CN113024544A - Cyano-containing heterocyclic compound and application thereof - Google Patents
Cyano-containing heterocyclic compound and application thereof Download PDFInfo
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- CN113024544A CN113024544A CN201911251772.1A CN201911251772A CN113024544A CN 113024544 A CN113024544 A CN 113024544A CN 201911251772 A CN201911251772 A CN 201911251772A CN 113024544 A CN113024544 A CN 113024544A
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
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- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003911 antiadherent Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 238000012200 cell viability kit Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005249 lung adenocarcinoma Diseases 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000009149 molecular binding Effects 0.000 description 1
- DOTMOQHOJINYBL-UHFFFAOYSA-N molecular nitrogen;molecular oxygen Chemical compound N#N.O=O DOTMOQHOJINYBL-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000002733 pharmacodynamic assay Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000012744 reinforcing agent Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
The invention relates to a cyano-containing heterocyclic ring compound and application thereof, wherein the cyano-containing heterocyclic ring compound is a compound shown as a formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, wherein R is1～R2And X, A, E, L and the K group are defined in the specification. The compound can be used for preparing a medicament for treating and/or preventing cancers.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and relates to a cyano-containing heterocyclic compound and application thereof.
Background
In the field of cancer research, KRAS is one of the most well-known oncogenes, and the oncogene RAS is mutated in human tumors, accounting for about one-third of all malignant mutations in humans. The RAS family includes HRAS, NRAS and KRAS. KRAS is the major subtype of the RAS protein family, with mutations accounting for 86% of all RAS protein mutations and prevalent in pancreatic, colorectal and lung cancers. KRAS gene mutation is existed in 15-30% of patients with non-small cell lung cancer (NSCLC), wherein lung adenocarcinoma accounts for 30-50% and is higher than EGFR, ALK and the like; the probability of KRAS gene mutation abnormality of colorectal cancer patients is 30-35%; in pancreatic cancer, more than 90% of patients present KRAS gene mutations. The KRAS signal pathway is an important anti-tumor pathway, and targeting KRAS signals is becoming an important field for discovering anti-tumor drugs. However, due to the lack of a good small molecule binding cavity on the surface of the KRAS protein, the research and development of KRAS-based small molecule inhibitors is one of the difficulties in the field of medicine, and currently, no KRAS inhibitor medicine is available on the market all over the world, so that the research and development of new KRAS small molecule inhibitors have huge clinical value and broad market prospect.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a compound with a novel structure, a pharmaceutical composition thereof and application thereof. The compound provided by the invention has KRAS G12C inhibitory activity, and provides a new commercial choice for KRAS G12C inhibitors.
The invention solves the technical problem through the following technical scheme.
According to a first aspect of the present invention, there is provided a cyano-containing heterocyclic compound comprising a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof:
wherein the content of the first and second substances,
the above-mentionedA is selected from optionally substituted with 0 to 3R3Substituted C5-C8Mono-heterocycloalkyl optionally substituted with 0-3R3Substituted C6-C12Bridged heterocycloalkyl, or optionally substituted with 0-3R3Substituted C6-C12Spiroheterocycloalkyl when interrupted by multiple R3When substituted, R3May be the same or different
L is independently selected from the group consisting of a single bond, - (CH)2)n-、-O(CH2)n-、-N(R4)n-, C ═ O or C (O) C (R)4)n-, where n is independently selected from 0 to 3, when represented by a plurality of R4When substituted, R4May be the same or different;
said K is independently selected from hydrogen, -N (R)3)2、-C(O)-N(R3)2、-OR3、C3-C8Cycloalkyl radical, C3-C12Heterocycloalkyl radical, C6-C12Aryl, or C5-C13Heteroaryl of said C3-C8Cycloalkyl radical, C3-C12Heterocycloalkyl radical, C6-C12Aryl or C5-C13Heteroaryl is optionally substituted with one or more R3Substituted when by more than one R3When substituted, R3May be the same or different;
