CN115894520A - Macrocyclic K-RAS G12C inhibitor, preparation method and pharmaceutical application thereof - Google Patents

Macrocyclic K-RAS G12C inhibitor, preparation method and pharmaceutical application thereof Download PDF

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CN115894520A
CN115894520A CN202210217410.6A CN202210217410A CN115894520A CN 115894520 A CN115894520 A CN 115894520A CN 202210217410 A CN202210217410 A CN 202210217410A CN 115894520 A CN115894520 A CN 115894520A
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alkyl
substituted
deuterium
radical
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寻国良
喻红平
陈椎
徐耀昌
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Abbisko Therapeutics Co Ltd
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Abbisko Therapeutics Co Ltd
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Abstract

The invention relates to a macrocyclic K-RAS G12C inhibitor, a preparation method and pharmaceutical application thereof. The series of compounds can be widely applied to preparing medicines for treating at least part of cancers or tumors mediated by K-RAS G12C mutation, particularly medicines for treating lung, liver and gall bladder, gastrointestinal tract, blood system, skin, bone, genitourinary tract, nervous system, gynecological and adrenal related malignant tumors or cancers, and are expected to be developed into a new generation of K-RAS G12C inhibitor medicines.

Description

Macrocyclic K-RAS G12C inhibitor, preparation method and pharmaceutical application thereof
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a macrocyclic K-RAS G12C inhibitor, a preparation method thereof and pharmaceutical application thereof.
Background
The RAS gene family includes HRAS, KRAS and NRAS, which are frequently mutated as oncogenes in cancer. RAS proteins are mutated in 20-30% of human tumors. Activated RAS proteins contribute to the malignant phenotype of cancer cells, including dysregulation of cell growth and programmed cell death, invasiveness and increased neovascularization. The development of RAS protein-targeting drugs has been slow due to their high affinity for GTP/GDP and lack of a clear binding pocket.
Under normal conditions, RAS proteins function as molecular switches, alternating between a GDP-bound inactive state and a GTP-bound active state. Upon stimulation by exogenous growth factors, RAS proteins are converted from an inactive GDP-bound form to an activated GTP-bound form, facilitated by guanine nucleotide exchange factors (GEFs), which are capable of binding to and activating downstream signaling pathways. Subsequently, RAS reverts to the inactive GDP-bound form with the help of its intrinsic GTPase activity and GTPase activating/accelerating protein (GAP).
12. Missense mutations at codon 13 or 61 result in aberrant activation of RAS. These mutations prolong the time that RAS proteins stay in the GTP-bound state, leading to sustained activation of downstream signaling pathways. K-RAS is the most common mutant subtype in the RAS family of human cancers, including pancreatic (71%), small bowel (35%), colon (35%), biliary (26%), endometrial (17%) and lung (19%). Regarding the mutation sites, G12D/G12V/G12C/G13D is the most common mutation type of K-RAS in pancreatic cancer, lung cancer and colorectal cancer.
Because this protein lacks a distinct pocket, the development of inhibitors of the K-RAS is challenging. Recent studies have found that there is a previously undiscovered pocket in the K-RAS and GDP bound state. Based on these new findings, covalently bound inhibitors targeting the codon 12 mutated cysteine became a hot spot for the development of K-RAS inhibitors. Previously, the mutated K-RAS was thought to lock in the GTP-binding activation state. However, it was later found that the G12C mutation still has a relatively high level of GTP hydrolysis activity and is therefore more susceptible to covalent inhibitors of GDP-bound K-RAS. Recently, several covalent inhibitors targeting the K-RAS G12C mutation were sequenced into early clinical trials.
Disclosure of Invention
The inventor of the application researches extensively and deeply, develops a macrocyclic K-RAS G12C inhibitor for the first time, and provides a preparation method and application thereof in pharmacy, the series of compounds of the invention have strong inhibiting effect on K-RAS enzymology and cell activity, can be widely applied to the preparation of medicaments for treating cancers or tumors mediated by K-RAS G12C mutation at least partially, in particular to medicaments for treating lung, liver and gall, gastrointestinal tract, blood system, skin, bone, urogenital tract, nervous system, gynecological and adrenal gland related malignant tumors or cancers, and is expected to be developed into a new generation of K-RAS G12C inhibitor medicaments.
In a first aspect, the present invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure BDA0003535562350000021
wherein X is C (R) 7 ) Or N; l is selected from-CR 8 ＝CR 9 -、-C(R 10 R 11 )-C(R 12 R 13 )-、-N(R 14 )-C(O)-、-N(R 15 )-C(R 16 R 17 ) -and-O-C (R) 18 R 19 )-；
R 1 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 4-6 membered heteroaryl, acetamido, and-SF 5 ；
Each R 2 Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 4-6 membered heteroaryl, acetamido, and-SF 5 ；
R 3 Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-to 10-membered heteroaryl, = O, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
each R 4 Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, -SF 5 、C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, cyano-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, halo-substituted C 1-4 Alkyl and deuterium substituted C 1-4 Alkyl, or, when m.gtoreq.2, two R 4 Together with the parts to which they are attached form C 3-12 Cycloalkyl or 3-12 membered heterocyclyl;
R 5 and R 6 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl and di-C 1-4 An alkyl amino methyl group;
R 7 selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, = O, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
R 8 and R 9 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 4-12 membered heterocyclyl and-C 1-4 alkyl-NR 23 R 24 Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, hydroxy, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, = O, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(＝NR 23 )R 22 、-N(R 23 )-C(＝NR 24 )R 22 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
R 10 、R 11 、R 12 、R 13 、R 16 、R 17 、R 18 and R 19 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(＝NR 23 )R 22 、-N(R 23 )-C(＝NR 24 )R 22 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Or, R 10 And R 11 、R 12 And R 13 、R 16 And R 17 、R 18 And R 19 Together with the carbon atom to which they are directly attached form a C (O), 3-12 membered cycloalkyl or 3-12 membered heterocyclyl, optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, = O, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(＝NR 23 )R 22 、-N(R 23 )-C(＝NR 24 )R 22 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
R 14 and R 15 Each independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C (O) OR 21 、-C(O)R 22 and-C (O) NR 23 R 24 Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitroGroup, azido group, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, = O, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
each R 20 Independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl and-NR 23 R 24 Independently, the above groups are optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, = O, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 23 R 24 Substituted with the substituent(s);
each R 21 Independently selected from hydrogen, deuterium, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, = O, cyano, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 23 R 24 Substituted with the substituent(s);
each R 22 Selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 23 R 24 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, cyano, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 23 R 24 Substituted with the substituent(s);
each R 23 And R 24 Each independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 Alkanoyl, said groups being independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 Alkylamino radical, di-C 1-10 Alkylamino and C 1-10 Substituted by the substituent of the alkanoyl group,
or, R 23 And R 24 Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, said 4-10 membered heterocyclyl or 5-10 membered heteroaryl being optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 Substituted by alkanoyl group;
m is 0, 1,2, 3 or 4;
n is 0, 1,2, 3 or 4;
each r is independently 0, 1 or 2.
As a preferred embodiment, R in said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof 10 、R 11 、R 12 、R 13 、R 16 、R 17 、R 18 And R 19 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Or, or R 10 And R 11 、R 12 And R 13 、R 16 And R 17 、R 18 And R 19 Together with the carbon atom to which they are directly attached form a C (O), 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuteriumGeneration C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
R 14 and R 15 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C (O) OR 21 、-C(O)R 22 and-C (O) NR 23 R 24 Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -C 0-4 alkyl-SF 5 、-C 0-4 alkyl-S (O) r R 20 、-C 0-4 alkyl-O-R 21 、-C 0-4 alkyl-C (O) OR 21 、-C 0-4 alkyl-C (O) R 22 、-C 0-4 alkyl-O-C (O) R 22 、-C 0-4 alkyl-NR 23 R 24 、-C 0-4 alkyl-C (= NR) 23 )R 22 、-C 0-4 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-4 alkyl-C (O) NR 23 R 24 and-C 0-4 alkyl-N (R) 23 )-C(O)R 22 Substituted with a substituent of (a);
wherein R is 20 、R 21 、R 22 、R 23 、R 24 And r is as described for the compound of formula (I).
As a preferred embodiment, R in said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof 8 And R 9 Each independently selected from hydrogen, deuterium,Halogen, cyano, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl and-C 1-4 alkyl-NR 23 R 24 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
wherein R is 20 、R 21 、R 22 、R 23 、R 24 And r is as described for the compound of formula (I).
As a preferred embodiment, R in said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof 7 Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(＝NR 23 )R 22 、-N(R 23 )-C(＝NR 24 )R 22 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(＝NR 23 )R 22 、-N(R 23 )-C(＝NR 24 )R 22 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
wherein R is 20 、R 21 、R 22 、R 23 、R 24 And r is as described for compounds of formula (I).
As a preferred embodiment, R in said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof 3 Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(＝NR 23 )R 22 、-N(R 23 )-C(＝NR 24 )R 22 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(＝NR 23 )R 22 、-N(R 23 )-C(＝NR 24 )R 22 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
wherein R is 20 、R 21 、R 22 、R 23 、R 24 And r is as described for compounds of formula (I).
As a preferred embodiment, the compound of formula (I), its stereoisomer or its pharmaceutically acceptable saltIn R 1 Selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, ethenyl, ethynyl, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkoxy, cyclopropyl, acetamido and-SF 5 。
As a preferred embodiment, each R in said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof 2 Each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkoxy, cyclopropyl, acetamido and-SF 5 。
As a preferred embodiment, each R in said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof 4 Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, -SF 5 、C 1-4 Alkyl radical, C 2-4 Alkynyl, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, cyano-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, halo-substituted C 1-4 Alkyl and deuterium substituted C 1-4 An alkyl group.
As a preferred embodiment, R in said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof 5 And R 6 Each independently selected from hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, isopropyl, cyclopropyl and dimethylaminomethyl.
