CN110950884B - Di-ring derivative-containing inhibitor, preparation method and application thereof - Google Patents

Di-ring derivative-containing inhibitor, preparation method and application thereof Download PDF

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CN110950884B
CN110950884B CN201910924783.5A CN201910924783A CN110950884B CN 110950884 B CN110950884 B CN 110950884B CN 201910924783 A CN201910924783 A CN 201910924783A CN 110950884 B CN110950884 B CN 110950884B
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王峰
苏熠东
牛纪凤
李凯龙
黄志强
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
Shanghai Hansoh Biomedical Co Ltd
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Abstract

The invention relates to an inhibitor containing a bicyclo derivative, a preparation method and application thereof. In particular, the present invention relates to a compound represented by the general formula (I),Processes for their preparation, pharmaceutical compositions containing them and their use as inhibitors of Acetyl-CoA carboxylase (ACC) in the treatment of diseases or conditions caused by dysregulated fatty acid metabolism.

Description

Di-ring derivative-containing inhibitor, preparation method and application thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a bicyclo-derivative inhibitor, a preparation method and application thereof.
Background
Acetyl-CoA carboxylase (ACC) is a biotin-dependent enzyme with Biotin Carboxylase (BC) and Carboxytransferase (CT) activities that catalyzes the irreversible carboxylation of Acetyl-CoA to malonyl-CoA, a first rate limiting reaction in fatty acid biosynthesis. The ACC protein is divided into three distinct regions, biotin carrier protein (biotin carrier protein), biotin carboxylase (biotin carboxylase) and carboxytransferase (transcarbonylase), respectively.
ACC mainly has two subtypes, ACC1 and ACC2, with different tissue distributions and functions, respectively. ACC1 is mainly responsible for regulating fatty acid biosynthesis, whereas ACC2 is mainly responsible for regulating fatty acid oxidative degradation. ACC1 is distributed in cytoplasm of all cells, and has high expression level in adipose tissue, and ACC2 has high expression ratio in oxidized tissue such as skeletal muscle and cardiac muscle. Fatty acid production and oxidation are both present in the liver and both subtypes are expressed very high.
The most important function of ACC is to provide malonyl-coa substrate for fatty acid biosynthesis and to regulate fatty acid metabolism. The activity of ACC in human body is strictly regulated by diet, hormone and other physiological reactions, and can be regulated by various modes such as citric acid allosteric activation, long-chain fatty acid negative feedback inhibition, phosphorylation inactivation, expression quantity and the like. The disorder of fatty acid metabolism is a major pathological feature of various metabolic diseases such as insulin resistance, hepatic steatosis, dyslipidemia, obesity, metabolic syndrome and nonalcoholic steatohepatitis (NASH), and can lead to various diseases such as type II diabetes, NASH, acne, atherosclerosis, etc. Abnormal fatty acid metabolism is also an important feature of cancer and can lead to abnormal cellular malignant hyperplasia. Inhibiting ACC activity can inhibit fatty acid synthesis and promote fatty acid oxidative decomposition, and has great potential for treating ACC related diseases such as NASH, type II diabetes, obesity, acne, atherosclerosis and tumor.
The use of the ACC inhibitor GS-0976 developed by Gilead company for treating NASH is currently in the clinical phase II study, the use of the ACC inhibitor PF-05221304 developed by the best company for treating NASH is also in the phase II clinical study, and the ACC inhibitor Olumacostat glasaretil developed by Dermira completes the clinical phase III study, but does not reach the clinical main end point, and has been stopped.
At present, no commercially available ACC inhibitor is developed for treating diseases such as NASH, type II diabetes, obesity, acne, atherosclerosis, tumor and the like. Therefore, development of an ACC inhibitor with good pharmaceutical property for treating ACC related diseases is urgently needed, and the ACC inhibitor can be used for treating various diseases such as NASH, type II diabetes, obesity, acne, atherosclerosis and tumors, and has great clinical application value.
Disclosure of Invention
The invention aims to provide a compound shown in a general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound shown in the general formula (I) has the following structure:
wherein:
ring a is selected from aryl or heteroaryl; phenyl and thienyl are preferred;
l is selected from bond, cycloalkyl, heterocyclyl, - (CR) aa R bb ) n1 -or- (CR) aa R bb ) n1 C(O)-，
R a Selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-N＝S＝O(R aa R bb )、-P(＝O)R aa R bb 、-P(＝O)(OR aa )(OR bb )、-BR aa R bb 、-B(OR aa )(OR bb )、-(CH 2 ) n1 NR aa C(＝O)R bb Or- (CH) 2 ) n1 S(O) m1 NR aa R bb Wherein said alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally further substituted with a member selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstitutedHaloalkyl, halogen, substituted or unsubstituted amino, oxo, thio, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH) 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NHR cc 、-(CH 2 ) n1 NR cc C(O)R dd And- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted by one or more substituents;
R 1 selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 C(O)NR aa R bb 、-NR aa C(S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 S(＝NR aa )(O) m1 R bb 、-(CH 2 ) n1 P(＝O) m1 R aa R bb 、-(CH 2 ) n1 [P(＝O) m1 (OR aa )(OR bb )]、-C(＝NOR aa )R bb 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 C(O)N(OR aa )R bb 、-C(O)C(O)R aa 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxo-heterocyclyl, thio-heterocyclyl, aryl, and heteroaryl are optionally further substituted with a substituent selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thio, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NHR cc 、-(CH 2 ) n1 NR cc C(O)R dd And- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted by one or more substituents;
R 2 、R 3 and R is 4 Each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR bb 、-NR aa C(S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 S(＝NR aa )(O) m1 R bb 、-(CH 2 ) n1 P(＝O) m1 R aa R bb 、-C(＝NR aa )R bb 、-(CH 2 ) n1 NR bb R cc 、-N＝S＝O(R aa R bb )、-(CH 2 ) n1 C(O)NR bb R cc 、-(CH 2 ) n1 C(O)N(OR bb )R cc 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with a substituent selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thio, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH) 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NHR cc 、-(CH 2 ) n1 NR cc C(O)R dd And- (C)H 2 ) n1 NR cc S(O) m1 R dd Is substituted by one or more substituents;
alternatively, R 2 、R 3 And R is 4 Any two groups are linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl group is optionally further substituted with a substituent selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thio, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH, 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NHR cc 、-(CH 2 ) n1 NR cc C(O)R dd And- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted by one or more substituents;
R aa 、R bb 、R cc and R is dd Each independently selected from the group consisting of hydrogen, deuterium, alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, deuteroalkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further selected from deuterium, substituted or unsubstituted alkyl, halogenA substituted or unsubstituted amino group, oxo group, nitro group, cyano group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alkoxy group, substituted or unsubstituted hydroxyalkyl group, substituted or unsubstituted cycloalkyl group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, and substituted or unsubstituted heteroaryl group;
alternatively, R aa And R is bb And wherein said cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with one or more substituents selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thio, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
n is 0, 1, 2, 3 or 4;
m 1 0, 1 or 2; and is also provided with
n 1 0, 1, 2, 3, 4 or 5;
wherein the general formula (I) excludes the following compounds:
in a preferred embodiment of the invention, ring A is selected from C 6-14 Aryl or 5-14 membered heteroaryl, preferably C 6-10 Aryl, 5-10 membered heteroaryl, more preferably phenyl, naphthyl, 5-10 membered heteroaryl containing 1-3N, O or S atoms, still more preferably phenyl, thiazolyl,Thienyl, furyl or pyridyl;
l is selected from bond, C 3-6 Cycloalkyl, 3-12 membered heterocyclyl, - (CR) L1 R L2 ) n1 -or- (CR) L1 R L2 ) n1 C (O) -, preferably bond, C 3-5 Cycloalkyl, 3-8 membered heterocyclyl containing 1-3N, O or S atoms, - (CR) L1 R L2 ) n1 -or- (CR) L1 R L2 ) n1 C (O) -, further preferably bond, cyclopropyl, cyclobutyl, cyclopentyl, bridged cycloalkyl, spirocycloalkyl, -CH 2 -、-CHCl-、-CHF-、-CCl 2 -、-CF 2 -、-CHCH 3 -、-C(CH 3 ) 2 -、-C(CH 2 F) 2 -、-CH 2 C(O)-、-CHClC(O)-、-CHFC(O)-、-CCl 2 C(O)-、-CF 2 C(O)-、-CHCH 3 C(O)-、-C(CH 3 ) 2 C (O) -or-C (CH) 2 F) 2 C (O) -; more preferably bond, -CH 2 -、-CHCl-、-CHF-、-CCl 2 -、-CF 2 -、-CHCH 3 -、-C(CH 3 ) 2 -、-C(CH 2 F) 2 -、-CH 2 C(O)-、-CHClC(O)-、-CHFC(O)-、-CCl 2 C(O)-、-CF 2 C(O)-、-CHCH 3 C(O)-、-C(CH 3 ) 2 C(O)-、-C(CH 2 F) 2 C(O)-、
R L1 Or R is L2 Each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, hydroxyalkyl, haloalkoxy, halogen, cyano, nitro, hydroxy, amino, alkenyl or alkynyl, preferably hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy, halogen, cyano, nitro, hydroxy or amino, more preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkoxy, halogen, cyano, nitro, hydroxy or amino, further preferably hydrogen, deuterium, methyl, ethyl, propyl, C containing 1-3F, cl or Br atoms 1-3 Alkyl, methoxy, ethoxy, propoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, C containing 1-3F, cl or Br atoms 1-3 Alkoxy, fluoro, chloro, bromo, cyano, nitro, hydroxy or amino;
each R a Independently selected from hydrogen, deuterium, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-6 Deuterated alkyl, substituted or unsubstituted C 1-6 Haloalkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Hydroxyalkyl, substituted or unsubstituted C 1-6 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-7 Cycloalkyl, substituted or unsubstituted 3-12 membered heterocyclyl, substituted or unsubstituted C 6-14 Aryl, substituted or unsubstituted 5-14 membered heteroaryl, - (CH) 2 ) n1 R a1 、-(CH 2 ) n1 OR a1 、-NR a1 C(O)(CH 2 ) n1 OR a1 、-NR a1 C(S)(CH 2 ) n1 OR a2 、-(CH 2 ) n1 SR a1 、-(CH 2 ) n1 C(O)R a1 、-(CH 2 ) n1 C(O)OR a1 、-(CH 2 ) n1 S(O) m1 R a1 、-(CH 2 ) n1 NR a1 R a2 、-(CH 2 ) n1 C(O)NR a1 R a2 、-N＝S＝O(R a1 R a2 )、-P(＝O)R a1 R a2 、-P(＝O)(OR a1 )(OR a2 )、-BR a1 R a2 、-B(OR a1 )(OR a2 )、-(CH 2 ) n1 NR a1 C(＝O)R a2 Or- (CH) 2 ) n1 S(O) m1 NR a1 R a2 Preferably hydrogen, deuterium, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 1-3 Deuterated alkyl, substituted or unsubstituted C 1-3 Haloalkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 1-3 Hydroxyalkyl, substituted or unsubstituted C 1-3 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, substituted or unsubstituted C 2-5 Alkenyl, substituted or unsubstituted C 2-5 Alkynyl, substituted or unsubstituted C 3-6 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl, - (CH) 2 ) n1 R a1 、-(CH 2 ) n1 OR a1 、-NR a1 C(O)(CH 2 ) n1 OR a2 、-NR a1 C(S)(CH 2 ) n1 OR a2 、-(CH 2 ) n1 SR a1 、-(CH 2 ) n1 C(O)R a1 、-(CH 2 ) n1 C(O)OR a1 、-(CH 2 ) n1 S(O) m1 R a1 、-(CH 2 ) n1 NR a1 R a2 、-(CH 2 ) n1 C(O)NR a1 R a2 、-N＝S＝O(R a1 R a2 )、-P(＝O)R a1 R a2 、-P(＝O)(OR a1 )(OR a2 )、-BR a1 R a2 、-B(OR a1 )(OR a2 )、-(CH 2 ) n1 NR a1 C(＝O)R a2 Or- (CH) 2 ) n1 S(O) m1 NR a1 R a2 More preferably hydrogen, deuterium, substituted or unsubstituted C 1-3 Alkyl, substituted or unsubstituted C 1-3 Deuterated alkyl, substituted or unsubstituted C 1-3 Haloalkyl, substituted or unsubstituted C 1-3 Alkoxy, substituted or unsubstituted C 1-3 Hydroxyalkyl, substituted or unsubstituted C 1-3 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, substituted or unsubstituted C 2-5 Alkenyl, substituted or unsubstituted C 2-5 Alkynyl, substituted or unsubstitutedC of (2) 3-6 Cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group containing 1-3N, O or S atoms, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1-3N, O or S atoms, - (CH) 2 ) n1 R a1 、-NR a1 C(O)(CH 2 ) n1 OR a1 、-NR a1 C(S)(CH 2 ) n1 OR a2 、-(CH 2 ) n1 S(O) m1 R a1 、-(CH 2 ) n1 NR a1 R a2 、-(CH 2 ) n1 C(O)NR a1 R a2 、-N＝S＝O(R a1 R a2 )、-P(＝O)R a1 R a2 、-P(＝O)(OR a1 )(OR a2 )、-B(OR a1 )(OR a2 )、-(CH 2 ) n1 NR a1 C(＝O)R a2 Or- (CH) 2 ) n1 S(O) m1 NR a1 R a2 Further preferred are hydrogen, deuterium, methyl, ethyl, propyl, fluorine, chlorine, bromine, cyano, cyclopropyl, cyclobutyl, cyclopentyl, -CH 2 F、-CH 2 CH 2 F、-CHF 2 、-CH 2 CHF 2 、-CF 3 、-CH 2 CF 3 、-CH 2 Cl、-CH 2 CH 2 Cl、-CHCl 2 、-CH 2 CHCl 2 、-CCl 3 、-CH 2 CCl 3 、