the R is1is-D-B-C-, wherein D is independently selected from the group consisting of a single bond, oxygen, sulfur, and-NR4(ii) a B is independently selected from a single bond, or (CH)2)n-, where n is independently selected from 0 to 6; c is independently selected from hydrogen, -N (R)4)2、-C(O)-N(R4)2、 -OR4、C3-C8Cycloalkyl radical, C3-C12Heterocycloalkyl radical, C6-C12Aryl, or C5-C13Heteroaryl of said C3-C8Cycloalkyl radical, C3-C12Heterocycloalkyl radical, C6-C12Aryl or C5-C13Heteroaryl is optionally substituted with one or more R4Substituted when by more than one R4When substituted, R4May be the same or different;
the R is2Selected from H, halogen, cyano, hydroxy, amino, optionally substituted with 0-3R3Substituted C1-C8Alkyl, optionally substituted with 0-3R3Substituted C1-C8Heteroalkyl, optionally with 0-3R3Substituted C1-C8Alkoxy, optionally substituted with 0-3R3Substituted C1-C3Haloalkoxy, optionally substituted with 0-3R3Substituted C3-C8Cycloalkyl optionally substituted by 0-3R3Substituted C3-C12Heterocycloalkyl optionally substituted with 0-3R3Substituted C2-C4Alkenyl or optionally substituted with 0-3R3Substituted C2-C4Alkynyl when interrupted by multiple R3When substituted, R3May be the same or different; n in the compound shown in the formula I is selected from 0, 1 or 2;
said E is independently-C (O) C (R)a)m 
C(Rb)por-SO2C(Ra)m 
C(Rb)p(ii) a Wherein R isaIndependently is hydrogen or C1-C3An alkyl group; rbIndependently of one another is hydrogen, C1-C3Alkyl, alkylaminoalkyl, dialkylaminoalkyl or heterocyclylalkyl groups; m is 0 or 1; p is 1 or 2; when in use
In the case of three bonds, m is equal to 0 and P is equal to 1; when in use
When it is a double bond, m is equal to 1 and P is equal to 2, when there are more than one RaOr RbWhen substituted, RaOr RbMay be the same or different;
"hetero" means heteroAn atom or heteroatom group, wherein "hetero" of said mesoheteroalkyl, heterocycloalkyl, bridged heterocycloalkyl, spiroheterocycloalkyl, heteroaryl is independently selected from-C (═ O) N (R)4)-、-N(R4)-、-NH-、N、 -O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-and-N (R)4)C(＝O)N(R4)-；
In any of the above cases, the number of heteroatoms or heteroatom groups is independently selected from 1,2 and 3, respectively.
In some embodiments of the invention, A is optionally substituted with 0-7R3Substituted by
More preferably
Other variables are as defined herein.
In some embodiments of the invention, R1 is optionally substituted with 0-7R3Substituted H, CN, methoxy, ethyl, isopropyl,
In some embodiments of the invention, L is independently selected from the group consisting of a single bond, - (CH)2)n-、-O(CH2)n-、 -N(R4)n-, C ═ O or C (O) C (R)4)n-, more preferably-O-, OCH2-or-NH-, the other variables being as defined herein;
in some embodiments of the invention, K is optionally substituted with 0-7R3Substituted by
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
Methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl, piperidinyl, cyclopentenyl, cyclohexenyl, and other variables as defined herein.
In some embodiments of the invention, R is2Is selected from H, F, Cl, Br, I, CN, OH, NH2， CONH2、CH3、CH3CH2、(CH3)2CH. Cyclopropyl, methoxy, ethoxy, isopropoxy, CF3、 CHF2、CH2CHF2，CH2CH2F. Cyclopentyl, cyclohexyl, morpholinyl, vinyl, ethynyl, more preferably H, F, Cl, CN, CH3Methoxy, CF3Or CHF2The other variables are as defined herein.
In some embodiments of the invention, E is independently selected from
Wherein R isaIs H, F, CH3, RbIs H, CH3, CH2F、CHF2、
More preferably
For other variables as defined herein.
In some embodiments of the invention, R is3Independently selected from hydrogen, halogen, hydroxy, amino, cyano, C1-C8Alkyl radical, C2-C8Heteroalkyl group, C5-C6Cycloalkyl radical, C4-C6Heterocycloalkyl and C5-C6Heteroaryl group, C2-C4Alkenyl radical, C2-C4Alkynyl, -OR9、-SR9、-C(O)OR9、-C(O)N(R9)2、-N(R9)2In which C is1-C8Alkyl radical, C2-C8Heteroalkyl group, C5-C6Cycloalkyl radical, C4-C6Heterocycloalkyl and C5-C6Heteroaryl group, C2-C4Alkenyl and C2-C4Alkynyl is optionally substituted by one OR more cyano, hydroxy, halogen, -OR9Or heteroaryl, and the other variables are as defined herein.
In some embodiments of the invention, R is4Independently selected from hydrogen, chlorine, fluorine, amino, hydrogen radical, hydroxyl, C1-C8Alkyl radical, C2-C8Heteroalkyl group, C5-C6Cycloalkyl radical, C4-C6Heterocycloalkyl and C5-C6Heteroaryl of said C1-C8Alkyl radical, C2-C8Heteroalkyl group, C5-C6Cycloalkyl radical, C4-C6Heterocycloalkyl radical 56-C6Heteroaryl is selected from optionally substituted with 1,2 or 3R. Wherein R is selected from the group consisting of hydrogen, chloro, fluoro, amino, hydro, hydroxy, methyl, ethyl, propyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CH2OH、-OCH2CH3、-OCH2CHF2N (CH3)2, NH (CH3) or-OCH2CF3The other variables are as defined herein.
