Polycyclic compounds as KRAS g12d inhibitors

Abstract

The invention provides a compound serving as a KRAS G12D inhibitor, and particularly provides a compound with a structure as shown in a formula (I), or an optical isomer, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate and a solvate of the compound. The compound can be used for treating or preventing diseases or symptoms related to the activity or expression quantity of KRAS G12D. # imgabs0 #

Description

Polycyclic compounds as KRAS G12D inhibitors Technical Field

[0001] The present invention relates to the field of medicinal chemistry; specifically, the present invention relates to a novel class of derivatives containing tricyclic heteroaryl groups, a synthesis method thereof, and its use as a KRAS G12D inhibitor in the preparation of drugs for treating various tumor-related diseases. Background Art

[0002] KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) is a small GTPase and a member of the RAS family. Currently, there are three known RAS genes: HRAS, NRAS, and KRAS. RAS proteins play a crucial role in the development and progression of cancer. RAS mutations are found in 20%-30% of human tumors, with KRAS mutations being the most common, particularly in lung, pancreatic, and colon cancers.

[0003] The KRAS protein consists of 188 amino acid residues and has multiple functional motifs, including a nucleotide-binding domain, transition I and II domains, a nucleotide exchange factor (GEF) binding domain, a GTPase-activating protein (GAP) binding domain, and an effector protein binding domain. Under normal circumstances, KRAS activity is regulated by multiple upstream signaling factors, such as receptor tyrosine kinases, integrins, and G protein-coupled receptors. KRAS acts as a molecular switch in the cell, switching between GTP- and GDP-bound states to activate (on) or inactivate (off), respectively, transmitting signals received upstream to downstream effector proteins. The KRAS protein itself has a relatively slow nucleotide exchange rate and weak GTP hydrolysis. Upon receiving upstream stimulation, the KRAS protein releases GDP and binds GTP with the assistance of guanine nucleotide exchange factors such as SOS1 (Son of Sevenless 1). GTP-bound RAS is activated, recruiting downstream effector proteins and activating signaling pathways such as Raf-MEK-ERK and PI3K-AKT-mTOR, promoting cell growth, proliferation, survival, metabolism, and angiogenesis. Binding of the GTPase-activating protein GAP to KRAS significantly promotes KRAS's GTP hydrolysis, converting GTP to GDP. GDP-bound KRAS then switches to an inactive state, effectively shutting off the molecular switch. When RAS mutates, its intrinsic or GAP-induced GTPase activity is inhibited, leaving RAS permanently GTP-bound and the molecular switch open. This leads to persistent activation of multiple downstream signaling pathways and abnormal cell proliferation and growth.

[0004] In pancreatic cancer, up to 90% of patients have KRAS mutations, of which approximately 40% are point mutations. KRAS G12D mutations are also found in approximately 13.3% of colorectal cancer, approximately 10% of rectal cancer, approximately 4% of non-small cell lung cancer, and approximately 1.7% of small cell lung cancer patients.

[0005] 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 inhibitors on the market. Based on this background, we have developed a class of novel KRAS G12D inhibitors.

[0006] Summary of the Invention

[0007] The purpose of the present invention is to provide a new type of KRAS G12D inhibitor.

[0008] The first aspect of the present invention provides a compound having a structure shown in the following formula (I), or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof:

[0009] In formula (I):

[0010] Structural fragments Selected from formula (Ia), (Ib), (Ic), or (Id):

[0011] in, and Respectively represent the connection sites between the above structural fragments and the groups at corresponding positions in formula (I); Represents the above structural fragment and the formula (I) The attachment site;

[0012] Ar is selected from aryl or heteroaryl;

[0013] Each R 11 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkynyl, C 3-6 Cycloalkyl, or CN;

[0014] Each R 12 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -CH2OC(O)NRh R h 、C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic 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 ; Among them, each R h Each 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;

[0015] Each R 13 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, =O, hydroxy, or CN;

[0016] Each R 14 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 2-4 Haloalkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group, C 3-6 Cycloalkyl-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; where R k Selected from C 1-4 Alkyl, wherein the alkyl group is optionally substituted by one or more groups selected from the group consisting of hydroxyl, C 1-4Alkoxy, NR h R h 、C(O)OH、C(O)OC 1-2 Alkyl, or CN; R m Selected from hydrogen, C 1-4 Alkyl groups or metal ions form corresponding salts; R n Selected from hydrogen or C 1-4 Alkyl; R h The definition of is as above;

[0017] Each R 15 are each independently selected from hydrogen, halogen, or C 1-4 alkyl;

[0018] k is selected from 0, 1, or 2;

[0019] m is selected from 0, 1, 2, or 3;

[0020] n is selected from 0, 1, or 2;

[0021] p is selected from 0, 1, 2, 3, 4, or 5;

[0022] “*” indicates chiral center;

[0023] wherein each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups is optionally and independently substituted with 1-3 substituents each independently selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO2, 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)2R t , or S(O)2R t , the prerequisite is that the chemical structure formed is stable and meaningful; among them, R t C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 cycloalkyl, 4- to 8-membered heterocyclyl, aryl, or heteroaryl; each R hEach is independently hydrogen, C 1-4 Alkyl, or C 1-4 haloalkyl; or two R h Together with the nitrogen atom to which it is attached, it forms a 3- to 8-membered heterocyclic group containing 1 or 2 nitrogen atoms and 0 or 1 heteroatom selected from O and S;

[0024] Unless otherwise specified, the above-mentioned aryl group is an aromatic group containing 6 to 12 carbon atoms; the heteroaryl group is a 5- to 15-membered (preferably 5- to 12-membered) heteroaromatic group.