R a1 Or R is a2 Independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or amino, preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or amino, more preferably hydrogen, deuterium, methyl,Ethyl, propyl, methoxy, ethoxy, propoxy, amino, -NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-NHCH 2 CH 3 or-N (CH) 2 CH 3 ) 2 ；
Alternatively, R a1 And R is a2 Linked to one or more N, O, S, P, B heteroatoms to form a 3-8 membered heterocyclyl or 5-10 membered heteroaryl, preferably a 3-6 membered heterocyclyl or 5-8 membered heteroaryl, more preferably a 3-5 membered heterocyclyl or 5-6 membered heteroaryl, even more preferably
R 1 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, C 6-12 Aryl, 5-12 membered heteroaryl, - (CH) 2 ) n1 C(O)OR 1a 、-(CH 2 ) n1 C(O)NR 1a R 1b 、-NR 1a C(S)(CH 2 ) n1 OR 1b 、-(CH 2 ) n1 SR 1a 、-(CH 2 ) n1 C(O)R 1a 、-(CH 2 ) n1 S(O) m1 R 1a 、-(CH 2 ) n1 S(＝NR 1a )(O) m1 R 1b 、-(CH 2 ) n1 P(＝O) m1 R 1a R 1b 、-(CH 2 ) n1 [P(＝O) m1 (OR 1a )(OR 1b )]、-C(＝NOR 1a )R 1b 、-(CH 2 ) n1 NR 1a R 1b 、-(CH 2 ) n1 C(O)NR 1a R 1b 、-(CH 2 ) n1 C(O)N(OR 1a )R 1b 、-C(O)C(O)R 1a 、-(CH 2 ) n1 NR 1a C(O)R 1b Or- (CH) 2 ) n1 NR 1a S(O) m1 R 1b Preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, - (CH) 2 ) n1 C(O)OR 1a 、-(CH 2 ) n1 C(O)NR 1a R 1b 、-NR 1a C(S)(CH 2 ) n1 OR 1b 、-(CH 2 ) n1 SR 1a 、-(CH 2 ) n1 C(O)R 1a 、-(CH 2 ) n1 S(O) m1 R 1a 、-(CH 2 ) n1 S(＝NR 1a )(O) m1 R 1b 、-(CH 2 ) n1 P(＝O) m1 R 1a R 1b 、-(CH 2 ) n1 [P(＝O) m1 (OR 1a )(OR 1b )]、-C(＝NOR 1a )R 1b 、-(CH 2 ) n1 NR 1a R 1b 、-(CH 2 ) n1 C(O)NR 1a R 1b 、-(CH 2 ) n1 C(O)N(OR 1a )R 1b 、-C(O)C(O)R 1a 、-(CH 2 ) n1 NR 1a C(O)R 1b Or- (CH) 2 ) n1 NR 1a S(O) m1 R 1b More preferably cyano, 3-6 membered heterocyclic group containing 1-4N, O or S atoms, C 6-10 Aryl, 5-to 10-membered heteroaryl containing 1-4N, O or S atoms, - (CH) 2 ) n1 C(O)OR 1a 、-(CH 2 ) n1 C(O)NR 1a R 1b 、-(CH 2 ) n1 S(＝NR 1a )(O) m1 R 1b 、-(CH 2 ) n1 P(＝O) m1 R 1a R 1b 、-(CH 2 ) n1 [P(＝O) m1 (OR 1a )(OR 1b )]、-C(＝NOR 1a )R 1b 、-(CH 2 ) n1 NR 1a R 1b 、-(CH 2 ) n1 C(O)NR 1a R 1b 、-(CH 2 ) n1 C(O)N(OR 1a )R 1b 、-C(O)C(O)R 1a 、-(CH 2 ) n1 NR 1a C(O)R 1b Or- (CH) 2 ) n1 NR 1a S(O) m1 R 1b Wherein said 3-6 membered heterocyclyl or 5-10 membered heteroaryl is optionally further substituted with one or more substituents selected from oxo, thio, hydroxy, methyl, ethyl, propyl, amino, fluoro, chloro, bromo, methoxy, ethoxy or propoxy; further preferred are-C (O) OH, -C (O) NH 2 、-C(O)NHCH(CH 3 ) 2 、-C(O)N(CH 3 ) 2 、-CN、-C(O)NHOCH 3 、-C(O)NHOH、-C(O)NHOC(CH 3 ) 3 、-C(O)NOHCH 3 、-C(O)C(O)NH 2 、
R 1a Or R is 1b Each independently selected from hydrogen, deuterium, hydroxy, amino, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 6-10 Aryloxy, preferably hydrogen, deuterium, hydroxy, amino, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy or C 6-9 Aryloxy, more preferably hydrogen, deuterium, hydroxy, amino, -CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 、-OCH 3 、-OCH 2 CH 3 、-OCH 2 CH 2 CH 3 、-OC(CH 3 ) 3 Or (b)
Alternatively, R 1a And R is 1b Linked to 1-4N, O or S atoms to form a heterocyclic or heteroaryl group, preferably C 3-8 Heterocyclyl or 3-8 membered heteroaryl, more preferably C 3-6 Heterocyclyl or 3-6 membered heteroaryl, further preferred
R 2 、R 3 And R is 4 Each independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl, - (CH) 2 ) n1 R 2a 、-(CH 2 ) n1 OR 2a 、-NR 2a C(O)(CH 2 ) n1 OR 2b 、-NR 2a C(S)(CH 2 ) n1 OR 2b 、-(CH 2 ) n1 SR 2a 、-(CH 2 ) n1 C(O)R 2a 、-(CH 2 ) n1 C(O)OR 2a 、-(CH 2 ) n1 S(O) m1 R 2a 、-(CH 2 ) n1 S(＝NR 2a )(O) m1 R 2b 、-(CH 2 ) n1 P(＝O) m1 R 2a R 2b 、-C(＝NR 2a )R 2b 、-(CH 2 ) n1 NR 2b R 2c 、-N＝S＝O(R 2a R 2b )、-(CH 2 ) n1 C(O)NR 2b R 2c 、-(CH 2 ) n1 C(O)N(OR 2b )R 2c 、-(CH 2 ) n1 NR 2a C(O)R 2b Or- (CH) 2 ) n1 NR 2a S(O) m1 R 2b Preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl, 5-12 membered heteroaryl, - (CH) 2 ) n1 R 2a 、-(CH 2 ) n1 OR 2a 、-NR 2a C(O)(CH 2 ) n1 OR 2b 、-NR 2a C(S)(CH 2 ) n1 OR 2b 、-(CH 2 ) n1 SR 2a 、-(CH 2 ) n1 C(O)R 2a 、-(CH 2 ) n1 C(O)OR 2a 、-(CH 2 ) n1 S(O) m1 R 2a 、-(CH 2 ) n1 S(＝NR 2a )(O) m1 R 2b 、-(CH 2 ) n1 P(＝O) m1 R 2a R 2b 、-C(＝NR 2a )R 2b 、-(CH 2 ) n1 NR 2b R 2c 、-N＝S＝O(R 2a R 2b )、-(CH 2 ) n1 C(O)NR 2b R 2c 、-(CH 2 ) n1 C(O)N(OR 2b )R 2c 、-(CH 2 ) n1 NR 2a C(O)R 2b Or- (CH) 2 ) n1 NR 2a S(O) m1 R 2b More preferably hydrogen, deuterium, C 1-3 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl, 5-12 membered heteroaryl, - (CH) 2 ) n1 R 2a 、-(CH 2 ) n1 OR 2a 、-N＝S＝O(R 2a R 2b ) Or- (CH) 2 ) n1 NR 2a S(O) m1 R 2b Wherein said C 1-3 Alkoxy, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl, optionally further substituted with a member selected from deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, fluoro, chloro, bromo, amino, oxo, thio, nitro, cyano, hydroxy, -CH 2 F、-CH 2 CH 2 F、-CH 2 CH 2 CH 2 F、-CH 2 CHFCH 3 、-CHFCH 2 CH 3 、-CHF 2 、-CH 2 CHF 2 、-CH 2 CH 2 CHF 2 、-CH 2 CF 2 CH 3 、-CF 2 CH 2 CH 3 、-OCH 2 F、-OCH 2 CH 2 F、-OCH 2 CH 2 CH 2 F、-OCH 2 CHFCH 3 、-OCHFCH 2 CH 3 、-OCHF 2 、-OCH 2 CHF 2 、-OCH 2 CH 2 CHF 2 、-OCH 2 CF 2 CH 3 or-OCF 2 CH 2 CH 3 Is further preferably hydrogen, deuterium, -OCH (CH) 3 ) 2 、
Alternatively, R 2 、R 3 And R is 4 Any two groups being linked to form a C 3-20 Cycloalkyl, 3-20 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, wherein said C 3-20 Cycloalkyl, 3-20 membered heterocyclyl, C 6-14 Aryl OR 5-14 membered heteroaryl, optionally further substituted with a member selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, fluoro, chloro, bromo, oxo, thio, nitro, cyano, hydroxy OR-OR 2d Is substituted by one or more substituents; preferably C 3-14 Cycloalkyl, 6-14 membered heterocyclyl, C 6-10 Aryl or 5-to 10-membered heteroaryl, more preferably C 6-14 Cycloalkyl, 6-14 membered heterocyclyl containing 1-4N, O or S atoms, C 6-10 Aryl or 5-to 10-membered heteroaryl containing 1-4N, O or S atoms, further preferred
R 2a 、R 2b 、R 2c And R is 2d Each independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen,Amino, nitro, hydroxy, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, wherein said C 1-6 Alkyl, C 3-14 Cycloalkyl, 3-14 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, optionally further substituted with one or more substituents selected from fluoro, chloro, bromo, methyl, ethyl, propyl, hydroxy, amino, oxo, thio, formyl, acetyl, methanesulfonyl, ethanesulfonyl; preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-to 12-membered heteroaryl, more preferably hydrogen, deuterium, C 1-3 Alkyl, C 3-10 Cycloalkyl or 3-to 10-membered heterocyclic group containing 1 to 3N, O or S atoms, more preferably hydrogen, deuterium, methyl, ethyl, propyl,
Alternatively, R 2a 、R 2b And R is 2c And 1 to 4N, O or S atoms, preferably 3 to 6 membered heterocyclic groups, more preferably 5 to 6 membered heterocyclic groups, even more preferably 5 to 6 membered heterocyclic groups containing S.
In a preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (II):
wherein:
R 5 selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl,alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl or heteroaryl;
R 6 selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-N＝S＝O(R aa R bb )、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-P(＝O)(R aa )(R bb )、-P(＝O)(OR aa )(OR bb )、-B(OR aa )(OR bb )、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 S(O) m1 NR aa R bb Wherein said alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally further substituted with a substituent selected from deuterium, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted haloalkyl, halogen, substituted or unsubstituted amino, oxo, thio, nitro, cyano, hydroxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, - (CH) 2 ) n1 R cc 、-(CH 2 ) n1 OR cc 、-(CH 2 ) n1 SR cc 、-(CH 2 ) n1 C(O)R cc 、-(CH 2 ) n1 C(O)OR cc 、-(CH 2 ) n1 S(O) m1 R cc 、-(CH 2 ) n1 NR cc R dd 、-(CH 2 ) n1 C(O)NR cc R dd 、-(CH 2 ) n1 C(O)NHR cc 、-(CH 2 ) n1 NR cc C(O)R dd And- (CH) 2 ) n1 NR cc S(O) m1 R dd Is substituted by one or more substituents;
L、R 1 ～R 4 、R aa 、R bb 、R cc 、R dd m1 and n1 are as defined in formula (I).
In a preferred embodiment of the invention, R 5 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl, 3-8 membered heterocyclic group, C 6-12 Aryl or 5-to 12-membered heteroaryl, preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, 3-6 membered heterocyclic group, C 6-10 Aryl or 5-to 10-membered heteroaryl, more preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, halogen, cyano, C 3-6 Cycloalkyl or C 3-6 Halogenated cycloalkyl, more preferably hydrogen, deuterium, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluoro, chloro, bromo, cyano, acetonitrile, propionitrile,
R 6 Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, halogen, amino, nitro, hydroxy, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, C 6-12 Aryl, 5-12 membered heteroaryl, -n=s=o (R a1 R bb )、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-P(＝O)(R aa )(R bb )、-P(＝O)(OR aa )(OR bb )、-B(OR aa )(OR bb )、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 S(O) m1 NR aa R bb Wherein said C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, C 6-12 Aryl and 5-12 membered heteroaryl, optionally further substituted with one or more substituents selected from deuterium, halogen, oxo or thioxo; preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, halogen, amino, nitro, hydroxy, cyano, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-5 Cycloalkyl, 3-6 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, -n=s=o (R a1 R a2 )、-(CH 2 ) n1 S(O) m1 NR a1 R a2 、-P(＝O)(R a1 )(R a2 )、-P(＝O)(OR a1 )(OR a2 )、-B(OR a1 )(OR a2 )、-(CH 2 ) n1 NR a1 C(O)R a2 Or- (CH) 2 ) n1 S(O) m1 NR a1 R a2 More preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Hydroxyalkyl group containing 1-4N,O, S, P or 3-6 membered heterocyclyl for B heteroatoms, 5-10 membered heteroaryl containing 1-4N, O, S, P or B heteroatoms, -n=s=o (R a1 R a2 )、-(CH 2 ) n1 S(O) m1 NR a1 R a2 、-P(＝O)(R a1 )(R a2 )、-P(＝O)(OR a1 )(OR a2 )、-B(OR a1 )(OR a2 )、-(CH 2 ) n1 NR a1 C(O)R a2 Or- (CH) 2 ) n1 S(O) m1 NR a1 R a2 More preferably hydrogen, deuterium, methyl, ethyl, propyl, hydroxymethyl, hydroxyethyl,
R a1 Or R is a2 Independently selected from hydrogen, deuterium, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, amino, -NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-NHCH 2 CH 3 or-N (CH) 2 CH 3 ) 2 ；
Alternatively, R a1 And R is a2 Linked to one or more N, O, S, P, B heteroatoms to form a single unit
n1 or m1 is 0, 1, 2 or 3.
In a preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (III):
wherein:
ring B is selected from monocyclic aryl or fused ring aryl;
R b selected from the group consisting of hydrogen, deuterium, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, oxo-heterocyclyl, thioheterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(＝S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-N＝S＝O(R aa R bb )、-P(O)R aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb ；
Alternatively, any two adjacent or non-adjacent R b Linking to form a cycloalkyl, heterocyclyl, aryl and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl group is optionally further substituted with a moiety selected from deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n1 -、-(CH 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Is substituted by one or more substituents;
R 3 selected from- (CH) 2 ) n1 OR aa Or-n=s=o (R aa R bb )；
m is 0, 1, 2 or 3;
L、R 1 、R aa 、R bb 、R cc 、R dd m1 and n1 are as defined in formula (I).
