CN117164605A

CN117164605A - KRAS G12D inhibitors and related uses thereof

Info

Publication number: CN117164605A
Application number: CN202311000483.0A
Authority: CN
Inventors: 吕佳声; 吉祥; 张玉华; 孔宪起; 陈大为
Original assignee: Risen Suzhou Pharma Tech Co Ltd
Current assignee: Risen Suzhou Pharma Tech Co Ltd
Priority date: 2023-08-09
Filing date: 2023-08-09
Publication date: 2023-12-05

Abstract

The present invention relates to KRAS G12D inhibitors and uses thereof. In particular, the invention relates to a compound of formula (Ia) or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof, including pharmaceutical compositions thereof, and the use of the above compound or composition in the manufacture of a medicament for the treatment, inhibition or prevention of KRAS G12D mutation-related diseases.

Description

KRAS G12D inhibitors and related uses thereof

Technical Field

The invention relates to a KRAS G12D inhibitor or pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof, and application thereof in preparing medicines for treating, inhibiting or preventing KRAS G12D mutation related diseases.

Background

The KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) gene belongs to the RAS family and is one of the common genetic mutations in human cancers, and the encoded protein is a small GTPase (small GTPase). The KRAS gene is involved in kinase signaling pathways that control gene transcription, thereby regulating cell growth and differentiation. In cells, KRAS protein transitions between inactive and active states, is in an inactive state when KRAS binds Guanosine Diphosphate (GDP), is in an active state when it binds Guanosine Triphosphate (GTP), and can activate downstream signaling pathways. KRAS in most cells is in an inactive state and when activated, downstream signaling pathways that can be activated include the MAPK signaling pathway, PI3K signaling pathway, and Ral-GEFs signaling pathway. These signaling pathways play an important role in promoting cell survival, proliferation and cytokine release, affecting tumorigenesis and progression.

In human cancers, KRAS gene mutations occur in nearly 90% of pancreatic cancers, about 30% to 40% of colon cancers, about 17% of endometrial cancers, about 15% to 20% of lung cancers (mostly Non-small cell lung cancers, non-Small Cell Lung Cancer, NSCLC). It also occurs in the types of cancers such as cholangiocarcinoma, cervical cancer, bladder cancer, liver cancer, and breast cancer. That is, in the above-described various cancers, there are a high proportion of KRAS gene mutations. Most KRAS missense mutations occur at codon 12, resulting in glycine to other amino acids. Depending on the particular mutation present, G12C, G D and G12R are the most common KRAS mutations in patients, such as KRAS G12D and KRAS G12V mutations, both found in about 90% of pancreatic cancers, with KRAS G12D being the most common KRAS mutation in colon cancer. At present, KRAS G12C muteins have attracted much research as a leading edge target, but unfortunately, since mutation site amino acid residues are difficult to chemically bind, very few inhibitor compounds related to KRAS G12D are reported, and WO2021041671, WO2021106231 and WO2022002102 disclose some compounds, however, the search for more kinds of more active, better therapeutic inhibitors of KRAS G12D has very important significance for anti-tumor research.

Disclosure of Invention

The invention mainly solves the technical problem of providing a KRAS G12D inhibitor with good effect. The applicant finds that the compound of the formula A or pharmaceutically acceptable salts, esters, hydrates, solvates or stereoisomers thereof have good anti-tumor activity:

wherein X is ² Independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted acyl (including saturated or unsaturated aliphatic acyl and aroyl), amino acid residues, oligopeptide (dipeptide, tripeptide, tetrapeptide) residues, phosphoryl, phosphono, aminophosphonyl, sulfonyl, thioacyl, substituted or unsubstituted benzyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted mercaptothiocarbonyl, substituted or unsubstituted alkylthio (thiocarbonyl), substituted or unsubstituted esteralkyl, substituted or unsubstituted benzyloxycarbonyl, glycosyl, cholic acid substituents;

a is an organic group containing a cyclic structure, including monocyclic, bicyclic, fused, bridged, spiro, heterocyclic, aromatic, heteroaromatic, alicyclic, and combinations thereof, and the cyclic structure contains two or more substituents;

Group A ¹ 、A ² 、A ³ And A ⁴ Independently selected from hydrogen or C ₁ To C ₆ Or a short chain hydrocarbon group of A) ¹ 、A ² 、A ³ And A ⁴ One or both groups of (a) and (b) to which they are attachedThe linked piperazine rings together form a bridged, fused or spiro ring; and the nitrogen heterocycle may be a saturated heterocycle or an unsaturated heterocycle;

m is selected from nitrogen or carbon.

In some embodiments, the compound of formula (a) may be a compound of formula (B) or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof, having good antitumor activity:

group A ¹ 、A ² 、A ³ And A ⁴ Independently selected from hydrogen or C ₁ To C ₆ Or a short chain hydrocarbon group of A) ¹ 、A ² 、A ³ And A ⁴ Together with the piperazine ring to which they are attached, form a bridged or fused ring, and the nitrogen heterocycle may be a saturated or unsaturated heterocycle.

In some embodiments, the compound of formula (a) or formula (B) may be a compound of formula (I) or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof, and has good antitumor activity:

A is an organic group containing a cyclic structure, including monocyclic, bicyclic, fused, bridged, spiro, heterocyclic, aromatic, heteroaromatic, alicyclic, and combinations thereof, and the cyclic structure contains two or more substituents.

In further embodiments, the compound of formula (I) may be a compound of formula (Ia) or formula (Ib) or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof, and the compound of formula (Ia) or formula (Ib) has excellent antitumor activity:

wherein,

x is selected from nitrogen (N), carbon (CH), C-F, C-Cl, C-Br, C-CN, C-OH, C-OMe, C-OEt, C-OiPr, C-OPr, C-OCH ₂ (C ₃ H ₅ )、C-CH ₃ 、C-C ₂ H ₅ Or C-C ₃ H ₇ ；

W is selected from oxygen (O), sulfur (S), nitrogen (NH) or is absent;

X ¹ and X ² Independently selectFrom hydrogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted acyl (including saturated or unsaturated aliphatic acyl and aroyl), amino acid residues, oligopeptide (dipeptide, tripeptide, tetrapeptide) residues, phosphoryl, phosphono, aminophosphono, sulfonyl, thioacyl, substituted or unsubstituted benzyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted mercaptothiocarbonyl, substituted or unsubstituted alkylthio (thiocarbonyl), substituted or unsubstituted esteralkyl, substituted or unsubstituted benzyloxycarbonyl, glycoside, sugar acid glycoside, cholic acid substituents;

X ³ Independently selected fromOr lone pair electrons; when X is ³ X in the case of lone pair electrons ¹ And X ² Are not hydrogen at the same time; and when X ³ Is->When in combination with X ³ The attached N atoms form quaternary ammonium ions with a positive charge and either form internal salts with anions within the molecule or pair with additional acid molecules including, but not limited to, halogen acid salts, wherein R ^6a 、R ^6b Optionally selected from hydrogen, C ₁ To C ₂₀ Is a hydrocarbon or cyclic hydrocarbon group, ->

Y ^1a 、Y ^1b Independently selected from hydrogen, halogen (F, cl, or Br), hydroxy, amino, hydroxymethyl, alkoxy, or acyloxy;

in the formula (Ia), Y ² Independently selected from hydrogen, halogen, hydroxy, amino, hydroxymethyl, alkoxy, acyloxy, or lower alkyl;

Y ³ 、Y ⁴ independently selected from H, halogen, halomethyl (monohalomethyl, dihalomethyl, and trihalomethyl), cyano, or Y ³ 、Y ⁴ It is provided withThe benzene ring structures to which they are attached together form a substituted or unsubstituted benzo-fused ring, including but not limited to naphthalene ring structures.

The compound provided by the application, or pharmaceutically acceptable salts, esters, hydrates, solvates or stereoisomers thereof, can be used as a KRAS G12D inhibitor, is used for treating diseases related to KRAS G12D mutation, and has good curative effect.

Further, X ¹ And X ² Independently selected from hydrogen, C ₁ -C ₂₀ Saturated or unsaturated alkoxycarbonyl, C ₁ -C ₂₀ Saturated or unsaturated alkanoyl, C ₁ -C ₂₀ Alkylthio group,

Wherein R is ¹ Selected from hydrogen, methyl, ethyl, propyl or isopropyl, C ₃ -C ₆ Cycloalkyl groups, aryl groups,

R ² selected from hydrogen, C ₁ To C ₂₀ Saturated or unsaturated alkyl, C ₅ -C ₈ Aryl hydrocarbon, heterocyclic aryl hydrocarbon, C ₃ -C ₈ Carbocyclic or heterocyclic hydrocarbyl, fused ring, bridged cyclic hydrocarbyl,

R ³ selected from the group consisting of hydrogen, methyl, ethyl or propyl,

R ⁴ selected from the group consisting of hydrogen, methyl, ethyl or propyl,

R ⁵ selected from the group consisting of ethyl substituted at the 2-position and substituents at the 2-position including, but not limited to, amino, alkoxycarbonyl, alkanoyloxy, and acyloxy derived from amino acids,

R ^6a 、R ^6b optionally selected from hydrogen or C ₁ To C ₂₀ Is a hydrocarbon of (2)A radical or cyclic hydrocarbon radical, an aryl radical,

R ⁷ Selected from lower alkyl or substituted or unsubstituted aryl,

R ⁸ selected from substituted or unsubstituted C ₂ To C ₂₀ Saturated or unsaturated alkanoyl, saturated or unsaturated alkoxycarbonyl;

R ⁹ selected from lower alkyl, substituted or unsubstituted benzyl, substituted or unsubstituted imidazole-5-methyl, oligoethylene glycol (- [ CH) ₂ CH ₂ O] _n CH ₃ Wherein n is an integer of 0 to 4), C ₂ To C ₂₀ Saturated or unsaturated alkanoyl of (a);

R ¹⁰ selected from hydrogen, C ₁ -C ₆ Alkoxy or C of (2) ₂ To C ₂₀ Saturated or unsaturated alkanoyloxy groups of (a);

R ¹¹ 、R ¹² 、R ¹³ Selected from hydrogen, C ₂ To C ₂₀ Alkyl, isopropyl, isobutyl, arylalkyl, carbocycle or heterocycloalkyl, C ₂ To C ₂₀ Alkanoyloxy of (C).

n is an integer from 0 to 4.

