WO2023198078A1 - 作为kras g12d抑制剂的多环化合物 - Google Patents

作为kras g12d抑制剂的多环化合物 Download PDF

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WO2023198078A1
WO2023198078A1 PCT/CN2023/087690 CN2023087690W WO2023198078A1 WO 2023198078 A1 WO2023198078 A1 WO 2023198078A1 CN 2023087690 W CN2023087690 W CN 2023087690W WO 2023198078 A1 WO2023198078 A1 WO 2023198078A1
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alkyl
hydrogen
formula
cancer
compound
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PCT/CN2023/087690
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French (fr)
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张汉承
蔡聪聪
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杭州英创医药科技有限公司
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Priority claimed from PCT/CN2022/086183 external-priority patent/WO2022214102A1/zh
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Publication of WO2023198078A1 publication Critical patent/WO2023198078A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the field of medicinal chemistry; specifically, the present invention relates to a new class of derivatives containing tricyclic heteroaryl groups, their synthesis methods and their use as a KRAS G12D inhibitor in the preparation of drugs for the treatment of tumors and other related Applications in diseases.
  • KRAS Kerrsten Rat Sarcoma Viral Oncogene Homolog
  • HRAS Resten Rat Sarcoma Viral Oncogene Homolog
  • NRAS NRAS
  • KRAS KRAS protein plays an important role in the occurrence and development of cancer.
  • RAS mutations are present in 20%-30% of human tumors, among which KRAS mutations are the most frequent and are more common in lung cancer, pancreatic cancer, and colon cancer.
  • the KRAS protein contains 188 amino acid residues and has multiple functional motifs, including nucleotide binding region, switch I region and switch II region, nucleotide exchange factor (GEF) binding region, and GTPase activating protein (GAP) binding region. region and effector protein binding region, etc.
  • GEF nucleotide exchange factor
  • GAP GTPase activating protein
  • region and effector protein binding region etc.
  • upstream signaling factors such as receptor tyrosine kinases, integrins, G protein-coupled receptors, etc.
  • KRAS as a molecular switch in cells, exhibits activation (on) or inactivation (off) states respectively through the conversion of GTP or GDP binding state, and transmits signals received upstream to downstream effector proteins.
  • the KRAS protein itself has a relatively slow nucleotide exchange rate and a weak GTP hydrolysis function.
  • the KRAS protein After receiving the upstream stimulation signal, with the assistance of guanine nucleotide exchange factors such as SOS1 (Son of Sevenless 1), the KRAS protein releases GDP and binds to GTP.
  • the GTP-bound RAS protein is in an activated state, recruiting downstream effector proteins, activating signaling pathways such as Raf-MEK-ERK and PI3K-AKT-mTOR, and promoting cell growth, proliferation, survival, metabolism, and angiogenesis.
  • GTPase activating protein GAP After the GTPase activating protein GAP binds to KRAS, it will significantly promote the GTP hydrolysis function of KRAS. GTP is hydrolyzed into GDP.
  • KRAS in the GDP-bound state changes to an inactive state, and the molecular switch is turned off.
  • RAS mutates its intrinsic or GAP-induced GTPase activity is inhibited, RAS remains in a GTP-bound state, and the molecular switch continues to open, which leads to continuous activation of multiple downstream signaling pathways and abnormal cell proliferation and growth.
  • KRAS mutations In pancreatic cancer, up to 90% of patients have KRAS mutations, of which about 40% point mutations are KRAS G12D mutations. In addition, about 13.3% of colorectal cancers, about 10% of rectal cancers, about 4% of non-small cell lung cancers, and about 1.7% of small cell lung cancers have KRAS G12D mutations.
  • KRAS G12D Due to its important role in tumorigenesis and its high mutation frequency, KRAS G12D has become a very attractive anti-tumor target. To date, there are no effective KRAS G12D inhibitor drugs on the market. Based on the above background, we developed a class of structurally novel KRAS G12D inhibitors.
  • the purpose of the present invention is to provide a new class of KRAS G12D inhibitors.
  • the first aspect of the present invention provides a compound with the structure shown in the following formula (I), or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate :
  • connection sites between the above structural fragments and the groups at the corresponding positions in formula (I); represents the above structural fragment and formula (I) in The connection site;
  • Ar is selected from aryl or heteroaryl
  • Each R 11 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkynyl, C 3-6 cycloalkyl, or CN;
  • Each R 12 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, -CH 2 OC(O)NR h R h , C 2-4 alkenyl, C 2-4 alkyne group, C 3-8 cycloalkyl group, 3- to 8-membered heterocyclyl group, CN, OR h , SR h , NR h R h , -(CR a R b ) q -OR h , -(CR a R b ) q -NR h R h ; wherein each R h is independently hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl; R a and R b are each independently selected from hydrogen, halogen, or C 1-4 alkyl; each q is independently selected from 0, 1, 2, or 3;
  • Each R 14 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl , C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl , C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 3-6 cycloalkyl Base -O-, 3- to 6-membered heterocyclyl -O-, NR h R h , CN, SR h , -OC(O)R k , -OP(O)(OR m ) 2 , -O- CH(R n )-OP(O)(OR m ) 2 ; wherein R k is selected from C 1-4 alkyl, wherein the alkyl is optionally substituted by one or more groups selected from the group consisting of: hydroxy
  • Each R 15 is independently selected from hydrogen, halogen, or C 1-4 alkyl
  • k is selected from 0, 1, or 2;
  • n is selected from 0, 1, 2, or 3;
  • n is selected from 0, 1, or 2;
  • p is selected from 0, 1, 2, 3, 4, or 5;
  • each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups is optionally and independently Positionally substituted by 1-3 substituents each independently selected from the group consisting of: halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3 -8 cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO 2 , OR h , SR h , NR h R h , C(O)R t , C(O) OR h , C(O)NR h R h , NR h C(O)R t , NR h S(O) 2 R t , or S(O) 2 R t , provided that the formed chemical structure is stable and meaningful; wherein, R t is C
  • the above-mentioned aryl group is an aromatic group containing 6-12 carbon atoms; the heteroaryl group is a 5- to 15-membered (preferably 5- to 12-membered) heteroaromatic group.
  • formula (I) is formula (II),
  • X is selected from N or CR 11 ;
  • Each R 11 is independently selected from hydrogen, halogen, C 1-4 alkyl, or CN;
  • Each R 14 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl , C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl, NR h R h , CN, SR h , -OC(O)R k , -OP(O)( OR m ) 2 , -O-CH(R n )-OP(O)(OR m ) 2 ; wherein each R h is independently hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl; R k is selected from C 1-4 alkyl, wherein the alkyl is optionally substituted by one or more groups selected from the group consisting of: hydroxyl, C 1-4 alkoxy, NR h R h , C(O)OH , C
  • Each R 15 is independently selected from hydrogen or fluorine
  • k is selected from 0, 1, or 2;
  • n is selected from 0, 1, or 2;
  • p is selected from 0, 1, 2, 3, 4, or 5;
  • formula (I) is formula (II-A),
  • R 11 , R 13 , R 14 , X, k, m, and p are as mentioned above.
  • formula (I) is formula (III),
  • R 11 , R 13 , R 14 , k, and p are as mentioned above.
  • formula (I) is formula (IV),
  • R 11 , R 13 , R 14 , k, m, and p are as mentioned above.
  • formula (I) is formula (V),
  • Ar is selected from aryl or heteroaryl
  • R 11 , R 12 , R 13 , R 14 , R 15 , k, m, n, and p are as mentioned above.
  • formula (I) is formula (VI),
  • Y is selected from N or CR 14 ;
  • R 11 , R 12 , R 13 , R 14 , R 15 , k, m, n, and p are as mentioned above.
  • formula (I) is formula (VII),
  • Each R 14 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl , C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl , C 3-6 cycloalkyl, 3- to 6-membered heterocyclyl, C 3-6 cycloalkyl Base -O-, 3- to 6-membered heterocyclyl -O-, NR h R h , CN, SR h 2 ; wherein each R h is independently hydrogen, C 1-4 alkyl, or C 1- 4 haloalkyl;
  • p is selected from 0, 1, 2, 3, 4, or 5.
  • formula (I) is formula (VIII),
  • Ar is selected from aryl or heteroaryl
  • R 11 , R 12 , R 13 , R 14 , R 15 , k, m, n, and p are as mentioned above.
  • formula (I) is formula (IX),
  • Ar is selected from benzene ring and naphthalene ring;
  • Each R 14 is independently selected from hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, hydroxyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl , C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl, NR h R h , CN, SR h , -OC(O)R k , -OP(O)( OR m ) 2 , -O-CH(R n )-OP(O)(OR m ) 2 ; wherein each R h is independently hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl; R k is selected from C 1-4 alkyl, wherein the alkyl is optionally substituted by one or more groups selected from the group consisting of: hydroxyl, C 1-4 alkoxy, NR h R h , C(O)OH , C
  • p is selected from 0, 1, 2, 3, 4, or 5.
