CN115466258A - ATR inhibitors and uses thereof - Google Patents
ATR inhibitors and uses thereof Download PDFInfo
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- CN115466258A CN115466258A CN202210627789.8A CN202210627789A CN115466258A CN 115466258 A CN115466258 A CN 115466258A CN 202210627789 A CN202210627789 A CN 202210627789A CN 115466258 A CN115466258 A CN 115466258A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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Abstract
The application belongs to the field of pharmaceutical chemistry, and provides a novel compound with a structure shown in a specific formula I and application thereof in preparing medicines. Further, the application also provides application of the deuterated compound with the structure shown in the formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in preparing medicines for treating cancers. Compared with the existing ATR inhibitor, the compound provided by the application has certain advantages in the aspects of biological activity and pharmacy.
Description
Technical Field
The invention relates to a novel compound with ATR (attenuated total reflectance) inhibition effect and application thereof in preparation of medicaments.
Background
Ataxia telangiectasia mutant gene and Rad 3 The related kinase ATR (ataxia telangiectasia mutated and Rad3-related, ATR) is a member of the phosphatidylinositol 3-kinase related protein kinase (PIKK) family, which also includes ataxia telangiectasia mutated kinase (ATM), DNA-dependent protein kinase (DNA-PK), genital formation suppressor-1 (SMG-1), mammalian target of rapamycin (mTOR), and transformation/transcription related protein (TRAPP). ATR and ATM are key regulators of the cellular DNA Damage Response (DDR) pathway and are involved in maintaining genomic integrity in response to DNA damage. ATR is a key member of DDR response to impaired DNA replication and is critical for maintaining genomic stability and integrity, promoting cell survival. When intracellular DNA damage occurs, ATR is recruited to the site of DNA damage, and a variety of proteins are then involved in regulating ATR activation, which in turn regulates several important cellular processes. Many cancer cells lack key tumor suppressor genes, which may make cancer cells more dependent on the ATR pathway to regulate cellular DNA damage repair than normal cells to promote cell survival, making ATR a promising target for cancer therapy. Inhibition of ATR may enhance the efficacy of replication inhibitors. In addition ATR inhibition may have a killing effect on cells with high RS levels, such as cells expressing proto-oncogenes or lacking tumor suppressor factors. Inhibition of ATR activity in these cells will produce a lethal amount of RS, leading to cell death.
Some ATR inhibitors have been reported (WO 2015/084384, WO2017/180723, WO2016/061097, WO2014/140644, etc.), and all existing ATR inhibitors are on the market without corresponding drugs in the clinical trial process. There may therefore be a need to develop more potent ATR inhibitor drugs with fewer side effects.
Disclosure of Invention
The invention provides a compound shown as a formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
the A ring is selected from 3-10 membered carbocyclyl, 4-10 membered heterocycloalkyl, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; wherein carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four R A1 Substitution;
each R A1 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-OR A2 、-C 0～4 alkylene-OC (O) R A2 、-C 0～4 alkylene-SR A2 、-C 0～4 alkylene-S (O) 2 R A2 、-C 0～4 alkylene-S (O) R A2 、-C 0～4 alkylene-S (O) 2 NR A2 R A3 、-C 0～4 alkylene-S (O) NR A2 R A3 、-C 0～4 alkylene-C (O) R A2 、-C 0～4 alkylene-C (O) OR A2 、-C 0～4 alkylene-C (O) NR A2 R A3 、-C 0～4 alkylene-NR A2 R A3 、-C 0～4 alkylene-NR A2 C(O)R A3 、-C 0～4 alkylene-NR A2 S(O) 2 R A3 、-C 0～4 alkylene-NR A2 S(O)R A3 (ii) a Or, two independent R A1 Together with the linking atom form
R A2 、R A3 Each independently selected from hydrogen and-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 An alkynyl group;
b ring selected from
Wherein the ring selected from B may be further optionally substituted by one, two, three or four R B1 Substitution;
each R B1 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-OR B2 、-C 0～4 alkylene-OC (O) R B2 、-C 0～4 alkylene-C (O) R B2 、-C 0～4 alkylene-C (O) OR B2 、-C 0～4 alkylene-C (O) NR B2 R B3 、-C 0～4 alkylene-NR B2 R B3 、-C 0～4 alkylene-NR B2 C(O)R B3 ；
R B2 、R B3 Each independently selected from hydrogen and-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl;
R 1 selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 An alkyl group;
x is selected from N or CR 3 ；
And X is selected from N, R 1 And R 2 Together with the linking atom form
Wherein R is 1 And R 2 The ring formed with the atoms to which it is attached may further optionally be substituted by one, two, three or four R C1 Substitution;
and X is selected from CR 3 When R is 2 And R 3 Together with the linking atom form
Wherein R is 2 And R 3 The ring formed with the atoms to which it is attached may further optionally be substituted by one, two, three or four R C1 Substitution;
each R C1 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-OR C2 、-C 0～4 alkylene-OC (O) R C2 、-C 0～4 alkylene-SR C2 、-C 0～4 alkylene-S (O) 2 R C2 、-C 0～4 alkylene-S (O) R C2 、-C 0～4 alkylene-S (O) 2 NR C2 R C3 、-C 0～4 alkylene-S (O) NR C2 R C3 、-C 0～4 alkylene-S (O) (NH) R C2 、-C 0～4 alkylene-S (O) (NH) NR C2 R C3 、-C 0～4 alkylene-C (O) R C2 、-C 0～4 alkylene-C (O) OR C2 、-C 0～4 alkylene-C (O) NR C2 R C3 、-C 0～4 alkylene-NR C2 R C3 、-C 0～4 alkylene-NR C2 C(O)R C3 、-C 0～4 alkylene-NR C2 S(O) 2 R C3 、-C 0～4 alkylene-NR C2 S(O)R C3 、-C 0～4 alkylene-P (O) R C2 R C3 、-C 0～4 alkylene-P (O) (OR) C2 )R C3 、-C 0～4 alkylene-P (O) (OR) C2 )(OR C3 )、-C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle); wherein alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R C4 Substitution;
or, two independent R C1 Together with the linking atom form
5-8 membered carbocyclyl, 5-8 membered heterocycloalkyl, benzene ring, 5-6 membered aromatic heterocycle; wherein, the carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may be further optionally substituted with one, two, three or four independent R C4 Substitution
R C2 、R C3 Each independently selected from hydrogen and-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle);
each R C4 Each independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-OR C5 、-C 0～4 alkylene-OC (O) R C5 、-C 0～4 alkylene-SR C5 、-C 0～4 alkylene-S (O) 2 R C5 、-C 0～4 alkylene-S (O) R C5 、-C 0～4 alkylene-S (O) 2 NR C5 R C6 、-C 0～4 alkylene-S (O) NR C5 R C6 、-C 0～4 alkylene-S (O) (NH) R C5 、-C 0～4 alkylene-S (O) (NH) NR C5 R C6 、-C 0～4 alkylene-C (O) R C5 、-C 0～4 alkylene-C (O) OR C5 、-C 0～4 alkylene-C (O) NR C5 R C6 、-C 0～4 alkylene-NR C5 R C6 、-C 0～4 alkylene-NR C5 C(O)R C6 、-C 0～4 alkylene-NR C5 S(O) 2 R C6 、-C 0～4 alkylene-NR C5 S(O)R C6 、-C 0～4 alkylene-P (O) R C5 R C6 、-C 0～4 alkylene-P (O) (OR) C5 )R C6 、-C 0～4 alkylene-P (O) (OR) C5 )(OR C6 ) (ii) a Or, two independent R C4 Together with the linking atom form
R C5 、R C6 Each independently selected from hydrogen and-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle).