[0025] In another preferred embodiment, formula (I) is formula (II),

[0026] X is selected from N or CR 11 ;

[0027] Each R 11 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, or CN;

[0028] Each R 13 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, =O, hydroxy, or CN;

[0029] Each R 14 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, 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 Each is independently hydrogen, C 1-4 Alkyl, or C 1-4 Haloalkyl; R k Selected from C 1-4 Alkyl, wherein the alkyl group 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(O)OC 1-2Alkyl, or CN; R m Selected from hydrogen, C 1-4 Alkyl groups or metal ions form corresponding salts; R n Selected from hydrogen or C 1-4 alkyl;

[0030] Each R 15 are each independently selected from hydrogen or fluorine;

[0031] k is selected from 0, 1, or 2;

[0032] m is selected from 0, 1, or 2;

[0033] p is selected from 0, 1, 2, 3, 4, or 5;

[0034] “*” indicates a chiral center.

[0035] In another preferred embodiment, formula (I) is formula (II-A),

[0036] R 11 、R 13 、R 14 The definitions of ,X, k, m, and p are as described above.

[0037] In another preferred embodiment, formula (I) is formula (III),

[0038] R 11 、R 13 、R 14 The definitions of , k, and p are as described above.

[0039] In another preferred embodiment, formula (I) is formula (IV),

[0040] R 11 、R 13 、R 14 The definitions of , k, m, and p are as described above.

[0041] In another preferred embodiment, formula (I) is formula (V),

[0042] Ar is selected from aryl or heteroaryl;

[0043] R 11 、R 12 、R 13 、R 14 、R 15 The definitions of , k, m, n, and p are as described above.

[0044] In another preferred embodiment, formula (I) is formula (VI),

[0045] Y is selected from N or CR 14 ;

[0046] R 11 、R 12 、R 13 、R 14 、R 15 The definitions of , k, m, n, and p are as described above.

[0047] In another preferred embodiment, formula (I) is formula (VII),

[0048] Each R 14 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 2-4 Haloalkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group, C 3-6 Cycloalkyl-O-, 3- to 6-membered heterocyclyl-O-, NR h R h 、CN、SR h 2; where each R h Each is independently hydrogen, C 1- 4 alkyl, or C 1-4 alkyl halide;

[0049] p is selected from 0, 1, 2, 3, 4, or 5.

[0050] In another preferred embodiment, formula (I) is formula (VIII),

[0051] Ar is selected from aryl or heteroaryl;

[0052] R 11 、R 12 、R 13 、R 14 、R 15 The definitions of , k, m, n, and p are as described above.

[0053] In another preferred embodiment, formula (I) is formula (IX),

[0054] Ar is selected from a benzene ring and a naphthalene ring;

[0055] Each R 14are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, 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 Each is independently hydrogen, C 1-4 Alkyl, or C 1-4 Haloalkyl; R k Selected from C 1-4 Alkyl, wherein the alkyl group 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(O)OC 1-2 Alkyl, or CN; R m Selected from hydrogen, C 1-4 Alkyl groups or metal ions form corresponding salts; R n Selected from hydrogen or C 1-4 alkyl;

[0056] p is selected from 0, 1, 2, 3, 4, or 5.

[0057] In another preferred embodiment, formula (I) is formula (X),

[0058] R 11 Selected from hydrogen, fluorine, chlorine, C 1-4 Alkyl, or CN;

[0059] R 14’ is selected from hydrogen, fluorine, and chlorine;

[0060] R 14” Selected from hydroxyl, -OP(O)(OR m )2、or -O-CH(R n )-OP(O)(OR m )2; wherein each R m are each independently selected from hydrogen, C 1-4 Alkyl groups or metal ions form corresponding salts; R n Selected from hydrogen or C1-4 alkyl;

[0061] Each R 15 are each independently selected from hydrogen or fluorine.

[0062] In another preferred embodiment, the compound of formula (I) is selected from the following group:

[0063] In the above structural formula, "*" represents a chiral center, which can be optionally in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.

[0064] Another aspect of the present invention provides a compound having a structure shown in the following formula, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof:

[0065] The second aspect of the present invention provides a pharmaceutically acceptable salt, wherein the pharmaceutically acceptable salt is selected from the group consisting of potassium salt, sodium salt, magnesium salt, calcium salt, sulfate, hydrochloride, phosphate, sulfonate, or carbonate.

[0066] The third aspect of the present invention provides a pharmaceutical composition comprising the compound described in the first aspect of the present invention, or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates, and pharmaceutically acceptable carriers.