In a preferred embodiment of the invention, ring B is selected from monocyclic aryl or C 6-14 Condensed ring aryl groups, preferably phenyl, naphthyl, More preferably phenyl, naphthyl,
R b Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 3-8 membered oxo-heterocyclyl, 3-8 membered thioheterocyclyl, C 6-12 Aryl or 5-to 12-membered heteroaryl, preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy or halogen, more preferably hydrogen, deuterium, methyl, ethyl, propyl, -CH 2 F、-CH 2 CH 2 F、-CH 2 Cl、-CH 2 CH 2 Cl, methyl etherOxy, ethoxy, propoxy, 1-3 fluorine, chlorine or bromine substituted C 1-3 Alkoxy, further preferably hydrogen, deuterium, -OCH 3 、-OCH 2 CH 3 、-OCH 2 F、-OCHF 2 、-OCH 2 Cl、-OCHCl 2 Fluorine, chlorine or bromine;
R 3 selected from- (CH) 2 ) n1 OR 2a Or-n=s=o (R 2a R 2b )；
R 2a Selected from hydrogen, deuterium, methyl, ethyl, propyl,/>
R 2b Selected from hydrogen, deuterium, methyl, ethyl or propyl;
alternatively, R 2a And R is 2b And 1 to 4N, O or S atoms, preferably 3 to 6 membered heterocyclic groups, more preferably 5 to 6 membered heterocyclic groups, even more preferably 5 to 6 membered heterocyclic groups containing S.
n1 is 0, 1, 2 or 3.
In a preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (IV):
wherein:
R aa and R is bb Each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 A haloalkyl group; or R is aa And R is bb To form a cycloalkyl group, which is optionally further substituted by a member selected from hydrogen, halogen, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl or C 1-6 Substituted by one or more substituents in alkoxy radicals；
Ring B, R 1 、R 3 、R 5 、R 6 、R b 、R aa 、R bb And m is as in formula (III).
In a preferred embodiment of the invention, R aa And R is bb Each independently selected from hydrogen, halogen, C 1-3 Alkyl or C 1-3 Haloalkyl, preferably hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, -CH 2 F、-CH 2 Cl、-CH 2 Br、-CH 2 CH 2 F、-CH 2 CH 2 Cl or-CH 2 CH 2 Br, more preferably hydrogen, methyl, ethyl, fluoro, -CH 2 F、-CH 2 Cl、-CH 2 CH 2 F or-CH 2 CH 2 Cl；
Or R is aa And R is bb Is connected to form C 3-8 Cycloalkyl group, C 3-8 Cycloalkyl is optionally further selected from hydrogen, halogen, cyano, hydroxy, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl or C 1-63 One or more substituents in the alkoxy group; preferably C 3-6 Cycloalkyl groups, more preferably C 3-5 Cycloalkyl, further preferably cyclopropyl, cyclobutyl or cyclopentyl.
In Sup>A preferred embodiment of the present invention, the compound of formulSup>A (I), sup>A stereoisomer thereof or Sup>A pharmaceutically acceptable salt thereof is further represented by formulSup>A (IV-Sup>A):
wherein:
ring B, R 1 、R 3 、R 5 、R b 、R aa 、R bb And m is as in formula (III).
In a preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (V):
wherein:
ring C is selected from cycloalkyl or heterocyclyl; wherein the cycloalkyl comprises a saturated or unsaturated 3-to 12-membered monocyclic alkyl, a saturated or unsaturated 6-to 14-membered spirocycloalkyl, a saturated or unsaturated 6-to 14-membered bridged cycloalkyl, a saturated or unsaturated 6-to 14-membered fused ring alkyl, and the heterocyclyl comprises a saturated or unsaturated 3-to 12-membered mono-heterocyclyl, a saturated or unsaturated 6-to 14-membered spirocycloalkyl, a saturated or unsaturated 6-to 14-membered bridged heterocyclyl, or a saturated or unsaturated 6-to 14-membered fused ring heterocyclyl;
R c selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2-6 Alkenyl, C 2-6 Alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocyclyl, 6-12 membered aryl, 5-12 membered heteroaryl, - (CH) 2 ) n1 R aa 、-(CH 2 ) n1 OR aa 、-NR aa C(O)(CH 2 ) n1 OR aa 、-NR aa C(S)(CH 2 ) n1 OR bb 、-(CH 2 ) n1 SR aa 、-(CH 2 ) n1 C(O)R aa 、-(CH 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 S(O) m1 R aa 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-N＝S(＝O)R aa R bb 、-P(O)R aa R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb ；
x is 0, 1, 2 or 3;
R 1 、R 5 、R 6 、R aa and R is bb As described in general formula (III).
In a preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (VI):
wherein:
ring C, R 1 、R 5 、R aa 、R bb 、R c And x is as described in formula (V).
In a preferred embodiment of the invention, ring C is selected from the group consisting of saturated or unsaturated 3-12 membered monocyclic alkyl, saturated or unsaturated 6-14 membered spirocycloalkyl, saturated or unsaturated 6-14 membered bridged cycloalkyl, saturated or unsaturated 6-14 membered fused ring alkyl, saturated or unsaturated 3-12 membered mono-heterocyclyl, saturated or unsaturated 6-14 membered spiroheterocyclyl, saturated or unsaturated 6-14 membered bridged heterocyclyl, or saturated or unsaturated 6-14 membered fused ring heterocyclyl, preferably saturated or unsaturated 3-10 membered monocyclic alkyl, saturated or unsaturated 6-12 membered spirocycloalkyl, saturated or unsaturated 6-12 membered bridged cycloalkyl, saturated or unsaturated 6-12 membered fused ring alkyl, saturated or unsaturated 3-10 membered mono-heterocyclyl, saturated or unsaturated 6-12 membered bridged or unsaturated 6-12 membered heterocyclic group, more preferably a saturated or unsaturated 3-to 8-membered monocycloalkyl group, a saturated or unsaturated 6-to 10-membered spirocycloalkyl group, a saturated or unsaturated 6-to 10-membered bridged cycloalkyl group, a saturated or unsaturated 6-to 10-membered fused ring alkyl group, a saturated or unsaturated 5-to 10-membered mono-heterocyclic group containing 1 to 3N, O or S atoms, a saturated or unsaturated 6-to 10-membered spiroheterocyclic group containing 1 to 3N, O or S atoms, a saturated or unsaturated 6-to 10-membered bridged heterocyclic group containing 1 to 3N, O or S atoms, or a saturated or unsaturated 6-to 10-membered bridged heterocyclic group containing 1 to 3N, condensed ring heterocyclic groups of 6 to 10 members of O or S atoms, further preferably-CH 3 、-CH 2 CH 3 、-CH 2 CH 2 CH 3 、-CH(CH 3 ) 2 Cyclopropyl, cyclobutyl, cyclopentyl,
R c Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, halogen, amino, nitro, hydroxy, cyano, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, - (CH) 2 ) n1 C(O)R aa Or- (CH) 2 ) n1 S(O) m1 R aa Preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, hydroxy, cyano, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl, - (CH) 2 ) n1 C(O)R aa Or- (CH) 2 ) n1 S(O) m1 R aa More preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, hydroxy, cyano, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl containing 1-3N, O or S atoms, phenyl, naphthyl, 5-10 membered heteroaryl containing 1-3N, O or S atoms, - (CH) 2 ) n1 C(O)R aa Or- (CH) 2 ) n1 S(O) m1 R aa Further preferred are hydrogen, methyl, ethyl, propyl, hydroxy, formyl, acetyl, propionyl,
R aa Selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy, preferably hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy groupOr C 1-3 Haloalkoxy, more preferably hydrogen, deuterium, methyl, ethyl or propyl.
In a preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (VII):
Wherein:
ring E is selected from saturated or unsaturated 6-14 membered fused ring alkyl, saturated or unsaturated 6-14 membered spirocycloalkyl, saturated or unsaturated 6-14 membered spiroheterocyclyl or saturated or unsaturated 6-14 membered fused ring heterocyclyl;
R d selected from hydrogen, alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or- (CH) 2 ) n1 OR aa ；
Alternatively, any two adjacent or non-adjacent R d Linking to form a cycloalkyl, heterocyclyl, aryl, and heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl, and heteroaryl group is optionally further substituted with one or more substituents selected from deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R aa selected from hydrogen, alkyl, cycloalkyl or heterocyclyl;
q is 0, 1, 2 or 3;
R 1 、R 5 and n1 is as described in formula (IV).
In a preferred embodiment of the invention, ring E is selected from saturated or unsaturated 6-14 membered bicyclic, tricyclic or tetracyclic fused ring alkyl groups, saturated or unsaturated 6-14 membered mono-, bi-or trispirocyclic heterocyclyl groups, saturated or unsaturated 6-14 membered bicyclic, tricyclic or tetracyclic fused ring heterocyclyl groups, preferably saturated or unsaturated A 6-14 membered bicyclic or tricyclic fused ring alkyl group, a saturated or unsaturated 6-14 membered mono-or bi-spirocyclic heterocyclic group, a saturated or unsaturated 6-14 membered bicyclic or tricyclic fused ring heterocyclic group, more preferably
R d Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl, 5-14 membered heteroaryl or- (CH) 2 ) n1 OR aa Preferably hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-12 Aryl, 5-12 membered heteroaryl or- (CH) 2 ) n1 OR aa More preferably hydrogen, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl,
Alternatively, any two adjacent or non-adjacent R d Linking to form a C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein said C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, cyano or hydroxy; preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C 6-10 Aryl and containing 1-3N, O or S atomsMore preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxybutyl, epoxypentyl, epoxyhexyl, phenyl, naphthyl, pyridinyl or pyranyl;
R aa selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclyl, preferably hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group containing 1-3N, O or S atoms, more preferably hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
n1 is as shown in the general formula (VII).
In a preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (VIII):
wherein:
ring W is selected from saturated or unsaturated 6-14 membered fused ring alkyl, saturated or unsaturated 6-14 membered spirocycloalkyl, saturated or unsaturated 6-14 membered spiroheterocyclyl or saturated or unsaturated 6-14 membered fused ring heterocyclyl;
R e selected from hydrogen, alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or- (CH) 2 ) n1 OR aa ；
Alternatively, any two adjacent or non-adjacent R e Linking to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl group is optionally further substituted with one or more substituents selected from deuterium, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
R aa Selected from hydrogen, alkyl, cycloalkyl or heterocyclyl;
t is 0, 1, 2 or 3;
R 1 、R 5 and n1 is as described in formula (II).
In a preferred embodiment of the invention, ring W is selected from the group consisting of saturated or unsaturated 6-14 membered bicyclic, tricyclic or tetracyclic fused ring alkyl, saturated or unsaturated 6-14 membered single-, double-, or tricyclic spirocyclic heterocyclic or saturated or unsaturated 6-14 membered bicyclic, tricyclic or tetracyclic fused ring heterocyclic, preferably saturated or unsaturated 6-14 membered double-or tricyclic fused ring alkyl, saturated or unsaturated 6-14 membered single-or bicyclic spirocyclic alkyl, saturated or unsaturated 6-14 membered single-or double-spirocyclic heterocyclic or saturated or unsaturated 6-14 membered double-or tricyclic fused ring heterocyclic, more preferably saturated or unsaturated 6-14 membered double-cyclic fused ring alkyl, saturated or unsaturated 6-14 membered single-cyclic heterocyclic or saturated or unsaturated 6-14 membered single-cyclic heterocyclic containing 1-3N, O or S atoms, or saturated or unsaturated 6-14 membered single-cyclic heterocyclic or containing 1-3N, O or S atoms, further preferably
R e Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-10 Aryl, 6-10 membered heteroaryl or- (CH) 2 ) n1 OR aa Preferably hydrogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 2-5 Alkenyl, C 2-5 Alkynyl, C 3-6 Cycloalkyl, 3-to 6-membered heterocyclyl containing 1-3N, O, or S atoms, C 6-10 Aryl, 6-to 10-membered heteroaryl containing 1-3N, O, or S atoms, or- (CH) 2 ) n1 OR aa More preferably hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy, epoxybutyl,An epoxypentyl group, an epoxyhexyl group,
Alternatively, any two adjacent or non-adjacent R e Linking to form a C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein said C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with one or more substituents selected from deuterium, halogen, amino, oxo, cyano or hydroxy; preferably C 3-6 Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C 6-10 Aryl and 5-10 membered heteroaryl containing 1-3N, O or S atoms, more preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, epoxybutyl, epoxypentyl, epoxyhexyl, phenyl, naphthyl, pyridinyl or pyranyl;
R aa selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclyl, preferably hydrogen, C 1-3 Alkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclic group containing 1-3N, O or S atoms, more preferably hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
n1 is as defined in formula (VIII).
In a preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is further represented by formula (IX):
wherein:
R 7 selected from hydrogen, alkyl, cyano, halogen, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R aa and R is bb Each independently selectFrom hydrogen, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group; or R is aa And R is bb To form a cycloalkyl group, which is optionally further substituted by a member selected from hydrogen, halogen, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl or C 1-6 One or more substituents in the alkoxy group;
z is 0, 1, 2, 3 or 4;
R 1 and R is 3 As described in general formula (III).
In a preferred embodiment of the invention, R 7 Selected from hydrogen, C 1-6 Alkyl, cyano, halogen, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-10 Aryl or 3-6 membered heteroaryl, preferably hydrogen, C 1-3 Alkyl, cyano, halogen, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl containing 1-3N, O or S atoms, C 6-10 Aryl or 3-to 6-membered heteroaryl containing 1 to 3N, O or S atoms, more preferably hydrogen, methyl, ethyl, propyl, cyano, fluoro, chloro, bromo, cyclopropyl, cyclopentyl, cyclohexyl, epoxybutyl, epoxypentyl, epoxyhexyl, phenyl, naphthyl,
R aa And R is bb Each independently selected from hydrogen, halogen, C 1-3 Alkyl or C 1-3 Haloalkyl, preferably hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl or-CH 2 F、-CH 2 CH 2 F、-CH 2 Cl or-CH 2 CH 2 Cl, more preferably hydrogen, methyl, ethyl, fluorine or-CH 2 F；
Or R is aa And R is bb Linking to form a C 3-8 Cycloalkyl group, C 3-8 Cycloalkyl optionally further substituted with one or more substituents selected from hydrogen, halogen, cyano or hydroxy; preferably C 3-6 Cycloalkyl, more preferably cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
In a preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (X):
wherein:
ring C, R 1 、R 5 、R aa 、R bb 、R c And x is as described in formula (V).