As a further preferred embodiment, the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt has the following structure:
Figure BDA0003535562350000061
wherein X is CH or N, L is-CR 8 ＝CR 9 -or-C (R) 10 R 11 )-C(R 12 R 13 )-；
R 1 Selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, acetamido, and-SF 5 ；
R 2 Selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, acetamido and-SF 5 ；
R 3 Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, di-C 1-4 Alkylaminomethyl and-SF 5 ；
R 4a 、R 4b 、R 4c Each independently selected from hydrogen, deuterium, halogen, cyano, methyl, cyclopropyl, cyanomethyl, hydroxymethyl, trifluoromethyl, trideuteromethyl, difluoromethyl, and dideuteromethyl;
R 8 and R 9 Each independently selected from hydrogen, deuterium, fluoro, cyano, methyl, ethyl, isopropyl and cyclopropyl;
R 10 、R 11 、R 12 and R 13 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Or, R 10 And R 11 、R 12 And R 13 Together with the carbon atom to which they are directly attached to form C (O),3-6 membered cycloalkyl or 3-6 membered heterocyclyl, optionally further substituted by one or more substituents selected from deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
wherein R is 20 、R 21 、R 22 、R 23 、R 24 And r is as described for compounds of formula (I).
As a further preferred embodiment, the compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, the compound of formula (I) has the structure of the compound of formula (iii):
Figure BDA0003535562350000071
wherein L is-CH = CH-or-C (R) 10 R 11 )-C(R 12 R 13 )-；
R 1 Selected from the group consisting of hydrogen, deuterium, fluoro, chloro, cyano, methyl, methoxy, cyclopropyl and-SF 5 ；
R 2 Selected from the group consisting of hydrogen, deuterium, fluoro, chloro, cyano, methyl, methoxy, cyclopropyl and-SF 5 ；
R 3 Selected from the group consisting of hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, cyclopropyl, cyclobutyl, cyclobutoxy and-SF 5 ；
R 10 、R 11 、R 12 And R 13 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl,5-8 membered heteroaryl, -O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 and-NR 23 R 24 Or, or R 10 And R 11 、R 12 And R 13 Together with the carbon atom to which they are directly attached form a C (O), 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
each R 20 Independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl and-NR 23 R 24 Independently, the above groups are optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, amino, = O, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, and 3-6 membered heterocyclyloxy;
each R 21 Independently selected from hydrogen, deuterium, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, amino, = O, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy;
each R 22 Selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 23 R 24 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, amino, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, and 3-6 membered heterocyclyloxy;
each R 23 And R 24 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 Alkanoyl, said groups being independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 Substituted by the substituent of the alkanoyl group,
or, R 23 And R 24 Together with the nitrogen atom to which they are directly attached form a 4-6 membered heterocyclyl or 5-8 membered heteroaryl, said 4-6 membered heterocyclyl or 5-8 membered heteroaryl being optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 Substituted by alkanoyl group;
each r is independently 0, 1 or 2.
As a still further preferred embodiment, in said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, L is-CH = CH-or-C (R) 10 R 11 )-C(R 12 R 13 )-；
R 1 Selected from hydrogen, deuterium, fluoro, chloro, cyano, methyl, methoxy and cyclopropyl;
R 2 selected from hydrogen, deuterium, fluoro, chloro, cyano, methyl, methoxy and cyclopropyl;
R 3 selected from the group consisting of hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, cyclopropyl, cyclobutyl, and cyclobutoxy;
R 10 is hydrogen;
R 11 selected from the group consisting of hydrogen, deuterium, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, oxolanyl, aziridinyl, -O-R 21 、-C(O)OR 21 、-C(O)R 22 and-O-C (O) R 22 Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 and-O-C (O) R 22 Substituted with the substituent(s);
R 12 is hydrogen;
R 13 selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methylEthyl, propyl, butyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, oxolanyl, aziridinyl, -O-R 21 、-C(O)OR 21 、-C(O)R 22 and-O-C (O) R 22 Optionally further substituted with one or more groups selected from deuterium, fluoro, chloro, bromo, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 and-O-C (O) R 22 Substituted with a substituent of (a);
each R 21 Independently selected from hydrogen, deuterium, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, oxolanyl, azacyclopentyl and phenyl, which are independently optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, bromo, hydroxy, amino, = O, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy;
each R 22 Selected from the group consisting of hydrogen, deuterium, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, methoxy, ethoxy, propoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopropoxy, cyclobutoxy, oxetanyl, azetidinyl, oxolanyl, aziridinyl and phenyl, which are independently optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, bromo, hydroxy, amino, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy.
As a most preferred embodiment, the compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, includes, but is not limited to, the following compounds:
Figure BDA0003535562350000091
/>
Figure BDA0003535562350000101
in a second aspect, the present invention provides a process for the preparation of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, comprising the steps of: reacting a compound of formula (I') to obtain a compound of formula (I):
Figure BDA0003535562350000111
wherein R is H or an amino protecting group, preferably, the amino protecting group is t-butyloxycarbonyl; r 1 、R 2 、R 3 、R 4 、R 5 、R 6 L, X, m and n are as described for compounds of formula (I).
In a third aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described above, and a pharmaceutically acceptable carrier.
In a fourth aspect, the present invention provides the use of a compound of formula (I) as hereinbefore defined, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as hereinbefore defined, in the manufacture of a medicament for the treatment of a tumour or cancer mediated at least in part by the K-RAS G12C mutation.
Preferably, the cancer or tumor is selected from the group consisting of a lung malignancy or cancer, a hepatobiliary malignancy or cancer, a gastrointestinal malignancy or cancer, a hematologic malignancy or cancer, a sarcoma, a skin malignancy or cancer, a bone malignancy or cancer, a urogenital malignancy or cancer, a nervous system malignancy or cancer, a gynecological malignancy or cancer, and an adrenal malignancy or cancer.
As a further preferred embodiment, the pulmonary malignancy or cancer is selected from bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell, undifferentiated large cell or adenocarcinoma), non-small cell lung carcinoma, bronchial adenoma, sarcoma, lymphoma, chondrogenic hamartoma or mesothelioma; the hepatobiliary malignancy or cancer is selected from liver cancer, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampulla cancer, or cholangiocarcinoma; the gastrointestinal malignancy or cancer is selected from an esophageal malignancy or cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma or lymphoma), a gastric malignancy or cancer (carcinoma, lymphoma or leiomyosarcoma), a pancreatic malignancy or cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, uveoma), a small intestine (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), a large intestine cancer malignancy or cancer (adenocarcinoma, adenoma, tubular adenoma), or leiomyoma; the hematologic malignancy or cancer is selected from acute or chronic myeloleukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, hodgkin's disease or non-hodgkin's lymphoma; the sarcoma is selected from angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma or teratoma; the malignant tumor or cancer of the skin is selected from malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, nevus, moles hyperplasia, lipoma, hemangioma, dermatofibroma, keloids or psoriasis; the bone malignancy or cancer is selected from osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondrosis, benign chondroma, chondroblastoma, cartilaginous mucosa fibroma, osteoid tumor, or giant cell tumor; the genitourinary tract malignancy or cancer is selected from a renal malignancy or cancer (adenocarcinoma, wilm's tumor or wilm's tumor), lymphoma, leukemia, bladder or urinary tract malignancy or cancer (squamous cell carcinoma, transitional cell carcinoma or adenocarcinoma), prostate malignancy or cancer (adenocarcinoma or sarcoma), testicular malignancy or cancer (blood, teratoma, embryo or teratoma), choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, or lipoma; the nervous system malignancy or cancer is selected from an osteoma, hemangioma, granuloma, xanthoma, osteitis deformans, meningioma, meningosarcoma, glioma, astrocytoma, medulloblastoma, glioma, ependymoma, genital tumor, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, spinal neurofibroma, meningioma, glioma, or sarcoma; the gynecological malignant tumor or cancer is selected from endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma or unclassified carcinoma), granular-sheath cell tumor, leydig cell tumor, sarcolemma anomaly, malignant teratoma, squamous epithelial cancer, fibroepithelial cancer, adenoepithelial cancer, melanoma, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma or fallopian tube carcinoma; the adrenal malignancy or cancer is selected from neuroblastoma.
In a fifth aspect, the present invention provides a compound of formula (I) as hereinbefore defined, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use as a medicament in the treatment of a tumour or cancer mediated at least in part by a K-RAS G12C mutation.
In a sixth aspect, the present invention provides a method for the prevention and/or treatment of tumors or cancers mediated at least in part by K-RAS G12C mutation, comprising administering to a patient a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing.
Detailed Description
The inventors of the present application have studied extensively and intensively and have developed for the first time a macrocyclic K-RAS G12C inhibitor, and have provided a preparation method and a pharmaceutical use thereof. The series of compounds of the invention have strong inhibiting effect on K-RAS enzymology and cell activity, can be widely applied to the preparation of medicaments for treating at least part of cancers or tumors mediated by K-RAS G12C mutation, in particular to medicaments for treating malignant tumors or cancers related to lung, liver, gall bladder, gastrointestinal tract, blood system, skin, bone, genitourinary tract, nervous system, gynecology and adrenal gland, and are expected to be developed into a new generation of K-RAS G12C inhibitor medicaments. On the basis of this, the present invention has been completed.
Detailed description: unless stated to the contrary or otherwise indicated, the following terms used in the specification and claims have the following meanings.
"alkyl" means a straight or branched chain saturated aliphatic hydrocarbon group, preferably including straight chain and branched chain alkyl groups of 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 3-methylpentyl, 4-methylpentyl, 3525-dimethylbutyl, 353584-dimethylbutyl, 3584-dimethylbutyl, 42 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, or various branched isomers thereof, and the like. "C 1-10 Alkyl "refers to straight and branched alkyl groups comprising 1 to 10 carbon atoms," C 1-8 Alkyl "refers to straight and branched alkyl groups comprising 1 to 8 carbon atoms," C 0-8 Alkyl "refers to straight and branched alkyl groups of 0 to 8 carbon atoms," C 1-4 Alkyl "refers to straight and branched alkyl groups containing 1 to 4 carbon atoms," C 0 The alkyl group means that the number of carbon atoms is 0.
Alkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, halo-substituted C 1-10 Alkoxy, deuterium substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, = O, -SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Substituted with a substituent (b).
"cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, by which is meant a cyclic hydrocarbon which may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings have a fully conjugated pi-electron system, and is classified as monocyclic cycloalkyl, polycyclic cycloalkyl, preferably cycloalkyl containing from 3 to 10 or from 3 to 8 or from 3 to 6 carbon atoms, e.g., "C 3-10 Cycloalkyl "refers to a cycloalkyl group comprising 3 to 10 carbon atoms," C 3-8 Cycloalkyl "refers to a cycloalkyl group comprising 3 to 8 carbon atoms," C 3-6 Cycloalkyl "refers to a cycloalkyl group comprising 3 to 6 carbon atoms, wherein:
monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.
Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "spirocycloalkyl" refers to polycyclic groups which share a carbon atom (referred to as a spiro atom) between single rings, and these may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings have a completely conjugated pi-electron system. Spirocycloalkyl groups are classified as mono-, di-or multi-spirocycloalkyl depending on the number of spiro atoms shared between rings, including but not limited to:
Figure BDA0003535562350000131
"fused cyclic alkyl" refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings has a completely conjugated pi-electron system. And may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyl groups depending on the number of constituent rings, including, but not limited to:
Figure BDA0003535562350000132
"bridged cycloalkyl" refers to all-carbon polycyclic groups in which any two rings share two carbon atoms not directly attached, and these may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings have a completely conjugated pi-electron system. They may be classified according to the number of constituent rings as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups, including, but not limited to:
Figure BDA0003535562350000133
the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring to which the parent structure is attached is a cycloalkyl group, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.
Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) ofGroups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, = O, -SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Substituted with the substituent(s).
"Heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which means that the cyclic hydrocarbon may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings has a completely conjugated pi-electron system, and heterocyclyl, in which one or more (preferably 1,2, 3 or 4) ring atoms are selected from nitrogen, oxygen, S (O) (= NH) or S (O) r (wherein r is an integer of 0, 1, 2) heteroatoms, but excludes the ring moieties of-O-O-, -O-S-, and-S-S-, the remaining ring atoms being carbon, preferably a heterocyclic group comprising 3 to 10 or 3 to 8 or 3 to 6 ring atoms, e.g., "3-6 membered heterocyclic group" means a cyclic group comprising 3 to 6 ring atoms, "4-6 membered heterocyclic group" means a cyclic group comprising 4 to 6 ring atoms, and "3-10 membered heterocyclic group" means a cyclic group comprising 3 to 10 ring atoms.
Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups. "Spiroheterocyclyl" refers to polycyclic heterocyclic groups sharing one atom (referred to as a spiro atom) between single rings, one or more of which (preferably 1,2, 3, or4) ring atoms are selected from nitrogen, oxygen, S (O) (= NH) or S (O) r (wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1,2 or 3), but none of the rings has a completely conjugated pi-electron system. Spiro heterocyclic groups are classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multi-spiro heterocyclic group according to the number of spiro atoms shared between rings. Spiroheterocyclyl groups include, but are not limited to:
Figure BDA0003535562350000141
"fused heterocyclyl" means a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more (preferably 1,2, 3 or 4) rings may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more (preferably 1,2, 3 or 4) ring atoms is selected from nitrogen, oxygen, S (O) (= NH) or S (O) r (wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. They may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocycloalkyl depending on the number of rings comprising, but not limited to:
Figure BDA0003535562350000142
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Figure BDA0003535562350000151
"bridged heterocyclyl" means polycyclic heterocyclic groups in which any two rings share two atoms which are not directly attached, which may contain one or more (preferably 1,2 or 3) double bonds, but none of the rings has a completely conjugated pi-electron system, where one or more (preferably 1,2, 3 or 4) ring atoms are selected from nitrogen, oxygen, S (O) (= NH) or S (O) r (wherein r is an integer of 0, 1, 2) and the remaining ring atoms are carbon. According to the number of constituent rings, they may be bicyclic, tricyclic, tetracyclic or polycyclicBridged heterocyclic groups, including but not limited to:
Figure BDA0003535562350000152
the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl, including but not limited to:
Figure BDA0003535562350000153
the heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, halo-substituted C 1-10 Alkoxy, deuterium substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, = O, -SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Substituted with the substituent(s).
"aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group, having a common occurrencePolycyclic (i.e. rings with adjacent pairs of carbon atoms) groups of conjugated pi-electron systems, preferably all-carbon aryl groups containing 5-10 or 5-8 carbons, e.g. "C 5-10 Aryl "refers to all-carbon aryl groups containing 5 to 10 carbons, including but not limited to phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, including but not limited to:
Figure BDA0003535562350000154
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Figure BDA0003535562350000161
"aryl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, halo-substituted C 1-10 Alkoxy, deuterium substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, = O, -SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Substituted with the substituent(s).
"heteroaryl" refers to a heteroaromatic system containing one or more (preferably 1,2, 3, or 4) heteroatoms including nitrogen, oxygen, and heteroatoms of S (O) r (where r is an integer of 0, 1, 2), preferably a heteroaromatic system containing 5 to 10 or 5 to 8 ring atoms, for example, "5-10 membered heteroaryl" refers to a heteroaromatic system containing 5 to 10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring, including, but not limited to:
Figure BDA0003535562350000162
"heteroaryl" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, halo-substituted C 1-10 Alkoxy, deuterium substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, = O, -SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Substituted with the substituent(s).
"alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched chain alkenyl group containing 2 to 10 or 2 to 4 carbons, e.g., "C 2-10 Alkenyl "means a straight or branched chain alkenyl group having 2 to 10 carbons," C 2-4 Alkenyl "means a straight or branched chain alkenyl group containing 2 to 4 carbons. Including but not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like.
"alkenyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, halo-substituted C 1-10 Alkoxy, deuterium substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, = O, -SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Substituted with the substituent(s).
"alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight or branched chain alkynyl group containing 2-10 or 2-4 carbons, e.g., "C 2-10 Alkynyl "refers to straight chains containing 2-10 carbonsChain or branched alkynyl group containing "C 2-4 Alkynyl "refers to straight or branched chain alkynyl groups containing 2-4 carbons. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl, and the like.
"alkynyl" groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, halo-substituted C 1-10 Alkoxy, deuterium substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, = O, -SF 5 -C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Substituted with the substituent(s).
"alkoxy" refers to-O-alkyl, wherein alkyl is as defined above, e.g., "C 1-10 Alkoxy "means an alkyloxy group having 1 to 10 carbons," C 1-4 Alkoxy "refers to an alkyloxy group containing 1 to 4 carbons including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
"alkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituents, preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, halo-substituted C 1-10 Alkoxy, deuterium substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, = O, -SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Substituted with the substituent(s).
"Cycloalkoxy" refers to-O-cycloalkyl wherein cycloalkyl is as defined above, e.g., "C 3-10 Cycloalkoxy "refers to cycloalkyloxy groups containing 3-10 carbons, including but not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
"Cycloalkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, halo-substituted C 1-10 Alkoxy, deuterium substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkoxy radical, C 3-10 Cycloalkyl, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, = O, -SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Substituted with a substituent (b).
"heterocyclyloxy" refers to-O-heterocyclyl, wherein heterocyclyl is defined above, heterocyclyloxy including, but not limited to, azetidinyloxy, oxetanyloxy, cyclopentyloxy, nitrogen, oxacyclohexyloxy, and the like.
"heterocyclooxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, halo-substituted C 1-10 Alkoxy, deuterium substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkoxy radical, C 3-10 Cycloalkyl radical, C 3-10 Cycloalkoxy, 3-to 10-membered heterocyclic group, 3-to 10-membered heterocyclic oxy, C 5-10 Aryl radical, C 5-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, = O, -SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Substituted with the substituent(s).
“C 1-10 Alkanoyl "means C 1-10 The monovalent radical remaining after removal of the hydroxyl group from the alkyl acid, also commonly referred to as "C 0-9 -C (O) - ", e.g.," C 1 -C (O) - "means acetyl; "C 2 -C (O) - "refers to propionyl; "C 3 -C (O) - "means butyryl or isobutyryl.
“-C 0-8 alkyl-S (O) r R 20 "means-S (O) r R 20 With sulfur atoms bound to C 0-8 On the alkyl radical, C 0-8 The alkyl group is as defined above.
“-C 0-8 alkyl-O-R 21 "means-O-R 21 In which the oxygen atom is bound to C 0-8 On the alkyl radical, C 0-8 The alkyl group is as defined above.
“-C 0-8 alkyl-C (O) OR 21 "means-C (O) OR 21 In which the carbonyl group is attached to C 0-8 On the alkyl radical, C 0-8 The alkyl group is as defined above.
“-C 0-8 alkyl-C (O) R 22 "means-C (O) R 22 Wherein the carbonyl group is bound to C 0-8 On the alkyl radical, C 0-8 The alkyl group is as defined above.
“-C 0-8 alkyl-O-C (O) R 22 "means-O-C (O) R 22 In which the oxygen atom is bound to C 0-8 On the alkyl radical, C 0-8 The alkyl group is as defined above.
“-C 0-8 alkyl-NR 23 R 24 "means-NR 23 R 24 In which the nitrogen atom is bound to C 0-8 On the alkyl radical, C 0-8 The alkyl group is as defined above.
“-C 0-8 alkyl-C (= NR) 23 )R 22 "means-C (= NR) 23 )R 22 In which the nitrogen atom is bound to C 0-8 On the alkyl radical, C 0-8 The alkyl group is as defined above.
“-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 "means-N (R) 23 )-C(＝NR 24 )R 22 In which the nitrogen atom is bound to C 0-8 On the alkyl radical, C 0-8 The alkyl group is as defined above.
“-C 0-8 alkyl-C (O) NR 23 R 24 "means-C (O) NR 23 R 24 Wherein the carbonyl group is bound to C 0-8 On the alkyl radical, C 0-8 The alkyl group is as defined above.
“-C 0-8 alkyl-N (R) 23 )-C(O)R 22 "means-N (R) 23 )-C(O)R 22 In which the nitrogen atom is bound to C 0-8 On the alkyl radical, C 0-8 The alkyl group is as defined above.
"halogen substituted C 1-4 Alkyl "refers to a 1-4C alkyl group optionally substituted with fluorine, chlorine, bromine, iodine atoms for the hydrogen on the alkyl group, including but not limited to difluoromethyl (-CHF) 2 ) Dichloromethyl (-CHCl) 2 ) Dibromomethyl (-CHBr) 2 ) Trifluoromethyl (-CF) 3 ) Trichloromethyl (-CCl) 3 ) Tribromomethyl (-CBr) 3 ) And the like.
