CN117624190A - KRAS G12D inhibitor and application thereof in medicine - Google Patents

KRAS G12D inhibitor and application thereof in medicine Download PDF

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Publication number
CN117624190A
CN117624190A CN202311003135.9A CN202311003135A CN117624190A CN 117624190 A CN117624190 A CN 117624190A CN 202311003135 A CN202311003135 A CN 202311003135A CN 117624190 A CN117624190 A CN 117624190A
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alkylene
compound
substituted
alkyl
cycloalkyl
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CN202311003135.9A
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Inventor
吴颢
路渊
徐人奇
李波燕
何将旗
杨晓峰
林远望
杜亚军
赵志昌
李腾飞
高锜
田凯
方龙城
周全
兰宏
王家炳
丁列明
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Betta Pharmaceuticals Co Ltd
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Betta Pharmaceuticals Co Ltd
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Abstract

The present invention relates to compounds of formula (I), stereoisomers, tautomers, deuterides or pharmaceutically acceptable salts thereof, to processes for their preparation, to pharmaceutical compositions containing them and to their use as medicaments for the treatment and/or prophylaxis of diseases mediated by KRAS.

Description

KRAS G12D inhibitor and application thereof in medicine
Technical Field
The present invention relates to a novel compound having KRAS inhibitory activity, in particular KRAS G12D inhibitory activity. The invention also relates to a preparation method of the compounds and a pharmaceutical composition containing the compounds.
Background
Clinical data indicate that RAS is the most mutated gene in human tumors, with RAS mutations occurring in about 20-30% of all tumors, about 98% of pancreatic cancers, 52% of colon cancers, 43% of multiple myeloma, and 32% of lung adenocarcinomas. The most common mode of mutation in RAS is point mutation, frequently occurring at codons 12, 13, 61, where again the mutation at codon 12 is most common, e.g. G12C, G D or G12V.
Drug development against KRAS mutations is currently one of the current research hotspots for new drugs. KRAS G12C inhibitor AMG510 (WO 2018217651 A1) and MRTX849 (WO 2019099524 A1) have entered the later clinical stage.
Based on the importance of KRAS aberrant activation in cancer progression and the prevalence of KRAS gene mutations in human cancers, KRAS has been the target of interest to drug developers. Despite advances in this area, there remains a need in the art for improved KRAS G12D mutein inhibitors.
Disclosure of Invention
The invention provides a novel-structure small-molecule KRAS G12D inhibitor which has good anti-tumor activity.
The invention provides a compound shown in a general formula (I), a stereoisomer, a tautomer, a deuterated compound or a medicinal salt thereof:
wherein,
represents a single bond or a double bond;
X 1 selected from O or NR 5 ；R 5 Selected from H, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 1-6 Haloalkyl, substituted C 1-6 Haloalkyl, C 2-6 Alkenyl or substituted C 2-6 Alkenyl groups;
X 2 selected from O, (CH) 2 ) 0-3 、C(R 6 ) 1-2 C (O) or NR 6 ；R 6 Selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, substituted C 1-6 Alkyl, halogen, C 2-6 Alkenyl, substituted C 2-6 Alkenyl, C 3-6 Cycloalkyl or substituted C 3-6 Cycloalkyl;
X 3 selected from CR 7 Or N; r is R 7 Selected from the absence or H;
X 4 selected from O, (CH) 2 ) 0-3 、C(R 8 ) 1-2 C (O) or NR 8 ；R 8 Selected from H, halogen, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 1-6 Alkoxy, -O (CH) 2 ) 0-3 R 13 、C 3-6 Cycloalkyl or substituted C 3-6 Cycloalkyl;
X 5 selected from O, NR 9 、(CH 2 ) 0-3 、C(R 9 ) 2 Or C (O); r is R 9 Each independently selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, substituted C 1-6 Alkyl, halogen, C 2-6 Alkenyl, substituted C 2-6 Alkenyl, C 3-6 Cycloalkyl or substituted C 3-6 Cycloalkyl;
X 6 selected from O, NR 10 、(CH 2 ) 0-3 、C(R 10 ) 2 Or C (O); r is R 10 Each independently selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, substituted C 1-6 Alkyl, halogen, C 2-6 Alkenyl, substituted C 2-6 Alkenyl, C 3-6 Cycloalkyl or substituted C 3-6 Cycloalkyl;
X 7 selected from CR 11 Or N; r is R 11 Selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, substituted C 1-6 Alkyl or halogen;
l is selected from the group consisting of bond, -O-C 0-4 Alkylene-, -S-C 0-4 Alkylene-, -NR 9 -C 0-4 Alkylene-or C 2-4 Alkynylene group, the-O-C 0-4 Alkylene-, -S-C 0-4 Alkylene-, -S (O) 2 -C 0-4 Alkylene-, -NR 9 -C 0-4 Alkylene-or C 2-4 Alkynylene optionally being substituted with one or more R 12 Substitution; r is R 12 Selected from H, halogen, cyano, hydroxy or C 1-6 Alkyl, or two on the same carbon atomR 12 Together with the atoms to which they are attached form C 3-6 Cycloalkyl or 3-6 membered heterocyclyl;
R 1 selected from C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, amido, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl;
R 2 selected from-OR a 、-OC(O)N(R a ) 2 、-N(R a ) 2 、-NR a C(O)R a 、-NR a C(O)N(R a ) 2 、-NR a S(O)R a 、-NR a S(O) 2 R a 、-S(＝O)R a 、-S(＝O) 2 R a 、-SR a 、-S(R a ) 5 、-C(＝O)R a 、-C(＝O)OR a 、-C(＝O)N(R a ) 2 、C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 6-14 membered heteroaryl optionally further substituted with one or more R 10 Substitution; r is R 10 Selected from H, cyano, halogen, C 1-6 Alkyl, -C 0-6 alkylene-OR a 、-C 0-6 alkylene-OC (O) N (R) a ) 2 、-C 0-6 alkylene-N (R) a ) 2 、-C 0-6 alkylene-NR a C(O)R a 、-C 0-6 alkylene-NR a C(O)N(R a ) 2 、-C 0-6 alkylene-NR a S(O)R a 、-C 0-6 alkylene-NR a S(O) 2 R a 、-C 0-6 alkylene-S (=o) R a 、-C 0-6 alkylene-S (=o) 2 R a 、-C 0-6 alkylene-SR a 、-C 0-6 alkylene-S (R) a ) 5 、-C 0-6 alkylene-C (=o) R a 、-C 0-6 alkylene-C (=o) OR a 、-C 0-6 alkylene-C (=O) N (R) a ) 2 、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-14 membered heteroaryl), said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-14 membered heteroaryl) optionally may also be substituted with 1 or more R a Substituted;
R 3 selected from C 6-14 Aryl or 5-14 membered heteroaryl, said C 6-14 Aryl or 5-14 membered heteroaryl optionally further substituted with one or more R 13 Substitution; r is R 13 Selected from H, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 alkylene-OR a 、-C 0-6 alkylene-OC (O) N (R) a ) 2 、-C 0-6 alkylene-N (R) a ) 2 、-C 0-6 alkylene-NR a C(O)R a 、-C 0-6 alkylene-NR a C(O)N(R a ) 2 、-C 0-6 alkylene-NR a S(O)R a 、-C 0-6 alkylene-NR a S(O) 2 R a 、-C 0-6 alkylene-S (=o) R a 、-C 0-6 alkylene-S (=o) 2 R a 、-C 0-6 alkylene-SR a 、-C 0-6 alkylene-S (R) a ) 5 、-C 0-6 alkylene-C (=o) R a 、-C 0-6 alkylene-C (=o) OR a 、-C 0-6 alkylene-C (=O) N (R) a ) 2 、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-14 membered heteroaryl), said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-14 membered heteroaryl) optionallyMay also be substituted with 1 or more R a Substituted;
R 4 selected from H, cyano, C 1-6 Alkyl or C 1-6 A haloalkyl group;
R a each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl;
in some embodiments, a compound of formula (I), a stereoisomer, tautomer, deuterate, or pharmaceutically acceptable salt thereof, wherein X is 4 Selected from O, (CH) 2 ) 0-3 、C(R 8 ) 1-2 C (O) or NR 8 ；R 8 Selected from H, halogen, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or substituted C 3-6 Cycloalkyl;
the L is selected from the group consisting of bond, -O-C 0-4 Alkylene-, -S-C 0-4 Alkylene-, -NR 9 -C 0-4 Alkylene-or C 2-4 Alkynylene group, the-O-C 0-4 Alkylene-, -S-C 0-4 Alkylene-, -NR 9 -C 0-4 Alkylene-or C 2-4 Alkynylene optionally being substituted with one or more R 12 Substitution; r is R 12 Selected from H, halogen, cyano, hydroxy or C 1-6 Alkyl, or two R's on the same carbon atom 12 Together with the atoms to which they are attached form C 3-6 Cycloalkyl or 3-6 membered heterocyclyl.
In some embodiments, the compound of formula (I), a stereoisomer, tautomer, deuterate, or pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formulas (IA) through (IB):
wherein X is 1 、X 5 、X 6 、L、R 1 、R 2 、R 3 、R 4 、R 6 、R 8 Is defined as in formula (I).
In some embodiments, the compound of formula (I), a stereoisomer, tautomer, deuterate, or pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (IA-1), formula (IB-1), a tautomer, deuterate, or pharmaceutically acceptable salt thereof:
wherein X is 1 、L、R 1 、R 2 、R 3 、R 6 、R 8 Is defined as in formula (I).
In some embodiments, the compound of formula (I), a stereoisomer, tautomer, deuterate, or pharmaceutically acceptable salt thereof is selected from the group consisting of a compound of formula (IA-1-1), formula (IA-1-2), formula (IB-1-1), formula (IB-1-2), a tautomer, deuterate, or pharmaceutically acceptable salt thereof:
wherein X is 1 、L、R 1 、R 2 、R 3 、R 6 、R 8 Is defined as in formula (I).
In some embodiments, R in formula (I) 2 Is a 3-14 membered fused heterocyclyl, said 3-14 membered fused heterocyclyl optionally being further substituted with one or more R 10 Substitution, said R 10 Selected from halogen or C 2-6 Alkenyl groups optionally further represented by 1 or more R a Substituted; the R is a Each independently selected from H or halogen.
In some embodiments, the fused heterocyclic group in formula (I) is selected from The fused heterocyclyl is optionally further substituted with one or more R 10 Substitution, said R 10 Selected from H, halogen or C 2-6 Alkenyl groups optionally further represented by 1 or more R a Substituted; the R is a Each independently selected from H or halogen.
In some embodiments, R in formula (I) 10 Is thatThe R is a Each independently is C 1-6 Alkyl or halogen, preferably F.
In some embodiments, R in formula (I) 10 Is thatThe R is a H.
In some embodiments, R in formula (I) 10 Halogen, preferably F.
In some embodiments, R in formula (I) 2 Selected from the group consisting of
In some embodiments, R in formula (I) 2 Selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 6-14 membered heteroaryl optionally further substituted with one or more R 10 Substitution, said R 10 Selected from H, cyano, halogen, C 1-6 Alkyl, -C 0-6 alkylene-OR a 、-C 0-6 alkylene-N (R) a ) 2 、-C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-14 membered heteroaryl), said-C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-14 membered heteroaryl) is further substituted with one or more R a Substituted, the R a Each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups.
