A part represents a benzene ring, a naphthalene ring;
q is independently selected from hydrogen atom, hydroxyl, halogen atom, carboxyl, nitro-NRbRcC optionally substituted by a substituent1-6Alkyl and C optionally substituted by substituents1-6An alkoxy group;
Cy2selected from optionally substituted by more than one R2Substituted 6-14 membered aryl and optionally substituted with more than one R2Substituted 5-10 membered heteroaryl, preferably, Cy2Selected from optionally substituted by more than one R2Substituted phenyl or naphthyl;
R2each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)ORdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6An alkoxy group; preferably, R is2Each independently selected from hydrogen atom, hydroxyl group, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group; preferably, R is2Each independently selected from hydrogen atom, hydroxyl, fluorine, chlorine, bromine、C1-4An alkyl group;
Cy3selected from optionally substituted by more than one R3A substituted 3-to 8-membered cycloalkyl group and optionally substituted with more than one R3A substituted 5-to 10-membered heteroaryl group when X1Or X2Represents NRbWhen is, Cy3May also be optionally substituted by more than one R3A substituted 6-10 membered aromatic group; preferably, Cy is3Selected from optionally substituted by more than one R3Substituted 3-6 membered cycloalkyl group, optionally substituted by more than one R3A substituted 5-6 membered heteroaryl group when X1Or X2Represents NRbWhen is, Cy3May also be optionally substituted by more than one R3Substituted phenyl or naphthyl; preferably, Cy is3Selected from optionally substituted by more than one R3Substituted pyrrole groups, optionally substituted by more than one R3Substituted pyridine group, optionally substituted by more than one R3Substituted pyrimidine radical, optionally substituted by more than one R3Substituted pyridazine radicals or radicals optionally substituted by more than one R3A substituted pyrazine group;
R3each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6An alkoxy group; preferably, R is3Each independently selected from hydrogen atom, hydroxyl group, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group; preferably, R is3Each independently selected from hydrogen atom, hydroxyl, fluorine, chlorine, bromine, C1-4An alkyl group;
Cy4selected from optionally substituted by more than one R4Substituted 5-10 membered heterocyclyl, optionally substituted with more than one R4Substituted 5-10 membered heteroaryl and optionally substituted with more than one R4Substituted 6-10 membered aryl; preferably, Cy is4Selected from optionally substituted by more than one R4Substituted 9-10 membered heteroarylOr optionally substituted by more than one R4Substituted phenyl or naphthyl;
R4each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6Alkoxy, or, two R4Form a 5-6 membered cyclic group with the attached atom; preferably, R is4Each independently selected from hydrogen atom, hydroxyl group, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkyl radical C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkoxy, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached; preferably, R is4Selected from hydrogen atom, hydroxyl group, mercapto group, halogen atom, C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkyl radical, C1-4Alkyl radical C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkoxy, halo C1-4Alkoxy, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-NRb-, -O-and-S-;
Rais absent or, at each occurrence, is independently selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6An alkoxy group; preferably, R isaIs absent or, at each occurrence, is independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, preferably, RaIs absent or, at each occurrence, is independently selected from hydrogen atom, C1-6Alkyl radical, C1-6An alkoxy group;
Rb、Rceach being absent or, at each occurrence, independently selected from a hydrogen atom, C optionally substituted by a substituent1-6An alkyl group; preferably, R isb、RcEach being absent or, at each occurrence, independently selected from hydrogen atom, C1-6Alkyl, halo C1-6An alkyl group; preferably, R isb、RcEach being absent or, at each occurrence, independently selected from hydrogen atom, C1-6An alkyl group;
Rdis absent or, at each occurrence, is independently selected from hydroxy, halogen atom, amino, -amino (C optionally substituted by a substituent)1-6Alkyl radical)1-2C optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6An alkoxy group; preferably, R isdIs absent or, at each occurrence, is independently selected from hydroxy, amino, -amino (C)1-6Alkyl radical)1-2、C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group; preferably, R isdIs absent or, at each occurrence, is independently selected from hydroxy, amino, C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy, halo C1-4An alkoxy group;
r' is selected from the group consisting of 3-8 membered cycloalkyl optionally substituted by a substituent, 3-8 membered cycloalkenyl optionally substituted by a substituent, 3-10 membered heterocyclyl optionally substituted by a substituent, 6-10 membered aryl optionally substituted by a substituent, and 5-6 membered heteroaryl optionally substituted by a substituent; preferably, R' is selected from the group consisting of 3-6 membered cycloalkyl optionally substituted by a substituent, 4-7 membered heterocyclyl optionally substituted by a substituent, 6-10 membered aryl optionally substituted by a substituent and 5-6 membered heteroaryl optionally substituted by a substituent; preferably, R' is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, oxetanyl, oxocyclopentyl, oxocyclohexyl, oxepanyl, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl;
the substituents in "optionally substituted with a substituent" are each independently selected from: hydroxy, mercapto, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkyl radical C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkoxy radical, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino group, C1-6Alkylaminocarbonyl, (C)1-6Alkyl radical)2Aminocarbonyl group, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkylcarbonylamino, C1-6Alkylsulfonylamino, halo C1-6Alkyl, halo C1-6Alkoxy radical, C1-6Alkylsulfonyl radical, C1-6Alkylthio, 3-8 membered cycloalkyl, 6-10 membered aryl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl and oxo; preferably, the substituents in "optionally substituted with a substituent" are each independently selected from: hydroxy, mercapto, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkyl radical C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkoxy radical, C1-4Alkylamino radical, (C)1-4Alkyl radical)2Amino group, C1-4Alkylaminocarbonyl, (C)1-4Alkyl radical)2Aminocarbonyl group, C1-4Alkylcarbonyl group, C1-4Alkylcarbonyloxy, C1-4Alkylcarbonylamino, C1-4Alkylsulfonylamino, halo C1-4Alkyl, halo C1-4Alkoxy radical, C1-4Alkylsulfonyl radical, C1-4Alkylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthyl, oxacyclopropyl, oxacyclobutyl, oxacyclopentyl, oxa-cycloCyclohexyl, oxepanyl, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl and oxo,
n is 0, 1,2,3 or 4,
q is 0, 1,2,3 or 4.
Scheme 3. the compounds according to scheme 1 or 2, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof, wherein,
X1is NRb，X2Is CRaRa，X3Is C ═ O; or
X1Is CRaRa，X2Is NRb，X3Is C ═ O; or
X1Is C ═ O, X2Is CRaRa，X3Is C ═ O; or
X1Is CRaRa，X2Is C ═ O, X3Is C ═ O; or
X1Is CRaRa，X2Is CRaRa，X3Is C ═ O; or
X1Is C ═ O, X2Is CRaRa，X3Is CRaRa(ii) a Or
X1Is CRaRa，X2Is C ═ O, X3Is CRaRa。
Scheme 4. the compounds of any one of schemes 1-3, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof,
wherein, X4Is selected from N, X5Selected from the group consisting of CRa(ii) a Or
X4Selected from the group consisting of CRa，X5Selected from the group consisting of CRa(ii) a Or
X4Is selected from N, X5Is selected from N; or
X4Selected from the group consisting of CRa，X5Is selected from N.
Scheme 5. the compound of any one of schemes 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, wherein,
X6is C ═ O, X7Is CRaRa(ii) a Or
X6Is CRaRa，X7Is C ═ O; or
X6Is C ═ O, X7Is NRb(ii) a Or
X6Is NRb，X7Is C ═ O.
Scheme 6. the compound of any one of schemes 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, wherein,
only one C ═ O is present on the rings of formula (a '), formula (b ') and formula (C ').
Scheme 7. the compound of any one of schemes 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, wherein,
Cy3represents an optional substitution by more than one R3Substituted by
R3each independently selected from hydrogen atom, hydroxyl group, halogen atom, and carboxyl groupRadical, nitro radical, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6An alkoxy group; preferably, R is3Each independently selected from hydrogen atom, hydroxyl group, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group; preferably, R is3Each independently selected from hydrogen atom, hydroxyl, fluorine, chlorine, bromine, C1-4An alkyl group;
Cy4represents an optional substitution by more than one R4Substituted by
R4each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6Alkoxy, or, two R4Form a 5-6 membered cyclic group with the attached atom; it is preferable thatIs, R4Each independently selected from hydrogen atom, hydroxyl group, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkyl radical C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkoxy, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached; preferably, R is4Selected from hydrogen atom, hydroxyl group, mercapto group, halogen atom, C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkyl radical, C1-4Alkyl radical C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkoxy, halo C1-4Alkoxy, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached;
l is selected from-NRb-or-O-.