"halogen substituted C 1-4 Alkoxy "refers to a 1-4 carbon alkoxy group wherein the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.
"deuterium substituted C 1-4 Alkyl "refers to a 1-4 carbon alkyl group optionally substituted with deuterium atoms for the hydrogen on the alkyl group. Including but not limited to, deuteromethyl (-CH) 2 D) Dideuteromethyl (-CHD) 2 ) Trideuteromethyl (-CD) 3 ) And the like.
"deuterium substituted C 1-4 Alkoxy "refers to a 1-4 carbon alkyl group optionally substituted with deuterium atoms for the hydrogen on the alkyl group. Including but not limited to mono-, di-, tri-deuteromethoxy, and the like.
"halogen" means fluorine, chlorine, bromine or iodine. "MeOH" refers to methanol. "KF" refers to potassium fluoride. "KHMDS" refers to potassium hexamethyldisilazide. "NBS" refers to N-bromosuccinimide. "DMF" refers to N, N-dimethylformamide. "Grubbs generation 2 catalyst" refers to the Glabra generation II catalyst. "IBX" refers to 2-iodoxybenzoic acid.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not occur, i.e., both substituted and unsubstituted. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the heterocyclic group is not substituted with an alkyl group.
"substituted" means that one or more "hydrogen atoms" in a group are substituted, independently of each other, with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with the chemical valence bond theory, and that the person skilled in the art is able to determine (experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated bonds (e.g., olefins).
"stereoisomers", whose english name is stereooisomer, refer to isomers produced by different arrangement of atoms in a molecule in space, and can be divided into cis-trans isomers, enantiomers, and also into enantiomers and diastereomers. Stereoisomers resulting from rotation of single bonds are called conformational isomers (conformational stereo-isomers) and sometimes rotamers (rotamers). Stereoisomers caused by bond length, bond angle, double bond in a molecule, ring and the like are called configurational isomers (configurational isomers), and the configurational isomers are divided into two types. Wherein the isomer caused by the fact that the double bond or the single bond of the ring-forming carbon atoms can not rotate freely becomes a geometric isomer (cis-trans isomer), which is also called cis-trans isomer, and is divided into two configurations Z, E. For example: cis-2-butene and trans-2-butene are a pair of geometric isomers, and the compounds of the present invention, if containing a double bond, are understood to contain the E and/or Z forms, if not specifically indicated. Stereoisomers with different optical activity due to lack of trans-axial symmetry in the molecule are called optical isomers (optical isomers) and are classified as R, S configurations. In the present invention, the term "stereoisomer" is understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers, unless otherwise specified.
"pharmaceutically acceptable salts" as used herein refers to pharmaceutically acceptable acid addition salts or base addition salts, including inorganic acid salts and organic acid salts, which salts may be prepared by methods known in the art.
"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient, and exert biological activity.
The present invention will be described more fully with reference to the following examples, but the present invention is not limited thereto, and the present invention is not limited to the examples.
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker AVANCE-400/500 nuclear magnetic resonance spectrometer using deuterated dimethyl sulfoxide (DMSO-d) as the solvent 6 ) Deuterated methanol (CD) 3 OD) and deuterated chloroform (CDCl) 3 ) Internal standard is Tetramethylsilane (TMS).
LC-MS was measured using an Agilent 6120 mass spectrometer. HPLC was carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18X 4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18X 4.6mm column).
The thin layer chromatography silica gel plate adopts a tobacco yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to methods known in the art.
All reactions of the present invention are carried out under a dry nitrogen or argon atmosphere with continuous magnetic stirring, without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees centigrade (deg.C).
Preparation of intermediates
Intermediate 1:2,5,6-trichloronicotinoyl chloride preparation
Figure BDA0003535562350000201
2,5,6-trichloronicotinic acid (5.1g, 22.5 mmol) was dissolved in dichloromethane (50 mL) and N, N-dimethylformamide (0.5 mL) was added. Oxalyl chloride (4.29g, 33.8 mmol) was added dropwise to the above solution under nitrogen protection. After completion of the dropwise addition, the mixture was stirred at 25 ℃ for 1 hour, and the reaction mixture was concentrated under reduced pressure to remove the solvent to give 2,5,6-trichloronicotinoyl chloride (5.52 g, yield: 100%), and the crude product was directly subjected to the next reaction.
The preparation of intermediate 2 can be obtained by reference to the synthesis of intermediate 1:
Figure BDA0003535562350000202
preparation of examples
Example 1:2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-3 6 -fluoro-6,7-dihydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 Preparation of (E) -carbonitrile
Figure BDA0003535562350000203
/>
Figure BDA0003535562350000211
The first step is as follows: synthesis of 2-cyano-N- (2-isopropyl-4-vinylpyridin-3-yl) acetamide
2-isopropyl-4-vinylpyridin-3-amine (5g, 30.8mmol) was dissolved in 1,2-dichloroethane (50 mL), and 2-cyanoacetic acid (5.24g, 61.6mmol) and triethylamine (17.1mL, 123mmol) were added, respectively. Tri-n-propylcyclic phosphoric anhydride (50% ethyl acetate solution, 39g,61.6 mmol) was added dropwise under nitrogen protection, and the reaction solution was stirred at 50 ℃ for 1 hour. After 1,2-dichloroethane were removed by concentration under reduced pressure, 300mL of a saturated aqueous solution of sodium hydrogencarbonate was added to the residue, extraction was performed with ethyl acetate (300 mL), the organic phase was dried over anhydrous sodium sulfate and then the solvent was removed by concentration under reduced pressure, and the residue was separated by flash silica gel column to give 2-cyano-N- (2-isopropyl-4-vinylpyridin-3-yl) acetamide (3.75 g, yield: 53%). ESI-MS [ 230 ] M +H] + 。
The second step is that: synthesis of 6,7-dichloro-4-hydroxy-1- (2-isopropyl-4-vinylpyridin-3-yl) -2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile
2-cyano-N- (2-isopropyl-4-vinylpyridin-3-yl) acetamide (5.05g, 22.0 mmol) was dissolved in tetrahydrofuran (50 mL), and sodium hydride (1.32g, 33.0 mmol) was added slowly in portions under nitrogen protection at 0 ℃ and after the addition of sodium hydride was complete, the mixture was stirred at 0 ℃ for 30 minutes. 2,5,6-trichloronicotinoyl chloride (5.39g, 22.0 mmol) was dissolved in 50mL tetrahydrofuran and added dropwise to the above solution under nitrogen. After the dropwise addition, the reaction mixture was reacted at 70 ℃ for 6 hours. The reaction solution was slowly poured into 200mL of water, extracted with ethyl acetate (300 mL), washed with saturated aqueous sodium chloride solution (100 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated with flash silica gel column to give 6,7-dichloro-4-hydroxy-1- (2-isopropyl-4-vinylpyridin-3-yl) -2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (2 g, yield: 22.6%). ESI-MS 401[ deg. ] M + H ]] + 。
The third step: synthesis of tert-butyl 4- (6,7-dichloro-3-cyano-1- (2-isopropyl-4-vinylpyridin-3-yl) -2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl) piperazine-1-carboxylate
6,7-dichloro-4-hydroxy-1- (2-isopropyl-4-vinylpyridin-3-yl) -2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile (3.13g, 7.80mmol) was dissolved in acetonitrile (35 mL) and N, N-diisopropyl ether was added slowly under nitrogen protection at 0 deg.C, respectivelyYlethylamine (3.87mL, 23.4 mmol), phosphine oxychloride (1.09mL, 11.7 mmol). The mixture was reacted at 80 ℃ for 1 hour. LC-MS detected 60% of the product in the reaction solution, and N, N-diisopropylethylamine (2.23mL, 13.7 mmol) and tert-butylpiperazine-1-carboxylate (0.85g, 4.57mmol) were added to the reaction solution at room temperature. The mixture was reacted at room temperature overnight. The reaction solution was slowly poured into 200mL of water, extracted with ethyl acetate (200 mL), washed with saturated aqueous sodium chloride solution (100 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated with flash silica gel column to give tert-butyl 4- (6,7-dichloro-3-cyano-1- (2-isopropyl-4-vinylpyridin-3-yl) -2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl) piperazine-1-carboxylate (2.12 g, yield: 81.4%). ESI-MS 569[ 2 ] M + H] + 。
The fourth step: synthesis of tert-butyl 4- (6-chloro-3-cyano-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-vinylpyridin-3-yl) -2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl) piperazine-1-carboxylate
Tert-butyl 4- (6,7-dichloro-3-cyano-1- (2-isopropyl-4-vinylpyridin-3-yl) -2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl) piperazine-1-carboxylic acid ester (1.89g, 3.57mmol) was dissolved in a mixed solvent of 1,4-dioxane (20 mL) and water (5 mL). Trifluoro (2-fluoro-6-hydroxyphenyl) borate (1.01g, 4.64mmol), potassium acetate (0.7g, 7.14mmol) and Pd (dppf) Cl were added separately 2 (0.26g, 0.357mmol), and reacted at 90 ℃ for 1 hour under nitrogen protection. The reaction solution was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride (100 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated with a flash silica gel column to give tert-butyl 4- (6-chloro-3-cyano-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl-4-vinylpyridin-3-yl) -2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl) piperazine-1-carboxylate (1.42 g, yield: 65.7%). ESI-MS [ 645 ] M +H] + 。
The fifth step: synthesis of tert-butyl 4- (7- (2- (allyloxy) -6-fluorophenyl) -6-chloro-3-cyano-1- (2-isopropyl-4-vinylpyridin-3-yl) -2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl) piperazine-1-carboxylate
Tert-butyl 4- (6-chloro-3-cyano-7- (2-fluoro-6-hydroxyphenyl) -1- (2-isopropyl) methyl acetate-4-vinylpyridin-3-yl) -2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl) piperazine-1-carboxylate (1.42g, 3.57mmol) was dissolved in acetonitrile (20 mL). 3-bromoprop-1-ene (0.58mL, 6.60mmol) and potassium carbonate (608mg, 4.40mmol) were added, respectively, and reacted at 70 ℃ for 1 hour. The reaction solution was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride (100 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated with a flash silica gel column to give tert-butyl 4- (7- (2- (allyloxy) -6-fluorophenyl) -6-chloro-3-cyano-1- (2-isopropyl-4-vinylpyridin-3-yl) -2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl) piperazine-1-carboxylate (1.34 g, yield: 89.2%). ESI-MS 685[ sic ], [ M ] +H] + 。