In some embodiments, formula (I) is selected from compounds of formula (IA-1-2-1) or (IB-1-2-1), a tautomer, a deuterate, or a pharmaceutically acceptable salt thereof:
wherein the R is 10 Selected from H, cyano, halogen, C 1-6 Alkyl, -C 0-6 alkylene-OR a 、-C 0-6 alkylene-N (R) a ) 2 、-C 0-6 alkylene-C 3-14 Cycloalkyl or-C 0-6 Alkylene- (3-14 membered heterocyclyl), said-C 0-6 alkylene-C 3-14 Cycloalkyl or-C 0-6 Alkylene- (3-14 membered heterocyclyl) is further substituted with one or more R a Substituted, the R a Each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups.
In some embodiments, R in formula (I) 3 Selected from the group consisting of The said Optionally further by one or more R a Substitution, said R a Independently selected from H, hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or-C 0-3 alkylene-C 3-14 Cycloalkyl groups.
In some embodiments, R in formula (I) 3 Selected from the group consisting of
In some embodiments, R in formula (I) 1 Selected from C 1-6 Alkyl or C 3-8 Cycloalkyl is preferably methyl, ethyl, isopropyl or cyclopropyl.
In some embodiments, the compound of formula (I) is selected from the group consisting of compounds of the following formulas:
the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
The invention provides application of a compound or a pharmaceutical composition shown in a structural formula (I) in preparation of medicines.
The invention further provides a preferable technical scheme of the application:
preferably, the use is in the manufacture of a medicament for the treatment and/or prophylaxis of cancer.
Preferably, the use is the use for the manufacture of a medicament for the treatment of a disease mediated by KRAS G12D. Preferably, the disease is cancer.
Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, polymorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumor, hepatobiliary cell cancer, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, xu Wangshi cell tumor, lung squamous cell carcinoma, bryoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
The invention also provides a method of treating and/or preventing a disease comprising administering to a subject a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutical composition comprising the same.
The invention also provides a method for treating and/or preventing KRAS G12D mediated diseases comprising administering to a subject a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutical composition comprising the same.
The invention also provides a method of treating cancer comprising administering to a subject a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutical composition comprising the same.
Preferably, in the above method, the KRAS G12D mediated disease is cancer.
Preferably, in the above method, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, polymorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumor, hepatobiliary cell cancer, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, xu Wangshi cell tumor, lung squamous cell carcinoma, lichen-like keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
Unless otherwise indicated, general chemical terms used in the structural formulae have their ordinary meanings.
For example, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine unless otherwise indicated.
In the present invention, unless otherwise indicated, "alkyl" includes straight or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-methylpentyl and the like. Similarly, "C 1-6 "in" alkyl group " 1-6 "refers to a group comprising an array of straight or branched chain forms of 1,2, 3, 4, 5 or 6 carbon atoms. The term "alkylene" refers to a divalent alkyl linking group. Alkylene refers formally to an alkane in which two C-H bonds are replaced with points of attachment of the alkylene group to the rest of the compound. Similarly, C 1-3 "C" in alkylene 1-3 "refers to an alkylene group containing 1,2 or 3 carbon atoms and includes, but is not limited to, methylene, 1, 2-ethylene, 1, 3-propylene or 1, 2-isopropylene.
"alkoxy" refers to the oxyether form of the aforementioned straight or branched alkyl group, i.e., -O-alkyl.
The term "haloalkyl" refers to an alkyl group in which one or more H has been replaced with a halogen atom.
The term "haloalkoxy" refers to a group of an-O-haloalkyl group.
The term "oxo" or "oxo" refers to an oxygen atom in the form of a divalent substituent that forms a carbonyl group when attached to C and a sulfoxide or sulfone group or an N-oxide group when attached to a heteroatom.
In the present invention, unless otherwise indicated, the term "aromatic ring", "aromatic ring" or "aromatic heterocycle" is a carbocyclic or heterocyclic ring of polyunsaturated rings having aromatic character (having (4n+2) delocalized pi electrons, where n is an integer).
The term "aryl", in the present invention, unless otherwise indicated, refers to an unsubstituted or substituted monocyclic or fused ring aromatic group comprising atoms of a carbocyclic ring. Preferably C 6-12 Aryl, more preferably aryl is C 6-10 A monocyclic or bicyclic aromatic ring group. Phenyl and naphthyl are preferred. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include, but are not limited to, benzocyclopentyl.
The term "heterocyclyl" refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heteroatom selected from N, O and/or S. The heterocyclyl may include single or multiple rings (e.g., having 2, 3, or 4 fused rings, spiro rings, bridged rings, etc.). The heterocyclic group may be attached to the rest of the compound via a ring-forming carbon atom or a ring-forming heteroatom. Preferably a 3-14 membered heterocyclic group, and "3-14 membered" in a 3-14 membered heterocyclic group means a heterocyclic group consisting of 3-14 ring-forming atoms of C, N, O or S; more preferably a 3-8 membered heterocyclic group. Wherein the nitrogen or sulfur heteroatoms may be selectively oxidized and the nitrogen heteroatoms may be selectively quaternized. Examples of such heterocyclic groups include, but are not limited to Azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. The heterocyclic group may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclic group.
The term "heteroaryl", in the present invention, unless otherwise indicated, refers to a monocyclic or polycyclic (e.g., fused bicyclic) aromatic heterocycle having at least one heteroatom selected from N, O and/or S, and wherein the nitrogen or sulfur heteroatom may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. Preferably a 5-14 membered heteroaryl group, wherein "5-14 membered" in a 5-14 membered heteroaryl group refers to a heteroaryl group consisting of 5-14 ring-forming atoms of C, N, O or S. More preferred are 5-10 membered heteroaryl groups. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuryl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyladenine, quinolinyl, or isoquinolinyl. The heteroaryl group may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. Preferably C 3-12 Cycloalkyl radicals, where "C 3-12 "means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms. Cycloalkyl groups may include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings, spiro rings, bridged rings, etc.). Some embodiments include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like; the cycloalkyl groups may also be fused to aryl, heterocyclyl or heteroaryl rings, wherein the ring attached to the parent structure is cycloalkyl.
The term "substituted" means that one or more hydrogen atoms in the group are each replaced by the same or different substituents. Typical substituents include, but are not limited to, halogen (F, cl, br or I), C 1-8 Alkyl, C 3-12 Cycloalkyl, -OR 1 、-SR 1 、＝O、＝S、-C(O)R 1 、-C(S)R 1 、＝NR 1 、-C(O)OR 1 、-C(S)OR 1 、-NR 1 R 2 、-C(O)NR 1 R 2 Cyano, nitro, -S (O) 2 R 1 、-O-S(O 2 )OR 1 、-O-S(O) 2 R 1 、-OP(O)(OR 1 )(OR 2 ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is 1 And R is 2 Independently selected from-H, C 1-6 Alkyl, C 1-6 Haloalkyl or C 3-6 Cycloalkyl groups. In some embodiments of the present invention, in some embodiments, the substituents are independently selected from the group consisting of-F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH 3 、-SC 2 H 5 Formaldehyde, -C (OCH) 3 ) Cyano, nitro, -CF 3 、-OCF 3 Amino, dimethylamino, methylthio, sulfonyl and acetyl groups.
When the number of one linking group is 0, such as- (CH) 2 ) 0 -representing that the linking group is a bond.
The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
When the compounds provided herein are acids, the corresponding salts thereof can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (both higher and lower), ferric, ferrous, lithium, magnesium, manganese (both higher and lower), potassium, sodium, zinc and the like. Particularly preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Nontoxic organic bases capable of derivatizing into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and substituent-containing amines, such as naturally occurring and synthetic substituent-containing amines. Other pharmaceutically acceptable non-toxic organic bases capable of salt formation include ion exchange resins as well as arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compounds provided by the present invention are bases, the corresponding salts thereof can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydroiodic acid, perchloric acid, cyclamic acid, salicylic acid, 2-naphthalenesulfonic acid, saccharin acid, trifluoroacetic acid, tartaric acid, p-toluenesulfonic acid, and the like. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably formic acid and hydrochloric acid.
Prodrugs of the compounds of the present invention are included within the scope of the present invention. Typically, the prodrug refers to a functional derivative that is readily converted in vivo to the desired compound. For example, any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present application, which upon administration to a subject is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite or residue thereof.
The compounds of the present invention may contain one or more asymmetric centers and may thus produce diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers, and pharmaceutically acceptable salts thereof.
When a tautomer of the compound of formula (I) exists, the present invention includes any of the possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, unless otherwise indicated.
Substitution of the compounds of formula (I) with heavier isotopes (e.g., deuterium) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.
In the present invention, "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a mixture comprising "a" pharmaceutically acceptable adjuvant composition can be interpreted to mean that the pharmaceutical composition includes "one or more" pharmaceutically acceptable adjuvants.
The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
The pharmaceutical compositions of the present invention may be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.
Typical routes of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
The term "treatment" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a disease in a patient, including: (a) inhibiting the symptoms of the disease, i.e., arresting its development; or (b) alleviating a symptom of the disease, i.e., causing regression of the disease or symptom.
The term "effective amount" means an amount of a compound of the present application that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and disclosure.
Detailed Description
In order to make the above matters clearer and more obvious, the following examples are provided to further illustrate the technical aspects of the present invention. The following examples are presented only to illustrate specific embodiments of the invention so that those skilled in the art can understand the invention and are not intended to limit the scope of the invention. In the specific embodiment of the present invention, technical means, methods, and the like not specifically described are conventional technical means, methods, and the like in the art.
All temperatures in this invention refer to degrees celsius unless otherwise indicated.
The following abbreviations are used in the examples:
DCM: dichloromethane;
ESI-MS: electrospray ionization mass spectrometry;
MeOH: methanol;
THF: tetrahydrofuran;
TFA: trifluoroacetic acid;
TEA: triethylamine;
Pre-TLC: preparing a thin layer plate;
CDI: n, N' -carbonyldiimidazole;
NaH: sodium hydride;
PyBOP: 1H-benzotriazol-1-yloxy tripyrrolidinyl hexafluorophosphate;
Pd(DPEPhos)Cl 2 : bis (diphenylphosphinophenyl ether) palladium (II) dichloride;
DMAP: 4-dimethylaminopyridine;
TBDPSCl: t-butyldiphenylchlorosilane;
TBSCl: t-butyldimethylchlorosilane;
LAH: lithium aluminum tetrahydroide;
EA: ethyl acetate;
DMF: n, N-dimethylformamide;
DIEA: n, N-diisopropylethylamine;
synthesis of intermediate M1:
ethyl 2-methylene-5-oxo-1, 3,6, 7-tetrahydropyrrolizine-8-carboxylate (10.00 g) was dissolved in THF (150.00 mL) at room temperature in a reaction flask, LAH (2.5M/THF) (3.63 g) was slowly added and the temperature was controlled below 60℃and stirring was completed for 0.2h. Cooling to 0 ℃, adding 3.6ml of water to quench the reaction, adding 3.6ml of 15% sodium hydroxide aqueous solution, finally adding 10.8ml of water, stirring for 10min, adding anhydrous magnesium sulfate to dry, stirring for 10min, filtering, washing a filter cake with EA for three times, and concentrating mother liquor to obtain a target intermediate M1 (6.5 g,89.34% yield).