Further, the air conditioner is characterized in that,
the A ring is selected from the group consisting of a 3-membered carbocyclic group, a 4-membered carbocyclic group, a saturated or unsaturated 5-membered carbocyclic group, a saturated or unsaturated 6-membered carbocyclic group, a saturated or unsaturated 7-membered carbocyclic group, a saturated or unsaturated 8-membered carbocyclic group, a saturated or unsaturated 9-membered carbocyclic groupAnd 10-membered carbocyclyl, 4-membered heterocycloalkyl, saturated or unsaturated 5-membered heterocycloalkyl, saturated or unsaturated 6-membered heterocycloalkyl, saturated or unsaturated 7-membered heterocycloalkyl, saturated or unsaturated 8-membered heterocycloalkyl, saturated or unsaturated 9-membered heterocycloalkyl, saturated or unsaturated 10-membered heterocycloalkyl, 6-membered aromatic ring, 10-membered aromatic ring, 5-membered aromatic ring, 6-membered aromatic ring, 7-membered aromatic ring, 8-membered aromatic ring, 9-membered aromatic ring, 10-membered aromatic ring; wherein carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four R A1 And (4) substitution.
Further, in the case of a liquid crystal display device,
ring A is selected from 4-membered monocyclic heterocycloalkyl, 5-membered monocyclic heterocycloalkyl, 6-membered fused heterocycloalkyl, 7-membered fused heterocycloalkyl, 8-membered fused heterocycloalkyl, 6-membered bridged heterocycloalkyl, 7-membered bridged heterocycloalkyl, 8-membered bridged heterocycloalkyl, 9-membered bridged heterocycloalkyl, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle; wherein the heterocycloalkyl, heteroaromatic ring may be further optionally substituted by one, two, three or four R A1 And (4) substitution.
In a still further particular embodiment, the first and second,
a ring selected from
Wherein the ring selected from A is further optionally substituted by one, two, three or four R A1 Substitution;
each R A1 Each independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -OR A2 、-SR A2 、-NR A2 R A3 (ii) a Or, two independent R A1 Together with the linking atom form
R A2 、R A3 Each independently selected from hydrogen, -C 1～6 An alkyl group.
Still more particularly, it is contemplated that the first,
a ring is selected from
Further, the air conditioner is provided with a fan,
ring B is selected from
Wherein the ring selected from B may be further optionally substituted by one, two, three or four R B1 Substitution;
each R B1 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, halogen substituted-C 1～6 Alkyl, -OR B2 、-C(O)R B2 、-C(O)NR B2 R B3 、-NR B2 R B3 、-NR B2 C(O)R B3 ；
R B2 、R B3 Each independently selected from hydrogen and-C 1～6 An alkyl group.
Further, in the case of a liquid crystal display device,
b ring selected from
In some embodiments of the present invention, the first and second electrodes are,
x is selected from N;
R 1 and R 2 Together with the linking atom form
Wherein R is 1 And R 2 The ring formed with the atoms to which it is attached may further optionally be substituted by one, two, three or four R C1 And (4) substitution.
In some preferred embodiments of the present invention,
a ring is selected from
Wherein the ring selected from A is further optionally substituted by one, two, three or four R A1 Substitution;
each R A1 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -OR A2 、-SR A2 、-NR A2 R A3 (ii) a Or, two independent R A1 Together with the linking atom form
R A2 、R A3 Each independently selected from hydrogen, -C 1～6 An alkyl group;
b ring selected from
Wherein the ring selected from B may be further optionally substituted by one, two, three or four R B1 Substitution;
each R B1 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, halogen substituted-C 1～6 Alkyl, -OR B2 、-C(O)R B2 、-C(O)NR B2 R B3 、-NR B2 R B3 、-NR B2 C(O)R B3 ；
R B2 、R B3 Each independently selected from hydrogen, -C 1～6 An alkyl group;
x is selected from N;
R 1 and R 2 Together with the linking atom form
Wherein R is 1 And R 2 The ring formed with the attached atoms may be further optionally substituted by one, two, three or four R C1 Substitution;
each R C1 Are respectively independentSelected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-OR C2 、-C 0～4 alkylene-OC (O) R C2 、-C 0～4 alkylene-SR C2 、-C 0～4 alkylene-S (O) 2 R C2 、-C 0～4 alkylene-S (O) R C2 、-C 0～4 alkylene-S (O) 2 NR C2 R C3 、-C 0～4 alkylene-S (O) NR C2 R C3 、-C 0～4 alkylene-S (O) (NH) R C2 、-C 0～4 alkylene-S (O) (NH) NR C2 R C3 、-C 0～4 alkylene-C (O) R C2 、-C 0～4 alkylene-C (O) OR C2 、-C 0～4 alkylene-C (O) NR C2 R C3 、-C 0～4 alkylene-NR C2 R C3 、-C 0～4 alkylene-NR C2 C(O)R C3 、-C 0～4 alkylene-NR C2 S(O) 2 R C3 、-C 0～4 alkylene-NR C2 S(O)R C3 、-C 0～4 alkylene-P (O) R C2 R C3 、-C 0～4 alkylene-P (O) (OR) C2 )R C3 、-C 0～4 alkylene-P (O) (OR) C2 )(OR C3 )、-C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle); wherein alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R C4 Substitution;
R C2 、R C3 each independently selected from hydrogen and-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle);
each R C4 Each independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl; or, two independent R C4 Together with the linking atom form
In some more preferred embodiments of the present invention,
a ring is selected from
B ring selected from
X is selected from N;
R 1 and R 2 Together with the linking atom form
Wherein R is 1 And R 2 The ring formed with the attached atoms may be further optionally substituted by one, two, three or four R C1 Substitution;
each R C1 Each independently selected from hydrogen, halogen, methyl, trifluoromethyl, cyclopropyl,
Further, the compounds of formula I are as follows:
R C11 is selected from-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-S (O) 2 R C2 、-C 0～4 alkylene-S (O) R C2 、-C 0～4 alkylene-S (O) 2 NR C2 R C3 、-C 0～4 alkylene-S (O) NR C2 R C3 、-C 0～4 alkylene-S (O) (NH) R C2 、-C 0～4 alkylene-S (O) (NH) NR C2 R C3 、-C 0～4 alkylene-C (O) R C2 、-C 0～4 alkylene-C (O) OR C2 、-C 0～4 alkylene-C (O) NR C2 R C3 、-C 0～4 alkylene-P (O) R C2 R C3 、-C 0～4 alkylene-P (O) (OR) C2 )R C3 、-C 0～4 alkylene-P (O) (OR) C2 )(OR C3 )、-C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle); wherein alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R C4 Substitution;
each R C12 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-OR C2 、-C 0～4 alkylene-SR C2 、-C 0～4 alkylene-NR C2 R C3 、-C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle); wherein the alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R C4 Substitution;
R C2 、R C3 each independently selected from hydrogen and-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle);
each R C4 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 An alkynyl group; or, two independent R C4 Together with the linking atom form
Further, in the case of a liquid crystal display device,
R C11 is selected from
Each R C12 Each independently selected from hydrogen, halogen, methylTrifluoromethyl, cyclopropyl,
In some preferred embodiments of the invention, the compounds of formula I are as follows:
a ring selected from
Ring B is selected from
R C11 Is selected from
Each R C12 Each independently selected from hydrogen, halogen, methyl, trifluoromethyl, cyclopropyl,
In some embodiments of the present invention, the first and second electrodes are,
x is selected from CR 3 ；
R 2 And R 3 Together with the linking atom form
R of which 2 And R 3 The ring formed with the atoms to which it is attached may further optionally be substituted by one, two, three or four R C1 And (4) substitution.