In some embodiments of the present invention, the above compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, is selected from
Wherein R is1、R2、R3、Ra、RbAnd K is as defined above in the invention.
Thus, throughout this specification, the skilled person will be able to refer to the R in a compound of formula I, formula II, formula III or formula IV1～R4And A, L, K and substituents thereof are selected to provide a stable compound of formula I, formula II, or formula III, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, as described in embodiments of the invention.
In some embodiments of the present invention, the above compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, is selected from
In the present invention, the groups of the compounds represented by formula I, formula II, formula III or formula IV and their substituents can be selected by those skilled in the art to provide stable compounds represented by formula I, formula II, formula III or formula IV, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or tautomers thereof, or hydrates thereof, or solvates thereof, or metabolites thereof, or prodrugs thereof, including but not limited to I-1 to I-104 described in the examples of the present invention.
The reaction solvent used in each reaction step described in the present invention is not particularly limited, and any solvent that can dissolve the starting materials to some extent and does not inhibit the reaction is included in the present invention. Further, many equivalents, substitutions, or equivalents in the art to which this invention pertains, as well as different proportions of solvents, solvent combinations, and solvent combinations described herein, are deemed to be encompassed by the present invention.
According to a second aspect of the present invention, there is provided a pharmaceutical composition comprising an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, and at least one pharmaceutically acceptable excipient.
The pharmaceutically acceptable excipients may be those which are widely used in the field of pharmaceutical production. The excipients are used primarily to provide a safe, stable and functional pharmaceutical composition and may also provide methods for dissolving the active ingredient at a desired rate or for promoting the effective absorption of the active ingredient after administration of the composition by a subject. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients may include one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrating agents, lubricants, antiadherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents and sweeteners.
The pharmaceutical compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.
The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention may also be in a controlled release or delayed release dosage form (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations which can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.
Oral administration of the compounds of the invention is preferred. Intravenous administration of the compounds of the invention is also preferred. Depending on the circumstances, other application routes may be applied or even preferred. For example, transdermal administration may be highly desirable for patients who are forgetful or whose oral medications are irritable. In particular cases, the compounds of the invention may also be administered by transdermal, intramuscular, intranasal or intrarectal routes. The route of administration may vary in any manner, limited by the physical nature of the drug, the convenience of the patient and caregiver, and other relevant circumstances.
According to a third aspect of the present invention, the present invention provides a use of the compound (the compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof) or a pharmaceutical composition thereof in preparing a medicament for treating diseases caused by KRAS G12C mutation. The compound provided by the invention can be used for treating and/or preventing one or more diseases related to KRAS G12C activity, and has good clinical application and medical application.
According to a fourth aspect of the present invention, the present invention provides a use of the compound (the compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof) or a pharmaceutical composition thereof in preparation of a drug of a KRAS G12C inhibitor. The compound provided by the invention has good KRAS G12C inhibitory activity, can be effectively used as a KRAS G12C inhibitor, and is used as a therapeutic drug of the KRAS G12C inhibitor.
According to a fifth aspect of the present invention, the present invention provides a use of the compound (the compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof) or a pharmaceutical composition thereof in preparation of a medicament for treating and/or preventing cancer, where the compound according to the present invention can be used for treating and/or preventing cancer, and cancers which can be treated and/or prevented include, but are not limited to, pancreatic cancer, colorectal cancer, and lung cancer.
Terms and definitions
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
"alkyl" refers to a saturated aliphatic hydrocarbon group including straight and branched chain groups of 1 to 20 carbon atoms, such as straight and branched chain groups of 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In this context "alkyl" may be a monovalent, divalent or trivalent radical. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, and the various branched chain isomers thereof, and the like. Non-limiting examples also include methylene, methine, ethylene, ethylidene, propylidene, butylidene, and various branched chain isomers thereof. Alkyl groups may be optionally substituted or unsubstituted.
"cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 12 ring atoms, which may be, for example, 3 to 12, 3 to 10, or 3 to 6 ring atoms, or may be a 3,4, 5, 6 membered ring. Non-limiting examples of monocyclic radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl and the like. The cyclic group may be optionally substituted or unsubstituted.
"Heterocycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, which may be, for example, 3 to 16, 3 to 12, 3 to 10 or 3 to 6 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O)m(wherein m is 0, 1, or 2) but does not include the ring moiety of-O-O-, -O-S-, or-S-S-, and the remaining ring atoms are carbon. Preferably 3 to 12 ring atoms of which 1-4 are heteroatoms, more preferably a heterocycloalkyl ring comprising 3 to 10 ring atoms, most preferably a 5-or 6-membered ring of which 1-4 are heteroatoms, more preferably 1-3 are heteroatoms, most preferably 1-2 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused, or bridged heterocyclic groups.