Synthesis of intermediate M2:
step 1: synthesis of Compound M2-1
1-bromo-2, 5-difluoro-3-nitrobenzene was dissolved in ethanol (400 ml) and water (80 ml), ammonium chloride (28.1 g) was added, iron powder (20.53 g) was added with stirring, and the mixture was reacted at 75℃for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, filtered through celite, the residue was washed with DCM, the filtrate was washed once with water, saturated brine was washed once, the organic phase was dried, filtered and concentrated to give compound M2-1 (21.13 g yield 96.70%). The crude product was used directly in the next step. ESI-MS m/z 208.13[ M+H ]] + 。
Step 2: synthesis of Compound M2-2
Hydroxylamine hydrochloride (24.71 g) and chloral hydrate (25.2 g) were dissolved in water (435 ml), and anhydrous sodium sulfate (115.43 g) was added with stirring. M2-1 (21.13 g) was dissolved in ethanol (61 ml) and water (35 ml), concentrated hydrochloric acid (14.7 ml) was added, and the mixture was added to a reaction flask and reacted overnight at 60 ℃. After completion of the reaction, the reaction mixture was filtered under heating to give a cake, which was dried to give Compound M2-2 (25.10 g, yield 88.55%). The crude product was used directly in the next step.
Step 3: synthesis of Compound M2-3
Compound M2-2 (25.10 g) was added to concentrated sulfuric acid (250 ml) at 60℃and the temperature was raised to 90℃after the addition. The reaction was carried out for 1h. After the reaction was completed, the reaction solution was cooled, slowly added to ice water, a large amount of solids was precipitated, and the solid was obtained by filtration, dissolved with EA, washed twice with saturated brine, dried, filtered, and spin-dried to give Compound M2-3 (16.07 g yield 68.19%). The crude product was used directly in the next step.
Step 4: synthesis of Compound M2-4
Sodium hydroxide (22.08 g) was dissolved in water (280 ml), added to a reaction flask containing compound M2-3 (16.07 g), the temperature was lowered to 0℃after the addition, hydrogen peroxide (31 ml) was added, and the reaction was allowed to proceed to room temperature overnight. After completion of the reaction, the pH was adjusted to 7 with concentrated hydrochloric acid, and filtration was performed to obtain a filtrate, and the pH was further adjusted to 1 with concentrated hydrochloric acid, and filtration was performed to obtain a solid, which was dissolved with EA, washed with saturated brine once, dried, filtered, and concentrated to obtain Compound M2-4 (12.54 g yield 81.13%). ESI-MS m/z 252.14[ M+H ]] + 。
Step 5: synthesis of Compound M2-5
Compound M2-4 (12.34 g) was dissolved in DMF (120 ml), N-chlorosuccinimide (7.85 g) was added and reacted at 70℃for 0.5h. After completion of the reaction, the reaction mixture was cooled to 0℃and water (480 ml) was slowly added dropwise to give a large amount of solid, which was filtered to give a solid, which was dissolved with EA, washed with saturated brine once, dried, filtered, and concentrated to give Compound M2-5 (12.95 g, yield 92.32%). ESI-MS m/z 286.1[ M+H ]] + 。
Step 6: synthesis of Compound M2-6
Compound M2-5 (12.46 g) was dissolved in THF (120 ml), CDI (10.58 g) was added, and the reaction was carried out at 50℃for 0.5h, the reaction solution was cooled to room temperature, and slowly added dropwise to aqueous ammonia (120 ml) in ice, and the reaction was continued at room temperature for 0.5h. After the reaction is completed, the reaction solution is diluted by EA and water and then extracted by EA One pass, saturated brine, dry, filter and concentrate, and purify the concentrate by column chromatography to give compound M2-6 (9.64 g yield 77.63%). ESI-MS m/z 285.12[ M+H ]] + 。
Step 7: synthesis of Compound M2-7
Compound M2-6 (4 g) was dissolved in THF (50 ml), the temperature was raised to 40℃and NaH (1.4 g) was added in portions, stirred at 40℃for 10 minutes, N' -thiocarbonyldiimidazole (3.75 g) was added in portions, and the reaction was completed by raising the temperature to 60℃for 0.5h. After the reaction was completed, the reaction mixture was quenched with saturated ammonium chloride, the pH was adjusted to 5-6 with diluted hydrochloric acid, tetrahydrofuran was removed by vacuum concentration, a large amount of solids were precipitated, and the solid was obtained by filtration and dried to give Compound M2-7 (3.79 g yield 82.58%).
Step 8: synthesis of Compound M2
Compound M2-7 (3.59 g) was dissolved in methanol (60 ml), and sodium methoxide (0.89 g) and methyl iodide (1.36 ml) were added thereto to react at room temperature for 0.5h. After completion of the reaction, water (10 ml) was added to the reaction mixture, stirred for 10 minutes, and the resultant solid was filtered and dried to obtain Compound M2 (2.79 g, yield 74.53%). ESI-MS m/z 341.09[ M+H ]] + 。
Synthesis of intermediate M3:
step 1: synthesis of Compound M3-1
Compound M3-0 (208 g) was dissolved in anhydrous MeOH (2L) at room temperature, thionyl chloride (286 mL) was added dropwise thereto at 0℃and the reaction was carried out at 5℃for 1 hour, after the completion of the reaction, the reaction solution was concentrated, diluted with anhydrous DCM (1L) was added thereto, the diluted solution was added dropwise to a saturated sodium hydrogencarbonate solution at 0℃to separate the solution, and the organic layer was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate and concentrated. Purification of the concentrate by column chromatography (EA: dcm=0-50%) gave product M3-1 (240 g,95% yield). ESI-MS m/z=258.1 [ m+h ] ] + 。
Step 2: synthesis of Compound M3-2
The compound was taken up at room temperatureM3-1 (235 g) was dissolved in anhydrous THF (2.4L), lithium aluminum hydride (69.4 g) was added in portions at 0℃and stirred at 60℃for 30min after the addition. After the reaction was completed, the reaction solution was cooled, water (69.4 mL) was added dropwise under ice bath, then 15% aqueous sodium hydroxide solution (69.4 mL) was added dropwise, finally water (208.2 mL) was added dropwise, dried over anhydrous sodium sulfate, and the filtrate was filtered and concentrated to give the product M3-2 (165 g,90% yield) which was used directly in the next step. ESI-MS m/z=202.1 [ m+h ]] + . Step 3: synthesis of Compound M3-3
Compound M3-2 (160 g) was dissolved in trifluoroacetic acid (500 mL), water (67 mL) was added, the reaction was carried out overnight at 60℃and the reaction liquid was concentrated to give crude M3-3 (320 g, 259%) which was used directly in the next step. ESI-MS m/z=156.1 [ m+h ]] + 。
Step 4: synthesis of Compound M3-4
Compound M3-3 (308 g) was dissolved in DMF (350 mL) at room temperature, imidazole (540 g) was added at 0deg.C, TBDPSCl (170 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour after the addition was completed. After the reaction was completed, water and EA were added to dilute, and the aqueous phase was extracted with EA 3 times. The organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the concentrate by column chromatography (EA: pe=0-15%) gave product M3-4 (192 g,25% yield). ESI-MS m/z=394.1 [ M+H ] ] + 。
Step 5: synthesis of Compound M3
Compound M3-4 (187 g) and difluoromethyl (2-pyridyl) sulfone (184 g) were dissolved in anhydrous DMF (1.4L) at room temperature, a solution of potassium tert-butoxide (107 g) in DMF (460 mL) was added dropwise at-50℃and after the addition was completed, the reaction was carried out at-40℃for 2 hours, after the reaction was completed, saturated ammonium chloride solution was added dropwise until the solution became weakly acidic at-50℃and the reaction was carried out at room temperature for 18 hours by natural warming, the filtrate was obtained by filtration, EA (1.4L) was added for dilution, the filtrate was obtained by filtration, and the concentration was obtained. The concentrate was purified by column chromatography (MeOH: dcm=0-10%) to give product M3 (60 g,67% yield). 1 H NMR(500MHz,DMSO-d6)δ3.95-3.92(m,1H),3.70-3.67(m,1H),3.32-3.27(m,2H),2.94-2.89(m,1H),2.69-2.66(m,1H),2.50-3.45(m,1H),1.99-1.92(m,2H),1.88-1.75(m,2H)。ESI-MS m/z＝190.1[M+H] + 。
Synthesis of intermediate M4:
step 1: synthesis of Compound M4-1
The compound 1-methoxycarbonylcyclopropane-1-carboxylic acid (5.00 g) was dissolved in DCM (80.00 mL) at room temperature, DMF (0.27 mL) was added in ice bath, and oxalyl chloride (8.81 mL) was added dropwise thereto and stirred at 35℃for 3h after the addition. And finally, directly concentrating the reaction mixture to obtain a crude product of the target compound M4-1, wherein the crude product is directly used for the next reaction.
Step 2: synthesis of Compound M4-2
The crude M4-1 (5.64 g) was dissolved in DCM (80.00 mL) at room temperature, and TEA (24.11 mL) and dimethylamine hydrochloride (5.66 g) were added in ice bath and stirred at room temperature for 1h after the addition. Water was added to the reaction mixture, extraction was performed, and the organic phase was dried and concentrated. The concentrate was purified by a silica gel column to give the objective compound M4-2 (5.4 g, yield 91%).
Step 3: synthesis of Compound M4-3
Compound M4-2 (5.4 g) was dissolved in THF (120 mL) at room temperature, cooled to-20deg.C, and LiAlH was added in portions 4 (4.0 g), the mixture was slowly returned to room temperature after the completion of the addition, and stirred for 3 hours. After the reaction was completed, 4.0g of water, 4.0g of 15% aqueous NaOH solution and 12.0g of water were slowly added in this order under ice bath conditions, and stirring was continued for 1 hour. The mixture was filtered and the filtrate was concentrated. Purification of the concentrate on a silica gel column (MeOH: dcm=0-30%) afforded the title compound M4-3 (2.5 g, 61%). ESI-MS m/z 130[ M+H ]] + 。
Step 4: synthesis of Compound M4-4
DMSO (2.34 g) was dissolved in DCM (30 mL) at room temperature, oxalyl chloride (1.9 g) was added dropwise thereto at-78℃and stirred for 30min. A solution of compound 1-3 (1.3 g) in DCM (10 mL) was added dropwise thereto at-78deg.C and stirred for 1h. Triethylamine (3.1 g) was added dropwise thereto at-78℃and slowly returned to room temperature after completion of the addition. Adding water into the reaction solution, extracting, separating liquid, and separating water phase. The organic phase was concentrated to give crude product of the target compound M4-4.
Step 5: synthesis of Compound M4
The crude product of the above compounds 1 to 4, potassium carbonate (2.8 g) were dissolved in methanol (10 mL) at room temperature, and stirred at room temperature for 15min. Dimethyl (1-diazo-2-oxopropyl) phosphonate (2.5 g) was added dropwise and stirred overnight at room temperature after addition. Toluene and water are added into the reaction solution for extraction, the solution is separated, and the organic phase is washed once by saturated potassium carbonate solution and dried by anhydrous sodium sulfate, thus obtaining the target compound M4.