In some preferred embodiments of the present invention,
a ring is selected from
Wherein the ring selected from A is further optionally substituted by one, two, three or four R A1 Substitution;
each R A1 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -OR A2 、-SR A2 、-NR A2 R A3 (ii) a Or, two independent R A1 Together with the linking atom form
R A2 、R A3 Each independently selected from hydrogen, -C 1～6 An alkyl group;
ring B is selected from
Wherein the ring selected from B may be further optionally substituted by one, two, three or four R B1 Substitution;
each R B1 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, halogen substituted-C 1～6 Alkyl, -OR B2 、-C(O)R B2 、-C(O)NR B2 R B3 、-NR B2 R B3 、-NR B2 C(O)R B3 ；
R B2 、R B3 Each independently selected from hydrogen and-C 1～6 An alkyl group;
x is selected from CR 3 ；
R 2 And R 3 Together with the linking atom form
Wherein R is 2 And R 3 The ring formed with the attached atoms may be further optionally substituted by one, two, three or four R C1 Substitution;
each R C1 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-OR C2 、-C 0～4 alkylene-OC (O) R C2 、-C 0～4 alkylene-SR C2 、-C 0～4 alkylene-S (O) 2 R C2 、-C 0～4 alkylene-S (O) R C2 、-C 0～4 alkylene-S (O) 2 NR C2 R C3 、-C 0～4 alkylene-S (O) NR C2 R C3 、-C 0～4 alkylene-S (O) (NH) R C2 、-C 0～4 alkylene-S (O) (NH) NR C2 R C3 、-C 0～4 alkylene-C (O) R C2 、-C 0～4 alkylene-C (O) OR C2 、-C 0～4 alkylene-C (O) NR C2 R C3 、-C 0～4 alkylene-NR C2 R C3 、-C 0～4 alkylene-NR C2 C(O)R C3 、-C 0～4 alkylene-NR C2 S(O) 2 R C3 、-C 0～4 alkylene-NR C2 S(O)R C3 、-C 0～4 alkylene-P (O) R C2 R C3 、-C 0～4 alkylene-P (O) (OR) C2 )R C3 、-C 0～4 alkylene-P (O) (OR) C2 )(OR C3 )、-C 0～4 Alkylene- (3-to 10-membered carbocyclic group),-C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle); wherein alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R C4 Substitution;
R C2 、R C3 each independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle);
each R C4 Each independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl; or, two independent R C4 Together with the linking atom form
In some more preferred embodiments of the present invention,
a ring is selected from
Ring B is selected from
X is selected from CR 3 ；
R 2 And R 3 Together with the linking atom form
Wherein R is 2 And R 3 The ring formed with the atoms to which it is attached may further optionally be substituted by one, two, three or four R C1 Substitution;
each R C1 Each independently selected from hydrogen, halogen, methyl, trifluoromethyl, cyclopropyl,
Further, the compounds of formula I are as follows:
R C11 is selected from-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-S (O) 2 R C2 、-C 0～4 alkylene-S (O) R C2 、-C 0～4 alkylene-S (O) 2 NR C2 R C3 、-C 0～4 alkylene-S (O) NR C2 R C3 、-C 0～4 alkylene-S (O) (NH) R C2 、-C 0～4 alkylene-S (O) (NH) NR C2 R C3 、-C 0～4 alkylene-C (O) R C2 、-C 0～4 alkylene-C (O) OR C2 、-C 0～4 alkylene-C (O) NR C2 R C3 、-C 0～4 alkylene-P (O) R C2 R C3 、-C 0～4 alkylene-P (O) (OR) C2 )R C3 、-C 0～4 alkylene-P (O) (OR) C2 )(OR C3 )、-C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle); wherein the alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R C4 Substitution;
each R C12 Each independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-OR C2 、-C 0～4 alkylene-SR C2 、-C 0～4 alkylene-NR C2 R C3 、-C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle); wherein alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R C4 Substitution;
R C2 、R C3 each independently selected from hydrogen and-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle);
each R C4 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 An alkynyl group; or, two independent R C4 Is connected withTogether form
Further, in the present invention,
R C11 is selected from
Each R C12 Each independently selected from hydrogen, halogen, methyl, trifluoromethyl, cyclopropyl,
In some preferred embodiments of the invention, the compounds of formula I are as follows:
a ring is selected from
Ring B is selected from
R C11 Is selected from
Each R C12 Each independently selected from hydrogen, halogen, methyl, trifluoromethyl, cyclopropyl,
In some embodiments of the invention, preferred compounds represented by formula I include, but are not limited to, compounds:
the invention also provides the use of any one of the compounds, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for an ATR inhibitor.
The invention also provides the use of any one of the above compounds, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of cancer.
The invention also provides a pharmaceutical composition, which comprises a preparation prepared from any one of the compounds, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition further comprises a pharmaceutically acceptable carrier, an auxiliary material and a vector.
The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, columbus, OH) naming system.
Definitions of terms used in relation to the present invention: unless otherwise indicated, the initial definitions provided for by a group or term herein apply to that group or term throughout the specification; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced with a different atom or group; or the lone pair of electrons of the atoms in the molecule is replaced by another atom or group, e.g. the lone pair on the S atom can be replaced by an O atom
"can be further substituted" means that "substitution" can, but need not, occur, and that the description includes instances where it does or does not occur.
The minimum and maximum values of the content of carbon atoms in hydrocarbon groups are indicated by a prefix, e.g. prefix C a～b Alkyl means any alkyl group containing "a" to "b" carbon atoms. Thus, for example, C 1～6 Alkyl refers to an alkyl group containing 1 to 6 carbon atoms.
"alkyl" refers to a saturated hydrocarbon chain having the indicated number of member atoms. The alkyl group may be linear or branched. Representative branched alkyl groups have one, two, or three branches. An alkyl group may be optionally substituted by one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group may also be part of another group, such as-O (C) 1～6 Alkyl groups).
"alkylene" refers to a divalent saturated aliphatic hydrocarbon radical having the indicated number of member atoms. C a ～ b Alkylene refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbyl groups. For example, the term "propylene" can be exemplified by the following structure:
likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures:
of the invention-C 0 ～ 4 The alkylene group may be C 0 Alkylene radical, C 1 Alkylene (e.g. -CH) 2 -)、C 2 Alkylene (e.g. -CH) 2 CH 2 -etc.), C 3 Alkylene or C 4 An alkylene group; c 0 Alkylene means that the radicals therein are absent and are linked in the form of a bond, e.g. A-C 0 alkylene-B refers to A-B, i.e., the A group is directly chemically linked to the B group.