[0067] In a fourth aspect, the present invention provides a compound as described in the first aspect of the present invention, or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates for preparing a pharmaceutical composition for treating diseases, disorders, or conditions associated with KRAS G12D activity or expression.

[0068] In another preferred embodiment, the disease, disorder or condition is selected from the following group: 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, pharyngeal cancer, breast cancer, prostate cancer, glioma, 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, polycythemia vera, multiple eosinophilia syndrome, myeloma and other solid tumors and blood tumors. DETAILED DESCRIPTION

[0069] After extensive and in-depth research, the inventors unexpectedly discovered a novel class of KRAS G12D inhibitors, as well as methods for their preparation and use. These compounds can be used to treat various diseases associated with the activity of these small GTPases. Based on these findings, the inventors completed the present invention.

[0070] the term

[0071] Unless otherwise specified, "or" mentioned in this document has the same meaning as "and / or" (referring to "or" and "and").

[0072] Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom (chiral center) may be optionally in the R configuration or the S configuration, or a mixture of the R and S configurations.

[0073] As used herein, the term "alkyl" refers to a straight-chain (i.e., unbranched) or branched saturated hydrocarbon group containing only carbon atoms, or a combination of straight-chain and branched hydrocarbon groups. 1-10 ), it means that the alkyl group contains 1 to 10 carbon atoms. For example, C 1-8 The alkyl group refers to an alkyl group containing 1 to 8 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

[0074] As used herein, the term "alkenyl" when used alone or as part of another substituent refers to a straight or branched carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When the number of carbon atoms in the alkenyl group is limited (e.g., C 2-8 ), it means that the alkenyl group contains 2 to 8 carbon atoms. For example, C 2-8 Alkenyl refers to an alkenyl group containing 2 to 8 carbon atoms, including ethenyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups.

[0075] As used herein, the term "alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond, either alone or as part of another substituent. The alkynyl group may be straight-chain or branched, or a combination thereof. 2-8 When the term "alkynyl" is used, it means that the alkynyl contains 2 to 8 carbon atoms. 2-8 The term "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.

[0076] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated ring, bicyclic or polycyclic (fused, bridged or spiro) ring system group when used alone or as part of another substituent. 3-10 ) refers to a cycloalkyl group containing 3 to 10 carbon atoms. In some preferred embodiments, the term "C 3-8 "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or bicyclic alkyl group having 3-8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or similar groups. "Spirocycloalkyl" refers to a bicyclic or polycyclic group in which the monocyclic rings share a carbon atom (called a spiro atom), which may contain one or more double bonds, but no ring has a completely conjugated π electron system. "Fused cycloalkyl" refers to a full-carbon bicyclic or polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. "Bridged cycloalkyl" refers to a full-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. The atoms contained in the cycloalkyl group are all carbon atoms. The following are some examples of cycloalkyl groups, and the present invention is not limited to the following cycloalkyl groups.

[0077] Unless otherwise stated, the following terms used in the specification and claims have the following meanings. "Aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group with a conjugated π electron system, such as phenyl and naphthyl. The aryl ring can be fused to other cyclic groups (including saturated and unsaturated rings), but cannot contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be on a carbon atom on the ring with a conjugated π electron system. Aryl groups can be substituted or unsubstituted. The following are some examples of aryl groups, and the present invention is not limited to the aryl groups described below.

[0078] "Heteroaryl" refers to a monocyclic or polycyclic group having aromaticity containing one or more heteroatoms (selectively selected from nitrogen, oxygen, and sulfur), or a polycyclic group formed by condensing a heterocyclic group (containing one or more heteroatoms selected from nitrogen, oxygen, and sulfur) with an aryl group, wherein the attachment point is located on the aryl group. The heteroaryl group may be optionally substituted or unsubstituted. The following are some examples of heteroaryl groups, and the present invention is not limited to the following heteroaryl groups.

[0079] "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclyls refer to heterocyclyls including spirocyclic, fused, and bridged rings. "Spirocyclic heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares an atom (called a spiro atom) with the 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. "Fused-ring heterocyclyl" refers to a polycyclic heterocyclic group in which each ring in the system shares a pair of adjacent atoms with the other rings in the system, in which one or more rings may contain one or more double bonds, but in which no ring has a completely conjugated pi-electron system, and in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur, and the remaining ring atoms are carbon. "Bridged heterocyclic group" 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 completely conjugated pi-electron system, and one or more ring atoms are selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. If a heterocyclic group contains both saturated and aromatic rings (for example, a saturated ring and an aromatic ring are fused together), the point of attachment to the parent group must be on the saturated ring. Note: When the point of attachment to the parent group is on the aromatic ring, it is called a heteroaryl group, not a heterocyclic group. The following are some examples of heterocyclic groups, and the present invention is not limited to the following heterocyclic groups.

[0080] As used herein, the term "halogen," by itself or as part of another substituent, refers to F, Cl, Br, and I.