Synthesis of intermediate M5:
specific synthetic procedures refer to the synthesis of intermediate M4.
Example 1: compound 2-amino-4- ((1 r,13 ar) -11-chloro-9-fluoro-7- ((2 r,7 as) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -1-methyl-1, 2,3,4,13 a-hexahydropyrazine [2',1': synthesis of 3,4] [1,4] oxazine [5,6, 7-des ] quinazolin-10-yl) -7-fluorobenzo [ b ] thiophene-3-carbonitrile
Step 1: synthesis of Compound 1-1
The compound 3-methylpyrazine-2-carboxylic acid (6.0 g) was dissolved in methanol (150 mL), cooled below 0deg.C in an ice bath, and slowly added with SOCl dropwise 2 (15.5 g), and after completion of the dropping, reacted at room temperature for 12 hours. The reaction solution was concentrated, the concentrate was extracted with dichloromethane, saturated brine was washed, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrate was dissolved in dichloromethane (1 mL), crystallized from petroleum ether (20 mL), filtered and dried to give product 1-1 (4.5 g,68% yield). ESI-MS m/z 153[ M+H ]] + 。
Step 2: synthesis of Compounds 1-2
Compound 1-1 (4.5 g) was dissolved in absolute ethanol (20 mL) and PtO was added 2 (0.13 g) H was introduced 2 The reaction was stirred at 70℃for 12h. The reaction liquid is concentrated to obtain a concentrated solution,the product 1-2 (3.6 g,77% yield) was obtained and was directly fed to the next step.
Step 3: synthesis of Compounds 1-3
Compound 1-2 (3.6 g) was dissolved in tetrahydrofuran (20 mL) and LiAlH was added in portions under an ice bath 4 (2.25 g), and stirred at room temperature for 1h. The reaction was monitored to be complete and 2mL of H was slowly added dropwise 2 O, 2mL of 15% NaOH aqueous solution was added, and 6mL of H was added 2 O, stirring at room temperature for 0.5h, adding sodium sulfate for drying after stirring and quenching are completed, filtering to obtain filtrate, and spin-drying to obtain a product 1-3 (2.9 g,98% yield) which is directly added into the next step.
Step 4: synthesis of Compounds 1-4
Compounds 1-3 (2.9 g) were dissolved in methanol (100 mL), DIEA (14.39 g) and di-tert-butyl dicarbonate (12.15 g) were added, stirred at room temperature for 2h, monitored for a large amount of starting material remaining, and DMAP (0.27 g) and DIEA (5.75 g) were added and stirred at room temperature for 1h. The reaction was monitored to completion, the reaction mixture was concentrated, the resulting product was dissolved in ethanol, and an aqueous solution (50 mL) containing sodium hydroxide (2.6 g) was added thereto, followed by reflux reaction for 4 hours. The reaction solution was cooled to room temperature, the solvent was concentrated, then diluted with water (50 mL), pH was adjusted to about 8 with 6M hydrochloric acid, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to give the product 1-4 (4.0 g,78% yield) which was directly fed to the next step.
Step 5: synthesis of Compounds 1-5
Compounds 1-4 (4.0 g) were dissolved in methylene chloride (20 mL), TBSCl (5.24 g) and imidazole (5.91 g) were added, and the mixture was stirred at room temperature for 1h. After the reaction is completed, water is added for extraction, saturated saline water is used for washing, anhydrous sodium sulfate is used for drying, suction filtration is carried out, and filtrate is concentrated. The concentrate was purified by column chromatography on silica gel (PE/ea=3/2) to give the product 1-5 (2.6 g,43% yield).
Step 6: synthesis of Compounds 1-6
Compound 1-5 (1 g) was dissolved in DMF (10 mL), cesium fluoride (1.32 g) was added, reacted at room temperature for 14 hours, after the reaction was completed, the reaction solution was added to water, extracted with ethyl acetate, backwashed with saturated sodium chloride solution, the organic phase was concentrated, acetonitrile (5 mL) was added, then concentrated, tetrahydrofuran (5 mL) was added, and concentration was performed to obtain product 1-6, which was directly put into the next step.
Step 7: synthesis of Compounds 1-7
The above-mentioned compounds 1 to 6 were dissolved in tetrahydrofuran, sodium hydride (100 mg) was added thereto, and the mixture was stirred at room temperature for 30 minutes. Intermediate M2 (300 mg) was added, stirring was continued at room temperature for 30 minutes, after the reaction was completed, the reaction solution was added to an aqueous ammonium chloride solution, extraction was performed with ethyl acetate, the organic phase was concentrated, and the concentrate was purified by silica gel column separation to give the objective product 1-7 (102 mg,22% yield). 551[ M+H ] ESI-MS m/z] + 。
Step 8: synthesis of Compounds 1-8
Compounds 1 to 7 (102 mg) were dissolved in DMF (5 mL), DIEA (0.1 mL) was added at room temperature, pyBOP (192 mg) was added slowly in portions with stirring at room temperature, stirring at room temperature was completed for 30 minutes, after completion of the reaction, the reaction solution was added to water, extracted with ethyl acetate, backwashed with saturated sodium chloride solution, the organic phase was concentrated, and the concentrate was purified by column on silica gel to give the objective product 1 to 8 (62 mg,63% yield). ESI-MS m/z 533[ M+H ] ] + 。
Step 9: synthesis of Compounds 1-9
In a reaction flask was charged compound 1-8 (62 mg), (3-cyano-7-fluoro-4- (4, 5-tetramethyl-1, 3, 2-dioxan-2-yl) benzo [ b)]Thiophene-2-alkyl) carbamic acid tert-butyl ester (97 mg), pd (DPEPhos) Cl 2 (16 mg), potassium phosphate (74 mg), potassium fluoride (20 mg), cyclopentylmethyl ether (5 mL), nitrogen gas was purged, and the reaction was carried out at 80℃for 14 hours. After the reaction was cooled, it was added to water, extracted with ethyl acetate, the organic phase was concentrated, and the concentrate was purified by column chromatography on silica gel to give the desired product 1-9 (75 mg,86% yield). ESI-MS m/z 745[ M+H ]] + 。
Step 10: synthesis of Compounds 1-10
Compound 1-9 (75 mg) was dissolved in methylene chloride (5 mL), m-chloroperoxybenzoic acid (35 mg) was added in portions at room temperature, stirred at room temperature for 30 minutes, after completion of the reaction, the reaction mixture was added to water, extracted with ethyl acetate, the organic phase was concentrated, and the concentrate was purified by silica gel column separation to give the objective product 1-10 (55 mg,70% yield). 777[ M+H ] ESI-MS m/z] + 。
Step 11: synthesis of Compounds 1-11
Alcohol ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (33 mg) was dissolved in tetrahydrofuran (3 mL), sodium hydride (9 mg) was added, and the mixture was stirred at room temperature for 30 minutes. 1-10 (55 mg) was added thereto, stirring was continued at room temperature for 30 minutes, and after completion of the reaction, the reaction solution was added to an aqueous ammonium chloride solution, extracted with ethyl acetate, the organic phase was concentrated, and the concentrate was purified by silica gel column separation to give the objective product 1-11 (35 mg,58% yield). ESI-MS m/z 856[ M+H ] ] + 。
Step 12: synthesis of Compound 1
Compounds 1 to 11 (35 mg) were dissolved in methylene chloride (3 mL), and trifluoroacetic acid (1.5 mL) was added thereto, followed by stirring at room temperature for 30 minutes. After the reaction was complete, the reaction solution was concentrated and separated using preparative HPLC to give compound 1 (5.9 mg,22% yield). 656[ M+H ] ESI-MS m/z] + 。 1 H NMR(500MHz,DMSO-d 6 )δ8.08(d,J＝6.6Hz,2H),7.23(dt,J＝9.2,4.9Hz,1H),7.17-7.10(m,1H),5.47-5.16(m,1H),4.79(t,J＝14.3Hz,1H),4.43(ddd,J＝24.6,12.6,5.3Hz,1H),4.13-3.90(m,3H),3.08(d,J＝10.9Hz,2H),3.03(d,J＝8.5Hz,1H),2.88-2.77(m,2H),2.13(d,J＝9.3Hz,1H),2.07(q,J＝5.2,3.5Hz,1H),2.04-1.98(m,1H),1.77(dd,J＝11.9,5.6Hz,2H),1.34(t,J＝4.0Hz,1H),1.24(d,J＝7.4Hz,3H),1.08(q,J＝6.7,5.8Hz,3H),0.92(t,J＝7.1Hz,1H),0.88-0.80(m,1H)。
Example 13: synthesis of the Compound 2-amino-4- (11-chloro-1-ethyl-9-fluoro-7- ((2-methyltetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -1,2,3,4,13 a-hexahydropyrazine [2',1':3,4] [1,4] oxanitrogen [5,6,7-d ] quinazolin-10-yl) -7-fluorobenzo [ b ] thiophene-3-carbonitrile
Step 1: synthesis of Compound 13-1
Intermediate M1 (78 mg) was dissolved in anhydrous THF (1 mL), then NaH (30 mg) was added, reacted at room temperature for 20min, then compound 15-9 (200 mg) was added, and reacted at room temperature for 30min. Quenching with saturated ammonium chloride solution, extracting with EA and water, collecting the organic phase, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with column chromatography to obtain target compound 13-1 (134 mg).
Step 2: synthesis of Compound 13
Compound 13-1 (130 mg) was dissolved in 2mL of DCM, and TFA (1 mL) was added and reacted at room temperature for 20min. Concentrating under reduced pressure, and purifying by column chromatography to obtain the target compound 13 (56 mg). 1 H NMR(500MHz,Chloroform-d)δ7.18(dt,J＝8.2,5.0Hz,1H),6.99(t,J＝8.8Hz,1H),5.83(s,2H),4.98–4.93(m,2H),4.59–4.37(m,2H),4.26–4.21(m,2H),3.80(d,J＝14.6Hz,1H),3.34–3.22(m,2H),3.13(td,J＝12.0,3.3Hz,1H),2.96(dq,J＝6.7,3.5Hz,1H),2.91–2.79(m,2H),2.70(dt,J＝10.1,7.4Hz,1H),2.41(d,J＝15.8Hz,1H),2.23–2.17(m,1H),1.95–1.91(m,3H),1.81–1.62(m,3H),1.48(s,1H),1.33–1.23(m,2H),0.93(dt,J＝14.9,7.3Hz,3H).
Example 14: synthesis of the Compound 2-amino-4- (11-chloro-7- ((2- (difluoromethylene) tetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -1-ethyl-9-fluoro-1, 2,3,4,13 a-hexahydropyrazino [2',1':3,4] [1,4] oxazino [5,6,7-de ] quinazolin-10-yl) -7-fluorobenzo [ b ] thiophene-3-carbonitrile
Step 1: synthesis of Compound 14-1:
intermediate M3 (43 mg) was dissolved in anhydrous THF (1 mL), then NaH (14 mg) was added, reacted at room temperature for 20min, then compound 15-9 (90 mg) was added, and reacted at room temperature for 30min. Quenching with saturated ammonium chloride solution, extracting the reaction solution with EA and water, retaining the organic phase, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with column chromatography to obtain the target compound 14-1 (73 mg).
