CN114907284B - Compound with anti-tumor activity and application thereof - Google Patents

Compound with anti-tumor activity and application thereof Download PDF

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CN114907284B
CN114907284B CN202210122028.7A CN202210122028A CN114907284B CN 114907284 B CN114907284 B CN 114907284B CN 202210122028 A CN202210122028 A CN 202210122028A CN 114907284 B CN114907284 B CN 114907284B
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membered
alkyl
aryl
pharmaceutically acceptable
stereoisomer
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CN114907284A (en
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张朝再
胡继明
安会
范丽雪
齐非
滑新星
张颜
蒋春华
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CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

There is provided a class of compounds of formula (I), or stereoisomers, geometric isomers, tautomers, hydrates, solvates, isotopically-labelled analogues, prodrugs or pharmaceutically acceptable salts thereof, and uses thereof. Each group of the formula (I)As defined in the specification.

Description

Compound with anti-tumor activity and application thereof
Cross Reference to Related Applications
The present application claims priority and equity to chinese patent application No. 202110183102.1 filed on 10 months 2021 to the chinese national intellectual property agency, the disclosure of which is incorporated herein by reference in its entirety.
Technical Field
The application relates to the technical field of medicines, in particular to a compound serving as an SOS1 inhibitor, a preparation method of the compound and application of the compound.
Background
The currently known RAS family shares three genes: KRAS (Kirsten rat sarcoma viral oncogene homolog), NRAS (neuroblastoma RAS viral oncogene homolog) and HRAS (Harvey murine sarcoma viral oncogene). RAS family proteins are a class of small molecule GTPases, and are the first oncogenes identified in human tumors. RAS family proteins have weak intrinsic gtpase activity and slow nucleotide exchange rates. Binding of Gtpase Activating Proteins (GAPs) such as NF1 increases the gtpase activity of RAS family proteins.
Mutations in the RAS enzyme are closely related to tumorigenesis, and among different types of tumors, the RAS mutation type is also different. In human tumors, KRAS mutations (e.g., amino acids G12, G13, Q61, a 146) are most common, accounting for about 85%, NRAS (e.g., amino acids G12, G13, Q61, a 146) and HRAS (e.g., amino acids G12, G13, Q61) account for 12% and 3%, respectively. Alterations (e.g., mutations, overexpression, gene amplification) of RAS family proteins have also been described as resistance mechanisms against cancer drugs such as: EGFR antibody cetuximab (cetuximab) and panitumumab (panitumumab) and EGFR tyrosine kinase inhibitor octreotide (osimerinib). For oncogenic RAS mutants, GAP activity is impaired or greatly reduced, resulting in permanent activation, which is the basis for oncogenic RAS signaling. Direct inhibition of RAS has proven to be extremely challenging and difficult to formulate due to its picomolar affinity for its binding site, the lack of other well-defined pockets, and the interaction of RAS with GEF, GAP and effectors through extended and flat protein-protein interaction surfaces. Thus, by targeting the upstream guanine nucleotide exchange factor protein SOS, inhibition of RAS activation may be new hopefully.
SOS exists in two human isoforms, SOS1 and SOS2, but most research has focused on SOS 1. Human SOS1 comprises 1333 amino acids (15 kDa), consisting of an N-terminal domain, a Dbl Homology (DH) domain, a Pleckstrin Homology (PH) domain, including a Ras exchange motif (Rem) domain and a Cdc25 domain, as well as a C-terminal region. Wherein PH, rem and Cdc25 are SOS cat Components of the core catalytic domain.
Over the past few decades, RAS family protein-SOS 1 protein interactions have gained increasing acceptance. In addition, recently, studies have been conducted to combine rational design and screening platforms to identify small molecule inhibitors of SOS1, i.e., compounds that bind to SOS1 and inhibit protein-protein interactions with RAS family proteins. SOS1 inhibitors of quinazolines and analogues thereof are described, for example, in CN110167928/CN111372932 and WO2018172250/WO 2019201848.
Although some small molecule inhibitors of SOS1 have been disclosed, no SOS1 inhibitors are currently developed and marketed, so that the development of new compounds with market potential, better efficacy and drug generation results is still urgent. The application designs a series of compounds with new structures shown in the general formula, and discovers that the compounds with the structures have excellent effects and actions, and have positive significance in the development of SOS1 inhibitors.
Summary of The Invention
In one aspect of the present application, there is provided a compound represented by the following formula (I), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically-labeled analogues thereof,
wherein ,
represents a single bond or a double bond, "> and />Not simultaneously double bond,)> and />Not at the same time beA double bond;
when (when)X is selected from C (R A )(R A )、NR A O, S; when->X is selected from CR when it is a double bond A 、N；
R A Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl, -C (O) -C 1-6 Alkyl, -C (O) -C 3-10 Cycloalkyl, -C (O) -3-10 membered heterocyclyl, -C 1-6 alkyl-C (O) -C 1-6 Alkyl, -C 1-6 Alkyl C (O) -C 3-10 Cycloalkyl, -C 1-6 Alkyl C (O) -3-10 membered heterocyclyl and 5-10 membered heteroaryl; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl, -C (O) -C 1-6 Alkyl, -C (O) -C 3-10 Cycloalkyl, -C (O) -3-10 membered heterocyclyl, -C 1-6 alkyl-C (O) -C 1-6 Alkyl, -C 1-6 Alkyl C (O) -C 3-10 Cycloalkyl, -C 1-6 Alkyl C (O) -3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more R's, which may be the same or different a1 Substitution;
R a1 each occurrence is independently selected from-OR c 、-NR c R c Halogen, -CN, -C (O) R c 、-C(O)OR c 、-C(O)NR c R c 、-S(O) 2 R c 、-S(O) 2 NR c R c 、-NHC(O)R c 、-N(C 1-4 Alkyl) C (O) R c Oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl group,C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different c Substitution;
R c each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;
when (when)When a single bond is provided, Y is selected from C 1-6 An alkyl group; when->In the case of a double bond, Y is selected from O, S;
when (when)When Z is a single bond, Z is selected from CH, N, O, S, and when Z is selected from O, S, R 2 Absence of; when->Z is selected from C and N when Z is selected from N, R 2 Absence of;
when (when)In the case of double bonds, R 1 Is O; when->R is a single bond 1 Selected from the group consisting of-O-R B Optionally substituted C 2-4 Alkyl, C 2-4 Alkenyl, C 3-12 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl;
wherein whenIs a single bond, and R 1 Selected from the group consisting of-O-R B When R is B Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl are optionally substituted with one or more R's, which may be the same or different b1 Substitution;
R b1 each occurrence is independently selected from-OR c1 、-NR c1 R c1 Halogen, -CN, -C (O) R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、-S(O) 2 R c1 、-S(O) 2 NR c1 R c1 、-NHC(O)R c1 、-N(C 1-4 Alkyl) C (O) R c1 Oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more R's, which may be the same or different c1 Substitution;
R c1 each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;
alternatively, whenIs a single bond, and R 1 Selected from C 3-12 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl, said C 3-12 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different a2 Substitution;
R a2 each occurrence is independently selected from-OR c2 、-NR c2 R c2 Halogen, -CN, -C (O) R c2 、-C(O)OR c2 、-C 0-4 Alkyl C (O) NR c2 R c2 、-OC(O)R c2 、-S(O) 2 R c2 、-S(O) 2 NR c2 R c2 、-NHC(O)R c2 、-N(C 1-4 Alkyl) C (O) R c2 、-NHC(O)OR c2 Oxo, =nh, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different c2 Substitution;
R c2 each occurrence is independently selected from hydrogen, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;
or whenIs a single bond, and R 1 Selected from C 2-4 Alkyl and C 2-4 Alkenyl, the C 2-4 Alkyl and C 2-4 Alkenyl groups optionally being substituted by one or more R's, identical or different b2 Substitution;
R b2 each occurrence is independently selected from the group consisting of-C (O) R c3 、-C(O)OR c3 、-C(O)NR c3 R c3 、-C(O)NHOR c3 and-C (O) -N (C) 1-4 Alkyl) -OR c3 ；
R c3 Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;
R 2 selected from hydrogen, C 1-6 Alkyl, -O-C 1-4 Alkyl, -NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl) (C) 1-4 Alkyl) and halogen;
R 3 selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -O-C 1-4 Alkyl, -NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl) (C) 1-4 Alkyl) and halogen;
ring A is selected from C 4-12 Cycloalkyl, 4-12 membered heterocyclyl, C 6-10 Aryl, 5-12 membered heteroaryl;
R 4 each occurrence is independently selected from hydrogen, -NH 2 、C 1-4 Alkyl, halogen, C 1-4 Haloalkyl, -O-C 1-4 Alkyl, -O-C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclyl, -O-C 3-6 Cycloalkyl, -O-C 6-10 Aryl, -O-5-10 membered heteroaryl, -O-3-6 membered heterocyclyl, -O-CH 2 -C 3-6 Cycloalkyl, -O-CH 2 -C 6-10 Aryl, -O-CH 2 -5-to 10-membered heteroaryl, -O-CH 2 -3-6 membered heterocyclyl, -ch=ch-C 3-6 Cycloalkyl, -ch=ch-C 6-10 Aryl, -ch=ch-5-10 membered heteroaryl, -ch=ch-3-6 membered heterocyclyl, -ch=ch-CH 2 -C 3-6 Cycloalkyl, -ch=ch-CH 2 -C 6-10 Aryl, -ch=ch-CH 2 -5-10 membered heteroaryl, -ch=ch-CH 2 -3-6 membered heterocyclyl, -SO 2 -C 1-4 Alkyl, wherein C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclyl, -O-C 3-6 Cycloalkyl, -O-C 6-10 Aryl, -O-5-10 membered heteroaryl, -O-3-6 membered heterocyclyl, -O-CH 2 -C 3-6 Cycloalkyl, -O-CH 2 -C 6-10 Aryl, -O-CH 2 -5-to 10-membered heteroaryl, -O-CH 2 -3-6 membered heterocyclyl, -ch=ch-C 3-6 Cycloalkyl, -ch=ch-C 6-10 Aryl, -ch=ch-5-10 membered heteroaryl, -ch=ch-3-6 membered heterocyclyl, -ch=ch-CH 2 -C 3-6 Cycloalkyl, -ch=ch-CH 2 -C 6-10 Aryl, -ch=ch-CH 2 -5-10 membered heteroaryl, -ch=ch-CH 2 -3-6 membered heterocyclyl groups optionally substituted with one or more groups selected from hydroxy, oxo, C 1-6 Alkyl, amino, cyano, nitro, halogenElement, -C 1-4 alkyl-NH 2 、-C 1-4 alkyl-NH-C 1-4 Alkyl, -C 1-4 alkyl-N- (C) 1-4 Alkyl) (C) 1-4 Alkyl group, C 2-6 Alkenyl, C 2-6 Alkynyl groups are substituted; where w=0, 1,2,3,4.
In another aspect of the present application, there is provided a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, a hydrate, a solvate, an isotopically-labeled analog, a prodrug or a pharmaceutically acceptable salt thereof according to the present application, and a pharmaceutically acceptable adjuvant.
In another aspect of the application, there is provided the use of a compound of formula (I) according to the application or a stereoisomer, a geometric isomer, a tautomer, a hydrate, a solvate, an isotopically-labeled analog, a prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the application, for the manufacture of a medicament for the treatment of a disease mediated by an SOS1 inhibitor.
In another aspect of the application, there is provided the use of a compound of formula (I) according to the application or a stereoisomer, a geometric isomer, a tautomer, a hydrate, a solvate, an isotopically-labeled analog, a prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the application, for the preparation of a medicament for the treatment of a disease caused by RAS mutation.
Detailed Description
The application aims to provide a compound with a brand new structure serving as an SOS1 inhibitor, a preparation method of the compound and application of the compound in treating diseases mediated by the SOS1 inhibitor.
In one aspect of the present application, there is provided a compound represented by the following formula (I), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically-labeled analogues thereof,
wherein ,
represents a single bond or a double bond, "> and />Not simultaneously double bond,)> and />Are not double bonds at the same time;
when (when)X is selected from C (R A )(R A )、NR A O, S; when->X is selected from CR when it is a double bond A 、N；
R A Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl, -C (O) -C 1-6 Alkyl, -C (O) -C 3-10 Cycloalkyl, -C (O) -3-10 membered heterocyclyl, -C 1-6 alkyl-C (O) -C 1-6 Alkyl, -C 1-6 Alkyl C (O) -C 3-10 Cycloalkyl, -C 1-6 Alkyl C (O) -3-10 membered heterocyclyl and 5-10 membered heteroaryl; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl, -C (O) -C 1-6 Alkyl, -C (O) -C 3-10 Cycloalkyl, -C (O) -3-10 membered heterocyclyl, -C 1-6 alkyl-C (O) -C 1-6 Alkyl, -C 1-6 Alkyl C (O) -C 3-10 Cycloalkyl, -C 1-6 Alkyl C (O) -3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more R's, which may be the same or different a1 Substitution;
R a1 each occurrence is independently selected from-OR c 、-NR c R c Halogen, -CN, -C (O) R c 、-C(O)OR c 、-C(O)NR c R c 、-S(O) 2 R c 、-S(O) 2 NR c R c 、-NHC(O)R c 、-N(C 1-4 Alkyl) C (O) R c Oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different c Substitution;
R c each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;
when (when)When a single bond is provided, Y is selected from C 1-6 An alkyl group; when->In the case of a double bond, Y is selected from O, S;
when (when)When Z is a single bond, Z is selected from CH, N, O, S, and when Z is selected from O, S, R 2 Absence of; when->Z is selected from C and N when Z is selected from N, R 2 Absence of;
when (when)In the case of double bonds, R 1 Is O; when->R is a single bond 1 Selected from the group consisting of-O-R B Optionally substituted C 2-4 Alkyl, C 2-4 Alkenyl, C 3-12 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl;
wherein whenIs a single bond, and R 1 Selected from the group consisting of-O-R B When R is B Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl are optionally substituted with one or more R's, which may be the same or different b1 Substitution;
R b1 each occurrence is independently selected from-OR c1 、-NR c1 R c1 Halogen, -CN, -C (O) R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、-S(O) 2 R c1 、-S(O) 2 NR c1 R c1 、-NHC(O)R c1 、-N(C 1-4 Alkyl) C (O) R c1 Oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more R's, which may be the same or different c1 Substitution;
R c1 each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;
alternatively, whenIs a single bond, and R 1 Selected from C 3-12 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl, said C 3-12 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different a2 Substitution;
R a2 each occurrence is independently selected from-OR c2 、-NR c2 R c2 Halogen, -CN, -C (O) R c2 、-C(O)OR c2 、-C 0-4 Alkyl C (O) NR c2 R c2 、-OC(O)R c2 、-S(O) 2 R c2 、-S(O) 2 NR c2 R c2 、-NHC(O)R c2 、-N(C 1-4 Alkyl) C (O) R c2 、-NHC(O)OR c2 Oxo, =nh, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different c2 Substitution;
R c2 each occurrence is independently selected from hydrogen, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;
or whenIs a single bond, and R 1 Selected from C 2-4 Alkyl and C 2-4 Alkenyl, the C 2-4 Alkyl and C 2-4 Alkenyl groups optionally being substituted by one or more R's, identical or different b2 Substitution;
R b2 each occurrence is independently selected from the group consisting of-C (O) R c3 、-C(O)OR c3 、-C(O)NR c3 R c3 、-C(O)NHOR c3 and-C (O) -N (C) 1-4 Alkyl) -OR c3 ；
R c3 Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;
R 2 selected from hydrogen, C 1-6 Alkyl, -O-C 1-4 Alkyl, -NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl) (C) 1-4 Alkyl) and halogen;
R 3 selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -O-C 1-4 Alkyl, -NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl) (C) 1-4 Alkyl) and halogen;
ring A is selected from C 4-12 Cycloalkyl, 4-12 membered heterocyclyl, C 6-10 Aryl, 5-12 membered heteroaryl;
R 4 each occurrence is independently selected from hydrogen, -NH 2 、C 1-4 Alkyl, halogen, C 1-4 Haloalkyl, -O-C 1-4 Alkyl, -O-C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclyl, -O-C 3-6 Cycloalkyl, -O-C 6-10 Aryl, -O-5-10 membered heteroaryl, -O-3-6 membered heterocyclyl, -O-CH 2 -C 3-6 Cycloalkyl, -O-CH 2 -C 6-10 Aryl, -O-CH 2 -5-to 10-membered heteroaryl, -O-CH 2 -3-6 membered heterocyclyl, -ch=ch-C 3-6 Cycloalkyl, -ch=ch-C 6-10 Aryl, -ch=ch-5-10 membered heteroaryl, -ch=ch-3-6 membered heterocyclyl, -ch=ch-CH 2 -C 3-6 Cycloalkyl, -ch=ch-CH 2 -C 6-10 Aryl, -ch=ch-CH 2 -5-10 membered heteroaryl, -ch=ch-CH 2 -3-6 membered heterocyclyl, -SO 2 -C 1-4 Alkyl, wherein C 1-4 Alkyl, C 1-4 HaloalkanesRadical, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclyl, -O-C 3-6 Cycloalkyl, -O-C 6-10 Aryl, -O-5-10 membered heteroaryl, -O-3-6 membered heterocyclyl, -O-CH 2 -C 3-6 Cycloalkyl, -O-CH 2 -C 6-10 Aryl, -O-CH 2 -5-to 10-membered heteroaryl, -O-CH 2 -3-6 membered heterocyclyl, -ch=ch-C 3-6 Cycloalkyl, -ch=ch-C 6-10 Aryl, -ch=ch-5-10 membered heteroaryl, -ch=ch-3-6 membered heterocyclyl, -ch=ch-CH 2 -C 3-6 Cycloalkyl, -ch=ch-CH 2 -C 6-10 Aryl, -ch=ch-CH 2 -5-10 membered heteroaryl, -ch=ch-CH 2 -3-6 membered heterocyclyl groups optionally substituted with one or more groups selected from hydroxy, oxo, C 1-6 Alkyl, amino, cyano, nitro, halogen, -C 1-4 alkyl-NH 2 、-C 1-4 alkyl-NH-C 1-4 Alkyl, -C 1-4 alkyl-N- (C) 1-4 Alkyl) (C) 1-4 Alkyl group, C 2-6 Alkenyl, C 2-6 Alkynyl groups are substituted; where w=0, 1,2,3,4.