  • formula (I) is formula (X),
  • R 11 is selected from hydrogen, fluorine, chlorine, C 1-4 alkyl, or CN;
  • R 14' is selected from hydrogen, fluorine, and chlorine
  • R 14′′ is selected from hydroxyl, -OP(O)(OR m ) 2 , or -O-CH(R n )-OP(O)(OR m ) 2 ; wherein each R m is independently selected from hydrogen, C 1-4 alkyl, or metal ion forms the corresponding salt; R n is selected from hydrogen or C 1-4 alkyl;
  • Each R 15 is independently selected from hydrogen or fluorine.
  • the compound of formula (I) is selected from the following group:
  • Another aspect of the present invention provides a compound with the structure shown in the following formula, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate:
  • a second aspect of the present invention provides a pharmaceutically acceptable salt, the pharmaceutically acceptable salt being selected from the following group: potassium salt, sodium salt, magnesium salt, calcium salt, sulfate salt, hydrochloride salt , phosphate, sulfonate, or carbonate.
  • the third aspect of the present invention provides a pharmaceutical composition, the pharmaceutical composition comprising the compound described in the first aspect of the present invention, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated Derivatives, hydrates, solvates, and pharmaceutically acceptable carriers.
  • the fourth aspect of the present invention provides a compound as described in the first aspect of the present invention, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate Uses for the preparation of treatments related to KRAS Pharmaceutical compositions for diseases, disorders or conditions associated with G12D activity or expression.
  • the disease, disorder or condition is selected from the group consisting of: pancreatic cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, colorectal cancer, thyroid cancer, embryonic cancer Rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, liver cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, prostate cancer, glioblastoma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, Kidney cancer, skin cancer, lymphoma, gastric cancer, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly, eosinophilia multiplex, bone marrow cancer, etc. Solid and hematological tumors.
  • the inventor unexpectedly discovered a class of KRAS G12D inhibitors with novel structures, as well as their preparation methods and applications.
  • the compounds of the present invention can be applied in the treatment of various diseases related to the activity of the small GTPase. Based on the above findings, the inventor completed the present invention.
  • each chiral carbon atom can optionally be in R configuration or S configuration, or a mixture of R configuration and S configuration.
  • alkyl refers to a straight-chain (i.e., unbranched) or branched-chain saturated hydrocarbon radical containing only carbon atoms, or a combination of straight-chain and branched chains. .
  • the alkyl group contains 1-10 carbon atoms.
  • C 1-8 alkyl refers to an alkyl group containing 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or Similar groups.
  • alkenyl refers to a straight or branched, carbon chain radical having at least one carbon-carbon double bond. Alkenyl groups may be substituted or unsubstituted. When the number of carbon atoms in front of the alkenyl group is limited (such as C 2-8 ), it means that the alkenyl group contains 2-8 carbon atoms.
  • C 2-8 alkenyl refers to an alkenyl group containing 2 to 8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups group.
  • alkynyl refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond.
  • the alkynyl group may be linear or branched, or a combination thereof.
  • the alkynyl group contains 2-8 carbon atoms.
  • C 2-8 alkynyl refers to a straight or branched chain alkynyl group having 2 to 8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups.
  • cycloalkyl refers to a group having a saturated or partially saturated unit ring, bicyclic or polycyclic (fused, bridged or spiro) ring system .
  • a certain cycloalkyl group is preceded by a limited number of carbon atoms (such as C 3-10 ), it means that the cycloalkyl group contains 3-10 carbon atoms.
  • C 3-8 cycloalkyl refers to a saturated or partially unsaturated monocyclic or bicycloalkyl group with 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cycloalkyl, Pentyl, cycloheptyl, or similar groups.
  • Spirocycloalkyl refers to a bicyclic or polycyclic group that shares one carbon atom (called a spiro atom) between the single rings. These may contain one or more double bonds, but no ring has fully conjugated ⁇ electrons. system.
  • Condensed cycloalkyl refers to an all-carbon bicyclic or polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, in which one or more rings may contain one or more bicyclic bonds, but none of the rings has a fully conjugated ⁇ electron system.
  • Bridged cycloalkyl refers to an all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected. These may contain one or more double bonds, but no ring has a fully conjugated ⁇ electron system. . All the atoms contained in the cycloalkyl group are carbon atoms. The following are some examples of cycloalkyl groups. The present invention is not limited to the following cycloalkyl groups. base.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing pairs of adjacent carbon atoms) groups having a conjugated pi electron system, such as phenyl and naphthyl.
  • the aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but it cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of connection to the parent must be in a conjugated ⁇ electron system on the carbon atoms in the ring.
  • Aryl groups may be substituted or unsubstituted.
  • the following are some examples of aryl groups. The present invention is not limited to the following aryl groups.
  • Heteroaryl refers to an aromatic monocyclic or polycyclic group containing one to more heteroatoms (optionally selected from nitrogen, oxygen and sulfur), or a heterocyclic group (containing one to more heteroatoms optionally). (selected from nitrogen, oxygen and sulfur)) and an aryl group to form a polycyclic group, and the connection point is located on the aryl group. Heteroaryl groups may be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups. The present invention is not limited to the following heteroaryl groups.
  • Heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen or sulfur and the remaining ring atoms are carbon.
  • monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl.
  • Polycyclic heterocyclyl refers to heterocyclyl including spiro rings, fused rings and bridged rings.
  • Spirocyclic heterocyclyl refers to a polycyclic heterocyclic group in which each ring in the system shares one atom (called a spiro atom) with other rings in the system, in which one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon.
  • Condensed ring heterocyclyl refers to a polycyclic heterocyclyl in which each ring in the system shares an adjacent pair of atoms with other rings in the system. Ring group, one or more rings may contain one or more double bonds, but no ring has a fully conjugated ⁇ electron system, and one or more of the ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms for carbon.
  • “Bridged heterocyclyl” refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more double bonds, but no ring has a fully conjugated ⁇ electron system. , and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If there are both saturated rings and aromatic rings in the heterocyclyl group (for example, the saturated ring and the aromatic ring are fused together), the point of connection to the parent must be on the saturated ring. Note: When the point of connection to the parent is on the aromatic ring, it is called heteroaryl, not heterocyclyl. The following are some examples of heterocyclyl groups. The present invention is not limited to the following heterocyclyl groups.
  • halogen refers to F, Cl, Br and I, alone or as part of other substituents.
  • substituted means that one or more hydrogen atoms on a specified group are replaced by a specified substituent.
  • Specific substituents are the substituents described accordingly in the foregoing text, or the substituents appearing in each embodiment.
  • a certain optionally substituted group may have a substituent selected from a specific group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • a cyclic substituent, such as a heterocyclyl group can be linked to another ring, such as a cycloalkyl group, to form a spirobicyclic system, in which both rings have a common carbon atom.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are for example (but not limited to): C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3- to 12-membered heterocyclyl , Aryl group, heteroaryl group, halogen, hydroxyl group, carboxyl group (-COOH), C 1-8 aldehyde group, C 2-10 acyl group, C 2-10 ester group, amino group.
  • pharmaceutically acceptable salt refers to a salt suitable for contact with tissue of a subject (eg, a human) without causing undue side effects.
  • pharmaceutically acceptable salts of a certain compound of the present invention include salts of the compound of the present invention having an acidic group (for example, potassium salt, sodium salt, magnesium salt, calcium salt) or having a basic A salt of a compound of the present invention (eg, sulfate, hydrochloride, phosphate, nitrate, carbonate).
  • the invention provides a class of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if present), hydrates , pharmaceutically acceptable carriers or excipients for use in inhibiting KRAS G12D.
  • the compounds of the invention can be used as a KRAS G12D inhibitor.
  • the present invention is a single inhibitor of KRAS G12D, which can prevent, alleviate or cure diseases by regulating the activity of KRAS G12D.
  • the diseases referred to include pancreatic cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, colorectal cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, Liver cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, prostate cancer, glioblastoma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, acute Myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly, eosinophilic leukemia syndrome multiplex, bone marrow cancer and other solid tumor
  • compositions can be administered in vivo to mammals, such as men, women and animals, for the treatment of conditions, symptoms and diseases.
  • the composition may be: tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, and sterile injections. Sterile powder, etc.
  • pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate, mannitol, hydroxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin (increased), glycine, disintegrants (such as starch, croscarmellose sodium, complex silicates and polymer polyethylene glycol), granulation binders (such as polyvinylpyrrolidone, sucrose, gelatin and Arabic gum) and lubricants (such as magnesium stearate, glycerin and talc).
  • disintegrants such as starch, croscarmellose sodium, complex silicates and polymer polyethylene glycol
  • granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and Arabic gum
  • lubricants such as magnesium stearate, glycerin and talc
  • the pharmaceutical composition is in a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders.