Step 2: synthesis of Compound 14:
compound 14-1 (73 mg) was dissolved in 2mL of DCM, then TFA (1 mL) was added and reacted at room temperature for 20min. Concentrating under reduced pressure, and purifying by column chromatography to obtain target compound 14 (44 mg). 1 H NMR(500MHz,Chloroform-d)δ7.19(dt,J＝8.3,4.9Hz,1H),7.05–6.96(m,1H),5.66(d,J＝6.6Hz,2H),4.58–4.42(m,2H),4.27–4.20(m,2H),3.46–3.25(m,2H),3.23–3.10(m,2H),3.06–2.87(m,2H),2.81(d,J＝15.8Hz,1H),2.65(dt,J＝10.1,7.8Hz,1H),2.40(d,J＝16.0Hz,1H),2.24–2.17(m,1H),1.92(d,J＝7.0Hz,3H),1.83–1.80(m,1H),1.72–1.62(m,1H),1.57–1.45(m,1H),1.36–1.23(m,3H),0.95(dt,J＝14.8,7.3Hz,3H).
Example 15: synthesis of the Compound 2-amino-4- (11-chloro-1-ethyl-9-fluoro-7- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -1,2,3,4,13,13 a-hexahydropyrazino [2',1':3,4] [1,4] oxazino [5,6,7-de ] quinazolin-10-yl) -7-fluorobenzo [ b ] thiophene-3-carbonitrile
Step 1: synthesis of Compound 15-1
3-bromopyrazine-2-carboxylic acid methyl ester (3 g), vinyl potassium trifluoroborate (3.7 g), pdCl 2 (dppf) (1.13 g) and K 3 PO 4 (8.8 g) was dissolved in 1, 4-dioxane (50 mL) and water (10 mL), reacted at 80℃for 1 hour under nitrogen protection, cooled to room temperature, the reaction solution was extracted with EA and water, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the objective compound 15-1 (1.94 g).
Step 2: synthesis of Compound 15-2
Compound 15-1 (1.94 g) was dissolved in ethanol (30 mL), and PtO was then added 2 (194 mg) was added thereto, hydrogen was substituted for 5 times, the reaction was carried out at 80℃for 2 hours, celite was filtered, and the filtrate was concentrated under reduced pressure to give the objective compound 15-2 (2.14 mg).
Step 3: synthesis of Compound 15-3
Compound 15-2 (2.1 g) was dissolved in THF (30 mL), cooled to 0deg.C, then LAH (1.85 g) was slowly added, reacted at room temperature for 2h, cooled to 0deg.C, 1.85mL of water was added, then 1.85mL of 15% sodium hydroxide solution was added, followed by 5.55mL of water, stirred at room temperature for 20min, a proper amount of anhydrous sodium sulfate was added and stirred for 20min, celite was filtered, and the filtrate was concentrated under reduced pressure to give the objective compound 15-3 (1.87 g).
Step 4: synthesis of Compound 15-4
Compound 15-3 (1.8 g) was dissolved in methanol (30 mL) and Boc was then added 2 O (27.24 g), DMAP (0.15 g) and DIPEA (43.48 mL) were added, reacted overnight at room temperature, and concentrated under reduced pressure to give crude title compound 15-4, which was used directly in the next reaction.
Step 5: synthesis of Compound 15-5
The crude product of the compound 15-4 of the previous step was dissolved in ethanol (30 mL), then 5% sodium hydroxide solution (30 mL) was added, the reaction was refluxed for 2 hours, cooled to room temperature, concentrated under reduced pressure, and water (20 mL) was added to the residue, then the pH was adjusted to 8 with dilute hydrochloric acid, the reaction solution was extracted with DCM, the organic phase was retained, and concentrated under reduced pressure to give the crude product of the target compound 15-5, which was directly used for the next reaction.
Step 6: synthesis of Compound 15-6
The compound 15-5 (860 mg) of the previous step was dissolved in THF (8 mL), naH (350 mg) was then added, the reaction was carried out at room temperature for 20min, compound M2 (600 mg) was then added, the reaction was carried out at room temperature for 6h, the reaction solution was poured into saturated ammonium chloride to quench, EA and water were used to extract the reaction solution, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the objective compound 15-6 (760 mg).
Step 7: synthesis of Compound 15-7
Compound 15-6 (740 mg) was dissolved in ACN (10 mL), followed by sequential addition of DIPEA (1.14 mL) and PyBOP (1.36 g), reaction at room temperature for 1.5h, addition of silica gel to the reaction mixture, concentration under reduced pressure, and purification by column chromatography to give the title compound 15-7 (469 mg).
Step 8: synthesis of Compound 15-8
Compound 15-7 (440 mg), (3-cyano-4- (5, 5-dimethyl-1, 3, 2-dioxaborane-2-yl) -7-fluorobenzo [ b)]Thiophene-2-yl) carbamic acid tert-butyl ester (649 mg), pdCl 2 (DPEPhos)(115mg)、K 3 PO 4 (511 mg) and KF (186 mg) were dissolved in CPME (10 mL), and reacted at 80℃for 14 hours under nitrogen protection, cooled to room temperature, the reaction solution was extracted with EA and water, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the objective compound 15-8 (632 mg).
Step 9: synthesis of Compound 15-9
Compound 15-8 (625 mg) was dissolved in DCM (10 mL), then m-CPBA (568 mg) was added, reacted at room temperature for 0.5h, quenched by adding an appropriate amount of saturated sodium sulfite solution with stirring for 20min, the reaction solution was extracted with DCM and water, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound 15-9 (403 mg).
Step 10: synthesis of Compounds 15-10
The compound ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (40 mg) was dissolved in anhydrous THF (1 mL), then NaH (15 mg) was added, reacted at room temperature for 20min, then the compound 15-9 (100 mg) was added, and reacted at room temperature for 30min. Quenching with saturated ammonium chloride solution, extracting with EA and water, collecting the organic phase, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with column chromatography to obtain target compound 15-10 (77 mg).
Step 11: synthesis of Compound 15
Compounds 15-10 (77 mg) were dissolved in 2mL of DCM and TFA (1 mL) was added and reacted at room temperature for 20min. Concentrating under reduced pressure, and purifying by column chromatography to obtain the target compound 15 (44 mg). 1 H NMR (500 mhz, chloroform-d) delta 7.23-7.13 (m, 1H), 7.00 (t, j=8.8 hz, 1H), 5.91-5.67 (m, 2H), 4.48 (dqd, j=33.8, 12.7,6.5hz, 2H), 4.22 (ddd, j=27.5, 14.9,8.2hz, 2H), 3.41-3.29 (m, 2H), 3.29-3.19 (m, 2H), 3.13 (t, j=11.7 hz, 1H), 3.01 (dd, j=17.6, 9.9hz, 2H), 2.96-2.88 (m, 1H), 2.31-2.15 (m, 3H), 1.97-1.91 (m, 3H), 1.74-1.58 (m, 2H), 1.57-1.43 (m, 1.27 hz, 1.15 (J), 3.7 hz, 1H), 3.13 (t, j=11.7 hz, 1H), 3.01 (dd, j=17.9.9 hz, 2H). The compound 2-amino-4- (11-chloro-1-ethyl-9-fluoro-7- ((2-methyltetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -1,2,3,4, 13, 13 a-hexahydropyrazine [2',1':3,4][1,4]Oxanitrogen [5,6,7-de ]]Quinazolin-10-yl) benzo [ b]Synthesis of thiophene-3-carbonitriles
Step 1: synthesis of Compound 17-1:
intermediate M1 (48 mg) was dissolved in anhydrous THF (1 mL), then NaH (19 mg) was added, reacted at room temperature for 20min, then compound 18-4 (80 mg) was added, and reacted at room temperature for 30min. Quenching with saturated ammonium chloride solution, extracting with EA and water, collecting the organic phase, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with column chromatography to obtain the target compound 17-1 (50 mg).
Step 2: synthesis of Compound 17:
compound 17-1 (50 mg) was dissolved in 2mL of DCM, and TFA (1 mL) was added and reacted at room temperature for 20min. Concentrating under reduced pressure, and purifying by column chromatography to obtain the target compound 17 (33 mg). 1 H NMR(500MHz,DMSO-d 6 )δ7.92–7.64(m,3H),7.29–7.19(m,1H),7.19–7.11(m,1H),5.28–5.16(m,2H),5.02–4.71(m,2H),4.71–4.52(m,3H),4.30(d,J＝18.5Hz,1H),4.20(d,J＝13.8Hz,1H),3.93(d,J＝14.5Hz,1H),3.81(s,1H),3.30–3.16(m,3H),2.98–2.72(m,2H),2.31–2.10(m,2H),2.10–1.85(m,4H),1.77–1.65(m,1H),1.24(s,2H),1.01(td,J＝7.5,2.2Hz,3H).
Example 18: synthesis of the Compound 2-amino-4- (11-chloro-1-ethyl-9-fluoro-7- ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methoxy) -1,2,3,4,13 a-hexahydropyrazino [2',1':3,4] [1,4] oxa-nitrogen [5,6,7-de ] quinazolin-10-yl) benzo [ b ] thiophene-3-carbonitrile
Step 1: synthesis of Compound 18-1
Compound 15-5 (1.14 g) was dissolved in THF (10 mL), naH (375 mg) was then added, the reaction was carried out at room temperature for 20min, intermediate M2 (800 mg) was then added, the reaction was carried out at room temperature for 6h, the reaction solution was poured into saturated ammonium chloride to quench, EA and water were used to extract the reaction solution, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the objective compound 18-1 (838 mg).
Step 2: synthesis of Compound 18-2
Compound 18-1 (838 mg) was dissolved in ACN (15 mL), followed by sequential addition of DIPEA (1.03 mL) and PyBOP (1.54 g), reaction at room temperature for 1.5h, addition of silica gel to the reaction mixture, concentration under reduced pressure, and purification by column chromatography gave the title compound 18-2 (407 mg).
Step 3: synthesis of Compound 18-3
Tert-butyl (570 mg) carbamate of compound 18-2 (390 mg), (3-cyano-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzothien-2-yl) 2 (DPEPhos)(51mg)、K 2 CO 3 (295 mg) was dissolved in Tol (8 mL) and water (1 mL), reacted at 100℃for 6 hours under nitrogen protection, cooled to room temperature, the reaction solution was extracted with EA and water, the organic phase was kept, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the objective compound 18-3 (454 mg).
Step 4: synthesis of Compound 18-4
Compound 18-3 (430 mg) was dissolved in DCM (5 mL), then m-CPBA (400 mg) was added and reacted at room temperature for 0.5h, a proper amount of saturated sodium sulfite solution was added and stirred for 20min to quench, the reaction solution was extracted with DCM and water, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound 18-4 (188 mg).
Step 5: synthesis of Compound 18-5
The compound ((2R, 7 aS) -2-fluorotetrahydro-1H-pyrrolizine-7 a (5H) -yl) methanol (49 mg) was dissolved in anhydrous THF (1 mL), then NaH (20 mg) was added, reacted at room temperature for 20min, then the compound 18-4 (80 mg) was added, and reacted at room temperature for 30min. Quenching with saturated ammonium chloride solution, extracting with EA and water, collecting the organic phase, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with column chromatography to obtain the target compound 18-5 (61 mg).