"spiroheterocyclyl" refers to a 5 to 18 membered polycyclic group having two or more cyclic structures wherein the individual rings share a common atom with each other and wherein 1 or more double bonds are present within the ring, but none of the rings have a completely common electron system, wherein one or more of the ring atoms is selected from nitrogenOxygen or S (O)P(wherein p is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. Spiro heterocyclic groups are classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiro heterocyclic group or a double spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred is a 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic group. Wherein "a-membered/b-membered monocyclic spiroheterocyclyl" refers to a spiroheterocyclyl in which an a-membered monocyclic ring and a b-membered monocyclic ring share one atom with each other. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: diazaspiro [3.3]Heptane.
"bridged heterocyclyl" refers to a 5 to 14-membered, or 5 to 18-membered, polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more rings may contain one or more double bonds, but none of the rings has a completely co-extensive pi-electron aromatic system in which one or more ring atoms are selected from heteroatoms of nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: diazabicyclo [3.1.1] heptane.
"haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more of the same or different halogen atoms, and examples of preferred alkyl or alkoxy groups include, but are not limited to: trifluoromethyl, trifluoroethyl, trifluoromethoxy.
"aryl" means a monocyclic, bicyclic, and tricyclic carbon ring system containing 6 to 14 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3 to 7 atoms in the ring and one or more attachment points to the rest of the molecule. Examples include, but are not limited to: phenyl, naphthyl, anthracene, and the like. Preferably, the aryl group is a carbocyclic ring system of 6 to 10 or 6 to 7 ring atoms.
"heteroaryl" means monocyclic, bicyclic, and tricyclic ring systems containing 5 to 14 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". Examples include, but are not limited to: furyl, imidazolyl, 2-pyridyl, 3-pyridyl, thiazolyl, purinyl and quinolyl. Preferably, the heteroaryl group is a ring system of 5 to 10 ring atoms.
"halogen" means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example: "heterocyclic group optionally substituted with alkyl" means that alkyl may, but need not, be present, and this description includes the case where the heterocyclic group is substituted with alkyl and the heterocyclic group is not substituted with alkyl.
"substituted" means that one or more, preferably up to 5, more preferably 1 to 3, hydrogen atoms in a group are independently substituted with a corresponding number of substituents.
"pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from the compounds of the present invention found to have particular substituents, with relatively nontoxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and salts of organic acids including acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic, and the like; also included are Salts of amino acids (e.g., arginine, etc.), and Salts of organic acids such as glucuronic acid (see Berge et al, "Pharmaceutical Salts," Journal of Pharmaceutical Science 66:1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functionalities and can thus be converted to any base or acid addition salt. Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents.
"pharmaceutical composition" means a mixture containing one or more compounds of formula I, as described herein, or a pharmaceutically acceptable salt, or stereoisomer, or tautomer, or hydrate, or solvate, or metabolite, or prodrug thereof, in combination with other chemical components, as well as other components, such as pharmaceutically acceptable 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 invention synthesizes a series of novel compounds, and related enzyme and cell activity tests show that the compounds have excellent cell activity and IC for cell proliferation in vitro50Values reached the nM range. Can be applied to various tumors. The compound shown in the formula I has a very good inhibition effect on KRAS G12C mutant human non-small cell lung cancer cell NCI-H358. The compound can be used for preparing medicaments for preparing KRAS G12C inhibitors, preventing and/or treating KRAS G12C mutant diseases and preparing medicaments for treating and/or preventing cancers, wherein the treatment and/or preventionCancers include, but are not limited to, pancreatic cancer, colorectal cancer, lung cancer.
Compared with the prior art, the invention has the following advantages and effects:
the invention provides a compound which comprises a compound shown as a formula I, or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a hydrate, a solvate, a metabolite or a prodrug thereof; also provided are compositions comprising the compounds. The compound or the pharmaceutical composition has application in preparing a medicine for treating diseases caused by KRAS G12C mutation, or preparing a KRAS G12C inhibitor medicine, or preparing a medicine for treating and/or preventing cancer, and specific effects are shown in specific examples.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the embodiments described herein are merely illustrative of the present invention and are not intended to limit the present invention.
The preparation of the compound of formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, according to the present invention can be accomplished by the following exemplary methods and relevant publications used by those skilled in the art, which, however, are not intended to limit the scope of the present invention.
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). NMR was measured using a Bruker AVANCE-400 or Varian Oxford-300 nuclear magnetic instrument in deuterated dimethyl sulfoxide (DMSO-d)6) Deuterated chloroform (CDC 1)3) Deuterated methanol (CD)3OD) internal standard as Tetramethylsilane (TMS) chemical shift is 10-6(ppm) is given as a unit.
MS was measured using an Agilent SQD (ESI) mass spectrometer (manufacturer: Agilent, model: 6110) or Shimadzu SQD (ESI) mass spectrometer (manufacturer: Shimadzu, model: 2020).