  • the amount of the compound or pharmaceutical composition administered to the patient is not fixed, but is usually administered in a pharmaceutically effective amount.
  • the actual amount of the compound administered can be determined by the physician based on the actual situation, including the disease to be treated, the route of administration selected, the actual compound administered, the individual condition of the patient, etc.
  • the dosage of a compound of the present invention will depend on the specific use of the treatment, the mode of administration, the patient's condition, and the judgment of the physician.
  • the proportion or concentration of the compound of the present invention in the pharmaceutical composition depends on various factors, including dosage, physical and chemical properties, route of administration, etc.
  • compositions and methods of administration are provided.
  • the compound of the present invention has excellent inhibitory activity against KRAS G12D
  • the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention are the main active
  • Pharmaceutical compositions of ingredients can be used to treat, prevent and alleviate diseases related to KRAS G12D activity or expression.
  • the pharmaceutical composition of the present invention contains a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier within a safe and effective amount.
  • the “safe and effective dose” refers to the amount of compound that is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/dose, more preferably, it contains 5-200 mg of the compound of the present invention/dose.
  • the "dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility” here means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • the administration mode of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration modes include (but do not Limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) Binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) Humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarder, such as paraffin; (f) Absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl mono
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules may be prepared using coatings and shell materials such as enteric casings and other materials well known in the art. They may contain opacifying agents and the release of the active compound or compounds in such compositions may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxy substances. If necessary, the active compounds can also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils,
  • compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions may contain, in addition to the active compound, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.
  • compositions for parenteral injection may contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage when administered is a pharmaceutically effective dosage.
  • a mammal such as a human
  • the daily dose is usually 1 to 2000 mg, preferably 5 to 500 mg.
  • the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.
  • KRAS G12D inhibitor provides a structurally novel KRAS G12D inhibitor, its preparation and application.
  • the inhibitor can inhibit the activity of KRAS G12D at very low concentrations.
  • reaction solution was quenched with saturated aqueous ammonium chloride solution (5mL), then concentrated hydrochloric acid (3mL) was added, stirred at room temperature for 1 hour, water (30mL) was added, and extracted three times with ethyl acetate (30mL ⁇ 3), and the combined organic layers were Wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • the crude product obtained is separated and purified by silica gel column chromatography to obtain compound 1c (188 mg, 18%) as a light yellow oil.
  • Lithium aluminum hydride (58 mg, 0.77 mmol) was dissolved in tetrahydrofuran (1 mL), and a solution of compound 1c (188 mg, 0.77 mmol) in tetrahydrofuran (2 mL) was added under ice bath and nitrogen atmosphere. The reaction solution was heated and stirred at 65°C for 3 hours. Water (0.06mL), 15% sodium hydroxide (0.06mL), water (0.18 mL), stirred at room temperature for 15 minutes, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and separated and purified by silica gel column chromatography to obtain compound 1d (38 mg, 26%) as a light yellow oil.
  • Compound 1-P1 and compound 1-P2 one of them is compound 1S and the other is compound 1R.
  • Example 3 Preparation of compounds 2S or 2R and 2S-Na or 2R-Na
  • the first isomer 1-P1 (single chiral isomer, 1S or 1R, 552 mg, 0.88 mmol) obtained by chiral resolution in Example 1 was dissolved in methanol (6 mL), and ditert dicarbonate was added dropwise Butyl ester (201 mg, 0.92 mmol), the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and separated and purified by silica gel column chromatography to obtain compound 2bS or 2bR (616 mg, yield 96%). MS m/z 731.4[M+H] + .