Step 6: synthesis of Compound 18
Compound 18-5 (61 mg) was dissolved in 2mL of DCM, and TFA (1 mL) was added and reacted at room temperature for 20min. Concentrating under reduced pressure, and purifying by column chromatography to obtain the target compound 18 (33 mg). 1 H NMR(500MHz,DMSO-d 6 )δ7.90–7.74(m,3H),7.23(td,J＝7.1,6.4,4.9Hz,1H),7.19–7.10(m,1H),5.57(d,J＝52.0Hz,1H),5.02–4.72(m,2H),4.72–4.52(m,3H),4.32(t,J＝3.5Hz,1H),3.95–3.67(m,4H),2.63–2.51(m,1H),2.36–1.67(m,7H),1.32–1.21(m,2H),1.01(t,J＝7.4Hz,3H).
Example 90: synthesis of the Compound 6- (11-chloro-9- (3- (4-fluorophenyl) propoxy) -1-methyl-7- ((tetrahydro-2H-pyran-4-yl) oxy) -1,2,3,4,13 a-hexahydropyrazine [2',1':3,4] [1,4] oxazepino [5,6,7-de ] quinazolin-10-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine
Step 1: synthesis of Compound 90-1
Compound 3- (4-fluorophenyl) propan-1-ol (402 mg) was dissolved in THF (10 mL), naH (156 mg) was then added, reacted at room temperature for 20min, compound 1-7 (720 mg) was added, reacted at 50℃for 3h, the reaction solution was poured into saturated ammonium chloride to quench, EA and water extract the reaction solution, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the objective compound 90-1 (667 mg).
Step 2: synthesis of Compound 90-2
Compound 90-1 (667 mg) was dissolved in ACN (10 mL), followed by sequential addition of DIPEA (0.66 mL) and PyBOP (0.98 g), reaction at room temperature for 1.5h, addition of silica gel to the reaction mixture, concentration under reduced pressure, and purification by column chromatography to give the title compound 90-2 (338 mg).
Step 3: synthesis of Compound 90-3
Compound 90-2 (318 mg), intermediate 97-2 (606 mg), pd (PPh) 3 ) 4 (55 mg) was dissolved in 1, 4-dioxane (5 mL), reacted at 100℃for 2 hours under nitrogen protection, cooled to room temperature, the reaction solution was extracted with EA and water, the organic phase was kept, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the objective compound 90-3 (282 mg).
Step 4: synthesis of Compound 90-4
Compound 90-3 (260 mg) was dissolved in THF (4 mL), then TsOH (5 mg) was added, reacted at room temperature for 10min, then NIS (136 mg) was added, reacted at room temperature for 1h, the reaction solution was extracted with EA and water, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the objective compound 90-4 (295 mg).
Step 5: synthesis of Compound 90-5
Compound 90-4 (290 mg) was dissolved in DMAC (5 mL), then CuI (767 mg) and methyl fluorosulfonyl difluoroacetate (1.03 g) were added, reacted at 90℃for 3 hours under nitrogen protection, cooled to room temperature, the reaction solution was extracted with EA and water, the organic phase was kept, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the objective compound 90-5 (215 mg).
Step 6: synthesis of Compound 90-6
Compound 90-5 (215 mg) was dissolved in DCM (3 mL), then m-CPBA (145 mg) was added, reacted at room temperature for 0.5h, quenched by adding an appropriate amount of saturated sodium sulfite solution with stirring for 20min, the reaction solution was extracted with DCM and water, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound 90-6 (150 mg).
Step 7: synthesis of Compound 90-7
The compound tetrahydro-2H-pyran-4-ol (14 mg) was dissolved in anhydrous THF (1 mL), then NaH (8 mg) was added, reacted at room temperature for 20min, then compound 90-6 (70 mg) was added, and reacted at room temperature for 30min. Quenching with saturated ammonium chloride solution, extracting with EA and water, collecting the organic phase, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with column chromatography to obtain target compound 90-7 (50 mg).
Step 8: synthesis of Compound 90-8
Compound 90-7 (50 mg) was dissolved in DCM (2 mL), DDQ (80 mg) was then added, reacted overnight at room temperature, the reaction solution was extracted with DCM and water, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound 90-8 (18 mg).
Step 9: synthesis of Compound 90
Compound 90-8 (18 mg) was dissolved in 2mL of DCM, then TFA (1 mL) was added and reacted at room temperature for 20min. Concentrating under reduced pressure, and purifying by column chromatography to obtain the target compound 90 (14.8 mg). 1 H NMR(500MHz,Methanol-d 4 )δ7.06(dd,J＝8.3,5.4Hz,2H),6.96(t,J＝8.6Hz,2H),6.79(d,J＝5.2Hz,1H),5.34(dq,J＝8.4,4.1Hz,1H),5.23–5.13(m,1H),4.66(dddd,J＝35.4,21.8,13.7,3.5Hz,2H),4.42–4.29(m,1H),4.18–3.95(m,5H),3.65–3.43(m,5H),2.47(d,J＝20.9Hz,5H),2.19–2.07(m,2H),1.92–1.75(m,4H),1.52(dd,J＝27.2,6.8Hz,3H),1.31(d,J＝15.0Hz,1H).
Example 92: synthesis of the Compound 2-amino-4- (11-chloro-1-ethyl-9-fluoro-7- (methylsulfonyl) -1,2,3,4,13 a-hexahydropyrazino [2',1':3,4] [1,4] oxazino [5,6,7-de ] quinazolin-10-yl) benzo [ b ] thiophene-3-carbonitrile
Compound 18-4 (20 mg) was dissolved in 2mL of DCM, then TFA (1 mL) was added and reacted at room temperature for 20min. Concentrating under reduced pressure, and purifying by column chromatography to obtain the target compound 92 (7 mg). 1 H NMR(500MHz,DMSO-d 6 )δ7.99–7.69(m,3H),7.31–7.15(m,2H),5.07(dd,J＝24.0,13.9Hz,1H),4.96–4.56(m,2H),4.37(q,J＝6.7,5.2Hz,1H),3.85(s,1H),3.43(s,3H),2.12–1.85(m,2H),1.85–1.63(m,1H),1.24(s,3H),1.01(t,J＝7.4Hz,3H).
Example 93: synthesis of the Compound 2-amino-4- (11-chloro-9-fluoro-1-methyl-7- (methylsulfonyl) -1,2,3,4,13 a-hexahydropyrazino [2',1':3,4] [1,4] oxazino [5,6,7-de ] quinazolin-10-yl) benzo [ b ] thiophene-3-carbonitrile
Compounds 1-10 (50 mg) were dissolved in 2mL of DCM, then TFA (1 mL) was added and reacted at room temperature for 20min. Concentrating under reduced pressure, and purifying by column chromatography to obtain the target compound 93 (12 mg). 1 H NMR(500MHz,DMSO-d 6 )δ7.94–7.75(m,3H),7.31–7.15(m,2H),5.00(t,J＝13.0Hz,1H),4.76–4.51(m,2H),4.32(d,J＝8.1Hz,1H),3.40(d,J＝1.2Hz,3H),3.15–2.96(m,2H),1.99(dt,J＝16.7,7.0Hz,1H),1.24(d,J＝6.0Hz,3H),1.19(t,J＝7.6Hz,2H).
Example 94: synthesis of the Compound 11-chloro-9- ((4-fluorobenzyl) oxy) -1-methyl-10- (5-methyl-1H-indazol-4-yl) -7- (methylsulfanyl) -1,2,3,4,13 a-hexahydropyrazine [2',1':3,4] [1,4] oxanitrogen [5,6,7-de ] quinazoline
Compound 96-4 (10 mg) was dissolved in 2mL of DCM, and TFA (1 mL) was added and reacted at room temperature for 20min. Concentrating under reduced pressure, and purifying by column chromatography to obtain the target compound 94 (4 mg).
Example 95: synthesis of the Compound 11-chloro-9- ((4-fluorobenzyl) oxy) -1-methyl-10- (5-methyl-1H-indazol-4-yl) -7- (methylsulfonyl) -1,2,3,4,13 a-hexahydropyrazine [2',1':3,4] [1,4] oxanitrogen [5,6,7-de ] quinazoline
Compound 96-5 (10 mg) was dissolved in 2mL of DCM, and TFA (1 mL) was added and reacted at room temperature for 20min. Concentrating under reduced pressure, and purifying by column chromatography to obtain the target compound 95 (5 mg).
Example 96: synthesis of the Compound 11-chloro-9- ((4-fluorobenzyl) oxy) -1-methyl-10- (5-methyl-1H-indol-4-yl) -7- ((tetrahydro-2H-pyran-4-yl) oxy) -1,2,3,4,13 a-hexahydropyrazine [2',1':3,4] [1,4] oxazao [5,6,7-de ] quinazoline
Step 1: synthesis of Compound 96-1:
compound 1-3 (809 mg) was dissolved in THF (10 mL), naH (351 mg) was then added, reacted at room temperature for 20min, intermediate M2 (600 mg) was then added, reacted at room temperature for 6h, the reaction mixture was poured into saturated ammonium chloride to quench, EA and water were used to extract the reaction mixture, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the objective compound 96-1 (515 mg).
Step 2: synthesis of Compound 96-2:
compound (4-fluorophenyl) methanol (138 mg) was dissolved in THF (3 mL), naH (72 mg) was then added, the reaction was carried out at room temperature for 20min, compound 96-1 (200 mg) was added, the reaction was carried out at 50℃for 3h, the reaction solution was poured into saturated ammonium chloride for quenching, EA and water were used to extract the reaction solution, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the objective compound 96-2 (199 mg).
Step 3: synthesis of Compound 96-3:
compound 96-2 (190 mg) was dissolved in ACN (4 mL), followed by sequential addition of DIPEA (0.21 mL) and PyBOP (317 mg), reaction at room temperature for 1.5h, addition of silica gel to the reaction mixture, concentration under reduced pressure, and purification by column chromatography to give the title compound 96-3 (168 mg).
Step 4: synthesis of Compound 96-4:
compound 96-3 (160 mg), (5-methyl-1- (tetrahydro-2H-pyran-2-yl) -1H-indazol-4-yl) boronic acid (131 mg), pd 2 (dba) 3 (46mg)、Sphos(42mg)、K 3 PO 4 (160 mg) was dissolved in t-BuOH (4 mL) and water (0.4 mL), and reacted at 90℃for 14 hours under nitrogen protection, cooled to room temperature, the reaction solution was extracted with EA and water, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the objective compound 96-4 (140 mg).
Step 5: synthesis of Compound 96-5:
compound 96-4 (140 mg) was dissolved in DCM (3 mL), then m-CPBA (106 mg) was added, reacted at room temperature for 0.5h, quenched by adding an appropriate amount of saturated sodium sulfite solution with stirring for 20min, the reaction solution was extracted with DCM and water, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound 96-5 (38 mg).
Step 6: synthesis of Compound 96-6:
the compound tetrahydro-2H-pyran-4-ol (7 mg) was dissolved in anhydrous THF (1 mL), then NaH (4 mg) was added, reacted at room temperature for 20min, then compound 96-5 (25 mg) was added, and reacted at room temperature for 30min. Quenching with saturated ammonium chloride solution, extracting with EA and water, collecting the organic phase, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with column chromatography to obtain the target compound 96-6 (25 mg).