And a sixth step: tert-butyl (Z) -4- (2) 6 -chloro-2 3 -cyano-3 6 -fluoro-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocyclohepten-6-ene-2 4 Synthesis of (E) -yl) piperazine-1-carboxylic acid esters
Tert-butyl 4- (7- (2- (allyloxy) -6-fluorophenyl) -6-chloro-3-cyano-1- (2-isopropyl-4-vinylpyridin-3-yl) -2-oxo-1,2-dihydro-1,8-naphthyridin-4-yl) piperazine-1-carboxylate (1.24g, 1.82mmol) was dissolved in 1,2-dichloroethane (500 mL), grubbs's secondary catalyst (0.23g, 0.36mmol) was added under nitrogen and reacted overnight at 60 ℃. Concentrating the reaction solution under reduced pressure to remove the solvent, and separating the residue with a flash silica gel column to obtain tert-butyl (Z) -4- (2) 6 -chloro-2 3 -cyano-3 6 -fluoro-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocyclohepten-6-ene-2-ene 4 -yl) piperazine-1-carboxylic acid ester (1.1 g, purity: 80%, yield: 73.6%). ESI-MS 657[ 2 ] M + H] + 。
The seventh step: tert-butyl 4- (2) 6 -chloro-2 3 -cyano-3 6 -fluoro-6,7-dihydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 4 Synthesis of (E) -yl) piperazine-1-carboxylic acid esters
Mixing-butyl (Z) -4- (2) 6 -chloro-2 3 -cyano-3 6 -fluoro-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocyclohepten-6-ene-2 4 -yl) piperazine-1-carboxylate (400mg, 0.609mmol) was dissolved in acetone (5 mL), and ethylene glycol (151mg, 2.43mmol) and sodium bicarbonate (153mg, 1.83mmol) were added, respectively. Under the protection of nitrogen, the mixed solution is cooled to-20 ℃, and potassium permanganate (96.2mg, 0.609mmol) is added in batches. The reaction solution was slowly raised to 0 ℃ and reacted for 2 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium chloride (100 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated on flash silica gel to give tert-butyl 4- (2) 6 -chloro-2 3 -cyano-3 6 -fluoro-6,7-dihydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 4 -yl) piperazine-1-carboxylic acid ester (267 mg, yield: 63.5%). ESI-MS 691[ m ] +H ]] + 。
Eighth step: 2 6 -chloro-3 6 -fluoro-6,7-dihydroxy-1 2 -isopropyl-2 2 -oxo-2 4 - (piperazin-1-yl) -2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -Synthesis of carbonitrile
Reacting tert-butyl 4- (2) 6 -chloro-2 3 -cyano-3 6 -fluoro-6,7-dihydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 4 -yl) piperazine-1-carboxylate (135mg, 0.195mmol) was dissolved in dichloromethane (5 mL), the solution was cooled to 0 deg.C, and trifluoroacetic acid (0.8 mL) was added dropwise under nitrogen. The reaction was carried out at 0 ℃ for 1 hour. The reaction solution is directly decompressed and concentrated to remove the solvent, and a crude product is directly used for the next reaction. ESI-MS 591 (+H) (+)] + 。
The ninth step: 2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-3 6 -fluoro-6,7-dihydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -Synthesis of carbonitrile
Will 2 6 -chloro-3 6 -fluoro-6,7-dihydroxy-1 2 -isopropyl-2 2 -oxo-2 4 - (piperazin-1-yl) -2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -carbonitrile (100mg, 0.1699 mmol) was dissolved in anhydrous dichloromethane (5 mL), and triethylamine (85.6mg, 0.846mmol) was added. Cooled to-10 ℃, added with propane-2-enoyl chloride (15.3 mg, 0.1699 mmol) dropwise under the protection of nitrogen, and reacted for 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with a saturated aqueous solution of sodium chloride (30 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated by a reverse phase column to give 2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-3 6 -fluoro-6,7-dihydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -carbonitrile (24 mg, yield: 22.0%, purity: 98.84%). ESI-MS [ 645 ] M +H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ8.55-8.48(m,2H),8.01(br d,J＝4.8Hz,1H),7.46(q,J＝8.0Hz,1H),7.12(br d,J＝8.5Hz,1H),7.03-6.87(m,2H),6.21(br d,J＝16.6Hz,1H),5.83-5.73(m,2H),5.19(br d,J＝8.5Hz,1H),4.48(br dd,J＝4.8,8.0Hz,1H),4.05-3.69(m,10H),3.33-3.28(m,1H),2.88(td,J＝6.3,13.1Hz,1H),1.18(br d,J＝6.3Hz,3H),0.83(br d,J＝6.5Hz,3H).
Example 2: (Z) -2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-3 6 -fluoro-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocyclohepten-6-ene-2-ene 3 Preparation of (E) -carbonitrile
Figure BDA0003535562350000231
The first step is as follows: (Z) -2 6 -chloro-3 6 -fluoro-1 2 -isopropyl-2 2 -oxo-2 4 - (piperazin-1-yl) -2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocyclohepten-6-ene-2-ene 3 -Synthesis of carbonitrile
Reacting tert-butyl (Z) -4- (2) 6 -chloro-2 3 -cyano-3 6 -fluoro-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocyclohepten-6-ene-2-ene 4 -yl) piperazine-1-carboxylate (80mg, 0.12mmol) was dissolved in dichloromethane (3 mL), the solution was cooled to 0 deg.C, trifluoroacetic acid (0.5 mL) was added dropwise under nitrogen, and the reaction was carried out at 0 deg.C for 1 hour. The reaction solution is directly decompressed and concentrated to remove the solvent, and a crude product is directly used for the next reaction. ESI-MS 557[ m ] +H ]] + 。
The second step is that: (Z) -2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-3 6 -fluoro-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocyclohepten-6-ene-2-ene 3 -Synthesis of carbonitrile
Will (Z) -2 6 -chloro-3 6 -fluoro-1 2 -isopropyl-2 2 -oxo-2 4 - (piperazin-1-yl) -2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocyclohepten-6-ene-2 3 Carbonitrile (67mg, 0.120mmol) was dissolved in anhydrous dichloromethane (3 mL) and triethylamine (60.8mg, 0.60mmol) was added. Cooled to-10 ℃, added with propane-2-enoyl chloride (10.8mg, 0.12mmol) dropwise under the protection of nitrogen, and reacted for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium chloride (30 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated by a reverse phase column to give (Z) -2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-3 6 -fluoro-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocyclohepten-6-ene-2-ene 3 -carbonitrile (7 mg, yield: 9.52%, purity: 97.34%). ESI-MS [ sic ], [ solution ] M [ sic ] +H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ8.54(d,J＝4.8Hz,1H),8.45(s,1H),7.56-7.41(m,1H),7.18-6.86(m,1H),7.20-6.86(m,3H),6.38(d,J＝11.3Hz,1H),6.21(dd,J＝2.1,16.7Hz,1H),5.85-5.70(m,2H),4.75(dd,J＝2.9,9.7Hz,1H),3.98-3.76(m,8H),3.33(br s,1H),2.87(td,J＝6.5,13.4Hz,1H),1.18(d,J＝6.5Hz,3H),0.83(d,J＝6.5Hz,3H).
Examples 4 and 5:2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-7-ethoxy-3 6 -fluoro-6-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -carbonitriles and 2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-6-ethoxy-3 6 -fluoro-7-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 Preparation of (E) -carbonitrile
Figure BDA0003535562350000241
The first step is as follows: tert-butyl 4- (2) 6 -chloro-2 3 -cyano-7-ethoxy-3 6 -fluoro-6-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 4 -yl) piperazine-1-carboxylic acid ester and tert-butyl 4- (2) 6 -chloro-2 3 -cyano-6-ethoxy-3 6 -fluoro-7-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 4 Synthesis of (E) -yl) piperazine-1-carboxylic acid esters
Reacting tert-butyl 4- (2) 6 -chloro-2 3 -cyano-3 6 -fluoro-6,7-dihydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 4 -radical) piperazineOxazine-1-carboxylic acid ester (80mg, 0.17mmol) was dissolved in ethyl acetate (3 mL), and iodoethane (144mg, 0.93mmol), copper acetylacetonate (9.1mg, 0.04mmol), silver oxide (21.4mg, 0.09mmol), tetrabutylammonium bromide (22.4mg, 0.07mmol) were added, respectively. Stirring was carried out overnight at 60 ℃ under nitrogen. The reaction mixture was diluted with ethyl acetate (20 mL), filtered, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was separated with flash silica gel column to give tert-butyl 4- (2) 6 -chloro-2 3 -cyano-7-ethoxy-3 6 -fluoro-6-hydroxy-1 2 -isopropyl-2 2 -carbonyl-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 4 -yl) piperazine-1-carboxylic acid ester and tert-butyl 4- (2) 6 -chloro-2 3 -cyano-6-ethoxy-3 6 -fluoro-7-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 4 -yl) piperazine-1-carboxylic acid ester (74 mg, yield: 84.1%). ESI-MS [ 719 ] M +H] + 。
The second step is that: 2 6 -chloro-7-ethoxy-3 6 -fluoro-6-hydroxy-1 2 -isopropyl-2 2 -oxo-2 4 - (piperazin-1-yl) -2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -carbonitriles and 2 6 -chloro-6-ethoxy-3 6 -fluoro-7-hydroxy-1 2 -isopropyl-2 2 -oxo-2 4 - (piperazin-1-yl) -2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -Synthesis of carbonitrile
Reacting tert-butyl 4- (2) 6 -chloro-2 3 -cyano-7-ethoxy-3 6 -fluoro-6-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 4 -yl) piperazine-1-carboxylic acid ester and tert-butyl 4- (2) 6 -chloro-2 3 -cyano-6-ethoxy-3 6 -fluoro-7-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 4 The mixture of-yl) piperazine-1-carboxylate (70mg, 0.10 mmol) was dissolved in dichloromethane (3 mL), the solution was cooled to 0 deg.C, trifluoroacetic acid (0.5 mL) was added dropwise under nitrogen, and the reaction was carried out at 0 deg.C for 2 hours. The reaction solution is directly decompressed and concentrated to remove the solvent, and a crude product is directly used for the next reaction. ESI-MS [ 2 ] [ 619M + H ]] + 。
The third step: 2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-7-ethoxy-3 6 -fluoro-6-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -carbonitrile and 2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-6-ethoxy-3 6 -fluoro-7-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -Synthesis of carbonitrile
The mixture from the above step (50mg, 0.081mmol) was dissolved in anhydrous dichloromethane (3 mL), and triethylamine (40.8mg, 0.40mmol) was added. After cooling to-20 ℃, propan-2-enoyl chloride (7.15mg, 0.08mmol) was added dropwise under nitrogen protection, and the reaction was carried out for 2 hours. The reaction solution was diluted with ethyl acetate (20 mL), washed with saturated aqueous sodium chloride (30 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated by a reverse phase column to give 2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-7-ethoxy-3 6 -fluoro-6-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -carbonitrile (9.5 mg, yield: 17.3%, purity: 98.93%) and 2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-6-ethoxy-3 6 -fluoro-7-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -carbonitrile (7.8 mg, yield: 13.9%, purity: 97.10%). ESI-MS 673[ sic ] M +H] + 。
Example 4:2 4 - (4-acryloyl)Piperazin-1-yl) -2 6 -chloro-6-ethoxy-3 6 -fluoro-7-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -carbonitrile
1 H NMR(400MHz,DMSO-d 6 )δ8.50(s,1H),7.89(d,J＝5.0Hz,1H),7.51-7.43(m,1H),7.15(d,J＝8.3Hz,1H),7.02-6.88(m,2H),6.21(dd,J＝2.4,16.7Hz,1H),5.81-5.75(m,1H),5.30(d,J＝9.0Hz,1H),4.62(dd,J＝4.6,8.7Hz,1H),3.99(br dd,J＝3.8,9.0Hz,4H),3.82-3.67(m,6H),3.47-3.37(m,2H),3.32-3.29(m,1H),2.89(quin,J＝6.7Hz,1H),1.21-1.16(m,6H),0.84(d,J＝6.8Hz,3H).