[0081] As used herein, the term "substituted" (with or without the "arbitrarily" modifier) ​​refers to the replacement of one or more hydrogen atoms on a specific group with a specific substituent. The specific substituent is the substituent described accordingly in the preceding text, or the substituent appearing in the examples. Unless otherwise specified, an arbitrarily substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituent may be the same or different at each position. A cyclic substituent, such as a heterocyclic group, may be connected to another ring, such as a cycloalkyl group, to form a spirobicyclic system, i.e., the two rings have a common carbon atom. It will be understood by those skilled in the art that the combinations of substituents contemplated by the present invention are those that are stable or chemically feasible. 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 heterocyclic group, aryl, heteroaryl, halogen, hydroxyl, carboxyl (-COOH), C 1-8 Aldehyde, C 2-10 Acyl, C2-10 Ester group, amino group.

[0082] For the sake of convenience and in accordance with common understanding, the term "arbitrary substitution" or "optionally substituted" only applies to sites that can be substituted by substituents, and does not include those substitutions that are chemically unfeasible.

[0083] As used herein, unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for contact with the tissues of a subject (e.g., a human) without producing undue side effects. In some embodiments, a pharmaceutically acceptable salt of a compound of the present invention includes a salt of the compound of the present invention having an acidic group (e.g., potassium salt, sodium salt, magnesium salt, calcium salt) or a salt of the compound of the present invention having a basic group (e.g., sulfate, hydrochloride, phosphate, nitrate, carbonate).

[0084] use:

[0085] The present invention provides a class of compounds of formula (I), or their deuterated derivatives, their salts, isomers (enantiomers or diastereomers, if any), hydrates, pharmaceutically acceptable carriers or excipients for use in inhibiting KRAS G12D.

[0086] The compound of the present invention can be used as a KRAS G12D inhibitor.

[0087] The present invention is a single inhibitor of KRAS G12D that modulates KRAS G12D activity to prevent, alleviate, or cure diseases. These diseases 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, pharyngeal cancer, breast cancer, prostate cancer, glioma, 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, multiple eosinophilia syndrome, myeloma, and other solid tumors and hematologic malignancies.

[0088] The compounds of the present invention and their deuterated derivatives, as well as pharmaceutically acceptable salts or isomers thereof (if present), or hydrates thereof, and / or compositions thereof, can be formulated with pharmaceutically acceptable excipients or carriers. The resulting compositions can be administered to mammals, such as men, women, and animals, in vivo for the treatment of conditions, symptoms, and diseases. The compositions can be in the form of tablets, pills, suspensions, solutions, emulsions, capsules, aerosols, sterile injectable solutions, sterile powders, and the like. In some embodiments, pharmaceutically acceptable excipients include microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, calcium hydrogen phosphate, mannitol, hydroxypropyl-β-cyclodextrin, β-cyclodextrin (increased), glycine, disintegrants (such as starch, cross-linked sodium carboxymethyl cellulose, complex silicates, and high molecular weight polyethylene glycols), granulation binders (such as polyvinyl pyrrolidone, sucrose, gelatin, and gum arabic), and lubricants (such as magnesium stearate, glycerol, and talc). In a preferred embodiment, the pharmaceutical composition is a dosage form suitable for oral administration, including but not limited to tablets, solutions, suspensions, capsules, granules, and powders. The amount of the compound of the present invention or the pharmaceutical composition administered to the patient is not fixed and is usually administered in a pharmaceutically effective amount. At the same time, the amount of the compound actually administered can be determined by the physician based on actual conditions, including the condition being treated, the selected route of administration, the actual compound administered, the individual condition of the patient, etc. The dosage of the compound of the present invention depends on the specific use of the treatment, the mode of administration, the patient's condition, and the physician's judgment. The ratio or concentration of the compound of the present invention in the pharmaceutical composition depends on various factors, including dosage, physicochemical properties, route of administration, etc.

[0089] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions.

[0090] Pharmaceutical compositions and methods of administration

[0091] Since the compounds of the present invention have excellent inhibitory activity against KRAS G12D, the compounds of the present invention and their various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to treat, prevent and alleviate diseases related to KRAS G12D activity or expression.

[0092] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0093] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, 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, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0094] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0095] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, 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 extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0096] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0097] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used 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-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0098] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0099] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0100] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0101] 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.

[0102] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0103] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 5 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0104] The main advantages of the present invention include:

[0105] 1. Provided is a compound as shown in formula I.

[0106] 2. Provided is a novel KRAS G12D inhibitor, as well as its preparation and use. The inhibitor can inhibit the activity of KRAS G12D at extremely low concentrations.

[0107] 3. Provides a class of pharmaceutical compositions for treating diseases associated with KRAS G12D activity.

