CN116813646A - Substituted bridged ring inhibitors and preparation method and application thereof - Google Patents

Substituted bridged ring inhibitors and preparation method and application thereof Download PDF

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Publication number
CN116813646A
CN116813646A CN202210288030.1A CN202210288030A CN116813646A CN 116813646 A CN116813646 A CN 116813646A CN 202210288030 A CN202210288030 A CN 202210288030A CN 116813646 A CN116813646 A CN 116813646A
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alkyl
group
compound
substituted
substitution
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吕彬华
崔大为
张青
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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Suzhou Zelgen Biopharmaceutical Co Ltd
Shanghai Zelgen Pharmatech Co Ltd
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Priority to CN202210288030.1A priority Critical patent/CN116813646A/en
Priority to PCT/CN2023/082908 priority patent/WO2023179629A1/en
Publication of CN116813646A publication Critical patent/CN116813646A/en
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Abstract

The invention relates to a substituted bridged ring inhibitor, a preparation method and application thereof. Specifically, the compound has a structure shown in a formula (I), and the invention also discloses a preparation method of the compound and a KRAS (beta-glucosidase-beta-cyclodextrin) serving as the compound G12D Use of inhibitors against KRAS G12D Has good selective inhibition effect, better pharmacodynamics, pharmacokinetics performance and lower toxic and side effects.

Description

Substituted bridged ring inhibitors and preparation method and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a substituted bridged ring inhibitor, and a preparation method and application thereof.
Background
At allApproximately one quarter of human tumors are caused by RAS mutations, and nearly one million people lose life each year. In the RAS family, KRAS mutations account for 85% of all RAS mutations. KRAS mutations are found in nearly 90% of pancreatic cancers, 30-40% of colon cancers, and 15-20% of lung cancers (mainly non-small cell lung cancers). G12C and G12D mutations occur when the most predominant of KRAS mutations, with G12C mutations occurring primarily in hslc and G12D mutations occurring primarily in pancreatic cancer. Up to now, there is no yet a KRAS in the market G12D Mutated drugs are approved for marketing.
Current conventional treatment regimens for pancreatic cancer in clinic include gemcitabine monotherapy, gemcitabine in combination with albumin paclitaxel, the FOLFIRINOX regimen (oxaliplatin + irinotecan + 5-FU/LV), and the like. Wherein liposomal irinotecan is suitable for use in combination with fluorouracil and folinic acid in treating patients with advanced pancreatic cancer who are poorly treated with gemcitabine chemotherapy (second line therapy). However, in general, the current treatments for pancreatic cancer are limited and the overall survival time of patients is not more than 1 year. Although drug discovery for patients with advanced pancreatic cancer continues to be ongoing, research progress has been slow until now.
Due to KRAS G12D The target proteins are pathologically associated with a variety of diseases, particularly pancreatic cancer, and thus new KRAS is currently required G12D Inhibitors are used in clinical therapy. KRAS with high selectivity and high activity G12D The inhibitor can be used for KRAS G12D Diseases such as cancer caused by mutation are more effectively treated and the potential for off-target effects is reduced, so that more urgent clinical demands are placed on the diseases.
Disclosure of Invention
The invention aims to provide a novel pair KRAS G12D Compounds with selective inhibition and/or better pharmacodynamic properties and use thereof.
In a first aspect of the invention, there is provided a compound of formula (I), a stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof:
in the method, in the process of the invention,
u is selected from: n, CH, CD, CF;
x is selected from: n, CH, CD, CF, C (CN);
y is selected from: bond, O, NH, N (C) 1 -C 3 An alkyl group);
z is substituted or unsubstituted C 1 -C 6 An alkylene group; wherein the substitution refers to substitution with one or more R;
w is selected from: substituted or unsubstituted C 3 -C 14 Cycloalkyl, or a substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclyl; wherein the substitution refers to substitution with one or more R;
R 1 selected from: -L 1 -Q-L 2 -L 3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein:
L 1 selected from: substituted or unsubstituted C 1 -C 6 An alkylene group; wherein the substitution refers to substitution with one or more R;
q is selected from: o, S, SO 2 NH, or N (C) 1 -C 3 An alkyl group);
L 2 selected from: unsubstituted, or substituted or unsubstituted C 1 -C 6 An alkylene group; wherein the substitution refers to substitution with one or more R;
L 3 selected from the group consisting of substituted or unsubstituted: -C 1 -C 6 Alkyl, -C 3 -C 6 Cycloalkyl, -C 4 -C 6 Heterocyclyl, -C 1 -C 6 Alkylene (C) 3 -C 6 Cycloalkyl) -C 1 -C 6 Alkylene (C) 4 -C 6 Heterocyclyl) -C 1 -C 6 Alkylene (C) 1 -C 6 Alkoxy), -C 1 -C 6 Alkylene (C) 3 -C 6 Cycloalkyloxy), or-C 1 -C 6 Alkylene (C) 4 -C 6 Heterocyclyloxy); wherein the substitution refers to substitution with one or more R;
n is an integer of 1, 2, 3, 4, 5 or 6;
R 2 and R is 3 The same or different, each independently selected from the group consisting of substituted or unsubstituted: H. d, halogen, CN, C 1 -C 6 Alkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 An alkoxy group; wherein the substitution refers to substitution with one or more R;
R 4 selected from the group consisting of substituted or unsubstituted: halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl; wherein the substitution refers to substitution with one or more R;
R 8 selected from: OH, SONH 2 、NHSO 2 CH 3 ；
R 5 、R 6 、R 7 、R 9 The same or different, each independently selected from the group consisting of substituted or unsubstituted: H. d, halogen, CN, C 1 -C 6 Alkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 An alkoxy group; wherein the substitution refers to substitution with one or more R;
each R, which may be the same or different, is independently selected from: deuterium, C 1 -C 18 Alkyl, deuterated C 1 -C 18 Alkyl, halogenated C 1 -C 18 Alkyl, (C) 3 -C 18 Cycloalkyl) C 1 -C 18 Alkyl, (4-20 membered heterocyclic) C 1 -C 18 Alkyl, (C) 1 -C 18 Alkoxy) C 1 -C 18 Alkyl, (C) 3 -C 18 Cycloalkyloxy) C 1 -C 18 Alkyl, (4-20 membered heterocyclyloxy) C 1 -C 18 Alkyl, vinyl, ethynyl, (C) 1 -C 6 Alkyl) vinyl, deuteration (C) 1 -C 6 Alkyl) vinyl, halo (C) 1 -C 6 Alkyl) vinyl, (C 1 -C 6 Alkyl) ethynyl, deuteration (C) 1 -C 6 Alkyl) ethynyl group,Halo (C) 1 -C 6 Alkyl) ethynyl, (C 3 -C 14 Cycloalkyl) ethynyl, (4-14 membered heterocyclyl) ethynyl, C 1 -C 18 Alkoxy, deuterated C 1 -C 18 Alkoxy, halo C 1 -C 18 Alkoxy, C 3 -C 20 Cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 Aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amino, amido, sulfone or urea groups.
In another preferred embodiment, each R, which may be the same or different, is independently selected from: deuterium, C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, (C) 3 -C 10 Cycloalkyl) C 1 -C 6 Alkyl, (4-10 membered heterocyclic) C 1 -C 6 Alkyl, (C) 1 -C 6 Alkoxy) C 1 -C 6 Alkyl, (C) 3 -C 6 Cycloalkyloxy) C 1 -C 6 Alkyl, (4-20 membered heterocyclyloxy) C 1 -C 18 Alkyl, vinyl, ethynyl, (C) 1 -C 6 Alkyl) vinyl, deuteration (C) 1 -C 6 Alkyl) vinyl, halo (C) 1 -C 6 Alkyl) vinyl, (C 1 -C 6 Alkyl) ethynyl, deuteration (C) 1 -C 6 Alkyl) ethynyl, halo (C) 1 -C 6 Alkyl) ethynyl, (C 3 -C 10 Cycloalkyl) ethynyl, (4-10 membered heterocyclyl) ethynyl, C 1 -C 6 Alkoxy, deuterated C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkoxy, C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 Aryl, 5-to 10-membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amino, amido, sulfone or urea groups.
In another preferred embodiment, the compound of formula I has a structure of formula I
Preferably, having the structure shown in formula I'
Therein, n, U, X, Y, Z, W, L 1 、L 2 、L 3 、Q、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 Is defined as above.
In another preferred embodiment, the compound has a structure represented by formula (II):
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 The definitions of U, X, Z, W and n are as described above.
In another preferred embodiment, the compound has the structure of formula (III):
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 The definitions of U, Z, W and n are as described above.
In another preferred embodiment, R 3 Selected from: H. d, F, cl, br, CN methyl, ethyl, propyl, isopropyl, deuterated methyl, CH 2 F、CHF 2 、CF 3 Methoxy, ethoxy, propoxy, OCH 2 F、OCHF 2 、OCF 3 。
In another preferred embodiment, the compound has the structure of formula (IV):
wherein R is 1 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 The definitions of U, Z, W and n are as described above.
In another preferred embodiment, the compound has the structure of formula (V):
wherein R is 1 、R 4 、R 5 、R 6 、R 7 The definitions of U, Z, W and n are as described above.
In another preferred embodiment, the compound has the structure of formula (VI):
wherein R is 1 、R 4 、R 5 、R 6 、R 7 The definitions of Z, W and n are as described above.
In another preferred embodiment, the compound has the structure of formula (VII):
wherein R is 1 、R 4 、R 5 The definitions of Z, W and n are as described above.
In another preferred embodiment, the compound has the structure of formula (VIII):
wherein the method comprises the steps of，R 1 、R 4 、R 5 The definitions of Z, W and n are as described above.