HPLC measurements were carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfirc C18, 150X 4.6mm, 5wn, column) and a Waters 2695-.
The thin layer chromatography silica gel plate is Qingdao sea GF254 silica gel plate, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15mm-0.2mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5 mm.
Column chromatography generally uses Qingdao ocean 200-mesh and 300-mesh silica gel as a carrier.
Known starting materials of the present invention can be synthesized using or following methods known in the art, companies such as Shaoyuan chemical technology (Accela ChemBio Inc), Beijing coupled chemicals, and the like.
In the examples, the reaction was carried out under an argon atmosphere or a nitrogen atmosphere unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L. The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
In the examples, the reaction temperature was room temperature and the temperature range was 20 ℃ to 30 ℃ unless otherwise specified.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a system of developing reagents, A: dichloromethane and methanol systems; b: petroleum ether and ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound.
The system of eluents for column chromatography and developing agents for thin layer chromatography used for purifying compounds include a: dichloromethane and methanol systems; b: the volume ratio of the solvent in the petroleum ether and ethyl acetate system is adjusted according to different polarities of the compounds, and a small amount of triethylamine, an acidic or basic reagent and the like can be added for adjustment.
The present invention is described in detail below by way of examples, but is not meant to be limited to any of the disadvantages of the present invention. The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made in the specific embodiments of the invention without departing from the spirit and scope of the invention. The following synthetic schemes describe the steps for preparing the compounds disclosed herein. Unless otherwise indicated, each substituent has the definition as described herein.
Scheme A:
in scheme A above, compound 1A is reacted with cyanoacetyl chloride to provide compound 1B. Intramolecular ring closure of the compound 1B under basic conditions affords the compound 1C. And then refluxing the compound 1C by using phosphorus oxychloride to obtain a compound 1D, carrying out substitution reaction on the compound 1D and a piperazine derivative to obtain 1E, carrying out suzuki reaction or substitution reaction on the obtained 1E to obtain a compound 1F, carrying out substitution reaction on the compound 1 and amine or alcohol to obtain 1G, and removing Boc from the compound 1G under the condition of TFA to obtain 1H, carrying out 1H and appropriate acryloyl chloride to react to obtain the compound shown in the formula 1I.
Example 1: preparation of Compound represented by formula I-1
The synthetic route is as follows:
the preparation method comprises the following steps:
the first step is as follows: synthesis of Compound I-1B
Dissolving the raw material 1-1A (18.6g,100mmol) in DMF (200mL), cooling to 0 to 5 degrees, adding NaH (10g, 150mmol) in a mass fraction of 60% in portions, reacting to room temperature for 1 hour after the addition is completed, cooling again to 0 to 5 degrees, adding dropwise a DMF solution (10mL) of cyanoacetyl chloride (10.3g, 100mmol), reacting to room temperature for 4 hours after the addition is completed, after TLC showed that the reaction is completed, adding the reaction solution to ice water (800mL), adjusting PH to 4 to 5 with 1M hydrochloric acid, extracting the aqueous phase with ethyl acetate (300mL × 2), combining the organic phases, washing with a saturated sodium chloride solution, drying the organic phase with anhydrous sodium sulfate, and purifying the resulting residue by silica gel column chromatography (petroleum ether/ethyl acetate rotary-10/1 (V: V volume ratio)) to obtain compound I-1B (21.5g, light yellow liquid), yield: 85 percent.
MS m/z(ESI):254[M+1].
The second step is that: synthesis of Compound I-1C
Compound I-1B (20g,79mmol) was dissolved in methanol (200ml), followed by addition of sodium methoxide (6.4g,118mmol) in portions at room temperature, reflux reaction for 12 hours after the addition was complete, TLC showed the completion of the reaction, the reaction solution was cooled to room temperature, after removal of methanol by spin-drying, ice water (200ml) was added, and after PH was adjusted to 4-5 with 1M hydrochloric acid, the aqueous phase was extracted with ethyl acetate (100ml × 3), the organic phases were combined, washed with saturated sodium chloride solution, the organic phase was dried with anhydrous sodium sulfate, and the residue obtained by spin-drying was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 1/1(V: V volume ratio)) to obtain compound I-1C (13.2g, pale yellow solid) in yield: 78 percent.
MS m/z(ESI):222[M+1].
The third step: synthesis of Compound I-1D
Compound 1-1C (11g, 50mmol) was added to phosphorus oxychloride (120ml), after which time the mixture was heated to reflux and reacted overnight. After TLC showed the reaction was complete, the reaction solution was concentrated in vacuo, the resulting residue was dissolved in dichloromethane (300ml), then washed with saturated sodium bicarbonate (250ml), saturated sodium chloride (250ml) and water (150ml), the organic phase was separated, and after anhydrous sodium sulfate was washed, concentrated, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate: 10/1(V: V volume ratio)) to give compound I-1D (10.6g, pale yellow solid) in yield: 82 percent.