"carbocyclyl" as used herein refers to a saturated or non-aromatic partially saturated cyclic group having a single ring or multiple rings (fused, bridged, spiro) having multiple carbon atoms and no ring heteroatoms. The term "carbocyclyl" includes cycloalkenyl groups such as cyclohexenyl. Examples of monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of carbocyclyl groups of fused carbocyclyl systems include bicyclohexyl, bicyclopentyl, bicyclooctyl and the like, two such bicycloalkyl polycyclic structures being exemplified and named below:
dicyclohexyl and
a dicyclohexyl group. Carbon of bridged carbocyclic ring systemsExamples of cyclic groups include
Adamantyl, and the like. Examples of carbocyclyl groups of spiro-carbocyclyl systems include
And so on. The term "carbocyclic group" also includes the case where the aromatic ring is fused to a non-aromatic ring to form a partially saturated cyclic group, the attachment site of which may be at a non-aromatic or aromatic carbon atom, examples including 1,2,3, 4-tetrahydronaphthalen-5-yl, 5,6,7, 8-tetrahydronaphthalen-5-yl.
The unsaturated in the invention means that a group or a molecule contains carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds and the like.
"alkenyl" means having at least 1 site of vinyl unsaturation (>C＝C<) A straight or branched hydrocarbon group of (1). E.g. C a-b Alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1, 3-butadienyl, and the like.
"alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also meant to include those hydrocarbyl groups having one triple bond and one double bond. For example, C 2-6 Alkynyl is intended to include ethynyl, propynyl and the like.
"heterocycloalkyl" as used herein refers to a saturated or non-aromatic partially saturated ring with a single ring or multiple rings (fused, bridged, spiro) containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom and the like. Generally denotes a monovalent saturated or partially unsaturated monocyclic or polycyclic ring system of a plurality of ring atoms, comprising 1,2 or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heterocycloalkyl radicals of monoheterocycloalkyl systems are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuryl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrakis-heterocycloalkylHydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1-dioxo-thiomorpholin-4-yl, azepinyl, diazepanyl, homopiperazinyl, oxazepinyl, and the like. Examples of heterocycloalkyl groups of fused heterocycloalkyl systems include 8-aza-bicyclo [3.2.1]Octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, 9-aza-bicyclo [3.3.1]Nonyl, and the like. Examples of heterocycloalkyl groups bridging the heterocycloalkyl system include
And so on. Examples of heterocycloalkyl groups of spiroheterocycloalkyl systems include
And the like. Examples of partially saturated heterocycloalkyl groups are dihydrofuranyl, imidazolinyl, tetrahydro-pyridinyl, dihydropyranyl and the like. The term "heterocycloalkyl" also includes the case where an aromatic ring containing at least one heteroatom is fused with a non-aromatic ring to form a partially saturated cyclic group, the attachment site of which may be at a non-aromatic carbon atom, an aromatic carbon atom or a heteroatom, examples including
The "aromatic ring" as used herein refers to an aromatic hydrocarbon group having a plurality of carbon atoms. The aryl group is typically a monocyclic, bicyclic or tricyclic aryl group having multiple carbon atoms. Further, the term "aryl" as used herein refers to an aromatic substituent that may be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl.
The term "aromatic heterocyclic ring" as used herein refers to an aromatic unsaturated ring containing at least one heteroatom; wherein the hetero atom means a nitrogen atom, an oxygen atom, a sulfur atom, etc. Aromatic monocyclic or bicyclic hydrocarbons which generally contain a plurality of ring atoms, wherein one or more ring atoms are heteroatoms selected from O, N, S. Preferably there are one to three heteroatoms. Heterocyclic aryl represents, for example: pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl.
The "halogen" as used herein means fluorine, chlorine, bromine or iodine.
"halogen-substituted alkyl" as used herein means an alkyl group in which one or more hydrogen atoms are substituted with halogen; e.g. halogen-substituted C 1～4 Alkyl refers to an alkyl group containing 1 to 4 carbon atoms in which a hydrogen atom is substituted with one or more halogen atoms; also for example, monofluoromethyl, difluoromethyl, trifluoromethyl.
As used herein, "-OR", "-NRR", etc., means that the R group is attached to the oxygen atom OR the nitrogen atom by a single bond.
"-C (O) R", "-S (O) described in the present invention 2 The oxygen atom in R' or the like is bonded to a carbon atom or a sulfur atom with a double bond.
"-C (O) R", "-S (O) described in the present invention 2 R' and the like are those in which the oxygen atom is bonded to a carbon atom or a sulfur atom by a double bond and the R group is bonded to an oxygen atom or a sulfur atom by a single bond; as another example, "-S (O) (NH) R" means that the oxygen and nitrogen atoms are double bonded to the sulfur atom and the R group is single bonded to the sulfur atom.
Described in the invention
Means that the oxygen atom and the sulfur atom are bonded to the substitution position by a double bond.
In the description of the radicals of the invention "- - - - - -",
are used to describe the position of substitution of the group. For example, in
Means that the tetrahydropyrrole ring is fused to the other rings in the structure via the "- - -" position.
The term "deuterated compound" as used herein means a molecule or group wherein 1 or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.
The term "pharmaceutically acceptable" means that the carrier, cargo, diluent, excipient, and/or salt formed is generally chemically or physically compatible with the other ingredients that make up the pharmaceutical dosage form, and is physiologically compatible with the recipient.
The terms "salt" and "pharmaceutically acceptable salt" refer to acid and/or base salts of the above compounds or stereoisomers thereof, with inorganic and/or organic acids and bases, as well as zwitterionic salts (inner salts), and also quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound or a stereoisomer thereof may be obtained by appropriately (e.g., equivalently) mixing the above compound or a stereoisomer thereof with a predetermined amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered by evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization.
In certain embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition for modulating cellular function or treating a disease. If a group of compounds is used, the compounds may be administered to the subject simultaneously, separately or sequentially.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The structure of the compounds was determined by Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS). NMR shifts (. Delta.) are given in units of 10-6 (ppm). NMR was measured using (Bruker AvanceIII 400 and Bruker Avance 300) nuclear magnetic instrument in deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), internal standard Tetramethylsilane (TMS).
LC-MS was measured using Shimadzu LC-MS 2020 (ESI). HPLC was performed using Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A). MPLC (Medium pressure preparative chromatography) Gilson GX-281 reverse phase preparative chromatography was used. The thin layer chromatography silica gel plate is a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
Known starting materials for the present invention can be synthesized by or according to methods known in the art, or can be purchased from companies such as Enduragi chemistry, chengdulong chemistry, shaoshi chemistry technology, and Bailingwei technology.
In the examples, the reaction was carried out under a nitrogen atmosphere without specific mention. In the examples, the solution means an aqueous solution without specific indication. In the examples, the reaction temperature is room temperature, unless otherwise specified. In the examples, M is mole per liter, unless otherwise specified.
Example 1
First step of
Compound 1a (588mg, 3.1mmol) was dissolved in a borane dimethylsulfide tetrahydrofuran (25.0ml, 2.0mol/L) solution, and the reaction was stirred at 75 ℃ for 4 hours. After the reaction was complete, the reaction was cooled to 0 ℃ and quenched by the addition of water (1.8g, 100.6 mmol). The mixture was then brought to 80 ℃ and stirred for 4 hours. After the end of the quenching, the reaction mixture is quenched,water (70.0 ml) was added for dilution, and ethyl acetate (70.0 ml. X.3) was extracted, concentrated under reduced pressure, and purified by column chromatography to obtain Compound 1b (234.0 mg,1.2mmol, yield: 38.7%). MS-ESI calculated value [ M + H%] + 189.0, found 189.1.