In another preferred embodiment, W is a substituted or unsubstituted group of: c (C) 3 -C 6 Monocyclic cycloalkyl, C 7 -C 10 A bicyclic or tricyclic cycloalkyl, 4-6 membered saturated or unsaturated monocyclic heterocyclyl, 7-10 membered bicyclic or tricyclic heterocyclyl; preferably, W is selected from: substituted or unsubstituted 7-10 membered saturated or unsaturated bridged heterocyclic group, substituted or unsubstituted 7-10 membered saturated or unsaturated condensed ring heterocyclic group.
In another preferred embodiment, W is selected from:wherein n' is an integer of 0, 1, 2, 3, 4, 5, or 6; r is as defined above.
In another preferred embodiment, Z is substituted or unsubstituted C 1 -C 3 Alkylene, preferably methylene, ethylene, propylene.
In another preferred example, n, U, X, Y, Z, W, L 1 、L 2 、L 3 、Q、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 Has the corresponding groups of each specific compound in the examples.
In another preferred embodiment, the compound has the structure of formula (IX):
wherein n' is an integer of 0, 1, 2, 3, 4, 5, or 6;
R 5 、R、L 1 、Q、L 2 、L 3 and n is as defined above.
In another preferred embodiment, R 4 Selected from the group consisting of substituted or unsubstituted: halogen, methyl, ethyl, propyl, ethenyl, propenyl, allyl, butenyl, ethynyl, propynyl, butynyl.
In a further preferred embodiment of the present invention,selected from: />
In another preferred embodiment, L 1 Selected from: a substituted or unsubstituted methylene group or a substituted or unsubstituted ethylene group; q is selected from: o; l (L) 2 Selected from: an unsubstituted, or substituted or unsubstituted methylene group; l (L) 3 Selected from the group consisting of substituted or unsubstituted: -C 1 -C 6 Alkyl, -C 3 -C 6 Cycloalkyl, -C 4 -C 6 Heterocyclyl, -C 1 -C 6 Alkylene (C) 3 -C 6 Cycloalkyl) -C 1 -C 6 Alkylene (C) 4 -C 6 Heterocyclyl) -C 1 -C 6 Alkylene (C) 1 -C 6 Alkoxy), -C 1 -C 6 Alkylene (C) 3 -C 6 Cycloalkyloxy), or-C 1 -C 6 Alkylene (C) 4 -C 6 Heterocyclyloxy); wherein said substitution means substitution with one or more groups selected from the group consisting of: deuterium, C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, vinyl, ethynyl, C 1 -C 6 Alkoxy, deuterated C 1 -C 6 Alkoxy, halo C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl, 4-6 membered heterocyclyl, C 6 -C 14 Aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amino, amido, sulfone or urea groups.
In another preferred embodiment, -L 1 -Q-L 2 -L 3 Selected from:
in a further preferred embodiment of the present invention,is->Preferably +.>
In a further preferred embodiment of the present invention,is->Preferably +.>
In another preferred embodiment, the compound is selected from the group consisting of:
/>
/>
/>
in another preferred embodiment, the compound is preferably the compound prepared in the examples.
In a second aspect of the present invention, there is provided a process for the preparation of a compound of formula (I), a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein the process comprises the steps of:
(i) Reacting a compound of formula V-1 with a compound of formula V-2 in an inert solvent, in the presence or absence of a Pd catalyst, and in the presence or absence of a condensing agent, to obtain a compound of formula V-3;
(ii) Reacting a compound of formula V-3 with a compound of formula V-4 in an inert solvent, in the presence of a base, with or without a Pd catalyst, to obtain a compound of formula V-5;
(iii) Reacting a compound of formula V-5 with a compound of formula V-6 in the presence of a Pd catalyst in an inert solvent in the presence of a base to obtain a compound of formula V-7;
(iv) Removing the protecting group PG1 of the compound of the formula V-7 under the action of acid (such as TFA, HCl and the like) or Pd catalytic hydrogenation condition to obtain a compound of the formula (I);
in the method, in the process of the invention,
X 1 、X 2 and X 3 Each independently selected from: OH, halogen, OTf, OTs or OMs;
PG1 is selected from: boc, cbz, or Bn;
LG1 is selected from: -B (OH) 2 、-B(KBF 3 )、-Sn( n Bu) 3 、
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 The definitions of U, X, Y, Z, W and n are as described above.
In a third aspect of the invention, there is provided a pharmaceutical composition comprising one or more compounds of the first aspect, stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof; and a pharmaceutically acceptable carrier.
In another preferred embodiment, the pharmaceutical composition further comprises a drug selected from the group consisting of: PD-1 inhibitors (e.g., nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009, or a biosimilar of the above), PD-L1 inhibitor (e.g., durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311, or a biosimilar of the above), CD20 antibody (e.g., rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritimomab, 90 In-ibritimomab, ibritumomab tiuxetan, etc.), CD47 antibody (e.g., hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM 01), ALK inhibitor (e.g., ceritinib, alectinib, brigatinib, lorlatinib, ocotinib), PI3K inhibitor (e.g., idelalisib, duvelisib, dactolisib, taselisib, bimiralisib, omipalisib, buparlisib, etc.), BTK inhibitor (e.g., ibrutinib, tirabrutinib, acalabrutinib, zanubrutinib, vecabrutinib, etc.), EGFR inhibitor (e.g., afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canertinib, sapitinib, naquotinib, pyrotinib, rociletinib, osimertinib, etc.), FR inhibitor (e.g., sorafenib, pazopanib, regorafenib, sitravatinib, ningetinib, cabozantinib, sunitinib, e.g., UK 5-G4, CC-90024), KK inhibitor (e.g., UK-11252), KK (e.g., K2), KK-11252, etc.), KK inhibitor (e.g., K2, etc., K2, KK-11252, etc mTOR inhibitors (e.g., vistuertib, etc.), SHP2 inhibitors (e.g., RMC-4630, JAB-3068, TNO155, etc.), or combinations thereof.
In a fourth aspect the present invention provides the use of a compound according to the first aspect, a stereoisomer, a tautomer, a crystal, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, or a pharmaceutical composition according to the third aspect, for the preparation of a medicament for the prophylaxis and/or treatment of a disease associated with KRAS G12D A drug for diseases associated with the activity or expression level of the polypeptide.
In another preferred embodiment, the disease is a tumor or a disorder.
In another preferred embodiment, the disease is selected from the group consisting of: lung cancer, breast cancer, prostate cancer, esophageal cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, colorectal cancer, melanoma, lymphoma, leukemia, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, and skin cancer.
In a fourth aspect of the invention, there is provided a non-diagnostic, non-therapeutic inhibition of KRAS G12D Comprising the steps of: administering to a subject in need thereof an effective amount of a compound as described in the first aspect, a stereoisomer, tautomer, crystal, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, or a pharmaceutical composition as described above.
In another preferred embodiment, the subject is a mammal, preferably a human.
In a fifth aspect of the invention, there is provided an in vitro KRAS inhibition method G12D A method of activity comprising the steps of: the compound according to the first aspect, its stereoisomerismContacting a construct, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug, or pharmaceutical composition as described above, with a protein or cell, thereby inhibiting KRAS G12D Is a compound of formula (I).
In another preferred embodiment, the cells are selected from the group consisting of: macrophages, intestinal cells (including intestinal stem cells, intestinal epithelial cells), or combinations thereof.
In another preferred embodiment, the cells are from a rodent (e.g., mouse, rat), or a primate (e.g., human).
It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Detailed Description
The inventor has studied intensively for a long time, and unexpectedly prepared a novel KRAS G12D Compounds with selective inhibition and/or better pharmacodynamic properties. On this basis, the inventors completed the present invention.
Terminology
In the present invention, unless otherwise indicated, terms used have the ordinary meanings known to those skilled in the art.
The term "alkyl" refers to straight or branched chain alkanyl radicals containing 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, especially 1 to 18 carbon atoms, preferably 1 to 10 carbon atoms (C1-C10), more preferably 1 to 6 carbon atoms (C1-C6). Typical "alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, and,Pentyl, isopentyl, heptyl, 4-dimethylpentyl, octyl, 2, 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. In the present invention, alkyl groups also include substituted alkyl groups. "substituted alkyl" means that one or more positions in the alkyl group are substituted, especially 1-4 substituents, and thatSubstituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., a single halogen substituent or a multiple halogen substituent, the latter such as trifluoromethyl or containing Cl) 3 Alkyl group of (c), nitrile group, nitro group, oxygen (e.g., =o), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, OR a 、SR a 、S(＝O)R e 、S(＝O) 2 R e 、P(＝O) 2 R e 、S(＝O) 2 OR e ,P(＝O) 2 OR e 、NR b R c 、NR b S(＝O) 2 R e 、NR b P(＝O) 2 R e 、S(＝O) 2 NR b R c 、P(＝O) 2 NR b R c 、C(＝O)OR d 、C(＝O)R a 、C(＝O)NR b R c 、OC(＝O)R a 、OC(＝O)NR b R c 、NR b C(＝O)OR e ,NR d C(＝O)NR b R c 、NR d S(＝O) 2 NR b R c 、NR d P(＝O) 2 NR b R c 、NR b C(＝O)R a Or NR b P(＝O) 2 R e Wherein R occurs therein a Can independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, a 5-to 14-membered heterocycle or a C6-C14-aromatic ring, R b 、R c And R is d Can independently represent hydrogen, deuterium, C1-C6 alkyl, C3-C8 cycloalkyl, a 5-to 14-membered heterocycle or a C6-C14-aromatic ring, or R b And R is c Together with the N atom, may form a heterocyclic ring; r is R e Can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C6 cycloalkenyl, C2-C6 alkynyl, a 5-to 14-membered heterocycle, or a C6-C14 aromatic ring. Typical substituents described above, such as alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aromatic ring, may be optionally substituted.