In some embodiments of the application, in formula (I) above,
represents a single bond or a double bond, "> and />Not simultaneously double bond,)> and />Are not double bonds at the same time;
when (when)X is selected from C (R A )(R A )、NR A O, S; when->X is selected from CR when it is a double bond A 、N；
R A Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl, -C (O) -C 1-6 Alkyl, -C (O) -C 3-10 Cycloalkyl, -C (O) -3-10 membered heterocyclyl, -C 1-6 alkyl-C (O) -C 1-6 Alkyl, -C 1-6 Alkyl C (O) -C 3-10 Cycloalkyl, -C 1-6 Alkyl C (O) -3-10 membered heterocyclyl and 5-10 membered heteroaryl; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl, -C (O) -C 1-6 Alkyl, -C (O) -C 3-10 Cycloalkyl, -C (O) -3-10 membered heterocyclyl, -C 1-6 alkyl-C (O) -C 1-6 Alkyl, -C 1-6 Alkyl C (O) -C 3-10 Cycloalkyl, -C 1-6 Alkyl C (O) -3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more R's, which may be the same or different a1 Substitution;
R a1 each occurrence is independently selected from-OR c 、-NR c R c Halogen, -CN, -C (O) R c 、-C(O)OR c 、-C(O)NR c R c 、-S(O) 2 R c 、-S(O) 2 NR c R c 、-NHC(O)R c 、-N(C 1-4 Alkyl) C (O) R c Oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with oneOr a plurality of R's, which may be the same or different c Substitution;
R c each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;
when (when)When a single bond is provided, Y is selected from C 1-6 An alkyl group; when->In the case of a double bond, Y is selected from O, S;
when (when)When Z is a single bond, Z is selected from CH, N, O, S, and when Z is selected from O, S, R 2 Absence of; when->Z is selected from C and N when Z is selected from N, R 2 Absence of;
when (when)In the case of double bonds, R 1 Is O; when->R is a single bond 1 Selected from the group consisting of-O-R B Optionally substituted C 2-4 Alkyl, C 2-4 Alkenyl, C 3-12 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl;
wherein whenIs a single bond, and R 1 Selected from the group consisting of-O-R B When R is B Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl, wherein the C 3-10 Cycloalkyl and 3-10 membered heterocyclyl are optionally substituted with one or more R's, which may be the same or different b1 Substitution;
R b1 each occurrence is independently selected from-OR c1 、-NR c1 R c1 Halogen, -CN, -C (O) R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、-S(O) 2 R c1 、-S(O) 2 NR c1 R c1 、-NHC(O)R c1 、-N(C 1-4 Alkyl) C (O) R c1 Oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are each optionally substituted with one or more R's, which may be the same or different c1 Substitution;
R c1 each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;
alternatively, whenIs a single bond, and R 1 Selected from C 3-12 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl, said C 3-12 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different a2 Substitution;
R a2 each occurrence is independently selected from-OR c2 、-NR c2 R c2 Halogen, -CN, -C (O) R c2 、-C(O)OR c2 、-C 0-4 Alkyl C (O) NR c2 R c2 、-OC(O)R c2 、-S(O) 2 R c2 、-S(O) 2 NR c2 R c2 、-NHC(O)R c2 、-N(C 1-4 Alkyl) C (O) R c2 、-NHC(O)OR c2 Oxo, =nh, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different c2 Substitution;
R c2 each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;
or whenIs a single bond, and R 1 Selected from C 2-4 Alkyl and C 2-4 Alkenyl, the C 2-4 Alkyl and C 2-4 Alkenyl groups optionally being substituted by one or more R's, identical or different b2 Substitution;
R b2 each occurrence is independently selected from the group consisting of-C (O) R c3 、-C(O)OR c3 、-C(O)NR c3 R c3 、-C(O)NHOR c3 and-C (O) -N (C) 1-4 Alkyl) -OR c3 ；
R c3 Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl;
R 2 selected from hydrogen, C 1-6 Alkyl, -O-C 1-4 Alkyl, -NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl) (C) 1-4 Alkyl) and halogen;
R 3 selected from hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -O-C 1-4 Alkyl, -NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl) (C) 1-4 Alkyl) and halogen;
ring A is selected from C 4-12 Cycloalkyl, 4-12 membered heterocyclyl, C 6-10 Aryl, 5-12 membered heteroaryl;
R 4 each occurrence is independently selected from hydrogen, -NH 2 、C 1-4 Alkyl, halogen, C 1-4 Haloalkyl, -O-C 1-4 Alkyl, -O-C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclyl, -O-C 3-6 Cycloalkyl, -O-C 6-10 Aryl, -O-5-10 membered heteroaryl, -O-3-6 membered heterocyclyl, -O-CH 2 -C 3-6 Cycloalkyl, -O-CH 2 -C 6-10 Aryl, -O-CH 2 -5-to 10-membered heteroaryl, -O-CH 2 -3-6 membered heterocyclyl, -ch=ch-C 3-6 Cycloalkyl, -ch=ch-C 6-10 Aryl, -ch=ch-5-10 membered heteroaryl, -ch=ch-3-6 membered heterocyclyl, -ch=ch-CH 2 -C 3-6 Cycloalkyl, -ch=ch-CH 2 -C 6-10 Aryl, -ch=ch-CH 2 -5-10 membered heteroaryl, -ch=ch-CH 2 -3-6 membered heterocyclyl, -SO 2 -C 1-4 Alkyl, wherein C 1-4 Alkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclyl, -O-C 3-6 Cycloalkyl, -O-C 6-10 Aryl, -O-5-10 membered heteroaryl, -O-3-6 membered heterocyclyl, -O-CH 2 -C 3-6 Cycloalkyl, -O-CH 2 -C 6-10 Aryl, -O-CH 2 -5-to 10-membered heteroaryl, -O-CH 2 -3-6 membered heterocyclyl, -ch=ch-C 3-6 Cycloalkyl, -ch=ch-C 6-10 Aryl, -ch=ch-5-10 membered heteroaryl, -ch=ch-3-6 membered heterocyclyl, -ch=ch-CH 2 -C 3-6 Cycloalkyl, -ch=ch-CH 2 -C 6-10 Aryl, -ch=ch-CH 2 -5-10 membered heteroaryl, -ch=ch-CH 2 -3-6 membered heterocyclyl groups optionally substituted with one or more groups selected from hydroxy, oxo, C 1-6 Alkyl, amino, cyano, nitro, halogen, -C 1-4 alkyl-NH 2 、-C 1-4 alkyl-NH-C 1-4 Alkyl, -C 1-4 alkyl-N- (C) 1-4 Alkyl) (C) 1-4 Alkyl group, C 2-6 Alkenyl, C 2-6 Alkynyl groups are substituted; where w=0, 1,2,3,4.
In some embodiments of the present application,is a single bond, X is selected from C (R A )(R A )、NR A O, S; wherein R is A Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-8 Aryl, 3-6 membered heterocyclyl, -C (O) -C 1-6 Alkyl, -C (O) -C 4-6 Cycloalkyl, -C (O) -3-6 membered heterocyclyl, -C 1-6 alkyl-C (O) C 1-6 Alkyl, -C 1-6 alkyl-C (O) -C 4-6 Cycloalkyl, -C 1-6 alkyl-C (O) -3-6 membered heterocyclyl and 5-6 membered heteroaryl; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-8 Aryl, 3-6 membered heterocyclyl, -C (O) -C 1-6 Alkyl, -C (O) -C 4-6 Cycloalkyl, -C (O) -3-6 membered heterocyclyl, -C 1-6 alkyl-C (O) -C 1-6 Alkyl, -C 1-6 alkyl-C (O) -C 4-6 Cycloalkyl, -C 1-6 alkyl-C (O) -3-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different a1 And (3) substitution.
In some embodiments of the application, R a1 Each occurrence is independently selected from-OR c 、-NR c R c Halogen, -CN, -C (O) R c 、-C(O)OR c 、-C(O)NR c R c 、-S(O) 2 R c 、-S(O) 2 NR c R c 、-NHC(O)R c 、-N(C 1-4 Alkyl) C (O) R c Oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 4-6 Cycloalkyl, C 6-10 Aryl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 4-6 Cycloalkyl, C 6-10 Aryl, 4-6 membered heterocyclyl and 5-6 memberedHeteroaryl is optionally substituted with one or more R, which may be the same or different c And (3) substitution.
In some embodiments of the application, R c Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 4-6 Cycloalkyl, C 6-10 Aryl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl.
In some embodiments of the present application,is a single bond, X is selected from C (R A )(R A )、NR A O, S; wherein R is A Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 4-6 Cycloalkyl, C 6-8 Aryl, 3-6 membered heterocyclyl, -C (O) -C 1-6 Alkyl, -C (O) -C 4-6 Cycloalkyl, -C (O) -3-6 membered heterocyclyl, -C 1-6 alkyl-C (O) C 1-6 Alkyl, -C 1-6 alkyl-C (O) -C 4-6 Cycloalkyl, -C 1-6 alkyl-C (O) -3-6 membered heterocyclyl and 5-6 membered heteroaryl; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 4-6 Cycloalkyl, C 6-8 Aryl, 3-6 membered heterocyclyl, -C (O) -C 1-6 Alkyl, -C (O) -C 4-6 Cycloalkyl, -C (O) -3-6 membered heterocyclyl, -C 1-6 alkyl-C (O) C 1-6 Alkyl, -C 1-6 alkyl-C (O) -C 4-6 Cycloalkyl, -C 1-6 alkyl-C (O) -3-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different a1 And (3) substitution.
In some embodiments of the application, R a1 Each occurrence is independently selected from-OR c 、-NR c R c Halogen, -CN, -C (O) R c 、-C(O)OR c 、-C(O)NR c R c 、-S(O) 2 R c 、-S(O) 2 NR c R c 、-NHC(O)R c 、-N(C 1-4 Alkyl) C (O) R c Oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl group,C 4-6 Cycloalkyl, C 6-10 Aryl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 4-6 Cycloalkyl, C 6-10 Aryl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different c And (3) substitution.
In some embodiments of the application, R c Each occurrence is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, cyclobutyl, vinyl, ethynyl, C 4-6 Cycloalkyl, C 6 Aryl, 5-6 membered heterocyclyl and 5-6 membered heteroaryl.
In some embodiments of the present application,is a single bond, and R 1 is-O-R B ；
wherein ,RB Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl are optionally substituted with one or more R's, which may be the same or different b1 Substitution;
R b1 each occurrence is independently selected from-OR c1 、-NR c1 R c1 Halogen, -CN, -C (O) R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、-S(O) 2 R c1 、-S(O) 2 NR c1 R c1 、-NHC(O)R c1 、-N(C 1-4 Alkyl) C (O) R c1 Oxo, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different c1 Substitution;
R c1 each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl group3-10 membered heterocyclyl and 5-10 membered heteroaryl.
In some embodiments of the present application,is a single bond, and R 1 is-O-R B ；
wherein ,RB Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl, wherein the C 3-10 Cycloalkyl and 3-10 membered heterocyclyl are optionally substituted with one or more R's, which may be the same or different b1 Substitution;
R b1 each occurrence is independently selected from-OR c1 、-NR c1 R c1 Halogen, -CN, -C (O) R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、-S(O) 2 R c1 、-S(O) 2 NR c1 R c1 、-NHC(O)R c1 、-N(C 1-4 Alkyl) C (O) R c1 Oxo, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different c1 Substitution;
R c1 each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl.
In some embodiments of the present application, Is a single bond, and R 1 is-O-R B； wherein ,RB Selected from C 1-4 Alkyl, C 4-6 Cycloalkyl and 4-6 membered heterocyclyl, said C 1-4 Alkyl, C 4-6 Cycloalkyl and 4-6 membered heterocyclyl are optionally substituted with one or more R's, which may be the same or different b1 Substitution; in some embodiments, R B Selected from n-propyl, isopropyl, n-butyl, isobutyl, and anyOptionally one or more R b1 Substituted methyl, optionally substituted with one or more R b1 Substituted ethyl, optionally substituted with one or more R b1 Substituted C 5-6 Cycloalkyl, optionally substituted with one or more R b1 Substituted 5-6 membered heterocyclyl.
In some embodiments of the present application,is a single bond, and R 1 is-O-R B； wherein ,RB Selected from C 1-4 Alkyl, C 4-6 Cycloalkyl and 4-6 membered heterocyclyl, said C 4-6 Cycloalkyl and 4-6 membered heterocyclyl are optionally substituted with one or more R's, which may be the same or different b1 Substitution; in some embodiments, R B Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, optionally substituted with one or more R b1 Substituted C 5-6 Cycloalkyl, optionally substituted with one or more R b1 Substituted 5-6 membered heterocyclyl.
In some embodiments, R b1 Each occurrence is independently selected from-OR c1 、-NR c1 R c1 Halogen, -CN, -C (O) R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、-S(O) 2 R c1 、-S(O) 2 NR c1 R c1 、-NHC(O)R c1 、-N(C 1-4 Alkyl) -C (O) R c1 Oxo, C 1-4 An alkyl group.
In some embodiments, R b1 Each occurrence is independently selected from-OR c1 、-NR c1 R c1 Halogen, -CN, -C (O) R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、-S(O) 2 R c1 、-S(O) 2 NR c1 R c1 、-NHC(O)R c1 、-N(C 1-4 Alkyl) -C (O) R c1 Oxo groups.
In some embodiments, R c1 Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroarylA base; still more preferably, R c1 Each occurrence is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, cyclobutyl.
In some embodiments of the present application,is a single bond, and R 1 Selected from C 3-10 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 3-10 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different a2 And (3) substitution.
In some embodiments of the present application, in some embodiments,is a single bond, and R 1 Selected from C 4-9 Cycloalkyl, C 4-9 Cycloalkenyl, C 6-10 Aryl, 4-10 membered heterocyclyl and 5-10 membered heteroaryl, said C 4-9 Cycloalkyl, C 4-9 Cycloalkenyl, C 6-10 Aryl, 4-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different a2 And (3) substitution.
In some embodiments, R 1 Is selected from C 4 Monocycloalkyl, C 5 Monocycloalkyl, C 6 Monocycloalkyl, C 7 Monocycloalkyl, 3-membered/4-membered spirocycloalkyl, 4-membered/3-membered spirocycloalkyl, 4-membered/4-membered spirocycloalkyl, 4-membered/5-membered spirocycloalkyl, 5-membered/4-membered spirocycloalkyl, 5-membered/5-membered spirocycloalkyl, 4-membered/6-membered spirocycloalkyl, 6-membered/4-membered spirocycloalkyl, 3-membered/4-membered fused-ring alkyl, 4-membered/3-membered fused-ring alkyl, 4-membered/4-membered fused-ring alkyl, 4-membered/5-membered fused-ring alkyl, 5-membered/4-membered fused-ring alkyl, 5-membered/5-membered fused-ring alkyl, 4-membered/6-membered fused-ring alkyl, 6-membered/4-membered fused-ring alkyl, C 4 Monocycloalkenyl, C 5 Monocycloalkenyl, C 6 Monocycloalkenyl, C 7 Monocycloalkenyl, 3-membered/4-membered spirocycloalkenyl, 4-membered/3-membered spirocycloalkenyl, 4-membered/4-membered spirocycloalkenyl, 4-membered/5-membered spiroalkenyl, 5-membered/4-membered spiroalkenyl, 5-membered/5-membered spiroalkenyl, 4-membered/6-membered spiroalkenylA spirocycloalkenyl group, a 6-membered/4-membered spirocycloalkenyl group, a 4-membered/3-membered fused ring alkenyl group, a 4-membered/4-membered fused ring alkenyl group, a 4-membered/5-membered fused ring alkenyl group, a 5-membered/5-membered fused ring alkenyl group, a 4-membered/6-membered fused ring alkenyl group, a 6-membered/4-membered fused ring alkenyl group, a 4-membered single heterocyclic group, a 5-membered single heterocyclic group, a 6-membered single heterocyclic group, a 7-membered single heterocyclic group, a 3-membered/4-membered spiroheterocyclic group, a 4-membered/3-membered spiroheterocyclic group, a 4-membered/4-membered spiroheterocyclic group, a 4-membered/5-membered spiroheterocyclic group, a 5-membered/5-membered spiroheterocyclic group, a 4-membered/6-membered spiroheterocyclic group, a 6-membered/4-membered spiroheterocyclic group, a 3-membered/4-membered fused heterocyclic group, a 4-membered/3-membered fused heterocyclic group, a 4-membered/5-membered fused heterocyclic group, a 4-membered/6-membered fused heterocyclic group, a 6-membered/6-membered fused heterocyclic group 6 Aryl, 5 membered heteroaryl, 6 membered heteroaryl groups, wherein the groups are optionally substituted with one or more R's, which may be the same or different a2 And (3) substitution.
In some embodiments, R a2 Each occurrence is independently selected from C 1-6 Alkyl, -OR c2 、-NR c2 R c2 Halogen, -CN, -C (O) R c2 、-C(O)OR c2 、-C(O)NR c2 R c2 、-OC(O)R c2 、-S(O) 2 R c2 、-S(O) 2 NR c2 R c2 、-NHC(O)R c2 、-N(C 1-4 Alkyl) C (O) R c2 、-NHC(O)OR c2 、-C 0-4 alkyl-C (O) NR c2 R c2 Oxo, =nh.
In some embodiments, R a2 Each occurrence is independently selected from C 1-6 Alkyl, -OR c2 、-NR c2 R c2 Halogen, -CN, -C (O) R c2 、-C(O)OR c2 、-C(O)NR c2 R c2 、-OC(O)R c2 、-S(O) 2 R c2 、-S(O) 2 NR c2 R c2 、-NHC(O)R c2 、-N(C 1-4 Alkyl) C (O) R c2 、-NHC(O)OR c2 、-C 0-4 alkyl-C (O) NR c2 R c2 Oxo, =nh, wherein the C 1-6 Alkyl groups optionally being one or more of the same or differentWith R as c2 And (3) substitution.
In some embodiments, R c2 Each occurrence is independently selected from hydrogen, OH, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl; in some embodiments, R c2 Each occurrence is independently selected from hydrogen, OH, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, C 3-6 Cycloalkyl, phenyl, 3-6 membered heterocyclyl.
In some embodiments, R c2 Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl; in some embodiments, R c2 Independently at each occurrence selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, C 3-6 Cycloalkyl, phenyl, 3-6 membered heterocyclyl.
In some embodiments of the application, when Is a single bond, and R 1 Selected from C 2-4 Alkyl and C 2-4 Alkenyl, the C 2-4 Alkyl and C 2-4 Alkenyl is optionally substituted with one or more R b2 Substitution;
R b2 each occurrence is independently selected from the group consisting of-C (O) R c3 、-C(O)OR c3 、-C(O)NR c3 R c3 、-C(O)NHOR c3 and-C (O) N (C) 1-4 Alkyl) -OR c3 ；
R c3 Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl.
In some embodiments of the application, whenIn the case of double bond->Is a single bond.
In some embodiments of the application, whenIn case of single bond, the drug is added>Is a double bond.
In some embodiments of the application, whenX is selected from C (R A )(R A )、NR A O, S; when->X is selected from CR when it is a double bond A 、N；
R A Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C (O) -C 1-6 Alkyl, -C 1-6 alkyl-C (O) -C 1-6 An alkyl group; wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C (O) -C 1-6 Alkyl, -C 1-6 alkyl-C (O) -C 1-6 Alkyl groups are each optionally substituted with one or more (e.g., 1, 2 or 3) same or different R a1 Substitution; r is R a1 Each occurrence is independently selected from halogen, -CN, C 1-6 An alkyl group.
In some embodiments of the application, whenX is selected from C (R A )(R A )、NR A O, S; when->X is selected from CR when it is a double bond A 、N；R A Each occurrence is independently selected from hydrogen and C 1-6 An alkyl group.
In some embodiments of the application, whenX is selected from NR when it is a single bond A And O; when->When the double bond is formed, X is N; r is R A Each occurrence is independently selected from hydrogen and C 1-6 Alkyl (e.g., methyl, ethyl).
In some embodiments of the application, whenWhen the bond is single, Z is N; when->In the case of double bonds, Z is C.
In some embodiments of the application, whenIn the case of double bonds, R 1 Is O; when->R is a single bond 1 Selected from the group consisting of-O-R B Optionally substituted C 3-12 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl.
In some embodiments of the application, whenR is a single bond 1 Selected from the group consisting of-O-R B Optionally substituted C 3-6 Carbocyclyl, C 6-10 Aryl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl.
In some embodiments of the application, whenR is a single bond 1 Selected from the group consisting of-O-R B ，R B Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one or more (e.g., 1, 2 or 3) same or different R b1 And (3) substitution.
In some embodiments of the application, whenR is a single bond 1 Selected from the group consisting of-O-R B ，R B Selected from C 1-6 Alkyl, C 5-6 Cycloalkyl and 5-6 membered heterocyclyl, wherein the C 1-6 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl are optionally substituted with one or more (e.g., 1, 2 or 3) same or different R b1 And (3) substitution.
In some embodiments, R b1 Each occurrence is independently selected from-OR c1 、-NR c1 R c1 Halogen, -CN, -C (O) R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、-S(O) 2 R c1 、-S(O) 2 NR c1 R c1 、-NHC(O)R c1 、-N(C 1-4 Alkyl) C (O) R c1 Oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl groups are each optionally substituted with one or more (e.g., 1, 2 or 3) identical or different R c1 Substitution; r is R c1 Each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocyclyl and 5-6 membered heteroaryl.
In some embodiments, R b1 Each occurrence is independently selected from-OR c1 、-C(O)R c1 、-C(O)OR c1 and C1-6 Alkyl, wherein the C 1-6 Alkyl is optionally substituted with one or more (e.g., 1, 2, or 3) same or different R c1 Substitution; r is R c1 Each occurrence is independently selected from hydrogen, C 1-6 Alkyl (e.g., methyl, t-butyl) and C 3-6 Cycloalkyl (e.g., cyclopropyl).
In some embodiments of the application, whenIs a single bond, and R 1 Selected from C 3-8 Carbocyclyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, said C 3-8 Carbocyclyl, C 6-10 Aryl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more (e.g., 1, 2 or 3) same or different R a2 Substitution;
R a2 each occurrence is independently selected from-OR c2 、-NR c2 R c2 Halogen, -CN, -C (O) R c2 、-C(O)OR c2 、-C 0-4 Alkyl C (O) NR c2 R c2 、-OC(O)R c2 、-S(O) 2 R c2 、-S(O) 2 NR c2 R c2 、-NHC(O)R c2 、-N(C 1-4 Alkyl) C (O) R c2 、-NHC(O)OR c2 Oxo, =nh, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, wherein said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl groups optionally being substituted by one or more R, which may be the same or different c2 Substitution;
R c2 each occurrence is independently selected from hydrogen, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 3-6 membered heterocyclyl and 3-6 membered heteroaryl.