In some embodiments, X ¹ And X ² May be

In some embodiments, X ¹ And X ² Can be independently hydrogen,

In some embodiments, Y ^1a 、Y ^1b 、Y ² Independently selected from hydrogen, or halogen (F, cl, or Br, especially F).

In some embodiments, X ³ Selected from the group consisting ofOr lone pair electrons.

In some embodiments, Y ³ 、Y ⁴ Independently selected from H, cl, CF ₃ Or the benzene ring structures to which they are attached together form a substituted or unsubstituted naphthalene ring, e.gWherein R is ¹¹ Selected from hydrogen, halogen atoms (especially F), hydroxy, substituted hydroxy, and lower alkyl; y is Y ⁴ Selected from the group consisting of hydrogen, halogen atoms, hydroxy groups, substituted hydroxy groups, and lower alkyl groups.

Further, the compound (Ia) is a compound represented by the formulae (IIa) and (IIIa):

wherein R is ¹¹ Selected from hydrogen, halogen atoms, hydroxy groups, substituted hydroxy groups, and lower alkyl groups; y is Y ⁴ Selected from the group consisting of hydrogen, halogen atoms, hydroxy groups, substituted hydroxy groups, and lower alkyl groups.

In some embodiments, W in formula (IIa) is oxygen, R ¹¹ Is hydrogen. In some embodiments, W in formula (IIa) is oxygen, R ¹¹ Is fluorine. In some embodiments Wherein W in formula (IIIa) is oxygen, Y ⁴ Is chlorine. In some embodiments, W in formula (III) is NH, Y ⁴ Is hydrogen. In some embodiments, W in formula (IIIa) is NH, Y ⁴ Is chlorine.

Further, the compound (Ib) is a compound represented by the formula (IIb):

wherein in some embodiments W in formula (IIb) is oxygen, Y ⁴ Is chlorine. In some embodiments, W in formula (IIb) is NH, Y ⁴ Is hydrogen. In some embodiments, W in formula (IIb) is NH, Y ⁴ Is chlorine.

In some embodiments, Y ⁵ Selected from dimethylamino,

Further, Y in any one of the above chemical formulas ^1b And Y ² And is hydrogen.

In some embodiments, compound (Ia) is a compound represented by formulas (IVa) to (VIa):

in some embodiments, compound (Ib) is a compound represented by formula (IIIb):

in some embodiments, the compound may be selected from derivatives of the A1 to a26 based compounds; in other embodiments, the compounds may be selected from derivatives of the B1 to B21 based compounds. The chemical structures of the compounds A1 to a26 and B1 to B21 are shown in tables 1 and 2. The compound can be represented by a corresponding structure, and can also be pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof.

TABLE 1

TABLE 2

/>

In some embodiments, the compound is a compound as shown in table 3 below, or a pharmaceutically acceptable salt, ester, hydrate, solvate, or stereoisomer thereof:

TABLE 3 Table 3

/>

The compound has better biological activity and can be used for treating diseases related to KRAS G12D mutation. In some embodiments, the compounds provided herein may be administered as a prodrug to a subject and disintegrate into the effective bioactive components, thereby acting to treat KRAS G12D-related disorders.

In some embodiments, the compounds provided herein may be naturally abundant or isotopically substituted compounds; the isotope may be ¹ H、D、 ¹⁶ O、 ¹² C、 ¹⁸ O、 ¹⁷ O、 ¹⁵ N and ¹³ c, etc.

The application also provides a pharmaceutical composition comprising any of the compounds described above or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof.

Further, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient or carrier or diluent.

Further, the pharmaceutically acceptable excipients include one or more of binders, fillers, disintegrants, lubricants and glidants.

Further, pharmaceutically acceptable carriers include one or more of creams, emulsions, gels, liposomes, and nanoparticles.

Further, the composition is suitable for oral administration or injection administration.

The application also provides the use of a compound as described in any of the above, or a pharmaceutically acceptable salt or ester or isomer or hydrate or composition thereof, in the manufacture of a medicament for the treatment, inhibition or prevention of hyperproliferative disorders. Also, the present application provides a method for treating, inhibiting or preventing a hyperproliferative disorder, comprising administering to a subject an effective amount of a compound and/or pharmaceutical composition described above, thereby effecting a treatment of the associated disorder.

In some embodiments, the hyperproliferative disorder is a malignancy or cancer associated with KRAS G12D.

Further, the malignancy or cancer is selected from: sarcomas (hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and malformation tumor; lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyoma, lymphoma), stomach (carcinoma, lymphoma, leiomyoma), pancreas (ductal adenocarcinoma, insulinoma, glucomonas, gastrinoma, carcinoid tumor, schwann intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hematoma, leiomyoma); urogenital tract: kidney (adenocarcinoma, wilms 'tumor (Wilms' tumor), lymphoma, leukemia), bladder and urinary tract (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, malformed tumor, embryonal carcinoma, malformed carcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder cancer, ampoule cancer, bile duct cancer; bone: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticuloma), multiple myeloma, malignant giant cell tumor chordoma, osteochondral tumor (osteochondral tumor), benign chondrioma, chondroblastoma, chondromyxofibroma, osteoid tumor and giant cell tumor; the nervous system: skull (bone tumor, hemangioma, granuloma, xanthoma, amoebonite), meninges (meningioma, glioma disease), brain (astrocytoma, myeloblastoma, glioma, epididymal tumor, germ cell tumor (pineal tumor), glioblastoma in various forms, oligodendroglioma, glioma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); gynaecology: uterus (endometrial carcinoma (serous bladder carcinoma, myxocystis carcinoma, unclassified carcinoma), granulosa sheath cell carcinoma, serointerstitial cell carcinoma, dysplasia, malignant malformation tumor), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, uveal sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), hematology blood (myelogenous leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphoblastic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-hodgkin's lymphoma (malignant lymphoma), skin malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, mole dysplastic nevi, lipoma, hemangioma, skin fibroma, keloids, psoriasis, adrenal gland neuroblastoma.

In some embodiments, the malignancy is one or more of non-small cell lung cancer, pancreatic cancer, colorectal cancer, cholangiocarcinoma, cervical cancer, bladder cancer, liver cancer, or breast cancer.

The application also provides a kit comprising any of the above compounds or pharmaceutically acceptable salts, esters, hydrates, solvates or stereoisomers, or any of the above compositions, for use in the preparation of a medicament for the treatment, inhibition or prevention of a KRAS G12D mutation-related disease or disorder.

The compound provided by the application, or pharmaceutically acceptable salt, ester, isomer or hydrate thereof, has a good KRAS G12D inhibition effect, and can be applied to the preparation of medicines for treating, inhibiting or preventing diseases or symptoms related to KRAS G12D mutation.

Detailed Description

In order to provide a clear and consistent understanding of the terms used in the description of the present application, some definitions are provided below. Furthermore, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

The use of the word "a" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "an" but it is also known to the meaning of "one or more", "at least one" and "one or more". Similarly, the word "another" may mean at least a second or a plurality.

The word "comprising" (and any form of comprising, such as "comprising" and "comprises"), "having" (and any form of having, "having", "including" and "containing") as used in this specification and claims is inclusive and open-ended and does not exclude additional unrecited elements or process steps. The terms "about" or "approximately" are used to indicate that the value includes errors in the instruments and methods used in determining the value.

The term "pharmaceutically acceptable" as used herein refers to medicaments, pharmaceuticals, inert ingredients, etc., as defined by the term, suitable for use in contact with human and lower animal tissue without undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.

"pharmaceutically acceptable stereoisomers" of a compound refer to isomers resulting from the spatial arrangement of atoms in the molecule. Further, isomers which are caused by the same order of connection of atoms or groups of atoms in a molecule but different spatial arrangements are called stereoisomers, and are mainly classified into two main types: stereoisomers due to bond length, bond angle, double bonds within the molecule, rings, etc. are known as configurational isomers (configuration stereo-isomers). In general, configurational isomers cannot or are difficult to interconvert. Stereoisomers that are caused by rotation of a single bond alone are referred to as conformational isomers (conformational stereo-isomers), sometimes also referred to as rotamers. When the rotation of the rotamers is blocked and cannot be rotated, the rotamers are "stereoisomers", for example, when large and different substituents exist at the α -and α' -positions in the biphenyl structure, the single bond rotation between two benzene rings cannot be freely rotated due to the blocking between the substituents, and thus two stereoisomers are produced.

The term "Kras G12D" refers to a mutant form of mammalian Kras protein comprising an amino acid substituting glycine with aspartic acid or the like at codon 12.