In a preferred embodiment of the present invention, the compound of formula (X), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (X-a):
In a preferred embodiment of the present invention, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is further represented by formula (XI):
wherein:
ring B, R 1 、R 5 、R b 、R aa 、R bb And m is as in formula (III).
In a preferred embodiment of the present invention, the compound of formula (XI), its stereoisomer or its pharmaceutically acceptable salt is further represented by formula (XI-A):
in Sup>A preferred embodiment of the present invention, any of the compounds of formulSup>A (III), (IV-Sup>A), (VII) or (VIII), stereoisomers thereof, or pharmaceutically acceptable salts thereof, wherein:
ring B, ring E, ring W are selected from the following groups:
in a preferred embodiment of the present invention, the compound represented by any one of the general formulae (V) and (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein:
ring C is selected from the following groups:
in a preferred embodiment of the present invention, any of the compounds of formula (I), stereoisomers thereof or pharmaceutically acceptable salts thereof, wherein,
R 1 selected from hydrogen, cyano, amino, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, 3-12 membered heterocyclyl, 6-10 membered aryl, 5-12 membered heteroaryl, - (CH) 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 S(＝NR aa )(O) m1 R bb 、-(CH 2 ) n1 P(＝O) m1 R aa R bb 、-(CH 2 ) n1 [P(＝O) m1 (OR aa )(OR bb )]、-C(＝NOR aa )R bb 、-(CH 2 ) n1 NR aa R bb 、-(CH 2 ) n1 C(O)NR aa R bb 、-(CH 2 ) n1 C(O)N(OR aa )R bb 、-(CH 2 ) n1 NR aa C(O)R bb Or- (CH) 2 ) n1 NR aa S(O) m1 R bb Wherein said C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-12 membered heteroaryl, optionally further substituted with a member selected from deuterium atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, amino, oxo, thio, nitro, cyano, hydroxy, C 1-6 Alkenyl, C 1-6 Alkynyl, C 1-6 Alkoxy or C 1-6 One or more substituents in the hydroxyalkyl group are substituted;
R 5 selected from C 1-6 Alkyl, halogen, cyano, C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkyl or C 5-12 Halogenated bridged cycloalkyl;
R 6 selected from hydroxyalkyl, 3-8 membered heterocyclyl, 5-12 membered heteroaryl, 5-8 membered oxo heteroaryl, -n=s=o (R aa R bb )、-(CH 2 ) n1 S(O) m1 NR aa R bb 、-P(＝O)(R aa )(R bb )、-P(＝O)(OR aa )(OR bb ) OR-B (OR) aa )(OR bb )；
R aa And R is bb Each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 An alkoxy group; or R is aa And R is bb Is connected to form C 3-8 Cycloalkyl or 3-12 membered heterocyclyl, wherein said cycloalkyl and heterocyclyl are optionally further selected from hydrogen, halogen, cyano, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl or C 1-6 One or more substituents in the alkoxy group.
In a preferred embodiment of the present invention, any of the compounds of formula (I), stereoisomers thereof, or pharmaceutically acceptable salts thereof, shown below, are selected from the group consisting of:
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The invention also relates to a method for preparing the compound shown in the general formula (I) or the stereoisomer and the pharmaceutically acceptable salt thereof, which comprises the following steps,
reacting the general formula (I-A) with the general formula (1-B) to obtain a compound shown in the general formula (I) or a stereoisomer and a pharmaceutically acceptable salt thereof;
wherein:
R 8 selected from halogen or hydroxy;
ring A, L, R 1 ～R 4 、R a And n is of the formula (I).
The invention also relates to a method for preparing the compound shown in the general formula (I) or the stereoisomer and the pharmaceutically acceptable salt thereof, which comprises the following steps,
reacting the general formula (I-C) with the general formula (I-B) to obtain the general formula (I-D), and further reacting the general formula (I-D) to obtain a compound shown in the general formula (I) or a stereoisomer and a pharmaceutically acceptable salt thereof;
wherein:
x is halogen;
ring A, L, R 1 ～R 4 、R a And n is of the formula (I)
The invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any of the compounds of formula (I), stereoisomers or pharmaceutically acceptable salts thereof, as shown in any of the formulae shown herein, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to the application of any compound shown in the general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing ACC inhibitor medicines.
The invention also relates to a method for the therapeutic prophylaxis and/or treatment of a condition mediated by ACC, which comprises administering to a patient a therapeutically effective dose of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
The invention further relates to a method of inhibiting fatty acid production, stimulating fatty acid oxidation, or both in a patient comprising the step of administering to the patient a compound of the invention or a composition comprising the compound. According to certain embodiments, the present invention relates to a method of inhibiting fatty acid production, stimulating fatty acid oxidation, or both in a patient, thereby reducing obesity or alleviating symptoms of metabolic syndrome comprising the step of administering to said patient a compound of the present invention or a composition comprising said compound. In other embodiments, the invention provides a method of treating an ACC-mediated condition in a patient in need thereof, comprising the step of administering to said patient a compound of the invention or a pharmaceutically acceptable composition thereof.
In some embodiments, the compounds and compositions of the present invention are useful in methods of treating obesity or another metabolic disorder. In certain embodiments, the compounds and compositions of the present invention are useful for treating obesity or another metabolic disorder in a mammal. In certain embodiments, the mammal is a human patient. In certain embodiments, the compounds and compositions of the present invention are useful for treating obesity or another metabolic disorder in a human patient.
In some embodiments, the invention provides a method of treating obesity or another metabolic disorder comprising administering a compound or composition of the invention to a patient suffering from obesity or another metabolic disorder. In certain embodiments, the methods of treating obesity or another metabolic disorder comprise administering to a mammal a compound and composition of the invention. In certain embodiments, the mammal is a human. In some embodiments, the metabolic disorder is dyslipidemia or hyperlipidemia. In some embodiments, the obesity is a symptom of Prader-Willi syndrome (Prader-Willi syndrome), barde-pidem syndrome (barset-Biedl syndrome), coben syndrome (Cohen syndrome), or MOMO syndrome.
The invention also provides methods of treating disease conditions, including but not limited to conditions associated with acetyl-coa carboxylase modulating dysfunction, using the compounds or pharmaceutical compositions of the invention.
The invention also relates to a method of treating an application disorder in a mammal for the treatment of an acetyl-coa carboxylase mediated disease, cancer, bone disease, inflammatory disease, immune disease, neurological disease, metabolic disease, respiratory disease and heart disease comprising administering to said mammal a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.
In some embodiments, the methods relate to cancers of insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, breast cancer, pancreatic cancer, non-small cell lung cancer (NSCLC), thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, renal cancer, myelodysplastic syndrome (MDS), acute Myelogenous Leukemia (AML), and colorectal cancer；
In some embodiments, the cancer treated by the compounds or compositions of the present invention is melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, renal cancer, esophageal cancer, brain cancer, lymphoma, or colon cancer. In certain embodiments, the cancer is Primary Effusion Lymphoma (PEL). In certain preferred embodiments, the cancer to be treated by the compounds or compositions of the invention is a cancer having an activated MAPK pathway. In some embodiments, the cancer having an activated MAPK pathway is melanoma. In certain preferred embodiments, the cancer treated by the compounds or compositions of the invention is a cancer associated with BRCA1 mutations. In a particularly preferred embodiment, the cancer treated by the compounds or compositions of the invention is triple negative breast cancer.
Detailed description of the invention
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 8 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms, still more preferably an alkyl group containing from 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl 4, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy or carboxylate, with methyl, ethyl, isopropyl, t-butyl, haloalkyl, deuteroalkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl being preferred.
The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" means-CH 2 - "ethylene" means- (CH) 2 ) 2 - "propylene" means- (CH) 2 ) 3 "butylene" means- (CH) 2 ) 4 -and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 8 carbon atoms, and most preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl, more preferably cyclopropyl and cyclobutyl.
The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (referred to as a spiro atom) between 5-to 20-membered monocyclic rings, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
spirocycloalkyl groups also containing a spiro atom common to both the monocyclocycloalkyl and heterocycloalkyl groups, non-limiting examples include:
the term "fused ring alkyl" refers to a 5 to 20 membered, all carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic ring, more preferably a 4-membered/4-membered, 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of fused ring alkyl groups include:
The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
the cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen, boron, phosphorus, S (O) m (wherein m is an integer of 0 to 2) or P (O) n (wherein n is an integer from 0 to 2), but does not include a ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms; most preferably containing 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include oxetanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, and the like, with oxetanyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, piperazinyl, and pyranyl being preferred. More preferably an oxetanyl group. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups; the heterocyclic groups of the spiro ring, the condensed ring and the bridged ring are optionally connected with other groups through single bonds, or are further connected with other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups through any two or more atoms on the ring in a parallel ring mode. Non-limiting examples of heterocyclyl groups include:
Etc.
The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having 3 to 20 membered monocyclic rings sharing one atom (referred to as the spiro atom) wherein one or more of the ring atoms is nitrogen, oxygen, boron, phosphorus, S (O) m (wherein m is an integer of 0 to 2) or P (O) n (wherein n is an integer from 0 to 2) and the remaining ring atoms are carbon. Which may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably 3-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclyl. Non-limiting examples of spiroheterocyclyl groups include:
etc.
The term "fused heterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, but none of which has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 3-membered/5-membered, 4-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:
Etc. />
The term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, but none of the rings has a fully conjugated pi electron system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O) m (wherein m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, non-limiting examples of which include:
etc.
The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. More preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:
etc.
Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered, more preferably 5 or 6 membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, oxadiazole, pyrazinyl, and the like, preferably oxazolyl, oxadiazole, tetrazole, triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably oxazolyl, oxadiazole, tetrazole, triazolyl, thienyl, thiazolyl and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate groups.
"haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined above.
"haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
"hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
"alkenyl" refers to alkenyl groups, also known as alkenyl groups, wherein the alkenyl groups may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"alkynyl" refers to (CH≡C-), wherein the alkynyl group may be further substituted with other related groups, such as: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.
"hydroxy" refers to an-OH group.
"halogen" means fluorine, chlorine, bromine or iodine.
"amino" means-NH 2 。
"cyano" refers to-CN.
"nitro" means-NO 2 。
"carboxy" means-C (O) OH.
"THF" refers to tetrahydrofuran.
"EtOAc" refers to ethyl acetate.
"MeOH" refers to methanol.
"DMF" refers to N, N-dimethylformamide.
"DIPEA" refers to diisopropylethylamine.
"TFA" refers to trifluoroacetic acid.
"MeCN" refers to acetonitrile.
"DMA" refers to N, N-dimethylacetamide.
“Et 2 O "refers to diethyl ether.
"DCE" refers to 1,2 dichloroethane.
"DIPEA" refers to N, N-diisopropylethylamine.
"NBS" refers to N-bromosuccinimide.
"NIS" refers to N-iodosuccinimide.
"Cbz-Cl" refers to benzyl chloroformate.
“Pd 2 (dba) 3 "means tris (dibenzylideneacetone) dipalladium.
"Dppf" refers to 1,1' -bis-diphenylphosphino ferrocene.
"HATU" refers to 2- (7-oxo-benzotriazol) -N, N' -tetramethylurea hexafluorophosphate.
"KHMDS" refers to potassium hexamethyldisilazide.
"LiHMDS" refers to lithium bis (trimethylsilylamide).
"MeLi" refers to lithium-based.
"n-BuLi" refers to n-butyllithium.
“NaBH(OAc) 3 "means sodium triacetoxyborohydride.
The terms "X is selected from A, B or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C", etc. all express the same meaning, that is, X may be any one or several of A, B, C.
The hydrogen atoms of the invention can be replaced by the isotope deuterium thereof, and any hydrogen atom in the compound of the embodiment of the invention can be replaced by deuterium atoms.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.
"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
By "pharmaceutically acceptable salts" is meant salts of the compounds of the present invention which are safe and effective when used in a mammal, and which possess the desired biological activity.
Detailed Description
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.
Examples
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS).
An Agilent 1200 affinity Series mass spectrometer was used for LC-MS measurement. HPLC was performed using Agilent 1200DAD high pressure liquid chromatography (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18X 4.6mm column).
The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.
All reactions of the invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being a dry solvent and the reaction temperature being in degrees celsius, without specific explanation.
Example 1
1- [1- {2- [ (5-hydroxy-octahydro-pent-2-yl) oxo ] -2- (2-methoxyphenyl) ethyl } -5-methyl-6- (1, 3-oxazol-2-yl) -2, 4-dicarbonyl-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl ] cyclopropanecarboxylic acid
First step
Trimethylsulfoxide iodide (28.61 g,130mmol,1.3 eq) and potassium tert-butoxide (16.83 g,150mmol,1.5 eq) were dissolved in dimethyl sulfoxide (200 mL) at room temperature, and stirred at room temperature for 2 hours. 2-Methoxybenzaldehyde 1a (13.62 g,100mmol,1.0 eq) was added in portions and stirred at room temperature for 3 hours after the addition until TLC showed complete reaction of starting material. Water (300 mL) was added to the reaction solution, which was extracted with petroleum ether (200 mL. Times.3), the organic phases were combined, washed with saturated brine (200 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give Compound 1b (8.15 g, yield: 54%) as a colorless liquid.
1 HNMR(CDCl 3 ,400MHz)δ:7.24-7.28(m，1H)，7.14(d，J＝8.0Hz，1H)，6.93(t，J＝8.0Hz，1H)，6.88(d，J＝8.0Hz，1H)，4.20(m，1H)，3.86(s，3H)，3.12-3.14(m，1H)，2.69-2.71(m，1H)。
Second step
Cis-bicyclo [3.3.0] octane-3, 7-dione (1 c,13.82g,100mmol,1.0 eq), ethylene glycol (6.52 g,105mmol,1.05 eq) and p-toluenesulfonic acid monohydrate (1.00 g) were dissolved in toluene (100 mL) and reacted under reflux for 5 hours. The reaction was cooled, 1% sodium bicarbonate (200 mL) was added, extracted with ethyl acetate (100 mL x 3), the organic phases combined, dried over anhydrous sodium sulfate, and the residue purified by silica gel column, petroleum ether: ethyl acetate=95: 5 to 75:25 to give compound 1d (11.30 g, yield: 62%) as a colorless oil.
ESIMS m/z:183[M+H] + .