Second step of
Compound 1b (234.0 mg,1.2 mmol) was dissolved in methylene chloride (15.0 ml), N-diisopropylethylamine (320.0 mg,2.5 mmol) was added at 20 ℃ and the reaction was stirred at that temperature for 10 minutes. Methanesulfonyl chloride (170.2mg, 1.5 mmol) was then slowly added dropwise to the resulting mixture at 0 deg.C, and the mixture was stirred at 20 deg.C for 10 minutes. Water (10 mL) was added to the above reaction solution, and extracted with dichloromethane (10 mL. Multidot.3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent, to give Compound 1c (117.1mg, 0.4mmol, yield: 35%).
MS-ESI calculated value [ M + H%] + 267.0, found 266.9.
The third step
Compound 1c (117.1mg, 0.4 mmol), 1-Boc-indole-4-boronic acid pinacol ester (135.4mg, 0.4 mmol), bis (triphenylphosphine) palladium (II) dichloride (30.8mg, 0.04mmol), and sodium carbonate (93.0mg, 0.8mmol) were dissolved in a mixed solvent of dioxane (6.0 ml) and water (3.0 ml) and reacted at 120 ℃ for 2.0 hours under nitrogen protection. After the reaction was completed, the reaction mixture was diluted with water (50.0 ml), and extracted with ethyl acetate (50.0 ml. Multidot.3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, and purified by column chromatography to give Compound 1d (68.0mg, 0.4mmol, yield: 34%).
MS-ESI calculated value [ M + H%] + 448.1, found 448.3.
The fourth step
Compound 1d (68.0mg, 0.1mmol), (R) -3-methylmorpholine (30.7mg, 0.3mmol), (SP-4-1) - [1, 3-bis [2, 6-bis (1-ethylpropyl) phenyl ] -4, 5-dichloro-1, 3-dihydro-2H-imidazol-2-ylidene ] dichloro (3-chloropyridine-KN) palladium (24.3mg, 0.03mmol), cesium carbonate (98.9mg, 0.03mmol) were dissolved in toluene (10.0 ml) and reacted at 120 ℃ for 16 hours under nitrogen. After the reaction was completed, the reaction mixture was diluted with water (30.0 ml) and extracted with ethyl acetate (30.0 ml. Multidot.3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, and purified by column chromatography to give compound 1e (9.3mg, 0.01mmol, yield: 11.2%).
MS-ESI calculated value [ M + H%] + 513.2, found 513.3.
The fifth step
Compound 1e (9.3 mg, 0.01mol) was dissolved in a solution of dichloromethane (10.0 ml), and trifluoroacetic acid (2.0 ml) was slowly added at 0 ℃ and the reaction was continued for 2.0 hours with warming to 20 ℃ on completion. After the reaction is finished, the solvent and the unreacted trifluoroacetic acid are removed by reduced pressure distillation to obtain a crude product. The crude product was separated by HPLC to give compound 1 (2.0 mg,0.05mmol, yield: 25.4%), HPLC purity: 95 percent.
MS-ESI calculated value [ M + H%] + 413.2, found 413.2.
1H NMR(400MHz,DMSO-d 6 )δ:11.26(s,1H),7.51–7.42(m,3H),7.36(s,1H),7.18(t,J＝7.7Hz,1H),6.82(s,1H),4.18–4.10(m,1H),4.06–3.96(m,2H),3.90(d,J＝11.1Hz,1H),3.76–
3.70(m,1H),3.67–3.56(m,3H),3.21(t,J＝8.4Hz,3H),3.12(s,3H),1.17(d,J＝6.6Hz,3H).
Example 2
Compound 2a (237.5mg, 1.2mmol) was dissolved in acetonitrile (7.0 ml), and N, N-diisopropylethylamine (306.9mg, 2.4mmol), (R) -3-methylmorpholine (126.1mg, 1.3mmol) was added in this order at 20 ℃. The reaction mixture was stirred at 20 ℃ for 2 hours. After the reaction is finished, the solvent is removed by decompression and concentration to obtain a crude product. The obtained crude product was purified by column chromatography to obtain Compound 2b (314.3mg, 0.6mmol, yield: 49.5%).
MS-ESI calculated value [ M + H%] + 265.1, found 265.2.
Second step of
Compound 2b (114.0mg, 0.4mmol) and platinum dioxide (21.5mg, 0.09mmol) were dissolved in tetrahydrofuran (4.0 ml). After three times of replacement with hydrogen, the reaction was carried out at 20 ℃ for 16 hours. After the reaction is finished, the solvent is removed by decompression concentration to obtain a crude product. The obtained crude product was purified by column chromatography to give compound 2c (110.0 mg, yield: 91.2%).
MS-ESI calculated value [ M + H%] + 269.1, found 269.3.
The third step
Compound 2c (122.0 mg,0.4 mmol) was dissolved in dichloromethane (3.0 ml). Then, N-diisopropylethylamine (117.3mg, 0.9mmol) was added to the above reaction solution, and stirred at 20 ℃ for 10 minutes. Then, the above reaction solution was cooled to 0 ℃ and methanesulfonyl chloride (62.4 mg,0.5 mmol) was slowly added thereto. The resulting reaction mixture was warmed to room temperature and reacted for 10 minutes. After completion of the reaction, water (5 mL) was added to quench the reaction, ethyl acetate (5.0mL. Multidot.3) was extracted, the obtained organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the obtained filtrate was subjected to distillation under reduced pressure to remove compound 2d (141.7mg, 0.4mmol, yield: 90%) as a solvent.
MS-ESI calculated value [ M + H%] + 347.1, found 347.2.
The fourth step
Compound 2d (184.0mg, 0.5mmol), 4-indolboronic acid pinacol ester (129.0mg, 0.5mmol), bis (triphenylphosphine) palladium (II) dichloride (37.2mg, 0.05mmol) and sodium carbonate (112.5mg, 1.1mmol) were added to a mixed solution of dioxane (4.0 ml) and water (2.0 ml), and reacted at 100 ℃ for 2.5 hours under nitrogen protection. After completion of the reaction, water (50.0 ml) was added to dilute the reaction mixture, ethyl acetate (50.0 ml. Multidot.3) was extracted, the resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was distilled under reduced pressure to remove the crude compound as a solvent. The crude product was separated by column chromatography and HPLC to give Compound 2 (226.8 mg, yield: 41.9%), HPLC purity: 96.1 percent.
MS-ESI calculated value [ M + H%] + 428.2, found 428.2.
1H NMR(400MHz,DMSO-d6)δ:11.30(s,1H),8.04(d,J＝7.5Hz,1H),7.56(d,J＝8.0Hz,1H),7.47(t,J＝2.8Hz,1H),7.35-7.30(m,1H),7.21(t,J＝7.8Hz,1H),4.52–4.37(m,3H),3.93(d,J＝11.0Hz,1H),3.75(dd,J＝11.3,3.0Hz,2H),3.64(dd,J＝12.5,10.1Hz,2H),3.52(dd,J＝12.3,7.0Hz,2H),3.34(dt,J＝12.0,5.6Hz,1H),3.06(s,3H),2.86(s,2H),1.29(d,J＝6.6Hz,3H).
Example 3
First step of
Compound 3a (380.0 mg,1.3 mmol) was placed in a solution of hydrogen chloride in 1, 4-dioxane (2M, 5.0 ml) at 0 ℃. The reaction was warmed to 20 ℃ and allowed to react at this temperature for 1 hour. After completion of the reaction, the solvent was removed by concentration under reduced pressure to obtain Compound 3b (235.6 mg,1.2mmol, yield: 95.8%).