In some embodiments of the application, whenIs a single bond, and R 1 Selected from C 5-6 Carbocyclyl, C 6 Aryl, 5-10 membered heterocyclyl and 5-10 membered heteroaryl, said C 5-6 Carbocyclyl, C 6 Aryl, 5-10 membered heterocyclyl and 5-10 membered heteroarylThe radicals optionally being identical or different by one or more (e.g. 1, 2 or 3) R' s a2 Substitution;
R a2 each occurrence is independently selected from-OR c2 、-C(O)R c2 、-C 0-4 Alkyl C (O) NR c2 R c2 Oxo, C 1-6 Alkyl, wherein the C 1-6 Alkyl is optionally substituted with one or more (e.g., 1, 2, or 3) same or different R c2 Substitution;
R c2 each occurrence is independently selected from hydrogen, OH, C 1-6 Alkyl and 5-6 membered heterocyclyl.
In some embodiments of the application, whenIs a single bond, R 1 Selected from->/>
In some embodiments of the application, R 2 Selected from hydrogen, C 1-4 Alkyl, -O-C 1-4 Alkyl and halogen; in some embodiments, R 2 Selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -O-CH 3 、-O-CH 2 CH 3 、-O-CH 2 CH 2 CH 3 、-O-CHCH 3 CH 3 、-O-CH 2 CHCH 3 CH 3 、-O-CH 2 CH 2 CH 2 CH 3 The method comprises the steps of carrying out a first treatment on the surface of the When Z is selected from O, S, R 2 Is not present.
In some embodiments of the application, R 2 is-O-CH 3 。
In some embodiments of the application, R 3 Selected from hydrogen, C 1-4 Alkyl, -O-C 1-4 Alkyl and halogen; in some embodiments, R 3 Selected from the group consisting ofHydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl.
In some embodiments of the application, ring A is selected from C 4-8 Cycloalkyl, 4-8 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl; in some embodiments, ring a is selected from C 5-6 Cycloalkyl, 5-6 membered heterocyclyl, C 6-10 Aryl, 5-6 membered heteroaryl; in some embodiments, ring a is selected from C 6 Aryl and 5-6 membered heteroaryl.
In some embodiments, ring a is phenyl or thienyl。
In some embodiments of the application, R 4 Each occurrence is independently selected from hydrogen, -NH 2 、C 1-4 Alkyl, halogen, C 1-4 Haloalkyl, -O-C 1-4 Alkyl, -O-C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclyl, -O-C 3-6 Cycloalkyl, -O-C 6-10 Aryl, -O-5-10 membered heteroaryl, -O-3-6 membered heterocyclyl, -O-CH 2 -C 3-6 Cycloalkyl, -O-CH 2 -C 6-10 Aryl, -O-CH 2 -5-to 10-membered heteroaryl, -O-CH 2 -3-6 membered heterocyclyl, wherein C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclyl, -O-C 3-6 Cycloalkyl, -O-C 6-10 Aryl, -O-5-10 membered heteroaryl, -O-3-6 membered heterocyclyl, -O-CH 2 -C 3-6 Cycloalkyl, -O-CH 2 -C 6-10 Aryl, -O-CH 2 -5-to 10-membered heteroaryl, -O-CH 2 -3-6 membered heterocyclyl optionally substituted with one or more groups selected from hydroxy, oxo, C 1-6 Alkyl, amino, cyano, nitro, halogen, -C 1-4 alkyl-NH 2 、-C 1-4 alkyl-NH-C 1-4 Alkyl, -C 1-4 alkyl-N- (C) 1-4 Alkyl) (C) 1-4 Alkyl group, C 2-6 Alkenyl, C 2-6 Alkynyl groups are substituted; where w=0, 1,2,3,4.
In some embodiments, R 4 Each occurrence is independently selected from hydrogen, -NH 2 、C 1-4 Alkyl, halogen, C 1-4 Haloalkyl, -O-C 1-4 Alkyl, -O-C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclyl, -O-C 3-6 Cycloalkyl, -O-C 6-10 Aryl, -O-5-10 membered heteroaryl, -O-3-6 membered heterocyclyl, -O-CH 2 -C 3-6 Cycloalkyl, -O-CH 2 -C 6-10 Aryl, -O-CH 2 -5-to 10-membered heteroaryl, -O-CH 2 -3-6 membered heterocyclyl, wherein C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclyl, -O-C 3-6 Cycloalkyl, -O-C 6-10 Aryl, -O-5-10 membered heteroaryl, -O-3-6 membered heterocyclyl, -O-CH 2 -C 3-6 Cycloalkyl, -O-CH 2 -C 6-10 Aryl, -O-CH 2 -5-to 10-membered heteroaryl, -O-CH 2 -3-6 membered heterocyclyl optionally substituted with one or more groups selected from hydroxy, oxo, C 1-6 Alkyl, amino, cyano, nitro, halogen, -C 1-4 alkyl-NH 2 、-C 1-4 alkyl-NH-C 1-4 Alkyl, -C 1-4 alkyl-N- (C) 1-4 Alkyl) (C) 1-4 Alkyl) is substituted with a group; where w=0, 1,2,3,4.
In some embodiments, R 4 Each occurrence is independently selected from hydrogen, -NH 2 Methyl, ethyl, n-propyl, isopropyl, F, cl, br, CHF 2 、CF 3 、-O-CH 3 、-O-CF 3 3-membered heterocyclyl, 4-membered heterocyclyl, 5-membered heterocyclyl, 6-membered heterocyclyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 6 Aryl, 5 membered heteroaryl, 6 membered heteroaryl, said 3 membered heterocyclyl, 4 membered heterocyclyl, 5 membered heterocyclyl, 6 membered heterocyclyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C 6 Aryl, 5 membered heteroaryl, 6 membered heteroaryl optionally substituted with one or more groups, the same or different, selected from hydroxy, oxo, C 1-6 Alkyl, amino, cyano, nitro, halogen, -C 1-4 alkyl-NH 2 、-C 1-4 alkyl-NH-C 1-4 Alkyl, -C 1-4 alkyl-N- (C) 1-4 Alkyl) (C) 1-4 Alkyl group) Is substituted by a group of (2); where w=0, 1,2,3,4.
In some embodiments, R 4 Each occurrence is independently selected from hydrogen, -NH 2 、C 1-4 Alkyl, halogen, C 1-4 Haloalkyl, -O-C 1-4 Alkyl, -O-C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 6 Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, -O-C 3-6 Cycloalkyl, -O-C 6 Aryl, -O-5-6 membered heteroaryl, -O-3-6 membered heterocyclyl, -O-CH 2 -C 3-6 Cycloalkyl, -O-CH 2 -C 6 Aryl, -O-CH 2 -5-6 membered heteroaryl, -O-CH 2 -3-6 membered heterocyclyl, wherein C 3-6 Cycloalkyl, C 6 Aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, -O-C 3-6 Cycloalkyl, -O-C 6 Aryl, -O-5-6 membered heteroaryl, -O-3-6 membered heterocyclyl, -O-CH 2 -C 3-6 Cycloalkyl, -O-CH 2 -C 6 Aryl, -O-CH 2 -5-6 membered heteroaryl, -O-CH 2 The 3-to 6-membered heterocyclic group optionally being identical or different by one or more (e.g. 1,2 or 3) groups selected from hydroxy, oxo, C 1-6 Alkyl, amino, cyano, nitro, halogen, -C 1-4 alkyl-NH 2 、-C 1-4 alkyl-NH-C 1-4 Alkyl, -C 1-4 alkyl-N- (C) 1-4 Alkyl) (C) 1-4 Alkyl group, C 2-6 Alkenyl, C 2-6 Alkynyl groups are substituted; where w=0, 1,2,3,4.
In some embodiments, R 4 Each occurrence is independently selected from hydrogen, -NH 2 、C 1-4 Alkyl, halogen, C 1-4 Haloalkyl, C 6 Aryl, 3-6 membered heterocyclyl, wherein C 6 Aryl and 3-6 membered heterocyclyl optionally being identical or different by one or more (e.g. 1,2 or 3) groups selected from hydroxy, -C 1-4 alkyl-NH 2 、-C 1-4 alkyl-NH-C 1-4 Alkyl, -C 1-4 alkyl-N- (C) 1-4 Alkyl) (C) 1-4 Alkyl) is substituted with a group; where w=0, 1,2 or 3.
In some embodiments, R 4 Each occurrence is independentSelected from the group consisting of-NH 2 、-CF 3 、-F、-CHF 2 、-CF 2 CH 3 、 And w=0, 1,2 or 3.
In some embodiments of the application, the building blocksSelected from->/>
In some embodiments of the present application, a compound of formula (I), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically-labeled analogs thereof, wherein the compound of formula (I) has a structure as shown in formula (Ia):
in some embodiments of the application, a compound of formula (I), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically-labeled analogs thereof, wherein the compound of formula (I) has a structure selected from the group consisting of formula (ii) to formula (x):
wherein each substituent in the formulas (II) to (X) is defined as the formula (I).
In some embodiments of the application, the compound of formula (I), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically-labeled analogs thereof, wherein the compound of formula (I) further has a structure selected from the group consisting of formula (ii) to formula (xa):
The substituents in the formulae (II) to (Xa) are as defined in the formula (I).
In some embodiments of the application, a compound of formula (I), and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically-labeled analogs thereof, wherein said compound is selected from the group consisting of:
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the object of the present application is also to provide a process for the preparation of the compounds of formula (I), as well as stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates or isotopically-labelled analogues thereof.
The method can be prepared, for example, by using the method shown in the scheme below, and the target compound can be synthesized by coupling through halogenation and nucleophilic substitution.
In another aspect, the application also provides a pharmaceutical composition comprising a compound of the application, or a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a solvate, or an isotopically labeled analog thereof, and a pharmaceutically acceptable adjuvant.
Administration of the compounds of the present application, or stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts, prodrugs, hydrates, solvates, or isotopically-labeled analogs thereof, may be carried out in any acceptable manner of administration, either in pure form or in the form of a suitable pharmaceutical composition. The pharmaceutical compositions of the present application may be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients. The pharmaceutical compositions of the present application may be formulated as solid or liquid formulations. In general, the above pharmaceutical compositions may be prepared by conventional preparation methods using excipients conventional in the formulation arts.
In another aspect, the application also provides the use of a compound of the application, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate or isotopically-labeled analog thereof, or a pharmaceutical composition of the application, in the manufacture of a medicament for the treatment of a disease mediated by an SOS1 inhibitor.
In some embodiments, the SOS1 inhibitor-mediated disease is cancer or tumor, and related diseases thereof.
In another aspect, the application also provides the use of a compound of the application, or a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a solvate or an isotopically labeled analog thereof, or a pharmaceutical composition of the application, in the manufacture of a medicament for treating a disease caused by RAS mutation.
In some embodiments, the disease caused by the RAS mutation includes type 1 neurofibromatosis (NF 1), noonan SYNDROME (NS), noonan SYNDROME with multiple plaques (NSML), capillary malformation-arteriovenous malformation SYNDROME (CM-AVM), costerol SYNDROME (CS), cardio-facial-skin SYNDROME (CFC), leggus SYNDROME (LEGIUS SYNDROME), and hereditary gum fibromatosis.
In another aspect, the application also provides a method for the prophylaxis and/or treatment of a disease mediated by an SOS1 inhibitor, which comprises administering to a patient a therapeutically effective amount of a compound as shown in the application, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopically-labeled analogue or pharmaceutical composition of the application.
In some embodiments, the SOS1 inhibitor-mediated disease is cancer or tumor, and related diseases thereof.
In another aspect, the application also provides a method for preventing and/or treating a disease caused by a RAS mutation, comprising administering to a patient a therapeutically effective amount of a compound of the application, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopically-labeled analog or pharmaceutical composition of the application.
In some embodiments, the disease caused by the RAS mutation includes type 1 neurofibromatosis (NF 1), noonan SYNDROME (NS), noonan SYNDROME with multiple plaques (NSML), capillary malformation-arteriovenous malformation SYNDROME (CM-AVM), costerol SYNDROME (CS), cardio-facial-skin SYNDROME (CFC), leggus SYNDROME (LEGIUS SYNDROME), and hereditary gum fibromatosis.
In another aspect, the application also provides a compound of the application, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate, isotopically-labeled analog or pharmaceutical composition of the application, for use in the prevention and/or treatment of a disease mediated by an SOS1 inhibitor.
In another aspect, the present application also provides a compound of the present application, or a stereoisomer, a geometric isomer, a tautomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, a solvate, an isotopically labeled analog or a pharmaceutical composition of the present application, for use in the prevention and/or treatment of a disease caused by a RAS mutation.
In another aspect, the application also provides the use of a compound of the application, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate or isotopically-labeled analog thereof, or a pharmaceutical composition of the application, in the treatment of a disease mediated by an SOS1 inhibitor.
In another aspect, the application also provides the use of a compound of the application, or a stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, prodrug, hydrate, solvate or isotopically-labeled analog thereof, or a pharmaceutical composition of the application, in the treatment of a disease caused by a RAS mutation.
In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the application. However, it will be understood by those skilled in the art that the present application may be practiced without these details.
Throughout this specification and in the claims, unless the context requires otherwise, the words "comprise" and variations such as "comprises" and "comprising" are to be construed in an open-ended inclusive sense, i.e. as "including, but not limited to.
Reference throughout this specification to "one embodiment" or "some embodiments" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present application. Thus, the appearances of the phrases "in one embodiment" or "in some embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It should be understood that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.
Definition of the definition
The following terms used in the present application have the following meanings unless otherwise indicated. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The term "compound" as used herein includes all stereoisomeric forms, geometric isomeric forms, tautomeric forms and isotopic forms of the compounds.
The term "substituted" or "substituted" means that any one or more hydrogen atoms on a particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =o), it means that two hydrogen atoms on the same carbon atom are replaced with oxygen atoms. It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.
The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl may be unsubstituted (CH 2 CH 3 ) Monosubstituted (e.g. CH 2 CH 2 F) Polysubstituted (e.g. CHFCH 2 F、CH 2 CHF 2 Etc.) or fully substituted (CF) 2 CF 3 ). Those skilled in the art will appreciate that for a container comprising one or more fetchesAny group of substituents does not introduce any substitution or substitution pattern that is sterically impossible and/or impossible to synthesize.
C herein m-n It is that the moiety has an integer number of carbon atoms in the given range. For example "C 1-6 By "is meant that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms.
When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if one group is substituted with 2R's, then each R has an independent option.
"amino" means-NH 2 A group.
"carboxy" refers to a-COOH group.
"cyano" refers to a-CN group.
"hydroxy" refers to an-OH group.
"nitro" means-NO 2 A group.
"oxo" refers to an =o substituent.
"thio" refers to a = S substituent.
"Boc" refers to t-butoxycarbonyl.
"halogen" and "halo" refer to F, cl, br, I.
Unless otherwise specified, "carbocyclyl" or "carbocycle" refers to a non-aromatic cyclic hydrocarbon radical having from 3 to 14 ring carbon atoms ("C 3-14 Carbocyclyl "), and has no heteroatoms in the non-aromatic ring system. "carbocyclyl" includes "cycloalkyl" and "cycloalkenyl". In some embodiments, the carbocyclyl group has 3 to 12 ring carbon atoms ("C 3-12 Carbocyclyl "), or 4-12 ring carbon atoms (" C 4-12 Carbocyclyl "), or 3 to 10 ring carbon atoms (" C 3-10 Carbocyclyl "). In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 Carbocyclyl "). In some embodiments, the carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 Carbocyclyl "). In some embodimentsCarbocyclyl groups having 4 to 6 ring carbon atoms ("C 4-6 Carbocyclyl "). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 Carbocyclyl "), or 5 to 7 ring carbon atoms (" C 5-7 Carbocyclyl "). Exemplary C 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C 3 ) Cyclopropenyl (C) 3 ) Cyclobutyl (C) 4 ) Cyclobutenyl (C) 4 ) Cyclopentyl (C) 5 ) Cyclopentenyl (C) 5 ) Cyclohexyl (C) 6 ) Cyclohexenyl (C) 6 ) Cyclohexadienyl (C) 6 ) Etc. Exemplary C 3-8 Carbocyclyl groups include, but are not limited to, C as previously mentioned 3-6 Carbocyclyl groups and cycloheptyl (C) 7 ) Cycloheptenyl (C) 7 ) Cycloheptadienyl (C) 7 ) Cycloheptatrienyl (C) 7 ) Cyclooctyl (C) 8 ) Cyclooctenyl (C) 8 ) Bicyclo [2.2.1]Heptyl (C) 7 ) Bicyclo [2.2.2]Octyl (C) 8 ) Etc. Exemplary C 3-10 Carbocyclyl groups include, but are not limited to, C as previously mentioned 3-8 Carbocyclyl groups and cyclononyl (C) 9 ) Cyclononenyl (C) 9 ) Cyclodecyl (C) 10 ) Cyclodecenyl (C) 10 ) octahydro-1H-indenyl (C) 9 ) Decalin group (C) 10 ) Spiro [4.5 ]]Decyl radical (C) 10 ) Etc.
As illustrated by the above examples, in certain embodiments, the carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or is a fused (fused ring group), bridged (bridged ring group), or spiro-fused (spiro ring group) ring system, such as a bicyclic system ("bicyclic carbocyclyl") and may be saturated or may be partially unsaturated. "carbocyclyl" also includes ring systems in which the carbocyclyl ring is fused by one or more aryl or heteroaryl groups as defined above, wherein the point of attachment is on the carbocyclyl ring, and in such cases the number of elements of the carbocyclyl ring system is the number of carbons of the carbocyclyl system after fusion. In certain embodiments, each instance of a carbocyclyl group is independently optionally substituted, e.g., unsubstituted (an "unsubstituted carbocyclyl") or substituted with one or more substituents (a "substituted carbocyclyl"). In certain embodiments, the carbocyclyl group is unsubstituted C 3-10 Carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C 3-10 Carbocyclyl.
Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, straight or branched chain group containing 1 to 20 carbon atoms, preferably containing 1 to 10 carbon atoms (i.e., C 1-10 Alkyl groups), further preferably containing 1 to 8 carbon atoms (C 1-8 Alkyl groups), more preferably containing 1 to 6 carbon atoms (i.e. C 1-6 Alkyl) or 1 to 4 carbon atoms (i.e. C 1-4 Alkyl) or 2 to 4 carbon atoms (i.e. C 2-4 Alkyl), e.g. "C 1-6 Alkyl "means that the group is alkyl and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1,2, 3, 4, 5 or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, and the like.
The term "haloalkyl" means that one, two or more hydrogen atoms or all hydrogen atoms in an alkyl group as defined above are replaced by halogen. "haloalkyl" may be C 1-8 Haloalkyl, C 1-6 Haloalkyl or C 1-4 A haloalkyl group. Representative examples of haloalkyl groups include CCl 3 、CF 3 、CHCl 2 、CH 2 Cl、CH 2 Br、CH 2 I、CH 2 CF 3 、CHF 2 、CF 2 CH 3 、CF 2 CF 3 Etc.
The term "alkoxy", unless otherwise specified, refers to an-O-alkyl group, which is as defined above, i.e. comprising 1 to 20 carbon atoms, preferably comprising 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms (in particular 1,2, 3, 4, 5 or 6). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1-dimethylpropoxy, 1, 2-dimethylpropoxy, 2-dimethylpropoxy, 1-ethylpropoxy, and the like.
The term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group having at least one double bond consisting of carbon atoms and hydrogen atoms. In some embodiments, the alkenyl group may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkenyl groups), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkenyl groups), more preferably containing 2 to 6 carbon atoms (i.e. C 2-6 Alkenyl), 2 to 5 carbon atoms (i.e. C 2-5 Alkenyl), 2 to 4 carbon atoms (i.e. C 2-4 Alkenyl), 2 to 3 carbon atoms (i.e. C 2-3 Alkenyl), 2 carbon atoms (i.e. C 2 Alkenyl), e.g. "C 2-6 Alkenyl "means that the group is alkenyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1, 3-butadienyl, and the like.
The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms having at least one triple bond. In some embodiments, alkynyl groups may contain 2 to 20 carbon atoms, preferably 2 to 10 carbon atoms (i.e., C 2-10 Alkynyl groups), further preferably containing 2 to 8 carbon atoms (C 2-8 Alkynyl groups), more preferably containing 2 to 6 carbon atoms (i.e. C 2-6 Alkynyl), 2 to 5 carbon atoms (i.e. C 2-5 Alkynyl), 2 to 4 carbon atoms (i.e. C 2-4 Alkynyl), 2 to 3 carbon atoms (i.e. C 2-3 Alkynyl), 2 carbon atoms (i.e. C 2 Alkynyl groups), e.g. "C 2-6 Alkynyl "means that the group is alkynyl and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, and the like.
Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic radical having a particular number of carbon atoms, preferablyContaining 3 to 12 carbon atoms (i.e. C 3-12 Cycloalkyl), more preferably containing 4 to 12 carbon atoms (C 4-12 Cycloalkyl), 3 to 10 carbon atoms (C 3-10 Cycloalkyl), more preferably 4 to 9 carbon atoms (C 4-9 Cycloalkyl), 4-8 carbon atoms (C 4-8 Cycloalkyl), 3-6 carbon atoms (C 3-6 Cycloalkyl), 4-6 carbon atoms (C 4-6 Cycloalkyl), 5-6 carbon atoms (C 5-6 Cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, and the like.
Unless otherwise specified, "cycloalkenyl" refers to compositions of the sub-groups mono-, bi-and spiro-hydrocarbon rings, however, the system is unsaturated, i.e., at least one C-C double bond is present but no aromatic system is present. In some embodiments, a "cycloalkenyl" preferably comprises 3 to 12 carbon atoms (i.e., C 3-12 Cycloalkenyl), more preferably containing 3 to 10 carbon atoms (C 3-10 Cycloalkenyl), more preferably 4 to 9 carbon atoms (C 4-9 Cycloalkenyl), 3 to 6 carbon atoms (C 3-6 Cycloalkenyl), 4 to 6 carbon atoms (C 4-6 Cycloalkenyl), 5-6 carbon atoms (C 5-6 Cycloalkenyl group).
Unless otherwise specified, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon substituent, which is a non-aromatic structure, containing 3 to 20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S and the remaining ring atoms are C. In some embodiments, a "heterocyclyl" preferably contains from 3 to 12 ring atoms, more preferably from 4 to 12 ring atoms, or from 4 to 10 ring atoms, or from 3 to 8 ring atoms, or from 4 to 8 ring atoms, or from 3 to 6 ring atoms, or from 4 to 6 ring atoms, or from 5 to 6 ring atoms. The heteroatoms are preferably 1 to 4, more preferably 1 to 3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclic groups include oxetanyl, pyrrolidinyl, 1, 4-isoxazolyl, pyrazolyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, and the like. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups.
The term "spirocyclic group" means fully saturatedAnd or partially unsaturated (but not fully saturated aromatic), polycyclic rings sharing one carbon atom (called spiro atom) between 5 and 20 membered monocyclic rings. The spirocyclic group is preferably 6 to 14 membered, more preferably 6 to 10 membered, 7 to 9 membered, 9 membered or 10 membered. The spiro ring is classified into a single spiro ring, a double spiro ring or a multiple spiro ring according to the number of common spiro atoms between rings, preferably a single spiro ring, more preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro ring. Non-limiting examples of spirocyclic rings include
The term "spirocycloalkyl" refers to a fully saturated spirocycloalkyl group.
The term "spiroheterocyclyl" refers to a spiro ring in which one or more ring atoms are selected from heteroatoms (preferably 1 or 2 heteroatoms, preferably selected from N, O and/or S) of sulfur, silicon, phosphorus, oxygen and/or nitrogen, the remaining ring atoms being carbon. The spiroheterocyclyl group is preferably 6 to 14 membered, more preferably 6 to 10 membered or 7 to 9 membered or 10 membered. The spiro heterocycle is classified as a mono-, bi-or multi-spiro heterocycle according to the number of common spiro atoms between rings, preferably a mono-spiro heterocycle, more preferably a 4/4-, 4/5-, 4/6-, 5/5-or 5/6-membered mono-spiro heterocycle, preferably each ring contains 1 heteroatom selected from N, O and/or S. Non-limiting examples of spiroheterocycles include
The term "spiroheterocycloalkyl" refers to a fully saturated spiroheterocyclyl.
The term "bridged ring radical" refers to an all-carbon polycyclic ring having 5 to 20 ring atoms which may be fully saturated or partially unsaturated (but not fully saturated) and two rings sharing 3 or more ring atoms. Preferably 6 to 14 membered, more preferablySelected to be 6 to 10 yuan. The number of constituent rings may be classified as a double ring, a triple ring, a tetra ring or a polycyclic bridged ring, preferably a double ring or a triple ring, more preferably a double ring. Non-limiting examples of bridge rings include:
the term "bridged cycloalkyl" refers to a fully saturated bridged ring radical.
The term "bridged heterocyclyl" means that one or more ring atoms in the bridged ring are selected from heteroatoms (preferably 1 or 2 heteroatoms, preferably selected from N, O and/or S) of sulfur, silicon, phosphorus, oxygen and/or nitrogen, the remaining ring atoms being carbon. The bridged heterocyclic group is preferably 6 to 14 membered, more preferably 6 to 10 membered, 7 to 9 membered, 7 membered or 8 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycle, preferably bicyclic or tricyclic, more preferably bicyclic. Non-limiting examples of bridged heterocycles include
The term "bridged heterocycloalkyl" refers to a fully saturated bridged heterocyclyl.
The term "fused ring group" refers to an all-carbon polycyclic ring having 5 to 20 ring atoms which may be fully saturated or partially unsaturated (but not fully saturated) and two rings sharing 2 ring atoms. Preferably 6 to 14 membered, more preferably 6 to 10 membered. The number of constituent rings may be classified as a double ring, a triple ring, a tetra ring or a polycyclic bridged ring, preferably a double ring or a triple ring, more preferably a double ring. Non-limiting examples of union rings include:
the term "fused ring alkyl" refers to a fully saturated fused ring group.
The term "fused heterocyclyl" refers to a heteroatom (preferably 1 or 2 heteroatoms, preferably heteroatoms selected from N, O and/or S) in which one or more ring atoms in the ring are selected from sulfur, silicon, phosphorus, oxygen and/or nitrogen, the remaining ring atoms being carbon. The fused heterocyclic group is preferably 6 to 14 membered, more preferably 6 to 10 membered, 7 membered, 8 membered or 9 membered. The number of constituent rings may be classified as a bicyclic, tricyclic or polycyclic bridged heterocycle, preferably bicyclic. Non-limiting examples of fused heterocycles include
The term "fused heterocycloalkyl" refers to a fully saturated fused heterocyclyl.
Unless otherwise specified, "heterocycloalkyl" means a monocyclic, saturated "heterocyclyl" or "heterocycle" as defined above, ring atoms being as defined above, i.e., comprising 3 to 20 ring atoms ("3-20 membered heterocycloalkyl"), the number of heteroatoms being 1 to 4 (1, 2, 3 or 4), preferably 1 to 3 (1, 2 or 3), wherein each heteroatom is independently selected from N, O or S. Preferably containing 3 to 12 ring atoms ("3 to 12 membered heterocycloalkyl"), more preferably containing 3 to 10 ring atoms ("3 to 10 membered heterocycloalkyl"), still more preferably containing 3 to 8 ring atoms ("3 to 8 membered heterocycloalkyl"), still more preferably containing 4 to 7 ring atoms ("4 to 7 membered heterocycloalkyl"), still more preferably containing 5 to 10 ring atoms ("5 to 10 membered heterocycloalkyl"), still more preferably containing 5 to 6 ring atoms ("5 to 6 membered heterocycloalkyl"). In certain embodiments, each instance of heterocycloalkyl is independently optionally substituted, e.g., unsubstituted (an "unsubstituted heterocycloalkyl") or substituted with one or more substituents (a "substituted heterocycloalkyl"). The "heterocyclyl" or "heterocyclic" moiety above has given some exemplary "heterocycloalkyl" groups, and also includes, but is not limited to, aziridine, oxetane, thietanyl, tetrahydrofuranyl, oxahexidine, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxathiacyclohexyl, oxazolidinyl, dioxanyl, dithianyl, thiazolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolinidine, and the like.
Unless otherwise specified, the term "aryl" means a monocyclic, bicyclic and tricyclic aromatic carbocyclic ring system containing 6 to 16 carbon atoms, or 6 to 14 carbon atoms, or 6 to 12 carbon atoms, or 6 to 10 carbon atoms, preferably 6 to 10 carbon atoms, and the term "aryl" may be used interchangeably with the term "aromatic ring". Examples of aryl groups may include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, pyrenyl, and the like.
Unless otherwise specified, the term "heteroaryl" means an aromatic monocyclic or polycyclic ring system containing a 5-12 membered structure, or preferably a 5-10 membered structure, a 5-8 membered structure, more preferably a 5-6 membered structure, wherein 1,2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms being independently selected from O, N or S, the number of heteroatoms preferably being 1,2 or 3. Examples of heteroaryl groups include, but are not limited to, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo [2,3-b ] pyridyl, imidazo [1,2-a ] pyridyl, pyrazolo [1,5-a ] pyrimidinyl, imidazo [1,2-b ] pyridazinyl, [1,2,4] triazolo [4,3-b ] pyridazinyl, [1,2,4] triazolo [1,5-a ] pyrimidinyl, [1,5-a ] triazolo [1,5-a ] pyridyl, and the like.
The above groups may be optionally substituted with one or more (e.g., 1, 2, or 3) substituents.
The term "pharmaceutically acceptable salt", "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" refers to salts which are, unless otherwise specified, suitable for use in contact with the tissues of mammals, especially humans, without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment. The salts may be prepared in situ during the final isolation and purification of the compounds of the application, or by reacting the free base or the free acid with a suitable reagent alone. For example, the free base function may be reacted with a suitable acid.
The term "solvate" means, unless otherwise specified, the physical association of a compound of the application with one or more solvent molecules (whether organic or inorganic). The physical association includes hydrogen bonding. In some cases, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate will be able to be isolated. The solvent molecules in the solvate may be present in a regular arrangement and/or in a disordered arrangement. The solvate may comprise a stoichiometric or non-stoichiometric solvent molecule. "solvate" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolamides. Solvation methods are well known in the art.
Unless otherwise specified, the term "isotopically-labeled analog" refers to isotopically-labeled molecules in compounds of formulae I to II, thereby providing isotopically-labeled analogs that potentially have improved pharmacological activity. Isotopes commonly used as isotopic labels are: the hydrogen isotope is selected from the group consisting of, 2H and 3 h is formed; carbon isotopes: 11 C, 13C and 14 C, performing operation; chlorine isotopes: 35Cl and 37 Cl; fluorine isotopes: 18 f, performing the process; iodine isotopes: 123I and 125 i, a step of I; nitrogen isotopes: 13N and 15 n; oxygen isotopes: 15 O, 17O and 18 isotopes of O and sulfur 35 S, S. These isotopically-labeled compounds can be used to study the distribution of a pharmaceutical molecule in a tissue. In particular deuterium 3 H and carbon 13 C, because they are easily labeled and conveniently detected, the application is wider. Certain heavy isotopes, such as heavy hydrogen @, for example 2 H) The substitution can enhance the metabolic stability and prolong the half-life period, thereby achieving the aim of reducing the dosage and providing curative effect advantages.Isotopically-labeled compounds generally begin with a starting material that has been labeled, and are synthesized using known synthetic techniques like synthesizing non-isotopically-labeled compounds.
The term "prodrug" refers to a drug that is converted in vivo to the parent drug, unless otherwise specified. Prodrugs are often useful because, in some instances, they may be easier to administer than the parent drug. For example, they may be bioavailable orally, whereas the parent is not. The solubility of the prodrug in the pharmaceutical composition is also improved compared to the parent drug. An example of a prodrug, but not limited thereto, may be any compound of formula I that is administered as an ester ("prodrug") to facilitate transport across the cell membrane, where water solubility is detrimental to mobility, but once inside the cell is beneficial, it is then metabolically hydrolyzed to the carboxylic acid, the active entity. Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, wherein the peptide is metabolized to reveal an active moiety.
Unless otherwise specified, the terms "optionally substituted", "optionally substituted by … …", "optionally … …" mean that the hydrogen at the substitutable site of the group is unsubstituted or substituted with one or more substituents, preferably selected from the group consisting of: halogen, hydroxy, mercapto, cyano, nitro, amino, azido, oxo, carboxyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl sulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-10 membered heteroaryl ring group, wherein the C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Cycloalkyl sulfonyl, 3-10 membered heterocycloalkyl, C 6-14 Aryl or 5-to 10-membered heteroaryl ring groups may optionally be selected from halogen, hydroxy, amino, cyano, C 1-6 Alkyl or C 1-6 One or more of the alkoxy groups are substituted, the oxo group refers to a group in which two H's at the same substitution position are replaced by the same O to form a double bond, and the "=NH" refers to the same substitutionThe two H's in the position are replaced by the same-NH-group forming a double bond.
The term "treatment" generally refers to the administration of a compound or formulation of the application to achieve a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) Inhibiting the symptoms of, i.e., preventing the development of, diseases, disorders, and conditions; or (b) alleviating symptoms of diseases, disorders, and conditions, i.e., causing regression of the disease or symptoms; or (c) ameliorating or eliminating a disease, disorder, and condition or one or more symptoms associated with the disease.
The term "therapeutically effective amount" means an amount of a compound of the application that (i) treats a particular disease, disorder or condition, (ii) alleviates, ameliorates or eliminates one or more symptoms of the particular disease, disorder or condition, or (iii) delays the onset of one or more symptoms of the particular disease, disorder or condition described herein. The amount of the compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and disclosure.
The term "pharmaceutically acceptable excipients" refers to those excipients which have no significant irritating effect on organisms (e.g., humans) and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
The beneficial effects of the application are as follows:
the application designs a compound with novel structure, and provides a new direction for the development of SOS-1 inhibitor medicines. In vitro enzyme activity inhibition activity researches show that the compounds have strong inhibition effect on SOS-1 and can be used as a prospect compound for treating SOS-1 inhibitor-mediated diseases. In addition, the application researches a specific synthesis method, and the synthesis method has simple process and convenient operation, and is beneficial to large-scale industrial production and application.
Detailed Description
The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present application. The preferred methods and materials are presented herein for illustrative purposes only.
The structure of the compounds of the application is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS) or/and liquid chromatography (HPLC) and/or electrospray ion source mass spectrometry (ESI-MS). The NMR was performed using Bruker AVANCE III 600MHz and the LC-MS was performed using LCMS WATERS ACQUITY UPLC H-Class PLUS or/and SQD2; the instrument used for HPLC is WATERS 2695_2998 or/and Agilent 1100.
The starting materials in the examples of the present application are known and commercially available or may be synthesized using or according to methods known in the art.
Description of terms or abbreviations:
et: ethyl group
Boc: boc-group
BOP: benzotriazol-1-yloxy tris (dimethylamino) phosphonium hexafluorophosphate
DIEA: diisopropylethylamine
DMF: n, N-dimethylformamide
EA: acetic acid ethyl ester
DCM: dichloromethane (dichloromethane)
THF: tetrahydrofuran (THF)
DMSO: dimethyl sulfoxide
DIPEA: n, N-diisopropylethylamine
ACN: acetonitrile
HATU: o- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate
Pd(dppf)Cl 2 : [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride
Pd(amphos) 2 Cl 2 : dichloro bis [ di-tert-butyl- (4-dimethylaminophenyl) phosphine]Palladium (II)
HEPES:4- (2-hydroxyethyl) piperazine-1-ethanesulfonic acid
EDTA: ethylenediamine tetraacetic acid
DTT: dithiothreitol
BSA: bovine serum albumin
IGEPAL: octyl phenyl polyethylene glycol
FRET: fluorescence energy resonance transfer
1. Preparation example
1. Synthesis of intermediate A-6a
Synthesis of intermediate A-2
A100 mL reaction flask was charged with A-1 (1.00 g,5.05 mmol), BOP (1.12 g,2.53 mmol), DIEA (1.30 g,10.10 mmol) and DMF (25 mL) and NH was added dropwise 4 OH, stirring at room temperature and reacting for 2 hours. After the reaction was completed, the reaction solution was poured into 150mL of water, EA was extracted three times, the organic phases were combined and washed three times with water, anhydrous Na 2 SO 4 After drying, the solvent was concentrated and removed, followed by separation and purification by silica gel column chromatography to give the desired product A-2 (897 mg,4.55mmol, 90%). ESI-MS (m/z): 198.07[ M+H ]] + 。
Synthesis of intermediate A-3
A-2 (500 mg,2.54 mmol), pyridine (2 mL), 15mL of acetonitrile were added to a 100mL reaction flask, ethyl chloroformate (551 mg,5.08 mmol) dissolved in 5mL of acetonitrile was added dropwise at 0℃and after the completion of the addition, the temperature was slowly raised to reflux the system. After the completion of the reaction, the heating and cooling were stopped to room temperature, and the reaction solution was poured into cold water to precipitate a white solid, which was filtered to obtain A-3 (460 mg,2.08mmol, 82%). ESI-MS (m/z))：224.05[M+H] + 。
Synthesis of intermediate A-4
To a suspension of A-3 (460 mg,2.08 mmol) in methanesulfonic acid (5 mL) was added DL-methionine (463 mg,3.12 mmol) at room temperature. The reaction mixture was heated to 80 ℃ for 16h. The reaction mixture was quenched with ice water and basified with 2N NaOH solution. The precipitate was filtered off to give product A-4 (261 mg,1.25mmol, 60%). ESI-MS (m/z): 210.03[ M+H ]] + 。
Synthesis of intermediate A-5
A-4 (261 mg,1.25 mmol), (S) -tetrahydrofuran-3-yl 4-methylbenzenesulfonate (605 mg,2.50 mmol) and Cs 2 CO 3 A suspension of (652 mg,2.00 mmol) in DMF (10 mL) was heated to 100deg.C for 12h. The solvent was removed under reduced pressure and the residue was dissolved in DCM with NaHCO 3 The saturated solution was extracted and the aqueous phase was washed with DCM. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and the solvent removed in vacuo. The crude product was purified by chromatography to give product A-5 (252 mg,0.90mmol, 72%). ESI-MS (m/z): 280.07[ M+H ]] + 。
Synthesis of intermediate A-6a
A-5, DIEA and a proper volume of phosphorus oxychloride were added to a 100mL reaction flask and reacted at 80℃for 2 hours. After the reaction was completed, the heating and cooling to room temperature were stopped, and the solvent was removed by concentration to obtain a pale yellow solid, namely A-6a. ESI-MS (m/z): 298.04[ M+H ]] + 。
Synthesis of intermediates A-6b to A-6d
Intermediates A-6b to A-6d were synthesized starting from different A-1 by the same method as intermediate A-6a was synthesized
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2. Synthesis of intermediate B-7a
Synthesis of intermediate B-2
B-1 (1.00 g,3.70 mmol) was dissolved in 1, 4-dioxane (10 mL). NEt is then added 3 (1.03 mL) and the solution was purged with nitrogen for 5min. Tributyl (1-ethoxyvinyl) tin (1.74 g,4.82 mmol) and bis (triphenylphosphine) palladium (II) chloride (0.26 g,0.37 mmol) were added and the reaction mixture was heated to 110 ℃ for 12h. The reaction was quenched with 1N HCl and extracted with ethyl acetate. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and the solvent removed in vacuo. Purification by column chromatography on silica gel (ethyl acetate/petroleum ether) afforded product B-2 (550 mg,2.36mmol, 64%). ESI-MS (m/z): 234.03[ M+H ] ] + 。
Synthesis of intermediate B-3
B-2 (529 mg,2.27 mmol) was dissolved in THF. (R) - (+) -2-methyl-2-propane sulfinamide (413 mg, 3.41 mmol) and Ti (OEt) were added at room temperature 4 (1.29 g,5.68 mmol) and the resulting reaction mixture was heated to 80℃for 5h. The reaction mixture was cooled to room temperature and quenched with ice water. The precipitate was dissolved in ethyl acetate and filtered through celite. The organic layer was concentrated in vacuo. Purification by column chromatography on silica gel (ethyl acetate/petroleum ether) afforded product B-3 (404 mg,1.20mmol, 53%). ESI-MS (m/z): 337.08[ M+H ]] + 。
Synthesis of intermediate B-4
To a stirred solution of B-3 (3.36 g,10.00 mmol) in THF (50 mL) and water (5 mL) at-78deg.C was added sodium borohydride (0.68 g,18.00 mmol). The reaction temperature was warmed to room temperature and monitored by TLC. The reaction mixture was quenched with ice water, extracted with ethyl acetate and concentrated in vacuo. Silica gel column chromatography separation and purification (ethyl acetate/petroleum ether) separates the diastereomeric mixture. B-4 was the main product (2.33 g,6.90mmol, 69%). ESI-MS (m/z): 339.09[ M+H ]] + 。
Synthesis of intermediate B-6
To a stirred solution of B-4 (1.70 g,5.02 mmol) in 1, 4-dioxane (10 mL) was added a 4M HCl dioxane solution (10 mL). The reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo Contracted, filtered and treated with Et 2 O was washed to obtain the product B-6. Intermediate B-6 was obtained as HCl salt. ESI-MS (m/z): 235.06[ M+H ]] + 。
Synthesis of intermediate B-7a
B-6 (976 mg,4.17 mmol) was dissolved in MeOH (10 mL), 10% Palladium on carbon (200 mg) was added, and the reaction was carried out using H 2 And (5) gas purging. The reaction was monitored by TLC. After completion, the reaction mixture was filtered over celite, and the filtrate was concentrated in vacuo. The residue was washed with water to give product B-7a. ESI-MS (m/z): 205.09[ M+H ]] + 。
Intermediates B-7B to B-7f were synthesized starting from different B-1 by the same method as intermediate B-7a was synthesized
3. Synthesis of intermediates C-8a, C-8b
Synthesis of intermediate C-2 into a 100mL reaction flask were charged C-1 (1.00 g,4.74 mmol), sodium hydride (60%, 379mg,9.48 mmol), and the reaction was stirred at 0℃for 30min, followed by dropwise addition of methyl iodide (1009 mg,7.11 mmol), and after completion of the dropwise addition, the temperature was slowly raised to 80 ℃. After the reaction was completed, the heating and cooling to room temperature were stopped, the reaction solution was poured into cold water, extracted with EA three times, the organic phases were combined, and anhydrous Na 2 SO 4 After drying, the solvent was concentrated and removed, followed by separation and purification by silica gel column chromatography to give the desired product C-2 (981 mg,4.36mmol, 92%). ESI-MS (m/z): 226.10[ M+H ]] + 。
Synthesis of intermediate C-3
In a 100mL reaction flask, C-2 (981 mg,4.36 mmol), THF (10 mL), water (5 mL) and sodium hydroxide were added sequentially(523 mg,13.08 mmol) was reacted at 60℃for 3 hours. After the completion of the reaction, TLC was monitored, the reaction solution was cooled to room temperature, the pH was adjusted to 5 with 1N hydrochloric acid, a solid was precipitated, the solid was collected by suction filtration, and the solid was rinsed with water and dried to give C-3 (699 mg,3.31mmol, 76%). ESI-MS (m/z): 212.08[ M+H ]] + 。
Synthesis of intermediate C-4
In a 100mL reaction flask, C-3 (699 mg,3.31 mmol), BOP (732 mg,1.66 mmol), DIEA (254 mg,6.62 mmol) and DMF (25 mL) were added dropwise with NH 4 A DMF solution of OH (5 mL) was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into 150mL of water, EA was extracted three times, the organic phases were combined and washed three times with water, anhydrous Na 2 SO 4 After drying, the solvent was concentrated and removed, followed by separation and purification by silica gel column chromatography to give the desired product C-4 (598 mg,2.85mmol, 86%). ESI-MS (m/z): 211.10[ M+H ]] + 。
Synthesis of intermediate C-5
To a 100mL reaction flask, C-4 (598 mg,2.85 mmol), pyridine (2 mL), and 15mL of acetonitrile were added dropwise ethyl chloroformate (616 mg,5.70 mmol) dissolved in 5mL of acetonitrile at 0℃and, after the completion of the addition, the temperature was slowly raised to reflux. After the completion of the reaction, the heating and cooling were stopped to room temperature, and the reaction mixture was poured into cold water to precipitate a white solid, followed by filtration to give C-5 (552 mg,2.34mmol, 85%). ESI-MS (m/z): 237.08[ M+H ] ] + 。
Synthesis of intermediate C-6
DL-methionine (463 mg,3.12 mmol) is added to a suspension of C-5 (552 mg,2.34 mmol) in methanesulfonic acid (5 mL) at room temperature. The reaction mixture was heated to 80 ℃ for 16h. The reaction mixture was quenched with ice water and basified with 2N NaOH solution. The precipitate was filtered off to give product C-6 (353 mg,1.59mmol, 68%). ESI-MS (m/z): 223.06[ M+H ]] + 。
Synthesis of intermediate C-7
C-6 (353 mg,1.59 mmol), (S) -tetrahydrofuran-3-yl 4-methylbenzenesulfonate (3.18 mmol) and Cs 2 CO 3 A suspension of (1037 mg,3.18 mmol) in DMF (15 mL) was heated to 100deg.C for 12h. The solvent was removed under reduced pressure and the residue was dissolved in DCM with NaHCO 3 (saturated) extraction and the aqueous phase was washed with DCM. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and the solvent removed in vacuo. Silica gel column chromatography separation and purification gave product C-7 (242 mg,0.83mmol, 52%). ESI-MS (m/z): 293.11[ M+H ]] + 。
Synthesis of intermediate C-8a
In a 100mL reaction flask, C-5 (200 mg,0.85 mmol), DIEA (219 mg,1.70 mmol) and phosphorus oxychloride (5 mL) were added and reacted at 80℃for 2 hours. After the reaction was completed, the heating and cooling to room temperature were stopped, and the solvent was removed by concentration to obtain a pale yellow solid, namely C-8a. ESI-MS (m/z): 255.05[ M+H ] ] + 。
Synthesis of intermediate C-8b
In a 100mL reaction flask, C-7 (150 mg,0.51 mmol), DIEA (133 mg,1.02 mmol) and phosphorus oxychloride (5 mL) were added and reacted at 80℃for 2 hours. After the reaction was completed, the heating and cooling to room temperature were stopped, and the solvent was removed by concentration to obtain a pale yellow solid, namely C-8b. ESI-MS (m/z): 311.07[ M+H ]] + 。
The following intermediates were obtained in the same manner as for the synthesis of C-8a, C-8b starting from different C-1.