The term "alkylene" refers to a group formed by the removal of one more hydrogen atom from an "alkyl group or substituted alkyl group", such as methylene, ethylene, propylene, isopropylene(e.g) Butylene (e.g.)> ) Pentylene (e.g.)>) Hexyl ene (e.g.)>) Heptyl (e.g.)>)、/>Etc. In addition, the term also includes the replacement of a methylene group of an alkylene group (e.g., a C1-C18 alkylene group) with a cycloalkylene group (e.g., a C3-C20 cycloalkylene group), such as "C1-C18 alkylene C3-C20 cycloalkylene" or "C3-C20 cycloalkylene C1-C18 alkylene".
The term "C1-C18 alkylene-C3-C20 cycloalkylene" or "C3-C20 cycloalkylene-C1-C18 alkylene" has the same meaning and refers to groups formed by the removal of two hydrogen atoms from a cycloalkylalkyl or alkylcycloalkyl group, e.g. Etc.
In the present invention, the term "alkenyl" means a straight or branched hydrocarbon group containing one or more double bonds and typically having a length of 2 to 20 carbon atoms. Alkenyl is preferably C2-C6 alkenyl, more preferably C2-C4 alkenyl. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. In the present invention, alkenyl includes substituted alkenyl.
The term "alkynyl" denotes a straight or branched hydrocarbon radical containing one or more triple bonds and typically ranging in length from 2 to 20 carbon atoms. Alkynyl is preferably C2-C6 alkynyl, more preferably C2-C4 alkynyl. Alkynyl groups include, but are not limited to, ethynyl, propynyl, or the like. In the present invention, alkynyl also includes substituted alkynyl groups, and substituents may be halo, hydroxy, cyano, nitro, and the like.
In the present invention, the term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon compound group comprising 1 to 4 rings, each ring containing 3 to 8 carbon atoms. The term "C 3 -C 20 "means a cyclic alkyl group containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. Cycloalkyl is preferably C 3 -C 14 Cycloalkyl, more preferably C 3 -C 10 Cycloalkyl, more preferably C 3 -C 6 Monocyclic cycloalkyl, C 7 -C 10 Bicyclic or tricyclic cycloalkyl groups. "substituted cycloalkyl" means that one or more positions in the cycloalkyl group are substituted, especially 1-4 substituents, and can be substituted at any position. In the present invention, "cycloalkyl" includes substituted cycloalkyl groups, typical substitutions including, but not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., a single halogen substituent or a multiple halogen substituent, the latter such as trifluoromethyl or containing Cl) 3 Alkyl group of (c), nitrile group, nitro group, oxygen (e.g., =o), trifluoromethyl group, trifluoromethoxy group, cycloalkyl group, alkenyl group, cycloalkenyl group, alkynyl group, heterocycle, aromatic ring, OR a 、SR a 、S(＝O)R e 、S(＝O) 2 R e 、P(＝O) 2 R e 、S(＝O) 2 OR e ,P(＝O) 2 OR e 、NR b R c 、NR b S(＝O) 2 R e 、NR b P(＝O) 2 R e 、S(＝O) 2 NR b R c 、P(＝O) 2 NR b R c 、C(＝O)OR d 、C(＝O)R a 、C(＝O)NR b R c 、OC(＝O)R a 、OC(＝O)NR b R c 、NR b C(＝O)OR e ,NR d C(＝O)NR b R c 、NR d S(＝O) 2 NR b R c 、NR d P(＝O) 2 NR b R c 、NR b C(＝O)R a Or NR b P(＝O) 2 R e Wherein R occurs therein a Can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R b 、R c And R is d Can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R b And R is c Together with the N atom, may form a heterocyclic ring; r is R e Can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aromatic ring. Typical substituents described above may be optionally substituted. Typical substitutions also include spiro, bridged or fused ring substituents, especially spiro-cycloalkyl, spiro-alkenyl, spiro-heterocycle (excluding heteroaryl), bridged-cycloalkyl, bridged-cycloalkenyl, bridged-heterocycle (excluding heteroaryl), fused-ring alkyl, fused-ring alkenyl, fused-ring heterocyclyl or fused-ring aryl groups, which cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl groups may be optionally substituted. Examples of cycloalkyl groups include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, and the like.
The term "C3-C20 cycloalkylene" refers to a group formed by the removal of two hydrogen atoms from a cycloalkyl group, such as:etc.
In the present invention, the term "heterocyclyl" refers to a fully saturated or partially unsaturated cyclic group (including, but not limited to, e.g., 3-7 membered monocyclic, 4-7 membered monocyclic, 6-11 membered bicyclic, or 8-16 membered tricyclic or polycyclic ring systems) wherein at least one heteroatom is present in a ring having at least one carbon atom. The term "4-20 membered heterocyclyl" refers to heterocyclyl containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 ring atoms. "heterocyclyl" has the same meaning as "saturated or unsaturated heterocyclyl". The "heterocyclyl" is preferably a 4-14 membered heterocyclyl (including but not limited to, e.g., 4-6 membered monocyclic, 7-10 membered bicyclic or 8-14 membered tricyclic or polycyclic systems), more preferably a 4-12 membered heterocyclyl, more preferably a 4-10 membered heterocyclyl, such as a 4-6 membered monocyclic heterocyclyl, 7-10 membered bicyclic or tricyclic heterocyclyl, more preferably a 4-8 membered heterocyclyl, more preferably a 4-6 membered heterocyclyl. Each heteroatom-containing heterocycle may bear 1,2,3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms, where the nitrogen or sulfur atoms may be oxidized and the nitrogen atoms may also be quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom residue of a ring or ring system molecule, preferably to an N or C atom of a ring or ring system molecule. Typical monocyclic heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, oxetanyl, pyrazolinyl, imidazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, hexahydroazepinyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1, 3-dioxanyl, and tetrahydro-1, 1-dioxythiophene, and the like. Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups; wherein the heterocyclic groups of the spiro ring, the condensed ring and the bridged ring are optionally connected with other groups through single bonds, or are further connected with other cycloalkyl groups, heterocyclic groups, aryl groups and heteroaryl groups through any two or more atoms on the ring in a parallel ring manner; the heterocyclic group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate.
The term "C4-C20 heterocyclylene" refers to a group formed by the removal of two hydrogen atoms from a heterocyclic group, such as:etc.
In the present invention, the term "aryl" refers to aromatic cyclic hydrocarbon groups having 1 to 5 rings, especially monocyclic and bicyclic groups. Wherein "C 6 -C 14 Aryl "refers to an aromatic cyclic hydrocarbon compound group containing 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms. Aryl includes phenyl, biphenyl, or naphthyl. The aromatic ring of the aryl group may be linked by a single bond (e.g., biphenyl), or condensed (e.g., naphthalene, anthracene, etc.), where the aromatic ring contains two or more aromatic rings (bicyclic, etc.). "substituted aryl" means that one or more positions in the aryl group are substituted, especially 1 to 3 substituents, and can be substituted at any position. Typical substitutions include, but are not limited to, one or more of the following groups: such as hydrogen, deuterium, halogen (e.g., a single halogen substituent or a multiple halogen substituent, the latter such as trifluoromethyl or containing Cl) 3 Alkyl, nitrile, nitro, oxo (e.g., =o), trifluoromethyl, trifluoromethoxy, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, aromatic ring, OR a 、SR a 、S(＝O)R e 、S(＝O) 2 R e 、P(＝O) 2 R e 、S(＝O) 2 OR e ,P(＝O) 2 OR e 、NR b R c 、NR b S(＝O) 2 R e 、NR b P(＝O) 2 R e 、S(＝O) 2 NR b R c 、P(＝O) 2 NR b R c 、C(＝O)OR d 、C(＝O)R a 、C(＝O)NR b R c 、OC(＝O)R a 、OC(＝O)NR b R c 、NR b C(＝O)OR e ,NR d C(＝O)NR b R c 、NR d S(＝O) 2 NR b R c 、NR d P(＝O) 2 NR b R c 、NR b C(＝O)R a Or NR b P(＝O) 2 R e Wherein R occurs therein a Can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle or aromatic ring, R b 、R c And R is d Can independently represent hydrogen, deuterium, alkyl, cycloalkyl, heterocycle or aromatic ring, or R b And R is c Together with the N atom, may form a heterocyclic ring; r is R e Can independently represent hydrogen, deuterium, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aromatic ring. Typical substituents described above may be optionally substituted. Typical substitutions also include fused ring substituents, especially fused ring alkyl, fused ring alkenyl, fused ring heterocyclyl or fused ring aryl groups, which cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl groups may be optionally substituted.
The term "heteroaryl" refers to an aromatic cyclic hydrocarbon group containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur. Wherein "5-14 membered heteroaryl" refers to a heteroaromatic system containing 1-4 heteroatoms, 5-14 ring atoms. Heteroaryl is preferably a 5-to 10-membered ring, more preferably 5-or 6-membered ring, such as pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. "heteroaryl" may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more groups independently selected from alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylthio, oxo, carboxyl, and carboxylate.
In the present invention, the term "alkoxy" means having a straight or branched chain alkoxy group, including alkyl-O-, alkyl-O-alkyl groups, wherein "C 1 -C 18 Alkoxy "means a straight or branched chain alkoxy group having 1 to 18 carbon atoms containing C 1 -C 18 alkyl-O-, -C 1 -C 6 alkyl-O-C 1 -C 6 Alkyl groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and the like. Preferably C 1 -C 8 Alkoxy, more preferably C1-C 6 An alkoxy group.
In the present invention, the term "cycloalkaneBy "acyloxy" is meant a cycloalkyl-O-group in which "C 3 -C 20 Cycloalkyloxy "means C 3 -C 20 cycloalkyl-O-, wherein C 3 -C 20 Cycloalkyl groups are defined as above.