Step 7: synthesis of Compound 96:
compound 96-6 (25 mg) was dissolved in 2mL of DCM, and TFA (1 mL) was added and reacted at room temperature for 20min. Concentrating under reduced pressure, and purifying by column chromatography to obtain the target compound 96 (14 mg). 1 H NMR(500MHz,DMSO-d 6 )δ13.06(s,1H),7.57–7.31(m,3H),6.95(td,J＝8.9,1.9Hz,2H),6.70(ddd,J＝8.4,5.6,2.3Hz,2H),5.20(dt,J＝9.5,4.9Hz,1H),5.04–4.84(m,2H),4.69(t,J＝3.6Hz,2H),4.62(dd,J＝15.6,10.9Hz,1H),4.25(s,1H),3.99(s,1H),3.87–3.83(m,3H),2.16–1.93(m,6H),1.68(dtd,J＝16.4,9.3,7.5,4.4Hz,2H),1.39(dd,J＝6.8,3.8Hz,3H).
Example 97: synthesis of the Compound 6- (11-chloro-9- ((4-fluorobenzyl) oxy) -1-methyl-7- ((tetrahydro-2H-pyran-4-yl) oxy) -1,2,3,4,13 a-hexahydropyrazine [2',1':3,4] [1,4] oxazepin [5,6,7-de ] quinazolin-10-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine
Step 1: synthesis of Compound 97-1
6-bromo-4-methylpyridin-2-amine (5 g), K 2 CO 3 (13.8 g) and KI (6.6 g) are dissolved in NMP (50 mL), PMBCl (8.58 g) is slowly dripped into the mixture, the mixture is reacted for 0.5h at 60 ℃, the temperature is reduced to room temperature, the reaction solution is poured into 100mL of water, 50mL of methyl tertiary butyl ether is added to extract the reaction solution, the organic phase is extracted for 2 times by saturated saline, the organic phase is reserved, anhydrous sodium sulfate is dried, filtered, concentrated under reduced pressure, PE (30 mL) is pulped, filtered and dried to obtain the target compound 97-1 (12.3 g).
Step 2: synthesis of Compound 97-2
Compound 97-1 (11.3 g), hexa-n-butylditin (43 g), pd 2 (dba) 3 (2.42 g), tricyclohexylphosphine (1.48 g) and lithium chloride (3.36 g) were dissolved in 1, 4-dioxane (100 mL), reacted at 80℃for 10 hours under nitrogen protection, cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to give the objective compound 97-2 (15 g).
Step 3: synthesis of Compound 97-3
Compounds 97-2 (270 mg), ITM-1 (537 mg), pd (PPh) 3 ) 4 (49 mg) was dissolved in 1,4-Dioxa-ring (4 mL) under nitrogen protection, reacting at 100deg.C for 2h, cooling to room temperature, extracting the reaction liquid with EA and water, reserving organic phase, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying by column chromatography to obtain the target compound 97-3 (290 mg).
Step 4: synthesis of Compound 97-4
Compound 97-3 (270 mg) was dissolved in THF (4 mL), then TsOH (5 mg) was added, reacted at room temperature for 10min, then NIS (136 mg) was added, reacted at room temperature for 1h, the reaction solution was extracted with EA and water, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the objective compound 97-4 (260 mg).
Step 5: synthesis of Compound 97-5
Compound 97-4 (150 mg) was dissolved in DMAC (4 mL), then CuI (420 mg) and methyl fluorosulfonyl difluoroacetate (620 mg) were added, reacted at 90℃for 3 hours under nitrogen protection, cooled to room temperature, the reaction solution was extracted with EA and water, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the objective compound 97-5 (86 mg). Step 6: synthesis of Compound 97-6
Compound 97-5 (85 mg) was dissolved in DCM (2 mL), then m-CPBA (60 mg) was added, reacted at room temperature for 0.5h, quenched by adding an appropriate amount of saturated sodium sulfite solution with stirring for 20min, the reaction solution was extracted with DCM and water, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound 97-6 (48 mg).
Step 7: synthesis of Compound 97-7
The compound tetrahydro-2H-pyran-4-ol (9 mg) was dissolved in anhydrous THF (1 mL), then NaH (8 mg) was added, reacted at room temperature for 20min, then compound 97-6 (45 mg) was added, and reacted at room temperature for 30min. Quenching with saturated ammonium chloride solution, extracting with EA and water, collecting the organic phase, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying with column chromatography to obtain the target compound 97-7 (35 mg).
Step 8: synthesis of Compound 97-8
Compound 97-7 (35 mg) was dissolved in DCM (2 mL), DDQ (53 mg) was then added, reacted overnight at room temperature, the reaction solution was extracted with DCM and water, the organic phase was retained, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound 97-8 (7 mg).
Step 9: synthesis of Compound 97
Compound 97-8 (7 mg) was dissolved in 2mL of DCM, then TFA (1 mL) was added and reacted at room temperature for 20min. Concentrating under reduced pressure, and purifying by column chromatography to obtain the target compound 97 (3.4 mg). 1 H NMR(500MHz,Methanol-d 4 )δ7.22–7.08(m,2H),7.05–6.91(m,2H),6.65(s,1H),5.33(d,J＝4.4Hz,1H),5.22(d,J＝11.3Hz,1H),5.17(s,1H),5.03(s,1H),4.66(d,J＝3.8Hz,2H),4.31(s,1H),4.04(dd,J＝6.9,2.4Hz,1H),3.95(dq,J＝11.2,5.2Hz,2H),3.50(dt,J＝12.3,8.6Hz,3H),3.45–3.39(m,2H),2.46–2.41(m,3H),2.12(d,J＝13.1Hz,2H),2.03(s,2H),1.83(dq,J＝13.2,4.4Hz,2H),1.51(d,J＝6.8Hz,3H).
Example 98: synthesis of the Compound 6- (11-chloro-9- (4-fluorophenylethoxy) -1-methyl-7- ((tetrahydro-2H-pyran-4-yl) oxy) -1,2,3,4,13 a-hexahydropyrazine [2',1':3,4] [1,4] oxazino [5,6,7-de ] quinazolin-10-yl) -4-methyl-5- (trifluoromethyl) pyridin-2-amine
The synthesis procedure of example 98 refers to the synthesis of example 90. 1 H NMR(500MHz,Methanol-d 4 )δ7.05(ddd,J＝8.8,5.1,1.6Hz,2H),6.91(td,J＝8.8,1.4Hz,2H),6.56(d,J＝2.6Hz,1H),5.34(tq,J＝6.9,4.0Hz,1H),5.21–5.09(m,1H),4.72–4.55(m,3H),4.33–4.21(m,3H),4.01(dtd,J＝16.7,8.7,8.3,5.0Hz,3H),3.61(qd,J＝8.2,3.8Hz,2H),3.53–3.41(m,3H),2.85(td,J＝6.0,3.8Hz,2H),2.43–2.35(m,3H),2.18–2.11(m,2H),2.07–1.99(m,1H),1.86(ddt,J＝17.4,9.0,3.9Hz,2H),1.51(dd,J＝24.6,6.8Hz,3H).
The examples described below were synthesized using the methods described above, or similar methods using the corresponding intermediates.
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Biological testing
Pharmacological experiment 1: cell proliferation Assay (AGS)
KRAS-G12D mutant tumor cells AGSCRL-1739 TM ) According to 1X 10 3 Cell density of/well was plated in a low adsorption 96-well plate and cultured overnight in a cell incubator. After the cells are attached, adding the compound to be tested into a 96-well plate according to final concentrations of 10000, 2000, 400, 80, 16, 3.2, 0.64, 0.128, 0.025 and 0nM (DMSO final concentration is 0.5%), culturing at 37 ℃ for 96 hours, adding 50 mu L of Cell-titer GLO working solution into each well, shaking and mixing uniformly, incubating for 10 minutes at room temperature, reading Luminescence values of Luminecence in a multifunctional enzyme-labeled instrument, and converting the Luminescence value data into inhibition percentage. And the percent inhibition of cell proliferation was calculated according to the following formula:
percent inhibition = (max-measured)/(max-Blank) ×100
("maximum" from 0.5% DMSO control wells, "Blank" from Blank control wells, "measured value" from compound treated wells).
Curve fitting and IC acquisition using GraphPad Prism software 50 Values.
The detection result shows that the compound has good activity.
TABLE 1
Names of Compounds AGS IC 50 (nM)
1 17.7
13 390
15 404
17 242
18 161
Pharmacological experiment 2: cell p-ERK assay
KRAS-G12D mutant tumor cells AGSCRL-1739 TM ) According to 4X 10 4 Cell density of/well was plated in 96-well plates and incubated overnight in a cell incubator. After cell attachment, the test compounds were added to 96-well plates at final concentrations of 3000nM, 600nM, 120nM, 24nM, 4.8nM, 0.96nM, 0.19nM, 0.5% DMSO, incubated for 3h, and after completion of the complete lysis, each treated cell sample (40 ul/well) in the 96-well plates was lysed by using lysate in pERK HTRF Kit (Cisbio) and assayed for 9 HTRF separately16 ul/well of protein solution and 4ul of premixed pERK-d2 antibody and pERK-Eu Cryptate antibody were added to the 6-well plate. After overnight incubation at 4 ℃, the ratio signal values of 665nM/620nM were read on a multifunctional microplate reader and raw data was collected. And the percent p-ERK inhibition was calculated according to the following formula: />
Percent inhibition = (max-measured)/(max-Blank) ×100
("maximum" from 0.5% DMSO control wells, "Blank" from Blank control wells, "measured value" from compound treated wells).
Curve fitting and IC acquisition using GraphPad Prism software 50 Values.