  • the second isomer 1-P2 (single chiral isomer, 1R or 1S, 200 mg, 0.32 mmol) obtained by chiral resolution in Example 1 was dissolved in methanol (3 mL), and ditert dicarbonate was added dropwise Butyl ester (73 mg, 0.33 mmol), the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and separated and purified by silica gel column chromatography to obtain compound 2bR or 2bS (211 mg, yield 91%). MS m/z 731.4[M+H] + .
  • the first isomer 1-P1 (single chiral isomer, 1S or 1R, 200 mg, 0.32 mmol) obtained by chiral resolution in Example 1 was dissolved in methanol (3 mL), and ditert dicarbonate was added dropwise Butyl ester (73 mg, 0.33 mmol), the reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography to obtain compound 2bS or 2bR (199 mg, yield 86%). MS m/z 731.4[M+H] + .
  • Compound activity was measured for AGS (human gastric cancer cell line, KRAS G12D mutation), GP2D (human colon cancer cell line, KRAS G12D mutation), HPAC (human pancreatic cancer cell line, KRAS G12D mutation) and AsPC1 (human pancreatic cancer cell line, KRAS G12D mutation) 3D cell proliferation inhibition was expressed using the Cell Titer-Glo (CTG) method.
  • CCG Cell Titer-Glo
  • Inhibition% (Ave_H-Sample)/(Ave_H-Ave_L) x 100%.
  • Ave_H represents the average reading value of the DMSO well
  • Sample represents the average reading value of the compound well
  • Ave_L represents the average reading value of the 10 ⁇ M positive control group.
  • the activities of some representative compounds are shown in Table 1.

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Abstract

本发明提供了作为KRAS G12D抑制剂的化合物，具体地，本发明提供了一种如下式(I)所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物。所述的化合物可以用于治疗或预防与KRAS G12D的活性或表达量相关的疾病或病症。

Description

作为KRAS G12D抑制剂的多环化合物 技术领域
本发明涉及药物化学领域；具体地说，本发明涉及一类新型含有三环杂芳基的衍生物，其合成方法及其作为一种KRAS G12D抑制剂在制备药物用于治疗肿瘤等相关多种疾病中的应用。
背景技术
KRAS(Kirsten Rat Sarcoma Viral Oncogene Homolog)是一种小GTP酶，属于RAS家族成员。目前已知的RAS基因有三种，HRAS、NRAS和KRAS。RAS蛋白在癌症发生发展中起着重要的作用，20％-30％的人类肿瘤中都存在RAS突变，其中KRAS突变频率最高，多见于肺癌、胰腺癌和结肠癌等。
KRAS蛋白包含188个氨基酸残基，有多个功能基序，包括核苷酸结合区、转换I区和转换II区、核苷酸交换因子(GEF)结合区域、GTP酶激活蛋白(GAP)结合区域和效应蛋白结合区域等。正常情况下，KRAS的活性受多种上游信号因子的调控，如受体酪氨酸激酶、整合素、G蛋白偶联受体等。KRAS作为细胞中的一种分子开关，通过GTP或GDP结合状态的转换，分别表现出激活(开)或失活(关)的状态，将上游接收到的信号传递给下游的效应蛋白。KRAS蛋白本身有比较慢的核苷酸交换速率和较弱的GTP水解功能。接收上游刺激信号后，在SOS1(Son of Sevenless 1)等鸟嘌呤核苷酸交换因子的辅助下，KRAS蛋白释放GDP，结合GTP。GTP结合的RAS蛋白处于激活状态，招募下游效应蛋白，激活Raf-MEK-ERK和PI3K-AKT-mTOR等信号通路，促进细胞的生长、增殖、存活、代谢以及血管生成等。GTP酶激活蛋白GAP和KRAS结合后，会显著促进KRAS的GTP水解功能，GTP水解为GDP，GDP结合状态的KRAS转变为失活状态，分子开关关闭。当RAS发生突变时，其固有或GAP诱导的GTP酶活性受到抑制，RAS一直处于GTP结合状态，分子开关持续开放，进而导致下游的多种信号通路处于持续性激活状态，细胞异常增殖和生长。
在胰腺癌中，高达90％左右的患者都有KRAS突变，其中约40％的点突变为KRAS G12D突变。另外，约13.3％的结直肠癌，10％左右的直肠癌，4％左右的非小细胞肺癌和1.7％左右的小细胞肺癌患者中都有KRAS G12D突变。
由于在肿瘤生成中发挥的重要作用和其高发的突变频率，KRAS G12D成为一个非常有吸引力的抗肿瘤靶点。目前为止，市场上还没有任何有效的KRAS G12D抑制剂药物。基于以上背景，我们开发了一类结构新颖的KRAS G12D抑制剂。
发明内容
本发明的目的是提供一类新型的KRAS G12D抑制剂。
本发明的第一方面，提供了一种如下式(I)所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物：
式(I)中：
结构片段选自式(Ia)、(Ib)、(Ic)、或(Id)：
其中，和分别表示上述结构片段与式(I)中相应位置上的基团的连接位点；表示上述结构片段与式(I)中的连接位点；
Ar选自芳基或杂芳基；
各个R11各自独立地选自氢、卤素、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C2-4炔基、C3-6环烷基、或CN；
各个R12各自独立地选自氢、卤素、C1-4烷基、C1-4卤代烷基、-CH2OC(O)NRhRh、C2-4烯基、C2-4炔基、C3-8环烷基、3-至8-元杂环基、CN、ORh、SRh、NRhRh、-(CRaRb)q-ORh、-(CRaRb)q-NRhRh；其中，各个Rh各自独立为氢、C1-4烷基、或C1-4卤代烷基；Ra和Rb各自独立地选自氢、卤素、或C1-4烷基；各个q各自独立地选自0、1、2、或3；
各个R13各自独立地选自氢、卤素、C1-4烷基、＝O、羟基、或CN；
各个R14各自独立地选自氢、卤素、C1-4烷基、C1-4卤代烷基、羟基、C1-4烷氧基、C1-4卤代烷氧基、C2-4烯基、C2-4卤代烯基、C2-4炔基、C2-4卤代炔基、C3-6环烷基、3-至6-元杂环基、C3-6环烷基-O-、3-至6-元杂环基-O-、NRhRh、CN、SRh、-OC(O)Rk、-O-P(O)(ORm)2、-O-CH(Rn)-O-P(O)(ORm)2；其中，Rk选自C1-4烷基，其中烷基任选地被一个或多个选自下组的基团取代：羟基、C1-4烷氧基、NRhRh、C(O)OH、C(O)OC1-2烷基、或CN；Rm选自氢、C1-4烷基、或金属离子形成相应的盐；Rn选自氢或C1-4烷基；Rh的定义如上所述；
各个R15各自独立地选自氢、卤素、或C1-4烷基；
k选自0、1、或2；
m选自0、1、2、或3；
n选自0、1、或2；
p选自0、1、2、3、4、或5；
“*”表示手性中心；
其中，各个上述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独 立地被1-3个各自独立地选自下组的取代基取代：卤素、C1-4烷基、C1-4卤代烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO2、ORh、SRh、NRhRh、C(O)Rt、C(O)ORh、C(O)NRhRh、NRhC(O)Rt、NRhS(O)2Rt、或S(O)2Rt，前提条件是所形成的化学结构是稳定的和有意义的；其中，Rt为C1-4烷基、C2-4烯基、C2-4炔基、C3-8环烷基、4-至8-元杂环基、芳基、或杂芳基；各个Rh各自独立为氢、C1-4烷基、或C1-4卤代烷基；或两个Rh与其连接的氮原子一起形成3-至-8元杂环基，此杂环基含有1或2个N原子以及0或1个选自O、S的杂原子；
除非特别说明，上述的芳基为含有6-12个碳原子的芳香基团；杂芳基为5-至15-元(优选为5-至12-元)杂芳香基团。
在另一优选例中，式(I)为式(II)，
X选自N或CR11；
各个R11各自独立地选自氢、卤素、C1-4烷基、或CN；
各个R13各自独立地选自氢、卤素、C1-4烷基、＝O、羟基、或CN；
各个R14各自独立地选自氢、卤素、C1-4烷基、C1-4卤代烷基、羟基、C1-4烷氧基、C1-4卤代烷氧基、C2-4烯基、C2-4卤代烯基、C2-4炔基、C2-4卤代炔基、NRhRh、CN、SRh、-OC(O)Rk、-O-P(O)(ORm)2、-O-CH(Rn)-O-P(O)(ORm)2；其中，各个Rh各自独立为氢、C1-4烷基、或C1-4卤代烷基；Rk选自C1-4烷基，其中烷基任选地被一个或多个选自下组的基团取代：羟基、C1-4烷氧基、NRhRh、C(O)OH、C(O)OC1-2烷基、或CN；Rm选自氢、C1-4烷基、或金属离子形成相应的盐；Rn选自氢或C1-4烷基；
各个R15各自独立地选自氢或氟；
k选自0、1、或2；
m选自0、1、或2；
p选自0、1、2、3、4、或5；
“*”表示手性中心。
在另一优选例中，式(I)为式(II-A)，
R11、R13、R14、X、k、m、p的定义如上文中所述。
在另一优选例中，式(I)为式(III)，
R11、R13、R14、k、p的定义如上文中所述。