4. Synthesis of intermediate D-7a
Synthesis of intermediate D-2
D-1 (15.00 g,78.53 mmol) was dissolved in toluene (150 mL) and ethylene glycol (4.87 g,78.53 mmol) and catalytic amounts of p-toluene sulfonic acid (1.35 g,7.85 mmol) were added. The reaction mixture was refluxed until complete conversion of the starting material was observed. The solvent was evaporated under reduced pressure, the residue diluted with DCM and washed with aqueous sodium bicarbonate. Combining the organic layers, na 2 SO 4 Dried and concentrated under reduced pressure. Silica gel column chromatography separation and purification(n-hexane: ethyl acetate=10:1) to give product D-2 (13.41 g,57.33mmol, 73%). ESI-MS (m/z): 235.00[ M+H ]] + 。
Synthesis of intermediate D-3
D-2 (3135 mg,11.50 mmol) and B-7B (1450 mg,7.67 mmol) were dissolved in anhydrous DMSO (10 mL) and DIPEA (2670. Mu.L, 15.33 mmol) was added. The reaction mixture was stirred at 80 ℃ for 6 hours until complete conversion of B-5a was achieved. The reaction mixture was filtered and purified by basic reverse phase chromatography (water: acetonitrile=1:4-3:4) to give product D-3 (2.52 g,6.52mmol, 85%). ESI-MS (m/z): 388.10[ M+H ] ] + 。
Synthesis of intermediate D-4
D-3 (80.00 g,340.33 mmol) was dissolved in DMSO (400 mL), and cesium carbonate (220.53 g,680.66 mmol) and dimethyl malonate (49.42 g,374.36 mmol) were added to react. The resulting mixture was heated to 80 ℃ for 10 hours. After complete conversion of the starting material, the reaction mixture was diluted with ethyl acetate and poured onto ice-cold water. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with 0.1N aqueous formic acid. Na (Na) 2 SO 4 The organic layer was dried and concentrated under reduced pressure. Silica gel column chromatography purification (n-hexane: ethyl acetate=10:3) gave product D-4 (92.08 g,190.58mmol, 56%). ESI-MS (m/z): 484.16[ M+H ]] + 。
Synthesis of intermediate D-5
D-4 (40.00 g,120.95 mmol) was added to DMSO (120 mL), lithium chloride (20.32 g,483.79 mmol) was added and the reaction was stirred and heated to 120℃for 2 hours. After complete conversion of the starting material, the resulting reaction mixture was diluted with diethyl ether and poured into ice water. Extracting the aqueous layer with diethyl ether, combining the organic layers, na 2 SO 4 Dried and concentrated under reduced pressure. Purification by column chromatography on silica gel (n-hexane; ethyl acetate=5:1) afforded product D-5 (24.68 g,58.06mmol, 48%). ESI-MS (m/z): 426.16[ M+H ]] + 。
Synthesis of intermediate D-7a
D-5 (200.0 mg,0.470 mmol) was dissolved in DMSO (2 mL) and ACN (1 mL). Aqueous sodium hydroxide solution (20%, 313. Mu.L, 1.881 mmol) was added and the resulting mixture was stirred 30 minutes until complete conversion of the starting material was observed. Triethylamine (130. Mu.L, 0.933 mmol), 1-methyl-propylamine hydrochloride (62.8 mg,0.583 mmol) and HATU (266.3 mg,0.700 mmol) were added and the resulting mixture stirred for 20 minutes until complete conversion was observed. Water was added and the mixture was diluted with DCM. The aqueous layer was extracted with DCM and the organic layers were combined and dried over magnesium sulfate. The product D-7a was obtained. ESI-MS (m/z): 467.22[ M+H ]] + 。
The following intermediates were obtained in the same manner as D-7a.
5. Synthesis of intermediate E-6a
Synthesis of intermediate E-2E-1 (1.00 g,4.74 mmol) and sodium hydride (60%, 379mg,9.48 mmol) were added to a 100mL reaction flask, and the reaction was stirred at 0℃for 30min, followed by dropwise addition of methyl iodide (1009 mg,7.11 mmol), and after completion of the dropwise addition, the temperature was slowly raised to 80 ℃. After the reaction was completed, the heating and cooling to room temperature were stopped, the reaction solution was poured into cold water, extracted with EA three times, the organic phases were combined, and anhydrous Na 2 SO 4 After drying, the solvent was concentrated and removed, followed by separation and purification by silica gel column chromatography to give the desired product E-2 (981 mg,4.36mmol, 92%). ESI-MS (m/z): 226.10[ M+H ] ] + 。
Synthesis of intermediate E-3
E-2 (981 mg,4.36 mmol), THF (10 mL), water (5 mL) and sodium hydroxide (323 mg,13.08 mmol) were sequentially added to a 100mL reaction flask, and the mixture was heated to 60℃to react for 3h. After the completion of the reaction, TLC was monitored, the reaction solution was cooled to room temperature, the pH was adjusted to 5 with 1N hydrochloric acid, a solid was precipitated, the solid was collected by suction filtration, and the solid was rinsed with water and dried to give E-3 (699 mg,3.31mmol, 76%). ESI-MS (m/z): 212.08[ M+H ]] + 。
Synthesis of intermediate E-4
In a 100mL reaction flaskE-3 (699 mg,3.31 mmol), BOP (732 mg,1.66 mmol), DIEA (254 mg,6.62 mmol) and DMF (25 mL) was added dropwise with NH 4 A DMF solution of OH (5 mL) was stirred at room temperature for 2h. After the reaction was completed, the reaction solution was poured into 150mL of water, EA was extracted three times, the organic phases were combined and washed three times with water, anhydrous Na 2 SO 4 After drying, the solvent was concentrated and removed, followed by separation and purification by silica gel column chromatography to give the desired product E-4 (598 mg,2.85mmol, 86%). ESI-MS (m/z): 211.10[ M+H ]] + 。
Synthesis of intermediate E-5
E-4 (598 mg,2.85 mmol), pyridine (2 mL), 15mL of acetonitrile were added to a 100mL reaction flask, ethyl chloroformate (616 mg,5.70 mmol) dissolved in 5mL of acetonitrile was added dropwise at 0℃and after the addition was completed, the temperature was slowly raised to reflux the system. After the completion of the reaction, the heating and cooling were stopped to room temperature, and the reaction mixture was poured into cold water to precipitate a white solid, which was filtered to give E-5 (552 mg,2.34mmol, 85%). ESI-MS (m/z): 237.08[ M+H ] ] + 。
Synthesis of intermediate E-6a
E-5, DIEA and a proper volume of phosphorus oxychloride were added to a 100mL reaction flask, and reacted at 80℃for 2 hours. After the reaction was completed, the heating and cooling to room temperature were stopped, and the solvent was removed by concentration to obtain a pale yellow solid, E-6a. ESI-MS (m/z): 334.94[ M+H ]] + 。
The following intermediates can be obtained in the same manner as E-6a was synthesized starting from different E-1.
6. Synthesis of intermediate E-7a
To a suspension of E-6a (100 mg,0.32 mmol) in EtOH (10 mL) was added B-7B (86 mg,0.42 mmol). The resulting reaction mixture was heated to 100 ℃ in a sealed tube for 16h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Will remain behindThe material was dissolved in ethyl acetate and saturated NaHCO 3 Washing the solution. The organic layer was concentrated in vacuo, and the resulting solid was crystallized from a mixture of ethyl acetate and hexane to give compound E-7a (49 mg,0.10mmol, 32%). ESI-MS (m/z): 479.18[ M+H ]] + 。
The following intermediates can be obtained in the same manner as E-7a was synthesized starting from different E-6a to E-6 d.
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7. Synthesis of intermediate E-10a
Synthesis of intermediate E-8a
The reaction is carried out under an inert atmosphere. E-7a (146 mg,0.3 mmol) was dissolved in THF (2 mL) and 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2 (1H) -pyrimidinone (58.5. Mu.L, 0.5 mmol) and cooled to-20deg.C. Isopropyl magnesium bromide (0.3 ml,0.9 mmol) was then added dropwise and the reaction mixture stirred for 1h. Addition of 6-oxo-2-azaspiro [3.3 ] ]Heptane-2-carboxylic acid tert-butyl ester ketone (84 mg,0.4 mmol) and the reaction mixture was stirred at room temperature for 12h. NH for reaction 4 The saturated Cl solution was quenched and extracted with DCM. The solvent was removed under reduced pressure and the residue was dissolved in DMF. The crude product was purified by chromatography using acetonitrile/water to give product E-8a (141 mg,0.25mmol, 82%). ESI-MS (m/z): 573.26[ M+H ]] + 。
Synthesis of intermediate E-9a
E-8a (57.2 mg,0.1 mmol) was dissolved in dioxane (3 mL) and HCl in dioxane (73.9. Mu.L, 4M) was added. The reaction mixture was stirred at room temperature for 4d. The solvent was removed under reduced pressure to give product E-9a. ESI-MS (m/z): 509.19[ M ]+H] + 。
Synthesis of intermediate E-10a
E-9a (70 mg, 138. Mu. Mol) was dissolved in DMF (1 mL), DIPEA (93.6. Mu.L, 555. Mu. Mol) and TBTU (66.4 mg, 207. Mu. Mol) were added and the mixture was stirred at room temperature for 15min. Acetic acid (12.4 mg, 207. Mu. Mol) was then added and the reaction mixture was stirred at room temperature for 1h. The reaction mixture was purified by chromatography (acetonitrile/water) to give product E-10a (55 mg, 100.74. Mu. Mol, 73%). ESI-MS (m/z): 551.20[ M+H ]] + 。
The following intermediates were obtained in the same manner as E-10a starting from different E-7a to E-7 h.
8. Synthesis of intermediate F-7a
Synthesis of intermediate F-2
F-1 (530 mg,2.27 mmol) was dissolved in THF. (R) - (+) -2-methyl-2-propane sulfinamide (413 mg, 3.41 mmol) and Ti (OEt) were added at room temperature 4 (1.29 g,5.68 mmol) and the resulting reaction mixture was heated to 80℃for 5h. The reaction mixture was cooled to room temperature and quenched with ice water. The precipitate was dissolved in ethyl acetate and filtered through celite. The organic layer was concentrated in vacuo. Purification by column chromatography on silica gel (ethyl acetate: n-hexane=1:10-1:4) afforded product F-2 (418 mg,1.36mmol, 60%). ESI-MS (m/z): 307.97[ M+H ]] + 。
Synthesis of intermediate F-3
To a stirred solution of F-2 (3.50 g,10.00 mmol) in THF (50 mL) and water (5 mL) at-78deg.C was added sodium borohydride (0.61 g,18.00 mmol). The reaction was allowed to warm to room temperature and monitored by TLC. The reaction mixture was quenched with ice water, extracted with ethyl acetate and concentrated in vacuo. Silica gel column chromatography separation and purification (ethyl acetate/petroleum)Ether), the diastereomer mixture was separated to give F-3 as the major product (2.16 g,7.00mmol, 75%). ESI-MS (m/z): 309.99[ M+H ]] + 。
Synthesis of intermediate F-5
F-3 (500 mg,1.61 mmol) was dissolved in 1, 4-dioxane (15 mL) followed by the addition of pinacol biborate (1.60 g,6.45 mmol), potassium acetate (632 mg,6.45 mmol), pd (dppf) Cl 2 (943 mg,1.29 mmol) in N 2 The reaction mixture was heated to 100 ℃ with protection for 12 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, the solvent was removed by concentration, the residue was dissolved in water (50 mL) and extracted three times with ethyl acetate, and the organic phases were combined and dried, and then the solvent was removed by concentration under reduced pressure. The crude product was purified by silica gel column chromatography (DCM: meoh=30:1) to give F-5 (356 mg,1.00mmol, 62%). ESI-MS (m/z): 358.16[ M+H ]] + 。
Synthesis of intermediate F-6
F-5 (500 mg,1.40 mmol) was dissolved in 1, 4-dioxane (15 mL) and water (3 mL), followed by 1- (2-bromophenyl) -N, N-dimethylamine (360 mg,1.68 mmol), cesium carbonate (1369 mg,4.2 mmol), pd (dppf) Cl 2 (205 mg,0.28 mmol), in N 2 The reaction mixture was heated to 100 ℃ with protection for 6 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, the organic solvent was removed by concentration under reduced pressure, the residue was dissolved in 50mL of water and extracted three times with ethyl acetate, and the organic phases were combined and dried, and the solvent was removed by concentration under reduced pressure. The crude product was purified by column chromatography over silica gel (DCM: meoh=25:1) to give F-6 (362 mg,0.99mmol, 71%). ESI-MS (m/z): 365.16[ M+H ]] + 。
Synthesis of intermediate F-7a
F-6 (1.70 g,5.02 mmol) was dissolved in 1, 4-dioxane (10 mL), stirred and 4M HCl dissolved in dioxane (10 mL) was added to the solution. The reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, filtered and taken up with Et 2 O was washed to give product F-7a (1.16 g,4.47mmol, 89%). ESI-MS (m/z): 261.13[ M+H ]] + . The compound was isolated as HCl salt.
The following intermediates were obtained in the same manner as F-7 a.