TABLE 2
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Claims (19)

1. A compound of formula (I), a stereoisomer, tautomer, deuterate or pharmaceutically acceptable salt thereof:
Wherein,
represents a single bond or a double bond;
X 1 selected from O or NR 5 ；R 5 Selected from H, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 1-6 Haloalkyl, substituted C 1-6 Haloalkyl, C 2-6 Alkenyl or substituted C 2-6 Alkenyl groups;
X 2 selected from O, (CH) 2 ) 0-3 、C(R 6 ) 1-2 C (O) or NR 6 ；R 6 Selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, substituted C 1-6 Alkyl group,Halogen, C 2-6 Alkenyl, substituted C 2-6 Alkenyl, C 3-6 Cycloalkyl or substituted C 3-6 Cycloalkyl;
X 3 selected from CR 7 Or N; r is R 7 Selected from the absence or H;
X 4 selected from O, (CH) 2 ) 0-3 、C(R 8 ) 1-2 C (O) or NR 8 ；R 8 Selected from H, halogen, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 1-6 Alkoxy, -O (CH) 2 ) 0-3 R 13 、C 3-6 Cycloalkyl or substituted C 3-6 Cycloalkyl;
X 5 selected from O, NR 9 、(CH 2 ) 0-3 、C(R 9 ) 2 Or C (O); r is R 9 Each independently selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, substituted C 1-6 Alkyl, halogen, C 2-6 Alkenyl, substituted C 2-6 Alkenyl, C 3-6 Cycloalkyl or substituted C 3-6 Cycloalkyl;
X 6 selected from O, NR 10 、(CH 2 ) 0-3 、C(R 10 ) 2 Or C (O); r is R 10 Each independently selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, substituted C 1-6 Alkyl, halogen, C 2-6 Alkenyl, substituted C 2-6 Alkenyl, C 3-6 Cycloalkyl or substituted C 3-6 Cycloalkyl;
X 7 selected from CR 11 Or N; r is R 11 Selected from H, amino, substituted amino, cyano, C 1-6 Alkyl, substituted C 1-6 Alkyl or halogen;
l is selected from the group consisting of bond, -O-C 0-4 Alkylene-, -S-C 0-4 Alkylene-, -NR 9 -C 0-4 Alkylene-or C 2-4 Alkynylene group, the-O-C 0-4 Alkylene-, -S-C 0-4 Alkylene-, -S (O) 2 -C 0-4 Alkylene-, -NR 9 -C 0-4 Alkylene-or C 2-4 Alkynylene optionally being substituted with one or more R 12 Substitution; r is R 12 Selected from H, halogen, cyano, hydroxy or C 1-6 Alkyl, or two R's on the same carbon atom 12 Together with the atoms to which they are attached form C 3-6 Cycloalkyl or 3-6 membered heterocyclyl;
R 1 selected from C 1-6 Alkyl, C 1-6 Haloalkyl, cyano, amido, C 3-8 Cycloalkyl or 3-8 membered heterocyclyl;
R 2 selected from-OR a 、-OC(O)N(R a ) 2 、-N(R a ) 2 、-NR a C(O)R a 、-NR a C(O)N(R a ) 2 、-NR a S(O)R a 、-NR a S(O) 2 R a 、-S(＝O)R a 、-S(＝O) 2 R a 、-SR a 、-S(R a ) 5 、-C(＝O)R a 、-C(＝O)OR a 、-C(＝O)N(R a ) 2 、C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 6-14 membered heteroaryl optionally further substituted with one or more R 10 Substitution; r is R 10 Selected from H, cyano, halogen, C 1-6 Alkyl, -C 0-6 alkylene-OR a 、-C 0-6 alkylene-OC (O) N (R) a ) 2 、-C 0-6 alkylene-N (R) a ) 2 、-C 0-6 alkylene-NR a C(O)R a 、-C 0-6 alkylene-NR a C(O)N(R a ) 2 、-C 0-6 alkylene-NR a S(O)R a 、-C 0-6 alkylene-NR a S(O) 2 R a 、-C 0-6 alkylene-S (=o) R a 、-C 0-6 alkylene-S (=o) 2 R a 、-C 0-6 alkylene-SR a 、-C 0-6 alkylene-S (R) a ) 5 、-C 0-6 alkylene-C (=o) R a 、-C 0-6 alkylene-C (=o) OR a 、-C 0-6 alkylene-C (=O) N (R) a ) 2 、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-14 membered heteroaryl), said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-14 membered heteroaryl) optionally may also be substituted with 1 or more R a Substituted;
R 3 selected from C 6-14 Aryl or 5-14 membered heteroaryl, said C 6-14 Aryl or 5-14 membered heteroaryl optionally further substituted with one or more R 13 Substitution; r is R 13 Selected from H, cyano, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 alkylene-OR a 、-C 0-6 alkylene-OC (O) N (R) a ) 2 、-C 0-6 alkylene-N (R) a ) 2 、-C 0-6 alkylene-NR a C(O)R a 、-C 0-6 alkylene-NR a C(O)N(R a ) 2 、-C 0-6 alkylene-NR a S(O)R a 、-C 0-6 alkylene-NR a S(O) 2 R a 、-C 0-6 alkylene-S (=o) R a 、-C 0-6 alkylene-S (=o) 2 R a 、-C 0-6 alkylene-SR a 、-C 0-6 alkylene-S (R) a ) 5 、-C 0-6 alkylene-C (=o) R a 、-C 0-6 alkylene-C (=o) OR a 、-C 0-6 alkylene-C (=O) N (R) a ) 2 、C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-14 membered heteroaryl), said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-14 membered heteroaryl) optionally may also be substituted with 1 or more R a Substituted;
R 4 selected from H, cyano, C 1-6 Alkyl or C 1-6 A haloalkyl group;
R a each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl.
2. A compound according to claim 1 (I), a stereoisomer, tautomer, deuterate or a pharmaceutically acceptable salt thereof, characterized in that: the X is 4 Selected from O, (CH) 2 ) 0-3 、C(R 8 ) 1-2 C (O) or NR 8 ；R 8 Selected from H, halogen, C 1-6 Alkyl, substituted C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or substituted C 3-6 Cycloalkyl;
the L is selected from the group consisting of bond, -O-C 0-4 Alkylene-, -S-C 0-4 Alkylene-, -NR 9 -C 0-4 Alkylene-or C 2-4 Alkynylene group, the-O-C 0-4 Alkylene-, -S-C 0-4 Alkylene-, -NR 9 -C 0-4 Alkylene-or C 2-4 Alkynylene optionally being substituted with one or more R 12 Substitution; r is R 12 Selected from H, halogen, cyano, hydroxy or C 1-6 Alkyl, or two R's on the same carbon atom 12 Together with the atoms to which they are attached form C 3-6 Cycloalkyl or 3-6 membered heterocyclyl.
3. A compound of formula (I), a stereoisomer, tautomer, deuterate, or pharmaceutically acceptable salt thereof, selected from the group consisting of compounds of formulas (IA) through (IB):
wherein X is 1 、X 5 、X 6 、L、R 1 、R 2 、R 3 、R 4 、R 6 、R 8 Is as defined in claim 1.
4. A compound of formula (I), a stereoisomer, tautomer, deuterate, or pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of formula (IA-1), formula (IB-1), a tautomer, deuterate, or pharmaceutically acceptable salt thereof:
Wherein X is 1 、L、R 1 、R 2 、R 3 、R 6 、R 8 Is as defined in claim 1.
5. A compound of formula (I), a stereoisomer, tautomer, deuterate, or pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of formula (IA-1-1), formula (IA-1-2), formula (IB-1-1), formula (IB-1-2), tautomer, deuterate, or pharmaceutically acceptable salt thereof:
wherein X is 1 、L、R 1 、R 2 、R 3 、R 6 、R 8 Is as defined in claim 1.
6. A compound of the general formula (IA-1-1) or (IB-1-1), a tautomer, a deuterate or a pharmaceutically acceptable salt thereof according to claim 5, wherein R 2 Is a 3-14 membered fused heterocyclyl, said 3-14 membered fused heterocyclyl optionally being further substituted with one or more R 10 Substitution, said R 10 Selected from halogen or C 2-6 Alkenyl groups optionally further represented by 1 or more R a Substituted; the R is a Each independently selected from H or halogen.
7. A compound of the general formula (IA-1-1) or (IB-1-1), a tautomer, a deuterate or a pharmaceutically acceptable salt thereof according to claim 6 wherein said fused heterocyclic group is selected from The fused heterocyclyl is optionally further substituted with one or more R 10 Substitution, said R 10 Selected from H, halogen or C 2-6 Alkenyl groups optionally further represented by 1 or more R a Substituted; the R is a Each independently selected from H or halogen.
8. The compound of formula (IA-1-1) or (IB-1-1), tautomer, deuterate or pharmaceutically acceptable salt thereof according to any one of claims 5-7 wherein R 10 Is thatThe R is a Each independently is C 1-6 Alkyl or halogen, preferably F.
9. The compound of formula (IA-1-1) or (IB-1-1), tautomer, deuterate or pharmaceutically acceptable salt thereof according to any one of claims 5-8 wherein R 10 Is thatThe R is a H.
10. The compound of formula (IA-1-1) or (IB-1-1), tautomer, deuterate or pharmaceutically acceptable salt thereof according to any one of claims 5-7 wherein R 10 Halogen, preferably F.
11. A compound of formula (IA-1-1) or (IB-1-1), a stereoisomer, a tautomer, a deuterate, or a pharmaceutically acceptable salt thereof according to any one of claims 5-10, wherein R 2 Selected from the group consisting of
12. A compound of the formula (IA-1-2) or (IB-1-2), a tautomer, a deuterate or a pharmaceutically acceptable salt thereof according to claim 5, wherein R 2 Selected from C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 5-14 membered heteroaryl, said C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 6-14 Aryl or 6-14 membered heteroaryl optionally further substituted with one or more R 10 Substitution, said R 10 Selected from H, cyano, halogen, C 1-6 Alkyl, -C 0-6 alkylene-OR a 、-C 0-6 alkylene-N (R) a ) 2 、-C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-14 membered heteroaryl), said-C 0-6 alkylene-C 3-14 Cycloalkyl, -C 0-6 Alkylene- (3-14 membered heterocyclyl), -C 0-6 alkylene-C 6-14 Aryl or-C 0-6 Alkylene- (5-14 membered heteroaryl) is further substituted with one or more R a Substituted, the R a Each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups.
13. A compound of formula (IA-1-2) or (IB-1-2), a tautomer, a deuterate or a pharmaceutically acceptable salt thereof according to claim 12 selected from the group consisting of compounds of formula (IA-1-2-1) or (IB-1-2-1), a tautomer, a deuterate or a pharmaceutically acceptable salt thereof:
wherein the R is 10 Selected from H, cyano, halogen, C 1-6 Alkyl, -C 0-6 alkylene-OR a 、-C 0-6 alkylene-N (R) a ) 2 、-C 0-6 alkylene-C 3-14 Cycloalkyl or-C 0-6 Alkylene- (3-14 membered heterocyclyl), said-C 0-6 alkylene-C 3-14 Cycloalkyl or-C 0-6 Alkylene- (3-14 membered heterocyclyl) is further substituted with one or more R a Substituted, the R a Each independently selected from H, halogen, hydroxy, amino, oxo, nitro, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy or C 1-6 Haloalkoxy groups.
14. The compound, stereoisomer, tautomer, deuterate, or pharmaceutically acceptable salt thereof according to any one of claims 1-13 wherein R 3 Selected from the group consisting of The said Optionally further by one or more R a Substitution, said R a Independently selected from H, hydroxy, cyano, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl or-C 0-3 alkylene-C 3-14 Cycloalkyl groups.
15. The compound, stereoisomer, tautomer, deuterate, or pharmaceutically acceptable salt thereof according to any one of claims 1-14 wherein R 3 Selected from the group consisting of
16. The compound, stereoisomer, tautomer, deuterate, or pharmaceutically acceptable salt thereof according to any one of claims 1-15 wherein R 1 Selected from C 1-6 Alkyl or C 3-8 Cycloalkyl is preferably methyl, ethyl, isopropyl or cyclopropyl.
17. The compound of any one of claims 1-16, a stereoisomer, tautomer, deuterate, or pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the group consisting of compounds of formula:
18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-17, or a stereoisomer, tautomer, deuterate, or pharmaceutically acceptable salt thereof.
19. Use of a compound according to any one of claims 1 to 17 or a pharmaceutical composition according to claim 18 for the manufacture of a medicament for KRAS G12D mediated diseases.
CN202311003135.9A 2022-08-24 2023-08-10 KRAS G12D inhibitor and application thereof in medicine Pending CN117624190A (en)

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