[0108] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0109] Example

[0110] Example 1: Preparation of Compound 1, Compound 1S, and Compound 1R

[0111] Compound 1b was synthesized using the method described in the European Journal of Organic Chemistry, 2015, vol. 2015, #4, p. 871-875. Potassium tert-butoxide (851 mg, 7.58 mmol) was dissolved in DMF (10 mL). The mixture was cooled to -50°C under a nitrogen atmosphere. A solution of compound 1a (890 mg, 4.21 mmol, racemate) and compound 1b (733 mg, 3.79 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 0.5 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution (5 mL), and concentrated hydrochloric acid (3 mL) was added. The mixture was stirred at room temperature for 1 hour, and water (30 mL) was added. The mixture was extracted three times with ethyl acetate (30 mL × 3). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography to obtain compound 1c (188 mg, 18%) as a light yellow oil. 1 H 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] +

[0112] Lithium aluminum hydride (58 mg, 0.77 mmol) was dissolved in tetrahydrofuran (1 mL). A solution of compound 1c (188 mg, 0.77 mmol) in tetrahydrofuran (2 mL) was added under an ice bath and nitrogen atmosphere. The reaction mixture was heated and stirred at 65°C for 3 hours. Water (0.06 mL), 15% sodium hydroxide (0.06 mL), and water (0.18 mL) were added sequentially under an ice bath. The mixture was stirred at room temperature for 15 minutes, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified by silica gel column chromatography to afford compound 1d (38 mg, 26%) as a pale yellow oil.

[0113] Compound 1e was synthesized according to the method described in patent WO2021041671. Compound 1e (80 mg, 0.19 mmol) and compound 1d (38 mg, 0.20 mmol) were dissolved in dioxane (1 mL), and diisopropylethylamine (72 mg, 0.56 mmol) was added. The reaction solution was heated and stirred at 90°C under a nitrogen atmosphere for 24 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain an off-white solid compound 1f (33 mg, 30%). MS m / z 581.5, 583.4 [M+H] + .

[0114] Compound 1f (307 mg, 0.53 mmol), compound 1g (406 mg, 0.79 mmol, synthesized or purchased according to the method in patent WO2021041671), potassium phosphate (337 mg, 1.59 mmol) and methanesulfonic acid [n-butyldi(1-adamantyl)phosphine] (2-amino-1,1'-biphenyl-2-yl) palladium (II) (38 mg, 0.05 mmol) were added to the reaction flask, and the nitrogen was replaced three times. Then 1,4-dioxane (5 mL) and water (1 mL) were added. The reaction mixture was stirred at 100°C for 2 hours under nitrogen protection. Cooled to room temperature and water was added. The mixture was extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol=25:1) to obtain a yellow oily product 1h (486 mg, yield 99%). MS m / z 931.9 [M+H] + .

[0115] Compound 1h (486 mg, 0.52 mmol) was dissolved in acetonitrile (10 mL), and then a 4 M solution of hydrogen chloride in 1,4-dioxane (3 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain the yellow solid product 1i (411 mg, 100% yield). MS m / z 787.7 [M+H] + .

[0116] Compound 1i (411 mg, 0.52 mmol) obtained in the previous step was dissolved in DMF (10 mL), and cesium fluoride (790 mg, 5.20 mmol) was added. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain compound 1 (174 mg, 53% yield) as a yellow solid. Compound 1 was separated by HPLC using a chiral column (CHIRALPAK AD-H, ADH0CE-XG136, 0.46 cm ID×25 cm L; Hexane / EtOH / DEA=60 / 40 / 0.1 (V / V / V); 1.0 ml / min) to give the first isomer, compound 1-P1 (rt=4.93 min, 41 mg), and the second isomer, compound 1-P2 (rt=6.18 min, 43 mg).

[0117] Compound 1-P1 and Compound 1-P2: one of them is Compound 1S, and the other is Compound 1R.

[0118] Compound 1-P1: 1 H 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] + .

[0119] Compound 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] + .

[0120] Example 2: Preparation of Compound 2 and 2-Na

[0121] Compound 1h (100 mg, 0.11 mmol) was dissolved in dichloromethane (3 mL), and a 1,4-dioxane solution of hydrogen chloride (4 M, 0.1 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (dichloromethane:methanol = 20:1) to obtain compound 2a (67 mg, yield 71%). MS m / z 887.1 [M+H] + .

[0122] Compound 2a (39 mg, 0.04 mmol) was dissolved in N,N-dimethylformamide (1 mL), and cesium fluoride (67 mg, 0.44 mmol) was added. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain compound 2b (23 mg, yield 73%) as a yellow solid. MS m / z 731.3 [M+H] + .

[0123] Compound 2b (10 mg, 0.014 mmol) and N,N-diisopropylethylamine (6 mg, 0.05 mmol) were dissolved in acetonitrile (2 mL) and phosphorus oxychloride (3 mg, 0.02 mmol) was added dropwise under ice-cooling. The reaction mixture was stirred in an ice-cooling bath for 10 minutes, and then a saturated aqueous sodium bicarbonate solution (0.5 mL) was added and stirred at room temperature for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 2c (10 mg, 91% yield) as a yellow solid. MS m / z 811.3 [M+H] + .

[0124] Compound 2c (10 mg, 0.012 mmol) was dissolved in acetonitrile (2 mL) and a 1,4-dioxane solution of hydrogen chloride (4 M, 0.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (dichloromethane:methanol = 10:1) to afford compound 2 (4 mg, 45% yield) as a yellow solid. MS m / z 711.1 [M+H] + Compound 2 (4 mg, 0.005 mmol) was dissolved in acetonitrile (1 mL), and a sodium hydroxide (0.4 mg, 0.01 mmol) aqueous solution (0.5 mL) was added. The reaction mixture was lyophilized to obtain the disodium salt of compound 2 (2-Na) as a yellow solid (4 mg, 100% yield). 1 H 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),3.44–3.4 0(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] + .