Third step
Compound 1d (10.86 g,58.9mmol,1.0 eq) was dissolved in methanol (100 mL), sodium borohydride (1.20 g,31.7mmol,0.54 eq) was added in portions with ice-water bath cooling, and after the addition was completed, the reaction mixture was allowed to warm to room temperature naturally, and stirred for 3 hours. The reaction was quenched by addition of water (200 mL), extracted with ethyl acetate (100 mL x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 60:40 to give compound 1e (10.12 g, yield: 92%) as a white solid.
ESIMS m/z:185[M+H] + .
Fourth step
Compound 1e (9.87 g,53.6mmol,1.2 eq) and anhydrous ferric trichloride (0.50 g,3.1mmol,0.07 eq) were added to anhydrous tetrahydrofuran (100 mL), and the reaction was continued for 2 hours after the dropwise addition of compound 1b (6.70 g,44.6mmol,1 eq) was completed with ice-water bath cooling, and TLC showed complete disappearance of compound 1 b. Toluene (200 mL) was added, washed successively with water (100 mL x 4), saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by silica gel column, petroleum ether: ethyl acetate=95: 5 to 20:80 to give compound 1f (2.12 g, yield: 14%) as a colorless oil.
ESIMS m/z:335[M+H] + .
Fifth step
2-amino-4-methyl-thiophene-3-carboxylic acid methyl ester 1f (17.12 g,100mmol,1.0 eq) was dissolved in dichloromethane (200 mL), and carbonyldiimidazole (17.84 g,110mmol,1.1 eq) was added in portions under a water bath and reacted overnight at room temperature. TLC showed complete disappearance of compound 1 f. Triethylamine (12.14 g,120mmol,1.2 eq) was added to the reaction mixture, stirred at room temperature for 1 hour, and methyl 1-aminocyclopropane carboxylate hydrochloride (18.19 g,120mmol,1.2 eq) was added thereto and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 0:100 to give compound 1i (21.23 g, yield: 68%) as an off-white solid.
ESIMS m/z:313[M+H] + .
Sixth step
Compound 1i (21.09 g,67.5mmol,1.0 eq) and potassium tert-butoxide (37.55 g,338mmol,5 eq) were added to dioxane (400 mL), heated to 80℃and reacted overnight. The reaction solution was cooled, concentrated under reduced pressure, saturated ammonium chloride (600 mL) was added to the residue, stirred for 1 hour, filtered, and the solid was washed with water (100 ml×3) and dried in vacuo to give compound 1j (18.87 g, yield: 100%) as a pale yellow solid.
ESIMS m/z:281[M+H] + .
Seventh step
Compound 1j (10.00 g,35.7mmol,1.0 eq) was dissolved in dichloromethane (200 mL), and bromosuccinimide (7.00 g,39.3mmol,1.1 eq) was added to the solution in ice water and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 20:80 to give compound 1k (11.51 g, yield: 90%) as an off-white solid.
ESIMS m/z:359[M+H] + .
Eighth step
Compound 1k (1.00 g,2.78mmol,1.0 eq), compound 1f (1.02 g,3.06mmol,1.1 eq) and triphenylphosphine (875 mg,3.34mmol,1.2 eq) were dissolved in anhydrous tetrahydrofuran (20 mL), diisopropyl azodicarboxylate (843 mg,4.17mmol,1.5 eq) was added dropwise to the solution in ice water, and the mixture was reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 50:50 to give 1l (933 mg, yield: 50%) of the compound as an off-white solid.
ESIMS m/z:675[M+H] + .
Ninth step
1l (400 mg,0.59mmol,1.0 eq), 2- (tri-n-butylstannyl) oxazole (233 mg,0.65mmol,1.1 eq) and tetrakis (triphenylphosphine) palladium (100 mg) were dissolved in toluene (10 mL) under nitrogen and reacted overnight at 120 ℃. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 50:50 to give compound 1m (137 mg, yield: 35%) as a white solid.
ESIMS m/z:664[M+H] + .
Tenth step
Compound 1m (137 mg,0.21mmol,1.0 eq) was dissolved in tetrahydrofuran (5 mL), lithium hydroxide monohydrate (13 mg,0.31mmol,1.5 eq) was added, and the mixture was reacted overnight at room temperature. To the reaction mixture was added 2M hydrochloric acid (5 mL), and the mixture was stirred at room temperature for 4 hours. The organic solvent was removed under reduced pressure, the aqueous phase was extracted with ethyl acetate (3 ml. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was prepared with a high-performance liquid phase to give compound 1n (85 mg, yield: 68%) as a white solid.
ESIMS m/z:606[M+H] + .
Eleventh step
Compound 1n (50 mg,0.082mmol,1.0 eq) was dissolved in methanol (3 mL), sodium borohydride (5 mg,0.13mmol,1.6 eq) was added under ice-water bath cooling, and after the addition, the reaction mixture was naturally warmed to room temperature and stirred for 3 hours. The reaction was quenched by addition of water (5 mL), extracted with ethyl acetate (3 mL x 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was prepared by high performance liquid chromatography to give compound 1 (17 mg, yield: 34%) as a white solid.
ESIMS m/z:606[M+H] + .
Example 4
1- (1- (2- (2-methoxyphenyl) -2- ((octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclopropanecarboxylic acid
Referring to example 1, compound 4 was synthesized from compound 1 k.
1 HNMR(400MHz,CDCl 3 )δ:7.70(br,1H),7.39(dd,J＝7.2,7.6Hz,1H),7.26(m,1H),7.23(br,1H),7.03(t,J＝7.6Hz,2H),4.64-5.02(m,3H),3.98(s,3H),3.18-3.45(m,3H),2.98(m,1H),2.89(s,3H),1.07-2.68(m,11H)；
ESIMS m/z:593.1[M+H] + .
Example 5
1- (1- (2- (2-methoxyphenyl) -2- ((2- (methylsulfonyl) octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclopropanecarboxylic acid
Referring to example 1, compound 5 was synthesized from compound 1 k.
1 HNMR(400MHz,CDCl 3 )δ:7.69(s,1H),7.42(m,1H),7.30(m,1H),7.24(s,1H),6.99(m,1H),6.89(d,J＝7.2Hz,1H),5.18(m,1H),4.51(m,1H),3.94(m,1H),3.85(d,J＝6.8Hz,3H),3.15-3.44(m,4H),2.90(s,3H),2.77(d,J＝4.4Hz,3H),2.64(m,2H),1.20-2.22(m,9H)；
ESIMS m/z:669.2[M-H] - .
Example 7
1- (1- (2- (2-methoxyphenyl) -2- ((2-methyl octahydrocyclopenta [ c ] pyrrol-5-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclopropanecarboxylic acid
Referring to example 1, compound 7 was synthesized from compound 1 k.
1 HNMR(400MHz,CDCl 3 )δ:7.69(s,1H),7.34(m,2H),7.22(s,1H),7.00(t,J＝7.2Hz,1H),6.92(d,J＝7.2Hz,1H),5.16(br,1H),4.58(m,2H),4.02-4.20(m,1H),3.87(s,3H),3.52-3.75(m,2H),2.90-3.15(m,3H),2.89(s,3H),1.05-2.26(m,12H)；
ESIMS m/z:607.2[M+H] + .
Example 19A
(R) -N-hydroxy-2- (1- (2- (2-methoxyphenyl) -2 (- (tetrahydro-2H-pyran-4-yl) oxyethyl) 5-methyl-6- (oxazol-2-yl) -1, 4-dioxo-1, 4-dihydrothieno [2,3] pyrimidin-3 (2H) -yl-2-methylpropanamide
Compound 19a (ND-630, 50mg,0.088mmol,1.0 eq), hydroxylamine hydrochloride (10 mg,0.14mmol,1.6 eq), HOBt (15 mg,0.11mmol,1.2 eq) and N-methylmorpholine (20 mg,0.20mmol,2.2 eq) were dissolved in dichloromethane (3 mL), EDCI (20 mg,0.10mmol,1.2 eq) was added and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure. The residue was purified by column on silica gel, dichloromethane: methanol=100: 0 to 95:5 to give compound 19A (10.12 g, yield: 92%) as a white solid.
1 HNMR(CDCl 3 ,400MHz)δ:7.71(s,1H),7.55(d,J＝7.2Hz,1H),7.31(d,J＝6.4,1H),7.22(s,1H),7.03(t,J＝7.2Hz,1H),6.88(d,J＝7.6Hz,1H),5.37(m,1H),4.20-4.35(m,2H),3.99(m,1H),3.89(s,3H),3.82(m,1H),2.85(s,3H),2.22-2.31(m,2H),1.90-2.05(m,4H),1.50-1.77(m,4H),0.90-1.20(m,4H)；
ESIMS m/z:585[M+H] + .
Example 20A
(R) -N-methoxy-2- (1- (2- (2-methoxyphenyl) -2 (- (tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropanamide
Compound 19a (ND-630, 20mg,0.035mmol,1.0 eq), methoxyamine hydrochloride (6 mg,0.07mmol,2 eq) and diisopropylethylamine (18 mg,0.14mmol,4 eq) were dissolved in dichloromethane (2 mL), HATU (40 mg,0.11mmol,3 eq) was added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. The residue was purified by preparative HPLC to give compound 20A (10 mg, yield: 48%) as a white solid.
1 HNMR(CDCl3,400MHz)δ:8.15(br,1H),7.70(s,1H),7.56(d,J＝7.6Hz,1H),7.21(s,1H),7.02(t,J＝7.6Hz,1H),6.86(d,J＝7.6Hz,1H),5.38(dd,J＝6.0,7.2Hz,1H),4.14(m,1H),4.02(m,1H),3.84(s,3H),3.82(s,3H),3.31-3.75(m,5H),2.83(s,3H),1.85(s,3H),1.80(s,3H),1.40-1.74(m,4H)；
ESIMS m/z:552[M-46] + ；597[M-1] - .
Example 26
1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-3- (2-methyl-1, 3-dioxoisoindolin-5-yl) -6- (oxazol 2-yl) thieno [2,3-d ] pyrimidine-2, 4 (1H, 3H) -dione
First step
Ethyl 2-amino-4-methyl-thiophene-3-carboxylate 26a (18.52 g,100mmol,1.0 eq) and triethylamine (12.14 g,120mmol,1.2 eq) were dissolved in dichloromethane (500 mL), and triphosgene (10.38 g,35.0mmol,0.35 eq) was added to the solution under ice-water bath to react for 2 hours at room temperature. N-methyl-4-amino-phthalimide 26b (21.14 g,120mmol,1.2 eq) and triethylamine (12.14 g,120mmol,1.2 eq) were added and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 0:100 to give compound 26c (21.23 g, yield: 55%) as a pale yellow solid.
ESIMS m/z:388[M+H] + .
Second step
Compound 26c (21.10 g,63.4mmol,1.0 eq) and potassium tert-butoxide (37.80 g,337mmol,5 eq) were added to dioxane (400 mL), heated to 80℃and reacted overnight. The reaction solution was cooled, concentrated under reduced pressure, saturated ammonium chloride (600 mL) was added to the residue, stirred for 1 hour, filtered, and the solid was washed with water (150 ml×3) and dried in vacuo to give compound 26d (16.78 g, yield: 77%) as a pale yellow solid.
ESIMS m/z:342[M+H] + .
Third step
Compound 26d (10.00 g,29.3mmol,1.0 eq) was dissolved in dichloromethane (200 mL) and bromosuccinimide (5.74 g,32.2mmol,1.1 eq) was added to the solution in ice water and reacted overnight at room temperature. The reaction was washed with 10% potassium carbonate solution (100 ml x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 40:60 to give compound 26e (12.03 g, yield: 98%) as a yellow solid.
ESIMS m/z:421[M+H] + .
Fourth step
Compound 26e (2.00 g,4.76mmol,1.0 eq) was dissolved in N, N-dimethylformamide (30 mL), 26f (1.65 g,5.24mmol,1.1 eq) and anhydrous potassium carbonate (1.31 g,9.52mmol,2 eq) were added at room temperature and reacted overnight at 100 ℃. The reaction mixture was added with water (100 ml), extracted with ethyl acetate (30 ml x 3), the organic phases combined, washed successively with water (50 ml x 3), saturated brine (30 ml x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 50:50 to give 26g (1.86 g, yield: 60%) of the compound as a yellow solid.
ESIMS m/z:655[M+H] + .
Fifth step
26g (200 mg,0.306mmol,1.0 eq), 2- (tri-n-butylstannyl) oxazole (120 mg,0.34mmol,1.1 eq) and tetrakis (triphenylphosphine) palladium (100 mg) were dissolved in toluene (5 mL) under nitrogen and reacted overnight at 110 ℃. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 60:40 to give compound 26 (35 mg, yield: 18%) as a yellow solid.
1 HNMR(CDCl 3 ,400MHz)δ:8.45(d,J＝7.6Hz,1H),8.33(d,J＝7.2Hz),7.85(t,J＝7.6Hz,1H),7.72(s,1H),7.56(d,J＝7.2Hz,1H),7.29(br,1H),7.20(s,1H),7.03(t,J＝7.2Hz,1H),6.86(d,J＝7.6Hz,1H),5.35(m,1H),3.85(s,3H),3.24-3.74(m,7H),3.02(s,3H),2.85(s,3H),1.41-1.78(m,4H)；
ESIMS m/z:643[M+H] + .
Example 40
2- (1- (chroman-2-ylmethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl ] -2-methylpropanoic acid
First step
Ethyl 2-amino-4-methyl-thiophene-3-carboxylate 26a (18.52 g,100mmol,1.0 eq) and triphosgene (10.38 g,35.0mmol,0.35 eq) were dissolved in dichloromethane (500 mL) and stirred at room temperature for 1 hour. Triethylamine (40.48 g,400mmol,4 eq) was added to the reaction mixture in an ice-water bath and reacted at room temperature for 1 hour. Ethyl 2-aminoisobutyrate hydrochloride 40a (20.11 g,120mmol,1.2 eq) was added while cooling in an ice-water bath, and stirred overnight at room temperature. The reaction was washed with 0.5M diluted hydrochloric acid (300 ml x 3), water (300 ml x 2), concentrated under reduced pressure and the residue purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 0:100 to give compound 40b (29.56 g, yield: 86%) as an off-white solid.
ESIMS m/z:343[M+H] + .
Second step
Compound 40b (29.33 g,85.6mmol,1.0 eq) was added to a freshly prepared sodium ethoxide/ethanol solution (prepared from 10.00g sodium metal in 500mL absolute ethanol) under nitrogen and allowed to react under reflux overnight. The reaction solution was cooled, concentrated under reduced pressure, saturated ammonium chloride (500 mL) was added to the residue, stirred for 1 hour, filtered, and the solid was washed with water (100 ml×3) and dried in vacuo to give compound 40c (23.76 g, yield: 94%) as a pale yellow solid.