"pharmaceutically acceptable salt" of a compound refers to a salt of a pharmaceutically acceptable compound. Salts of desirable compounds (basic, acidic or charged functional groups) may retain or improve the biological activity and properties of the parent compound as defined herein and are not biologically undesirable. Pharmaceutically acceptable salts can be synthesized from the parent compound containing a basic or acidic fragment by conventional chemical methods. Typically, such salts are prepared by reacting a compound (free acid or base) with an isostoichiometric amount of base or acid in water or an organic solvent or in a mixture of both. Salts may be prepared in situ during the final isolation or purification of the pharmaceutical agent or by separately reacting the purified compound of the invention in free acid or base form with the corresponding base or acid desired and isolating the salt formed thereby. The term "pharmaceutically acceptable salts" also includes zwitterionic compounds comprising cationic groups covalently bonded to anionic groups, which are referred to as "inner salts".

The term "ester" as used herein refers to a compound that may be represented by the general formula RCOOR (carboxylic acid ester). These compounds can generally be obtained by reacting carboxylic acids with alcohols (elimination of a portion of water).

The term "substituted" or "having a substituent" means that the parent compound or moiety has at least one substituent. The term "unsubstituted" or "without substituents" means that the parent compound or moiety has no substituents other than chemical saturation of the undefined valence with a hydrogen atom.

In some embodiments, as the present invention refers to alkyl, acyl, cycloalkyl, heterocycloalkyl, alkoxy, aryloxy, heteroalkoxy, heteroaryloxy, aryl, heteroaryl groups, amino acid residues, oligopeptide (dipeptide, tripeptide, tetrapeptide) residues, phosphoryl, phosphono, aminophosphonyl, sulfonyl, thioacyl, benzyl, alkoxycarbonyl, aminocarbonyl, mercaptothiocarbonyl, alkylthio, thiocarbonyl, benzyloxycarbonyl, glycosyl, and glucono groups, which are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl groups).

Unless otherwise indicated, a "substituted" group has one substituent at one or more substitutable positions of the group, and when substituting more than one position in any given structure, the substituent is the same or different at each position.

As used herein, "substituent" or "substituent group" refers to a moiety selected from halogen (F, cl, br or I), hydroxy, mercapto, amino, nitro, carbonyl, carboxyl, alkyl, alkoxy, alkylamino, aryl, aryloxy, arylamino, acyl, sulfinyl, sulfonyl, phosphonyl, or other organic moieties conventionally used and accepted in organic chemistry.

The term "hydrocarbyl" refers to a group containing only two atoms, carbon and hydrogen, and the hydrocarbyl may be saturated or unsaturated, and alkyl, alkenyl and alkynyl groups all belong to the group of hydrocarbyl. Common hydrocarbyl groups include methyl, ethyl, propyl, n-butyl, isobutyl, vinyl, propynyl, and the like.

As used herein, "lower" in "lower aliphatic", "lower hydrocarbyl", "lower alkyl", "lower alkenyl" and "lower alkynyl" means that the moiety has at least one (at least two for alkenyl and alkynyl) and equal to or less than 6 carbon atoms, unless the carbon number is limited.

The terms "cycloalkyl", "alicyclic", "carbocycle" and equivalents refer to a group comprising a saturated or partially unsaturated carbocycle in a monocyclic, spiro (sharing one atom) or fused (sharing at least one bond) carbocycle system, wherein the carbocycle system has 3 to 15 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-cycloheptyl, bicyclo [4,3,0] nonyl, norbornyl, and the like. The term cycloalkyl includes unsubstituted cycloalkyl and substituted cycloalkyl

The terms "aryl" and "aromatic" as used herein refer to aromatic groups having "4n+2" electrons (pi) in conjugated single or multiple ring systems (fused or non-fused), and having 6 to 14 ring atoms, wherein n is an integer from 1 to 3. The polycyclic ring system includes at least one aromatic ring. Aryl groups may be attached directly or through a C1-C3 alkyl (also known as arylalkyl or aralkyl). Examples of aryl groups include, but are not limited to, phenyl, benzyl, phenethyl, 1-phenylethyl, tolyl, naphthyl, biphenyl, terphenyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, azulenyl, acenaphthylenyl, fluorenyl, phenanthryl, anthracenyl, and the like. The term aryl includes unsubstituted aryl and substituted aryl. Aryl groups are linked through hydrocarbyl groups, also known as arylalkyl groups.

The term "heterocycle" and equivalents as used herein refers to a group comprising a saturated or partially unsaturated carbocycle having 3 to 15 carbon atoms, including 1 to 6 heteroatoms (e.g., N, O, S, P) or containing heteroatoms (e.g., NH, NRx (Rx is alkyl, acyl, aryl, heteroaryl or cycloalkyl), PO, in a monocyclic, spiro (sharing one atom) or fused (sharing at least one bond) carbocyclic ring system ₂ 、SO、SO ₂ Etc.). The heterocycloalkyl group may be attached to C or to a heteroatom (e.g., through a nitrogen atom). "heterocycle" or "heterocyclic" includes heterocycloalkyl and heteroaryl. Examples of heterocycles include, but are not limited to, acridinyl, azecinyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzotriazole, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, 4αh-carbazolyl, carbolinyl, chromanyl, chromene, cinnolateA pinyl group, a decahydroquinolinyl group, a 2H,6H-1,5,2-dithiazinyl group, a dihydrofuro [2,3-b ]]Tetrahydrofuran, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, 3H-indolyl, isoquinolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, and 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, and pharmaceutical compositions containing the same pyrazolinyl, pyrazolyl, pyridazinyl, pyridoxazolyl, pyridoimidazole, pyridothiazole, pyridinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2, 5-thiadiazinyl, 1,2, 3-thiadiazinyl, 1,2, 4-thiadiazinyl, 1,2, 5-thiadiazolyl, 1,3, 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazinyl, thienoimidazolyl, thienyl, triazinyl, 1,2, 3-triazolyl, 1,2, 5-triazolyl, 3, 4-triazolyl, xanthenyl and the like. The term heterocycle includes unsubstituted heterocyclyl and substituted heterocyclyl. The heterocycle is attached through a hydrocarbyl group, also known as a heterocycloalkyl group.

The term "acyl" as used herein refers to the-C (=O) R left after one molecule of carbonic acid has been dehydroxylated _a The term "acyl" refers to a compound or fragment in which at least one carbon or heteroatom is covalently bonded to a carbon atom on-c=o. As used herein, the term "amine group" or "amino group" refers to an unsubstituted or substituted group of the general formula-NR _b R _c Is a fragment of (a). R is R _a 、R _b And R is _c Each independently is a substituted or unsubstituted hydrogen, hydrocarbyl, aryl, cyclic or heterocyclic group, or the like, or R _b And R is _c Together with the nitrogen atom to which they are attached form a heterocyclic ring. The term "amide" refers to the structure-C (=o) where the amino group is directly attached to the acyl group)NR _b R _c . The term "amido" refers to a compound or fragment in which at least one carbon or heteroatom is covalently bonded to a carbon atom on the amide group.

The term "alkanoyloxy" refers to R on an acyl group _a Is alkyl, the oxygen atom of the oxygen group is attached at one end to a carbon atom on the acyl group and at the other end is covalently bonded to at least one carbon or heteroatom in the compound or fragment.

"thioacyl" refers to the radical-C (=S) R formed by substitution of the oxygen atom on the acyl group with a sulfur atom _a Fragments of (2)

"aliphatic acyl" refers to an acyl group wherein the aliphatic group is attached to a carbon atom on the acyl group, i.e., R _a Is aliphatic. "aroyl" refers to an acyl group in which the aryl group is attached to a carbon atom on the acyl group, i.e., R _a Is aryl.

"phosphonyl" OR "phosphoryl" refers to the fragment-P (=O) (OR) remaining after dehydroxylation of a molecule of phosphoric acid _d )R _e "phosphonyl" refers to a compound or fragment in which at least one carbon or heteroatom is covalently bonded to a phosphorus atom on the phosphonyl group. R is R _d For substituted or unsubstituted hydrogen, hydrocarbon, aryl, cyclic or heterocyclic groups, etc., an "aminophosphonyl" group means that the amine group is attached to a phosphono group, i.e., R _e Is an amine group.

"sulfonyl" refers to the fragment that remains after one molecule of sulfonic acid has been dehydroxylated, and "sulfonyl" refers to a compound or fragment in which at least one carbon or heteroatom is covalently bonded to the sulfur atom on the sulfonyl.

The term "carbonyl" refers to a radical of formula-c=or, formed by the double bond connection of two atoms of carbon and oxygen _f The fragment, "carbonyl" is a constituent of a functional group such as an aldehyde, ketone, acid, etc., the term "carbonyl" refers to a compound OR fragment in which at least one carbon OR heteroatom is bonded to-c=or _f Covalent bonding of carbon atoms thereon, R _f Is a substituted or unsubstituted hydrogen, hydrocarbyl, aryl, cyclic or heterocycloalkyl group, or the like. The term "alkoxycarbonyl" refers to R _f Is an alkoxy group, i.e., the oxygen atom on the alkoxy group is attached to a carbon atom on the carbonyl group. The term "aminocarbonyl" refers to R _f Is an amine group, i.e., the nitrogen atom on the amine group is attached to a carbon atom on the carbonyl group. The term' Benzyloxycarbonyl "refers to an oxygen atom on a benzyloxy group attached to a carbon atom on a carbonyl group.