Example 5:2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-7-ethoxy-3 6 -fluoro-6-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -carbonitrile
1 H NMR(400MHz,DMSO-d 6 )δ8.56(d,J＝5.0Hz,1H),8.50(s,1H),8.01(d,J＝5.3Hz,1H),7.53-7.42(m,1H),7.14(d,J＝8.3Hz,1H),7.05-6.87(m,2H),6.21(dd,J＝2.4,16.7Hz,1H),5.82-5.74(m,1H),5.70(d,J＝4.8Hz,1H),4.46(dd,J＝4.9,8.7Hz,1H),4.25(qd,J＝4.7,9.3Hz,1H),4.04-3.71(m,10H),3.33(br d,J＝2.5Hz,1H),3.17-3.09(m,1H),2.87(td,J＝6.7,13.3Hz,1H),1.18(d,J＝6.8Hz,3H),0.94(t,J＝6.9Hz,3H),0.83(d,J＝6.8Hz,3H).
Example 14:2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-2 3 -cyano-3 6 -fluoro-6-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 Preparation of-dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocyclohepten-7-yl acetate
Figure BDA0003535562350000261
The first step is as follows: tert-butyl 4- (7-acetoxy-2) 6 -chloro-2 3 -cyano-3 6 -fluoro-6-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 4 Synthesis of-yl) piperazine-1-carboxylic acid esters
Reacting tert-butyl 4- (2) 6 -chloro-2 3 -cyano-3 6 -fluoro-6,7-dihydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 4 -yl) piperazine-1-carboxylic acid ester (80mg, 0.17mmol) was dissolved in dichloromethane (3 mL), and triethylamine (35.1mg, 0.35mmol), acetyl chloride (9.1mg, 0.04mmol), silver oxide (21.4mg, 0.09mmol), tetrabutylammonium bromide (27.3mg, 0.35mmol) were added, respectively, at 0 ℃. Stirring was carried out overnight at 0 ℃ under nitrogen. The reaction was diluted with ethyl acetate (20 mL), filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was used directly in the next step. ESI-MS719[ M + H ]] + 。
The second step: 2 6 -chloro-2 3 -cyano-3 6 -fluoro-6-hydroxy-1 2 -isopropyl-2 2 -oxo-2 4 - (piperazin-1-yl) -2 1 ,2 2 Synthesis of-dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocyclohepten-7-yl acetate
Reacting tert-butyl 4- (7-acetoxy-2) 6 -chloro-2 3 -cyano-3 6 -fluoro-6-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 4 -yl) piperazine-1-carboxylate (45mg, 0.06mmol) was dissolved in dichloromethane (3 mL), the solution was cooled to 0 deg.C, trifluoroacetic acid (0.5 mL) was added dropwise under nitrogen, and the reaction was carried out at 0 deg.C for 1 hour. The reaction solution is directly decompressed and concentrated to remove the solvent, and a crude product is directly used for the next reaction. ESI-MS 2 [ 2 ], [ M ] +H] + 。
The third step: 2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-2 3 -cyano-3 6 -fluoro-6-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-Synthesis of 7-yl acetate
Will 2 6 -chloro-2 3 -cyano-3 6 -fluoro-6-hydroxy-1 2 -isopropyl-2 2 -oxo-2 4 - (piperazin-1-yl) -2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocyclohepten-7-yl acetate (35mg, 0.06mmol) was dissolved in anhydrous dichloromethane (3 mL) and triethylamine (16.7 mg, 0.17mmol) was added. Cooled to-20 ℃, added with propane-2-enoyl chloride (4.98mg, 0.06mmol) dropwise under the protection of nitrogen, and reacted for 2 hours. The reaction mixture was diluted with ethyl acetate (20 mL), washed with a saturated aqueous solution of sodium chloride (30 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated by a reverse phase column to give 2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-2 3 -cyano-3 6 -fluoro-6-hydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocyclohepten-7-yl acetate (6 mg, yield: 14.5%, purity: 91.20%). ESI-MS 687[ deg. ] C [ M ] +H ]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ8.62(d,J＝5.0Hz,1H),8.54(s,1H),8.17(d,J＝5.0Hz,1H),7.53-7.42(m,1H),7.12(d,J＝8.3Hz,1H),7.02-6.86(m,2H),6.27-6.12(m,2H),5.82-5.74(m,1H),5.35(d,J＝3.3Hz,1H),4.57(dd,J＝5.3,8.8Hz,1H),4.21-4.08(m,1H),4.06-3.72(m,10H),1.87(s,3H),1.16(d,J＝6.5Hz,3H),0.89-0.84(m,3H).
Example 16:2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-3 6 -fluoro-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 Preparation of (E) -carbonitrile
Figure BDA0003535562350000271
The first step is as follows: tert-butyl 4- (2) 6 -chloro-2 3 -cyano-3 6 -fluoro-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 4 Synthesis of (E) -yl) piperazine-1-carboxylic acid esters
Reacting tert-butyl (Z) -4- (2) 6 -chloro-2 3 -cyano-3 6 -fluoro-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocyclohepten-6-ene-2 4 -yl) piperazine-1-carboxylate (30mg, 0.05mmol) was dissolved in methanol (10 mL) and added to a hydrogenation flask. Under nitrogen protection, tris (triphenylphosphine) rhodium (I) chloride (4.2mg, 0.01mmol) was added. The solution was replaced with hydrogen several times and stirred overnight at 50 ℃ under hydrogen atmosphere (50 psi). The reaction was filtered through celite, concentrated under reduced pressure and the crude was used directly in the next step. ESI-MS 659[ sic ] M +H] + 。
The second step: 2 6 -chloro-3 6 -fluoro-1 2 -isopropyl-2 2 -oxo-2 4 - (piperazin-1-yl) -2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -Synthesis of carbonitrile
Crude tert-butyl 4- (2) obtained in the previous step 6 -chloro-2 3 -cyano-3 6 -fluoro-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 4 -yl) piperazine-1-carboxylate (20mg, 0.030mmol) was dissolved in dichloromethane (3 mL), the solution was cooled to 0 ℃, trifluoroacetic acid (0.5 mL) was added dropwise under nitrogen protection, and the reaction was carried out at 0 ℃ for 1 hour. The reaction solution is directly decompressed and concentrated to remove the solvent, and a crude product is directly used for the next reaction. ESI-MS 559[ 2 ] M + H] + 。
The third step: 2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-3 6 -fluoro-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -Synthesis of carbonitrile
Will 2 6 -chloro-3 6 -fluoro-1 2 -isopropyl-2 2 -oxo-2 4 - (piperazin-1-yl) -2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -carbonitrile (15mg, 0.03mmol) was dissolved in anhydrous dichloromethane (3 mL), and triethylamine (10.8mg, 0.11mmol) was added. Cooled to-10 ℃ and added dropwise with 2.43mg (0.03mmol) of prop-2-enoyl chloride under nitrogen protection to react for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), washed with a saturated aqueous solution of sodium chloride (30 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, and the residue was separated by a reverse phase column to give 2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-3 6 -fluoro-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -, naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -carbonitrile (1.8 mg, yield: 10.9%, purity: 100%). ESI-MS [ 613 ] M +H] + 。
1 H NMR(400MHz,DMSO-d 6 )δ8.58-8.41(m,2H),7.53-7.41(m,1H),7.33(d,J＝5.1Hz,1H),7.10(d,J＝8.4Hz,1H),7.02-6.85(m,2H),6.21(dd,J＝2.3,16.6Hz,1H),5.77(dd,J＝2.2,10.4Hz,1H),4.46(br d,J＝5.8Hz,1H),4.09-3.66(m,8H),2.90(td,J＝6.6,13.3Hz,1H),2.40-2.23(m,3H),2.05-1.98(m,2H),1.17(d,J＝6.6Hz,3H),0.86(d,J＝6.6Hz,3H).