Scheme 8. the compounds of any one of schemes 1-7, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof,
wherein R represents a group represented by the formula (b '), and a six-membered ring in the group represented by the formula (b') is represented by any one of the following formulaeRepresents a single bond or a double bond,
X1and X2As defined in schemes 1-7.
Scheme 9. the compounds of any one of schemes 1-8, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof,
wherein, Cy3Selected from optionally substituted by more than one R3Substituted of the following groups:
preferably, Cy is3Selected from optionally substituted by more than one R3Substituted of the following groups:
Cy4selected from optionally substituted by more than one R4Substituted of the following groups:
R4each independently selected from hydrogen atom, hydroxyl group, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkyl radical C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkoxy, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached; preferably, R is4Selected from hydrogen atom, hydroxyl group, mercapto group, halogen atom, C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkyl radical, C1-4Alkyl radical C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkoxy radicalHalogen substituted C1-4Alkoxy, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached.
Scheme 10. the compounds of any of schemes 1-9, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof, have the structure shown in general formula (II),
wherein each group is as defined in schemes 1-9.
Scheme 11. the compounds of any of schemes 1-9, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof, have the structure of formula (III),
wherein M is1、M2Each independently selected from C1-6Alkyl, or, M1And M2May form a 3-6 membered cycloalkyl group with the atom to which it is attached; preferably, M is1And M2May form a cyclopropyl group with the atom attached;
X1、X2、X3each independently selected from CRaRa、C＝O、NRbAnd wherein at least one is C ═ O; preferably, X is1、X2Each independently selected from CRaRaAnd NRb，X3The expression C is O, or C is O,
Y2and Y3Each independently selected from CH or N, and at least one is N;
l is selected from-NRb-or-O-;
t2、t3、t4each independently selected from an integer of 1 to 5,
the remaining groups are as defined in schemes 1-9.
Scheme 12. the compounds of schemes 1-9, or pharmaceutically acceptable salts, esters, stereoisomers, tautomers thereof, have the structure shown in general formula (iv),
wherein M is1、M2Each independently selected from C1-6Alkyl radicals, or, M1And M2May form a 3-6 membered cycloalkyl group with the atom to which it is attached; preferably, M1And M2May form a cyclopropyl group with the atom attached;
X1、X2、X3each independently selected from CRaRa、C＝O、NRbAnd wherein at least one is C ═ O; preferably, X is1、X2Each independently selected from CRaRaAnd NRb，X3The expression C is O, or C is O,
Y6and Y7Each independently selected from CH or N, and at least one is N,
l is selected from-NRb-or-O-;
t2、t3、t4each independently selected from an integer of 1 to 5,
the remaining groups are as defined in schemes 1-9.
In one embodiment of the present invention, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, wherein the compound is:
the invention also provides a pharmaceutical composition which comprises at least one of the compounds shown in any one of the formula (I), the formula (II), the formula (III) and the formula (IV) and pharmaceutically acceptable salts, esters, stereoisomers and tautomers thereof.
The present invention also provides pharmaceutical compositions comprising a compound of any one of the above formulas (I), (II), (III) and (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, which may optionally contain one or more pharmaceutically acceptable carriers.
The present invention also provides pharmaceutically acceptable dosage forms comprising a compound of any of the above formulas (I), (II), (III) and (IV), 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 therapeutically active agents.
In one embodiment of the present invention, there is provided a pharmaceutical composition comprising a compound represented by any one of formula (I), formula (II), formula (III) and formula (IV) above, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, which may optionally contain at least one second therapeutically active agent.
In one embodiment of the invention, the second therapeutically active 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.; it can also be made into oral liquid, 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 any one of the above formulae (I), (II), (III) and (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, pharmaceutical composition thereof, and dosage form thereof, for use in the manufacture of a medicament for the treatment and/or prevention of a disease mediated by aberrant expression of a TAM family kinase receptor and/or a ligand 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, there is provided a compound represented by any one of the above formula (I), formula (II), formula (III) and formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, pharmaceutical composition thereof, and dosage form thereof, for use in the treatment and/or prevention of a disease mediated by aberrant expression of a TAM family kinase receptor and/or a ligand 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, there is provided a compound represented by any one of the above formula (I), formula (II), formula (III) and formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, pharmaceutical composition thereof, and dosage form thereof, for use in the manufacture of a medicament for the treatment and/or prevention of a disease mediated by aberrant expression of a TAM family kinase/CSF 1R kinase receptor and/or a ligand thereof, wherein the disease mediated by aberrant expression of a TAM family kinase/CSF 1R kinase receptor and/or a ligand thereof comprises 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 compound represented by any one of the above formula (I), formula (II), formula (III) and formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, the pharmaceutical composition thereof, and the dosage form thereof, are used for treating and/or preventing a disease mediated by abnormal expression of TAM family kinase/CSF 1R kinase receptor and/or ligand 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, there is provided a use of a compound represented by any one of the above formula (I), formula (II), formula (III) and formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, pharmaceutical composition thereof, and dosage form thereof for preparing a medicament for treating and/or preventing related diseases caused by NTRK, including but not limited to non-small cell lung cancer, colorectal cancer, breast-like secretory carcinoma, sarcoma, astrocytoma, glioblastoma, Spitz-like melanoma, cholangiocarcinoma, papillary thyroid carcinoma, mammary secretory carcinoma, breast cancer-pathological type unknown, etc., particularly a drug-resistant type related disease caused by NTRK mutation.
In one embodiment of the present invention, there is provided a compound represented by any one of the above formula (I), formula (II), formula (III) and formula (IV) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, pharmaceutical composition thereof, and dosage form thereof for use in the treatment and/or prevention of related diseases caused by NTRK, especially related diseases caused by mutation of NTRK, including but not limited to non-small cell lung cancer, colorectal cancer, breast-like secretory cancer, sarcoma, astrocytoma, glioblastoma, Spitz-like melanoma, cholangiocarcinoma, papillary thyroid cancer, mammary secretory cancer, breast cancer-pathological type unknown, etc., and drug-resistant type related diseases caused by mutation of NTRK.
In one embodiment of the present invention, there is provided a compound represented by any one of the above formula (I), formula (II), formula (III) and formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof, pharmaceutical composition thereof, and dosage form thereof, for use in the treatment and/or prevention of diseases associated with NTRK, especially diseases associated with drug-resistant forms caused by mutations in NTRK.
In one embodiment of the invention, the tumor includes sarcoma, lymphoma and cancer, and specifically may be lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal carcinoma of the breast, head and neck cancer, endometrial cancer, uterine body cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-hodgkin's lymphoma, large intestinal villous adenoma, melanoma, cell tumor and sarcoma.
Effects of the invention
The compounds of the invention have inhibitory effects on TAM family kinases. In addition, the compound of the invention can also target CSF1R kinase and has an inhibitory effect on CSF1R kinase. 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. In addition, the compounds of the present invention are useful for the treatment and/or prevention of diseases mediated by aberrant expression of TAM family kinase/CSF 1R kinase receptors and/or their ligands. The compound can reverse immunosuppression in a tumor microenvironment, inhibit growth, migration and/or drug resistance of tumors and exert tumor immune effect and anti-tumor curative effect by simultaneously inhibiting TAM family kinase and CSF1R kinase in a targeted manner.
In addition, the compound provided by the invention has very good NTRK mutant target activity, has a very good application prospect in patients with acquired drug resistance treated by a first generation NTRK inhibitor, and can be used for treating and/or preventing related diseases caused by NTRK, especially drug-resistant related diseases caused by NTRK mutation.
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 understand that the following description of the embodiments is only for illustrating 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, a hydrocarbon or hydrocarbon derivative group of 3 or more carbon atoms (e.g., propyl, propoxy, butyl, butane, butene, butenyl, hexane, etc.) has the same meaning when not headed "plus" as when headed "plus". 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 the present specification, anything or things which are not mentioned, except where explicitly stated, are directly applicable to those known in the art without any changes. 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, "Ca-bThe 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. C1-4Alkyl, i.e. representing an alkyl group having 1 to 4 carbon atoms, C1-4Alkoxy, i.e. alkoxy having 1 to 4 carbon atoms, C3-10Cycloalkyl, i.e. a cycloalkyl group having 3 to 10 carbon atoms, C1-4Alkoxy radical C1-4The 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 valence (for example, 1 valence, 2 valence, 3 valence, 4 valence, 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.
"halo" as used herein means that a hydrogen on any carbon atom in a substituent is replaced by one or more halogen atoms which may be the same or different. The "halogen atom" is as defined above.