In the present invention, the term "heterocyclyloxy" means a heterocyclic group-O-, in which "4-20 membered heterocyclyloxy" means a 4-20 membered heterocyclic group-O-, in which 4-20 membered heterocyclic group is defined as above.
In the present invention, the term "C 1 -C 18 Alkyloxy "means" C 1 -C 18 The "alkoxy group" is a group obtained by removing one hydrogen atom.
In the present invention, the term "halogen" or "halo" refers to chlorine, bromine, fluorine, iodine.
In the present invention, the term "halo" refers to substitution with halogen.
In the present invention, the term "deuterated" refers to substitution with deuterium.
In the present invention, the term "hydroxyl group" means a group having the structure OH.
In the present invention, the term "nitro" means a compound having the structure NO 2 Is a group of (2).
In the present invention, the term "cyano" refers to a group with the structure CN.
In the present invention, the term "ester group" refers to a group having the structure-COOR, wherein R represents hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle.
The term "amine group" refers to a group having the structure-NRR ', wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different in the dialkylamine fragment.
The term "amide" refers to a group with the structure-CONRR ', wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different in the dialkylamine fragment.
The term "sulfone group" refers to a group having the structure-SO 2 The radicals of R, wherein R may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above.
The term "ureido" refers to a group bearing the structure-NRCONR 'R ", wherein R, R' and R" may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R "may be the same or different in the dialkylamine fragment.
The term "alkylaminoalkyl" refers to a group with the structure-RNHR ', wherein R and R' may independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R and R' may be the same or different.
The term "dialkylaminoalkyl" refers to a group with the structure-RNHR 'R ", wherein R, R' and R" may independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl, heterocycle or substituted heterocycle, as defined above. R, R' and R "may be the same or different in the dialkylamine fragment.
The term "heterocyclylalkyl" refers to a group bearing the structure-RR', wherein R may independently represent alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, aryl or substituted aryl; r' represents a heterocycle or a substituted heterocycle.
In the present invention, the term "substituted" means that one or more hydrogen atoms on a particular group are replaced with a particular substituent. The specific substituents are those described in the foregoing for each of the examples or are those found in each of the examples. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, which may be the same or different at each position. Those skilled in the art will appreciate that combinations of substituents contemplated by the present invention are those that are stable or chemically achievable. Such as (but not limited to): halogen, hydroxy, cyano, carboxyl (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-to 12-membered heterocyclyl, aryl, heteroaryl, C1-C8 aldehyde, C2-C10 acyl, C2-C10 ester, amine, C1-C6 alkoxy, C1-C10 sulfonyl, C1-C6 ureido, and the like.
Unless otherwise indicated, it is assumed that any heteroatom in an underfilling state has sufficient hydrogen atoms to complement its valence.
When the substituent is a non-terminal substituent, it is a subunit of the corresponding group, e.g., alkyl corresponds to alkylene, cycloalkyl corresponds to cycloalkylene, heterocyclyl corresponds to heterocyclylene, alkoxy corresponds to alkyleneoxy, and the like.
In the present invention, a plurality means 2, 3, 4, 5.
Active ingredient
As used herein, "compounds of the invention" refers to compounds of formula I, and also includes stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates of the compounds of formula I.
Salts which may be formed with the compounds of the present invention are also within the scope of the present invention. Unless otherwise indicated, the compounds of the present invention are understood to include salts thereof. The term "salt" as used herein refers to salts formed with inorganic or organic acids and bases in the acid or base form. Furthermore, when the compound of the present invention contains a basic moiety, it includes, but is not limited to, pyridine or imidazole, and an acidic moiety, including, but not limited to, carboxylic acids, the possible formation of zwitterions ("inner salts") are included within the term "salts". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps during the preparation process. The compounds of the invention may form salts, for example, by reacting compound I with an amount of, for example, an equivalent of, an acid or base, salting out in a medium, or lyophilizing in aqueous solution.
The compounds of the present invention contain basic fragments, including but not limited to amine or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that may be salified include acetates (e.g., with acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecyl sulfate, ethane sulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, caproate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, mesylate, naphthalene sulfonate (e.g., 2-naphthalene sulfonate), nicotinate, nitrate, oxalate, pectate, persulfate, phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., formed with sulfuric acid), sulfonate, tartrate, thiocyanate, toluene sulfonate such as p-toluenesulfonate, dodecanoate, and the like.
Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, that may form salts with various organic or inorganic bases. Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, potassium salts, alkaline earth metal salts such as calcium, magnesium salts, and salts with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, sea-bamine (salts with N, N-bis (dehydroabietyl) ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, t-butylamine, and salts with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can be combined with halide quaternary ammonium salts, such as small molecule alkyl halides (e.g., methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, dibutyl and dipentyl sulfates), long chain halides (e.g., decyl, dodecyl, tetradecyl and tetradecyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenyl bromides), and the like.
Prodrugs and solvates of the compounds of the invention are also within the scope of coverage. The term "prodrug" as used herein refers to a compound that undergoes chemical conversion by metabolic or chemical processes to produce a compound, salt, or solvate of the invention when used in the treatment of a related disorder. The compounds of the present invention include solvates, such as hydrates.
The compounds, salts or solvates of the present invention, may exist in tautomeric forms (e.g., amides and imine ethers). All of these tautomers are part of the present invention.
Stereoisomers of all compounds (e.g., those having asymmetric carbon atoms which may be present as a result of various substitutions), including enantiomeric and diastereoisomeric forms thereof, are contemplated as falling within the scope of the present invention. The individual stereoisomers of the compounds of the invention may not be present simultaneously with the other isomers (e.g., having particular activity as one pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures with all or a portion of the other stereoisomers. The chiral center of the present invention has two configurations, S or R, defined by the International Association of theory and application chemistry (IUPAC) 1974. The racemic forms can be resolved by physical methods, such as fractional crystallization, or by separation of crystals by derivatization into diastereomers, or by chiral column chromatography. Individual optical isomers may be obtained from the racemates by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.
The compounds of the present invention are prepared, isolated and purified in sequence to give the compounds in an amount of 90% by weight or more, for example 95% or more and 99% or more ("very pure" compounds), as listed in the text description. Such "very pure" compounds of the invention are also included herein as part of the invention.
All configurational isomers of the compounds of the present invention are within the scope of coverage, whether in mixtures, pure or very pure form. The definition of compounds in the present invention includes both the cis (Z) and the trans (E) olefin isomers, as well as the cis and trans isomers of carbocycles and heterocycles.
Throughout the specification, groups and substituents may be selected to provide stable fragments and compounds.
Specific functional groups and chemical term definitions are described in detail below. For the purposes of the present invention, chemical elements are described in conjunction with Periodic Table of the Elements, CAS version, handbook of Chemistry and Physics,75 th Ed.. The definition of specific functional groups is also described herein. Furthermore, the basic principles of organic chemistry and specific functional groups and reactivities are described in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato 1999, which is incorporated by reference in its entirety.
Certain compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures thereof. In addition, an asymmetric carbon atom may represent a substituent such as an alkyl group. All isomers and mixtures thereof are encompassed by the present invention.
According to the invention, the mixture of isomers may contain various isomer ratios. For example, in a mixture of only two isomers, there may be a combination of: all ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0 isomers are within the scope of the invention. Similar ratios, as well as ratios for more complex mixtures of isomers, are within the scope of the present invention, as would be readily understood by one of ordinary skill in the art.
The present invention also includes isotopically-labeled compounds, equivalent to those disclosed herein as original compounds. In practice it will often occur that one or more atoms are replaced by an atom of a different atomic weight or mass number than it is. Examples of isotopes that can be listed as compounds of the invention include hydrogen, carbon, nitrogen Isotopes of oxygen, phosphorus, sulfur, fluorine and chlorine, respectively, e.g 2 H、 3 H、 13 C、 11 C、 14 C、 15 N、 18 O、 17 O、 31 P、 32 P、 35 S、 18 F and F 36 Cl. The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, wherein isotopes or other isotopic atoms containing such compounds are within the scope of the present invention. Certain isotopically-labeled compounds of the present invention, e.g 3 H and 14 radioisotopes of C are also useful in, among other things, tissue distribution experiments of drugs and substrates. Tritium, i.e. tritium 3 H and carbon-14, i.e 14 C, their preparation and detection are relatively easy. Is the first choice in isotopes. In addition, heavier isotopic substitutions such as deuterium, i.e 2 H may be preferred in some cases because of its good metabolic stability, which may be advantageous in certain therapies, such as increasing half-life or decreasing dosage in vivo. Isotopically-labeled compounds can be prepared by conventional methods by using readily available isotopically-labeled reagents in place of non-isotopically-labeled reagents using the protocols disclosed in the examples.
If one is to design the synthesis of a particular enantiomer of a compound of the invention, it may be prepared by asymmetric synthesis or by derivatization with chiral auxiliary, separating the resulting diastereomeric mixture and removing the chiral auxiliary to give the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed therewith using an appropriate optically active acid or base, and then the resulting mixture can be separated by conventional means such as fractional crystallization or chromatography to give the pure enantiomer.
As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to extend their inclusion. In general, the term "substituted", whether appearing before or after the term "optional", in the formulas of the present invention includes substituents, means that the specified structural substituent is substituted for the hydrogen radical. When multiple of a particular structure are substituted at a position with multiple particular substituents, the substituents may be the same or different at each position. The term "substitution" as used herein includes all permissible organic compound substitutions. In a broad sense, permissible substituents include acyclic, cyclic, branched, unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. In the present invention, the heteroatom nitrogen may have a hydrogen substituent or any of the permissible organic compounds described hereinabove to supplement the valence state thereof. Furthermore, the present invention is not intended to be limited in any way to allow substitution of organic compounds. The present invention contemplates that the combination of substituents and variable groups is useful in the treatment of diseases, such as infectious or proliferative diseases, in the form of stable compounds. The term "stable" as used herein refers to a compound that is stable for a period of time sufficient to maintain structural integrity of the compound, preferably for a period of time sufficient to be effective, as used herein for the purposes described above.