9. Synthesis of intermediate G-3a
Synthesis of intermediate G-1
Methyl 2-amino-4-methoxybenzoate (500 mg,2.76 mmol) was dissolved in N, N-dimethylformamide (20 mL), followed by the addition of methyl iodide (588 mg,4.14 mmol) and anhydrous cesium carbonate (1.80 g,5.52 mmol), the system was reacted at 100deg.C for 48h and LCMS monitored no starting material remained. Cooled to room temperature, water (50 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated sodium chloride (50 ml×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol=80:1-30:1) to give G-1 (300 mg,1.54mmol, 56%). ESI-MS (m/z): 196.12[ M+H ]] + 。
Synthesis of intermediate G-2
G-1 (300 mg,1.54 mmol) was dissolved in glacial acetic acid (15 mL), followed by the addition of an aqueous solution of potassium cyanate (250 mg,3.08mmol,5 mL), the system was reacted at room temperature for 24h, then continued at 100deg.C for 4h, LCMS monitored no starting material remained. Cooling to room temperature, water (50 mL) was added to the reaction solution to precipitate a large amount of solid, which was filtered and dried to give G-2 (250 mg,1.21mmol, 79%). ESI-MS (m/z): 207.10[ M+H ] ] + 。
Synthesis of intermediate G-3 a:
g-2 (250 mg,1.21 mmol) was dissolved in carbon tetrachloride (20 mL), followed by addition of bromine (233 mg,1.45 mmol), the system was stirred at room temperature for 24h, LCMS monitored the starting material for no residue, water (50 mL) was added to the reaction solution, dichloromethane extraction (20 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (50 mL. Times.2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol=50:1-20:1) to give G-3a (300 mg,1.05mmol, 87%). ESI-MS (m/z): 284.98/286.98[ M+H ]] + 。
10. Synthesis of intermediate G-3b
Synthesis of intermediate G-3b-1
Methyl 2-amino-5-methoxybenzoate (0.50 g,2.76 mmol) was dissolved in tetrahydrofuran (50 mL), followed by cesium carbonate (1.80 g,5.52 mmol) and methyl iodide (0.59 g,4.14 mmol). The system was reacted at 65℃for 3h, and LCMS monitored no starting material remained. The reaction solution was filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was purified by column chromatography (n-hexane: ethyl acetate=40:1-20:1) to give G-3b-1 (0.21G, 1.08mmol, yield 39%). ESI-MS (m/z): 196.08[ M+H ]] + 。
Synthesis of intermediate G-3b
G-3b-1 (0.21G, 1.08 mmol) was dissolved in glacial acetic acid (10 mL), followed by the addition of an aqueous solution of potassium cyanate (0.17G, 2.16mmol,2 mL). The system was reacted at room temperature overnight. The next day, the system was reacted at 80 ℃ for 3h, lcms monitored no starting material remaining. Filtration and washing of the filter cake with water gave G-3b (0.16G, 0.78mmol, 72% yield). ESI-MS (m/z): 207.11[ M+H ] ] + 。
11. Synthesis of intermediate G-3c
Synthesis of intermediate G-3c-1
Methyl 2-amino-4, 5-dimethoxybenzoate (500 mg,2.37 mmol) was dissolved in dichloromethane (20 mL), then acetaldehyde (115 mg,2.61 mmol) and sodium borohydride acetate (962 mg,4.54 mmol) were added, the whole system was stirred at room temperature for 48h, TLC was monitored and followed until no starting material remained, water (50 mL) was added to the reaction solution, dichloromethane extraction (50 mL. Times.3), the organic phases were combined, washing with saturated sodium chloride (50 mL. Times.2), drying over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and the residue was isolated and purified by column chromatography (n-hexane: ethyl acetate=20:1-4:1) to give G-3c-1 (500 mg,2.09mmol, 88%). ESI-MS (m/z): 240.10[ M+H ]] + 。
Synthesis of intermediate G-3c
G-3c-1 (500 mg,2.09 mmol) was dissolved in glacial acetic acid (15 mL), followed by addition of aqueous potassium cyanate (399 mg,4.18mmol,5 mL), the whole system was stirred at room temperature for 24h, then stirred at 100deg.C for 4h, and TLC monitoring was followed until no starting material remained. Cooling to room temperature, water (50 mL) was added to the reaction solution to precipitate a large amount of solid, which was filtered and dried to give G-3c (300 mg,1.19mmol, 57%). ESI-MS (m/z): 251.12[ M+H ]] + 。
2. Examples
EXAMPLE 1 Synthesis of Compound 1
To a suspension of A-6B (94 mg,0.39 mmol) in EtOH (100 mL) was added B-7a (103 mg,0.50 mmol) and DIPEA (126 mg,0.97 mmol). The resulting reaction mixture was heated to 100 ℃ in a sealed tube for 16h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and taken up with saturated NaHCO 3 The solution was washed to give Compound 1 (49 mg,0.12mmol, 31%). ESI-MS (m/z): 410.12[ M+H ]] + 。
The following compounds may be obtained in a similar manner starting from different intermediates,
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EXAMPLE 2 Synthesis of Compound 7
D-7a (272 mg,0.586 mmol) was dissolved in 2-propanol (0.5 mL). 5N aqueous HCl (586. Mu.L, 2.928 mmol) was added and the resulting mixture stirred at 50deg.C for 1 hour until complete conversion of the starting material was observed. The reaction mixture was basified with aqueous ammonia, filtered and purified by basic reverse phase chromatography (acetonitrile: water=1:5-2:5) to give compound 7 (128 mg,0.32mmol, 54%). ESI-MS (m/z): 405.18[ M+H ]] + 。
The following compounds were obtained in the same manner as in the synthesis of compound 7 starting from intermediates D-7b to D-7 e.
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EXAMPLE 3 Synthesis of Compound 14
E-7d (95 mg, 206. Mu. Mol), 1-ethyl-5- (tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 2-dihydropyridin-2-one (103 mg, 412. Mu. Mol), pd (amphos) 2 Cl 2 (15 mg, 21. Mu. Mol) and Na 2 CO 3 (44 mg, 412. Mu. Mol) was dissolved in a mixture of dioxane (5 mL), water (0.2 mL) and EtOH (0.2 mL) and stirred at 50℃for 3h. The reaction mixture was filtered through celite, quenched with water and extracted with DCM. The combined organic layers were dried over MgSO 4 Dried, filtered and the solvent removed in vacuo. Purifying the crude product by silica gel chromatography to obtainCompound 14 (61 mg, 122. Mu. Mol, 59%). ESI-MS (m/z): 505.24[ M+H ]] + 。
The following compounds may be obtained in the same manner as for the synthesis of compound 14, starting from different intermediates.
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EXAMPLE 4 Synthesis of Compound 15
E-10a (10 mg, 18.18. Mu. Mol) was dissolved in THF (1 mL) and NaH (3 mg, 72.70. Mu. Mol) was added. The reaction mixture was stirred at room temperature for 5d, then the reaction was quenched with water, extracted with DCM and the solvent was removed under reduced pressure. The crude product was purified by chromatography (acetonitrile/water) to give product 15 (7 mg, 14. Mu. Mol, 79%). ESI-MS (m/z): 515.22[ M+H ]] + 。
The following compounds were obtained starting from intermediates E-10b to E-10c in the same manner as for the synthesis of compound 15.
EXAMPLE 5 Synthesis of Compound 37
The reaction is carried out under an inert atmosphere. E-7H (158 mg,0.30 mmol) was dissolved in ultra-dry THF (10 mL), 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2 (1H) -pyrimidinone (60. Mu.L, 0.50 mmol) was added and cooled to-20deg.C. Then isopropyl magnesium bromide (0.3 mL,0.90 mmol) was added dropwise and The reaction mixture was stirred for 1h. N-acetyl-4-piperidone (63 mg,0.45 mmol) was added and the reaction was stirred at room temperature for 12h. The reaction solution was treated with NH 4 The Cl (saturated) was quenched and extracted three times with DCM (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The crude product was purified by chromatography (acetonitrile/water) to give compound 37 (113 mg,0.19mmol, 64%). ESI-MS (m/z): 590.27[ M+H ]] + 。
Compound 44
Compound 44 was obtained in the same manner as in the synthesis of compound 37, ESI-MS (m/z): 534.22[ M+H ]] + 。
EXAMPLE 6 Synthesis of Compound 40
C-6-2 (50 mg,0.21 mmol) was dissolved in N, N-dimethylformamide (15 mL), followed by the addition of B-7B (72 mg,0.32 mmol), benzotriazol-1-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (124 mg,0.28 mmol), 1, 8-diazabicyclo undec-7-ene (97 mg,0.64 mmol) and the reaction was carried out at room temperature for 8h. LCMS monitored no starting material remained, water (30 mL), ethyl acetate extraction (30 ml×3), combined organic phases, washed with saturated sodium chloride (30 ml×2), dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by thin layer chromatography (dichloromethane: methanol=30:1) to give compound 40 (30 mg,0.074mmol, 35%). ESI-MS (m/z): 408.12[ M+H ] ] + 。 1 HNMR(600MHz，DMSO-d 6 )δ8.26(d,J＝7.8Hz,1H),7.74(s,1H),7.72-7.70(m,2H),7.61-7.56(m,2H),6.79(s,1H),5.64-5.61(m,1H),3.93(s,3H),3.86(s,3H),3.45(s,3H),1.59(d,J＝6.6Hz,3H)。
EXAMPLE 7 Synthesis of Compound 45
Synthesis of Compound 45
G-3b (50 mg,0.24 mmol) was dissolved in N, N-dimethylformamide (1)5 mL) was added followed by B-7a (74 mg,0.36 mmol), benzotriazole-1-oxybis (dimethylamino) phosphorus hexafluorophosphate (140 mg,0.31 mmol), 1, 8-diazabicycloundec-7-ene (55 mg,0.36 mmol) and the system reacted at room temperature for 8h. LCMS monitored no starting material remained, water (30 mL), ethyl acetate extraction (30 ml×3), combined organic phases, washed with saturated sodium chloride (30 ml×2), dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by thin layer chromatography (dichloromethane: methanol=25:1) to give compound 45 (37 mg,0.094mmol, 39%). ESI-MS (m/z): 393.13[ M+H ]] + 。 1 HNMR(600MHz，DMSO-d 6 )δ8.39(d,J＝7.8Hz,1H),7.83(d,J＝3.0Hz,1H),7.36-7.30(m,2H),6.83-6.80(m,2H),6.71(s,1H),5.56(s,2H),5.49-5.47(m,1H),3.85(s,3H),3.42(s,3H),1.53(d,J＝7.2Hz,3H)。
EXAMPLE 8 Synthesis of Compound 46
Synthesis of Compound 46:
g-3c (40 mg,0.16 mmol) was dissolved in N, N-dimethylformamide (30 mL), then B-7a (50 mg,0.24 mmol), 1, 8-diazabicyclo undec-7-ene (73 mg,0.48 mmol), benzotriazol-1-oxy tris (dimethylamino) phosphorus hexafluorophosphate (93 mg,0.21 mmol), the whole system was stirred at room temperature for 24h, TLC was monitored and followed until no starting material remained, water (50 mL), ethyl acetate extraction (30 mL. Times.3) and the organic phases were combined, washed with saturated sodium chloride (50 mL. Times.2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purification (dichloromethane: methanol=60:1-15:1) was separated by column chromatography to give compound 46 (40 mg,0.092mmol, 58%). ESI-MS (m/z): 437.20[ M+H ] ] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.18(d,J＝6.0Hz,1H),7.74(s,1H),6.83-6.80(m,3H),6.72(s,1H),5.57(s,2H),5.50-5.48(m,1H),4.14(q,J＝6.0Hz,2H),3.93(s,3H),3.86(s,3H),1.53(d,J＝6.0Hz,3H),1.16(t,J＝6.0Hz,3H)。
EXAMPLE 9 Synthesis of Compound 47
Synthesis of intermediate 47-1:
c-6 (100 mg,0.45 mmol) was dissolved in N, N-dimethylformamide (15 mL), followed by the addition of iodoisopropane (84 mg,0.50 mmol), potassium carbonate (124 mg,0.90 mmol), the system was reacted at 100deg.C for 2h and LCMS monitored no starting material remained. Water (30 mL), ethyl acetate extraction (30 mL. Times.3) and the combined organic phases were added to the reaction mixture, which was washed with saturated sodium chloride (30 mL. Times.2) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol=80:1-40:1) to give 47-1 (75 mg,0.28mmol, 63%) as ESI-MS (m/z): 264.98[ M+H)] + 。
Synthesis of Compound 47:
47-1 (75 mg,0.28 mmol) was dissolved in N, N-dimethylformamide (15 mL), followed by addition of B-7B (96 mg,0.42 mmol), benzotriazol-1-oxy tris (dimethylamino) phosphonium hexafluorophosphate (163 mg,0.36 mmol), 1, 8-diazabicyclo undec-7-ene (130 mg,0.84 mmol) and reaction of the system at room temperature for 8h. LCMS monitored no starting material remained, water (30 mL), ethyl acetate extraction (30 ml×3), combined organic phases, washed with saturated sodium chloride (30 ml×2), dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by thin layer chromatography (dichloromethane: methanol=33:1) to give compound 47 (40 mg,0.092mmol, 33%). ESI-MS (m/z): 436.14[ M+H ] ] + 。 1 HNMR(600MHz，DMSO-d 6 )δ8.25(d,J＝12Hz,1H),7.83(s,1H),7.75(s,1H),7.71(d,J＝6.0Hz,1H),7.61-7.57(m,2H),6.79(s,1H),5.64-5.61(m,1H),4.66-4.63(m,1H),3.90(s,3H),3.46(s,3H),1.59(d,J＝6.0Hz,3H),1.33-1.24(m,6H)。
EXAMPLE 10 Synthesis of Compound 48
Synthesis of intermediate 48-1
N, N-dimethylformamide (10 mL), C-6 (50 mg,0.23 mmol), (S) were successively added to a 50mL reaction flask-3-hydroxytetrahydrofuran p-toluenesulfonate (56 mg,0.23 mmol) and cesium carbonate (90 mg,0.28 mmol). The reaction system is heated to 100 ℃ to react for 2 hours. After the completion of the reaction by TLC, the reaction was concentrated to dryness and the residue was purified by thin layer chromatography (dichloromethane: methanol=50:1) to give 48-1 (30 mg,0.10mmol, 45%). ESI-MS (m/z): 293.12[ M+H ]] + 。
Synthesis of Compound 48
To a 50mL reaction flask were successively added N, N-dimethylformamide (10 mL), 48-1 (25 mg,0.086 mmol), B-7B (29 mg,0.13 mmol), benzotriazole-1-oxybis (dimethylamino) phosphorus hexafluorophosphate (53 mg,0.12 mmol) and 1, 8-diazabicyclo undec-7-ene (41 mg,0.27 mmol), and the mixture was stirred at room temperature overnight. After the completion of the reaction by TLC, the reaction was concentrated to dryness and the residue was purified by thin layer chromatography (dichloromethane: methanol=50:1) to give 48 (5 mg,0.01 mmol, 13%). ESI-MS (m/z): 464.17[ M+H ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.24(d,J＝7.8Hz,1H),7.79(s,1H),7.74(s,1H),7.71(d,J＝7.2Hz,1H),7.62-7.58(m,2H),6.82(s,1H),5.65-5.62(m,1H),5.10-5.08(m,1H),3.95(s,3H),3.92-3.89(m,2H),3.86-3.84(m,1H),3.82-3.78(m,1H),3.46(s,3H),2.25-2.19(m,1H),2.00-1.98(m,1H),1.60(d,J＝7.2Hz,3H).
EXAMPLE 11 Synthesis of Compound 49
Synthesis of intermediate 49-1
The synthesis method is the same as that of the compound 48-1 except that (R) -3-hydroxytetrahydrofuran p-toluenesulfonate is used for replacing (S) -3-hydroxytetrahydrofuran p-toluenesulfonate, so that 49-1 is obtained, the yield is 72%, and ESI-MS (m/z): 293.11[ M+H ] ] + 。
Synthesis of Compound 49
The synthesis method was identical to that of compound 48 except that 49-1 was used instead of 48-1, yielding 49 in 22% yield. ESI-MS (m/z): 464.20[ M+H ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.23(d,J＝7.8Hz,1H),7.78(s,1H),7.74(s,1H),7.71(d,J＝7.2Hz,1H),7.61-7.57(m,2H),6.81(s,1H),5.65-5.60(m,1H),5.09-5.08(m,1H),3.94(s,3H),3.91-3.87(m,2H),3.84-3.82(m,1H),3.81-3.77(m,1H),3.45(s,3H),2.24-2.18(m,1H),2.00-1.98(m,1H),1.58(d,J＝7.2Hz,3H).
EXAMPLE 12 Synthesis of Compound 50
Synthesis of intermediate 50-1
The synthesis method is the same as that of the compound 48-1 except that (R) -3- (tosyloxy) pyrrolidine-1-carboxylic acid tert-butyl ester is used for replacing (S) -3-hydroxytetrahydrofuran p-toluenesulfonate to obtain 50-1 with the yield of 80 percent and ESI-MS (m/z): 392.17[ M+H ]] + 。
Synthesis of Compound 50
The synthesis procedure was identical to compound 48, giving compound 50 in 18% yield. ESI-MS (m/z): 563.24[ M+H ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.24-8.23(m,1H)，7.84(d,J＝9.0Hz,1H),7.73(s,1H),7.70(d,J＝7.2Hz,1H),7.61-7.56(m,2H),6.82(s,1H),5.64-5.59(m,1H),5.04-4.98(m,1H),3.93(s,3H),3.56-3.53(m,1H),3.45(s,3H),3.43-3.39(m,3H),2.08-2.05(m,2H),1.58(d,J＝6.6Hz,3H),1.41(d,J＝13.2Hz,9H).
EXAMPLE 13 Synthesis of Compound 51
Synthesis of Compound 51
Into a 50mL reaction flask was added dichloromethane (5 mL), 50 (120 mg,0.21 mmol) and trifluoroacetic acid (1 mL) in this order. The reaction was stirred at room temperature for 2h. After the completion of the reaction, TLC was monitored, the solvent was removed by concentration under reduced pressure, the residue was dissolved in methylene chloride (30 mL), the organic phase was washed with saturated sodium hydrogencarbonate solution, and the solvent was removed after drying the organic phase over anhydrous sodium sulfate to give a crude product. The crude product was purified by thin layer chromatography (dichloromethane: methanol=20:1) to give compound 51 (80 mg,0.17mmol, 82%). ESI-MS (m/z): 463.19[ M+H ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.23(d,J＝7.8Hz,1H),7.84(s,1H),7.74-7.71(m,2H),7.62-7.57(m,2H),6.84(s,1H),5.65-5.60(m,1H),5.10-5.09(m,1H),3.95(s,3H),3.51-3.49(m,1H),3.48(s,3H),3.44-3.41(m,1H),3.40-3.35(m,2H),2.18-2.15(m,2H),1.91(s,1H),1.60(d,J＝7.2Hz,3H).
EXAMPLE 14 Synthesis of Compound 52
51 (20 mg,0.043 mmol), formic acid (1 mL) and aqueous formaldehyde (2 mL) were added sequentially to a 50mL reaction flask. The reaction was stirred at 70℃for 6h. TLC monitored the completion of the reaction, the reaction was poured into saturated sodium bicarbonate solution, ethyl acetate extracted the aqueous phase (50 ml×3), the organic phases combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the residue was purified by thin layer chromatography (dichloromethane: methanol: triethylamine=100:3:1) to give compound 52 (15 mg,0.031mmol, 73%). ESI-MS (m/z): 477.20[ M+H ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.31(d,J＝7.8Hz,1H),7.83(s,1H),7.76(s,1H),7.73(d,J＝7.2Hz,1H),7.62-7.57(m,2H),6.84(s,1H),5.67-5.62(m,1H),5.13-5.09(m,1H),3.96(s,3H),3.46(s,3H),3.12-3.08(m,2H),2.78-2.75(m,2H),2.50(s,3H),2.14-2.02(m,2H),1.60(d,J＝7.2Hz,3H).
EXAMPLE 15 Synthesis of Compound 53
Synthesis of intermediate 53-1:
c-6 (150 mg,0.68 mmol) was dissolved in N, N-dimethylformamide (15 mL), followed by the addition of tert-butyl (S) -3- (tosyloxy) pyrrolidine-1-carboxylate (255 mg,0.75 mmol), cesium carbonate (264 mg,0.82 mmol), the system was reacted at 100deg.C for 3h, and LCMS monitored no starting material remained. Water (30 mL), ethyl acetate extraction (30 mL. Times.3) and the combined organic phases were added to the reaction mixture, which was washed with saturated sodium chloride (30 mL. Times.2) and dried over anhydrous sodium sulfate. Vacuum evaporating solventThe residue was purified by column chromatography (dichloromethane: methanol=50:1-25:1) to give 53-1 (105 mg,0.27mmol, 40%). ESI-MS (m/z): 392.10[ M+H ] ] +
Synthesis of Compound 53:
53-1 (105 mg,0.27 mmol) was dissolved in N, N-dimethylformamide (15 mL), followed by the addition of B-7B (91 mg,0.41 mmol), benzotriazol-1-oxy tris (dimethylamino) phosphonium hexafluorophosphate (154 mg,0.35 mmol), 1, 8-diazabicyclo undec-7-ene (122 mg,0.81 mmol) and the reaction was carried out at room temperature for 8h. LCMS monitored no starting material remained, water (30 mL), ethyl acetate extraction (30 ml×3), combined organic phases, washed with saturated sodium chloride (30 ml×2), dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by thin layer chromatography (dichloromethane: methanol=25:1) to give compound 53 (88 mg,0.16mmol, 59%). ESI-MS (m/z): 563.22[ M+H ]] + 。
1 H NMR(600MHz，DMSO-d 6 )δ8.27(m,1H),7.83(s,1H),7.75-7.66(m,2H),7.61-7.53(m,2H),6.82(s,1H),5.62-5.61(m,1H),5.03-5.00(m,1H),3.93(s,3H),3.54-3.43(m,4H),3.41(s,3H),2.09-2.05(m,2H),1.56(d,J＝7.2Hz,3H),1.42-1.40(m,9H).
EXAMPLE 16 Synthesis of Compound 54
53 (70 mg,0.12 mmol) was dissolved in dichloromethane (15 mL) followed by trifluoroacetic acid (2 mL) and the system was reacted at room temperature for 3h. LCMS monitored no starting material remained, the reaction solvent was distilled off under reduced pressure, water (5 mL) was added to the residue, the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate, extracted with ethyl acetate (10 ml×3), the organic phases combined, washed with saturated sodium chloride (10 ml×2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by thin layer chromatography (dichloromethane: methanol=5:1) to give compound 54 (25 mg,0.054mmol, 45%). ESI-MS (m/z): 463.13[ M+H ] ] + 。 1 H NMR(600MHz，DMSO-d 6 )δ8.32(d,J＝7.8Hz,1H),7.88(s,1H),7.75-7.72(m,2H),7.61-7.58(m,2H),6.81(s,1H),5.64-5.62(m,1H),5.03-5.02(m,1H),3.93(s,3H),3.45(s,3H),3.25-3.11(m,4H),2.10-2.08(m,3H),1.60(d,J＝7.2Hz,3H).