[0125] Compound 2 (racemate) can be chirally resolved to give Compound 2S and Compound 2R.

[0126] Example 3: Preparation of Compounds 2S or 2R and 2S-Na or 2R-Na

[0127] 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 di-tert-butyl dicarbonate (201 mg, 0.92 mmol) was added dropwise. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 2bS or 2bR (616 mg, 96% yield). MS m / z 731.4 [M+H] + .

[0128] Compound 2bS or 2bR (462 mg, 0.63 mmol) and N,N-diisopropylethylamine (244 mg, 1.89 mmol) were dissolved in acetonitrile (5 mL) and phosphorus oxychloride (145 mg, 0.95 mmol) was slowly added dropwise under ice bath. The reaction solution was stirred in ice bath for 0.5 hours, then quenched by adding saturated aqueous sodium bicarbonate solution (3 mL) and stirred at room temperature for 1 hour. Water was added to the reaction system and extracted with ethyl acetate. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude yellow solid compound 2cS or 2cR (455 mg, yield 89%). MS m / z 811.3 [M+H] + .

[0129] Compound 2cS or 2cR (455 mg, 0.56 mmol) was dissolved in acetonitrile (5 mL) and a 1,4-dioxane solution of hydrogen chloride (4 M, 1 mL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The crude product was purified by reverse-phase preparative chromatography to afford compound 2S or 2R as a yellow solid (156 mg, 39% yield). MS m / z 711.1 [M+H] + .

[0130] Compound 2S or 2R (156 mg, 0.22 mmol) was dissolved in acetonitrile (3 mL), and a sodium hydroxide (17.6 mg, 0.44 mmol) aqueous solution (5 mL) was added. The reaction mixture was lyophilized to obtain a yellow solid compound 2S-Na or 2R-Na (166 mg, 100% yield). 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).

[0131] Example 4: Preparation of Compound 3R or 3S and 3R-Na or 3S-Na

[0132] 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 di-tert-butyl dicarbonate (73 mg, 0.33 mmol) was added dropwise. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain compound 2bR or 2bS (211 mg, 91% yield). MS m / z 731.4 [M+H] + .

[0133] Compound 2bR or 2bS (211 mg, 0.29 mmol) and cesium carbonate (307 mg, 0.58 mmol) were dissolved in N,N-dimethylformamide (3 mL), and di-tert-butyl chloromethyl phosphate (113 mg, 0.43 mmol) was slowly added dropwise. The mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 3aR or 3aS (271 mg, 98% yield). MS m / z 953.4 [M+H] + .

[0134] Compound 3aR or 3aS (270 mg, 0.28 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by reverse phase preparative chromatography to afford compound 3R or 3S (137 mg, 65% yield). MS m / z 741.3 [M+H] + .

[0135] Compound 3R or 3S (137 mg, 0.19 mmol) was dissolved in water (4 mL), and sodium hydroxide (14.8 mg, 0.37 mmol) was added. The mixture was stirred at room temperature for 0.5 h. The reaction solution was concentrated and lyophilized to obtain compound 3R-Na or 3S-Na (141 mg, yield 97%). 1 H 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).

[0136] Example 5: Preparation of Compounds 3S or 3R and 3S-Na or 3R-Na

[0137] 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 di-tert-butyl dicarbonate (73 mg, 0.33 mmol) was added dropwise. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain compound 2bS or 2bR (199 mg, 86% yield). MS m / z 731.4 [M+H] + .

[0138] Compound 2bS or 2bR (35 mg, 0.05 mmol) and cesium carbonate (33 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide (1 mL). Di-tert-butyl chloromethyl phosphate (19 mg, 0.08 mmol) was slowly added dropwise. The mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound 3bS or 3bR (21 mg, 46% yield). MS m / z 953.4 [M+H] + .

[0139] Compound 3bS or 3bR (20 mg, 0.02 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.5 mL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by reverse phase preparative chromatography to afford compound 3S or 3R (5.5 mg, 36% yield). MS m / z 741.3 [M+H] + .

[0140] Compound 3S or 3R (5.5 mg, 0.007 mmol) was dissolved in water (2 mL), and sodium hydroxide (0.6 mg, 0.014 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was concentrated and lyophilized to obtain compound 3S-Na or 3R-Na (5.9 mg, 100%). 1 H 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).

[0141] Example 6: Preparation of Compound 4S

[0142] Compound 4a (70 mg, 0.08 mmol) (the synthesis of intermediate 4a refers to patent WO2022161443) was dissolved in tetrahydrofuran (2 mL), cooled to -15 ° C, sodium tert-butoxide (18 mg, 0.16 mmol) was added, and the reaction was continued to stir at this temperature for 10 minutes. Compound 4b (16 mg, 0.08 mmol, single chiral isomer, S-configuration tentative) was then added and stirring was continued for 0.5 hours. After the reaction was completed, the system was quenched with saturated aqueous ammonium chloride solution, and the mixed solution was extracted with ethyl acetate (3×5 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 20:1) to obtain white solid compound 4c (46 mg, yield 57%). MS m / z 952.4 [M+H] + .