MS-ESI calculated value [ M + H%] + 190.0, found 190.1.
Second step of
Compound 3b (216.0mg, 1.1mmol) was dissolved in methylene chloride (5.0 ml), and N, N-diisopropylethylamine (323.2mg, 2.5mmol) was slowly added thereto at 20 ℃ to complete the reaction for 10 minutes. Then, the reaction solution was cooled to 0 ℃ and methanesulfonyl chloride (156.3mg, 1.4 mmol) was added slowly. The reaction mixture was stirred at 20 ℃ for 10 minutes. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain Compound 3c (304.8mg, 1.1mmol, yield: 100%).
MS-ESI calculated value [ M + H%] + 268.0, found 268.0.
The third step
Compound 3c (240.0mg, 0.8mmol) was dissolved in acetonitrile (5.0 ml), and N, N-diisopropylethylamine (231.4mg, 1.8mmol) and (R) -3-methylmorpholine (108.7mg, 1.1mmol) were added in this order at 20 ℃. The reaction was then warmed to 40 ℃ and stirred for 2.5 hours. After the reaction, the solvent was distilled off under reduced pressure, and the mixture was subjected to column chromatography to obtain Compound 3d (232.4mg, 0.7mmol, yield: 87%).
MS-ESI calculated value [ M + H%] + 333.1 found 333.1.
The fourth step
Compound 3d (202.4 mg,0.6 mmol), 4-indoleboronic acid pinacol ester (147.9mg, 0.6 mmol), bis (triphenylphosphine) palladium (II) dichloride (42.7mg, 0.06mmol) and sodium carbonate (128.9mg, 1.2mmol) were added to a mixed solution of dioxane (2.0 ml) and water (1.0 ml), and reacted at 100 ℃ for 2.5 hours under nitrogen protection. After completion of the reaction, water (50.0 ml) was added for dilution, ethyl acetate (50.0 ml × 3) was extracted, and the resulting organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. And distilling the obtained filtrate under reduced pressure to remove the solvent to obtain a crude product. The obtained crude product was separated, prepared and purified by column chromatography and high performance liquid chromatography to obtain compound 3 (90.0 mg, yield: 35.4%), HPLC purity: 98.9 percent.
MS-ESI calculated value [ M + H%] + 414.2, found 414.2.
1H NMR(400MHz,DMSO-d6)δ:11.42(s,1H),7.97(d,J＝7.5Hz,1H),7.62(d,J＝8.0Hz,1H),7.51(t,J＝2.8Hz,1H),7.24(t,J＝8.0Hz,1H),7.18(t,J＝2.4Hz,1H),5.03–4.91(m,1H),4.85(d,J＝13.0Hz,1H),4.64(s,2H),4.57(s,1H),4.13(s,1H),4.00(d,J＝8.0Hz,1H),3.79(d,J＝11.5Hz,1H),3.70(dd,J＝11.7,3.1Hz,1H),3.55(d,J＝6.1Hz,2H),3.11(s,3H),1.36(d,J＝6.8Hz,3H).
Biological examples
Example 1: cell proliferation assay
In the present invention, a cell proliferation assay is used to evaluate the biological activity of a compound on tumor cells. HT-29 (Chengdu Zhongyuan Co-creation science Co., ltd.) cells and LOVO (Nanjing Ke Bai Biotech Co., ltd.) cells were seeded in 96-well plates, respectively, in which HT-29 cells were seeded at 5000 cells per well and LOVO cells were seeded at 10000 cells per well. HT-29 cells were cultured in RPMI-1640 Medium containing 10% fetal bovine serum and 100. Mu.g/mL Normocin, and LOVO cells were cultured in Dulbecco's Modified Eagle Medium (DMEM) Medium containing 10% fetal bovine serum and 100. Mu.g/mL Normocin. CO at 37 ℃ and 5% 2 Culturing overnight under the condition to ensure that the cells are attached to the wall. The following day, the medium was removed from the cells, 150. Mu.L of fresh medium was added, 50. Mu.L of medium containing 4-fold final concentration of the compound (final concentration range 1nM to 10. Mu.M) was added, and the cells were placed in an incubator and cultured for a further 72 hours at 37 ℃ and 5% CO2. After 72h of culture, the medium in the cells was removed again and serum-free RPMI-1640 basic medium containing 10% of CCK8 reagent was added. After incubation for 1h at 37 ℃ the plate reader (BMG LABTECH) was used at 450The absorbance (OD) values were read at nm wavelength. Data were analyzed using GraphPad Prism software, and compound inhibition growth curves were fitted and IC calculated 50 The value is obtained.
Table 1:
| compound numbering | IC 50 (HT-29,μM) | IC 50 (LOVO,μM) |
| 1 | 4.418 | 1.975 |
| 2 | 10.86 | 3.314 |
| 3 | 1.860 | 0.225 |
Example 2: pCHK1 cell level assay
HT-29 cells were seeded into a 96-well clear-bottomed blackboard (Greiner Bio-one, cat # 655090) at a density of 10000 cells per well, and cultured overnight in a 5-% CO2 incubator at 37 ℃. The following day, the medium in the cells was removed, 150. Mu.L of fresh medium was added, 50. Mu.L of medium containing 4-fold final concentration of compound (final concentration range 1nM to 10. Mu.M) was added, and the mixture was placed in an incubator at 37 ℃ and 5% 2 Culturing for 60min under the condition. Then 600. Mu.M of 4NQO 1. Mu.L treatment (final concentration of 3. Mu.M) was added to each well and the treatment was continuedCulturing for 60min. An equal volume of DMSO was added to the negative control wells instead of 4NQO. Thereafter, the medium in the cells was removed, and the cells were fixed with 4% paraformaldehyde, 150. Mu.L per well, and incubated at room temperature for 15min. After cell fixation, 150. Mu.L of 0.1% (v/v) Triton X-100 permeabilized cells were used and incubated at room temperature for 15min. Cells were blocked with 1% blocking reagent (Roche) at 100. Mu.L per well and incubated for 60min at room temperature. After blocking, 50. Mu.L of pCHK1 antibody (CST, cat # 2348, dilution ratio 1: 250) diluted with 1% (w/v) blocking reagent was added to each well and incubated overnight at 2-8 ℃. The following day, the antibody in the wells was removed and the cells were washed with 0.05% (v/v) PBST, 200. Mu.L per well, repeated 3 times. Then, 1% (w/v) blocking reagent-diluted goat anti-rabbit fluorescent secondary antibody (Invitrogen, cat # A32731) and DAPI stain (Thermofisiher, cat # 62247) (fluorescent secondary antibody dilution ratio 1, DAPI dilution ratio 1, 50. Mu.L per well, and incubation at 300rpm on a shaker for 2h at room temperature were added. The wells were then removed of antibody and the cells were washed with 0.05% (v/v) PBST, 200. Mu.L per well, in 3 replicates (the wash in the wells was retained last). The fluorescence value of pCHK1 In the nucleus was obtained using a high content imaging analysis system (GE, in Cell Analyzer, model 2200), the relative level of pCHK1 was analyzed using GraphPad Prism software, the inhibition curve of the compound to pCHK1 was fitted and IC was calculated 50 The value is obtained.