"C" according to the invention1-6Alkyl "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 C1-6Alkyl and branched C1-6An alkyl group. In fact, C is well known to those skilled in the art1-6The alkyl group having a branch (branch C)1-6Alkyl) having at least 3 carbon atoms. As "C1-6Examples of "alkyl" include, for example, methyl, ethyl, n-propyl, isopropyl, n-propylButyl, 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, and the like. Said "C1-4Alkyl "refers to the above examples containing 1 to 4 carbon atoms.
The "hydroxy group C" of the present invention1-6Alkyl, cyano C1-6Alkyl, amino C1-6Alkyl radical, C1-6Alkylamino radical C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl "means more than one hydroxy, cyano, amino, C1-6Alkylamino, halogen, C1-6Alkoxy is independently substituted for C1-6Hydrogen atoms on alkyl groups.
“C1-6Alkylamino "," (C)1-6Alkyl radical)2Amino group and C1-6Alkylaminocarbonyl group and C1-6Alkylcarbonyl group and C1-6Alkylcarbonyloxy group and C1-6Alkylsulfonylamino group and "C1-6Alkylsulfonyl group "," C1-6Alkylthio "and the like include" C1-6The radical of alkyl "denotes C1-6Alkyl is independently linked to-NH-, -CO-O-, -NH-CO-, -SO2NH-、-SO2-, -S-, etc. corresponding groups are linked to form a group. For example, the above-mentioned "C" may be mentioned1-6The radicals listed under alkyl are each independently substituted with-NH-, -CO-O-, -NH-CO-, -SO2NH-、-SO2-, -S-, etc. corresponding groups are linked to form a group.
"C" according to the invention2-8The "alkenyl group" refers to a straight-chain or branched alkenyl group derived by removing one or more hydrogen atoms from an olefin moiety of 2 to 8 carbon atoms having 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, and 2-penten-1-yl-1-yl, 3-penten-2-yl, 1, 3-pentadien-1-yl, 1, 4-pentadien-3-yl, 1-hexen-3-yl, 1, 4-hexadien-1-yl. Preferably, "C" is2-8Alkenyl "contains one carbon-carbon double bond.
"C" according to the invention2-8The 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" is2-8Alkynyl "contains a carbon-carbon triple bond.
"C" according to the invention1-6Alkoxy "means" C "as defined hereinbefore1-6Alkyl "radicals attached to the parent moiety through an oxygen atom, i.e." C1-6Examples of the alkyl-O- "group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentoxy, and n-hexoxy. Said "C1-4Alkoxy "refers to the above examples containing 1 to 4 carbon atoms, i.e." C1-4An alkyl-O- "group.
The "halo C" of the present invention1-6Alkoxy group "," C1-6Alkoxy radical C1-6Alkoxy group "," C1-6Alkyl radical C1-6Alkoxy "etc. contain" C1-6The radical of alkoxy "means more than one halogen atom, C1-6Alkoxy radical, C1-6Alkyl and the like corresponding groups each independently substituted for C1-6A 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 one 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 higher) 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:
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 required. Examples of spiro rings include, but are not limited to:
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 the form of a parallel, spiro, or bridge) groups 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, the following 6-12 membered fused ring group, 7-10 membered fused ring group, 6-12 membered saturated fused ring group, 6-12 membered spiroheterocycle, 7-11 membered spiroheterocycle, 6-12 membered saturated spiroheterocycle, 7-11 membered saturated spiroheterocycle, 6-12 membered bridged heterocycle, 7-11 membered bridged heterocycle, 6-12 membered saturated bridged heterocycle, 7-8 membered saturated bridged heterocycle may be mentioned.
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)2And 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".
The monovalent or (if necessary) divalent or more monocyclic heterocyclic 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. 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, 2, 5-dihydrooxazolyl, 2, 3-dihydrooxazolyl, 2, 5-dihydro,2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4, 5-tetrahydropyridinyl, 1, 2-isooxazinyl, 1, 4-isooxazinyl, 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, 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 one 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 one hydrogen atom from the same carbon atom or different carbon atoms, respectively, as required, and examples of the spiroheterocyclic group include, but are not limited to:
the bridged heterocyclic group may be a monovalent group obtained by removing one 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 one 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:
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 it 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 be an aromatic cyclic hydrocarbon group having 5,6,7,8, 9, 10, 11, 12, 13 or 14 ring-forming atoms and containing at least one heteroatom selected from O, S, N. That is, 5-14 membered heteroaryl, 5-10 membered heteroaryl, 5-6 membered heteroaryl may be mentioned. 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)2And S (═ O) (═ N). Heteroaryl includes both mono-and fused heteroaryl, where a single heteroaryl includes all monocyclic, fused, wholly aromatic, and partially aromatic moieties that may be formed, unless otherwise specified. 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 certain 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 heteroaryi, 9-10 membered heteroaryi, examples include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzooxadiazolyl, benzothiadiazolyl, benzothiophenylThiazolyl, 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 ] benzo [ c ] 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 "5-14 membered cyclic group" as referred to herein means a group having 5,6,7,8, 9, 10, 11, 12, 13, 14 ring-constituting atoms, which may be the case where the above-mentioned cycloalkyl group, cycloalkenyl group, heterocyclic group, aryl group, heteroaryl group of the present invention have 5-14 ring-constituting atoms. Specifically, it may be a 5-to 10-membered cyclic group or a 5-to 6-membered cyclic group. In addition, the "5-6 membered cyclic group" according to the present invention means a chemically feasible cyclic structure of 5-6 ring atoms, which may be optionally selected from C, N, O, S, C (═ O), S (═ O)2The 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" 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.
Specifically, the present invention provides a compound represented by the general formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof:
wherein W is selected from hydrogen or C optionally substituted by a substituent1-6An alkyl group;
r represents a group represented by the following general formula (a '), (b ') or (c '):
in the formula (a'), the ring A part represents a 6-to 10-membered aromatic ring having a structure selected from NRb5-6 membered heteroaromatic ring with 1-3 heteroatoms in O and S or with a heteroatom selected from NRb5-6 membered heterocycle of 1-4 heteroatoms in O and S;
q is independently selected from hydrogen atom, cyano, hydroxyl, sulfhydryl, halogen atom, carboxyl, nitro and-NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6Alkoxy, C optionally substituted by substituents2-8Alkenyl, C optionally substituted by substituents2-8Alkynyl, -C optionally substituted by substituents1-6alkyl-R', -C optionally substituted with a substituent1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl optionally substituted by a substituent, 3-12 membered cycloalkenyl optionally substituted by a substituent, 3-14 membered heterocyclyl optionally substituted by a substituent, 6-14 membered aryl optionally substituted by a substituent, 5-10 membered heteroaryl optionally substituted by a substituent;
in the formula (a'), in the presence of a catalyst,
in the formula (a'), X6、X7Each independently selected from CRaRaC ═ O and NRbAnd wherein at least one is C ═ O;
in the formula (b'), in the presence of a catalyst,moiety through a linking group withPartially connecting;
in the formula (c'),
X4、X5each independently selected from CRaOr N;
M1、M2each independently selected from a hydrogen atom, C optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6Alkoxy, C optionally substituted by substituents2-8Alkenyl, C optionally substituted by substituents2-8Alkynyl, -C optionally substituted by substituents1-6alkyl-R', -C optionally substituted with a substituent1-6alkoxy-R', or, M1And M2May form, together with the atoms to which they are attached, a 3-8 membered cycloalkyl group optionally substituted by a substituent, or
Cy2selected from optionally substituted by more than one R2Substituted 3-12 membered cycloalkyl, optionally substituted with more than one R2Substituted 3-12 membered cycloalkenyl, optionally substituted with more than one R2Substituted 3-14 membered heterocyclyl, optionally substituted with more than one R2Substituted 6-14 membered aryl and optionally substituted with more than one R2Substituted 5-10 membered heteroaryl, R2Each independently selected from hydrogen atom, cyano group, hydroxyl group, mercapto group, halogen atom, carboxyl group, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6Alkoxy, C optionally substituted by substituents2-8Alkenyl, C optionally substituted by substituents2-8Alkynyl, -C optionally substituted by substituents1-6alkyl-R', -C optionally substituted with a substituent1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl optionally substituted by a substituent, 3-12 membered cycloalkenyl optionally substituted by a substituent, 3-14 membered heterocyclyl optionally substituted by a substituent, 6-14 membered aryl optionally substituted by a substituent, 5-10 membered heteroaryl optionally substituted by a substituent;