ESIMS m/z:297[M+H] + .
Third step
Compound 40c (20.00 g,67.5mmol,1.0 eq) was dissolved in dichloromethane (500 mL) and bromosuccinimide (13.21 g,74.2mmol,1.1 eq) was added under ice-water bath and reacted overnight at room temperature. The reaction was washed with 10% potassium carbonate solution (200 ml x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 20:80 to give compound 40d (24.11 g, yield: 95%) as an off-white solid.
ESIMS m/z:375[M+H] + .
Fourth step
Compound 40d (10.00 g,26.6mmol,1.0 eq) and benzhydryl bromide (7.24 g,29.3mmol,1.1 eq) were dissolved in N, N-dimethylformamide (200 mL), 60% sodium hydride (1.28 g,32.0mmol,1.2 eq) was added to the solution in an ice-water bath, and the reaction was carried out overnight at room temperature. The reaction was quenched with saturated ammonium chloride (200 mL), extracted with ethyl acetate (150 mL x 3), the organic phases combined, washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue purified on a silica gel column, petroleum ether: ethyl acetate=95: 5 to 60:40 to give compound 40e (10.73 g, yield: 74%) as a white solid.
ESIMS m/z:541[M+H] + .
Fifth step
Compound 40e (5.00 g,9.23mmol,1.0 eq), 2- (tri-n-butylstannyl) oxazole (3.64 g,1.02mmol,1.1 eq) and tetrakis (triphenylphosphine) palladium (1.00 g) were dissolved in toluene (150 mL) under nitrogen and reacted overnight at 110 ℃. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 60:40 to give compound 40f (2.31 g, yield: 47%) as a pale yellow solid.
ESIMS m/z:530[M+H] + .
Sixth step
Compound 40f (2.27 g,4.29mmol,1.0 eq) was dissolved in trifluoroacetic acid (50 mL) under nitrogen, and trifluoromethanesulfonic acid (2 mL) was added dropwise to the solution in an ice-water bath and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, saturated sodium hydrogencarbonate (100 mL) was added to the residue, stirred for 0.5 hours, filtered, and the solid was purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 40:60 to give 40g (1.45 g, yield: 93%) of the compound as an off-white solid.
ESIMS m/z:364[M+H] + .
Seventh step
40g (100 mg,0.28mmol,1.0 eq), chroman-2-ylmethanol (50 mg,0.30mmol,1.1 eq) and triphenylphosphine (86 mg,0.33mmol,1.2 eq) were dissolved in anhydrous tetrahydrofuran (3 mL) and diisopropyl azodicarboxylate (83 mg,0.41mmol,1.5 eq) was added dropwise in an ice water bath and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 50:50 to give compound 40i (65 mg, yield: 46%) as a white solid.
ESIMS m/z:510[M+H] + .
Eighth step
Compound 40i (63 mg) was dissolved in tetrahydrofuran (5 mL), and lithium hydroxide monohydrate (10 mg) was added thereto and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was prepared with a high-performance liquid phase to give compound 40 (35 mg, yield: 59%) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.68(s,1H),7.21(s,1H),6.99-7.04(m,2H),6.81(t,J＝8.0Hz,1H),6.72(d,J＝8.0Hz,1H),4.45-4.49(m,1H),4.29-4.33(m,1H),4.00-4.06(m,1H),2.75-2.91(m,5H),2.14-2.18(m,1H),1.85(s,6H)1.78-1.84(m,1H)；
ESIMS m/z:482.1[M+H] + .
Example 48
2- (1- (2- ((dimethyl (oxo) -lambda) 6 -sulfanylidene) amino) -2- (2-methoxyphenyl) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d]Pyrimidin-3 (2H) -yl) -2-methylpropanoic acid
Referring to example 40, compound 48 was synthesized from compound 40 g.
1 H NMR(400MHz,CDCl 3 )δ7.63(s,1H),7.49-7.53(m,1H),7.31-7.33(m,1H),7.16(s,1H),6.97-7.01(m,1H),6.81(d,J＝8.0Hz,1H),5.84-6.05(br,1H),4.32-4.48(br,1H),3.85-3.98(br,1H),3.72(s,3H),3.19-3.44(m,6H),2.72(s,3H),1.80(s,3H)1.74(m,3H)；
MS m/z(ESI):561.1[M+H] + .
Example 54
2- (1- (2, 3-dihydrobenzofuran-7-yl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropanoic acid
First step
Trimethylsulfoxide iodide (5.79 g,26.3mmol,1.3 eq) and potassium tert-butoxide (3.40 g,30.3mmol,1.5 eq) were dissolved in dimethyl sulfoxide (50 mL) at room temperature, and stirred at room temperature for 3 hours. 2, 3-dihydro-1-benzofuran-7-carbaldehyde 54a (3.00 g,20.2mmol,1.0 eq) was added in portions and stirred overnight at room temperature after the addition. Water (200 mL) was added to the reaction solution, the mixture was extracted with petroleum ether (100 mL. Times.3), the organic phases were combined, washed with saturated brine (100 mL. Times.3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 54b (1.95 g, yield: 60%) as a colorless oil.
1 HNMR(CDCl 3 ,400MHz)δ:7.12-7.24(m,3H),4.16-4.24(m,3H),2.95-3.14(m，3H),2.73(m,1H)；
Second step
Tetrahydropyran-4-ol (2.52 g,24.7mmol,4 eq) and boron trifluoride diethyl etherate (0.3 mL) were added to toluene (30 mL), and a solution of compound 54b (1.00 g,6.16mmol,1 eq) in toluene (5 mL) was added dropwise with cooling in an ice-water bath, and the reaction was continued for 2 hours after the completion of the dropwise addition. The reaction was washed successively with water (10 ml x 3), saturated brine (10 ml x 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column, petroleum ether: ethyl acetate=95: 5 to 40:60 to give compound 54c (671 mg, yield: 41%) as a colorless oil.
ESIMS m/z:265[M+H] + .
Third step
40g (100 mg,0.28mmol,1.0 eq), 54c (80 mg,0.30mmol,1.1 eq) and triphenylphosphine (86 mg,0.33mmol,1.2 eq) were dissolved in anhydrous tetrahydrofuran (3 mL), diisopropyl azodicarboxylate (83 mg,0.41mmol,1.5 eq) was added dropwise in an ice water bath and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 60:40 to give compound 54e (60 mg, yield: 36%) as a white solid.
ESIMS m/z:610[M+H] + .
Fourth step
Compound 54e (55 mg) was dissolved in tetrahydrofuran (3 mL), and lithium hydroxide monohydrate (10 mg) was added thereto and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was prepared with a high-performance liquid phase to give compound 54 (18 mg, yield: 34%) as a white solid.
1 HNMR(CDCl 3 ,400MHz)δ:7.72(s,1H),7.49(d,J＝7.2Hz,1H),7.30(t,J＝7.2Hz,1H),7.20(s,1H),7.12(d,J＝7.2Hz,1H),5.40(dd,J＝6.4,7.6Hz,1H),4.34(m,2H),3.25-3.80(m,7H),2.90-3.10(m,2H),2.82(s,3H),1.84(s,3H),1.80(s,3H),1.41-1.72(m,4H)；
ESIMS m/z:582[M+H] + .
Example 70A
(R) -2- (6- ((dimethyl (oxo) -lambda) 6 -sulfanylidene) amino) -1-2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d]Pyrimidin-3 (2H) -yl) -2-methylpropanoic acid
First step
Compound 40d (100 mg,0.25mmol,1.0 eq), (R) -2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethan-1-ol (69 mg,0.27mmol,1.1 eq) and triphenylphosphine (78 mg,0.30mmol,1.2 eq) were dissolved in anhydrous tetrahydrofuran (3 mL) and diisopropyl azodicarboxylate (75 mg,0.37mmol,1.5 eq) was added dropwise under ice-water bath and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 60:40 to give compound 70a (78 mg, yield: 49%) as a white solid.
ESIMS m/z:637[M+H] + .
Second step
Compound 70a (78 mg), cuprous iodide (5 mg), sodium iodide (50 mg), N, N' -dimethylethylenediamine (5 mg) were added to dioxane (2 mL) under nitrogen, and reacted overnight at 110 ℃. The reaction mixture was cooled, and (dimethanesulfinyl) amine (10 mg) and cesium carbonate (50 mg) were added thereto to react overnight at 110 ℃. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 20:80 to give compound 70b (38 mg, yield: 48%) as a yellow solid.
ESIMS m/z:650[M+H] + .
Third step
Compound 70b (38 mg) was dissolved in trifluoroacetic acid (3 mL) and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was prepared with a high-performance liquid phase to give compound 70A (15 mg, yield: 43%) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ7.53–7.45(m,1H),7.37–7.29(m,1H),7.06–6.94(m,1H),6.93–6.82(m,1H),5.46–5.22(m,1H),4.63–4.33(m,2H),4.08–3.79(m,5H),3.60–3.44(m,1H),3.45–3.22(m,2H),2.63(s,6H),2.33(s,3H),2.04–1.90(m,2H),1.89–1.77(m,6H),1.70–1.56(m,2H)；
ESIMS m/z:594.2[M+H] + .
Example 76A
(R) -2- (6- (2-hydroxypropyl-2-yl) -1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl-5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methylpropanoic acid
First step
Acetylacetone (20.00 g,200mmol,1.0 eq), ethyl cyanoacetate 76a (22.62 g,200mmol,1.0 eq), sulfur (6.41 g,100mmol,1.0 eq) and diethylamine (14.63 g,100mmol,1.0 eq) were added to absolute ethanol (400 mL) at room temperature, heated at 70 ℃ for 4 hours, and stirred at room temperature overnight. The reaction was filtered, and the solid was washed with ethanol (200 ml x 2) and recrystallized from ethanol to give compound 76b (38.92 g, yield: 86%) as a yellow solid.
ESIMS m/z:228[M+H] + .
Second step
Compound 76b (22.73 g,100mmol,1.0 eq) and triphosgene (10.38 g,35.0mmol,0.35 eq) were dissolved in dichloromethane (500 mL) and stirred at room temperature for 1 hour. Triethylamine (40.48 g,400mmol,4 eq) was added to the reaction mixture in an ice-water bath and reacted at room temperature for 1 hour. Ethyl 2-aminoisobutyrate hydrochloride (20.11 g,120mmol,1.2 eq) was added while cooling in an ice-water bath, and stirred overnight at room temperature. The reaction was washed with 0.5M diluted hydrochloric acid (300 ml x 3), water (300 ml x 2), concentrated under reduced pressure and the residue purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 0:100 to give compound 76c (30.56 g, yield: 79%) as a yellow solid.
ESIMS m/z:385[M+H] + .
Third step
Compound 76c (15.00 g,39.0mmol,1.0 eq) was added to a fresh sodium ethoxide/ethanol solution (prepared from 5.00g sodium metal added to 250mL absolute ethanol) under nitrogen and allowed to reflux overnight. The reaction was cooled, concentrated under reduced pressure, saturated ammonium chloride (300 mL) was added to the residue, stirred for 0.5 h, filtered, and the solid was washed with water (50 mL x 2) and dried in vacuo to give compound 76d (11.35 g, yield: 86%) as a yellow solid.
ESIMS m/z:339[M+H] + .
Fourth step
Compound 76d (500 mg,1.48mmol,1.0 eq), R) -2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethan-1-ol (4476 mg,1.77mmol,1.2 eq) and triphenylphosphine (503 mg,1.92mmol,1.3 eq) were dissolved in anhydrous tetrahydrofuran (20 mL), diisopropyl azodicarboxylate (449 mg,2.22mmol,1.5 eq) was added dropwise under ice-water bath and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 50:50 to give compound 76e (489 mg, yield: 58%) as a yellow solid.
ESIMS m/z:573[M+H] + .
Fifth step
Compound 76e (250 mg,0.436mmol,1.0 eq) was dissolved in anhydrous tetrahydrofuran (50 mL), 3M methyl magnesium bromide/diethyl ether solution (180. Mu.L, 0.54mmol,1.2 eq) was added dropwise at-20℃and stirred for 1 hour at-20℃and allowed to slowly warm to room temperature overnight. The reaction mixture was quenched with saturated ammonium chloride (1 mL), concentrated under reduced pressure, and the residue was purified by silica gel column, petroleum ether: ethyl acetate = 90:10 to 40:60 to give compound 76f (208 mg, yield: 81%) as an off-white solid.
ESIMS m/z:589[M+H] + .
Sixth step
Compound 76f (100 mg) was dissolved in tetrahydrofuran (2 mL), and lithium hydroxide monohydrate (10 mg) was added thereto and reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was prepared with a high-performance liquid phase to give compound 76A (53 mg, yield: 56%) as a white solid.
1 HNMR(CDCl 3 ,400MHz)δ:7.48(d,J＝7.2Hz,1H),7.33(br,1H),7.01(t,J＝7.2Hz,1H),6.90(d,J＝7.6Hz,1H),5.32(m,1H),3.82(s,3H),3.24-3.70(m,7H),2.87(s,3H),1.85(s,3H),1.81(s,3H),1.41-1.72(m,4H),1.31(s,3H),1.34(s,3H)；
ESIMS m/z:561[M+H] + .
Example 88
1- (6- ((dimethyl (oxo) -lambda) 6 -sulfanylidene) amino) -1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ]]Pyrimidin-3 (2H) -yl) cyclopropanecarboxylic acids
Referring to example 70A, compound 88 was synthesized from compound 1 k.
1 HNMR(400MHz,CD 3 OD)δ:7.50(d,J＝7.2Hz,1H),7.31(t,J＝7.2Hz,1H),7.01(m,2H),5.37(m,1H),4.26-4.47(m,2H),3.80-4.00(m,4H),3.57(m,1H),3.24-3.50(m,9H),2.32(s,3H),1.26-2.02(m,8H)；
ESIMS m/z:590.1[M-H] - .
Example 89
1- (1- (2- ((2-acetyloctahydrocyclopenta [ c ] pyrrol-5-yl) oxy) -2- (2-methoxyphenyl) -ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) cyclopropanecarboxylic acid
Referring to example 1, compound 89 was synthesized from compound 1 k.