[0143] Compound 4c (46 mg, 0.05 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was slowly added dropwise. The reaction mixture was stirred at room temperature for 1 hour. Upon completion, the mixture was concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer plate separation (dichloromethane:methanol = 20:1) to afford compound 4S (tentatively S-configuration, 19 mg, 64% yield). 1 H 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] + .

[0144] Example 7: 3D cell proliferation inhibition experiment

[0145] The activity of the compound was expressed as the inhibition of 3D cell proliferation of 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) using the Cell Titer-Glo (CTG) method. The compound was dissolved in DMSO and prepared into a 10mM stock solution, and then the compound was diluted accordingly with culture medium. The upper layer of the cell culture medium was removed, rinsed once with DPBS, 2mL of trypsin was added, and placed at 37°C for a while. After the cells were detached from the culture dish, 5mL of fresh culture medium was added, the cells were suspended, and centrifuged at 1000rpm at room temperature for 5 minutes. The upper layer of culture medium was removed, and the cells were resuspended with 5mL of fresh culture medium and Countess was used. TMII Count the number of cells. Use Echo 550 to add 200nL of compound to the Ultra-low attachment 384-well plate, and then add 40μL of cells to each well. After seven days of culture at 37°C and 5% CO2, add CTG and use Envision to record the signal. Calculate the inhibition rate according to the following formula: Inhibition% = (Ave_H-Sample) / (Ave_H-Ave_L) x 100%. Where Ave_H represents the average reading of the DMSO well, Sample represents the average reading of the compound well, and Ave_L represents the average reading of the 10μM positive control group. Use the log value of the concentration as the X-axis and the percentage inhibition rate as the Y-axis. Use the analysis software GraphPad Prism 5's log (inhibitor) vs. response-Variable slope to fit the dose-effect curve, so as to obtain the IC value of each compound on cell proliferation inhibition. 50 The activities of some representative compounds are shown in Table 1.

[0146] Table 1 Cell 3D proliferation inhibitory activity

[0147] Example 8: Solubility Test

[0148] Preheat 0.1M NaPO4 buffer, pH 7.4. Add 11g Na2HPO4 (FW: 141.96) and 3.5g NaH2PO4_2H2O (FW: 156.03) to 1L of ultrapure water. Adjust the pH to 7.4 with phosphoric acid or sodium hydroxide. Add 8μL of aliquots of the positive compound and test compound stock solution (10mM) to 792μL of 100mM phosphate buffer (pH 7.4) (final DMSO concentration: 1%) and shake at room temperature for 1 hour (1000 rpm). Prepare a calibration curve: Prepare a 300μM spike solution (SS) in MeOH / CAN (4:1). Add 6μL of the 10mM compound to 194μL of MeOH / CAN (4:1). Prepare a standard curve in MeOH:CAN (4:1) as shown below:

[0149] The samples were centrifuged (10 minutes, 12,000 rpm) to precipitate undissolved particles, and the supernatant was transferred to a fresh tube. The supernatant was diluted 10-fold and 100-fold with 100 mM buffer. Samples were prepared for LC-MS / MS analysis: 5 μL of sample (undiluted, 10-fold diluted, and 100-fold diluted) and standard curve samples were added to 95 μL of CAN (containing IS) for LC-MS / MS analysis. The solubility data for the compounds were obtained, as shown in Table 2:

[0150] Table 2 Solubility

[0151] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound having a structure represented by the following formula (I), or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof: In formula (I): Structural fragments Selected from formula (Ia), (Ib), (Ic), or (Id): in, and Respectively represent the connection sites between the above structural fragments and the groups at corresponding positions in formula (I); Represents the above structural fragment and the formula (I) The attachment site; Ar is selected from aryl or heteroaryl; Each R 11 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkynyl, C 3-6 Cycloalkyl, or CN; Each R 12 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -CH2OC(O)NR h R h 、C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclic 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 ; Among them, each R h Each 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 13 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, =O, hydroxy, or CN; Each R 14 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 2-4 Haloalkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group, C 3-6 Cycloalkyl-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; where R k Selected from C 1-4 Alkyl, wherein the alkyl group 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(O)OC 1-2 Alkyl, or CN; R m Selected from hydrogen, C 1-4 Alkyl groups or metal ions form corresponding salts; R n Selected from hydrogen or C 1-4 Alkyl; R h The definition of is as above; Each R 15 are each independently selected from hydrogen, halogen, or C 1-4 alkyl; k is selected from 0, 1, or 2; m 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; "*" indicates a chiral center; wherein each of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups is optionally and independently substituted with 1-3 substituents each independently selected from the group consisting of halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 Cycloalkyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, CN, NO2, 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)2R t , or S(O)2R t , the prerequisite is that the chemical structure formed is stable and meaningful; among them, R t C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-8 cycloalkyl, 4- to 8-membered heterocyclyl, aryl, or heteroaryl; each R h Each is independently hydrogen, C 1-4 Alkyl, or C 1-4 haloalkyl; or two R h Together with the nitrogen atom to which it is attached, it forms a 3- to 8-membered heterocyclic group containing 1 or 2 nitrogen atoms and 0 or 1 heteroatom selected from O and S; Unless otherwise specified, the above-mentioned aryl group is an aromatic group containing 6 to 12 carbon atoms; the heteroaryl group is a 5- to 15-membered (preferably 5- to 12-membered) heteroaromatic group.