EXAMPLE 17 Synthesis of Compound 55
54 (30 mg,0.065 mmol) was dissolved in formic acid (4 mL) followed by the addition of 37% aqueous formaldehyde (2 mL) and the system reacted at 70℃for 12h. LCMS monitored no starting material remained, the reaction was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate, extracted with ethyl acetate (15 ml×3), the organic phases combined, washed with saturated sodium chloride (15 ml×2) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by thin layer chromatography (dichloromethane: methanol: triethylamine=100:2.5:1) to give compound 55 (18 mg,0.038mmol, 58%). ESI-MS (m/z): 477.23[ M+H ]] + 。 1 H NMR(600MHz，DMSO-d 6 )δ8.30(d,J＝7.8Hz,1H),7.75-7.72(m,3H),7.62-7.57(m,2H),6.81(s,1H),5.66-5.62(m,1H),5.04-5.03(m,1H),3.94(s,3H),3.46(s,3H),3.05(m,1H),2.84-2.80(m,2H),2.66(m,1H),2.42(s,3H),2.40-2.34(m,1H),1.88-1.86(m,1H),1.60(d,J＝7.2Hz,3H).
EXAMPLE 18 Synthesis of Compound 56
Synthesis of intermediate 56-1
C-6 (150 mg,0.68 mmol) was dissolved in N, N-dimethylformamide (15 mL), followed by the addition of tert-butyl 4- (tosyloxy) piperidine-1-carboxylate (264 mg,0.74 mmol), potassium carbonate (186 mg,1.36 mmol) and the system reacted at 100℃for 3h, LCMS monitored no starting material remained. Water (30 mL), ethyl acetate extraction (30 mL. Times.3) and the combined organic phases were added to the reaction mixture, which was washed with saturated sodium chloride (30 mL. Times.2) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol=70:1-20:1) to give 56-1 (120 mg,0.30mmol, yield 44%). ESI-MS (m/z): 406.11[ M+H ] ] + 。
Synthesis of intermediate 56-2
56-1 (120 mg,0.30 mmol) was dissolved in N, N-dimethylformamide (15 mL), followed by the addition of B-7B (100 mg,0.45 mmol), benzotriazol-1-oxy tris (dimethylamino) phosphonium hexafluorophosphate (170 mg,0.39 mmol), 1, 8-diazabicyclo undec-7-ene (135 mg,0.90 mmol) and the reaction was carried out at room temperature for 8h. LCMS monitored no starting material remained, water (30 mL), ethyl acetate extraction (30 ml×3), combined organic phases, washed with saturated sodium chloride (30 ml×2), dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by thin layer chromatography (dichloromethane: methanol=25:1) to give 56-2 (70 mg,0.12mmol, 41%). ESI-MS (m/z): 577.26[ M+H ]] + 。
Synthesis of intermediate 56-3
56-2 (35 mg,0.061 mmol) was dissolved in dichloromethane (15 mL) followed by trifluoroacetic acid (2 mL) and the system was reacted at room temperature for 3h. LCMS monitored no starting material remained, the reaction solvent was distilled off under reduced pressure, water (5 mL) was added to the residue, the pH was adjusted to 8-9 with saturated aqueous sodium bicarbonate, extracted with ethyl acetate (10 ml×3), the organic phases combined, washed with saturated sodium chloride (10 ml×2), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by thin layer chromatography (dichloromethane: methanol=5:1) to give 56-3 (23 mg,0.048mmol, 79%). ESI-MS (m/z): 477.15[ M+H ] ] + 。
Synthesis of Compound 56
56-3 (23 mg,0.048 mmol) was dissolved in formic acid (4 mL), followed by the addition of 37% aqueous formaldehyde (2 mL) and the system reacted at 70℃for 12h. LCMS monitored no starting material remained, the reaction was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate, extracted with ethyl acetate (15 ml×3), the organic phases combined, washed with saturated sodium chloride (15 ml×2) and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by thin layer chromatography (dichloromethane: methanol: triethylamine=100:2.5:1) to give compound 56 (10 mg,0.020mmol, 42%). ESI-MS (m/z): 491.17[ M+H ]] + 。 1 H NMR(600MHz，DMSO-d 6 )δ8.34(d,J＝6.0Hz,1H),7.96(s,1H),7.76(s,1H),7.72(d,J＝12.0Hz,1H),7.62-7.57(m,2H),6.81(s,1H),5.63-5.60(m,1H),4.41-4.40(m,1H),3.95(s,3H),3.45(s,3H),3.05-2.91(m,4H),2.43(s,3H),1.99-1.97(m,2H),1.80-1.78(m,2H),1.59(d,J＝6.0Hz,3H).
EXAMPLE 19 Synthesis of Compound 57
Synthesis of intermediate 57-1:
g-3a (300 mg,1.05 mmol) was dissolved in N, N-dimethylformamide (30 mL), then B-7B (239 mg,1.27 mmol), 1, 8-diazabicyclo undec-7-ene (284 mg,3.18 mmol), benzotriazol-1-oxy tris (dimethylamino) phosphorus hexafluorophosphate (610 mg,1.38 mmol), the whole system was stirred at room temperature for 24h, TLC was monitored and followed until no starting material remained, water (50 mL), ethyl acetate extraction (30 mL. Times.3) was added, the organic phases were combined, washed with saturated sodium chloride (50 mL. Times.2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was isolated and purified by column chromatography (dichloromethane: methanol=60:1-15:1) to give 57-1 (350 mg,0.77mmol, 73%). ESI-MS (m/z): 456.10[ M+H ] ] + 。
Synthesis of Compound 57:
57-1 (50 mg,0.11 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by cesium carbonate (72 mg,0.22 mmol), 1-methyl-6-oxo-1, 6-dihydropyridine-3-boronic acid pinacol ester (40 mg,0.17 mmol) and [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride (4.4 mg, 0.006mmol) was replaced three times with nitrogen and the whole system was left under nitrogen atmosphere. The system was stirred at 100℃under reflux and reacted for 3h, with no starting material remaining as monitored by TLC. To the reaction solution was added water (50 mL), extracted with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated sodium chloride (50 ml×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, followed by separation and purification by column chromatography (dichloromethane: methanol=50:1-20:1) to give compound 57 (27 mg,0.056mmol, 51%). ESI-MS (m/z): 485.21[ M+H ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.39(d,J＝6.0Hz,1H),8.19(s,1H),7.91(s,1H),7.76(s,1H),7.73(d,J＝6.0Hz,1H),7.63-7.58(m,3H),6.83(s,1H),6.48(d,J＝12Hz,1H),5.63-5.59(m,1H),3.95(s,3H),3.52(s,3H),3.49(s,3H),1.58(d,J＝6.0Hz,3H).
EXAMPLE 20 Synthesis of Compound 58
Synthesis of intermediate 58-1:
g-3a (300 mg,1.05 mmol) was dissolved in N, N-dimethylformamide (30 mL), then B-7a (260 mg,1.27 mmol), 1, 8-diazabicyclo undec-7-ene (254 mg,3.18 mmol), benzotriazol-1-oxy tris (dimethylamino) phosphorus hexafluorophosphate (610 mg,1.38 mmol), the whole system was stirred at room temperature for 24h, TLC was monitored and followed until no starting material remained, water (50 mL) was added to the reaction solution, ethyl acetate extraction (30 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (50 mL. Times.2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was isolated and purified by column chromatography (dichloromethane: methanol=60:1-15:1) to give 58-1 (320 mg,0.68mmol, 65%). ESI-MS (m/z): 471.10[ M+H ] ] + 。
Synthesis of Compound 58:
58-1 (52 mg,0.11 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by cesium carbonate (72 mg,0.22 mmol), 1-methyl-6-oxo-1, 6-dihydropyridine-3-boronic acid pinacol ester (40 mg,0.17 mmol) and [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride (4.4 mg, 0.006mmol) was replaced three times with nitrogen and the whole system was left under nitrogen atmosphere. The system was stirred at 100℃under reflux and reacted for 3h, with no starting material remaining as monitored by TLC. To the reaction solution was added water (100 mL), extracted with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated sodium chloride (50 ml×2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and purified by column chromatography (dichloromethane: methanol=50:1-20:1) to give compound 58 (31 mg,0.062mmol, 56%). ESI-MS (m/z): 500.21[ M+H ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.31(d,J＝6.0Hz,1H),8.21(s,1H),7.90(s,1H),7.63(d,J＝12Hz,1H),6.84-6.81(m,3H),6.71(s,1H),6.49(d,J＝6.0Hz,1H),5.56(s,2H),5.50-5.45(m,1H),3.96(s,3H),3.52(s,3H),3.50(s,3H),1.52(d,J＝6.0Hz,3H).
EXAMPLE 21 Synthesis of Compound 59
Synthesis of compound 59:
57-1 (50 mg,0.11 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by cesium carbonate (72 mg,0.22 mmol), 3-hydroxymethylphenylboronic acid (21 mg,0.14 mmol) and [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride (4.4 mg, 0.006mmol) was replaced three times with nitrogen and the whole system was left under nitrogen atmosphere. The system was stirred at 100℃under reflux and reacted for 3h, with no starting material remaining as monitored by TLC. To the reaction solution was added water (100 mL), extracted with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated sodium chloride (50 ml×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol=50:1-15:1) to give compound 59 (30 mg,0.062mmol, 56%). ESI-MS (m/z): 484.22[ M+H ] ] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.46(d,J＝6.0Hz,1H),8.23(s,1H),7.75(s,1H),7.72(d,J＝6.0Hz,1H),7.59-7.57(m,2H),7.44-7.40(m,2H),7.37-7.32(m,2H),6.85(s,1H),5.63-5.59(m,1H),5.25(t,J＝6.0Hz,1H),4.58(d,J＝4Hz,2H),3.93(s,3H),3.51(s,3H),1.57(d,J＝6.0Hz,3H).
EXAMPLE 22 Synthesis of Compound 60
57-1 (50 mg,0.11 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of (4-carbamoylphenyl) boronic acid (27 mg,0.17 mmol), [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex (10 mg,0.01 mmol) and cesium carbonate (107 mg,0.33 mmol), nitrogen was substituted three times and the system was reacted at 100℃for 3h. LCMS monitored no starting material remained, solvent was distilled off under reduced pressure, water (5 mL) was added to the residue, ethyl acetate extraction (10 ml×3), the organic phases were combined, washed with saturated sodium chloride (10 ml×2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by thin layer chromatography (dichloromethane: methanol=20:1) to give compound 60 (25 mg,0.050mmol, 46%). ESI-MS(m/z)：497.16[M+H] + 。 1 H NMR(600MHz，DMSO-d 6 )δ8.47(d,J＝6.0Hz,1H),8.29(s,1H),8.03(s,1H),7.97-7.96(m,2H),7.75(s,1H),7.72(d,J＝6.0Hz,1H),7.63-7.57(m,4H),7.41(s,1H),6.87(s,1H),5.61-5.60(m,1H),3.95(s,3H),3.51(s,3H),1.56(d,J＝6.0Hz,3H).
EXAMPLE 23 Synthesis of Compound 61
57-1 (50 mg,0.11 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by the addition of (3-carbamoylphenyl) boronic acid (27 mg,0.17 mmol), [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane complex (10 mg,0.01 mmol) and cesium carbonate (107 mg,0.33 mmol), nitrogen was substituted three times and the system was reacted at 100℃for 3h. LCMS monitored no starting material remained, solvent was distilled off under reduced pressure, water (10 mL) was added to the residue, ethyl acetate extraction (10 ml×3), the organic phases were combined, washed with saturated sodium chloride (10 ml×2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by thin layer chromatography (dichloromethane: methanol=33:1) to give compound 61 (30 mg,0.060mmol, 55%). ESI-MS (m/z): 497.15[ M+H ] ] + 。 1 H NMR(600MHz，DMSO-d 6 )δ8.47(d,J＝6.0Hz,1H),8.28(s,1H),8.04-8.02(m,2H),7.88(d,J＝7.2Hz,1H),7.75(s,1H),7.72(d,J＝6.0Hz,1H),7.65(d,J＝6.0Hz,1H),7.59-7.54(m,3H),7.43(s,1H),6.87(s,1H),5.61-5.60(m,1H),3.94(s,3H),3.52(s,3H),1.56(d,J＝6.0Hz,3H).
EXAMPLE 24 Synthesis of Compound 62
Synthesis of intermediate 62-1:
57-1 (300 mg,0.66 mmol) was dissolved in dioxane (10 mL) and water (2 mL), followed by cesium carbonate (420 mg,1.29 mmol), N-Boc-1,2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester (263 mg,0.85 mmol) and [1,1' -bis (diphenylphosphine) ferrocene]Dichloro-sPalladium (29 mg,0.04 mmol) was reacted with nitrogen three times to make the whole system under nitrogen atmosphere. The system was stirred at 100℃under reflux and reacted for 3h, with no starting material remaining as monitored by TLC. To the reaction solution was added water (100 mL), extracted with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated sodium chloride (50 ml×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated and purified by column chromatography (dichloromethane: methanol=50:1-20:1) to give 62-1 (220 mg,0.39mmol, 60%). ESI-MS (m/z): 559.31[ M+H ]] + 。
Synthesis of Compound 62:
62-1 (150 mg,0.27 mmol) was dissolved in 2M hydrochloric acid/methanol solution (10 mL) and the system stirred overnight at room temperature, with no starting material remaining as monitored by TLC. The solvent was removed under reduced pressure and used directly as the next step. The concentrated crude product was redissolved in dichloromethane (20 mL) followed by triethylamine (54 mg,0.54 mmol) and acetyl chloride (25 mg,0.32 mmol) and the system was stirred at room temperature for 24h with no starting material remaining as monitored by TLC. The solvent was removed under reduced pressure, and the mixture was purified by column chromatography (dichloromethane: methanol=60:1-15:1) to give compound 62 (55 mg,0.11mmol, 41%). ESI-MS (m/z): 501.20[ M+H ] ] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.40(d,J＝6.0Hz,1H),8.05(s,1H),7.76(s,1H),7.72(d,J＝6.0Hz,1H),7.61-7.57(m,2H),6.75(s,1H),5.87-5.85(m,1H),5.61-5.59(m,1H),4.16-4.10(m,2H),3.94(s,3H),3.66-3.61(m,2H),3.46(s,3H),2.08-2.06(m,2H),2.30(s,3H),1.57(d,J＝6.0Hz,3H).
EXAMPLE 25 Synthesis of Compound 63
Synthesis of compound 63:
62-1 (151 mg,0.27 mmol) was dissolved in 2M hydrochloric acid/methanol solution (10 mL) and the system stirred overnight at room temperature, with no starting material remaining as monitored by TLC. The solvent was removed under reduced pressure and used directly as the next step. The concentrated crude product was redissolved in formic acid (20 mL) and then aqueous formaldehyde (5 mL) was added. The system was stirred at 70 ℃ for 24h, and tlc monitored no starting material remained. The solvent was removed under reduced pressure,the residue was purified by column chromatography (dichloromethane: methanol=60:1-10:1) to give compound 63 (37 mg,0.078mmol, 29%). ESI-MS (m/z): 473.25[ M+H ]] + 。 1 H NMR(600MHz,DMSO-d 6 )δ8.40(d,J＝7.8Hz,1H),8.04(s,1H),7.75(s,1H),7.71(d,J＝7.2Hz,1H),7.60-7.57(m,2H),6.78(s,1H),5.81-5.77(m,1H),5.60-5.58(m,1H),3.92(s,3H),3.45(s,3H),3.05-3.00(m,2H),2.57-2.55(m,2H),2.49-2.46(m,2H),2.30(s,3H),1.56(d,J＝7.2Hz,3H).
EXAMPLE 26 Synthesis of Compound 64
Synthesis of intermediate 64-1
C-6 (300 mg,1.35 mmol) was dissolved in N, N-dimethylformamide (30 mL), followed by ethyl bromoacetate (336 mg,2.03 mmol), potassium carbonate (373 mg,2.70 mmol) and the system was reacted at 100℃for 2h, and LCMS monitored no starting material remained. Water (50 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (40 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (40 mL. Times.2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol=70:1-50:1) to give 64-1 (142 mg,0.46mmol, 34%). ESI-MS (m/z): 309.07[ M+H ] ] + 。
Synthesis of Compound 64
64-1 (142 mg,0.46 mmol) was dissolved in N, N-dimethylformamide (30 mL), followed by the addition of B-7B (156 mg,0.69 mmol), benzotriazol-1-oxy tris (dimethylamino) phosphonium hexafluorophosphate (265 mg,0.60 mmol), 1, 8-diazabicyclo undec-7-ene (210 mg,1.38 mmol) and the reaction was carried out at room temperature for 8h. LCMS monitored no starting material remained, water (50 mL) was added to the reaction, ethyl acetate extracted (40 ml×3), the organic phases combined, washed with saturated sodium chloride (40 ml×2), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol=80:1-50:1) to give compound 64 (90 mg,0.19mmol, 41%). ESI-MS (m/z): 480.18[ M+H ]] + 。 1 H NMR(600MHz，DMSO-d 6 )δ8.25(d,J＝7.8Hz,1H),7.76(s,1H),7.73(s,1H),7.71(d,J＝6.0Hz,1H),7.61-7.59(m,2H),6.83(s,1H),5.64-5.59(m,1H),4.84(s,2H),4.20-4.19(m,2H),3.96(s,3H),3.46(s,3H),1.58(d,J＝12.0Hz,3H),1.22(t,J＝6.0Hz,3H).
EXAMPLE 27 Synthesis of Compound 65
64 (20 mg,0.042 mmol) was dissolved in tetrahydrofuran (10 mL), lithium borohydride (2 mg,0.092 mmol) was added under ice-bath, and the system was reacted at room temperature for 3h. LCMS monitored no starting material remained, the reaction was quenched with water, then water (10 mL), ethyl acetate extraction (10 ml×3), combined organic phases, washed with saturated sodium chloride (10 ml×2), dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by thin layer chromatography (dichloromethane: methanol=50:3) to give compound 65 (10 mg,0.023mmol, 54%). ESI-MS (m/z): 438.12[ M+H ] ] + 。 1 H NMR(600MHz，DMSO-d 6 )δ8.30(d,J＝7.8Hz,1H),7.75-7.72(m,3H),7.61-7.60(m,2H),6.80(s,1H),5.65-5.60(m,1H),4.97(d,J＝6.0Hz,1H),4.09-4.07(m,2H),3.94(s,3H),3.80-3.79(m,2H),3.46(s,3H),1.59(d,J＝12.0Hz,3H).
EXAMPLE 28 Synthesis of Compound 66
C-6-2 (70 mg,0.30 mmol) was dissolved in N, N-dimethylformamide (15 mL), followed by addition of B-7e (107 mg,0.45 mmol), benzotriazole-1-oxybis-tris (dimethylamino) phosphate (170 mg,0.39 mmol) and 1, 8-diazabicyclo undec-7-ene (135 mg,0.90 mmol), and the system was reacted at room temperature for 8h. LCMS monitored no starting material remained, and the reaction was extracted with 30mL of water, ethyl acetate (30 mL x 3), the combined organic phases washed with saturated sodium chloride (30 mL x 2) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by thin layer chromatography (dichloromethane: methanol=50:1) to give compound 66 (40 mg,0.095mmol, 32%). ESI-MS (m/z): 422.18[ M+H ]] + 。 1 HNMR(600MHz，DMSO-d 6 )δ8.26(d,J＝7.8Hz,1H),7.80(s,1H),7.59(s,1H),7.49-7.45(m,1H),7.28(d,J＝6.0Hz,1H),6.80(s,1H),5.78-5.76(m,1H),3.94(s,3H),3.89(s,3H),3.45(s,3H),2.04(t,J＝12Hz,3H),1.58(d,J＝6.0Hz,3H).
EXAMPLE 29 Synthesis of Compound 67
C-6-2 (250 mg,1.06 mmol) was dissolved in N, N-dimethylformamide (30 mL), then B-7f (263 mg,1.27 mmol), 1, 8-diazabicycloundec-7-ene (284 mg,3.18 mmol) and benzotriazol-1-yloxytris (dimethylamino) phosphate (610 mg,1.38 mmol) were added, the whole system was stirred at room temperature for 24h, TLC was monitored and followed until no starting material remained, water (50 mL) was added to the reaction solution, ethyl acetate extraction (30 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (50 mL. Times.2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol=60:1-15:1) to give compound 67 (302 mg,0.71mmol, 67%). ESI-MS (m/z): 426.17[ M+H ] ] + 。 1 HNMR(600MHz,DMSO-d 6 )δ8.28(d,J＝7.8Hz,1H),7.78(s,1H),7.76-7.74(m,1H),7.68-7.66(m,1H),7.40-7.37(m,1H),6.79(s,1H),5.77-5.72(m,1H),3.93(s,3H),3.88(s,3H),3.44(s,3H),1.58(d,J＝7.2Hz,3H).