1 HNMR(400MHz,CDCl 3 )δ:7.69(s,1H),7.39(m,1H),7.29(m,1H),7.22(s,1H),6.99(t,J＝7.2Hz,1H),6.89(d,J＝7.2Hz,1H),5.15(m,1H),4.23-4.58(m,2H),3.84(d,J＝6.8Hz,3H),3.27-3.73(m,3H),2.89(s,3H),1.05-2.69(m,15H)；
ESIMS m/z:633.3[M-H] - .
Example 90A
(R) -2- (6- ((dimethyl (oxo) -lambda) 6 -sulfanylideneGroup) amino) -1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ]]Pyrimidin-3 (2H) -yl) -N-isopropyl-N, 2-dimethylpropionamide
Referring to example 20A, compound 90A was synthesized from compound 70A.
1 H NMR(400MHz,CDCl 3 )δ7.52–7.44(m,1H),7.34–7.29(m,1H),7.06–6.95(m,1H),6.94–6.82(m,1H),5.40–5.28(m,1H),4.56–4.45(m,1H),4.44–4.33(m,1H),4.01–3.79(m,5H),3.60–3.43(m,1H),3.42–3.23(m,3H),3.23–3.09(m,6H),2.69–2.57(m,3H),2.34(s,3H),2.07–1.92(m,2H),1.90–1.70(m,6H),1.69–1.51(m,2H),1.51–1.35(m,6H)；
MS m/z(ESI):649.3[M+H] + .
Example 91A
(R) -6- ((dimethyl (oxo) -lambda 6 -sulfanylidene) amino) -1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-3- (2-methyl-1-oxo-1- (pyrrolidin-1-yl) propan-2-yl) thieno [2,3-d]Pyrimidine-2, 4 (1H, 3H) -diones
Referring to example 20A, compound 91A was synthesized from compound 70A.
1H NMR(400MHz,CDCl 3 )δ7.56–7.44(m,1H),7.34–7.28(m,1H),7.06–6.94(m,1H),6.94–6.83(m,1H),5.40–5.24(m,1H),4.57–4.29(m,2H),4.06–3.75(m,5H),3.68–3.46(m,3H),3.45–3.25(m,4H),3.24–3.05(m,6H),2.34(s,3H),2.10–1.98(m,2H),1.87–1.77(m,6H),1.74–1.42(m,6H)；
MS m/z(ESI):647.3[M+H] + .
Example 92A
(R) -2- (6- ((dimethyl (oxo) -lambda) 6 -sulfanyl subunit) Amino) -1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ]]Pyrimidin-3 (2H) -yl) -N-isopropyl-2-methylpropanamide
Referring to example 20A, compound 92A was synthesized from compound 70A.
1H NMR(400MHz,CDCl 3 )δ7.52–7.44(m,1H),7.34–7.29(m,1H),7.06–6.95(m,1H),6.94–6.82(m,1H),5.40–5.28(m,1H),4.56–4.45(m,1H),4.44–4.33(m,1H),4.01–3.79(m,5H),3.60–3.43(m,1H),3.42–3.23(m,3H),3.23–3.09(m,6H),2.69–2.57(m,3H),2.07–1.92(m,2H),1.90–1.70(m,6H),1.69–1.51(m,2H),1.51–1.35(m,6H)；
MS m/z(ESI):635.3[M+H] + .
Example 93A
(R) -6- ((dimethyl (oxo) -lambda 6 -sulfanylidene) amino) -1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-3- (2-methyl-1-morpholino-1-oxopropan-2-yl) thieno [2,3-d ]Pyrimidine-2, 4 (1H, 3H) -diones
Referring to example 20A, compound 93A was synthesized from compound 70A.
1H NMR(400MHz,CDCl 3 )δ7.55–7.44(m,1H),7.36–7.28(m,1H),7.07–6.96(m,1H),6.95–6.78(m,1H),5.43–5.25(m,1H),4.59–4.30(m,2H),4.14–3.78(m,7H),3.59–3.46(m,3H),3.43–3.22(m,6H),3.22–3.01(m,6H),2.34(s,3H),2.10–1.91(m,2H),1.91–1.76(m,6H),1.69–1.51(m,2H)；
MS m/z(ESI):663.3[M+H] + .
Example 94A
(R) -N-cyclopropyl-2- (6- ((dimethyl (oxo) -lambda) 6 -sulfanylidene) amino) -1- (2- (2-methoxyphenyl) -2-(tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d]Pyrimidin-3 (2H) -yl) -2-methylpropanamides
Referring to example 20A, compound 94A was synthesized from compound 70A.
1 H NMR(400MHz,CDCl 3 )δ7.53–7.42(m,1H),7.35–7.28(m,1H),7.05–6.95(m,1H),6.93–6.78(m,1H),5.55(br,1H),5.39–5.23(m,1H),4.54–4.23(m,2H),4.05–3.78(m,5H),3.61–3.46(m,1H),3.42–3.25(m,2H),3.14(s,6H),2.80–2.64(m,1H),2.33(s,3H),2.10–1.89(m,2H),1.83–1.73(m,6H),1.69–1.43(m,2H),0.79–0.66(m,2H),0.59–0.41(m,2H)；
MS m/z(ESI):633.3[M+H] + .
Example 95A
(R) -2- (6- ((dimethyl (oxo) -lambda) 6 -sulfanylidene) amino) -1- (2- (2-methoxyphenyl) -2- ((tetrahydro-2H-pyran-4-yl) oxy) ethyl) -5-methyl-2, 4-dioxo-1, 4-dihydrothieno [2,3-d ]]Pyrimidin-3 (2H) -yl) -2-methylpropanamides
Referring to example 20A, compound 95A was synthesized from compound 70A.
1 H NMR(400MHz,CDCl 3 )δ7.52–7.42(m,1H),7.33–7.27(m,1H),7.06–6.93(m,1H),6.93–6.81(m,1H),5.47–5.22(m,3H),4.53–4.31(m,2H),4.02–3.78(m,5H),3.59–3.45(m,1H),3.42–3.25(m,2H),3.14(s,6H),2.33(s,3H),2.02–1.92(m,2H),1.91–1.80(m,6H),1.80–1.48(m,2H)；
MS m/z(ESI):593.2[M+H] + .
Example 96
2- (1- (chroman-2-ylmethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ] pyrimidin-3 (2H) -yl) -2-methacrylamide
Referring to example 20A, compound 96 was synthesized from compound 40.
1 H NMR(400MHz,CDCl 3 )δ7.69(s,1H),7.21(s,1H),7.03-7.05(m,2H),6.84(t,J＝8.0Hz,1H),6.73(d,J＝8.0Hz,1H),5.32-5.48(br,2H),4.43-4.49(m,1H),4.32-4.36(m,1H),3.96-4.02(m,1H),2.76-2.94(m,5H),2.09-2.18(m,1H),1.85(s,6H)1.63-1.77(m,1H)；
MS m/z(ESI):481.2[M+H] + .
Example 97
2- (1- (2- ((dimethyl (oxo) -lambda) 6 -sulfanylidene) amino) -2- (2-methoxyphenyl) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d ]Pyrimidin-3 (2H) -yl) -2-methylpropanamides
Referring to example 20A, compound 97 was synthesized from compound 48.
1 H NMR(400MHz,CDCl 3 )δ7.65(s,1H),7.49(t,J＝7.6Hz,1H),7.36(t,J＝7.6Hz,1H),7.16(s,1H),7.01(t,J＝7.6Hz,1H),6.86(d,J＝8.0Hz,1H),5.62-5.96(br,1H),4.49-4.63(br,1H),3.80-3.92(br,1H),3.77(s,3H),3.17-3.56(m,6H),2.81(s,3H),1.87(s,3H)1.83(m,3H)；
MS m/z(ESI):560.1[M+H] + .
Example 98
2- (1- (2- ((dimethyl (oxo) -lambda) 6 -sulfanylidene) amino) -2- (2-methoxyphenyl) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d]Pyrimidin-3 (2H) -yl) -N-isopropyl-2-methylpropanamide
Referring to example 20A, compound 98 was synthesized from compound 48.
1 H NMR(400MHz,CDCl 3 )δ7.65(s,1H),7.46-7.52(m,1H),7.33(t,J＝8.0Hz,1H),7.16(s,1H),7.00(t,J＝7.6Hz,1H),6.86(d,J＝8.0Hz,1H),5.68-5.87(br,1H),4.54-4.70(br,1H),3.98-4.10(m,1H),3.82-3.95(m,1H),3.65(s,3H),3.01-3.50(m,6H),2.80(s,3H),1.85(s,3H)1.78(m,3H),1.10(d,J＝6.8Hz,3H),1.06(d,J＝6.8Hz,3H)；
MS m/z(ESI):602.2[M+H] + .
Example 99
N-cyclohexyl-2- (1- (2- ((dimethyl (oxo) -lambda) 6 -sulfanylidene) amino) -2- (2-methoxyphenyl) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d]Pyrimidin-3 (2H) -yl) -2-methylpropanamides
Referring to example 20A, compound 99 was synthesized from compound 48.
1 H NMR(400MHz,CDCl 3 )δ7.65(s,1H),7.57(d,J＝8.0Hz,1H),7.31(t,J＝7.6Hz,1H),7.18(s,1H),7.00(t,J＝7.6Hz,1H),6.84(d,J＝8.0Hz,1H),5.84-5.99(m,1H),5.56-5.74(m,1H),4.42-4.54(m,1H),3.63-3.75(m,5H),3.05(s,3H),2.95(s,3H),2.81(s,3H),1.74-1.83(m,8H)1.55-1.67(m,3H),1.26-1.36(m,2H),0.86-1.09(m,3H)；
MS m/z(ESI):642.2[M+H] + .
Example 100
2- (1- (2- ((dimethyl (oxo) -lambda) 6 -sulfanylidene) amino) -2- (2-methoxyphenyl) ethyl) -5-methyl-6- (oxazol-2-yl) -2, 4-dioxo-1, 4-dihydrothieno [2,3-d]Pyrimidin-3 (2H) -yl) -N-isopropyl-N, 2-dimethylpropionamide
Referring to example 20A, compound 100 was synthesized from compound 48.
1 H NMR(400MHz,CDCl 3 )δ7.59-7.67(m,2H),7.30(br,1H),7.20(s,1H),6.96(br,1H),6.84(d,J＝8.0Hz,1H),5.35-5.52(m,1H),4.39-4.87(m,1H),3.73-3.85(m,4H),3.00(s,3H),2.94(s,3H),2.85(s,3H),2.34(br,1H),1.75-1.87(m,8H),0.92-1.04(m,4H),0.54-0.60(m,2H)；
MS m/z(ESI):616.2[M+H] + .
Example 101
1- (2- ((dimethyl (oxo) -lambda) 6 -sulfanylidene) amino) -2- (2-methoxyphenyl) ethyl) -5-methyl-3- (2-methyl-1-oxo-1- (pyrrolidin-1-yl) propan-2-yl) -6- (oxazol-2-yl) thieno [2,3-d ]Pyrimidine-2, 4 (1H, 3H) -diones
Referring to example 20A, compound 101 was synthesized from compound 48.
1 H NMR(400MHz,CDCl 3 )δ7.68(s,1H),7.65(d,J＝7.6Hz,1H),7.31(t,J＝7.6Hz,1H),7.21(s,1H),6.98(t,J＝7.6Hz,1H),6.84(d,J＝8.0Hz,1H),5.31-5.58(br,1H),4.27-4.73(br,1H),3.74(m,4H),3.21-3.33(m,3H),3.04(s,3H),2.96(s,3H),2.86(s,3H),1.86(s,3H),1.74(m,3H),1.30-1.57(m,5H)；
MS m/z(ESI):614.2[M+H] + .
Synthetic routes for other embodiments refer to the above embodiments.
Biological test evaluation
The invention is further illustrated below in conjunction with test examples, which are not meant to limit the scope of the invention.
Test example 1 determination of the inhibition of ACC1 enzyme Activity by the Compounds of the invention
The purpose of the experiment is as follows: the purpose of this test case was to test compounds for their activity against inhibition of ACC1 enzyme activity.
Experimental instrument: the centrifuge (5702R) was purchased from Eppendorf corporation, the pipettor from Eppendorf or Rainin corporation, and the microplate reader from BioTek corporation, USA under the model SynergyH1 full function microplate reader.
The experimental method comprises the following steps: the experiment adopts ADP chemiluminescence detection method of Promega company, adopts ADP-Glo TM Kinase Assay reagent (Promega#V9101), ACC1 catalyzes a reaction in the presence of substrates acetyl coenzyme A and ATP to form ADP, the ADP content in the reaction is measured to characterize the activity of ACC1 enzyme, and half inhibition concentration IC of the compound on ACC1 enzyme activity inhibition is obtained 50 。
The specific experimental operation is as follows:
ACC1 enzyme reaction was performed in a white 384 well plate (Perkin Elmer # 6007299) with 0.5-2. Mu.L of ddH with DMSO per well 2 O diluted compounds of different concentrations, positive control wells were added with 0.5-2. Mu.L of ddH containing DMSO 2 O, 1-5 mu L of ACC1 enzyme protein (Sigma, # A6986) diluted by reaction buffer solution is added to each well, the final enzyme concentration is 1-20 nM, 0.5-2 mu L of reaction buffer solution is added to a negative control well, 1-10 mu L of acetyl coenzyme A (Sigma, # A2056) and ATP substrate mixture solution are added to all wells to start the reaction, the final concentration of acetyl coenzyme A is 5-50 mu M, the final concentration of ATP is 10-50 mu M, after 30-120 minutes of reaction at room temperature, 10 mu L of ADP-Glo Reagent is added to each well to remove redundant ATP in the reaction at room temperature, 20 mu L Kinase Detection Reagent is added to each well, and after 10-60 minutes of reaction at room temperature, the chemiluminescent value is detected by a BioTek Synergy H1 enzyme label instrument.
The experimental data processing method comprises the following steps:
percent inhibition data {% inhibition = 100- [ (test compound value-negative control value) for wells treated with compound were calculated by positive control wells (DMSO control wells) and negative control wells (no kinase or substrate added) on the plate]/(positive control value-negative control value) ×100}. Calculation of IC using GraphPad prism to fit different concentrations and corresponding percent inhibition data to a 4 parameter nonlinear logic formula 50 Values.
Test example 2 determination of the inhibition of ACC2 enzyme Activity by the Compounds of the invention
The purpose of the experiment is as follows: the purpose of this test case was to test compounds for their activity against inhibition of ACC2 enzyme activity.