The term "thiocarbonyl" refers to the radical-C (=S) R formed by substitution of the oxygen atom on the carbonyl group with a sulfur atom _f Is a fragment of (a). The term "mercaptothiocarbonyl" refers to R _f Is a mercapto group, i.e., the carbon atom on the thiocarbonyl group is attached to the sulfur atom on the mercapto group.

The term "alkylthio" refers to an alkyl group having a mercapto group attached thereto. Suitable alkylthio groups include groups having from 1 to about 12 carbon atoms, preferably from 1 to about 6 carbon atoms.

The term "alkoxy" or "lower alkoxy" as used herein refers to a structure in which an alkyl group is attached to an oxygen atom. Representative alkoxy groups include groups having from 1 to about 6 carbon atoms, such as methoxy, ethoxy, propoxy, t-butoxy, and the like. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, pentyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, and the like. The term "alkoxy" includes unsubstituted or substituted alkoxy, and perhaloalkoxy and the like.

The term "cholic acid substitution" as used herein refers to the substitution of cholic acid compounds including bile acids synthesized by hepatocytes, including cholic acid, chenodeoxycholic acid, glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid, especially chenodeoxycholic acid, ursodeoxycholic acid.

The term "ester-forming group" or "ester" as used herein refers to a structure containing an ester functional group-RCOOR '(R' is typically an alkyl group or other non-H group) in the fragment. Wherein R is, for example, lower alkyl or aryl, such as methylene, ethylene, isopropylidene, phenylene, etc., but is not limited thereto; r' is, for example, lower alkyl or aryl, such as methyl, ethyl, propyl, isopropyl, butyl, phenyl, etc., but is not limited thereto. The term "salt forming moiety" as used herein refers to a moiety capable of forming a salt with an acidic group, such as a carboxyl group, for example, but not limited to, sodium, potassium, tetraethylamine, tetrabutylamine, and the like.

"pharmaceutically acceptable salt" of a compound refers to a salt of a pharmaceutically acceptable compound. Salts of desirable compounds (basic, acidic or charged functional groups) may retain or improve the biological activity and properties of the parent compound as defined herein and are not biologically undesirable. Pharmaceutically acceptable salts may be those mentioned by Berge et al, "Pharmaceutical Salts", J.Pharm.Sci.66,1-19 (1977). Including but not limited to:

(1) Salts formed by adding acids to basic or positively charged functional groups, inorganic acids including hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, carbonates, and the like. Organic acids include acetic acid, propionic acid, lactic acid, oxalic acid, glycolic acid, pivalic acid, t-butyl acetic acid, β -hydroxybutyric acid, valeric acid, caproic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, succinic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, cyclohexylsulfamic acid, benzenesulfonic acid, sulfanilic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 3-phenylpropionic acid, lauryl sulfonic acid, lauryl sulfuric acid, oleic acid, palmitic acid, stearic acid, lauric acid, pamoic acid, pantothenic acid, lactobionic acid, alginic acid, galacturonic acid, gluconic acid, glucoheptonic acid, glutamic acid, naphthoic acid, hydroxynaphthoic acid, salicylic acid, ascorbic acid, stearic acid, muconic acid, and the like.

(2) When acidic protons are present in the parent compound or are replaced by metal ions, a base may be added to give a salt. The metal ions include alkaline metal ions (e.g., lithium, sodium, potassium), alkaline earth metal ions (magnesium, calcium, barium) or other metal ions such as aluminum, zinc, iron, etc. Organic bases include, but are not limited to, N' -dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, piperazine, chloroprocaine, procaine, choline, lysine, and the like.

Pharmaceutically acceptable salts can be synthesized from the parent compound containing a basic or acidic fragment by conventional chemical methods. Typically, such salts are prepared by reacting a compound (free acid or base) with an isostoichiometric amount of base or acid in water or an organic solvent or in a mixture of both. Salts may be prepared in situ during the final isolation or purification of the pharmaceutical agent or by separately reacting the purified compound of the invention in free acid or base form with the corresponding base or acid desired and isolating the salt formed thereby. The term "pharmaceutically acceptable salts" also includes zwitterionic compounds comprising cationic groups covalently bonded to anionic groups, which are referred to as "inner salts". All acids, salts, bases and other ionic and nonionic forms are encompassed by the compounds of the present invention. For example, if the compound of the present invention is an acid, the salt form of the compound is also included. Also, if the compounds of the present invention are salts, the acid and/or base forms of the compounds are also included.

As used herein, the term "effective amount" refers to the amount or dose of a therapeutic agent (e.g., a compound) that provides a desired therapeutic, diagnostic, or prognostic effect in a subject after administration to the subject in a single dose or multiple doses. The effective amount can be readily determined by the attending physician or diagnostician by known techniques and by observing results obtained under similar circumstances. In determining an effective amount or dose of a compound to be administered, a number of factors are considered, including, but not limited to: the weight, age, and general health of the subject; specific diseases involved; the degree of involvement or severity of the disease or condition to be treated; responses of the subject individual; the particular compound being administered; mode of administration; bioavailability characteristics of the administered formulation; a selected dosage regimen; use of concomitant medications; and other related considerations.

The present invention also provides a pharmaceutical composition, which in one embodiment comprises: the disclosed compounds or pharmaceutically acceptable salts or esters or isomers or hydrates thereof, and pharmaceutically acceptable excipients or carriers or diluents.

Specifically, the pharmaceutically acceptable excipients include one or more of binders, fillers, disintegrants, lubricants and glidants. Pharmaceutically acceptable carriers or diluents include one or more of creams, emulsions, gels, liposomes, and nanoparticles.

"pharmaceutical composition" is meant to include a compound as described herein, and at least one component, including pharmaceutically acceptable carriers, diluents, adjuvants, excipients or vehicles, such as preserving, bulking, disintegrating, wetting, emulsifying, suspending, sweetening, flavoring, perfuming, antibacterial, antifungal, lubricating, dispersing agents and the like, depending on the mode of administration and the requirements of the dosage form. "preventing" or "prevention" is used to mean at least reducing the likelihood of acquiring a disease or disorder (or susceptibility) to acquire a disease or disorder (i.e., not allowing the clinical symptoms of at least one disease to develop into a patient that may be exposed to or susceptible to the disease but has not experienced or displayed symptoms of the disease).

In some embodiments, "treating" or "treating" any disease or disorder refers to alleviating at least one disease or disorder. In certain embodiments, treatment "or" treatment "refers to alleviation of at least one physical parameter, which may be distinguishable or indistinguishable by the patient. In certain embodiments, "treatment" or "treatment" refers to inhibiting a disease or disorder physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In certain embodiments, "treatment" or "treatment" refers to an adverse effect of improving quality of life or disease in a subject in need thereof. By "therapeutically effective amount" is meant an amount of a compound administered to a subject for treating or preventing a disease that is sufficient to achieve an effect of treating or preventing the disease. "therapeutically effective amount" will depend on the compound; disease and severity thereof; the age, weight, etc. of the subject to be treated or prevented from suffering from the disease. As used herein, a "therapeutically effective amount" refers to a compound or composition that is sufficient to prevent, treat, inhibit, reduce, alleviate or eliminate one or more etiologies, symptoms, or complications of a disease, such as cancer.

The term "subject" refers to animals, including mammals and humans, and particularly humans.

The term "prodrug" or its equivalent refers to an agent that is converted directly or indirectly to an active form in vitro or in vivo (see, e.g., r.b. silverman,1992, "The Organic Chemistry of Drug Design and Drug Action," Academic Press, chap.8; bundegaard, hans; editor.neth. (1985), "Design of Prodrugs".360pp.elsevier, amsterdam; stilla, v.; borchard, r.; hageman, m.; oliyai, r.; maag, h.; tilley, j.; (eds.) (2007), "produgs: challenges and Rewards, XVIII,1470p. Springer). Prodrugs can be used to alter the biodistribution (e.g., such that the agent does not normally enter the protease reaction site) or pharmacokinetics of a particular drug. Various groups have been used to modify compounds to form prodrugs, such as esters, ethers, phosphates, and the like. When the prodrug is administered to a subject, the group is cleaved off enzymatically or non-enzymatically, reduced, oxidized, or hydrolyzed, or otherwise releasing the active compound. As used herein, "prodrug" includes pharmaceutically acceptable salts or esters, or pharmaceutically acceptable solvates or chelates, as well as any crystalline form of the above.

The term "amino acid" generally refers to an organic compound that contains both carboxylic acid groups and amino groups. The term "amino acid" includes "natural" and "unnatural" amino acids. In addition, the term amino acid includes O-alkylated amino acids or N-alkylated amino acids, as well as amino acids having a side chain containing nitrogen, sulfur or oxygen (e.g., lys, cys or Ser), where the nitrogen, sulfur or oxygen atom may or may not be acylated or alkylated. The amino acid may be a pure L-isomer or D-isomer, or a mixture of L-and D-isomers, including but not limited to a racemic mixture.

The term "natural amino acid" and equivalent expression refers to an L-amino acid that is typically found in naturally occurring proteins. Examples of natural amino acids include, but are not limited to, alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (gin), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), beta-alanine (beta-Ala), and gamma-aminobutyric acid (GABA).