在另一优选例中，式(I)为式(IV)，
R11、R13、R14、k、m、p的定义如上文中所述。
在另一优选例中，式(I)为式(V)，
Ar选自芳基或杂芳基；
R11、R12、R13、R14、R15、k、m、n、p的定义如上文中所述。
在另一优选例中，式(I)为式(VI)，
Y选自N或CR14；
R11、R12、R13、R14、R15、k、m、n、p的定义如上文中所述。
在另一优选例中，式(I)为式(VII)，
各个R14各自独立地选自氢、卤素、C1-4烷基、C1-4卤代烷基、羟基、C1-4烷氧基、C1-4卤代烷氧基、C2-4烯基、C2-4卤代烯基、C2-4炔基、C2-4卤代炔基、C3-6环烷基、3-至6-元杂环基、C3-6环烷基-O-、3-至6-元杂环基-O-、NRhRh、CN、SRh 2；其中，各个Rh各自独立为氢、C1- 4烷基、或C1-4卤代烷基；
p选自0、1、2、3、4、或5。
在另一优选例中，式(I)为式(VIII)，
Ar选自芳基或杂芳基；
R11、R12、R13、R14、R15、k、m、n、p的定义如上文中所述。
在另一优选例中，式(I)为式(IX)，
Ar选自苯环和萘环；
各个R14各自独立地选自氢、卤素、C1-4烷基、C1-4卤代烷基、羟基、C1-4烷氧基、C1-4卤代烷氧基、C2-4烯基、C2-4卤代烯基、C2-4炔基、C2-4卤代炔基、NRhRh、CN、SRh、-OC(O)Rk、-O-P(O)(ORm)2、-O-CH(Rn)-O-P(O)(ORm)2；其中，各个Rh各自独立为氢、C1-4烷基、或C1-4卤代烷基；Rk选自C1-4烷基，其中烷基任选地被一个或多个选自下组的基团取代：羟基、C1-4烷氧基、NRhRh、C(O)OH、C(O)OC1-2烷基、或CN；Rm选自氢、C1-4烷基、或金属离子形成相应的盐；Rn选自氢或C1-4烷基；
p选自0、1、2、3、4、或5。
在另一优选例中，式(I)为式(X)，
R11选自氢、氟、氯、C1-4烷基、或CN；
R14’选自氢、氟、氯；
R14”选自羟基、-O-P(O)(ORm)2、或-O-CH(Rn)-O-P(O)(ORm)2；其中，各个Rm各自独立地选自氢、C1-4烷基、或金属离子形成相应的盐；Rn选自氢或C1-4烷基；
各个R15各自独立地选自氢或氟。
在另一优选例中，所述的式(I)化合物选自下组：


上述结构式中“*”表示手性中心，可以任选地为R构型或S构型，或R构型和S构型的混合物。
本发明的另一方面，提供了一种如下式所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物：
本发明的第二方面，提供了一种药学上可接受的盐，所述的药学上可接受的盐选自下组：钾盐、钠盐、镁盐、钙盐、硫酸盐、盐酸盐、磷酸盐、磺酸盐，或碳酸盐。
本发明的第三方面，提供了一种药物组合物，所述药物组合物包含本发明第一方面所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，以及药学上可接受的载体。
本发明的第四方面，提供了一种如本发明第一方面所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，其用于制备治疗与KRAS  G12D活性或表达量相关的疾病，病症或病状的药物组合物。
在另一优选例中，所述疾病，病症或病状选自下组：胰腺癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、结肠癌、结直肠癌、甲状腺癌、胚胎性横纹肌肉瘤、皮肤颗粒细胞肿瘤、黑色素瘤、肝癌、直肠癌、膀胱癌、咽喉癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、皮肤癌、淋巴瘤、胃癌、急性髓系白血病、骨髓纤维化、B细胞淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征多发性、骨髓癌等各种实体瘤和血液瘤。
具体实施方式
本发明人经过长期而深入的研究，意外地发现了一类结构新颖的KRAS G12D抑制剂，以及它们的制备方法和应用。本发明化合物可以应用于与所述小GTP酶的活性相关的各种疾病的治疗。基于上述发现，发明人完成了本发明。
术语
除特别说明之处，本文中提到的“或”具有与“和/或”相同的意义(指“或”以及“和”)。
除特别说明之处，本发明的所有化合物之中，各手性碳原子(手性中心)可以任选地为R构型或S构型，或R构型和S构型的混合物。
如本文所用，在单独或作为其他取代基一部分时，术语“烷基”指只含碳原子的直链(即，无支链)或支链饱和烃基，或直链和支链组合的基团。当烷基前具有碳原子数限定(如C1-10)时，指所述的烷基含有1-10个碳原子。例如，C1-8烷基指含有1-8个碳原子的烷基，包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“烯基”是指直链或支链，具有至少一个碳-碳双键的碳链基团。烯基可以是取代的或未取代的。当烯基前具有碳原子数限定(如C2-8)时，指所述的烯基含有2-8个碳原子。例如，C2-8烯基指含有2-8个碳原子烯基，包括乙烯基、丙烯基、1,2-丁烯基、2,3-丁烯基、丁二烯基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“炔基”是指具有至少一个碳-碳三键的脂肪族碳氢基团。所述的炔基可以是直链或支链的，或其组合。当炔基前具有碳原子数限定(如C2-8炔基)时，指所述的炔基含有2-8个碳原子。例如，术语“C2-8炔基”指具有2-8个碳原子的直链或支链炔基，包括乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、仲丁炔基、叔丁炔基、或类似基团。
如本文所用，在单独或作为其他取代基一部分时，术语“环烷基”指具有饱和的或部分饱和的单元环，二环或多环(稠环、桥环或螺环)环系基团。当某个环烷基前具有碳原子数限定(如C3-10)时，指所述的环烷基含有3-10个碳原子。在一些优选实施例中，术语“C3-8环烷基”指具有3-8个碳原子的饱和或部分不饱和的单环或二环烷基，包括环丙基、环丁基、环戊基、环庚基、或类似基团。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的二环或多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳二环或多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。所述环烷基所含原子全部为碳原子。如下是环烷基的一些例子，本发明并不仅局限下述的环烷 基。
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。“芳基”指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，例如苯基和萘基。所述芳基环可以稠合于其它环状基团(包括饱和和不饱和环)，但不能含有杂原子如氮，氧，或硫，同时连接母体的点必须在具有共轭的π电子体系的环上的碳原子上。芳基可以是取代的或未取代的。如下是芳基的一些例子，本发明并不仅局限下述的芳基。
“杂芳基”指包含一个到多个杂原子(任选自氮、氧和硫)的具有芳香性的单环或多环基团，或者包含杂环基(含一个到多个杂原子任选自氮、氧和硫)与芳基稠合形成的多环基团，且连接位点位于芳基上。杂芳基可以是任选取代的或未取代的。如下是杂芳基的一些例子，本发明并不仅局限下述的杂芳基。
“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基。多环杂环基指包括螺环、稠环和桥环的杂环基。“螺环杂环基”指系统中的每个环与体系中的其他环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。“稠环杂环基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂 环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，而且其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。“桥环杂环基”指任意两个环共用两个不直接连接的原子的多环杂环基团，这些可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，而且其中一个或多个环原子选自氮、氧或硫，其余环原子为碳。如果杂环基里同时有饱和环和芳环存在(比如说饱和环和芳环稠合在一起)，连接到母体的点一定是在饱和的环上。注：当连接到母体的点在芳环上时，称为杂芳基，不称为杂环基。如下是杂环基的一些例子，本发明并不仅局限下述的杂环基。
如本文所用，在单独或作为其他取代基一部分时，术语“卤素”指F、Cl、Br和I。
如本文所用，术语“取代”(在有或无“任意地”修饰时)指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个任意取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。环状取代基，例如杂环基，可以与另一个环相连，例如环烷基，从而形成螺二环系，即两个环具有一个共用碳原子。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：C1-8烷基、C2-8烯基、C2-8炔基、C3- 8环烷基、3-至12-元杂环基，芳基、杂芳基、卤素、羟基、羧基(-COOH)、C1-8醛基、C2-10酰基、C2-10酯基、氨基。
为了方便以及符合常规理解，术语“任意取代”或“任选取代”只适用于能够被取代基所取代的位点，而不包括那些化学上不能实现的取代。
如本文所用，除非特别说明，术语“药学上可接受的盐”指适合与对象(例如，人)的组织接触，而不会产生不适度的副作用的盐。在一些实施例中，本发明的某一化合物的药学上可接受的盐包括具有酸性基团的本发明的化合物的盐(例如，钾盐，钠盐，镁盐，钙盐)或具有碱性基团的本发明的化合物的盐(例如，硫酸盐，盐酸盐，磷酸盐，硝酸盐，碳酸盐)。
用途：
本发明提供了一类式(I)化合物，或它们的氘代衍生物、它们的盐、异构体(对映异构体或非对映异构体，如果存在的情况下)、水合物、可药用载体或赋形剂用于抑制KRAS G12D的用途。
本发明化合物可用作一种KRAS G12D抑制剂。
本发明是KRAS G12D的单一抑制剂，通过调节KRAS G12D的活性达到预防、缓解或治愈疾病的目的。所指疾病包括胰腺癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、结肠癌、结直肠癌、甲状腺癌、胚胎性横纹肌肉瘤、皮肤颗粒细胞肿瘤、黑色素瘤、 肝癌、直肠癌、膀胱癌、咽喉癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、皮肤癌、淋巴瘤、胃癌、急性髓系白血病、骨髓纤维化、B细胞淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征多发性、骨髓癌等各种实体瘤和血液瘤。