Cy3selected from optionally substituted by more than one R3Substituted 3-12 membered cycloalkyl group, optionally substituted with more than one R3A substituted 3-to 14-membered heterocyclic group, optionally substituted with more than one R3Substituted 5-to 10-membered heteroaromatic radical, R3Each independently selected from hydrogen atom, cyano group, hydroxyl group, mercapto group, halogen atom, carboxyl group, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6Alkoxy, C optionally substituted by substituents2-8Alkenyl, C optionally substituted by substituents2-8Alkynyl, -C optionally substituted by substituents1-6alkyl-R', -C optionally substituted with a substituent1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl optionally substituted by a substituent, 3-12 membered cycloalkenyl optionally substituted by a substituent, 3-14 membered heterocyclyl optionally substituted by a substituent, 6-14 membered aryl optionally substituted by a substituent, 5-10 membered heteroaryl optionally substituted by a substituent; when X is present1Or X2Represents NRbWhen is, Cy3May also be optionally substituted by more than one R3A substituted 6-14 membered aromatic group;
Cy4selected from optionally substituted by more than one R4Substituted 3-12 membered cycloalkyl, optionally substituted with more than one R4Substituted 3-14 membered heterocyclyl, optionally substituted with more than one R4Substituted 5-14 membered heteroaryl and optionally substituted with more than one R4Substituted 6-14 membered aryl, R4Each independently selected from hydrogen atom, cyano group, hydroxyl group, mercapto group, halogen atom, carboxyl group, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6Alkoxy, C optionally substituted by substituents2-8Alkenyl, C optionally substituted by substituents2-8Alkynyl radicalC optionally substituted by a substituent1-6alkyl-R', -C optionally substituted with a substituent1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl optionally substituted by a substituent, 3-12 membered cycloalkenyl optionally substituted by a substituent, 3-14 membered heterocyclyl optionally substituted by a substituent, 6-14 membered aryl optionally substituted by a substituent, 5-10 membered heteroaryl optionally substituted by a substituent, or two R4May form a 5-14 membered cyclic group with the atom to which it is attached;
l is selected from-NRb-, -O-, -S-and- (CR)aRa)m-, m is an integer from 1 to 3;
Rais absent or, at each occurrence, is independently selected from the group consisting of a hydrogen atom, cyano group, hydroxyl group, mercapto group, halogen atom, carboxyl group, nitro group, -NRbRc、-C(O)Rd、-C(O)NRbRc、-OC(O)NRbRc、-NRbC(O)Rd、-SO2-NRbRc、-SO2Rd、-NRbSO2RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6Alkoxy, C optionally substituted by substituents2-8Alkenyl, C optionally substituted by substituents2-8Alkynyl, -C optionally substituted by substituents1-6alkyl-R', -C optionally substituted with a substituent1-6alkoxy-R ', -O-R ', -C (O) -R ', -SO2-R’、-NRbC (O) -R', 3-12 membered cycloalkyl optionally substituted by a substituent, 3-12 membered cycloalkenyl optionally substituted by a substituent, 3-14 membered heterocyclyl optionally substituted by a substituent, 6-14 membered aryl optionally substituted by a substituent, 5-10 membered heteroaryl optionally substituted by a substituent;
Rb、Rceach being absent or, at each occurrence, independently selected from the group consisting of a hydrogen atom, a hydroxyl group, C optionally substituted with a substituent1-6Alkyl, -C optionally substituted by substituents1-6alkyl-R ', -C (O) -R', -SO2-R', optionally substituted by substituents3-12 membered cycloalkyl optionally substituted by a substituent, 3-12 membered cycloalkenyl optionally substituted by a substituent, 3-14 membered heterocyclyl optionally substituted by a substituent, 6-14 membered aryl optionally substituted by a substituent, 5-10 membered heteroaryl optionally substituted by a substituent;
Rdis absent or, at each occurrence, is independently selected from hydroxy, halogen atom, amino, -amino (C optionally substituted by a substituent)1-6Alkyl radical)1-2C optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6Alkoxy, -C optionally substituted by substituents1-6alkyl-R', -C optionally substituted with a substituent1-6alkoxy-R ', -O-R', 3-12 membered cycloalkyl optionally substituted by a substituent, 3-12 membered cycloalkenyl optionally substituted by a substituent, 3-14 membered heterocyclyl optionally substituted by a substituent, 6-14 membered aryl optionally substituted by a substituent, 5-10 membered heteroaryl optionally substituted by a substituent;
r' is each independently selected from the group consisting of 3-12 membered cycloalkyl optionally substituted by a substituent, 3-12 membered cycloalkenyl optionally substituted by a substituent, 3-14 membered heterocyclyl optionally substituted by a substituent, 6-14 membered aryl optionally substituted by a substituent, and 5-10 membered heteroaryl optionally substituted by a substituent;
q is an integer of 0 to 4;
n is an integer of 0 to 4;
the substituents in said "optionally substituted with substituents" are each independently selected from: hydroxy, mercapto, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkyl radical C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkoxy radical, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino group, C1-6Alkylaminocarbonyl, (C)1-6Alkyl radical)2Aminocarbonyl group, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkylcarbonylamino, C1-6Alkylsulfonylamino, halo C1-6Alkyl, halo C1-6Alkoxy radical, C1-6An alkylsulfonyl group,C1-6Alkylthio, 3-12 membered cycloalkyl, 6-14 membered aryl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, and oxo;
in the groups of the formulae (a '), (b ') and (c ')
with the proviso that, in the groups of the formulae (a ') and (c'),
with the proviso that, in the group of formula (b'), X1And X3Selected from C ═ O, X4When selected from N, as Cy2R of the substituent(s)2Does not represent a halogen atom.
In another embodiment of the present invention, the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof is represented by formula (II) below.
In another embodiment of the present invention, the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof is represented by the following formula (III).
Y2And Y3Each independently selected from CH or N, and at least one is N;
t2、t3、t4each independently selected from integers of 1 to 5.
In another embodiment of the present invention, the compound represented by formula (I) of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof is represented by the following formula (IV).
Y6And Y7Each independently selected from CH or N, and at least one is N;
t2、t3、t4each independently selected from integers of 1 to 5.
In one embodiment of the present invention, M1、M2Each independently selected from a hydrogen atom, C optionally substituted by a substituent1-6Alkyl and C optionally substituted by substituents2-8Alkenyl radicals, or, M1And M2May form, together with the atoms to which they are attached, a 3-8 membered cycloalkyl group optionally substituted by a substituent, or
In one embodiment of the present invention, M1、M2Each independently selected from C optionally substituted with a substituent1-6Alkyl, or, M1And M2May form, together with the atoms to which they are attached, a 3-8 membered cycloalkyl group optionally substituted by a substituent, orMoieties may be formed as hydrogen atoms.
In one embodiment of the present invention, M1、M2Each independently selected from C1-6Alkyl, or, M1And M2May form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group together with the atom to which it is attached.
In one embodiment of the present invention, X1Is NRb，X2Is CRaRa，X3Is C ═ O.
In one embodiment of the present invention, X1Is CRaRa，X2Is NRb，X3Is C ═ O.
In one embodiment of the present invention, X1Is C ═ O, X2Is CRaRa，X3Is C ═ O.
In one embodiment of the present invention, X1Is CRaRa，X2Is C ═ O, X3Is C ═ O.
In one embodiment of the present invention, X1Is CRaRa，X2Is CRaRa，X3Is C ═ O.
In one embodiment of the present invention, X1Is C ═ O, X2Is CRaRa，X3Is CRaRa。
In one embodiment of the present invention, X1Is CRaRa，X2Is C ═ O, X3Is CRaRa。
In one embodiment of the present invention, X4Is selected from N, X5Selected from the group consisting of CRa。
In one embodiment of the present invention, X4Selected from the group consisting of CRa，X5Selected from the group consisting of CRa。
In one embodiment of the present invention, X4Is selected from N, X5Is selected from N.
In one embodiment of the present invention, X4Selected from the group consisting of CRa，X5Is selected from N.
In one embodiment of the present invention, X6Is C ═ O, X7Is CRaRa。
In one embodiment of the present invention, X6Is CRaRa，X7Is C ═ O.
In one embodiment of the present invention, X6Is C ═ O, X7Is NRb。
In one embodiment of the present invention, X6Is NRb，X7Is C ═ O.
In one embodiment of the present invention, in formula (a'), ring a moiety represents a 6-10 membered aromatic ring.
In one embodiment of the present invention, in formula (a'), the ring a moiety represents a benzene ring or a naphthalene ring.
In one embodiment of the present invention, in formula (a'), the ring a moiety represents a benzene ring, a naphthalene ring, a furan ring, a thiophene ring, a pyrrole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, a pyrazole ring, a thiazole ring, an imidazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a pyran ring, a thiopyran ring, a pyrrolidine ring, a pyrroline ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a piperidine ring or a tetrahydropyran ring.