The term "unnatural amino acid" refers to any derivative of a natural amino acid, including D-form amino acids, as well as alpha-and beta-amino acid derivatives. The terms "unnatural amino acid" and "not a natural amino acid" are used interchangeably herein. It should be noted that certain amino acids (e.g., hydroxyproline) that may be categorized as unnatural amino acids in the present invention may also be found in certain biological tissues or in certain proteins in nature. Amino acids having many different protecting groups suitable for direct use in solid phase peptide synthesis are commercially available. In addition to the twenty most common natural amino acids, the following exemplary unnatural amino acids and amino acid derivatives (common abbreviations in brackets) can be used in accordance with the invention: 2-aminoadipic acid (Aad), 3-aminoadipic acid (β -Aad), 2-aminobutyric acid (2-Abu), α, β -dehydro-2-aminobutyric acid (8-AU), 1-aminocyclopropane-1-carboxylic Acid (ACPC), aminoisobutyric acid (Aib), 3-aminoisobutyric acid (β -Aib), 2-aminothiazoline-4-carboxylic acid, 5-aminopentanoic acid (5-Ava), 6-aminocaproic acid (6-Ahx), 2-aminoheptanoic acid (Ahe), 8-aminocaprylic acid (8-Aoc), 11-aminoundecanoic acid (11-Aun), 12-aminododecanoic acid (12-Ado), 2-aminobenzoic acid (2-Abz), 3-aminobenzoic acid (3-Abz), 4-aminobenzoic acid (4-Abz), 4-amino-3-hydroxy-6-methylheptanoic acid (aprotinin, sta), aminooxyacetic acid (Aoa), 2-aminotetralin-2-carboxylic Acid (ATC), 4-aminohexyl-3-hydroxypentanoic acid (acnh) and (4-acp-hydroxy-3-alanine) ₂ -Phe), 2-aminopimelic acid (Apm), biphenylalanine (Bip), p-bromophenylalanine (4-Br-Phe), o-chlorophenylalanine (2-Cl-Phe), m-chlorophenylalanine (3-Cl-Phe), p-chlorophenylalanine (4-Cl-Phe), m-chlorotyrosine (3-Cl-Tyr), p-benzoylphenylalanine (Bpa), t-butylglycine (TLG), cyclohexylalanine (Cha), cyclohexylglycine (Chg), desmin (Des), 2-diaminopimelic acid (Dpm), 2, 3-diaminopropionic acid (Dpr), 2, 4-diaminobutyric acid (Dbu), 3, 4-dichlorophenylalanine (3, 4-Cl 2-Phe), 3, 4-difluorophenylalanine (3, 4-F2-Phe), 3, 5-diiodotyrosine (3, 5-I2-Tyr), N-ethyl (EtGly), N-ethylaspartic acid (Asn),o-fluorophenylalanine (2-F-Phe), m-fluorophenylalanine (3-F-Phe), p-fluorophenylalanine (4-F-Phe), m-fluorophenylalanine (3-F-Tyr), homoserine (Hse), homophenylalanine (Hfe), homotyrosine (Htyr), hydroxylysine (Hyl), isohydroxylysine (aHyl), 5-hydroxytryptophan (5-OH-Trp), 3-or 4-hydroxyproline (3-or 4-Hyp), p-iodophenylalanine-iso-tyrosine (3-I-Tyr), indoline-2-carboxylic acid (Idc), iso Ai Dumei prime (Ide), isoleucine (alpha-Ile), iso-pipecolic acid (Inp), N-methylisoleucine (MeLys), m-methyltyrosine (3-Me-Tyr), N-methylvaline (MeVal), 1-naphthylalanine (1-Nal), 2-naphthylalanine (2-Nal), p-nitrophenylalanine (4-NO 2-Phe), 3-nitro-3-NO (3-NO-2-Tyr), norvaline (Ovaline (On-Tyr), norvaline (Oh-Tyr), penicillamine (Pen), pentafluorophenylalanine (F5-Phe), phenylglycine (Phg), piperidinic acid (Pip), propargylglycine (Pra), pyroglutamic acid (PGLU), sarcosine (Sar), tetrahydroisoquinoline-3-carboxylic acid (Tic), thiazolidine-4-carboxylic acid (thioproline, th).

The term "peptide" or "oligopeptide" refers to a compound formed by the intermolecular dehydration condensation of two or more amino acids, which are then linked together by amide bonds. Generally, the number of amino acids constituting a peptide is 2 (dipeptide) to 20 (eicosapeptide).

The term "residue" refers to the major portion of a molecule after removal of a group, e.g., an amino acid residue (e.g., structure H ₂ NCH ₂ CO-which is a glycyl group, is a moiety after removal of one hydroxyl group from glycine) and a peptide residue.

The term "base compound" or "base molecule" refers to a particular compound or drug molecule that is biologically active; in addition to being a drug molecule itself, can be further modified or derivatized to form new compounds, such as prodrug compounds or derivative compounds.

In other embodiments, the invention provides methods of treating and/or preventing immune-related diseases, disorders and conditions, diseases having an inflammatory component, and disorders associated with the foregoing using at least one KRAS G12D inhibitor compound or composition provided herein.

Other diseases, disorders and conditions that may be treated or prevented in whole or in part by inhibiting KRAS G12D activity are also candidate indications for KRAS G12D inhibitor compounds and compositions provided herein.

The term "treating" refers to initiating an action (e.g., administering a KRAS G12D inhibitor or a pharmaceutical composition comprising the same) after a disease, disorder or condition or symptom thereof has been diagnosed, observed, so as to temporarily or permanently eliminate, alleviate, inhibit, slow or ameliorate at least one underlying cause of, or afflict a disease, disorder or condition in a subject. Thus, treatment includes inhibiting (e.g., preventing or alleviating the development or further development of a disease, disorder or condition or clinical symptoms associated therewith) active disease. In particular, the term "treatment" as used in the present application is used to specifically denote the administration of a therapeutic comprising a compound or composition according to the present application to a patient already suffering from an infection. The term "treatment" also relates to the administration of a compound or composition according to the application, optionally together with one or more antibacterial agents, to alleviate or mitigate KRAS G12D mutation or one or more symptoms associated with KRAS G12D mutation; or slowing the progression of KRAS G12D mutation or one or more symptoms associated with KRAS G12D mutation; or lessening the severity of the KRAS G12D mutation or the severity of one or more symptoms associated with the KRAS G12D mutation; or inhibit the clinical manifestation of KRAS G12D mutation; or inhibiting the manifestation of undesirable symptoms of KRAS G12D mutation.

The term "preventing" refers to initiating an action (e.g., administering a KRAS G12D inhibitor or a pharmaceutical composition comprising the same) in a manner (e.g., prior to the onset of a disease, disorder, condition, or symptom thereof) that temporarily or permanently prevents, inhibits, suppresses, or reduces the risk of a subject suffering from a disease, disorder, or condition, etc. (as determined by, for example, lack of clinical symptoms) or delays the onset of a particular disease, condition, or symptom in the case of a subject susceptible to the disease, condition, or symptom. In some instances, the term also refers to slowing the progression of a disease, disorder, or condition or inhibiting the progression thereof to a deleterious or other undesirable state. In particular, the term "prevention" as used in the present application is intended to mean the administration of a compound or composition according to the present application to prevent the occurrence of a disease associated with KRAS G12D mutation. The term "preventing" also encompasses preventing at least one KRAS G12D mutation by administration of a compound or composition according to the application to a patient susceptible to KRAS G12D mutation or at risk of KRAS G12D mutation.

As used herein, the term "KRAS G12D mutation-related disease" or "KRAS G12D-related disease" or other synonymous expressions mean any disease, disorder or other pathological condition in which mutated KRAS G12D is known to play a role. Thus, in some embodiments, the application relates to treating or lessening the severity of one or more diseases in which KRAS G12D is known to play a role. In particular, KRAS G12D mutation-related diseases are hyperproliferative diseases, such as malignant tumors, preferably lung cancer such as non-small cell lung cancer, pancreatic cancer, cholangiocarcinoma, cervical cancer, bladder cancer, liver cancer or breast cancer, etc.

In some embodiments, the application further provides the use of KRAS G12D inhibitor compounds and compositions of the application in combination with one or more additional agents. The one or more additional agents may have KRAS G12D modulating activity and/or they may act through different mechanisms of action. In some embodiments, such agents comprise radiation (e.g., local or systemic radiation therapy) and/or other therapeutic forms of non-pharmacological nature. When a combination therapy is used, the KRAS G12D inhibitor and one additional agent may be in the form of a single composition or multiple compositions, and the treatment regimen may be administered simultaneously, sequentially or by some other regimen. For example, in some embodiments, embodiments are provided in which the radiation phase is followed by a chemotherapy phase. Combination therapies may have additive or synergistic effects.

Pharmaceutical compositions containing the active ingredient (e.g., KRAS inhibitors) may be in a form suitable for oral use, such as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads or elixirs. Pharmaceutical compositions for oral use may be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more agents, such as sweeteners, flavoring agents, coloring agents and preservatives to provide pharmaceutically acceptable formulations. Tablets, capsules and the like typically contain the active ingredient in admixture with non-toxic pharmaceutically acceptable carriers or excipients which are suitable for the manufacture of tablets. These carriers or excipients may be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.

In some embodiments, the composition is an injectable formulation. In other embodiments, the composition is formulated for oral administration to a subject.

In some embodiments, the pharmaceutical composition is contained in a single-use container (e.g., a single-use vial, ampoule, syringe, or auto-injector), while in other embodiments, is contained in a multi-use container (e.g., a multi-use vial).