Metabolites of the compounds and pharmaceutically acceptable salts thereof of the present application, as well as prodrugs that can be converted in vivo to structures of the compounds and pharmaceutically acceptable salts thereof of the present application are also encompassed by the claims of the present application.
Preparation method
The following more specifically describes the preparation method of the compounds of the structures of the formulae (I-A) and (I-B) of the present application, but these specific methods do not limit the present application in any way. The compounds of the present application may also be conveniently prepared by optionally combining the various synthetic methods described in this specification or known in the art, such combinations being readily apparent to those skilled in the art to which the present application pertains.
Typically, the compounds of the present application are prepared by the following process wherein the starting materials and reagents used, unless otherwise specified, are commercially available.
Preferably, the compounds of the present application are prepared by the following method
(i) Reacting a compound of formula V-1 with a compound of formula V-2 in an inert solvent, in the presence or absence of a Pd catalyst, and in the presence or absence of a condensing agent, to obtain a compound of formula V-3;
(ii) Reacting a compound of formula V-3 with a compound of formula V-4 in an inert solvent, in the presence of a base, with or without a Pd catalyst, to obtain a compound of formula V-5;
(iii) Reacting a compound of formula V-5 with a compound of formula V-6 in the presence of a Pd catalyst in an inert solvent in the presence of a base to obtain a compound of formula V-7;
(iv) Removing the protecting group PG1 of the compound of the formula V-7 under the action of acid (such as TFA, HCl and the like) or Pd catalytic hydrogenation condition to obtain a compound of the formula (I);
in the method, in the process of the invention,
X 1 、X 2 and X 3 Each independently selected from: OH, halogen, OTf, OTs or OMs;
PG1 is selected from: boc, cbz, or Bn;
LG1 is selected from: -B (OH) 2 、-B(KBF 3 )、-Sn( n Bu) 3 、
R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 The definitions of U, X, Y, Z, W and n are as described above.
Pharmaceutical compositions and methods of administration
The pharmaceutical composition provided by the invention is used for preventing and/or treating the following diseases: inflammation, cancer, cardiovascular disease, infection, immune disease, metabolic disease.
The compounds of formula (I) may be used in combination with other drugs known to treat or ameliorate similar conditions. When administered in combination, the mode of administration and dosage of the original drug may remain unchanged, while the compound of formula I is administered simultaneously or subsequently. When the compound of formula I is administered simultaneously with one or more other drugs, it may be preferable to use a pharmaceutical composition containing one or more known drugs together with the compound of formula I. Drug combinations also include administration of the compound of formula I with one or more other known drugs over overlapping time periods. When a compound of formula I is administered in combination with one or more other drugs, the dosage of the compound of formula I or the known drug may be lower than the dosage of the compound of formula I alone.
Drugs or active ingredients that may be used in combination with the compounds of formula (I) include, but are not limited to: PD-1 inhibitors (e.g., nivolumab, pembrolizumab, pidilizumab, cemiplimab, JS-001, SHR-120, BGB-A317, IBI-308, GLS-010, GB-226, STW204, HX008, HLX10, BAT 1306, AK105, LZM 009, or a biosimilar of the above), PD-L1 inhibitor (e.g., durvalumab, atezolizumab, avelumab, CS1001, KN035, HLX20, SHR-1316, BGB-A333, JS003, CS1003, KL-A167, F520, GR1405, MSB2311, or a biosimilar of the above), CD20 antibody (e.g., rituximab, obinutuzumab, ofatumumab, veltuzumab, tositumomab, 131I-tositumomab, ibritumomab, 90Y-ibritimomab, 90 In-ibritimomab, ibritumomab tiuxetan, etc.), CD47 antibody (e.g., hu5F9-G4, CC-90002, TTI-621, TTI-622, OSE-172, SRF-231, ALX-148, NI-1701, SHR-1603, IBI188, IMM 01), ALK inhibitor (e.g., ceritinib, alectinib, brigatinib, lorlatinib, ocotinib), PI3K inhibitor (e.g., idelalisib, duvelisib, dactolisib, taselisib, bimiralisib, omipalisib, buparlisib, etc.), BTK inhibitor (e.g., ibrutinib, tirabrutinib, acalabrutinib, zanubrutinib, vecabrutinib, etc.), EGFR inhibitor (e.g., afatinib, gefitinib, erlotinib, lapatinib, dacomitinib, icotinib, canertinib, sapitinib, naquotinib, pyrotinib, rociletinib, osimertinib, etc.), FR inhibitor (e.g., sorafenib, pazopanib, regorafenib, sitravatinib, ningetinib, cabozantinib, sunitinib, e.g., UK 5-G4, CC-90024), KK inhibitor (e.g., UK-11252), KK (e.g., K2), KK-11252, etc.), KK inhibitor (e.g., K2, etc., K2, KK-11252, etc mTOR inhibitors (e.g., vistuertib, etc.), SHP2 inhibitors (e.g., RMC-4630, JAB-3068, TNO155, etc.), or combinations thereof. Dosage forms of the pharmaceutical composition of the present invention include (but are not limited to): injection, tablet, capsule, aerosol, suppository, pellicle, dripping pill, external liniment, controlled release or sustained release preparation, or nanometer preparation.
The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical compositions contain 1-2000mg of the compound of the invention per dose, more preferably 10-1000mg of the compound of the invention per dose. Preferably, the "one dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween ) Wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water and the like.
The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, e.g., glycerin; (d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent, such as paraffin; (f) an absorption accelerator, e.g., a quaternary amine compound; (g) Wetting agents, such as cetyl alcohol and glycerol monostearate; (h) an adsorbent, for example, kaolin; and (i) a lubricant, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. The active compound may also be in the form of microcapsules with one or more of the above excipients, if desired.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like.
In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar-agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required if necessary.
The methods of treatment of the present invention may be administered alone or in combination with other therapeutic means or therapeutic agents.
When a pharmaceutical composition is used, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically effective dose, and the daily dose is usually 1 to 2000mg, preferably 50 to 1000mg, for a human having a body weight of 60 kg. Of course, the particular dosage should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled practitioner.
The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: mixing a pharmaceutically acceptable carrier with the compounds of general formula (I-A) and formula (I-B) or crystalline forms, pharmaceutically acceptable salts, hydrates or solvates thereof, thereby forming a pharmaceutical composition.
The invention also provides a treatment method, which comprises the following stepsThe steps are as follows: administering to a subject in need thereof a compound of formula (I) as described herein, or a crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as described herein, for selectively inhibiting KRAS G12D 。
Compared with the prior art, the invention has the following main advantages:
(1) The pair of compounds KRAS G12D Has good selective inhibition effect;
(2) The compound has better pharmacodynamics, pharmacokinetics and lower toxic and side effects.
The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedure, which does not address the specific conditions in the examples below, is generally followed by routine conditions such as Sambrook et al, molecular cloning: conditions described in the laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989) or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) and liquid chromatography-mass spectrometry (LC-MS).
NMR was performed using a Bruker AVANCE-400 nuclear magnetic resonance apparatus, and the measuring solvent contained deuterated dimethyl sulfoxide (DMSO-d 6 ) Deuterated acetone (CD) 3 COCD 3 ) Deuterated chloroform (CDCl) 3 ) Deuterated methanol (CD) 3 OD), etc., the internal standard being Tetramethylsilane (TMS), the chemical shifts being measured in parts per million (ppm).
Liquid chromatography (LC-MS) was performed using a Waters SQD2 mass spectrometer. HPLC was determined using an Agilent 1100 high pressure chromatograph (Microsorb 5micron C18 100x 3.0mm column).
The thin layer chromatography silica gel plate is Qingdao GF254 silica gel plate, TLC is 0.15-0.20mm, and the preparation thin layer chromatography is 0.4-0.5 mm. Column chromatography generally uses Qingdao silica gel 200-300 mesh silica gel as carrier.
The starting materials in the examples of the present invention are known and commercially available, or may be synthesized using or according to literature reported in the art.
Except for the special descriptions, all reactions of the invention are carried out by continuous magnetic stirring under the protection of dry inert gas (such as nitrogen or argon), and the reaction temperature is in degrees centigrade.
Examples
Preparation of intermediate 1-1 (3- (methoxymethyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methanol
The first step: preparation of 1-benzyl 2-methyl 2- (but-3-en-1-yl) pyrroline-1, 2-dicarboxylic acid ester
A solution of 1-benzyl-2-methyl (S) -pyrroline-1, 2-dicarboxylic acid ester (50.0 g,190mmol,1.00 eq) in THF (100 mL) at-70℃under nitrogen was added dropwise to LiHMDS (1.00M, 284 mL,1.50 eq). The resulting reaction solution was reacted at-70℃for 2 hours, followed by dropwise addition of 4-bromobut-1-ene (51.2 g,380mmol,38.6mL,2.00 eq). The reaction mixture obtained is warmed to 25℃and reacted for 16h and subsequently saturated with NH 4 Aqueous Cl (200 mL) was quenched and then extracted with EtOAc (100 mL x 3). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the desired product (38.0 g,120mmol,63.1% yield).
1 H NMR(400MHz,CDCl 3 )δ7.33(m,5H)5.77(m,1H)5.07(m,4H)3.72(m,3H)3.48(m,2H)2.01(m,8H)
And a second step of: preparation of 1-benzyl 2-methyl 2- (2- (propylene oxide-2-yl) ethyl) pyrroline-1, 2-dicarboxy late
1-benzyl 2-methyl-2- (but-3-en-1-yl) pyrroline-1, 2-dicarboxylic acid ester (37.5 g, 118) To a solution of mmol,1.00eq, in DCM (650 mL) was added m-CPBA (60.0 g,295mmol,85.0% purity,2.50 eq) in portions. The resulting reaction solution was reacted at 25℃for 16 hours, followed by saturated Na 2 SO 3 (300 ml x 3) washes. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the objective product (29.0 g,87.0mmol,73.6% yield).