In one embodiment of the present invention, in formula (a'), each Q is independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, -NRbRcC optionally substituted by a substituent1-6Alkyl and C optionally substituted by substituents1-6An alkoxy group.
In one embodiment of the present invention, Cy2Selected from optionally substituted by more than one R2Substituted 6-14 membered aryl and optionally substituted with more than one R2Substituted 5-10 membered heteroaryl.
In one embodiment of the present invention, Cy2Selected from optionally substituted by more than one R2Substituted phenyl or naphthyl.
In one embodiment of the present invention, Cy3Selected from optionally substituted by more than one R3A substituted 3-to 8-membered cycloalkyl group and optionally substituted with more than one R3A substituted 5-to 10-membered heteroaryl group when X1Or X2Represents NRbWhen is, Cy3May also be optionally substituted by more than one R3A substituted 6-10 membered aromatic group.
In one embodiment of the present invention, Cy3Selected from optionally substituted by more than one R3Substituted 3-6 membered cycloalkyl group, optionally substituted by more than one R3A substituted 5-6 membered heteroaryl group when X1Or X2Represents NRbWhen is, Cy3May also be optionally substituted by more than one R3Substituted phenyl or naphthyl.
In the inventionIn one embodiment of (1), Cy3Selected from optionally substituted by more than one R3Substituted pyrrole groups, optionally substituted by more than one R3Substituted pyridine group, optionally substituted by more than one R3Substituted pyrimidine radical, optionally substituted by more than one R3Substituted pyridazine radicals or radicals optionally substituted by more than one R3A substituted pyrazine group.
In one embodiment of the present invention, Cy3Represents an optional substitution by more than one R3Substituted byThe group shown, in the formula,
In one embodiment of the present invention, Cy3Represents an optional substitution by more than one R3Substituted by
In one embodiment of the present invention, Cy3Selected from optionally substituted by more than one R3Substituted of the following groups:
in one embodiment of the present invention, Cy3Selected from optionally substituted by more than one R3Substituted of the following groups:
In one embodiment of the present invention, Cy4Selected from optionally substituted by more than one R4Substituted 5-10 membered heterocyclyl, optionally substituted with more than one R4Substituted 5-10 membered heteroaryl and optionally substituted with more than one R4Substituted 6-10 membered aryl.
In one embodiment of the present invention, Cy4Selected from optionally substituted by more than one R4Substituted 9-10 membered heteroaryl or optionally substituted with more than one R4Substituted phenyl or naphthyl.
In one embodiment of the present invention, Cy4Represents an optional substitution by more than one R4Substituted by
In one embodiment of the present invention, Cy4Represents an optional substitution by more than one R4Substituted by
In one embodiment of the invention, ring B is a benzene ring or contains a group selected from NRbO, S, a 5-6 membered heteroaromatic ring of 1-3 atoms.
In one embodiment of the present invention, Cy4Selected from optionally substituted by more than one R4Substituted of the following groups:
in one embodiment of the present invention, Cy4Is selected from optionally oneAbove R4Substituted of the following groups:
in one embodiment of the invention, R2Each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)ORdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6An alkoxy group.
In one embodiment of the invention, R2Each independently selected from hydrogen atom, hydroxyl group, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group; preferably, R is2Each independently selected from hydrogen atom, hydroxyl, fluorine, chlorine, bromine, C1-4An alkyl group.
In one embodiment of the invention, R3Each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6An alkoxy group.
In one embodiment of the invention, R3Each independently selected from hydrogen atom, hydroxyl group, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group; preferably, R is3Each independently selected from hydrogen atom, hydroxyl, fluorine, chlorine, bromine, C1-4An alkyl group.
In one embodiment of the invention, R4Each independently selected from hydrogen atom, hydroxyl group, halogen atom, carboxyl group, nitro group, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6Alkoxy, or, two R4Form a 5-6 membered cyclic group with the atom to which it is attached.
In one embodiment of the present invention, it is preferable that R is4Each independently selected from hydrogen atom, hydroxyl group, halogen atom, C1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkyl radical C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkoxy, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached.
In one embodiment of the invention, R4Selected from hydrogen atom, hydroxyl group, mercapto group, halogen atom, C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkyl radical, C1-4Alkyl radical C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkoxy, halo C1-4Alkoxy, or, two R4May form a 5-6 membered oxygen containing cyclic group with the atom to which it is attached.
In one embodiment of the invention, RaIs absent or, at each occurrence, is independently selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, -NRbRc、-C(O)Rd、-C(O)NRbRc、-NRbC(O)RdC optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6An alkoxy group.
In one embodiment of the invention, RaIs absent or, at each occurrence, is independently selected from the group consisting of a hydrogen atom, a hydroxyl group, a halogen atom, a carboxyl group, a nitro group, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkyl group.
In the present inventionIn one embodiment of the invention, RaIs absent or, at each occurrence, is independently selected from hydrogen atom, C1-6Alkyl radical, C1-6An alkoxy group.
In one embodiment of the invention, Rb、RcEach being absent or, at each occurrence, independently selected from a hydrogen atom, C optionally substituted by a substituent1-6An alkyl group.
In one embodiment of the invention, Rb、RcEach being absent or, at each occurrence, independently selected from hydrogen atom, C1-6Alkyl, halo C1-6An alkyl group.
In one embodiment of the invention, Rb、RcEach being absent or, at each occurrence, independently selected from hydrogen atom, C1-6An alkyl group.
In one embodiment of the invention, RdIs absent or, at each occurrence, is independently selected from hydroxy, halogen atom, amino, -amino (C optionally substituted by a substituent)1-6Alkyl radical)1-2C optionally substituted by a substituent1-6Alkyl, C optionally substituted by substituents1-6An alkoxy group.
In one embodiment of the invention, RdIs absent or, at each occurrence, is independently selected from hydroxy, amino, -amino (C)1-6Alkyl radical)1-2、C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkoxy group.
In one embodiment of the invention, RdIs absent or, at each occurrence, is independently selected from hydroxy, amino, C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy, halo C1-4An alkoxy group.
In one embodiment of the invention, R' is selected from the group consisting of 3-8 membered cycloalkyl optionally substituted by a substituent, 3-8 membered cycloalkenyl optionally substituted by a substituent, 3-10 membered heterocyclyl optionally substituted by a substituent, 6-10 membered aryl optionally substituted by a substituent, and 5-6 membered heteroaryl optionally substituted by a substituent.
In one embodiment of the invention, R' is selected from the group consisting of 3-6 membered cycloalkyl optionally substituted by a substituent, 4-7 membered heterocyclyl optionally substituted by a substituent, 6-10 membered aryl optionally substituted by a substituent and 5-6 membered heteroaryl optionally substituted by a substituent.
In one embodiment of the invention R' is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, oxetanyl, oxolanyl, oxocyclohexyl, oxepanyl, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl.
In one embodiment of the present invention, the substituents in "optionally substituted with a substituent" are each independently selected from: hydroxy, mercapto, amino, carboxyl, cyano, nitro, halogen atom, C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkyl radical C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkoxy radical, C1-6Alkylamino radical, (C)1-6Alkyl radical)2Amino group, C1-6Alkylaminocarbonyl, (C)1-6Alkyl radical)2Aminocarbonyl group, C1-6Alkylcarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkylcarbonylamino, C1-6Alkylsulfonylamino, halo C1-6Alkyl, halo C1-6Alkoxy radical, C1-6Alkylsulfonyl radical, C1-6Alkylthio, 3-8 membered cycloalkyl, 6-10 membered aryl, 3-8 membered heterocyclyl, 5-6 membered heteroaryl and oxo.
In one embodiment of the present invention, the substituents in "optionally substituted with a substituent" are each independently selected from: hydroxy, mercapto, amino, carboxyl, cyano, nitro, halogen atom, C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkyl radical C1-4Alkoxy radical, C1-4Alkoxy radical C1-4Alkoxy radical, C1-4Alkylamino radical、(C1-4Alkyl radical)2Amino group, C1-4Alkylaminocarbonyl, (C)1-4Alkyl radical)2Aminocarbonyl group, C1-4Alkylcarbonyl group, C1-4Alkylcarbonyloxy, C1-4Alkylcarbonylamino, C1-4Alkylsulfonylamino, halo C1-4Alkyl, halo C1-4Alkoxy radical, C1-4Alkylsulfonyl radical, C1-4Alkylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, naphthyl, oxetanyl, oxolanyl, oxocyclohexyl, oxepanyl, pyrrolyl, furanyl, thienyl, oxazolyl, isoxazolyl, pyrazolyl, thiazolyl, pyridyl, pyrimidinyl, pyridazinyl and oxo.