可将本发明化合物及其氘代衍生物，以及药学上可接受的盐或其异构体(如果存在的情况下)或其水合物和/或组合物与药学上可接受的赋形剂或载体配制在一起，得到的组合物可在体内给予哺乳动物，例如男人、妇女和动物，用于治疗病症、症状和疾病。组合物可以是：片剂、丸剂、混悬剂、溶液剂、乳剂、胶囊、气雾剂、无菌注射液。无菌粉末等。一些实施例中，药学上可接受的赋形剂包括微晶纤维素、乳糖、柠檬酸钠、碳酸钙、磷酸氢钙、甘露醇、羟丙基-β-环糊精、β-环糊精(增加)、甘氨酸、崩解剂(如淀粉、交联羧甲基纤维素钠、复合硅酸盐和高分子聚乙二醇)，造粒粘合剂(如聚乙烯吡咯烷酮、蔗糖、明胶和阿拉伯胶)和润滑剂(如硬脂酸镁、甘油和滑石粉)。在优选的实施方式中，所述药物组合物是适于口服的剂型，包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂。向患者施用本发明化合物或药物组合物的量不固定，通常按药用有效量给药。同时，实际给予的化合物的量可由医师根据实际情况决定，包括治疗的病症、选择的给药途径、给予的实际化合物、患者的个体情况等。本发明化合物的剂量取决于治疗的具体用途、给药方式、患者状态、医师判断。本发明化合物在药物组合物中的比例或浓度取决于多种因素，包括剂量、理化性质、给药途径等。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。
药物组合物和施用方法
由于本发明化合物具有优异的对KRAS G12D的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与KRAS G12D活性或表达量相关的疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有5-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不 限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选5～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
1.提供了一种如式I所示的化合物。
2.提供了一种结构新颖的KRAS G12D抑制剂，及其制备和应用，所述的抑制剂在极低浓度下即可抑制KRAS G12D的活性。
3.提供了一类治疗与KRAS G12D活性相关疾病的药物组合物。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例
实施例1:化合物1、化合物1S、和化合物1R的制备
化合物1b采用文献(European Journal of Organic Chemistry,2015,vol.2015,#4,p.871-875)中的方法合成。将叔丁醇钾(851mg，7.58mmol)溶于DMF(10mL)中，氮气氛围下冷却至-50℃，滴加化合物1a(890mg，4.21mmol，外消旋体)和化合物1b(733mg，3.79mmol)的DMF(5mL)溶液，反应液缓慢升温至室温搅拌0.5小时。将反应液以饱和氯化铵水溶液(5mL)淬灭，再加入浓盐酸(3mL)，室温搅拌1小时，加水(30mL)，以乙酸乙酯(30mL×3)萃取三次，合并的有机层以饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经硅胶柱层析分离纯化得淡黄色油状物化合物1c(188mg，18％)。1H NMR(500MHz,CDCl3)δ4.39-4.33(m,1H),4.23(q,J＝7.1Hz,2H),3.78-3.72(m,1H),3.16-3.11(m,1H),2.85-2.76(m,1H),2.66-2.60(m,1H),2.53-2.46(m,1H),2.43-2.36(m,1H),2.19-2.11(m,1H),1.29(t,J＝7.1Hz,3H)。MS m/z 246.3[M+H]+
将氢化铝锂(58mg,0.77mmol)溶于四氢呋喃(1mL)中，冰浴、氮气氛围下加入化合物1c(188mg,0.77mmol)的四氢呋喃(2mL)溶液。反应液65℃加热搅拌3小时。反应液冰浴下依次加入水(0.06mL)，15％氢氧化钠(0.06mL)，水(0.18 mL)，室温搅拌15分钟，再以无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶柱层析分离纯化得淡黄色油状物化合物1d(38mg,26％)。
化合物1e参照专利WO2021041671中的方法合成。将化合物1e(80mg,0.19mmol)，化合物1d(38mg，0.20mmol)溶于二氧六环(1mL)中，再加入二异丙基乙基胺(72mg,0.56mmol)，反应液于氮气氛围下90℃加热搅拌24小时。将反应液减压浓缩，经硅胶柱层析分离纯化得类白色固体化合物1f(33mg,30％)。MS m/z 581.5,583.4[M+H]+。
将化合物1f(307mg，0.53mmol)、化合物1g(406mg，0.79mmol，参照专利WO2021041671中的方法合成或购买而得)、磷酸钾(337mg，1.59mmol)和甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(38mg，0.05mmol)加入反应瓶中，置换氮气3次。然后加入1,4-二氧六环(5mL)、水(1mL)。反应混合液在氮气保护下100℃搅拌2小时。冷却至室温，加水。混合液经乙酸乙酯萃取(3×30mL)。合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤后减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝25:1)得到黄色油状产物1h(486mg，收率99％)。MS m/z 931.9[M+H]+。
将化合物1h(486mg，0.52mmol)溶于乙腈(10mL)中，然后加入氯化氢的1,4-二氧六环溶液(4M，3mL)。反应混合液在室温下搅拌1小时。待反应完毕，反应液减压浓缩得到黄色固体产物1i(411mg，收率100％)。MS m/z 787.7[M+H]+。
将上一步得到的化合物1i(411mg，0.52mmol)溶于DMF(10mL)中，再加入氟化铯(790mg，5.20mmol)，反应混合物室温搅拌过夜。反应混合物加水，经乙酸乙酯萃取。合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤后减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝10:1)得到黄色固体化合物1(174mg，收率53％)。化合物1采用HPLC方法使用手性柱(CHIRALPAK AD-H,ADH0CE-XG136,0.46cm I.D.×25cm L；Hexane/EtOH/DEA＝60/40/0.1(V/V/V)；1.0ml/min)拆分得到第一个异构体为化合物1-P1(rt＝4.93min，41mg)和第二个异构体化合物1-P2(rt＝6.18min，43mg)。
化合物1-P1和化合物1-P2：其中一个为化合物1S，另一个为化合物1R。
化合物1-P1：1H NMR(500MHz,CD3OD)δ9.02(s,1H),7.86(dd,J＝9.1,5.7Hz,1H),7.35(d,J＝2.5Hz,1H),7.32(t,J＝8.9Hz,1H),7.20(d,J＝2.5Hz,1H),4.73-4.61(m,2H),4.42-4.25(m,2H),3.90-3.75(m,5H),3.47(d,J＝14.0Hz,1H),3.36(s,1H),3.21-3.15(m,1H),2.84-2.71(m,2H),2.58-2.50(m,1H),2.18-2.08(m,1H),2.06-1.85(m,7H)ppm。MS m/z 631.2[M+H]+。
化合物1-P2：1H NMR(500MHz,CD3OD)δ9.01(s,1H),7.85(dd,J＝9.1,5.7Hz,1H),7.34(d,J＝2.5Hz,1H),7.32(t,J＝9.0Hz,1H),7.20(d,J＝2.5Hz,1H),4.71-4.59(m,2H),4.43-4.23(m,2H),3.87-3.72(m,5H),3.45(d,J＝14.0Hz,1H),3.35(s,1H),3.19-3.13(m,1H),2.85-2.69(m,2H),2.56-2.47(m,1H),2.16-2.07(m,1H),2.05-1.83(m,7H)ppm。MS m/z 631.2[M+H]+。
实施例2:化合物2和2-Na的制备
将化合物1h(100mg,0.11mmol)溶于二氯甲烷(3mL)中，滴加氯化氢的1,4-二氧六环溶液(4M，0.1mL)。反应液室温搅拌2小时。将反应液减压浓缩，所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1)得化合物2a(67mg,收率71％)。MS m/z 887.1[M+H]+。
将化合物2a(39mg,0.04mmol)溶于N,N-二甲基甲酰胺(1mL)中，再加入氟化铯(67mg,0.44mmol)，反应混合物室温搅拌过夜。反应混合物加水，经乙酸乙酯萃取。合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤后减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝10:1)得到黄色固体化合物2b(23mg，收率73％)。MS m/z 731.3[M+H]+。
将化合物2b(10mg,0.014mmol)、N,N-二异丙基乙胺(6mg,0.05mmol)溶于乙腈(2mL)中，冰浴下滴加三氯氧磷(3mg,0.02mmol)。反应液冰浴搅拌10分钟，再加入饱和碳酸氢钠水溶液(0.5mL)，室温搅拌1小时。反应混合物加水，经乙酸乙酯萃取。合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤后减压浓缩得到黄色固体化合物2c(10mg，收率91％)。MS m/z 811.3[M+H]+。
将化合物2c(10mg,0.012mmol)溶于乙腈(2mL)中，滴加氯化氢的1,4-二氧六环溶液(4M，0.5mL)。反应液室温搅拌3小时，减压浓缩。所得粗品经制备型薄层板(二氯甲烷:甲醇＝10:1)分离纯化得到黄色固体化合物2(4mg，收率45％)。MS m/z 711.1[M+H]+。将化合物2(4mg,0.005mmol)溶于乙腈(1mL)，加入氢氧化钠(0.4mg,0.01mmol)水溶液(0.5mL)。反应混合物经冻干得黄色固体化合物2的二钠盐2-Na(4mg，收率100％)。1H NMR(500MHz,CD3OD)δ9.00(s,1H),8.07(d,J＝2.0Hz,1H),7.97(dd,J＝9.1,5.8Hz,1H),7.53(d,J＝2.0Hz,1H),7.33(t,J＝8.9 Hz,1H),4.64–4.56(m,2H),4.36(dd,J＝10.7,6.7Hz,1H),4.29–4.23(m,1H),3.82–3.77(m,1H),3.74–3.62(m,4H),3.44–3.40(m,1H),3.17–3.11(m,1H),2.84–2.76(m,1H),2.73–2.66(m,1H),2.54–2.48(m,1H),2.15–2.10(m,1H),2.04–1.79(m,7H)。MS m/z 711.1[M+H]+。