MS m/z(ESI):258[M+1].
The fourth step: synthesis of Compound I-1E
Compound I-1D (8.87g,34.4mmol) was added to acetonitrile (100ml) at room temperature, followed by 1-BOC piperazine (9.6g, 52mmol) and DIEA (6.7g,52mmol), followed by reflux reaction for 3 hours, TLC showed the reaction to be complete, the reaction was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate 10/1(V: V volume ratio)) to give compound I-1E (8.5g, light yellow solid), yield: 61 percent.
MS m/z(ESI):408[M+1].
The fifth step: synthesis of Compound I-1F
The compound 5-hydroxy-2-methyl-1, 2,3, 4-tetrahydroisoquinoline (3.6g, 22.5mmol) was added to DMF (50ml) at room temperature, then cooled to 0 to 5 degrees, added in portions with a mass fraction of 60% sodium hydride (0.9g, 22.5mmol), reacted at room temperature for 1 hour after the addition was completed, then added with compound I-1E (4.1g,10mmol), and after the addition was completed, the mixture was warmed to 90 degrees and stirred for 12 hours. After TLC showed completion, the reaction mixture was cooled to room temperature, the reaction was poured into water (150ml), the aqueous phase was extracted with ethyl acetate (50ml × 3), after combining the organic phases, the organic phase was washed successively with saturated sodium bicarbonate (50ml), saturated sodium chloride (50ml) and water (50ml), the organic phase was separated, after anhydrous sodium sulfate was removed, concentrated, and the resulting residue was purified by silica gel column chromatography (dichloromethane/methanol-50/1 (V: V vol.)) to give compound I-1F (2.8g, light yellow solid) in yield: and 43 percent.
MS m/z(ESI):662[M+1].
And a sixth step: synthesis of Compound I-1G
Compound I-1F (662mg,1mmol) was dissolved in ethyl acetate (5mL) at room temperature, then a solution of ethyl acetate hydrochloride (4N, 5mL) was added and the mixture was stirred at room temperature for 2 hours. The solution turned from clear to turbid and a solid precipitated out. The reaction was monitored by TLC, after completion of the reaction, the reaction solution was cooled to 0 deg.C, left to stand for 1 hour, filtered, and the solid was washed with ether and dried to give the hydrochloride of compound I-1G (516mg, white solid).
MS m/z(ESI):562[M+1].
The seventh step: synthesis of Compound I-1
The hydrochloride of the compound I-1G obtained in the previous step (516mg,0.92mmol) was dissolved in methylene chloride (10ml), and then cooled to-10 ℃ and triethylamine (200mg,2mmol) and acryloyl chloride (85mg, 0.93mmol) were added in this order, and then naturally warmed to room temperature to react for 1 hour, after which TLC showed the reaction to be complete. The reaction was quenched by addition of MeOH (1 mL). The resulting residue was isolated and purified by preparative HPLC to give Compound I-1(152mg, white solid). Yield: 24 percent.
MS m/z(ESI):616[M+1].
HNMR:(400MHz,CD3OD)7.89(d,J＝5.6MHz,1H),7.56(d,J＝5.6MHz,1H), 7.17-7.12(m,2H),7.03-7.02(m,1H),6.93-6.89(m,2H),6.32-6.28(m,1H), 5.85-5.82(m,1H),5.34(t,J＝4.8MHz,2H),3.99(brs,4H),3.86(brs,4H),2.77-2.76 (m,4H),2.67-2.64(m,2H),2.45(s,6H),2.18(t,J＝8.0MHz,2H),2.03-2.02(m, 4H).
TABLE 1-the following compounds are all obtained by reference to example 1
EXAMPLE 2 pharmacodynamic assay
Activity measurement of the compound of the invention on high-expression KRAS G12C human non-small cell lung cancer cell NCI-H358 and human pancreatic cancer cell Mia Paca-2
The following methods were used to determine the effect of the compounds of the invention on tumor cell proliferation.
For KRAS G12C subtype, high-expression KRAS G12C human non-small cell lung cancer cell NCI-H358 and human pancreatic cancer cell Mia Paca-2 were used for cancer cell activity inhibition assay, and NCI-H358 cells were cultured in DMEM medium containing 10% fetal calf serum, 100U penicillin and 100yg/mL streptomycin. Cultured at 37 ℃ in 5% CO2In the incubator. Cancer Cell Activity by Using Cell
The Cell growth inhibition was assessed by measuring the amount of ATP using a kit (luminecent Cell Viability Assay kit, methods of use see manufacturer's instructions).