1 H NMR(400MHz,CDCl 3 )δ7.33(br d,J＝7.88Hz,5H)5.11(m,2H)3.70(m,3H)3.48(m,2H)2.73(m,2H)2.36(m,2H)1.98(m,5H)1.50(m,2H)
And a third step of: preparation of methyl 3- (hydroxymethyl) tetrahydro-1H-bis-fused pyrrolidine-7 a (5H) -carboxylate
To a solution of 1-benzyl 2-methyl 2- (2- (propylene oxide-2-yl) ethyl) pyrroline-1, 2-dicarboxylic acid ester (28.0 g,84.0mmol,1.00 eq) in MeOH (600 mL) was added Pd/C (6.00 g,10.0% wt). The reaction was reacted at 25℃for 16h under a hydrogen atmosphere and then filtered. The filtrate was concentrated under reduced pressure to give the desired product (16.8 g). The reaction mixture was used in the next reaction without purification.
Fourth step: preparation of methyl 3- (methoxymethyl) tetrahydro-1H-bis-fused pyrrolidine-7 a (5H) -carboxylate
To a solution of 3- (hydroxymethyl) tetrahydro-1H-bis-pyrrolidine-7 a (5H) -carboxylic acid methyl ester (1.00 g,5.02mmol,1.00 eq) in THF (20 mL) at 0deg.C under nitrogen was added NaH (602 mg,15.1mmol,60.0% wt,3.00 eq). The reaction mixture was reacted at 25℃for 0.5h, followed by addition of MeI (1.42 g,10.0mmol, 235 uL,2.00 eq). The reaction mixture obtained was reacted at 25℃for 3 hours, then at 0℃with H 2 O (10 mL) was quenched and extracted with EtOAc (30 mL. Times.2). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the objective product (1.0 g,1.88mmol,37.5% yield).
1 H NMR(400MHz,CDCl 3 )δ3.66-3.72(m,3H)3.30-3.33(m,3H)2.22-2.43(m,1H)1.83-2.12(m,6H)1.56-1.72(m,1H)
Fifth step: preparation of (3- (methoxymethyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methanol
3- (methoxymethyl) tetrahydro-1H-bisbipyrrolidine-7 a (5H) at 0deg.C under nitrogen protectionTo a solution of methyl formate (1.00 g,4.69mmol,1.00 eq) in THF (10 mL) was added LiAlH 4 (356 mg,9.38mmol,2.00 eq). The reaction mixture was reacted at 25℃for 1H, followed by sequential addition of H at 0 ℃ 2 O (10 mL), 15% NaOH (10 mL) and H 2 O (30 mL) was quenched and extracted with EtOAc (50 mL x 2). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the objective product (1.1 g).
LC-MS：m/z 186(M+H) + 。 1 H NMR(400MHz,CDCl 3 )δ4.39(dd,J＝10.54,9.03Hz,1H)4.26(br d,J＝6.53Hz,1H)3.97-4.06(m,1H)3.80-3.96(m,2H)3.68-3.76(m,2H)3.50(s,3H)2.04-2.40(m,6H)1.78-1.93(m,2H)
The following compounds were synthesized from different starting materials according to the same synthesis method as intermediate 1-1:
intermediate 1-2 (3- ((ethoxy) methyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methanol
LC-MS：m/z 200(M+H) + 。
Intermediate 1-3 (3- ((isopropoxy) methyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methanol
LC-MS：m/z 214(M+H) + 。
Intermediate 1-4 (3- ((cyclopropylmethoxy) methyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methanol
LC-MS：m/z 226(M+H) + 。
Intermediate 1-5 (3- (cyclopropoxymethyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methanol
LC-MS：m/z 212(M+H) + 。
Intermediate 1-6 ((2R) -2-fluoro-5- (methoxymethyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methanol
LC-MS：m/z 204(M+H) + 。
Intermediate 1-7 ((2R) -2-fluoro-5- (cyclopropoxymethyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methanol
LC-MS：m/z 230(M+H) + 。
Preparation of intermediate 2-1 ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane
The first step: preparation of 7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalene-1, 3-diol
To a solution of 7-fluoronaphthalene-1, 3-diol (5 g,28.1mmol,1 eq), (bromoacetylene) triisopropylsilane (7.33 g,28.1mmol,1 eq) and potassium acetate (5.51 g,56.1mmol,2 eq) in dioxane (120 mL) at room temperature under nitrogen was added ruthenium dichloride 1-isopropyl-4-methyl-benzene (1.20 g,1.96mmol,0.07 eq). The reaction solution was reacted at 110℃for 16 hours and then filtered. The filter cake was washed with EtOAc (200 ml x 2). The combined organic phases were concentrated under reduced pressure. The residue was chromatographed on a column of silica gel to give the desired product (8 g,22.3mmol,79.5% yield).
1 H NMR(400MHz,CDCl 3 )δ9.19(m,1H)7.60(dd,J＝9.17,5.62Hz,1H)7.18(m,1H)6.73(m,2H)5.29(br s,1H)1.22(m,21H)
And a second step of: preparation of 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-ol
To a solution of 7-fluoro-8- ((triisopropylsilyl) ethynyl) naphthalene-1, 3-diol (7 g,19.5mmol,1 eq) and DIEA (5.05 g,39.0mmol,6.80mL,2 eq) in DCM (100 mL) at 0 ℃ was added MOMCl (1.66 g,20.6mmol,1.57mL,1.06 eq). The reaction mixture obtained was reacted at 25℃for 1.5H and then with H 2 O (200 mL) was quenched, pH 6-7 was adjusted with 1N HCl, and extracted with DCM (80.0 mL x 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the objective product (4.2 g,10.4mmol,53.4% yield).
1 H NMR(400MHz,DMSO-d 6 )δ8.94-9.20(m,1H)8.93-9.13(m,1H)7.58(dd,J＝9.07,5.69Hz,1H)7.10(t,J＝8.82Hz,1H)6.89(d,J＝2.50Hz,1H)6.73(d,J＝1.88Hz,1H)5.12-5.24(m,2H)3.43(s,3H)1.09-1.13(m,21H)
And a third step of: preparation of 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethane sulfonate
To a solution of 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-ol (4 g,9.94mmol,1 eq) in DCM (40 mL) at-40℃was added DIEA (3.85 g,29.8mmol,5.19mL,3 eq) and Tf 2 O (4.21 g,14.9mmol,2.46mL,1.5 eq). The reaction mixture obtained was reacted at-40℃for 0.5H, followed by H 2 O (20 mL) was diluted and extracted with DCM (50 mL. Times.2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the desired product (5 g,8.88mmol,89.4% yield,95% purity) was obtained as a yellow oil.
1 H NMR(400MHz,CDCl 3 )δ7.72(dd,J＝9.03,5.27Hz,1H)7.44(d,J＝2.26Hz,1H)7.36-7.39(m,1H)7.31-7.35(m,1H)5.20-5.37(m,2H)3.46-3.63(m,3H)1.17-1.33(m,17H)
Fourth step: preparation of ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane
Pd (dppf) Cl was added to a solution of 7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate (5 g,9.35mmol,1 eq), 4, 5-tetramethyl-2- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1,3, 2-dioxaborolan (4.75 g,18.70mmol,2 eq), acOK (2.75 g,28.06mmol,3 eq) in tolene (100 mL) under nitrogen 2 (684 mg, 935. Mu. Mol,0.1 eq). The resulting reaction solution was reacted at 130℃for 8 hours and then filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the objective product (3.5 g,6.49mmol,69.3% yield).
1 H NMR(400MHz,CDCl 3 )δ7.68(dd,J＝8.93,5.62Hz,1H)7.52(d,J＝2.45Hz,1H)7.39(d,J＝2.57Hz,1H)7.24(t,J＝8.80Hz,1H)5.18-5.39(m,2H)3.43-3.58(m,3H)1.45(s,12H)1.15-1.21(m,20H)
Preparation of intermediate 3-1 (1R, 5S) -3- (2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
The first step: preparation of 2-chloro-3-fluoro-5-iodopyridin-4-amine
To a solution of 2-chloro-3-fluoropyridin-4-amine (10 g,68.5 mmol) and NIS (18.5 g,82.2mmol,1.2 eq) in acetonitrile (50 mL) was added p-toluenesulfonic acid monohydrate (0.65 g,3.43mmol,0.05 eq). The reaction was stirred at 70℃for 16 hours, then diluted with water (30 mL) and EtOAc (200 mL). The separated organic phase was treated with S.aq.Na 2 CO 3 、S.aq.Na 2 SO 3 And saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the desired product (16.6 g,61mmol, yield: 89%). The reaction mixture was used in the next reaction without purification.
LC-MS：m/z 273(M+H) + 。
And a second step of: preparation of 4-amino-6-chloro-5-fluoronicotinic acid ethyl ester
2-chloro-3-fluoro-5-iodopyridin-4-amine (8.2 g,30mmol, 1) was run under nitrogen.0 eq) of EtOH (150 mL) was added Pd (PPh) 3 ) 2 Cl 2 (2.1 g,3mmol,0.1 eq) and TEA (11.1 g,0.11mmol,3.6 eq) in CO 2 The reaction was carried out at 80℃for 15 hours under an atmosphere, followed by filtration. The filtrate was concentrated under reduced pressure to 70-80% of the original volume and then filtered again. And collecting and combining filter cakes, and then drying in vacuum to obtain a target product (quantitative yield). The reaction mixture was used in the next reaction without purification.