Table 2:
| compound numbering | IC 50 (μM) |
| 2 | 1.313 |
| 3 | 0.168 |
Claims (18)
1. A compound represented by formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
wherein,
the A ring is selected from 3-10 membered carbocyclyl, 4-10 membered heterocycloalkyl, 6-10 membered aromatic ring, 5-10 membered aromatic heterocycle; wherein carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four R A1 Substitution;
each R A1 Each independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-OR A2 、-C 0～4 alkylene-OC (O) R A2 、-C 0～4 alkylene-SR A2 、-C 0～4 alkylene-S (O) 2 R A2 、-C 0～4 alkylene-S (O) R A2 、-C 0～4 alkylene-S (O) 2 NR A2 R A3 、-C 0～4 alkylene-S (O) NR A2 R A3 、-C 0～4 alkylene-C (O) R A2 、-C 0～4 alkylene-C (O) OR A2 、-C 0～4 alkylene-C (O) NR A2 R A3 、-C 0～4 alkylene-NR A2 R A3 、-C 0～4 alkylene-NR A2 C(O)R A3 、-C 0～4 alkylene-NR A2 S(O) 2 R A3 、-C 0～4 alkylene-NR A2 S(O)R A3 (ii) a Or, two independent R A1 Together with the linking atom form
R A2 、R A3 Each independently selected from hydrogen and-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 An alkynyl group;
ring B is selected from
Wherein the ring selected from B may be further optionally substituted by one, two, three or four R B1 Substitution;
each R B1 Each independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-OR B2 、-C 0～4 alkylene-OC (O) R B2 、-C 0～4 alkylene-C (O) R B2 、-C 0～4 alkylene-C (O) OR B2 、-C 0～4 alkylene-C (O) NR B2 R B3 、-C 0～4 alkylene-NR B2 R B3 、-C 0～4 alkylene-NR B2 C(O)R B3 ；
R B2 、R B3 Each independently selected from hydrogen and-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 An alkynyl group;
R 1 selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 An alkyl group;
x is selected from N or CR 3 ；
And X is selected from N, R 1 And R 2 Together with the linking atom form
Wherein R is 1 And R 2 The ring formed with the atoms to which it is attached may further optionally be substituted by one, two, three or four R C1 Substitution;
and X is selected from CR 3 When R is 2 And R 3 Together with the linking atom form
Wherein R is 2 And R 3 The ring formed with the attached atoms may be further optionally substituted by one, two, three or four R C1 Substitution;
each R C1 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-OR C2 、-C 0～4 alkylene-OC (O) R C2 、-C 0～4 alkylene-SR C2 、-C 0～4 alkylene-S (O) 2 R C2 、-C 0～4 alkylene-S (O) R C2 、-C 0～4 alkylene-S (O) 2 NR C2 R C3 、-C 0～4 alkylene-S (O) NR C2 R C3 、-C 0～4 alkylene-S (O) (NH) R C2 、-C 0～4 alkylene-S (O) (NH) NR C2 R C3 、-C 0～4 alkylene-C (O) R C2 、-C 0～4 alkylene-C (O) OR C2 、-C 0～4 alkylene-C (O) NR C2 R C3 、-C 0～4 alkylene-NR C2 R C3 、-C 0～4 alkylene-NR C2 C(O)R C3 、-C 0～4 alkylene-NR C2 S(O) 2 R C3 、-C 0～4 alkylene-NR C2 S(O)R C3 、-C 0～4 alkylene-P (O) R C2 R C3 、-C 0～4 alkylene-P (O) (OR) C2 )R C3 、-C 0～4 alkylene-P (O) (OR) C2 )(OR C3 )、-C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle); wherein alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R C4 Substitution;
or, two independent R C1 Together with the linking atom form
5-8 membered carbocyclyl, 5-8 membered heterocycloalkyl, benzene ring, 5-6 membered aromatic heterocycle; wherein carbocyclyl, heterocycloalkyl, aryl, heteroaryl may be further optionally substituted with one, two, three or four independent R C4 Substitution
R C2 、R C3 Each independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle);
each R C4 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-OR C5 、-C 0～4 alkylene-OC (O) R C5 、-C 0～4 alkylene-SR C5 、-C 0～4 alkylene-S (O) 2 R C5 、-C 0～4 alkylene-S (O) R C5 、-C 0～4 alkylene-S (O) 2 NR C5 R C6 、-C 0～4 alkylene-S (O) NR C5 R C6 、-C 0～4 alkylene-S (O) (NH) R C5 、-C 0～4 alkylene-S (O) (NH) NR C5 R C6 、-C 0～4 alkylene-C (O) R C5 、-C 0～4 alkylene-C (O) OR C5 、-C 0～4 alkylene-C (O) NR C5 R C6 、-C 0～4 alkylene-NR C5 R C6 、-C 0～4 alkylene-NR C5 C(O)R C6 、-C 0～4 alkylene-NR C5 S(O) 2 R C6 、-C 0～4 alkylene-NR C5 S(O)R C6 、-C 0～4 alkylene-P (O) R C5 R C6 、-C 0～4 alkylene-P (O) (OR) C5 )R C6 、-C 0～4 alkylene-P (O) (OR) C5 )(OR C6 ) (ii) a Or, two independent R C4 Together with the linking atom form
R C5 、R C6 Each independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered heteroaromatic ring).
2. The compound of claim 1, wherein:
the A ring is selected from 3-membered carbocyclyl, 4-membered carbocyclyl, saturated or unsaturated 5-membered carbocyclyl, saturated or unsaturated 6-membered carbocyclyl, saturated or unsaturatedAn unsaturated 7-membered carbocyclyl, a saturated or unsaturated 8-membered carbocyclyl, a saturated or unsaturated 9-membered carbocyclyl, a saturated or unsaturated 10-membered carbocyclyl, a 4-membered heterocycloalkyl, a saturated or unsaturated 5-membered heterocycloalkyl, a saturated or unsaturated 6-membered heterocycloalkyl, a saturated or unsaturated 7-membered heterocycloalkyl, a saturated or unsaturated 8-membered heterocycloalkyl, a saturated or unsaturated 9-membered heterocycloalkyl, a saturated or unsaturated 10-membered heterocycloalkyl, a 6-membered aromatic ring, a 10-membered aromatic ring, a 5-membered aromatic heterocycle, a 6-membered aromatic heterocycle, a 7-membered aromatic heterocycle, an 8-membered aromatic heterocycle, a 9-membered aromatic heterocycle, a 10-membered aromatic heterocycle; wherein carbocyclyl, heterocycloalkyl, aryl, heteroaryl may be further optionally substituted with one, two, three or four R A1 And (4) substitution.
3. The compound of claim 2, wherein:
ring A is selected from 4-membered monocyclic heterocycloalkyl, 5-membered monocyclic heterocycloalkyl, 6-membered fused heterocycloalkyl, 7-membered fused heterocycloalkyl, 8-membered fused heterocycloalkyl, 6-membered bridged heterocycloalkyl, 7-membered bridged heterocycloalkyl, 8-membered bridged heterocycloalkyl, 9-membered bridged heterocycloalkyl, 5-membered aromatic heterocycle, 6-membered aromatic heterocycle; wherein the heterocycloalkyl, heteroaromatic ring may be further optionally substituted by one, two, three or four R A1 And (4) substitution.