In one embodiment of the invention, n is 0, 1,2,3 or 4.
In one embodiment of the invention, q is 0, 1,2,3 or 4.
In one embodiment of the invention, L is selected from-NRb-, -O-and-S-.
In one embodiment of the present invention, R represents a group represented by the formula (b '), and a six-membered ring in the group represented by the formula (b') is represented by any one of the following formulae
in the present invention, among the groups represented by the formulae (a '), (b ') and (c ')
In one embodiment of the present invention, in the compound represented by formula (I) of the present invention, there is no case where three or more N atoms as ring-constituting atoms are directly bonded.
In one embodiment of the present invention, in the compound represented by formula (I) of the present invention, two or more carbonyl groups (C ═ O) are not present in the ring in a direct bond.
In one embodiment of the present invention, only one C ═ O is present on the ring of formula (a').
In one embodiment of the present invention, only one C ═ O is present on the ring of formula (b').
In one embodiment of the present invention, only one C ═ O is present on the ring of formula (C').
In one embodiment of the present invention, X1、X2Each independently selected from CRaRaAnd NRb，X3Represents C ═ O.
In one embodiment of the present invention, X1Or X2When C is not O, X4Is not NRb。
In one embodiment of the present invention, X4Is not NRb。
In one embodiment of the present invention, X1And X2At least one is NRb，X3Represents C ═ O.
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 and 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" of the present invention includes sarcoma, lymphoma and cancer, and specifically may include lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal carcinoma of breast, head and neck cancer, endometrial cancer, corpus carcinoma, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-hodgkin's lymphoma, large intestinal villous adenoma, melanoma, cytoma and sarcoma.
The related diseases caused by NTRK comprise non-small cell lung cancer, colorectal cancer, similar breast secretory carcinoma, sarcoma, astrocytoma, glioblastoma, Spitz-like melanoma, cholangiocarcinoma, papillary thyroid carcinoma, mammary secretory carcinoma, breast cancer-unknown pathological type and the like.
In the present invention, the expression "A/and B" means A alone or both A and B. For example, "TAM family kinase/and CSF1R kinase" refers to "TAM family kinase" alone or both "TAM family kinase" and "CSF 1R kinase".
"stereoisomers" of the compounds of formulae (I), (II), (III) and (IV) of the present invention means that when asymmetric atoms are present in the compounds of formulae (I), (II), (III) and (IV), enantiomers are produced; cis-trans isomers are produced when the compound has a carbon-carbon double bond or a cyclic structure, and all enantiomers, diastereomers, racemates, cis-trans isomers, geometric isomers, epimers and mixtures thereof of the compounds of formulae (I), (II), (III) and (IV) 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 the compounds of the formulae (I), (II), (III) and (IV) according to the invention means that the isomers of the functional groups resulting from the rapid movement of an atom in two positions in the compounds of the formulae (I), (II), (III) and (IV) are referred to as tautomers, keto tautomers occur when the hydrogen in the α position of the carbonyl-containing functional group is on the α carbon, and alcoholic tautomers occur when the hydrogen in the α position of the carbonyl-containing functional group is on the oxygen of the carbonyl group.
The pharmaceutical composition comprises at least one of the compounds shown in the formulas (I), (II), (III) and (IV), and pharmaceutically acceptable salts, esters, stereoisomers and tautomers thereof.
The pharmaceutical composition comprises the compounds shown in formula (I), formula (II), formula (III) and formula (IV), or pharmaceutically acceptable salts, esters, stereoisomers, tautomers and one or more optional 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 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 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, parabens, 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 administration of the active compound may be, for example, from about 0.01 to about 100mg, from about 0.05 to about 75 mg/day, from about 0.1 to about 50 mg/day, or from about 5 to about 10 mg/day 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.
The invention relates to a method for preparing a compound of general formula (I)
The compounds of the present invention may be prepared by a variety of methods, including standard chemical methods. Any previously defined variables will continue to have the previously defined meanings unless otherwise indicated. Exemplary general synthetic methods are set forth in the schemes below and can be readily modified to prepare other compounds of the invention. The following reactions can be carried out by one skilled in the art according to conventional methods as taught in the art (e.g., Organic Synthesis 2nd, Michael b. smith etc.). Specific compounds of the invention are specifically prepared in the examples section.
A process for the preparation of a compound of formula (I),
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); alternatively, the first and second electrodes may be,
adding the formula (I-a) and the formula (I-b) into alkali, dripping a coupling reagent, stirring for complete reaction, separating to obtain the formula (I),
wherein M is1、M2、R、n、W、Cy3L and Cy4As 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.
The preparation intermediate of the compound of the general formula (I) has a structure shown as the following formula (I-a) or formula (I-c):
wherein R is1Is C1-6An alkyl group, a carboxyl group,
X1、X2、X3、X4、X5、M1、M2、R、Cy2n and
Reaction type
The compound of formula (I) can be prepared by reacting a compound of formula (I-a) with a compound of formula (I-b).
Wherein M is1、M2、R、n、W、Cy3L and Cy4As defined above.
The compounds of formula (I) can be prepared by the person skilled in the art from compounds of formula (I-a) and compounds of formula (I-b) according to methods customary in the art, the following scheme providing a process for preparing compounds of formula (I) by reacting compounds of formula (I-a) and compounds of formula (I-b):
for example, the compound of formula (I-a) is added to a suitable solvent (e.g., tetrahydrofuran, N-dimethylformamide, N-dimethylacetamide, etc., preferably N, N-dimethylformamide), a suitable peptide coupling reagent (preferably 2- (7-oxybenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate) is added, a suitable base (e.g., triethylamine, pyridine, N-diisopropylethylamine, etc., preferably N, N-diisopropylethylamine) is added, the temperature is lowered to a suitable temperature (e.g., 0 ℃) and stirring is carried out for a suitable time (e.g., 10 to 30 minutes), the compound of formula (I-b) is added, and the stirring is carried out at a suitable temperature (e.g., 0 ℃ to ambient temperature) for a suitable time (e.g., 1 to 16 hours). Concentrating the reaction solution under reduced pressure, adding appropriate amount of water, extracting with suitable extractant (such as ethyl acetate), concentrating the extractive solution, and separating the crude product by conventional purification method (such as silica gel column chromatography) to obtain compound of formula (I).
For another example, the compound of formula (I-a) and the compound of formula (I-b) are added to a suitable base (e.g., pyridine), the temperature is reduced to a suitable temperature (e.g., 0 ℃), a coupling reagent (e.g., phosphorus oxychloride) is added dropwise, stirring is carried out for a suitable time (e.g., 0.5 to 3 hours) until the reaction is completed, the reaction solution is concentrated under reduced pressure, a suitable amount of water is added, an appropriate amount of an extracting agent (e.g., ethyl acetate) is used for extraction, the extract is concentrated, and the crude product is separated by a conventional purification method (e.g., silica gel column chromatography) to obtain the compound of formula (I.
The compound of formula (I-a) can be prepared from the compound of formula (I-c).
Wherein R is1Is C1-6Alkyl radical, M1、M2R and n are as defined above. The compounds of formula (I-a) can be prepared from compounds of formula (I-c) by methods conventional to those skilled in the art, and the following scheme provides a method for preparing compounds of formula (I-a) from compounds of formula (I-c):
for example, the compound of formula (I-c) is dissolved in a suitable solvent (e.g., methanol, ethanol, tetrahydrofuran, dioxane, etc., preferably methanol), a suitable base (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, etc., preferably lithium hydroxide) is added, the mixture is stirred at a suitable temperature (e.g., room temperature) for a suitable time (e.g., 0.5 to 3 hours), after the reaction is completed, the mixture is concentrated under reduced pressure, the pH is adjusted to a suitable range (e.g., 2 to 5) with a suitable aqueous solution of an acid (e.g., hydrochloric acid, citric acid), and the compound of formula (I-a) is obtained by filtration.
The compound of formula (I-c) can be prepared by reacting a compound of formula (I-d) with a compound of formula (I-e).