The experimental method is operated according to the steps of the kit specification, and is briefly as follows: test compounds were first dissolved in DMSO to prepare stock solutions, which were then diluted in a gradient of the corresponding cell culture medium to prepare test samples, with the final concentration of compound ranging from 30uM to 0.01 nM. Tumor cells in logarithmic growth phase were seeded at appropriate density into 96-well cell culture plates at 37 ℃ in 5% CO2After overnight in the incubator, cells were incubated for a further 72 hours after addition of test compound samples. After the culture is completed, an appropriate volume of Cell is added to each well
Reagents and incubation at 37 ℃ for 1-4 hours, followed by reading absorbance values at 450nM for each well of the sample on a microplate reader. Percent inhibition of compound at each concentration point was calculated by comparison with absorbance values of control (0.3% DMSO), followed by non-linear regression analysis in GraphPad Prism 5 software at compound concentration log-inhibition to obtain IC of compound inhibition of cell proliferation50The values, experimental results are shown in table 2.
TABLE 2 IC inhibition of human non-small cell Lung cancer cells NCI-H358 and human pancreatic cancer cells Mia Paca-2 by Compounds of formula I of the invention50Data of
+ represents more than 10 μ M; + means less than 10. mu.M, greater than 1. mu.M; + + + + denotes less than 1 μ M
As can be seen from Table 2, the compound disclosed by the invention has a very good inhibition effect on KRAS G12C mutant human non-small cell lung cancer cell NCI-H358 and human pancreatic cancer cell Mia Paca-2 cells, and the activity of part of the compound is less than 1 mu M, so that the compound can be used as a medicament for preparing KRAS G12C inhibitors.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example" or "some examples" or the like are intended to mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above do not necessarily refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
It should be noted that the above embodiments belong to the same inventive concept, and the description of each embodiment has a different emphasis, and reference may be made to the description in other embodiments where the description in individual embodiments is not detailed. The invention is not to be considered as limited to the particular embodiments shown, but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (12)
1. A cyano-containing heterocyclic compound, comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof:
wherein the content of the first and second substances,
a is selected from optionally substituted by 0-3R3Substituted C5-C8Mono-heterocycloalkyl optionally substituted with 0-3R3Substituted C6-C12Bridged heterocycloalkyl, or optionally substituted with 0-3R3Substituted C6-C12Spiroheterocycloalkyl when interrupted by multiple R3When substituted, R3The same or different;
l is independently selected from the group consisting of a single bond, - (CH)2)n-、-O(CH2)n-、-N(R4)n-, C ═ O or C (O) C (R)4)n-, where n is independently selected from 0 to 3, when represented by a plurality of R4When substituted, R4The same or different;
said K is independently selected from hydrogen, -N (R)3)2、-C(O)-N(R3)2、-OR3、C3-C8Cycloalkyl radical, C3-C12Heterocycloalkyl radical, C6-C12Aryl, or C5-C13Heteroaryl of said C3-C8Cycloalkyl radical, C3-C12Heterocycloalkyl radical, C6-C12Aryl or C5-C13Heteroaryl is optionally substituted with one or more R3Substituted when by more than one R3When substituted, R3The same or different;
the R is1is-D-B-C-, wherein D is independently selected from the group consisting of a single bond, oxygen, sulfur, and-NR4B is independently selected from a single bond, or (CH)2)n-, where N is independently selected from 0 to 6, C is independently selected from hydrogen, -N (R)4)2、-C(O)-N(R4)2、-OR4、C3-C8Cycloalkyl radical, C3-C12Heterocycloalkyl radical, C6-C12Aryl, or C5-C13Heteroaryl of said C3-C8Cycloalkyl radical, C3-C12Heterocycloalkyl radical, C6-C12Aryl or C5-C13Heteroaryl is optionally substituted with one or more R4Substituted when by more than one R4When substituted, R4The same or different;
the R is2Selected from H, halogen, cyano, hydroxy, amino, optionally substituted with 0-3R3Substituted C1-C8Alkyl, optionally substituted with 0-3R3Substituted C1-C8Heteroalkyl, optionally with 0-3R3Substituted C1-C8Alkoxy, optionally substituted with 0-3R3Substituted C1-C3HalogenatedAlkoxy, optionally substituted with 0-3R3Substituted C3-C8Cycloalkyl optionally substituted by 0-3R3Substituted C3-C12Heterocycloalkyl optionally substituted with 0-3R3Substituted C2-C4Alkenyl or optionally substituted with 0-3R3Substituted C2-C4Alkynyl when interrupted by multiple R3When substituted, R3The same or different; n in the compound shown in the formula I is selected from 0, 1 or 2;
e is independently-C (O) C (Ra) m
C(Rb)por-SO 2C (Ra) m
C(Rb)p(ii) a Wherein Ra is independently hydrogen or C1-C3An alkyl group; rbIndependently of one another is hydrogen, C1-C3Alkyl, alkylaminoalkyl, dialkylaminoalkyl or heterocyclylalkyl groups; m is 0 or 1; p is 1 or 2; when in use
In the case of three bonds, m is equal to 0 and P is equal to 1; when in use
When it is a double bond, m is equal to 1 and P is equal to 2, when there are more than one RaOr RbWhen substituted, RaOr RbThe same or different;
the R is3Independently selected from hydrogen, halogen, hydroxy, amino, cyano, C1-C8Alkyl radical, C2-C8Heteroalkyl group, C5-C6Cycloalkyl radical, C4-C6Heterocycloalkyl and C5-C6Heteroaryl group, C2-C4Alkenyl radical, C2-C4Alkynyl, -OR4、-SR4、-C(O)OR4、-C(O)N(R4)2、-N(R4)2；
The R is4Independently selected from hydrogen, chlorine, fluorine, amino, hydrogen radical, hydroxyl, C1-C8Alkyl radical, C2-C8Heteroalkyl group, C5-C6Cycloalkyl radical, C4-C6Heterocycloalkyl and C5-C6A heteroaryl group;
"hetero" represents a heteroatom or group of heteroatoms, and the "hetero" of the above-mentioned mesoheteroalkyl, heterocycloalkyl, bridged heterocycloalkyl, spiroheterocycloalkyl, heteroaryl are each independently selected from-C (═ O) N (R)4)-、-N(R4)-、-NH-、N、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-and-N (R)4)C(＝O)N(R4)-；
In any of the above cases, the number of heteroatoms or heteroatom groups is independently selected from 1,2 and 3, respectively.