化合物2(外消旋体)经手性拆分可得到化合物2S和化合物2R。
实施例3:化合物2S或2R和2S-Na或2R-Na的制备
将实施例1通过手性拆分得到的第一个异构体1-P1(单一手性异构体，1S或1R，552mg,0.88mmol)溶于甲醇(6mL)，滴加二碳酸二叔丁酯(201mg,0.92mmol),反应液在室温下搅拌1小时。将反应液减压浓缩，经硅胶柱层析分离纯化得化合物2bS或2bR(616mg,收率96％)。MS m/z 731.4[M+H]+。
将化合物2bS或2bR(462mg,0.63mmol)、N,N-二异丙基乙胺(244mg,1.89mmol)溶于乙腈(5mL)中，冰浴下缓慢滴加三氯氧磷(145mg,0.95mmol)。反应液在冰浴继续搅拌0.5小时，再加入饱和碳酸氢钠水溶液(3mL)淬灭，室温搅拌1小时。向反应体系中加水，经乙酸乙酯萃取。合并的有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤减压浓缩得到粗品黄色固体化合物2cS或2cR(455mg，收率89％)。MS m/z811.3[M+H]+。
将化合物2cS或2cR(455mg,0.56mmol)溶于乙腈(5mL)中，缓慢滴加氯化氢的1,4-二氧六环溶液(4M，1mL)。反应液在室温下继续搅拌3小时，减压浓缩。所得粗品经反相制备色谱分离纯化得到黄色固体化合物2S或2R(156mg，收率39％)。MS m/z 711.1[M+H]+。
将化合物2S或2R(156mg,0.22mmol)溶于乙腈(3mL)，加入氢氧化钠(17.6mg,0.44mmol)水溶液(5mL)。反应混合物经冻干得黄色固体化合物2S-Na或2R-Na(166mg，收率100％)。1H NMR(500MHz,CD3OD)δ9.00(s,1H),8.07(d,J＝2.3Hz,1H),7.97(dd,J＝9.2,5.8Hz,1H),7.53(d,J＝2.3Hz,1H),7.32(t,J＝8.9Hz,1H),4.64–4.56(m,2H),4.36(dd,J＝10.6,7.1Hz,1H),4.28–4.23(m,1H),3.81–3.76(m,1H),3.74–3.63(m,4H),3.43–3.39(m,1H),3.17–3.11(m,1H),2.82–2.76(m,1H),2.72–2.65(m,1H),2.52–2.47(m,1H),2.14–2.10(m,1H),2.00–1.78(m,7H)。
实施例4:化合物3R或3S和3R-Na或3S-Na的制备
将实施例1通过手性拆分得到的第二个异构体1-P2(单一手性异构体，1R或1S，200mg,0.32mmol)溶于甲醇(3mL)，滴加二碳酸二叔丁酯(73mg,0.33mmol)，反应液室温搅拌1小时。将反应液减压浓缩，经硅胶柱层析分离纯化得化合物2bR或2bS(211mg,收率91％)。MS m/z 731.4[M+H]+。
将化合物2bR或2bS(211mg,0.29mmol)、碳酸铯(307mg,0.58mmol)溶于N,N-二甲基甲酰胺(3mL)，然后缓慢滴加二叔丁基氯甲基磷酸酯(113mg,0.43mmol)。混合体系在室温下搅拌过夜。反应混合物过滤，滤液减压浓缩，所得粗品经硅胶柱层析分离纯化得化合物3aR或3aS(271mg，收率98％)。MS m/z 953.4[M+H]+。
将化合物3aR或3aS(270mg,0.28mmol)溶于二氯甲烷(3mL)中，缓慢滴加三氟乙酸(1mL)。反应液室温下搅拌3小时。将反应液减压浓缩，所得粗品经反相制备色谱纯化得化合物3R或3S(137mg，收率65％)。MS m/z 741.3[M+H]+。
将化合物3R或3S(137mg，0.19mmol)溶于水(4mL)，加入氢氧化钠(14.8mg,0.37mmol)，室温搅拌0.5小时，反应液浓缩冻干后得化合物3R-Na或3S-Na(141mg，收率97％)。1H NMR(500MHz,CD3OD)δ9.00(s,1H),8.03(dd,J＝9.1,5.7Hz,1H),7.86(d,J＝2.5Hz,1H),7.41–7.34(m,2H),5.71(d,J＝9.5Hz,2H),4.63–4.56(m,2H),4.38–4.32(m,1H),4.29–4.23(m,1H),3.78(d,J＝13.7Hz,1H),3.75–3.63(m,4H),3.44–3.39(m,1H),3.35(s,1H),3.17–3.11(m,1H),2.82–2.77(m,1H),2.72–2.66(m,1H),2.53–2.48(m,1H),2.15–2.10(m,1H),2.01–1.78(m,7H)。
实施例5:化合物3S或3R和3S-Na或3R-Na的制备
将实施例1通过手性拆分得到的第一个异构体1-P1(单一手性异构体，1S或1R，200mg,0.32mmol)溶于甲醇(3mL)，滴加二碳酸二叔丁酯(73mg,0.33mmol)，反应液室温搅拌1小时。将反应液减压浓缩，所得粗品经硅胶柱层析分离纯化得化合物2bS或2bR(199mg,收率86％)。MS m/z 731.4[M+H]+。
将化合物2bS或2bR(35mg,0.05mmol)、碳酸铯(33mg,0.10mmol)溶于N,N-二甲基甲酰胺(1mL)，缓慢滴加二叔丁基氯甲基磷酸酯(19mg,0.08mmol)，混合体系在室温下搅拌过夜。将反应混合物过滤，滤液减压浓缩，所得粗品经硅胶柱层析分离纯化得化合物3bS或3bR(21mg，收率46％)。MS m/z 953.4[M+H]+。
将化合物3bS或3bR(20mg,0.02mmol)溶于二氯甲烷(1mL)，缓慢滴加三氟乙酸(0.5mL)，反应液室温搅拌3小时。将反应液减压浓缩，所得粗品经反相制备色谱纯化得化合物3S或3R(5.5mg，收率36％)。MS m/z 741.3[M+H]+。
将化合物3S或3R(5.5mg，0.007mmol)溶于水(2mL)，加入氢氧化钠(0.6mg,0.014mmol)，室温搅拌0.5小时，将反应液浓缩，冻干得化合物3S-Na或3R-Na(5.9mg，100％)。1H NMR(500MHz,MeOD)δ9.00(s,1H),8.04(dd,J＝9.0,5.8Hz,1H),7.91(d,J＝2.2Hz,1H),7.40-7.33(m,2H),5.71(d,J＝8.2Hz,2H),4.63-4.57(m,2H),4.35(dd,J＝10.5,7.3Hz,1H),4.30-4.23(m,1H),3.78(d,J＝14.0Hz,1H),3.75-3.64(m,4H),3.41(d,J＝12.8Hz,1H),3.34(s,1H),3.17-3.11(m,1H),2.82-2.77(m,1H),2.72-2.66(m,1H),2.53-2.47(m,1H),2.14-2.10(m,1H),2.03-1.78(m,7H)。
实施例6:化合物4S的制备
将化合物4a(70mg,0.08mmol)(中间体4a的合成参照专利WO2022161443)溶于四氢呋喃(2mL)，冷却至-15℃，加入叔丁醇钠(18mg,0.16mmol)，反应在该温度下继续搅拌10分钟。再加入化合物4b(16mg,0.08mmol，单一手性异构体，S-构型 暂定)，继续搅拌0.5小时。反应完毕，体系用饱和氯化铵水溶液淬灭，混合液经乙酸乙酯萃取(3×5mL)。合并有机相经饱和食盐水洗涤、无水硫酸钠干燥、过滤后减压浓缩。所得粗品经硅胶柱层析分离纯化(二氯甲烷:甲醇＝20:1)得到白色固体化合物4c(46mg，收率57％)。MS m/z 952.4[M+H]+。
将化合物4c(46mg,0.05mmol)溶于二氯甲烷(2mL)，缓慢滴加三氟乙酸(1mL)。反应液室温搅拌1小时。待反应完毕，减压浓缩，所得粗品经制备型薄层板分离纯化(二氯甲烷:甲醇＝20:1)得化合物4S(S-构型暂定，19mg，收率64％)。1H NMR(500MHz,MeOD)δ7.24(d,J＝8.6Hz,1H),6.84(t,J＝8.5Hz,1H),5.11(dd,J＝11.2,4.2Hz,1H),4.81(d,J＝13.6Hz,1H),4.67(d,J＝13.6Hz,1H),4.22-4.08(m,3H),3.80-3.73(m,1H),3.57-3.48(m,3H),3.44-3.37(m,2H),3.24(dd,J＝17.8,11.3Hz,1H),3.15-3.08(m,1H),3.04(d,J＝12.5Hz,1H),2.84(dd,J＝17.8,4.1Hz,1H),2.78-2.72(m,1H),2.70-2.65(m,1H),2.50-2.43(m,1H),2.12-2.05(m,1H),2.03-1.78(m,6H),1.73-1.65(m,1H)。MS m/z 611.2[M+H]+。
实施例7:3D细胞增殖抑制实验
化合物活性用AGS(人胃癌细胞系，KRAS G12D突变)、GP2D(人结肠癌细胞系，KRAS G12D突变)、HPAC(人胰腺癌细胞系，KRAS G12D突变)和AsPC1(人胰腺癌细胞系，KRAS G12D突变)3D细胞增殖抑制表示，采用Cell Titer-Glo(CTG)方法。将化合物用DMSO溶解，配置成10mM的母液，再用培养基将化合物进行相应的稀释。去掉细胞上层培养基，用DPBS冲洗一次，加入2mL的胰酶，37℃条件下放置一会，待细胞从培养皿上脱离后，加入5mL新鲜的培养基，混悬细胞，1000rpm，室温离心5分钟。去掉上层培养基，重新用5mL新鲜的培养基混悬细胞，使用CountessTMII数细胞个数。使用Echo 550加入200nL的化合物到Ultra-low attachment 384孔板中，每孔再加入40μL的细胞。在37℃，5％的CO2条件下培养七天后，加入CTG，使用Envision记录信号。根据以下公式计算抑制率：Inhibition％＝(Ave_H-Sample)/(Ave_H-Ave_L)x 100％。其中Ave_H代表DMSO孔平均读值，Sample代表化合物孔的平均读值，Ave_L代表10μM的阳性对照组平均读值。以浓度的log值作为X轴，百分比抑制率为Y轴，采用分析软件GraphPad Prism 5的log(inhibitor)vs.response-Variable slope拟合量效曲线，从而得出各个化合物对细胞增殖抑制的IC50值或抑制率。部分代表性化合物的活性如表1所示。
表1细胞3D增殖抑制活性
实施例8:溶解度测试
预热0.1M NaPO4缓冲液，pH 7.4，将11g Na2HPO4(FW:141.96)和3.5g的NaH2PO4_2H2O(FW:156.03)加入1L的超纯水中。用磷酸或氢氧化钠调节pH值至7.4。将等份的8μL阳性化合物和测试化合物原液(10mM)添加到792μL的100mM磷酸盐缓冲液(pH 7.4)中(DMSO最终浓度:1％)，在室温下摇晃1小时(1000转/分)。制备校准曲线：在MeOH/CAN(4:1)中制备300μM的spike溶液(SS)，将6μL的10mM化合物加入到194μL的MeOH/CAN(4:1)中。在MeOH:CAN(4:1)溶液中制备标准曲线，如下图所示：