Wherein R and R1LG is a leaving group such as chloro, bromo, iodo, mesylate or besylate or a boronic acid, boronic ester, M1、M2And n is as defined above. The compounds of formula (I-c) can be prepared by one skilled in the art from compounds of formula (I-d) and compounds of formula (I-e) according to methods conventional in the art, and the following scheme provides a method for preparing compounds of formula (I-c) by reacting compounds of formula (I-d) and compounds of formula (I-e):
for example, the compound of formula (I-d) and the compound of formula (I-e) (LG is a leaving group) are dissolved in a suitable solvent (such as acetonitrile, tetrahydrofuran, N-dimethylformamide, etc., preferably N, N-dimethylformamide), a suitable base (such as sodium carbonate, potassium carbonate, cesium carbonate, etc., preferably potassium carbonate) is added, the reaction is stirred at a suitable temperature (such as 50 ℃) for a suitable time (such as 10 to 16 hours), water and a suitable extractant are added after the reaction is finished, and the crude product is separated by a conventional purification means (such as silica gel column chromatography) to obtain the compound of formula (I-c).
As another example, the compound of the formula (I-d) and the compound of the formula (I-e) (LG is boric acid or a boric acid ester) are dissolved in a suitable solvent (e.g., acetonitrile, dichloromethane, chloroform, pyridine, N, N-dimethylformamide, etc., preferably N, N-dimethylformamide), and a suitable base (e.g., triethylamine, pyridine, etc.) and a suitable catalyst (e.g., copper acetate, copper chloride, etc.) are added and reacted under air or oxygen at a suitable temperature (e.g., room temperature to 50 ℃ C.) for a suitable time (e.g., 14 hours). After the reaction is finished, the crude product is obtained by conventional post-treatment (such as extraction and concentration), and the product is obtained by conventional purification means (such as silica gel column chromatography).
The compound of formula (I-b) can be prepared by reacting a compound of formula (I-b') with W-LG.
Wherein, Cy3、L、Cy4W and LG are as defined above. The compounds of formula (I-b) can be prepared from compounds of formula (I-b ') by methods conventional to those skilled in the art, and the following scheme provides a method for preparing compounds of formula (I-b) from compounds of formula (I-b'):
for example, the compound of formula (I-b') and the compound of formula W-LG are dissolved in a suitable solvent (e.g., acetonitrile, tetrahydrofuran, N-dimethylformamide, etc., preferably N, N-dimethylformamide), a suitable base (e.g., sodium carbonate, potassium carbonate, cesium carbonate, etc., preferably potassium carbonate) is added, the mixture is stirred at a suitable temperature (e.g., 50 ℃) for a suitable time (e.g., 10 to 16 hours), water and a suitable extractant are added after the reaction is completed, and the crude product is separated by a conventional purification means (e.g., silica gel column chromatography) to obtain the compound of formula (I-b).
The compound of formula (I-b) can be prepared by reacting a compound of formula (I-f).
Wherein, Cy3L and Cy4As defined above. The compounds of formula (I-b) can be prepared from compounds of formula (I-f) by one skilled in the art according to methods conventional in the art, and the following scheme provides a method for preparing compounds of formula (I-b) from compounds of formula (I-f):
for example, the compound of formula (I-f) and a suitable reducing agent (e.g., iron powder, zinc powder, stannous chloride, sodium dithionite, etc., preferably iron powder) are added to an appropriate solvent (e.g., ethanol, aqueous ammonium chloride, acetic acid, a mixture of ethanol and aqueous ammonium chloride, etc.) and reacted at an appropriate temperature (e.g., 80 ℃) for an appropriate time (e.g., 4 hours). After the reaction is completed, filtering, concentrating under reduced pressure, extracting with a suitable extracting agent (such as dichloromethane), and concentrating under reduced pressure to obtain the product.
The compound of formula (I-f) can be prepared by reacting a compound of formula (I-g) with a compound of formula (I-h).
Wherein, L, Cy4、Cy3And LG is as defined above. The preparation of compounds of formula (I-f) from compounds of formula (I-g) and compounds of formula (I-h) can be carried out by one skilled in the art according to methods conventional in the art, and is provided schematically below:
for example, the compound of the formula (I-g) and the compound of the formula (I-h) are added to an appropriate solvent (e.g., tetrahydrofuran, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, etc., preferably N, N-dimethylformamide), an appropriate base (e.g., potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine, etc., preferably potassium carbonate) is added, and stirred at an appropriate temperature (e.g., room temperature to 80 ℃) for an appropriate time (e.g., 14 hours). After the reaction is finished, a crude product is obtained by a conventional post-treatment method (such as filtration, extraction and the like), and then a product is obtained by separation (such as silica gel column chromatography) through a conventional purification means.
In certain embodiments, the compounds of formula (I-b) may be prepared by the following reaction.
Wherein LG, Cy3，L，Cy4And W is as defined hereinbefore. The compounds of formula (I-b) can be prepared from compounds of formula (I-l) by one skilled in the art according to methods conventional in the art, and the following scheme provides a method for preparing compounds of formula (I-b) from compounds of formula (I-l):
for example, the compound of formula (I-l) and the compound of formula (I-k) are added to an appropriate solvent (e.g., toluene, xylene, trimethylbenzene, N, N-dimethylformamide, N, N-dimethylacetamide, etc., preferably xylene), heated to an appropriate temperature (e.g., 140 ℃) and stirred for an appropriate time (e.g., 15 hours). After the reaction is finished, the compound of formula (I-I) is obtained by conventional post-treatment methods (e.g., filtration, extraction, etc.).
Adding the compound of formula (I-I) and the compound of formula (I-j) into a suitable solvent (e.g., ethanol, water, etc.), heating to a suitable temperature (e.g., 90 ℃), and after the reaction is completed, obtaining the compound of formula (I-b) by a conventional post-treatment method (e.g., concentration, extraction, filtration, etc.).
Specifically, when R represents a group represented by the general formula (b), the compound of the formula (I-c) can be produced by the following reaction.
In certain embodiments, the compounds of formula (I-c) may be prepared by the following reaction
Wherein, X1，X2，X5，X4Each independently selected from C, CH or CH2，X3Is C ═ O, R2Is alkoxy or disubstituted amino, Cy2，R1，M1、M2And n is as defined above. The compounds of formula (I-c) can be prepared from compounds of formula (I-m) by one skilled in the art according to methods conventional in the art, and the following scheme provides a method for preparing compounds of formula (I-c) from compounds of formula (I-m):
for example, the compound of the formula (I-m) is added to an appropriate solvent (e.g., toluene, xylene, trimethylbenzene, N, N-dimethylformamide, N, N-dimethylacetamide and the like, preferably toluene), an appropriate reagent (e.g., N, N-dimethylformamide dimethyl acetal, trimethyl orthoformate, triethyl orthoformate and the like, preferably N, N-dimethylformamide dimethyl acetal) is added, and heated to an appropriate temperature (e.g., 100 ℃) and stirred for an appropriate time (e.g., 15 hours). After the reaction is completed, the compound of formula (I-n) is obtained by conventional post-treatment methods (e.g., filtration, extraction, concentration, etc.).
The compound of formula (I-n) and the compound of formula (I-o) are added to a suitable solvent (e.g., ethanol, isopropanol, toluene, etc.), heated to a suitable temperature (e.g., 100 ℃) and reacted for a suitable time (e.g., 3 hours). After the reaction is completed, the compound of formula (I-c) is obtained by a conventional purification method such as silica gel column chromatography.
In still other embodiments, the compounds of formula (I-c) may be prepared by the following reaction
Wherein, X1，X5，X4Each independently selected from C, CH or CH2，X3Is C ═ O, Cy2，R1，M1、M2And n is as defined above. The compounds of formula (I-c) can be prepared from compounds of formula (I-p) by one skilled in the art according to methods conventional in the art, and the following scheme provides a method for preparing compounds of formula (I-c) from compounds of formula (I-p):
for example, the compound of formula (I-p) and the compound of formula (I-q) are added into a suitable solvent (such as dichloromethane, chloroform, 1, 2-dichloroethane, etc., preferably dichloromethane), cooled to a suitable temperature (such as 0 ℃), added with a suitable base (such as potassium carbonate, sodium hydroxide, etc., preferably potassium carbonate), slowly warmed to room temperature for a suitable time (such as 3-15 hours), and after the reaction is finished, the compound of formula (I-r) is obtained by a conventional purification method (such as silica gel column chromatography).
The compound of formula (I-r) is added to a suitable solvent (e.g., toluene, xylene, trimethylbenzene, N, N-dimethylformamide, N, N-dimethylacetamide, etc., preferably toluene), a suitable reagent (e.g., N, N-dimethylformamide dimethyl acetal, trimethyl orthoformate, triethyl orthoformate, etc., preferably N, N-dimethylformamide dimethyl acetal) is added, and heated to a suitable temperature (e.g., 110 ℃) and stirred for a suitable time (e.g., 15 hours). After the reaction is finished, the compound of formula (I-c) is obtained by conventional post-treatment methods (such as filtration, extraction, concentration, etc.) and purification methods (such as silica gel column chromatography).