EXAMPLE 30 Synthesis of Compound 68
40 (301 mg,0.74 mmol) was dissolved in toluene (30 mL), then Lawson's reagent (599 mg,1.48 mmol) was added, the whole system was refluxed and stirred for 3h, TLC was monitored and tracked until no starting material remained, water (50 mL) was added to the reaction solution, ethyl acetate was extracted (30 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride (50 mL. Times.2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the mixture was isolated and purified by column chromatography (dichloromethane: methanol=50:1-15:1) to give compound 68 (156 m)g,0.37mmol,50％)。ESI-MS(m/z)：424.10[M+H] + 。 1 HNMR(600MHz,DMSO-d 6 )δ8.58(d,J＝7.9Hz,1H),7.78(s,1H),7.76-7.74(m,2H),7.63-7.59(m,1H),6.97(s,1H),5.80-5.76(m,1H),4.07(s,3H),3.96(s,3H),3.90(s,3H),1.63(d,J＝7.2Hz,3H)。
EXAMPLE 31 Synthesis of Compound 69
Synthesis of intermediate 69-1:
7-dimethoxy-2, 4-quinazolinedione (140 mg,0.63 mmol) was dissolved in phosphorus oxychloride (20 mL), the whole system was stirred at 105℃for 8h, and TLC monitoring was followed until no starting material remained. The solvent was removed from the reaction solution directly under reduced pressure, and the residue was purified by column chromatography (n-hexane: ethyl acetate=20:1-4:1) to give 69-1 (140 mg,0.54mmol, 86%). ESI-MS (m/z): 259.01[ M+H ]] + 。
Synthesis of intermediate 69-2:
69-1 (140 mg,0.54 mmol) was dissolved in isopropanol (20 mL) followed by B-7B (123 mg,0.65 mmol) and N, N-diisopropylethylamine (279 mg,2.16 mmol) and the whole system was stirred at 105℃for 48h and monitored by TLC until no starting material remained. After completion of the reaction, the reaction system was cooled to room temperature, 50mL of water was added to the reaction mixture to quench the reaction, followed by extraction with ethyl acetate (30 mL. Times.3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride (50 ml×2), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane: methanol=60:1-20:1) to give 69-2 (100 mg,0.24mmol, yield 45%). ESI-MS (m/z): 412.12[ M+H ] ] + 。
Synthesis of Compound 69:
69-2 (100 mg,0.24 mmol) was dissolved in glacial acetic acid (20 mL) and the whole system was stirred at 90 ℃ for 8h, the tlc monitoring was followed until no starting material remained, the solvent was directly removed under reduced pressure after completion of the reaction, and the residue was isolated and purified by column chromatography (dichloromethane: methanol=60:1-15:1) to give compound 69 (60 mg,0.15mmol, 63% yield). ESI-MS (m-z):394.13[M+H] + 。 1 HNMR(600MHz,DMSO-d 6 )δ10.51(s,1H),8.26(d,J＝6.0Hz,1H),7.75(s,1H),7.73(d,J＝6.0Hz,1H),7.68(s,1H),7.63-7.58(m,2H),6.67(s,1H),5.65-5.61(m,1H),3.84(s,3H),3.81(s,3H),1.60(d,J＝6.0Hz,3H).
3. Biological Activity assay:
1.K-Ras G12D binding assays to hSOS1
This assay can be used to examine the efficacy of compounds to inhibit protein-protein interactions between SOS1 and KRAS G12D. Detection of GST-KRAS bound by anti-GST-Europium (FRET donor) by Homogeneous Time Resolved Fluorescence (HTRF) G12D Binding of His-tagged hSOS1 (FRET receptor) to anti-6 His-XL665 binding, assaying Compounds for K-Ras G12D Inhibition with hSOS 1.
Reagent(s)
Buffer (5mM HEPES pH 7.4,150mM NaCl,10mM EDTA,1mM DTT,0.05%BSA pH 7.0,0.0025%IGEPAL) and 100mM KF;
GST-tag hK-RasG12D (commercially available)
His-tag hSOS1 (commercially available)
Ras mixed liquor
GST-hK-RasG12D 10nM (final concentration) and anti-GST-Europium 2nM (final concentration) were mixed in assay buffer and kept at room temperature prior to use.
SOS mixed solution
His-tagged hSOS1, 20nM (final concentration) and anti-6 His-XL665, 10nM (final concentration) were mixed in assay buffer and kept at room temperature prior to use.
Test compounds were dissolved in DMSO at 100-fold experimental concentrations. 50nL was removed by using Hummingbird liquid handler or Echo acoustic system and transferred into a black microplate.
All experimental steps were completed at 20 ℃. In the experiment, 2.5. Mu.L of Ras mixture was added to all wells on the assay plate via a multi-point dispenser (Multidrop dispenser). After 2 minutes of pre-incubation, 2.5 μl of SOS mix was added to all wells to be tested, except for the edge wells, which were added to 2.5 μl of compound control solution. After 60 minutes incubation, the sample was passed through a Pheraster HTRF module (excitation light 337nm, emission light 1:620nm, emission light 2:665 nm).
And (3) calculating results:
computing and analyzing ICs using 4-parameter logic models 50 Values.
SOS-1 inhibitory Activity of Compounds:
the representative compounds in the examples were tested according to the above procedure and found to inhibit SOS-1 activity. The activity data of the compounds are shown in the following table.
The above data illustrate that the compounds of the present application exhibit good inhibition activity against SOS-1.

Claims (39)

1. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, having the structure:
wherein ,
represents a single bond or a double bond;
is a single bond, X is selected from NR A 、O、S；
R A Each occurrence is independently selected from hydrogen, C 1-6 An alkyl group;
is a double bond, Y is selected from O, S;
is a double bond, Z is selected from C and N, when Z is selected from N, R 2 Absence of;
is a single bond, R 1 Selected from the group consisting of-O-R B 、C 3-12 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl;
wherein when R is 1 Selected from the group consisting of-O-R B When R is B Selected from C 1-6 Alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl, wherein the C 1-6 Alkyl, C 3-10 Cycloalkyl and 3-10 membered heterocyclyl are optionally substituted with one or more R's, which may be the same or different b1 Substitution;
R b1 each occurrence is independently selected from-OR c1 、-C(O)R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、C 1-6 An alkyl group;
R c1 each occurrence is independently selected from hydrogen, C 1-6 Alkyl, C 3-10 Cycloalkyl;
alternatively, when R 1 Selected from C 3-12 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl, said C 3-12 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different a2 Substitution;
R a2 each occurrence is independently selected from-OR c2 、-C(O)R c2 、-C(O)OR c2 、-C 0-4 Alkyl C (O) NR c2 R c2 、-OC(O)R c2 Oxo, C 1-6 Alkyl, wherein the C 1-6 Alkyl groups optionally being substituted by one or moreMultiple R's, identical or different c2 Substitution;
R c2 each occurrence is independently selected from hydrogen, OH, C 1-6 An alkyl group;
R 2 selected from hydrogen, C 1-6 Alkyl, -O-C 1-4 Alkyl and halogen;
R 3 selected from hydrogen, C 1-4 alkyl-O-C 1-4 Alkyl and halogen;
ring A is selected from C 6-10 Aryl, 5-12 membered heteroaryl;
R 4 each occurrence is independently selected from hydrogen, -NH 2 、C 1-4 Alkyl, halogen, C 1-4 Haloalkyl, -O-C 1-4 Alkyl, -O-C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5-10 membered heteroaryl, 3-6 membered heterocyclyl, wherein said C 3-6 Cycloalkyl, C 6-10 Aryl, 5-to 10-membered heteroaryl and 3-to 6-membered heterocyclyl groups optionally being substituted by one or more identical or different groups selected from hydroxy, -C 1-4 alkyl-NH 2 、-C 1-4 alkyl-NH-C 1-4 Alkyl, -C 1-4 alkyl-N- (C) 1-4 Alkyl) (C) 1-4 Alkyl) is substituted with a group; wherein w=0, 1,2,3,4;
wherein the carbocyclyl is a non-aromatic cyclic hydrocarbyl group;
wherein the heterocyclic group is of a non-aromatic structure, hetero atoms in the heterocyclic group are selected from N, O or S, and the number of the hetero atoms is 1-4; and
wherein the heteroatoms in the heteroaryl group are selected from N, O or S, the number of heteroatoms being 1,2 or 3.
2. The compound according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,is a single bond, and R 1 is-O-R B ；
wherein RB Selected from C 1-4 Alkyl, C 4-6 Cycloalkyl and 4-6 membered heterocyclyl, provided thatThe C is 1-4 Alkyl, C 4-6 Cycloalkyl and 4-6 membered heterocyclyl are optionally substituted with one or more R's, which may be the same or different b1 And (3) substitution.
3. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, whereinIs a single bond, and R 1 is-O-R B ；
R B Selected from n-propyl, isopropyl, n-butyl, isobutyl, optionally substituted with one or more R b1 Substituted methyl, optionally substituted with one or more R b1 Substituted ethyl, optionally substituted with one or more R b1 Substituted C 5-6 Cycloalkyl, optionally substituted with one or more R b1 Substituted 5-6 membered heterocyclyl.
4. The compound according to claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R b1 Each occurrence is independently selected from-OR c1 、-C(O)OR c1 、C 1-6 An alkyl group.
5. The compound according to any one of claims 1 to 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R c1 Each occurrence is independently selected from hydrogen, C 1-6 An alkyl group.
6. The compound according to any one of claims 1 to 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: r is R b1 Each occurrence is independently selected from-OR c1 、-C(O)OR c1 、C 1-4 An alkyl group.
7. The compound according to any one of claims 1 to 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: r is R c1 Each occurrence is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl,Cyclopropyl, n-butyl, isobutyl, cyclobutyl.
8. The compound according to any one of claims 1 to 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: r is R c1 Each occurrence is independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclobutyl.
9. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:is a single bond, and R 1 Selected from C 3-10 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl, wherein said C 3-10 Carbocyclyl, C 6-10 Aryl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different a2 And (3) substitution.
10. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:is a single bond, and R 1 Selected from C 6-10 Aryl and 3-12 membered heterocyclyl, wherein said C 6-10 Aryl and 3-12 membered heterocyclyl are optionally substituted with one or more R's, which may be the same or different a2 And (3) substitution.
11. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: Is a single bond, and R 1 Selected from C 4-9 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclyl and 5-10 membered heteroaryl, said C 4-9 Cycloalkyl, C 6-10 Aryl, 4-10 membered heterocyclyl and 5-10 membered heteroaryl are optionally substituted with one or more R's, which may be the same or different a2 And (3) substitution.
12. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:is a single bond, and R 1 Selected from C 6-10 Aryl and 4-10 membered heterocyclyl, said C 6-10 Aryl and 4-10 membered heterocyclyl are optionally substituted with one or more R's, which may be the same or different a2 And (3) substitution.
13. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: r is R 1 Is selected from C 4 Monocycloalkyl, C 5 Monocycloalkyl, C 6 Monocycloalkyl, C 7 Monocycloalkyl, 3-membered/4-membered spirocycloalkyl, 4-membered/3-membered spirocycloalkyl, 4-membered/4-membered spirocycloalkyl, 4-membered/5-membered spirocycloalkyl, 5-membered/4-membered spirocycloalkyl, 5-membered/5-membered spirocycloalkyl, 4-membered/6-membered spirocycloalkyl, 6-membered/4-membered spirocycloalkyl, 3-membered/4-membered fused ring alkyl, 4-membered/3-membered fused ring alkyl, 4-membered/4-membered fused ring alkyl, 4-membered/5-membered fused ring alkyl, 5-membered/5-membered fused ring alkyl, 4-membered/6-membered fused ring alkyl, 6-membered/4-membered fused ring alkyl, 4-membered monocycloheterocyclyl, 5-membered monocycloheterocyclyl, 6-membered monocycloheterocyclyl 7 membered mono-, 3-and 4-membered spiroheterocyclyl, 4-and 5-membered spiroheterocyclyl, 5-and 5-membered spiroheterocyclyl, 4-and 6-membered spiroheterocyclyl, 6-and 4-membered spiroheterocyclyl, 3-and 4-membered fused heterocyclyl, 4-and 3-membered fused heterocyclyl, 4-and 4-membered fused heterocyclyl, 4-and 5-membered fused heterocyclyl, 5-and 5-membered fused heterocyclyl, 4-and 6-fused heterocyclyl, 6-and 4-fused heterocyclyl, 5-and 6-fused heterocyclyl, C 6 Aryl, 5 membered heteroaryl, 6 membered heteroaryl groups, optionally substituted with one or more R's, which may be the same or different a2 And (3) substitution.
14. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: r is R 1 Is selected from the group consisting of 4-membered mono-heterocyclic group, 5-membered mono-heterocyclic group, 6-membered mono-heterocyclic group, 7-membered mono-heterocyclic group, 3-membered/4-membered spiro-heterocyclic group, 4-membered/3-membered spiro-heterocyclic group, 4-membered/4-membered spiro-heterocyclic group, 4-membered/5-membered spiro-heterocyclic group, 5-membered/4-membered spiro-heterocyclic group, 5-membered/5-membered spiro-heterocyclic group, 4-membered/6-membered spiro-heterocyclic group, 6-membered/4-membered spiro-heterocyclic group, 3-membered/4-membered fused heterocyclic group, 4-membered/3-membered fused heterocyclic group, 4-membered/4-membered fused heterocyclic group, 4-membered/5-membered fused heterocyclic group, 4-membered/6-membered fused heterocyclic group, 6-membered/4-membered fused heterocyclic group, 5-membered/6-fused heterocyclic group, C 6 Aryl, said groups optionally being substituted with one or more R, which may be the same or different a2 And (3) substitution.
15. The compound of any one of claims 1 and 9-14, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: r is R a2 Each occurrence is independently selected from C 1-6 Alkyl, -OR c2 、-C(O)R c2 、-C 0-4 alkyl-C (O) NR c2 R c2 Oxo, wherein the C 1-6 Alkyl optionally substituted with one or more R's, which may be the same or different c2 And (3) substitution.
16. The compound of any one of claims 1 and 9-14, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
R c2 each occurrence is independently selected from hydrogen, OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl.
17. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of
18. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein R 1 Selected from the group consisting of
19. A compound according to any one of claims 1 to 4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: r is R 2 Selected from hydrogen, C 1-4 Alkyl, -O-C 1-4 Alkyl and halogen.
20. A compound according to any one of claims 1 to 4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: r is R 2 Selected from hydrogen, C 1-6 Alkyl and-O-C 1-4 An alkyl group.
21. A compound according to any one of claims 1 to 4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: r is R 2 Selected from hydrogen and-O-C 1-4 An alkyl group.
22. A compound according to any one of claims 1 to 4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein: r is R 2 Selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, -O-CH 3 、-O-CH 2 CH 3 、-O-CH 2 CH 2 CH 3 、-O-CHCH 3 CH 3 、-O-CH 2 CHCH 3 CH 3 、-O-CH 2 CH 2 CH 2 CH 3 。
23. The compound according to any one of claims 1 to 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: r is R 3 Selected from hydrogen and C 1-4 An alkyl group.
24. The compound according to any one of claims 1 to 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: r is R 3 Selected from hydrogen, -F, -Cl, -Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl.
25. The compound according to any one of claims 1 to 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: ring A is selected from C 6-10 Aryl, 5-10 membered heteroaryl.
26. The compound according to any one of claims 1 to 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: ring A is selected from C 6-10 Aryl, 5-6 membered heteroaryl.
27. The compound according to any one of claims 1 to 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: ring a is phenyl or thienyl.
28. The compound according to any one of claims 1 to 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: r is R 4 Each occurrence is independently selected from hydrogen, -NH 2 、C 1-4 Alkyl, halogen, C 1-4 Haloalkyl, -O-C 1-4 Alkyl, -O-C 1-4 Haloalkyl, C 6-10 Aryl and 5-10 membered heteroaryl, wherein said C 6-10 Aryl and 5-to 10-membered heteroaryl optionally being one or more identical or different radicals selected from C 1-4 alkyl-NH 2 、C 1-4 alkyl-NH-C 1-4 Alkyl group、C 1-4 alkyl-N- (C) 1-4 Alkyl) (C) 1-4 Alkyl) is substituted with a group; w=0, 1,2,3,4.
29. The compound according to any one of claims 1 to 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: r is R 4 Each occurrence is independently selected from hydrogen, -NH 2 Halogen, C 1-4 Haloalkyl, C 6-10 Aryl group, wherein C 6-10 Aryl groups optionally being one or more of the same or different from C 1-4 alkyl-NH 2 、C 1-4 alkyl-NH-C 1-4 Alkyl, C 1-4 alkyl-N- (C) 1-4 Alkyl) (C) 1-4 Alkyl) is substituted with a group; w=0, 1,2,3,4.
30. The compound according to any one of claims 1 to 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: r is R 4 Each occurrence is independently selected from hydrogen, -NH 2 Methyl, ethyl, n-propyl, isopropyl, F, cl, br, CHF 2 、CF 3 、-O-CH 3 、-O-CF 3 、C 6 Aryl, 5 membered heteroaryl, 6 membered heteroaryl, said C 6 Aryl, 5 membered heteroaryl, 6 membered heteroaryl optionally substituted with one or more groups, the same or different, selected from C 1-4 alkyl-NH 2 、C 1-4 alkyl-NH-C 1-4 Alkyl, C 1-4 alkyl-N- (C) 1-4 Alkyl) (C) 1-4 Alkyl) is substituted with a group; where w=0, 1,2,3,4.
31. The compound according to any one of claims 1 to 4, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: r is R 4 Each occurrence is independently selected from the group consisting of-NH 2 、-CF 3 、-F、-CHF 2 、-CF 2 CH 3 、And w=0, 1,2 or 3.
32. The compound according to any one of claims 1 to 4, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structural unitSelected from->
33. A compound selected from the following, or stereoisomers or pharmaceutically acceptable salts thereof:
34. a pharmaceutical composition comprising a compound of any one of claims 1-33, or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
35. Use of a compound according to any one of claims 1 to 33, or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34, in the manufacture of a medicament for the treatment of a disease mediated by an SOS1 inhibitor.
36. The use of claim 35, wherein the disease mediated by SOS1 inhibitors is cancer or tumor.
37. Use of a compound according to any one of claims 1 to 33, or a stereoisomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 34, in the manufacture of a medicament for the treatment of a disease caused by a RAS mutation.
38. The use according to claim 37, wherein the disease caused by RAS mutation is selected from the group consisting of neurofibromatosis type 1 (NF 1), noonan SYNDROME (NS), capillary malformation-arteriovenous malformation SYNDROME (CM-AVM), costerol SYNDROME (CS), cardio-facial-skin SYNDROME (CFC), leggus SYNDROME (LEGIUS SYNDROME), and hereditary gum fibromatosis.
39. The use of claim 37, wherein the disease caused by RAS mutation is Noonan Syndrome (NSML) with multiple plaques.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018172250A1 (en) * 2017-03-21 2018-09-27 Bayer Pharma Aktiengesellschaft 2-methyl-quinazolines
WO2018215798A1 (en) * 2017-05-26 2018-11-29 Cancer Research Technology Limited 2-quinolone derived inhibitors of bcl6
CN110167928A (en) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 The quinazoline and derivative that Novel warp benzylamino as SOS1 inhibitor replaces
WO2019201848A1 (en) * 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-methyl-aza-quinazolines
CN111372932A (en) * 2017-12-21 2020-07-03 勃林格殷格翰国际有限公司 Novel benzylamino-substituted pyridopyrimidinones and derivatives as SOS1 inhibitors
WO2020239951A1 (en) * 2019-05-31 2020-12-03 Chiesi Farmaceutici S.P.A. Amino quinazoline derivatives as p2x3 inhibitors

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110167928A (en) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 The quinazoline and derivative that Novel warp benzylamino as SOS1 inhibitor replaces
WO2018172250A1 (en) * 2017-03-21 2018-09-27 Bayer Pharma Aktiengesellschaft 2-methyl-quinazolines
WO2018215798A1 (en) * 2017-05-26 2018-11-29 Cancer Research Technology Limited 2-quinolone derived inhibitors of bcl6
CN111372932A (en) * 2017-12-21 2020-07-03 勃林格殷格翰国际有限公司 Novel benzylamino-substituted pyridopyrimidinones and derivatives as SOS1 inhibitors
WO2019201848A1 (en) * 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-methyl-aza-quinazolines
WO2020239951A1 (en) * 2019-05-31 2020-12-03 Chiesi Farmaceutici S.P.A. Amino quinazoline derivatives as p2x3 inhibitors

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