将样品离心(10分钟，12000转)以析出未溶解的颗粒，然后将上清液转移到一个新的管子里。将上清液用100mM的缓冲液分别稀释10倍和100倍。准备样品进行LC-MS/MS分析：将5μL样品(未稀释，10倍稀释和100倍稀释)和标准曲线样品加入95μL CAN(含IS)中，进行LC-MS/MS分析，得到化合物的溶解度数据，如表2中所示：
表2溶解度
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (17)

  1. 一种如下式(I)所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物：
    式(I)中：
    结构片段选自式(Ia)、(Ib)、(Ic)、或(Id)：
    其中，和分别表示上述结构片段与式(I)中相应位置上的基团的连接位点；表示上述结构片段与式(I)中的连接位点；
    Ar选自芳基或杂芳基；
    各个R11各自独立地选自氢、卤素、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C2-4炔基、C3-6环烷基、或CN；
    各个R12各自独立地选自氢、卤素、C1-4烷基、C1-4卤代烷基、-CH2OC(O)NRhRh、C2-4烯基、C2-4炔基、C3-8环烷基、3-至8-元杂环基、CN、ORh、SRh、NRhRh、-(CRaRb)q-ORh、-(CRaRb)q-NRhRh；其中，各个Rh各自独立为氢、C1-4烷基、或C1-4卤代烷基；Ra和Rb各自独立地选自氢、卤素、或C1-4烷基；各个q各自独立地选自0、1、2、或3；
    各个R13各自独立地选自氢、卤素、C1-4烷基、＝O、羟基、或CN；
    各个R14各自独立地选自氢、卤素、C1-4烷基、C1-4卤代烷基、羟基、C1-4烷氧基、C1-4卤代烷氧基、C2-4烯基、C2-4卤代烯基、C2-4炔基、C2-4卤代炔基、C3-6环烷基、3-至6-元杂环基、C3-6环烷基-O-、3-至6-元杂环基-O-、NRhRh、CN、SRh、-OC(O)Rk、-O-P(O)(ORm)2、-O-CH(Rn)-O-P(O)(ORm)2；其中，Rk选自C1-4烷基，其中烷基任选地被一个或多个选自下组的基团取代：羟基、C1-4烷氧基、NRhRh、C(O)OH、C(O)OC1-2烷基、或CN；Rm选自氢、C1-4烷基、或金属离子形成相应的盐；Rn选自氢或C1-4烷基；Rh的定义如上所述；
    各个R15各自独立地选自氢、卤素、或C1-4烷基；
    k选自0、1、或2；
    m选自0、1、2、或3；
    n选自0、1、或2；
    p选自0、1、2、3、4、或5；
    “*”表示手性中心；
    其中，各个上述的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基任选地且各自独立地被1-3个各自独立地选自下组的取代基取代：卤素、C1-4烷基、C1-4卤代烷基、C2-4烯基、C2-4炔基、C3-8环烷基、3-至8-元杂环基、芳基、杂芳基、CN、NO2、ORh、SRh、NRhRh、C(O)Rt、C(O)ORh、C(O)NRhRh、NRhC(O)Rt、NRhS(O)2Rt、或S(O)2Rt，前提条件是所形成的化学结构是稳定的和有意义的；其中，Rt为C1-4烷基、C2-4烯基、C2-4炔基、C3-8环烷基、4-至8-元杂环基、芳基、或杂芳基；各个Rh各自独立为氢、C1-4烷基、或C1-4卤代烷基；或两个Rh与其连接的氮原子一起形成3-至-8元杂环基，此杂环基含有1或2个N原子以及0或1个选自O、S的杂原子；
    除非特别说明，上述的芳基为含有6-12个碳原子的芳香基团；杂芳基为5-至15-元(优选为5-至12-元)杂芳香基团。
  2. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，其特征在于，式(I)为式(II)，
    X选自N或CR11；
    各个R11各自独立地选自氢、卤素、C1-4烷基、或CN；
    各个R13各自独立地选自氢、卤素、C1-4烷基、＝O、羟基、或CN；
    各个R14各自独立地选自氢、卤素、C1-4烷基、C1-4卤代烷基、羟基、C1-4烷氧基、C1-4卤代烷氧基、C2-4烯基、C2-4卤代烯基、C2-4炔基、C2-4卤代炔基、NRhRh、CN、SRh、-OC(O)Rk、-O-P(O)(ORm)2、-O-CH(Rn)-O-P(O)(ORm)2；其中，各个Rh各自独立为氢、C1-4烷基、或C1-4卤代烷基；Rk选自C1-4烷基，其中烷基任选地被一个或多个选自下组的基团取代：羟基、C1-4烷氧基、NRhRh、C(O)OH、C(O)OC1-2烷基、或CN；Rm选自氢、C1-4烷基、或金属离子形成相应的盐；Rn选自氢或C1-4烷基；
    各个R15各自独立地选自氢或氟；
    k选自0、1、或2；
    m选自0、1、或2；
    p选自0、1、2、3、4、或5；
    “*”表示手性中心。
  3. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，其特征在于，式(I)为式(II-A)，
    R11、R13、R14、X、k、m、p的定义如权利要求2所述。
  4. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，其特征在于，式(I)为式(III)，
    R11、R13、R14、k、p的定义如权利要求2所述。
  5. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，其特征在于，式(I)为式(IV)，
    R11、R13、R14、k、m、p的定义如权利要求2所述。
  6. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，其特征在于，式(I)为式(V)，
    Ar选自芳基或杂芳基；
    R11、R12、R13、R14、R15、k、m、n、p的定义如权利要求1所述。
  7. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，其特征在于，式(I)为式(VI)，
    Y选自N或CR14；
    R11、R12、R13、R14、R15、k、m、n、p的定义如权利要求1所述。
  8. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，其特征在于，式(I)为式(VII)，
    各个R14各自独立地选自氢、卤素、C1-4烷基、C1-4卤代烷基、羟基、C1-4烷氧基、C1-4卤代烷氧基、C2-4烯基、C2-4卤代烯基、C2-4炔基、C2-4卤代炔基、C3-6环烷基、3-至6-元杂环基、C3-6环烷基-O-、3-至6-元杂环基-O-、NRhRh、CN、SRh 2；其中，各个Rh各自独立为氢、C1- 4烷基、或C1-4卤代烷基；
    p选自0、1、2、3、4、或5。
  9. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，其特征在于，式(I)为式(VIII)，
    Ar选自芳基或杂芳基；
    R11、R12、R13、R14、R15、k、m、n、p的定义如权利要求1所述。
  10. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，其特征在于，式(I)为式(IX)，
    Ar选自苯环和萘环；
    各个R14各自独立地选自氢、卤素、C1-4烷基、C1-4卤代烷基、羟基、C1-4烷氧基、C1-4卤代烷氧基、C2-4烯基、C2-4卤代烯基、C2-4炔基、C2-4卤代炔基、NRhRh、CN、SRh、-OC(O)Rk、-O-P(O)(ORm)2、-O-CH(Rn)-O-P(O)(ORm)2；其中，各个Rh各自独立为氢、C1-4烷基、或C1-4卤代烷基；Rk选自C1-4烷基，其中烷基任选地被一个或多个选自下组的基团取代：羟基、C1-4烷氧基、NRhRh、C(O)OH、C(O)OC1-2烷基、或CN；Rm选自氢、C1-4烷基、或金属离子形成相应的盐；Rn选自氢或C1-4烷基；
    p选自0、1、2、3、4、或5。
  11. 如权利要求1所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，其特征在于，式(I)为式(X)，
    R11选自氢、氟、氯、C1-4烷基、或CN；
    R14’选自氢、氟、氯；
    R14”选自羟基、-O-P(O)(ORm)2、或-O-CH(Rn)-O-P(O)(ORm)2；其中，各个Rm各自独立地选自氢、C1-4烷基、或金属离子形成相应的盐；Rn选自氢或C1-4烷基；
    各个R15各自独立地选自氢或氟。
  12. 如权利要求1所述的化合物，其特征在于，所述的式(I)化合物选自下组：


    上述结构式中“*”表示手性中心，可以任选地为R构型或S构型，或R构型和S构型的混合物。
  13. 一种如下式所示结构的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物：
  14. 如权利要求1-13任一所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，其特征在于，所述的药学上可接受的盐选自下组：钾盐、钠盐、镁盐、钙盐、硫酸盐、盐酸盐、磷酸盐、磺酸盐，或碳酸盐。
  15. 一种药物组合物，其特征在于，包含权利要求1至14中任一项所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，以及药学上可接受的载体。
  16. 一种权利要求1至14中任一项的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，其特征在于，用于制备治疗与KRAS G12D活性或表达量相关的疾病，病症或病状的药物组合物。
  17. 如权利要求16所述的用途，其特征在于，所述疾病，病症或病状选自下组：胰腺癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、结肠癌、结直肠癌、甲状腺癌、胚胎性横纹肌肉瘤、皮肤颗粒细胞肿瘤、黑色素瘤、肝癌、直肠癌、膀胱癌、咽喉癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、皮肤癌、淋巴瘤、胃癌、急性髓系白血病、骨髓纤维化、B细胞淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征多发性、骨髓癌等各种实体瘤和血液瘤。
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