The formulation may also include a carrier to protect the composition from rapid degradation or disappearance from the body, such as controlled release formulations, including liposomes, hydrogels, and microencapsulated delivery systems. For example, a time delay material such as glycerol monostearate or glycerol stearate alone or in combination with a wax may be used. Any drug delivery device may be used to deliver the KRAS G12D inhibitor, including implants (e.g., implantable pumps) and catheter systems, slow injection pumps and devices. All of which are well known to those skilled in the art.

The pharmaceutical compositions may also be in the form of sterile injectable aqueous or oleaginous suspensions. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents which are mentioned in connection with the present application. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Acceptable diluents, solvents and dispersion media that may be used include water, ringer's solution, isotonic sodium chloride solution, cremophor ELTM (BASF, parippany, NJ) or Phosphate Buffered Saline (PBS), ethanol polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol) and suitable mixtures thereof. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. Furthermore, fatty acids (such as oleic acid) find use in the preparation of injectables. Prolonged absorption of a particular injectable formulation can be brought about by the inclusion of agents which delay absorption (e.g., aluminum monostearate or gelatin).

The KRAS G12D inhibitor compounds and compositions provided herein may be administered to a subject in any suitable manner known in the art. Suitable routes of administration include, but are not limited to, oral; parenteral, e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implantation), intraperitoneal, intracisternal, intra-articular, intracerebral (intraparenchymal and intracerebroventricular; nasal; vaginal; sublingual; intraocular; rectal; topical (e.g., transdermal); buccal and inhalation.

The application also provides kits comprising KRAS G12D inhibitor compounds or compositions. Kits are generally in the form of physical structures that house the various components and can be used, for example, to practice the methods provided herein. For example, a kit may include one or more KRAS G12D inhibitors of the present disclosure (e.g., provided in a sterile container), which may be in the form of a pharmaceutical composition suitable for administration to a subject. The KRAS G12D inhibitor may be provided in a ready-to-use (e.g., tablet or capsule) form or in a form that requires reconstitution or dilution (e.g., powder) prior to administration, for example. When the KRAS G12D inhibitor is in a form that requires reconstitution or dilution by the user, the kit may further comprise a diluent (e.g., sterile water), buffer, pharmaceutically acceptable excipient, etc., packaged with or separately from the KRAS G12D inhibitor. When combination therapies are employed, the kit may contain several therapeutic agents independently, or they may already be combined in the kit. Each component of the kit may be packaged in a separate container, and all of the various containers may be in a single package. The kit of the present application may be designed to properly maintain the conditions (e.g., refrigeration or freezing) required for the components contained therein.

Examples

The application will be more readily understood by reference to the following examples, which are provided to illustrate the application and should not be construed to limit the scope of the application in any way.

Unless defined otherwise or the context clearly indicates otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. It should be understood that any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application. Materials and instruments used in the present application are conventionally commercially available unless otherwise indicated.

Preparation example:

synthesis of intermediates

Synthesis of M1

Step 1: compound M1-1 was dissolved in methanol, followed by slow addition of 4M dioxane hydrochloride solution. The reaction solution was stirred at room temperature for 1 hour, and then dried by spin. The crude product is adjusted to pH 8 by sodium bicarbonate aqueous solution, diluted by methanol and filtered and dried. The residue was dissolved in dichloromethane and filtered and dried to give crude M1-2.

Step 2: the crude product M1-2 is added into dioxane of the compound M1-3, then water solution of cesium carbonate is added, and finally [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex is added. After the mixture was nitrogen-substituted three times, it was heated to 100℃under a nitrogen atmosphere and stirred at this temperature for 2 hours. After the reaction solution was cooled, water and methylene chloride were added to dilute the solution. Separating out an organic phase, washing the organic phase with water, washing with brine, drying, and filtering and spin-drying. The residue was purified by column chromatography to give compounds M1-4.

A1M concentration TBAF tetrahydrofuran solution was added to the tetrahydrofuran solution of compounds M1-4. The reaction solution was stirred at room temperature for 1 hour and then concentrated in vacuo. The residue was purified by column chromatography to give compound M1.

Synthesis of M2

Step 1: the 4M dioxane hydrochloride solution was slowly added to the dichloromethane solution of compounds M1-3. The mixture was stirred at room temperature for 1 hour and then concentrated in vacuo, and the residue was purified by column chromatography to give compound M2-1.

Step 2: the compound M2-1 was added to a dioxane solution of the compound M1-1, followed by an aqueous solution of cesium carbonate and finally a [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex. After the mixture was nitrogen-substituted three times, it was heated to 100℃under a nitrogen atmosphere and stirred at this temperature for 2 hours. After the reaction solution is cooled, water and ethyl acetate are added for dilution. Separating out an organic phase, washing the organic phase with water, washing with brine, drying, and filtering and spin-drying. The residue was purified by column chromatography to give compound M2-2.

Step 3:1M TBAF in tetrahydrofuran was added to the tetrahydrofuran solution of compound M2-2. The reaction solution was stirred at room temperature for 1.5 hours, then concentrated in vacuo, and the residue was purified by column chromatography to give compound M2.

Synthesis of Compound 1

60% sodium hydride was added to anhydrous tetrahydrofuran and cooled to 0℃under nitrogen. Then, compound 1-1 was added, and when the bubbles in the reaction liquid disappeared, the mixture was stirred at room temperature for 30 minutes, and then cooled to 0 ℃. Acetyl chloride was slowly added dropwise, and the reaction solution was stirred at 0℃for 30 minutes and then warmed to room temperature, followed by stirring at room temperature for 2 hours. The reaction was quenched with saturated aqueous sodium bicarbonate solution, and water and ethyl acetate were added. The separated organic phase was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was dried by spin to give a residue, which was purified by column chromatography to give compounds 1-2.

Triethylamine was added to the dichloromethane solution of compound 1-2, followed by p-nitrophenyl chloroformate. The reaction solution was stirred at room temperature for 6 hours, and then concentrated. The residue was purified by column chromatography to give compounds 1-3.

Triethylamine was added to a dichloromethane solution of compound M-1, followed by DMAP and compounds 1-3. The reaction solution was heated to 40℃and stirred at this temperature for 3 hours. The reaction solution was cooled and concentrated, and the residue was purified by column chromatography to give crude compounds 1 to 4.

A4M solution of dioxane hydrochloride was added to a dichloromethane solution of compounds 1-4. The reaction solution was stirred at room temperature for 2 minutes and then concentrated in vacuo, and the residue was purified by preparative chromatography to give compound 1.

Synthesis of Compound 52

Triethylamine was added to a methylene chloride solution of p-nitrophenol, followed by slow addition of compound 52-1 at 0 ℃. After the mixture was warmed to room temperature and stirred for 1 hour, it was washed with water, brine, dried over anhydrous sodium sulfate, and then filtered to dryness. The residue was purified by column chromatography to give compound 52-2.

Compound 52-2 was dissolved in acetone, followed by the addition of sodium iodide. After nitrogen displacement of the mixture, it was heated to 50 ℃ and stirred at temperature for 30 hours. The mixture was filtered and the filtrate was dried by spinning. The residue was purified by column chromatography to give compound 52-3.

N-butyric acid is dissolved in a mixed solvent of acetonitrile and water, and silver oxide is added. After the mixture was reacted at room temperature for 16 hours in the dark, it was filtered. And spin-drying the filtrate to obtain silver butyrate.

Silver butyrate was added to a toluene solution of compound 52-3. The reaction was heated to 50℃and stirred at this temperature overnight. The reaction solution was cooled to room temperature, and then filtered, and the filtrate was collected to give a solid. This solid was purified by column chromatography to give compound 52-4.

Compound 52-3 was added to a dichloromethane solution of compound M1, followed by triethylamine and DMAP. The mixture was stirred at 40 degrees for 1 hour and then dried by spinning. The residue was purified by column chromatography to give compound 52-5.

Compound 52-5 was dissolved in a mixed solvent of dichloromethane and methanol, and then 4M dioxane hydrochloride solution was slowly added. The reaction solution was stirred at room temperature for 15 minutes and then dried rapidly at 40 ℃. The residue was dissolved in dichloromethane, pH was adjusted to alkaline with triethylamine, and then dried by spinning. The residue was dissolved again by adding dichloro, washed twice to three times with water, brine, dried over anhydrous sodium sulfate and filtered. The filtrate was dried by spin to give crude 52. The crude product was purified by column chromatography to give compound 52.

Synthesis of Compound 81

Decanoic acid was added to a dichloromethane solution of compound M2, followed by DMAP and DCC. The reaction solution was stirred at room temperature for 1.5 hours, then concentrated in vacuo, and the residue was purified by column chromatography to give compound 81-1.

Trifluoroacetic acid (1 mL) was added to a dichloromethane solution of compound 81-1. The reaction solution was stirred at room temperature for 5 minutes and then concentrated in vacuo, and the residue was purified by reverse phase preparative chromatography to give compound 81.

Synthesis of Compound 82

DMF was added to the thionyl chloride solution of compound 82-1. The reaction solution was heated to 85℃and stirred at this temperature for 3 hours, and then cooled to room temperature. And concentrating the reaction solution to obtain a crude product of the acyl chloride. Dihydroxyacetone is dissolved in dichloromethane, pyridine is added, and finally, crude acyl chloride is slowly added. After stirring the reaction solution at room temperature overnight, water and methylene chloride were added. The organic phase was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography to give compound 82-2.