Experimental instrument: the centrifuge (5702R) was purchased from Eppendorf corporation, the pipettor from Eppendorf or Rainin corporation, and the microplate reader from BioTek corporation, USA under the model SynergyH1 full function microplate reader.
The experimental method comprises the following steps: the experiment adopts ADP chemiluminescence detection method of Promega company, adopts ADP-Glo TM Kinase Assay reagent (Promega#V9101), ACC2 is catalyzed by the presence of substrates acetyl coenzyme A and ATP to form ADP, the ADP content in the reaction is measured to characterize the activity of ACC2 enzyme, and half inhibition concentration IC of the compound on ACC2 enzyme activity inhibition is obtained 50 。
The specific experimental operation is as follows:
ACC2 enzyme reaction was performed in a white 384 well plate (Perkin Elmer # 6007299) with 0.5-2. Mu.L of ddH with DMSO per well 2 O diluted compounds of different concentrations, positive control wells were added with 0.5-2. Mu.L of ddH containing DMSO 2 O, 1-5 mu L of ACC2 enzyme protein (Sigma, #A6861) diluted by reaction buffer solution is added to each well, the final enzyme concentration is 1-20 nM, 0.5-2 mu L of reaction buffer solution is added to a negative control well, 1-10 mu L of acetyl coenzyme A (Sigma, #A2056) and ATP substrate mixture solution are added to all wells to start the reaction, the final concentration of acetyl coenzyme A is 5-50 mu M, the final concentration of ATP is 10-50 mu M, after 30-120 minutes of reaction at room temperature, 10 mu L of ADP-Glo Reagent is added to each well to remove redundant ATP in the reaction at room temperature, 20 mu L Kinase Detection Reagent is added to each well, and after 10-60 minutes of reaction at room temperature, the chemiluminescent value is detected by a BioTek Synergy H1 enzyme label instrument.
The experimental data processing method comprises the following steps:
percent inhibition data {% inhibition = 100- [ (test compound value-negative control value) for wells treated with compound were calculated by positive control wells (DMSO control wells) and negative control wells (no kinase or substrate added) on the plate]/(positive control value-negative control value) ×100}. Different concentrations and corresponding percent inhibition were fitted using GraphPad prismIC is calculated by a nonlinear logic formula from the control rate data to 4 parameters 50 Values.
The compounds of the present invention show specific test data for bioactivity in ACC inhibition assays as follows:
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test example 3, analysis of the compounds of the invention on mouse PK
The pharmacokinetic experiments in mice according to the preferred embodiment of the present invention were performed using Balb/c male mice (Shanghai Jieshijie laboratory animal Co., ltd.)
■ The administration mode is as follows: single gastric lavage administration.
■ Dosage of administration: 5 mg/10 ml/kg.
■ Formulation recipe: CMC-Na 0.5% and dissolved by ultrasound.
■ Sampling points: 0.5, 1, 2, 4, 6, 8 and 24 hours after administration.
■ Sample treatment:
1) The orbit is sampled by 0.1mL and placed in K 2 In EDTA test tube, the plasma is separated by centrifugation at 1000-3000 Xg for 5-20 min at room temperature and stored at-80 ℃.
2) The plasma sample 40uL was precipitated by adding 160uL acetonitrile, and after mixing, it was centrifuged at 500 to 2000 Xg for 5 to 20 minutes.
3) The concentration of the test compound was analyzed by LC/MS/MS by taking 100uL of the supernatant solution after the treatment.
■ LC-MS/MS analysis
● Liquid phase conditions: shimadzu LC-20AD pump
● Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer
● Chromatographic column: phenomenex Gemiu 5um C18.times.4.6 mm
● Mobile phase: solution A is 0.1% formic acid water solution, solution B is acetonitrile
Flow rate: 0.8mL/min
● Elution time: gradient elution for 0-3.5 min
■ Pharmacokinetics:
the main parameters are calculated by WinNonlin 6.1, and the results of the mouse drug substitution experiments are shown in the following table:
from the results of the mouse drug substitution experiments in the table, it can be seen that: the compounds of the examples of the present invention exhibit good metabolic properties, exposure AUC and maximum blood concentration C max All perform well.
Test example 4, in vivo efficacy test procedure and results of the Compounds of the invention
1. The purpose of the experiment is as follows:
evaluation of the efficacy and safety of the preferred embodiment of the invention on the CDAA feed-induced C57 mouse NASH model
2. Experimental main instrument and reagent
2.1 instrument:
1. full-function enzyme-labeled instrument (BioTek, H1 MFD)
2. Refrigerated centrifuge (Eppendorf 5810R)
3. Constant temperature flume (Shanghai Yihengzheng science HWS 12)
4. Balance (Sidoris, CPA 2202S)
5. Desk type blast drying oven (Shanghai Jing Hongjing, DHG-9123A)
2.2 reagents:
1. CDAA feed (Research Diets, A06071302)
2. Alanine Aminotransferase (ALT) test box (Nanjing built, C009-2-1)
3. Aspartic acid Aminotransferase (AST) test box (Nanjing built, C010-2-1)
4. Total Cholesterol (TC) determination kit (Nanjing built, A111-1-1)
3. Experimental animals:
c57BL/6 Male mice, 37, 8-10 weeks old, weighing 20-25 g purchased from Shanghai Sipule-BiKai laboratory animal Co., ltd
4. The experimental steps are as follows:
37C 57 mice were randomly divided into 5 groups according to body weight, 5 Blank groups, 8 animals per group, CDAA feed was induced for 9 weeks altogether, animal body weights were weighed once a week after the start of the experiment, food intake was measured twice a week, feed administration was started after 2 weeks of feed induction, the dosing schedule was shown in the following table, animal body weights were measured twice a week during the dosing period, mice were sacrificed after 7 weeks of dosing, and ALT and AST in serum were detected.
5. Test data:
6. experimental results
From the above results, it can be seen that the above examples of this patent significantly improve ALT and AST in animal serum on the CDAA-induced C57 mouse NASH model.

Claims (13)

1. A compound of formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Wherein:
ring B is phenyl;
l is selected from bond, C 3-6 Cycloalkyl, - (CR) aa R bb ) n1 -or- (CR) aa R bb ) n1 C(O)-；
R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, (CH) 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 C(O)NR aa R bb 、(CH 2 ) n1 C(O)R aa Or- (CH) 2 ) n1 S(＝NR aa )(O) m1 R bb Wherein said C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclyl, optionally further substituted with one or more substituents selected from hydroxy or methyl;
R 5 selected from hydrogen or C 1-6 An alkyl group;
R 6 selected from hydrogen, C 1-6 Alkyl, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, or-n=s=o (R aa R bb )；
R aa And R is bb Each independently selected from hydrogen or C 1-6 An alkyl group;
alternatively, R aa And R is bb Linking to form 3-8 membered heterocyclic groups or C 3-6 Cycloalkyl;
R b selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups;
R 3 is-n=s=o (R aa R bb )；
m is 0, 1 or 2;
m 1 0, 1 or 2; and is also provided with
n 1 0, 1 or 2.
2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the formula (III) being further represented by formula (IV):
wherein:
ring B, R 1 、R 3 、R 5 、R 6 、R aa 、R bb 、R b And m is as defined in claim 1.
3. The compound of claim 1, sup>A stereoisomer thereof, or Sup>A pharmaceutically acceptable salt thereof, the formulSup>A (III) being further represented by formulSup>A (IV-Sup>A):
wherein:
ring B, R 1 、R 3 、R 5 、R b 、R aa 、R bb And m is as defined in claim 1.
4. A compound of the general formula (x), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
Wherein:
R c selected from hydrogen or C 1-6 An alkyl group;
x is 0, 1 or 2;
R 1 selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-8 membered heterocyclyl, (CH) 2 ) n1 C(O)OR aa 、-(CH 2 ) n1 C(O)NR aa R bb 、(CH 2 ) n1 C(O)R aa Or- (CH) 2 ) n1 S(＝NR aa )(O) m1 R bb Wherein said C 1-6 Alkyl, C 3-6 Cycloalkyl or 3-8 membered heterocyclyl, optionally further substituted with one or more substituents selected from hydroxy or methyl;
R 5 selected from hydrogen or C 1-3 An alkyl group;
R aa and R is bb Each independently selected from hydrogen or C 1-6 An alkyl group;
or R is aa And R is bb Linking to form 3-8 membered heterocyclic groups or C 3-6 Cycloalkyl;
n 1 0, 1 or 2; and is also provided with
m 1 0, 1 or 2.
5. The compound of claim 1, a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is a pharmaceutically acceptable salt of the compound
L is selected from the group consisting of bond, -C (CH) 3 ) 2 -、-CHCH 3 C(O)-、-C(CH 3 ) 2 C(O)-、
R 1 Selected from hydrogen, C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl containing 1-4N, O or S atoms, (CH) 2 )n1C(O)OR aa 、-(CH 2 )n1C(O)NR aa R bb 、(CH 2 )n1C(O)R aa Or- (CH) 2 )n1S(＝NR aa )(O)m1R bb Wherein said C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, optionally further substituted with one or more substituents selected from hydroxy or methyl;
R 5 selected from hydrogen or C 1-3 An alkyl group;
R 6 selected from hydrogen, 3-8 membered heterocyclyl, 5-10 membered heteroaryl, or-n=s=o (R aa R bb )；
R aa And R is bb Each independently selected from hydrogen or C 1-6 An alkyl group;
alternatively, R aa And R is bb Linking to form 3-8 membered heterocyclic groups or C 3-6 Cycloalkyl;
R b selected from hydrogen and OCH 3 or-OCH (CH) 3 ) 2 ；
R 3 Is-n=s=o (R aa R bb )；
m is 0, 1 or 2;
m 1 0, 1 or 2; and is also provided with
n 1 0, 1 or 2.
6. The compound of claim 1, a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound is a pharmaceutically acceptable salt of the compound
L is selected from the group consisting of bond, -C (CH) 3 ) 2 -、-C(CH 3 ) 2 C (O) -or
R 1 Selected from hydrogen, C 3-6 Cycloalkyl, -C (O) OH, -C (O) NH 2 、-C(O)NHCH(CH 3 ) 2 、
R 5 Is methyl;
R 6 selected from hydrogen,
R b Is OCH 3 。
7. The compound of claim 4, a stereoisomer or pharmaceutically acceptable salt thereof, further represented by the general formula (X-a):
8. the compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the formula (III) being further represented by formula (XI):
wherein:
R 1 、R 5 、R b 、R aa 、R bb and m is as defined in claim 1Said.
9. The compound of claim 8, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, the formula (XI) being further represented by formula (XI-a):
10. a compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of:
11. a pharmaceutical composition comprising a therapeutically effective amount of a compound as set forth in any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
12. Use of a compound according to any one of claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11 for the preparation of an ACC inhibitor medicament.
13. Use of a compound according to any one of claims 1 to 10, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11 for the preparation of a medicament for the treatment of an acetyl-coa carboxylase modulating disease, cancer; wherein said acetyl-coa carboxylase modulating disease is selected from the group consisting of membrane island resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis; wherein the cancer is a cancer selected from the group consisting of breast cancer, pancreatic cancer, non-small cell lung cancer, thyroid cancer, seminoma, melanoma, bladder cancer, liver cancer, kidney cancer, myelodysplastic syndrome, acute myelogenous leukemia, and colorectal cancer.
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CN111848678A (en) * 2019-04-30 2020-10-30 正大天晴药业集团股份有限公司 Phosphorus-containing thienopyrimidine derivatives
CN112574253B (en) * 2019-09-29 2021-08-27 上海喀露蓝科技有限公司 Phosphoric acid or phosphate ester derivative, preparation method and medical application thereof
TW202233632A (en) * 2021-02-07 2022-09-01 大陸商正大天晴藥業集團股份有限公司 Thienopyrimidine derivative
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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104105485A (en) * 2011-11-11 2014-10-15 尼普斯阿波罗有限公司 Acc inhibitors and uses thereof
WO2015003879A1 (en) * 2013-07-08 2015-01-15 Syngenta Participations Ag Microbiocidal heterobicylic derivatives
CN105358155A (en) * 2013-05-10 2016-02-24 尼普斯阿波罗有限公司 Acc inhibitors and uses thereof
CN107106873A (en) * 2015-01-09 2017-08-29 吉利德阿波罗公司 ACC inhibitor combined therapies for treating non-alcoholic fatty liver disease
WO2017147161A1 (en) * 2016-02-23 2017-08-31 Raju Mohan Treatment of dermatological disorders or conditions
CN107629069A (en) * 2017-11-06 2018-01-26 中国药科大学 The preparation method of a kind of acetyl-CoA carboxylase inhibitor
CN108349994A (en) * 2015-11-25 2018-07-31 吉利德阿波罗公司 Triazole ACC inhibitor and application thereof
CN108349995A (en) * 2015-11-25 2018-07-31 吉利德阿波罗公司 Pyrazoles ACC inhibitor and application thereof
CN110382503A (en) * 2017-03-03 2019-10-25 吉利德科学公司 The method for preparing ACC inhibitor and its solid form

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7696365B2 (en) * 2003-08-01 2010-04-13 Chugai Seiyaku Kabushiki Kaisha Heterocyclic compounds useful as malonyl-CoA decarboxylase inhibitors

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104105485A (en) * 2011-11-11 2014-10-15 尼普斯阿波罗有限公司 Acc inhibitors and uses thereof
CN105358155A (en) * 2013-05-10 2016-02-24 尼普斯阿波罗有限公司 Acc inhibitors and uses thereof
WO2015003879A1 (en) * 2013-07-08 2015-01-15 Syngenta Participations Ag Microbiocidal heterobicylic derivatives
CN107106873A (en) * 2015-01-09 2017-08-29 吉利德阿波罗公司 ACC inhibitor combined therapies for treating non-alcoholic fatty liver disease
CN108349994A (en) * 2015-11-25 2018-07-31 吉利德阿波罗公司 Triazole ACC inhibitor and application thereof
CN108349995A (en) * 2015-11-25 2018-07-31 吉利德阿波罗公司 Pyrazoles ACC inhibitor and application thereof
WO2017147161A1 (en) * 2016-02-23 2017-08-31 Raju Mohan Treatment of dermatological disorders or conditions
CN110382503A (en) * 2017-03-03 2019-10-25 吉利德科学公司 The method for preparing ACC inhibitor and its solid form
CN107629069A (en) * 2017-11-06 2018-01-26 中国药科大学 The preparation method of a kind of acetyl-CoA carboxylase inhibitor

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