4. A compound according to claim 3, characterized in that:
a ring selected from
Wherein the ring selected from A is further optionally substituted by one, two, three or four R A1 Substitution;
each R A1 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -OR A2 、-SR A2 、-NR A2 R A3 (ii) a Or, two independent R A1 Together with the linking atom form
R A2 、R A3 Each independently selected from hydrogen and-C 1～6 An alkyl group.
5. The compound of claim 4, wherein:
a ring selected from
6. The compound of claim 1, wherein:
ring B is selected from
Wherein the ring from which B is selected may be further optionally substituted by one, two, three or four R B1 Substitution;
each R B1 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, halogen substituted-C 1～6 Alkyl, -OR B2 、-C(O)R B2 、-C(O)NR B2 R B3 、-NR B2 R B3 、-NR B2 C(O)R B3 ；
R B2 、R B3 Each independently selected from hydrogen, -C 1～6 An alkyl group.
7. The compound of claim 6, wherein:
b ring selected from
8. The compound of claims 1-7, wherein:
x is selected from N;
R 1 and R 2 Together with the linking atom form
Wherein R is 1 And R 2 The ring formed with the atoms to which it is attached may further optionally be substituted by one, two, three or four R C1 And (4) substitution.
9. The compound of claim 8, wherein: the compounds of formula I are shown below:
R C11 is selected from-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-S (O) 2 R C2 、-C 0～4 alkylene-S (O) R C2 、-C 0～4 alkylene-S (O) 2 NR C2 R C3 、-C 0～4 alkylene-S (O) NR C2 R C3 、-C 0～4 alkylene-S (O) (NH) R C2 、-C 0～4 alkylene-S (O) (NH) NR C2 R C3 、-C 0～4 alkylene-C (O) R C2 、-C 0～4 alkylene-C (O) OR C2 、-C 0～4 alkylene-C (O) NR C2 R C3 、-C 0～4 alkylene-P (O) R C2 R C3 、-C 0～4 alkylene-P (O) (OR) C2 )R C3 、-C 0～4 alkylene-P (O) (OR) C2 )(OR C3 )、-C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle); wherein the alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, or aromatic heterocycle may be further optionally substituted with oneTwo, three or four independent R C4 Substitution;
each R C12 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-OR C2 、-C 0～4 alkylene-SR C2 、-C 0～4 alkylene-NR C2 R C3 、-C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle); wherein alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R C4 Substitution;
R C2 、R C3 each independently selected from hydrogen and-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle);
each R C4 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl; or, two independent R C4 Together with the linking atom form
10. The compound of claim 9, wherein:
R C11 is selected from
Each R C12 Each independently selected from hydrogen, halogen, methyl, trifluoromethyl, cyclopropyl,
11. The compound of claims 1-7, wherein:
x is selected from CR 3 ；
R 2 And R 3 Together with the linking atom form
R of which 2 And R 3 The ring formed with the attached atoms may be further optionally substituted by one, two, three or four R C1 And (4) substitution.
12. The compound of claim 11, wherein: the compounds of formula I are shown below:
R C11 is selected from-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-S (O) 2 R C2 、-C 0～4 alkylene-S (O) R C2 、-C 0～4 alkylene-S (O) 2 NR C2 R C3 、-C 0～4 alkylene-S (O) NR C2 R C3 、-C 0～4 alkylene-S (O) (NH) R C2 、-C 0～4 alkylene-S (O) (NH) NR C2 R C3 、-C 0～4 alkylene-C (O) R C2 、-C 0～4 alkylene-C (O) OR C2 、-C 0～4 alkylene-C (O) NR C2 R C3 、-C 0～4 alkylene-P (O) R C2 R C3 、-C 0～4 alkylene-P (O) (OR) C2 )R C3 、-C 0～4 alkylene-P (O) (OR) C2 )(OR C3 )、-C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle); wherein alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R C4 Substitution;
each R C12 Each independently selected from hydrogen, halogen, cyano, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 alkylene-OR C2 、-C 0～4 alkylene-SR C2 、-C 0～4 alkylene-NR C2 R C3 、-C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle); wherein alkylene, carbocyclyl, heterocycloalkyl, aromatic ring, aromatic heterocycle may further optionally be substituted with one, two, three or four independent R C4 Substitution;
R C2 、R C3 each independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 Alkynyl, -C 0～4 Alkylene- (3-to 10-membered carbocyclic group), -C 0～4 Alkylene- (4-to 10-membered heterocycloalkyl), -C 0～4 Alkylene- (6-to 10-membered aromatic ring), -C 0～4 Alkylene- (5-to 10-membered aromatic heterocycle);
each R C4 Are respectively and independently selected from hydrogen, halogen, cyano-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen substituted-C 1～6 Alkyl, halogen substituted-C 2～6 Alkenyl, halogen substituted-C 2～6 An alkynyl group; or, two independent R C4 Together with the linking atom form
13. The compound of claim 12, wherein:
R C11 is selected from
Each R C12 Each independently selected from hydrogen, halogen, methyl, trifluoromethyl, cyclopropyl,
14. The compound of claim 1, wherein: the compound shown in the formula I is specifically:
15. use of a compound of any one of claims 1-14, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for an ATR inhibitor.
16. Use of a compound of any one of claims 1-14, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of cancer.
17. A pharmaceutical composition comprising a formulation prepared from the compound of any one of claims 1 to 14, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
18. The pharmaceutical composition of claim 17, further comprising a pharmaceutically acceptable carrier, adjuvant, vehicle.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023227139A1 (en) * | 2022-05-25 | 2023-11-30 | 沈阳药科大学 | Fused pyrimidine derivative and application thereof |
| CN117820340A (en) * | 2022-12-01 | 2024-04-05 | 成都硕德药业有限公司 | ATR inhibitors and uses thereof |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102171194A (en) * | 2008-07-31 | 2011-08-31 | 健泰科生物技术公司 | Pyrimidine compounds, compositions and methods of use |
| WO2015084384A1 (en) * | 2013-12-06 | 2015-06-11 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
| CN105051047A (en) * | 2013-03-15 | 2015-11-11 | 卡洛斯三世国家癌症研究中心基金会 | Chemical entities |
| WO2020103897A1 (en) * | 2018-11-22 | 2020-05-28 | 上海迪诺医药科技有限公司 | Heterocyclic fused pyrimidine derivative, pharmaceutical composition thereof, and application thereof |
-
2022
- 2022-06-06 CN CN202210627789.8A patent/CN115466258A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102171194A (en) * | 2008-07-31 | 2011-08-31 | 健泰科生物技术公司 | Pyrimidine compounds, compositions and methods of use |
| CN105051047A (en) * | 2013-03-15 | 2015-11-11 | 卡洛斯三世国家癌症研究中心基金会 | Chemical entities |
| WO2015084384A1 (en) * | 2013-12-06 | 2015-06-11 | Vertex Pharmaceuticals Incorporated | Compounds useful as inhibitors of atr kinase |
| WO2020103897A1 (en) * | 2018-11-22 | 2020-05-28 | 上海迪诺医药科技有限公司 | Heterocyclic fused pyrimidine derivative, pharmaceutical composition thereof, and application thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023227139A1 (en) * | 2022-05-25 | 2023-11-30 | 沈阳药科大学 | Fused pyrimidine derivative and application thereof |
| CN117164590A (en) * | 2022-05-25 | 2023-12-05 | 沈阳药科大学 | Fused pyrimidine derivative and application thereof |
| CN117820340A (en) * | 2022-12-01 | 2024-04-05 | 成都硕德药业有限公司 | ATR inhibitors and uses thereof |
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