Compound 82-2 was dispersed into a mixed solution of tetrahydrofuran and water, and then cooled to 0 ℃. Then, sodium borohydride was added, and the reaction solution was stirred at 0℃for 2 minutes. The pH was adjusted to 7 with 0.5N aqueous hydrochloric acid while maintaining the internal temperature at 0℃and then extracted with methylene chloride. The separated organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo, and the resulting residue was purified by column chromatography to give compound 82-3.

Triethylamine was added to a dichloromethane solution of compound 82-3, followed by DMAP, and finally p-nitrophenyl chloroformate. The reaction was stirred at room temperature for 5 hours and the solvent was removed in vacuo. The residue was purified by column chromatography to give compound 82-4.

Triethylamine was added to a dichloromethane solution of compound M2, followed by DMAP, and finally compound 82-4. The reaction solution was stirred at room temperature for 3 hours and then dried by spin. The residue was purified by column chromatography to give crude compound 82-5.

Trifluoroacetic acid was added to a dichloromethane solution of compound 82-5. The reaction solution was stirred at room temperature for 10 minutes and then concentrated in vacuo, and the residue was purified by reverse phase preparative chromatography to give compound 82.

Synthesis of Compound 83

Triethylamine was added to the dichloromethane solution of compound 62, followed by DMAP and pivaloyl chloride. The reaction solution was stirred at room temperature for 1.5 hours, and then methylene chloride and water were added. The separated organic phase was washed with water, brine, dried over anhydrous sodium sulfate and filtered. The filtrate was dried by spin-drying and the residue was purified by column chromatography to give compound 83.

Synthesis of Compound 84

Pyridine is added into a carbon tetrachloride solution of a compound 84-1, cooled to a temperature of minus 20 ℃ to a temperature of minus 10 ℃ under the protection of nitrogen, and triphosgene is slowly added. The mixture was slowly allowed to warm to room temperature, then heated to 40 degrees and stirred at this temperature for 1 hour. The reaction solution was cooled to room temperature and then filtered. The filtrate was dried by spin to give compound 84-2.

Triethylamine was added to a tetrahydrofuran solution of p-nitrophenol, followed by addition of compound 84-2. After the reaction solution was stirred at room temperature for 1.5 hours, methylene chloride and water were added. The separated organic phase was washed with water, brine, and then dried over anhydrous sodium sulfate and filtered. The residue after drying the filtrate was purified by column chromatography to give compound 84-3.

Compound 84-3 was dissolved in acetone, followed by the addition of sodium iodide. The mixture was heated to 50 degrees and stirred at this temperature for 15 hours. The reaction solution was cooled to room temperature and then filtered. The residue after drying the filtrate was purified by column chromatography to give compound 84-4.

Compound 84-4 was dissolved in toluene and silver butyrate was added. The mixture was warmed to 50 degrees and stirred at the temperature again for 15 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to give compound 84-5.

Compound 84-5 was added to a dichloromethane solution of compound M1, followed by DMAP and triethylamine. The mixture was heated to 40 degrees and stirred at this temperature for 1.5 hours. The reaction solution was cooled, concentrated in vacuo, and the residue was purified by column chromatography to give compound 84-6.

Compound 84-6 was dissolved in methylene chloride and then 4M dioxane hydrochloride solution was added. The reaction was stirred at room temperature for 15 minutes and then concentrated in vacuo. The residue was basified with triethylamine and then purified by column chromatography to give compound 84.

Biological assays

Experimental example 1 pharmacokinetic experiments

The experimental animals were divided into 16 groups of 48 ICR mice, 30-34g in weight, 3 animals per group. Blood samples were collected at 0.167, 0.5, 1, 2, 4, 6, 8, 24h after oral administration, and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8h after intravenous administration. Test compounds were formulated as experimental solutions in 5% DMSO, 5% Solutol and 90% 20% sbe- β -CD vehicle. Animals were fasted for 12 hours and given by intravenous infusion 3mg/kg and gavage 10mg/kg of Compound A1 equivalent tail vein intravenous infusion or gavage. After administration, blood was collected at a predetermined time point (about 50. Mu.L/serving), 20. Mu.L of whole blood was quantitatively aspirated into an EP tube containing 200. Mu.L of internal standard acetonitrile, and the supernatant was collected after centrifugation at 12000rpm for 5min at 4℃and stored at low temperature. Taking supernatant for LC-MS/MS analysis, and detecting the content of corresponding drugs and metabolites in plasma.

Experimental example 2. Tumor proliferation inhibition experiment of AsPC-1 mouse drug effect model: study of tumor growth inhibition in mice treated with oral administration

5x 10 of AsPC-1 human metastatic pancreatic adenocarcinoma cells ⁶ 12 animals were randomly assigned to vehicle control group (4), test compound dosed group (4) and control compound group (4) on day 11 after subcutaneous implantation of 6-8 week old Balb/C6-8 nude mice right side, suspended in 0.1mL PBS. The test compound and the control compound were orally administered by gavage twice daily with equimolar equivalents. Tumor length and diameter were measured twice weekly by vernier calipers, and tumor volume (tv= (long diameter x short diameter)/2) was calculated. Inhibition of tumor growth was assessed by tumor (volume) inhibition TGI.

TGI＝[1-(V _t -V ₀ (experimental group))/(V _t -V ₀ (vehicle control group)]x 100％。

While the body weight of the test animal is periodically observed and calculated.

Experimental example 3 cell 3D proliferation experiment

To evaluate the inhibitory effect of the compounds on KRAS G12D, cells with different KRAS genotypes, i.e., human non-small cell lung cancer cells (NCI-H358G 12C) and human metastatic pancreatic cancer cells (AsPC-1G 12D), were individually seeded in 96-well plates and grown into suspended spherical cultures. After a treatment period of 5 days, lead to Cross CellCell viability assays detect the effect of compounds on cell proliferation. The specific experimental procedure is as follows.

Cell culture: 2 cells were resuscitated with the corresponding medium, cells were maintained to grow to log phase, and cells were collected with a centrifuge at 1000rpm for 5 minutes. After centrifugation, the supernatant was removed and appropriate amount of medium was added to resuspend the cells.

Preparation of 1% methylcellulose solution: weighing 1g of methyl cellulose, placing the mixture in a glassware, and sterilizing the glassware under high pressure; after cooling, 100mL of the corresponding culture medium is added, mixed vigorously and stirred by a magnetic stirrer at 4 ℃; after 48h, the mixture was completely dissolved and stored at 4 ℃.

Cell plating: counting the cell suspension; the cell suspension concentration was adjusted to 1.5X10 by dilution with medium ⁵ Uniformly mixing 3.5mL of cell suspension and 6.5mL of 1% methyl cellulose per mL, and avoiding generating bubbles as much as possible; cell plating is carried out according to the required test quantity, 90 mu L of cell suspension is added to each well of a 96-well plate, and a T0 plate is arranged; at 37℃with 5% CO ₂ Cell culture was performed under 95% air conditions.

T0 plate read: CTG analysis was performed after adding 10 μl of medium containing vehicle per well; thawing CTG reagent and equilibration of cell plates to room temperature for 30 min; add 100. Mu.L of CTG solution per well; vibrating on an orbital shaker for 2 minutes to lyse cells; the cell plates were left at room temperature for 10 minutes to stabilize the luminescence signal; luminescence values were read with EnVision.

Adding a drug to be tested; dissolving a tested compound by using a solvent to form a storage solution, carrying out gradient dilution, and then diluting by 100 times by using a culture medium to obtain a 10-time solution; preparing 10 times solution of positive medicine with culture medium; mu.L of 10 Xdrug solution was added to each well (3 multiplex wells were set per cell concentration). The highest concentration of the medicine to be tested is 10 mu M,9 concentrations and 4 times dilution; at 37℃with 5% CO ₂ Cell culture was performed under the conditions.

Test plate read value: thawing CTG reagent and equilibration of cell plates to room temperature for 30 min; add and 100. Mu.L of CTG solution per well; vibrating on an orbital shaker for 2 minutes to lyse cells; the cell plates were left at room temperature for 10 minutes to stabilize the luminescence signal; luminescence values were read with EnVision.

Experimental example 4 cellular p-ERK HTRF experiment

The RAS-RAF-ERK and RAS-PI3K-AKT pathways are the primary hyperactivated downstream pathways in RAS mutations, promoting the infinite life cycle of cancer cells and their metastasis in humans. Inhibition of KRAS inhibits phosphorylation and activation of ERK, thereby reducing the level of p-ERK in the cell.

The p-ERK level was measured on test compounds and positive controls, respectively, using a CisBio HTRF Advanced phospho-ERK1/2 (Thr 202/Tyr 204) assay kit, and the test cells included human non-small cell lung cancer cells (NCI-H358) and human metastatic pancreatic cancer cells (AsPC-1).

The donor is excited with a light source (laser or flash lamp) to trigger Fluorescence Resonance Energy Transfer (FRET) to the acceptor, thereby emitting fluorescence at a specific wavelength (665 nm). The specific signal is positively correlated with higher phospho-ERK1/2 (Thr 202/Tyr 204). See in particular CisBio HTRF Advanced phospho-ERK1/2 (Thr 202/Tyr 204) detection kit instructions.

The compound disclosed by the application has a good KRAS G12D inhibition effect. Thus, such compounds are useful in the preparation of a medicament for the treatment, inhibition or prevention of diseases associated with KRAS G12D mutations.