LC-MS：m/z 219(M+H) + 。
And a third step of: preparation of 7-chloro-8-fluoropyridine [4,3-d ] pyrimidine-2, 4-diol
To a solution of ethyl 4-amino-6-chloro-5-fluoronicotinate (657 mg,3 mmol) obtained above in THF (7 mL) was added trichloroacetyl isocyanate (673 mg,3.6mmol,1.2 eq) at 0deg.C. The reaction solution was reacted at rt for 30min and then concentrated under reduced pressure. MeOH (15 mL) was added to the residue and cooled to 0deg.C, followed by NH addition 3 Methanol solution (7M in MeOH,15mL,105mmol). The resulting reaction solution was reacted at rt for 16 hours and then filtered. The filter cake was washed with methanol and then dried in vacuo to give the desired product (quantitative yield). The reaction mixture was used in the next reaction without purification.
LC-MS：m/z 216(M+H) + 。
Fourth step: preparation of 2,4, 7-trichloro-8-fluoropyridine [4,3-d ] pyrimidine
7-chloro-8-fluoropyridine [4,3-d ]]POCl of pyrimidine-2, 4-diol (500 mg,2.4 mmol) and DIPEA (1.55 g,12mmol,5.0 eq) 3 The (5 mL) solution was reacted at 100℃for 1 hour, followed by concentration under reduced pressure to give the objective compound (quantitative yield). The reaction mixture was used in the next reaction without purification.
LC-MS：m/z 252(M+H) + 。
Fifth step: preparation of (1R, 5S) -3- (2, 7-dichloro-8-fluoropyridine [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
To a solution of the above-obtained 2,4, 7-trichloro-8-fluoropyridine [4,3-d ] pyrimidine and DIPEA (2 g,15.5 mmol) in DCM (2 mL) was added 3, 8-diazabicyclo [3.2.l ] octane-8-carboxylic acid tert-butyl ester (500 mg,2.4 mmol) at-40 ℃. The resulting reaction solution was reacted at the current temperature for 0.5h, then diluted with water (2 mL) and extracted with DCM (2X 2 mL). The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the desired product (400 mg, crude yield: 38.9%). The reaction mixture was used in the next reaction without purification.
LC-MS：m/z 428(M+H) + 。
Preparation of intermediate 4-1 (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (2, 2-trifluoroethoxy) pyridin [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
The first step: preparation of (1R, 5S) -3- (7-chloro-8-fluoro-2- (2, 2-trifluoroethoxy) pyridine [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
(1R, 5S) -3- (2, 7-dichloro-8-fluoropyridine [4, 3-d)]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (8.00 g,18.7mmol,1.00 eq) and 2, 2-trifluoroethanol (56.1 g,560mmol,40.3mL,30.0 eq) were added DIEA (7.24 g,56.0mmol,9.76mL,3.00 eq). The resulting reaction solution was reacted at 70℃for 2 hours and then concentrated under reduced pressure. Residue with H 2 O (100 mL) was diluted and then extracted with EtOAc (100 mL x 3). The combined organic phases were washed with saturated test water (100 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the desired product (9 g,18.3mmol,97.9% yield).
LC-MS：m/z 492(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ8.71(s,1H),4.82(q,J＝8.4Hz,2H),4.44(br d,J＝12.0Hz,2H),4.31(br s,2H),3.63(br s,2H),1.95-1.83(m,2H),1.68-1.58(m,2H),1.45(s,9H)
And a second step of: preparation of (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (2, 2-trifluoroethoxy) pyridin [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
Under the nitrogen atmosphere, (1R, 5S) -3- (7-chlorine-8-fluorine-2- (2),2, 2-trifluoroethoxy) pyridine [4,3-d]Pyrimidine-4-yl) -3, 8-diazabicyclo [3.2.1]Tert-butyl octane-8-carboxylate (9.00 g,18.3mmol,1.00 eq), ((2-fluoro-6- (methoxymethoxy) -8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) triisopropylsilane (9.85 g,19.2mmol,1.05 eq) and Cs 2 CO 3 (11.9 g,36.6mmol,2.00 eq) H 2 To a mixed solution of O (20.0 mL) and dioxane (100 mL) was added CataCXium Pd G2 (611 mg, 910 umol,0.05 eq). The reaction mixture obtained is reacted at 100℃for 1H, then H is used 2 Quench O (50 mL) and extract with EtOAc (100 mL x 3). The combined organic phases were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the objective product (14.8 g,17.6mmol,96.10% yield).
LC-MS：m/z 842(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ9.25(s,1H),8.11(dd,J＝5.9,9.2Hz,1H),7.75(d,J＝2.5Hz,1H),7.57(t,J＝8.9Hz,1H),7.35(d,J＝2.4Hz,1H),5.76(s,1H),5.46-5.27(m,2H),5.21-4.91(m,2H),4.81(d,J＝12.4Hz,1H),4.38-4.17(m,3H),3.81(d,J＝12.0Hz,1H),3.60-3.52(m,1H),3.43(s,3H),1.63(d,J＝7.4Hz,1H),1.46(s,9H),0.80(t,J＝7.8Hz,20H),0.57-0.38(m,3H).
Example 14 preparation of- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((3- (methoxymethyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
The first step: preparation of (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((3- (methoxymethyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester
(3- (methoxymethyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methanol (1.01 g,5.45mmol,4.59 eq) and (1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- (2, 2-trifluoroethoxy) pyridine [4,3-d ]Pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1]To a solution of tert-butyl octane-8-carboxylate (1.00 g,1.19mmol,1.00 eq) in THF (20 mL) was added t-Buona (913 mg,9.50mmol,8.00 eq). The reaction mixture was reacted at 25℃for 16H, then with H 2 O (10 mL) was quenched and extracted with EtOAc (30 mL. Times.3). The combined organic phases were washed with saturated test water (100 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography to give the objective product (723 mg, 255 umol,21.7% yield, 33.0% purity). The reaction mixture was used in the next reaction without purification.
And a second step of: preparation of 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((3- (methoxymethyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methoxymethyl) pyridin [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol
(1R, 5S) -3- (8-fluoro-7- (7-fluoro-3- (methoxymethoxy) -8- ((triisopropylsilyl) ethynyl) naphthalen-1-yl) -2- ((3- (methoxymethyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (640 mg,238umol,33.0% purity, 1.00 eq) in DCM (6 mL) was added HCl/dioxane (4.00M, 945uL,15.8 eq). The reaction solution was reacted at 25℃for 2 hours, and then concentrated under reduced pressure to give the objective product (430 mg, crude). The reaction mixture was used in the next reaction without purification.
And a third step of: preparation of 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((3- (methoxymethyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
To a solution of 4- (4- ((1 r,5 s) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((3- (methoxymethyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methoxymethyl) pyridin [4,3-d ] pyrimidin-7-yl) -6-fluoro-5- ((triisopropylsilyl) ethynyl) naphthalen-2-ol (400 mg, 400 umol,32.0% purity,1.00 eq) in DMF (6 mL) was added CsF (497 mg,3.27mmol,121ul,20.0 eq). The reaction solution was reacted at 25℃for 16 hours, followed by filtration. The filtrate was concentrated under reduced pressure, and the residue was separated by prep-HPLC to give the desired product (63.0 mg).
LC-MS：m/z 627(M+H) + 。
Chiral SFC separation gave isomer 1 of example 1 (11.3 mg,17.6umol,10.8% yield) and isomer 2 of example 1 (19.2 mg,29.9umol,18.3% yield)
Example 1 isomer 1
LC-MS：m/z 627(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ10.17(br s,1H)9.03(s,1H)7.98(dd,J＝9.16,5.90Hz,1H)7.47(t,J＝8.91Hz,1H)7.39(d,J＝2.51Hz,1H)7.18(d,J＝2.26Hz,1H)4.48(br d,J＝11.80Hz,1H)4.31(br d,J＝12.30Hz,1H)3.95-4.08(m,2H)3.94(s,1H)3.64(br d,J＝12.05Hz,1H)3.57(br s,3H)3.17-3.28(m,5H)2.79-2.94(m,2H)2.65-2.70(m,1H)1.90-2.06(m,2H)1.78(br d,J＝4.52Hz,3H)1.51-1.69(m,8H).
Example 1 isomer 2
LC-MS：m/z 627(M+H) + 。 1 H NMR(400MHz,DMSO-d 6 )δ10.17(br s,1H)9.04(s,1H)7.98(dd,J＝9.16,5.90Hz,1H)7.47(t,J＝9.03Hz,1H)7.40(d,J＝2.51Hz,1H)7.18(d,J＝2.26Hz,1H)4.49(br d,J＝12.05Hz,1H)4.32(br d,J＝12.30Hz,1H)3.96-4.10(m,2H)3.94(s,1H)3.65(br d,J＝14.31Hz,1H)3.56-3.62(br s,3H)3.17-3.28(m,5H)2.80-2.95(m,2H)2.68(br d,J＝1.76Hz,1H)1.90-2.03(m,2H)1.78(br s,3H)1.51-1.72(m,8H).
The following examples were synthesized according to the procedure of example 1 starting from different starting materials:
example 2 4 preparation of- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((3- ((ethoxy) methyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
LCMS:m/z 641(M+H) + .
Example 3 4 preparation of- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((3- ((isopropoxy) methyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
LCMS:m/z 655(M+H) + .
Example 4 4 preparation of- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- ((3- ((cyclopropylmethoxy) methyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
LCMS:m/z 667(M+H) + .
Example 5 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- ((3- (cyclopropoxymethyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
LCMS:m/z 653(M+H)+.
Example 6 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -8-fluoro-2- (((2R) -2-fluoro-5- (methoxymethyl) tetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methoxy) pyridin [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
LCMS:m/z 645(M+H)+.