In still other embodiments, the compounds of formula (I-c) may be prepared by the following reaction scheme
Wherein, X2，X5，X4Each independently selected from C, CH or CH2，X3Is C ═ O, Cy2，R1，M1、M2And n is as defined above. The compounds of formula (I-c) can be prepared from compounds of formula (I-s) by one skilled in the art according to methods conventional in the art, and the following scheme provides a method for preparing compounds of formula (I-c) from compounds of formula (I-s):
for example, the compound of formula (I-s) and the compound of formula (I-t) are added to an appropriate solvent (e.g., methanol, ethanol, isopropanol, etc., preferably ethanol) and reacted at an appropriate temperature (e.g., 80 ℃) for an appropriate time (e.g., 15 hours). After the reaction is finished, the compound of formula (I-u) is obtained by a conventional purification method (e.g., silica gel column chromatography).
The compound of formula (I-u) is added to a suitable solvent (e.g., tetrahydrofuran, 2-methyltetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide, ethanol, etc., preferably 2-methyltetrahydrofuran), cooled to a suitable temperature (e.g., 0 deg.C), added with a suitable base (e.g., sodium hydride, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, etc., preferably potassium tert-butoxide), and stirred at a suitable temperature (e.g., room temperature) for a suitable time (e.g., 15 hours). After the reaction is finished, adjusting the pH value of the reaction solution to a proper value (such as 5-6), and obtaining the compound shown in the formula (I-v) by a conventional post-treatment method (such as filtration, extraction, concentration and the like) and a purification method (such as silica gel column chromatography).
Adding the compound of formula (I-v) into a suitable solvent (such as acetonitrile), adding a suitable oxidant (such as copper chloride), and raising the temperature (such as 80 ℃) to react for a suitable time (such as 2-4 hours). After the reaction is finished, the compound of formula (I-c) is obtained by conventional post-treatment methods (such as filtration, extraction, concentration, etc.) and purification methods (such as silica gel column chromatography).
Wherein the compound of formula (I-t) can be prepared by the following reaction formula:
wherein, X2，X5Each independently selected from CH or CH2PG is a protecting group (e.g., tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, p-methoxybenzyl, etc.), R1，M1、M2And n is as defined above, n.gtoreq.1. The compounds of formula (I-t) can be prepared from compounds of formula (I-w) by one skilled in the art according to methods conventional in the art, and the following scheme provides a method for preparing compounds of formula (I-t) from compounds of formula (I-w):
for example, the compound of formula (I-w) and the compound of formula (I-x) are added to a suitable solvent (e.g., dichloromethane, methanol, ethanol, etc., preferably dichloromethane), an appropriate acid (e.g., acetic acid) and a dehydrating agent (e.g., magnesium sulfate) are added, an appropriate reducing agent (e.g., sodium triacetoxyborohydride, sodium cyanoborohydride, etc.) is further added, and the reaction is carried out at an appropriate temperature (e.g., room temperature) for an appropriate time (e.g., 15 hours). After the reaction is completed, the compound of formula (I-y) is obtained by conventional post-treatment methods (e.g., filtration, extraction, concentration, etc.).
The compound of formula (I-y) and the compound of formula (I-z) are added to an appropriate solvent (e.g., ethanol) and reacted at an appropriate temperature (e.g., 80 ℃) for an appropriate time (e.g., 15 hours). After the reaction is finished, the compound of the formula (I-a1) is obtained by conventional post-treatment methods (such as filtration, extraction, concentration and the like) and purification methods (such as silica gel column chromatography).
The compound of formula (I-a1) is treated by a suitable deprotection method (e.g., acid, base, hydrogenation, oxidation, etc.), and the compound of formula (I-t) is obtained by conventional post-treatment methods (e.g., filtration, extraction, concentration, etc.) and purification methods (e.g., recrystallization, silica gel column chromatography, etc.).
In still other embodiments, the compound of formula (I-a1) may be prepared by the following reaction scheme:
wherein, X2，X5Each independently selected from CH or CH2PG is a protecting group (e.g., tert-butoxycarbonyl, benzyloxycarbonyl, acetyl, p-methoxybenzyl, etc.), LG is a leaving group (e.g., benzenesulfonate, methanesulfonate, etc.), R is1，M1、M2And n is as defined above. The compounds of formula (I-a1) can be prepared from compounds of formula (I-o) by methods conventional to those skilled in the art, and the following scheme provides a method for preparing compounds of formula (I-a1) from compounds of formula (I-o):
for example, the compound of formula (I-o) is dissolved in a suitable solvent (e.g., ethanol), and the compound of formula (I-z) is added at a suitable temperature (e.g., 0 ℃ to room temperature) and reacted for a suitable time (2 to 15 hours). After the reaction is finished, the compound of the formula (I-a2) is obtained by conventional post-treatment methods (such as filtration, extraction, concentration and the like) and purification methods (such as recrystallization, silica gel column chromatography and the like).
The compound of formula (I-a2) is added to a suitable solvent (e.g. dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, etc.), a suitable base (e.g. triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, etc.) is added, the temperature is lowered to a suitable temperature (e.g. -5 ℃), the compound of formula (I-a3) is added and allowed to warm to room temperature for a suitable time (e.g. 14 hours). After the reaction is finished, the compound of the formula (I-a1) is obtained by conventional post-treatment methods (such as filtration, extraction, concentration and the like) and purification methods (such as recrystallization, silica gel column chromatography and the like).
When R represents a group represented by the general formula (b),
wherein, X1，X4，X5Each independently selected from C, CH or CH2，X2Is N, X3Is C ═ O, Cy2As hereinbefore describedAs defined. The compounds of formula (I-d) can be prepared by the following reaction scheme:
wherein LG is a leaving group (e.g. chloro), PG is a protecting group (preferably t-butyloxycarbonyl), R1As defined above. The compounds of formula (I-d) can be prepared from compounds of formula (I-d3) by methods conventional to those skilled in the art, and the following scheme provides a method for preparing compounds of formula (I-d) from compounds of formula (I-d 3):
for example, the compound of formula (I-d3) is dissolved in a suitable solvent (e.g., ethyl acetate), cooled to a suitable temperature (e.g., 0 deg.C), and the compound of formula (I-d4) is added and allowed to warm to room temperature for a suitable time (e.g., 15 hours). After the reaction is finished, adding a proper base (such as potassium carbonate) for quenching, and obtaining the compound of the formula (I-d5) by a conventional post-treatment method (such as filtration, extraction, concentration and the like) and a purification method (such as recrystallization, silica gel column chromatography and the like).
The compound of formula (I-d5) is dissolved in a suitable solvent (e.g. methyl tert-butyl ether), cooled to a suitable temperature (e.g. 0 deg.C), and an appropriate reducing agent (e.g. triphenylphosphine, tri-n-butylphosphine etc., preferably tri-n-butylphosphine) is added and allowed to warm to room temperature for a suitable time (e.g. 15 hours). After the reaction is finished, the compound of formula (I-d6) is obtained by conventional post-treatment methods (such as filtration, extraction, concentration and the like) and purification methods (such as recrystallization, silica gel column chromatography and the like).
The compound of formula (I-d6) is dissolved in a suitable solvent (e.g. dichloromethane, tetrahydrofuran, etc.), cooled to a suitable temperature (e.g. 0 deg.C), added with a suitable base (e.g. triethylamine, N, N-diisopropylethylamine, potassium carbonate, sodium carbonate, etc., preferably triethylamine) and a suitable protecting group reagent (e.g. di-tert-butyl dicarbonate), and allowed to react at room temperature for a suitable period of time (e.g. 15 hours). After the reaction is finished, the compound of formula (I-d7) is obtained by conventional post-treatment methods (such as filtration, extraction, concentration and the like) and purification methods (such as recrystallization, silica gel column chromatography and the like).
The compound of formula (I-d7) is added to a suitable solvent (e.g., toluene, xylene, trimethylbenzene, N, N-dimethylformamide, N, N-dimethylacetamide, etc., preferably toluene), a suitable reagent (e.g., N, N-dimethylformamide dimethyl acetal, trimethyl orthoformate, triethyl orthoformate, etc., preferably N, N-dimethylformamide dimethyl acetal) is added, and the mixture is heated to a suitable temperature (e.g., 60 ℃) and stirred for a suitable time (e.g., 15 hours). After the reaction is finished, the compound of formula (I-d) is obtained by conventional post-treatment methods (such as filtration, extraction, concentration, etc.) and purification methods (such as recrystallization, silica gel column chromatography, etc.).
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 gas, 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.
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