Although the present application has been described in detail with reference to the embodiments thereof, these embodiments are provided for the purpose of illustration and not limitation of the application. Other embodiments that can be obtained according to the principles of the present application fall within the scope of the application as defined in the claims.

Claims

1. A compound of formula (a) or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof:

wherein X is ² Independently selected from hydrogen, substituted or unsubstituted alkylOr heteroalkyl, substituted or unsubstituted acyl (including saturated or unsaturated aliphatic acyl and aroyl), amino acid residues, oligopeptide (dipeptide, tripeptide, tetrapeptide) residues, phosphoryl, phosphono, aminophosphonyl, sulfonyl, thioacyl, substituted or unsubstituted benzyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted mercaptothiocarbonyl, substituted or unsubstituted alkylthio (thiocarbonyl), substituted or unsubstituted esteralkyl, substituted or unsubstituted benzyloxycarbonyl, glycosyl, glyconic acid glycosyl, cholic acid substituents;

group A ¹ 、A ² 、A ³ And A ⁴ Independently selected from hydrogen or C ₁ To C ₆ Or a short chain hydrocarbon group of A) ¹ 、A ² 、A ³ And A ⁴ Together one or both of the groups of (a) and the piperazine ring to which they are attached form a bridged, fused or spiro ring; and the nitrogen heterocycle may be a saturated heterocycle or an unsaturated heterocycle;

m is selected from nitrogen or carbon; wherein the compound of formula (a) is a compound of formula (B) or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof:

wherein X is ² Independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted acyl (including saturated or unsaturated aliphatic acyl and aroyl), amino acid residues, oligopeptide (dipeptide, tripeptide, tetrapeptide) residues, phosphoryl, phosphono, aminophosphonyl, sulfonyl, thioacyl, substituted or unsubstituted benzyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted mercaptothiocarbonyl A group, a substituted or unsubstituted alkylthio group (thiocarbonyl group), a substituted or unsubstituted ester alkyl group, a substituted or unsubstituted benzyloxycarbonyl group, a glycoside group, a sugar acid glycoside group, a cholic acid substituent;

group A ¹ 、A ² 、A ³ And A ⁴ Independently selected from hydrogen or C ₁ To C ₆ Or a short chain hydrocarbon group of A) ¹ 、A ² 、A ³ And A ⁴ Together one or both of the groups of (a) and the piperazine ring to which they are attached form a bridged, fused or spiro ring; and the nitrogen heterocycle may be a saturated heterocycle or an unsaturated heterocycle; the compound is a compound of formula (I) or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof:

2. The compound of claim 1, wherein the compound is a compound of formula (Ia) or formula (Ib) or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof:

wherein,

x is selected from nitrogen (N), carbon (CH), C-F, C-Cl, C-CH ₃ 、C-C ₂ H ₅ Or C-C ₃ H ₇ ；

W is selected from oxygen (O), sulfur (S) or Nitrogen (NH);

X ¹ and X ² Independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl or heteroalkyl, substituted or unsubstituted acyl (including saturated or unsaturated aliphatic acyl, and aroyl), amino acid residues, oligopeptide (dipeptide, tripeptide, tetrapeptide) residues, phosphoryl, phosphono, aminophosphonyl, sulfonyl, thioacyl, substituted or unsubstituted benzyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted mercaptothiocarbonyl, substituted or unsubstituted alkylthio, substituted or unsubstituted esteralkyl, thiocarbonyl, substituted or unsubstituted benzyloxycarbonyl, glycosyl, cholic acid substituents;

X ³ Independently selected fromOr lone pair electrons; wherein when X is ³ X in the case of lone pair electrons ¹ And X ² Are not hydrogen at the same time; when X is ³ Is->When in combination with X ³ The N atoms being linked to form quaternary ammonium ions having a positive charge and forming internal salts with anions in the molecule or pairing with further acid moleculesSalts, acid molecules include, but are not limited to, halogen acid salts, wherein R ^6a 、R ^6b Optionally selected from hydrogen, C ₁ To C ₂₀ Is a hydrocarbon or cyclic hydrocarbon group, ->

Y ³ 、Y ⁴ independently selected from H, halogen, halomethyl (monohalomethyl, dihalomethyl, and trihalomethyl), or Y ³ 、Y ⁴ And the benzene ring structures to which they are attached together form a substituted or unsubstituted benzo-fused ring, including but not limited to naphthalene ring structures;

in the formula (Ia), Y ² Independently selected from hydrogen, halogen, hydroxy, amino, hydroxymethyl, alkoxy, acyloxy, or lower alkyl; the compound of claim 1, wherein said X ¹ And X ² Independently selected from hydrogen, C ₁ -C ₂₀ Saturated or unsaturated alkoxycarbonyl, C ₁ -C ₂₀ Saturated or unsaturated alkanoyl, C ₁ -C ₂₀ Alkylthio group,

Wherein R is ¹ Selected from hydrogen, methyl, ethyl, propyl or isopropyl, C3-C6 cycloalkyl, aryl,

R ³ selected from hydrogen, methyl, ethyl orA propyl group, a hydroxyl group,

R ⁴ selected from the group consisting of hydrogen, methyl, ethyl or propyl,

R ^6a 、R ^6b optionally selected from hydrogen or C ₁ To C ₂₀ Is a hydrocarbon or cyclic hydrocarbon, aryl,

R ⁷ Selected from lower alkyl or substituted or unsubstituted aryl,

3. The compound according to claim 2, wherein the compound is a compound represented by formula (IIa), formula (IIIa), formula (IIb):

Wherein in formula (IIa)，R ¹¹ Selected from hydrogen, halogen, hydroxy, substituted hydroxy, and lower alkyl;

in formula (IIIa) or (IIb), Y ⁴ Selected from hydrogen, halogen, hydroxy, substituted hydroxy, and lower alkyl;

in formula (IIb), Y ⁵ Selected from dimethylamino,Wherein W in formula (IIa) is oxygen and R ¹¹ Hydrogen or fluorine; wherein in formula (IIIa) or (IIb), W is oxygen and Y ⁴ Is chlorine; wherein in formula (IIIa) or (IIb), W is NH and Y ⁴ Hydrogen or chlorine; wherein Y is ^1b And Y ² Hydrogen at the same time; wherein the compound of formula (Ia) is a compound of formula (IVa), (Va) or (VIa):

wherein the compound of formula (Ib) is a compound of formula (IIIb):

4. the compound is the following compound or pharmaceutically acceptable salts, esters, hydrates, solvates or stereoisomers thereof:

5. a pharmaceutical composition comprising a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer thereof; wherein, also include at least one pharmaceutically acceptable excipient or carrier or diluent; wherein the pharmaceutically acceptable excipients include one or more of binders, fillers, disintegrants, lubricants and glidants; wherein the pharmaceutically acceptable carrier comprises one or more of a cream, emulsion, gel, liposome, and nanoparticle; characterized in that the composition is suitable for oral administration or injection administration.

6. Use of a compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt or ester or isomer or hydrate thereof, or a pharmaceutical composition of claim 5, in the manufacture of a medicament for the treatment, prevention or inhibition of a hyperproliferative disorder; wherein the hyperproliferative disorder is a malignancy or cancer associated with a KRAS G12D mutation; wherein the malignancy or cancer is selected from: sarcomas (hemangiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and malformation tumor; lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroma, mesothelioma; gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyoma, lymphoma), stomach (carcinoma, lymphoma, leiomyoma), pancreas (ductal adenocarcinoma, insulinoma, glucomonas, gastrinoma, carcinoid tumor, schwann intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hematoma, leiomyoma); urogenital tract: kidney (adenocarcinoma, wilms 'tumor (Wilms' tumor), lymphoma, leukemia), bladder and urinary tract (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, malformed tumor, embryonal carcinoma, malformed carcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder cancer, ampoule cancer, bile duct cancer; bone: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma (reticuloma), multiple myeloma, malignant giant cell tumor chordoma, osteochondral tumor (osteochondral tumor), benign chondrioma, chondroblastoma, chondromyxofibroma, osteoid tumor and giant cell tumor; the nervous system: skull (bone tumor, hemangioma, granuloma, xanthoma, amoebonite), meninges (meningioma, glioma disease), brain (astrocytoma, myeloblastoma, glioma, epididymal tumor, germ cell tumor (pineal tumor), glioblastoma in various forms, oligodendroglioma, glioma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); gynaecology: uterus (endometrial carcinoma (serous bladder carcinoma, myxogenic bladder carcinoma, unclassified carcinoma), granulosa sheath cell carcinoma, serointerstitial cell carcinoma, dysplasia, malignant malformation tumor), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, uveal sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma), hematology blood (myelogenous leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disease, multiple myeloma, myelodysplastic syndrome), hodgkin's disease, non-hodgkin's lymphoma (malignant lymphoma), skin malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, mole dysplastic nevi, lipoma, hemangioma, skin fibroma, keloids, psoriasis, adrenal gland neuroblastoma, characterized in that the malignancy is one or more of non-small cell lung cancer, pancreatic cancer, colorectal cancer, cholangiocarcinoma, cervical cancer, breast cancer, or carcinoma.

7. Use of a kit for the manufacture of a medicament for the treatment, inhibition or prevention of a disease associated with KRAS G12D mutation, wherein the kit comprises a compound or pharmaceutically acceptable salt, ester, hydrate, solvate or stereoisomer according to any one of claims 1 to 4, or a composition according to claim 5.