Example 7 4- (4- ((1R, 5S) -3, 8-diazabicyclo [3.2.1] oct-3-yl) -2- (((2R) -5- (cyclopropoxymethyl) -2-fluorotetrahydro-1H-bis-fused pyrrolidin-7 a (5H) -yl) methoxy) -8-fluoropyridine [4,3-d ] pyrimidin-7-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
LCMS:m/z 671(M+H)+.
Example 8 biological test example
Biological test evaluation
The following biological test examples further illustrate the invention, but these examples are not meant to limit the scope of the invention.
KRAS Gl2D Binding inhibition assay
Experimental procedure
Detection of compounds and KRAS Using TR-FRET technology G12D Binding ability of proteins. Loading of biotin-labeled GDP with KRAS G12D Recombinant human protein and Cy 5-labeled tracer, europium-labeled streptavidin, and compound (2% DMSO final concentration) in buffer (HEPES (pH 7.5), mgCl 2 Tween-20 and DTT). After incubation at 22 ℃ for 60min, the reactivity was detected by the EnVision multifunctional microplate reader dual wavelength technique and the protein binding (POC) was calculated using ratiometric emission factor.
100POC represents no compound; 0POC indicates complete inhibition of tracer and KRAS at this concentration for the control compound G12D Is a combination of (a) and (b). POC values are fitted by four-parameter Logistic model curves, and IC 50 Representing a 50POC concentration value.
The results indicate that the compounds of the examples of the present invention are specific to KRAS G12D Shows good inhibitory activity.
ERK phosphorylation inhibition assay
Experimental procedure
GP2D cells were seeded in 384-well plates and incubated overnight at 37 ℃ in a 5% co2 incubator.
200nL of diluted compound was added to Echo 500, and the mixture was incubated in a 5% CO2 incubator at 37℃for 1 hour at a final DMSO concentration of 0.5%. hEGF was added for 10 min.
Removing the culture medium, adding cell fixing solution, and fixing cells
PBS was washed 1 time, incubated with cold 100% methanol,
methanol was removed and washed 1 time with PBS.
PBS was removed, li-Cor blocking buffer was added to each well and blocked at room temperature for 1hr.
The blocking solution was removed, primary antibody mix was added to each well and incubated overnight at 4℃at room temperature.
The primary antibody mixture was removed and washed 3 times with PBST.
Adding the secondary antibody mixed solution, and incubating for 45min at room temperature in a dark place.
And removing the secondary antibody mixture, adding PBST for washing for 3 times, finally sucking out the PBST, reversely buckling and centrifuging, and centrifuging at 1000rpm for 1min.
Odyssey CLx readings.
TABLE 1ERK phosphorylation inhibition assay results
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The results indicate that the compounds of the examples of the present invention are specific to KRAS G12D Shows good inhibitory activity.
Pharmacokinetic test evaluation
Male SD rats weighing around 220g, were fed overnight, and were given a solution of 30mg/kg of the compound of the invention or control compound [10% cortisol (captisol) and 50mM sodium citrate (sodium citrate), pH 5 as vehicle ] by intraperitoneal injection. The concentrations of the compounds of the invention or control compounds in plasma were determined by LC/MS after 0.083,0.25,0.5,1.0,2.0,4.0,6.0,8.0, 12.0 and 24h, respectively, of blood collection after administration of the compounds of the invention.
From the detection results, the compound has good pharmacokinetic properties.
Evaluation of antitumor Activity pharmacodynamics test (MIA PaCa-2 CDX tumor model)
100uL of the mixture contains 5x10 6 MIA PaCa-2 tumor cell suspensions were inoculated subcutaneously into the right posterior flank of nude mice. Mice were monitored daily for health status when tumors grew to be palpableThe measurement is started in time. The calculation formula of the tumor volume adopts 0.5xLxW 2 Wherein L, W represents tumor length and width, respectively. Tumors grow to 200mm 3 Mice were randomly grouped. Mice were given daily gavage with the corresponding dose of compound, while monitoring their general status. Tumors were measured 3 times per week and body weights were measured twice per week.
The detection result shows that the compound has good anti-tumor effect.
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (10)

1. A compound of formula (I), stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof:
In the method, in the process of the invention,
u is selected from: n, CH, CD, CF;
x is selected from: n, CH, CD, CF, C (CN);
y is selected from: bond, O, NH, N (C) 1 -C 3 An alkyl group);
z is substituted or unsubstituted C 1 -C 6 An alkylene group; wherein the substitution refers to substitution with one or more R;
w is selected from: substituted or unsubstituted C 3 -C 14 Cycloalkyl, or a substituted or unsubstituted 4-14 membered saturated or unsaturated heterocyclyl; wherein the substitution refers to substitution with one or more R;
R 1 selected from: -L 1 -Q-L 2 -L 3 The method comprises the steps of carrying out a first treatment on the surface of the Wherein:
L 1 selected from: substituted or unsubstituted C 1 -C 6 An alkylene group; wherein the substitution refers to substitution with one or more R;
q is selected from: o, S, SO 2 NH, or N (C) 1 -C 3 An alkyl group);
L 2 selected from: unsubstituted, or substituted or unsubstituted C 1 -C 6 An alkylene group; wherein the substitution refers to substitution with one or more R;
L 3 selected from the group consisting of substituted or unsubstituted: -C 1 -C 6 Alkyl, -C 3 -C 6 Cycloalkyl, -C 4 -C 6 Heterocyclyl, -C 1 -C 6 Alkylene (C) 3 -C 6 Cycloalkyl) -C 1 -C 6 Alkylene (C) 4 -C 6 Heterocyclyl) -C 1 -C 6 Alkylene (C) 1 -C 6 Alkoxy), -C 1 -C 6 Alkylene (C) 3 -C 6 Cycloalkyloxy), or-C 1 -C 6 Alkylene (C) 4 -C 6 Heterocyclyloxy); wherein the substitution refers to substitution with one or more R;
n is an integer of 1, 2, 3, 4, 5 or 6;
R 2 and R is 3 The same or different, each independently selected from the group consisting of substituted or unsubstituted: H. d, halogen, CN, C 1 -C 6 Alkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 An alkoxy group; wherein the substitution refers to substitution with one or more R;
R 4 selected from the group consisting of substituted or unsubstituted: halogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl; wherein the substitution refers to substitution with one or more R;
R 8 selected from: OH, SONH 2 、NHSO 2 CH 3 ；
R 5 、R 6 、R 7 、R 9 Identical or different, each independentlySelected from the group consisting of substituted or unsubstituted: H. d, halogen, CN, C 1 -C 6 Alkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 An alkoxy group; wherein the substitution refers to substitution with one or more R;
each R, which may be the same or different, is independently selected from: deuterium, C 1 -C 18 Alkyl, deuterated C 1 -C 18 Alkyl, halogenated C 1 -C 18 Alkyl, (C) 3 -C 18 Cycloalkyl) C 1 -C 18 Alkyl, (4-20 membered heterocyclic) C 1 -C 18 Alkyl, (C) 1 -C 18 Alkoxy) C 1 -C 18 Alkyl, (C) 3 -C 18 Cycloalkyloxy) C 1 -C 18 Alkyl, (4-20 membered heterocyclyloxy) C 1 -C 18 Alkyl, vinyl, ethynyl, (C) 1 -C 6 Alkyl) vinyl, deuteration (C) 1 -C 6 Alkyl) vinyl, halo (C) 1 -C 6 Alkyl) vinyl, (C 1 -C 6 Alkyl) ethynyl, deuteration (C) 1 -C 6 Alkyl) ethynyl, halo (C) 1 -C 6 Alkyl) ethynyl, (C 3 -C 14 Cycloalkyl) ethynyl, (4-14 membered heterocyclyl) ethynyl, C 1 -C 18 Alkoxy, deuterated C 1 -C 18 Alkoxy, halo C 1 -C 18 Alkoxy, C 3 -C 20 Cycloalkyl, 4-20 membered heterocyclyl, C 6 -C 14 Aryl, 5-14 membered heteroaryl, halogen, nitro, hydroxy, oxo, cyano, ester, amino, amido, sulfone or urea groups.
2. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof according to claim 1, having a structure according to formula (II):
wherein R is 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 U, X, Z, W and n are as defined in claim 1.
3. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof according to any one of claims 1 to 2, having a structure according to formula (V):
wherein R is 1 、R 4 、R 5 、R 6 、R 7 U, Z, W and n are as defined in claim 1.
4. A compound according to any one of claims 1 to 3, a stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, having the structure of formula (VI):
wherein R is 1 、R 4 、R 5 、R 6 、R 7 Z, W and n are as defined in claim 1.
5. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof according to any one of claims 1 to 4, having a structure according to formula (VII):
Wherein R is 1 、R 4 、R 5 Z, W and n are as defined in claim 1.
6. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof according to any one of claims 1 to 5, having a structure according to formula (VIII):
wherein R is 1 、R 4 、R 5 Z, W and n are as defined in claim 1.
7. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof according to claim 1, having a structure according to formula (IX):
wherein n' is an integer of 0, 1, 2, 3, 4, 5, or 6;
R 5 、R、L 1 、Q、L 2 、L 3 and n is as defined in claim 1.
8. The compound, stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof according to any one of claims 1 to 7, wherein the compound is selected from the group consisting of:
9. a pharmaceutical composition comprising one or more compounds of any one of claims 1-8, stereoisomers, tautomers, crystalline forms, pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof; and a pharmaceutically acceptable carrier.
10. Use of a compound according to any one of claims 1 to 8, a stereoisomer, a tautomer, a crystal, a pharmaceutically acceptable salt, a hydrate, a solvate, or a prodrug thereof, or a pharmaceutical composition according to claim 9, for the preparation of a medicament for the prophylaxis and/or treatment of a disease associated with KRAS G12D Correlation of activity or expression level of (C)Is a medicine for treating diseases.
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