Example 17: (R) -2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-3 6 -fluoro-6,7-dihydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 Preparation of (E) -carbonitrile
Figure BDA0003535562350000281
2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-3 6 -fluoro-6,7-dihydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -carbonitrile resolution by SFC to give compound (R) -2 4 - (4-acryloylpiperazin-1-yl) -2 6 -chloro-3 6 -fluoro-6,7-dihydroxy-1 2 -isopropyl-2 2 -oxo-2 1 ,2 2 -dihydro-4-oxa-2 (1,7) -naphthyridine-1 (3,4) -pyridine-3 (1,2) -benzocycloheptane-2 3 -carbonitrile.
1 H NMR(400MHz,DMSO-d 6 )δ8.55-8.47(m,2H),8.00(d,J＝5.0 Hz,1H),7.51-7.42(m,1H),7.12(d,J＝8.4 Hz,1H),7.02-6.88(m,2H),6.21(dd,J＝2.2,16.7 Hz,1H),5.81-5.74(m,2H),5.19(d,J＝8.6 Hz,1H),4.52-4.44(m,1H),4.06-3.67(m,10H),2.93-2.84(m,1H),1.18(d,J＝6.6 Hz,3H),0.83(br d,J＝6.6 Hz,4H).
The preparation of the compounds of examples 3,6 to 13, 15 can be obtained by the synthesis methods referred to in examples 1,2 or 4 and 5, or by the conventional synthesis of the compounds of examples 1 or 2:
Figure BDA0003535562350000282
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Figure BDA0003535562350000291
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Figure BDA0003535562350000301
biological test evaluation
1. H358 and MiaPaCa-2 cell line antiproliferative 2D CTG assay
1. Experimental procedure
1) Plating on day 0:
when the cells were approximately 80% confluent, the cells were detached with 0.25% trypsin. The separated cells were resuspended in 5mL of fresh cell culture medium and centrifuged to collect the cells. The number of cells was also counted. The cells were then suspended in medium concentration medium. Cells were placed in 96-well plates with H358 at 1500 cells/well and MIAPACA-2 at 500 cells/well. The 96-well plate was incubated overnight at 37 ℃ in an incubator.
2) Compound treatment on the first day:
from 2mM stock solution as 1: ratio 3 serial dilutions 10 points. Transfer 5X compound-containing medium to the corresponding well of the 96 wells. The final highest compound concentration was 10. Mu.M and the final DMSO concentration was 0.5%. The 96-well plate was placed in an incubator at 37 ℃ and incubated for 5 days.
3) A baseline reading.
4) On the sixth day, the signal was read, 50. Mu.L/well of detection reagent (CTG) was added, and the signal was read in an Envision machine.
2. Data processing
Percent inhibition (%) at each compound concentration was calculated from the signals in the HPE and ZPE control wells contained in each assay plate and the fluorescence signal in each compound well. The inhibition rate of ZPE control Kong Hanmei and the substrate is 0%, and the inhibition rate of HPE control hole only containing the substrate is 100%. 50% Inhibition (IC) was determined by testing the concentration of the compound and the value of percent inhibition using a four parameter log dose response equation 50 ) The desired concentration of the compound. The endpoint value (IC) of the reference compound was evaluated in each experiment 50 ) As a quality control measure. The experiment was considered acceptable if the endpoint value was within three times the expected value.
Table 1: biological test results
Figure BDA0003535562350000311
From the activity data of the compounds of specific examples, the series of compounds of the invention have strong inhibition effect on the activity of K-RAS cells.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Further, it should be understood that various changes or modifications of the present invention can be made by those skilled in the art after reading the above disclosure of the present invention, and these equivalents also fall within the scope of the present invention defined by the appended claims.

Claims (18)

1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0003535562340000011
wherein X is C (R) 7 ) Or N; l is selected from-CR 8 ＝CR 9 -、-C(R 10 R 11 )-C(R 12 R 13 )-、-N(R 14 )-C(O)-、-N(R 15 )-C(R 16 R 17 ) -and-O-C (R) 18 R 19 )-；
R 1 Selected from hydrogen, deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 4-6 membered heteroaryl, acetamido and-SF 5 ；
Each R 2 Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, phenyl, 4-6 membered heteroaryl, acetamido and-SF 5 ；
R 3 Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, = O, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Substituted with a substituent of (a);
each R 4 Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, -SF 5 、C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, cyano-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, halo-substituted C 1-4 Alkyl and deuterium substituted C 1-4 Alkyl, or, when m.gtoreq.2, two R 4 Together with the parts to which they are attached form C 3-12 Cycloalkyl or 3-12 membered heterocyclyl;
R 5 and R 6 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl and di-C 1-4 An alkyl amino methyl group;
R 7 selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-to 10-membered heteroaryl, = O, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
R 8 and R 9 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 4-12 membered heterocyclyl and-C 1-4 alkyl-NR 23 R 24 The above-mentionedThe radicals are optionally further substituted by one or more radicals selected from deuterium, halogen, cyano, hydroxy, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-to 10-membered heteroaryl, = O, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(＝NR 23 )R 22 、-N(R 23 )-C(＝NR 24 )R 22 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
R 10 、R 11 、R 12 、R 13 、R 16 、R 17 、R 18 and R 19 Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(＝NR 23 )R 22 、-N(R 23 )-C(＝NR 24 )R 22 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Or, R 10 And R 11 、R 12 And R 13 、R 16 And R 17 、R 18 And R 19 Together with the carbon atom to which they are directly attached form a C (O), 3-12 membered cycloalkyl or 3-12 membered heterocyclyl group, optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, = O, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(＝NR 23 )R 22 、-N(R 23 )-C(＝NR 24 )R 22 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
R 14 and R 15 Each independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, -C (O) OR 21 、-C(O)R 22 and-C (O) NR 23 R 24 Optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 5-10 Aryl, 5-10 membered heteroaryl, = O, -C 0-8 alkyl-SF 5 、-C 0-8 alkyl-S (O) r R 20 、-C 0-8 alkyl-O-R 21 、-C 0-8 alkyl-C (O) OR 21 、-C 0-8 alkyl-C (O) R 22 、-C 0-8 alkyl-O-C (O) R 22 、-C 0-8 alkyl-NR 23 R 24 、-C 0-8 alkyl-C (= NR) 23 )R 22 、-C 0-8 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-8 alkyl-C (O) NR 23 R 24 and-C 0-8 alkyl-N (R) 23 )-C(O)R 22 Substituted with a substituent of (a);
each R 20 Independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl and-NR 23 R 24 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, = O, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 23 R 24 Substituted with the substituent(s);
each R 21 Independently selected from hydrogen, deuterium, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl and 5-10 membered heteroaryl, independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, = O, cyano, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR 23 R 24 Substituted with the substituent(s);
each R 22 Selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and-NR 23 R 24 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, cyano, C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and-NR 23 R 24 Substituted with the substituent(s);
each R 23 And R 24 Each independently selected from hydrogen, deuterium, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-to 10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonylAlkyl, dimethylaminosulfonyl, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 Alkanoyl, said groups being independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-to 10-membered heteroaryl, 5-to 10-membered heteroaryloxy, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 Substituted by the substituent of the alkanoyl group,
or, R 23 And R 24 Together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, said 4-10 membered heterocyclyl or 5-10 membered heteroaryl being optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, C 1-10 Alkyl radical, C 2-10 Alkenyl radical, C 2-10 Alkynyl, halo-substituted C 1-10 Alkyl, deuterium substituted C 1-10 Alkyl radical, C 1-10 Alkoxy radical, C 3-12 Cycloalkyl radical, C 3-12 Cycloalkoxy, 3-12 membered heterocyclic group, 3-12 membered heterocyclic oxy, C 6-10 Aryl radical, C 6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono C 1-10 Alkylamino, di-C 1-10 Alkylamino and C 1-10 Substituted by alkanoyl group;
m is 0, 1,2, 3 or 4;
n is 0, 1,2, 3 or 4;
each r is independently 0, 1 or 2.
2. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is 10 、R 11 、R 12 、R 13 、R 16 、R 17 、R 18 And R 19 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Or, R 10 And R 11 、R 12 And R 13 、R 16 And R 17 、R 18 And R 19 Together with the carbon atom to which they are directly attached form a C (O), 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
R 14 and R 15 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -C (O) OR 21 、-C(O)R 22 and-C (O) NR 23 R 24 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -C 0-4 alkyl-SF 5 、-C 0-4 alkyl-S (O) r R 20 、-C 0-4 alkyl-O-R 21 、-C 0-4 alkyl-C (O) OR 21 、-C 0-4 alkyl-C (O) R 22 、-C 0-4 alkyl-O-C (O) R 22 、-C 0-4 alkyl-NR 23 R 24 、-C 0-4 alkyl-C (= NR) 23 )R 22 、-C 0-4 alkyl-N (R) 23 )-C(＝NR 24 )R 22 、-C 0-4 alkyl-C (O) NR 23 R 24 and-C 0-4 alkyl-N (R) 23 )-C(O)R 22 Substituted with a substituent of (a);
wherein R is 20 、R 21 、R 22 、R 23 、R 24 R is as defined in claim 1.
3. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is 8 And R 9 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl and-C 1-4 alkyl-NR 23 R 24 Optionally, the above groups are further substituted by one or more groups selected from deuterium, halogen, cyano, hydroxy, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Substituted with a substituent of (a);
wherein R is 20 、R 21 、R 22 、R 23 、R 24 R is as defined in claim 1.
4. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is 7 Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl radical、C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(＝NR 23 )R 22 、-N(R 23 )-C(＝NR 24 )R 22 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(＝NR 23 )R 22 、-N(R 23 )-C(＝NR 24 )R 22 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
wherein R is 20 、R 21 、R 22 、R 23 、R 24 And r is as defined in claim 1.
5. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is 3 Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(＝NR 23 )R 22 、-N(R 23 )-C(＝NR 24 )R 22 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 The above radicalsOptionally further substituted with one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(＝NR 23 )R 22 、-N(R 23 )-C(＝NR 24 )R 22 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
wherein R is 20 、R 21 、R 22 、R 23 、R 24 R is as defined in claim 1.
6. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is 1 Selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, ethenyl, ethynyl, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkoxy, cyclopropyl, acetamido and-SF 5 。
7. The compound of formula (I), its stereoisomers, or pharmaceutically acceptable salts thereof, according to claim 1, wherein each R is 2 Each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkoxy, cyclopropyl, acetamido and-SF 5 。
8. A compound of formula (I), its stereoisomers or pharmaceutically acceptable salts thereof, according to claim 1, characterized in thatAt each R 4 Each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, -SF 5 、C 1-4 Alkyl radical, C 2-4 Alkynyl, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, 4-6 membered heterocyclyl, cyano-substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, halo-substituted C 1-4 Alkyl and deuterium substituted C 1-4 An alkyl group.
9. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein R is 5 And R 6 Each independently selected from hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, isopropyl, cyclopropyl and dimethylaminomethyl.
10. The compound of formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein the compound of formula (I) has the structure of formula (ii):
Figure FDA0003535562340000051
wherein X is CH or N, L is-CR 8 ＝CR 9 -or-C (R) 10 R 11 )-C(R 12 R 13 )-；
R 1 Selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, ethynyl, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, acetamido, and-SF 5 ；
R 2 Selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, acetamido and-SF 5 ；
R 3 Selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy, halogen substituted C 1-4 Alkoxy, deuterium substituted C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, di-C 1-4 Alkylaminomethyl and-SF 5 ；
R 4a 、R 4b 、R 4c Each independently selected from hydrogen, deuterium, halogen, cyano, methyl, cyclopropyl, cyanomethyl, hydroxymethyl, trifluoromethyl, trideuteromethyl, difluoromethyl, and dideuteromethyl;
R 8 and R 9 Each independently selected from hydrogen, deuterium, fluoro, cyano, methyl, ethyl, isopropyl and cyclopropyl;
R 10 、R 11 、R 12 and R 13 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Or, or R 10 And R 11 、R 12 And R 13 Together with the carbon atom to which they are directly attached form a C (O), 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
wherein R is 20 、R 21 、R 22 、R 23 、R 24 R is as defined in claim 1.
11. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, characterized in that: the compound of formula (I) has the following structure:
Figure FDA0003535562340000061
wherein L is-CH = CH-or-C (R) 10 R 11 )-C(R 12 R 13 )-；
R 1 Selected from the group consisting of hydrogen, deuterium, fluoro, chloro, cyano, methyl, methoxy, cyclopropyl and-SF 5 ；
R 2 Selected from the group consisting of hydrogen, deuterium, fluoro, chloro, cyano, methyl, methoxy, cyclopropyl and-SF 5 ；
R 3 Selected from the group consisting of hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, cyclopropyl, cyclobutyl, cyclobutoxy and-SF 5 ；
R 10 、R 11 、R 12 And R 13 Each independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 Alkyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered heteroaryl, -O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 and-NR 23 R 24 Or, R 10 And R 11 、R 12 And R 13 Together with the carbon atom to which they are directly attached form a C (O), 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-S(O) r R 20 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 、-O-C(O)R 22 、-NR 23 R 24 、-C(O)NR 23 R 24 and-N (R) 23 )-C(O)R 22 Substituted with the substituent(s);
each R 20 Independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl and-NR 23 R 24 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, amino, = O, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy;
each R 21 Independently selected from hydrogen, deuterium, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl and 5-8 membered heteroaryl, independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, amino, = O, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, and 3-6 membered heterocyclyloxy;
each R 22 Selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR 23 R 24 The above groups are independently optionally further substituted by one or more groups selected from deuterium, halogen, hydroxy, amino, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy;
each R 23 And R 24 Each independently selected from hydrogen, deuterium, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 6-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 Alkanoyl, said groups being independently optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 Alkylamino, di-C 1-4 Alkylamino and C 1-4 Substituted by the substituent of the alkanoyl group,
or, R 23 And R 24 Together with the nitrogen atom to which they are directly attached form a 4-6 membered heterocyclyl or 5-8 membered heteroaryl, said 4-6 membered heterocyclyl or 5-8 membered heteroaryl being optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, C 1-4 Alkyl radical, C 2-4 Alkenyl radical, C 2-4 Alkynyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclic group, 3-6 membered heterocyclic oxy group, C 6-8 Aryl radical, C 6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, mono C 1-4 Alkylamino radical, di-C 1-4 Alkylamino and C 1-4 Substituted by a substituent of alkanoyl;
each r is independently 0, 1 or 2.
12. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1 or 11, characterized in that: l is-CH = CH-or-C (R) 10 R 11 )-C(R 12 R 13 )-；
R 1 Selected from hydrogen, deuterium, fluorine,Chloro, cyano, methyl, methoxy and cyclopropyl;
R 2 selected from hydrogen, deuterium, fluoro, chloro, cyano, methyl, methoxy and cyclopropyl;
R 3 selected from the group consisting of hydrogen, deuterium, fluoro, chloro, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, trideuteromethoxy, cyclopropyl, cyclobutyl, and cyclobutoxy;
R 10 is hydrogen;
R 11 selected from the group consisting of hydrogen, deuterium, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, oxolanyl, aziridinyl, -O-R 21 、-C(O)OR 21 、-C(O)R 22 and-O-C (O) R 22 The above groups are optionally further substituted by one or more groups selected from deuterium, halogen, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 and-O-C (O) R 22 Substituted with a substituent of (a);
R 12 is hydrogen;
R 13 selected from the group consisting of hydrogen, deuterium, fluoro, chloro, bromo, cyano, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, oxolanyl, aziridinyl, -O-R 21 、-C(O)OR 21 、-C(O)R 22 and-O-C (O) R 22 Optionally further substituted with one or more groups selected from deuterium, fluoro, chloro, bromo, cyano, C 1-4 Alkyl, halo-substituted C 1-4 Alkyl, deuterium substituted C 1-4 Alkyl radical, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, C 5-8 Aryl, 5-8 membered heteroaryl, = O, -SF 5 、-O-R 21 、-C(O)OR 21 、-C(O)R 22 and-O-C (O) R 22 Substituted with the substituent(s);
each R 21 Independently selected from hydrogen, deuterium, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, oxolanyl, azacyclopentyl and phenyl, which are independently optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, bromo, hydroxy, amino, = O, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl, and 3-6 membered heterocyclyloxy;
each R 22 Selected from the group consisting of hydrogen, deuterium, hydroxy, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, methoxy, ethoxy, propoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopropoxy, cyclobutoxy, oxetanyl, azetidinyl, oxolanyl, aziridinyl and phenyl, which are independently optionally further substituted by one or more groups selected from deuterium, fluoro, chloro, bromo, hydroxy, amino, cyano, C 1-4 Alkyl radical, C 1-4 Alkoxy radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkoxy, 3-6 membered heterocyclyl and 3-6 membered heterocyclyloxy.
13. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it is selected from the following compounds:
Figure FDA0003535562340000081
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Figure FDA0003535562340000091
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Figure FDA0003535562340000101
14. a process for the preparation of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13, which comprises the steps of: reacting a compound of formula (I') to obtain a compound of formula (I):
Figure FDA0003535562340000102
wherein R is H or an amino protecting group, preferably, the amino protecting group is t-butyloxycarbonyl; r is 1 、R 2 、R 3 、R 4 、R 5 、R 6 L, X, m and n are as in claim 1.
15. A pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 13, and a pharmaceutically acceptable carrier.
16. Use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 15, for the preparation of a medicament for the treatment of a tumor or cancer which is at least partially mediated by a K-RAS G12C mutation.
17. The use according to claim 16, wherein said cancer or tumor is selected from the group consisting of a lung malignancy or cancer, a hepatobiliary malignancy or cancer, a gastrointestinal malignancy or cancer, a hematologic malignancy or cancer, a sarcoma, a skin malignancy or cancer, a bone malignancy or cancer, a urogenital malignancy or cancer, a nervous system malignancy or cancer, a gynecological malignancy or cancer, and an adrenal malignancy or cancer.
18. The use according to claim 17, characterized in that the pulmonary malignancy or cancer is selected from bronchial carcinomas (squamous cell carcinoma, undifferentiated small cell, undifferentiated large cell or adenocarcinoma), non-small cell lung carcinomas, bronchial adenomas, sarcomas, lymphomas, chondrogenic hamartomas or mesotheliomas;
the hepatobiliary malignancy or cancer is selected from liver cancer, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, gallbladder cancer, ampulla cancer, or cholangiocarcinoma;
the gastrointestinal malignancy or cancer is selected from esophageal malignancy and cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma or lymphoma), gastric malignancy and cancer (carcinoma, lymphoma or leiomyosarcoma), pancreatic malignancy and cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, uveoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine cancer malignancy or cancer (adenocarcinoma, adenoma, tubular adenoma), or leiomyoma;
the hematologic malignancy or cancer is selected from acute or chronic myeloleukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, hodgkin's disease or non-hodgkin's lymphoma;
the sarcoma is selected from angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma or teratoma;
the malignant tumor or cancer of the skin is selected from malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, nevus, moles hyperplasia, lipoma, hemangioma, dermatofibroma, keloids or psoriasis;
the malignant tumor or cancer of bone is selected from osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondral tumor, benign chondroma, chondroblastoma, cartilage mucosa fibroma, osteoid tumor, or giant cell tumor;
the genitourinary tract malignancy or cancer is selected from a renal malignancy or cancer (adenocarcinoma, wilm's tumor or wilm's tumor), lymphoma, leukemia, bladder or urinary tract malignancy or cancer (squamous cell carcinoma, transitional cell carcinoma or adenocarcinoma), prostate malignancy or cancer (adenocarcinoma or sarcoma), testicular malignancy or cancer (blood cancer, teratoma, embryo cancer or teratoma), choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, or lipoma;
the nervous system malignancy or cancer is selected from an osteoma, hemangioma, granuloma, xanthoma, osteitis deformans, meningioma, meningosarcoma, glioma, astrocytoma, medulloblastoma, glioma, ependymoma, genital tumor, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, spinal neurofibroma, meningioma, glioma, or sarcoma;
the gynecological malignant tumor or cancer is selected from endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma or unclassified carcinoma), granular-sheath cell tumor, leydig cell tumor, sarcolemma anomaly, malignant teratoma, squamous epithelial cancer, fibroepithelial cancer, adenoepithelial cancer, melanoma, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma or fallopian tube carcinoma;
the adrenal malignancy or cancer is selected from neuroblastoma.
CN202210217410.6A 2021-09-23 2022-03-07 Macrocyclic K-RAS G12C inhibitor, preparation method and pharmaceutical application thereof Pending CN115894520A (en)

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