2. The cyano-containing heterocyclic compound according to claim 1, wherein the compound is selected from the group consisting of compounds of formula II, III, IV, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof;
3. the cyano-containing heterocyclic compound of any of claims 1-2, wherein a is optionally substituted with 0 to 7R3Substituted by
4. The method of any one of claims 1-2A cyano-containing heterocyclic compound, wherein R is1Is optionally substituted by 0 to 7R3Substituted H, CN, methoxy, ethyl, isopropyl,
5. The cyano-containing heterocyclic compound of any of claims 1-2, wherein E is independently selected from the group consisting of
Wherein R isaIs H, F, CH3，RbIs H, CH3，CH2F、CHF2、
6. The cyano-containing heterocyclic compound according to any of claims 1 to 2, wherein K is optionally substituted with 0 to 7R3Substituted by
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
A base,
Methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, morpholinyl, piperazinyl, piperidinyl, cyclopentenyl, cyclohexenyl.
7. The cyano-containing heterocyclic compound according to any of claims 1 to 2, wherein R is2Is H, F, Cl, Br, I, CN, OH, NH2，CONH2，CH3、CH3CH2、(CH3)2CH. Cyclopropyl, methoxy, ethoxy, isopropoxy, CF3、CHF2、CH2CHF2，CH2CH2F. Cyclopentyl, cyclohexyl, morpholinyl, vinyl, ethynyl.
8. The cyano-containing heterocyclic compound according to any of claims 1 to 2, wherein R is3C in (1)1-C8Alkyl radical, C2-C8Heteroalkyl group, C5-C6Cycloalkyl radical, C4-C6Heterocycloalkyl and C5-C6Heteroaryl group, C2-C4Alkenyl and C2-C4Alkynyl is optionally substituted by one OR more cyano, hydroxy, halogen, -OR4Heteroaryl or R4And (4) substituting.
9. The cyano-containing heterocyclic compound according to any of claims 1 to 2, wherein R is4C in (1)4-C6Heterocycloalkyl or C5-C6Heteroaryl is selected from optionally substituted with 1,2 or 3R; wherein R is selected from the group consisting of hydrogen, chloro, fluoro, amino, hydro, hydroxy, methyl, ethyl, propyl, cyclopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethoxy, -CH2OH、-OCH2CH3、-OCH2CHF2、N(CH3)2、NH(CH3) or-OCH2CF3。
10. A pharmaceutical composition comprising an effective amount of a compound of formula I, formula II, formula III or formula IV, or a pharmaceutically acceptable salt of a compound of formula I, formula II, formula III or formula IV, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, or a metabolite thereof, or a prodrug thereof, according to any one of claims 1 to 9, and at least one pharmaceutically acceptable excipient.
11. Use of a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 for the manufacture of a medicament comprising a medicament for the treatment of a disease caused by a mutation in KRAS G12C, or a KRAS G12C inhibitor medicament, or a medicament for the treatment and/or prevention of cancer.
12. The use of claim 11, wherein the cancer comprises lung cancer, lymphoma, esophageal cancer, ovarian cancer, pancreatic cancer, rectal cancer, brain glioma, cervical cancer, urothelial cancer, gastric cancer, endometrial cancer, liver cancer, bile duct cancer, breast cancer, colon cancer, leukemia, and melanoma.
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| WO2022235870A1 (en) | 2021-05-05 | 2022-11-10 | Revolution Medicines, Inc. | Ras inhibitors for the treatment of cancer |
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