2. The compound according to claim 1, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate, characterized in that: Formula (I) is formula (II), X is selected from N or CR 11 ; Each R 11 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, or CN; Each R 13 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, =O, hydroxy, or CN; Each R 14 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, 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 Each is independently hydrogen, C 1-4 Alkyl, or C 1-4 Haloalkyl; R k Selected from C 1-4 Alkyl, wherein the alkyl group 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(O)OC 1-2 Alkyl, or CN; R m Selected from hydrogen, C 1-4 Alkyl groups or metal ions form corresponding salts; R n Selected from hydrogen or C 1-4 alkyl; Each R 15 are each independently selected from hydrogen or fluorine; k is selected from 0, 1, or 2; m is selected from 0, 1, or 2; p is selected from 0, 1, 2, 3, 4, or 5; "*" indicates a chiral center.

3. The compound according to claim 1, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate, wherein: Formula (I) is formula (II-A), R 11 、R 13 、R 14 , X, k, m, p are defined as described in claim 2.

4. The compound according to claim 1, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate, wherein: Formula (I) is formula (III), R 11 、R 13 、R 14 , k, and p are defined as described in claim 2.

5. The compound according to claim 1, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate, wherein: Formula (I) is Formula (IV), R 11 、R 13 、R 14 , k, m, and p are defined as described in claim 2.

6. The compound according to claim 1, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate, wherein: 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, p are defined as described in claim 1.

7. The compound according to claim 1, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate, wherein: 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, p are defined as described in claim 1.

8. The compound according to claim 1, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate, wherein: Formula (I) is formula (VII), Each R 14 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, C 2-4 Alkynyl, C 2-4 Haloalkynyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocyclic group, C 3-6 Cycloalkyl-O-, 3- to 6-membered heterocyclyl-O-, NR h R h 、CN、SR h 2; where each R h Each is independently hydrogen, C 1- 4 alkyl, or C 1-4 alkyl halide; p is selected from 0, 1, 2, 3, 4, or 5.

9. The compound according to claim 1, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate, wherein: 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, p are defined as described in claim 1.

10. The compound according to claim 1, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate, wherein: Formula (I) is Formula (IX), Ar is selected from a benzene ring and a naphthalene ring; Each R 14 are each independently selected from hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, hydroxy, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 2-4 Alkenyl, C 2-4 Halogenated alkenyl, 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 Each is independently hydrogen, C 1-4 Alkyl, or C 1-4 Haloalkyl; R k Selected from C 1-4 Alkyl, wherein the alkyl group 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(O)OC 1-2 Alkyl, or CN; R m Selected from hydrogen, C 1-4 Alkyl groups or metal ions form corresponding salts; R n Selected from hydrogen or C 1-4 alkyl; p is selected from 0, 1, 2, 3, 4, or 5.

11. The compound according to claim 1, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate, characterized in that: Formula (I) is formula (X), R 11 Selected from hydrogen, fluorine, chlorine, C 1-4 Alkyl, or CN; R 14’ is selected from hydrogen, fluorine, and chlorine; R 14” Selected from hydroxyl, -OP(O)(OR m )2、or -O-CH(R n )-OP(O)(OR m )2; wherein each R m are each independently selected from hydrogen, C 1-4 Alkyl groups or metal ions form corresponding salts; R n Selected from hydrogen or C 1-4 alkyl; Each R 15 are each independently selected from hydrogen or fluorine.

12. The compound according to claim 1, wherein The compound of formula (I) is selected from the following group: In the above structural formula, "*" represents a chiral center, which can be optionally in R configuration or S configuration, or a mixture of R configuration and S configuration.

13. A compound having the structure shown in the following formula, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof:

14. The compound according to any one of claims 1 to 13, or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, or solvates, characterized in that: The pharmaceutically acceptable salt is selected from the group consisting of potassium salt, sodium salt, magnesium salt, calcium salt, sulfate, hydrochloride, phosphate, sulfonate, or carbonate.

15. A pharmaceutical composition, characterized in that Comprising the compound according to any one of claims 1 to 14, or an optical isomer thereof, a pharmaceutically acceptable salt, a prodrug, a deuterated derivative, a hydrate, a solvate, and a pharmaceutically acceptable carrier.

16. Use of a compound according to any one of claims 1 to 14, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate or solvate thereof, characterized in that: For preparing a pharmaceutical composition for treating diseases, disorders or conditions associated with KRAS G12D activity or expression.

17. The use according to claim 16, characterized in that The disease, disorder or condition is selected from the following group: 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, pharyngeal cancer, breast cancer, prostate cancer, glioma, 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, polycythemia vera, multiple myeloma, myeloma and other solid tumors and blood tumors.

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